Human Tissue Engineered Products –Todays Markets and Future ProspectsFinal Report for Work Package 1:Analysis of the actual market situation – Mapping of industry andproductsDr. Bärbel HüsingDr. Bernhard BührlenDr. Sibylle GaisserFraunhofer Institute for Systems and Innovation ResearchKarlsruhe, GermanyApril 28, 2003
iTable of contentsPageList of tables.............................................................................................................. vList of figures.........................................................................................................viii1. Terms of reference ............................................................................................ 12. Methodology applied......................................................................................... 32.1 Definition of tissue engineering....................................................... 32.2 List of tissue engineering companies ............................................... 32.3 List of tissue engineering products on the market and inclinical trials ..................................................................................... 42.4 Market volumes................................................................................ 42.5 Interviews......................................................................................... 53. Market volumes for tissue engineering ........................................................... 63.1 Overview of potential applications .................................................. 63.2 Challenges in estimating market volumes in tissueengineering....................................................................................... 63.2.1 Characteristics of tissue engineering................................................ 63.2.2 Purpose of market estimations ......................................................... 63.2.3 Sources of information for market estimations................................ 63.2.4 Consequences for market estimations in this study ......................... 63.3 Actual sales and potential market volumes...................................... 63.3.1 Actual sales ...................................................................................... 63.3.2 Potential market volumes................................................................. 6
ii4. Tissue engineered skin products...................................................................... 64.1 Overview of potential applications .................................................. 64.2 Overview of important companies and products.............................. 64.2.1 Treatment of full-thickness burns .................................................... 64.2.2 Treatment of chronic wounds........................................................... 64.2.3 Aesthetic surgery, cosmetic dermatology ........................................ 64.2.4 In-vitro human skin models.............................................................. 64.3 Actual sales and potential market volumes...................................... 64.3.1 Actual sales of tissue-engineered skin products............................... 64.3.2 Potential market volumes................................................................. 64.3 Factors influencing the market situation .......................................... 65. Tissue engineered cartilage products .............................................................. 65.1 Overview of potential applications .................................................. 65.2 Overview of important companies and products.............................. 65.3 Actual sales and potential market volumes...................................... 65.3.1 Actual sales of tissue-engineered cartilage products........................ 65.3.2 Potential market volumes................................................................. 65.4 Factors influencing the market situation .......................................... 66. Tissue engineered bone products..................................................................... 66.1 Overview of potential applications .................................................. 66.2 Overview of important companies and products.............................. 66.3 Potential market volumes................................................................. 66.4 Factors influencing the market situation .......................................... 67. Tissue engineered cardiovascular products.................................................... 67.1 Overview of potential applications .................................................. 67.1.1 Heart valves...................................................................................... 6
iii7.1.2 Blood vessels.................................................................................... 67.1.3 Myocardial infarction....................................................................... 67.2 Overview of companies and their R&D activities ........................... 67.2.1 Heart valves...................................................................................... 67.2.2 Blood vessels.................................................................................... 67.2.3 Myocardial infarction....................................................................... 67.3 Potential market volumes................................................................. 67.3.1 Prevalences and incidences for cardiovascular diseases.................. 67.3.2 Market figures related to CVD......................................................... 68. Tissue engineered organs.................................................................................. 68.1 Overview of potential applications .................................................. 68.1.1 Tissue-engineered pancreas for the treatment of Diabetesmellitus............................................................................................. 68.1.2 Bioartificial liver assist devices........................................................ 68.2 Overview of companies and their R&D activities ........................... 68.2.1 Tissue-engineered pancreas.............................................................. 68.2.2 Bioartificial liver assist devices........................................................ 68.3 Overview of potential market volumes ............................................ 68.3.1 Overview of organ donation and organ transplantationinternationally................................................................................... 68.3.2 Diabetes mellitus.............................................................................. 68.3.3 Acute hepatic failure ........................................................................ 69. Tissue engineered CNS products ..................................................................... 69.1 Overview of potential applications .................................................. 69.2 Overview of companies and their R&D activities ........................... 69.3 Overview of potential market volumes ............................................ 610. Characterization of the tissue engineering industry...................................... 6
iv10.1 Structure of the tissue engineering industry..................................... 610.1.1 Europe .............................................................................................. 610.1.2 USA.................................................................................................. 610.1.3 Common features of the European and US-Americantissue engineering industry............................................................... 610.2 Differences between Europe and the USA....................................... 610.2.1 Science and technology base............................................................ 610.2.2 Companies........................................................................................ 610.2.3 Regulatory situation ......................................................................... 610.2.4 Market .............................................................................................. 610.3 Business models and business strategies.......................................... 611. Overview of tissue engineering products on the market and inclinical trials....................................................................................................... 611.1 Skin products.................................................................................... 611.2 Cartilage products ............................................................................ 611.3 Bone products................................................................................... 611.4 Cardiovascular products................................................................... 611.5 Tissue engineered organs ................................................................. 611.6 CNS products ................................................................................... 611.7 Miscellaneous products.................................................................... 612. Cited Literature................................................................................................. 6
viTable 3.1: Revenue from tissue engineering products, cell therapiesand biomolecules 1997................................................................ 6Table 3.2: Overall potential market for tissue engineering............................... 6Table 3.3: Potential US markets for tissue engineering and organregeneration products 1999......................................................... 6Table 4.1: Sales figures for selected tissue engineered skin products............... 6Table 4.2: World wound management sales market and its segments.............. 6Table 4.3: Maximum market potential for tissue engineered skinproducts worldwide/USA............................................................ 6Table 4.4: Realistic market potential for tissue engineered skinproducts for the treatment of chronic wounds, modelcalculation for Germany.............................................................. 6Table 5.1: Sales figures of autologous chondrocyte implants........................... 6Table 5.2: Overview of frequencies of cartilage defects................................... 6Table 5.3: Market sizes correlated with cartilage defects/cartilagerepair ........................................................................................... 6Table 6.1: Comparison of different bone repair approaches ............................. 6Table 6.2: Sales 2002 of bone products by tissue engineeringcompanies.................................................................................... 6Table 6.3: Market for bone replacement and repair .......................................... 6Table 7.1: Global heart valve market 2001 ....................................................... 6Table 8.1: Artificial and bioartificial liver assist devices with clinicalexperience ................................................................................... 6Table 8.2: Overview of organ transplantations (absolute numbers) in2001............................................................................................. 6Table 8.3: Overview of organ transplantations in 2001 (numbers per 1mio. inhabitants).......................................................................... 6Table 8.4: Organ donations in selected countries in 2001................................. 6Table 10.1: Tissue engineering companies in Europe......................................... 6Table 10.2: Overview of tissue engineering companies in Europeancountries...................................................................................... 6Table 10.3: Categorisation of SME European tissue engineeringcompanies according to employee numbers ............................... 6
viiTable 10.4: Economic parameters for contemporary tissue engineering(2001).......................................................................................... 6Table 10.5: Sector analysis of tissue engineering companies in theUSA 2001.................................................................................... 6Table 10.6: Differences in the regulatory situation in the USA and theEU ............................................................................................... 6Table 10.7: Business models for pharmaceuticals, medical devices andtissue engineering products......................................................... 6Table 11.1: Skin products of European companies............................................. 6Table 11.2: Skin products of US companies ....................................................... 6Table 11.3: Clinical trials on skin products of European and UScompanies.................................................................................... 6Table 11.4: Autologous chondrocyte transplantation products ofEuropean companies ................................................................... 6Table 11.5: Autologous chondrocyte transplantation products of UScompanies.................................................................................... 6Table 11.6: Clinical trials on cartilage products of European and UScompanies.................................................................................... 6Table 11.7: Bone products of European companies............................................ 6Table 11.8: Bone products of US companies ...................................................... 6Table 11.9: Clinical trials on bone products of European and UScompanies.................................................................................... 6Table 11.10: Cardiovascular products of European and US companies ............... 6Table 11.11: Clinical trials on cardiovascular products of European andUS companies ............................................................................. 6Table 11.12: Clinical trials on tissue engineered organs of European andUS companies ............................................................................. 6Table 11.13: Tissue engineered CNS products of US companies......................... 6Table 11.14: Clinical trials on tissue engineered CNS products of UScompanies.................................................................................... 6Table 11.15: Miscellanous products on the market and in clinical trials.............. 6
viiiList of figuresPageFigure 4.1: Contribution of cost factors to overall cost of healing insectors of the wound management market.................................. 6Figure 8.1: Evolutionary cladogram on commercial efforts to developa bioartificial pancreas ................................................................ 6Figure 10.1: Tissue engineering companies in European countries ..................... 6Figure 10.2: Company size of European tissue engineering companies .............. 691491735 20%10%20%30%40%50%60%70%80%90%100%All TE companies Core TE companiesShareofcompanies(%)not knownLargeSME..................................................................................................... 6Figure 10.3: Company type of European tissue engineering companies.............. 6
11. Terms of referenceTissue engineering (TE) is an emerging interdisciplinary area comprising differentspecialties such as medicine, materials science, cell biology, genomics and chemicalengineering. Its aim is to develop biological substitutes to restore, maintain or im-prove tissue function, thus offering patients the chance to regain a normally func-tioning body. The European Commission, DG Enterprise, is considering a directiveto cover human tissue-engineered products to harmonise legislation in the EU andto enable a common European market while safeguarding consumer protection.As the whole field of tissue engineering is relatively young, a comprehensive pic-ture of the state-of-the-art of tissue engineering in the EU in terms of research ac-tivities, actual market-industry structure and probable future developments will beprepared.This report is part of this comprehensive study. It maps the relevant industry andproducts on the market or in clinical trials, respectively, and analyses the actualmarket situation. In order to compile the report, the following tasks were carriedout:• Listing and description of products already on the market or in clinical trialphase (I to III), as well as their present market volume where applicable.• Categorization of the companies involved according to their main productionportfolio (medical devices industry, biotech industry, pharmaceutical industry)and according to size (SME, large company). The most important companiesshould be described in more detail (e.g. size, turnover, product portfolio…).• Analysis of the potential market volume for different product categories, for ex-ample:− Skin substitutes− Orthopaedic cartilage and bone replacement− Cardiovascular substitutes− Organs (e.g. kidney, liver, lung)− Nervous system− Soft tissue (e.g. breast implants)• The possible influences tissue-engineered products might have on the marketsfor medical devices and medicinal products should be analysed. What productsmight be replaced, how would the respective market shares change?Demographical changes as well as lifestyle changes should be taken into accountand fed into the analysis of potential market volumes.
2The scope of the analysis is the EU member states, the first round enlargementcountries (Czech Republic, Estonia, Hungary, Latvia, Lituania, Poland, Sloveniaand Slovakia) and the USA as a reference. Any visible trends that distinguishAmerican approaches from European ones should be pointed out.
32. Methodology applied2.1 Definition of tissue engineeringThe following defininition was agreed upon consultation with IPTS and DG Enter-prise and applied in this study:Tissue engineering is the regeneration of biological tissue through the use of cells,with the aid of supporting structures and/or biomolecules (Scientific Committee onMedicinal Products and Medical Devices 2001).The definition chosen for this study primarily relates to therapeutic applications oftissue engineering, not to in vitro applications. It excludes gene therapy and simpletransplantations. It includes autologous and allogeneic human cells, tissues and or-gans, and also xenogeneic cells, tissues and organs, that have been substantiallymodified by treatments. In addition, autologous chondrocyte transplants are inclu-ded.2.2 List of tissue engineering companiesIn order to compile a list of companies in EU member states as well as in the acces-sion countries Czech Republic, Estonia, Hungary, Latvia, Lituania, Poland, Slove-nia and Slovakia involved in tissue engineering, the following sources were ana-lysed:• analysis of international and national biotechnology directories,• analysis of reports on national biotechnology innovation systems, compiled byresearch groups or foreign investment bureaus,• analysis of internet tissue engineering platforms and link lists,• analysis of scientific literature on tissue engineering, identified by data basesearches,• analysis of market studies and company reports, identified by data base andinternet searches,• in some countries direct requests for information on TE companies in academicresearch institutes and/or national biotechnology associations.
4Despite several efforts, it was not possible to obtain information from member listsof several professional societies (European Tissue Engineering Society (ETES),European Society for Biomaterials (ESB)) due to data protection reasons.After identification of company names from the above mentioned sources, the rele-vance of the company was checked by obtaining more detailed information from itsinternet home page where available.2.3 List of tissue engineering products on the market and inclinical trialsIn order to compile a list of products on the market or in clinical trials the followingsources were analysed:• analysis of scientific literature on tissue engineering, identified by data basesearches,• analysis of tissue engineering companies home pages in the internet,• analysis of market studies and company reports, identified by data base andinternet searches,• interviews with tissue engineering experts.2.4 Market volumesThe actual and potential market volumes for tissue engineering as a whole or differ-ent product categories, respectively, were compiled by analysing existing marketstudies and company reports. Moreover, factors which influence market develop-ment and dynamics (e. g. scientific-technical developments, legal situation, compet-ing technologies, trends in health care systems, demographical and lifestylechanges) were assessed through literature analysis and interviews with tissue engi-neering experts from companies. In addition, health statistics and scientific litera-ture were analysed for figures on disease prevalences and incidences for certaindiseases which are representative for selected tissue engineering market segments,and put into perspective with published market estimations and with influencingfactors.Foreign currencies were transformed into €. The following exchange reference rateswere used (Source: European Central Bank,http://www.ecb.int/stats/eurofxref/eurofxref-xml.html, retrieved March 27, 2003,
5and for the conversion rates of the EURO-Member Countries:http://www.ecb.int/change/conversion.htm, retrieved March 27, 2003):AUD Australian dollar 1.7852 GBP Pound sterling 0.68110BEF Belgian Francs 40.3399 SEK Swedish krona 9.2527CAD Canadian dollar 1.5711 USD US dollar 1.0000FRF Francs Français 6.559572.5 InterviewsThe information compiled in desk research were verified and completed duringquestionnaire-guided telephone interviews with management staff from leadingcompanies (see annex). Each of these interviews lasted one to 1.5 hours.In addition, interim results were presented and discussed with the EuropaBio cellsand tissues expert group in April 2003.
63. Market volumes for tissue engineering3.1 Overview of potential applicationsTissue engineering is the regeneration of biological tissue through the use of cells,with the aid of supporting structures and/or biomolecules (SCMPMD 2001). It of-fers the potential of a paradigm shift in medicine: new forms of therapy can be en-visioned which allow the repair or regeneration of cells, tissues and organs whichhave lost their function due to disease, injury or congenital defects.Potential applications of tissue engineering are envisioned in the following fields:• Skin,• Cartilage,• Bone,• Cardiovascular diseases,• Organs,• Central nervous system,• Miscellanous, e. g. soft tissue, ligaments.Although tissue engineering research is being carried out in all these fields, onlyfew products have already entered the market, and the present state of the art inscience and technology does not allow a precise assessment which of these deve-lopments will finally yield new therapeutic options and commercially viable pro-ducts. Therefore, a broad variety of information sources and methods has to be usedin order to estimate the actual and potential market volumes for tissue engineering.The following chapter gives an overview how this task can be addressed.
73.2 Challenges in estimating market volumes in tissue engi-neering3.2.1 Characteristics of tissue engineeringTissue engineering is a new, emerging, highly dynamic and interdisciplinary field.Due to its infant stage of development and its continuing evolution, no clear andgenerally recognised definition has emerged, and no established "official" statisticsare available which provide tissue-engineering specific data. Moreover, most of itspotentials still remain to be revealed in the future, so that the present database andknowledge regarding future applications, products and potentials is incomplete anduncertain.3.2.2 Purpose of market estimationsIn emerging technologies such as tissue engineering, two different types of marketestimations can be distinguished which fulfill two different purposes:• Analysis of potential applications and markets. The analysis of potential applica-tions and markets is the only type of market estimations which can be carried outin very early stages of development. These potential market estimations can pro-vide information on the overall scope of tissue engineering, the significance ofthis field, and its potential for solving health problems and for commercial activi-ties. The main purpose of these estimations of potential markets is to mobilizeressources and to support decisions whether and to which extent to engage in thisfield.• Analysis of actual applications and markets. The analysis of actual applicationsand markets can only be performed if tissue engineered products have alreadybeen developed and brought onto the market. Comparing actual and potentialmarket analysis makes it possible to assess how far the development has alreadyprogressed, to which extent the potential has already been realised, to which ex-tent the potentials may have to be reassessed, and whether there are hindranceswhich cause a deviation of actual markets from potential markets.3.2.3 Sources of information for market estimationsMarket estimations require the combination of two types of information: informati-on on the number or frequency for the (actual or potential) application of the tissueengineered product, and monetary information regarding the price or costs. Thesetypes of information can be retrieved from a broad variety of sources.
8For the analysis of potential applications and markets, a broad scope of informationsources and data can be used. For information on the number or frequency, for e-xample the following data can be used• prevalences and incidences of the diseases which could be targeted by tissue en-gineering products,• number of conventional treatments for the given disease; number of conventio-nally treated patients with the given disease,• number of conventional drug doses/medical devices etc. sold for the targeteddiseases.For the corresponding monetary information, sources such as• retail prices for conventional drugs/medical devices,• expenditures of the health care system for a given treatment/disease,• willingness of users/patients to pay for treatments of a given diseasecan be used.For the analysis of actual applications and markets,• the number of tissue engineering treatments or the number of patients treatedwith the tissue engineering product,• the expenditure of the health care system for tissue engineering treatments,• sales figures for tissue engineering products or sales figures of tissue engineeringcompaniescan be used.Often, combinations of the above mentioned approaches and data sources are ap-plied. The resulting market figures depend on which sources of data were used forcalculating the market figures. Therefore, different market figures may be due to thefact that – for example – they were calculated in case 1 by using prevalence data forthe given disease, and by using sold conventional drug doses in case 2. Moreover,consistent data of good quality are often not available for all aspects required in themarket analysis. Then extrapolations of existing data (e. g. extrapolations of datafrom country A to region B) and plausible assumptions must be made.3.2.4 Consequences for market estimations in this studyIn this study, a secondary analysis of published market data was carried out bycompiling and analysing existing market studies for tissue engineering. A secondaryanalysis has several inherent limitations:
9• Incomplete information of data sources and methodology applied. Most publis-hed market studies present their results in aggregated form, but do not reveal indetail which definitions, data sources, calculation methods, and assumptions inextrapolations have been applied. Therefore, it is often not possible to explaindifferences in the results which may be due to methodological reasons.• Definition of tissue engineering. Due to the dynamic development of tissue engi-neering, several definitions are in use which differ from one another regardingthe scope of included subfields. In this study, tissue engineering was defined as"the regeneration of biological tissue through the use of cells, with the aid ofsupporting structures and/or biomolecules". However, the secondary analysis ofpublished market studies also had to rely on studies which used other definitionsof tissue engineering. In several cases, no information was available how tissueengineering had precisely been defined for the respective study. This makescomparison of the results of different studies difficult.• Regional scope. Most market estimations relate to the USA. If one assumes thatworldwide disease incidence and prevalence rates were equal to those in theUSA, the estimated number of patients worldwide would be about 20 times lar-ger than the US figures. However, in general, it is assumed that the worldwidemarket is at two to three times that in the USA, because incidences and preva-lences vary widely and in most parts of the world there is a lack of access to ad-vanced health care services. If the European market is considered in the marketstudies, it is assumed that it is as big as the US market, and is appr. 30-40 % ofthe worldwide market (Medtech Insight 2000).• Scenarios for market dynamics. In most published market studies on tissue engi-neering, no information is available to which extent and with which level ofmethodological sophistication market dynamics have been taken into account.Dynamic factors are, among others, increase or decrease in disease prevalenceand incidence due to demographic trends, limited regional availability of certaintissue engineered products, competition with established products and treatmentsetc.Due to these limitations inherent in secondary analysis of published market studies,differences and inconsistencies between market estimations from different studiescan be explained or compensated only to a limited extent.
103.3 Actual sales and potential market volumes3.3.1 Actual salesAlthough tissue engineering offers the potential to provide novel treatments in theareas of skin, cartilage, bone, cardiovascular disease, central nervous system, andorgans, only tissue engineered skin and cartilage (and to a limited extent bone)products have been commercialised until today. These are markets in which thevalue of the products is primarily based on quality of life, not survival. Although thedata base is fragmentary, total annual worldwide sales for tissue engineered skinreplacement products are in the order of magnitude of € 20 millions, and worldwidesales of autologous chondrocyte transplants are presently unlikely to exceed theorder of magnitude of € 40 mio./year1. Therefore, actual sales of tissue engineeredproducts amount to approximately € 60 millions/year.Table 3.1: Revenue from tissue engineering products, cell therapies and bio-molecules 1997Revenue 1997EstimatedMarket 2007Average an-nual growthrate (%)€ mio. € mio. 1997-2007Cell therapies(Bone marrow transplants, stem celltransplants, lymphocyte therapy, xeno-grafts for treatment of Parkinson’s dis-ease)0 14,572 --Tissue Engineering 61 3,867 55Proteins and peptides(cytokines, morphogenetic proteins, aner-genic peptides used in supporting thera-pies)91 1,819 35Total 152 20,258 60Source: (Business Communication Company 1998)Similar market assessments have also been published: according to (Lysaght 2002),the total sales of tissue engineered products (i. e. skin and cartilage products) wereabout € 40 mio. in 2001, with European combined sales under € 1 mio. Revenuesfrom tissue engineering products (which were not specified in detail) were esti-1 For a detailed presentation and discussion of the underlying figures and factors influencing themarket situation please refer to chapters 4-6.
11mated at € 61 mio. in 1997 (table 3.1). However, the estimated annual growth rateof 55 %, leading to a global € 3,867 mio. market ten years later, seems over-optimistic. A different source uses a narrower definition of tissue engineering andestimates the global cell-based tissue engineering market at € 47 mio. in 2001. Italso assumes vital growth over the following years, with a € 270 mio. market inskin repair alone by 2007 (Medmarket Diligence 2002).3.3.2 Potential market volumesWhen estimating the overall potential market for tissue engineering, most publica-tions refer to estimates for the USA published in 1993 (Langer et al. 1993) and up-dated in 1999 (Vacanti et al. 1999). In this publication, medical procedures weretaken into account which require some type of replacement structure for the area ofdefect or injury, and it was assumed that these medical procedures in principlecould also be amenable to tissue engineering applications. Table 3.2 gives an over-view of the indications and procedures or patients per year in the USA. In total,annually more than 11 mio. medical procedures which are also potentially relevantfor tissue engineering are performed in the USA. This corresponds to a total na-tional health care cost of appr. € 400 billion/year (this estimation only includes costsfor patients with cardiovascular disease and coronary artery disease, for stents usedin angioplasty and costs of care for diabetes).A different definition of tissue engineering was applied by (Lysaght et al. 2000),who additionally included organ transplantations and dialysis, but excluded neuro-logical disorders and skin replacement. They concluded that worldwide, more than20 mio. patients are affected, and the costs associated with organ replacementtherapies amount to more than € 300 billion /year worldwide, with appr.€ 100 billion/year in the USA. This amounts to appr. 8 % of the worldwide medicalspending (Lysaght et al. 2000).These two studies focus on the total health care costs caused by organ replacementtherapies. Another market study focuses on potential industry sales. It estimates theHuman Tissue Products Market at more than € 80 billion in the USA alone. This isput into perspective with the global medical devices market, estimated at€ 130 billion and the global pharmaceuticals market of € 265 billion (Medtech In-sight 2000). In another study, however, the total market for the regeneration andrepair of tissues and organs is estimated to be € 25 billion worldwide (Bassett2001). It is not known whether different definitions of tissue engineering were usedwhich could explain these differences in market potentials.
