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Background:Blood flow restriction therapy (BFRT) has been increasingly applied to improve athletic performance and injury recovery. Validation of BFRT has lagged behind commercialization, and currently the mechanism by which this therapy acts is unknown. BFRT is one type of ischemic therapy, which involves exercising with blood flow restriction. Repetitive restriction of muscle blood flow (RRMBF) is another ischemic therapy type, which does not include exercise.Hypothesis/Purpose:The purpose was to develop a rat model of ischemic therapy, characterize changes to muscle contractility, and evaluate local and systemic biochemical and histologic responses of 2 ischemic therapy types. We hypothesized that ischemic therapy would improve muscle mass and strength as compared with the control group.Study Design:Controlled laboratory study.Methods:Four groups of 10 Sprague-Dawley rats were established: control, stimulation, RRMBF, and BFRT. One hindlimb of each subject underwent 8 treatment sessions over 4 weeks. To simulate exercise, the stimulation group underwent peroneal nerve stimulation for 2 minutes. The RRMBF group used a pneumatic cuff inflated to 100 mm Hg with a 48-minute protocol. The BFRT group involved 100–mm Hg pneumatic cuff inflation and peroneal nerve stimulation for a 5-minute protocol. Four methods of evaluation were performed: in vivo contractility testing, histology, immunohistochemistry, and ELISA. Analysis of variance with post hoc Tukey test and linear mixed effects modeling were used to compare the treatment groups.Results:There was no difference in muscle mass among groups ( P = .40) or between hindlimbs ( P = .73). In vivo contractility testing showed no difference in maximum contractile force among groups ( P = .64) or between hindlimbs ( P = .30). On histology, myocyte cross-sectional area was not different among groups ( P = .55) or between hindlimbs ( P = .44). Pax7 immunohistochemistry demonstrated no difference in muscle satellite cell density among groups ( P = .06) or between hindlimbs ( P = .046). ELISA demonstrated the RRMBF group as eliciting elevated GH levels as compared with the other groups ( P < .001).Conclusion:Ischemic therapy did not induce gains in muscle mass, contractility strength, fiber cross-sectional area, or satellite cell density locally or systemically in this model, although the RRMBF group did have elevated GH levels on ELISA.Clinical Relevance:This animal model does not support ischemic therapy as a method to improve muscle mass, function, or satellite cell density.

Summary Objective Joint injury-induced perturbations to the endocannabinoid system (ECS), a regulator of both inflammation and nociception, remain largely uncharacterized. We employed a mouse model of ACL rupture to assess alterations to nociception, inflammation, and the ECS while using in vitro models to determine whether CB2 agonism can mitigate inflammatory signaling in macrophages and fibroblast-like synoviocytes (FLS). Design Mice underwent noninvasive ACL rupture (ACLR) via tibial compression-based loading. Nociception was measured longitudinally using mechanical allodynia and knee hyperalgesia testing. Synovitis was assessed using histological scoring and histomorphometry. Gene and protein markers of inflammation were characterized in whole joints and synovium. Immunohistochemistry assessed injury-induced alterations to CB1+, CB2+, and F4/80+ cells in synovium. To assess whether CB2 agonism can inhibit pro-inflammatory macrophage polarization, murine bone marrow-derived macrophages (mBMDM) were stimulated with IL-1β or conditioned medium from IL-1β-treated FLS and treated with vehicle (DMSO), the CB2 agonist HU308, or cannabidiol (CBD). Macrophage polarization was assessed as the ratio of M1-associated (IL1b, MMP1b, and IL6) to M2-associated (IL10, IL4, and CD206) gene expression. Human FLS (hFLS) isolated from synovial tissue of OA patients were treated with vehicle (DMSO) or HU308 following TNF-α or IL-1β stimulation to assess inhibition of catabolic/inflammatory gene expression. Results ACLR induces synovitis, progressively-worsening PTOA severity, and an immediate and sustained increase in both mechanical allodynia and knee hyperalgesia, which persist beyond the resolution of molecular inflammation. Enrichment of CB2, but not CB1, was observed in ACLR synovium at 3d, 14d, and 28d, and CB2 was found to be associated with F4/80 (+) cells, which are increased in number in ACLR synovium at all time points. The CB2 agonist HU308 strongly inhibited mBMDM M1-type polarization following stimulation with either IL-1β or conditioned medium from IL-1β-treated mFLS, which was characterized by reductions in Il1b, Mmp1b, and Il6 and increases in Cd206 gene expression. Cannabidiol similarly inhibited IL-1β-induced mBMDM M1 polarization via a reduction in Il1b and an increase in Cd206 and Il4 gene expression. Lastly, in OA hFLS, HU308 treatment inhibited IL-1β-induced CCL2, MMP1, MMP3, and IL6 expression and further inhibited TNF-α-induced CCL2, MMP1, and GMCSF expression, demonstrating human OA-relevant anti-inflammatory effects by targeting CB2. Conclusions Joint injury perturbs the intra-articular ECS, characterized by an increase in synovial F4/80(+) cells, which express CB2, but not CB1. Targeting CB2 in murine macrophages and human FLS induced potent anti-inflammatory and anti-catabolic effects, which indicates that the CB2 receptor plays a key role in regulating inflammatory signaling in the two primary effector cells in the synovium. The intraarticular ECS is therefore a potential therapeutic target for blocking pathological inflammation in future disease-modifying PTOA treatments.

