Exploring the Application of Stem Cells in Tendon Repair and Regeneration

doi:10.1016/j.arthro.2011.12.009

Arthroscopy: The Journal of Arthroscopic & Related Surgery

Volume 28, Issue 7, July 2012, Pages 1018-1029

https://doi.org/10.1016/j.arthro.2011.12.009 Get rights and content

Purpose

To conduct a systematic review of the current evidence for the effects of stem cells on tendon healing in preclinical studies and human studies.

Methods

A systematic search of the PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane, and Embase databases was performed for stem cells and tendons with their associated terminology. Data validity was assessed, and data were collected on the outcomes of trials.

Results

A total of 27 preclinical studies and 5 clinical studies met the inclusion criteria. Preclinical studies have shown that stem cells are able to survive and differentiate into tendon cells when placed into a new tendon environment, leading to regeneration and biomechanical benefit to the tendon. Studies have been reported showing that stem cell therapy can be enhanced by molecular signaling adjunct, mechanical stimulation of cells, and the use of augmentation delivery devices. Studies have also shown alternatives to the standard method of bone marrow–derived mesenchymal stem cell therapy. Of the 5 human studies, only 1 was a randomized controlled trial, which showed that skin-derived tendon cells had a greater clinical benefit than autologous plasma. One cohort study showed the benefit of stem cells in rotator cuff tears and another in lateral epicondylitis. Two of the human studies showed how stem cells were successfully extracted from the humerus and, when tagged with insulin, became tendon cells.

Conclusions

The current evidence shows that stem cells can have a positive effect on tendon healing. This is most likely because stem cells have regeneration potential, producing tissue that is similar to the preinjury state, but the results can be variable. The use of adjuncts such as molecular signaling, mechanical stimulation, and augmentation devices can potentially enhance stem cell therapy. Initial clinical trials are promising, with adjuncts for stem cell therapy in development.

Level of Evidence

Level IV, systematic review of Level II-IV studies.

Section snippets

Methods

We performed a comprehensive search of the PubMed, Medline, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Embase databases using various combinations of the commercial names of each stem cell preparation and the following keywords over the years 1966-2011: tendon, rotator cuff, supraspinatus tendon, Achilles tendon, patellar tendon, jumpers knee, ACL, anterior cruciate ligament, plantar fasciopathy, flexor tendon, extensor tendon, lateral epicondylitis, tennis

Mesenchymal Stem Cells and Tendon Repair

Bone marrow stromal or mesenchymal stem cells (MSCs) can generate multiple cell lines including bone, cartilage, and fibrous connective tissue, such as tendon.¹⁶ They are non-immunogenic, not expressing major histocompatibility class II and co-stimulatory molecules.¹⁷ Therefore allogeneic transplantation of MSCs should not require immunosuppression of the host. In fact, MSCs themselves are immunosuppressive and suppress the proliferation of lymphocytes.¹⁸

Smith et al.¹⁹ in 2003 found that

Discussion

We have summarized publications detailing the in vitro, in vivo, and clinical findings of stem cell therapy in tendons. This has shown that stem cells in tendons can increase collagen fiber density, enhance tissue architecture, and restore a nearly normal tendon-bone interface. Studies have shown that the biomechanical benefit of stem cells can be seen if the study is followed up over a longer period. Stem cells have been shown to increase the presence of fibrocartilage at the defect site. This

