Better Together

Adding a drug or biologic to devices offers a wide range of benefits in orthopedics.

Stacey L. Bell
Editor-at-Large

Peanut butter and chocolate. Two-in-one shampoo and conditioner. Your favorite tunes and surround sound. Combining two great products into one new innovation often creates an even better user experience, and increasingly, orthopedic companies are finding that adding a new element—such as a drug or biologic—to an implant is giving products, and their users, a whole new life.

The medical device combination products market is growing exponentially, reaching nearly $6 billion in sales in 2003, with a projected $10 billion market share by 2009, according to Front Line Strategic Consulting, Inc. Within the orthopedics sector, however, probably less than 10% of the products currently available fall under the converged technology umbrella, estimated Mark N. Melkerson, director of the FDA’s Division of General, Restorative and Neurological Devices. Change is slower to come to a specialty in which devices are implanted within the human body.

“Many technologies are being worked on, but they’re being introduced gradually. In orthopedics, advances occur at a deliberate, evolutionary pace more often than at revolutionary speed,” agreed John McCormick, managing director at HealthPoint Capital, a private equity and research firm in New York City. “Many of these new technologies seem promising, but remember that very little revenue today is coming from such technologies. The vast majority of revenue is generated by metal screws, joints, cages and the like. People talk about these fantastic technologies coming down the road, but in many cases, they’re still very far down the road.”

True, much development continues to be focused within scientific settings rather than in clinics. That said, newer innovations will have a tremendous impact in years to come. From devices that incorporate antimicrobial agents to prevent surgical infection, to smart implants that monitor not only themselves but surrounding tissue, to bioengineered tissue that promotes faster healing, change is in the air.
    

Battling Bacterial Colonization

“After decades of experience, we have well-defined designs for the hip and knee,” noted Ozan Akkus, PhD, associate professor at the Weldon School of Biomedical Engineering, Purdue University in West Lafayette, IN. “One area still ripe for development is spinal implants. The artificial disc concept is a blooming field. But another overarching question for manufacturers is, what can be done to improve implants further? So they’re looking for better materials and technologies to optimize their designs. Increasingly, they’re finding a synergy between orthopedic implants and drugs. One emerging technology is implants that have drugs associated with them to fight against infection as well as anti-resorptive agents that block the loss of bone in the immediate vicinity of implants.”

One product that incorporates antimicrobial agents is TyRx Pharma, Inc.’s PIVIT AB, a surgical mesh coated with a proprietary bioresorbable polymer containing the antimicrobial agents rifampin and minocycline. PIVIT AB was introduced to the marketplace in late 2006, nearly one year after TyRx’s first, tyrosine-based bioresorbable polymer-coated surgical mesh debuted. Tyrosine is a naturally occurring, benign amino acid in the human body. As TyRx’s mesh resorbs, it releases antimicrobial agents into the body over a period of one to two weeks.

To use INFUSE Bone Graft, surgeons reconstitute the rhBMP-2 powder with supplied sterile water and then apply it to collagen sponges. The sponges are inserted inside each of two LT-CAGE Lumbar Tapered Fusion Devices, which are then implanted between the vertebrae. Photo courtesy of Medtronic, Inc.

“The unique properties associated with PIVIT give the surgical mesh good handling characteristics that facilitate precise placement during the surgical repair and leave less implant material following the resorption of the bioresorbable polymer coating,” said Bill Edelman, CEO of TyRx, which is based in Monmouth Junction, NJ. “We believe that less implant material will help to facilitate patient comfort…and the addition of antimicrobial agents in PIVIT AB will help provide protection from microbial colonization of the device during surgical implantation.”

External fixation devices have rates of infection in the double digits, because wire penetrates the skin or bone and acts as a conduit between the inside of the body and the outside, germ-ridden world, Edelman noted. But even implants can have a relatively high incidence of infection.

Edelman pointed out that several independent studies have confirmed the high cost of infections in the US healthcare system today. Infection Control Today reported in 2003 that treatment of each infection related to invasive medical devices can cost from $34,000 to $56,000, adding up to nearly $2.3 billion annually in avoidable expenditures. In 2004, the New England Journal of Medicine noted that half of the two million cases of nosocomial infection that occur each year in the United States are associated with indwelling devices.
 
“Many states now are considering legislation and the public gathering of data on the incidence of infection,” Edelman said, noting that such data may soon be a criterion on which hospitals are measured. As new markets develop for technology that counteracts infections, TyRx has positioned itself to take advantage of the opportunity. In January, it signed a strategic alliance agreement with C.R. Bard.

