Michael Barbella, Managing Editor06.11.12
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 be caused by another bone spur 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 can impinge 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 to technology that possibly could permanently eradicate the discomfort. Fair is president, founder and CEO of Amniox Medical Inc., a Marietta, Ga.-based developer of regenerative tissue therapies. The company’s signature product is a graft harvested from human amniotic membrane (AM), or the inner-most layer of the placenta. These membranes are considered ideal candidates for tissue regeneration due to their abundance of epithelial cells (which scientists 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. Human amniotic 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 implants.
Virtually since the dawn of medicine, mankind has tried—and failed—to replicate Mother Nature’s biological masterwork with his own concoctions, using both natural materials and synthetic substances ranging 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 emulate the biochemical ingenuity of the human body.
“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 regenerative biologic therapies,” Fair noted. “If you look at medicine in general, patients are closer to becoming the buyer so they are becoming more educated. Patients are much more educated now than they were five years ago and I see that trend continuing. So, if patients 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 a biologic product that can replace the synthetic, the biologic product will take over.”
Such a coup, though, already is well underway, having begun thousands of years ago with the discovery of fermentation, a metabolic process used to make food, fuel and alcoholic beverages. Ancient civilizations used the process (without really understanding the way in which it worked) to produce wine, beer, vinegar, bread, yogurt and cheese.
Though it was quite a few millennia before the fermentation process was truly understood (an explanation officially came in 1897 from German scientist and zymologist Eduard Buchner, who received a Nobel Prize in chemistry for his work in the field), the ancients’ dabble in micro-organisms was mankind’s introduction to biotechnology, one of the oldest forms of science on the planet.
Like most older branches of science, the biotechnology sector has evolved considerably since its prehistoric inception. But its fundamental definition has remained consistent throughout the centuries—the discipline still is categorized (in its simplest form) as technology based on biology. Modeled after the core principles of animal health and pharmaceutical research and development, the biotechnology field harnesses cellular and biomolecular processes to develop technologies and products that improve the lives and health of humanity. The breadth of the biotechnology industry is far-reaching—advancements over the last 50 years have helped doctors better detect and successfully treat diseases, and scientists to develop crops that significantly are less dependent upon chemical pesticides. Biotechnology also has led to cleaner manufacturing processes that produce less waste and use far fewer resources.
As an industry, biotechnology is defined not by the products it produces but rather by the technologies it employs during production. The industry, according to a report prepared for the U.S. Department of Labor, is based on the commercial application, research and development of these technologies through companies that research, develop, manufacture and market the innovation.
For most of the last two decades, America’s biotechnology industry has experienced dramatic growth—total revenue has swelled nearly eight-fold since the early 1990s, going from $8 billion in 1992 to $61.6 billion in 2010. Revenue fell by 9 percent during the Great Recession, though experts attribute much of that decline to Roche Holding’s $46.8 billion acquisition of biotechnology behemoth Genentech Inc. in 2009 (had the company’s earnings been excluded from 2008 and 2009 industry revenue totals, proceeds would have risen 8 percent, according to global advisory services firm Ernst & Young). Still, total revenue generated by publicly-traded U.S. biotechnology firms in 2010 remained 29 percent below the $86.8 billion companies generated in 2008, Ernst & Young data indicate. Industry experts are skeptical that revenue quickly will return to pre-recession levels as companies wrestle with the challenges of uncertain capital funding, increasing regulation, pricing pressures, shrinking reimbursement rates, and an evolving global healthcare environment.
The federal government identifies biotechnology firms as those “that use cells and biological molecules for applications in medicine, agriculture and environmental management.” Healthcare, however, provides one of the most lucrative applications for biotechnology, thanks to an aging population that is driving demand for pharmaceuticals and medical devices.
Much of this demand is occurring in orthopedics, where implant manufacturers such as Smith & Nephew plc, Zimmer Holdings Inc., Stryker Corp. and DePuy Orthopaedics Inc. 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. Zimmer, for instance, is collaborating 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.