12Table 3.2: Overall potential market for tissue engineeringVacanti and Langer 1999 Lysaght and Loughlin 2000USA WorldPatient Population 2000IndicationProcedures or pa-tients/year (1996)prevalence treatment cost/a(mio. €) Incidence Prevalence at MidyearTotal TherapyCost 2000 (mio €)Cardiovascular 58,000,000Heart-Including coronary artery bypass graft-ing1,821,000 14,000,000 274,000heart-lung 733,000 6,000,000 65,000Angioplasty of coronary vessels, stents 1,000,000 2,000 1,750,000 2,500,000 48,000Blood vessels 272,000Valves 245,000 2,400,000 27,000Pacemakers 670,000 5,500,000 44,000Spinal cord (neural and neuromuscular) 469,000Orthopaedic and plastic reconstructiveBone, cartilage, tendon, and ligament 1,977,000Hips 610,000 7,000,000 41,000Knees 675,000Breast 479,000GastrointestinalLiver, gallbladder, bile duct 205,000Pancreas (diabetes)† 728,000 100,000Intestinal 100,000Other
14Tissue Engineering has the potential to offer new treatment options for orthopedicindications (cartilage, bone), skin damage, cardiovascular diseases, neurologicaldisorders and organ failure. Table 3.3 gives an overview of the number of affectedpatients, and, based on these numbers, estimation of the tissue engineering and or-gan regeneration market in the USA. These derived market figures take into accountto which extent the tissue engineered products could satisfy unmet medical needs(e. g. above average in the case of neurological disorders, where currently mostlysymptomatic treatments are available), which degree of market penetration and re-placement of existing therapies could be achieved (e. g. below average in the caseof skin repair), and willingness to pay/prices and costs of existing treatments (e. g.assessment of pancreas regeneration as a very profitable market segment due to thehigh health care costs of diabetes management in these chronically ill patients andthe increasing incidence and prevalence of diabetes in the US).Table 3.3: Potential US markets for tissue engineering and organ regenerationproducts 1999Affected patients1999Potential US SalesDisease/Application Segmentmio.% oftotalbillion €% oftotalOrthopedics(repair of joints and cartilage, fracture fixation,bone repair, vertebral disc repair)3.2 22 7.8 20Cardiovascular disease(tissue-engineered bypass grafts, regenerationof damaged cardiac muscle tissue, restenosisprevention, angiogenesis for revascularization,repair of heart valves, repair of congenital ab-normalities of the heart, treatment of stroke)3.2 22 6.8 17Neurological disorders(Parkinsons Disease, Huntingtons Disease,epilepsy, regeneration of nerves)1.6 11 7.2 18Ulcers, skin repair(diabetic foot ulcers, pressure sores, venousulcers)2.8 20 4.3 11Muscle repair 1.8 13 4.5 11Pancreas Regeneration(Diabetes)0.1 1 2.5 6Other(bladder, renal tubule, small intestine replace-ment, skin, breast and urethra repair, liver,ureter and bone marrow regeneration, penileprosthesis)1.6 11 6.8 17Total 14.3 100 39.9 100Source: (Medtech Insight 2000)
15The above mentioned figures, however, have to be met with caution. They refer to apotential market which could in principle be addressed by tissue engineering. How-ever, these estimations include several indications or application areas which arestill in the early R&D phase and far from market entry (e. g. all organ replacementapproaches, treatments for CNS disorders, see also chapters 8 and 9 of this report).Moreover, it is not clear to which extent it has been (unrealisticly) assumed thatevery patient is treated with the tissue engineering option although tissue engineer-ing products will have to compete with other treatment options.Although most markets for tissue engineering products have not yet emerged, twoimportant characteristics can already be noted:• The value of most products which are already commercialised or are likely to doso in the coming years is based on quality of life, not patient survival. Superior-ity regarding quality of life may, however, be rather difficult to prove if there arealready conventional, established treatments which have to be outcompeted.• Most tissue engineering products target markets which are much more focussedthan attractive market for pharmaceuticals (> € 1 billion/year).
164. Tissue engineered skin products4.1 Overview of potential applicationsThe human skin is a complex organ composed of three principal components(Schulz et al. 2000):• Epidermis. The epidermis is the superficial layer of the skin. It is the interfacewith the environment, providing immediate protection from microbial entry andloss of water, electrolytes, and proteins. The epidermis, if damaged, can regene-rate.• Dermis. The dermis is the inner and thicker of the two skin layers. it is responsi-bel for the strength, elasticity, and tactile qualities attributed to skin. If damaged,the dermis can only regenerate to a limited extent.• Epidermal appendages. Epidermal appendages are hair follicles, sweat glandsand sebaceous glands. They are involved in maintaining the barrier and thermo-regulatroy functions of the skin.For the past 30 years, attempts have been made to develop products that can be usedas a temporary or permanent natural skin substitute. These artificial skin substitutesshould ideally fulfill the following functions (Schulz et al. 2000):• Thermoregulation,• microbial defense (both mechanical barrier and immune defense),• desiccation barrier,• mechanical defense and wound repair, elicit a regeneration response from thewound bed without evoking an inflammatory or rejection response,• cosmetic appearance, pigmentation and control of contraction,• durable and elastic to provide normal function and cosmetic appearance,• be easy to use, be readily available immediately after damage of the natural skin.Indications and market segments for tissue engineered skin sustitutes are• Burns. Severe burns can be life-threatening. In the USA every year 75,000 ofburned patients require inpatient care, and 5,000-12,000 die of their injuries(Schulz et al. 2000). The number of burnt patients requiring tissue engineeredskin grafts is estimated at appr. 150 patients/year in Western Europe. Althoughthere is a medical need for skin replacement therapies in burns treatment, prod-
17ucts aimed at burn wound closure are unlikely to be as economically profitableas products that could be used for chronic wounds, which are substantially moreprevalent (see below) (Jones et al. 2002).• Chronic wounds. Chronic wounds are defined as wounds which do not healwithin six weeks. Chronic wounds can be devided into− pressure ulcers, which form during sitting or lying without moving. Especiallyelderly and severely ill people are at risk.− Ulcus cruris, venous ulcers, which are caused by venous insufficiency.− Diabetic ulcers, diabetic foot, which can emerge in diabetic patients with anill-controlled blood glucose level.Chronic wounds often prevail for several years, require cost-intensive treatmentsand can also have significant psychosocial consequences for the affected patient.From epidemiological studies it is known that underlying diseases which resultin the development of chronic wounds (e. g. venous diseases, diabetes) areamong the most frequent disorders in Western populations, are increasing due tothe prevailing life style changes, and are also age-correlated. Therefore, thedemographic development will also lead to an increase in chronic wounds. It isestimated that appr. 2-3 mio. people suffer from chronic wounds in Germany(pressure ulcers 46 %, Ulcus Curis 28 %, diabetic foot 21 %, others 5 %)(Landesbank Baden-Württemberg Equity Research 2001). The direct and indi-rect costs of leg ulcers in the UK as well as Germany are higher than one bil-lion € per year (Augustin et al. 1999).• Indications in plastic surgery or with cosmetic character. Indications are e. g.the treatment or prevention of scarring and the treatment of vitiligo or otherpigmentation disorders. The worldwide incidence of vitiligo is 1-2 % of thepopulation with marked regional differences (incidences of 3-4 % in In-dia/Asia/Arabia versus 0.5 % in Scandinavia) (Landesbank Baden-WürttembergEquity Research 2001).• Defects in oral mucosa. Large and painful defects in oral mucosa are associatedwith certain forms of cancer. In addition, they play a role in dental surgery (e. g.tooth implantation).4.2 Overview of important companies and productsSeveral different approaches have been pursued, many of them involving tissueengineering, to generate skin substitutes that fulfill at least some of the functionsoutlined in chapter 4.1. At present, approximately two dozens of tissue engineeringproducts for skin replacement are already on the market in Europe and the USA. Atleast seven additional products are in clinical trials (for details see chapter 11.1). UScompanies concentrate on allogenic skin products, European companies favourautologous skin products.
184.2.1 Treatment of full-thickness burnsThe first products on the market were for the treatment of severe, full-thicknessburns, e. g.• Epicel, produced by Genzyme Biosurgery (formerly Genzyme Tissue Re-pair)(USA). Genzyme Biosurgery brought one of the first tissue engineered skinproducts on the market. This was Epicel® for the treatment of life-threateningburns. Approximately 75 burn patients are treated with Epicel® per year. Over600 patients have been treated worldwide since the product was introduced in1987.• Integra, produced by Integra Life Sciences (USA).• Transcyte, marketed by Smith & Nephew (UK).However, these products are unlikely to be economically as profitable as skin re-placements that could be used for chronic wounds, due to their being much moreprevalent (Jones et al. 2002).4.2.2 Treatment of chronic woundsSeveral products are on the market which target chronic wounds, such as venous ordiabetic ulcers. Products in this category are e. g.:• Apligraf, developed and manufactured by Organogenesis (USA), marketed byNovartis (CH/USA) until June 2003. The worldwide distribution and marketingrights of Apligraf will then be transferred back to Organogenesis.• Dermagraft, developed by Advanced Tissue Sciences, marketed by Smith &Nephew (UK)• Hyalograft™ 3D, Laserskin™, produced by Fidia Advanced Biopolymers (Italy)• BioSeed-S, produced by BioTissueTechnologies (Germany), marketed by BaxterHealthcare• autologous Autoderm and allogeneic CryoCeal, produced by XCELLentis (Bel-gium)• Epidex, production stopped by Modex Therapeutics, product licensed to Auto-derm (Germany) in spring 2003• Collatamp, produced by Innocoll GmbH (Germany)• Epibase, produced by Laboratoire Genevrier (France)• CellActiveSkin, production stopped in late 2002 by IsoTis SA, because productwas not profitable• OrCell, produced by Ortec (USA)
19• VivoDerm, produced by Convatec (USA)As will be explained in more detail in the following chapter and in WP 2, the cost-effectiveness of tissue engineered skin replacements for the treatment of chronicwounds has – in general – not yet been clearly established. Therefore, statutory andprivate health insurance schemes do not routinely cover the costs for these treat-ments which is a major restriction in realising the full market potential (see below).As a consequence, tissue engineering companies increasingly develop productswhich target the "self-payer" patients segment.4.2.3 Aesthetic surgery, cosmetic dermatologyIn order to develop economically profitable products, tissue engineering companiesincreasingly target the "self-payer" patients segment by specifically tailored appli-cations in aesthetic surgery or cosmetic dermatology. Such products comprisetreatment or prevention of scarring, treatment of pigmentation disorders such asvitiligo, and others. Products in this category are e. g.• BioSeedM, produced by BioTissueTechnologies (Germany)• MelanoSeed, produced by BioTissueTechnologies (Germany)4.2.4 In-vitro human skin modelsSeveral companies develop in-vitro applications of skin replacement products. Theproducts can be used as skin models for in vitro testing for toxicity, pharmacologyand cosmetics. Products in this category are e. g.• Skin model developed by Biopredic (France)• Skin model developed by SkinEthicLaboratories (France)4.3 Actual sales and potential market volumes4.3.1 Actual sales of tissue-engineered skin productsNo comprehensive data on actual sales figures of tissue-engineered skin replace-ment products is publicly available. However, some data can be obtained from pub-lic sources by scanning literature or making educated guesses from data in compa-
20nies annual reports. Table 4.1 gives the best available, albeit very fragmentaryoverview of actual sales figures.Table 4.1: Sales figures for selected tissue engineered skin productsTrade name Company Year Sales (€)ApligrafOrganogenesis Inc (USA),Novartis (USA/CH)2000 12,000,000DermagraftAdvanced Tissue Sciences (USA)2,Smith & Nephew (UK)2002 4,405,000CellActiveSkin IsoTis (NL) 2002 545,000Epidex Modex Therapeutics (CH) 2002 157,000BioSeedS,BioSeedM,MelanoSeedBioTissueTechnologies (D) 2002 450,000Epicel Genzyme Biosurgery (USA) 2001n.a.75 patients treatedannually worldwideSource: Fraunhofer ISI, compiled from literature and companies annual reportsAlthough the data in table 4.1 only cover some of the tissue engineered skin re-placement products which are commercially available, it can be deduced that thetotal annual worldwide sales for tissue engineered skin replacement products will atpresent be in the order of magnitude of € 20 millions.However, none of the products on the market seems to have reached profitabilityyet. As a consequence, two leading US companies, Organogenesis Inc and Ad-vanced Tissue Sciences, which were the first to introduce tissue-engineered skinreplacements into the market, had to file for bancruptcy in autumn 2002. The prod-ucts CellActiveSkin and Epidex were not profitable, and their commercialisation byIsoTis SA (recent merger of IsoTis BV and Modex Therapeutics) has been stoppedby the end of 2002. BioTissueTechnologies which commercialises the productsBioSeedS, BioSeedM, and MelanoSeed, in spring 2003 is at risk of not being ableto meet its financial obligations.2 Advanced Tissue Sciences (USA); had a marketing agreement with Smith & Nephew for Der-magraft and Transcyte; both products were completely taken over by Smith & Nephew in 2002after Advanced Tissue Sciences had to file for bancrupcy.
214.3.2 Potential market volumesMost tissue engineered skin replacement and repair products target the wound caremarket. The wound care market can be devided into three segments:• Traditional wound management, such as traditional gaze and tape, first aid dress-ings.• Advanced wound management, e. g. moist wound healing, hydrocolloid dress-ings.• Active wound management, e. g. tissue engineered skin, growth factors, antim-icrobials, enzymes (e. g. collagenase).Advanced and active wound management concepts aim at actively stimulating thebiological processes of wound healing and at removing the barriers to normal heal-ing present in these types of wounds. Tissue engineered skin products are a sub-segment of the active wound management market. Table 4.2 gives an overview ofthe worldwide wound management sales market and its segments.Table 4.2: World wound management sales market and its segmentsWound ManagementMarket SegmentSales in 2001(mio. €)Share of overallmarket (%)Annual growth rate(%)Traditional 1,950 50.5 -3Advanced 1,515 39.3 + 8Active 392 10.2 + 28Total 3,857 100.0 + 6Source: Smith & Nephew 2002Table 4.2 shows that traditional wound care is still the largest segment of theworldwide wound care market. However, dynamic growth comes from both theadvanced and active wound management segments. Their growth is coming largelyat the expense of the traditional wound care products. The leading companies in theadvanced and active wound management market are Smith & Nephew (marketshare 21 %), Johnson & Johnson (16 %), Convatec (13 %), 3M (12 %) and KCI(9 %). Key drivers in the advanced and active wound care market are• demographic development,• quality of life,• health economics,• improved outcomes,• nursing shortages, and• technological developments.
22The market leader, Smith & Nephew, follows the strategy to be well representedwith its products and services in all stages of the treatment process (wound assess-ment and diagnosis, systemic stabilisation, wound bed preparation, wound healingand aftercare/prevention). The most differentiating factor between traditional andadvanced wound treatment strategies are staff costs, because traditional wounddressings required daily dressing changes while advanced hydrocolloid dressingsare changed only every 2-4 days (Augustin et al. 1999). Therefore, it is assumedthat the cost of healing will be reduced in advanced and active wound managementas compared to traditional management due to the above mentioned driving factors,but that the proportion of the "material" of the total cost base will increase (fig-ure 4.1).Figure 4.1: Contribution of cost factors to overall cost of healing in sectorsof the wound management marketDriving factors: demographic development quality of life, health economics, technological developments,improved outcomes, nursing shortages0102030405060708090100Traditional Advanced ActiveWound careCostofHealingOtherMaterialsNursing TimeSource: Smith and Nephew 2002Another source assumes that the global wound management market potential sumsup to appr. € 6,250 mio., and that a maximum of 10 % can be accessed by – therelatively costly – tissue engineered skin products which will remain restricted tochronic wound management (Landesbank Baden-Württemberg Equity Research2001, p. 17). Therefore, a maximum global market potential of € 625 mio. is calcu-lated. This is in the same order of magnitude as estimations from other sources(Russell et al. 2001).
23Table 4.3: Maximum market potential for tissue engineered skin productsworldwide/USAMarketMarket Size2001 (mio. €)Region SourceGlobal wound management market po-tential6,250 worldMaximum market potential for tissueengineered skin, only applicable tochronic wounds625 world(Landesbank Baden-Württemberg EquityResearch 2001, p. 17)Global market for skin replacementproducts for wound repair800 world (Russell et al. 2001)Market for skin substitutes 300 USA (Russell et al. 2001)Although tissue engineered skin products are already on the market for severalyears, the annual worldwide sales are in the order of magnitude of € 20 mio. (seeabove) and thus stay far behind the market potentials listed in table 4.3. Reasons forthis discrepancy between forcasted market potentials and actual sales figures aregiven in chapter 126.96.36.199 Factors influencing the market situationAlthough the incidence and prevalence of acute and chronic wounds is high (seechapter 4.1), tissue engineered skin is not the preferred treatment for most of thesewounds. Generelly, skin defects can be treated by three therapeutic options:• classical wound treatment by traditional and advanced dressings and ointments,• surgical procedures, such as split skin transplantation,• transplantation of tissue engineered skin.Approximately 80 % of chronic wounds can be treated with classical wound treat-ments which have direct material costs in the order of € 1/day. The remaining 10-20 % therapy-resistant wounds can in principle be treated with tissue-engineeredskin products. To which extent this potential market can be accessed depends heav-ily on the fact whether the health insurances pay the treatment. Experts estimate thatonly up to 15 % of the patients suffering from chronic wounds are willing to pay thewound treatment by themselves, even if sustainable healing could be expected. Theskin transplant costs are appr. € 2,000/treatment. Up to now, in Europe no generalcost coverage by health insurance companies has been achieved. An application forgeneral reimbursement for EpiDex (produced by Modex Therapeutics, Switzerland)was turned down by the Swiss Federal Office for Social Security in late 2002. Ex-perts have different views whether the existing skin products are likely to gain ap-proval at all, regarding reimbursement. At least, this is unlikely to be achieved be-
24fore 2005 because additional data from clinical trials supporting application for re-imbursement approval cannot be expected earlier. Table 4.4 gives a model calcula-tion for the "realistic" market potential, based on data for Germany. The model cal-culation yields a market potential of appr. € 40 mio. to max. 120 mio./year tissueengineered skin products for hard-to-heal wounds for Germany.Table 4.4: Realistic market potential for tissue engineered skin products forthe treatment of chronic wounds, model calculation for GermanyPatients with chronic wounds 2 mio. patientsWounds resistant to conventional wound treatmentprocedures10-20 % of all patients200,000 – 400,000 patientsPatients with therapy-resistant wounds willing topay the treatment by themselves10 % to max. 15%20,000 to max. 60,000 patientsReal market potential for tissue engineered skinproducts2,000 € transplant costs/treatment40 mio. € to max. 120 mio. €/yearAccording to experts‘ opinion, the general reimbursement of tissue engineered skintreatments by health insurance companies would be a prerequisite to fully explorethe real market potential. In addition, structural changes in patient care are required:treatment with tissue engineered skin products will largely be confined to special-ized wound healing centres – at least in the beginning – and not readily availablefrom general practitioners who, however, care for the majority of chronic woundpatients.Experts‘ opinions are devided over the question whether significant cost reductionscan be achieved by using allogenic instead of autologous grafts. Allogenic graftsshould allow for a continuous, automated graft production. However, actual pricesare in the same order of magnitude, irrespective of whether the cell source is al-logenic or autologous. Allogenic Apligraf costs appr. € 1.000/50 cm², autologousBioSeedS € 2000/100 cm² (sales prices only for the transplant; treatment costs addi-tionally include preparation of the wound, transplantation of the skin graft, andcosts for aftercare).Other market segments which do not rely so heavily on the reimbursement policy ofhealth insurances are products which traditionally must be paid by the patientsthemselves (e. g. aesthetic surgery, dental implants) or which are paid from hospitalbudgets (e. g. oral mucosa products used in the treatment of oral cancer). However,the number of affected patients for these indications is much lower than the numberof patients with chronic wounds. In 2002, sales of BioTissueTechnologies productsMelanoSeed and BioSeedM which target the above mentioned niche markets werein the order of magnitude of € 150,000/year and product.
