Kwang Hwan Park

Generalized Ligamentous Laxity Is an Independent Predictor of Poor Outcomes After the Modified Broström Procedure for Chronic Lateral Ankle Instability

Background: The modified Broström procedure for chronic lateral ankle instability (CLAI) has presented outstanding clinical results. However, after the procedure, some patients with generalized ligamentous laxity have experienced a recurrence of ankle instability. Purpose: To understand the effect of generalized ligamentous laxity on prognosis and risk of recurrence in a cohort of patients with CLAI after the modified Broström procedure. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 199 ankles from 188 patients underwent the modified Broström procedure for CLAI with a mean follow-up of 60.1 months (range, 48-108 months). Generalized ligamentous laxity was assessed in all patients. The Karlsson-Peterson ankle score (Karlsson score), talar tilt angle, and anterior displacement of the talus were used to evaluate clinical and radiological outcomes. Risk factors associated with clinical outcomes were evaluated using bivariate analysis and logistic regression analysis. Survival outcomes were compared using Kaplan-Meier analysis. Results: Generalized ligamentous laxity was evident in 42 cases (21.1%). The average Karlsson score improved from 54.6 ± 7.1 preoperatively to 87.9 ± 7.2 at last follow-up (P < .001). The presence of generalized ligamentous laxity was significantly associated with poor clinical and radiological outcomes. The rates of clinical failure were 10.8% and 45.2% in the nonlaxity group and the laxity group, respectively (P < .001). According to bivariate analysis, generalized ligamentous laxity, syndesmosis widening, osteochondral lesion of the talus, high preoperative talar tilt angle (>15°), and high preoperative anterior displacement of the talus (>10 mm) were significantly associated with clinical failure. Multivariate logistic regression analysis revealed that generalized ligamentous laxity was the most important independent predictor of clinical failure after the modified Broström procedure. The cumulative success rates for the nonlaxity group were significantly superior to those for the laxity group in Kaplan-Meier curves (P < .001). Conclusion: Generalized ligamentous laxity is an independent predictor of poor outcomes and a risk factor of recurrent instability following the modified Broström procedure for CLAI.

Synergistic Action of IL-8 and Bone Marrow Concentrate on Cartilage Regeneration Through Upregulation of Chondrogenic Transcription Factors

The objective of this study was to determine whether a biphasic scaffold loaded with a combination of a chemokine and bone marrow concentrate (BMC) could improve tissue regeneration in knee articular cartilage of beagles with cylindrical osteochondral defects. For this investigation, an osteochondral defect (6 mm in diameter and 8 mm deep) was created in the weight-bearing articular surface of the femoral medial condyle in beagles. Bone marrow was aspirated from the posterior iliac crests of beagles to obtain mesenchymal stem cells (MSCs) for in vitro assay. Hematoxylin and eosin (HE), Massons trichrome (MT), safranin O/fast green staining, and immunohistochemistry were performed for histological analysis. Quantitative real-time polymerase chain reaction was performed to understand the roles of BMC in chondrogenic differentiation of MSCs. At 12 weeks after transplantation of biphasic scaffolds, we observed that interleukin-8 (IL-8) or the combination of IL-8 and BMC induced massive bone regeneration compared to saline, BMC only, and MSCs. In gross appearance, the osteochondral defect site was nearly completely filled with repair tissue in the group that received the combination of IL-8 and BMC but not in the other groups. Moreover, histological analysis showed obvious differences in cartilage regeneration among groups. HE and MT staining showed that the cartilage defect sites of the group receiving the combination of IL-8 and BMC were regenerated with cartilage-like tissues showing chondrocyte morphology. Safranin O staining showed hyaline cartilage regeneration in the group receiving IL-8 and BMC, whereas fibrous-like tissues were formed in the other groups. Furthermore, immunostaining revealed the presence of type II collagen and aggrecan in regenerated cartilage tissue of the group receiving IL-8 and BMC, whereas regenerated cartilage tissues of the other groups weakly expressed type II collagen and aggrecan. These results indicate that the combination of a chemokine IL-8 and BMC has significant positive effects on osteochondral regeneration in a beagle model through enhancing expression of the chondrogenic transcription factors and markers such as Sox9 and type II collagen.

