More research needed to fully harness power of stem cells in sports medicine

Stem cells have demonstrated promise across all facets of medicine, including sports medicine, where early results have exhibited the potential for enhanced cartilage, tendon and meniscal healing.

These results have increased demand among patients. Several high-profile professional athletes, including National Football League players Chris Johnson and Peyton Manning and Cy Young-winning pitcher Bartolo Colon, have sought relatively untested cell-based therapies for sports-related injuries.

Still, many aspects of stem cells remain unknown. In this issue, Orthopedics Today talks to leaders in stem cell research and medicine to find out how these burgeoning therapies can be applied in sports medicine, whether there is sufficient evidence to support their widespread use and what obstacles block their use.

Stem cells are unspecialized cells that have a capacity for prolonged self-renewal and the ability to differentiate into a variety of specialized cell types, according to the National Institutes of Health (NIH).

There are three types of stem cell types: embryonic, adult and induced pluripotent stem cells (iPSCs), according to the NIH.

Adult stem cells, found in nearly every part of the body, are the cells used most commonly in sports medicine.

There are several types of adult stem cells: hematopoietic stem cells, neural stem cells, epithelial stem cells and mesenchymal stem cells (MSCs), which Arnold I. Caplan, PhD, and his colleagues first isolated from bone marrow 25 years ago. Caplan, a professor of biology and director of the Skeletal Research Center at Case Western Reserve University in Cleveland, Ohio, found these cells were able to differentiate into a variety of tissues, including cartilage, bone and tendon.

“Our vision was that this cell could be used in tissue engineering to replace damaged or diseased tissue,” Caplan told Orthopedics Today. “Fast forward to today — we now appreciate that MSCs come from perivascular cells that sit on every blood vessel in the body,” Caplan said. “Primarily, [MSCs] turn down the local immune cells, inhibits the formation of scars, and sets up an environment in which the injured tissue can actually regenerate itself. Not repair itself, but regenerate itself.”

There are several reasons why surgeons may choose to treat patients with stem cells. “There are probably a few reasons for stem cell therapy,” said Lisa A. Fortier, DVM, PhD, professor of surgery at Cornell University in Ithaca, NY. “One is going to be the biologics concept where you can harness your own body’s ability to heal, rather than taking an off-the-shelf drug. You are using your cells to heal your tissues.

“We know that they can help restore cartilage, help restore tissue in general, but that they are also potent modulators of an injury environment,” Fortier said.

Disease modifying role

In addition, “they offer significant promise to modify disease,” said Brian J. Cole, MD, MBA, professor in the department of orthopedics and section head at the Rush Cartilage Research Center at Rush University in Chicago. “Not necessarily recreate tissue, rebuild joints or rebuild lost tissue, but rather to modify the environment in a way that, simply stated, makes people feel better. In addition, they may also have some benefit in terms of augmenting healing with surgical procedures.”

Although there is a lot of excitement around cell-based therapies, some leaders warn that surgeons should remain cautious. “There is a lot of basic science evidence for their use, but when we go to human translation of those research papers I am afraid it does not happen,” said Nicola Maffulli, MD, PhD, FRCS, professor of musculoskeletal disorders and a consultant orthopedic surgeon at the London Independent Hospital, in London.

With demand increasing significantly, it is critical to get “good scientifically reproducible and verifiable results,” Maffulli said.

Cole agreed: “Their current clinical use is outstripping the evidence to support their use. The way they are being used is not necessarily categorically supported by evidence, either in vivo or in vitro or clinically.”

Stem cells in sports medicine

Research is ongoing, assessing stem cells in several sports medicine applications, including augmenting cartilage-related surgical procedures, relieving the pain and inflammation of osteoarthritis and meniscal repair.

Augmenting cartilage repair with stem cell therapies has received a lot of attention in the literature. Animal studies have shown good results when using bone marrow aspirates for cartilage repair. In one study, Fortier and colleagues treated extensive, full-thickness cartilage defects on the femurs of 12 horses. They injected the defects with bone marrow concentrate after microfracture or with just microfracture. Their findings indicated that bone marrow concentrate increased how much the defect filled in and improved how the repaired tissue integrated into the surrounding undamaged cartilage, according to the manuscript published in the Journal of Bone and Joint Surgery in 2010.