255. Tissue engineered cartilage products5.1 Overview of potential applicationsCartilage tissue is composed of chondrocytes and an extracellular matrix that con-sists of proteoglycans, collagen, and water. It is avascular and has no nerve struc-tures (Laurencin et al. 1999). One can distinguish• unstressed cartilage, e. g. ear and nose,• stressed cartilage, e. g. in joints or intervertebral discs.Once damaged, cartilage is generally considered to have a limited capacity for self-repair. Therefore, tissue-engineered cartilage products aim at cultivating chondro-cytes in vitro, and to reintroduce the cultured cartilage tissue into the damaged re-gion.In the field of unstressed cartilage, few patients have been treated with tissue-engineered cartilage grown on preformed scaffolds. In these cases, cartilaginousparts of the maxillofacial region (e. g. outer ear, nasal septum) have been recon-structed. Due to the still limited clinical success, these applications seem to be re-stricted to single cases (Bücheler 2002).At present commercially more important are tissue-engineered cartilage productswhich target defects of stressed cartilage. Defects of stressed cartilage can be due totrauma, and over time even minor lesions of the articular cartilage may progress tochronic defects, such as osteoarthritis. Defects of stressed cartilage can, however, bealso due to rheumatoid arthritis. In addition to causing pain and restricted mobility,chronic injuries to joint cartilage may lead to further deterioration of the joint sur-faces. These manifestations can severly hinder a persons normal activities and oc-cupation. Established forms of therapy for cartilage damage in joints are• arthroscopic surgery to smooth the surface of the damaged cartilage area,• surgical procedures, such as microfracture, drilling, abrasion, in order to let bonemarrow cells infiltrate the defect, resulting in the formation of fibrous cartilagetissue,• analgesic therapy,• full or partial artificial joint prostheses, often after years of progredient joint de-fects. As artificial joints generally last 10-15 years and revision surgery is prob-
26lematic, joint replacement therapy is recommended mainly for patients over theage of 50.In 1994, another treatment option, based on tissue engineered cartilage, becameavailable for cartilage defects in the knee joint which are due to traumatic injury:autologous chondrocyte implantation, also termed autologous chondrocyte trans-plantation (ACT) (Brittberg et al. 1994). This technique and several modificationsof it are presently the most important clinical application of tissue engineered carti-lage.The following applications may become relevant in the future:• further development and adaptation of the ACT technique for the treatment oftraumatic cartilage defects in other joints than the knee,• further development and adaptation of the ACT technique for the treatment ofjoint cartilage defects with different etiology (e. g. osteoarthritis, rheumatoid ar-thritis),• development of tissue-engineered grafts combining cartilage and bone,• tissue engineered products for the treatment of intervertebral disc damage.5.2 Overview of important companies and productsAt present, most tissue engineered cartilage products target cartilage defects in theknee joint which are due to traumatic injury. They are based on the method devel-oped in 1994 (Brittberg et al. 1994). At present, at least three types of ACT arecommercially available:• "Classical" ACT. In a first arthroscopic surgery, a biopsy of healthy cartilage istaken from the patients knee from a minor load bearing area. The chondrocytesare isolated and cultured in vitro for about three weeks. In a second, this timeopen-knee surgery, a periosteal flap is taken from the patient and is sutured overthe cartilage lesion. Then the cultured chondrocytes are injected under the flapinto the lesion. The knee is surgically closed. Movement of the knee and weightbearing must be gradually introduced and increased to the full extent over a pe-riod of 2-6 months after surgery.• ACT with artificial cover. This variant of the classical ACT uses an artificialcover, e. g. a collagen or hyaluronic acid membrane, instead of a periosteal flap.• Matrix-induced ACT. In this variant of the classical ACT, the cultured chondro-cytes are applied to a biodegradable three-dimensional scaffold before retrans-plantation. The pre-formed graft is then cut to the required size and fitted into thedefect with the aid of anchoring stitches. This method does no longer require the
27complicated sueing of the periosteal flap or artificial cover, therefore signifi-cantly reduces the surgery time and also makes arthroscopic instead of open-knee surgery possible. It is assumed, but not yet proven, that the three-dimensional scaffold also yields a hyaline cartilage of superior biomechanicalproperties than in "classical" ACT, so that the treatment of osteoarthritic defectswill also become possible in this way.At present, all autologous chondrocyte products on the market fall into one of thesethree categories. Additionally, the commercially available products differ in theirtechnical specifications (e. g. details and duration of the cell culturing process, addi-tives to the cell transplant (e. g. antibiotics)), the extent of quality standards andquality control applied to the production process and resulting product, the logisticservice provided by the company, and the educational support provided by thecompany for the orthopedic surgeons. At present, it is difficult to assess whetherand which of these factors give companies a clear market advantage over theircompetitors.There is a large number of companies which offer autologous chondrocyte trans-plants. The most important companies for chondrocyte transplants are describedbelow.• Genzyme Biosurgery (USA). Genzyme Biosurgery is a division of GenzymeCorporation. It develops, produces and sells biotherapeutic and biomaterialproducts especially in the markets of orthopaedics and heart disease, and inbroader surgical applications. Genzyme Biosurgery was the first company whichintroduced autologous chondrocyte transplantation into the market. With itsproduct Carticel®, Genzyme Biosurgery is market leader in the USA. Activitieswith Carticel in Europe seem to have been terminated recently. Genzyme Bio-surgery had treated appr. 4,000 patients worldwide with its product Carticel® inthe period from 1995 to 2000. This corresponds to cumulated sales of appr.20 mio. US-$ in five years. Sales of Carticel® amounted to 18.4 mio. US-$ in2001 and 20.4 mio. US-$ in 2002, which corresponds to 2,000-3,000 transplants/year.• Fidia Advanced Biomaterials (IT). Fidia Advanced Biomaterials is one of theEuropean market leaders and has a good market position in Europe, especially inItaly. FAB sells about 300-400 transplants/year. Its product HYALOGRAFT® Cis a cartilage substitute made of autologous chondrocytes delivered on a biocom-patible tridimensional matrix, entirely composed of a derivative of hyaluronicacid (HYAFF®).• Verigen (Germany). Verigen, founded in 1999 and headquartered in Leverku-sen, Germany with offices in the United Kingdom, Denmark, Italy, and Austra-lia, is one of the European market leaders. It has currently three chondrocyteproducts for the treatment of knee cartilage defects on the market: CACI (cultu-red autologous chondrocytes which are covered by a collagen membrane), MACI
28(matrix-induced autologous chondrocyte implantation), and MACI® (A) whichis the minimally-invasive variant of MACI®, in which the implantation is doneby arthroscopy. By 2002, more than 800 patients in Europe and Australia havebeen treated with Verigen products. Verigen has a cooperation with Mitek formarketing MACI® (A) in the USA. No data on sales figures and revenues areavailable.• co.don (Germany). co.don was one of the first companies to offer autologouschondrocyte transplantations in Europe and is one of the European market lead-ers. Its product is co.don chondrotransplant®. In 2000, sales of chondrotrans-plant® were appr. 550,000 € (corresponding to sales of 100 transplants plus ap-plication of 100 without reimbursement (e. g. in clinical trials), and appr.1 mio. € in 2001 (corresponding to ca. 260 transplants plus 80 transplants with-out reimbursement).• BioTissueTechnologies (Germany). BioTissueTechnologies is a tissue-engineering company founded in 1997. Its chondrocyte product is BioSeedC®,an autologous 3D chondrocyte graft which can also be applied by arthroscopy.BioSeedC® is in controlled clinical use since 2001. Sales in 2002 were approxi-mately 500.000 €. BioSeed®-C is currently available throughout Germany. In2003, in co-operation with industrial partners, the company plans to increase itsavailability to include other European countries.• TETEC® AG (Germany). TETEC® AG was founded in 2000. It develops andmanufactures autologous cell transplants for cartilage repair which are distrib-uted by its co-operation partner AESCULAP® AG, a medical device companyspecialised as a system supplier in the surgical area ("All it takes to operate").TETEC® has a manufacturing permit for the autologous chondrocyte productNOVOCART® in accordance with the German Drug Act (AMG). TETEC® AGhas one product on the market, NOVOCART®. TETECs R&D activitiescomprise a scaffold implant technology for ACT which can be applied byarthroscopic surgery, treatment of larger articular cartilage defects including me-niscal lesions, degenerative arthritis or osteoarthritis by cartilage cells seeded onscaffolds in the medium-term, and treatment for Intervertebral disk (IVD) lesi-ons.Other companies, also active in this sector are• IsoTis SA (Switzerland/The Netherlands). Before the merger with the Swisscompany Modex Therapeutics, IsoTis BV (NL) had the autologous chondrocyteproduct CellActive Cart on the market, mainly in Spain. Sales amounted to187,000 € in 2002. As the product was not profitable, the production and marke-ting of CellActive Cart was stopped in late 2002.• ARS ARTHRO AG® (Germany). The company was founded in 2001, receivedmanufacturing approval according to the German drug act in October 2002 and
29has its product CaReS® (Cartilage Repair System) in clinical use since Novem-ber 2002. CaReS® is a 3D mechanically stable chondrocyte transplant based oncultured autologous cartilage cells and a collagen matrix. It is applied by mini-mally invasive surgery. Since late 2002 a prospective randomized study compar-ing ACT with the ARS ARTHRO® transplant is carried out at the UniversityHospital in Aachen (Germany) for the indication of focal defects of the articularcartilage of the knee joint.• Ormed (Germany). Ormed is a medical device company specialised in thera-pies in orthopaedics, traumatology, athroscopy, sports medicine and rehabilita-tion. It offers the autologous chondrocyte transplant ARTROcell®. The autolo-gous chondrocytes are cultured by the cooperation partner Metreon BioproductsGmbH , a subsidy of the biotechnology company CellGenix Technologie Trans-fer GmbH. The chondrocyte implant is covered by a collagen matrix derivedfrom porcine type-I and type III collagen (Chondro-Gide®, supplied by Geist-lich). Ormed also offers training courses for ACT and carries out R&D on AR-TROcell® follow-up products.• Orthogen AG (Germany). Founded in 1993, Orthogen develops and produces"molecular orthopaedics" products for orthopaedic specialists and surgeons, suchas genetic diagnostic tests and autologous chondrocyte transplants. Since 2000,Orthogen AG has the authorization of a GMP-clean room, where it manufacturesArthromatrix®. Arthromatrix® is being distributed by Arthrex Biosystems(Germany).• CellTec (Germany). CellTec, founded in 1997, holds a manufacturing permit incompliance with §13 AMG (German Drug Act) to manufacture culturechondrocytes according to GMP since 1999. CellTec has one autologouschondrocyte product on the market, ChondroTec™ which is applied by open-knee surgery and covered with a periosteal flap. In an ongoing research project,CellTec develops Matrix-Bound Chondrocyte Transplantation (MACT).• TiGenix (Belgium). TiGenix develops cell-based tissue-engineered products inthe areas of joint-surface defects, bone defects and heart valves. Its lead productis ChondroCelect®, an ACI, which entered randomised, prospective, multicenterclinical trials in March 2002. In preclinical development are ChondroCelect-P®(i. e. ChondroCelect with introduction of adult stem cell technology), Chon-droSealTM(use of a biodegradable membrane to replace the periosteal flap in theACI-procedure), and Osteochondral Repair (Expanded osteoprogenitor cellpopulations, combined with adequate biomaterials, to be used in combinationwith ChondroCelect products in order to treat osteochondral defects).• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held devel-opment stage company, focusing on cellular therapeutic products for the regen-eration and functional restoration of damaged and diseased tissue. The therapeu-tic products are derived from human mesenchymal stem cells (hMSCs) ex-tracted, isolated and purified from adult bone marrow. Osiris specialises in the
30differentiation of hMSCs into different specialised cell types, among them carti-lage. Osiris has a preclinical research programme to develop a treatment for me-niscal injury in the knee, based on human mesenchymal stem cells. The productChondrogen is an injectable preparation of Mesenchymal Stem Cells suspendedin hyaluronan which is delivered to the joint by simple intraarticular injection. Aclinical trial is planned.5.3 Actual sales and potential market volumes5.3.1 Actual sales of tissue-engineered cartilage productsNo comprehensive data on actual sales figures of tissue-engineered cartilage repairproducts is publicly available. However, some data could be obtained from expertinterviews, and they were backed up and checked for plausibility by data from pub-lic sources, such as literature or data from companies annual reports. Table 5.1gives the best available, albeit very fragmentary overview of actual transplantationand sales figures. The sales volume per country is calculated from the number ofperformed ACTs/year, assuming average prices of the transplants of € 5,000 inEurope and € 8,000 in the USA. As a plausibility check, sales information on indi-vidual products are also given. As can be seen from table 5.1, worldwide sales ofautologous chondrocyte transplants are presently unlikely to exceed the order ofmagnitude of € 40 mio./year.
31Table 5.1: Sales figures of autologous chondrocyte implantsCountry n ACT/year Calculated sales volume*Important companies/products Sales information from important companiesUSA 2,000-3,000 € 16 – 24 mio. Genzyme Biosurgery/Carticel®Sales of Carticel ®:Sales 2001: 18.4 mio. US-$Sales 2002: 20.4 mio. US-$Germany 600 € 3 mio.Verigen/ACI/MACI/MACI-Aco.don/co.don chondrotransplant®BioTissue Technologies/BioSeedC®Sales of co.don chondrotransplant®:2000: 550,000 € (ca. 100 transplants plus 100 withoutreimbursement),2001: 1,000,000 € (260 transplants plus 80 without re-imbursement)Sales by BioTissueTechnologies2002: 500.000 €, ca. 100 transplantsUK 300-850**€ 1.5-4.3 mio. Verigen/ACI/MACI/MACI-A**Estimates by NICE of the number of potential ACToperations in England and WalesItaly 300-400 € 1.5-2 mio.Fidia Advanced Biomaterials/HYALOGRAFT® CSpain 40 € 187,000 IsoTis/CellActive Cart Sales of IsoTis CellActive Cart: 187,000 € in 2002Total 3,240-4,850 € 22.2-33.3 mio.* retail prices of €5,000 /autologous chondrocyte transplant in Europe and € 8,000/transplant in USA. These costs do not include costs for sur-gery and rehabilitation.Source: Fraunhofer ISI Research 2003
325.3.2 Potential market volumesTissue-engineered cartilage products aim at repairing defects in stressed cartilage,due to trauma or progressive degeneration. Table 5.2 gives an overview of the inci-dences and prevalences of these defects, table 5.3 gives an overview of the corre-lated monetary markets.Table 5.2: Overview of frequencies of cartilage defectsRegion Size Year SourceGermany 1.5 mio.annual incidence oftreatable arthrosis3 2000(Landesbank Baden-WürttembergEquity Research 2001, p. 19)Germany 1.4 mio.patients sufferingfrom arthrosis2002(Concord Corporate Finance Re-search 2002)Germany 1.5 miopatients sufferingfrom osteoarthrosis2002(Concord Corporate Finance Re-search 2002)Europe 7 mio.* annual incidence oftreatable arthrosis2000USA 5 mio.* annual incidence oftreatable arthrosis2000World 15-20 mio.annual incidence oftreatable arthrosis2000(Landesbank Baden-WürttembergEquity Research 2001, p. 19)World 20 mio.patients with jointcartilage defects2002(Concord Corporate Finance Re-search 2002)Germany 50.000annual incidence forknee injuries2000(Landesbank Baden-WürttembergEquity Research 2001, p. 19)Germany 40.000annual joint re-placements withknee prosthesis1999 Biomet MerckEurope 250.000* annual incidence forknee injuries2000(Landesbank Baden-WürttembergEquity Research 2001)USA 600.000arthroscopies linkedto cartilage defectsor injuries2000(Landesbank Baden-WürttembergEquity Research 2001)USA 400.000articular cartilageprocedures1997(Isotis Corporate Communications& Investor Relations 2003)World 1.000.000** injuries or defects ofthe knee2000(Landesbank Baden-WürttembergEquity Research 2001)*estimation based on incidence in Germany**estimation based on data from Germany and USA3 Due to the limited availibitiy of effective therapeutic options, patients with symptoms of arthrosisare often not treated until the disease has progressed to a stage in which analgesic therapy or aknee implant is indicated.
33Table 5.3: Market sizes correlated with cartilage defects/cartilage repairRegionMarketsize (€)Year Remarks SourceEurope 2 billions 1999Market value for joint implants(prosthesis costs only)Biomet MerckWorld 1.5 billions 1999Market value for knee implants(prosthesis costs only)DatamonitorUSA 5.2 billions 2001annual spending for total kneereplacement; estimation based onincidence (200.000 patients/year)and cost per treatment (26.000US-$)(Russell et al. 2001)World 6.5 billions 2001market potential of surgical pro-cedures for cartilage regeneration(Landesbank Baden-Württemberg EquityResearch 2001)World 25 billions 2011market potential of surgical pro-cedures for cartilage regeneration(Landesbank Baden-Württemberg EquityResearch 2001)As can be seen from table 5.3, the potential markets for cartilage repair amount toseveral billion €, and are thus very attractive. However, actual worldwide sales fig-ures for ACT are unlikely to exceed € 40 mio.That the presently accessible market for cartilage repair by tissue engineering ismuch smaller than the potential market is due to the following factors:• Restriction to traumatic cartilage defects. With the present technology of trans-planting autologous chondrocytes in suspension and covering the transplantedcells with a cover (e.g. periosteum, artificial cover), only those joint cartilage de-fects can be treated which are due to traumatic injury (e. g. sports injuries).However, the majority of joint defects is due to osteoarthritis or rheumatoid ar-thritis.• Restriction to knee joints. The surgical techniques by which the chondrocytescan be introduced into the damaged joint are established only for knees, but can-not readily be applied to other joints (e. g. hip, shoulder etc.). Due to these tworeasons approximately 90 % of the joint cartilage defects in the affected popula-tion are not an indication for autologous chondrocyte transplantation using cellsuspensions.• Compliance of patients. As it takes approximately six months of rehabilitation,during which the treated knee cannot be fully used, a high compliance of the pa-tients with a strict rehabilitation protocol is required. This restricts the market tohighly motivated, mostly younger patients. An artificial knee prosthesis, how-ever, can bear weight already a few days after the surgery.• Alternative treatment options. Because a partial or full knee prosthesis can bearweight already a few days after the surgery, this option is preferred especially for
34elder patients whose life expectancy correlates with the life span of the prosthe-sis. The suppliers of joint prostheses continually optimize their products so thatthe competition between cell based and prosthesis-based treatment options willcontinue.Company experts interviewed for this study assumed that the ACT variant of ma-trix-induced ACT, which has recently become clinically and commercially avail-able, much larger and lucrative market segments could be opened up which are notaccessible for cell suspensions:• on the one hand, the easier surgical technique of matrix-induced ACT will sup-port the further use of this technique among orthopedic surgeons,• on the other hand, it may be possible to treat also osteoarthritic defects in theknee, and perhaps also several types of cartilage lesions in other joints than theknee.In addition, new tissue-engineered products are in preclinical development whichcombine cartilage and bone and might be used for the treatment of defects whichaffect both cartilage and bone.If the above mentioned assumptions proved true, matrix-induced chondrocyte trans-plants could partially replace knee prostheses, could also offer an option for defectswhich are presently not treated at all, and could – in the long term – postpone theneed for joint prosthesis for several years. The size of this additional segment can-not be estimated with accuracy because the results from the ongoing clinical trialsmust still be awaited. For the USA, the annual market for effective new repair tech-niques is estimated at € 300 mio. to € 1 billion (Russell et al. 2001). Given the fact,that actual worldwide sales for ACT do not exceed € 40 mio., this would be a morethan tenfold increase over the present market.5.4 Factors influencing the market situationIn orthopedic surgery, the concept of cell therapy is rather new. Therefore, a certainscepticism among orthopedic surgeons who are more used to prostheses, screws andplates, must be overcome. Therefore, relatively large efforts have to be taken toeducate, convince and train these medical doctors. This also implies that the market-ing activities are knowledge-intensive and must be carried out by relatively highlyqualified staff. Although strategic cooperations with medical device companieswhich are active in the orthopedics market have been formed to improve the accessto the customers, experts are sceptical whether their marketing activities are appro-priate for cell-based products.
35The therapeutic success does not only depend on the quality of the chondrocytetransplant, but also on the quality of the surgical procedure and the rehabilitationprotocol. Some companies, e. g. co.don in Germany, therefore follow a "Centre ofExcellence" concept. This means that also their customers must comply with qualitystandards. This concept also makes it easier to obtain reimbursement for the trans-plants either from health insurers or hospital funds.At present, the main hindrance for expanding the ACT sales in the segment oftraumatic knee injuries is the fact that no general reimbursement of this treatmentby health insurances has been obtained so far in Europe, the only exception up tonow being Austria. In Austria, autologous chondrocyte transplantation is listed inthe "Leistungskatalog BMSG 2003 – Leistungsorientierte Krankenanstaltenfinan-zierung" (Editor Bundesministerium für soziale Sicherheit und Generationen) as an"costly diagnostic or therapeutic procedure". Since January 2003, Austrian hospitalsmust document their health services according to this Leistungskatalog in order toget reimbursement. As this "Leistungskatalog" came into force not before January2003, figures are not yet available whether this different reimbursement practice inAustria corresponds to an increase in autologous chondrocyte transplant sales.Moreover, Austria is not the market which has been primarily targeted by the lead-ing companies.Review and approval procedures have been initiated e. g. in Germany with theBundesausschuss der Ärzte und Krankenkassen and in the UK with the NationalInstitute of Clinical Excellence (NICE). However, in 2000, these institutions cameto the conclusion that the evidence on ACT does not yet support the widespreadintroduction of this technology into the respective national health systems(Geschäftsführung des Arbeitsausschusses "Ärztliche Behandlung" des Bunde-sausschusses der Ärzte und Krankenkassen 2000; Gibis et al. 2001; NHS Centre forReviews and Dissemination 2003; Jobanputra et al. 2003; Jobanputra et al. 2001).Reviews of these decisions are ongoing, and may be due in 2003.As decisions on general reimbursement of ACT are still pending, in the presentsituation the reimbursement of the treatment costs has to be negotiated on a case-by-case basis. Moreover, the policy of the health insurers seems to differ fromcountry to country, with companies perceiving Germany as being more prohibitiveand the Benelux countries as being more permissive. Some companies hold special"reimbursement departments" which support patients and doctors in obtainingtreatment cost reimbursements.
366. Tissue engineered bone products6.1 Overview of potential applicationsTissue engineered bone addresses the bone repair market which is in principle avery huge market of several billion €/year worldwide. Indications and market seg-ments for tissue engineered bone products are (Concord Corporate Finance Re-search 2002)• Bone fractures. Most bone fractures are treated by standard therapies (see be-low); however, appr. 10 % cannot be treated this way because the damaged sitesare too big. If tissue engineered bone could be used, it could be applied world-wide in 1.5 mio. patients per annum. The most important markets are the USAwith 700,000 patients and Europe with 600,000 patients.• Jaw bone surgery and periodontal surgery. The number of patients in this fieldamounts to approximately 1.5 mio. patients in Europe and 4.5 mio. patientsworldwide.• Osteoporosis and bone tumors. In Europe there are 10 mio. cases annually, theworldwide potential sums up to 30 mio. applications.Most bone fractures are treated by standard therapies. These are gypsum/plaster,tape, nailing, screws and plates. Larger defects, due to fractures, surgery or tumors,can be treated with autologous bone grafts which are taken from another site of thepatient’s body in a second surgical procedure. These grafts normally give the bestclinical results compared to other options. Another option are allogenic bone graftswhich are taken from other patients undergoing bone surgery or from cadavers andstored in bone banks until used. Problems with these allogenic grafts lie in risk ofinfection, higher bone resorption rates and variations in quality due to donor varia-tion. A third option are synthetic bone materials such as calcium phosphate, hy-droxylapatite etc. These materials, however, lack the power of rapidly inducingbone formation. Moreover, bone from animal sources is being used. Most of thesexenogeneic bone materials are prepared from deproteinized bovine bone. In general,xenogeneic bone can have better toxicological and bone-inducing properties thansynthetic bone materials, but bear the risk of infections (e. g. viruses, prions) andrejection.Table 6.1 gives an overview of the advantages and disadvantages of the differenttreatment options in bone repair.
37Table 6.1: Comparison of different bone repair approachestype ofgraftrejection type ofmaterialinfection availabil-itytype ofsurgerysize ofgraftingshapingautolo-gousgraftsno rejec-tionown ma-terialno risk ofinfectionimmedi-ate butlimitedlargebiopsyandtransplan-tationlimited no indi-vidualshapingalloge-neicgraftsrisk ofrejectionforeignsubstancerisk ofinfectionimmedi-ate butlimitedonlytransplan-tationlimited no indi-vidualshapingsynthetics generallyno rejec-tiontransfor-mationinto ownmaterialno risk ofinfectionimmedi-ate, un-limitedonlytransplan-tationnot lim-itedspecialshapeavailablexenoge-neicgraftsrisk ofrejectionforeignsubstancerisk ofinfectionimmedi-ate, un-limitedonlytransplan-tationlimited no indi-vidualshapingautolo-gous TEproductsno rejec-tionown ma-terialwith os-teoblastsno risk ofinfectionunlimitedbut de-layedsmallbiopsyandtransplan-tationnot lim-itedshapingby in-jectablebonematerial6.2 Overview of important companies and productsThere are only few companies which have tissue engineered bone developmentprogrammes. These companies are• IsoTis SA (CH/NL). Until recently, IsoTis had a research programme for theautologous bone product VivescOs, and an associated bioreactor production plat-form. However, in the course of the recent restructuring and reorganisation, thisprogramme was cancelled. Instead, the scaffold OsSatura (without cells) hasbeen brought onto the market in 2003 after receiving approval in Europe. Os-Satura is osteoconductive, i.e., it guides bone formation through its macroporousstructure, and also osteoinductive, i.e., it actively induces bone to grow in and onthe scaffold. OsSatura replaces an earlier product launched in late 2001, Os-Satura PCH. The company expects OsSatura to become a major product. Thesales expectations are > 10 mio. € by 2005/2006, equivalent to 15-20 % of thesynthetic bone substitute market (see table 6.3). Although OsSatura is less pow-erful than the tissue engineering approach followed until recently, the companyassesses OsSaturas cost of goods as much more favourable than the tissue engi-neering option, whose additional therapeutic benefit would not justify the addi-
38tional high costs (IsoTis press releases January 7, 2003; February 5, 2003; March27, 2003). IsoTis best selling product in 2002 was SynPlug, a cement restrictorfor cemented hip replacements. It is CE certified. It was launched in 2001 and ispresently being sold through orthopaedic companies such as Smith & Nephew,Centerpulse France, and ScandiMed (Biomet Merck), as well as through a rangeof national distributors. Sales for the SynPlug in Europe amounted to € 646,000in 2002.• BioTissue Technologies (Germany). This company has an autologous boneproduct on the market since November 2001. BioSeed®-Oral Bone is a three-dimensional, jawbone graft from cultured autologous periosteum cells. It can beused in the treatment of tooth loss with fixed dental prostheses. By strengtheningand replacing missing upper jaw bone material it supports the anchoring of den-tal implants firmly into the jaw. Sales of BioSeed®-Oral Bone amounted to€ 250,000 in 2002.• co.don (Germany). Since 1997, co.don® has been manufacturing autologousosteoblast transplants according to the German Drug Act (AMG) under the brandname co.don osteotransplant®. The product is indicated in complicated fractures,tumour based bone damages, pseudoarthroses, sarcomata and calcifications inloosening or change of prostheses. Further indications are the reconstructive andplastic surgery, jaw bone surgery and bonechip blocking of spine segments incase of severe degenerated disks.• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held devel-opment stage company, focusing on cellular therapeutic products for the regen-eration and functional restoration of damaged and diseased tissue. The therapeu-tic products are derived from human mesenchymal stem cells (hMSCs) ex-tracted, isolated and purified from adult bone marrow. Osiris specialises in thedifferentiation of hMSCs into different specialised cell types, among them bone.The product Osteocel is bone regenerated from autologous mesenchymal stemcells for orthopedic and dental defects. In 2002, a small Phase 1 human safetytrial was completed in which autologous hMSCs were delivered on a hydroxya-patite matrix into the jaw to promote new bone formation in preparation for den-tal implants. The results of that study demonstrated significant new bone forma-tion with no adverse events. Moreover, the feasibility of fully MHC mis-matchedallogeneic MSCs to repair large segmental defects have been demonstrated in ababoon preclinical model. Ongoing studies are focused on the ideal compositionof a matrix and the Adult Universal Cell hMSC product for delivery to load-bearing, long bone defects.• CellFactors (UK). CellFactors focusses on the development of human cell-based therapies by generation and manipulation of immortalized, partially diffe-rentiated human cells. One of the companys areas of focus are protein matrices(orthobiologics) for bone regeneration. CellFactors lead product for bone regene-ration is SkeletexTM. This osteoinductive material consisting of growth factors
39and collagens has the potential to increase the strength of weak or damaged bo-nes, or to create new bone where required. CellFactors is developing Skeletex™for use in conjunction with existing orthopaedic devices and prosthetics (e.g. inspinal fusion, artificial hips and knees), as well as for dental applicati-ons.CellFactors plc demonstrated its ability in January 2003 to manufacture Ske-letex™ consistently to meet industrial requirements so that the material can beproduced in sufficient quantities for full-scale commercial production. CellFac-tors is currently in negotiations with a number of orthopaedic companies tosupply Skeletex™ for a range of applications. Contract Manufacturing Organisa-tions have now been identified and assessed for commercial-scale production ofSkeletex™.Several companies are offering growth factors and bone morphogenic proteins.Among them are• Curis, Inc. (USA). Curis resulted from a merger of Creative BioMolecules Inc.(USA) with Ontogeny, Inc. (USA) and Reprogenesis Inc. (USA) in July 2000.Curis is a therapeutic drug development company. The Companys technologyfocus is on regulatory pathways that control repair and regeneration, among themthe Hedgehog (Hh) pathway and the Bone Morphogenetic Protein (BMP) path-way. Development of several therapeutic products is in early to late preclinicalstages.• Wyeth (USA). Wyeth carries out discovery, development, manufacture, distribu-tion and sale of pharmaceuticals and over-the-counter consumer health careproducts. Among its products in the pipeline is hBMP-2, a recombinant humanbone morphogenetic protein 2. It is approved in the EU and is currently in U.S.regulatory review for treating patients with acute long-bone fractures requiringsurgical management. Its use in spinal fusion is being investigated in cooperationwith Medtronic Sofamor Danek. The product is approved and launched in theU.S. for lumbar interbody spinal fusion. It is in Phase III trials for lumbar poster-olateral spinal fusion. Additional uses for rhBMP-2 are being investigated in ear-lier development phases.• Medtronic Sofamor Danek (USA). Medtronic Sofamor Danek develops andmanufactures products that treat a variety of disorders of the cranium and spine,including traumatically induced conditions, degenerative conditions, deformitiesand tumors. In 2002, U.S. Food and Drug Administration (FDA) approved Med-tronic Sofamor Daneks INFUSE™ Bone Graft/LT-CAGE™ Lumbar TaperedFusion Device. This device is used to apply INFUSE™ Bone Graft in spine sur-gery in order to treat degenerative disc disease. The bone graft contains recombi-nant human bone morphogenetic protein (rhBMP-2), that is capable of initiatingbone growth, or bone regeneration, in specific, targeted areas in the spine. De-velopment projects of combining threaded cortical dowels and Bone Morphoge-netic Proteins (BMP) are underway.
