Biomaterials Research Focuses on Developing New Applications


April 1, 1998

14 Min Read
Biomaterials Research Focuses on Developing New Applications

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI April 1998 Column


From drug release to tissue scaffolding, new biomaterials and engineering techniques may change the way we think about medicine.

The development of new biomaterials involves a complicated mix of materials science and cell biology. Current and future research promises to introduce not just a new crop of materials, but an entirely new way of treating illness. Intriguing work is being conducted in areas such as bioresorbables, collagen-based materials, fibrin sealants and glues, hyaluronic acid derivatives, engineered tissues, and other products for the cardiovascular, musculoskeletal, and surgical markets.

Silk elastin sponges are polymers being developed to provide a matrix for wound healing and drug delivery. Photos courtesy of Protein Polymer Technologies (San Diego).


One particularly dynamic area of research is controlled drug delivery. The demand for different delivery technologies has reached a critical point because many engineered drugs are large, high-molecular-weight proteins and enzymes that can't be administered orally. Also, without a targeted release mechanism, drug levels tend to fluctuate, which means that more of the drug must be administered, increasing the likelihood of side effects and raising health-care costs.

Noted researcher Robert Langer, Germeshausen professor of chemical and biomedical engineering at the Massachusetts Institute of Technology, is among those pursuing more precise and sustainable drug-delivery mechanisms. In the most common current approaches, the drug is encased in a reservoir, from which it gradually leaches out, or else it is compounded into a degradable polymer, from which it is gradually released as the polymer breaks down inside the body. This latter approach is the basic principle behind the Gliadel system for treating brain cancer, approved by FDA just last year, which Langer was instrumental in developing.

Langer describes Gliadel as the first new treatment modality approved by FDA for brain tumors in more than 20 years. "The issue," says Langer, "is that with certain cells—with endothelial cells—it's extremely hard for the drugs to get through." Surgical implantation is currently the only FDA-approved way to overcome this "blood-brain barrier." The Gliadel product is a small white polymer disk compounded with the chemotherapeutic drug carmustine. Implanted in the cavities left by surgical removal of malignant gliomas, the biodegradable disk gradually erodes, delivering carmustine directly to the affected area in larger concentrations than can be achieved through conventional methods. Up to eight of the disks, each about the size of a dime, can be implanted at once.

"Of course," Langer notes, "most existing implants are not regulated systems," meaning that drug release is solely a function of the rate of polymer decomposition or drug diffusion. Ideally, Langer would someday like to see a drug-delivery system that could respond to biological signals to release more or less medication as needed—"sort of what we call a smart system," he says. Langer is currently studying systems that could be triggered magnetically, ultrasonically, or enzymatically. The now-familiar paradigm of an insulin-delivery system encased in a wristwatch is one good example of a smart system; in such a device, an external controller would regulate the infusion of insulin. Another approach might involve an implantable polymer containing reservoirs of insulin and glucose oxidase; in this case, the enzymatic reaction between the patient's glucose and the polymer's glucose oxidase would generate acids that would increase insulin solubility and hence speed insulin diffusion through the polymer, causing it to release proportionally more insulin. Such a system—indeed all implantable drug-delivery systems—would be limited by the amount of medication the polymer matrix could hold, although this limitation could be overcome by replenishing the reservoir through injection or implanting a fresh system.


There may be another way around this problem, however. Several biotech companies have achieved some success in encasing living cells in a protective medium that withstands implantation while allowing passage of the substances naturally produced by those cells—not an actual organ but perhaps the next best thing. The most obvious use for this approach would be in insulin delivery, and indeed most of the companies working in this area are investigating pancreatic islets and organic media. For example, Islet Technology, Inc. (North Oaks, MN), employs a proprietary encapsulation technology that uses a purified alginate (seaweed-derived) material to coat insulin-producing islet cells. Others use carbon-based microspheres. Solgene Therapeutics LLC (Westlake Village, CA), on the other hand, is working with a purely synthetic encapsulation matrix—silica gel.

