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[C&EN, June 26, 2000]
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[C&EN, June 28, 1999]

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Joachim B. Kohn
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SCIENCE & TECHNOLOGY
February 5, 2001
Volume 79, Number 6
CENEAR 79 6 pp.30-35
ISSN 0009-2347
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CUSTOM-MADE BIOMATERIALS
Applying engineering, materials, and chemistry principles, researchers produce safe, smart, and effective implantable devices

MITCH JACOBY, C&EN CHICAGO

 Medicine and improvisation hardly seem a likely pair, but since ancient times, resourceful doctors have carried out difficult procedures, often making do with materials on hand. Wounds were sewn shut with plant fibers and animal-derived materials by ancient Egyptians and Greeks, and prosthetic limbs were fashioned from wood. Metals eventually came to be used in dentistry, and early this past century, when stainless steel became available, the corrosion-resistant alloy was used to make a variety of prostheses.

7906sci3xx
COURTESY OF JOACHIM B. KOHN

DISAPPEARING ACT Made of poly(DTE carbonate), a new material developed at Rutgers University, a bone pin (shown in cross-section) biodegrades while new bone tissue (stained red) grows and takes its place.

Like their counterparts of long ago, medical practitioners today often seek to cure ailments or improve a patient's quality of life by replacing a defective body part with a substitute. But until quite recently, physicians were limited to using off-the-shelf supplies that weren't designed for the application. Early artificial hearts, for example, included polyurethanes that were derived from women's girdles because the material's good flexural properties were desirable. And a material once selected for use in breast implants had been used in mattress stuffings.

Motivated by a need for custom-made materials for specific medical applications, materials scientists, chemists, chemical engineers, and researchers in other disciplines have turned their attention to creating high-performance biomaterials. Among the new crop of substances are novel biodegradable polymers and modified natural substances designed for use in a wide range of implantable applications including orthopedic and dental devices, drug-delivery systems, tissue engineering scaffolds, and other uses.

Without a doubt, medical implants have made an indelible mark on our world. Well over 10 million Americans carry at least one major implanted medical device, for example. And the medical device industry has topped $50 billion in annual sales. But despite the trade's large size, most medical device designers have been forced to work with a small handful of classic biomaterials such as stainless steel and chromium alloys, ceramics, a few composites, and industrial plastics.

"These materials do not provide a biologically functional interface with the surrounding tissue," asserts Joachim B. Kohn, a chemistry professor at Rutgers University. As a result, the great majority of implants elicit a mild foreign-body response at the implant site, he says.

 
7906Microchip1 7906chip4b
COURTESY OF FELICE FRENKEL COURTESY OF RICHARD HOLMAN/MIT
DRUG DELIVERY Sealing medications in millimeter-sized packages with many tiny compartments may open a route to delivering multiple drugs in complex patterns. A poly(lactic acid) disk (right, in an early processing stage) can deliver its contents as it biodegrades and exposes inner chambers. A silicon device (left) developed by MicroCHIPS, Cambridge, Mass., can be programmed or activated externally to release chemical substances by dissolving thin films that seal drug-filled wells.

WHAT'S NEEDED are new materials whose designs stem from an understanding of mechanisms that control interactions between materials and cells, Kohn says. Biomaterials researchers like Kohn, who directs the New Jersey Center for Biomaterials, work at preparing the next generation of implantable materials with carefully tailored physical, mechanical, and chemical properties.

7906langer 7906sci4x
INNOVATORS Langer (left) and Kohn
Some of the newest substances function as scaffolds that promote tissue growth by providing a three-dimensional framework with qualities that invite favorable cell responses. These 3-D biological interfaces enable specific types of cells to attach to the scaffold, grow, and organize into functional tissues.

Biodegradable polymers take center stage in a great variety of research efforts. Materials that can decompose and disappear from the body are desirable for short-term applications in orthopedics, tissue engineering, and other areas, where, for example, a physician may need a device to hold a bone in place long enough for the body to heal.

