Search

Osteochondral lesion of the talus (OLT) is a common cause of ankle pain that often occurs in the talar dome and leads to talar cartilage and subchondral bone damage. Osteochondral autograft transplantation is a logical treatment option. It is known that if the cartilage does not heal properly after injury, it degenerates, and osteoarthritis worsens. A three dimensional (3D)-printed guide plate can be used to find the curved articular surface from the donor site which optimally fits the defect in the talus. Herein, we present the case of a 28-year-old man who had an open injury from the crash of a tricycle in the right ankle at the age of 5. Radiographs revealed a large defect in the medial talar dome that affected nearly half of the talar dome. We performed the debridement of the ankle lesion. An osteochondral autograft was harvested from the medial femoral condyle (MFC) with the help of a personalised 3D-printed guide plate. This 3D-printed guide plate simulated the contour of a specific area in the talar dome, which involved the site of the defect. The autograft was then transplanted into the talus defect. The efficacy of this technique was evaluated at 2, 4, and 7 months after surgery and proven to be reliable.

Interleukin-12 (IL-12) and IL-23 are thought to have central roles in inflammation and are critical to pathologies associated with inflammation-induced bone disorders. The deletion of IL-12p40 (a common subunit of IL-12 and IL-23) can improve bone regeneration. However, the relative roles of IL-12 and IL-23 in bone disorders are largely unknown. Methods: Ectopic bone formation and skull defect models were established to evaluate the relative roles of IL-12 and IL-23 in inflammatory bone disorders. Differences in bone mass among WT, IL-12p35-/-, and IL-12p40-/- mice (young and elderly) were detected by micro-CT. Osteogenic and osteoclastic activities were explored using ELISA, qRT-PCR, and histological analysis. Moreover, the mechanisms by which IL-12 and IL-23 regulated the differentiation of BMMSCs and RAW264.7 cells were explored using Alizarin Red and tartrate-resistant acid phosphatase staining in vitro. Apilimod was used to inhibit IL-12 and IL-23 production in vivo. Results: Mice deficient in IL-12p40 promoted bone formation and protected against aging-related bone loss. By contrast, bone loss was aggravated in IL-12-/- mice, suggesting that IL-23 may play a dominant role in inflammation-related bone disorders. Mechanistically, IL-12 and IL-23 coupled osteogenesis and osteoclastic activities to regulate bone homeostasis and repair. IL-23 deficiency increased bone formation and inhibited bone resorption. Finally, apilimod treatment significantly improved bone regeneration and calvarial defect repair. Conclusion: These data collectively uncover a previously unrecognized role of IL-23 in skeletal tissue engineering. Thus, IL-23 can act as a biomarker to predict diseases and treatment efficacy, and apilimod can be used as an effective therapeutic drug to combat inflammatory bone disorders.

Background With the development of medical technology, credible options for defect reconstructions after the resection of benign bone tumors of the lower extremities have become a high priority. As the current reconstructive methods commonly used in clinical practice have some flaws, new methods of reconstruction need to be explored. We aimed to prepare a new kind of bioactive scaffold for the repair of bone defects through a stem cell rapid screening–enrichment–composite technology system developed by our team. Furthermore, we aimed to investigate the curative effects of these bioactive scaffolds. Methods Firstly, cell count, trypan blue exclusion rate, and ALP staining were used to evaluate changes in enrichment efficiency, cell activity, and osteogenic ability before and after enrichment. Then, the scaffolds were placed under the skin of nude mice to verify their osteogenic effects in vivo. Finally, the scaffolds were used for the reconstruction of bone defects after operations for benign bone tumors in a patient’s lower limb. The healing status of the defect site at 1 and 3 months was assessed by X-ray, and the Musculoskeletal Tumor Society (MSTS) score was applied to reflect the recovery of patient limb function. Results The system effectively enriched stem cells without affecting the activity and osteogenic abilities of the bone marrow mesenchymal stem cells (BMSCs). Meanwhile, the bioactive scaffolds obtained better osteogenic effects. In patients, the active scaffolds showed better bone integration and healing status, and the patients also obtained higher MSTS scores at 1 and 3 months after surgery. Conclusion As a new technique, the rapid screening–enrichment–composite technology of stem cells demonstrates a better therapeutic effect in the reconstruction of bone defects after surgery for benign bone tumors of the lower extremities, which will further improve patient prognosis.

