Biomaterials in the sustainability of regenerative medicine

Biomaterials in Sustainability of
Regenerative Medicine
Michael N. Helmus, Ph.D., Consultant
Medical Devices, Biomaterials, Drug Delivery, and Nanotechnology
mnhelmus@msn.com

Biomaterials in Sustainability of Tissue Engineering
Biomaterials for Regenerative Medicine Scaffolds
Biomaterials
- Categories
- Biocompatibility
- Regenerative Medicine applications
Identification of Drivers for New Technology
- Leverage Potential Emergent/Disruptive Technology
Enhanced biocompatibility for Regenerative Medicine
is a Disruptive Medical Technology

HYBRID ARTIFICIAL ORGANS
Galletti P. M. Chairman; Hori, M.; Sharp, D.
W.; Stanley, J. C.ASAIO Journal: April
1982 - Volume 28 - Issue 1 - ppg 639-646

– FDA Web Page - Center For Devices: MDR’s, Press Releases
http://www.fda.gov/MedicalDevices/default.htm
– 510K Home page
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClear
ances/510kClearances/default.htm
– International Standards Organization (ISO):
http://www.iso.org/iso/iso_catalogue/catalogue_ics/catalogue_ics_browse.htm?ICS1=11Standa
rds
– FDA recognized consensus standards are listed at
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm
•Medical devices
– AdvaMed http://www.advamed.org/MemberPortal/
– Email updates: http://www.smartbrief.com/news/ADVAMED/index.jsp?categoryid=7B651A9C-
543B-43A9-909D-CC5F80F69335
– Medical Device and Diagnostic Industry: http://www.mddionline.com/
•Web sources for Biomaterials, Guidelines and Standards

•Materials information
– Society for Biomaterials: http://www.biomaterials.org/
– Biomaterials.net: http://www.biomat.net/
– ASM International (subscription required):
http://products.asminternational.org/meddev/index.aspx
– MatWeb (General materials with search term medical grade):
http://www.matweb.com/index.aspx
– History of Biomaterials http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-
4965/homepage/VirtualIssuesPage.html
– Advances in Biomaterials http://www.intechopen.com/books/advances-in-biomaterials-science-and-
biomedical-applications
•Clinical information
– General: http://www.medscape.com
– NIH Reporter http://projectreporter.nih.gov/reporter.cfm

mnhelmus@msn.com
STRUCTURAL MATERIALS
SURFACE MATERIALS:
BIOLOGIC INTERACTIONS AND LUBRICITY
CONTROLLED DRUG
DELIVERY MATERIALS
METALS ENGINEERING
PLASTICS
PLASTICS
ELASTOMERS
CERAMICS
BIOACTIVE
CERAMICS
BIOACTIVE
COATINGS
BIOLOGICS
BIODERIVED
MACROMOLECULES
HYDROPHILIC
COATINGS
HIGH STRENGTH
MODERATE
STRENGTH
HIGH
PERMEABILITY
SURFACE
COATINGS
SPECTRUM OF MATERIALS AND PROPERTIES
Bioactivity
COMPOSITES
AEROSPACE
DEFENSE
ORTHOPEDIC
DENTAL
RESEARCH PHARMACEUTICAL AND BIOTECH
Plastics
& Textiles
Industry

mnhelmus@msn.com
STRUCTURAL MATERIALS
SURFACE MATERIALS:
BIOLOGIC INTERACTIONS AND LUBRICITY
CONTROLLED DRUG
DELIVERY MATERIALS
METALS ENGINEERING
PLASTICS
PLASTICS
ELASTOMERS
CERAMICS
BIOACTIVE
CERAMICS
BIOACTIVE
COATINGS
BIOLOGICS
BIODERIVED
MACROMOLECULES
HYDROPHILIC
COATINGS
HIGH STRENGTH
MODERATE
STRENGTH
HIGH
PERMEABILITY
SURFACE
COATINGS
SPECTRUM OF MATERIALS AND PROPERTIES
Bioactivity
COMPOSITES
AEROSPACE
DEFENSE
ORTHOPEDIC
DENTAL
RESEARCH PHARMACEUTICAL AND BIOTECH
Plastics
& Textiles
IndustryMEMS
Nano technology
Self Assembled Molecules
Biomimetics
Tissue Engineering/Regenerative Medicine
3D Printing

mnhelmus@msn.com
Materials Selection Guide
Identify:
• Predicate Devices
• Corporate/Institutional Predicate Devices, Testing, and
Regulatory Approvals (510(k)s, PMA’s, and NDA’s)
• Corporate/Institutional Guidelines, Procedures and Protocols
• FDA Guidelines, CEN Guidelines, and
Standards (ASTM, ANSI, ISO)
• Corporate/Institutional R&D Reports
• Materials, Uses, Properties, ASTM and ISO Standards
Develop an Approach for Selection and Testing

Materials used in medical devices, particularly in those
applications in which the device either contacts or is
temporarily inserted or permanently implanted in the body,
are typically described as biomaterials and have unique
design requirements. The National Institute of Health
Consensus Development Conference of November 1982
defined a biomaterial as “any substance (other than a
drug) or combination of substances, synthetic or natural in
origin, which can be used for any period of time, as a
whole or as a part of a system which treats, augments, or
replaces any tissue, organ, or function of the body”
http://tpx.sagepub.com/content/36/1/70.full.pdf
Biomaterials

mnhelmus@msn.com
• Scaffolding for tissue regeneration and replacement
• hybrid artificial organs and bioegineered tissues. Acceptable scaffolding
materials
• Biocompatible
• allow cellular interactions that result in tissue that mimics
• naturally occurring material
• biochemical
• biomechanical
Scaffolds are Biomaterials for
Regenerative Medicine Applications