When a temporary implant is no longer needed, ideally it would decompose--sidestepping the need for surgical removal. By using degradable materials for short-term implants, patients avoid follow-up surgeries and associated risks, discomfort, and cost. Doing away with certain types of follow-up surgeries also benefits health care systems by easing patient loads.

As Kohn points out, biodegradable materials may be the only option for some potential applications. For example, reconstructing functioning blood vessels requires materials that degrade in the body, he says, because nondegradable scaffolds occupy too much volume to allow tissues to regrow completely. But regardless of the intended applications, candidate materials for implant use must be evaluated carefully for toxicity, Kohn stresses, because all degradation products are released into a patient's body.

SYNTHETIC degradable sutures have been available commercially since the 1970s. Originally made from poly(glycolic acid) (PGA), early versions of the products degraded and lost their mechanical strength in just two to four weeks--too fast for some applications.

To broaden the range of uses, alternative sutures were made from copolymers of PGA and a more hydrophobic compound, poly(lactic acid) (PLA). PLA's hydrophobicity limits the extent of water uptake in the copolymer, which in turn reduces the rate at which the polymer backbone is hydrolyzed relative to PGA.

PLA, PGA, and their copolymers have been commercialized more than any other degradable polymer. The family of compounds is used to make sutures, bone pins, periodontal membranes, and other devices. And the polymers are currently under investigation for use as skin substitutes and still more applications. However, many cells do not attach themselves and grow efficiently on the PLA-PGA group of materials, suggesting that these substances may not be ideal tissue-engineering scaffolds.

 
7906microsperesSEM1 7906PLGA-Macrophage
COURTESY OF MIT
PLASTIC BALLS Micrometer-sized spheres made of biodegradable polymers such as poly(lactic-co-glycolic acid) (red in right photo) and poly( -amino ester) (left photo) can be used to transport therapeutic agents to specified targets like macrophage cells (nucleus appears blue) that can engulf multiple spheres.

SEARCHING FOR more effective scaffold materials, Kohn's research group examined the performance of novel polycarbonates in animal-bone-defect studies. The researchers found that polycarbonates derived from desaminotyrosyltyrosine ethyl ester [poly (DTE carbonate)] and a polymer made from the hexyl ester analog supported new bone growth throughout a yearlong investigation, unlike PLA reference specimens.

The group also noted that PLA implants elicited a mild foreign-body response. Specifically, a fibrous tissue layer encapsulated the PLA device, thereby separating the bone from the implant. According to the researchers, the interfering tissue was absent in the polycarbonate cases.

7906eye
COURTESY OF DUKE UNIVERSITY

SEALING WOUNDS Close-up of a rabbit eye shows a photoreactive polymer (stained green) that is used to seal a corneal wound with light and not sutures.

7906BigToe
ANCIENT PROSTHESIS
Applying modern pathology methods to a 3,000-year-old mummy, researchers at Ludwig Maximilians University, Munich, showed thatancient Egyptian physicians crafted wooden prostheses to help their ailing patients--in this case, a 50–60-year-old woman whose toe was amputated.
In a related study, Kohn and J. Russell Parsons, who is director of orthopedic research at New Jersey Medical School, and their coworkers discovered that small variations in the structure of polymers can have a large effect on bone-implant interfaces. Comparing implanted bone pins made of poly(DTE carbonate) with the butyl, hexyl, and octyl ester analogs, the team observed unexpected differences in the polymers' performance. Although the four polymers have very similar structures, poly(DTE carbonate) elicited the most favorable bone response [Biomaterials, 20, 2203 (1999)]. The novel degradable polymer is presently under review by the Food & Drug Administration, a preliminary step toward use in clinical trials.