Fracture nonunion, a serious bone fracture complication, remains a challenge in clinical practice. Although the molecular pathogenesis of nonunion remains unclear, a better understanding may provide better approaches for its prevention, diagnosis and treatment at the molecular level. This review tries to summarise the progress made in studies of the pathogenesis of fracture nonunion. We discuss the evidence supporting the concept that the development of nonunion is related to genetic factors. The importance of several cytokines that regulate fracture healing in the pathogenesis of nonunion, such as tumour necrosis factor-α, interleukin-6, bone morphogenetic proteins, insulin-like growth factors, matrix metalloproteinases and vascular endothelial growth factor, has been proven in vitro, in animals and in humans. Nitric oxide and the Wnt signalling pathway also play important roles in the development of nonunion. We present potential strategies for the prevention, diagnosis and treatment of nonunion, and the interaction between genetic alteration and abnormal cytokine expression warrants further investigation. The translational potential of this article: A better understanding of nonunion molecular pathogenesis may provide better approaches for its prevention, diagnosis and treatment in clinical practice. Keywords: Cytokine, Gene, Molecular pathogenesis, Nonunion

Background/Aims: Bone nonunion remains a challenge for orthopaedists. The technological advancements that have been made in precisely silencing target genes have provided promising methods to address this challenge. Methods: We detected the expression levels of the bone morphogenetic protein (BMP) inhibitors Chordin, Gremlin and Noggin using realtime PCR in bone mesenchymal stem cells (BMSCs) isolated from patients with normal fracture healing and those with bone nonunion. Moreover, we detected the expression of Chordin, Gremlin and Noggin during the osteogenic differentiation of human BMSCs (hBMSCs) using real-time PCR and Western blot. We delivered Chordin siRNA to hBMSCs using a previously reported cationic polymer, polyspermine imidazole-4,5-imine (PSI), as a pH-responsive and non-cytotoxic transfection agent. The apoptosis and cellular uptake efficiency were analysed by flow cytometry. Results: We identified Chordin as the most appropriate potential therapeutic target gene for enhancing the osteogenic differentiation of hBMSCs. Chordin knockdown rescued the osteogenic capacity of hBMSCs isolated from patients with bone nonunion. Highly efficient knockdown of Chordin was achieved in hBMSCs using PSI. Chordin knockdown promoted hBMSC osteogenesis and bone regeneration in vitro and in vivo. Conclusions: Our results suggest that Chordin is a potential target for improving osteogenesis and bone nonunion therapy and that responsive and non-toxic cationic polyimines such as PSI are therapeutically feasible carriers for the packaging and delivery of Chordin siRNA to hBMSCs.

Bone defects are a common challenge in clinic, usually warranting bone grafts. However, current strategies to obtain effective graft materials have many drawbacks. Mesenchymal stem cell (MSC)-based therapy is a promising alternative. We designed an innovative appliance named the stem cell screen–enrich–combine(-biomaterials) circulating system (SECCS). In this study, 42 patients who required bone graft underwent SECCS-based treatment. Their bone marrow samples and beta-tricalcium phosphate (β-TCP) granules were processed in the SECCS for 10–15 minutes, to produce MSC/β-TCP composites. These composites were grafted back into bone defect sites. The results showed 85.53% ± 7.95% autologous MSCs were successfully screened, enriched, and seeded on the β-TCP scaffolds synchronously. The cell viability remained unchanged after SECCS processing. Clinically, all patients obtained satisfactory bone healing. Thus, without in vitro culture, the SECCS can produce bioactive MSC/β-TCP composites for bone regeneration during surgery. The SECCS represents a convenient, rapid, low-cost, and safe method for bone regeneration.

