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Tendinous heterotopic ossification can cause pain and restricted joint mobility in affected areas, and it is a common and severe complication following tendon injuries. This condition significantly reduces the postoperative quality of life of patients, and its incidence is increasing year by year. Due to the unclear pathogenesis, there are currently no effective treatment methods. Although recent studies suggest that macrophages affect the process of traumatic heterotopic ossification (HO) in mice, their role in HO still requires further clarification. Here, it is disclosed that the formation of trauma‐induced HO is accompanied by the polarization of macrophages toward the M1 phenotype. Additionally, secretion containing periostin (POSTN) that is secreted by M1 macrophages reduces fatty acid β – oxidation in tendon‐derived stem cells (TDSCs) and facilitates the formation of heterotopic bone. Mechanistically, M1 macrophages release POSTN during the HO process, which directly binds to PTK7 in TDSCs,  thereby increasing AKT phosphorylation at the S124 site and initiating osteogenic differentiation. This study demonstrates the role of M1 macrophages and their secreted POSTN in traumatic heterotopic ossification, highlighting the potential of POSTN as a therapeutic target for HO. The mechanism diagram reveals that the formation of trauma‐induced heterotopic ossification (HO) is accompanied by the polarization of macrophages toward the M1 phenotype. Additionally, the extracellular vesicles secreted by M1 macrophages, which contain periostin (POSTN), directly bind to PTK7 in tendon‐derived stem cells (TDSCs). This binding increases the phosphorylation of AKT at the S124 site, thereby reducing fatty‐acid β‐oxidation in TDSCs and promoting the formation of heterotopic bone.

Restoring the normal structure and function of injured tendons is one of the biggest challenges in orthopedics and sports medicine department. The discovery of tendon-derived stem cells (TDSCs) provides a novel perspective to treat tendon injuries, which is expected to be an ideal seed cell to promote tendon repair and regeneration. Because of the lack of specific markers, the identification of tenocytes and TDSCs has not been conclusive in the in vitro study of tendons. In addition, the morphology of tendon derived cells is similar, and the comparison and identification of tenocytes and TDSCs are insufficient, which causes some obstacles to the in vitro study of tendon. In this review, the characteristics of tenocytes and TDSCs are summarized and compared based on some existing research results (mainly in terms of biomarkers), and a potential marker selection for identification is suggested. It is of profound significance to further explore the mechanism of biomarkers in vivo and to find more specific markers.

Long-term chronic inflammation after Achilles tendon injury is critical for tendinopathy. Platelet-rich plasma (PRP) injection, which is a common method for treating tendinopathy, has positive effects on tendon repair. In addition, tendon-derived stem cells (TDSCs), which are stem cells located in tendons, play a major role in maintaining tissue homeostasis and postinjury repair. In this study, injectable gelatine methacryloyl (GelMA) microparticles containing PRP laden with TDSCs (PRP–TDSC–GM) were prepared by a projection-based 3D bioprinting technique. Our results showed that PRP–TDSC–GM could promote tendon differentiation in TDSCs and reduce the inflammatory response by downregulating the PI3K–AKT pathway, thus promoting the structural and functional repair of tendons in vivo. Graphical Abstract

To investigate the effect and mechanism of simvastatin on cell components of tendon-bone healing interface. The tendon-bone healing model was established by inserting the end of the Achilles tendon into the tibial tunnel on 24 rats, and simvastatin was used locally at the tendon-bone interface. Healing was evaluated at 8 weeks by mechanical testing, micro-CT, and qualitative histology including H&E, Toluidine blue, and immunohistochemical staining. In vitro, bone marrow stromal cells (BMSCs) and tendon-derived mesenchymal stem cells (TDSCs) underwent osteogenic and chondrogenic differentiation respectively by plate co-culture. An analysis was performed on days 7 and 14 of cell differentiation. Biomechanical testing demonstrated a significant increase in maximum stiffness in the simvastatin-treated group. Micro-CT analysis showed that the bone tunnels in the simvastatin group were smaller in diameter and had higher bone density. H&E and Toluidine blue staining demonstrated that tendon-bone healing was significantly greater with better tissue arrangement and more extracellular matrix in the simvastatin-treated group than that in the control group, and immunohistochemical staining showed the expression of VEGF in simvastatin group was significantly higher. Histological staining and RT-PCR confirmed that simvastatin could promote the differentiation of co-cultured BMSCs and TDSCs into osteoblasts and chondroblasts, respectively. The effect of promoting osteogenic differentiation was more tremendous at 14 days, while its effect on promoting chondroblast differentiation was more evident on the 7th day of differentiation. In conclusion, local administration of simvastatin can promote the tendon-bone healing by enhancing neovascularization, chondrogenesis, and osteogenesis in different stages of the tendon-bone healing process.

