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Category: Midfoot/Forefoot; Bunion Introduction/Purpose: The pathology of the bunion deformity consists of deformities in the axial, coronal, and sagittal planes of the first metatarsal and its articular surface with the medial cuneiform. While weightbearing radiographs have been utilized for assessment of these deformities, such methods have limitations with regard to image magnification, patient position, and superimposition of bone alignments. With advances with weightbearing computed tomography (WBCT), evaluation of the 3- dimensional components of the first metatarsal along with its proximal articular surface can be assessed with greater precision. This study aims to observe the effect of the midshaft osteotomy on the alignment of the tarsometatarsal joint in three dimension Methods: Ten feet in 10 subjects underwent midshaft first metatarsal osteotomies. Weight-bearing (using a load equivalent to body weight) CT scans with .3mm cubic voxel size using an original loading device preoperatively and postoperatively were collected from each of the subjects in neutral standing position. Scans were segmented, and 3D renderings of the medial cuneiform, first metatarsal, and the first phalanx were also generated from the segmentations followed by definition of reference frames to evaluate changes in the metatarsal in relationship to the medial cuneiform. (Fig.1) Results: The measurements of the rotational parameters showed greater changes in the sagittal plane postoperatively with dorsiflexion of the first metatarsal relative to the medial cuneiform at the first tarsometatarsal joint (p

Category: Basic Sciences/Biologics; Basic Sciences/Biologics; Sports; Other Introduction/Purpose: Recently, purposes of medicinal marijuana including analgesia and reduction in inflammation. The active component activates the CB1 and CB2 receptors, thus mimicking the action of endogenous cannabinoids. CB1 and CB2 are important regulators of bone metabollism. In particular, endocannabinoid signaling has shown to regulate proliferation and differentiation of MSCs and the activities of osteoblasts and osteoclasts. Cannabinoids may be prescribed to patients suffering bone fractures involving prolonged immobilization and discomfort. Thus, there is an important need to understand more completely the role of cannanbinoid signaling in fracture healing. In this study, we examine the influence of a synthetic cannabinoid agonist, Win-55,212-2 (Win) on adult, human MSC-derived osteoblast activity. Cell viability and osteogenic phenotype were assessed by MTS assay, RT-PCR, and alizarin red staining. Methods: With an IRB approved protocol, MSCs were isolated from healthy human bone marrow and expanded to the passage five for experimentation. Cells were then plated at 5,200 cells/cm2 (6-well plate) and osteogenically stimulated for 21 days before treatment with increasing concentrations of Win (0.01, 0.1, or 1 µM) for an additional 48 hours. The MTS assay was employed to determine the half-maximal (50%) inhibitory concentration (IC50) at different time points. The cell phenotype was assessed by real-time PCR and alizarin red staining. Results: We first used the MTS assay (for metabolism and proliferation) to test 7 doses of Win-55, from 0.001µM up to 5 µM and determined that the human osteoblast IC50 of Win-55 over 1-7 days of exposure was ~ 1.5 µM (Figure 1), a dose slightly lower than concentrations found to affect chondrocytes in a previous study. At 1µM Win-55, RT-PCR revealed that the expression of inflammatory cytokines IL-1beta and TNF-alpha was significantly reduced, while that of IL-6 and COX2 was unchanged. The expression of most osteogenic markers was unchanged by Win, but we did observe significant increases in BMP2, RUNX2 and OPN (Figure 2). Alizarin Red staining revealed increased calcium deposition and mineralization in the presence of 1µM Win, corroborating the RT-PCR results (Figure 3). Conclusion: Win-55,212-2 may be beneficial to osteogenesis. 1 µM Win enhanced the osteoblastic phenotype over control, untreated MSC-derived osteoblasts, reduced inflammatory mediators and increased calcium deposition and mineralization. This suggests that cannabidiol treatment might lead to improvements in fracture healing and provide a novel therapeutic option for the bone regeneration. Future studies are aimed at characterizing the CB-1 and CB-2 signaling associated with the changes observed here and the effects of Win on MSC-derived osteoblasts in the context of inflammation.

