September 2019, Volume XXXIII, No 6
Understanding regenerative medicine
An effective treatment for orthopedic degeneration
egenerative medicine holds great promise in treating pain caused by orthopedic degeneration, a family of conditions that has previously been treatable only with corticosteroid injections or costly joint replacement. Unfortunately, rapid changes in the field and a lack of clearly defined protocols and definitions has led to confusion about what regenerative medicine is and what it can do for patients. Many people conflate live autologous stem cell treatments with dead-cell amniotic preparations, and others have made unfounded claims about non-treatable conditions that have drawn the attention of the FTC. But despite these “bad actors,” there are many more well-trained physicians performing high-quality, image-guided, evidence-based, FDA-compliant regenerative procedures, effectively reducing pain without the need for surgery. This article will attempt to clarify the various boundaries and tiers within regenerative medicine, and to demonstrate the cutting edge of this exciting field.
Regenerative medicine refers to therapies that harness the patient’s own cellular healing response to repair a painful and degenerated tissue in vivo. While it may one day be used to regrow cardiomyocytes or neural glia, at this time the only FDA-compliant and evidence-based use of these cell-based therapies in the clinic is for orthopedic degeneration. There has been an explosion of “stem cell clinics” in Minnesota and around the country, many of which make broad claims about incurable neurological conditions. Such clinics have defied FDA regulations and continue to market with impunity, believing they are too numerous for the FDA to effectively police. However, recent actions against two large clinic chains—US Stem Cell, Inc., and Cell Surgical Network—highlight the FDA’s dedication to protecting consumers while supporting the ethical and compliant use of orthobiologics.
Regenerative medicine has become synonymous with stem cells in the public’s mind, but Platelet Rich Plasma (PRP) procedures are far more commonly used, are less invasive, and are supported by a larger evidence base. Most cases of mild-to-moderate osteoarthritis, tendonitis, or partial thickness tendon tears, fasciitis, and ligamentous laxity or strain can be effectively treated with PRP.
PRP treatment of chronic injuries simply re-starts an acute repair.
Harnessing natural responses
Platelets are fragments of megakaryocyte cells which do not contain nuclei and are therefore unable to divide, but which are primed to release growth factors that can orchestrate repair. PRP is a concentrate of platelets derived from the patient’s own blood, which is then re-injected into the precise area of degeneration, typically into a tissue with poor innate bloodflow. Upon injection, the platelets degranulate and cause a temporary spike in inflammation and pain. Platelet-derived cytokines stimulate native stem cells to bring about repair and increase blood flow to bring circulating progenitor cells to the area.
This is the same response that the body mounts to any acute injury, so PRP treatment of chronic injuries simply re-starts an acute repair when the initial response was inadequate. For instance, a chronically loose ankle moves beyond its healthy range of motion and risks developing post-traumatic arthritis. Similarly, a whiplash injury in the spine can strain the posterior ligaments and allow excessive movement between the vertebrae, movement which shears on disks, jams facet joints, and causes paraspinal muscles to spasm in an attempt to provide stability. The ability of platelets to tighten ligaments and repair tendons thus makes it a useful tool for treating subfailure instability, which would otherwise accelerate wear-and-tear.
Stem cells have gotten more of the press for their unique ability to differentiate into the target tissues, allowing us to fill larger cartilage defects or tendon tears with progenitor cells. Their mechanism of action, however, likely extends beyond simply becoming the target tissue, as results are often seen just weeks after injection with relatively mild changes on imaging. Cytokines released by stem cells can have paracrine effects which stimulate local cells to divide or modulate inflammatory pain signals. Mesenchymal stem cells (MSCs) have also been shown to donate healthy mitochondria to native cells whose mitochondria are damaged, another possible mechanism for their therapeutic effect. It should be noted that no groups are using embryonic stem cells, an ethically fraught tissue whose controversy became irrelevant once pluripotent adult mesenchymal stem cells were discovered.
It becomes necessary to consider FDA regulations when working with human tissues, as outlined in FDA Regulation 21 CFR 1271. While the FDA regulates food, drugs, and devices, they have determined that use of a patient’s own tissue—such as with PRP, bone marrow concentrate, or autologous fat graft—falls under “practice of medicine” if it is compliant with three criteria: same-day procedure, homologous use, and minimal manipulation. Conversely, if one were to store a patient’s cells for another day, use them for purposes the cells do not naturally perform in the body, or manipulate those cells outside the body, it would be as if the practitioner were manufacturing a drug, which would be regulated as such by the FDA. Autologous Bone Marrow Aspirate Concentrate (BMAC) is “FDA Compliant” for homologous use in orthopedics and has been used clinically since 2005. The mesenchymal stem cell fractions of the bone marrow can be concentrated and purified without manipulating the cells, making a same-day reinjection of BMAC FDA-compliant. Most systems that process adipose tissue require enzymes to digest mesenchymal stem cells away from the fat (stromal vascular fraction, or SVF), which the FDA has said constitutes more than minimal manipulation. Both clinics cited above were sued by the FDA for using SVF—which is more than minimally manipulated—for purposes that were nonhomologous, such as the treatment of neurologic conditions.
More often than not, treatments advertised as stem cell therapies actually fall into a third category, which are amniotic or placental tissues. In comparison to autologous bone marrow concentrate or fat graft, these are allogenic tissues—donated byproducts of the birth process which are then processed in a centralized facility, freeze dried, and irradiated for safety and transportation. When multiple independent labs have attempted to grow stem cells out of these products, they have been found to have no viable cells. There have also been several cases of infection from amniotic products, and concern of immune incompatibility has been raised. Extracellular matrix proteins and low levels of growth factor may explain some of the positive effects of these treatments. Unfortunately, many sales reps and the providers they’ve sold to continue to refer to these as “stem cell treatments,” despite the lack of viable cells capable of self-replication or secretory functions.
