Around Philadelphia, where Orthopedics This Week is based, there are well over three dozen clinics and hospitals offering ‘stem cell’ treatments.
“Stem cell” treatments are available from acupuncture clinics, The University of Pennsylvania’s Perelman School of Medicine, hair restoration clinics, The Rothman Institute, Willis Eye Hospital, Stem Cell Centers of America, Wellness Institutes and Temple Lung Center.
They can’t all be offering the same thing, right?
So, we turned to four top biologics researchers and clinicians to help us sort what is real from what is not in the Wild West of “Stem Cells”.
James P. Bradley, M.D. is clinical professor of Orthopedic Surgery at the University of Pittsburgh School of Medicine
Constance R. Chu, M.D. is Professor of Orthopaedic Surgery at Stanford University
Brian Cole, M.D., M.B.A. is associate chairman and professor in the Department of Orthopaedic Surgery at Midwest Orthopaedics at Rush
Jason L. Dragoo, M.D. is associate professor of Orthopaedic Surgery at Stanford University
Defining Our Terms
Constance Chu, M.D., professor of Orthopedic Surgery at Stanford University and principal investigator of several federally funded projects including study of induced pluripotent stem cells and a clinical trial for platelet rich plasma treatment of knee osteoarthritis, is very clear about what a “stem cell” is. She explains that the term “stem cell” has an accepted definition in the scientific community of being undifferentiated cells that are capable of long-term self-renewal and that can differentiate into specialized cells.
“Not surprisingly,” says Dr. Chu, “stem cells are heavily investigated around the world to repair and regenerate damaged tissues and have captured the attention of patients seeking treatment for a variety of ills.”
Unfortunately, over the past decade or so, the term “stem cell” has arguably devolved into a marketing brand.
“Thus,” says Dr. Chu, “there is an urgent need for clinicians and scientists in this area to clarify the terminology, and to help educate the public concerning what is being offered in clinics around the country. Additional study of the types of cells patients actually receive and high-quality research on clinical outcomes after treatment is needed to responsibly harness the tremendous potential benefit of cell therapies.”
“Adult ‘stem cells’ may be more accurately referred to as progenitor cells. While progenitor cells do not have the same ability to differentiate as embryonic stem cells (known as ‘plasticity’), they can differentiate into a limited number of potentially clinically valuable cells. For orthopedic indications, the most studied group of living progenitor cells are the mesenchymal stromal cells (MSCs). These are repair cells that are culture expanded from mesenchymal tissues and have demonstrated the ability to differentiate into bone, fat, and cartilage cells.”
Because MSCs are isolated and cultured in the laboratory, clinical use requires FDA approval. “Therefore,” says Dr. Chu, “the majority of products in current clinical use are minimally manipulated cell preparations that contain living cells, but relatively few cells that can be considered stem or progenitor cells.”
Living Cell Therapies
There are numerous features of living cell treatments that make them tantalizing targets for researchers. And while there is no conclusive evidence that undergoing living cell treatments will provide patients with a lifetime cure, select cell therapies do hold promise for managing the symptoms of conditions such as osteoarthritis (OA). Of course, many questions remain …
James P. Bradley, M.D. is clinical professor of Orthopedic Surgery at the University of Pittsburgh School of Medicine. “To begin with,” states Dr. Bradley, “patient safety is paramount. Unfortunately, there is a bit of a frenzy these days when it comes to ‘stem cells’, with questionable ‘clinics’ offering treatments that are not supported by the current science. Before surgeons can feel entirely comfortable recommending stem cell treatments there are quite a few issues that need clarification.”
One of those, says Dr. Bradley, is the optimal extraction site. “As of yet we cannot get stem cells from peripheral blood. So, the question is, ‘Which extraction site—adipose or bone marrow concentrate (BMC)—is best for a particular malady?’ Unfortunately, the jury is still out. My general preference is BMC because it is closer to the target tissue. And we are limited by there being only two commercially available sources (BMC/adipose tissue) and by the fact that we are not allowed to manipulate the cells.”
“In addition, we have few clinical outcomes regarding the safety of autologous versus allogeneic progenitor cell use in cartilage repair. Although allogeneic cells are an attractive alternative to autologous cells as they don’t require a second procedure, we don’t know if they will differentiate, with accompanying changes in their ability to modulate the inflammatory cascade.”
“As for the optimal method of administration—injection, scaffold, hybrid bioactive adjuncts with growth factors—we don’t have a good answer. Also undetermined are the ideal dosage, timing, and frequency of treatment necessary for various indications. Importantly, we need additional information on potential in-vivo effects—such as plasticity, fragility, inflammation, and systemic infusion—that may alter the efficacy of living, progenitor cells.”
Do Progenitor Cells Actually Work?
Brian Cole, M.D., M.B.A., associate chairman and professor in the Department of Orthopaedic Surgery at Midwest Orthopaedics at Rush. Dr. Cole, section head of the Cartilage Restoration Center at Rush, told OTW, “We shouldn’t get ahead of ourselves. In some ways we are still at square one, namely, ‘Do living, progenitor cells actually work?’ The fact is that we don’t know enough about the intermingling of the cells and their environments, and how these factors are related to cell proliferation and differentiation.”