Robert S. Langer, a chemical and biomedical engineering professor at Massachusetts Institute of Technology, has addressed the cell-affinity problem on PLA-PGA copolymers by designing new polymers with built-in adhesion sites for specific types of cells. Langer and coworkers have synthesized copolymers of lactic acid and lysine with pendant amino groups on the polymer backbone. The researchers attach peptides via the amino groups in lysine. The result is a polymer that can be custom-fit with amino acid sequences that can help guide cell behavior.

If polymers that function as effective cell hosts can be molded into shapes that mimic organs, then the synthetic materials can be used to engineer functional tissues. Langer and colleagues have followed that strategy successfully in several cases.

In one clinical trial, the research team implanted cartilage cells on a polymer scaffold shaped like a rib cage that was placed over the heart of a young boy who had severe chest deformities. The procedure caused new cartilage to grow, giving protection to the boy's vulnerable heart.

In another example, polymer tubes were seeded with urothelial cells, generating a replacement for an incomplete organ. The MIT group and their coworkers have used similar techniques in animal studies to grow blood vessels and pulmonary valves.

Polypyrrole is an electrically conducting polymer that Langer's group examined as a substrate to regrow nerves. The team experimented with the conducting polymer because PLA-PGA copolymers failed to support attachment of nervelike cells. The group reports that polypyrrole is an effective support for this application and that nerve regeneration activity doubles when a small voltage is applied to the polymer films.

New types of polyanhydrides have made a mark on the biomaterials world as part of drug-delivery devices. Langer's group designed and synthesized high-molecular-weight polyanhydrides composed of carboxyphenoxypropane units and sebacic acid functions. The materials were tailored to provide control over the degradation mechanism and rate and to have suitable physical properties.

Guilford Pharmaceuticals markets polyanhydride Gliadel wafers for treating a type of brain cancer called gliobla stoma multiforme, one of the most rapidly progressive and fatal of all cancers. The wafers consist of the new polymers impregnated with carmustine, a toxic antitumor medication. Langer explains that by implanting the wafers at the tumor site, the drug is contained in the brain where it is needed and does not cause liver and kidney damage, as it would if the drug were administered intravenously.

A new route to sutureless wound closing calls for polymerizing a sealing material directly in the wound site. Mark W. Grinstaff, an assistant professor of chemistry and ophthalmology at Duke University, approaches the medical problem using in situ photopolymerization.

Working with graduate student Kimberly A. Smeds and postdoctoral fellow Anne Pfister-Serres, Grinstaff prepares flexible hydrogels by photo-cross-linking hyaluronan, a polysaccharide [J. Biomed. Mat. Res., 54, 115 (2001)]. The material has the potential to seal irregularly shaped defects using a minimally invasive procedure, Grinstaff says. The Duke researcher points out that, in principle, the extent of covalent cross-linking can be tailored to prepare optimized hydrogels for specific applications. The method has been used successfully in recent animal studies to seal corneal perforations.

Like their organic counterparts, degradable inorganic compounds also play a part in biomaterials research. For example, a porous form of -tricalcium phosphate has recently been commercialized by Orthovita, a supplier of orthopedic materials in Malvern, Pa., for repair ing bone voids and other defects in the spine, pelvis, and extremities.

Orthovita's vice president for research and development, Erik M. Erbe, says the company's low-temperature redox precipitation process leads to nanosized particles that form scaffolds with 90% interconnecting porosity. "The porosity of the scaf-fold allows cells, blood, and nutrients to flow through the defect site, helping the body heal normally by converting calcium phosphate into bone mineral."

Neil M. Blumenthal, a professor of periodontics at the University of Illinois, notes that biomaterials have advanced oral medicine in many ways. For example, polymer tubes containing antibiotics are placed under patients' gums to prevent periodontal diseases. The devices that were available five to 10 years ago, he says, released medication too quickly and were difficult to implant successfully. Today's devices are more effective.

Likewise, synthetic graft materials used a decade ago to correct bone defects were simply filler materials that may have had toxicity problems, Blumenthal says. Today, periodontists can complete those procedures using biodegradable polymers that carry growth factors and support tissue regeneration. Blumenthal adds that multilayered polymers that release various growth factors at predetermined intervals may be available in the future.

