Tendon-related problems are one of the main causes of disability in modern times, and even if their prevalence is underestimated, they cause marked reduction in working ability and sport practice.
Tendinopathy is characterized by prolonged pain and is often activity related. Many studies [
Among treatment strategies, injective treatments are commonly adopted, with “traditional” agents such as hyaluronic acid [
The aim of the present scoping review is to summarize the available clinical evidence on the application of cell-based therapies to treat the most common upper limb tendinopathies, i.e., elbow and rotator cuff tendinopathies. Our review has therefore the following goals: (1) highlighting the current application methods, (2) describing the clinical outcomes of this biologic approach, and (3) understanding current limitations and areas of uncertainty that need to be elucidated by future researches.
A review of the literature was performed on the use of cell-based therapies to treat tendon disorders of the shoulder and elbow. The search was made on the PubMed and Scopus databases on December 2020, using the following formulas:
To identify clinical studies regarding rotator cuff tendinopathy: (rotator cuff tear OR partial rotator cuff tear OR rotator cuff repair) AND (cells OR stem OR MSCs OR bone marrow aspirate or BMAC or BMC OR fibroblasts OR tenocytes) To identify clinical studies regarding elbow tendinopathies: (Epicondylitis OR Epicondylosis OR tennis elbow OR Elbow Tendinosis) AND (stem cells OR MSCs OR bone marrow aspirate or BMAC or BMC OR fibroblasts OR tenocytes)
The screening process and analysis were performed separately by 2 independent researchers (RR and AM). First, the articles were screened by title and abstract. The following inclusion criteria for relevant articles were used during the initial screening of titles and abstracts: clinical reports of any level of evidence, written in the English language, with no time limitation, on the use of MSCs or other cell-based approaches to treat rotator cuff or elbow tendinopathies, including cases of biological augmentation during surgical procedure. Exclusion criteria were instead as follows: case reports or mini case series (<5 patients), articles written in other languages, and reviews. In the second step, the full texts of the selected articles were screened, with further exclusions according to the previously described criteria. Moreover, articles not reporting clinical results were excluded. Reference lists from the selected papers were also screened. A PRISMA [
Flowchart resuming the paper’s selection process for the present review.
Relevant data were then extracted and collected in a single database with the consensus of the two observers to be analyzed for the purposes of the present manuscript. In particular, the following data were retrieved: (1) study design, (2) sample size, (3) delivery method, (4) eventual concurrent treatments (surgery or other substances), (5) outcome measures and timepoints of follow-up evaluations, and (6) summary of clinical results. Any discrepancy was discussed with and resolved by the senior investigator (AC), who made the final judgement. The primary outcome of the present scoping review was the variation in patients’ reported subjective scores and pain evaluation in order to understand if the cell-based approach may provide any clinical benefit.
Furthermore, a quality assessment of each included trial was done by using the modified Coleman Methodology Score [
Thirteen studies [
The assessment through the modified Coleman score (range: 0–100) revealed modest results for all the trials analyzed, mainly due to the low number of patients included, the short follow-up, and the frequent presence of concurrent treatments, i.e., surgery or other substances used, thus resulting in a bias to the understanding of the contribution of cell-based approaches. The average scores were as follows: 54.4 (range 47–64) for rotator cuff studies and 47.7 (range 47–52) for elbow tendinopathy studies. The individual score for each included trial has been reported in Tables
Synopsis of clinical studies dealing with cell-based approaches in rotator cuff pathology.
