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The Role of Mesenchymal Stem Cells in Augmenting Rotator Cuff Repairs.

Rotator cuff pathology is the most common cause of shoulder pain for which patients seek treatment, and it is an increasing cause of upper extremity disability in the elderly. (1-3) This is significant because Americans 55 years and older comprise 35% of our labor force. (4-6) The estimated prevalence of tears dramatically increases with age, with 78.3% occurring in patients between the ages of 50 and 89. (7) While the etiology of rotator cuff injuries is multifactorial, it is in part due to degenerative changes associated with advancing age. (6,8-15) Despite recent improvements in reattaching the rotator cuff to its footprint, estimated re-tear rates range from 10.3% to 34.9%, and unsurprisingly these re-tear rates are particularly high in the elderly population. (11,14,16-19) Additionally, a substantial proportion of these tears are large tears that are more prone to unsuccessful surgical repair. (7,11)

As mechanical advancements in rotator cuff repairs (RCR) begin to plateau, some researchers have moved toward trying to optimize the shoulder joint's biologic environment. These investigations have sought a potential role for mesenchymal stem cells (MSC). Although a great deal of work has been done on MSC, their use in clinical practice is still in its infancy. The goal of this study is to review the current literature on the safety and efficacy of injections of MSC in the shoulder joint in the context of augmenting RCR in the future.

Materials and Methods

A review of the literature of MSC in the shoulder joint was conducted. PubMed and Cochrane Reviews databases were queried for studies reporting treatment outcomes of an injection of MSC during arthroscopic RCR published between 1980 and 2017. The initial search was conducted on November 5, 2017, using the key words "mesenchymal stem cells" and "rotator cuff repair" and yielded 116 results. Studies were manually reviewed and included if they compared RCR and an injection of MSC to a control RCR group or if they described a technique for the isolation of MSC from a source in the shoulder joint. Studies were excluded if they were not in the English language and did not involve the shoulder joint. Case reports were also excluded.

Further screening based on the inclusion and exclusion criteria narrowed the results down to two human clinical studies utilizing an injection of MSC to enhance RCR. Seven studies with safe and reproducible techniques for harvesting MSC from sources in the human shoulder joint were also included as a recommended direction for future research. A second search was conducted on November 20, 2017, to ensure inclusion of all relevant studies. The final review on MSC included nine critically analyzed studies.

Results

Rotator Cuff Tendon Repair Biology

A rotator cuff repair relies on the body's natural ability to heal tendons. The sutures and anchors merely provide temporary fixation to ensure stable apposition of the tendon to the bony surface while biologic healing occurs. When tendon injury occurs, the inflammatory phase initiates within the first 24 hours. Leukocytes, erythrocytes, and platelets migrate to the site of injury. In response to chemotactic factors released by these inflammatory cells, the repair phase ensues 2 to 3 days later. During this phase, tenocytes synthesize collagen and other extracellular matrix components such as proteoglycans. Approximately 6 weeks later, the remodeling phase occurs, and the cellularity of the initial scar tissue decreases. Importantly, the original haphazard arrangement of collagen type III (Col-III) is replaced by longitudinally arranged collagen type I (Col-I), enhancing the mechanical strength of the tendon. Ultimately, this scar tissue repairs the tendon and reattaches it to the greater tuberosity of the humerus. Histological studies affirm that functional restoration of the rotator cuff occurs through this repair process and that the original fibrocartilage enthesis between the tendon and bone does not regenerate. (20-26)

Current research aims to identify molecular expression pattern differences in individuals with non-healing rotator cuff repairs. (27) In a model using in vitro human Achilles tendons, Maffulli et al. (28) reported an abnormal molecular healing pattern with a greater proportion of Col-III compared to Col-I, predisposing the tendons to rupture and compromising their tensile strength. Matthews et al. (29) noted that as rotator cuff tears increase in size, tenocyte cellularity and metabolic activity decreases. Additionally, expression of leukocyte and vascular markers also decreases with increased tear size, indicating diminished biologic potential for inflammatory and reparative processes. (30) Chillemi et al. (27) found that as patients with rotator cuff tears aged, histopathological evidence of inflammation decreased. This may implicate a role for MSC in older patients with larger tears due to a weakened natural healing ability.

Benson et al. (31) found a correlation between BNip3, a proapoptotic protein, and age in patients with rotator cuff tears. Elevated levels of the pro-apoptotic BNip3 is significant because studies have shown that excessive autophagy and apoptosis contribute to the rotator cuff degeneration that often occurs with age. In torn rotator cuffs, apoptotic rates have been found to be 21% greater than controls. (32,33) For this reason, it is possible that loss of regulation of BNip3 contribute to greater apoptotic rates in elderly patients with torn rotator cuffs, impeding their ability to sufficiently heal their tendons after rotator cuff repair. Moreover, with increasing age, p27, a cell cycle inhibitor, is upregulated leading to diminished tenocyte proliferation. (34) This growing body of evidence supporting older patients' diminished biologic capacity to heal suggests that they may be the ideal candidates for augmentation with MSC during RCR.

