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Biological Building Blocks

The shortcomings of man-made materials are driving research and innovation in the growing orthobiologics market.

Time machines are fictional contraptions, existing solely in the creative imaginations of writers like H.G. Wells and the mesmerizing ingenuity of filmmakers such as Steven Spielberg and James Cameron. If they really did exist, though, Chris Fair would readily hop on one and travel back a decade to the day he underwent surgery on his big toe.


Months before that day, Fair was diagnosed with bone spurs in the metatarsophalangeal (MTP) joint in his right foot, a condition that keeps the toe from bending properly. Such rigidity can be painful, particularly during activities such as walking or running, when the MTP joint acts as a springboard for movement. Fair was suffering from hallux rigidus—clinical jargon for a stiff big toe.


Not one to delay surgery when necessary, Fair underwent a 1st MTP cheilectomy, a fairly common procedure that removes bone spurs and part of the foot bone to improve flexibility in stiff big toes. The remedy is most effective for patients such as Fair who have bone spurs on the top part of their big toes; it generally is not used to treat people with arthritis throughout the MTP joint.


Though the surgery was successful, Fair still experiences pain in his big toe once in a while—mostly when he wears new shoes, runs for long periods of time, or bounces his right MTP joint in certain ways. The pain could signal another problem with bone spurs or arthritis, but Fair knows enough about the condition and about biology to recognize the true source of his occasional discomfort: scar tissue.


“In a cheilectomy, the surgeon goes in and cleans out the toe joint. You’re left with a big scar on top of your toe,” Fair said. “If I was to have my toe opened up again, there would be a tremendous amount of scar tissue on top of the bone and that canimpinge upon the joint. But if you perform surgery on that area again, what are you going to end up creating? More scar tissue.”


Fair has no desire to create any more scar tissue in his big toe. And since he’s not a candidate for a great toe fusion or a first MTP joint replacement (those procedures are reserved for patients with particularly damaging arthritis in the big toe joint), Fair has little choice but to live with the pain from his scar.


Few outside the medical device industry can truly appreciate (or understand) the irony of Fair’s current lot in life: Enduring the sporadic pain from his big toe scar despite having access totechnology that possibly could permanently eradicate the discomfort. Fair is president, founder and CEO of Amniox Medical Inc., aMarietta, Ga.-based developer of regenerative tissue therapies. The company’s signature product is a graft harvested from humanamniotic membrane (AM), or the inner-most layer of the placenta. These membranes are considered ideal candidates for tissueregeneration due to their abundance of epithelial cells (whichscientists claim are better suited to tissue regeneration than stem cells) and their ability to help reduce swelling, guard against infection, and—much to Fair’s delight—minimize scarring. Humanamniotic membrane tissue also has low immunogenicity, meaning it will not trigger an attack from the body’s own immune system, a fairly common consequence of man-made orthopedic implants.


Virtually since the dawn of musculoskeletal medicine, mankind has tried—and failed—to replace Mother Nature’s biological masterpieces with synthetic substances, using everything from glass, rubber, wood, ivory and copper to stainless steel, aluminum, titanium, tantalum, cobalt chromium, ceramic and plastic. While some of these materials have shown promise, none have been able to replicate the biochemical ingenuity of the human body.


Metals such as stainless steel and cobalt chromium, forinstance, have been used alone or paired with plastics such as highly crosslinked polyethylene (known by the trade name Durasul) to replace worn-out or diseased hips and knees. But concerns over potentially harmful wear debris have inspired implantdesigns that incorporate alternative materials like ceramic, which is naturally hard, smooth and less susceptible to wear than either metal or plastic. Ceramic, though, is not without its own drawbacks: The toughness that makes it so resistant to wear also makes the substance brittle and somewhat inflexible. As a result, ceramic hip replacements are more prone to “catastrophic failures” than their metal or combination metal/plastic counterparts. (Proponents of ceramic joint replacements argue that improvements in production have significantly lowered the risk of “catastrophic failures” to about 1 in 25,000).