Publication | Level of evidence | Modified Coleman score | Pathology |
|
Therapeutic protocol | MSC manipulation | Outcomes and imaging | Follow-up | Results |
---|---|---|---|---|---|---|---|---|---|
WITH ROTATOR CUFF SURGICAL REPAIR | |||||||||
Ellera Gomes et al., KSSTA [ |
IV case series | 58 | Full-thickness tear | 14 | Transosseous mini |
100 ml of bone marrow: MSC fractions were obtained according to good manufacturing practices by Ficoll–Hypaque density gradient and then resuspended in saline solution enriched with 10% autologous serum to a final volume of 10 ml |
|
12 months | (i) Good functional results |
Hernigou et al., Int Orthop.[ |
III case control study | 64 | Full-thickness supraspinatus tear (1.5–2.5 cm) | 90 (45 with and 45 without ASC) | Arthroscopic single-row repair with suture anchors with or without BMAC from anterior iliac crest (same time of surgery) | 150 ml of bone marrow aspirate concentrated in the cellular and molecular therapy laboratory | US (every month), MRI (3 months, 6 months, 1 year, 2 years, and last minimum 10 years) | Minimum 10 years | (i) MSCs improved the healing rate at 6 months and decreases the retear rate at 10 years |
Kim et al., AJSM [ |
III cohort study | 63 | Full-thickness RCT | 70 (35 with and 35 without ASC) | Arthroscopic double-row repair with or without a-dMSC (from the |
Liposuction of 120 ml of adipose tissue: MSC lab. isolation and preparation followed by injection with fibrin glue scaffold—Greenplast kit (Green Cross) | VAS, CS, UCLA, and |
Minimum 24 months | (i) No significant functional difference |
WITHOUT ROTATOR CUFF SURGICAL REPAIR | |||||||||
Centeno et al., Journal of Pain Research [ |
IV case series | 52 | G-H OA and/or partial or full-thickness tear |
|
BMAC from post iliac |
BMAC centrifugation followed by addition of PRP and PL | DASH, NPS | 3 and 24 months | (i) Significant improvement of DASH and pain (NPS) |
Kim et al., Cell Transplantation [ |
IV case series | 47 | Partial thickness tear | 12 | BMAC from iliac |
BMAC centrifugation with BIOMET MarrowStim™ mini kit followed by injection of 2 ml of BMACs mixed with 1 ml of PRP | ASES, |
3 months | (i) Significant improvement of VAS and ASES |
Kim et al., JOSR [ |
III case control study | 49 | Partial thickness tear | 24 (12 BMAC-PRP vs 12 rehabilitation) | BMAC from iliac |
BMAC centrifugation with BIOMET MarrowStim™ mini kit followed by injection of 2 ml of BMACs mixed with 1 ml of PRP | ASES, |
3 months | (i) Significantly higher VAS and ASES in the BMAC-PRP group |
Jo et al., Stem Cells [ |
IV case series | 48 | Partial thickness tear | 18 (3 low, 3 mid, and 3 high dose for safety review and then the other 9 pts are high dose) | Injection of a-dMSC (from abdomen) (liposuction 3 weeks before injections) | Cells from stromal vascular fraction isolated and cultured in keratinocyte-SFM- (Invitrogen) based media containing 0.2 mM ascorbic acid, 0.09 mM calcium, 5 ng/ml recombinant epidermal growth factor, and 5% fetal bovine serum | SPADI, CS, |
6 months | (i) No serious adverse event |
RCT: rotator cuff tear; G-H OA: gleno-humeral osteoarthritis; BMAC: bone marrow aspirate concentrate; MSC: mesenchymal stem cells; a-dMSC: adipose-derived mesenchymal stem cells; PRP: platelet-rich plasma; PL: platelet lysate; VAS: visual analogue scale; NPS: numeric pain scale; CS: Constant-Murley Score; ASES: American Shoulder and Elbow Surgeons; UCLA: University of California, Los Angeles; DASH: shoulder and hand score; SPADI: Pain And Disability Index; ROM: range of motion; MRI: magnetic resonance imaging; US: ultrasound.
Synopsis of clinical studies dealing with cell-based approaches in elbow tendon pathology.