40• Stryker Corporation (USA). Stryker Corporation develops, manufactures andmarkets specialty surgical and medical products globally. The products includeorthopaedic implants, trauma and spinal systems, powered surgical instruments,endoscopic systems, and the bone growth factor osteogenic protein-1 (OP-1).Marketing authorization was obtained in 2001 for OP-1 by Australia, the Euro-pean Union and the United States for specific indications involving long-bonefractures. Stryker is also investigating spinal applications for OP-1 through clini-cal trials in North America and Japan.• Orquest, Inc. (USA). Founded in 1994 and employing a staff of 25, Orquest,Inc. is a orthobiologics company that designs, develops, manufactures and sellsmaterials that accelerate and enhance bone repair and regeneration. Orquestsunique product portfolio is based on two proprietary core technologies. Its bonegraft substitute Healos® is approved for sale in Europe, and Ossigel®, an in-jectable product designed to improve fracture healing, is currently under clinicalinvestigation in Europe. Healos®MP52 is combination of Healos and the boneinducing protein MP52. MP52 is under clinical investigation in Europe.There are many companies which offer biomaterials and synthetic bone fillers.Among them are• Biomet Merck Group (The Netherlands). Founded in 1998 as a joint ventureof Biomet Inc. (USA) and Merck KGaA (Germany), the company is specialisedin the development, production and marketing of products for the therapy ofbone and soft tissue diseases. It combines expertise in pharma and chemistry,biomaterials, drugs, orthopaedics and implants.• Interpore Cross International (USA). Interpore Cross International developsand applies biologic biomaterials to speed bone repair. It has three products onthe market: AGF technology, which allows the surgeon to collect autologousgrowth factors from the patients blood and to combine it with bone grafting ma-terial in order to support healing. ProOsteon is a hydroxyapatite bone graftingmaterial harvested from marine coral exoskeletons. BonePlast is an extrudable,moldable bone void filler based on calcium sulfate.• Orthovita (USA). Orthovita is a biomaterials company which develops novelproducts for use in spine surgery and in the repair of osteoporotic fractures. It hastwo products on the European market: VITOSS®, a resorbable calcium phos-phate bone void filler, and CORTOSS®, a Synthetic Bone Void Filler, is a high-strength, bone-bonding, self-setting composite engineered specifically to mimicthe strength characteristics of human cortical bone.Other players and competitors in the field are large orthopedic companies, whichoffer “conventional” treatments, e. g.• Stryker Corporation (see above).
41• Johnson & Johnson (USA). Johnson & Johnson is a comprehensive and broadlybased manufacturer of health care products, and a provider of related services,for the consumer, pharmaceutical and medical devices and diagnostics markets.Johnson & Johnson has 198 operating companies in 54 countries. Johnson &Johnsons business segment "Medical Devices and Diagnostics" includes surgicalimplants, instruments, needles and sutures; blood glucose monitoring systems;wound closure devices; endoscopic instruments; orthopaedic products for jointrepair and replacement and for correcting spinal deformities; contact lenses;clinical chemistry systems; medical devices, including cardiovascular monitoringand vascular access products; intravenous catheters and shunts; coronary and bil-iary stents; and diagnostics.• Smith & Nephew (UK) (see annex).• Zimmer Inc. (USA). Zimmer Inc. is a global player in the design, development,manufacture and marketing of reconstructive orthopaedic implants and fracturemanagement products.• Biomet Merck (see above).• Synthes-stratec (Switzerland). Synthes-Stratec is an international medical devicecompany, specializing in the development, manufacturing and marketing of in-struments and implants for the surgical treatment of bones (osteosynthesis). Syn-thes-Stratec’s activities also include new technologies such as implant coatings,synthetic bone replacement materials, bioresorbable implants, and computer-assisted surgery.• Mitek (USA). Mitek Worldwide is a developer, manufacturer and marketer ofinnovative medical devices for surgery, with focus on sports medicine and re-construction. It is a division of Ethicon, a Johnson & Johnson company. Thecompanys main products, suture anchoring implants are primarily used to reat-tach damaged ligaments and tendons in the shoulder, rotator cuff, wrist, thumband ankle.In hip and knee prostheses, important companies are mainly from the USA, while intrauma repair, European companies are better positioned.6.3 Potential market volumesMost bone products on the market do not fall into the definition of core tissue engi-neering products used in this study, because they either use only cells or growthfactors or scaffolds, but not combinations thereof. Moreover, only few figures onactual sales could be retrieved from publicly available sources (table 6.2). However,market data on conventional bone replacement materials are available (table 6.3).The worldwide market is in the order of magnitude of € 300 mio. These market fig-
42ures may represent the market potential for tissue engineered bone as long as nounique applications for tissue engineered bone emerge.Table 6.2: Sales 2002 of bone products by tissue engineering companiesCompany Product Description Sales 2002 (€)IsoTis BV SynPlugCE certified cement restrictor for cementedhip replacements.646,000BioTissueTechnologiesBioSeedOralBonethree-dimensional, jawbone graft from cul-tured autologous periosteum cells for use offixing dental implants into the jaw bone250,000Table 6.3: Market for bone replacement and repairType ofbone replacementUSA 1998 World 2002Autologous bone € 105 mio. 47 %Allogenic bone € 97 mio. 43 %Xenogeneic bone no data available no data available€ 249 mio.Synthetic bone material € 23 mio. 10 % € 51 mio.Total € >225 mio. € 300 mio.Source(Concord Corporate Finance Research2002)IsoTis 20036.4 Factors influencing the market situationAlthough tissue engineered bone can be grown successfully, experts are of opinionthat at present there are only minor applications for commercialisation due to thefollowing reasons: At the present state of the art in bone tissue engineering, onlysmaller defects could be treated. However, for these defects existing treatments(autologous or allogenic bone grafts, synthetic bone fillers) fulfil the clinical needssatisfactory, so that tissue engineered bone would have to edge out these establishedoptions. In addition, most bone defects come from trauma and accident and requireacute treatment, so that there is not enough time to grow an autologous bone bytissue engineering. Only a minor fraction of bone surgery are planned operations.This is mainly the case in revision surgery when a prosthesis is replaced by a sec-ond one. Then the gaps between the prosthesis and the bone could be filled withtissue engineered bone. Nevertheless, experts have doubts that tissue engineeredbone in the mentioned applications could be competitive on a monetary cost basesbecause its production costs would be in the order of magnitude of chondrocytetransplants (appr. 5,000 €). Therefore, a significant reduction in costs of the tissueengineered bone would be required. It is discussed controversially among experts
43how this can be achieved (e. g. highly automated graft production procedures inspecially designed bioreactors).As a consequence, present applications seem to be restricted to rather small nichemarkets, e. g. in dental and maxillofacial surgery. This market is targeted e. g. byBioTissue Technologies product BioSeed®-Oral Bone. Here, making the surgeryeasier and giving the patient less pain are advantages that the patients are willing topay for.Established bone defect treatment options have relative weaknesses in the treatmentof large bone defects, so that there would be a medical need for new treatments forthis type of defects. However, the technology of bone tissue engineering is not yetadvanced enough to provide such large bones with the required biomechanicalproperties.According to the experts interviewed, medical device companies which are active inthe orthopedics market have recognised the potentials of tissue engineering for thefuture development of their field, and they closely monitor the progress of tissueengineering in this area. However, despite being aware of the future relevance oftissue engineering for the competitiveness of these companies, present investmentinto tissue engineering research projects is still rather limited. This is due to the factthat decisions must be made regarding the allocation of research funds to differentprojects. In these decision process, R&D projects in advanced "traditional" medicaldevices are often preferred over tissue engineering projects, because in direct com-parison, the "traditional" projects promise a larger, quicker and less risky return ofinvestment. In addition, it is difficult for these companies to carry out tissue engi-neering, because tissue engineering requires different "thinking", competencies andprocedures than those established in medical device companies.
447. Tissue engineered cardiovascular products7.1 Overview of potential applicationsCardiovascular diseases (CVD) include hypertension, coronary heart disease, stroke(cerebrovascular disease), peripheral vascular disease, heart failure, rheumatic heartdisease, congenital heart disease and cardiomyopathies. In the EU, 240-260 deathsper 100,000 population must be attributed to cardiovascular diseases. Thus, CVDare responsible for about half of the total mortality and therefore remain one of themain causes of death (World Health Organization (WHO) 2002).At present, tissue engineering R&D in the field of CVD comprises three fields ofactivities:• Heart valves,• Vessel grafts,• Cell grafting into the heart muscle after myocardial infarction.To grow complete hearts by tissue engineering will remain science fiction for atleast several decades.At present, there are no tissue engineered cardiovascular products on the market;they are all still in the R&D phase.7.1.1 Heart valvesThe surgical replacement of a heart valve is a common treatment for end-stage val-vular diseases. Currently, three major types of valves are available for replacement(Zeltinger et al. 2001; Von Oppell et al. 2001):• Mechanical heart valves. Mechanical heart valves are manufactured primarilyfrom titanium steel and pyrolytic carbon. They have superior durability com-pared to biological valves. However, life-long anticoagulation therapy is requiredto reduce the risk of thromboembolic complications due to the thrombogenic po-tential of the mechanical prostheses. This anticoagulation therapy is associatedwith a dose-related risk of bleeding complications. Moreover, they are suscepti-ble to infection.• Biological tissue valves. Biological valves show better haemodynamic propertiesthan mechanical valves, therefore do not require administration of anticoagula-
45tion drugs, but in general have a shorter life-span than mechanical valves due tocalcification and non-calcium-related degeneration. Therefore, reoperation sur-gery is often required to replace degenerated biological valves. Biological valvesfrom different sources are in clinical use:− Allogeneic valves from human cadaver. Biological allogeneic valves are inclinical use which were taken from human cadavers. They are processed bydifferent processes, such as cryopreservation, freeze-drying, irradiation, fixa-tion with glutaraldehyde or sterilisation with ethylene-oxide). A major draw-back in comparison with the other valve options is their limited availability,most pronounced for children. Moreover, there is a risk of rejection.− Biological xenogeneic valves from porcine or bovine sources. Biologicalvalves have predominantly been manufactured from bovine pericardium orporcine aortic valves. They are preserved and sterilised by different tech-niques (e. g. fixation with glutaraldehyde) and therefore do not contain anyliving cells.− Autografts. Autografts are valves that have been moved from one position toanother position within the same individual (such as transferring of a pulmo-nary valve to the aortic position).So far, none of these valves is ideal, having problems of thrombogenicity, limiteddurability and shortage of supply, respectively. They are not able to grow, repairand remodel to the functional needs. To overcome this, tissue engineered heartvalve replacements are being developed. The general goal is to provide a "custom-made", living valve replacement with growth potential, non-thrombogenicity andlifetime durability. The general approach is to seed a scaffold with cells in vitro, to"condition" the cell culture with special emphasis on dynamic tissue culture, and totransplant these "cell-coated" structures into the patient, where the scaffold isgradually replaced by a new matrix produced by the cultured cells. However, TEresearch on heart valves is still in the preclinical phase, yielding first results fromlarge animal models. Research issues comprise (Stock et al. 2002):• Choice of appropriate cells and cell sources. Cells from arteries, veins, microvas-cular endothelial cells, progenitor cells and stem cells both from allogeneic andautologous sources are being tested,• Choice of an appropriate scaffold. Several approaches use decellularized biologi-cal allogeneic and xenogeneic matrixes, others use scaffolds from biomaterials.Here, still unsolved problems are materials with appropriate biomechanical andbiocompatible properties as well as the optimal design of the scaffold. 3D imag-ing, injection molding and stereolithography are being researched.• Achieving long-term function and adaptability as well as absence of degenera-tion, thrombogenicity, and infection in large animal models as well as humans.
467.1.2 Blood vesselsAtherosclerosis, a process that causes narrowing of the arteries, is a risk factor formyocardial infarction. For coronary arteries, this narrowing leads to a weaking ofthe myocardium (i. e. the wall of the heart), and ultimately to myocardial infarction.When a myocardial infarction is either imminent or occurs, the most common formof treatment is coronary bypass surgery.Usually, the patients internal mammary artery or the saphenous vein is used (auto-graft). However, autologous vessels are not always available, either because of be-ing diseased themselves, or because of previous surgery. If autologous vessels areunavailable, then synthetic blood vessel substitutes can be used. They are madefrom Dacron or expanded polytetra fluoroethylene (ePTFE). When replacing largervessels, i. e. 6-10 mm in diameter, these grafts can be successfully used, but whenused in the coronary system where diameters are 3-4 mm, thrombotic events rapidlyclose them off (Nerem et al. 2001).Against this background, R&D is underway to develop tissue engineered blood ves-sels which may be used as a small vessel diameter substitute. The significance ofdeveloping tissue engineered blood vessels, however, reaches far beyond vessels forbypass grafts. As blood is the major form of supplying tissues and organs with nu-trients and of removing metabolic products, blood vessels are of crucial importancefor the tissue engineering of more complicated tissues and structures.Tissue engineering of blood vessels aims at developing blood vessel substitutes,which exhibit all the functional characteristics of a natural blood vessel, especially• no thrombogenicity,• vasoactivity,• appropriate mechanical properties (Nerem et al. 2001).Several approaches are being followed in order to engineer a blood vessel substitute(Nerem et al. 2001):• EC-seeded synthetic grafts. This approach remains the most studied vasculartissue-engineering application. In this approach, synthetic blood vessel substi-tutes made from ePTFE or Dacron are coated with a monolayer of endothelialcells (EC). This approach is presently limited to the use of autologous endothe-lial cells. Autologous cells are required because immunological complicationsassociated with nonautologous EC cannot be controlled satisfactory. These EC-seeded synthetic grafts lack vasoactivity. Long-term experience with clinical ap-plication in humans has been published (Deutsch et al. 1999; Meinhart et al.2001). Clinical trials have been carried out involving the in vitro endothelializa-tion of vascular grafts prior to implantation which have shown conclusively that
47tissue engineering results in a significantly enhanced clinical performance insmall-diameter grafts (Seifalian et al. 2002).• Collagen-based blood vessel grafts. In this approach, collagen instead of syn-thetic polymers act as substrate for cell attachment. This approach, in principle,offers the potential to engineer a vasoactive graft with cell-mediated in vivo re-modelling. However, these properties still remain to be demonstrated. Moreover,the inherent physical weakness of collagen must be overcome in order to growvessel substitutes which are able to withstand the physical load imposed by he-modynamics. Today, the collagen-based constructs can withstand a pressure ofapproximately 225 mm Hg, which is not acceptable for arterial replacement sur-gery.• Biodegradable synthetic polymer based blood vessel grafts. This approach usesbiodegradable synthetic polymers such as polyglycolic acid as biodegradablescaffold on which the cells are grown. Cultivation under pulsatile conditions wasrequired to generate vessels with significant rupture strength.• Cell self-assembly blood vessel grafts. In this approach, vascular cells are cul-tured to form a continuous sheet of cells and extracellular matrix and then rolledover a central mandrel. The construct is matured over several weeks, allowingthe cells to organise into a mechanically stable tubular construct. Layers of dif-ferent cell types can be combined.• Decellularized approaches to blood vessel grafts. In this approach, a noncellularconstruct is implanted and thereafter recruits cells from the surrounding host tis-sue. Due to the presently poor understanding of in vivo vascular cell migrationand of engineering this response into a vascular construct, this approach is likelyto require several more years until clinical application.As the growing of tissue engineered blood vessel graft in the laboratory is still theobjective of research, few R&D efforts have been devoted to the question how toproduce these vessel grafts on a commercial and cost-competitive scale. Recentresearch results indicate that bioreactors will be required which provide engineeredvessels with mechanical stimulation. Moreover, the long-term integration of a livingcell construct into a living system still remains to be demonstrated in large animalmodels and man, overcoming – among others – also the immunological responsewhen using non-autologous constructs. Therefore, the approval of a small-diameterblood vessel substitute by regulatory authorities is at least a decade from now(Nerem et al. 2001).7.1.3 Myocardial infarctionEven with current medical management, over one third of acute heart attacks arefatal. After a non-lethal coronary infarction a rehabilitation of the patient is possible
48to a certain extent, but larger impairments cannot be fully healed. Treatments toprevent tissue damage after a heart attack include drugs that break down fibrin clotsand open up blocked arteries. These drugs have greatly influenced morbidity andmortality, but must be administered within a short interval after a heart attack to beeffective. Cardiac catheterization and angioplasty to dislodge the clot and open theblocked vessel have proven effective in restoring blood flow, but cannot reversepreexisting tissue damage. The transplantation of a healthy donor heart is a compli-cated surgery, which is also severely limited by the lack of donor organs.In order to complement these established therapies, there is a medical need fortreatments that contribute to the restoration of the damaged heart. One option is thetransplantation of healthy cells into the area where the infarction took place. For thispurpose, different types of cells can be considered, among them (Rosenthal et al.2001; Kessler et al. 1999):• Fibroblasts.• Skeletal muscle cells. Of all approaches listed here, this approach is the mostadvanced one at present. A clinical trial phase I was successfully completed byProf. Menasché, Paris (Menasche et al. 2001; Pouzet et al. 2001; Menasche2002; Hagège et al. 2003). A clinical trial phase II has started in 2002 in coop-eration with Genzyme Biosurgery (see below).• Primary heart muscle cells.• Hematopoietic stem cells. The therapeutic concept to implant autologous bloodstem cells after an infarction to restore the damaged area has already been testedin humans (Strauer et al. 2001; Stamm et al. 2003).• Embryonic stem cells. Embryonic stem cell transplantation for heart failure hasbeen tested in rodent models (Roell et al. 2002), but not yet in humans.7.2 Overview of companies and their R&D activities7.2.1 Heart valvesThere is a large number of companies which offer heart valves. Strong market posi-tions are occupied by• Centerpulse (Switzerland)• Edwards Lifesciences (USA)• Medtronic, Inc. (USA)
49• Sorin Biomedica (Italy)• St. Jude Medical, Inc (USA)Other companies, also offering heart valves, are• ATS Medical, Inc. (USA)• CryoLife, Inc (USA/UK)• Jostra AG (Germany)• Jyros Medical Devices (UK)• Labcor Laboratories (Canada)• Medical Carbon Research Institute, LLC (USA)• Medical Incorporated (USA)• Shelhigh, Inc. (USA)• Sulzer (Switzerland)It can be assumed that leading heart valve companies closely monitor the develop-ment in tissue engineering of heart valves, and may also have own R&D activitiesin this field. However, due to the preclinical stage of tissue engineered heart valveR&D, information of companies activities in this field is scarce. The followingcompanies have been reported to have R&D activities in the tissue engineering ofheart valves:• AorTech International, plc (UK/Australia). The company investigates the use ofits polymer Elast-EonTMand other polyurethanes for use e. g. in heart valves, butpresently undergoes a change in its business strategy.• Autogenics (USA). Autogenics is a start-up company which carries out R&D inthe field of autologous tissue cardiac valves.• CryoLife, Inc (USA/UK). The company has proprietary processes for preservinghuman heart valves, veins and connective tissue making them available for car-diac, vascular and orthopaedic surgical reconstruction. Over 75% of all cardio-vascular procedures involving allograft (homograft) tissue in the U.S. are per-formed with cryopreserved human heart valves from CryoLife (Product Cry-oValve®). Since 1996 and 1998, the company offers the CryoLife-OBrien®stentless porcine aortic heart valve and the CryoLife-Ross® pulmonary porcineheart valve on the European market. Both valves have been awarded the Euro-pean CE (product certification) mark, allowing distribution throughout the Euro-pean Union. CryoLifes Research Staff has developed a tissue engineered heartvalve and vascular graft replacement called the SynerGraft® family of products.• TiGenix (Belgium). TiGenix develops cell-based tissue-engineered products inthe areas of joint-surface defects, bone defects and heart valves. It carries out a
50collaborative research project with the Centre for Experimental Surgery and An-aesthesiology of the University of Leuven, a leading test centre for heart valves,to develop tissue engineered heart valves. Upon selection of the appropriate celllines and scaffolds, TiGenix aims to further develop these valves into a stagewhere they can be out-licensed to a partner specialising in cardiac valve re-placement.7.2.2 Blood vesselsDue to the mostly preclinical or early clinical stage of tissue engineered blood ves-sel R&D, information of companies activities in this field is scarce. The followingcompanies have been reported to have activities in the tissue engineering of bloodvessels:• Advanced Tissue Sciences (USA). ATS had tissue-engineered vascular grafts indevelopment (Huynh et al. 1999), but most probably stopped this programme af-ter filing for bancruptcy in autumn 2002.• Organogenesis (USA). Organogenesis did research into cell self-assembly bloodvessel grafts (Huynh et al. 1999), but most probably stopped this programme af-ter filing for bancruptcy in autumn 2002.• Vascular Biotech GmbH (Germany). Founded in 1998, Vascular Biotech GmbHis a tissue engineering company which focusses on the development, productionand marketing of products for the treatment of vascular and heart diseases. Since2001, the company has their patented tissue-engineered aorto-coronary bypassgraft in clinical trials. The vessel graft consists of cryopreserved donor veins,lined with recipient-own endothelial cells.• co.don (Germany). co.don has endothelialized vessels in clinical trials, phase I.• BioTissueTechnologies (Germany). BioTissueTechnologies intends to commer-cialize vessel prostheses coated with autologous cells which are in preclinicaldevelopment at Cell-Lining (Germany).• Angio Genetics AB (Sweden). Probably not working in the core area of tissue-engineering of blood vessels is Angio Genetics AB. Founded in 2001 as a spin-out from Gothenburg University and the Karolinska Institute, Angio GeneticsAB is a drug discovery company focusing on the formation of new blood vessels(angiogenesis). The focus of Angio Genetics AB is early drug discovery in thearea of angiogenesis regulation, for pro- or anti-angiogenic therapies, whichcould be applied in the treatment of e. g. cancer, ischemic heart disease, diabeticmicroangiopathy and chronic wounds.• Ark Therapeutics Oy (Finland). Probably not working in the core area of tissue-engineering of blood vessels is Ark Therapeutics. Ark Therapeutics is a Europe-an biotechnology company. It focuses on research, development and commercia-
51lisation of therapeutic products for vascular disease and cancer. Its product Tri-nam™ is in preparation for a Phase II/III study. It is a combination of a vascularendothelial growth factor gene packaged in an adenoviral vector and Arks bio-degradable local drug delivery device (termed EG001). Once the VEGF gene istransfected locally, muscle cells in the vessel wall express the VEGF proteinwhich triggers the release of nitric oxide and prostacyclin. These two agents havea protective effect, preventing the blocking of the blood vessels. The product willinitially target the market for haemodialysis graft access surgery. Trinam™ hasbeen granted Orphan Drug Status by the FDA.7.2.3 Myocardial infarctionAt present, no cell therapy for the treatment of myocardial infarction has been ap-proved. All activities in this field are preclinical research, or phase I to phase IIclinical trials. The following companies have reported R&D activities in this field:• Genzyme Biosurgery (USA/Europe). In December 2002, Genzyme Biosurgerystarted a randomized, double blind, placebo controlled clinical trial phase II withthe aim of testing the safety and effectiveness of cardiac myoblast cell transplan-tation for the prevention of the progression of heart failure in patients who havehad a heart attack. The trial uses the methodology developed by Prof. Menasché:autologous skeletal muscle cells are taken from the patient prior to bypass sur-gery through a small biopsy in the leg. The cells are multiplied over the course ofthree weeks in the laboratory, and injected into a scarred region of the heart dur-ing a coronary artery bypass operation. It is planned to enroll up to 300 patientsin 30 medical centers throughout Europe and North America during the first halfof 2003. Measures to be evaluated include monitoring the area into which thecells were injected to determine whether the engrafted cells restore the heartsability to contract in that area; changes in left ventricular ejection fraction; and acomparison of the incidence of Major Adverse Cardiac Events (MACE) betweentreated and non-treated groups. Monitoring of all patients will continue for up totwo years after treatment. The trial is being principally funded by GenzymeBiosurgery, with support from Assistance Publique - Hôpitaux de Paris. It is be-ing conducted in partnership with Myosix SA of Paris.• Diacrin (USA). Diacrin develops a treatment for ischemia damaged myocardiumwith autologous skeletal myoblasts. In 2002, two Phase 1 clinical trials were car-ried out treating patients with damaged heart muscle. In one clinical trial six pa-tients are treated with the implantation of 300 million myoblasts at the same timethey receive a ventricular assist device (VAD) in order to maintain heart functionwhile they wait for a donor heart to become available. The other trial is a doseescalation trial, in which 12 patients, as they undergo coronary bypass surgery(CABG), receive cell implant doses ranging from 10 million to 300 million cells.The trials are carried out at six medical centers in the USA.
