Repair potential of self-assembling peptide hydrogel in a mouse model of anterior cruciate ligament reconstruction.

Purpose: Establishing zonal tendon-to-bone attachment could accelerate the anterior cruciate ligament reconstruction (ACLR) rehabilitation schedule and facilitate an earlier return to sports. KI24RGDS is a self-assembling peptide hydrogel scaffold (SAPS) with the RGDS amino acid sequence. This study aimed to elucidate the therapeutic potential of KI24RGDS in facilitating zonal tendon-to-bone attachment after ACLR. Methods: Sixty-four C57BL/6 mice were divided into the ACLR + SAPS and ACLR groups. ACLR was performed using the tail tendon. To assess the maturation of tendon-to-bone attachment, we quantified the area of mineralized fibrocartilage (MFC) in the tendon graft with demeclocycline. Immunofluorescence staining of α-smooth muscle actin (α-SMA) was performed to evaluate progenitor cell proliferation. The strength of tendon-to-bone attachment was evaluated using a pull-out test. Results: The MFC and maximum failure load in the ACLR + SAPS group were remarkably higher than in the ACLR group on Day 14. However, no significant difference was observed between the two groups on Day 28. The number of α-SMA-positive cells in the tendon graft was highest on Day 7 after ACLR in both the groups and was significantly higher in the ACLR + SAPS group than in the ACLR group. Conclusion: This study highlighted the latent healing potential of KI24RGDS in facilitating early-stage zonal attachment of tendon grafts and bone tunnels post-ACLR. These findings may expedite rehabilitation protocols and shorten the timeline for returning to sports. Level of Evidence: Not applicable.

Targeting the hedgehog signaling pathway to improve tendon-to-bone integration.

OBJECTIVE: While the role of hedgehog (Hh) signaling in promoting zonal fibrocartilage production during development is well-established, whether this pathway can be leveraged to improve tendon-to-bone repair in adults is unknown. Our objective was to genetically and pharmacologically stimulate the Hh pathway in cells that give rise to zonal fibrocartilaginous attachments to promote tendon-to-bone integration. DESIGN: Hh signaling was stimulated genetically via constitutive Smo (SmoM2 construct) activation of bone marrow stromal cells or pharmacologically via systemic agonist delivery to mice following anterior cruciate ligament reconstruction (ACLR). To assess tunnel integration, we measured mineralized fibrocartilage (MFC) formation in these mice 28 days post-surgery and performed tunnel pullout testing. RESULTS: Hh pathway-related genes increased in cells forming the zonal attachments in wild-type mice. Both genetic and pharmacologic stimulation of the Hh pathway increased MFC formation and integration strength 28 days post-surgery. We next conducted studies to define the role of Hh in specific stages of the tunnel integration process. We found Hh agonist treatment increased the proliferation of the progenitor pool in the first week post-surgery. Additionally, genetic stimulation led to continued MFC production in the later stages of the integration process. These results indicate that Hh signaling plays an important biphasic role in cell proliferation and differentiation towards fibrochondrocytes following ACLR. CONCLUSION: This study reveals a biphasic role for Hh signaling during the tendon-to-bone integration process after ACLR. In addition, the Hh pathway is a promising therapeutic target to improve tendon-to-bone repair outcomes.

Sonographic evaluation of the abductor pollicis brevis muscle reflects muscle strength recovery after carpal tunnel release.

PURPOSE: This study aimed to examine the associations between sonographic measurements of the abductor pollicis brevis (APB), grip and pinch strength, and distal motor latency (DML) in patients with carpal tunnel syndrome (CTS) before and after surgery. METHODS: We prospectively studied patients (46 hands) who underwent 1 year of postoperative follow-up after endoscopic carpal tunnel release. The patients underwent ultrasound (US) scans, grip and pinch strength assessment, a nerve conduction study, and patient-reported outcome measures (Carpal Tunnel Syndrome Instrument and Michigan Hand Outcomes Questionnaire) before and 1 year after surgery. The standardized response mean was calculated to compare the sensitivity of clinical changes in these measurements. RESULTS: US measurements (thickness of the APB and the cross-sectional area of the APB) and muscle strength (grip strength, key pinch, and tip pinch) were greater, and DML was reduced after surgery compared with those before surgery (all P < 0.05). Patient-reported outcome measures also showed clinical improvement 1 year after surgery (P < 0.05). US measurements of the APB were significantly correlated with grip and pinch strength (all P < 0.05), but not with DML, before surgery and 1 year after surgery. The standardized response mean showed a large responsiveness for US measurements of the APB and patient-reported outcome measures. CONCLUSION: US evaluation of the APB after CTS can complement the evaluation of grip and pinch strength in the clinical setting. Postoperative recovery of the APB leads to improved motor dysfunction in CTS. Therefore, US measurement of the APB could be a useful tool for evaluating motor function.

Impairment and restoration of the blood-nerve barrier and its correlation with pain following gradual nerve elongation of the rat sciatic nerve.