Conclusions

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Subacromial bursal preservation can enhance rotator cuff tendon regeneration: a comparative rat supraspinatus tendon defect model study
2021, Journal of Shoulder and Elbow Surgery
The role of subacromial bursa in rotator cuff surgery is unknown. This study aimed to assess the subacromial bursa's role in the healing of supraspinatus tendon injury in a rat model.
Twenty-three male Sprague-Dawley rats (9 weeks old; weight, approximately 296 g) were used in this study. Three rats used as biomechanical study controls were killed at 12 weeks of age. A supraspinatus tendon defect was made bilaterally in 20 rats, whereas an additional subacromial bursa sectioning was performed on the left side. Six rats were killed for biomechanical testing and 4 were killed for histologic observation at 3 and 9 weeks, respectively.
The regenerated tendon in the bursal preservation group showed significantly superior biomechanical properties in maximum load to failure at 3 and 9 weeks and stiffness at 9 weeks after surgery compared with the bursal removal group. The modified Bonar scale scores showed better regenerated supraspinatus tendons in the bursal preservation group.
The present study found that the subacromial bursa plays an important role in rotator cuff regeneration in this rat supraspinatus injury model. Extensive bursectomy of the subacromial bursa may not be recommended in rotator cuff repair surgery, though future in vivo human studies are needed to confirm these observations.
Analysis of Time to Form Colony Units for Connective Tissue Progenitor Cells (Stem Cells) Harvested From Concentrated Bone Marrow Aspirate and Subacromial Bursa Tissue in Patients Undergoing Rotator Cuff Repair
2020, Arthroscopy, Sports Medicine, and Rehabilitation
To evaluate the time required for colonies to develop from concentrated bone marrow aspirate (cBMA) and subacromial bursal tissue samples.
Samples of cBMA and subacromial bursa tissue were harvested from patients undergoing rotator cuff repair surgery between November 2014 and December 2019. Samples were analyzed for time to form colonies and number of colonies formed. The impact of age, sex, and cellularity (cBMA only) was analyzed. Samples were cultured and evaluated daily for colony formation in accordance with the guidelines of the International Society for Cellular Therapy. Demographic factors were analyzed for impact on time to form colonies and number of colonies formed.
Samples of cBMA were obtained from 92 patients. Subacromial bursa tissue was obtained from 54 patients. For cBMA, older age was associated with more days to form colonies (P = .003), but sex (P = .955) and cellularity (P = .623) were not. For bursa, increased age was associated with longer time to form colonies (P = .002) but not sex (P = .804). Conclusions: Increased age (in cBMA and subacromial bursa tissue) and lower initial cellularity (in cBMA) are associated with longer time to form colonies in culture.
Although connective tissue progenitor cells are widely used in orthopaedic practice, there are few metrics to determine their efficacy. Time to form colonies may serve as an important measurement for determining connective tissue progenitor cell viability for augmentation of rotator cuff repair. Subacromial bursa tissue may represent a viable alternative to cBMA for augmentation of rotator cuff repair, capable of forming colonies expediently in vivo.
Examining the Potency of Subacromial Bursal Cells as a Potential Augmentation for Rotator Cuff Healing: An In Vitro Study
2019, Arthroscopy - Journal of Arthroscopic and Related Surgery
To compare the potency of mesenchymal stem cells between the cells derived from the subacromial bursa to concentrated bone marrow aspirate (cBMA) taken from patients undergoing rotator cuff (RC) repair.
Subacromial bursa and cBMA were harvested arthroscopically from 13 patients (age 57.4 ± 5.2 years, mean ± standard deviation) undergoing arthroscopic primary RC repair. Bone marrow was aspirated from the proximal humerus and concentrated using an automated system (Angel System; Arthrex). Subacromial bursa was collected from 2 sites (over the RC tendon and muscle) and digested with collagenase to isolate a single cellular fraction. Proliferation, number of colony-forming units, differentiation potential, and gene expression were compared among the cells derived from each specimen.
The cells derived from subacromial bursa showed significantly higher proliferation compared with the cells derived from cBMA after 5, 7, and 10 days (P = .018). Regarding colony-forming units, the subacromial bursa had significantly more colonies than cBMA (P = .002). Subacromial bursal cells over the RC tendon produced significantly more colonies than cells over both the RC muscle and cBMA (P = .033 and P = .028, respectively). Moreover, when compared with cBMA, cells derived from subacromial bursa showed significantly higher differentiation ability and higher gene expression indicative of chondrogenesis, osteogenesis, and adipogenesis.
The subacromial bursa is an easily accessible tissue that can be obtained during RC repair, with significant pluripotent stem cell potency for tendon healing. Compared with cBMA taken from the proximal humerus, bursal cells showed significantly increased differentiation ability and gene expression over time.
Failed RC repairs have been partly attributed to a poor healing environment. Biologic augmentation of the repair site may help increase healing potential and incorporation of the cuff at the tendon–bone interface.
Tendon regeneration
2019, Biointegration of Medical Implant Materials
The complex three-dimensional structure of the tendon allows for transmission of force generated by muscles to bone. This transmission is what makes joint movement possible. During movement, tendons are exposed to different forces in a variety of directions. These forces can lead to tendon injury. Currently, tendon injuries are treated utilizing either the conservative or surgical approach or some combination of the two. Experimentation in several niches of tissue regeneration has yielded promising results regarding their eventual clinical implementation. These treatment modalities include growth factor delivery, stem cell therapy, grafts utilizing biomimetic scaffolds, gene therapy, application of mechanical forces, and administration of sound and electromagnetic waves to the affected tissue. Therapies aim to either improve the mechanical durability of the tendon or augment its healing potential.
Therapeutic Strategies and Enhanced Production of Stem Cell-Derived Exosomes for Tissue Regeneration
2023, Tissue Engineering - Part B: Reviews
Applications of functionally-adapted hydrogels in tendon repair
2023, Frontiers in Bioengineering and Biotechnology

