BB&T Contributing Editor

PITTSBURGH – If there is anything likely to be seen as a key med-tech milestone in the 21st century, it could well be the realization of a promise loudly and frequently issued, but largely unseen commercially in the 20th century – that the preponderance of metal and plastic medical materials will be augmented or even replaced by bioengineered materials and engineered living tissues.

That realization is still largely in the early stages, but the wealth and diversity of bioengineered materials is currently so broad and deep that it is reaching the level of “tipping point” critical mass, meaning that it cannot help but break out into a multiplicity of commercial uses in every possible clinical application.

These multiple evolving products and their potential uses could be found in plenteous array at this year’s annual gathering of the Society for Biomaterials (Mount Laurel, New Jersey), its 31st, held here at the David L. Lawrence Convention Center in late April.

The meeting was held in conjunction with the World Congress on Tissue Engineering and Regenerative Medicine, which is essentially a consortium-style group of academic research groups active in this area. Together, the meetings drew more than 2,000 attendees to contemplate the possibilities offered through 682 oral and poster presentations.

Bio going ‘absorbable’

One key problem with traditional metal and plastic is that such material, when remaining as artifacts in the body, can produce a variety of unpredictable side effects. This has driven the continuing impulse to create “living” device materials or to develop materials so similar to living tissue that they can “disappear” via absorption.

Bioabsorable polymers have historically been used as encapsulants for drug delivery and in biodegradable sutures. Now, they are finding increasing use in bioabsorbable medical implants which stay in place while the body heals, thus eliminating the need for follow-up surgery to remove a metallic implant.

These device applications include screws, plates, pins and rods for bone fractures and reconstructive surgery and suture anchors and tacks for repairing soft tissue from sports injuries. Such uses are basic, but more sophisticated uses of bioabsorbable polymers are beginning to emerge as well. These include bone fusion and spinal applications, urinary and arterial stents – the latter represented by the bioabsorbable stent being developed by Biotronics (Pittsburgh) – and tissue-engineered vascular grafts.

One type of material exhibiting this strategy is biodegradable polylglycolide/lactide (PGLA), and many exhibitors were demonstrating its uses in medical devices and for drug delivery applications, such as in injectable rods or microcapsules.

Among these products: Purasorb from Purac America (Lincolnshire, Illinois), a subsidiary of CSM (Gorinchem, the Netherlands); Resomer from Boehringer-Ingelheim (Wallingford, Connecticut/Ingelheim, Germany); Lactel from Durect (Cupertino, California); Medisorb from Lakeshore Biomaterials (Birmingham, Alabama); and Altasorb from Ortec (Piedmont, South Carolina). TESco Associates (Tyngsborough, Massachusetts) is a contract manufacturer of bioabsorbable devices made from PGLA as well as from e-caprolactone-lactide and methylene carbonate-lactide.

Among the broad range of products made from PGLA are:

• Bone screws sold by Arthrex (Naples, Florida), Stryker (Kalamazoo, Michigan), Linvatec (Largo, Florida), a subsidiary of ConMed (Utica, New York), Biomet (Warsaw, Indiana) and Inion (Tampere, Finland).
• Trauma screws from Small Bone Innovations (New York).
• Suture anchors from DePuy Mitek (Raynham, Massachusetts), a subsidiary of Johnson & Johnson (New Brunswick, New Jersey), and Smith & Nephew Orthopaedics (Memphis, Tennessee), a subsidiary of Smith & Nephew (London).
• Tubular nerve guides and adhesion barrier films from Polyganics (Groningen, the Netherlands).
• A device for guided tissue regeneration from Luitpold Pharmaceuticals (Shirley, New York).

Even attractive to Big Pharma

Purac’s PGLA also has been found useful by Big Pharma.

Astra-Zeneca (London) uses it in its Zoladex injectable rods for treating prostate cancer, and Novartis (Basel, Switzerland), for its Sandostatin LAR injectable suspension for treating acromegaly.

The Commonwealth Scientific and Industrial Research Organization (CSIRO; Dickson, Australia) is Australia’s premier life sciences research organization. PolyNovo Biomaterials (Clayton South, Australia) was spun out of CSIRO to commercialize NovoSorb, a bioabsorbable polyurethane. The company has signed a partnering and licensing agreement with Medtronic (Minneapolis) for use of NovoSorb in a biodegradable stent.

Researchers from PolyNovo Biomatetrials presented several posters that describe its development of an injectable form of NovoSorb which, when mixed with cartilage cells (chondrocytes), acts as a scaffold to support a recovering knee joint. The company is also working on scaffolds for the directed repair of peripheral vessels.

Natural materials in tissue engineering, dental uses

Natural materials are increasingly being used to facilitate or augment the natural processes of the body or to facilitate the delivery of various natural materials and drugs.

NovaMatrix (Oslo, Norway), a subsidiary of FMC (Philadelphia), is a leading commercial supplier of biomedical grade chitosan, sodium hyaluronate and alginates that are used in wound care products and in drug delivery systems. The company recently introduced Novatach peptide-coupled alginates that mimic the body’s extracellular matrix and facilitate the interaction between cells and alginate-based scaffolds and matrices developed for use in tissue engineering applications.