52• BioHeart Inc. (USA). Bioheart, Inc. is a privately held company which is focusedon the discovery, development and commercialization of cell-based therapyproducts for the treatment of cardiovascular diseases. Biohearts lead productcandidates are:− MyoCell, an autologous cell-based product used for the treatment of myocar-dial infarction, currently in clinical trials in the United States and Europe.Since May 2001, Bioheart has completed 13 MyoCell™ cases at various cen-ters in The Netherlands, Germany and Italy. These Phase I/II studies wereprimarily designed to evaluate safety and provide preliminary efficacy infor-mation for the therapy and the delivery systems used in the procedure. Thecompany plans to continue its trials in the USA in 2003, expand it to phase IIIby late 2003, resulting in a commercial release in 2006.− MyoCath - SR 200, a percutaneous needle injection catheter for deliveringcell therapy or other compounds to the myocardial tissue, currently in clinicaltrials in Europe.− MyoCell VT, a cell-based product for the treatment of ventricular tachycardia,currently in pre-clinical development.− BioPace, a cell-based product used for the treatment of sinoatrial nodaldysfunction disease, currently in pre-clinical development.• Osiris Therapeutics, Inc (USA). Osiris Therapeutics is a privately held develop-ment stage company, focusing on cellular therapeutic products for the regenera-tion and functional restoration of damaged and diseased tissue. The therapeuticproducts are derived from human mesenchymal stem cells (hMSCs) extracted,isolated and purified from adult bone marrow. Osiris specialises in the differen-tiation of hMSCs into different specialised cell types, among them myocardialtissue. Financed by a research award from the Department of Commerce, Na-tional Institute of Standards and Technology/Advanced Technologies Program(NIST/ATP), Osiris has developed culture conditions to induce myogenic differ-entiation of hMSCs and has implanted hMSCs into the hearts of small and largeanimal models. Clinical trials are scheduled to start in 2003 in the USA to exam-ine the ability of MSCs to prevent the progression to heart failure following in-farction. In March 2003, Osiris and Boston Scientific Corporation (USA), aworldwide developer, manufacturer and marketer of medical devices which areused in a broad range of interventional medical specialties announced their alli-ance in this field. Osiris will manufacture the MSCs. Boston Scientific will pro-vide a specialized injection catheter for the safe and effective injection of thecells to the affected area of the heart, and will sell both the cells and the injectioncatheters globally.Other companies with preclinical R&D programmes are Morphogen (USA), Geron(USA) and Cardion (Germany).
537.3 Potential market volumes7.3.1 Prevalences and incidences for cardiovascular diseasesIn the EU, cardiovascular diseases are responsible for about half of the total mortal-ity and are therefore one of the main causes of death. Giving CVD high priority inhealth politics has already yielded some success: The mortality from CVD in theEU is now 240-260 deaths per 100,000 population. This is a remarkable decline,because it is only around half the 1970 level. Nevertheless, CVD are the leadingcause of disease burden in 2000, accounting for 33.4 million DALYs4 (this is21.8 % of the overall burden of disease and injury). Mortality indicators for cardio-vascular disease reflect aspects of health status that are influenced more by determi-nants such as lifestyles and the socioeconomic situation rather than performance ofhealth care services (World Health Organization (WHO) 2002).The surgical replacement of a heart valve is a common treatment for end-stage val-vular diseases. More than 50,000 heart valve replacement procedures are conductedannually in the United States alone. Worldwide, there are about 175,000 valve re-placements performed each year.Coronary and peripheral vascular bypass grafting are now performed approximately240,000-320,000 annually in Europe for cardiovascular diseases, and 560,000-480,000 of these procedures performed in the USA.In 2001, approximately 4,600 heart transplantations were carried out in Europe andthe USA. Of these, 1,900 were performed in the EU.7.3.2 Market figures related to CVDIn most of the industrialised countries, cardiovascular diseases cause relatively highhealth costs. Despite a decrease of the mortality caused by cardiovascular diseases,growing patient populations and more sophisticated treatments lead to an increaseof health expenditures caused by CVD. The direct costs for the treatment of cardio-vascular diseases in the USA amounted to € 171 billions in 1998 (Reuters BusinessInsights 1999). According to an estimation of the US-Centers for Medicaid andMedicare, heart failure alone costs € 10 billion a year and accounts for roughly60,000 deaths (Jahania et al. 2002). In Germany, CVD caused total costs of4 DALY (disability-adjusted life-years) is a measure of disease burden. The DALY expresses yearsfo life lost to premature death and years lived with a disability of specified severity and duration.One DALY is thus one lost year of healthy life.
5416 billion € in 1990, about half of them direct costs for drugs, ambulant treatments,hospital stays and rehabilitation. The other half were indirect costs due to mortality,inability to work and disablement (Kohlmeier et al. 1993).The prescribed pharmaceuticals have a relatively small share of the total costs, butcan easily be determined. In the USA, the share of prescribed drugs for the treat-ment of CVD were only 9 % of the total direct costs in 1998, amounting to drugsales of € 14.8 billions (Reuters Business Insights 1999). The world-wide marketfor pharmaceuticals prescribed for cardiovascular diseases reached approx.€ 64 billions in 1998. This corresponds to 23 % of the market for pharmaceuticalproducts world-wide. 50 % of the market volume are made up by anti-hypertensives(Reuters Business Insights 1999). For the future it is expected, that on the one handthe leading cardiovascular medicines will get under substantial pressure by genericmedicines what will lead to a limited growth of the market for pharmaceuticalsagainst cardiovascular diseases. On the other side, under a global perspective, anincrease in prevalence and incidence of cardiovascular diseases is expected (ReutersBusiness Insights 1999).In 2001, global heart valve sales amounted to 830 mio. US-$, with tissue valves andmechanical valves contributing about equally to the total sales: Global sales in tis-sue valves were 390 mio. US-$ in 2001. Due to progress regarding the lifetime oftissue valves, especially in the prevention of calcification, the tissue heart valvesegment is expected to grow at the expense of the mechanical heart valve segment.Table 7.1 gives an overview of the market segmentation.Table 7.1: Global heart valve market 2001Type of heart valve Global sales 2001Tissue heart valve (allogeneic, xenogeneic) 390 mio. US-$Mechanical heart valve 380 mio. US-$Repair 60 mio. US-$Total 830 mio. US-$Source: Edwards Lifesciences, Investor Conference 2002
558. Tissue engineered organs8.1 Overview of potential applicationsThe "holy grail" of tissue engineering is the tissue engineering of entire organs. Re-search activities have been published regarding the tissue-engineering of• urinary bladder (Oberpenning et al. 1999),• kidney (Humes 1996; Woods et al. 1997; Humes 2000),• heart valves and heart muscle (see chapter 7),• liver (see this chapter),• pancreas (see this chapter).Despite high medical needs, tissue engineering of complete organs is far from themarket. Important scientific-technical hurdles must be overcome, e. g. vasculariza-tion of tissue engineered organs, controlled three-dimensional structure, coordinatedaction of different cell types. The concept of "organ printing", i. e. computer-aided,jet-based 3D tissue engineering of organs, has been proposed as a possible means toachieve this goal (Mironov et al. 2003). If feasible at all, those organs are mostlikely to be the first to be developed whose function can be replaced by cell thera-pies or in bioartificial biomedical devices. Belonging to this category are free orencapsulated islet cells for diabetes therapy and extracorporal bioartificial liver as-sist devices. At the present stage of development, high scientific-technical hurdlesmust be overcome before diabetes or acute hepatic failure can be treated by tissueengineering approaches.8.1.1 Tissue-engineered pancreas for the treatment of Diabetes mel-litusDiabetes mellitus is the most frequent metabolic disease in the world. It is a chronicdisease caused by inherited and/or acquired deficiency in production of insulin bythe pancreas, or by the ineffectiveness of the insulin produced. Such a deficiencyresults in increased concentrations of glucose in the blood, which in turn damagemany of the bodys systems, in particular the blood vessels and nerves. The standardtherapy for type I diabetes is the regular injection of insulin.Currently, research is carried out in different fields to optimise the standard therapyof diabetes in two areas: on the one hand, the quality of life of the patients would be
56enhanced by making them independent of the periodic injection of insulin. On theother hand a regulation of the blood glucose level is strived for which is more pre-cise and sustainable compared to the state that can be reached by manual insulininjection, to prevent long term damage. The following therapeutic options are avail-able or are under development:• New insulin delivery forms. Among the options are inhalation as an aerosol; in-sulin as tablets; devices that release insulin automatically ("artificial pancreas").• Gene therapy.• Pancreas transplantation. Since the first pancreas transplantation in 1966, up tonow more than 14,000 pancreas transplantations have been carried out world-wide. At the moment, approx. 1,000 pancreases are transplanted per year, mostof them in the USA. The surgical procedure is complicated and stressful for thepatient. Therefore, only in few cases is this the therapeutic option of choice, ascompared to the established treatment with insulin.• Transplantation of allogenic insulin producing cells. An alternative to the trans-plantation of the whole pancreas is the transfer of isolated islet cells, which ismuch less traumatic for the patient. Between 1990 and 2000, 394 allogenic isletcell transplantations took place world-wide. Only 81 transplants worked for morethan one year. Therefore, only in 20 % of the treated patients was the treatmentsuccessful on the long run. Recently, a new and improved therapy protocol hasbeen developed which is perceived by experts as a break-through in the trans-plantation of allogenic islet cell transplantation. In a first study, this protocol,that does without steroids as immuno-suppressive agents and that makes use of alarger amount of unencapsulated islet cells, has led to a long-term independencefrom insulin in 18 out of 19 patients (Shapiro et al. 2000; Ryan et al. 2001). Amulticenter clinical trial in the USA and Europe is underway in order to confirmand extend these results, to standardize procedures of islet isolation and trans-plantation, and to implement cell processing standards in accordance with clini-cal good manufacturing practice.• Transplantation of xenogeneic insulin producing cells. If diabetes cell therapiesbased on allogeneic islet cells prove to be successful in larger patient popula-tions, the need for additional islet sources (xenogenic, from stem cells) becomesmore urgent. Preclinical research into xenogeneic islet transplantation has beencarried out for many years, but was even less successful than allogeneic islettransplantation regarding the achievement of long-term insulin independence.Moreover, the use of xenogeneic cell sources is controversially discussed due tothe fact that a risk of infection with unknown infectious agents cannot totally beruled out. There is a general consensus in the scientific community that at thepresent knowledge, xenotransplantations of solid organs should not be performed(see e. g. (Cooper et al. 2000)). However, the clinical application of cellular xe-notransplantation is not totally excluded at present because the risk-benefit as-sessment may come to more favourable results than for organ xenotransplantati-
57on (Hüsing et al. 2001). Nevertheless, concern has been expressed on clinical tri-als for the treatment of diabetes in which porcine islet cells are transplanted intodiabetes patients. Because they are performed in Mexico, and may be expandedin cooperation with the New Zealand based company Diatranz to the Cook Is-lands, doubts have been raised whether these trials are in line with high interna-tional safety and ethics standards (Archer et al. 2002; Mckenzie et al. 2002; Col-lignon 2002; Valdes 2002; Dalton 2002; Valdes Gonzalez 2002; Anonymous2002).In diabetes, neither pancreas transplantation nor islet transplantation has become thepreferred therapeutic option, because they do not compare favourably with estab-lished insulin replacement therapies. However, since 2000, there are encouragingresults from allogenic islet transplantation which may indicate that the concept ofcellular therapy may work for diabetes. Transplantation of insulin producing cellsand a bioartificial pancreas are options where tissue engineering approaches cancontribute. It is investigated in preclinical and clinical trials whether insulin produc-ing cells isolated from pigs (Hüsing et al. 2001) or differentiated from human adultstem cells (Bonner-Weir et al. 2000) or human embryonic stem cells can be used(Schuldiner et al. 2000; Assady et al. 2001). According to (Lysaght et al. 2001),more than 200 mio. US-$ of private sector funds have been invested in the devel-opment of a bioartificial pancreas in the USA. However, no design capable of rou-tine success in large animal models could be developed.8.1.2 Bioartificial liver assist devicesIn Europe, around one thousand people develop acute liver failure each year – anillness that can appear suddenly, as a result of poisoning for example, or developslowly following chronic jaundice, for example. Acute liver failure causes progredi-ent brain dysfunction leading to the patients death. This development occurs usu-ally within 2-10 days. Acute hepatic failure can only be treated reliably by livertransplantation although 10-30 % of the affected patients could recover withouttransplantation. However, reliable markers are not available which could predictwhich patients definitively require a liver transplant for recovery.Although it does not seem feasible in the nearer future to develop a tissue engi-neered liver, tissue engineering could provide important contributions to the devel-opment of some type of artificial liver support. This liver support has the followingaims:• stabilize the patients condition so that a liver transplantation can be performed,• bridging the time until a liver transplant becomes available,• support the patients liver function to make regeneration of the patients own liverpossible.
58Over the last four decades, several approaches have been taken to support liverfunction. Initially, the development of extracorporeal liver support was focused onpurely physical and chemical systems or processes. These included hemodialysis,plasmapheresis, hemofiltration, plasma exchange, resin perfusion, and charcoal he-moperfusion. There are at least two artificial liver support systems on the marketwhich do not incorporate a biological component (table 8.1). In addition, extracor-poreal perfusions of whole or partial livers showed promising results, but have sig-nificant limitations to its practical application. As a result, the concept of hybridbioartificial devices evolved in which technical systems are equipped with a bio-logical component. Tissue engineering can contribute to engineer this biologicalcomponent in order to perform physiological functions similar to native livers. Al-though some implantable bioartificial systems have been developed and tested inanimals, presently R&D focusses on extracorporeal liver assist devices which sup-port the detoxification functions performed by the liver for a limited period of time(in the order of hours to days) (Tzanakakis et al. 2000).At present, at least four types of extracorporeal bioartificial liver support systemshave been tested in clinical trials. These systems differ in the type of hepatocytes,the amount of hepatocytes incorporated into the devices, the design of the bioreac-tor, and whether the reactor is perfused with the patients blood or plasma (see ta-ble 8.1).In the development of bioartificial liver assist devices which incorporate livingcells, the following crucial points have not yet been solved satisfactory:• Type and source of the used cells (human primary isolates; differentiated fromhuman adult or embryonic stem cells; primary porcine isolates or porcine celllines),• Production of the required liver cells in suitable quantity, quality and physiologi-cal activity,• Cultivation of the liver cells while maintaining their physiological activity,• Appropriate bioreactor concept,• Logistic aspects (e. g. shelflife of the cells, time to get the reactor running),• Clinical application, outcome, safety and efficacy.
59Table 8.1: Artificial and bioartificial liver assist devices with clinical experienceDevice Company Clinical Phase Design Cell LineLiver Dialysis UnitTM(for-merly BioLogic-DT)HemoTherapies (formerlyHemoCleanse) (USA)FDA approvedMulticenterMembrane Separated He-modialysis UnitNoncellular (Charcoal)Molecular Adsorbent Recy-cling System (MARS®)Teraklin (Germany) I/II/II CE-approvedMulticenterHollow Fiber Bioreactor Human AlbuminExtracorporeal Liver AssistDevice (ELAD®)Vitagen (USA) I/II Multicenter Hollow Fiber MembraneBioreactorImmortalized Human Hepa-tocytesHepatAssist® 2000 System Circe Biomedical (USA) II Multicenter completed Hollow Fiber MembraneBioreactorPorcine HepatocytesBioartificial Liver SupportSystem (BLSS®)Excorp Medical, Inc. (USA) I/II Multicenter Hollow Fiber MembraneBioreactorPrimary Porcine Hepato-cytesModular ExtracorporealLiver System (MELS®)Hybrid Organ (Germany) I/II Multicenter Hollow Fiber MembraneBioreactorHuman HepatocytesLIVERX2000 System Algenix, Inc. (USA) I planned Hollow Fiber MembraneBioreactorPrimary Porcine Hepato-cytes
608.2 Overview of companies and their R&D activities8.2.1 Tissue-engineered pancreasAccording to (Lysaght et al. 2001), more than 200 mio. US-$ of private sector fundshave been invested in the development of a bioartificial pancreas in the USA. How-ever, no design capable of routine success in large animal models could be devel-oped. As a consequence, there has been considerable change in the companies en-gaged in this field. Figure 8.1 gives an overview. In the last years, three large coop-erations (Baxter, Gore, WR Grace, all USA) have discontinued their pancreas pro-grammes, and other companies previously engaged in this field (Cytotherapeutics,Modex, BioHybrid, Metabolix, Encelle, Circe, Vivorx, Neocrin, all USA) either nolonger exist or are no longer serious contenders in this area (Lysaght et al. 2001).Therefore, only few companies are still active with clinical R&D activities or haveincreased their preclinical research intensity. Whether bioartificial pancreas has thechance to become a market-relevant application of tissue engineering dependslargely on the ability of these companies to achieve scientific-technical break-throughs (Lysaght et al. 2001).• AmCyte, Inc. (USA). Founded in 1991, AmCyte is developing a cell therapy,BetaRxTM, for transplantation into patients with diabetes that require insulin. Thecompany has preclinical and clinical experience with islet cell transplantationfrom allogeneic and xenogeneic sources: From 1993-1995, it carried out threeclinical encapsulated human islet transplantations in the USA, and in 1997, atransplantation of porcine encapsulated islet cells in New Zealand. At present, itpursues a "proliferative human islet programme" BetaRxTM. Human insulin-producing cells are isolated, expanded in vitro, encapsulated in alginate andtransplanted into the peritoneal cavity.• Diatranz (New Zealand). Founded in 1994, Diatranzs core business is the devel-opment of alginate-encapsulated porcine insulin-producing islet cells suitable fortransplantation into people with type 1 diabetes mellitus. Its product, DiaBcell®,are alginate-encapsulated porcine islet cells obtained from the pancreases of cus-tom-bred, disease-free pigs and isolated in a GMP manufacturing facility. Thisproduct has been transplanted into two patients. A second product, DiaVcell®,contains porcine islet cells together with porcine Sertoli cells. The latter cellsserve as "nursery cells" to protect against rejection. These cells are injected into astainless-steel mesh tube which is implanted under the skin of the patient. SinceApril 2000, 12 diabetic patients have been treated with DiaVcell® in MexicoCity, and the company plans to extend the trials to the Cook Islands. Concern has
61been expressed by the scientific community whether these trials comply with in-ternational standards (see above).• Novocell (USA). Novocell is a biopharmaceutical company which was formed inAugust 1999 by acquiring all of the assets and liabilities of a predecessor com-pany, Neocrin Company. It develops encapsulated human insulin producing cellsfor the treatment of diabetes. These cells are processed from primary humanpancreases, expanded and differentiated, and encapsulated with polyethylen gly-col. The R&D is presently in the preclinical stage. Novocell hopes to receiveFDA approval after completion of animal studies in order to begin human trialsin 2003. Since 2000, Novocell has a cooperative R&D agreement with BDTechnologies to study the feasibility of growing and differentiating human pan-creatic progenitor cells into insulin-producing cells, and since 2001, a collabora-tion with SurModics, Inc. for the development of encapsulation materials.• Circe Biomedical (USA). Circe Biomedical is a privately held biomedical com-pany engaged in the development, production, and commercialization of extra-corporeal and implantable bioartificial organs and therapeutic cell systems. It hasthe PancreAssist® System in pre-clinical development. The PancreAssist® Sys-tem is an implantable, membrane-based system bioartificial pancreas incorporat-ing living pancreatic islets, and is designed to improve blood glucose control indiabetics by providing insulin in response to changes in the patients blood glu-cose level. Circe Biomedical is designing the PancreAssist System to be im-planted near the kidney and surgically connected directly to the patients circula-tory system.• Islet Sheet Medical LLC (USA). Islet Sheet Medical is a research and develop-ment company which develops a thin-sheet bio-artificial pancreas for the treat-ment of diabetes. R&D is in the preclinical stage, no clinical trials are planned atpresent.• MicroIslet Inc. (USA). MicroIslet Inc. is a biotechnology company engaged inthe research, development, and commercialization of of insulin-producing isletcells from porcine sources. MicroIslet has licensed several technologies fromDuke University Medical Center developed over the last decade for the isolation,culture, storage, and encapsulation (microencapsulation) of insulin-producing is-let cells from porcine sources. MicroIslet is working to develop, obtain FDA ap-proval for and commercialize a first product, called MicroIslet-P™. This ismicroencapsulated porcine islet cells used for islet transplantation for patientswith insulin dependent diabetes. R&D is in the preclinical stage, no clinical trialsare scheduled yet.
