Michigan Initiative for Anterior Cruciate Ligament Rehabilitation (MiACLR): A Protocol for a Randomized Clinical Trial.

OBJECTIVE: Restoring quadriceps muscle strength following anterior cruciate ligament reconstruction (ACLR) may prevent the posttraumatic osteoarthritis that affects over 50% of knees with ACLR. However, a fundamental gap exists in our understanding of how to maximize muscle strength through rehabilitation. Neurological deficits and muscle atrophy are 2 of the leading mechanisms of muscle weakness after ACLR. High-intensity neuromuscular electrical stimulation (NMES) and eccentric exercise (ECC) have been shown to independently target these mechanisms. If delivered in succession, NMES and then ECC may be able to significantly improve strength recovery. The objectives of this study were to evaluate the ability of NMES combined with ECC to restore quadriceps strength and biomechanical symmetry and maintain cartilage health at 9 and 18 months after ACLR. METHODS: This study is a randomized, double-blind, placebo-controlled, single-center clinical trial conducted at the University of Michigan. A total of 112 participants between the ages of 14 and 45 years and with an anterior cruciate ligament rupture will be included. Participants will be randomly assigned 1:1 to NMES combined with ECC or NMES placebo combined with ECC placebo. NMES or NMES placebo will be delivered 2 times per week for 8 weeks beginning 10 to 14 days postoperatively and will be directly followed by 8 weeks of ECC or ECC placebo delivered 2 times per week. The co-primary endpoints are change from baseline to 9 months and change from baseline to 18 months after ACLR in isokinetic quadriceps strength symmetry. Secondary outcome measures include isometric quadriceps strength, quadriceps activation, quadriceps muscle morphology (cross-sectional area), knee biomechanics (sagittal plane knee angles and moments), indexes of patient-reported function, and cartilage health (T1ρ and T2 relaxation time mapping on magnetic resonance imaging). IMPACT: The findings from this study might identify an intervention capable of targeting the lingering quadriceps weakness after ACLR and in turn prevent deterioration in cartilage health after ACLR, thereby potentially improving function in this patient population.

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone.

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non-OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low-dose SclAb (TRL, 2.5 µg/mL), or high-dose SclAb (TRH, 25 µg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using µCT and histomorphometry. Expression of Wnt/Wnt-related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone-forming response to SclAb via µCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients' genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision-making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Combination of eccentric exercise and neuromuscular electrical stimulation to improve quadriceps function post-ACL reconstruction.

BACKGROUND: Neuromuscular electrical stimulation (NMES) has been shown to reduce quadriceps activation failure (QAF), and eccentric exercise has been shown to lessen muscle atrophy post-ACL reconstruction. Given that these are two critical components of quadriceps strength, intervention combining these therapies may be effective at reinstituting quadriceps function post-reconstruction. Thus, the aim of this study was to evaluate the effectiveness of a combined NMES and eccentric exercise intervention to improve the recovery of quadriceps activation and strength post-reconstruction. METHODS: Thirty-six individuals post-injury were placed into four treatment groups (N&E, NMES and eccentrics; E-only, eccentrics only; N-only, NMES-only; and STND, standard of care) and ten healthy controls participated. N&E and N-only received the NMES protocol 2× per week for the first 6 weeks post-reconstruction. N&E and E-only received the eccentric exercise protocol 2× per week beginning 6 weeks post-reconstruction. Quadriceps activation was assessed via the superimposed burst technique and quantified via the central activation ratio. Quadriceps strength was assessed via maximal voluntary isomeric contractions (Nm/kg). Data was gathered on three occasions: pre-operative, 12-weeks-post-surgery and at return-to-play. RESULTS: No differences in pre-operative measures existed (P>0.05). E-only recovered quadriceps activation better than N-only or STND (P<0.05). N&E and E-only recovered strength better than N-only or the STND (P<0.05) and had strength values that were similar to healthy at return-to-play (P>0.05). CONCLUSION: Eccentric exercise was capable of restoring levels of quadriceps activation and strength that were similar to those of healthy adults and better than NMES alone. LEVEL OF EVIDENCE: Level 3, Parallel longitudinal study.