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Tissue engineering9

  1. 1. 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
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. vList of tablesPage
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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.
  11. 11. 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.
  12. 12. 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.
  13. 13. 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,
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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:
  18. 18. 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.
  19. 19. 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.
  20. 20. 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.
  21. 21. 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
  22. 22. 13Urinary system including kidney 740,000Maintenance dialysis 188,000 1,030,000 67,000Skin 2,509,000Hernia 988,000Organ transplants 48,000 275,000 13,000Total 11,288,000 376,000 4,919,000 24,705,000 305,000
  23. 23. 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)
  24. 24. 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).
  25. 25. 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-
  26. 26. 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.
  27. 27. 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)
  28. 28. 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-
  29. 29. 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.
  30. 30. 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.
  31. 31. 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).
  32. 32. 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 4.3.4.3 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-
  33. 33. 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.
  34. 34. 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-
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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.
  40. 40. 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
  41. 41. 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.
  42. 42. 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
  43. 43. 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.
  44. 44. 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.
  45. 45. 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.
  46. 46. 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-
  47. 47. 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
  48. 48. 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.
  49. 49. 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).

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