Researchers demonstrate tremendous progress but caution that field is in its ‘infancy’

Researchers are harnessing the power of biologics and cell-based therapies to solve some of today’s most challenging clinical problems in the arena of orthopaedic sports medicine. Augustus D. Mazzocca, MD; Scott A. Rodeo, MD; and Brian J. Cole, MD, MBA, discussed various aspects of this emerging technology at the 2007 annual meeting of the American Orthopaedic Society of Sports Medicine.

The panel members addressed a wide range of developing therapies and clinical applications. Dr. Mazzocca discussed soft-tissue augmentation and its use in repairing rotator cuff and anterior cruciate ligament (ACL) injuries. Dr. Rodeo presented research in bone augmentation and its clinical applications—from helping to heal problem fractures in athletes to its use in arthrodesis. Dr. Cole covered scaffolds, synthetics, and emerging technology, focusing on articular cartilage and menisci.

Although much progress has been made in biologics, Dr. Mazzocca cautions, “this field is in its infancy and needs to be treated with the utmost in scientific rigor.”

Biologic agents in healing
Dr. Mazzocca describes his research as “translational” and himself as “practical.” “We need something to help our patients in the near future. The mantra of our lab is to go from the bench to the bedside with simple surgical techniques that all surgeons can use in a time-efficient and cost-effective manner. In other words,” he says, “we try and use products that are already available and have been approved by the Food and Drug Administration (FDA), or known substances that are accepted by the body. It is our goal to harness the body’s own healing potential and maximize it with various biologic augmentations.”

He believes it is important to understand the healing cascade and how various substances interact to promote healing. Growth factors, which are also known as “proteins” and “signals,” have different properties that determine their function in the body. Dr. Mazzocca emphasizes that surgeons should know two critical facts about any growth factor that they administer—the appropriate dose and the time it should be administered to maximize healing.

Dr. Mazzocca has been able to use biologics to improve sutures and thereby improve healing. Because tendon and bone cells do not naturally bond with suture materials (polyester or polyethylene), he coats high-strength sutures with collagen. By doing so, he has found that bone and tendon cells will not only adhere to the sutures, they will proliferate, thus enhancing the healing process.

Another aspect of his research is focused on developing a single, biologic procedure to repair torn rotator cuffs. His goal is to harvest the mesenchymal stem cells (MSCs) from the bone marrow of the greater tuberosity and to implant the cells at the rotator cuff site during the same surgical session. The dilemma, he says, is “keeping the cells where you want to put them.”

Developing scaffolds and carrier vehicles
Finding an appropriate “scaffold” or mechanism to hold the MSCs for implantation is a common problem for researchers. Dr. Mazzocca and Dr. Rodeo have both been trying to develop a “fibrin clot”—which Dr. Mazzocca refers to as “the holy grail”—as a scaffold.

“Using the patient’s own blood,” Dr. Rodeo explains, “you place it in a centrifuge and isolate the platelets, which contain a number of different growth factors.” The end product has the same consistency as chewing gum.

For rotator cuff repairs, Dr. Rodeo applies the substance exactly where it is needed. “The scaffold is formed from the fibrin clot. You can actually put a suture through it because it acts as its own matrix,” he explains. “The fibrin clot contains the platelets and their growth factors.”

He underscores the importance of “time dependence” in using growth factors. “If the platelets are activated too early, all of the growth factors go with them. So these techniques aim to concentrate the platelets without activating them prematurely.” (For more information on the use of platelet-rich plasma, see the article “Clinical use of platelet-rich plasma in orthopaedics” on page 44.)

Dr. Rodeo is currently participating in a randomized, clinical trial to measure the effectiveness of using a platelet-rich fibrin matrix in enhancing the healing of rotator cuff repairs. Participants will be randomized to receive either a standard arthroscopic rotator cuff repair or an arthroscopic rotator cuff repair with placement of the platelet-rich fibrin matrix.

“If the participant is randomized to receive the matrix, it will be inserted at the tendon-bone attachment site and sutured in. We will use ultrasound at serial time points to objectively evaluate tendon-to-bone healing,” explains Dr. Rodeo. Because the trial is currently ongoing, he is unable to report the results yet.

“We’ll see,” he says. “I’ve used this material for meniscal repairs and in a bone tunnel for ACL repairs. It is a neat way to deliver autologous growth factors. It’s one of the techniques that are now available to try to improve the biology of healing.” The fibrin matrix is osteoconductive and may also be osteoinductive due to the contained growth factors.

Dr. Cole believes “on the scaffold side, there are some bioreabsorbable, biotolerated adjuncts to marrow stimulation that look very promising. They are easy to use in the operating room, and they are compatible with current surgical procedures.” They are also relatively inexpensive.