Publication | Level of evidence | Modified Coleman score | Pathology |
|
Therapeutic protocol | MSC manipulation | Outcomes and imaging | Follow-up | Results |
---|---|---|---|---|---|---|---|---|---|
Moon et al., Ann Acad Med Singapore [ |
IV case series | 48 | Medial and/or lateral epicondylitis | 24 (26 elbows) | Arthroscopic |
20 ml of bone marrow plasma was centrifuged and kept in the refrigerator. Only the clear upper layer and the buffy coat layer were used obtaining 8 to 9 ml mixed with 3 ml of bupivacaine before injection | VAS, |
8 weeks and 6 months | (i) Statistically significant improvement in VAS and MEPS |
Connell et al., Br J Sports Med [ |
IV case series (pilot study) | 45 | Lateral epicondylitis | 12 | Injection of collagen-producing cells from dermal fibroblasts | 4 mm skin sample obtained from the lateral side of the hip. Lab preparation of the cells and injections of |
|
6 weeks, 3 weeks, and 6 months | (i) Statistically significant improvement in PRTEE |
Wang et al., AJSM [ |
IV case series | 47 | Lateral epicondylitis | 18 | Injections of expanded autologous tenocytes from patellar tendon | A |
VAS, qDASH, grip strength, +MRI score (12 months) | 1, 2, 3, 12, 12 months | (i) Statistically significant improvement in VAS score, qDASH, grip strength score, and MRI scores after surgery and at last follow-up |
Singh et al., J Nat Sci Biol Med [ |
IV case series | 45 | Lateral epicondylitis | 30 | BMAC from iliac crest | 10 ml of bone marrow plasma was centrifuged; only the clear upper layer and the buffy coat layer was used obtaining 4 to 5 ml mixed with 1 ml of 2% lignocaine solution before injection | PRTEE | 2 weeks, 6 weeks, and 3 months | (i) Statistically significant improvement in PRTTE |
Lee et al., Stem Cells [ |
IV case series | 49 | Lateral epicondylitis | 12 | allo-adMSC mixed with fibrin glue injection | Lipoaspirates of human subcutaneous fat tissue obtained from healthy donors were treated in the lab obtaining allo-a-dMSC. All the procedures followed the “Cell Bank process”. Injections of 0.5 ml thrombin mixed with 106 or 107 (2 doses) of allo-ASCs in the first syringe and 0.5 ml fibrinogen in the other syringe | MEPI, |
2 weeks, 6 weeks, 12 weeks, and 52 weeks | (i) VAS and MEPI score significantly improved and tendon defect decreased at US over the course of the follow-up |
Wang et al., AJSM [ |
IV case series | 52 | Lateral epicondylitis | 15 | Injections of expanded autologous tenocytes from patellar tendon | As above | VAS, qDASH, UEFS, grip |
4 years, 5 years | (i) Significant improvements from preop were maintained in all clinical and MRI scores for up to 5 years after treatment |
BMAC: bone marrow aspirate concentrate; allo-adMSC: allogeneic adipose-derived mesenchymal stem cells; MEPS: Mayo Elbow Performance Scoring; PRTEE: Patient-Rated Tennis Elbow Evaluation; qDASH: Quick Disability of the Arm, Shoulder, Hand Score; VAS: visual analog scale; UEFS: upper extremity functional scale; MRI: magnetic resonance imaging; US: ultrasound.
Seven papers in total met the inclusion criteria and were analyzed [
Looking at MSCs in association with surgical repair, two comparative studies [
Regarding the use of simple MSC injections, there are only one case-control study and three case series. Kim et al. [
Six papers in total met the inclusion criteria and were analyzed [
The main finding of the present scoping review is the lack of high-level literature regarding the application of cell therapy in the management of tendinopathies involving both shoulder and elbow, thus making it very hard for clinicians and researchers to clearly understand the role of this biological approach to treat these degenerative injuries. Up to the present, 13 studies have been published and most of them are case series, with overall modest methodological quality, as revealed by the modified Coleman score, mainly due to the low number of patients included and the heterogeneity of procedures and therapeutic protocols adopted. Due to these limitations, it was not possible to perform a sounding quantitative analysis of the data extracted from the included trials.
Considering rotator cuff tendinopathy, even if all the reports suggest a favorable role of MSCs in stimulating tendon healing and symptomatic relief [
Despite the well-established rationale for the use of cell-based therapies, as testified by several preclinical in vitro and in vivo studies, current clinical literature offers very low and weak evidence and randomized controlled trials appear necessary in the near future.
Besides considerations regarding the level of evidence of the available studies, other controversial aspects should be acknowledged. First of all, the marked interproduct variability and the different application strategies must be underlined. In fact, similarly to other biologic approaches [
The use of cell-based approaches for treating elbow and rotator cuff tendinopathies showed overall safety and positive preliminary clinical findings. The most commonly adopted strategy entails the use of autologous MSCs harvested from bone marrow, but even fibroblasts and tenocytes have been tested with good outcomes. Cells can be injected locally or even applied as an augmentation during the surgical procedure, but despite encouraging clinical results, current data does not allow to endorse the routine use of cell-based approaches and well-designed RCTs are needed to confirm their real therapeutic efficacy against traditional options.
All the data analyzed for the purpose of the review have been already included into the manuscript.
The authors declare that they have no conflicts of interest.
Berardo Di Matteo and Riccardo Ranieri contributed equally to this paper and should be both considered as first authors.