(1) Background: Reconstruction of Achilles tendon defects and prevention of postoperative tendon adhesions were two serious clinical problems. In the treatment of Achilles tendon defects, decellularized matrix materials and mesenchymal stem cells (MSCs) were thought to address both problems. (2) Methods: In vitro, cell adhesion, proliferation, and tenogenic differentiation of tendon-derived stem cells (TDSCs) on small intestinal submucosa (SIS) were evaluated. RAW264.7 was induced by culture medium of TDSCs and TDSCs–SIS scaffold groups. A rat Achilles tendon defect model was used to assess effects on tendon regeneration and antiadhesion in vivo. (3) Results: SIS scaffold facilitated cell adhesion and tenogenic differentiation of TDSCs, while SIS hydrogel coating promoted proliferation of TDSCs. The expression of TGF-β and ARG-1 in the TDSCs-SIS scaffold group were higher than that in the TDSCs group on day 3 and 7. In vivo, the tendon regeneration and antiadhesion capacity of the implanted TDSCs–SIS scaffold was significantly enhanced. The expression of CD163 was significantly highest in the TDSCs–SIS scaffold group; meanwhile, the expression of CD68 decreased more significantly in the TDSCs–SIS scaffold group than the other two groups. (4) Conclusion: This study showed that biologically prepared SIS scaffolds synergistically promote tendon regeneration with TDSCs and achieve antiadhesion through M2 polarization of macrophages.

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.

Tendon is composed of dense fibrous connective tissues, connecting muscle at the myotendinous junction (MTJ) to bone at the enthesis and allowing mechanical force to transmit from muscle to bone. Tendon diseases occur at different zones of the tendon, including enthesis, MTJ and midsubstance of the tendon, due to a variety of environmental and genetic factors which consequently result in different frequencies and recovery rates. Self-healing properties of tendons are limited, and cell therapeutic approaches in which injured tendon tissues are renewed by cell replenishment are highly sought after. Homologous use of individual’s tendon-derived cells, predominantly differentiated tenocytes and tendon-derived stem cells, is emerging as a treatment for tendinopathy through achieving minimal cell manipulation for clinical use. This is the first review summarizing the progress of tendon-derived cell therapy in clinical use and its challenges due to the structural complexity of tendons, heterogeneous composition of extracellular cell matrix and cells and unsuitable cell sources. Further to that, novel future perspectives to improve therapeutic effect in tendon-derived cell therapy based on current basic knowledge are discussed.

Traumatic tendon injuries generate reactive oxygen species and inflammation, which may account for slow or poor healing outcomes. Selenium is an essential trace element presented in selenoproteins, many of which are strong antioxidant enzymes. Selenium nanoparticles (SeNPs) have been reported to promote tissue repair due to their anti-oxidative, anti-inflammatory, anti-apoptotic, and differentiation-modulating properties. However, its effects on the functions of tendon-derived stem/progenitor cells (TDSCs) and tendon healing have not been reported. This study examined the effects of SeNPs on the functions of hydroperoxide (H2O2)-stimulated TDSCs. Rat patellar TDSCs were treated with H2O2 with or without SeNPs. The viability, marker of proliferation, oxidative stress, inflammation, apoptosis, and tenocyte marker expressions of H2O2-stimulated TDSCs after SeNPs treatment were assessed. Our results showed that SeNPs increased the viability and expression of the marker of proliferation of TDSCs exposed to H2O2, while concurrently reducing oxidative stress, inflammation, and apoptosis. Additionally, the expressions of tenocyte markers were significantly elevated in H2O2-treated TDSCs after treatment with SeNPs. Furthermore, the expressions of Sirt1 and Nrf2 also increased after SeNPs treatment in H2O2-stimulated TDSCs. In conclusion, SeNPs mitigated oxidative stress, inflammation, and apoptosis while enhancing the survival and expression of the marker of proliferation of TDSCs in an oxidative stress environment. Additionally, it promoted the fate of TDSCs towards the tenocyte lineage in the presence of such oxidative stress. The increased expressions of Sirt1 and Nrf2 likely mediated the anti-oxidative and anti-inflammatory effects of SeNPs. SeNPs hold promise as a novel intervention for promoting tendon healing.

Tendinopathy is a common musculoskeletal disorder that mainly affects athletes and people of older age. Tumor necrosis factor-α (TNF-α) plays an important role in initiating tendinopathy. Tectorigenin, an extract component of Belam-canda Chinesis , possesses anti-inflammatory and anti-apoptosis activity. The present study was established to investigate the role of tectorigenin against the pathogenetic effects of TNF-α on tendon-derived stem cells (TDSCs) in vivo and in vitro . The findings indicated that TNF-α is able to induce TDSC inflammation, apoptosis, and ossification, as well as activate nuclear factor-kappa B and mitogen-activated protein kinase (MAPK). Furthermore, the results confirmed that tectorigenin is able to inhibit the TNF-α-induced inflammation, apoptosis, and ossification. Tectorigenin treatment decreases activation of NF-kappa B and MAPK signaling in TDSCs. Tectorigenin ameliorates tendinopathy in the in vivo rat model. Thus, these data reveal that tectorigenin can serve as a potential treatment for tendinopathy.

This paper presents a nanoscale sensor based on a metal–insulator–metal (MIM) waveguide coupled with a composite resonant cavity, where the ring resonator is embedded with triangular, semicircular, and rectangular structural elements. The transmission characteristics and sensing performance of the structure were systematically analyzed using the finite element method. The results indicate that the interference between the continuous mode in the waveguide and the discrete mode in the resonant cavity generates a distinct asymmetric Fano resonance. The optimized sensor achieves a sensitivity of 2960 nm/RIU and a figure of merit (FOM) of 59.79. Experimental verification confirms that the structure exhibits high responsiveness in temperature sensing, providing an effective solution for integrated photonic devices.