Early clinical studies involving stem cells and cartilage repair have been promising. Researchers in Singapore have compared autologous chondrocyte implantation (ACI) to an open implantation of autologous bone marrow derived stem cells. “They found similar improvement in both groups,” Adam W. Anz, MD, medical director of clinical research at the Andrews Research and Education Institute in Gulf Breeze, Fla., told Orthopedics Today.

As a follow-up study, one of the authors compared open stem cell implantation with arthroscopic microfracture augmented with postoperative stem cell injections. The arthroscopic group achieved superior results in IKDC and Lysholm scoring, Anz said.

Anz and colleagues have been collaborating with Khay-Yong Saw, FRCS, a researcher from Malaysia. “Since 2007, [Saw] has been clinically augmenting marrow stimulation with postoperative stem cells” Anz said. In three separate studies, Saw has demonstrated that stem cells improved cartilage regeneration.

“To me, his histology is the most impressive,” Anz said.

There are challenges when using stem cells in people. “In terms of cartilage repair, what we are finding out after collaborating with some people who have been involved, you are probably going to need multiple injections at multiple time points,” Anz said. “We do not have the cell source available to do multiple injections. You would have to do multiple bone marrow aspirates, which is technically and logistically difficult.”

The solution to this problem may be to harvest a lot of cells at one time and store them. “But, if we store cells, then it is a drug and it has to go down the FDA pathway,” Anz said.

Osteoarthritis

“In the area of osteoarthritis [OA], where [stem cells from bone marrow concentrate are] being used at increasing rates … there is little evidence to date to support its indications,” Cole said.

Anz and colleagues have been studying the use of stem cells from bone marrow concentrate in patients with OA. They have a series of more than 200 patients who have been treated with autogenous stem cells harvested from the iliac crest. They harvest stem cells from bone marrow aspirate and immediately put them back into the patient.

“We have been doing that, for example, in the osteoarthritic knee,” said James R. Andrews, MD, a founding partner and medical director for the Andrews Institute for Orthopaedics & Sports Medicine, in Gulf Breeze, Fla. “We believe that this treatment controls swelling and inflammation as well as eases pain in osteoarthritic knees.”

Results of a pilot study, which included 31 NFL players who had early arthritic wear patterns in their knees, showed that at 10 months post-injection, all patients were satisfied, according to Anz.

“We have been going after the indication of early OA and for that indication, we have found it effective for symptoms and keeping people active,” he said.

Their next study, a randomized trial that will include pre-intervention scores, is currently underway.

“The problem is finding the athletic population that will go into a double-blind study,” Andrews said. “These NFL players already know about stem cells, and they come asking for it. They will not go into the study. Filling the numbers from the research standpoint has not been easy.”

Meniscal repair

Stem cells may be useful in enhancing meniscal repair. In a randomized, double-blind study by Vangsness and colleagues, 55 patients underwent partial medial meniscectomy. The researchers administered a superolateral knee injection of allogeneic MSCs within 7 days to 10 days of surgery. The patients in group A received a 50 x 10⁶ injection of MSCs, the patients in group B received a 150 x 10⁶ injection and the control group received a sodium hyaluronate control.

Twelve months post meniscectomy, quantitative MRI results revealed significantly increased meniscal volume in patients in groups A (24%) and B (6%); no control group patients met the 15% threshold for increased meniscal volume. Furthermore, based on Visual Analog Scale results, pain was significantly reduced in patients with OA changes who received stem cells vs. the control group.

Rotator cuff

Stem cells may be useful as an augment to rotator cuff repair. “In the area of the rotator cuff, there is an interesting clinical trial that looked at bone marrow concentrate and healing rates in the long-term that was published outside the United States — an interesting study looking at improved healing rates when the rotator cuff repair was done in the presence of stem cells compared to without,” Cole said.

That study, led by Philippe Hernigou, MD, compared 45 patients undergoing arthroscopic single row rotator cuff repair augmented with bone marrow-derived MSCs with a control group of 45 patients who did not receive MSCs.

