Peptides For Tendon Repair: A Promising Therapeutic Approach

Peptides are short chains of amino acids, whose length can range from 2-50 amino acids. In recent days, peptides such as BPC 157 have gained a lot of attention on social media, because of their alleged healing and performance enhancing properties. In this blog post, we take a closer look at how peptides can be used for tendon repair and analyze the scientific research behind these claims. Peptides can act as hormones, neurotransmitters, and/or growth factors, which allows them to regulate a diverse range of physiological functions. By binding to cognate cell surface receptors or intracellular molecules, peptides can trigger various intracellular pathways, making them an integral part of many biological mechanisms and healing processes.
Faith Wershba

Faith Wershba

Postgraduate researcher at the University of Cambridge.

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What are tendons? What is the function of tendons?

Tendons are connective tissues which are rich in extracellular matrix fibers. The main function of tendons is to transfer mechanical forces from muscle to bone, which enables movement. These tissues are essential for locomotion and often transmit large physical forces between muscle and bone, which makes tendons particularly vulnerable to injury [1, 2].

Tendon injuries may occur in any part of the body that contains tendons, with the most commonly affected joints being the shoulders, elbows, ankles, knees, and fingers. Unfortunately, tendon injuries are quite common, accounting for up to 50% of musculoskeletal injuries in the United States [3].

Tendon Injury

Tendon damage can occur due to a variety of reasons. Acute tendon injuries may result from lacerations that cut through the tendon, or from injuries sustained playing contact sports such as football, wrestling, and rugby. Chronic injuries, on the other hand, often occur due to overuse and age-related tendon degeneration, which triggers inflammation, further weakening, and potential rupture [2, 3].

In response to injury, mammalian tendons often heal slowly and imperfectly due to their poor vascularization and cellular composition. The repair process often results in disorganized fibrotic scar tissue with reduced biomechanical function compared to the healthy tendon, which can leave patients with a weaker tendon that is more likely to re-rupture and may increase the chances of developing degenerative tissue conditions [1].

Treatments for Tendon Injury

Tendon repair surgery is often performed to treat torn or severely damaged tendons. The primary goal of surgery is to repair tendon structure and restore functionality [4, 5]. However, such repair is often imperfect and many patients fail to regain full tendon function. Moreover, re-rupture of the tendon often occurs following surgery [5]. As such, many researchers have sought novel treatment methods to repair damaged tendons [6].

Recent therapeutic advances include treatments such as gene therapy, stem cell therapy, platelet-rich plasma (PRP) therapy, growth factor therapy, and tissue engineering. These therapies aim to enhance tendon repair by applying stem cells, growth factors, natural and/or artificial biomaterials to promote tissue regeneration and functional restoration [6].

Despite such advances, managing tendon injuries remains a clinical challenge. As such, many current research efforts are geared towards developing novel therapeutic approaches to improve treatment outcomes [6].

Peptides: Properties, Physiological Functions, and Potential Applications

What are peptides?

Peptides are short chains of amino acids, whose length can range from 2-50 amino acids [7]. Peptides are smaller than proteins, but nonetheless play crucial roles in various biological processes. Peptides can act as hormones, neurotransmitters, and/or growth factors, which allows them to regulate a diverse range of physiological functions [7]. By binding to cognate cell surface receptors or intracellular molecules, peptides can trigger various intracellular pathways, making them an integral part of many biological mechanisms and healing processes.

Peptides for Tendon Repair

Yes, peptides can be used for tendon repair. For instance, the exendin-4 (Ex-4) peptide has been shown to promote cell proliferation and tendonogenic differentiation in bone marrow-derived human mesenchymal stem cells, enhancing tendon healing 1. Similarly, the sensory neuropeptide substance P (SP) has been found to promote early tissue proliferation and regulate sensory nerve ingrowth, suggesting potential for novel treatment in tendinopathy

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Evidence suggests that certain peptides may play an important role in the process of tendon repair. For example, the peptide glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (Ex-4) has been shown to induce tenocyte (tendon-specific fibroblasts) differentiation in human mesenchymal stem cells (hMSCs) in vitro [8]. It is hypothesized that Ex-4 functions by promoting cell proliferation and tendonogenic differentiation, leading to enhanced tendon healing.

Peptides derived from bovine tendon collagen, such as C2 and E1, have also been shown to increase cellular stress tolerance levels and support faster wound healing processes in vitro compared to the full collagen protein [9]. In addition to providing a suitable surface for cellular adhesion, which is important for repairing torn tendons, these peptides also protect cells against oxidative stress, thereby boosting their beneficial impact on tendon healing [9].

Platelet-rich plasma (PRP) has also been explored in the context of tendon repair. PRP is a rich source of various peptides, including growth factors and cytokines, and therefore researchers are interested in its potential to enhance tissue healing. PRP therapies have repeatedly shown positive effects on tendon healing, influencing physiological factors such as inflammation, cell migration, angiogenesis, and proliferation and synthesis of extracellular matrix components [10].

Overall, peptides play a significant role in a wide range of biological processes. Some specific peptides have been shown to promote tendon repair through enhancing cell proliferation, differentiation, and cellular stress tolerance. While research on the clinical efficacy of peptides remains ongoing, preliminary studies suggest that peptides may eventually be used as therapeutic agents to improve tendon repair following injury.

Studies on Peptides for Tendon Repair

Which peptides promote tendon repair? How do these peptides promote tendon healing?