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: The authors report the following source of funding: the Technology Strategy Board and National Institute for Health Research.

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Systematic ReviewExploring the Application of Stem Cells in Tendon Repair and Regeneration

Purpose

Methods

Results

Conclusions

Level of Evidence

Section snippets

Methods

Mesenchymal Stem Cells and Tendon Repair

Discussion

Conclusions

J Arthroplasty

Exp Hematol

Arthroscopy

J Orthop Res

Biomaterials

J Hand Surg Am

J Hand Surg Am

Biomaterials

Arthroscopy

Arthroscopy

Hospital Episodes StatisticsPrimary diagnosis

Biomechanical and biologic augmentation for the treatment of massive rotator cuff tears

Am J Sports Med

Tendon of the normal supraspinatus muscle: Correlations between MR imaging and histology

Surg Radiol Anat

Histopathology of common tendinopathiesUpdate and implications for clinical management

Sports Med

Tendinopathy—From basic science to treatment

Nat Clin Pract Rheumatol

Reconstruction of a ruptured patellar tendon with Achilles tendon allograft following total knee arthroplasty

J Bone Joint Surg Am

Evaluation of hamstring strength and tendon regrowth after harvesting for anterior cruciate ligament reconstruction

Am J Sports Med

Functional tissue engineering for tendon repair: A multidisciplinary strategy using mesenchymal stem cells, bioscaffolds, and mechanical stimulation

J Orthop Res

Tendon injury and tendinopathy: Healing and repair

J Bone Joint Surg Am

Augmentation of tendon attachment to porous ceramics by bone marrow stromal cells in a rabbit model

Int Orthop

BMP-12 treatment of adult mesenchymal stem cells in vitro augments tendon-like tissue formation and defect repair in vivo

PLoS One

Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells

Knee Surg Sports Traumatol Arthrosc

Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy

Am J Sports Med

Treatment of lateral epicondylitis using skin-derived tenocyte-like cells

Br J Sports Med

Stem cell therapy in bone repair and regeneration

Ann N Y Acad Sci

T cell responses to allogeneic human mesenchymal stem cells: Immunogenicity, tolerance, and suppression

J Biomed Sci

Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment

Equine Vet J

Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon

Equine Vet J

Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model

Stem Cell Res Ther

Systematic Review
Exploring the Application of Stem Cells in Tendon Repair and Regeneration