62Figure 8.1: Evolutionary cladogram on commercial efforts to develop a bio-artificial pancreasSource: http://www.isletmedical.com/company_competition.htm, accessed March31, 20038.2.2 Bioartificial liver assist devicesAt present, there are no bioartificial liver assist devices on the market. The onlyproducts which have been FDA approved or were granted the CE mark do not in-corporate any living bio-components. Some companies, mainly in the USA, but alsoin Germany, are engaged in research and develop of bioartificial devices, and somehave progressed to clinical trials:• Circe Biomedical (USA). Circe Biomedical is a privately held biomedical com-pany engaged in the development, production, and commercialization of extra-corporeal and implantable bioartificial organs and therapeutic cell systems. Thecompanys lead product is the HepatAssist® Liver Support System which is be-ing developed since 1994. The device has four components: a hollow fiber biore-actor containing primary porcine hepatocytes, two charcoal filters, a membraneoxygenator, and a pump. Additionally, the device must be used in conjunctionwith a commercially available plasma separation machine, a heater, and tempera-ture and oxygen monitors. Circe completed phase I/II clinical trials in 1997.These trials were found to demonstrate safety and showed encouraging signs intreatment of fulminant hepatic failure and primary liver nonfunction, either as a
63bridge to transplant or in some cases as a bridge to recovery of normal liver func-tion. Circe then proceeded on to phase II/III trials, which concluded enrollmentin 2001 after a four-year run. The trials treated approximately 180 patients at 20clinical centers in the US and Europe, with the desired endpoint being the 30-daysurvival of acute liver failure patients with or without transplant. Circe’sHepatAssist 2000 device was long considered the most promising of the bioarti-ficial liver devices currently in development, but has recently run into substantialroadblocks. In 1999, its corporate parent, W.R. Grace and Co., decided to with-draw as part of a unilateral withdrawal from the biotech industry. From then on,Circe was financed by venture capital funding as the HepatAssist went throughphase II/III prospective, randomized, controlled clinical trials. In 2002, the FDAconcluded that the device’s efficacy was still unproven making a full phase IIIefficacy trial the mandatory next step, if Circe wishes to continue the quest tobring the device to market. As of now, the company’s plans are unknown, and itremains unclear as to whether Circe will continue to invest in the HepatAssistproduct, divest, or keep the project shelved for an extended period.• HybridOrgan GmbH (Germany). HybridOrgan GmbH was founded in 1997 as auniversity spin off in cooperation with the Virchow Clinic of the Humboldt Uni-versität of Berlin. It develops the liver support system BELS, which originallyused primary porcine hepatocytes, but was then changed to using human hepato-cytes isolated from human donor livers which were not suitable for whole organtransplantation.• Excorp Medical (USA). Excorp Medical develops a liver assist device BLSS incooperations with the University of Pittsburgh Medical Center. The BLSS is anextracorporeal hemofiltration device. It contains a hollow fiber membrane (with100kDa cutoff) bioreactor that separates the patients blood from approximately100 grams of primary porcine hepatocytes that have been harvested from pur-pose-raised, pathogen-free pigs (raised by Midwest Research Swine). The actualBLSS device consists of a blood pump, heat exchanger to control blood tempera-ture, an oxygenator to control oxygenation and pH, a hollow fiber bioreactor, andassociated pressure and flow alarm systems. Since 1998, Excorp Medical is un-dergoing phase I/II clinical trials. At least nine patients have been treated this de-vice. Moreover, the risk of infection with porcine endogenous retroviruses hasbeen assessed. However, there is still concern regarding the safety of such a de-vice, especially regarding the threat of viral infection from animal hepatocytes.While initial studies regarding the safety of the BLSS are promising, more stud-ies are required to prove safety to the FDA before the product can be approvedfor phase II/III trials.• VitaGen Inc. (formerly Hepatix)(USA). VitaGen Incorporated, founded in 1990,is a biotechnology and medical products company, which develops the ELAD®(Extracorporeal Liver Assist Device) Artificial Liver. ELAD® is a two-chambered hollow-fiber cartridge containing a cultured human liver cell line(C3A). In April 1999, the company initiated the phase I/II clinical trial. The
64company anticipated the completion of a FDA approved Phase 2 Clinical trial toevaluate the safety and efficiency of the ELAD® artificial liver device in patientswith Fulminant Hepatic Failure while bridging them to liver transplantation inMarch 2002. This trial was planned to enrol twenty-four patients at seven USsites.• Algenix (USA). Algenix Inc. is a spin-off of the University of Minnesota. Thecompany focusses on the development of the bioartifical liver LIVERx2000which is the result of a 10 year preclinical research project at the University ofMinnesota. Several patents have been obtained. LIVERx2000 uses fresh porcinehepatocytes. The company is planning to begin FDA approved Phase I ClinicalTrials to evaluate the safety of the Algenix LIVERx 2000 Bioartifical Liver forthe treatment of hepatic diseases such as fulminant hepatic failure.• Diacrin (USA). At least until 2002, Diacrin developed porcine liver cells foracute liver failure (HepatoCell™) for the treatment of liver failure; no up-to-dateinformation is available whether this programme is still continued, or whetherthe company now focusses on the transplantation of muscle cells for ischemicheart failure.8.3 Overview of potential market volumes8.3.1 Overview of organ donation and organ transplantation inter-nationallyDuring the past three decades transplantations of organs, tissues and cells have be-come routine surgical procedures. Irreversibly damaged organs, tissues and cells arereplaced by functional ones. In many cases transplantations are life-saving, e. g.liver transplantation after fulminant hepatic failure. In addition, the patients qualityof life can be substantially improved, e. g. in the case of kidney transplantationwhich makes the transplant recipient independent of dialysis.Organs transplanted are heart, kidney, liver, lung, pancreas/islet cells and small in-testine. In Europe, the USA, Canada, and Australia a total of nearly 42,000 organswere transplanted in 2001 (Table 8.2). More than the half of these transplantationswere kidney transplantations, followed by liver transplantations (nearly 11,000),hearts, lungs and pancreas. Bowels are very rarely transplanted(126 transplantations), nearly all of them in the USA. The transplantation of kid-neys, hearts and livers is surgical routine today while lung transplantation is in theprocess of achieving this phase.
66Table 8.3: Overview of organ transplantations in 2001 (numbers per 1 mio.inhabitants)Country Kidney+ Liver Heart* Lung* Pancreas Bowels TotalGermany 23.9 9.2 5.0 2.4 0.0 40.5Spain 46.0 23.6 8.3 1.3 79.2France 32.0 13.4 5.7 0.9 0.0 52.0UK 22.6 11.4 3.4 0.7 0.0 38.1Ireland 30.2 9.4 2.9 2.4 44.9Italy 25.0 13.7 5.5 1.1 0.1 45.4Belgium 35.8 19.7 8.2 2.0 65.7Luxemburg 22.5 22.5Austria 44.8 15.9 8.2 2.4 0.1 71.4Sweden 21.1 11.4 2.8 35.3Denmark 22.3 5.9 5.7 33.9Finland 31.9 7.3 2.5 41.7Greece 7.4 1.8 0.5 9.7The Neth-erlands21.1 6.7 2.3 1.4 0.1 31.6Portugal 34.9 18.4 1.7 0.4 55.4EU-15total28.1 12.0 4.5 1.5 0.1 44.5Poland 21.8 2.7 3.3 0.4 28.2CzechRepublic30.1 5.6 4.8 1.9 42.4Switzerland 22.0 12.2 5.3 1.7 41.2Turkey 2.4 1.6 0.4 4.4Norway 27.7 8.2 4.0 2.7 42.6Hungary 25.9 1.9 0.9 0.7 29.4Slovacia 0.0Bulgaria 0.5 0.5Croatia 13.9 4.5 2.1 20.5Slovenia 23.5 4.5 2.0 30.0Lithuania 0.0Cyprus 0.0Estonia 21.4 0.7 22.1USA 33.0 19.3 8.2 3.2 0.4 64.1Canada 21.3 12.5 5.3 1.1 40.2Australia 16.9 6.2 3.5 1.1 27.7Total 24.4 9.5 4.1 1.5 0.1 34.2* including heart-lung transplantationsSource: http://www.msc.es/ont/ing/f_data.htm, accessed Feb. 11, 2003The frequency of organ transplantations depends on – among other factors – thefrequency of organ donation. The number of organ donors differs largely fromcountry to country, as well as the share of multi-organ donations (Table 8.4). InEurope, Spain, Austria and Belgium/Luxembourg hold the leading positions with32.5 to 23.7 donors per 1 mio. inhabitants. As a consequence of the gap between
67demand and supply of donated organs, the waiting times for an organ transplanta-tion have become longer. The longest waiting times exist for kidney- and heart-lungtransplantations, the waiting times for heart transplantations are the shortest. World-wide, several thousand patients die while still on the waiting list because no suitableorgan was available in time. This holds especially true for patients waiting for aheart or a lung, because for these organs there are hardly any life-saving alternativesto organ transplantation.
68Table 8.4: Organ donations in selected countries in 2001CountryNumber of or-gan donorsOrgan donors permillion inhabitantsMultiorgandonorsSpain 1335 32.5 84.4%Austria 191 23.7 77.8%USA 6081 22.6 n. a.Belgium 222 21.6 47.7%Portugal 202 20.2 78.7%R.Ireland 68 18.2 81%France 1066 17.8 n. a.Latvia 41 17.8 n. a.Italy 988 17.1 n. a.Finland 88 17 48.9%Czech.Rep 172 16.7 48.3%Malta 6 15 100%Norway 65 14.4 83%Hungary 137 13.7 19%Canada 420 13.5 n. a.Switzerland 95 13.2 76.8%Germany 1073 13.1 77%United Kingdom 777 13.1 83%Denmark 70 12.9 74.3%Luxemburg 5 12.5 100%Sweden 108 12.1 75.9%The Netherlands 187 11.7 61.4%Poland 450 11.6 38.4%Slovenia Rep. 23 11.5 85%Estonia 14 10 7.14%Australia 180 9.3 81%Israel 59 9 37.2%Croatia 32 7.3 62.5%Greece 32 3.2 n. a.Turkey 89 1.3 n. a.Romania 21 0.95 76.19%Bulgaria 2 0.26 n. a.n. a. data not availableSource: Organización Nacional de Trasplantes; http://www.msc.es/ont/ing/data/organo.asp?O=2&DO=DONORS&aO=2001; accessed on October 15, 2002
698.3.2 Diabetes mellitusDiabetes is a serious and costly disease which is becoming increasingly common,especially in developing countries and disadvantaged minorities. According to thelatest WHO estimate worldwide 177 million people had diabetes mellitus in 2000which is a sharp increase over the last decades (1985: 30 million people; 1995:135 million people). In the European Region, about 22.5 million adults are affected.The number of affected people will double to at least 300 million worldwide by2025. Much of this increase will occur in developing countries and will be due topopulation growth, ageing, unhealthy diets, obesity and sedentary lifestyles. By2025, while most people with diabetes in developed countries will be aged 65 yearsor more, in developing countries most will be in the 45-64 year age bracket andaffected in their most productive years.Generally, people suffering from diabetes have a 3-4 times higher risk of dyingprematurely from cardiovascular disease than the rest of the population. The num-ber of deaths attributed to diabetes was previously estimated at just over 800,000.However, it has long been known that the number of deaths related to diabetes isconsiderably underestimated. A more plausible figure is likely to be around 4 mil-lion deaths per year related to the presence of the disorder. This is about 9% of theglobal total. Many of these diabetes related deaths are from cardiovascular compli-cations. Most of them are premature deaths when the people concerned are eco-nomically contributing to society.Besides mortality, Diabetes has additional severe impacts: it is the commonestcause of blindness in people of working age, one of the most commonest causes ofkidney failure, and the commonest cause of leg amputation (World Health Organi-zation (WHO) 2002). Because of its chronic nature, the severity of its complicationsand the means required to control them, diabetes is a costly disease, not only for theaffected individual and his/her family, but also for the health authorities. The totalhealth care costs of a person with diabetes in the USA are between twice and threetimes those for people without the condition. It was calculated, for example, that thecost of treating diabetes in the USA in 1997 was US$ 44 billion. Overall, directhealth care costs of diabetes range from 2.5% to 15% annual health care budgets,depending on local diabetes prevalence and the sophistication of the treatmentavailable. For most countries, the largest single item of diabetes expenditure is hos-pital admissions for the treatment of long-term complications, such as heart diseaseand stroke, kidney failure and foot problems. Many of those are potentially prevent-able given prompt diagnosis of diabetes, effective patient and professional educa-tion and comprehensive long term care (WHO 2002, Fact Sheet N° 236).In 2000, world wide sales of therapeutics for the treatment of diabetes were8.1 billion US-$, a growth of 19 % compared to the previous year. Nearly two thirdsof this market are covered by oral antidiabetic drugs. The top selling product (Glu-
70cophage, distributed by the US pharmaceutical company Bristol-Myers Squibb) hassales of more than 1.6 billion US-$. Other leading companies are Novo Nordisk(Denmark) and Eli Lilly (USA).8.3.3 Acute hepatic failureIn the EU, 4,844 liver transplantations were carried out in 2001. In France, the totalcost (staff wages, pharmacy and blood, laboratory and radiology, supplies, overheadhospital services) for adults who received a liver transplant between 1994 and 1996were € 85,500. Care outside the hospital induced 10% of the total cost (Fourquet etal. 2001). Assuming that costs in other European countries are similar to the costs inFrance, this corresponds to total costs for liver transplantation in the EU of414 mio. € per year.
719. Tissue engineered CNS products9.1 Overview of potential applicationsDuring the past decades, knowledge on the regeneration of neural tissue has beenenlarged considerably, bringing tissue engineering approaches to the repair of dis-eased or damaged neural tissue into the range of feasibility. Tissue engineering ap-proaches, especially approaches based on cell therapies, can exploit several mecha-nisms (Björklund et al. 2000):• Structural and functional integration of the graft into the damaged tissue, form-ing of three-dimensional networks.• Production of therapeutically active substances at the diseased or damaged site,e. g. neurotransmitters, neurotrophic or neuroprotective factors.• Repair of damaged structures, e. g. coating nerves with a new myelin sheath.These tissue engineering approaches can target different types of CNS damage ordisease:• Neurodegenerative diseases. Neurodegenerative diseases comprise Parkinsonsdisease, Chorea Huntington, Alzheimers disease, amyotrophic lateral sclerosis,and multiple sclerosis.• Paralysis, damage of nerve fibres, spinal cord injury.• Epilepsy, impaired generation of nerve impulses.• Stroke• Pain.For most of these diseases and damages, no fully satisfactory treatments are avail-able. Drug treatment which is long-term effective, is often difficult to achieve or notpossible at all. As the central nervous system is responsible for the cognitive abili-ties of a person and controls most body functions, diseases of the central nervoussystem severely impair a patients life and that of his contact persons. The preva-lence of especially the neurodegenerative diseases increases with age and requireintensive nursing, so that a significant increase in health care costs can be expectedin the coming decades in industrialised nations due to the demographic develop-ment. On the other hand, multiple sclerosis (MS) or spinal cord injury can affectyoung persons and lead to life-long incapability to work and needs for nursing.
729.2 Overview of companies and their R&D activitiesAt present, there are no approved cell therapies for CNS disorders available. How-ever, several clinical trials have been carried out, are underway or planned. Thefollowing companies are reported to be engaged in cell-therapy-related R&D ofCNS disorders, however, most of them in the preclinical stage:• Diacrin Inc. (USA). Diacrin is a biotechnology company which develops celltransplantations for treating human diseases. In 2001, Diacrin had several prod-ucts in development for treatment of CNS disorders. These products are:− NeuroCell-PD. NeuroCell-PD are porcine fetal neural cells for Parkinson’sdisease. in 1999 to 2001, Diacrin in cooperation with Genzyme carried out aphase 1 clinical trial with 12 patients and a double-blind, randomized, pla-cebo-controlled phase II trial for the evaluation of the safety and efficacy ofNeuroCell-PD in 10 patients plus 8 patients in the placebo control group. Noimprovement in the treated group over the control group could be achieved.− NeuroCell-HD for Huntington’s disease. Genzyme and Diacrin established ajoint venture in 1996 to develop NeuroCell-PD and NeuroCell-HD for celltherapies for the treatment of Parkinson’s and Huntington’s diseases.− Porcine neural cells for stroke, focal epilepsy and intractable pain. Diacrincarried out a phase I clinical trial using porcine neural cells for stroke, focalepilepsy, and intractable pain. In 2000, Diacrin halted the stroke trial after twopatients had developed adverse events.− Porcine spinal cord cells for spinal cord injury; In 2001, Diacrin receivedpermission by the Food and Drug Administration for a phase I trial on trans-plantations of porcine fetal spinal cord cells from a pig, treated with antibod-ies to reduce the immunogenicity of the graft, into the spinal cord of a total ofsix quadriplegic patients in cooperation with two US medical centers.All these trials seem to have been discontinued since 2001. It is not knownwhether they will be continued by Diacrin.• StemCells Inc. (USA). The company carries out research and development intostem-cell based cell therapies based on human adult stem cells. It has – amongothers – a preclinical research programme on human neural stem cells for strokeand Parkinsons disease therapy. Its near-term goals in this programme are the es-tablishment of strategic alliances, and the filing of an IND.• Neuronyx, Inc. (USA). Neuronyx, Inc. is a development-stage biopharmaceuticalcompany. It discovers and develops treatments for diseases of the brain, centralnervous system and heart utilizing human adult bone marrow-derived stem cells.It has a programme on Parkinson’s Disease in the research stage, is consideringprogrammes on stroke and ALS, and plans filing an IND with FDA to com-mence human clinical trials of spinal cord injury therapy in 2003.
73• Acorda Therapeutics, Inc. (USA). Acorda Therapeutics, Inc. was established inMarch 1995 to develop therapeutic products for spinal cord injury and other cen-tral nervous system disorders. Among others, it also has a preclinical R&D pro-gramme on developing neural stem cell-based technologies and approachesbased on L1 axonal guidance proteins for regeneration and repair of the spinalcord and brain.• NeuroNova AB (Sweden). Founded in 1998, NeuroNova AB is a Swedish bio-pharmaceutical company engaged in both the discovery and the development ofadult neural stem cell-based therapies for the treatment of disorders of the centralnervous system such as Parkinsons disease, Alzheimers disease, stroke, and spi-nal cord injury. NeuroNova is targeting Parkinsons disease as its first area fordevelopment. The research is in the preclinical stage.• ReNeuron Holding (UK). Founded in 1997, ReNeuron is a bio-pharmaceuticalcompany developing treatments for neurological disorders based on its murineand human conditionally immortalized neuroepithelial stem cell lines. The com-pany intends to develop cell lines for the treatment of stroke, followed by Park-insons, Alzheimers and Huntingtons disease and cerebral palsy. These researchprogrammes are in the preclinical stage; and the human transplantation pro-gramme had to be postponed because the cell lines became genetically unstable.• CellFactors (UK). CellFactors focusses on the development of human cell-basedtherapies by generation and manipulation of immortalized, partially differenti-ated human cells. One of the companys focusses are whole cell therapies forneuro-degenerative disorders. It has its product Volante, a whole cell therapy forthe treatment of Parkinsons disease, in preclinical development. Human fetalcells from aborted fetuses are immortalised, and the resulting dopamine-producing cell lines are genetically engineered to become temperature sensitiveand to build in a molecular control mechanism.• ReInnervate Limited (UK). Founded in 2002, ReInnervate Limited is a spin-offbiotechnology company from the University of Durham. The company con-centrates on neural stem cell research and development to facilitate cell lines, as-says, enabling systems and therapeutic patents, which in turn are licensed andsold to major pharmaceutical and biotechnology companies for final commercia-lisation in the market place. ReInnervate is currently in the process of developingits core enabling technologies and of fund raising.9.3 Overview of potential market volumesFor the year 2000, the world market for pharmaceuticals for the central nervoussystem (CNS) is estimated to approx. US$ 44 billion (Informa Pharmaceuticals2000). Drugs with the highest sales volume globally target depression, schizo-
74phrenia and epilepsy. Therefore, medicines against neuro-degenerative diseases arenot among top sellers (Informa Pharmaceuticals 2000; Pardridge 2002). The onlyexception are drugs for the treatment of multiple sclerosis. Several therapeutics areon the market which reduce the severety and frequency of disease episodes (e. g.interferon-beta-1a, marketed as Avonex and Rebif by Biogen (USA) or Serono(Switzerland), respectively; interferon-beta-1b, marketed as Betaseron by Schering(Germany), and other therapeutics such as Copaxone (Teva Pharmaceuticals, Israel)and Novantrone (Immunex, USA). The market for drugs for the treatment of multi-ple sclerosis is estimated at 2.3 Mrd. US-$ in 2001, with an estimated growth to4 billion US-$ by 2005 (Frost & Sullivan 2001).Most of the actually authorised pharmaceuticals are not able to treat acute stroke.This is why in general medicines are used to prevent the development of blood clotsor reduce the risk for coagulation. It is estimated that the market potential for phar-maceuticals to treat stroke is about € 5 billion per year (Frost & Sullivan 2002). Forthe years to come, mainly because of shifts in the age structure of the population inmost of the industrialised countries the number of stroke patients is expected togrow (Reuters Business Insights 1999) The direct costs of a stroke for hospitaltreatment and primary care were estimated in the late 1980s to about € 10,000(Isard et al. 1992). According to data from the USA the total costs (direct and indi-rect) of a stroke incident at the beginning of the 1990s were about€ 113,000 (Taylor et al. 1996).The present market structure for CNS drugs reflects the present state of pharmaco-logy where only few effective drugs for the treatment of CNS diseases and damagesare available. This can be interpreted as an – in principle – favourable market situa-tion for tissue engineering cell therapies, provided, they can be developed as effec-tive treatments. For the future, a rising number of patients with neuro-degenerativepatients is expected, not least because of the shift in the age structure of the popula-tions in the industrialised countries. Several analysts estimate, that the market forCNS products will grow more quickly than the global pharma market. This assess-ment is based on the fact that up to now only for few diseases in this area adequatetreatments exist and therefore rising pressure by patients and therapists on researchin this field can be expected. The future growth of the market for CNS productssignificantly depends on the solution of scientific problems (e.g., a major part of thepotential active substances for CNS-diseases cannot pass the blood-brain barrier),the potential of the pharmaceutical industry to develop effective and safe newpharmaceuticals as well as on politically motivated pressure to replace original me-dicaments by generic products.
7510. Characterization of the tissue engineering industry10.1 Structure of the tissue engineering industry10.1.1 EuropeIn order to characterise European tissue engineering companies, three differentcategories were distinguished:• Core TE companies: Core TE companies are companies whose activity fullycomplies with the tissue engineering definition chosen for this study: Their tissueengineering activities are carried out with the aid of cells and biomaterials and/orbiomolecules, and have a therapeutic purpose.• Broader TE definition: Companies which carry out actitivities which are di-rectly relevant for tissue engineering, but do not comply with the tissue engineer-ing definition chosen for this study. Companies in this category, for example, areprimarily engaged in marketing and distribution of tissue engineering products,in biomaterials, or in bioreactors for tissue engineering. Moreover, medical de-vice or pharma companies are listed in this category if they are involved in jointR&D projects in tissue engineering, but if this is only a minor activity withintheir overall company activities.• In-vitro-use of TE: Companies in this category carry out tissue engineering ac-tivities with the aid of cells and biomaterials and/or biomolecules, but without atherapeutic purpose. In general, these companies have developed in-vitro modelsof e. g. skin or liver through tissue engineering, and use these in-vitro models forscreening of drugs, toxicity tests etc.In these three categories, a total of 113 companies were identified in Europe (ta-ble 10.1, 10.2). 54 of these companies are core tissue engineering companies, 48 arecompanies in the category "Broader definition", and 11 companies focus on in-vitrouse of tissue engineering (table 10.2). Most of the European tissue engineeringcompanies are located in Germany (39), followed by the United Kingdom (18),France (10), the Scandinavian countries and the Benelux countries (table 10.2, fig-ure 10.1). Only few companies could be identified in the Mediterranian EU coun-tries, and, with the exception of the Czech Republic, no companies could be identi-fied in the first round accession countries (table 10.2).