The results showed that 100% of patients in the stem cell group healed by 6 months compared with 67% in the control group, according to the abstract. At 10-year follow-up, 87% of patients in the MSC-treated group had intact rotator cuffs vs. 44% in the control group. There was a link between the number of transplanted MSCs and outcome; patients with a loss of tendon integrity during the follow-up period received fewer MSCs.

Obstacles to widespread use

Several obstacles remain before stem cell therapies can be used commonly in sports medicine. “The biggest obstacle is the regulatory burden at this juncture,” Cole said. “We still have a lot to learn … we just need the room to perform good clinical research using stem cell models that seem to be compelling based on what we know at this juncture.”

Caplan agreed that the regulatory process is a challenge. “It is a severe problem for the physician because there are many patients who could use this technology,” he said. “One of the problems is that you are taking live stem cells, the MSC for example, and you are using it as a therapeutic, but all of the rules and regulations for its approval are based on the experience of the FDA with single drugs.”

The FDA should consider changes to the regulatory process, according to Caplan. “I think the procedures are antiquated, and the rules are okay for drugs but not for cells.”

The flip side is that when FDA approval is not needed — when stems cells are harvested, manipulated and reimplanted in the same patient that same day — insurers will not cover the procedure because there is no data to support its use.

Particularly in those cases, the financial burden for cell-based therapies must be completely borne by the patient, according to Cole. “These are non-reimbursable events as far as third-party payors go,” he said.

The lack of solid clinical data remains a problem, Maffulli said. “For one, we have to prove that they are effective,” Maffulli said. Further, the stem cell study results must be reproducible. “We have to make sure that they are safe.”

Ability to expand in culture

Researchers must find a way to expand the number of stem cells in culture, which is challenging given the regulatory burden, according to Cole. “There is evidence about using bone marrow extract, adipose tissue and synovial tissue in a way that can isolate stem cells and expand them in number,” he said. “The problem with that is that in the United States, that is beyond the limits of what can be approved for use today. Much of that data comes from outside the United States.

“We are currently performing a clinical trial of umbilical cord blood, looking at maternal blood from the umbilical cord that has been cultured, expanded into millions of MSCs and using it as a procedure to augment marrow stimulation,” Cole continued. This phase 1 clinical has a small number of patients, but early clinical outcomes seem promising. “This will hopefully have enough legs to drive a clinical study to a phase 3 trial, which will be a pivotal trial that would be used … to overcome the regulatory burden of the FDA.”

Immunogenicity concerns

Concerns about stem cell immunogenicity exist, Fortier said. “The early evidence, even 10 or 15 years ago, said that stem cells were ‘immunoprivileged,”’ she said. “That you could take stem cells from you and give them to me or vice versa.”

The results of a horse study, conducted by Fortier and colleagues, showed that stem cells can elicit an immune response. According to their findings, MSCs should be categorized as major histocompatibility complex class II negative before injection.

“It never made sense to us in basic science that they are immunoprivileged,” Fortier said. “And there is a tremendous amount of data now that says indeed, they are not immunoprivileged. [Patients] need to be cross-matched.”

Caplan refers to MSCs as being “immuno-evasive” in that they put up a curtain of molecules that turn off the interrogating immune cells.

To overcome this, researchers in Korea are in the process of establishing a large bank of stem cells, according to Fortier. It would be similar to a blood bank, she said, “So you can know if you have certain antigens on stem cells, just like your blood grouping. They are trying to identify a universal donor.”

Public misconceptions must also be addressed, according to Cole. “There is a tremendous public misperception of what they are and what they do,” he said. “People think that stem cells can rewind the clock and give us something we had at one point when we were well. The reality is that that is not likely the way they are going to be implemented.” Ultimately, Cole thinks that cell-based therapies will be used as disease-modifiers not as a cure for disease.

Change in medical practice

Caplan sees cell-based therapies as a game changer in medical practice. “Years from now, some guy who just had a heart attack will be able to drive to an urgent care center to be infused with a bag of MSCs that will be therapeutic; it is just mind blowing,” he said.

“The medicine of the future inside and outside of orthopedics is how to manage your body’s MSCs,” Caplan said. “If you do not have enough, we have to figure out ways of getting you a supplement at the right time, in the right way to do the right thing.”