Smith & Nephew, meanwhile, made a similar high-profile investment in biological technologies earlier this year with the January spinoff of its Biologics & Clinical Therapies operation and the February introduction of a new hip replacement system to the U.S. market. The biologics unit will be owned by global life sciences investing firm Essex Woodlands and will operate under the new name Bioventus LLC. Under terms of the deal, Essex Woodlands will own 51 percent of Bioventus while London, United Kingdom-headquartered Smith & Nephew will retain a 48 percent stake in the joint venture.
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 for 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 those suffering from such ailments as damaged Achilles tendons, diabetic ulcers and back pain. The company began its formal introductions 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 only recently 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 has developed 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 to company data, are 50-100 µm thick and available in four sizes to fit any sized ocular 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 to repair 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, tendinitis and wound healing are the primary markets for this,” Fair told Medical Product Outsourcing. “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 a patient population out there that subscribes to the theory that you have to live with what you have. People have always accepted 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 Debate
Fair also may want to pack some other revolutionary technology for his illusory trip through time. But the choice could prove difficult considering the 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 mainstream acceptance as those amniotic membrane transplants. By the late 2000s, the treatment had become so popular that patients with orthopedic injuries—arthritis and tendinitis —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 game because everyone was calling me asking, ‘Is that what you do?’“
The answer is more complicated than a simple yes or no. Rosendale is CEO of Cytomedix 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 a patient 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 effective as saltwater.
Regardless of its perceived efficacy, PRP remains a viable and widespread treatment for many orthopedic afflictions. Cytomedix uses the technology to produce a gel containing 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 or surgically debrided wounds. It also increasingly 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, which develops medical technology for cardiac surgery and 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 technology, like many others in the healthcare, is being driven in part by aging baby boomers who are looking for new ways to stay active and healthy.
Inspired by Science Fiction?
Some of the technologies currently in development or out on the market seem like they were pulled directly from the pages of a science-fiction/fantasy novel. A team of Massachusetts Institute of Technology (MIT) researchers, for example, have created a biological dressing that can stop bleeding almost instantly.
The nanoscale spray coating of thrombin (a blood-clotting protein) and tannic acid (a component of black tea with antibacterial properties) specifically was developed for medical sponges. The researchers tested their design by applying a thrombin-coated sponge to a bleeding porcine spleen for 60 seconds with minimum pressure from an MIT researcher’s thumb. The bleeding, much to their delight, stopped; by contrast, sponges without thrombin took 160 seconds, or nearly three minutes, to stop the bleeding. Uncoated cotton patches were ineffective, failing to stop bleeding even after 12 minutes.
Similarly, Nottingham, United Kingdom-based Novozymes Biopharma has developed a range of animal-free recombinant human albumins (rAlbumins), derived from a proprietary Saccharomyces yeast strain. Albumin is a carrier protein found in blood plasma and can be used in a range of applications, from drug development to medical device coating. One of Novozymes’ rAlbumin products, Albucult, currently is being used by a number of medical device companies in the manufacture of surgical wound sealants. Unlike its MIT counterpart, Albucult does not stop bleeding, but instead provides a barrier to fluid leakage. “Albucult offers a range of unique advantages such as sustainability of supply, GMP compliance and improved biocompatibility, along with unprecedented performance and quality benefits in medical applications” explained Dermot Pearson, marketing director for Novozymes Biopharma, a part of Bagsvaerd, Denmark-based Novozymes A/S. “One of our customers, Neomend, currently uses Albucult in a flexible gel which is used to seal lung tissue after surgery. Our recombinant albumins are also utilized by many customers to coat medical devices for cardiovascular surgery. Here, the devices are used in the artificial heart valves where the blood is in direct contact with them. In this case, the Albumin helps to reduce the possibility of blood clots forming on the surface of the devices during surgery.”