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• Tissue Engineered devices have a design requirement that meet the physical
properties of the device/replaced organ
•Acute
•Chronic
•Non-degradable
•Biodegradable

mnhelmus@msn.com
•Remodeled biologic
•Homograft, allograft, xenograft
•Calicification mitigation
•Decellularization
•Growth factors
•Bioactive agents
•incorproated into the substrates to encourage the proper
cell
•Reconstituted macromolecules
•Recellularization
•bioreactor
•in situ

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SELECTED HISTORY
• Noshiki 1996 presaged this work when he used bone marrow cells to recellularize
traditional polyester prostheses.
•Work by Van Kampen 1979 at Case showed that mononuclear cells formed islands of
endothelium on the coagulum of vascular implants, also seen in work of M. Helmus
• Cell adhesion proteins like fibronectin and RGD peptides help in capturing circulating
endothelial precursor cells.

mnhelmus@msn.com
• Immobilized Fibronectin and Type IV Collagen on ePTFE and porous
polyurethane by BioMetrics Systems( now Surmodics ) demonstrated enhanced
endothelialization (Clapper).
• RGD peptides (Peptite 2000 from Telios Pharmaceuticals) on PET and PTFE
fabric in canine carotid and femoral patches demonstrated enhanced
reendothelialization
• Orbus has developed an immobilized antibody to capture circulating endothelial
progenitor cells (EPCs) in order to enhance this process.
• BioSet has growth factor mimetics which may have a role in enhancing
recellularization.

mnhelmus@msn.com
(Van Kampen 1979)

mnhelmus@msn.com
Reendothelialized Fibrin Coated
ePTFE Vascular Graft
Tricuspid SIS
Heart Valve
Mesenchymal
Mesh for Hernia
Repair
Biomaterial Scaffolds for Medtech
Tissue Engineered Bone
Segments
Porous tantalum
Mesenchymal Stem Cell
Spinal Fusion
Control of Wound
Healing RGD Peptides
Scaffolds for
Tissue engineering
Bioactive and
Bioresorbable Fabrics
Type 3
collagen
acellular
vascular graft
Acelllular Uterine Sling -human dermis

mnhelmus@msn.com
Implantation of tissue
engineered construct.
Tissue Engineered Devices
Biopsy/tissue sample for autologous cell
&/or isolation of stem cells.
Culturing of cells to expand if needed.
Scaffolds: Decellularized tissue,
Polymer, Biodegradables,
Bioderived, eg collagen
Seeded scaffolds for
direct implantation or
growth of tissue in
bioreactor
Healed device

mnhelmus@msn.com
Small Molecules
Proteins/Growth Factors
Gene Transfection
Remodeled Organ
In Situ Healing
Injectables to recruit
bmc’s/tissue stem
cells to Regenerate in
situ.

•Materials for FDA-approved implantable devices
•ASM International/Granta
•M. N. Helmus, Ph.D.
•Chair Medical Materials Database Committee
•http://mio.asminternational.org/mmd/
New Tools for
Medical Device Design

Materials for Medical Devices
Biological Materials
Bioprosthetic, Autologous, Allografts, Xenografts, ECM, Polysaccharides
Carbonaceous Materials
Pyrolytic, Graphitic, Graphene, Nanotube
Ceramics
Metals and Alloys
Cobalt Base, Nitinol, Precious, Refractory Metals, Stainless Steels,
Titanium Base
Polymers/Plastics and Textiles
Elastomers, Thermoplastics, Hydrogels, Engineering

mnhelmus@msn.com

The Research Portfolio Online Reporting
site is a tool to search the NIH database of
projects http://projectreporter.nih.gov
This unique tool allows searching by fiscal
year, NIH Center and Spending Category.
A copy of the full search page is shown
below.
NIH Reporter
Search NIH research projects

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3-D Printing: Unique fabrication method for biomaterials and devices
Polymers, macromolecules, metals, ceramics, cells
Scaffolds
Textured and Porous surfaces
Cellular tissue engineered structures
16 APRIL 2015 | VOL 520 | NATURE | 273

mnhelmus@msn.com
16 APRIL 2015 | VOL 520 | NATURE | 273

mnhelmus@msn.com
At the Inside 3D Printing conference this week in New York, researchers from
academia and industry are gathering to discuss the growing interest in using three-
dimensional (3D) printing to make replacement body parts. Although surgeons are
already using 3D-printed metal and plastic implants to replace bones, researchers
are looking ahead to printing organs using cells as 'ink'. The structures shown here
were all 3D printed at Wake Forest Baptist Medical Center in Winston-Salem, North
Carolina, and include a rudimentary proto-kidney (top left), complete with living
cells
16 APRIL 2015 | VOL 520 | NATURE | 273

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Artificial Organs May Finally Get a Blood Supply
Artificial tissue has always lacked a key ingredient: blood
vessels. A new 3-D printing technique seems poised to
change that.
•By Susan Young Rojahn on March 6, 2014
Why It Matters
Thousands of people die each year waiting for donor organs.
http://www.technologyreview.com/news/525161/artificial-organs-may-finally-get-a-
blood-supply/

mnhelmus@msn.com
Living layers: Harvard researchers demonstrate their method for creating vascularized
tissue constructs by printing cell-laden inks in a layered zig-zag pattern. In what may be
a critical breakthrough for creating artificial organs, Harvard researchers say they have
created tissue interlaced with blood vessels.
Using a custom-built four-head 3-D printer and a “disappearing” ink, materials scientist
Jennifer Lewis and her team created a patch of tissue containing skin cells and
biological structural material interwoven with blood-vessel-like structures. Reported by
the team in Advanced Materials, the tissue is the first made through 3-D printing to
include potentially functional blood vessels embedded among multiple, patterned cell
types.