Edward Pope, chairman and CEO of Solgene, explains, "Sol-gel (solution-gelation) is a process for polymerizing inorganic network structures from a liquid solution at room temperature or thereabout. Now, that in and of itself would not be enough to encapsulate living cells, because most traditional sol-gel process conditions are still damaging—because of pH, alcohols, lack of saline, and so on. We've developed the sol-gel process to a point where we can incorporate living cells into that liquid solution and form the gel around them." The sol-gel process protects the cells—without the need for artificial immunosuppression—while allowing them to carry on their normal biological functions. "We're not inventing an islet; we're stealing it from Mother Nature," Pope says.

Pope thinks the standard degrading-polymer model of drug delivery will ultimately prove inadequate for complex molecules. For example, in the case of diabetes, he says, "There's a very sophisticated feedback mechanism that the beta cells of the pancreas perform that can't be duplicated." Such sophisticated natural feedback loops enable the human body to use proteins and enzymes with a very short shelf life—because they're used fairly quickly. "We manufacture what we need on demand," Pope says. "If it's only stable for a couple of hours, that's not a problem." A reservoir-based delivery system, on the other hand, will always have to deal with the problem of drug stability. Early efforts at an implantable insulin pump, for example, were stymied by the need to keep a supply of insulin at body temperature for extended periods of time.

Pope hopes that the sol-gel process can be applied to other compounds, and he is investigating its use with bone-morphogenic substances. The market is certainly ready. Pope notes, "Many biotech drugs are sitting on the shelf for the simple reason that the developers couldn't solve their delivery problems."


Bone repair is another important market for biomaterials. Speaking at the recent Biomaterials of the Future conference sponsored by Medical Data International (Irvine, CA), Thomas Einhorn, professor and chairman of the department of orthopedic surgery at Boston University School of Medicine and chief of orthopedic surgery at Boston Medical Center, explained that the paradigm in orthopedic surgery—which has passed from resection (amputation, excision) to reconstruction (osteotomy, fusion) to replacement (implant arthroplasty, allograft transplants)—is shifting again, as the regeneration of bone, cartilage, tendons, and ligaments becomes possible. Studies are under way to induce a patient's own cells to manufacture and deliver bone-growth factors, to make bone in silicone molds using muscle cells seeded with bone-morphogenic proteins, and to refine regulated gene-therapy processes for musculoskeletal applications. Once again, the sticking point, according to Einhorn, is effective delivery, and he counsels scientists "to stop making new gene agents—we know you can make them—and figure out a way to deliver the last one you made!"

Companies active in orthopedic product development include Osteotech, Inc. (Eatontown, NJ), which produces demineralized allograft bone material in solid, moldable, and gel forms; Therics, Inc. (Princeton, NJ), whose proprietary manufacturing technology can fashion scaffolds with unique microarchitectures for bone grafting; Orthovita (Malvern, PA), which is engaged in developing osteobiologic bone substitutes, including bioactive glasses and resorbable cements; and Bionx Implants, Inc. (Blue Bell, PA), which makes self-reinforced, resorbable polymer implants for bone healing. The first synthetic bone-graft material to receive FDA market clearance was developed by Interpore International (Irvine, CA), whose products are derived from a coral that mimics cancellous bone. The bone substitute, known as Pro Osteon, may soon be available for use in spinal procedures.


Many biomaterials have potential applications in slightly different but overlapping disciplines. The same basic polymer used for controlled drug release might also hold potential as a scaffolding material for supporting the growth of tissue—particularly when seeded with appropriate morphogenic compounds. The information gained from investigating the mechanisms of cell attachment and endothelialization, for example, might yield useful insights into the nature of nonthrombogenic coatings or tissue sealants. A case in point is Protein Polymer Technologies (San Diego), which has developed a technique for producing novel biomaterials based on protein engineering. Specific protein compositions with a variety of different properties can be generated by manipulating the constituent amino acids.