OK-432 Sclerotherapy for Malleolar Bursitis of the Ankle

Background: The purpose of this study was to evaluate the clinical outcomes and usefulness of OK-432 (Picibanil) sclerotherapy as a new option in the conservative treatment of patients with malleolar bursitis of the ankle. Methods: Retrospectively, we reviewed a total of 20 consecutive patients (20 feet) in whom OK-432 sclerotherapy had been performed between March 2009 and June 2010. After aspiration of fluid in the malleolar bursal sac, 0.05 mg of OK-432 was injected into the malleolar bursal sac. We evaluated the clinical outcomes and side effects at the following time points: 2 weeks, 1 month, 3 months, 6 months, and 1 year after OK-432 sclerotherapy. The responses to the treatment were assessed according to the degree of fluctuation, shrinkage of the bursal sac, and soft tissue swelling. Results: Complete resolution was observed in 19 patients (95%) after the first or second application of OK-432 sclerotherapy, and a partial response was observed in 1 patient (5%) after a second application of OK-432 sclerotherapy. The physical component scores of SF-36 improved from 70.0 ± 6.8 to 76.5 ± 7.3 at the last follow-up (P = .0002). Conclusion: OK-432 sclerotherapy was a useful procedure for patients not responding to the usual conservative treatment of malleolar bursitis of the ankle. Level of Evidence: Level IV, retrospective case series.

Effects of structurally stabilized EGF and bFGF on wound healing in type I and type II diabetic mice

Diabetes mellitus comprises a multiple metabolic disorder that affects millions of people worldwide and consequentially poses challenges for clinical treatment. Among the various complications, diabetic ulcer constitutes the most prevalent associated disorder and leads to delayed wound healing. To enhance wound healing capacity, we developed structurally stabilized epidermal growth factor (ST-EGF) and basic fibroblast growth factor (ST-bFGF) to overcome limitations of commercially available EGF (CA-EGF) and bFGF (CA-bFGF), such as short half-life and loss of activity after loading onto a matrix. Neither ST-EGF nor ST-bFGF was toxic, and both were more stable at higher temperatures than CA-EGF and CA-bFGF. We loaded ST-EGF and ST-bFGF onto a hyaluronate-collagen dressing (HCD) matrix, a biocompatible carrier, and tested the effectiveness of this system in promoting wound healing in a mouse model of diabetes. Wounds treated with HCD matrix loaded with 0.3 μg/cm2 ST-EGF or 1 μg/cm2 ST-bFGF showed a more rapid rate of tissue repair as compared to the control in type I and II diabetes models. Our results indicate that an HDC matrix loaded with 0.3 μg/cm2 ST-EGF or 1 μg/cm2 ST-bFGF can promote wound healing in diabetic ulcers and are suitable for use in wound dressings owing to their stability for long periods at room temperature. STATEMENT OF SIGNIFICANCE Various types of dressing materials loaded with growth factors, such as VEGF, EGF, and bFGF, are widely used to effect wound repair. However, such growth factor-loaded materials have several limitations for use as therapeutic agents in healing-impaired diabetic wounds. To overcome these limitations, we have developed new materials containing structurally stabilized EGF (ST-EGF) and bFGF (ST-bFGF). To confirm the wound healing capacity of newly developed materials (ST-EGF and ST-bFGF-loaded hyaluronate-collagen dressing [HCD] matrix), we applied these matrices in type I and type II diabetic wounds. Notably, these matrices were able to accelerate wound healing including re-epithelialization, neovascularization, and collagen deposition. Consequentially, these ST-EGF and ST-bFGF-loaded HCD matrix may be used as future therapeutic agents in patients with diabetic foot ulcers.