mnhelmus@msn.com
BIOMATERIALS
Material Applications
Synthetic Plastics, Engineering Plastics and Textiles
Acrylics Housing materials for extracorporeal
devices, such as blood pumps and
oxygenators
Ethylene vinyl acetate Wound dressings, drug delivery
Epoxies Potting compound, fiber composites
Fluorocarbons Vascular grafts, catheters, catheter
components
Hydrogels Coatings, drug delivery, contact lenses,
sealants, embolics
Polyacetal Heart valve components, catheter and
structural components
Poly(amides)
Catheters and components, wound dressings,
angioplasty balloons
Poly(amide) elastomers Catheters, wound dressings, angioplasty
balloons
Poly(carbonates)
Housing materials for extracorporeal
devices
Poly(esters)
Angioplasty balloons, films and structural
components
Poly(ester) fibers Textile vascular grafts, fabrics
Poly(ester) elastomers Catheters, angioplasty balloons
Poly(etherketones)
Structural components, fiber composites,
orthopedic devices
Poly(imides)
devices
Poly(methylpentene)
devices
Poly(olefins) Sutures, angioplasty balloons, catheters

mnhelmus@msn.com
Expanded
Polypropylene
Membrane
Hemodialysis Membranes, Controlled
Drug delivery
Poly(olefin)
elastomers
Tubing, artificial heart bladder,
catheters, spinal discs
High crystallinity
poly(olefin) films Angioplasty balloons
Poly(sulfones) Structural components, orthopedic
devices, fiber composites
Poly(urethanes) Catheters, artificial heart, wound
dressings
Poly(vinyl
chloride)
Tubing, blood
Polyvinylidene
fluoride Tubing, piezoelectric material
Silicones Heart valve poppets, wound
dressings, finger joints,
reconstructive surgery
Ultra-high
molecular weight
polyethylene
Acetabular cup, high strength
textiles

mnhelmus@msn.com
Membranes to control diffusion - oxygenators, batteries
Bioreactor components, Cell culture Scaffold
Celgard 20- 80 nm pores, from the mid 1960’s

mnhelmus@msn.com
Medtech Strategist Nov. 2014

mnhelmus@msn.com
UPDATED: J&J goes all in with ViaCyte,
hands over BetaLogics assets in hunt for
diabetes cure Feb 4,
2016

mnhelmus@msn.com
Biocompatibility Issues of Biomaterials
Synthetic Plastics, Engineering Plastics, Textiles, and
Hydrogels
 Extractables
 Hypersensitivity reactions (e.g. latex materials)
 2 part systems and cytotoxic residuals
 Lipid uptake
 Hydrolytic stability
 Biostability
 Biodegradation by-products
 Calcification
 Sterilization residuals
 Fatigue and wear particulates
 Protein adsorption: hydrophilic, hydrogel and hydrophobic

mnhelmus@msn.com
Hydrogels
Hydrocolloids
Hydroxyethyl-methacrylate
Ionic Acrylics – eg Acrylic
acid based polymers
Poly(acrylamide)
Poly(ethylene oxide)
Polysaccharides –
eg Chitosans
Hyaluronic acid
Poly(vinlyalcohol)
Poly(vinyl-pyrrolidone)
Protein based – eg Gelatin,
Albumin
 Extractables
 Hypersensitivity reactions
 Lipid uptake
 Biostability
 Calcification
 Blood Element Consumption
 Low protein adsorption
 Poor tissue adherence

mnhelmus@msn.com
Bioresorbables
Poly(amino acids)
Controlled release, cell adhesion
peptides, scaffolds for tissue engineering
Poly(anhydrides) Wound dressings, scaffolds
Poly(caprolactones) Controlled release, sutures, scaffolds
Poly(lactic/glycolic
acid) copolymers
Sutures, bone plates, controlled release,
scaffolds
Poly(lactide-
caprolactone)
Sutures, controlled release, bone plates,
scaffolds
Poly(lactic acid co
lysine)
Anti-adhesion spray for wounds, controlled
release
Poly(hydroxybutyrates
)
Scaffolds for recellularization
Poly(orthoesters) Controlled release, bone plates, scaffolds
Poly(ester)
elastomers
Controlled release, bone plates
Poly(dioxanone)
Wound dressings, tympanic implants,
sutures
Poly(dimethyl
trimethylene
carbonate co-
tirmethylene
carbonate)
Sutures
Poly(phosphazenes) Controlled release
Collagen Controlled release, scaffolds, sutures
Low-density
hydroxyapatite
Coatings, soft tissue reconstruction,
scaffold for recellularization bone
implants, reconstructive surgery

mnhelmus@msn.com
Biodegradables
 Rate of biodegradation
 Surface vs. bulk
 Particulates
 Biodeposition
 Tissue partitioning and excretion
 Effect of infection (acidic pH) or hematoma (basic pH) on
degradation rates

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Tissue Engineering of Vascular Prosthetic Grafts by P. P. Zilla, Howard P. Greisler (Eds)

mnhelmus@msn.com
Biologically Derived Materials
Bovine arteries
and veins
Vascular grafts
Bovine pericardium Pericardial substitute, heart valves
Human umbilical
vein
Vascular grafts
Human dura-mater Dura-mater replacement,
reconstructive surgery
Porcine heart
valve
Heart valves
Bovine ligaments Ligaments
Bovine tendons Tendons
Decellularized
tissues: SIS,
Bladder
Scaffolds for recellularization in
vitro or in situ
Decalcified bovine
bone
Bone implants
Cross-linked
bovine bone
Bone implants