With continued development, stem cells may one day allow surgeons to procure off-the-shelf replacement parts for orthopedic procedures, “We will have replacement parts similar to when you have an automobile nowadays. If you have trouble with your transmission, they do not repair your transmission; they replace your transmission with a new one.” – by Colleen Owens

References:

Fortier LA. J Bone Joint Surg Am. 2010;doi:10.2106/JBJS/.I.01284.
Hernigou P. Int Orthop. 2014;doi:10.1007/s00264-014-2391-1.
Lee KB. Ann Acad Med Singapore. 2012;41(11):511-517.
National Institutes of Health. Stem cell basics. http://stemcells.nih.gov/info/basics/Pages/Default.aspx.
Nejadnik H. Am J Sports Med. 2010;doi:10.1177/0363546509359067.
Schnabel LV. Stem Cell Res Ther. 2014;doi:10.1186/scrt402.
Vangsness CT. J Bone Joint Surg Am. 2014;doi:10.2106/JBJS.M.00058.

For more information:

James R. Andrews, MD, can be reached at the Andrews Institute for Orthopaedics & Sports Medicine, 1040 Gulf Breeze Pkwy., Gulf Breeze, FL 32561; email: info@theandrewsinstitute.com.

Adam Anz, MD, can be reached at the Andrews Research and Education Institute, 1040 Gulf Breeze Pkwy., Suite 210, Gulf Breeze, FL 32561; email: adam.anz@andrewsortho.com.

Arnold I. Caplan, PhD, can be reached at Case Western Reserve University, 10900 Euclid Ave., Room 118, Millis Hall, Cleveland, Ohio 44106; email: arnold.caplan@case.edu.

Brian J. Cole, MD, MBA, can be reached at Rush University Medical Center, 1611 W. Harrison, Suite 300, Chicago IL; email: brian.cole@rushortho.com.

Lisa A. Fortier, DVM, PhD, can be reached at Cornell University Hospital for Animals, Box 20, Ithaca, NY 14853; email: laf4@cornell.edu.

Nicola Maffulli, MD, PhD, FRCS, can be reached at the London Independent Hospital, 1 Beaumont Square, Stepney Green, London GBR E1; email: n.maffulli@qmul.ac.uk.

Disclosures: Anz is on the scientific advisory boards of Biologic Therapies and Intellicell Biosciences and is a paid consultant to Arthrex; Case Western Reserve University receives royalties from Osiris Therapeutics Inc. (a cell therapy company that Caplan founded), a portion of which he receives.; Fortier and Cole are a paid consultants to Arthrex; Andrews and Maffulli have no relevant disclosures to announce.

 

Has the clinical use of stem cell therapies started to outpace the available evidence?

 

Indiscriminate use of stem cells is premature

I believe that the current use of “stem cell” therapy has outpaced the available clinical data. One concern is simple nomenclature: The term is used to refer to what is typically just bone marrow aspirate concentrate. Although there are some true stem cells in the bone marrow aspirate, the number is small. Until we have techniques that allow us to isolate and concentrate the cells, I think that it is a bit of a leap to say that we can routinely use “stem cells.”

Even if we can obtain a population of such cells, we need more information about the basic biology of the cells to know how to best use them for various clinical applications. It has become clear that a cell’s behavior is very much influenced by its microenvironment. Once the cell is removed from its native environment — such as bone marrow or adipose tissue — it may behave differently. It is naïve of us to think that these cells from different sources will behave in a predictable manner when implanted into all of the various types of tissues where they are currently being used. Another concern is that it is clear that much of the effect of stem cells is due to a paracrine effect, from cytokines and other factors produced by the cell. Consideration of the myriad effects of cytokines further points out the need to obtain more data before widespread use. For example, bone marrow aspirate is being used following surgery in some applications in an effort to try to improve healing. However, the biologic milieu in healing tissues is an evolving and continuously changing process during healing, and thus the indiscriminate injection of cells seems premature until we obtain further information about the behavior of cells in different tissues.

Scott A. Rodeo, MD, is a clinician-scientist at the Hospital for Special Surgery in New York City.
Disclosure: Rodeo is a consultant for Cytori Inc. and Pluristem, and has stock in Cayenne Medical.

