Successful tendon healing requires sufficient deposition and remodeling of new extracellular matrix at the site of injury, with this process mediating in part through fibroblast activation via communication with macrophages. Moreover, resolution of healing requires clearance or reversion of activated cells, with chronic interactions with persistent macrophages impairing resolution and facilitating the conversion the conversion to fibrotic healing. As such, modulation of the macrophage environment represents an important translational target to improve the tendon healing process. Circulating monocytes are recruited to sites of tissue injury, including the tendon, via upregulation of cytokines including Ccl2, which facilitates recruitment of Ccr2+ macrophages to the healing tendon. Our prior work has demonstrated that Ccr2-/- can modulate fibroblast activation and myofibroblast differentiation. However, this approach lacked temporal control and resulted in healing impairments. Thus, in the current study we have leveraged a Ccr2 antagonist to blunt macrophage recruitment to the healing tendon in a time-dependent manner. We first tested the effects of Ccr2 antagonism during the acute inflammatory phase and found that this had no effect on the healing process. In contrast, Ccr2 antagonism during the late inflammatory/ early proliferative period resulted in significant improvements in mechanical properties of the healing tendon. Collectively, these data demonstrate the temporally distinct impacts of modulating Ccr2+ cell recruitment and Ccr2 antagonism during tendon healing and highlight the translational potential of transient Ccr2 antagonism to improve the tendon healing process.

There is mounting evidence to suggest that exogenous electromagnetic fields (EMF) may play a significant role in various biological processes that are crucial to therapeutic interventions. EMFs have been identified as a non-invasive, safe, and effective therapy that appears to have no apparent side effects. Numerous studies have demonstrated that pulsed EMFs (PEMFs) have the potential to become a stand-alone or adjunctive treatment modality for managing musculoskeletal disorders. However, several questions remain unresolved. Before their widespread clinical application, further research from well-designed, high-quality studies is required to standardize treatment parameters and determine the optimal protocol for healthcare decision-making. This article provides a comprehensive overview of the impact of musculoskeletal diseases on overall well-being, the limitations of conventional treatments, and the need to explore alternative therapeutic modalities such as electromagnetic field (EMF) therapy. EMF therapy uses low-frequency electromagnetic waves to stimulate tissue repair, reduce inflammation, and modulate pain signals, making it a safe and convenient alternative to conventional treatments. The article also discusses the historical perspective of EMF therapy in medicine. The article highlights the potential of EMF therapy as a personalized and comprehensive care option for musculoskeletal diseases, either alone or in conjunction with other therapies. It emphasizes the imperative for further research in this field and presents a compelling case for the use of EMF therapy in managing musculoskeletal diseases. Overall, the available findings on the underlying cellular and molecular biology support the use of EMF therapy as a viable option for the management of musculoskeletal disorders and stresses the need for continued research in this area.

Tendon injury is a common disorder of the musculoskeletal system, with a higher possibility of occurrence in elderly individuals and athletes. After a tendon injury, the tendon suffers from inadequate and slow healing, resulting in the formation of fibrotic scar tissue, ending up with inferior functional properties. Therapeutic strategies involving the application of growth factors have been advocated to promote tendon healing. Growth and differentiation-5 (GDF-5) represents one such factor that has shown promising effect on tendon healing in animal models and in vitro cultures. Although promising, these studies are limited as the molecular mechanisms by which GDF-5 exerts its effect remain incompletely understood. Starting from broadly introducing essential elements of current understanding about GDF-5, the present review aims to define the effect of GDF-5 and its possible mechanisms of action in tendon healing. Nevertheless, we still need more in vivo studies to explore dosage, application time and delivery strategy of GDF-5, so as to pave the way for future clinical translation.