Background Aneurysmal bone cyst (ABC) secondary to Giant Cell Tumor of bone (GCT) is a rare lesion, of which the incidence is about 0.011 to 0.053 per 100,000 every year. There are only a few previous case reports, and most of them occur in the spine, long bones or flat bones. Case presentation We report one case of a patient who complained of “progressive enlargement of the mass on right-hand fifth finger for 5 years with ulceration for 6 months”. After the imaging examination in our hospital, it was diagnosed as a “huge bone tumor on the proximal phalanx of the right-hand fifth finger”, then wide excision and amputation of the fifth finger were made. The pathological examination diagnosed the mass as aneurysmal bone cyst secondary to giant cell tumor, 13 × 8 × 6 cm3, with no local infiltration observed. No recurrence and metastasis occurred 18 months after the operation, and the patient recovered well. Conclusion In this report, we discuss the etiology, diagnosis, differentiation, and management of Aneurysmal bone Cyst secondary to Giant Cell Tumor of bone, and review previous case studies.

Background When bone marrow is repeatedly filtered through porous material, the mesenchymal stem cells (MSCs) in the bone marrow can adhere to the outer and inner walls of the carrier material to become enriched locally, and this is a promising method for MSC enrichment. In this process, the enrichment efficiency of MSCs involved in the regulation of the cell ecology of postfiltration composites containing other bone marrow components is affected by many factors. This study compared the enrichment efficiency and characterized the phenotypes of enriched MSCs obtained by the filtration of autologous bone marrow through different porous bone substitutes. Methods Human bone marrow was filtered through representative porous materials, and different factors affecting MSC enrichment efficiency were evaluated. The soluble proteins and MSC phenotypes in the bone marrow before and after filtration were also compared. Results The enrichment efficiency of the MSCs found in gelatin sponges was 96.1% ± 3.4%, which was higher than that of MSCs found in allogeneic bone (72.5% ± 7.6%) and porous β-TCP particles (61.4% ± 5.4%). A filtration frequency of 5–6 and a bone marrow/material volume ratio of 2 achieved the best enrichment efficiency for MSCs. A high-throughput antibody microarray indicated that the soluble proteins were mostly filtered out and remained in the flow through fluid, whereas a small number of proteins were abundantly (> 50%) enriched in the biomaterial. In terms of the phenotypic characteristics of the MSCs, including the cell aspect ratio, osteogenetic fate, specific antigens, gene expression profile, cell cycle stage, and apoptosis rate, no significant changes were found before or after filtration. Conclusion When autologous bone marrow is rapidly filtered through porous bone substitutes, the optimal enrichment efficiency of MSCs can be attained by the rational selection of the type of carrier material, the bone marrow/carrier material volume ratio, and the filtration frequency. The enrichment of bone marrow MSCs occurs during filtration, during which the soluble proteins in the bone marrow are also absorbed to a certain extent. This filtration enrichment technique does not affect the phenotype of the MSCs and thus may provide a safe alternative method for MSC enrichment.

Aim: To evaluate the clinical efficacy of mesenchymal stem cell/β-tricalcium phosphate composites (MSC/β-TCP) prepared with a screen-enrich-combine circulating system (SECCS) in patients with depressed tibial plateau fractures. Materials & methods: Bone defects in depressed tibial plateaus were filled with MSC/β-TCP (n = 16) or with β-TCP only (n = 23). Enrichment efficiency and effect of enrichment on cell viability were evaluated. Clinical results were assessed by imaging examination and Lysholm score. Results: SECCS effectively integrated MSCs with β-TCP. At 18 months postimplantation, new bone ratio was significantly higher in patients treated with MSC/β-TCP than in those treated with β-TCP only (p = 0.000). Patients with MSC/β-TCP implants had better functional recovery (p = 0.028). Conclusion: MSC/β-TCP prepared by SECCS were effective in the treatment of bone defects in patients with depressed tibial plateau fractures, promoted bone regeneration and improved joint function recovery.

