Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

High tibial osteotomy combined with cartilage restoration: A systematic review of clinical outcomes and prognostic factors.

Background: Focal chondral defects are often treated with cartilage restoration procedures. Malalignment often accompanies chondral defects. High tibial osteotomy (HTO), classically utilized to treat uni-compartmental knee osteoarthritis, corrects malalignment. HTO combined with cartilage restoration procedures can treat uni-compartmental osteoarthritis and focal chondral defects. Purpose: To assess outcomes of combined HTO and cartilage restoration procedures and review prognostic factors that may assist in preoperative planning and patient counseling. Study design: Systematic Review of published literature. Methods: A systematic review of PubMed and Scopus was performed following PRISMA guidelines. Thirty-four papers were included in qualitative considerations. Results: Thirty-four papers that reported the combined outcome of HTO and cartilage repair were included. Twenty of the 34 included papers reported prognostic factors that affected the success or failure of combined HTO and cartilage repair surgery for focal articular defect and uni-compartmental knee osteoarthritis. Cartilage repair techniques that were combined with HTO and included in this review are bone marrow stimulation, allograft transplantation, osteochondral autograft transplantation, autologous chondrocyte implantation, and mesenchymal stem cell implantation. Conclusions: HTO with adjunctive cartilage repair procedures improve clinical outcome scores and restore alignment in patients with medial compartment osteoarthritis and isolated focal chondral defects. HTO with adjunctive cartilage procedures produces optimal results in younger, non-obese patients with focal chondral defects and varus malalignment, without significant lateral compartment and patellofemoral involvement.

Successful Return to Sport and Daily Activities After Suture Augmentation of Both the Anterior Talofibular Ligament and Calcaneofibular Ligament.

Purpose: To evaluate the return to sport and daily activities in addition to clinical outcomes after modification of the Brostöm repair, specifically using suture augmentation for concomitant fixation of both the anterior talofibular ligament and calcaneofibular ligament. Methods: Patients who had grade III ankle sprains and lateral ankle instability, all of whom failed supervised conservative management, were included. Patients underwent a modified Broström procedure consisting of suture augmentation for both the anterior talofibular ligament and calcaneofibular ligament. For clinical outcome evaluation, Foot and Ankle Ability Measure (FAAM) and Karlsson-Peterson Scoring System for Ankle Function questionnaires coupled with questions regarding time of return to sport and level of sports activity were used. Results: Thirty-one patients were included. The differences in preoperative and postoperative FAAM scores for both the Activities of Daily Living subscale and Sports subscale were significant (P < .001). The FAAM Activities of Daily Living score improved from an average of 46.06 preoperatively to 77.49 postoperatively (P < .001, 99% confidence interval, 26.4-36.4). The FAAM Sports score improved from an average of 4 preoperatively to 19.31 postoperatively (P < .001, 99% confidence interval, 11.6-19.0). For the Karlsson-Peterson Scoring System for Ankle Function, the surveyed population reported a mean of 82.74 points out of 100 post-op (standard deviation 20.14). The mean time to return to sport activity was 5.72 months. Mean follow-up time was 24.12 months. Conclusions: This variant Broström procedure with suture anchors and augmentation of both the anterior talofibular ligament and calcaneofibular ligament was effective in helping patients return to their preinjury functionality level in both daily life and sports activity. Level of Clinical Evidence: Level IV, therapeutic case series.

Accuracy of radiographic techniques in detection of the calcaneofibular ligament calcaneal insertion for lateral ankle ligament complex surgery.

BACKGROUND: Grade III ankle sprains that fail conservative treatment can require surgical management. Anatomic procedures have been shown to properly restore joint mechanics, and precise localization of insertion sites of the lateral ankle complex ligaments can be determined through radiographic techniques. Ideally, radiographic techniques that are easily reproducible intraoperatively will lead to a consistently well-placed CFL reconstruction in lateral ankle ligament surgery. PURPOSE: To determine the most accurate method to locate the calcaneofibular ligament (CFL) insertion radiographically. METHODS: MRIs of 25 ankles were utilized to identify the "true" insertion of the CFL. Distances between the true insertion and three bony landmarks were measured. Three proposed methods (Best, Lopes, and Taser) for determining the CFL insertion were applied to lateral ankle radiographs. X and Y coordinate distances were measured from the insertion found on each proposed method to the three bony landmarks: the most superior point of the postero-superior surface of the calcaneus, the posterior most aspect of the sinus tarsi, and the distal tip of the fibula. X and Y distances were compared to the true insertion found on MRI. All measurements were made using a picture archiving and communication system. The average, standard deviation, minimum, and maximum were obtained. Statistical analysis was performed using repeated measures ANOVA, and a post hoc analysis was performed with the Bonferroni test. RESULTS: The Best and Taser techniques were found to be closest to the true CFL insertion when combining X and Y distances. For distance in the X direction, there was no significant difference between techniques (P = 0.264). For distance in the Y direction, there was a significant difference between techniques (P = 0.015). For distance in the combined XY direction, there was a significant difference between techniques (P = 0.001). The CFL insertion as determined by the Best method was significantly closer to the true insertion compared to the Lopes method in the Y (P = 0.042) and XY (P = 0.004) directions. The CFL insertion as determined by the Taser method was significantly closer to the true insertion compared to the Lopes method in the XY direction (P = 0.017). There was no significant difference between the Best and Taser methods. CONCLUSION: If the Best and Taser techniques can be readily used in the operating room, they would likely prove the most reliable for finding the true CFL insertion.

