Robotic-assisted foot and ankle surgery: a review of the present status and the future.

The surgical application of robotics has increased significantly since its first application in 1985 for a brain biopsy acquisition. Robotic-assisted surgery has been one of the viable options in various surgical areas, and also in orthopaedic surgery. Robotic-assisted orthopaedic surgery has gained popularity as a mean of improving accuracy, reducing complications and achieving better patient satisfaction. Numerous clinical research studies have demonstrated advantages of robotic-assisted orthopaedic surgery, however, most of that researches were about the total knee arthroplasty, total hip arthroplasty and spine surgery. The application of robotic technology in foot and ankle surgery is in a very nascent stage. Furthermore, there has been little research on intraoperative use of robotics in foot and ankle surgery in literature. A review of previous preclinical studies in foot and ankle robotics and clinical research studies in various fields of robot-assisted orthopaedic surgery shows that its potential application and benefits over conventional techniques, such as total ankle arthroplasty, minimally invasive surgery for foot and ankle trauma or other corrective procedure, and intraoperative biomechanical testing. More studies on practical application of robotic technology to surgical procedure in the field of foot and ankle surgery are needed to confirm its clinical usefulness and cost effectiveness.

Medial Reduction in Sesamoid Position after Hallux Valgus Correction Surgery Showed Better Outcome in S.E.R.I. Osteotomy than DCMO.

BACKGROUND: The purpose of the present study was to compare the degree of sesamoid reduction after hallux valgus correction between distal chevron metatarsal osteotomy (DCMO) and S.E.R.I. (simple, effective, rapid, and inexpensive) osteotomy, and to analyze the effects on the recurrence of hallux valgus. METHODS: We retrospectively analyzed the foot radiographs of 60 feet (30 DCMO and 30 SERI) treated for hallux valgus from August 2013 to July 2017. Radiographic assessments were performed preoperatively, at early follow-up (at a mean of 3.1 months) and at the most recent follow-up (at a mean of 16.7 months). The location of the medial sesamoid was classified into seven stages, in accordance with the method described by Hardy and Clapham; stage IV or less was defined as the normal position for the medial sesamoid, and stage V or greater was defined as lateral displacement of the sesamoid. The pre- and post-operative hallux valgus angle, 1-2 intermetatarsal angle, and sesamoid position were compared between the two groups. RESULTS: The mean follow-up period was 18.4 (12-36) months in the DCMO group and 15.0 (12-36) months in the S.E.R.I. group (p = 0.108). The radiologic results showed that the hallux valgus angles were not significantly different between the two groups preoperatively and at the early follow-up: preoperatively, they were 28.8 ± 7.7 in the DCMO group and 32.6 ± 9.5 in the S.E.R.I. group (p = 0.101), and they were 10.4 ± 4.0 and 8.7 ± 5.0 (p = 0.148) at the early follow-up, respectively. However, at the most recent follow-up, the DCMO group (13.9 ± 5.6) showed significantly higher hallux valgus angles than the S.E.R.I. group (10.4 ± 6.4, p = 0.030), and there were no differences between the recurrence of hallux valgus in the DCMO group (13%)and that in the S.E.R.I. group (10%) (p = 0.553). There were no significant differences in the 1-2 intermetatarsal angles between the two groups at the early follow-up (6.1 ± 2.5 vs. 4.8 ± 3.1, p = 0.082) and at the most recent follow-up (7.3 ± 2.9 vs. 6.6 ± 3.5, p = 0.408). After hallux-valgus-correction surgery, the stage change of the tibia sesamoid position from the preoperative stage to the initial follow-up was significantly larger in the S.E.R.I. group (-4.4 ± 1.4) than in the DCMO group (-3.4 ± 1.1) (p = 0.003); the changes from the preoperative stage to the last follow-up were also significantly larger in the SERI group (-3.3 ± 1.7) than in the DCMO group (-2.4 ± 1.5) (p = 0.028); however, the changes from the initial follow-up to the last follow-up showed no significant differences between the two groups (+1.0 ± 1.1 in the DCMO group vs. +1.1 ± 1.2 in the S.E.R.I. group) (p = 0.822). The medial sesamoid was laterally subluxated in all the preoperative cases in the DCMO and S.E.R.I. groups. The lateral subluxation of the tibia sesamoid was more frequently observed in the DCMO group (four cases, 13%) than in the S.E.R.I. group (0 cases, 0%) (p = 0.038) at the early follow-up. CONCLUSION: In conclusion, our results demonstrated that the S.E.R.I. procedure is superior to DCMO in decreasing the hallux valgus angle and showed that the early post-operative reduction in the sesamoids can be a risk factor for the recurrence of hallux valgus.