Transforming growth factor-β1 (TGF-β1) is a key factor in bone reconstruction. However, its pathophysiological role in non-union and bone repair remains unclear. Here we demonstrated that TGF-β1 was highly expressed in both C57BL/6 mice where new bone formation was impaired after autologous bone marrow mesenchymal stem cell (BMMSC) implantation in non-union patients. High doses of TGF-β1 inhibited BMMSC osteogenesis and attenuated bone regeneration in vivo. Furthermore, different TGF-β1 levels exhibited opposite effects on osteogenic differentiation and bone healing. Mechanistically, low TGF-β1 doses activated smad3, promoted their binding to bone morphogenetic protein 2 (Bmp2) promoter, and upregulated Bmp2 expression in BMMSCs. By contrast, Bmp2 transcription was inhibited by changing smad3 binding sites on its promoter at high TGF-β1 levels. In addition, high TGF-β1 doses increased tomoregulin-1 (Tmeff1) levels, resulting in the repression of Bmp2 and bone formation in mice. Treatment with the TGF-β1 inhibitor SB431542 significantly rescued BMMSC osteogenesis and accelerated bone regeneration. Our study suggests that high-dose TGF-β1 dampens BMMSC-mediated bone regeneration by activating canonical TGF-β/smad3 signaling and inhibiting Bmp2 via direct and indirect mechanisms. These data collectively show a previously unrecognized mechanism of TGF-β1 in bone repair, and TGF-β1 is an effective therapeutic target for treating bone regeneration disability. © 2019 American Society for Bone and Mineral Research.

Bone non-union after fracture, considered a therapeutic challenge for orthopedics, always needs a reversion surgery, including autograft transplantation (AGT). However, adverse events related to autograft harvest cannot be ignored. Our group designed a novel system called the bone marrow stem cell Screen-Enrich-Combine Circulating System (SECCS) by seeding mesenchymal stem cells (MSCs) into β-tricalcium phosphate (β-TCP) during surgery to thereafter rapidly process bioactive bone implantation. In this retrospective case-control study, 30 non-union patients who accepted SECCS therapy and 20 non-union patients who accepted AGT were enrolled. By SECCS therapy, the MSC-enriched β-TCP particles were implanted into the non-union gap. During the enrichment procedure, a significant proportion of MSCs were screened and enriched from bone marrow into porous β-TCP particles, and the cells possessed the capacity for three-line differentiation and were CD90+/CD105+/CD34-/CD45-. Approximately 82.0±10.7% of MSCs were enriched from 60 mL bone marrow without damaging cell viability, and approximately 11,444.0±6,018 MSCs were transplanted per patient. No implant-related infections occurred in any case. After 9 months of follow-up, 27 patients (90%) in the SECCS group acquired clinical union, compared with 18 patients (90%) in the AGT group (clinical union time, P = 0.064), and postoperative radiographic union score at 9 months post-operation was similar between the two groups. In conclusion, the SECCS could concentrate a large proportion of MSCs from bone marrow to acquire enough effective cells for therapy without in vitro cell culture. Bone substitutes processed by SECCS demonstrated encouraging promotion of bone regeneration and showed a satisfactory clinical curative effect for diaphyseal bone non-union, which was non-inferior to AGT.