Opening wedge high tibial osteotomy for medial compartment knee osteoarthritis: Planning and improving outcomes: Case series and literature review.

Background: Opening wedge high tibial osteotomy (OWHTO) is a safe surgical procedure to treat medial compartmental osteoarthritis caused by a varus deformity. Over-correction of this varus deformity can lead to lateral compartment over-loading. In our study, we planned our correction by using the mechanical axis deviation (MAD). Purpose: The purpose of this study is to evaluate the clinical and radiological results of OWHTO based on planning using the MAD measurements. Study Design: Retrospective Case Series. Methods: 14 patients with Kellgren- Lawrence classification (KL) grade 3 or above underwent OWHTO, with plans to have the mechanical axis pass through 5-15 mm lateral to the center of the tibial plateau. Pre-operative and post-operative radiographic measurements were made and compared using the student t-test. SF-36 scores were obtained for clinical performance. Results: Our patients experienced MAD from 25.9 mm medial to the center of the tibial plateau pre-operatively to 12.7 mm lateral to the center of the plateau post-operatively. The mean change in MAD was 38.7 mm (p < 0.0001). The accuracy of our correction compared to the planned MAD was 98.3%. The mechanical axis angle shifted from 7.35° of varus to 3.5° of valgus (p < 0.0001). All patients had post-operative alignments of 1-6° of valgus, with 11 of out the 14 patients with alignments less than 5° of valgus, preventing over-loading of the lateral compartment. Conclusion: Using MAD measurements is an accurate planning method for OWHTO that corrects varus deformity without over-loading the lateral compartment, and leads to improved clinical outcomes.

Compliant Buckled Foam Actuators and Application in Patient-Specific Direct Cardiac Compression.

We introduce the use of buckled foam for soft pneumatic actuators. A moderate amount of residual compressive strain within elastomer foam increases the applied force ∼1.4 × or stroke ∼2 × compared with actuators without residual strain. The origin of these improved characteristics is explained analytically. These actuators are applied in a direct cardiac compression (DCC) device design, a type of implanted mechanical circulatory support that avoids direct blood contact, mitigating risks of clot formation and stroke. This article describes a first step toward a pneumatically powered, patient-specific DCC design by employing elastomer foam as the mechanism for cardiac compression. To form the device, a mold of a patient's heart was obtained by 3D printing a digitized X-ray computed tomography or magnetic resonance imaging scan into a solid model. From this model, a soft, robotic foam DCC device was molded. The DCC device is compliant and uses compressed air to inflate foam chambers that in turn apply compression to the exterior of a heart. The device is demonstrated on a porcine heart and is capable of assisting heart pumping at physiologically relevant durations (∼200 ms for systole and ∼400 ms for diastole) and stroke volumes (∼70 mL). Although further development is necessary to produce a fully implantable device, the material and processing insights presented here are essential to the implementation of a foam-based, patient-specific DCC design.

Morphing Metal and Elastomer Bicontinuous Foams for Reversible Stiffness, Shape Memory, and Self-Healing Soft Machines.

A metal-elastomer-foam composite that varies in stiffness, that can change shape and store shape memory, that self-heals, and that welds into monolithic structures from smaller components is presented.

Poroelastic Foams for Simple Fabrication of Complex Soft Robots.

Open-celled, elastomeric foams allow the simple design of fully 3D pneumatic soft machines using common forming techniques. This is demonstrated through the fabrication of simple actuators and an entirely soft, functional fluid pump formed in the shape of the human heart. The device pumps at physiologically relevant frequencies and pressures and attains a flow rate higher than all previously reported soft pumps.