Schnurri-3 inhibition suppresses bone and joint damage in models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of Shn3 in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT/ß-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in Shn3 that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT/ß-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.

Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone regeneration and prevents OVX-induced bone loss.

BACKGROUND: Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner. METHODS: In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis. RESULTS: Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. CONCLUSION: Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis.

RUNX2 stabilization by long non-coding RNAs contributes to hypertrophic changes in human chondrocytes.

Background: Chondrocyte hypertrophy has been implicated in endochondral ossification and osteoarthritis (OA). In OA, hypertrophic chondrocytes contribute to the destruction and focal calcification of the joint cartilage. Although studies in this field have remarkably developed the modulation of joint inflammation using gene therapy and regeneration of damaged articular cartilage using cell therapy, studies that can modulate or prevent hypertrophic changes in articular chondrocytes are still lacking. Methods: In vitro hypertrophic differentiation and inflammation assays were conducted using human normal chondrocyte cell lines, TC28a2 cells. Human cartilage tissues and primary articular chondrocytes were obtained from OA patients undergoing total knee arthroplasty. Long non-coding RNAs (lncRNAs), LINC02035 and LOC100130207, were selected through RNA-sequencing analysis using RNAs extracted from TC28a2 cells cultured in hypertrophic medium. The regulatory mechanism was evaluated using western blotting, real-time quantitative polymerase chain reaction, osteocalcin reporter assay, RNA-immunoprecipitation (RNA-IP), RNA-in situ hybridization, and IP. Results: LncRNAs are crucial regulators of various biological processes. In this study, we identified two important lncRNAs, LINC02035 and LOC100130207, which play important roles in hypertrophic changes in normal chondrocytes, through RNA sequencing. Interestingly, the expression level of RUNX2, a master regulator of chondrocyte hypertrophy, was regulated at the post-translational level during hypertrophic differentiation of the normal human chondrocyte cell line, TC28a2. RNA-immunoprecipitation proved the potential interaction between RUNX2 protein and both lncRNAs. Knockdown (KD) of LINC02035 or LOC100130207 promoted ubiquitin-mediated proteasomal degradation of RUNX2 and prevented hypertrophic differentiation of normal chondrocyte cell lines, whereas overexpression of both lncRNAs stabilized RUNX2 protein and generated hypertrophic changes. Furthermore, the KD of the two lncRNAs mitigated the destruction of important cartilage matrix proteins, COL2A1 and ACAN, by hypertrophic differentiation or inflammatory conditions. We also confirmed that the phenotypic changes raised by the two lncRNAs could be rescued by modulating RUNX2 expression. In addition, the KD of these two lncRNAs suppressed hypertrophic changes during chondrogenic differentiation of mesenchymal stem cells. Conclusion: Therefore, this study suggests that LINC02035 and LOC100130207 contribute to hypertrophic changes in normal chondrocytes by regulating RUNX2, suggesting that these two novel lncRNAs could be potential therapeutic targets for delaying or preventing OA development, especially for preventing chondrocyte hypertrophy.

WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects.

Treating osteoporosis and associated bone fractures remains challenging for drug development in part due to potential off-target side effects and the requirement for long-term treatment. Here, we identify recombinant adeno-associated virus (rAAV)-mediated gene therapy as a complementary approach to existing osteoporosis therapies, offering long-lasting targeting of multiple targets and/or previously undruggable intracellular non-enzymatic targets. Treatment with a bone-targeted rAAV carrying artificial microRNAs (miRNAs) silenced the expression of WNT antagonists, schnurri-3 (SHN3), and sclerostin (SOST), and enhanced WNT/ß-catenin signaling, osteoblast function, and bone formation. A single systemic administration of rAAVs effectively reversed bone loss in both postmenopausal and senile osteoporosis. Moreover, the healing of bone fracture and critical-sized bone defects was also markedly improved by systemic injection or transplantation of AAV-bound allograft bone to the osteotomy sites. Collectively, our data demonstrate the clinical potential of bone-specific gene silencers to treat skeletal disorders of low bone mass and impaired fracture repair.

