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Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H2S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H2S accumulation within the tHO region. Increased production of endogenous H2S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H2S production or directly absorption of H2S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca2+/ERK pathway was the downstream molecular event of H2S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H2S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R–ZnO nanoparticles in both clearing of H2S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO.

Summary: Two-dimensional (2D) materials, especially graphene-based materials, have important implications for tissue regeneration and biomedicine due to their large surface area, transport properties, ease of functionalization, biocompatibility, and adsorption capacity. Despite remarkable progress in the field of tissue regeneration and biomedicine, there are still problems such as unclear long-term stability, lack of in vivo experimental data, and detection accuracy. This paper reviews recent applications of graphene-based materials in tissue regeneration and biomedicine and discusses current issues and prospects for the development of graphene-based materials with respect to promoting the regeneration of tendons, neuronal cells, bone, chondrocytes, blood vessels, and skin, as well as applications in sensing, detection, anti-microbial activity, and targeted drug delivery.

Background: Inadequate repair capacity and disturbed immune compartments are the main pathological causes of tendinopathy. Transplantation of mesenchymal stem cells (MSCs) become an effective clinic option to alleviate tendinopathy. Interleukin-1β (IL-1β) could confer on MSCs enhanced immunoregulatory capability to remodel the repair microenvironment favoring tissue repair. Therefore, IL-1β activated UC-MSCs (1βUC-MSCs) may exert favorable efficacy in promoting tendon repair in a preclinical tendinopathy rat model. Methods: Tendon-derived stem cells (TDSCs) were isolated and characterized. In vitro, the levels of immunoregulatory-related cytokines such as IL-1β, IL-6, IL-10, and TGF-β secreted by 1βUC-MSCs and unprimed UC-MSCs was measured. And tendon-specific markers expressed by TDSCs cultured with primed cultured medium (CM) or unprimed CM were detected. In vivo, Achilles tendinopathy was induced by 30 μL collagenase I injection in Sprague Dawley rats. One week later, the rats were randomly injected with UC-MSCs primed with IL-1β (106 cells per tendon), UC-MSCs, or PBS. After rats were sacrificed, histological evaluation, electron microscopy, biomechanical tests, gait performance were conducted to evaluate the structural and functional recovery of Achilles tendons. The inflammation and metabolic state of the extracellular matrix, and the potential mechanism were assessed by immunohistochemical staining and Western blot. Results: UC-MSCs were activated by IL-1β to secrete higher levels of IL-10 and TGF-β while the secretion levels of IL-6 and IL-1β were not changed significantly, promoting a higher expression level of COL I and TNMD in TDSCs under proinflammatory environment. In vivo, the transplanted 1βUC-MSCs could survive up to 5 weeks after injection with tenogenic differentiation and improved tendon healing histologically semi-quantified by modified Bonar scores. This structural regeneration was further confirmed by observation of ultrastructural morphology, and led to good functional recovery including improved biomechanical properties and gait performance. During this process, the inflammatory response and metabolism of the extracellular matrix was improved through TGF-β/IL-10 pathway. Conclusion: This study demonstrated that the transplantation of UC-MSCs activated by IL-1β exhibited satisfactory ability for promoting tendon functional repair in a tendinopathy rat model. During this process, the balance of inflammatory response and extracellular matrix metabolism was remodeled, and the TGF-β/Smad2/3 and IL-10 signaling pathways were activated simultaneously. We cautiously conclude that the IL-1β primed UC-MSCs could be a promising strategy for enhancing the ability of MSCs to treat tendinopathy.

Peritendinous adhesion is one of the most common postoperative or posttraumatic complications of tendon injury, which severely limits functional rehabilitation and raises the risk of re-rupture. This study prepared a multifunctional composite composed of a “sandwich” electrospun nanofibrous membrane with sustained drug release property and adhesives for sutureless application. The composite was assessed here through microscopic, spectroscopic, wettability, rheological, mechanical, and drug release analyses. The results of these characterizations are consistent with the characteristics of anti-adhesion biomaterials. In addition, the anti-adhesion effectiveness was demonstrated in fibroblasts and rats. Briefly, the composite not only decreased the proliferation, viability, and penetration of fibroblasts but also repressed cell spreading on the material surface by regulating Yes-associated protein (YAP) and inhibited oxidative stress by scavenging reactive oxygen species (ROS) simultaneously in vitro. Meanwhile, histological analysis, functional tests, gross observation, and protein analysis in vivo showed that composite was effective in reducing tendon adhesion formation. Hence, we draw the conclusion that our composite can protect tendons from peritendinous adhesion after injury and provide a new direction for future application of peritendinous anti-adhesion.