Mesenchymal Stem Cells

According to the International Society for Cellular Therapy, the minimal criteria for defining a mesenchymal stem cell is as follows. First, they must be plastic-adherent. Second, they must express CD105, CD73, and CD90 while lacking CD45, CD34, CD14 or CD11b, DC79a or CD19, and HLA-DR surface molecules. Last, they must have the capacity to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro. (35)

While there is a great deal of excitement surrounding the use of MSC in orthopedic conditions, many people remain skeptical. After the hype surrounding platelet rich plasma (PRP) injections to augment rotator cuff repairs was met with failure, physicians and patients alike are especially doubtful of a role for MSC in the shoulder joint. (11,36,37) Mesenchymal stem cell therapy can be performed in the United States by any qualified physician because autologous MSC are not currently considered biological drugs or devices and therefore fall outside of the jurisdiction of the FDA. The problem with this is the lack of standardization. Not only can the quality and quantity of MSC injected into each patient differ immensely, but also the technique and formulation used to deliver MSC into the joint can vary. Consequently, it is difficult to prove that the clinical successes of MSC treatment presented in the literature are more than a placebo effect. (38) Therefore, it is not covered by most insurance plans and it is very costly. Finally, there is a facade referred to as "stem cell tourism," in which some physicians have falsified the clinical indications of stem cell treatments, thus misleading patients and having deleterious effects on the future advancements of evidence-based stem cell therapy. (39,40)

There is the concern of MSC transformation, potential tumorigenicity, and possible ectopic tissue formation. (41-45) In a systematic review and meta-analysis of clinical trials, however, Lalu et al. (46) did not identify any significant adverse reactions associated with MSC treatment other than a transient fever. A huge appeal of MSC is their ability to evade the immune system's defenses. Mesenchymal stem cells by definition do not express major histocompatibility complex class II (MHC-II), avoiding detection by the host's T-lymphocytes. (38,47) This permits future development and use of standardized and regulated ex-vivo expanded allogenic stems cell products. (38)

Mesenchymal stem cells can be isolated from a variety of adult tissues, but bone marrow aspirate and adipose tissue, and more recently synovium and periosteum, have been under the most investigation. (48,49) Mesenchymal stem cells have also reportedly been harvested from alveoli, cardiac tissue, and peripheral blood. (50-52) In addition to adult sources, MSC can be isolated from neonatal tissues, such as from the placenta and umbilical cord, but there are ethical questions surrounding these sources. (48) This review focuses on MSC derived from bone marrow and adipose tissue.

Bone marrow derived stem cells (BM-MSC) are typically aspirated from the iliac crest, which is both invasive and painful for the patient, but it is attractive in that it is readily attainable. (48,53) Additionally, there is always the risk of infection. (48) Bone marrow appears to have a higher proliferative ability, chondrogenic potential, and osteogenic potential compared to adipose tissue. (54) However, the clonogenicity and chondrogenic potential of the MSC harvested from bone marrow decreases with age. (38,55,56) This is critical to recognize, especially when MSC therapy is being discussed in the context of rotator cuff tears in the elderly population. However, if allogenic MSC therapy becomes an option in the future, this potential drawback would be ameliorated. The osteogenic potential of MSC does not exhibit this age-related decline. (55)

Adipose derived stem cells (AD-MSC) are usually isolated from lipoaspirates, but have been obtained from the infrapatellar fat pad for the treatment of knee osteoarthritis. (48,57-60) They secrete angiogenic and anti-apoptotic cytokines that decrease tissue degeneration and enable regeneration. (61,62) Adipose derived stem cells tend to be more abundant, more accessible, and more proliferative than BM-MSC. (62) Importantly, they do not appear to exhibit the age-related decline seen with BM-MSC. (63) In a rat model, adipose-derived stem cells have been shown to accelerate muscle repair based on increased tetanus strength and number of centro-nucleated regenerating myofibers present at 2 weeks post-injection. (62) Treatment with both AD-MSC and a RCR in a rabbit model resulted in a larger compound muscle action potential area and a higher load-to-failure ratio compared to the group treated with only a RCR. (64) Thus, animal models indicate that muscle repair may be accelerated and enhanced with AD-MSC treatment, but analysis in humans is necessary to determine if these findings have clinical merit.