 

Great promise, not enough data

Stem cells provide great promise for the development of new, ground-breaking treatments for a variety of orthopedic conditions. Not only have they been shown to have abilities to repair or regenerate musculoskeletal tissues, but also stem cells have been shown to exhibit anti-inflammatory effects that can reduce pain and degeneration. To date, however, the primary evidence for these capabilities has been through laboratory studies and small animal models. Despite a number of ongoing clinical trials, there is still a dearth of evidence — particularly level 1 studies — that support their efficacy or safety in humans.

Unfortunately, this lack of evidence has not prevented the growing use of unregulated stem cell therapies, which are often marketed to professional athletes as well as the general public, or offered as medical tourism outside the United States where their use is less strictly regulated. Within the United States, stem cell therapies are being offered without supporting clinical evidence and in direct violation of FDA guidelines. In many cases, the benefits are overstated and the risks understated.

If we have learned anything about stem cells in the past 20 years, it is that they are highly complex and simply not “magic bullets” that will automatically cure every ailment simply by being injected into the body. Moreover, not all stem cells are create equal — they show highly different capabilities depending on their source, and their properties may differ dramatically from one person to another, making their effects unpredictable.

We are only now scratching the surface in terms of understanding the fundamental properties of stem cells and how to harness them properly. If we continue to use them prematurely, we run the risk of catastrophic complications that could set the field back for decades, similar to early experiences in gene therapy. Stem cells may very well hold the cure for many orthopedic conditions, but we first need direct clinical evidence of their safety and efficacy as well as a more in-depth understanding of their properties. Only then will the hope be able to catch up with the hype.

Farshid Guilak, PhD, is the Laszlo Ormandy Professor and Vice Chair for Research in the Department of Orthopedic Surgery at Duke University Medical Center.
Disclosure: Guilak is a founder of Cytex Therapeutics Inc.

 

Limited evidence to support the use of stem cells in orthopedics

I have a lot of hope and faith and it is based on good scientific evidence that stem cells will have a role to play in the future of musculoskeletal injuries and conditions in the future, but right now, there is a limited amount of information that we could reasonably refer to as evidence to support it. In particular, the idea that stem cells are a treatment for early arthritis is based on little evidence. I have heard stories of patients coming to doctors’ offices, paying cash and having their stem cells harvested and then just injected into their knee. If there is any improvement that is obtained from doing that, I would argue that it is a placebo effect until I saw some evidence that the cartilage itself was getting better or was improved or was restored. I do not have any information on that.

There are some animal studies that support that, but they involve an invasive procedure that is different from just injecting stem cells into the synovial fluid of somebody’s knee.

Now there are some applications that stem cells may be working, and the two areas that I can think of are the treatment of fractures and nonunions and the treatment avascular necrosis of the femoral head. I personally have been involved in both of those treatments. I do not have any organized data that I would refer to as evidence to address the issue of the use of stem cells to treat nonunions, but we are now in the process of putting together a rather large study that was done using all of the correct scientific procedures, IRB approval [and] a prospective protocol, and we have got good evidence that in the case of stage 1 and stage 2 avascular necrosis (AVN) of the femoral head, stem cells can lead to a reduction in the number of patients who go on to collapse and need total hip replacement. And those patients whose femoral heads survive, there is an improvement in function and a reduction in pain.

I do not have the exact figures in front of me because the numbers are still being crunched, but I have seen several iterations of the data as they are coming along from my collaborators and the data are good.

There is going to be some good evidence for that diagnosis or disease-specific application, AVN of the femoral head of the hip, but I am not aware of similar types of evidence from other applications.

Of course, there is the work from Paris. There have been some randomized controlled trials from Valerie Gondry and some extensive data developed by Philippe Hernigou, again [for] AVN for the femoral head.

There is good evidence that stem cells play a potential role for stem cells to play in that disease-specific environment but beyond that, I am not aware of a lot of good evidence.

Thomas Einhorn, MD, is professor and chairman of orthopedic surgery at Boston University.
Disclosure: Einhorn is a consultant for Harvest Technologies and is a stockholder and scientific advisory board member of NeoStem.