Controversy, cost may not dim potential of stem cells in the shoulder

It is widely known and reported in the literature that shoulder injuries, including rotator cuff tears, tend to heal slowly and the management of glenoid labral tears, subacromial impingement and the degenerative, arthritic shoulder may be challenging. Therefore, research into biologic treatments for these conditions is underway. This includes exploring the effect in the laboratory and the OR of various types of stem cells on healing when injected or used to augment arthroscopic or open surgery.

The stem cell treatment approach is controversial, according to sources who spoke with Orthopedics Today. Stem cells injected in the shoulder or introduced during arthroscopic or open surgery, for example, can be costly and may not be covered by many insurance plans. In addition, the effectiveness of cell therapy for these indications is largely unproven. Ultimately, this may mean some patients will need to undergo a traditional treatment later, and thereby withstand two or more treatments for the same condition, sources said.

“One way to ideally improve rotator cuff healing rates is to augment the mechanical repair that we do, whether it be a double-row repair, a single-row repair or a transosseous equivalent type repair, with some biologic activity to help promote healing,” Alexander E. Weber, MD, told Orthopedics Today.

“We now know we have the surgical techniques and equipment to robustly tack down the rotator cuff tendon back to the bone so the mechanical environment is strong. What is lacking is the biologic environment to help heal the rotator cuff and that is where stem cells, platelet-rich plasma (PRP) and biologic factors have been associated to hopefully improve healing rates, improve patient satisfaction and improve postoperative strength and function,” said Weber, who is assistant professor at the University of Southern California Department of Orthopedic Surgery, Section of Sports Medicine and Shoulder Surgery.

Image: Janine Gelineau – UConn Health

Athletes with an intramuscular pectoralis tear or another muscle injury may benefit from stem cells as may patients with early shoulder arthritis, according to Claude T. Moorman III, MD, who is professor and vice chair of the Department of Orthopedics and executive director of the James R. Urbaniak, MD Sports Sciences Institute at Duke University.

“We can debride the joint and perhaps do some releases of some of the tissues that are contracted and get the patient some temporary relief [from arthritis] by increasing the tolerances of the joint, but the long-term effect is limited because there is not any biology that you are changing in the structure,” Moorman told Orthopedics Today. “Whereas, the stem cells have a potential to affect [number] one, through providing a more long-lasting anti-inflammatory effect from the stem cells. Secondly, the hope is the cells will grow to heal the surfaces that are involved,” he said.

Marrow vs fat-derived cells

There are adult, embryonic and induced pluriopotent stem cells, according to Cato T. Laurencin, MD, PhD.

“The adult stem cells have the most promise for clinical translation right now. Of the adult stem cells, adipose-derived cells and bone marrow-derived cells are most commonly used,” said Laurencin, who believes adult stem cells may ultimately find numerous clinical uses for shoulder injuries.

James P. Bradley, MD, said there is a debate about whether better outcomes are provided by fat-derived or marrow-derived stem cells.

“I have always been of the belief that you have to get as close to the target tissue as you can,” Bradley said. “Marrow cells, to me, are closer to cartilage than fat.”

Therefore, he said his group tends to use just marrow-derived stem cells.

Bone marrow aspirate (BMA) concentrate is the most common form of marrow-derived stem cells, according to Moorman. It consists of fluid removed from a patient’s bone marrow that is then concentrated.

Augustus D. Mazzocca, MD, prefers site-specific stem cell harvesting to decrease surgical time and morbidity.

Mazzocca said, “Many surgeons find it advantageous to obtain the stem cells from the iliac crest; however, stem cells can be harvested from a variety of site-specific areas, such as the proximal humerus with rotator cuff surgery. All are reproducible harvest methods and have reports in the literature.”

Moorman said there are potential advantages of using fat-derived or adipose stem cells vs. stem cells derived from bone marrow, the first of which is easy to harvest.

“The second [advantage] is, over the course of a [person’s] lifetime the number of stem cells in bone marrow decreases with age, whereas the number of stem cells in fat stays constant over your lifetime,” he said. “The third advantage is there is an order of magnitude more cells in fat than there is in marrow. In other words, you get more ‘bang for your buck’ with fat in terms of having more cells per unit volume.”

Bradley said previous literature has shown promising results using bone marrow-derived stem cells for shoulder injuries. In a presentation at the American Academy of Orthopaedic Surgeons Annual Meeting in 2015, Philippe Hernigou, MD, PhD, and colleagues reported significantly improved healing at 10-year follow-up among patients who underwent rotator cuff repair with bone marrow concentrate that contained mesenchymal stem cells.