FibroGen (South San Francisco, California) has launched human clinical trials of its recombinant human collagen. The company claims that this type of collagen has a longer duration after injection than the bovine-derived collagen that is currently marketed and resorbs within three to four months. The product will compete with Evolence dermal filler from ColBar LifeScience (Herzliya, Israel), used to restore shape to facial wrinkles and sold in Europe but not yet approved in the U.S. Evolence is porcine-derived collagen that utilizes the company’s Glymatrix crosslinking technology which extends its biodegradable lifetime beyond a 12-month period. Johnson & Johnson (New Brunswick, New Jersey) recently licensed marketing rights to this product.

EnColl (Carlsbad, California) featured its Helicoll sterile collagen-based wound dressing that recently received market clearance from the FDA. It is made from type-1 bovine-derived collagen that is purified by a patented process. It is made into a semi-occlusive and self-adhesive flexible dressing for use on second-degree burns, skin donor sites, chronic skin ulcers and post-operative wounds.

Aesthetic Bioscience (Irving, Texas) is a startup company that has proprietary collagen technology which allows for controlled tissue revascularization to occur as the collagen is slowly resorbed.

Inamed (Santa Barbara, California), a subsidiary of Allergan (Irvine, California) featured in its exhibit its PureCol and Nutragen type 1 collagen solutions for use in tissue engineering and cell culture.

Genzyme Biosurgery (Cambridge, Massachusetts) has begun offering its crosslinked hyaluronic acid for use by other companies, such as for drug delivery applications. This material is currently used in Genzyme Biosurgery’s Synvisc viscoelastic material for treating osteoarthritis and in Hylaform dermal filler licensed for sale by Inamed.

Bioengineered to be tissue-‘friendly’

Though not natural biologically, many of the new materials can be said to be bioengineered in order to be compatible with natural human tissues, usually polymers.

AorTech International (Mulgrave, Australia), also formed from research that originated within CSIRO, has developed the Elast-Eon family of biostable polyurethanes. The company recently entered into a licensing agreement with St. Jude Medical (St. Paul. Minnesota) for use of its Elast-Eon polymer in implantable cardiac rhythm pacing leads and implantable neuromodulation devices. The company featured in a poster session its biologically stable urethane-silicone copolymer gel that is being investigated for use in breast implants.

Invibio (Greenville, South Carolina), a subsidiary of Victrex (Lancashire, UK), provides PEEK (polyetheretherketone)-Optima for use in implantable medical devices. The company has compounded PEEK-Optima with short carbon fibers in a combination offering biocompatibility and artifact-free imaging compatibility of PEEK-Optima with the benefit of modulus similar to that of cortical bone, thus eliminating stress shielding concerns. It also shows promising wear properties against hard surfaces (metal and ceramic), as compared to ultra-high molecular weight polyethylene.

About 20 FDA approved devices are made with carbon fiber reinforced PEEK-Optima compound. Most of these are cage systems in spinal fusion applications. The material also is being investigated for use as a hip component due to its good wear properties. It also has won FDA approval for cardiovascular applications.

Endolign is the newest product from Invibio (Greenville, South Carolina). It is composed of continuous carbon fibers in a PEEK-Optima polymer matrix and is characterized by high mechanical strength, making it suitable as a metal replacement in structural parts.

It has the added benefit of being non-metallic, thus avoiding metal ion concerns and imaging artifacts. Endolign is being investigated for use in orthopedic, traumatology and spinal applications, for example in a snake plate and for intramedullary nails. Endolign has been used to fabricate the translaminar pin manufactured by Icoteg (Altstatten Switzerland), which has received CE-marking for the product. Signus Medizintechnik (Alzenau, Germany) has FDA and CE-mark approval for its Kimba lumbar cage made from Endolign.

The Polymer Technology Group (Berkeley, California) has developed a family of biostable polyurethane-based polymers for use in implantable devices. Its current focus is on the use of elastomeric copolymers in orthopedic applications to restore motion in hip, knee and spinal implants. Its patented surface-modifying end group technology is used to covalently bond surface-active oligomers to the base polymer during synthesis. The surface-modifying end groups can include silicone, sulfonate, fluorocarbon, polyethylene oxide, and hydrocarbons. They modify the surface chemistry without compromising the bulk properties of the polymer, resulting in surface properties such as thrombo-resistance and abrasion resistance.

Proxy Biomedical (Galway, Ireland) is a four-year-old company that is developing soft tissue implants made from proprietary biomaterials. These films are machined into porous scaffolds for use in hernia repair and for fascial defects. Proxy says that MotifMESH combines the strength of large-pore monofilament polypropylene with the reduced adhesion attributes of expanded PTFE. VitaMESH is a macroporous polypropylene surgical mesh that is machined into a film using a CAD file.