“People are realizing the shortcomings of man-made synthetic technologies and as a result, there is a move away from the man-made synthetic materials to re-generative biologic therapies,” Fair noted. “If you look at medicine in general, patients are closer tobecoming the buyer so they are becoming more educated. Patients are much moreeducated now than they were five years ago and I see that trend continuing. So, ifpatients are given the option of having something synthetic implanted versus something that is made from humans and has a clinical history, I think patients are going to request the biologic product. As for companies that focus on synthetics—if there is abiologic product that can replace the synthetic, the biologic product will take over.”


Such a conquest already has begun. While companies have not totally abandoned man-made implants—DePuyOrthopaedics Inc., Smith & Nephew plc and Zimmer Holdings Inc., among others, all have recently introduced new jointreplacements using man-made materials—they are making significant investments in orthobiologics firms and pouring millions of research dollars into regenerative medicine and stem cell technology to treat various musculoskeletal maladies.


Stryker Corp. perhaps best illustrated the importance of this growing industry to traditional implant manufacturers with the $316 million purchase of Orthovita Inc. last spring. Based in Malvern, Pa., Orthovita considers itself a leader in the nearly $5billion global orthobiologics sector, having developed bone graft and regenerative products that include the Vitoss Bone Graft substitute, Cortoss Bone Augmentation material, Vitagel Surgical Hemostat (acollagen-based matrix that controls both intra and post-operative bleeding) andVitasure Absorbable Hemostat (a plant-based product that can be deployed quickly throughout surgery). The companyreported about $95 million in 2010 sales, but had yet to turn a profit at the time of its purchase. Stryker executives hope to end that revenue drought by integrating Orthovita’s products into its own varied stock, which consequently, will leverage the Kalamazoo, Mich.-based firm’stechnologies and expertise in biomaterials.


Both Smith & Nephew and Zimmer are targeting similar goals with their own ventures into the orthobiologics sector. Just two months after the U.S. debut of its CLS Brevius Hip Stem with Kinectiv technology, Zimmer announced a collaboration with ISTO Technology Inc. on a Phase III clinical study to evaluate the efficacy of engineered juvenile cartilage to repair damaged knees. The randomized, controlled clinical trial will involve 225 patients at up to 25 centers in the United States who will help researchers determine whether ISTO Technology’s DeNovo ET Engineered Tissue Graft is better at treating damaged knee cartilage than traditional methods.


In preclinical studies, cartilage cells harvested from juvenile tissue demonstrated a significantly greater capacity for regenerating cartilage compared with cells taken from adult cartilage, according to ISTO, a St. Louis, Mo.-based developer of spinal therapy, sports medicine and trauma products.


Smith & Nephew performed a similar juggling act earlier this year with the spinoff of its Biologics & Clinical Therapiesoperation in January and the introduction of a new hip replacement system to the U.S. market in February. The biologics unit will be owned by global life sciencesinvesting firm Essex Woodlands and will operate under the new name Bioventus LLC. Under terms of the deal, Essex Wood-lands will own 51 percent of Bioventus while London, United Kingdom-headquartered Smith & Nephew will retain a 49 percent stake in the joint venture. The deal also calls for Smith & Nephew to receive $98 million in cash, which will be used to pay down debt, as well as a $160 million five-year note from Bioventus.


The Biologics & Clinical Therapies division is one of three global units at Smith & Nephew. Revenue has more than quadrupled over the last six years, going from $52 million in 2004 to $223 million in 2010. Its focus on less invasive treatments to musculoskeletal disorders has resulted in the development of Durolane Hyaluronic Acid (available in Europe and Canada but not yet in the United States) and Exogen, a bone healing system that uses ultrasound to heal fresh fractures up to 38 percent faster than traditional methods. The unit’s Exogen technology also can effectively treat non-healing fractures.


“We see tremendous growth potential with this new venture as more patients discover how active products can help heal and treat joint and bone ailments without invasive surgery,” Marty Sutter, founding partner and managing director of Essex Woodlands, said when the partnership with Smith & Nephew was announced. “We applaud Smith & Nephew for their forward thinking in working with Essex Woodlands and our partners in this venture. No one has created such a platform for innovation before.”