Specific peptides can promote tendon healing by inducing tenocyte differentiation from human mesenchymal stem cells (hMSCs). For example, the GLP1 receptor agonist Exendin-4 (Ex-4) has been shown to induce tenocyte differentiation in hMSCs in vitro. When hMSCs were treated with Ex-4, levels of tendon-related transcription factors and extracellular matrix genes and proteins were elevated compared to controls, which suggests that Ex-4 may enhance tendon regeneration [8]. However, it is important to note that these outcome measures are indirect readouts of tendon repair, and human studies are needed to determine whether such findings are at all generalizable and/or clinically significant.

Some research suggests that elastin-derived peptides can enhance tendon healing. In one experimental study, elastin-derived peptides increased cellularity and vascularity of connective tissue, especially during the early stages of the healing process. Elastin-derived peptides also positively influenced tissue fiber alignment, which is an important factor in the structural integrity and functionality of tendons [11].

In rats, substance P (a neuropeptide belonging to the tachykinin family) has been found to stimulate fibroblast proliferation, angiogenesis, and collagen organization during tendon healing. Both the initial stages of tendon healing and the reparative phase occurred more rapidly in rats treated with substance P compared to those without, suggesting that substance P may play a positive role in promoting tendon healing in rats [12].

Platelet-rich plasma (PRP) contains a variety of peptides and has been shown to induce tendon stem/progenitor cell (TSC) differentiation into active tenocytes in vitro [10]. However, it is important to note that the effects of PRP can vary depending on its composition. For example, leukocyte-rich PRP (L-PRP) typically promotes catabolic and inflammatory changes in differentiated tenocytes, which may hinder the healing process and prolong the time needed for tendon repair [13]. Conversely, pure PRP (P-PRP) mainly induces anabolic changes, which can potentially lead to the formation of excessive scar tissue [13]. It is critical to consider these differential effects if PRP therapy is to be developed for use in humans.

Lastly, a study [14] found that rats treated with the synthetic mechano-growth factor E peptide (MGF-C25E) demonstrated significantly increased Achilles functional index compared to rats treated with saline (control). The Achilles functional index is a measure which compares Achilles tendon function between injured and non-injured sides of the body based on walking patterns. Moreover, histological analysis of tendon tissues from treated versus non-treated rats revealed differences in tissue remodeling and cell alignment, suggesting that MGF-C25E may play a therapeutic role in tendon repair [14].

To recap what has been covered in this section: peptides can promote tendon healing by interacting with connective tissue cells and the extracellular matrix; modulating inflammatory processes; and affecting scar formation through regulation of catabolism/anabolism. Critically, the specific effects of peptides on tendon healing varies depending on the type of peptide, its concentration, and other contextual factors in the cellular microenvironment.

Challenges and Future Directions for Peptide-Based Therapies

Although peptide-based therapies have shown promise in preclinical studies, various scientific and practical challenges remain. Tendons are complex tissues with highly structured morphologies, and the organizational integrity of tendons is crucial to ensure that the tissues can bear large mechanical loads [15]. If peptides are to guide proper tendon regeneration and growth, delivery scaffolds must be carefully designed so as to provide a fibrous network that mimics the natural arrangement of collagen fibers within the extracellular matrix [15]. If these structural features are aberrant, there is a risk of disorganized tissue regeneration, which can lead to tendon dysfunction [16].

Current research on peptide-based therapies for tendon repair is promising, but remains limited in scope and generalizability. To date, most studies have been conducted in vitro using mesenchymal stem cells or in vivo using animal models. Additional studies will be needed that consistently demonstrate the benefits of peptides on tendon healing before such therapies can be tested in human trials. Then, multi-phase clinical trials will be necessary to demonstrate the safety, tolerability, and efficacy of peptide therapies in patients with tendon injury. As such, clinical application of peptide therapy for tendon repair remains somewhat far off.

Nonetheless, it is possible that tendons could play a role in stimulating the body's own repair system to produce de novo connective tissue and facilitate healing. Empirical research will ultimately serve as the arbiter of whether peptides play a role in human tendon repair and can be used for therapeutic purposes.

Conclusion

Tendons are a specialized form of connective tissue which connect muscles to bones to allow musculoskeletal movement. These tissues are rich in extracellular matrix fibers such as collagen and elastin and are highly organized in their structure.

Injuries to tendons can result from acute strain or chronic overuse and age, and such injuries are particularly common amongst older individuals.

Current treatments often focus on pain management and retaining functionality of the tendon rather than permanent repair. In some cases, surgery may be conducted to repair the injured tissue, but such operations demonstrate variable success rates and patients may be prone to re-injury.

As such, there is a need for novel treatments which can stimulate the healing process and protect against tendon re-repture. Peptide-based therapies have sparked interest amongst scientists for their ability to stimulate the growth of tenocytes, promote the formation of extracellular matrix fibers, modulate inflammation, and regulate the alignment and organization of extracellular fibers. Such molecules may represent a promising therapeutic approach for patients with tendon injury.

However, it is crucial to note that studies using peptides for tendon repair have mainly been conducted in vitro or using animal models, and measures of tendon healing are often based on indirect biomarkers rather than functionality. As such, these studies may or may not hold clinical significance. Human trials will be needed to confirm whether peptides are safe, efficacious, and effective for ameliorating peptide injury in patients.

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Faith Wershba

Faith Wershba

Faith obtained her Honour’s Bachelor Degree in Human Biology, Immunology and History & Philosophy of Science at the University of Toronto. Currently, she is a postgraduate researcher at the University of Cambridge, focusing on the philosophy of medicine, science, biomedical research methods, and bioethics.