76The large majority of tissue engineering companies are biotechnology companies(n=80). Moreover, medical device companies (n=24) and several pharmaceuticalcompanies (n=9) are also involved (figure 10.3), but in most cases, they do not fallinto the definition of core tissue engineering companies (table 10.1). Among thetissue engineering companies, small companies prevail (figure 10.2): 91 out of113 companies are small and medium-sized companies with less than500 employees. In fact, most of the companies are even significantly smaller: for 44out of the 91 tissue engineering companies, more detailed data on employee num-bers were available (table 10.3). Table 10.3 shows that 75 % of these small and me-dium sized tissue engineering companies have less than 50 employees (expressed asfull time equivalents). No significant difference regarding this size distribution canbe discovered between the core tissue engineering companies and all TE SMEs(which also include the broader definition and in-vitro-use companies). Only onecore tissue engineering SME could be identified which has more than100 employees, this is IsoTis SA (Switzerland/The Netherlands).To sum up, the majority of the European tissue engineering companies can be char-acterised as young, small, research-based and technology-oriented companies. Thisstructure of the European tissue engineering industry reflects that tissue engineeringis a new, growing, dynamic field which is still in an infant stage of development.In order to put the situation in Europe into perspective, results from recent surveysof the US-American tissue engineering industry are presented in the following sec-tion.Table 10.1: Tissue engineering companies in EuropeCountry Company Company TypeCompanySizeTE RelevanceAustria Educell Zellkultivierung F&EGmbHBiotech SME CoreAustria InnovaCell Biotech SME CoreAustria igor – Institut für Gewebe- undOrganrekonstruktionBiotech SME CoreBelgium Genzyme Europe Biotech large CoreBelgium TIGenix NV Biotech SME CoreBelgium beta-cell Biotech SME CoreBelgium XCELLentis Biotech SME CoreCzech Republic Altius Co.Ltd. Biotech SME CoreCzech Republic Educell Biotech SME CoreCzech Republic CPN, Ltd. Biotech unknown CoreDenmark Interface Biotech SA Biotech SME CoreDenmark Nordic Bioscience A/S Biotech SME Broader def.Denmark Coloplast A/S Medical Device large Broader def.Finnland Ark Therapeutics Oy Biotech SME Broader def.
77Finnland Cellomeda Oy Biotech SME Broader def.Finnland Fibrogen Europe Oy Biotech SME Broader def.France Imedex Biomateriaux Pharma SME CoreFrance Laboratoires Genevrier Pharma SME CoreFrance Myosix SA Biotech SME CoreFrance Neurotech SA Biotech SME CoreFrance Biopredic International Biotech unknown in vitro useFrance Coletica Biotech SME in vitro useFrance Galderma R & D Pharma large in vitro useFrance Groupe Dermscan Biotech SME in vitro useFrance LOreal Recherche Medical Device Large in vitro useFrance SkinEthic Laboratories Biotech SME in vitro useGermany Ars Arthro AG Biotech SME CoreGermany ARTISS GmbH Biotech SME CoreGermany BioTissue Technologies AG Biotech SME CoreGermany Cell Lining GmbH Biotech SME CoreGermany CO.DON AG Biotech SME CoreGermany MeGa Tec GmbH Biotech SME CoreGermany Switch Biotech AG Biotech SME CoreGermany TETEC Tissue EngineeringGmbH Technologies GmbHBiotech SME CoreGermany Vascular Biotech GmbH Biotech SME CoreGermany Verigen Transplantation Ser-vice International AGBiotech SME CoreGermany IBFB GmbH Biotech SME CoreGermany Innocoll GmbH Medical Device SME CoreGermany CellMed AG Biotech SME CoreGermany Cytonet AG Biotech SME CoreGermany DeveloGen Biotech SME CoreGermany Trans Tissue TechnologiesGmbHBiotech SME CoreGermany Kourion Therapeutics GmbH Biotech SME CoreGermany CellTec GmbH Biotech SME CoreGermany Hybrid Organs Biotech SME CoreGermany CellSystems BiotechnologieVertrieb GmbHBiotech SME in vitro useGermany ACM-Biotech GmbH Biotech SME in vitro useGermany EDI GmbH Biotech SME in vitro useGermany In Vitro Biotec GmbH Biotech SME in vitro useGermany ALVITO BiotechnologieGmbHBiotech SME Broader def.Germany B.Braun Melsungen Medical Device Large Broader def.Germany Biomet Merck BiomaterialsGmbHMedical Device SME-LargeBroader def.Germany Aventis Behring GmbH Pharma Large Broader def.Germany Beiersdorf AG Pharma Large Broader def.Germany Biovision GmbH Biomaterial Biotech SME Broader def.Germany Cardion AG Biotech SME Broader def.
78Germany Curasan Biotech SME Broader def.Germany Dr. Suwelack Skin & HealthCare AGPharma SME Broader def.Germany Teraklin AG Medical Device SME Broader def.Germany Aesculap AG & Co. Medical Device Large Broader def.Germany In Vitro Systems & ServicesGmbHBiotech SME Broader def.Germany Innovent Technologieentwick-lung e.V.Biotech SME Broader def.Germany Osartis GmbH & Co. KG Biotech SME Broader def.Germany ProBioGen AG Biotech SME Broader def.Germany Minucells and Minutissue Ver-triebs GmbHBiotech SME Broader def.Italy Fidia Advanced BiopolymerssrlPharma large CoreItaly Novamont SpA Medical Device unknown Broader def.Luxembourg Cellon S.A. Biotech SME Broader def.Spain Advancell Biotech SME in vitro useSpain Grupo Ferrer InternacionalS.A.Pharma Large Broader def.Spain Genetrix SL Biotech SME Broader def.Sweden Cell Therapeutics Scandinavia Biotech SME CoreSweden Cellfactory Biotech SME CoreSweden Karocell Tissue EngineeringABBiotech SME CoreSweden Neuronova Biotech SME CoreSweden Vitrolife AB Medical Device SME CoreSweden AnaMar Medical Biotech SME Broader def.Sweden Biora AB Medical Device SME Broader def.Sweden Medicarb Biotech SME Broader def.Sweden Q-Med Medical Device SME Broader def.Sweden Angio genetics AB Biotech SME Broader def.Switzerland Kuros Biotech SME CoreSwitzerland/TheNetherlandsIsoTis SA Biotech SME CoreSwitzerland Novartis Pharma Large Broader def.Switzerland Centerpulse AG Medical Device large Broader def.Switzerland Degradable Solutions AG Medical Device SME Broader def.Switzerland Nisco Engineering Inc. Medical Device SME Broader def.Switzerland Synthes stratec AG Medical Device Large Broader def.Switzerland BD Biosciences Biotech Large Broader def.The Netherlands Matrix Medical BV Biotech SME CoreThe Netherlands Biomat BV Medical Device SME Broader def.The Netherlands Bioscan BV Medical Device SME Broader def.The Netherlands Leadd Biotech SME Broader def.The Netherlands Pharming Group NV Biotech SME Broader def.The Netherlands Polyganics BV Medical Device SME Broader def.United Kingdom Axordia Biotech SME CoreUnited Kingdom Cell Factors Biotech SME Core
79United Kingdom Cerestem Biotech SME CoreUnited Kingdom Intercytex Limited Biotech SME CoreUnited Kingdom Multicell Biotech unknown CoreUnited Kingdom Odontis Biotech SME CoreUnited Kingdom Regentec Biotech SME CoreUnited Kingdom ReInnervate Biotech SME CoreUnited Kingdom Reneuron Biotech SME CoreUnited Kingdom Renovo Ltd Biotech SME CoreUnited Kingdom Smith & Nephew Ltd Medical Device large CoreUnited Kingdom Advanced Medical Solutions Medical Device SME Broader def.United Kingdom Apatech Medical Device SME Broader def.United Kingdom Enact Pharma Biotech unknown Broader def.United Kingdom Johnson & Johnson AdvancedWound CareMedical Device large Broader def.United Kingdom PPL Therapeutics plc Biotech SME Broader def.United Kingdom Tissuemed Ltd Medical Device SME Broader def.United Kingdom TissueScience Laboratories Medical Device SME Broader def.SME: <500 employees, large: >500 employeesTable 10.2: Overview of tissue engineering companies in European countriesNumber of TE companiesCountryCoreTE companybroaderTE definitionin-vitro useof TETotalAustria 3 0 0 3Belgium 4 0 0 4Czech Republic 3 0 0 3Denmark 1 2 0 3Finnland 0 3 0 3France 4 0 6 10Germany 19 16 4 39Italy 1 1 0 2Luxembourg 0 1 0 1Spain 0 2 1 3Sweden 5 5 0 10Switzerland 2 6 0 8The Netherlands 1 5 0 6United Kingdom 11 7 0 18Total 54 48 11 113
80Figure 10.1: Tissue engineering companies in European countries0510152025303540GermanyUnitedKingdomFranceSwedenSwitzerlandTheNetherlandsBelgiumCzechRepublicDenmarkFinnlandSpainItalyAustriaLuxembourgCountryNumberofCompaniesCore TE company broader TE definition in-vitro use of TEFigure 10.2: Company size of European tissue engineering companies91491735 20%10%20%30%40%50%60%70%80%90%100%All TE companies Core TE companiesShareofcompanies(%)not knownLargeSME
81Table 10.3: Categorisation of SME European tissue engineering companiesaccording to employee numbersEmployees/company (full time equivalents) TotalNumber of SMEs≤ 20 ≤ 50 ≤ 100 ≥ 100all TE SMEs 25 8 7 4 44Core TE SMEs 13 4 5 1 23Share of SMEsall TE SMEs 57 % 18 % 16 % 9 % 100 %Core TE SMEs 57 % 17 % 22 % 4 % 100 %Figure 10.3: Company type of European tissue engineering companiesBiotech71%Pharma8%Medical device21%10.1.2 USAA characterisation of the tissue engineering industry with significant emphasis onthe USA based on several surveys has recently been published (Lysaght et al. 1998;Lysaght et al. 2001; The Pittsburgh Tissue Engineering Initiative 2000). Tissue en-gineering was defined as the development of products or services that• combine living cells and biomaterials,• utilize living cells as therapeutic or diagnostic reagents,• generate tissues or organs in vitro for subsequent implantation, and/or• provide materials or technologies to enable such approaches.
82• In addition, newer areas such as therapeutic cloning, regenerative medicine andstem cell-based organogenesis were specifically included.The following activities were especially excluded: allotransplantation, transgenicorgan xenotransplantation, gene therapy, blood substitutes, porcine heart valves,and blood banking as well as classic orthopedic biomaterials, bone marrow trans-plantation and basic research into stem cell biology. Thus, this scope is rather simi-lar to, but a bit broader than the definition applied in this report.Tables 10.4 and 10.5 give an overview of the results.Table 10.4: Economic parameters for contemporary tissue engineering (2001)Number of firms 73 (14 not in the USA)Number of scientists and support staff 3,300Annual spending rate, calendar 2000 610 million €Compound annual growth rate, 1995-2001 16 %Capital value of post IPO companies (n=16) 2.6 billion €Cumulative investment, 1990-2001 3.5 billion €Source: (Lysaght et al. 2001). Data are referenced to January 1, 2001, exceptwhere noted.According to the 2001 survey conducted by (Lysaght et al. 2001), approximately70 startups or business units are currently active in the field of tissue engineering.This figure includes 56 US companies and 14 non-US companies. These70 companies employ a workforce of appr. 3,500 full time equivalents, whichmeans an average of 50 full time equivalents per company. Most of the companiesare young and small. Two fifth have less than 16 employees, two fifth less than 51employees, and only one fifth has more than 51 employees. The spending is nearly€ 600 mio. annually. The spending has been growing at a compound annual rate of16 %, and the cumulative spending since 1990 exceeds € 3.5 billion. Appr. twodozens of companies are listed on stock exchanges; these publicly traded companiesaccount for appr. 35 % of the workforce. On the other hand, no profitable producthas yet been launched, and the size of sales stays far behind the high-flying expecta-tions and market potentials. For example, the FDA-approved products Carticel andApligraf together had annual sales of less than 40 mio. US-$ in 2001 (Lysaght et al.2001). Neither of them is profitable which led to the situation that the companiesAdvanced Tissue Sciences and Organogenesis went bancrupt in 2002 (Bouchie2002). These low sales are in disproportion to the rate of investment that currentlyattends tissue engineering.The majority of companies focus on developing structural applications (skin, heartvalves, bone, arteries, myocardial, particles) (2/3 of the companies in US), this sec-tor is expanding rapidly (table 10.5). Cellular applications (cell transplantation,therapeutic cloning) is the second largest segment. As it has remained about con-
83stant since 1998, the foundation of new companies with activities in the field ofhuman embryonic stem cells and cell therapies based on human adult stem cellsmust have compensated the reduction of activities in other subfields of this sector(Hüsing et al. 2003). Metabolic applications (bioartificial organs and encapsulatedcell therapies) have shrunken since 1998 and presently only represent 10 % of tissueengineering in the USA. This reflects the very early stage of development of thissector where basic research questions still have to be solved and break-throughs tobe achieved before clinically applicable therapies or devices can be expected(Lysaght et al. 2001; Hüsing et al. 2001).Table 10.5: Sector analysis of tissue engineering companies in the USA 2001Sector Structural Cellular MetabolicExamplesSkin, bone, heartvalves, arteries, myo-cardial particlesCell transplantation,therapeutic cloningBioartificial organs,encapsulated celltherapyEmployees (FullTime Equivalents)1980 890 570Percent of total 60 % 27 % 11 %Spending in 2000(€ mio.)363 174 68Growth since 1998survey5 +85 % 0 % - 30 %Source: (Lysaght et al. 2001)10.1.3 Common features of the European and US-American tissueengineering industryIn Europe as well as in the USA, a rather similar structure of the tissue engineeringindustry can be observed: This structure reflects that tissue engineering is a new,growing, dynamic field which is still in an infant stage of development.As can be deduced from the information given in chapters 4-6, there are many com-panies firms with a similar technology base and similar products. They invest intoR&D and market development to an extent which cannot sustainably be financed bycurrent product sales: Sales are far too small to cover or outpace operating costs(high costs to produce, maintain and ship the products, high investments in R&D,spending of money for the development of marketable products and market devel-opment). The markets are not yet fully developed and amount to only several5 Lysaght, M.; Nguy, N. A. P.; Sullivan, K. (1998): An Economic Survey of the Emerging TissueEngineering Industry. In: Tissue Engineering 4, No. 3, pp. 231-238
84€ mio./year. Thus, these markets are not only orders of magnitude smaller than ex-pected, but also orders of magnitude smaller than markets for pharmaceutical prod-ucts. In most markets, several tissue engineering companies compete with one an-other, and also with established simpler, cheaper, more familiar therapeutic options.Therefore, it can be concluded that there is significant redundancy and overcapac-ity.As a consequence of high operating costs and low sales revenues, firms run out ofmoney or are chronically underfinanced and have to struggle for more funds frominvestors in the currently unfavourable economic climate (Petit-Zeman 2001). As isobvious from companies press releases and company reports, most companies haveimplemented strict cost reduction programmes in the last few years, and have alsostarted rationalization, downsizing, and realignment. This consolidation process willcontinue, and will also reduce the number of low-profit "me-too" companies andproducts in the coming years.10.2 Differences between Europe and the USA10.2.1 Science and technology baseSeveral experts interviewed for this study had the impression that tissue engineeringis treated as a strategic R&D area in USA, which receives focussed and intensivesupport. Although tissue engineering also receives relatively intensive support onthe R&D side in the EU, the experts felt this support to be not as intensive and fo-cussed as in the USA. Some were of opinion that funding is broad and - in the wishto advance the field - also second-class R&D and "me-too"-approaches get funding.According to the experts characterisation of the EU situation, the R&D efforts seemnot to be very well coordinated, and networks and cooperations can still be devel-oped significantly. Several experts noted that networking and cooperation recentlyhad improved due to efforts to submit proposals for networks of excellence andintegrated projects within the 6thframework programme.Most experts interviewed for this study were of opinion that the scientific and tech-nological level of R&D is on a comparable high level both in USA and Europe, andthe scientific progress is at about the same pace in both regions. Due to shorter timeto market in Europe (see below), Europe is in certain subfields and applicationsahead of the USA because it already has experience with clinical application in hu-mans.
85In the USA; there are significantly more acedemic groups and companies whichexplore "borderline", controversial approaches (e. g. use of xenogeneic cells, tissuesand organs, use of human embryonic stem cells, cell transplantations into the brain)than in Europe. Moreover, approaches based on allogeneic cell sources are favouredin the USA, companies in Europe focus on autologous cells.10.2.2 CompaniesIn the USA as well as in Europe, the majority of tissue engineering companies aresmall, young, research-intensive, technology-based companies which are typicallyfinanced by venture capital or listing on the stock exchange. Few have products onthe market. Most companies are characterised by a high burn rate and low income,and presently many run into severe financial problems because the public invest-ment markets are down. This company situation is typical for an emerging fieldsuch as tissue engineering, and is similar in the USA and Europe.The experts interviewed for this study are of opinion, that commercialisation oftissue engineering started earlier in the USA than in Europe. The reason given forthis situation is a more favourable general climate for start-up companies and aspirit of entrepreneurship in the USA: In the past years, the conditions for foundingbiotechnology companies were better in the USA than in Europe (e. g. venture capi-tal, stock markets, entrepreneurship etc.); but the experts acknowledge that theseconditions have significantly improved in Europe in recent years. Both in the USAand in Europe, the first of leading tissue engineering companies go bancrupt or runinto severe financial problems. This, however, should not be overrated, according toexperts opinions, but is part of a healthy, necessary consolidation process withinthe tissue engineering field which will continue in the next years.10.2.3 Regulatory situationThe experts interviewed for this study pointed out significant differences in the re-gulatory situation in the USA and the EU. The main points are summarised intable 10.6.
86Table 10.6: Differences in the regulatory situation in the USA and the EUUSA EUcentralized agency for approval approval procedure decentralised, on national level, in different institu-tions, country-specific approach requiredclear regulatory scheme ("biologics" for tissue engineered products) withrather strict, yet clear criteria and requirementsno uniform approval procedure, regulatory scheme not uniformly appliedin different countries,lack of an approval procedure especially tailored for innovative productsand therapiesgood support by regulatory bodies during the approval process,relatively open-minded to innovative treatmentsunsatisfactory support from regulatory bodiesbodies relatively conservative regarding innovative treatmentstransparency regarding the requirements for and duration of the approvalprocessin case of successful approval, access to the largest and rather homoge-nous health market in the worldin case of successful approval, only access to the national market due tothe country-specific approval approachpreclinical research must be completed before clinical trials in humanscan be started. If in clinical trials, product costs can already be reimbursed(commercialisations during clinical trials), there is the possibility of pre-approval for first line treatmentsIn Europe, permission to distribution can be obtained with preclinicalwork (this gives European companies a clear time advantage over UScompanies because they can start trials in humans much earlier than in theUSA).in case of successful approval, reimbursement of product costs no majorproblemHowever, this time advantage can in practice not be exploited commer-cially because successful biologics commercialization requires generalreimbursement of costs in order to reach increased sales. General reim-bursement by health insurers requires the proof of safety, efficacy, andclinical durability in clinical trials which take 3-5 years.