“As far as rotator cuff healing is concerned, to me it looks like bone marrow cells have the edge,” Bradley said.

Specific indications

Laurencin, who is the Alberta and Wilda Van Dusen Distinguished Endowed Professor of Orthopaedic Surgery and director of The Institute for Regenerative Engineering at University of Connecticut, is a member of the International Society for Cellular Therapy. He said although there may be a role for stem cells used clinically in orthopedic surgery, cells may not be useful for all musculoskeletal disorders.

“Finding their proper place is important,” Laurencin said.

Bradley, who is clinical professor of orthopedics at the University of Pittsburgh Medical Center and head team physician for the Pittsburgh Steelers, said he does not think stem cells should be used for some shoulder injuries, such as a full thickness rotator cuff tear.

“For the shoulder, I use [stem cells] for subacromial impingement. I use them for partial rotator cuff tears; and I use them primarily for glenohumeral osteoarthritis,” Bradley told Orthopedics Today. “There are some people who will treat non-retracted rotator cuff tears with stem cells, but I do not do that yet. I think once the patient has a full thickness tear, there is a time where you can get them fixed well and that the size of the tear is almost proportional to the success of the surgery.”

According toMazzocca, who is chairman of the Department of Orthopedic Surgery and director of the UConn Musculoskeletal Institute at the University of Connecticut, he uses BMA and PRP in rotator cuff revision surgery to augment the biological activity in cases where it is suspected to be lacking, such as in a compliant patient who has not healed.

“Since rotator cuff healing is variable, eventually the use of BMA/PRP in primary repairs to avoid the revision surgery would be the goal,” Mazzocca said.

Stem cells vs PRP

Researchers have compared healing with stem cells to healing with PRP with the expectation that stem cells will prove more effective at generating healing. According to Weber, PRP provides some of the factors and signals that promote healing, but he said stem cells have the potential to become the tissues of the healing interface.

“One of the big differences that we can point out is that with the PRP, you are getting some of the signals for encouraging healing, but not the potential for the healing tissue itself,” Weber said. “You are getting the platelets and some of the downstream effects of healing factors, but you are not getting the full biologic complement of cells, which may become tendon or bone or cartilage. [Whereas,] the intent of stem cell augmentation of healing is you are getting the cells which can then, with the right signals, potentially become the tissues of the healing interface, which are tendon, fibrocartilage and bone.”

Stem cells and PRP both have advantages and disadvantages when used for shoulder injuries and conditions. They both need to be studied more extensively through prospective, randomized, controlled trials to determine the full extent of their possible benefits, Bradley said.

Stem cell administration

Injecting stem cells has advantages for some patients because the cell treatment is reportedly associated with reduced morbidity and faster recovery, according to Bradley.

Mazzocca noted that combining concentrated bone marrow with PRP and applying it to a scaffold may enhance healing. Other sources Orthopedics Today spoke with said stem cells may be administered arthroscopically and could be combined with a tissue matrix, demineralized bone matrix or fibrin glue.

Laurencin and his colleagues used nanotextured fabric seeded with stem cells in rats with torn rotator cuffs and published their findings earlier this year in PLoS One. They showed enhanced regeneration of the rotator cuff occurred at 6 weeks and 12 weeks postoperatively compared to suture repair or suture repair with their system.

The stem cells had a medicinal effect in this study and produced “bio-factors that changed the immune environment to allow better healing,” Laurencin said.

Variable costs for stem cells

A disadvantage of using adipose stem cells to treat shoulder injuries is the potential for harvest morbidity, Moorman said.

“When we do abdominal fat harvest, we should apply a compression dressing for 48 hours and that minimizes the discomfort and the bruising that some of the patients have felt from that,” he said.

The disadvantages of stem cell treatments go beyond donor site morbidity, according to sources who said there is considerable variability in the cost of stem cell treatments, depending on who administers the cells.

Moorman said kits for isolating stem cells cost between $600 and $1,800.

A single stem cell injection can range in price from $1,500 to $10,000 depending who does the injection, according to Weber. Importantly, stem cell therapy products are not FDA-approved and health insurance companies in general do not pay for the treatment. This means patients pay for the treatment out-of-pocket.

“In the United States [none] of the insurers are paying for the [stem cell] therapy, so it is all a cash business,” Moorman said. “That creates the whole stratification of care and concerns regarding folks who may not necessarily be able to afford the treatments.”

Unfortunately, some of the prime candidates for stem cell shoulder therapy are young athletes who should have this treatment, Moorman noted.

Let patients decide

Weber said orthopedic surgeons have an obligation to tell patients when a treatment is not covered by insurance. At this stage, patients will most likely have to pay out-of-pocket for PRP or stem cell treatment of any shoulder injury or condition.

