Faculty Bibliography

OBJECTIVE:Joint destruction in Charcot neuroarthropathy (CNA) is accompanied with abundant hyperplastic synovium. This study aimed to characterize the expression patterns of a group of neuropeptides in the CNA synovium. METHODS:Synovial specimens were collected during surgery from the CNA (n = 6) and non-CNA joints (n = 14). Tissue samples were processed for protein extraction and western blot for vasoactive intestinal peptide (VIP), galanin, and calcitonin gene-related peptide (CGRP). Immunohistochemistry was performed to localize CGRP in the CNA synovium. Additionally, CGRP was applied to fibroblast-like synoviocytes (FLS) isolated from CNA synovium for its effects on cell proliferation and collagenolysis in vitro. RESULTS:Western blot detected light bands of VIP in the CNA samples but abundant galanin in both CNA and non-CNA samples. Most of the CNA samples (5/6) increased expression of CGRP, with an average band density about 2 times that in the non-CNA group (p < .05). Immunohistochemistry of CGRP demonstrated intense staining in the intimal layer of the CNA synovium. In tissue culture, adding CGRP (10 nM) in the medium promoted FLS proliferation. In combination with TNF-α, CGRP enhanced FLS-mediated collagenolysis in vitro. CONCLUSION:This study revealed an increased expression of CGRP in the CNA synovium and demonstrated that CGRP regulates FLS proliferation and collagenolytic activity, suggesting CGRP may contribute to the bone and cartilage destruction in CNA.

OBJECTIVE:The aim of this study was to evaluate the association between 4-dimensional computed tomography (4DCT)-derived measurements of tibiofibular syndesmosis during active dorsiflexion-plantarflexion motion and the presence of tibiotalar osteoarthritis (OA). METHODS:Sixteen ankle joints underwent 4DCT imaging during active dorsiflexion-plantarflexion. Syndesmotic anterior distance (SAD) and syndesmotic translation (ST) were obtained by a foot-and-ankle surgeon. We used Kellgren-Lawrence (KL) grading to determine tibiotalar OA. RESULTS:Of 16 scanned ankles, 12 ankles had KL ≥2 at the tibiotalar joint. In these ankles, SAD (-0.4, P = 0.02) and ST (-0.9, P = 0.006) measurements significantly changed during the dorsiflexion-plantarflexion motion. Changes in SAD measurements were significantly correlated with the KL grades (correlation coefficient: -0.688, P = 0.003); however, the changes in ST measurements were not significantly correlated with the KL grade. CONCLUSIONS:Our exploratory cross-sectional analysis shows that SAD measurement changes during motion using 4DCT are correlated with the tibiotalar OA grading. This measurement may be used but requires confirmation in larger studies including patients with actual syndesmotic injuries.

BACKGROUND:The evidence supporting best practice guidelines in the field of cartilage repair of the ankle is based on both low quality and low levels of evidence. Therefore, an international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to report the consensus statements on "terminology for osteochondral lesions of the ankle" developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS:Forty-three international experts in cartilage repair of the ankle representing 20 countries were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within four working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed, and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held, and the strength of consensus was characterised as follows: consensus, 51%-74%; strong consensus, 75%-99%; unanimous, 100%. RESULTS:A total of 11 statements on terminology and classification reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. Definitions are provided for osseous, chondral and osteochondral lesions, as well as bone marrow stimulation and injury chronicity, among others. An osteochondral lesion of the talus can be abbreviated as OLT. CONCLUSIONS:This international consensus derived from leaders in the field will assist clinicians with the appropriate terminology for osteochondral lesions of the ankle.

OBJECTIVE:Biologics are increasingly used for cartilage repair and osteoarthritis (OA) treatment. This study aimed to provide an overview of the clinical trials conducted on this subject. DESIGN:Two-word combinations of two sets of key words "cartilage"; "joint"; "osteoarthritis" and "biologics"; "stem cells"; "cell implantation" were used to search the database of ClinicalTrials.gov and supplemented with searches of PubMed and EMbase. The registered trials were analyzed for clinical conditions, completion status, phases, and investigated biologics. Recently completed trials with posted/published results were summarized. RESULTS:From 2000 to 2022, a total of 365 clinical trials were registered at ClinicalTrials.gov to use biologics for cartilage repair and OA treatment. Since 2006, the number of registered trials accelerated at an annual rate of 16.4%. Of the 265 trials designated with a phase, 72% were early Phase 1, Phase 1, and Phase 2. Chondrocytes and platelet-rich plasma (PRP) were studied in nearly equal number of early- and late-stage trials. Mesenchymal stem/stromal cells (MSCs) were the most commonly investigated biologics (38%) and mostly derived from bone marrow and adipose tissue (70%). In last 5 years, 32 of the 72 completed trials posted/published results, among which seven Phase 3 trials investigated chondrocytes, PRP, bone marrow aspirate concentrate, hyaluronic acid, collagen membrane, and albumin. CONCLUSIONS:There was a rapid increase in the number of registered clinical trials in recent years, using a variety of biologics for cartilage repair and OA treatment. Majority of the biologics still require late-stage trials to validate their clinical effectiveness.