Deubiquitinating Enzyme USP7 Is Required for Self-Renewal and Multipotency of Human Bone Marrow-Derived Mesenchymal Stromal Cells.

Ubiquitin-specific protease 7 (USP7) is highly expressed in a variety of malignant tumors. However, the role of USP7 in regulating self-renewal and differentiation of human bone marrow derived mesenchymal stromal cells (hBMSCs) remains unknown. Herein, we report that USP7 regulates self-renewal of hBMSCs and is required during the early stages of osteogenic, adipogenic, and chondrogenic differentiation of hBMSCs. USP7, a deubiquitinating enzyme (DUB), was found to be downregulated during hBMSC differentiation. Furthermore, USP7 is an upstream regulator of the self-renewal regulating proteins SOX2 and NANOG in hBMSCs. Moreover, we observed that SOX2 and NANOG are poly-ubiquitinated and their expression is downregulated in USP7-deficient hBMSCs. Overall, this study showed that USP7 is required for maintaining self-renewal and multipotency in cultured hBMSCs. Targeting USP7 might be a novel strategy to preserve the self-renewal capacity of hBMSCs intended for stem cell therapy.

Sodium Tetradecyl Sulphate Sclerotherapy for Lateral Malleolar Bursitis of the Ankle.

Background: The aim of this study was to evaluate clinical outcomes of sodium tetradecyl sulphate (STS) sclerotherapy for conservative treatment of lateral malleolar bursitis of the ankle. Methods: We reviewed data from 20 consecutive patients (20 ankles) who underwent STS sclerotherapy between August 2018 and June 2019. After aspiration of fluid from the lateral malleolar bursal sac, 2 mL (20 mg) STS was injected into the sac. Clinical outcomes and side effects and complications were evaluated at 2 weeks, 3 months, 1 year, and 2 years after sclerotherapy. Responses to treatment were assessed according to degree of fluctuation, shrinkage of the bursal sac, and soft-tissue swelling. The 36-item short form survey (SF-36) was completed for each patient before and after therapy. Results: Complete response was observed in 17 patients (85%), and partial response was observed in 3 patients (15%) after STS sclerotherapy. SF-36 physical component scores improved from 62.2 (interquartile range, 5.2) before therapy to 70.0 (interquartile range, 7.9) at last follow-up (p < 0.05). One patient (5%) experienced transient hyperpigmentation at the injection site. No major complications occurred. Conclusions: STS sclerotherapy was an effective and safe treatment for patients with lateral malleolar bursitis of the ankle.

Long-Term Clinical Outcomes and Implant Survivorship of 151 Total Ankle Arthroplasties Using the HINTEGRA Prosthesis: A Minimum 10-Year Follow-up.

BACKGROUND: Few studies have investigated long-term clinical outcomes of a mobile-bearing total ankle arthroplasty (TAA) system. This study analyzed long-term outcomes of TAA using the HINTEGRA prosthesis at a single, non-developer center. METHODS: Primary TAAs were performed on 213 ankles in 194 patients, and 151 consecutive ankles [71%] in 136 patients with a minimum follow-up of 10 years after the primary TAA were included in this study. Clinical results were assessed using a visual analog scale (VAS) pain score, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale score, the Ankle Osteoarthritis Scale (AOS) pain and disability subscores, and ankle range of motion. Prosthesis survivorship, reoperations, and risk factors were also evaluated. RESULTS: The mean follow-up was 135.5 months (range, 120.0 to 204.0 months). All clinical scores and ankle range of motion improved significantly from preoperatively to 2 years, 4 to 6 years, and ≥10 years after TAA (p < 0.001). A total of 43 ankles (28.5%) required revision procedures, with the most common reason being periprosthetic osteolysis (32 ankles [21.2%]). The overall implant survivorship was 93.5% in Kaplan-Meier survival analysis at the mean follow-up of 11.3 years after the TAA. CONCLUSIONS: TAA using the HINTEGRA prosthesis with careful follow-up observation and appropriate adjunct procedures for the treatment of end-stage ankle arthritis produced satisfactory clinical results, which were maintained at a follow-up of ≥10 years, and resulted in 93.5% of implant survivorship. LEVEL OF EVIDENCE: Prognostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Outcomes of oblique supramalleolar osteotomy without fibular osteotomy for congruent- and incongruent-type medial ankle arthritis.