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BBiioollooggiiccaallllyy DDeerriivveedd MMaatteerriiaallss:: AArrtteerriieess,, vvaallvveess,, sskkiinn,,
dduurraa--mmaatteerr,, bboonnee,, lliiggaammeennttss
 Decellularization processes
 Viability of cells in fresh or Cryopreserved Allografts
 Cytotoxic preservatives
 Cross-linking
 Sterilizability and residuals
 Biodegradation
 Calcification
 Immune responses
 Biomechanical properties
 Infectious contamination- bacterial, viral, fungal, and
prion

mnhelmus@msn.com
Recently Approved Scaffold
Biocompatibility testing of the ACI-Maix porcine
membrane showed that the collagen membrane was not
toxic or incompatible with biological tissue. In addition,
the expansion process for chondrocytes did not induce
changes to the cellular karyotype.
MACI (autologous cultured chondrocytes on porcine
collagen membrane) is an autologous cellularized
scaffold product indicated for the repair of single or
multiple symptomatic, full-thickness cartilage defects of
the knee with or without bone involvement in adults.

mnhelmus@msn.com
Malone, J, et al, 1984

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Nature Medicine Published online: 13 January 2008
Perfusion-decellularized matrix: using nature's platform to engineer a
bioartificial heart
Harald C Ott1, Thomas S Matthiesen2, Saik-Kia Goh2, Lauren D Black3,
Stefan M Kren2, Theoden I Netoff3 & Doris A Taylor2,4
About 3,000 individuals in the United States are awaiting a donor heart;
worldwide, 22 million individuals are living with heart failure. A bioartificial
heart is a theoretical alternative to transplantation or mechanical left
ventricular support. Generating a bioartificial heart requires engineering of
cardiac architecture, appropriate cellular constituents and pump function. We
decellularized hearts by coronary perfusion with detergents, preserved the
underlying extracellular matrix, and produced an acellular, perfusable
vascular architecture, competent acellular valves and intact chamber
geometry. To mimic cardiac cell composition, we reseeded these constructs
with cardiac or endothelial cells. To establish function, we maintained eight
constructs for up to 28 d by coronary perfusion in a bioreactor that simulated
cardiac physiology. By day 4, we observed macroscopic contractions. By day
8, under physiological load and electrical stimulation, constructs could
generate pump function (equivalent to about 2% of adult or 25% of 16-week
fetal heart function) in a modified working heart preparation.

mnhelmus@msn.com
Nature Medicine Published online: 13 January 2008
Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart
Harald C Ott1, Thomas S Matthiesen2, Saik-Kia Goh2, Lauren D Black3, Stefan M
Kren2, Theoden I Netoff3 & Doris A Taylor2,4
About 3,000 individuals in the United States are awaiting a donor heart; worldwide, 22
million individuals are living with heart failure. A bioartificial heart is a theoretical
alternative to transplantation or mechanical left ventricular support. Generating a
bioartificial heart requires engineering of cardiac architecture, appropriate cellular
constituents and pump function. We decellularized hearts by coronary perfusion with
detergents, preserved the underlying extracellular matrix, and produced an acellular,
perfusable vascular architecture, competent acellular valves and intact chamber
geometry. To mimic cardiac cell composition, we reseeded these constructs with
cardiac or endothelial cells. To establish function, we maintained eight constructs for
up to 28 d by coronary perfusion in a bioreactor that simulated cardiac physiology. By
day 4, we observed macroscopic contractions. By day 8, under physiological load and
electrical stimulation, constructs could generate pump function (equivalent to about
2% of adult or 25% of 16-week fetal heart function) in a modified working heart
preparation.

Clinical transplantation of a tissue-engineered airway
Paolo Macchiarini MD et al
The Lancet, Early Online Publication, 19 November 2008
Bioengineered tubular tracheal matrices, using a tissue-engineering protocol,
and to assess the application of this technology in a patient with end-stage
airway disease.
Removed cells and MHC antigens from a human donor trachea, which was
then readily colonised by epithelial cells and mesenchymal stem-cell-derived
chondrocytes that had been cultured from cells taken from the recipient (a
30-year old woman with end-stage bronchomalacia). This graft was then
used to replace the recipient's left main bronchus.
The graft immediately provided the recipient with a functional airway,
improved her quality of life, and had a normal appearance and mechanical
properties at 4 months. The patient had no anti-donor antibodies and was not
on immunosuppressive drugs.

Wall Street Journal JUNE 25, 2010
Scientists Build a Rat Lung

14 April 2013 Last updated at 19:29 ET Scientists make 'laboratory-
grown' kidney
By James Gallagher Health and science reporter, BBC News
A kidney "grown" in the laboratory has been transplanted into animals
where it started to produce urine, US scientists say
Researchers at Massachusetts General Hospital have taken the first steps
towards creating usable engineered kidneys.
They took a rat kidney and used a detergent to wash away the old cells.
The remaining web of proteins, or scaffold, looks just like a kidney, including
an intricate network of blood vessels and drainage pipes.
the membrane of collagen and sugars that
remain are a perfect substrate for culturing
cells and encouraging recellularization and
functional tissue formation when stem and
autologous (from the patient) cells are
placed on this decellularized scaffold.
http://www.bbc.co.uk/news/health-
22123386

mnhelmus@msn.com
Bioderived Macromolecules
Albumin, crosslinked Vascular graft coatings, ultrasound contrast agent,
tissue adhesive
Alginate Cell encapsulation, rapidly erodable biomaterial, e.g.
urologic stent
Cellulose acetates Hemodialysis membranes
Cuprammonium cellulose Hemodialysis membranes
Chitin and chitosans Experimental, coatings, controlled release
Collagen Coatings, wound dressings, hybrid organs,
tissue engineering scaffold, sealant, embolic
Elastin Tissue engineering scaffold
Fibrin Sealant, adhesive, bulking agent, tissue engineering
scaffold
Gelatin, crosslinked Coatings, tissue adhesive
Hyaluronic acid Ocular and joint injectable, embolic,
tissue engineering scaffold, anti-adhesive
Phospholipids Liposomes, thromboresistant coating
Silk Sutures, experimental coatings of silk-like protein