“And do they work in specific applications?” asks Dr. Cole. “These cells are used either in disease care or in the operating room as an adjunct to surgery. In osteoarthritis (OA) for example, progenitor cells are not likely to be regenerative in any capacity.”
“Using them in disease management may result in an improved inflammatory profile; in the OR you may see an improved healing response, particularly in the early postoperative phase where you may see a reduction in pain and inflammation.”
“At the present time, we rarely use progenitor cells in a regenerative capacity … it is almost always disease modifying. In the case of osteoarthritis, for example, living, progenitor cells can have their growth factors send the body’s own stem cells to the area and thus reduce the symptoms of the disease.”
“As physicians, we have a responsibility to prove that living cell therapies make a clinically important difference—and the burden is heavier in these cases because we are dealing with a biotherapeutic. Not only that, but the sizable financial risk is translated to the patient. Within the realm of ethics, the fact is that a doctor is in a position to influence people whether they try to or not. And patients are asking about this in droves.”
“More well-controlled studies are in order … and just because something is a Level One study does not mean that it is or is not valuable. If it is properly structured with a control group, has good power, and is blinded, then that will have a high chance of being clinically important. The challenges are in the blinding, in the fact that the placebo group has a strong positive effect, and that the patient population is not representative of patients who present in the office.”
Asked what disease would merit initial investigation, Dr. Cole states, “I think it is wise to begin with something that has a large disease burden … like OA or rotator cuff tears. That way you could also address the downstream epidemic of youth injuries and the resultant post-traumatic arthritis.”
Jason Dragoo, M.D. is an associate professor of Orthopaedic Surgery at Stanford University. Dr. Dragoo, whose clinical trials are making inroads in the realm of stem cells, commented to OTW, “It is challenging to advance the academics of progenitor cells in an age when unregulated clinics are multiplying around the country. In the San Francisco Bay area alone 20 such clinics opened in the last year.”
“There are a couple of studies suggesting that MSCs can be used to regrow articular cartilage, but as of yet we do not have sufficient proof. This preliminary evidence is exciting and has led our team to undertake seven clinical trials to answer that important question, as well as others.”
“We are comparing arthroscopic debridement to debridement plus an injection of a patient’s own progenitor cells; patients will be monitored for how they feel and for the thickness of the cartilage. We will use functional magnetic resonance imaging (FMRI) to measure cartilage thickness over two years and thus determine if there is an actual regrowth.”
Safety Concerns
Turning to safety concerns, Dr. Dragoo tells OTW, “I am concerned that some clinics are injecting amniotic fluid and/or other allogenic cells. We just don’t have a clear idea of the safety of that approach—especially if cells are transplanted from one human into another. It’s time for more research on the possible immune response generated from foreign proteins entering the body; and we need more basic lab research to understand if there is an immune response from one human to another after transplantation of allogenic cells.”
“There are critical concerns with processing progenitor cells, which is primarily what concerns the FDA. What the doctor does with these cells—mixing them with enzymes or other things—can contaminate or change them. The FDA says that without a drug license you are permitted to take cells and tissue out of the body, but never out of the OR/clinic room where you harvest it. You cannot take cultured cells from an incubator and implant them, and you can’t mix them with anything such as enzymes.”
“Given the current FDA rules involving minimal manipulation, the question remains if we will be able to obtain enough cells to actually make a difference for patients. All of the stem cell clinical trials at Stanford are following the FDA’s rules, while concurrent studies in Korea allow for more manipulation of the cells. If our minimal manipulation technique does not work, then we will need to take a hard look at increasing the number of cells via culture.”
The FDA’s Take
Asked why the FDA has not approved more stem cell treatments, Jim Bradley notes, “The FDA states that if you manipulate (grow) the cells at that point they become a drug and are subject to more rigorous and expensive regulations. This pathway costs millions of dollars and there are no companies as of yet that are willing to pay such an exorbitant amount of money.”
“The bottom line is that the future of progenitor cell treatment for orthopedic conditions has only begun to take shape. Going forward we will face numerous complex hurdles—growing public demand not the least of them—that will require a prudent and scientific approach.”
“As it is now, clinics are telling 76-year olds, ‘We’ll take your stem cells, put them back in, and your cartilage will be just like when you were 26!’ THAT is a blatant lie. Not only are these charlatans preying on people, but they are causing substantial problems for researchers because the FDA is eventually going to come down hard on stem cell therapy and we may very well get caught in the crossfire.”
AAOS Steps In
But there is a ray of hope, says Dr. Bradley. “At the request of the American Academy of Orthopaedic Surgeons (AAOS), the American Orthopaedic Society for Sports Medicine, the Arthroscopy Association of North America, the American Orthopaedic Society for Sports Medicine, and the International Cartilage Regeneration and Joint Preservation, a number of academicians have formed a new entity called ‘The Biologic Alliance.’ Every subspecialty society has three members on board of the Alliance. We hope to make substantial headway by working with the FDA to forge reasonable regulations and to advance legitimate, science-based cell treatments.”
