Biological Strategies for Enhancing Rotator Cuff Repair: A Review and Comparative Analysis
Rotator cuff injuries are a common clinical problem, affecting millions of people worldwide. Traditional treatments often result in incomplete repair or healing, leading to reduced function and potential rupture. The study under review explores the potential of biological strategies, including the use of platelet-rich plasma (PRP), growth factors, stem cells, and exosomes, to enhance rotator cuff repair.
Current Treatment Limitations
Current treatments for rotator cuff injuries include conservative measures such as corticosteroids, nonsteroidal anti-inflammatory drugs, physical therapy, and extracorporeal shock wave therapy. Surgical intervention is considered for severe acute injuries. However, these treatments often result in incomplete healing, leading to reduced function and potential re-rupture. Moreover, they cannot fully restore the tendon’s native composition, structure, and mechanical properties, highlighting the need for more effective treatments.
Biological Strategies for Rotator Cuff Repair
Biological strategies for enhancing rotator cuff repair have shown promise in recent years. These strategies include the use of PRP, growth factors, stem cells, and exosomes.
Platelet-Rich Plasma (PRP)
PRP is an autologous source of various growth factors, including platelet-derived growth factor, transforming growth factor-beta, insulin-like growth factor, fibroblastic growth factor, and vascular endothelial growth factor. While the efficacy of PRP alone in enhancing tendon repair is unclear, combining PRP with stem cells may enhance the reparative ability of stem cells for tendon repair.
Growth factors such as bone morphogenetic protein-12 and transforming growth factor-beta1 have been used to induce tenogenic differentiation in mesenchymal stem cells (MSCs) before implantation, enhancing the repair of tendon defects in animal models.
Stem cells, particularly MSCs, have shown potential for differentiating into a variety of connective tissue cell types, including tenocytes. MSCs can be derived from various tissue sources, such as bone marrow, tendon, and adipose tissue. Numerous animal studies have demonstrated that cell-based approaches using MSCs can improve tendon repair.
Exosomes, or extracellular vesicles (EVs), are another promising biological strategy for tendon repair. They are small vesicles that carry various molecular constituents of their cell of origin, including proteins and RNA. They are involved in various physiological processes and have been shown to have regenerative potential in various tissues, including tendons.
Comparative Analysis of Biological Strategies
A comparative analysis of these biological strategies reveals that each has its unique advantages and potential limitations. For instance, PRP is readily available and can be autologously sourced, reducing the risk of immune rejection. However, its efficacy in enhancing tendon repair when used alone is unclear.
Stem cell-based therapies, particularly those using MSCs, have shown great promise in improving tendon repair. However, there are safety concerns and potential adverse effects associated with stem cell therapies, including the risk of ectopic bone and tumor formation.
Exosomes, being natural carriers of bioactive molecules, have the potential to enhance tendon repair without the risks associated with direct stem cell transplantation. However, more research is needed to fully understand their therapeutic potential and the mechanisms underlying their effects.
Biological strategies for enhancing rotator cuff repair, including the use of PRP, growth factors, stem cells, and exosomes, show promise in overcoming the limitations of current treatments. However, more research is needed to fully understand their therapeutic potential and to address safety concerns associated with these therapies. Future studies should also focus on developing standardized treatment protocols to evaluate and compare the treatment outcomes of these biological
Scaffolds and Cell Sheets in Tendon Repair
Various scaffolds have been used in tendon repair to provide mechanical support and topographical cues to mimic the native tendon microenvironment, and to enhance tenogenic differentiation of stem cells. Cell sheets, thick layers of confluent cultured cells with their produced extracellular matrix, have also been used in tendon regeneration. These cell sheets, generated by MSCs with enforced expression of transcription factor Mohawk (Mkx), promoted tendon repair in a mouse Achilles-tendon defect model.
Combining Multiple Strategies for Tendon Regeneration
There has been a trend for combining multiple strategies for tendon regeneration. For example, human embryonic stem cells (hESCs)-MSCs were engineered to overexpress Scleraxis (Scx) and seeded onto a silk-collagen sponge, prior to implantation in a rat Achilles tendon gap wound model. This three-factor combined treatment led to enhanced tendon repair.