BACKGROUND:An international consensus group of experts was convened to collaboratively advance toward consensus opinions based on the best available evidence on key topics within cartilage repair of the ankle. The purpose of this article is to present the consensus statements on osteochondral lesions of the tibial plafond (OLTP) and on ankle instability with ankle cartilage lesions developed at the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. METHODS:Forty-three experts in cartilage repair of the ankle were convened and participated in a process based on the Delphi method of achieving consensus. Questions and statements were drafted within 4 working groups focusing on specific topics within cartilage repair of the ankle, after which a comprehensive literature review was performed and the available evidence for each statement was graded. Discussion and debate occurred in cases where statements were not agreed on in unanimous fashion within the working groups. A final vote was then held. RESULTS:A total of 11 statements on OLTP reached consensus. Four achieved unanimous support and 7 reached strong consensus (greater than 75% agreement). A total of 8 statements on ankle instability with ankle cartilage lesions reached consensus during the 2019 International Consensus Meeting on Cartilage Repair of the Ankle. One achieved unanimous support, and seven reached strong consensus (greater than 75% agreement). CONCLUSION:These consensus statements may assist clinicians in the management of these difficult clinical pathologies. LEVEL OF EVIDENCE:Level V, mechanism-based reasoning.

BACKGROUND:Achilles tendinopathy is a common cause of posterior ankle and heel pain in both active and sedentary patients. Though the majority of patients respond to first-line non-operative management including activity modification, immobilization, orthotics, and physical therapy with stretching and eccentric strengthening, there is no consensus for patients who fail these treatments. We evaluate the role of iliac crest bone marrow aspirate (BMA) injections as a treatment option for recalcitrant cases. METHODS:A retrospective chart review was conducted of patients with refractory Achilles tendinopathy treated with iliac crest BMA concentrate injection. Symptoms were assessed using the numeric rating system (NRS) pain score at the pre-operative visit and at six, 12, 24, and 48 weeks postoperatively. Post-operative complications were recorded. RESULTS:(range, 18.4 to 34.4), and average duration of symptoms prior to BMA injection was 2.3 years (range, 1 to 7). Pre-operatively, average NRS was 6.26 (95% CI, 5.04 to 7.49), with significant improvement at six weeks (mean, 4.26; 95% CI, 2.94 to 5.59; p = 0.04), ten weeks (mean, 4.13; 95% CI, 2.91 to 5.35; p = 0.012), 24 weeks (mean, 3.40; 95% CI, 2.05 to 4.75; p = 0.03), and 48 weeks (mean, 2.60; 95% CI, 1.14 to 4.06; p = 0.007) post-operatively. Overall, there was trending improvement over the 48-week follow-up period, with a mean improvement in NRS of - 3.22 (95% CI, - 1.06 to - 5.38; p = 0.007) at final follow-up. There was no discernable difference between insertional and non-insertional tendinopathy, and there were no incidences of post-operative complications. CONCLUSION/CONCLUSIONS:Iliac crest BMA appears to be a safe, effective, and potentially lasting treatment option for patients with intractable, insertional and non-insertional Achilles tendinopathy. Patients demonstrated and maintained statistically significant decrease in NRS pain score post-operatively with no complications at the donor or injection site.

Foot fat pad (FFP) is a highly functionalized fat depot of great significance for weight bearing in the foot. Mesenchymal stromal cells (MSCs) in subcutaneous adipose tissues are widely studied for regenerative potentials. MSCs in FFP, which may contribute to the physiological and pathological conditions of the foot, have not been characterized. In this study, MSCs were isolated from FFP (designated as MSCs-ffp) and subcutaneous adipose tissue (designated as MSCs-sub) from rats. The cell surface markers, proliferation, and efficiency of colony formation were compared between MSCs-ffp and MSCs-sub. In addition, MSCs-ffp were induced for osteogenic, chondrogenic, and adipogenic differentiation. The tri-lineage differentiation potentials were compared between MSCs-ffp and MSCs-sub by the expression of Runx2, Sox9, and proliferator-activated receptor gamma (PPAR-γ), respectively, using quantitative polymerized chain reaction. The expression of elastin and associated genes by MSCs-ffp were also evaluated. MSCs-ffp, like MSCs-sub, expressed CD44, CD73, and CD90. MSCs-ffp and MSCs-sub proliferated at similar rates but MSCs-ffp formed more colonies than MSCs-sub. MSCs-ffp were capable of differentiating into osteogenic, chondrogenic, and adipogenic lineages. Under the conditions of osteogenic and adipogenic differentiation, MSCs-sub expressed more Runx2 and PPAR-γ, respectively, than MSCs-ffp. The undifferentiated MSCs-ffp upregulated the expression of fibulin-5. In conclusion, MSCs-ffp shared common biology with MSCs-sub but were more efficient in colony formation, less adipogenic and osteogenic, and participated in elastogenesis. The unique features of MSCs-ffp may relate to their roles in the physiological functions of FFP.

Level V, clinical tips.