Maybe not, but Smith & Nephew clearly is not the first (or only) company to develop biological therapies for the body’s skeletal system. Fair’s firm, Amniox Medical, aims to introduce the mind-boggling healing powers of amniotic membranes to the podiatric and orthopedic sectors, targeting thosesuffering from such ailments as damaged Achilles tendons, diabetic ulcers and back pain. The company began its formalintroductions in early March, debuting the technology at the 2010 Annual Scientific Conference of the American College of Foot and Ankle Surgeons in San Antonio, Texas.


Though the technology has existed for at least seven decades, AM grafts onlyrecently have become an accepted form of therapy; they mainly are used in the ophthalmology sector to treat conjunctival and corneal diseases, chemical and thermal burns, refractory and recalcitrant keratitis, dry eyes and corneal scars.


Amniotic membranes have various characteristics that make them ideal candidates for tissue regeneration. For starters, the epithelial layer of these membranes contain cells that act in a similar fashion to stem cells but can be differentiated into the three embryonic germ layers that are the embryonic source of all human cells—the mesoderm, endoderm and ectoderm. In addition, the extracellular matrix components of the basement membrane from the AM include collagen, fibronectin, laminin and other proteoglycans (heavily glycosylated proteins) important for over-lying cell growth, according to clinical data.


The AM grafts Amniox Medical hasdeveloped under the brand name NEOX are preserved through a patented process called Cryotek, which maintains the membrane’s innate biological potential. The company’s NEOX grafts come in various sizes and thicknesses—the NEOX 100 ranges from 2.0 x 2.0 cm. to 7.0 x 7.0 cm., while the thicker, more durable NEOX 1k run the gamut from 1.5 x 1.5 cm. and 2.5. x 2.5 cm. to 4.0 x 3.0 cm. and 6.0 x 3.0 cm.


The company is technology partners with Bio-Tissue Inc., a Miami, Fla.-based firm that procures, processes, stores and distributes cryopreserved human amniotic membrane. The company’s signature products are the AmnioGraft and Prokera, both of which are used strictly by ophthalmologists. The AmnioGraft, according tocompany data, are 50-100 µm thick and available in four sizes to fit any sizedocular defect, while the Prokera—classified by the U.S. Food and Drug Administration (FDA) as a Class II medical device—is a cryopreserved amniotic membrane clipped into a thermoplastic ring set.


Bio-Tissue’s products and Amniox Medical’s NEOX grafts have been used in more than 100,000 implant cases worldwide, Fair claims. In ophthalmology, the treatment’s efficacy is proven by 15 years of clinical research data that show AM grafts can replace the eye’s surface and temporarily act as a support matrix,helping eye tissue to heal. The abundance of such data is still missing in orthopedics, where surgeons have begun to use it torepair damaged Achilles tendons, reverse Tarsal Tunnel Syndrome (compression of the tibial nerve or its associated branches), improve the healing of dermal wounds, and in a cruel twist of irony for Fair, eliminate bone spurs on the big toe.


“In orthopedics, tendonitis and wound healing are the primary markets for this,” Fair told Orthopedic Design & Technology. “But we’re also looking at spinal procedures as well. When you have spinal surgery, the chances of you being operated on again are very high because scar tissue is one of the biggest problems for surgeons and patients. Scars adhere to blood vessels and other areas, and that just creates more complications for the surgeon. There’s apatient population out there that subscribes to the theory that you have to live with what you have. People have alwaysaccepted the fact that when you sustain an injury, you will get a scar. That’s a great door opener for us. It’s a great way for us to come in and say ‘How would you like not to have a scar?’ Let me tell you something, if I could go back in time and take this technology with me, I would absolutely be willing to use it on my first MTP.”


The Great PRP, BMP Debates
Fair also may want to pack some other revolutionary technology for his illusory trip through time. But the choice could prove difficult for him, consideringthe plethora of tools currently available in the orthobiologics sector: recombinant growth factors, synthetic matrices, bone void fillers, stem cell therapies, 3-D printing (also known as “bioprinting”) and platelet rich plasma.