Human Studies Evaluating the Efficacy of Mesenchymal Stem Cells in the Shoulder Joint

To our knowledge, there are two human studies supporting the clinical efficacy of MSC in the shoulder joint. In a case-control study of 45 patients conducted by Hernigou et al., (65) an injection with BM-MSC appeared to improve both short- and long-term outcomes. A volume of 150 mL of bone marrow was aspirated from the iliac crest and concentrated. The average number of MSC returned to each patient was 51,000 [+ or -] 25,000 per 12 mL of injected bone marrow concentrate. Mesenchymal stem cells were identified and estimated by counting the number of colony forming unit fibroblasts. Magnetic resonance imaging (MRI) and ultrasound analysis indicated that all 45 of the rotator cuff repairs that had been augmented with a BM-MSC injection healed by 6 months, but only 67% had healed in the control group. At 10-year follow-up, 87% of the rotator cuffs in the BM-MSC treated group were still intact compared to only 44% of the control group. The researchers quantified the number of BM-MSC injected into each patient at the time of their arthroscopic repair, and they found that the degree of tendon integrity in the BM-MSC treated group was correlated with the amount of MSC received. (65) While this study supports that BM-MSC treatment may enhance RCR, there are a few limitations. The authors do not mention the usage of cell surface markers to confirm the identity of the MSC. Additionally, their main inclusion criterion was patients with a symptomatic rupture of the rotator cuff. Thus, it would have been useful to utilize outcome scores measuring symptomatology postoperatively.

To date, there has been one retrospective cohort study evaluating the outcomes of patients who received AD-MSC during their RCR. (66) Thirty-five patients were injected with AD-MSC loaded in fibrin glue during their rotator cuff repairs, and 35 matched controls were treated only with rotator cuff repairs. At 12-months postoperatively, there were no significant differences in range of motion, functional measures of CS, UCLA scores, or VAS pain scores between the two groups. However, MRI assessment throughout an extended follow-up period indicated that the re-tear rate in the control group was twice that of the group that received the AD-MSC. (66) These results, taken with recent animal models, indicate that AD-MSC treatment could enhance tendon healing and muscle function postoperatively. (62,64,66) The evidence warrants further investigation into the effects of AD-MSC on the shoulder's biologic environment. This data also highlights an important point regarding mismatches between clinical symptoms and anatomic deficits. In this study, there were no difference in patient reported outcomes despite radiographic indications of a re-tear. With the patient at the center of our treatment plans, it is important to question the utility of a treatment in which the biologic improvements may not translate to a lessening in symptomology.

Human Studies Evaluating the Sources of Mesenchymal Stem Cells in the Shoulder Joint

Mazzocca et al. (67) conducted a cohort study in which bone marrow aspirate was harvested from the humeri of 23 patients during arthroscopic RCR. Cytochemical and molecular analysis confirmed that the humeral MSC had osteogenic potential and could be aspirated safely during arthroscopic RCR surgery without increasing morbidity. Beitzel et al. (68) reproduced the MSC harvesting technique from the proximal humerus and quantified the mean cell concentration. They found no differences based on age or gender in the initial quantity of MSC isolated. These studies indicate that obtaining bone marrow from the proximal humerus is safe. Taken together with the current notion that MSC have no known serious adverse effects, future randomized controlled studies should be considered. In addition to aspirating bone marrow from the proximal humerus, other studies demonstrated that MSC could be feasibly obtained from the rotator cuff itself, subacromial bursa, and long head of the biceps. (69-71) This makes obtaining and utilizing MSC to augment arthroscopic RCR more attractive to patients and more feasible for physicians by localizing the invasiveness of the procedure to the shoulder joint.

Conclusion

In conclusion, MSC show potential to augment rotator cuff repairs and lessen the burden of re-tears. This procedure is particularly relevant for elderly patients with larger tears, who have the highest incidences of re-tears due to an attenuated biologic ability to heal themselves. This may be in part due to weaker inflammatory processes, decreased tenocyte proliferation, and greater rates of apoptosis. The optimal source of MSC has yet to be determined. There are advantages to using either bone marrow or adipose derived MSC. Adipose derived stem cells do not appear to exhibit the age-dependent decline in proliferative ability seen with BM-MSC. However, future development and regulation of allogenic MSC injections may make this concern obsolete as BM-MSC can be harvested from younger donors.

The humeral head is an appealing source of bone marrow aspirate in the setting of shoulder arthroscopies because the procedure itself is straightforward for the physician, and it limits the invasiveness of the surgery to the shoulder joint. While ample human research supports the safety of MSC usage, there is not nearly enough research supporting their efficacy. Furthermore, other barriers to their use in clinical practice remain the lack of both insurance coverage and accepted standard of care practices. Future research should continue to quantify the improvements that MSC injections have on patient outcome scores and tendon regeneration and the degree of correlation between the two measurements. Researchers should also aim to determine the optimal source, scaffold, and formulation for MSC injections, driven by the shared goal of standardizing and maximizing the benefits of MSC therapy.

Disclosure Statement

None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

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Nicole D. Rynecki, BA, and David S. Pereira, MD

Nicole D. Rynecki, BA, Rutgers New Jersey Medical School, Newark, New Jersey, USA. David S. Pereira, MD, Department of Orthopedic Surgery, NYU Langone Orthopedic Hospital, NYU Langone Health, New York, New York, USA.

Correspondence: David S. Pereira, MD, Department of Orthopedic Surgery, NYU Langone Orthopedic Hospital, NYU Langone Health, 301 East 17th Street, New York, New York 10003, USA; david.pereira@nyumc.org.

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Publication:Bulletin of the NYU Hospital for Joint Diseases
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Date:Oct 1, 2018
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