A novel cartilage-targeting MOF-HMME-RGD sonosensitizer combined with sonodynamic therapy to enhance chondrogenesis and cartilage regeneration.

Articular cartilage regeneration is still a difficult task due to the cartilage's weak capacity for self-healing and the effectiveness of the available therapies. The engineering of cartilage tissue has seen widespread use of stem cell-based therapies. However, efficient orientation of line-specific bone marrow mesenchymal stem cells (BMSCs) to chondrogenesis and maintenance of chondrogenic differentiation challenged stem cell-based therapy. Herein, we developed a Fe-based metal-organic framework (MOF) loaded with hematoporphyrin monomethyl ether (HMME) and cartilage-targeting arginine-aspartate-glycine (RGD) peptide to form MOF-HMME-RGD sonosensitizer to regulate BMSCs chondrogenic differentiation for cartilage regeneration via the modulation of reactive oxygen species (ROS). By using sonodynamic therapy (SDT), the MOF-HMME-RGD demonstrated favorable biocompatibility, could generate a modest amount of ROS, and enhanced BMSCs chondrogenic differentiation through increased accumulation of glycosaminoglycan, an ECM component specific to cartilage, and upregulated expression of key chondrogenic genes (ACAN, SOX9, and Col2a1). Further, transplanted BMSCs loading MOF-HMME-RGD combined with SDT enhanced cartilage regeneration for cartilage defect repair after 8 weeks into treatment. This synergistic strategy based on MOF nanoparticles provides an instructive approach to developing alternative sonosensitizers for cartilage regeneration combined with SDT.

Ruboxistaurin maintains the bone mass of subchondral bone for blunting osteoarthritis progression by inhibition of osteoclastogenesis and bone resorption activity.

Osteoarthritis (OA) is a common degenerative disease with a series of changes occurring in aging cartilage, such as increased oxidative stress, decreased markers of healthy cartilage and alterations in the autophagy pathway. And increasing evidence indicates that osteoarthritis affects the whole joint, including both cartilage and subchondral bone. The agents that can effectively suppress chondrocyte degradation and subchondral bone deterioration are crucial for the prevention and treatment of OA. Ruboxistaurin (RU), an orally active protein kinase C inhibitor, can reduce macrophage adhesion to endothelial cells and relieve the local inflammation when applicating in diabetes and kinds of aging-related vasculopathy, which were realized by its effects on decreasing inflammatory cytokines' expression and increasing cell anti-oxidative stress ability. However, whether ruboxistaurin protects against OA remains unknown. In this study, we investigated the therapeutic effects of ruboxistaurin in an anterior cruciate ligament transection (ACLT)-induced OA model by preventing the bone mass loss of subchondral bone. We found that ruboxistaurin can effectively alleviate ACLT-induced osteoarthritis, as demonstrated by the phenomenon of correcting pathological bone loss caused by osteoclasts overactivated in the early stage of osteoarthritis and protecting against articular cartilage degeneration. Moreover, we found that ruboxistaurin inhibited osteoclast formation and resorption activity by suppressing the expressions of osteoclast-related genes and (PKCδ/MAPKs) signaling cascade. Taken together, these results show that ruboxistaurin may be a potential therapeutic agent for rescuing abnormal subchondral bone deterioration and cartilage degradation in OA and reverses the vicious cycle related to osteoarthritis.

A dual PMMA/calcium sulfate carrier of vancomycin is more effective than PMMA-vancomycin at inhibiting Staphylococcus aureus growth in vitro.