Like Fair’s amniotic membrane grafts, platelet rich plasma (PRP) is not a new concept. Born in the early 1970s as a byproduct of multicomponent apheresis (the withdrawal and separation of blood into several parts), the expertise originally was used for graft storage. But refinements in technique and technology as well as a general discontent with available treatment options put PRP on the same path to mainstreamacceptance as those amniotic membrane transplants. By the late 2000s, the treatment had become so popular that patients with orthopedic injuries—arthritis and tendonitis —were willing to foot the bill for it themselves. Endorsements from professional golfer Tiger Woods, Los Angeles Lakers shooting guard Kobe Bryant, U.S. Olympic swimmer Dara Torres, and Pittsburgh Steelers players Troy Polamalu and Hines Ward only added to PRP’s appeal.


“Orthopedic doctors and sports medicine doctors are reporting to us that they are getting phone calls from patients saying, ‘I don’t want steroid injections anymore because it’s damaging my knee. I just heard that Dara Torres got this biological injection and she’s doing great. That’s what I want,’ “ Martin Rosendale said. “Three years ago, when Hines Ward was in the Super Bowl, the announcer came on before the game started and said he [Ward] had just received knee injections of platelet rich plasma. My cell phone then began ringing and it continued throughout the gamebecause everyone was calling me asking, ‘Is that what you do?’ “


The answer is more complicated than a simple yes or no. Rosendale is CEO ofCytomedix Inc., a Gaithersburg, Md.-based biotechnology firm that develops advanced tissue regeneration technologies. Its two main FDA-approved products—the Angel Whole Blood Separation System and the AutoloGel PRP System—use platelets and platelet derivatives to better manage wound healing.


Most PRP procedures are fairly uncomplicated processes: Blood drawn from apatient is put in a centrifuge to separate the plasma from red blood cells. The resulting solution, containing concentrated amounts of growth factors and platelets (tiny colorless bodies that release tissue-repairing substances), then is injected back into the patient at his or her injury site. The procedure is, in its basic form, an attempt to mimic the healing process of wounds by accelerating the healing signals a swollen injury site sends to the body.


Proponents of PRP therapy have not been shy about touting its benefits. Bruce Reider, M.D., editor of The American Journal of Sports Medicine, claimed in a 2010 editorial that PRP should perhaps be called “platelet-rich panacea.” Skeptics have been just as vocal, noting that some studies have found the therapy to be about as effectiveas saltwater.


Regardless of its perceived efficacy, PRP remains a viable and widespread treatment for many orthopedic afflictions. Cytomedix uses the technology to produce a gelcontaining growth factors, cytokines and chemokines that is applied to the wound bed. The AutoloGel System, according to the company’s website, is used to treat leg ulcers, pressure ulcers, diabetic ulcers and in the management of mechanically orsurgically debrided wounds. It alsoincreasingly is being used during spinal

fusion procedures.


The Angel Whole Blood Separation System features adjustable volume and concentration settings that enable clinicians to customize indication-specific PRP formulations while the activAT Autologous Thrombin Processing Kit can produce autologous thrombin serum from platelet-poor plasma.
Cytomedix acquired both products in 2010 from the Sorin Group, a global firm that develops, manufactures and markets medical technology for cardiac surgery and the treatment of cardiac rhythm disorders. The technologies currently in development at Cytomedix straddle both the cardiac and orthopedic sectors, giving patients a new way to regenerate damaged or disease tissue. The technologies, like many others in the works throughout the orthopedic industry, is being driven in part by aging baby boomers who are looking for new ways to stay active and healthy as they approach retirement.


“Not only is demand growing because the population is increasing,” Rosendale noted, “but the need or the desire to findalternatives that allow individuals to maintain high levels of activity provides new

demand in the marketplace today and is driving development of these technologies.”


That demand is part of the driving force behind the proliferation of bone growth products as well. Initially isolated in 1965 by orthopedic surgeon Marshall Urist and first commercialized in the late 1990s, bone morphogenic proteins (BMP) and similar products have helped orthopedists manipulate cellular behavior in or near an injury or reconstruction site. BMPs are used primarily as a substitute for iliac crest bone grafts during spinal fusion and tibial fractures.


For much of the last decade, the U.S. market for recombinant human BMPs consisted of two main products—OP-1 (orrecombinant human BMP-7) from Stryker (the company has since sold its OP-1 product line to Japanese medical equipment maker Olympus Corp. for $60 million) and Infuse (known clinically as recombinant human BMP-2) from Medtronic Inc.’s Spinal and Biologics division.