mnhelmus@msn.com
Bioderived Macromolecules: eg albumin, Chitosans,
collagen, gelatin, elastin, fibrin, hyaluronic acid,
phospholipids, silk
 Purity
 Extractables
 Hydrolysis & Biodegradation
 Hypersensitivity reactions
 Lipid uptake
 Calcification
 Inflammatory and immune responses
 Permeability
 Water content
 Degree of cross-linking
 Effect of cross-linking on inflammation, immune response, and
thrombogenicity

Tissue engineered ecm’s and cells
• Collagen/ecm sheets (grown in culture - eg
smc and fibroblasts)
• Cell layers onto ecm sheets/tubes
• cultured endothelial cells

Cell based grafts cont..
• Ability to withstand over 2000mm Hg
• 50% effective after implantation (1998)
Uconn Tissue EngineeringBy Joanna Domka and
Madeline Larkin

Bioink Composition
Lifeink® 100 Type I Collagen, Methacrylated
Lifeink® 200 Type I Collagen, Highly Concentrated
Lifeink® 300 Gelatin, Methacrylated
Lifeink® 400 Hyaluronic Acid, Methacrylated
Native Material Bioinks
For 3D Printing

Methacrylated Type I Collagen
• Thermal gelation
• UV/Visible light crosslinkable
• Tunable construct strength
Lifeink® 100

Lifeink® 200
Watch a Lifeink® 200
printed structure flex
and recover like natural
tissue.
Concentrated Type I Collagen
•Thermal gelation
•Printed form integrity
•Shear Thinning and Recovery
•High resolution bioprinting
•Tissue-like mechanics

mnhelmus@msn.com
Passive Coatings
Albumin Thromboresistance
Alkyl chains
Adsorbs albumin for
thromboresistance
Diamond-like
coating
Resistance to wear
Fluorocarbons Reduced drag for catheters
Hydrogels Reduced drag for catheters
Ion beam modified
surfaces
Resistance to wear, reduced drag,
controlled biologic interactions
Plasma polymerized
films
Resistance to wear, reduced drag,
controlled biologic interactions
Silica-free
silicones
Thromboresistance
Silicone oils Lubricity for needles and catheters
Surface modifying
agents
Thromboresistance, biocompatibility
Surface modifying
groups at polymer
end groups
Thromboresistance, biocompatibility

mnhelmus@msn.com
Passive Coatings: eg Albumin, diamond-like,
fluorocarbons, hydrogels, PVD, CVD
 Adherence
 Wear
 Flaking
 Uniformity
 Sterilizability
 Shelf-life
 Durability
 Biostability
 Extractables
 Hypersensitivity
 Lipid uptake
 Calcification
 Fatigue

mnhelmus@msn.com
Bioactive Coatings
Anticoagulants,
e.g., heparin
Thromboresistance
Antimicrobials Infection resistance
Cell adhesion
peptides
Enhanced cell adhesion, endothelium
Cell adhesion
proteins
Enhanced cell adhesion, endothelium
Negative surface
charge
Thromboresistance
Plasma polymerized
coating
Enhanced cell adhesion
Thrombolytics Thromboresistance
Tissue Adhesives
Collagen/gelatin Coating, sealant, adhesive, embolic
Cyanoacrylates
Microsurgery for anastomosing vessels,
adhesive, embolic
Fibrin glue Coating, sealant, adhesive, embolic
Polyethylene
glycol
Coating, sealant, adhesive, embolic
Molluscan glue Enhancement of cell adhesion

mnhelmus@msn.com
Bioactive Coatings (heparin, antimicrobials, cell adhesion
peptides, surface charge) and Tissue Adhesives ( Collagen,
cyanoacrylates, fibrin glue, PEG)
 Degree of antithrombogenicity, cell adhesion & tissue binding
 Biostability
 Wear & Durability
 Uniformity
 Sterilizability
 Microbiologic contamination
 Shelf-life
 Calcification
 Immune responses
 Residuals
 Tissue Adhesives
- Purity
- Filtration sterilization
- Cure time
- Tissue Adhesion

mnhelmus@msn.com
Bioactive Molecules attached to surface

mnhelmus@msn.com
30 minute exposure to canine blood
Control (untreated) Duraflo® treated
Bioactive Heparin Coatings
Model for making a claim for a bioactive
macromolecule

mnhelmus@msn.com
Intramuscular Rabbit Implants 7 days
Coating concentration > 0.5% DurafloTM
Necrosis and increased host response compared to uncoated controls
Coating concentrations< 0.3 %
Biocompatible
Helmus, Michael N., Scott, Michael J., Enhanced
Biocompatibility Coatings for Medical Implants,
WO99/38547, Aug. 5, 1999
Ex Vivo Canine Shunt
100 ml/min flow
Bioactive Heparin Coatings
Edwards Duraflo coated
Annuloplasty Rings

•7,625,552 Bioactive polymers for
imparting bioactive character to hydrophobic
medical article surfaces
•20070269480 Medical devices having
bioactive surfaces
•7,709,439 Biomaterials for enhanced
healing
•20040093080 Bioactive coatings to prevent
tissue overgrowth on artificial heart valves
Bioctive coatings for enhanced healing