Both antibiotic-impregnated poly(methyl acrylate, methyl methacrylate) (PMMA) and antibiotic-impregnated calcium sulfate have been successfully used as local antibiotic delivery vehicles for the management of chronic osteomyelitis. Here, we examined the antibiotic elution characteristics and antibacterial properties of a composite drug delivery system consisting of PMMA/calcium sulfate carrying vancomycin (dual carrier-v) against Staphylococcus aureus, with PMMA loaded with vancomycin (PMMA-v) as a control. Vancomycin gradually degraded from dual carrier-v and PMMA-v up to about 8 and 6 weeks, respectively. At different elution time points, the inhibition zones of the dual carrier-v were larger than the inhibition zones of the PMMA-v (P < 0.05). The colony inhibition rate of the dual carrier-v was 95.57%, whereas it was 77.87% for PMMA-v. Scanning electron microscopy was used to demonstrate biofilm formation on the surface of plates treated with vancomycin-unloaded PMMA, whereas there was no biofilm formation on the surface of plates treated with dual carrier-v or PMMA-v. The dual carrier-v was more effective at antibacterial adhesion at each time point after immersion in simulated body fluid as compared with PMMA-v (P < 0.05). In conclusion, our results suggest that the dual carrier-v can release higher concentrations of antibiotics and inhibit bacteria growth more effectively in vitro as compared with PMMA-v. The dual carrier-v thus may have potential as an alternative strategy for osteomyelitis management.

Treatment of tumor-like lesions in the femoral neck using free nonvascularized fibular autografts in pediatric patients before epiphyseal closure.

OBJECTIVES: Surgical resection of benign bone tumors and tumor-like lesions at the femoral neck presents a difficult reconstructive challenge. However, the safety and efficacy of free nonvascularized fibular autografts (FNFAs) in the treatment of femoral neck tumor-like lesions before epiphyseal closure in young patients remain unknown. METHODS: Sixteen pediatric patients who had not yet undergone epiphyseal closure were treated with FNFAs after resection of tumor-like lesions in the femoral neck from August 2012 to September 2016. All patients underwent supplementary skeletal traction through the supracondylar femur for 4 to 6 weeks after resection. Demographic data were recorded and clinical and radiological outcomes were evaluated during the follow-up. RESULTS: All patients could walk with partial weight bearing 4 weeks postoperative, and full weight bearing was permitted after a mean of 8 weeks. Graft union was attained in all 16 patients at a mean of 2 months. The donor site of the fibular cortical strut showed good regeneration in all patients. The Harris hip score significantly improved from 65% to 95%. CONCLUSIONS: Application of an FNFA is a feasible method in the treatment of tumor-like lesions in the femoral neck before epiphyseal closure in pediatric patients. LEVEL OF EVIDENCE: Level IV.

Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis.

BACKGROUND: Chronic post-traumatic and postoperative osteomyelitis is a refractory disease which results in significant morbidity and mortality. The effect of combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded polymethyl methacrylate (PMMA) was unknown. METHODS: Fifty-one patients suffering from chronic post-traumatic or postoperative osteomyelitis of the lower extremities were included in the retrospective investigation. The patients were assigned to the study group of the combination therapy with antibiotic-loaded calcium sulfate and antibiotic-loaded PMMA or the control group of the antibiotic-loaded PMMA. Hematological parameters, eradication of infection, rate of infection recurrence and reoperation rate were evaluated during the follow-up. RESULTS: The cases were followed up for an average of 24 months (range, 15-48 months) after the first-stage surgical operation. In the study group, all the patients revealed complete calcium sulfate resorption at an average of 6 weeks (range, 30-60 days). In the study group, infection was primarily eradicated in 92.31% (24 of 26) of patients and re-operation rate of 7.69% (2 of 26) after the first-stage surgery. Two patients underwent further surgical operation in the study group. One case achieved infection eradication in the recurrent two cases, with a secondary infection eradication rate of 96.15% (25 of 26). There was no persistent infection in the study group. In the control group, infection was eradicated in 64.00% (16 of 25) of patients and re-operation rate was 36.00% (9 of 25) after the first-stage surgery. Nine patients in the control group underwent further surgical operation. Two case achieved infection eradication in these cases who suffered from persistent or recurrent infection, with a secondary infection eradication rate of 72.00% (18 of 25). There was more re-operation rate in the control group (PMMA group, 9 vs combination therapy group, 2; P = 0.034). CONCLUSION: The combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA possibly achieved more effective control of infection in the treatment of osteomyelitis through synergistic effect. The immediate structural stabilization and higher concentration of antibiotic at the local site of infection may be achieved through the combination of biodegradable and non-biodegradable devices in the treatment of chronic post-traumatic and postoperative osteomyelitis. The study was retrospectively registered at 11/16/2016 (TRN: NCT02968693).