Category: Basic Sciences/Biologics Introduction/Purpose: Medical marijuana is reported to have potent analgesic, immunomodulatory and anti-inflammatory properties. Some recent studies have shown that cannabinoids may attenuate joint damage in animal models of arthritis. However, the underlying mechanism has not been completely elucidated. Interleukin-1β (IL-1β), a proinflammatory cytokine that can result in the degradation of cartilage, is known to be associated with the pathogenesis of osteoarthritis. We hypothesize that cannabinoids can mitigate the detrimental effect of IL-1β on cartilage, thus slowing the progression of osteoarthritis. We exposed human chondrocyte-derived engineered cartilage pellet cultures to IL-1 β for 48 hours or not and then treated the samples with a synthetic cannabinoid agonist, Win-55,212-2(Win). The tissue phenotypes were thereafter assessed by real time polymerase chain reaction (RT-PCR), histology and western blotting. Methods: Medical marijuana is reported to have potent analgesic, immunomodulatory and anti-inflammatory properties. Some recent studies have shown that cannabinoids may attenuate joint damage in animal models of arthritis. However, the underlying mechanism has not been completely elucidated. Interleukin-1β (IL-1β), a proinflammatory cytokine that can result in the degradation of cartilage, is known to be associated with the pathogenesis of osteoarthritis. We hypothesize that cannabinoids can mitigate the detrimental effect of IL-1β on cartilage, thus slowing the progression of osteoarthritis. We exposed human chondrocyte-derived engineered cartilage pellet cultures to IL-1 β for 48 hours or not and then treated the samples with a synthetic cannabinoid agonist, Win-55,212-2(Win). The tissue phenotypes were thereafter assessed by real time polymerase chain reaction (RT-PCR), histology and western blotting. Results: RT-PCR revealed persistent increase in the expression of inflammatory mediators IL-1beta, TNF-alpha and COL2 in IL1beta+ cultures over IL1beta- controls at all levels of WIN exposure. In contrast there was clear decrease in IL-6 expression at high WIN doses coincident with a downward trend the other mediators. WIN was unable to rescue IL-1beta-induced reductions in COL2 and ACN, while inducing ALP, a marker of osteogenesis and cartilage hypertrophy. Safranin O/Fast Green histology revealed progressive loss in GAG deposition with increasing doses of WIN (Figure 2). Western blots confirmed reductions in COL2 and COMP protein, persistent COX2 production, and increasing translation of the osteogenic transcription factor RUNX2 and p-SMAD1/5/8 (Figure 3). Conclusion: At doses below 1µM, Win does not impact IL-1beta-induced chondrocyte inflammation. while inhibiting chondrogenesis and stimulating osteogenesis through RUNX2 as compared to IL-1β controls. In proper context, BMP2 stimulates osteogenesis through SMAD1/5/8 and the induction of RUNX2. We did observe an apparent anti-inflammatory role of WIN at 1µM, but this dose did not rescue a loss in cartilage pellet GAG loss. Our data suggests that cannabinoids are anti-inflammatory, but are unable to rescue cartilage degeneration by IL-1β and promote an osteogenic phenotype. However, the data are not conclusive with regarding the beneficial or detrimental to arthritic bones and cartilage

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: Hallux valgus (HV) is a tri-plane deformity of the foot corresponding to a medial deviation of the first metatarsal and a lateral deviation of the hallux. Understanding key angles between bones, as well as how these deformity changes in each plane, is critical to generating pre-operative insights into the most effective surgical correction of the deformity. While two- dimenional (2D) imaging can provide some information; utilizing three-dimensional (3D) imaging can include more precise and accurate measures of hallux valgus. The purpose of this study is to evaluate the metatarsal osteotomies for correction of hallux valgus deformity in axial, coronal and sagittal plane with 2D and 3D measurements with the hypothesis that 3D measurements will provide greater accuracy of pre and post surgical changes Methods: Ten cadaveric specimens were selected and weight-bearing CT scans were taken pre operatively with an applied an axial load of 80 pounds. Midshaft osteotomies were then performed on the cadaveric specimens followed by weight-bearing CT scans taken post-operatively.3D models of the pre-operative and post-operative specimens were created and differences in pre and post operative changes were analyzed using conventional 2D and 3D models of the first metatarsal (M1), second metatarsal (M2), fifth metatarsal (M5), and proximal phalanx of the hallux (PP1) using a paired student t-test. Quantitative examination of foot and ankle offset (FAO) alignment along with congruity of first metatarsal phalangeal and first tarsometatarsal joints Results: 3D measurements of the Inter-Metatarsal (IM) Angle, was 12.3 degrees pre-opeative and 10.4 degrees post-operative with no significant differences in all three planes while the M1M5 Angle, measured between the principle axes of the first metatarsal and fifth metatarsal was 25.3 degrees pre-operative and 22.0 degrees post-operative were statistically significant with the greatest change in the axial plane. 2D measurements of the hallux valgus angle, measured the longitudineal axes of the first metatarsal and proximal phalange of the hallux was 22.6 degrees pre opereative and 21.7 degrees post opereative with no statistical difference while the metatarsal parabola, measured in two dimensions projected onto the axial plane was 157.1 degrees before and 141.5 degrees after surgery was statistical significant. Conclusion: When comparing 2D and 3D pre and post surgical hallux valgus values, the only significant differences were identified in the absolute M1M5 values in the axial plane and a significant change was also observed in the metatarsal parabola angle. While the metatarsal parabola angle are sensitive measures, these results suggest that the M1 M5 angle allows for precise, efficient measurements in axial, coronal and sagittal planes that is previously unknown through two-dimensional radiographic measurements for quantifying the effect of metatarsal osteotomies on hallux valgus