A biomaterial comprising: a bioactive polymer comprised of at least
one peptide and/or protein subunit and at least one polysaccharide
and/or proteoglycan subunit; and a biocompatible polymer.
…polysaccharide and/or proteoglycan subunit of the bioactive polymer is selected
from the group consisting of aggrecan, agrin, bamacan, heparan sulfate, chondroitin
sulfate, keratan sulfate, perlecan, hyaluronan, decorin, dermatan sulfate, biglycan,
fibromodulin, alginate, polylactate, polyglycolic acid, starch, dextran, agarose and
heparin.
… cell adhesion peptide is a RGD peptide, a dRGD peptide, a YIGSR peptide or a
IVKAV peptide
…peptide and/or protein subunit of the bioactive polymer is a growth factor protein.
…growth factor protein is insulin, insulin like growth factors, interleukin-4, platelet
derived growth factor, TGF-.beta., EGF, NGF, IL-2, II-3, VEGF, GM-CSF, M-CSF, G-CSF,
EPO or FGF.
Biomaterials for enhanced healing

Example: RGD Peptides
Endothelial Cell adhesion to Synthetic
Surfactant Bound RGD Peptides
Surfactant Bound RGD
Hydrophobic (Leucine)
Rich polypeptide tail. Peptite 2000

mnhelmus@msn.com
Medical Textile Modified with
Cell Adhesion Peptide
RGD Coated Polyester and PTFE Fabric
Effect on Cell Adhesion
In vivo healing of fabric
K. Tweden, Chapter 8 in "Biomaterials in the design and reliability of medical devices", M. N. Helmus, ed.,
Landes Bioscience, Georgetown, TX, 2001
Tweden KS, Haraskai H, Jones M, Blevitt JM, Craig WS, Pierschbacher M, Helmus M, Accelerated healing
of cardiovascular textiles promoted by an RGD peptide, J. Heart Valve Dis 1995; 4 (Suppl. I):S90-97

mnhelmus@msn.com
K. Tweden, Chapter 8 in "Biomaterials in the design and reliability of medical devices", M. N. Helmus, ed., Landes Bioscience, Georgetown, TX, in press.
PETControl PepTite 2000 RGDCoating
RGD Peptide Coating: In Vivo Response PET Arterial
Patch Canine Implants at 3 weeks

mnhelmus@msn.com
K. Tweden, Chapter 8 in "Biomaterials in the design and reliability of medical devices", M. N. Helmus, ed., Landes Bioscience, Georgetown, TX, in press.

•Ceramic but with catalytic
properties
• Catalytic properties of the
oxide converts H202 to
water and oxygen,
reducinginflammatory
responses
•Successful history on
pacemaker electrodes
•Minimal proliferation of
smooth muscle cells
30 daysBarry O’Brien, Boston Scientific
Active Stent Coatings
Iridium Oxide

• Pre-clincal studies
show that iridium
oxide facilitates
endothelialization
and reduced
inflammatory
response
• Minimal proliferation
of smooth muscle
cells
30 days
Barry O’Brien, Boston Scientific
Active Stent Coatings
Iridium Oxide

mnhelmus@msn.com
Metals and Metallic Alloys
Cobalt chrome alloys
Nickel chrome alloys
Nitinol alloys
(shape memory
alloys)
Stainless steels
Tantalum
Titanium and
titanium alloys
Guide wires, mechanical heart valve orifices
and struts, biologic heart valve stents,
endovascular and urologic stents, vena cava
umbrellas, orthopedic and dental implants,
artificial heart housings, pacemaker leads
Platinum/iridium
Tungsten
Radioopaque markers, radioopaque coils for
guidewires
Ceramics, Inorganics, and Glasses
Bioglasses Bone attachment, reconstructive surgery
Bioactive
glass/ceramics
Bone attachment, reconstructive surgery
Hi-density alumina Orthopedic and dental implants
Hydroxyapatite Bone attachment, reconstructive surgery
Nanocrystalline
brushite
Biodegradable for drug delivery
Single crystal
alumina
Orthopedic and dental implants
Tricalcium
phosphates
Bone repair
Zirconia Bone attachment, reconstructive surgery

mnhelmus@msn.com
Metals and Metallic Alloys
 Passive layer durability
 Corrosion - pitting, fretting, stress
 Corrosion by-products
 Fracture toughness
 Fatigue life
 Stiffness compared to application
 Porous coatings
 Noble metal protein interactions;
 Antimicrobial activity, eg. Ag, Cu
 Wear
Ceramics, Inorganics, and Glasses
 Bioactivity and Degree of bone formation
 Bioresorption rate
 Biostability

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Bioactive Nature of Titanium Oxide Surfaces

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Carbons
Pyrolytic (low
temperature
isotropic) carbon
Heart valves, coatings for cardiovascular
implants
Ultra low
temperature
isotropic carbon
Coatings on heat sensitive polymers
Composites
Carbon fiber
composites based on
a matrix material
of:
Epoxy
Poly(etherketone
s)
Poly(imide)
Poly(sulfone)
Potential materials for orifices, disks,
and stents, orthopedic implants
Radioopacifiers
(BaSO4, BaCl2, TiO2)
blended into
polymers of:
Poly(olefins)
Poly(urethanes)
Silicones
Radioopaque on x-ray for identifying
location of the device

mnhelmus@msn.com
Polymethylmethacryla
te bone cements
Radioopaque bone cement
HA fiber composites
based on a matrix
material of
polylactic acid
copolymers
High-strength biodegradable bone plates
and rods
Polymethylmethacryla
te bone cements with
HA particles
Bone cement with enhanced bone formation
at the interface
Bis-GMA bone cements
with HA particles
Bone cement with enhanced bone formation
at the interface
Collagen/HA particle Bone repair
Plaster of Paris/
hydroxyapatite
particle bone filler
Bone repair
Calcium sodium
metaphosphate short
fiber reinforced
biodegradable
polymer
Bone and soft tissue repair