In the future, experts expect more implants, such as artificial knees, to be coated with polymers that will release successive doses of anti-inflammatory drugs as needed. “We see lots of points of light today in the market where convergence is starting to make real inroads,” McCormick said. “Much discussion today is centering around products such as putties—bone fillers with drug-eluting properties—and drug-eluting implants that incorporate anti-inflammatory, anti-infectious and other pharmaceutical layerings on implants.”

Of course, infection isn’t the only problem that can occur with implanted devices. Therefore, TyRx identified common areas of concern, regardless of an implant’s use, intent or location. It found that infection, associated pain and scar capsule entrapment were the most common morbidities associated with implanting a medical device, and thus, the company is focusing on creating products that will reduce these problems, Edelman said.
    

Getting Smart

Another emerging development is “smart” implants that alert health professionals about the state of a patient’s recovery. For instance, a smart implant, fitted with RFID technology, can warn the health team about an impending fracture or degradation.

“Say the polyethylene lining on a titanium implant is loosening. A smart implant can alert medical staff, allowing them to take corrective action early, before more extensive damage occurs,” Akkus said. “[These implants] also can warn if too much stress is being applied and help prevent bone destruction.”

Patient, Heal Thyself

Once considered a pipe dream, regenerative medicine—in which “smart” biomaterials trigger specific cellular responses at the molecular level, in effect, stimulating the body to heal itself—is closer to becoming a reality. Companies are searching to identify growth factors (or bone morphogenetic proteins, BMPs) that will allow patients to help heal themselves and, in the process, permit faster healing, less pain and more mobility.

“Everyone seems to be looking to identify growth factor products, mainly in the spine area,” Melkerson noted.

The first growth factor product to be approved by the FDA was the INFUSE Bone Graft/LT-CAGE lumbar-tapered fusion device by the Sofamor Danek division of Medtronic. The device is implanted in the lower region of the spine as a treatment for degenerative disc disease. The device is used in lieu of the patient’s own bone, which would have to be harvested from elsewhere in the body, adding risk, pain and weeks to the recovery period.

“INFUSE replaced autograft being packed into the spinal fusion cage. This product recruits cells that help the bone to form, in many instances, depressing other osteoclasts,” Melkerson noted, adding INFUSE originally gained approval in 2002.

INFUSE is composed of a solution containing rhBMP-2 (recombinant human bone morphogenetic protein 2) and an absorbable collagen sponge. The solution-soaked sponge dissolves over time, but first acts as a scaffold for the formation of the new bone that the protein stimulates, Medtronic noted. In 2004, the FDA granted approval for the use of INFUSE Bone Graft in open tibial fractures under certain conditions. Medtronic estimates that more than 250,000 patients have used the product to date.

BioMimetic Therapeutics, Inc. in Franklin, TN is in the midst of conducting a US pilot study for its GEM OS1 Bone Graft in foot and ankle fusion indications, in accordance with the FDA’s approved Investigational Device Exemption (IDE). In a December 2006 news release, the company reported that interim findings showed patients experience less pain and improved function with the GEM OS1, and the average operative time is less for the GEM OS1 group (118 minutes) compared with the autograft patients (144 minutes).

“The evidence supporting our GEM technology as a potent stimulus for bone regeneration continues to build,” Samuel Lynch, DMD, DMSc, president and CEO of BioMimetic said in that news release. “We have now seen similar performance of GEM OS1 in two different foot and ankle fusion studies, demonstrating bone regeneration at least comparable to autograft.”

Turning to Biologics

Another developing trend is increased use of biomaterials—new, alternative materials (as opposed to the metals, plastic and ceramics that are mainstays of orthopedics today). “The use of implants that are resorbable and that remodel bone or tissue along with the body’s own natural healing processes will become more common,” McCormick said. “Rather than have a metal plate construction to treat a fracture, surgeons may instead use a plastic version that degrades in the body over time.” Thus, the device would deliver healing medicine, provide a framework for the new tissue or bone to cling to as it grows and then ultimately be absorbed into the body.

McCormick also is seeing more companies making use of new materials such as pyrolitic carbon in small-joint procedures and diamond-on-diamond articulating surfaces in joint implants.

“Orthopedics is not just about bones. Orthopedics also is about muscle, ligaments, tendons and cartilage. Soft tissues can be characterized as more complex, so while solutions to address problems in these areas are being developed, they may be slower to come onto the market,” McCormick said.
 