Background Efficacious bone substitute is essential for the treatment of a critical size bone defect. Currently, the bone substitutes commonly used in clinical practice lack osteogenic capacity and the therapeutic efficacy is not ideal. Herein, a novel stem cell screen-enrich-combine(−biomaterials) circulating system (SECCS) was introduced to provide the substitutes with osteogenic ability. The stem cell screening, enrichment, and recombination with substitutes could be integrated during the surgical operation. Using SECCS, the bioactive mesenchymal stem cells (MSCs) and porous β-tricalcium phosphate (β-TCP) composites (MSCs/β-TCP) were rapidly prepared for critical size bone defect repair and validated in goat models of critical size tibia defects. Methods Twelve goats with right hind limb tibia defects of 30 mm were randomly divided into two groups: six (the experimental group) were treated with MSCs/β-TCP prepared by SECCS and the other six goats (the control group) were treated with pure porous β-TCP. The repair effect was assessed by x-ray, computed tomography (CT), micro-CT, histology and histomorphology 6 months after the operation. In addition, the enrichment efficacy of MSCs and the characteristics of the MSCs/β-TCP prepared by SECCS were evaluated. Results The SECCS could compound about 81.3 ± 3.0% of the MSCs in bone marrow to the porous β-TCP without affecting the cell viability. The average number of MSCs for retransplantation was 27,655.0 ± 5011.6 for each goat from the experimental group. In vitro, satisfactory biocompatibility of the MSCs/β-TCP was performed, with the MSCs spreading adequately, proliferating actively, and retaining the osteogenic potential. In vivo, the defect repair by MSCs/β-TCP with good medullary cavity recanalization and cortical remodeling was significantly superior to that of pure porous β-TCP. Conclusions The MSCs/β-TCP prepared through SECCS demonstrated significant therapeutic efficacy in goat models of critical size bone defect. This provides a novel therapeutic strategy for critical size bone defects caused by severe injury, infection, and bone tumor resection with a high profile of safety, effectiveness, simplicity, and ease.

Small-interfering RNA (siRNA) provides a rapid solution for drug design and provides new methods to develop customizable medicines. Polyethyleneimine 25 kDa (PEI25kDa) is an effective transfection agent used in siRNA delivery. However, the lack of degradable linkage causes undesirable toxicity, hindering its clinical application. We designed a low-molecular-weight cross-linked polyethylenimine named PEI-Et (Mn:1220, Mw:2895) by using degradable ethylene biscarbamate linkage with lower cytotoxicity and higher knockdown efficiency than PEI25kDa in delivery Chordin siRNA to human bone mesenchymal stem cells (hBMSCs). Suppression of Chordin by using anti-Chordin siRNA delivered by PEI-Et improved bone regeneration in vitro and in vivo associated with the bone morphogenetic protein-2 (BMP-2) mediated smad1/5/8 signaling pathway. Results of this study suggest that Chordin siRNA can be potentially used to improve osteogenesis associated with the BMP-2-mediated Smad1/5/8 signaling pathway and biodegradable biscarbamate cross-linked low-molecular-weight polyethylenimine (PEI-Et) is a therapeutically feasible carrier material to deliver anti-Chordin siRNA to hBMSCs.

Rationale Necrotizing fasciitis (NF) is defined as a rare, rapidly progressive, and highly lethal skin infection characterized by necrosis of the fascia and subcutaneous tissue. Patient concerns The present study aims to discuss the case of a 35-year-old man who developed NF following a routine sterile right distal radius bone plate removal surgery. Diagnoses The patient was suspected of NF based on his clinical manifestations, laboratory tests, and imaging results. The diagnosis of NF was confirmed by histological examinations. Interventions Serial prompt and extensive debridement was performed during the rapid and aggressive extension of the skin infection, together with antibiotics and supportive treatments. Outcomes The condition of the patient finally improved on the sixth day of disease progression. Skin grafting of his right forearm wound was performed successfully 2 months after the admission. Lessons NF can occur during the perioperative period for routine clean radius plate removal operation in patients with no risk factor for NF. The objective is to remind the physicians to stay aware of this disease, especially its early clinical signs and symptoms. Urgent subsequent treatment, including surgical debridement, antibiotic therapy, and supporting management, is the key to ensure the survival and better prognosis of patients.