Medtronic’s days of dominance in this market may be numbered, though. A U.S. Justice Department investigation intoalleged off-label marketing of Infuse and a simultaneous probe by the U.S. Senate over purported omissions of safety problems from the product’s clinical trials have triggered a double-digit slide in rhBMP-2 sales. Adding to the misery is a 2011 study in The Spine Journal that linked BMPs and pancreatic, breast and prostate cancers. Medtronic executives are hoping the product’s safety and efficacy will be validated by an independent review from Yale Universityresearchers. With Infuse sales sliding and confidence in the product waning, there’s little hope among analysts that Medtronic can ever regain its market supremacy, even if the Yale review confirms the bone graft’s safety. Not surprisingly, there are a slew of candidates ready to fight for Medtronic’s share of the bone morphogenic protein pie—the soldiers include NuVasive Inc., which sells Osteocel Plus (this company is one of Medtronic’s main rivals; the two currently are embroiled in a patent lawsuit); Orthofix Biologics, a division of Orthofix Holdings Inc., maker of Trinity Evolution; and Orthovita (now part of Stryker), developer of Vitoss.


These warriors, however, could face some serious competition from lesser-known firms with newer technologies in development. OsteoGeneX Inc., a tiny Kansas City, Kan., firm, is working on a treatment for osteoporosis through the manipulation of a bone-inhibiting gene called Sclerostin. Found in osteocytes, Sclerostin works its chemical magic byinterfering with a process known as Wnt signaling, which helps regulate bonecreation. Research indicates that Sclerostin also may promote the self-destruction of bone cells, further inhibiting growth.


With such a basic understanding of skeletal growth impediments, then, the recipe for building bone should be relatively simple: “Sclerostin binds to the Wnt pathway co-receptor [LRP] and this is how it regulates bone formation and density,” President, CEO and Board Chairman Debra Ellies, Ph.D., explained. “So if you inhibit the inhibitor, you’ll build bone.”


Bacterin International also is working to build bone with a demineralized graft material that resembles a small sponge (hence, the moniker OsteoSponge). The FDA-approved product is derived from

trabecular bone and provides a natural scaffold for cellular ingrowth. The material also exposes bone-forming proteins necessary for healing, company executives claim. Last fall, the Belgrade, Mont.-based firm published results of a small clinical trial that showed the OsteoSponge to be equally as effective as Infuse in spinal fusion procedures. If Bacterin can translate that positive data to a larger clinical trial, it might seriously have a shot at dethroning Infuse.


“I think surgeons will be looking now for products that have a more comprehensive growth signaling profile,” noted Caroline Corner, an analyst with investment bank MLV & Co. “Bacterin’s study does not include a huge data set but they’ll be adding to it. And it could be very promising for them. There have been some early adopter surgeons who really like the product. And [OsteoSponge] is broadly applicable. There’s a lot of promise here.”

* * *

Once Fair—Amniox Medical’s president and CEO—concluded his fictional trip to the past to repeat his bone spur surgery (only this time there would be no scarring), he might be tempted to jump ahead a few decades to preview future technology in orthobiologics. If he did give in to his temptation, he most likely would be amazed by the scientific advancements and treatment options available to

patients—remedies such as fracture putty that repairs broken bones in days; USB-sized implants that deliver osteoporosis drugs directly to diseased areas; fat cells that hold the key to more effective and longer-lasting soft-tissue substitute; cartilage grafts that help regenerate bone; and implants the size of mint candy that can replace small joints in the hands and feet. While these advancements will evolve in part from a natural progression of innovation, industry experts believe they also will be based on a better understanding of the body’s natural healing process. “Artificial joints don’t last forever,” Cytomedix’s Rosendale noted. “Keeping your own body parts for as long as you can is obviously the most desirable outcome. The Holy Grail here is that those of us in the orthobiologics industry believe we can fully heal these injuries. But to do that we have to understand the biological differences with our bodies as well as the inherited differences stemming from a disease or an injury. The more we can understand about these differences and about all the complex interactions in biology, the closer we will be to eliminating disease.”