Inhibition of miR-449a Promotes Cartilage Regeneration and Prevents Progression of Osteoarthritis in In Vivo Rat Models

Traumatic and degenerative lesions of articular cartilage usually progress to osteoarthritis (OA), a leading cause of disability in humans. MicroRNAs (miRNAs) can regulate the differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) and play important roles in the expression of genes related to OA. However, their functional roles in OA remain poorly understood. Here, we have examined miR-449a, which targets sirtuin 1 (SIRT1) and lymphoid enhancer-binding factor-1 (LEF-1), and observed its effects on damaged cartilage. The levels of chondrogenic markers and miR-449a target genes increased during chondrogenesis in anti-miR-449a-transfected hBMSCs. A locked nucleic acid (LNA)-anti-miR-449a increased cartilage regeneration and expression of type II collagen and aggrecan on the regenerated cartilage surface in acute defect and OA models. Furthermore, intra-articular injection of LNA-anti-miR-449a prevented disease progression in the OA model. Our study indicates that miR-449a may be a novel potential therapeutic target for age-related joint diseases like OA.

Arthroscopic Bone Marrow Stimulation in the Treatment of Osteochondral Lesions of the Talus: Outcomes Over Ten Years of Follow-up

Category: Arthroscopy Introduction/Purpose: Arthroscopic bone marrow stimulation for osteochondral lesions of the talus (OLT) has presented promising clinical outcomes in recent studies. However, there were few studies which had investigated long-term clinical outcomes. The purpose of this study is to evaluate the long-term outcomes of arthroscopic bone marrow stimulation for osteochondral lesion of the talus and to identify prognostic factors that affect the outcome. Methods: Between January 2001 and December 2007, 159 patients (172 ankles) with OLT underwent arthroscopic bone marrow stimulation as a primary surgery. Clinical outcomes were assessed using visual analog scale (VAS), American Orthopaedic Foot & Ankle Society (AOFAS) scores, Foot and Ankle Outcome Score (FAOS) and re-operation rate. Factors associated with re-operation were evaluated using bivariate analysis. Kaplan-Meier plot showed survival outcomes of OLT in long-term follow-up. Results: The mean follow-up time was 12.7 years (range 10.1-16.8) and the mean size of the lesion was 105.4 mm2 (range 19.8- 322.8). The mean VAS improved from 7.21 ± 1.71 to 1.76 ± 1.60. The mean preoperative AOFAS score was 57.98 ±14.43 and the mean postoperative AOFAS was 82.91 ± 11.58. FAOS at the time of final follow-up was comparable with those of previous literatures which showed outcomes of surgical treatments of OLT in short- and mid-term follow-up. Re-operation rate was 6.40% (11 patients with 12 revision surgery) including seven cases of re-arthroscopic bone marrow stimulation, and five cases of OAT. According to bivariate analysis, significant factor associated with re-operation was large sized OLT in preoperative MRI measurement. Conclusion: Arthroscopic bone marrow stimulation for osteochondral lesion of the talus has made satisfactory clinical outcomes through long-term follow-up over 10 years.

Long-term evaluation of Primary Osteochondral Autograft Transfer System (OATS) for large cystic type osteochondral lesion of talus

Category: Ankle Introduction/Purpose: Osteochondral lesions of talus (OLTs) are often treated primarily by fragment excision, abrasion, drilling, or microfracture. However, OLT accompanying with large cyst has been challenged to yield good outcome nevertheless of many surgical options. Recent study showed significant high failure rate of arthroscopic marrow stimulation treatment larger than 150mm2. The current study is to investigate the outcome of the primary osteochondral autograft transfer system (OATS) for large cystic type OLT (>150mm2). Methods: This retrospective analysis included 19 talus (19 patients) with diagnosed large cystic type OLT (>150mm2) who received primary OATS between September 2009 and March 2013. Defect size area was measured on magnetic resonance imaging (MRI) by the ellipse formula from coronal and sagittal length. The patients completed the visual analog scale (VAS) and the American Orthopaedic Foot & Ankle Society (AOFAS) score preoperatively and at follow-up. Plain radiographs were used to show the improvement of radiolucency postoperatively. Results: The mean follow up period was 83.9 months (57 – 99) and the average defect size area was 169.4 mm2 (151.3 – 392.6). The Mean VAS score decreased from 6.95 preoperatively to 2.6 postoperatively. Average AOFAS score improved from 66.8 preoperatively to 88.7 postoperatively. Eighty percent of patients rated their result excellent or good. The radiolucent area of the cysts disappeared on the plain radiographs in all cases. Conclusion: Long-term clinical results of primary OATS in large cystic type OLT showed good outcomes and patients could significantly benefit from this surgery.

