Mesenchymal Stem Cells for Shoulder Tendon and Arthritis

Zaid Yasan & Lennard Funk, 2019

Abstract
In recent years there has been a boom in the advancements and research in mesenchymal stem cells (MSCs) injections for tissue regeneration. This has led to commercial products and early adoption of the technology. High profile cases, media and internet prominence of stem cell therapies have led to a patient demand for the treatment for numerous traumatic and degenerative musculoskeletal conditions. In this article we aim to review the evidence for mesenchymal stem cell therapy so far, focussing on it’s use for the shoulder.
We identified 22 animal studies and 17 human studies for Osteoarthritis (OA), with a cumulation of 399 patients assessed. Rotator cuff tear studies yielded 8 animal studies and 3 human studies.
There is a reasonable body of evidence to support its use for the early stages of OA and as such phase III trials should be implicated. Evidence to support use of MSCs for rotator cuff tendon pathology is very early and limited, but promising. More trials need to be done to assess its efficacy for injection both at the point of surgical repair and in non-surgical patients. The treatment is expensive and one has to question whether the current evidence justifies the cost.

Introduction
The shoulder is a highly complex joint and is thus predisposed to a wide range of pathologies. Shoulder pain affects up to a quarter of the adult population at any given time(1), and injury is rife amongst the young, healthy athletes, with shoulder pathology accounting for up to 20% of athletic injuries(2). The most common pathology of the shoulder involves dysfunction of the rotator cuff, including inflammation and physical tearing leading to pain, weakness and instability of the shoulder joint. This affects 30-50% of patients over the age of 50 at some point in their life however is common across ages and activity levels. Osteoarthritis (OA) of the shoulder is another condition which can present in nearly any demographic of patient and, along with the former, can be highly problematic to treat.
Conservative treatment including analgesia, physiotherapy and intra-articular injections are commonly used in both conditions, however in the case of OA this does not work to slow progression of disease(3). Shoulder replacement surgery is the mainstay of treatment for the advanced stages of these conditions however treatment can be challenging when applied to the younger population as long-term revision may be required. Many older patients may not be suitable candidates for surgery due to the anaesthetic risk(4).
There has recently been a a large amount of research on to the potential of mesenchymal stem cells as a therapeutic target for the treatment of a huge range of diseases. The regenerative potential of these cells may be utilised to regenerate functional articular cartilage and tendon fibres, as well as providing a strong immunomodulatory function that may work to reduce inflammatory damage in acute injury(1). However, stem cell research is still in its early stages with the much of the research relating to in vitro and animal studies. As such it is unclear as to where we are in relation to incorporating stem cells into the treatment of everyday shoulder pathologies. This increase in research is well known and has been capitalised on by various companies who have opened clinics promising to cure various diseases, from osteoarthritis to motor-neuron disease, through the administration of autologous adipose-derived stem cells. This paper aims to evaluate the current existing evidence of autologous stem cells, with a focus on it’s use in the shoulder.

Osteoarthritis
Non-surgical treatment of osteoarthritis will usually start with analgesics and anti-inflammatories, in conjunction with a therapeutic exercise program and activity modification. Intra-articular corticosteroid injections may be used to reduce joint inflammation. While these measures provide improved symptomatic control and functionality, they fail to stop the progressive degeneration of articular cartilage and many patients may go on to require surgery due to worsening symptoms or osteophyte formation causing complications such as impingement(6). The treatment of choice for advanced glenohumeral arthritis is a total shoulder replacement. This is major surgery, with risks and potential for revision in younger patients.

Rotator cuff tears
In many instances rotator cuff tears can be managed without surgery, especially in the case of sedentary individuals who do not partake in athletic activities or manual labour. For those who require a return to full function, have large tears or ongoing symptoms following conservative treatment, repair of the rotator cuff is most commonly performed (10). However, it is estimated that 20-40% of cuff tears across age cohorts resulted in a re-tear. The most common reason for this is failure of the degenerate rotator cuff tissue. to adequately regenerate its transitional tissue. The repairing tissue formed following surgical repair is largely fibrovascular scar tissue, which has poor biomechanical properties.