Enhancements to the mechanical properties of modular designs for bone tissue engineering could increase their clinical applications. In this study, bone marrow mesenchymal stem cells (MSCs) and hydroxyapatite (HAP) microgranules were encapsulated in polyelectrolyte complex membranes composed of chondroitin 4-sulfate (C4S), carboxymethyl cellulose (CMC) and chitosan. Microcapsules were formed with and without HAP microgranules, and cultured in either osteoinduction medium (Osteo) or expansion medium (Exp) to produce four microcapsule conditions: Osteo, Osteo+HAP, Exp, and Exp+HAP. Microcapsules facilitated alkaline phosphatase secretion and deposition of bone specific proteins (osteocalcin and osteopontin) by encapsulated MSCs over 28 days of osteogenic culture. SEM and micro-CT analysis showed cell-deposited mineral covering the surfaces of the HAP microgranules and interior of the microcapsule membrane. The mineralized microcapsules could be combined and fused into cylindrical constructs (4 × 5 mm, W × H), and uniaxial compression tests confirmed that microcapsule mineralization greatly enhanced the yield stresses of Osteo and Osteo+HAP fused constructs (10.4 ± 4.4 MPa and 6.4 ± 2.8 MPa), compared to only HAP microgranules (Exp+HAP, 0.5 ± 0.3 MPa). The C4S/CMC/Chitosan microcapsules provide a platform allowing pre-mineralization of microcapsules in vitro for later assembly of larger load-bearing constructs, or for use as an injectable bone regeneration strategy. Statement of Significance Clinical translation of bone tissue engineering is limited by the difficulty of generating space filling implants that both resist compressive loading, and simultaneously deliver cells throughout the bone defect. Here, we present the design of a microcapsule system containing both stem cells capable of rebuilding bone tissue, and a mechanically tough bone-like mineral, that imparts compression resistance to the microcapsules. The microcapsules support stem cell differentiation to an osteogenic phenotype, that can mineralize the microcapsule membrane and interior. The mineralized microcapsules can be assembled into larger bone constructs, and have mechanical properties on par with trabecular bone.