Mechanisms Underlying Stem Cell-Based Implantation for Tendon Repair and Regeneration
Significant progress has been made in understanding mechanisms underlying the observed therapeutic effect of stem cell-based treatments. For example, fluorescently labelled hESC-MSCs in a fibrin gel that were injected into a patellar wound site were detected 2 weeks after injection, but the number of cells present in the wound declined at 4 weeks. The labelled cells exhibited a spindle-like shape and expressed tendon-specific genes, but not markers of pluripotency, suggesting that the injected stem cells differentiated towards the tenogenic lineage.
Recent studies suggest soluble factors, especially extracellular vesicles (EV), released from stem cells may play a key role in tissue repair. EVs, and in particular exosomes, carry various proteins, including those related to intracellular vesicle trafficking, cytoskeletal components, and signal transduction. Exosomes also contain DNA, RNA, and microRNA. In recent years, stem cell-derived exosomes have demonstrated the potential to treat many diseases and disorders, including cardiovascular ischaemia, kidney injury, liver fibrotic disease, and the healing of cutaneous wounds, and may bear potential for tendon repair and regeneration.
Challenges, Opportunities, and Future Directions
Although significant progress has been made recently, clinical data regarding the therapeutic efficacy of using stem cells to treat tendon injuries and diseases is limited. A recent systematic review identified four clinical trials using bone marrow and allogenic adipose-derived stem cells for the treatment of tendon disorders. These four studies found that stem cell treatment led to improved tendon healing, as assessed by imaging, functional outcomes, and pain scores. However, only one trial had a control group, and all four studies were not blinded, allowing for a high risk of biased results. Therefore, the results should be interpreted with caution. Clearly, many basic and translational studies are needed before stem cell-based therapies can be recommended as a routine clinical treatment for tendon injuries and diseases.
Furthermore, many challenging questions still remain to be addressed, such as: Which sources of stem cells are most promising or bear the best potential to be used? Are there subpopulations of cells among the heterogonous population of MSCs that may bring a more favourable outcome? What type of injuries or diseases require the implantation of stem cells? Can biologics such as stem cell-derived exosomes replicate the therapeutic effect of stem cells in tendon injury and/or disease, and to which extent? Moreover, as there are many significant biological differences between acute or chronic tendon injuries, and the repair mechanisms following these injuries, specific stem-cell therapy approaches may need to be tailored for each particular type of tendon injury. Research to address these questions and issues, may not only advance the basic understanding
Exosomes in Tissue Repair
Exosomes released by human umbilical cord mesenchymal stem cells have been shown to protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. They have also been found to alleviate liver fibrosis. Exosomes derived from human induced pluripotent stem cells (iPSCs)-MSCs have been shown to facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis.
Stem Cell Homing
Stem cell homing refers to the process by which stem cells migrate to the site of injury or disease. This process is crucial for the success of stem cell-based therapies. Research is ongoing to enhance the homing ability of stem cells to their destination, particularly to wounded or diseased tendon tissues using specific physical or chemical cues.
Clinical Trials Using Stem Cells for Tendon Disorders
A number of clinical trials have been conducted using stem cells for the treatment of tendon disorders. For instance, a study found that conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells improved healing and prevented further tears. Another study found that the use of mesenchymal stem cells during arthroscopy for rotator cuff repair improved healing. Allogeneic adipose-derived stem cells have been used for the treatment of lateral epicondylosis, and autologous bone marrow stem cells have been used for the treatment of chronic patellar tendinopathy.
The use of biological strategies, including the use of PRP, growth factors, stem cells, and exosomes, shows promise in enhancing rotator cuff repair. However, more research is needed to fully understand their therapeutic potential and to address safety concerns associated with these therapies. Future studies should also focus on developing standardized treatment protocols to evaluate and compare the treatment outcomes of these biological strategies. The use of stem cell-derived exosomes in particular may bear potential for tendon repair and regeneration, and further research in this area is warranted.