BACKGROUND: Although high talar tilt and ankle mortise incongruence are risk factors for supramalleolar osteotomy (SMO), no study on lateral talofibular joint congruence exists. We aimed to evaluate the outcomes of oblique SMO without fibular osteotomy for medial ankle arthritis and compare them according to the lateral talofibular joint congruity. METHODS: Forty-eight ankles were retrospectively reviewed and divided according to preoperative talofibular joint congruity (congruent, 22 [45.8%] vs. incongruent, 26 [54.2%]). RESULTS: The mean VAS score, AOFAS score, and modified Takakura stage were significantly improved. No significant differences were noted in clinical outcomes, but the mean postoperative tibiotalar angle and difference between the upper and lower talofibular gaps were significantly different in both groups (p = 0.004 and p = 0.009, respectively). The mean Takakura stage at 1 and 2 years after surgery was higher in the incongruent group (p = 0.013, p = 0.012). CONCLUSION: This procedure was effective against early- to mid-stage medial ankle arthritis. Radiographic arthritic grade changed according to the talofibular joint congruity.

Cellular and Tissue Selectivity of AAV Serotypes for Gene Delivery to Chondrocytes and Cartilage.

Background: Despite several studies on the effect of adeno-associated virus (AAV)-based therapeutics on osteoarthritis (OA), information on the transduction efficiency and applicable profiles of different AAV serotypes to chondrocytes in hard cartilage tissue is still limited. Moreover, the recent discovery of additional AAV serotypes makes it necessary to screen for more suitable AAV serotypes for specific tissues. Here, we compared the transduction efficiencies of 14 conventional AAV serotypes in human chondrocytes, mouse OA models, and human cartilage explants obtained from OA patients. Methods: To compare the transduction efficiency of individual AAV serotypes, green fluorescent protein (GFP) expression was detected by fluorescence microscopy or western blotting. Likewise, to compare the transduction efficiencies of individual AAV serotypes in cartilage tissues, GFP expression was determined using fluorescence microscopy or immunohistochemistry, and GFP-positive cells were counted. Results: Only AAV2, 5, 6, and 6.2 exhibited substantial transduction efficiencies in both normal and OA chondrocytes. All AAV serotypes except AAV6 and rh43 could effectively transduce human bone marrow mesenchymal stem cells. In human and mouse OA cartilage tissues, AAV2, AAV5, AAV6.2, AAV8, and AAV rh39 showed excellent tissue specificity based on transduction efficiency. These results indicate the differences in transduction efficiencies of AAV serotypes between cellular and tissue models. Conclusions: Our findings indicate that AAV2 and AAV6.2 may be the best choices for AAV-mediated gene delivery into intra-articular cartilage tissue. These AAV vectors hold the potential to be of use in clinical applications to prevent OA progression if appropriate therapeutic genes are inserted into the vector.

Ubiquitin-specific protease 53 promotes osteogenic differentiation of human bone marrow-derived mesenchymal stem cells.

The ubiquitin protease pathway plays important role in human bone marrow-derived mesenchymal stem cell (hBMSC) differentiation, including osteogenesis. However, the function of deubiquitinating enzymes in osteogenic differentiation of hBMSCs remains poorly understood. In this study, we aimed to investigate the role of ubiquitin-specific protease 53 (USP53) in the osteogenic differentiation of hBMSCs. Based on re-analysis of the Gene Expression Omnibus database, USP53 was selected as a positive regulator of osteogenic differentiation in hBMSCs. Overexpression of USP53 by lentivirus enhanced osteogenesis in hBMSCs, whereas knockdown of USP53 by lentivirus inhibited osteogenesis in hBMSCs. In addition, USP53 overexpression increased the level of active ß-catenin and enhanced the osteogenic differentiation of hBMSCs. This effect was reversed by the Wnt/ß-catenin inhibitor DKK1. Mass spectrometry showed that USP53 interacted with F-box only protein 31 (FBXO31) to promote proteasomal degradation of ß-catenin. Inhibition of the osteogenic differentiation of hBMSCs by FBXO31 was partially rescued by USP53 overexpression. Animal studies showed that hBMSCs with USP53 overexpression significantly promoted bone regeneration in mice with calvarial defects. These results suggested that USP53 may be a target for gene therapy for bone regeneration.