mnhelmus@msn.com
Carbons: Pyrolytic, Ultra low temp. isotropic
 Wear resistance
 Biostability
 Low heat of protein adsorption
 Thromboresistance
 Fatigue
Composites: Carbon fiber, nanoparticles,
radioopacifiers
 Surface exposure of compounded particles
 Extractables
 Residuals
 Lipid uptake
 Biostability
 Calcification
 Fatigue and particulates

mnhelmus@msn.com
Enhanced biocompatibility for
Regenerative Medicine
is a
Disruptive Medical
Technology

mnhelmus@msn.com
Technologies that introduce a different
performance package than mainstream
technologies and are inferior to mainstream
technologies… Technology disruption occurs
when, despite its inferior performance, the
new technology displaces mainstream
technology from the mainstream market
RON ADNER , WHEN ARE TECHNOLOGIES DISRUPTIVE? A DEMAND-BASED VIEW
OF THE EMERGENCE OF COMPETITION Strat. Mgmt. J. (in press)
Disruptive Technology

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Enhanced
Functionality
Enhanced
Biocompatibility
Anti-infectives
Thromboreistant
Reduced inflammation
Reduced hyperplastic
response
Recellularizaion
Neogenesis of Tissue
Enhanced
Biomechanics
Improved
biocompatibility by
matching tissue
properties

mnhelmus@msn.com
Surface Properties and Biologic Interactions
• Surface Energy
• Polar, Dispersion, Hydrogen bonding interactions
• Critical surface energy
• Wettability
• Surface heterogeneity
–Micro
–Nano
• Surface texture
•Micron vs nano
• Surface Mobility
• Hydrogel surfaces
• Grafted surfaces
• Bioactive Surfaces

Examples of Emergent Biomaterials to
control wound healing and
Inflammation

mnhelmus@msn.com
TEM micrograph of random, irregularly shaped polystyrene domains (white
phase) in a polybutadiene matrix. Stained with osmium tetroxide, Scale bar =
100 nm.
M. Helmus et al., Adv. Chem. Series, No. 199, 1982, pp. 81-93. Reprinted with
permission American Chemical Society.

mnhelmus@msn.com
TEM micrograph of ordered, spherically shaped polystyrene domains
(white phase) in a polybutadiene matrix. Stained with osmium tetroxide,
Scale bar = 100 nm.
M. Helmus et al., Adv. Chem. Series, No. 199, 1982, pp. 81-93. Reprinted with
permission American Chemical Society.

mnhelmus@msn.com
Effect of Mircophase Separation in SBS on
Fibrinogen Conversion. (Reprinted with permission from
(5), copyright 1982 American Chemical Society).
Material Normalized Platelet Adhesion %
Conversion
3 sec. Plasma
Exposure
3 min. Plasma
Exposure
SBS random 102 + 30 45 + 26 56
SBS ordered 97 + 24 64 + 18 34
Hydrophobic
Glass Control
104 + 25 100 + 31 4
Hydrophilic
Glass Control
79 + 5 1 + 1 99

mnhelmus@msn.com
Commercializing New Technology: Development Cycle
Start
Preclinical /Clinical
Animal testing
IDE/IND
Human Clinical
Concept
Prototype
Quality Systems
Packaging
CMC
Chemistry
Manufact.
Controls
Sterility
Inventory
Marketing
Epidemiology, Adverse
Reporting, Post-Market
Surveillance
Toxicology, Hazard Analysis, Study Design, Statistics
Toxicokinetics
Pharmacology,
Pharmacokinetics,
ADME, Biocompatibility
FMEA
Design Freeze
National
Materials
Components
Technology
Pharma
Biologics
Modified from
Helmus, Nature
Nanotechnology
1, 157 - 158
(2006)
510K, PMA,
NDA

COMBINATION MEDICAL DEVICE VALUE CHAIN
• Powders
• Dispersions
• Coatings
• Composites
• Biomaterials
• Proteomics
• Genomics
Technology Medicine
Develop IP Strategy: Composition of Matter Applications
File IP

Tissue Eng Part B Rev. 2010 Feb;16(1):41-54. doi: 10.1089/ten.TEB.2009.0449.
Considerations for tissue-engineered and regenerative medicine product development prior to
clinical trials in the United States.

The development of efficacious
therapeutic and diagnostic
procedures based on
nanotechnology will require the
early collaboration of clinicians
and an understanding of the
clinical environment
Nanomedicine

The Promise and the Challenge of Nano-enabled
technologies for Medical Applications
•Enhanced functionality and
biocompatibility
•Potential new paradigms required for
biocompatibility evaluations of nano-
structures and particles

NANOMATERIALS AND PROPERTIES
BIOMIMETICS
BIOACTIVE
Metal ceramic fiber
Ceramic metal filled
Polymer nanoparticulates
Polymer nanofibers
Polymer-layered silicate
nanocomposite(PLSN)
Polyelectrolyte layered
nanocomposites
NANOPARTICLES NANOCOMPOSITES
NANOSTRUCTURED
BULK, COATINGS & SURFACES
NANOPOROUS
DRUGDELIVERY
DIAGNOSTICS
Bottom up: CVD, PVD,
Deposition processes by Laser, EBeam
Self Assembly, Sintering
Top down: Nanolithography,
Nanomachining, Ablation, Dissolution
BIOSENSORS
MICROFLUIDICS
Microphase separated polymers
Nanograined ceramics & metals
Self-assembled monolayers
Surface nano-clusters
SWNT Fibers
Polymeric Fibers and yarns
Nanowires
Nanotubes – Carbon, BN, Metallic Metal
Nanoribbons
Quantum Dots
Dendrimers
Gold and metallic nanoshells
Buckminister Fullerenes
Paramagnetic nanoparticles
PHOTONICS
SEMICONDUCTO
RS
STRUCTURAL