Methods
The search database used for the paper was PubMed. Searches were focussed on mesenchymal stem cells for the treatment of osteoarthritis and rotator cuff tears through studies performed in vitro, animal models and clinical trials.

Results
Osteoarthritis
Animal studies
Of the 22 animal models reviewed, 12 used murine models, 3 were ovine, 4 were leporine, 1 equine, 1 canine and 1 guinea pig model was used. The most commonly used cell type was bone marrow derived stem cells which were used in 12 papers. 6 papers focused on adipose-derived stem cells, 3 used synovial stem cells and 1 paper used embryonic stem cells.

Author	Animal model	Type of MSC	Key findings
Prasadam (2018) (12)	Murine	BMSC	The application of BMSCs with articular cartilage chondrocytes resulted in raised chondrocyte gene expression, cartilage regeneration and decreased fibrosis in an OA model.
Ichiseki (2018) (13)	Murine	BMSC	Injection of MSCs produced increased expression of anti-inflammatory and chondroprotective factors, as well as decreased pain signalling. Thus, MSCs may be an ideal treatment for early arthritis.
Feng (2018) (14)	Ovine	ASC	This study found application of ASCs resulted in cartilage regeneration as well as decreased inflammatory factors in the synovial fluid. ASCs survived up to 14 weeks post injection
Zhang (2016) (17)	Murine	HESC	The OA model treated by the MSC group demonstrated complete cartilage repair with high levels of hyaline cartilage and ECM comparable to a healthy control, within 12 weeks. Control group of OA demonstrated fibrocartilage repair.
Yun (2016) (18)	Canine	ASC	MSCs taken in conjunction with platelet rich plasma showed improved cartilage proliferation, ECM formation and inhibition of inflammation than either treatment by itself.
Ozeki (2016) (19)	Murine	SSC	Weekly injections of MSCs displayed a far stronger chondroprotective effect than a single injection.
Mak (2016) (20)	Murine	SSC	Mice injected with synovial derived MSCs displayed increased cartilage repair 4 weeks after injury than the control.
Li (2016) (21)	Murine	ASC	MSC treated group demonstrated greater cartilage repair and cells were shown to persist for 10 weeks post injection.
Hermeto (2016) (22)	Murine	ASC	Improved tissue repair found in the MSC treated group as per histological and macroscopic inspection. No difference in outcome between undifferentiated MSC treatment and MSCs differentiated into chondrocytes.
Chiang (2016) (23)	Leporine	BMSC	Group treated by MSC and hyaluronic acid (HA) showed reduced cartilage loss and surface abrasion than treatment solely by HA alone. The MSCs were noted to be engrafted into the cartilage.
Wang (2015) (24)	Leporine	ASC	MSCs demonstrated increased cartilage repair in the OA model.
Song (2014) (25)	Ovine	BMSC	BMSCs promoted greater cartilage regeneration and reduced proteoglycan loss as compared to the control and the group treated with bone marrow mononuclear cells.
Kim (2014) (26)	Murine	BMSC	MSC combined with self-assembled peptide showed evidence of chondroprotection as compared to the control.
Toghraie (2012) (27)	Leporine	ASC	The stem cell treated group displayed significantly better recovery from the OA injury at 20 weeks as per radiographic, gross and histological analysis.
Sato (2012) (28)	Guinea pig	BMSC	Partial cartilage repair noted in the MSC treated group at 5 weeks post treatment compared to no improvement in the control group. Transplanted MSCs showed evidence of migration, differentiation and proliferation. Immunostaining showed high levels of type II collagen in the MSC treated group.
Horie (2012) (29)	Murine	BMSC	MSC treated group had increased signalling of Indian hedgehog, BMP2 and PTHLH allowing increased expression of type II collagen.
Al Faqeh (2012) (30)	Ovine	BMSC	MSC injections showed a slowing of the progression of OA in the sheep model however, MSCs induced into chondrocytes proved better for meniscal regeneration.
Mokbel (2011) (31)	Equine	BMSC	The MSC treated group performed significantly better both clinically and radiographically at 6 months. Furthermore, staining with green fluorescent protein demonstrated that the injected MSCs were integral to the formation of the new articulating cartilage.
Miller (2010) (32)	Leporine	BMSC	This study showed that injection of self-assembling peptide without the use of BMSCs produced a more favourable outcome. Including BMSCs in the treatment reduced the quality of repaired cartilage and increased osteophyte formation.
Horie (2009) (33)	Murine	SSC	Injected MSCs resulted in increased meniscal regeneration in the rat model. Furthermore, there was no evidence of migration of these cells to distant organs.