Bone Marrow Stimulation for Osteochondral Lesions of the Talus: Are Clinical Outcomes Maintained 10 Years Later?

BACKGROUND: Arthroscopic bone marrow stimulation (BMS) is considered the first-line treatment for osteochondral lesions of the talus (OLTs). However, the long-term stability of the clinical success of BMS remains unclear. PURPOSE: To investigate the long-term clinical outcomes among patients who underwent BMS for OLT and to identify prognostic factors for the need for revision surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective analysis was performed on 202 ankles (189 patients) that were treated with BMS for OLT and had a minimum follow-up of 10 years. The visual analog scale for pain, American Orthopaedic Foot & Ankle Society ankle-hindfoot score, and the Foot and Ankle Outcome Score (FAOS) were assessed by repeated measures analysis of variance. Prognostic factors associated with revision surgery were evaluated with Cox proportional hazard regression models and log-rank tests. RESULTS: The mean lesion size was 105.32 mm2 (range, 19.75-322.79); 42 ankles (20.8%) had large lesions (≥150 mm2). The mean visual analog scale for pain improved from 7.11 ± 1.73 (mean ± SD) preoperatively to 1.44 ± 1.52, 1.46 ± 1.57, and 1.99 ± 1.67 at 1, 3 to 6, and ≥10 years, respectively, after BMS (P < .001). The mean ankle-hindfoot score also improved, from 58.22 ± 13.57 preoperatively to 86.88 ± 10.61, 86.17 ± 10.23, and 82.76 ± 11.65 at 1, 3 to 6, and ≥10 years after BMS (P < .001). The FAOS at the final follow-up was 82.97 ± 13.95 for pain, 81.81 ± 14.64 for symptoms, 83.49 ± 11.04 for activities of daily living, 79.34 ± 11.61 for sports, and 78.71 ± 12.42 for quality of life. Twelve ankles underwent revision surgery after a mean 53.5 months. Significant prognostic factors associated with revision surgery were the size of the lesion (preoperative magnetic resonance imaging measurement ≥150 mm2; P = .014) and obesity (body mass index ≥25; P = .009). CONCLUSION: BMS for OLT yields satisfactory clinical outcomes at a mean follow-up of 13.9 years. The success of the surgery may depend on the lesion size and body mass index of the patient.

Primary Autologous Osteochondral Transfer Shows Superior Long-Term Outcome and Survival Rate Compared With Bone Marrow Stimulation for Large Cystic Osteochondral Lesion of Talus.

PURPOSE: To compare the results of bone marrow stimulation (BMS) versus autologous osteochondral transfer (AOT) as primary surgical option for large cystic osteochondral lesion of talus (OLT) and to further distinguish factors associated with clinical failures and overall survival. METHODS: We retrospectively analyzed patients with symptomatic large cystic OLT (>300 mm3) who underwent either primary BMS or AOT between January 2001 and January 2016 with a minimum follow-up of 36 months. Lesion surface area and volume were measured on magnetic resonance imaging. Clinical outcomes were assessed using pain visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, and Foot and Ankle Outcome Score (FAOS). Survival outcomes and factors associated with clinical failures were evaluated using Kaplan-Meier analysis and Cox regression analyses, respectively. RESULTS: Fifty of the total 853 patients had large cystic OLTs. Thirty-two patients underwent primary BMS, and 18 patients underwent primary AOT. Mean follow-up period was 118 months, and average lesion surface area and volume were 152.8 mm2 and 850.7 mm3, respectively. The primary AOT group showed significantly superior improvements in clinical outcomes compared with the BMS group at last follow-up (P = .001). Fourteen patients in the primary BMS group and 2 patients in the primary AOT group experienced clinical failure. Kaplan-Meier analysis showed a superior survival rate of primary AOT (P = .042). Syndesmosis widening (hazard ratio 12.361; P = .004) and large lesion surface area (hazard ratio 1.011; P = .014) were significant relative risks of clinical failure in the primary BMS group. However, lesion volume showed no significant relationship with clinical failure. CONCLUSION: Long-term results of primary AOT showed superior clinical improvements and survival rate in treating large cystic OLT. Risk factors for failure in the primary BMS group were large lesion surface area and syndesmosis widening. STUDY DESIGN: Retrospective comparative study LEVEL OF EVIDENCE: III.