Biocompatibility Evaluation and Issues

mnhelmus@msn.com
Tissue Engineered Devices
ASTM Committee F04 Tissue Engineered Medical Products
F2211-13 Standard Classification for Tissue Engineered Medical Products (TEMPs)
F2312-11 Standard Terminology Relating to Tissue Engineered Medical Products
F3163-16 Standard Guide for Classification of Cellular and/or Tissue-Based Products
(CTPs) for Skin Wounds

mnhelmus@msn.com
F2150-13
Standard Guide for Characterization and Testing of Biomaterial Scaffolds Used in
Tissue-Engineered Medical Products
F2027-16
Standard Guide for Characterization and Testing of Raw or Starting Materials for
Tissue-Engineered Medical Products
F2450-10
Standard Guide for Assessing Microstructure of Polymeric Scaffolds for Use in
Tissue Engineered Medical Products
F2103-11
Standard Guide for Characterization and Testing of Chitosan Salts as Starting
Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product
Applications
F2903-11
Standard Guide for Tissue Engineered Medical Products (TEMPs) for Reinforcement
of Tendon and Ligament Surgical Repair
F2883-11
Standard Guide for Characterization of Ceramic and Mineral Based Scaffolds used
for Tissue-Engineered Medical Products (TEMPs) and as Device for Surgical
Implant Applications

mnhelmus@msn.com
INTERNATIONAL STANDARDS FOR MEDICAL DEVICES
Part 1: Evaluation and testing (ANSI/AAMI/ISO 10993-1:2009)
Part 2: Animal welfare requirements, (ANSI/AAMI/ISO 10993-2:2006)
Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity, 2ed (ANSI/AAMI/ISO
10993-3:2003)
Part 4: Selection of tests for interactions with blood (ANSI/AAMI/ISO 10993-4:2002(R)2009 &
A1:2006(R)2009)
Part 5: Tests for in vitro cytotoxicity, 3ed (ANSI/AAMI/ISO 10993-5:2009)
Part 6: Tests for local effects after implantation, 2ed (ANSI/AAMI/ISO 10993-6:2007)
Part 7: Ethylene oxide sterilization residuals, 3ed (ANSI/AAMI/ISO 10993-7:2008
Part 9: Framework for identification and quantification of potential degradation products, 2ed
(ANSI/AAMI/ISO 10993-9:2009)
Part 10: Tests for irritation and delayed type hypersensitivity, 2ed (ANSI/AAMI BE78:2002
(R)2008; adoption of ISO 10993-10:2002 with national deviation)
Part 11: Tests for systemic toxicity (ANSI/AAMI 10993-11:2006)
Part 12: Sample preparation and reference materials, 3ed (ANSI/AAMI/ISO 10993-12:2007)
Part 13: Identification and quantification of degradation products from polymeric medical devices,
1ed (ANSI/AAMI/ISO 10993-13:1999/(R)2004)
Part 14: Identification and quantification of degradation products from ceramics, 1ed
(ANSI/AAMI/ISO 10993-14:2001/(R)2011)
Part 15: Identification and quantification of degradation products from metals and alloys, 1ed
(ANSI/AAMI/ISO 10993-15:2000/(R)2011)
Part 16: Toxicokinetic study design for degradation products and leachables, 2ed
(ANSI/AAMI/ISO 10993-16:2010)

mnhelmus@msn.com
Part 17: Establishment of allowable limits for leachable substances, 1ed (ANSI/AAMI/ISO
10993-17:2002(R)2008
Part 18:Chemical characterization of materials (ANSI/AAMI BE83:2006/(R)2011)
Part 19: Physicochemical, morphological, and topographical characterization of materials
(ANSI/AAMI/ISO 10993-19:2006)
Part 20: Principles and methods for immunotoxicology testing of medical devices
(ANSI/AAMI/ISO 10993-20:2006)
----------------------------------------------------------------------------------------------------------------
-Clinical investigation of medical devices for human subjects (ANSI/AAMI/ISO 14155:2011
-Guidance for ANSI/AAMI/ISO 10993-7:1995, Biological evaluation of medical devices-Part 7:
Ethylene oxide sterilization residuals, 1ed and Amendment (AAMI TIR19:1998; TIR19/A1:1999)
-22442-1:2007/(R)2011, Medical devices utilizing animal tissues and their derivatives - Part 1:
Application of risk management
Controls on sourcing, collection and handling
Validation of the elimination and/or inactivation of viruses and transmissible spongiform
encephalopathy (TSE) agents
-22442-4:2010, Medical devices utilizing animal tissues and their derivatives -- Part 4:
Principles for elimination and/or inactivation of transmissible spongiform encephalopathy (TSE)
agents and validation assays for those processes

mnhelmus@msn.com
Future Directions:
Tissue Engineering Approaches
Self Reparative Masked Immune Response
No Calcification No Anti-Coagulation
Unlimited Supply
Bioreactor
Recellularization
In Situ
Recellularization
Platform
Bioresorbable Exracellular-
Scaffolfds Matrix (ECM)
Cell Therapy

mnhelmus@msn.com
Tissue Engineering: The First Decade and Beyond Lawrence J. Bonassar* and Charles A. Vacanti
Journal of Cellular Biochemistry Supplements 30/31:297–303 (1998)

Biomaterials in Sustainability of
Tissue Engineering
Medical Devices, Biomaterials, Drug Delivery, and Nanotechnology
mnhelmus@msn.com

Biomaterials in the sustainability of regenerative medicine

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