Tendon injuries are common orthopedic ailments with a challenging healing trajectory, especially in cases like the Achilles tendon afflictions. The healing trajectory of tendon injuries is often suboptimal, leading to scar formation and functional impairment due to the inherent low metabolic activity and vascularization of tendon tissue. As pressing is needed for effective interventions, efforts are made to explore biomaterials to augment tendon healing. However, tissue engineering approaches face hurdles in optimizing tissue scaffolds and nanomedical strategies. To navigate these challenges, an injectable hydrogel amalgamated with human umbilical vein endothelial cells-derived exosomes (HUVECs-Exos) was prepared and named H-Exos-gel in this study, aiming to enhance tendon repair. In our research involving a model of Achilles tendon injuries in 60 rats, we investigated the efficacy of H-Exos-gel through histological assessments performed at 2 and 4 weeks and behavioral assessments conducted at the 4-week mark revealed its ability to enhance the Achilles tendon\'s mechanical strength, regulate inflammation and facilitate tendon regeneration and functional recovery. Mechanically, the H-Exos-gel modulated the cellular behaviors of macrophages and tendon-derived stem cells (TDSCs) by inhibiting inflammation-related pathways and promoting proliferation-related pathways. Our findings delineate that the H-Exos-gel epitomizes a viable bioactive medium for tendon healing, heralding a promising avenue for the clinical amelioration of tendon injuries.

OBJECTIVE: Several clinical and experimental studies have revealed that L-Arginine, which has antioxidant properties, accelerates tissue healing. This study examined the in vivo effects of oral L - Arginine supplementation on tendon regeneration in Wistar rats.
METHODS: For each weighting of an average of 250-300 g, 24 Wistar rats were separated into three equal groups. Each rat\'s right hind leg Achilles tendons were tenotomized and then repaired. The first group (Control) was followed up with a regimen of standard food and water. In the second group (L-Arg Low Dose), 300 mg/kg, and in the third group (L-Arg High Dose), 600 mg/kg L-Arginine was administered in water daily with a regimen of standard food and water ad libitum. After eight weeks, the rats were sacrificed, and the tendons were histologically and biomechanically analyzed.
RESULTS: Tendon peak strength values of the L-Arg Low Dose and L-Arg High Dose groups were similar but significantly higher than the control group. A statistically significant difference was observed between the groups in terms of ground substance, fiber arrangement, cellularity, hyalinization, and GAG properties ( p = 0.05, p = 0.002, p = 0.016, p = 0.027, p = 0.05). There was no statistically significant difference between the groups according to the histological examination of collagen properties, fiber structure, tenocyte properties, rounding of the nuclei, and collagen stainability. (p = 0.999, p = 0.061, p = 0.195, p = 0.195, p = 0.130). No mortality, wound complications, or re-ruptures were observed.
CONCLUSIONS: Compared with the control group, histologically and biomechanically distinct therapeutic effects of L-Arginine supplementation on tendon healing were determined.
METHODS: 5.

In the human body, ascorbic acid (AA) is known for its potent antioxidant and reducing properties and also plays a vital role in supporting the growth of bones and cartilage. It has been used extensively in orthopedic surgery. Ongoing studies under the umbrella of ascorbic acid research investigate its impact on bone and tendon physiology, as well as its influence on joint replacement and postoperative pain. The majority of both laboratory and human studies link the usage of ascorbic acid to enhanced bone health and improved tendon healing. Recent literature suggest that ascorbic acid administration may have a positive impact on the outcome of orthopedic procedures. On the other hand, controversy exists regarding the efficacy of ascorbic acid in reducing the incidence of complex regional pain syndrome. In brief, the effectiveness of ascorbic acid in enhancing orthopedic procedure outcomes remains a subject of ongoing investigation. Although certain studies have hinted at the potential positive influence of ascorbic acid on these outcomes, further research is required to validate its effectiveness and ascertain the ideal dosage and method of administration for maximizing its anticipated advantages. To establish the efficacy of ascorbic acid in improving orthopedic procedure outcomes, rigorous human trials of high quality are imperative. The aim of this review was to provide an overview of ascorbic acid\'s utilization in orthopedic practices and to pinpoint prospective areas for future research.