Table 1 showing animal studies for the use of MSCs in osteoarthritis ordered by year of publication. The table describes what animal model was used and the type of stem cell used.
Type of MSC: BMSC=Bone marrow-derived stem cells, ASD=adipose-derived stem cells, UCSC=umbilical cord-derived stem cells, HESC=Human embryonic-derived stem cells

Clinical trials

17 clinical trails were identified for the use of intra-articular injections of stem cells to treat osteoarthritis. All papers used the knee as the target site of therapy. Follow-up time period ranged between 6 months and 5 years, and in total 399 patients were included across the 17 studies. All papers used scoring systems of pain and functionality as part of their outcome measures and all but 3 radiographically evaluated the structural change to cartilage thickness in the knee through use of MRI. One study measured cartilage thickness through arthroscopy. The most commonly used cell type was bone marrow-derived stem cells, as used in 12 papers. 4 authors used adipose-derived stem cells and 1 used umbilical cord-derived stem cells.

Author	No. Patients	Target site of therapy	Type of MSC	Follow-up period	Outcome measures	Key findings
Bastos (2018) (34)	18	Knee	BMSC	12 months	KOOS Radiographic	Patients showed an increase in their global scores, pain and functionality outcome as well as increased cartilage thickness on radiographic analysis in the MSC and MSC with platelet rich plasma group. There did not appear to be an advantage to adding platelet rich plasma to the therapy. There were minimal adverse effects noted indicating that this is a safe procedure.
Song (2018) (35)	18	Knee	ASC	96 weeks	NRS-11 WOMAC Radiographic	Pain and functionality scores, as well as cartilage volumes were increased in the MSC treated group. The most effective dose used was 5x107  MSCs.
Shetty (2018) (36)	60	Knee	BMSC	5 years	Lysholm KOOS IKDC Radiographic	Study showed that MSC treatment resulted in regeneration of cartilage that is comparable to native cartilage. *cost effective
Al-Najar (2017) (37)	13	Knee	BMSC	24 months	KOOS Radiographic	KOOS scores and cartilage thickness improved in the 24-month period compared to control. No adverse reactions were recorded.
Wang (2017) (38)	17	Knee	Allogenic BMSC	26 weeks	KOOS Radiographic	Patients showed reduced pain scores, increased functionality and improved radiographic findings. Joint space increased and there was reduced tibial osteophyte formation.
Gupta (2016) (39)	60	Knee	Allogenic BMSC	12 months	VAS ICOAP WOMAC Radiographic	A 2.5x107 dose of MSCs was most effective in reducing knee pain scores, however this was not statistically significant as compared to the placebo. Higher doses were associated with increased minor adverse effects such as knee pain and swelling.
Wang (2016) (40)	36	Knee	UCSC	6 months	SF-36 Lysholm WOMAC	Treatment with umbilical cord MSCs found improved scores in all outcome measures by 3 months, which was sustained up to 6 months.
Lamo-Espinosa (2016) (41)	30	Knee	BMSC	12 months	VAS WOMAC Knee motion range Radiographic	Scores improved with treatment of high dose MSCs in all outcome measures used, and no adverse effects were recorded in any patients.
Pers (2016) (42)	18	Knee	ASC	6 months	WOMAC	Pain and function scores improved following treatment with MSCs, however there was no placebo group as a control. The primary focus was safety of the procedure – minimal adverse reactions were recorded and the procedure was deemed to be safe.
Koh (2016) (43)	80	Knee	ASC	24 months	KOOS VAS Radiographic	Application of MSCs in addition to microfracture produced improvements in pain and symptoms scores, as well as radiographic findings in large cartilage defects as compared with microfracture alone
Soler (2016) (44)	15	Knee	BMSC	12 months	VAS SF-36 WOMAC Lequesne functional index Radiographic	Treatment with stem cells was well tolerated, provided long lasting reduction in pain and regeneration of cartilage.
Davatchi (2016) (45)	3	Knee	BMSC	5 years	PGA	MSC treatment improved functionality in the patients. Earlier treatments may lead to better outcomes.
Vega (2015) (46)	30	Knee	Allogenic BMSC	12 months	VAS WOMAC Lequesne functional index Radiographic	Allogenic MSC treatment shows an improvement in all outcome measures, with increase in volume high-quality cartilage. This implies allogenic MSCs may be a feasible alternative to autologous MSCs as no surgery is required.
Akgun (2015) (47)	14	Knee	BMSC	24 months	KOOS VAS Tegner activity	Treatment with MSCs provided significantly greater improvement in various sub-scores of KOOS as well as VAS severity than autologous chondrocyte implantation. There was no difference in VAS frequency or Tegner activity.
Jo (2014) (48)	18	Knee	ASC	6 months	WOMAC Arthroscopy (cartilage thickness)	The WOMAC scores were improved 6 months post treatment, with an increase in hyaline-like cartilage regeneration using a high dose of MSCs – 1 x108. No adverse events were recorded.
Orozco (2013) (49)	12	Knee	BMSC	12 months	VAS WOMAC Lequesne Radiographic	Outcome measures improved significantly as compared to the control of conventional treatment. Radiographic comparison revealed an improvement in cartilage quality in 11/12 patients and a 27% decrease in poor cartilage volume.
Wong (2013) (50)	56	Knee	BMSC	24 months	IKDC Tegner Lysholm Radiographic	This study demonstrated favourable out comes upon treatment with MSC for patients undergoing microfracture treatment for cartilage defects.