Tendon injury is one of the most serious orthopedic diseases often leading to disability of patients. Major shortages of tendon healing are due to its multiple comorbidities, uncertainty of therapeutic efficacy and insufficient of angiogenesis. With a deeper understanding of angiogenic mechanism of tendon healing, we investigated an innovative microneedle patch loaded with platelet derived growth factor (PDGF) to achieve a constant systemic administration of PDGF to enhance topical tendon healing. Rat achilles tendon injury model was performed as in vivo animal models. Histological staining showed an enhancement of tendon healing quality, especially angiogenesis. Biomechanical studies demonstrated an increase of tendon stiffness, maximum load and maximum stress with treatment of PDGF-loaded microneedles. Furthermore, MAPK/p38/Cyclin D1 pathway and angiogenesis were found to play an important role in tendon healing process by using a biological high throughput RNA-sequence method and bioinformatic analysis. The high throughput RNA-seq tendon healing results were confirmed by histochemical staining and western blot. These results suggest the novel therapeutic potential of PDGF-loaded microneedle patch in tendon surgery.

Summary: Background: The elbow joint is sensitive to trauma from accidents, sports injuries, and surgical trauma. Some patients develop ossification or contracture of the medial collateral ligament (MCL) after elbow trauma. A less invasive reconstruction of the MCL can be performed after resection of diseased MCL. The biomechanical characteristics of this technique have been demonstrated and validated. However, its clinical effectiveness and safety require further confirmation in clinical practice. Methods: This open-label, non-randomised, prospective, multicentre trial included consecutive patients with elbow stiffness from five orthopaedic centres in China. Patients willing to participate in the study, with elbow stiffness caused by traumatic injury, who had reached skeletal maturity, and who had a range of motion of

Following tendon injury, the development of fibrotic healing response impairs tendon function and restricts tendon motion. Peritendinous tissue fibrosis poses a major clinical problem in hand surgery. Communication between macrophages and tendon cells has a critical role in regulating the tendon-healing process. Yet, the mechanisms employed by macrophages to control peritendinous fibrosis are not fully understood. Here we analyze the role of macrophages in tendon adhesion in mice by pharmacologically depleting them. Such macrophage-depleted mice have less peritendinous fibrosis formation around the injured tendon compared with wild-type littermates. Macrophage-depleted mice restart fibrotic tendon healing by treatment with bone marrow macrophage-derived exosomes. We show that bone marrow macrophages secrete exosomal miR-21-5p that directly targets Smad7, leading to the activation of fibrogenesis in tendon cells. These results demonstrate that intercellular crosstalk between bone marrow macrophages and tendon cells is mediated by macrophage-derived miR-21-5p-containing exosomes that control the fibrotic healing response, providing potential targets for the prevention and treatment of tendon adhesion. Keywords: bone marrow macrophage, peritendinous adhesion, exosome, miR-21-5p, Smad7

Summary: Inflammation and oxidative stress are major problems in peripheral nerve injury. Nanoceria can manipulate antioxidant factor expression, stimulate angiogenesis, and assist in axonal regeneration. We fabricate collagen/nanoceria/polycaprolactone (COL/NC/PCL) conduit by asymmetrical three-dimensional manufacture and find that this scaffold successfully improves Schwann cell proliferation, adhesion, and neural expression. In a 15-mm rat sciatic nerve defect model, we further confirm that the COL/NC/PCL conduit markedly alleviates inflammation and oxidative stress, improves microvessel growth, and contributes to functional, electrophysiological, and morphological nerve restoration in the long term. Our findings provide compelling evidence for future research in antioxidant nerve conduit for severe neurological defects. : Biomaterials; Nanotechnology; Neurosurgery Subject Areas: Biomaterials, Nanotechnology, Neurosurgery

The dysregulation of long non-coding RNAs (lncRNAs) is associated with the development of various diseases. However, little is known about the regulatory function of lncRNAs in peritendinous fibrosis. Therefore, the expression profiles of lncRNAs and mRNAs in normal tendon and fibrotic peritendinous tissues were analyzed in this study using RNA sequencing. In total, 219 lncRNAs and 3403 mRNAs were identified that were differentially expressed between the two sets of tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the dysregulated mRNAs were mainly associated with immune regulation, inflammation, extracellular matrix (ECM) production and remodeling, and cell cycle regulation. An lncRNA-mRNA co-expression network revealed 181 network pairs comprising eight dysregulated lncRNAs and 146 mRNAs. The results of the bioinformatics analysis indicated that the dysregulated lncRNAs play a role in fibrogenesis through regulation of the cell cycle, inflammation, and ECM production. Furthermore, silencing the lncRNA dnm3os prevented transforming growth factor (TGF)-β1-induced tenocyte proliferation and expression of genes related to fibrogenesis. These findings provide a basis for investigations into the regulatory mechanisms underlying the development and progression of peritendinous fibrosis. Keywords: Peritendinous tissue fibrosis, Long non-coding RNA, mRNA, Bioinformatics analysis, Co-expression network