Acute rupture of the Achilles tendon (AT) is a common but debilitating injury that requires immediate diagnosis and effective management. Spontaneous bilateral AT rupture is rare; however, it can lead to severe disability for a significant period. This case report presents a 76-year-old patient who suffered a bilateral AT rupture while engaging in a non-strenuous activity. Upon confirmation of the diagnosis by physical examination and radiologic evaluation, conservative treatment was decided due to the presence of numerous comorbidities. A personalized rehabilitation protocol was implemented, allowing weight-bearing activities using Achilles boots at six weeks. Healing of both ATs was confirmed by an MRI at three months. Our case shows that non-operative treatment of these injuries can result in exceptionally favorable outcomes and should not be disregarded. However, thorough patient compliance and surveillance are prerequisites.

Tendons are vital components of the musculoskeletal system, facilitating movement and supporting mechanical loads. Emerging evidence suggests that vitamin D, beyond its well-established role in bone health, exerts significant effects on tendon physiology. The aim of this manuscript is to review the impact of vitamin D on tendons, focusing on its mechanisms of action, clinical implications, and therapeutic applications. A comprehensive search of scientific electronic databases was conducted to identify articles on the effects of vitamin D on tendon health. Fourteen studies were included in this review. Five studies were performed in vitro, and nine studies were conducted in vivo. Despite some conflicting results, the included studies showed that vitamin D regulates collagen synthesis, inflammation, and mineralization within tendons through its interaction with vitamin D receptors. Epidemiological studies link vitamin D deficiency with tendon disorders, including tendinopathy and impaired healing. Supplementation with vitamin D shows promise in improving tendon strength and function, particularly in at-risk populations such as athletes and the elderly. Future research should address optimal supplementation strategies and explore the interplay between vitamin D and other factors influencing tendon health. Integrating vitamin D optimization into clinical practice could enhance tendon integrity and reduce the burden of tendon-related pathologies.

Rotator cuff tendon tears are a leading cause of shoulder pain. They are challenging to treat, and tendon-bone healing has a high failure rate despite successful surgery. Tendons connect the muscles and bones, which make them important for the body\'s overall mobility and stability. Metabolic diseases, including diabetes or high blood pressure, can affect the healing process after repair of a damaged tendon. With a global incidence of 9.3%, diabetes is considered as a significant risk factor for rotator cuff tendon healing because it causes structural, inflammatory, and vascular changes in the tendon. However, the mechanisms of how diabetes affects tendon healing remain unknown. Several factors have been suggested, including glycation product accumulation, adipokine dysregulation, increased levels of reactive oxygen species, apoptosis, inflammatory cytokines, imbalanced matrix-metalloproteinase-to-tissue-inhibitor ratio, and impaired angiogenesis and differentiation of the tendon sheath. Despite the effects of diabetes on tendon function and healing, few treatments are available to improve recovery in these patients. This review summarizes the current literature on the pathophysiological changes of the tendon in diabetes and hyperlipidemia. Preclinical and clinical evidence regarding the association between diabetes and tendon healing is presented. Moreover, current approaches to improve tendon healing in patients with diabetes are reviewed.

The subacromial bursa (SAB) plays an important role in the tendon healing process. Based on previous reports, co-culture of the rotator cuff (RC) and SAB have been shown to increase the tendon-related gene expressions, inflammatory cytokines, and tensile strength. However, the nature of the specific biochemical alterations during the inflammatory and repair phases of tendon healing with or without the SAB remain unknown. Using a full-thickness RC tear rat model, we determined how the presence or absence of the SAB alters the histological characteristics and gene expressions. After 3 and 6 weeks, tissues were collected for histological and real-time quantitative polymerase chain reaction (RT-qPCR) evaluations. Results showed greater cell density at 3 weeks, neovascularization and tendon thickening at 6 weeks with SAB preservation. Immunostaining revealed significant increases in type 3 collagen (COL3) expression at 6 weeks with SAB preservation. The RT-qPCR results showed that SAB preservation induced significant increases in the expression of scleraxis, matrix metalloproteinase-13 (MMP-13), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS) at 3 weeks and significant increases in COL3, IL-10, and arginase-1 (Arg-1) at 6 weeks. An RC tear undergoes more appropriate inflammatory and repair phases during the tendon healing process when the SAB is retained.