Table 2 showing human studies of the use of MSCs in osteoarthritis ordered by year of publication. This table details the number of patients, target site of therapy, type of stem cell used, follow up period and outcome measured used in each study.
Type of MSC: BMSC=Bone marrow-derived stem cells, ASD=adipose-derived stem cells, UCSC=umbilical cord-derived stem cells
Outcome measure: KOOS=Knee Injury and Osteoarthritis Outcome Score, VAS=Visual Analogue Scale of Pain, IKDC=International Knee Documentation Committee, WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index, Radiographic=Magnetic resonance imaging to assess cartilage thickness
Rotator cuff

Animal studies
Of the 8 papers reviewed, 6 used bone marrow-derived stem cells, 1 used adipose-derived stem cells and 1 used umbilical cord derived stem cells. 4 of the animal models were murine, 3 were leporine and 1 was canine.

Author	Animal model	Type of MSC	Key findings
Liu (2018) (51)	Canine	BMSC	Bone marrow derived mesenchymal stem cell sheet in conjunction with an engineered tendon-fibrocartilage-bone composite can enhance healing, collagen formation and mechanical strength in a canine model of rotator cuff tear.
Sevivas (2018) (52)	Murine	BMSC	Application of MSCs improved total elongation to rupture as well as stiffness in a rate model.
Rothrauff (2018) (53)	Murine	ASC	MSCs used in conjunction with surgical repair provided more benefit in chronic tears than acute.
Learn (2018)(54)	Leporine	BMSC	MSC-seeded scaffolds did not improve maximum load-bearing capacity as compared to non-seeded scaffolds.
Zong (2017) (55)	Murine	BMSC	Stem cells improved fibrocartilage formation in the healing rotator cuff. Key signalling factors identified were SOX9 and Indian hedgehog (IHH).
Sevivas (2017) (56)	Murine	BMSC	The group treated with single local injection MSCs displayed reduced atrophy of rotator cuff muscles following injury.
Park (2015) (57)	Leporine	UCSC	Local injection of umbilical cord-derived stem cells allowed repair of full thickness rotator cuff tears without surgery.
Kim (2013) (58)	Leporine	BMSC	MSCs applied to the tendon promoted type I collagen regeneration as compared to the control.