8710.2.4 MarketThe US market is the largest health market in the world which is – despite existingregional differences – much more homogenous than the European health market.The latter has pronounced national differences.After approval of an innovative treatment in the USA, in general, there is a ratherquick diffusion and reimbursement of this treatment. According to experts opin-ions, this is due to a health system in the USA which is more open to innovationthan in Europe. In Europe, large national differences regarding openness towardsinnovative treatments, both on the side of potential users (medical doctors) andregulatory or financing bodies (e. g. health insurers) are noted by the experts.10.3 Business models and business strategiesAccording to expert opinions, the tissue engineering field is too young and too dy-namic to already bet on companies or business strategies which will most likelydevelop successfully or which are in a "pole position". Nevertheless, several aspectswhich seem to be crucial for successful business in tissue engineering can be de-rived. These are:• Ability to access and integrate the required scientific-technical know-how. Arather large share of the tissue engineering companies have a narrow and notunique scientific-technological basis, e. g. profound knowledge only in cell cul-ture. However, to be successful in tissue engineering business, a much broaderknowledge base must be built, which encompasses cell culture, ma-trix/scaffolds/biomaterials, growth factors, surgical techniques, production andquality control according to GMP. The intellectual property and know-how is of-ten fragmented among different companies, and this limits them as to what theycan achieve. Therefore, profound knowledge in all these fields must be creativelycombined but it is too early to bet on a winning strategy of technology in tissueengineering. There are differences between technologies and different ap-proaches to achieving the same end point (Petit-Zeman 2001).• Profound preclinical knowledge base. Another weak point of many smallcompanies is that they are built on a narrow preclinical knowledge base. As aconsequence, several companies cooperate with clinicians with year-long re-search experience in this field, and take over advanced research results to adaptthem to marketable products.• Excellent clinical outcome of products. The value of most tissue engineeringproducts is often based on quality of life, not patient survival. Often, the prod-
88ucts cannot compete on a direct cost basis. As presently many products targetmarkets where conventional treatment options are already available, they mustoffer at least a similar or an even better clinical performance than conventionaltherapies. Although from a regulatory perspective, for many tissue engineeringproducts results from clinical trials are not necessarily required for commerciali-sation, clinical trials are required to convince users (medical doctors) of the su-periority of the tissue engineering application, and also to obtain cost reim-bursement from statutory and private health insurers.• Excellent manufacturing and quality control standards. At present, the qual-ity requirements for manufacturing tissue engineered products seem to varywidely among companies and EU member states. It is not yet settled whichquality standards will turn out to be necessary and sufficient.• Very good logistic and service for users. Most tissue engineered products re-quire complicated logistic procedures which may be comparable to the shipmentof living human organs. Moreover, the implants have a very limited shelflife.Therefore, it is important that the company which provides the implants is flexi-ble and reliable enough to adjust its implant production procedure to the sched-ule of the surgical procedure.• Orientation towards market and customer needs and requirements. Accord-ing to experts opinions, many companies are doing very good, also interdiscipli-nary science, but focus too much on scientifically challenging and interestingquestions, whereas a clear focus on the market has often been neglected. Indica-tors for this conclusions are the investment of large sums of money (from downpayments etc.) into research projects instead of product and market development,an inbalance between high burn rate and too low revenues from product sales,and neglecting intensive communication with the targeted medical community:too often high-tech solutions have been developed to a problem which can alsobe solved (by competing options) more simple. Therefore addressing the practi-cal aspects of product application (e. g. ease of handling the product in surgicalprocedures, shelflife and storability of the product, faster and/or more reproduci-ble production processes, cost savings in production processes) in product devel-opment is important. Therefore, a stronger focus on applications is required anda critical assessment of potential markets, applications and indications regardingthe question whether the customers are really willing and able to pay for theproduct. If these markets can be identified, then the technologies can be lookedfor with which to address these applications.• Willingness and ability to invest into the development of the market. On theone hand, the markets for individual tissue engineering products are by factor 10to 100 smaller than "usual" markets for pharmaceuticals so that the interest oflarge pharmaceutical companies in tissue engineering products is limited. On theother hand, the resources required for R&D, clinical trials and marketing oftenexceed the resources of the small tissue engineering companies. Therefore, mar-keting is often done in cooperation with larger companies which have good ac-
89cess to the targeted customers. However, according to expert opinions, the searchfor cooperations which really work for both partners is still ongoing. Expertsraise doubts whether biomedical device companies which have good access toe. g. orthopedic surgeons are really the suitable marketing partner for e. g. chon-drocyte transplants. Good contacts with potential customers alone are not suffi-cient. Tissue engineering products differ in many marketing-relevant respectsfrom biomedical devices and pharmaceuticals. They are more complicated, notyet very familiar to medical doctors and therefore require extensive education ofthe potential customers. As a consequence, highly educated marketing staff is re-quired, and also other marketing instruments (e. g. workshops, practical trainingsinstead of conferences) are required.• Ability to cope with regulatory bottlenecks.• Ability to cope with different corporate cultures and established procedures intissue engineering companies, pharmaceutical companies and medical devicecompanies.The above mentioned aspects are mainly derived from the commercialisation oftissue engineering products which are currently on the market (especially skin andcartilage products). For such products, the successful business model is still toemerge: it must account for high development costs (biologics operating model) andrelatively small margins (device-type business model) (Petit-Zeman 2001), ta-ble 10.7). However, tissue engineering can also deliver other types of products forwhich a pharmaceuticals of medical device business model can be applied.Table 10.7: Business models for pharmaceuticals, medical devices and tissueengineering productsPharmaceuticals Medical Devices Tissue Engineering productsHigh up-front investment inR&DLower up-front investment inR&DMedium up-front investmentin R&DLong development times Short development times Medium to long develop-ment timesHigh gross margins Low gross margins Low gross marginsLarge markets Focused markets Focused markets
9011. Overview of tissue engineering products on the mar-ket and in clinical trialsIn order to gain an overview of tissue engineering products which are already com-mercially available, or are likely to be introduced into the market in the foreseeablefuture, lists of products were compiled which are on the market or in clinical trials,conducted by tissue engineering companies. Although significant efforts were madeto compile as comprehensive lists as possible, it cannot be ruled out that some pro-ducts and clinical trials have been missed. As the methodological approach focussedon tissue engineering companies and the clinical trials conducted by these compa-nies, especially clinical trials may be underrepresented which are conducted by re-search institutions, but not companies.In many cases, it was difficult to draw the line whether a given product is "on themarket" or in clinical trials, because under certain regulatory regimes, both can bepossible simultaneously. Moreover, the list of products in clinical trials must not beinterpreted as "complete R&D pipeline" of products which are likely to be introdu-ced into the market in the foreseeable future. This would only hold true if an appro-val procedure which is based on the results of clinical trials would be required formarket access (as it is the case for pharmaceuticals and biologics). Tissue enginee-ring products are, however, subject to different regulatory regimes. Therefore itdepends on the product and on which regulatory regime is assigned to this productby the relevant national authorities, whether clinical trials are a prerequisite formarket approval or not.In order to draw a picture as complete as possible, not only tissue engineered pro-ducts were included in the following tables which fully comply with the definitionof tissue engineering chosen for this study6. In addition, products were also inclu-ded which are beyond the scope of the chosen definition, but can be understood astissue engineering products if broader definitions are applied. Products which fullycomply with the tissue engineering definition of this study are marked with "1" inthe column "Relevance" in the following tables. Products which are a combinationof either cells and scaffolds of cells and biomolecules or scaffolds and biomoleculesare marked with "2", and tissue engineering products for in-vitro use or productswhich are only scaffolds or biomolecules are marked with "3" in the column "Rele-vance".6 Tissue engineering is the regeneration of biological tissue through the use of cells, with the aidof supporting structures and/or biomolecules. The definition chosen for this study primarily re-lates to therapeutic applications of tissue engineering, not to in vitro applications. It excludesgene therapy and simple transplantations. It includes autologous and allogeneic human cells, tis-sues and organs, and also xenogeneic cells, tissues and organs, that have been substantially mo-dified by treatments. In addition, autologous chondrocyte transplants are included (also seechapter 2.1)
9111.1 Skin productsTable 11.1: Skin products of European companiesManufac-turer(productname)Coun-tryStatus Indications Cells BiomaterialsRele-vanceBioTissueTechnolo-gies (Bio-Seed-M)Ger-manyon themarket(2001)defects of theoral mucosaautologousoral mucosalcellsgel-like biomatrix 1BioTissueTechnolo-gies (Bio-Seed-S)Ger-manyon themarketchronic skin ul-cera (surfacewounds)autologouskeratinocytesgel-like bioadhe-sive1BioTissueTechnolo-gies(Melano-Seed)Ger-manyon themarketvitiligo autologousmelanocytesgel-like biomatrix 1Fidia Ad-vancedBiopoly-mers (Hya-lograft™3D)Italy on themarketnon healing ul-cers, burnsautologousfibroblastshyaluronic acidester biopolymerscaffold1Fidia Ad-vancedBiopoly-mers (La-serskin™)Italy on themarketskin wounds,ulcersautologouskeratinocyteshyaluronic acidester biopolymerscaffold with or-derly arrays oflaser-drilled mi-croperforations1Fidia Ad-vancedBiopoly-mers (TIS-SUEtechautograftsystemTM)Italy on themarketburns, chroniculcers, loss ofskin tissueautologousfibroblastsand keratino-cyteshyaluronic acidester biopolymerscaffold1IsoTis, AB(cellActiveSkin)NL produc-tionstoppedin late2002ulcer autologousfibroblastsand keratino-cytesbiodegradablePEG based poly-mer (polyactive)1Smith andNephew(Derma-graft)UK on themarket(2002)diabetic and ve-nous stasis ulcersallogeneicfibroblastsPLGA degradablepolymer1
92Smith andNephew(Trans-cyte)UK on themarketburns fibroblasts skin matrix com-bined with nylonlayer1XCELLen-tis (Auto-Derm)Bel-giumon themarketskin wounds,ulcersautologouskeratinocytesepithelial sheets 1XCELLen-tis (Cryo-Ceal)Bel-giumon themarketskin wounds,ulcersallogeneickeratinocytes,cryopreservedepithelial sheets 1IsoTis SA(formerlyModexTherapeu-tics (Epi-dex))NL/Switzerlandon themarket(1999),with-drawnDecem-ber 2002alternative tosplit thicknessskin graftautologouskeratinocytesnone 2Autoderm(Epidex,inlicensedproduct ofIsoTis SA)Ger-manyintendedmarketintroduc-tionspring2003alternative tosplit thicknessskin graftautologouskeratinocytesnone 2InnocollGmbH(Col-latamp)Ger-manyon themarketwound healing collagen matrixcovered with spe-cific bioactivecompounds2KarocellTissueEngineer-ingSweden on themarketautologousskin cells,melanocytes2Labora-toireGenevrier(Epibase)France on themarket(2002)wound healing autologouskeratinocytesnone 2MeGa TecGmbHGer-manyon themarketburns, scars autologousskin cells2Biopredic France on themarketin vitro testingfor toxicity andpharmacologyhuman kerati-nocytes, hu-man fibro-blasts3Skin EthicLaborato-riesFrance on themarketin vitro testingfor toxicity andpharmacologyhuman cellcultures3"relevance" specifies the extent of compliance with the definition of tissue engineering applied inthis study.1 = tissue engineering product (core definition)2 = tissue engineering product (broader definition)3 = tissue engineering product for in-vitro use or with marginal relevance for tissue engineering
93Table 11.2: Skin products of US companiesManufac-turer(productname)Coun-tryStatus Indications Cells BiomaterialsRele-vanceNovar-tis/Organogenesis(Apligraf)USA on themarketdiabetic and ve-nous stasis ulcersallogeneic fi-broblasts andkeratinocytesbovine collagen 1Ortec(OrCell)USA on themarket(2001)diabetic and ve-nous stasis ulcersallogeneic ke-ratinocytes andfibroblastsbovine collagen 1Smith andNephew(Derma-graft)USA on themarket(2002)diabetic and ve-nous stasis ulcersallogeneic fi-broblastsPLGA degrad-able polymer1Smith andNephew(Trans-cyte)USA on themarketburns fibroblasts skin matrix com-bined with nylonlayer1Convatec(Vi-voderm)USA on themarketskin ulcer, burns autologous skincells2GenzymeBiosur-gery(Epicel)USA on themarketburns autologous skincells2LifeCell(Repli-form)USA on themarket(1999)urological plasticsurgeryacellular tissuederived fromallogeneic skincells2LifeCellCorpora-tionUSA on themarketwound dressing human skin proc-essed to removeepidermal anddermal cellswhile preservingthe remainingbiological dermalmatrix2FibrogenIncUSA on themarketwound manage-mentnone; guidedtissue regenera-tioncollagen withgrowth factors2Organo-genesis(Forta-Flex)USA on themarket(2001)wound closure none; guidedtissue regenera-tionbioengineeredcollagen3LifeCellCorpora-tion (Cy-metra)USA on themarketwound manage-mentprocessed humantissue that resultsin micronizedcollagens, elastin,3
94and proteogly-cansCookBiotech(Oasis™)USA on themarket(1999)wound manage-mentporcine smallintestinal submu-cosa acellularcollagen matrix3BrennenMedical(EZ-Derm™)USA on themarketpartial thicknessburns, skin ul-cers, abrasionsacellular porcinederived collagenmatrix3IntegraLife Sci-ences(Integra)USA on themarketburns collagen com-bined with siliconlayers3Apart from the products mentioned in table 11.1 and 11.2 there is a huge number ofsynthetic skin replacement products, that compete with the products from biologicalsources.Table 11.3: Clinical trials on skin products of European and US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceXCEL-Lentis(Lypho-Derm)Belgium phase II ulcers, burns lysate of al-logeneic kerati-nocytesepithelial sheets 1IsoTisSA (Al-lox)CH/NL phase II skin leg ulcers allogeneic skincellsallogeneicgrowth factors1IsoTisSA (Acu-Dress)CH/NL phase Iplannedburns; also plas-tic reconstruc-tive surgery, andother woundconditions in-tendedautologousepidermal sheetfibrinalso to be combi-ned with Ethi-cons (Johnson &Johnson) In-tegra® Template1Organo-genesis(Vitrix)USA phaseII/III(presentstatusunknownafterOrgano-genesisfiled forban-crupcy inlate 2002diabetic andvenous stasisulcersallogeneic fi-broblasts andkeratinocytesbovine collagen 1
95medicarb Sweden phase II wound healing polysaccharidefilms and appli-cations partlycoated with bio-active com-pounds2Colla-genesis(Derma-logen,Derma-plant,Urogen,Duraderm)USA phase III aesthetic surgery collagen matrixfrom cadaverskin311.2 Cartilage productsTable 11.4: Autologous chondrocyte transplantation products of EuropeancompaniesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceEducellZellkul-tivierungF&EGmbH(Chon-droArt™)Austria on themarketcartilage repair autologouschondrocytes1InterfaceBiotechA/S(CartilinkTM-2)Denmark on themarketcartilage repair autologouschondrocytescollagen mem-brane1BioTis-sue Tech-nologies(Bio-Seed-C)Germany on themarket(2001)cartilagereplacementautologouschondrocytesgel-like bioma-trix1CellTecGmbH(Chon-droTec)Germany on themarket(1997)chrondrocytetransplantationautologouschondrocytes1co.don Germany on the articular carti- autologous 1
96(Chon-drotrans-plant)market lage repair chondrocytesTETECAG(Novo-cart)Germany on themarketchrondrocytetransplantationautologouschondrocytes1VerigenTrans-plantationServiceInterna-tional AG(CACI,MACI,MACI-A)Germany on themarket(1999)chrondrocytetransplantation,cartilage repairautologouschondrocytesCollagen mem-brane1Ar-sArthro(Ca-ReS®)Germany on themarket(2002)chrondrocytetransplantation,cartilage repairautologouschondrocytescollagen matrix 1Ormed(ARTROcell®)Germany on themarketchrondrocytetransplantation,cartilage repairautologouschondrocytescollagen matrix(Chondro-Gide®)1OrthogenAG (Ar-throma-trix®)Germany on themarketchrondrocytetransplantation,cartilage repairautologouschondrocytes1FidiaAd-vancedBiomate-rials(Hyalo-graft C®)Italy on themarketCartilage repair autologouschondrocytesbiocompatibletridimensionalmatrix composedof a derivative ofhyaluronic acidester1IsoTisNV (Cel-lActiveCart)NL on themarket(2001),produc-tion andmarket-ingstoppedin 2002cartilage repair(knee defects)autologouschondrocytespolyactive bio-degradable PEGbased polymer1KarocellTissueEngineer-ingSweden on themarketautologouschondrocytes1Vitrolife Sweden on themarketcell regenera-tioncryopreservedchondrocyteshyaluronic acidbased supportstructures1
97Table 11.5: Autologous chondrocyte transplantation products of US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceGenzymeBiosur-gery(Carticel)USA on themarketcartilage repairin the kneeautologouschondrocytes1Table 11.6: Clinical trials on cartilage products of European and US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceTIGenixNV(ChondroCelect®)Belgium phase II cartilage repair autologouschondrocytesnone 1Ar-sArthro(Ca-ReS®)Germany phase II 3 D cartilagerepair, focaldefects of thearticular carti-lage of theknee jointautologouschondrocytescollagen matrix 1BiometMerckGermany phase II 3 D cartilagerepairautologouschondrocytespolymer scaffold 1co.don(Chondrosphere)Germany phase III 3D cartilagerepair, arthritistherapyautologouschondrocytesspheroid tech-nology1Curis(Chon-drogel)USA phase III cartilage repair autologouschondrocyteshydrogel poly-mer1
9811.3 Bone productsTable 11.7: Bone products of European companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceBioTissueTech-nologies(BioSee-dOralBone)Germany on themarket(2001)jawbone sur-geryautologousjawbone graftgel-like bioma-trix1co.don(osteotransplant)Germany on themarketbone repair autologousosteoblastsnone 1aap Im-plantateAG (Ca-vat)Germany on themarket(2002,intended)bone defects none autologous bonegrowth factorson a hydroxyapatit ceramicsupport2TutogenMedicalGmbH(Tuto-plast)Germany/ USAon themarketbone repair allogeneic bonematerial proc-essed to removecells2Biora AB Sweden on themarketwound healingafter periodon-tal surgeryenamel matrixproteins in pro-pylene glycolalginate2SulzerMedica(PurosAllograft)Switzer-landon themarketspinal surgery allogeneic bonematerial2IsoTis SA(SynPlug)Switzer-land/TheNether-landson themarket(2001)hip replace-mentcement restric-torcement restrictor 3IsoTis SA(Os-Satura)Switzer-land/TheNether-landson themarket(2003)bone substitute osteoconductiveand osteoinduc-tive porous cal-cium phosphatescaffold3
99Table 11.8: Bone products of US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceOsteo-tech, Ea-tontown(Graftech)USA on themarketbone repair allogenic bone 2Osteotech(Grafton)USA on themarketbone repair allogeneic de-mineralised bonematerial2InterporeCrossInterna-tional(AGF)USA on themarketbone repair autologousgrowth factorsfrom patientsblood to be com-bined with bonegrafting material2Medtron-icSofamorDanek(INFUSE™)USA on themarketlumbar inter-body spinalfusioncollagen matrixfor use with bonegrowth factors2Regenera-tion Tech-nologies/distrib-uted byMSD(Osteofil)USA on themarket(2000)spinal fusion allogeneic bonematerial proc-essed to removecells2BectonDickinsonBiosci-ences (BDBio-Coat™)USA on themarketbone repair scaffolds for cellcultivation3InterporeCrossInterna-tional(Bone-Plast)USA on themarketbone repair extrudable bonevoid filler basedon calcium sul-fate3InterporeCrossInterna-tional(ProOs-teon)USA on themarketbone repair hydroxyapatitebone graftingmaterial har-vested frommarin coral exo-skeletons3
100Orquest(Hea-los®)USA on themarketbone repair bone graft substi-tute3Orthovita(CORTOSS®)USA on themarketspine surgeryand repair ofosteoporoticfracturessynthetic com-posite bone voidfiller3Orthovita(VITOSS®)USA on themarketspine surgeryand repair ofosteoporoticfracturesresorbable cal-cium phosphatebone void filler3StrykerCorp.(OP-1)USA on themarket(2001)long-bone frac-tures3Apart from the above mentioned materials which originate from human or animalbiological materials there is a huge number of synthetic bone substitutes on themarket. Most of them use hydroxyapatite, calcium phosphate, calcium sulfate, orpolymers such as poly(lactic acid), poly(glycolic acid) or the copolymer poly(lacticco-glycolic acid). An alternative source for bone fillers are marine coral exoscele-tons (ProOsteon).Table 11.9: Clinical trials on bone products of European and US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceNordicBiosci-ence A/SDenmark phaseunknownMonitoringbone turnover,osteoporosis,osteoarthritisskin and bonecellsCollagen 1Curasan Germany phaseunknownbone defects autologousosteoblastsgrowth factors(PRP, BMP) onCerasorb, a ce-ramic based ma-trix1IsoTis SA(VivescOs)TheNether-landsphase I/II(pro-grammecancelledin 2003)jawbone sur-gery, joint re-pair, spinalfusionautologousbone marrowcellsbiocompatibleand biodegrad-able poly (etherester) multiblockcopolymers(polyactive)1OsirisTherapeu-tics (Al-logen)USA phase II cancer therapy autologoushuman mesen-chymal stemcells (hMSCs)from humanbone marrowhydroxyapatitematrix1Osiris USA phase I jawbone sur- autologous hydroxyapatite 1
101Therapeu-tics (Os-teocel)gery human mesen-chymal stemcells (hMSCs)from humanbone marrowmatrixAastromBiosci-enceUSA phase I/II osteoporosis bone progenitorcells2Orquest(HealosMP52)USA phaseunknownbone repair bone graft substi-tute with boneinducing proteinMP522Orquest(Ossigel)USA phase III bone repair hyaluronic acidand fibroblastgrowth factors2StrykerCorp.(OP-1)USA phaseunknownspinal applica-tions of OP-13Wyeth(rhBMP-2)USA phase III lumbar poster-olateral spinalfusion311.4 Cardiovascular productsTable 11.10: Cardiovascular products of European and US companiesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceCryoLifeEurope(Cryo-Life-O-Brien®,CryoLife-Ross®)UK on themarketheart valves,vascular graftsporcine heartvalve processedto build neutralscaffolds2EdwardsLife-sciencesUSA on themarket(1998)heart valves various porcineand bovineheart valves(stented andstentless)2Cardiovascular products are dominated by mechanical solutions made from carbonor different metals as they are found to show higher stability.
102Table 11.11: Clinical trials on cardiovascular products of European and UScompaniesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceco.don(vas-cuplant)Germany phase I cardiovascularendoprothesisendothel cells vessel graft 1VascularBiotechGmbH(aorto-coronarybypassgraft)Germany phaseunknowngraft for by-pass surgeryrecipient-ownendothelialcellsallogeneiccryopreserveddonor veins1ArkThera-peuticsOy (Tri-nam™)Finland phaseII/IIIhaemodialysisgraft accesssurgery- biodegradablelocal drug deli-very device(termedEG001)vascular endo-thelial growthfactor, delive-red as gene byan adenoviralvector2OsirisThera-peutics(Cardio-cel)USA phase I heart surgery autologoushuman mesen-chymal stemcells (hMSCs)from humanbone marrow2Diacrin USA phase I cardiac disease human musclecells2GenzymeBiosur-geryUSA phase II left ventriculardysfunction/heart attackautologousskeletal musclecells2BioHeart(MyoCellTM)USA phase I/II post-infarctdeterioration ofcardiac func-tionautologousmyoblasts2
10311.5 Tissue engineered organsNo tissue engineered organs could be identified which are currently on the Euro-pean or US market.Table 11.12: Clinical trials on tissue engineered organs of European and UScompaniesManu-facturer(productname)Country Status Indications Cells BiomaterialsRele-vanceAmcyte(Be-taRx™)USA phase I Diabetes encapsulatedhuman insulin-producing cellsalginate 1Diatranz(DiaB-cell®)NZ phase I Diabetes encapsulatedporcine insulin-producing cellsalginate 1Diatranz(DiaVcell®)NZ phase I Diabetes porcine insulin-producing andSertoli cellsstainless-steelmesh tube1Novocell(formerlyNeocrin)USA phase Iplannedfor 2003Diabetes encapsulatedhuman pancre-atic celsPolyethylenglycol1HybridOrgan(MELS)Germany phase I/II fulminant he-patic failurehuman hepato-cytesHollow FiberMembraneBioreactor1Circe-Biomedi-cal(HepatAssist)USA phaseII/III(failed)fulminant he-patic failurecryopreservedporcine hepato-cytesHollow FiberMembraneBioreactor1Vitagen(ELAD)USA phase I/II fulminant he-patic failureimmortalizedhuman hepato-cytesHollow FiberMembraneBioreactor1Algenix(LIVERX 2000)USA phase Iplannedfulminant he-patic failureprimary porcinehepatocytesHollow FiberMembraneBioreactor2Diacrin(Hepato-Cell™)USA phase I;presentstatusunknownacute liverfailureporcine hepato-cytes2ExcorpMedical(BLSS)USA phase I/II fulminant he-patic failureprimary porcinehepatocytesHollow FiberMembraneBioreactor2
10411.6 CNS productsAt present, there are no approved cell therapies for CNS disorders available. Severalclinical trials have been carried out, are underway or planned. However, most of thecell-therapy-related R&D of CNS disorders is still in the preclinical stage.Table 11.13: Tissue engineered CNS products of US companiesManufac-turer(productname)Country Status Indications Cells BiomaterialsRele-vanceIntegra(NeuraGen)USA on themarketspinal cordinjuryabsorbablecollagen tube asa nerve guide3Integra(DuraGen)USA on themarketonlay graft fordural defectscollagen matrixfor dural clo-sure3Table 11.14: Clinical trials on tissue engineered CNS products of US companiesManufac-turer(productname)Country Status Indications Cells BiomaterialsRele-vanceDiacrin USA phase I spinal cordinjuryporcine spinalcord cells,treated withantibodies toreduce immu-nogenicity2Diacrin USA phase I(sus-pended)stroke porcine neuralcells3Diacrin USA phase I intractablepainporcine neuralcells3Diacrin USA phase I focal epilepsy porcine neuralcells3Diacrin(Neuro-Cell-PD)USA phase II(sus-pended)Parkinsonsdiseaseporcine fetalneural cells3
10511.7 Miscellaneous productsTable 11.15: Miscellanous products on the market and in clinical trialsManufac-turer(productname)Country StatusIndica-tionsCellsBiomate-rialsRelevanceco.don(Chondro-TransplantDisc)Germany phase III acute, her-niated in-tervertebraldisksautologouschondro-cytes1ArticularEngi-neering(ARC)USA phase un-knownarticularcartilageand in-tervertebraldisc disor-dersautologouschondro-cytesalginate 1InnovaCell Austria Phase I-II urinaryinconti-nenceautologousskeletalmusclecellsno infor-mationavailable1Artimplant(Artelon)Sweden phase III ligamentaugmenta-tion in theknee andthumbbiodegrad-able poly-uretha-nurea3ImedexBiomateri-aux (Flore-ane)France on themarketsurgery none;guided softtissue re-generationcollagen asfilm, seal-ant andfoam3Genopoi-eticFrance on themarketimmun-stimulationfor mela-nomatreatmentcartilagerepairtransgeneic(estrogenproducing)autologouscells3Q-Med Sweden on themarketUro-Gynecol-ogy, ortho-pedics,estetics,cell therapyand encap-sulationnone;guided softtissue re-generationstructuresfrom hya-luronicacids3Integra USA on the regenera- none; type I col- 3
106(BioMend) market(1999)tion proce-dures inperiodontaldefectsguided softtissue re-generationlagenmembraneprocessedfrom bo-vine achil-les tendonBectonDickinsonBioScience(BD™3DCollagenCompositeandOPLA®Scaffolds)USA on themarketbiologicalscaffoldsfor cellcultivation3Integra(Col-laTape)USA on themarketdental sur-gery prod-uctsabsorbablecollagenmatrix3
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