Proxy Biomedical is in partnership with the research laboratories of Dr. James Anderson at Case Western Reserve University (Cleveland). And it is working with a U.S. device company to develop a product for pelvic floor reconstruction. Proxy Biomedical is seeking a partner to develop a 3-D scaffold assembled by layering of porous films in a highly controlled architecture with controlled interconnectivity for use as a scaffold in tissue repair.

Modifying the surfaces

If not replacing a metal or plastic technology, the new forms of biological engineering can make metal or plastic more tissue compatible or improve bonding characteristics.

Surface Solutions Laboratories (Carlisle, California) offers customized surface treatments for medical devices and has formed a new subsidiary, Coatings2Go, which provides off-the-shelf surface treatments such as imparting hydrophilicity or hydrophobicity to device surfaces.

Spire (Bedford, Massachusetts) featured its new Ion Core treatment in a poster presentation. The treatment is similar to an ion plasma process and can be used to activate polymer surfaces within tubes having diameters as small as 2 mm to 3 mm. It is an integrated biological coating that uses passivation, anticoagulation and fibrinolytic mechanisms and is intended for use in cardiovascular and renal dialysis catheters to reduce the frequency of replacement. Spire is seeking corporate customers for this technology.

SurModics (Eden Prairie, Minnesota) has developed the Eureka system that uses a naturally biodegradable polysaccharide for parenteral delivery of proteins, and it is collaborating with drug companies on the use of this technology. The material forms in situ a solid after injection.

SurModics is also exploring its use for delivering demineralized bone or bone growth factors in bone and cartilage repair applications. It has licensed to Novocell (Irvine, California) its CELLabration photopolymerized cell encapsulation system that is being used in a Phase I/II cell therapy trial in Type 1 diabetic patients. SurModics recently reported that it has licensed to Devax (Irvine, California) its hydrophilic technology for producing a lubricious coating on its Axxess biolimus A-9 eluting bifurcation stent delivery system.

Affinergy (Research Triangle Park, North Carolina), a company spun out of research from Duke University (Durham, North Carolina), uses peptide linkers to selectively bind proteins, cells and drugs to biomaterials. It develops coatings for orthopedic and cardiovascular devices.

Systems and equipment for cell growth

In a small med-tech irony, the development of new bioengineered products has served to promote additional metal and plastic devices and equipment required to do bioengineering, as well as advanced computer strategies.

Tissue Growth Technologies (TGT; Minnetonka, Minnesota) displayed its DynaDen mechanical stimulator bioreactor for growing many types of cells. This technology is based on the rather obvious observation that the introduction of mechanical stresses and strains is a key factor for initiating cell differentiation and producing improved tissue properties. TGT’s GrowthWorks software controls dynamic stimulation culture conditions and monitors tissue response to achieve optimal growth.

Concordia Fibers (Coventry, Rhode Island) at the meeting featured its Biofelt product, a highly porous, non-woven 3-D felt made from absorbable polymer fibers, for rapidly growing cells and forming an organized tissue structure. It is being evaluated as a tissue engineering scaffold in orthopedic and vascular applications.

These felts were originally developed in the laboratories of Dr. Robert Langer at the Massachusetts Institute of Technology (Cambridge, Massachusetts) in collaboration with Albany International Research (Mansfield, Massachusetts).

Lampire Biological Laboratories (Pipersville, Pennsylvania), a provider of custom polyclonal and monoclonal antibody services, displayed its gas permeable cell culture bag made from ionomer plastic that provides more efficient gas exchange compared to cell culture dishes and greater production capacity. It competes with a comparable product from American Fluoroseal (Gaithersburg, Maryland).

The obligatory stem cell studies

One can hardly attend a medical conference these days and not find the program featuring numerous studies on stem cells and their clinical (meaning commercializable) possibilities.

Not disappointing, numerous presentations at this conference were devoted to research on stem cells. Posters on the application of adult stem cells with matrices for bone regeneration were presented by researchers from Aastrom Biosciences (Ann Arbor, Michigan) and from Bacterin (Belgrade, Montana) in collaboration with investigators from the University of Utah (Salt Lake City) and Inje Universiy (Pusan, South Korea).

A rapid technique for obtaining stem cells from human bone marrow was reported by Cell Factor Technologies (Irvine, California). Cell Factor employs its Gravitational Platelet Separation System for the isolation and concentration of viable adult stem cells from whole marrow.

CSIRO is collaborating with the Australian Stem Cell Centre (Clayton, Australia) and Monash University (Melbourne, Australia) to develop technology that will incorporate the required biological signals into smart reactor substrate materials in order to control the proliferation and differentiation of stem cells.

BioE (St. Paul, Minnesota) is a provider of Multi-Lineage Progenitor Cell (MLPC), a multi-potent, clonal cell isolated from post-partum umbilical cord blood for use in regenerative medicine. It is being sold for research purposes. MLPC lines are developed from a single cell which is genetically stable and expresses a normal phenotype, providing a tool to develop better differentiation methods and cell delivery systems. There are no other commercial sources for stem cells derived from umbilical cords.