Table 3 shows the papers involving animal models of rotator cuff tears as a therapeutic target for MSC injection. This table details the type of animal used as well as the type of MSC.
Type of MSC: BMSC=Bone marrow-derived stem cells, ASC=adipose-derived stem cells, UCSC=umbilical cord-derived stem cells

Clinical trials
Of the 3 papers included, 2 used BMSCs and one used ASDs. In total 106 patients were assessed. The two papers using BMSCs used bone marrow aspirate in conjunction with platelet rich plasma, and did not use solely BMSCs.

Author	No. Patients	Type of MSC	Key findings
Kim 2018 (59)	24	BMSC	The group treated with MSCs had a significant improvement in pain and functionality of the shoulder following partial thickness rotator cuff tear. Improvement only became significant at 3 months following treatment.
Kim 2017  (60)	70	ASC	No significant difference in visual analogue pain scale and range of motion. Re-tear rate was significantly reduced however in the group treated with MSCs
Kim 2017(61)	12	BMSC	There was an increase in rotator cuff healing, however the difference was not significant. BMSC in an aspirate combined with platelet-rich plasma prevented the chondrogenic and osteogenic differentiation of tendon derived stem-cells, thus promoting high quality repair of rotator cuff tendon.

Table 4 shows the current clinical trials for assessing the therapeutic effect of an intra-articular injection of MSCs in the healing of a rotator cuff tear.
Type of MSC: BMSC=Bone marrow-derived stem cells, ASC=adipose-derived stem cells

Discussion
Osteoarthritis
Animal Models
Preclinical models of the use of MSCs in osteoarthritis have been positive. Treatment with the use of various cell types has been shown to increase cartilage regeneration through the use of various cell types as an intra-articular injection(22). Most importantly, this has resulted in the growth of hyaline cartilage containing adequate levels of type II collagen(28), with the preservation of proteoglycan levels(25), thus providing the joint with the qualities required for smooth movement and shock absorbance.
Through the use of fluorescent staining it has been shown that MSCs can localise to the site of injury and subsequently differentiate and proliferate to instigate cartilage regeneration(28). Indian hedgehog (IHH), bone morphogenic protein 4 (BMP4) and parathyroid hormone-like related protein (PTHLH) signalling are indicated in this process, the expression of which was all detected in one study following transplantation of stem cells (29).
Studies also showed that groups treated by MSCs also produced reduced inflammatory factors, which may indicate the use of stem cell treatment in early arthritis for preventative use as well as late severe stages for regeneration(13). Multiple injections appeared to yield better results than a single injection (19), and adipose derived stem cells appeared to persist for 10-14 weeks (14) (21). This may give some indication as to the optimum dosing scheme for maximal efficiency, an important concept given the current huge expense for obtaining, isolating and administering stem cells.

Clinical trials
One of the primary outcome measures in clinical trials for MSC treatment has been in assessing the safety of the procedure. Across the 17 papers analysed, none of the authors reported a major adverse effect. The majority of papers quoted no adverse effects, while some noted some minor impact such as knee pain and swelling(34). One study found that higher doses of MSC implantation were associated with a greater frequency of adverse effects(39).
Most studies comparing stem cells to a placebo or conventional treatment saw an improvement in their outcome measures with stem cells. However, the studies have small sample sizes and most should be considered ‘preliminary’ or ‘pilot’ studies. Pain, symptoms and quality of life scores improved. Chondrogenic regeneration was seen in some studies. One trial contradicted the rest as although there was an improvement in outcome measures (study used VAS, ICOAP and WOMAC), the difference was not statistically significant(39).
Allogenic MSCs were shown to provide improvements comparable to the use of autogenic MSCs. This may be useful in patients who are not suitable for stem cell harvesting, such as the frail or the very young(46). Figures given for the most effective dose ranged from 2.5x107 to 1 x108(39,48).