Implantable silica-gel microspheres encapsulate active cells, protecting them from the body's immune system while allowing them to produce needed biological compounds. Courtesy Solgene Therapeutics (Westlake Village, CA)

For example, explains Joseph Cappello, Protein Polymer Technology's chief technical officer and vice president of R&D, the vascular endothelium presents an adhesive collagen membrane on one side, but its other side is a nonstick surface that prevents adhesion of blood cells and platelets. As it turns out, says Cappello, both membranes are composed of protein in one way or another. "Protein can change its profile," he explains. "Attachment is an active process. Specifically, certain epitopes have evolved that look for triggers—sort of a lock-and-key mechanism," and these cellular receptors promote active association or adhesion. "If you leave those out, most proteins in general are fairly noninteractive with cells," Cappello says—a property he's been able to exploit. "There are protein combinations we've created that are essentially a nonstick surface. By placing into those designs recognition factors for cell attachment, we can convert them to exactly the opposite."

The technology was a long time coming. "We spent about 12 years developing the methods and perfecting them to the point where we can produce any design of protein we come up with," Cappello remarks. "Our method is very general." Using the same general method, Protein Polymer Technology has been able to develop bioabsorbable protein-based materials that can be fabricated in a wide variety of forms, such as solid films and coatings for biomedical implants, porous sponges for wound dressings, fibrous materials in woven and nonwoven form, and liquid components and hydrogels that solidify when administered into tissue—which could, of course, be suitable for drug-delivery systems. Coating projects include long-term indwelling cardiovascular devices as well as more topical devices, Cappello says. The company has even developed coatings for polystyrene culture dishes that functionalize the surface so cells will recognize it and want to attach to it.

Despite the wide-ranging potential for the technology, Cappello predicts that these types of materials will find their highest utility in tissue engineering. In this field, he says, "you find very challenging situations where you have to accommodate cellular components either in an in vitro setting prior to implantation or shortly thereafter, and you have to encourage the right types of cells to populate the device or materials." The cellular signals for encouraging selective adhesion are fairly complex, Cappello says, and have not been satisfied by conventional synthetic biomaterials. "We can construct ours from natural components, so these types of signals can be embedded and engineered into our products."


Tissue engineering is an interdisciplinary science that focuses on the development of biological substitutes that restore, maintain, or improve tissue function. The most common tissue engineering strategies involve the use of isolated cells or cell substitutes, tissue-inducing substances, and cells seeded on or within matrices. Located in Providence, RI, Cell-Based Delivery, Inc., develops cell-based platforms for treating musculoskeletal, cardiovascular, and neurodegenerative diseases, including a bioartificial muscle that has been shown to help reduce skeletal-muscle wasting. The objective of Advanced Tissue Sciences (La Jolla, CA) is to grow human cells into tissues and organs for transplantation; the company produces a metabolically active, artificial skin product that it refers to as a "living dermal material." Matrigen, Inc. (Ann Arbor, MI), is working toward commercialization of DNA devices for localized gene therapy and gene-based tissue engineering. The company's patent covers situations in which cells actually go into a gene-activated matrix to become transfected with DNA.

Other companies involved in tissue engineering research include Fidia Advanced Biopolymers (Aban Terme, Italy), which processes hyaluronic acid into nonwovens, films, 3-D scaffolds, and sponges for tissue grafting and wound healing; Matrix Biotechnologies, Inc. (Melville, NY), which uses PGA matrices seeded with mesenchymal cells for articular cartilage repair; and DePuy Orthopedics, Inc. (Warsaw, IN), which makes tissue scaffolds from small intestine submucosa—also used for sausage casings—for replacing damaged tendons, ligaments, and other anatomical structures. Desmos, located in San Diego, has developed a proprietary adhesion molecule, Laminin-5, that fosters rapid attachment and proliferation of a wide variety of cell types (epithelial, mesenchymal, endothelial, neural). The molecule adsorbs very quickly to almost any surface, including silicone catheter material, hydroxyapatite, titanium, and Teflon.


Atrix Laboratories, Inc. (Fort Collins, CO), has discovered another crossover technology. Originally founded to develop a doxycycline-delivery system known as Atridox to treat periodontal disease, the company learned that its basic Atrigel technology could also be used without drugs in biomedical applications such as tissue supports. Even better, the technology can be used to create devices that perform both structural and drug-delivery functions.