Perhaps even more astounding than flexible tissue sealers and instantaneous blood-stopping sponges is a catheter or stent made almost entirely of water. Developed by Q Urological Corporation, with facilities in Woburn, Mass., the pAguamedicina Structural Hydrogel Pediatric Ureteral Stent consists of less than 10 percent polymer material. By using a liquid base, Q Urological has created a catheter or stent that more closely emulates body fluids and soft tissue. The device also acts like a spring or shock absorber, and it incorporates a differentially larger end that is big enough to maintain its position in the renal collection junction. Most importantly, though, the stent is likely to significantly reduce pain and biofilms.
The pAguamedicina Pediatric Ureteral Stent has received FDA approval, but the company is working to obtain additional clearance for upper and lower urinary drainage in adults before introducing its predominately aqueous catheter and stent technology to the market sometime this summer.
“Whether its anecdotal or you dig up the research, coatings may have been a good thing versus no coating at all,” Founder and CEO Scott M. Epstein said. “What I decided a long time ago was that I would like a device—a catheter, any widget—to be as hydrophillic as possible, so why not make the entire product out of hydrogel? So I came up with a new way to make something. I have a patented qualified manufacturing process that can make stents and catheters entirely out of hydrogel such that when saturated in water or saline, it’s 90 percent aqueous. There’s very little solid component there, yet it’s structural, you can stretch it 300 or 400 percent, just as you would a temporary latex or silicone catheter. The premise here is the device is mostly all water, it’s not a coating on conventional thermoplastic. What we’re trying to say is the device is comprised entirely of what essentially was only used as a coating.”
* * *
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 breakthroughs in biotechnology. If he did, he most likely would be amazed by the treatments available—remedies such as artificial blood vessels, a headset ultrasound monitor that can detect the aftereffects of brain injuries, and wireless pacemakers that regulate the heart’s rhythm through ultrasound pulses. While these advancements will evolve from a natural progression of innovation, experts believe they also will be based on a better understanding of the body’s natural healing process.
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 be caused by another bone spur 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 can impinge 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 to technology that possibly could permanently eradicate the discomfort. Fair is president, founder and CEO of Amniox Medical Inc., a Marietta, Ga.-based developer of regenerative tissue therapies. The company’s signature product is a graft harvested from human amniotic membrane (AM), or the inner-most layer of the placenta. These membranes are considered ideal candidates for tissue regeneration due to their abundance of epithelial cells (which scientists 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. Human amniotic 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 implants.
Virtually since the dawn of medicine, mankind has tried—and failed—to replicate Mother Nature’s biological masterwork with his own concoctions, using both natural materials and synthetic substances ranging 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 emulate the biochemical ingenuity of the human body.
“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 regenerative biologic therapies,” Fair noted. “If you look at medicine in general, patients are closer to becoming the buyer so they are becoming more educated. Patients are much more educated now than they were five years ago and I see that trend continuing. So, if patients 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 a biologic product that can replace the synthetic, the biologic product will take over.”
Such a coup, though, already is well underway, having begun thousands of years ago with the discovery of fermentation, a metabolic process used to make food, fuel and alcoholic beverages. Ancient civilizations used the process (without really understanding the way in which it worked) to produce wine, beer, vinegar, bread, yogurt and cheese.
Though it was quite a few millennia before the fermentation process was truly understood (an explanation officially came in 1897 from German scientist and zymologist Eduard Buchner, who received a Nobel Prize in chemistry for his work in the field), the ancients’ dabble in micro-organisms was mankind’s introduction to biotechnology, one of the oldest forms of science on the planet.
Like most older branches of science, the biotechnology sector has evolved considerably since its prehistoric inception. But its fundamental definition has remained consistent throughout the centuries—the discipline still is categorized (in its simplest form) as technology based on biology. Modeled after the core principles of animal health and pharmaceutical research and development, the biotechnology field harnesses cellular and biomolecular processes to develop technologies and products that improve the lives and health of humanity. The breadth of the biotechnology industry is far-reaching—advancements over the last 50 years have helped doctors better detect and successfully treat diseases, and scientists to develop crops that significantly are less dependent upon chemical pesticides. Biotechnology also has led to cleaner manufacturing processes that produce less waste and use far fewer resources.