Rotator Cuff
Animal Studies
The application of MSCs to rotator cuff pathology for tendon repair is far newer and less explored than that of OA. The aim of the treatment and therefore these studies should be restoring adequate, biomechanically sound tissue to the enthesis of the rotator cuff, rather than the fibrovascular tissue which typically accumulates following surgery. Seven of the eight papers reviewed demonstrated an improvement in outcomes as compared to the controls. Outcomes were typically defined by rate of healing, formation of collagen, mechanical loading and atrophy of the rotator cuff muscle. One of the studies stated an increase in type I collagen formation at the site of the tendon compared to the control(58), and another identified key signalling factors for tendon healing, IHH and SOX9, along with fibrocartilage formation around the healing rotator cuff(55). The study that utilised umbilical cord-derived stem cells allowed for the repair of a full thickness rotator cuff tear without the use of surgery, a finding which is extremely encouraging(57). One study did not see an increase in outcomes when comparing maximum-load bearing capacity of an MSC-seeded scaffold as compared to a non-MSC seeded scaffold(54). Overall, based on the results these studies further investigation is warranted.

Clinical trials
Clinical trials involving the use of MSC injections for rotator cuff repairs are sparse so far. Only 1 of the 3 papers showed an improvement in the pain and functionality scored following treatment with injection of MSC. In this study, patients with an existing rotator cuff tear were assigned 3 months physiotherapy, with one group receiving a treatment dose of MSCs. The treatment group improved significantly in scores of functionality and pain as elicited by the VAS score and American Shoulder and Elbow Surgeons score. The tear size however did not change. It should be noted this study used a bone marrow aspirate concentration in conjunction with platelet rich plasma.
Another study analysed the effect of injecting adipose derived MSCs to the rotator cuff during arthroscopic repair of the rotator cuff, as compared to the control who received the same surgical treatment with no administration of MSCs. The results found no difference between the two groups as per pain ratings, functionality and range of movement at 28 months. Interestingly however, the re-tear rate in the stem cell treated group was half that of the control group (14.3% compared to 28.5%).
The final study found no significant increase in the healing of the rotator cuff tendon with the application of BMSCs with platelet-rich plasma. In vitro studies did however show that this treatment stopped the aberrant differentiation of tendon-derived stem cells.
Across all studies there appeared to be no difference in change to tear size, although one study showed improved functionality and another found significantly reduced re-tear rates. It may be that application of MSCs does improve tendon tissue quality, although these results are very early with small sample sizes. Larger and more robust studies are warranted.

Safety
These studies have shown that the use of BMSCs, ASCs and UCSCs has not produced any major adverse effects in any patients participating in the studies. A paper which had previously been published claiming an oncogenic potential in BMSCs was later withdrawn, as it was the risk was found to be a problem of contaminated cell lines rather than an innate transformative potential(62).

Conclusion and future direction
Over the last 10 years there has been a growing interest and research into the use of MSCs in the recovery of joint pathology, as a means of regenerating tissue and diminishing inflammation through the immunomodulatory properties of stem cells. The evidence listed in this article shows that for OA there is an early indication that MSC therapy can aid in the regeneration of some cartilage. However, these early studies are small, mostly involve the knee joint and should be considered ‘preliminary’, rather than true evidence of efficacy. Larger studies with a longer follow-up period are required before it’s place in the management of joint pathology is clear. There is also a need for studies on other joints, particularly the upper limb.
In the case of rotator cuff repair, there is some limited evidence that MSCs may aid high-quality regeneration in humans, but this is still in its very early stages. The treatment is expensive and one has to question whether the current evidence justifies the cost. More independent robust clinical studies are required.

 

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