Intra-articular Injections of Hyaluronic Acid on Osteochondral Lesions of the Talus After Failed Arthroscopic Bone Marrow Stimulation.

BACKGROUND: The purpose of the study was to compare clinical and functional outcomes before and after hyaluronic acid (HA) injections in patients with osteochondral lesions of the talus who experienced a failure of their primary treatment with arthroscopic microfracture surgery. METHODS: A total of 40 patients were included in the final study. These patients had received microfracture surgery but continued to experience postoperative pain over an average of 13.0 months (range, 0-81 months) and were available for investigation with a mean follow-up for 29.1 months (SD 14.7; range 2.6-79.6 months). All patients received intra-articular injections of HA once per week for 3 weeks. We assessed clinical and functional outcomes before and after injection using the American Orthopaedic Foot & Ankle Society (AOFAS) score, Foot and Ankle Outcome Score (FAOS), Short Form Health Survey (SF-36), the visual analog scale (VAS) for pain, and the Alexander subjective scale. RESULTS: The AOFAS score significantly increased from 50.7 ± 13.8 to 79.9 ± 13.8 and the FAOS scores for symptom, pain, daily living, and sports were significantly higher postinjection compared to preinjection (all P < .001). Similarly, the mean VAS for pain was significantly decreased after 6 weeks following injection and continued to decrease over the follow-up period; the mean VAS was significantly lower postinjection compared to preinjection at 12 months (P < .001). CONCLUSION: Intra-articular HA injections on average significantly improved clinical and functional scores after failed primary operative treatment. HA injections may provide an alternative to secondary operative treatment and provide better clinical outcomes than other conservative treatments. LEVEL OF EVIDENCE: Level II, prospective observational cohort study.

Diagnosis and Operation Results for Chronic Lateral Ankle Instability with Subtle Cavovarus Deformity and a Peek-A-Boo Heel Sign.

Cavovarus deformity is considered an anatomical risk factor for chronic lateral ankle instability (CLAI). However, subtle deformity can be difficult to detect, and its correction is controversial. The current study aimed to evaluate clinical and radiographic outcomes of a modified Broström procedure (MBP) with additional procedures for CLAI with subtle cavovarus deformity and a positive peek-a-boo heel sign. We reviewed the records of 15 patients who underwent MBP with additional procedures for CLAI with a positive peek-a-boo heel sign between August 2009 and April 2015. Consecutive physical and radiographic examinations were performed. The visual analog scale (VAS) for pain, the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, and the Karlsson-Peterson (KP) ankle score were applied to assess clinical outcomes. Weight bearing radiographs, hindfoot alignment view, and ankle stress radiographs were also examined. The mean follow-up period was 58.5 months. Calcaneal lateral closing wedge osteotomy was performed in seven patients to correct fixed hindfoot varus, and first metatarsal dorsiflexion osteotomy was performed in 11 patients to correct plantarflexion of the first ray. Three patients underwent both procedures. Mean VAS, AOFAS, and KP ankle scores improved significantly (p=0.001), and instability did not recur. Radiographically, all stress parameters improved significantly (p=0.007). Simultaneous correction of a positive peek-a-boo heel sign and cavovarus deformity with MBP for CLAI improves clinical outcomes and prevents recurrent instability. A comprehensive evaluation and cautious approach for subtle cavovarus deformity should be followed when treating patients with CLAI. This trial is registered on Clinical Research Information Service (CRiS, KCT0003287).

Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis.

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.

A RUNX2 stabilization pathway mediates physiologic and pathologic bone formation.

