Musculoskeletal disorders represent an escalating global challenge that adversely affects both the quality of life and healthcare systems. Despite the availability of conventional therapeutic approaches, these methods are constrained by inadequate targeting, limited tissue regeneration capabilities, and potential long-term safety concerns. In recent years, exosomes have emerged as promising agents for precise intervention and functional regeneration, owing to their properties of active targeting, cargo delivery capability, modifiability, and biocompatibility, particularly when used in conjunction with engineering and biomaterial delivery strategies. While the therapeutic potential of exosomes in the management of musculoskeletal diseases is increasingly acknowledged, the current literature lacks a comprehensive integration of three critical dimensions: exosome engineering strategies, advanced biomaterial delivery systems, and their prospective therapeutic applications across various diseases. Therefore, this study concentrates on engineering methodologies aimed at augmenting the therapeutic efficacy of exosomes, encompassing the pretreatment of blast cells, the modification of exosomes, and their incorporation with biomaterials. Furthermore, we systematically introduce delivery systems utilizing hydrogels, scaffolds, microneedles, and fiber membranes, which enhance exosome delivery by facilitating spatial positioning control and achieving sustained release effects. Building on this foundation, we conduct an in-depth examination of the mechanisms and applications of exosomes in the treatment of musculoskeletal disorders. Additionally, this review provides the analysis of biogenesis, isolation, extraction, and preservation strategies of exosomes while also identifying the key factors impeding their clinical application. Based on this synthesis, we propose that exosomes represent a transformative paradigm for targeted, minimally invasive, and tissue-specific interventions in musculoskeletal medicine.

The etiology of osteonecrosis of the femoral head (ONFH) is not yet fully understood. However, ONFH is a common disease with high morbidity, and approximately one-third of cases are caused by glucocorticoids. We performed single-cell RNA sequencing of bone marrow to explore the effect of glucocorticoid on ONFH. Bone marrow samples of the proximal femur were extracted from four participants during total hip arthroplasty, including two participants diagnosed with ONFH for systemic lupus erythematosus (SLE) treated with glucocorticoids (the case group) and two participants with femoral neck fracture (the control group). Unbiased transcriptome-wide single-cell RNA sequencing analysis and computational analyses were performed. Seventeen molecularly defined cell types were identified in the studied samples, including significantly dysregulated neutrophils and B cells in the case group. Additionally, fatty acid synthesis and aerobic oxidation were repressed, while fatty acid beta-oxidation was enhanced. Our results also preliminarily clarified the roles of the inflammatory response, substance metabolism, vascular injury, angiogenesis, cell proliferation, apoptosis, and dysregulated coagulation and fibrinolysis in glucocorticoid-induced ONFH. Notably, we list the pathways that were markedly altered in glucocorticoid-induced ONFH with SLE compared with femoral head fracture, as well as their common genes, which are potential early therapeutic targets. Our results provide new insights into the mechanism of glucocorticoid-induced ONFH and present potential clues for effective and functional manipulation of human glucocorticoid-induced ONFH, which could improve patient outcomes.

Purpose. Hemophilic osteoarthropathy (HO) is a common cause of spontaneous bleeding in hemophiliacs. Surgical procedures are necessary for patients with severe HO. As a last resort, amputation is sometimes needed to treat complex HO cases. This study aimed to review the existing records of patients who underwent amputations in HO surgical treatment, summarize the risk factors, and provide relevant references for surgeons. Methods. We retrospectively reviewed the records of hemophilic patients received surgeries at Peking Union Medical College Hospital between 2000 and 2020. The amputation patients without neoplasm or acute trauma were screened out. Patient information was extracted from medical records. A literature retrieval of hemophilic amputation cases was conducted via PubMed. The risk factors of amputation were summarized and analyzed via descriptive statistics and Fishers precision probability test. Results. Four male hemophilia A patients out of 201 patients underwent lower limb amputation. The reasons of amputation contained severe pseudotumor with factor inhibitor and large bone defects, recurrent pathological fracture with pseudotumor, skin ulcer with chronic osteomyelitis, and pseudotumor with systematic infection. In cases reported in retrieved literature, severe pseudotumor with complications, bacterial infection and factor inhibitor were common factors. Discussion. As the first study on amputations in HO patients, we found that severe hemophilic pseudotumor, chronic bacterial infection, and coagulation factor inhibitor was potential risk factors for amputation. Sufficient factor replacement therapy is fundamental in the prevention of amputation. The early diagnosis and specially designed surgical techniques could improve the rate of limb salvage.

Background: No formal diagnostic criteria for progressive pseudo‐rheumatoid dysplasia (PPD) are available because of insufficient clinical data, which results in that PPD is often misdiagnosed with other diseases. Whole exome sequencing (WES) and Sanger sequencing were employed to reveal the novel mutations on CCN6 of five patients with PPD from China in order to increase the clinical data of PPD.Methods: Four suspected PPD pedigrees containing five patients in total were collected from 1998 to 2018 in our medical center. The phenotypes of each suspected PPD case were recorded in detail, and peripheral blood samples were collected for subsequent sequencing. Genomic DNA was extracted from peripheral blood samples, and Agilent liquid phase chip capture system was utilized for efficient enrichment of whole exome region DNA. After acquiring raw sequenced reads of whole exome region, bioinformatics analysis was completed in conjunction with reference or genome sequence (GRCh37/hg19). Sanger sequencing was performed to identify the results of WES.Results: In total, four novel PPD‐related mutation sites in CCN6 gene were identified including (CCN6):c.643 + 2T>C, (CCN6):c.1064_1065dupGT(p.Gln356ValfsTer33), (CCN6):c.1064G > A), and exon4:c.670dupA:p.W223fs.Conclusion: Our findings increase the clinical data of PPD including the CCN6 mutation spectrum, the clinical symptoms and signs. Moreover, the study highlights the utility of WES in reaching definitive diagnoses for PPD.