As an industry, biotechnology is defined not by the products it produces but rather by the technologies it employs during production. The industry, according to a report prepared for the U.S. Department of Labor, is based on the commercial application, research and development of these technologies through companies that research, develop, manufacture and market the innovation.
For most of the last two decades, America’s biotechnology industry has experienced dramatic growth—total revenue has swelled nearly eight-fold since the early 1990s, going from $8 billion in 1992 to $61.6 billion in 2010. Revenue fell by 9 percent during the Great Recession, though experts attribute much of that decline to Roche Holding’s $46.8 billion acquisition of biotechnology behemoth Genentech Inc. in 2009 (had the company’s earnings been excluded from 2008 and 2009 industry revenue totals, proceeds would have risen 8 percent, according to global advisory services firm Ernst & Young). Still, total revenue generated by publicly-traded U.S. biotechnology firms in 2010 remained 29 percent below the $86.8 billion companies generated in 2008, Ernst & Young data indicate. Industry experts are skeptical that revenue quickly will return to pre-recession levels as companies wrestle with the challenges of uncertain capital funding, increasing regulation, pricing pressures, shrinking reimbursement rates, and an evolving global healthcare environment.
The federal government identifies biotechnology firms as those “that use cells and biological molecules for applications in medicine, agriculture and environmental management.” Healthcare, however, provides one of the most lucrative applications for biotechnology, thanks to an aging population that is driving demand for pharmaceuticals and medical devices.
Much of this demand is occurring in orthopedics, where implant manufacturers such as Smith & Nephew plc, Zimmer Holdings Inc., Stryker Corp. and DePuy Orthopaedics Inc. 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. Zimmer, for instance, is collaborating 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.
Smith & Nephew, meanwhile, made a similar high-profile investment in biological technologies earlier this year with the January spinoff of its Biologics & Clinical Therapies operation and the February introduction of a new hip replacement system to the U.S. market. The biologics unit will be owned by global life sciences investing firm Essex Woodlands and will operate under the new name Bioventus LLC. Under terms of the deal, Essex Woodlands will own 51 percent of Bioventus while London, United Kingdom-headquartered Smith & Nephew will retain a 48 percent stake in the joint venture.
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 for 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 those suffering from such ailments as damaged Achilles tendons, diabetic ulcers and back pain. The company began its formal introductions 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 only recently 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 has developed 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 to company data, are 50-100 µm thick and available in four sizes to fit any sized ocular 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 to repair 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, tendinitis and wound healing are the primary markets for this,” Fair told Medical Product Outsourcing. “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 a patient population out there that subscribes to the theory that you have to live with what you have. People have always accepted 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 Debate
Fair also may want to pack some other revolutionary technology for his illusory trip through time. But the choice could prove difficult considering the 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 mainstream acceptance as those amniotic membrane transplants. By the late 2000s, the treatment had become so popular that patients with orthopedic injuries—arthritis and tendinitis —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 game because everyone was calling me asking, ‘Is that what you do?’“
The answer is more complicated than a simple yes or no. Rosendale is CEO of Cytomedix 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 a patient 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 effective as saltwater.
Regardless of its perceived efficacy, PRP remains a viable and widespread treatment for many orthopedic afflictions. Cytomedix uses the technology to produce a gel containing 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 or surgically debrided wounds. It also increasingly 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, which develops medical technology for cardiac surgery and 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 technology, like many others in the healthcare, is being driven in part by aging baby boomers who are looking for new ways to stay active and healthy.
Inspired by Science Fiction?