The osteoblast differentiation capacity of skeletal stem cells (SSCs) must be tightly regulated, as inadequate bone formation results in low bone mass and skeletal fragility, and over-exuberant osteogenesis results in heterotopic ossification (HO) of soft tissues. RUNX2 is essential for tuning this balance, but the mechanisms of posttranslational control of RUNX2 remain to be fully elucidated. Here, we identify that a CK2/HAUSP pathway is a key regulator of RUNX2 stability, as Casein kinase 2 (CK2) phosphorylates RUNX2, recruiting the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP), which stabilizes RUNX2 by diverting it away from ubiquitin-dependent proteasomal degradation. This pathway is important for both the commitment of SSCs to osteoprogenitors and their subsequent maturation. This CK2/HAUSP/RUNX2 pathway is also necessary for HO, as its inhibition blocked HO in multiple models. Collectively, active deubiquitination of RUNX2 is required for bone formation and this CK2/HAUSP deubiquitination pathway offers therapeutic opportunities for disorders of inappropriate mineralization.

Use Of Regional Anesthesia For Lower Extremity Amputation May Reduce The Need For Perioperative Vasopressors: A Propensity Score-Matched Observational Study.

PURPOSE: Lower extremity amputation (LEA) is associated with a high risk of postoperative mortality. The effect of type of anesthesia on postoperative mortality has been studied in various surgeries. However, data for guiding the selection of optimal anesthesia for LEA are limited. This study aimed to determine the effect of anesthesia type on perioperative outcomes in patients with diabetes and/or peripheral vascular disease undergoing LEA. PATIENTS AND METHODS: We reviewed the medical records of patients who underwent LEA at our center between September 2007 and August 2017, who were grouped according to use of general anesthesia (GA) or regional anesthesia (RA). Primary outcomes were 30-day and 90-day mortality. Secondary outcomes were postoperative morbidity, intraoperative events, postoperative intensive care unit admission, and postoperative length of stay. Propensity score-matched cohort design was used to control for potentially confounding factors, including patient demographics, comorbidities, medications, and type of surgery. RESULTS: Five hundred and nineteen patients (75% male, mean age 65 years) were identified to have received GA (n=227) or RA (n=292) for above-knee amputation (1.5%), below-knee amputation (16%), or more minor amputation (82.5%). Before propensity score matching, there was an association of GA with coronary artery disease (44% [GA] vs 34.5% [RA], p=0.028), peripheral arterial disease (73.1% vs 60.2%, p=0.002), and preoperative treatment with aspirin and clopidogrel (68.7% vs 55.1%, p=0.001; 63% vs 41.8%, p<0.001, respectively). Propensity score matching produced a cohort of 342 patients equally divided between GA and RA. There was no significant between-group difference in 30-day (3.5% vs 2.9%, p=0.737) or 90-day (6.4% vs 4.6%, p=0.474) mortality or postoperative morbidity. However, postoperative ICU admission (14.6% vs 7%, p=0.032), intraoperative hypotension (61.4% vs 14.6%, p<0.001), and vasopressor use (52% vs 14%, p<0.001) were more common with GA than with RA. CONCLUSION: Type of anesthesia did not significantly affect mortality or morbidity after LEA. However, intraoperative hypotension, vasopressor use, and postoperative ICU admission rates were lower with RA.

Enhancement of Mesenchymal Stem Cell-Driven Bone Regeneration by Resveratrol-Mediated SOX2 Regulation.

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine. However, MSCs age rapidly during long-term ex vivo culture and lose their therapeutic potential before they reach effective cell doses (ECD) for cell therapy. Thus, a prerequisite for effective MSC therapy is the development of cell culture methods to preserve the therapeutic potential during long-term ex vivo cultivation. Resveratrol (RSV) has been highlighted as a therapeutic candidate for bone disease. Although RSV treatment has beneficial effects on bone-forming cells, in vivo studies are lacking. The current study showed that long-term (6 weeks from primary culture date)-cultured MSCs with RSV induction retained their proliferative and differentiation potential despite reaching ECD. The mechanism of RSV action depends entirely on the SIRT1-SOX2 axis in MSC culture. In a rat calvarial defect model, RSV induction significantly improved bone regeneration after MSC transplantation. This study demonstrated an example of efficient MSC therapy for treating bone defects by providing a new strategy using the plant polyphenol RSV.