“I am direct in telling [patients] insurance will not pay for this therapy. Patients are interested in alternatives to undergoing surgery. I think it is best to provide as much education as a patient desires and allow them to share in the decision-making process about stem cell treatment,” Weber said.

In addition to providing patients with information about their responsibility in paying for any shoulder stem cell treatment, orthopedic surgeons should also provide patients with all the available information and research results on stem cells and any associated procedures, sources said.

Surgeons should be up front with patients and have a full conversation about stem cell therapy, including mention of risks, benefits and alternatives, Weber said. If after that, patients still want to proceed with the treatment plan, whether it is with a stem cell injection or multiple injections in the office, or with augmentation of their rotator cuff repair in the OR, and they are willing to pay for the procedure, “I do not think there is a major downside in terms of risk to the patient,” he said.

Research that answers questions

More long-term clinical data on outcomes of patients treated with stem cells in the shoulder will hopefully support the use of this treatment as a mainstream nonoperative or surgical approach, according to the sources interviewed.

“We need to have level 1, prospective, randomized trials like what is going on in Italy now in the rotator cuff, where we have a treatment group and a sham group and we look at the results long-term with over 2-year follow-up,” Moorman said.

In terms of the safety, early results of a study underway at Moorman’s institution are encouraging, but a larger group of patients should be studied to identify and quantify other risks when using stem cells, he said.

Laurencin told Orthopedics Today clinical trials to establish efficacy are still needed, as is research into methods that will direct the function of stem cells in vivo.

“The use of stem cells as a part of the new field we call regenerative engineering is of importance. Ultimately, it is not enough to use stem cells alone. We need to be able to control and modulate their actions using advanced biomaterials, developmental biology cues and physical forces,” he said.

“The basic healing pattern of human rotator cuff tendon to bone integration is still largely unknown. Using concentrated BMA/PRP on a demineralized bone matrix or fibrin scaffold may improve the issue healing, helping our patients heal successfully and return to activity faster,” Mazzocca told Orthopedics Today.

“We have had similar technologies that have been disappointing in the long term and we are hopeful [stem cells] will not work out that way, but certainly the promise of being able to help people stay away from more definitive and irreversible treatments is something we would like to do,” Moorman said. “Certainly, for patients who are indicated for joint replacement, we are hopeful we can either delay or perhaps even in some cases eliminate the need for that, but it all remains to be seen,” he said. – by Casey Tingle

• References:
• Bone marrow aspiration. Available at: www.aofas.org/footcaremd/treatments/Pages/Bone-Marrow-Aspirate-Concentrate.aspx?PF=1. Accessed April 20, 2017.
• Hernigou P, et al. Paper #533. Presented at: American Academy of Orthopaedic Surgeons Annual Meeting. March 24-18, 2015; Las Vegas.
• Peach SM, et al. PLoS One. 2017;doi:10.1371/journal.pone.0174789.
• Weber AE, et al. Operative Techniques in Orthopedics. 2016;doi:10.1053/j.oto.2016.01.005.
• What are stem cells? How are they regulated? Available at: www.fda.gov/aboutfda/transparency/basics/ucm194655.htm. Accessed April 20, 2017.

• For more information:
• James P. Bradley, MD, can be reached at University of Pittsburgh Medical Center, 200 Delafield Rd., #4010, Pittsburgh, PA 15215; email: pietzakr@upmc.edu.
• Cato T. Laurencin, MD, PhD, can be reached at UConn Health, 263 Farmington Ave., Farmington, CT 06030; email: laurencin@uchc.edu.
• Augustus D. Mazzocca, MD, can be reached at UConn Health, 263 Farmington Ave., Farmington, CT 06030; email: mazzocca@uchc.edu.
• Claude T. Moorman III, MD, can be reached at James R. Urbaniak, MD Sports Sciences Institute, Center for Living Campus, Wallave Clinic, 3475 Erwin Rd., Durham, NC 27705; email: sarah.avery@duke.edu.
• Alexander E. Weber, MD, can be reached at University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033; email: alexander.weber@med.usc.edu.

Disclosures: Laurencin reports he is a founder of Soft Tissue Regeneration, Healing Orthopaedic Technologies and HOT BONE INC., and is a scientific co-founder of Natural Polymer Devices Inc. Mazzocca reports he receives research support from and is a consultant for Arthrex. Moorman reports he is a consultant for Lipogems, is on the board of advisors for RegenMed and receives other financial/material support from Breg, DJO Global, Mitek, Smith & Nephew and Tornier. Bradley and Weber report no relevant financial disclosures.

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