Growth factors: a question of timing
Osteoinductive materials, such as bone morphogenic proteins (BMPs), are clinically available, according to Dr. Rodeo. BMP-2 is the best known biologic agent for bone formation. Osteogenic protein-1 (OP-1), also known as BMP-7, is another agent with a potent role in bone formation.

Dr. Rodeo believes that biologic agents will eventually replace conventional bone grafts and cites the success of BMP-2 in spinal fusions where it has, to some degree, replaced the iliac crest bone graft.

Although substantial gains have been made, the appropriate carrier vehicles for growth factors have yet to be identified. “BMP is a good example of a protein that we knew 15 years ago had a potent effect on making bone,” says Dr. Rodeo. “But it took time to find ways to deliver it to the surgical site in a biologically relevant concentration for a relevant period of time. We couldn’t just inject it because it needs to bind to the surgical site. We had to evaluate a number of different carrier vehicles.” An absorbable collagen sponge, in which the BMP binds the collagen and is released gradually over time, is currently being used.

Several unanswered questions and complicated issues remain. “Human biology is a pretty complex system,” says Dr. Rodeo. “BMP is very important in making bone but it’s not the only factor. In a biologic system, growth factor A is produced on day 1, growth factor B is produced on day 3, and growth factor C is produced on day 5. It’s a complex milieu and the fundamental question remains: How do you recapitulate that whole system?”

Bone resorption and tendon-to-bone healing
“Healing between tendon and bone is central to many common sports medicine procedures such as an ACL reconstruction that uses a tendon graft or a rotator cuff repair,” says Dr. Rodeo. “Both procedures require new bone formation and bone ingrowth into the soft tissue.” Excessive or abnormal bone resorption can impair that process.

Dr. Rodeo believes the systematic administration or local application of antiresorptive medications to “turn off” bone resorption could aid healing a tendon-to-bone attachment. He points to some promising research data in a rabbit model that showed improved healing of a tendon graft in the bone tunnel of an ACL reconstruction with the use of osteoprotegerin—a potent, experimental inhibitor of bone resorption—at the site.

Advances with articular cartilage and meniscus
Dr. Cole is working with “minced cartilage” or mechanical fragmentation of cartilage tissue. Based on his preclinical studies, this hyaline-like tissue may be superior to the type of tissue that is formed following microfracture. Two minced cartilage technologies are available—one that uses an “off-the-shelf” allograft (juvenile articular cartilage) and another that uses the patient’s own tissue.

Traumatic articular cartilage injuries do not heal well and can cause early onset osteoarthritis. An article co-authored by Dr. Cole and published in the June 2006 issue of the Journal of Orthopaedic Research presented evidence for delivering autologous chondrocyte implantation without the complex and costly process of ex vivo cell expansion. The outgrowth study, which was used to demonstrate chondrocyte migration and growth, “indicated that fragmented cartilage tissue is a rich source for chondrocyte redistribution.” Using “minced cartilage” with the appropriate polymeric scaffolds to deliver chondrocytes offers a promising intraoperative approach for cell-based cartilage.

Three-dimensional pieces of cartilage—cultured outside the body and reimplanted—are considered a “third-generation technique” and are currently in FDA Phase I trials.

“We use alternatives to periosteum—such as synthetic collagen membranes, hyaluronic acid scaffolds, and other synthetic scaffolds—in an attempt to reduce the complexity of autologous chondrocyte implantation and the complications associated with the periosteum,” explains Dr. Cole.

Dr. Cole also notes that two meniscal substitutes are currently in FDA trials—one made out of small intestinal submucosa (SIS) and the second made from highly purified bovine Achilles tendon. Both are being tested to replace segmental loss of the meniscus.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org.

Finding the balance in biologics: Science meets the economic realities
Brian J. Cole, MD, MBA, believes that patients who have bipolar disease in one compartment present one of the most formidable challenges in biologics today. “That is a far more difficult problem than the little potholes of cartilage that we are treating,” Dr. Cole says. None of the current biologic solutions can satisfactorily address this medical condition.

“This affects young people who are otherwise very active and are now inhibited and have pain and dysfunction.” Dr. Cole continues, “That’s a small group of patients when compared to the group of patients who are young and have arthritis.”

To help those patients, biologic technologies are needed. But getting even one product through the rigorous regulatory process—which he supports—can cost more than $40 million, he says. “You add these factors to a healthcare system where no one is willing to pay for these types of technologies and, all things being equal, the economics don’t line up very well. What we really need is a solution that is predictable, successful, has a low complication rate, is minimally invasive, possibly arthroscopic, and is off-the-shelf.

“Success is a patient saying, ‘You know what? I feel better. I have less pain. I can function at a higher level.’ Perhaps the emphasis we place on histology and biomechanics is not as important,” he continues.

Dr. Cole would like to see a balance between the science and cost. “It doesn’t make sense to explore very costly solutions when the incidence of a given problem is relatively low and the healthcare system doesn’t want to pay for it.”