Indeed, biomaterials have already made a huge impact on medical practices, Langer says. "But the opportunities that lie ahead of us are enormous." Tissue engineering and related subjects "have the potential to change paradigms" for treating diseases that today cannot be treated effectively--like certain forms of liver failure, paralysis, and cardiac disorders.

"Clearly we are faced with big challenges," Langer acknowledges. "But the message I try to get across, especially to young students, is that the field holds tremendous promise."

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7906VTScaffold 7906image1
COURTESY OF ORTHOVITA
MICROSCOPIC LABYRINTHS Scaffolds with micrometer-sized interconnecting passageways aid in tissue- and bone-healing processes by promoting vascularization and providing means for cell-to-cell contact. Bottom, poly(DTE carbonate) developed at Rutgers University, and top, -tricalcium phosphate.



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RAW MATERIALS

Legislation Helps Keep Supplies Coming

Thanks to recent advances in science and engineering, the field of biomaterials stands poised to increase the effectiveness and longevity of established devices as well as to provide new options to biomedical engineers who work at designing future products. Nevertheless, some experts warn that legal worries, regulatory concerns, and other issues are impeding innovation and hampering progress.

Just a few years ago, many medical researchers forecast a dismal future. High-profile product-liability lawsuits, such as silicone gel breast implant cases, were scaring biomaterials suppliers out of the marketplace. Costly litigation expenses had to be paid, even when manufacturers were found not liable for damages.

"Yes, there is a biomaterials crisis," testified Neil Kahanovitz before a House committee on Capitol Hill in 1997. Kahanovitz, who is director of orthopedic spine surgery at Washington Hospital Center in Washington, D.C., noted at that time that 14 raw material suppliers had already stopped supplying products for use in medical devices.

Kenneth M. Kent, director of the Washington Cardiology Center, Washington, D.C., pointed out at the same congressional hearing that raw material producers sell less than 0.005% of their industrial production to medical device manufacturers, yet they spend millions of dollars each year on medical-device-related legal costs defending themselves. Because of their large assets, major chemical companies are named in liability suits, even though a medical device at the center of a court case may include just a few pennies' worth of the suppliers' polymers, for example.

"What's happening in the industry is that the DuPonts and the Dows are getting out of the business because of the issues," James E. Brown, a vice president at Alza, a pharmaceutical company, told the committee. Brown added that small manufacturers were stepping in to fill the supply void. However, those companies were only supplying generic products and had no research programs in place to develop new and innovative materials.

Today, many researchers share an optimistic but cautious outlook. Following debates on Capitol Hill, President Bill Clinton, in August 1998, signed into law the Biomaterials Access Assurance Act, which provides liability protection to manufacturers that supply raw materials and components for making medical devices but are not involved in design, development, or other aspects of the end products.

"Clearly, the act has had a palpable positive effect on the availability of raw materials and components," Paul Citron tells C&EN. Citron is vice president for science and technology at Medtronic, a Minneapolis-based manufacturer of cardiac pacemakers and other implantable therapeutic medical devices.

Citron speaks of a colleague who, in the mid-1990s, spent "the vast majority of his time" visiting suppliers that had pulled out of the medical materials supply market, trying to convince the companies to resume manufacturing. "The mood is better now," Citron says. The legislation has offered the industry "a partial remedy" for its supply problems, he explains. "We're no longer in a crisis mode of operation."

Michael Jensen, a manager with CarboMer, a manufacturer of functionalized biopolymers and specialty chemicals in Westborough, Mass., says the law has encouraged his company to enter markets that it would have otherwise avoided. "We are entering carefully. There's no carte blanche to do whatever you want. Responsible companies still have to make sure that the materials they provide are of suitable quality." But CarboMer and other suppliers point out that the protection afforded by the legislation has not yet been tested thoroughly in court.

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