Enhanced articular cartilage regeneration with SIRT1-activated MSCs using gelatin-based hydrogel

To investigate the functional effects of resveratrol (RSV) on mesenchymal stem cells (MSCs), we treated MSCs with RSV continuously during ex vivo expansion. MSCs were continuously treated with RSV from passage (P) 0 to P5. A proliferative capacity of RSV-treated MSCs was higher than that of non-treated MSCs and similar with P1-MSCs. Continuous treatment of RSV on MSCs increased the stemness and inhibited the senescence. During chondrogenic differentiation in vitro, RSV-treated MSCs had higher differentiation potential and reduced hypertrophic maturation, which are limitations for hyaline cartilage formation. The histological analysis of micromass demonstrated increased chondrogenic differentiation potential. We further explored the therapeutic effectiveness of this method in a rabbit osteochondral defect model. A rabbit osteochondral defect model was established to investigate the hyaline cartilage regeneration potential of RSV-treated MSCs. Moreover, the cartilage regeneration potential of RSV-treated MSCs was greater than that of untreated MSCs. The expression levels of chondrogenic markers increased and those of hypertrophic markers decreased in RSV-treated MSCs compared with untreated MSCs. Sustained treatment of RSV on MSCs during ex vivo expansion resulted in the maintenance of stemness and enhanced chondrogenic differentiation potential. Consequentially, highly efficient MSCs promoted superior hyaline cartilage regeneration in vivo. This novel treatment method provides a basis for cell-based tissue engineering.

Primary Versus Secondary Osteochondral Autograft Transplantation for the Treatment of Large Osteochondral Lesions of the Talus

Background: Recent studies have reported promising clinical results after osteochondral autograft transplantation (OAT) for the treatment of large osteochondral lesions of the talus (OLT). However, no study has yet compared clinical outcomes between primary and secondary OAT for large OLT. Purpose: To compare clinical outcomes among patients with large OLT who receive primary OAT versus those who receive secondary OAT after failure of marrow stimulation and to identify factors associated with clinical failure. Study Design: Cohort study; Level of evidence, 3. Methods: From 2005 to 2014, 46 patients with large OLT (≥150 mm2) underwent OAT: 18 underwent OAT as initial surgical management (primary OAT group), and 28 patients underwent secondary OAT after failure of previous arthroscopic marrow stimulation (secondary OAT group). In both groups, OAT procedures included arthroscopic inspection and debridement of concomitant soft tissue injuries. Clinical outcomes were assessed using pain visual analog scale (VAS), the Roles and Maudsley score, Foot and Ankle Outcome Scores (FAOS), and revisional surgery rates. Factors associated with clinical failures were evaluated using bivariate and logistic regression analyses. Survival outcomes were compared using Kaplan-Meier analysis. Results: Mean follow-up time was 6 years (range, 2-10.8 years). Mean lesion size was 194.9 mm2 (range, 151.7-296.3 mm2). There were no significant differences between groups in patient demographics and preoperative findings. Postoperative pain VAS, Roles and Maudsley score, FAOS, and revisional surgery rates were not significantly different at last follow-up. Prior marrow stimulation was not significantly associated with clinical failure on bivariate analysis. Lesion size greater than 225 mm2 on preoperative magnetic resonance imaging was significantly associated with clinical failure. Survival probabilities from Kaplan-Meier plots were not significantly different between the primary and secondary OAT groups (P = .947). Conclusion: Clinical outcomes of patients with large OLT treated with secondary OAT after failed marrow stimulation were found to be comparable with those who were treated with primary OAT. These results may be helpful to orthopaedic surgeons deciding appropriate surgical options for patients with large OLT.

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.