Purpose: This study aimed to evaluate the time course of impairment and restoration of the blood-nerve barrier (BNB) following gradual elongation of the sciatic nerve and to clarify its association with nociception.Materials and Methods: The right femur was lengthened at a rate of 1.5 mm/day for 10 days. Von Frey tests were performed until 50 days after lengthening. Compound muscle action potentials (CMAPs) were measured to assess gross dysfunction of the elongated nerve. Evans blue-albumin tracing and immunohistochemistry for endothelial barrier antigen (EBA), rat endothelial cell antigen-1 (RECA-1), and CD68 for qualitative and quantitative analysis of the BNB and macrophage infiltration were performed for up to 50 days after cessation of lengthening in three segments of the sciatic nerves.Results: Paw-withdrawal threshold was significantly decreased at 7 days from initiation and began to recover from day 25 after lengthening. CMAPs showed delayed latency and attenuated amplitude but recovered at day 30 after cessation. On days 10 and 30 after cessation, spotted leakage of Evans blue-albumin in the endoneurium was observed, and the ratio of EBA/RECA-1-positive microvessels was significantly decreased, which subsequently recovered simultaneously in all segments on day 50 after cessation. Macrophages did not infiltrate the BNB at any time point.Conclusion: The restoration of BNB function following gradual nerve elongation was associated with the resolution of mechanical allodynia. Our findings provide insight into the association between nerve stretch injury and chronic nociception in adult male rats, which are potentially relevant to human orthopedic procedures and chronic neuropathic pain.

Amplifying Bone Marrow Progenitors Expressing α-Smooth Muscle Actin Produce Zonal Insertion Sites During Tendon-to-Bone Repair.

Traditional tendon-to-bone repair where the tendon is reattached to bone via suture anchors often results in disorganized scar production rather than the formation of a zonal insertion. In contrast, ligament reconstructions where tendon grafts are passed through bone tunnels can yield zonal tendon-to-bone attachments between the graft and adjacent bone. Therefore, ligament reconstructions can be used to study mechanisms that regulate zonal tendon-to-bone repair in the adult. Anterior cruciate ligament (ACL) reconstructions are one of the most common reconstruction procedures and while we know that cells from outside the graft produce the attachments, we have not yet established specific cell populations that give rise to this tissue. To address this knowledge gap, we performed ACL reconstructions in lineage tracing mice where α-smooth muscle actin (αSMACreERT2) was used to label αSMA-expressing progenitors within the bone marrow that produced zonal attachments. Expression of αSMA was increased during early stages of the repair process such that the contribution of SMA-labeled cells to the tunnel integration was highest when tamoxifen was delivered in the first week post-surgery. The zonal attachments shared features with normal entheses, including tidemarks oriented perpendicularly to collagen fibers, Col1a1-expressing cells, alkaline phosphatase activity, and proteoglycan-rich staining. Finally, the integration strength increased with time, requiring 112% greater force to remove the graft from the tunnel at 28 days compared with 14 days post-surgery. Future studies will target these progenitor cells to define the pathways that regulate zonal tendon-to-bone repair in the adult. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:105-116, 2020.

Sonographic morphometry of abductor pollicis brevis: can direct contact yield images comparable with those obtained by the water bath technique?

PURPOSE: This study sought to compare ultrasound-guided measurements of the abductor pollicis brevis (APB) using the water bath technique (WBT) and the direct contact method (DM) and investigate whether the DM can reproduce the measurements that would be obtained with a non-contact method, such as the WBT. METHODS: The APB muscles of 80 hands (40 healthy adults) were measured. The WBT was performed in a plastic container filled with water. The probe was placed adjacent to the skin surface without contact. In the DM, sonographic images were obtained with the probe and skin separated by sufficient transmission gel. The muscle thickness and cross-sectional area (CSA) were calculated with both methods. All subjects were examined three times by two examiners to estimate the inter- and intra-observer reliability. Bland-Altman analysis was performed to examine the agreement between the methods. RESULTS: No significant differences in the thickness or CSA of the APB were found. The interclass correlation coefficients for the WBT and DM showed almost perfect intra- and inter-observer reliability (range 0.87-0.94). There was no systematic bias between the techniques in the Bland-Altman analysis. CONCLUSION: Similar to the WBT, the DM provides measurements of the APB thickness and CSA without causing morphometric changes.

Sonographic monitoring of endoscopic carpal tunnel release.

We evaluated the effectiveness of sonographic monitoring of endoscopic carpal tunnel release for the prevention of median nerve or arterial injury and incomplete release of the flexor retinaculum (FR). When the outer tube (OT) was inserted, we used sonography to confirm the relationship of the OT, median nerve, ulnar artery, and superficial palmar arch. Under real-time US monitoring, the OT was lifted up before and after FR release, the so-called lift-up test, to evaluate its mobility under sonography and confirm complete FR release. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:597-599, 2016.