Category: Diabetes Introduction/Purpose: Complications associated with the diabetes include increased incidence of fracture healing, delayed fracture healing, delayed osteoblasts cell replication, decreased angiogenesis, migration and/or osteoblast cell differentiation. The cellular events involved in bone healing are adversely affected by diabetes; however, can be modulated by the Opioid Growth Factor (OGF)–OGF receptor (OGFr) is an inhibitory peptide that downregulates DNA synthesis in a tissue nonspecific manner. Diabetes is associated with elevated serum levels of OGF and dysregulation of the OGFr leading to multiple complications related to healing, sensitivity, and regeneration. This study explores the presence and function of the OGF-OGFr axis in bone tissue from type 1 diabetic rats examining intact and fractured femurs during early phases of the repair process Methods: Seven-week-old Sprague Dawley rats were injected with streptozotocin (40mg/kg i.p.) to induce T1D; other rats received buffer only and served as controls. After one month, hyperglycemia rats underwent surgery to produce a fracture at the distal third of the femur. Four diabetic rats received opioid antagoinist (naltrexone) and calcium sulfate and all remaining rats received calcium sulfate with water only. X-rays were taken immediately after surgery and after rats were euthanized on post-surgery; femur and tibia were collected for protein isolation, western blot analysis along with frozen or paraffin-embedded for histological analysis Results: Immunofluorescence indicated approximately 90% increase in opioid growth factor receptor expression in diabetic femurs compared to age-matched normal femurs. Western Blotting also suggested an increase in the receptor protein in diabetic bones relative to normal bone. TRAP staining for osteoclasts was greater in control and opioid antagonist-treated diabetic fractures when compared to the number of osteoclasts in vehicle-treated diabetic fractured femurs. Safranin O stained sections revealed approximately more bone in opioid growth receptor antagonist-treated diabetic bone fractures than in vehicle-treated bone fractures Conclusion: These data support our hypothesis that expression levels of OGFr are dysregulated in the bone of diabetic patients leading to complications in bone healing. Moreover, modulation of the OGF-OGFr pathway with receptor antagonists restored some aspects of bone healing. With further study, these preliminary results support the role of the OGF-OGFr axis in treatment of diabetic bone healing. New therapies to target dysregulation of the OGF-OGFr regulatory pathway in diabetes would provide a safe and effective disease-modifying treatment for delayed bone healing.

Category: Hindfoot Introduction/Purpose: Posterior Tibial Tendon Dysfunction (PTTD) is common disorder that can lead to changes in function during the gait cycle due to decreased arch, increased hindfoot valgus, and forefoot abduction. These kinematic changes can have a structural impact on the joints throughout the foot. While previous studies have evaluated anatomical three-dimensional (3D) position of the subtalar joint, the purpose of this study was to perform morphological analysis of the anterior, middle and posterior facets in patients with stage II posterior tibial tendon dysfunction compared to normal controls. Methods: Clinical computed tomography images from 10 matched feet (i.e., 10 normal and 10 stage II PTTD) were obtained and used for 3D reconstruction in Mimics software (Materialise). From the3D reconstructions, morphometric evaluations of the subtalar joint were completed including 3D anatomic point placement and measurements of the length and width of the anterior, middle and posterior facets (Fig. 1) by 3 independent evaluators. Evaluators were blinded to experimental groups and to one another’s measurements. A linear mixed-effects model was used to assess the differences between control and PTTD subtalar joints with respect to morphometric measurements (mm). The concordance correlation coefficient (CCC) was used to assess the agreement between the 3 evaluators with respect to their recorded morphometric measurements per location (e.g., anterior, middle, posterior). Results: Although the mean distance of the length and width of the middle facet trended higher in the stage II PTTD compared to controls, this difference was not statistically significant (Table 1). Similarly, there was no difference detected between control and PTTD with respect to morphometric measurements in the anterior and posterior facets (Table 1). The agreement among the 3 evaluators with respect to morphometric measurements was the strongest in the length and width of the middle facets. Conclusion: Stage II posterior tibial tendon dysfunction has been shown to cause increase subtalar joint kinematics, joint contact pressure. Based on the results, there is a positive correlation involving morphologic changes of subtalar joint with the middle facet measurements being larger in the PTTD group. Further studies are needed with weight bearing CT scans in correlation with advance stages of posterior tibial tendon dysfunction.