“The Holy Grail in orthopedics today is cartilage repair,” he continued. “There is no adequate solution on the market today. Evolutionary steps have been taken by companies such as OsteoBiologics, which was recently acquired by Smith & Nephew, but we’re a long way away from true cartilage replacement. Once cartilage is developed, it could supersede the need for hip and knee replacements. The cartilage could be replaced before the hip or knee ever becomes a problem.”

Indeed, as new innovations are introduced, the very way medicine is practiced has evolved. “Surgeons used to cut off the ends of bones and replace them with metal and polymers,” Melkerson noted. “Now, many manufacturers are looking at products and thinking, ‘Rather than cut off bone, is there any way to repair the cartilage?’ They’re moving away from hard plastics and materials and trying to develop products to replace actual tissue. In the joint area, they started by trying to fuse bone together, then they started using metal and plastic, and now they’re working to regrow tissue and repair damage.”

In fact, biologics eventually may be a good alternative to traditional implants, Akkus said. “Currently, biologics [artificial and reengineered tissues] don’t account for a lion’s share of the market, but the expectation is that this area will grow and ultimately be a technology that will replace metal and polymer implants,” he explained.

A meniscus fixation device currently under development by Schwartz Biomedical, LLC in Fort Wayne, IN is expected to come online by year’s end. Each year, more than one million people injure or suffer tears in their meniscus, a shock-absorbing tissue that provides articular cartilage in the knee. “This tissue doesn’t have a high propensity for healing, and it has to be removed surgically,” explained Herb Schwartz, PhD, president and CEO of Schwartz Biomedical. “This new product will allow surgeons to fix this tissue so that healing can occur without having to remove the tissue.” The synthetic product is implanted arthroscopically.

Schwartz also expects several more of his company’s innovations to improve the healing environments in other parts of the body and enter the marketplace soon. Among them are a rotator cuff device, an articulate cartilage application and a ligament-tendon application. He’s also interested in angiogenic factors (which cause blood vessel formation, further improving the healing environment as blood supply to the area increases). Schwartz added that since these types of products require IDE and pre-market approval applications, it will be years before they become available to the public.

Building a Bridge to Tomorrow

Even as manufacturers are developing biologically advanced scaffolds and other innovations, they are running into some very down-to-earth problems.

The regulatory pathway can be challenging, particularly for companies that are relatively new to the industry. “Commercial entities that focus on pre-clinical evaluation of product function and biocompatibility can help companies get their products approved more efficiently,” Akkus recommended. “Another resource is academia. We can help conduct experiments and evaluate products.”

Reimbursement is another hurdle.

“A 1960s’-style, straightforward metal hip implant might cost $700, and an antibiotic bone cement hip implant may cost four times more. A lot of healthcare decisions today are cost driven,” Melkerson noted. “Manufacturers have two hurdles to get through: regulatory [FDA] and reimbursement [CMS]. A lot of manufacturers don’t look at the second step until they get FDA approval. That can be a problem. Our threshold for product approval is, is it safe and effective? CMS’s is, is it reasonable and necessary? Although in practice that could be read, is it a cost-effective alternative? These two thresholds are not the same, so we recommend that product sponsors invite CMS to their meetings at the FDA so they’ll have the input of both organizations and can address all concerns in their study design.”
 
Another roadblock can be sterilizing these new innovations. “The toxicity due to residual amounts of ethylene oxide left in implants and biomaterials can be a concern. Autoclaving can melt plastic and natural components. Gamma radiation is most popular and convenient for these types of developments, but it can damage the mechanical properties of polymers and natural tissues,” Akkus said. “Therefore, sterilization that will preserve biomechanical properties while maintaining tissue sterility is another area ripe for development. Liquid carbon dioxide is one emerging technology used to sterilize these products. It protects polymers without protecting germs.”

Finally, some experts noted that surgeon acceptance of new innovations may be a barrier to market success as well. “There can be a high level of unwillingness to change one’s practices, so manufacturers need to prove to surgeons that the new innovation is much better than the existing solution,” Akkus said. Whether that’s because the product significantly reduces patient pain, recovery time or function, or streamlines or simplifies the actual surgery, gains must be documented, and it is best if those claims come from an independent source.

Independent verification of an innovation’s benefits, along with the outstanding gains the product delivers, will make for a winning combination.

Editor’s Note: The developers of Medtronic’s INFUSE bone graft, BioMimetic Therapeutic’s Gen OS1 bone graft matrix and TyRx Pharma’s PIVIT antimicrobial, bioabsorbable-coated surgical mesh will be discussing their technologies at PharmaMedDevice, April 24-26 in New York, NY. For more information, visit www.PharmaMedDevice.com.

Stacey L. Bell is a freelance writer who specializes in business and marketing issues. She is based in Tampa, FL.