Some of the technologies currently in development or out on the market seem like they were pulled directly from the pages of a science-fiction/fantasy novel. A team of Massachusetts Institute of Technology (MIT) researchers, for example, have created a biological dressing that can stop bleeding almost instantly.
The nanoscale spray coating of thrombin (a blood-clotting protein) and tannic acid (a component of black tea with antibacterial properties) specifically was developed for medical sponges. The researchers tested their design by applying a thrombin-coated sponge to a bleeding porcine spleen for 60 seconds with minimum pressure from an MIT researcher’s thumb. The bleeding, much to their delight, stopped; by contrast, sponges without thrombin took 160 seconds, or nearly three minutes, to stop the bleeding. Uncoated cotton patches were ineffective, failing to stop bleeding even after 12 minutes.
Similarly, Nottingham, United Kingdom-based Novozymes Biopharma has developed a range of animal-free recombinant human albumins (rAlbumins), derived from a proprietary Saccharomyces yeast strain. Albumin is a carrier protein found in blood plasma and can be used in a range of applications, from drug development to medical device coating. One of Novozymes’ rAlbumin products, Albucult, currently is being used by a number of medical device companies in the manufacture of surgical wound sealants. Unlike its MIT counterpart, Albucult does not stop bleeding, but instead provides a barrier to fluid leakage. “Albucult offers a range of unique advantages such as sustainability of supply, GMP compliance and improved biocompatibility, along with unprecedented performance and quality benefits in medical applications” explained Dermot Pearson, marketing director for Novozymes Biopharma, a part of Bagsvaerd, Denmark-based Novozymes A/S. “One of our customers, Neomend, currently uses Albucult in a flexible gel which is used to seal lung tissue after surgery. Our recombinant albumins are also utilized by many customers to coat medical devices for cardiovascular surgery. Here, the devices are used in the artificial heart valves where the blood is in direct contact with them. In this case, the Albumin helps to reduce the possibility of blood clots forming on the surface of the devices during surgery.”
Perhaps even more astounding than flexible tissue sealers and instantaneous blood-stopping sponges is a catheter or stent made almost entirely of water. Developed by Q Urological Corporation, with facilities in Woburn, Mass., the pAguamedicina Structural Hydrogel Pediatric Ureteral Stent consists of less than 10 percent polymer material. By using a liquid base, Q Urological has created a catheter or stent that more closely emulates body fluids and soft tissue. The device also acts like a spring or shock absorber, and it incorporates a differentially larger end that is big enough to maintain its position in the renal collection junction. Most importantly, though, the stent is likely to significantly reduce pain and biofilms.
The pAguamedicina Pediatric Ureteral Stent has received FDA approval, but the company is working to obtain additional clearance for upper and lower urinary drainage in adults before introducing its predominately aqueous catheter and stent technology to the market sometime this summer.
“Whether its anecdotal or you dig up the research, coatings may have been a good thing versus no coating at all,” Founder and CEO Scott M. Epstein said. “What I decided a long time ago was that I would like a device—a catheter, any widget—to be as hydrophillic as possible, so why not make the entire product out of hydrogel? So I came up with a new way to make something. I have a patented qualified manufacturing process that can make stents and catheters entirely out of hydrogel such that when saturated in water or saline, it’s 90 percent aqueous. There’s very little solid component there, yet it’s structural, you can stretch it 300 or 400 percent, just as you would a temporary latex or silicone catheter. The premise here is the device is mostly all water, it’s not a coating on conventional thermoplastic. What we’re trying to say is the device is comprised entirely of what essentially was only used as a coating.”
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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 breakthroughs in biotechnology. If he did, he most likely would be amazed by the treatments available—remedies such as artificial blood vessels, a headset ultrasound monitor that can detect the aftereffects of brain injuries, and wireless pacemakers that regulate the heart’s rhythm through ultrasound pulses. While these advancements will evolve from a natural progression of innovation, experts believe they also will be based on a better understanding of the body’s natural healing process.