Developing a treatment plan
Once a regenerative medicine physician has decided on the appropriate biologic therapy and desired concentrations, the next consideration would be which targets to inject. Unfortunately, some providers in this space are not trained musculoskeletal injectionists, and instead perform intravenous infusions as a treatment for peripheral joint pain. Following IV delivery, 95% of those cells would be trapped in the lung at first pass, and only a small fraction of the remaining 5% would reach the target joint. MSCs adhere and differentiate based on their surroundings, so it is essential that they be delivered directly onto the cartilage defect or into the visualized tendon tears. This requires image guidance—typically ultrasound for soft tissue and fluoroscopy for spinal joints or more difficult joints. The Interventional Orthopedics Foundation (IOF) is a nonprofit dedicated to research and education in this field, helping to define the skillset necessary to carry out a comprehensive and precise nonsurgical regenerative treatment. The American Academy of Orthopedic Medicine (AAOM) and The Orthobiologic Institute (TOBI) put on similar workshops and cadaver courses for physicians looking to improve their musculoskeletal injection skills.
As the regenerative physician develops his or her skills with ultrasound and fluoroscopy, additional targets become available, making interventional orthopedics a subspecialty truly distinct from sports medicine or interventional pain. Some of the more advanced treatments include fluoroscopy-guided injections of MSCs into both bundles of the anterior cruciate ligament (ACL) in select cases of ACL tears, which has helped athletes return from complete tears with normal ligament function and MRI appearance. We can also perform subchondral bone augmentation with BMAC to treat osteonecrosis or bone marrow edema in cases of severe osteoarthritis. In the spine, platelet lysate (PL) epidurals have been able to effectively treat radiculopathy and support resorption of bulging disks. In disks that do not respond to PL epidurals, intradiscal injection of BMAC is another therapeutic option before resorting to discectomy and fusion.
Providers both can and must work together to minimize cost and duration of care.
As physicians lead the way on developing protocols and uses for orthobiologics, it is also our responsibility to follow and publish our results. Regenexx has been doing this since 2005, and our registry now includes over 91,250 regenerative procedures whose results are publicly available online. Multiple early studies had conflicting results, often using different PRP preparations that failed to remove inflammatory leukocytes and/or red blood cells, had varying or unreported concentrations of platelets, or had insufficient follow-up. The more recent research using modern preparations of PRP have supported its use in most orthopedic settings, although they are still limited by small sample sizes. Most of the larger studies on regenerative medicine have been prospective registry datasets due to practical difficulties in designing and financing more powerful studies.
Unlike a pharmaceutical company that owns exclusive rights to market the final product, personalized cellular therapies are decentralized and without a single stakeholder to finance a multimillion-dollar study. It is impossible to blind a patient to a bone marrow harvest, and unethical to discard their cells and instead randomize them to a placebo. What we do have is a large base of prospective evidence demonstrating safety, with long-term satisfaction scores that are superior to the standards of care, even in patients with severe or chronic injuries.
Unfortunately, these regenerative medicine treatments remain outside of the covered benefits for Medicare and for most private insurers. One reason for this is the lack of standardization in both the research base and in clinical practice, with regenerative medicine preparation protocols varying widely and few providers qualified to use both ultrasound and fluoroscopic guidance.
Another barrier, particularly in the Medicare setting, is concern that high utilization in mild-to-moderate cases could offset the cost savings relative to a surgery that is performed on only the most severe cases. In that scenario, performing a high volume of corticosteroid injections with a low volume of invasive surgeries remains the cost-effective option. Yet orthopedic injuries continue to be the number one cause of missed work, and orthopedic treatments continue to be the number one expense in most companies’ health plans. Nearly one third of all health care expenditure is on orthopedics, representing $510 billion dollars or 5% of the GDP, and those costs continue to rise.
As a result, many of the self-insured companies that finance their own health plans have taken a second look at the data for nonsurgical regenerative therapies. Our outcome data supports the financial viability of providing $2k–$6k Regenexx procedures as a covered benefit in order to reduce the demand for a $30k–$50k joint replacement. This, of course, requires physicians to be stewards of the resources and only treat patients who are medically appropriate. We have found that about 70% of elective orthopedic surgeries can be avoided by first treating with regenerative medicine, while some findings like severe hip arthritis or myelomalacia are still best treated with surgery. To date, over 30 self-funded employers representing 6 million covered lives have decided to cover Regenexx procedures. This has the added benefit of getting workers back to full duty more quickly—typically in just 3 to 21 days following a regenerative procedure—versus much greater lost productivity following a more invasive procedure. As private insurers see more and more claims for joint replacements and spinal fusions in younger workers, they may also decide to reconsider regenerative therapies as a first-line option after rest and physical therapy.
Both patients and physicians are looking for a treatment that can treat the root cause of pain rather than relying on opiates or steroids to mask it. In the right patients, regenerative medicine fulfills that promise. Conditions that previously required major surgery are now being effectively treated with orthobiologic injections and minimal downtime. While more studies will help clarify the best protocols and the best prospective patients, the future is now with regards to regenerative medicine. As interventional orthopedics becomes more organized and professionalized, expect to see it enter the mainstream, with or without insurance coverage.
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