On the delivery side, explains Lee Southard, president and chief scientist at Atrix, the system is "particularly good" at delivering proteins and peptides. "We've had good results ranging all the way up to high-molecular-weight proteins like fibronectins and all the way down to leuprolide acetate." The company is also working on a leuprolide-delivery system for treating prostate cancer and hopes to begin clinical trials this year.

On the device side, the absorbable biomaterial forms the basis of the Atrisorb-guided tissue regeneration barrier, which is designed to promote healing after periodontal surgery. A logical extension of this application is in growth-factor delivery and tissue scaffolding—creating a template for tissue development. As Southard explains, "The Atrigel system, when fabricated into sheets and membranes, seems to be very biocompatible with live cells. We've had great success with fibroblasts and osteoblasts." Tissue engineering, he says, is "more of a long-term project—but nevertheless exciting. Growth-factor delivery is more near term, with exciting periodontal and orthopedic applications."

Like Solgene, Atrix spent years in the lab before developing a viable product. "Our periodontal product has taken us about eight years to develop," notes Southard, "and Atrisorb took about five years to approve." On the bright side, because the products use drugs that were already approved, the cost of development was not really as high as it would have been had they used entirely new drugs. The new drug application for Atridox was submitted in March 1997, and Southard expects approval in the first half of 1998.


A specialized subset of tissue engineering involves adhesion—which must be promoted in some cases and prohibited in others. Tissue adhesives—particularly fibrin compounds—have achieved considerable success in recent years. These sealants accelerate wound healing and could conceivably replace surgical sutures in some instances. Companies involved in adhesive biomaterials include Thermogenesis (Rancho Cordova, CA), which uses its blood-plasma processing technology to make a cryoprecipitated clotting factor that can function as an autologous surgical glue; Fusion Medical Technologies, Inc. (Mountain View, CA), whose lung-surgery patch was the first surgical sealant to receive FDA market clearance; and CryoLife, Inc. (Kennesaw, GA), which offers photoactivated fibrin sealants. V.I. Technologies (New York City) is developing a fibrin sealant that combines two clotting factors—fibrinogen and thrombin—that react to form a gelatinous clot. The adhesive would halve the time that a wound drain would need to remain in place, and it could also find application in cardiovascular surgery and spinal treatment, where it would be used to seal holes in the dura. Other companies pursuing adhesives include Haemacure Corp. (Sarasota, FL), Convatec/Bristol-Myers Squibb (Skillman, NJ), and BioSurgical Corp. (Pleasanton, CA).

On the other end of the spectrum are physiological adhesions that develop after surgery or as a result of inflammation or infection; these adhesions are in fact detrimental, and a number of biotech firms are investigating ways to prevent them. At Anika Therapeutics (Woburn, MA), antiadhesion products based on hyaluronic acid derived from rooster combs can be prepared as a viscous liquid, injectable gel, membrane, or particulate mesh. Biomatrix, Inc. (Ridgefield, NJ), also uses hyaluronic acid to develop viscoelastic products, and Life Medical Sciences, Inc. (Edison, NJ), makes bioresorbable polymers from polyethylene glycol and lactic acid—derived copolymers. Genzyme Corp. (Cambridge, MA) combines chemically derived hyaluronic acid and carboxymethyl cellulose to form a translucent bioresorbable membrane intended to separate damaged peritoneal structures during the period of healing when adhesions can form.


The biomaterials field is certainly dynamic and diverse. Medical device manufacturers benefit from the availability of biocompatible materials—particularly biocompatible coatings and implant materials—but may in fact find their devices competing with entirely new treatment modalities. A piece of equipment that mimics organ function may eventually give way to a complete synthetic organ, and a hip implant could be rendered unnecessary thanks to a newfound ability to regenerate the patient's natural bone. Such developments are still in the future, but medical device manufacturers should start considering how they can compete with or complement these emerging technologies.

Jon Katz is editor of Medical Plastics and Biomaterials, a Canon Communications llc publication. Gabriel Spera is editor of Medical Device Link and writes frequently for MD&DI.

Copyright ©1998 Medical Device & Diagnostic Industry

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