BackgroundAnterior cruciate ligament rupture (ACLR) is a well-known risk factor for the development of post-traumatic osteoarthritis (PTOA). While clinical and pre-clinical studies have characterized the onset and progression of PTOA in the tibiofemoral joint compartment, very little is known about degenerative changes in the patellofemoral compartment after ACL injury.Hypothesis/PurposeTo evaluate the extent to which ACL rupture induces acute patellofemoral joint degeneration by quantifying articular cartilage morphology and remodeling of subchondral and trabecular bone microarchitecture in the patellofemoral compartment.Study DesignDescriptive laboratory study.MethodsAdult female Lewis rats were randomized to undergo either a non-surgical ACL rupture or a Sham procedure (n = 6 per group). Ex vivo contrast-enhanced micro-computed tomography (µCT) and histological evaluation of the patellofemoral compartment were performed at 2-weeks post-injury, representing a timepoint of documented early PTOA in the tibiofemoral compartment in this model.ResultsACL rupture causes osteophyte formation in the patella and mild degeneration in the superficial zone of articular cartilage (AC), including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering at two weeks post-injury. Contrast-enhanced µCT analysis demonstrates significant increases in AC thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to trabecular microarchitecture in both the patella and trochlea, were indicative of catabolic bone remodeling.ConclusionThese results demonstrate that the patellofemoral joint develops mild but evident degenerative changes in the acute time period following ACL rupture, extending the utility of this rat model to the study of degenerative patellofemoral changes following joint trauma.Clinical RelevanceACL rupture causes mild degeneration and swelling of articular cartilage, coupled with catabolic bone remodeling in the patellofemoral compartment. Characterizing the pathophysiology of patellofemoral PTOA in its early stages may provide a better understanding of disease progression and provide opportunities for preventative therapeutic intervention.

This work aimed to develop an efficient R1ρ dispersion imaging method for clinical studies of human knee cartilage at 3 T. Eight constant magnetizations (Mprep ) were prepared by tailoring both the duration and amplitude (ω1 ) of a fully refocused spin-lock preparation pulse. The limited Mprep dynamic range was expanded by the measure, equivalent to that with ω1 = ∞, from the magic angle location in the deep femoral cartilage. The developed protocol with Mprep = 60% was demonstrated on one subject's bilateral and two subjects' unilateral asymptomatic knees. The repeatability of the proposed protocol was estimated by two repeated scans with a three-month gap for the last two subjects. The synthetic R1ρ and R2 derived from R1ρ dispersions were compared with the published references using state-of-the-art R1ρ and R2 mapping (MAPSS). The proposed protocol demonstrated good (

Background Sex-based differences in clinical outcomes following surgical treatment of femoroacetabular impingement remain largely uncharacterized; this prospective, multicenter study evaluated these differences both directly and adjusted for covariates. Methods Hips undergoing surgical treatment of symptomatic femoroacetabular impingement were prospectively enrolled in a multicenter cohort. Patient demographics, radiographic parameters, intraoperatively assessed disease severity, and history of surgical procedures, as well as patient-reported outcome measures, were collected preoperatively and at a mean follow-up of 4.3 years. A total of 621 (81.6%) of 761 enrolled hips met the minimum 1 year of follow-up and were included in the analysis; 56.7% of analyzed hips were female. Univariate and multivariable statistics were utilized to assess the direct and adjusted differences in outcomes, respectively. Results Male hips had greater body mass index and larger α angles. Female hips had significantly lower preoperative and postoperative scores across most patient-reported outcome measures, but also had greater improvement from preoperatively to postoperatively. The preoperative differences between sexes exceeded the threshold for the minimal clinically important difference of the modified Harris hip score (mHHS) and all Hip disability and Osteoarthritis Outcome Score (HOOS) domains except quality of life. Preoperative sex differences in mHHS, all HOOS domains, and Short Form-12 Health Survey physical function component score were greater than the postoperative differences. A greater proportion of female hips achieved the minimal clinically important difference for the mHHS, but male hips were more likely to meet the patient acceptable symptom state for this outcome. After adjusting for relevant covariates with use of multiple regression analysis, sex was not identified as an independent predictor of any outcome. Preoperative patient-reported outcome scores were a strong and highly significant predictor of all outcomes. Conclusions Significant differences in clinical outcomes were observed between sexes in a large cohort of hips undergoing surgical treatment of femoroacetabular impingement. Despite female hips exhibiting lower baseline scores, sex was not an independent predictor of outcome or reoperation. Level of evidence Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

BACKGROUND: The purpose of our study was to examine the effect of controlled delivery of TGF-β(3), BMP-4, and TIMP-2 with a biocompatible biopolymer, chitosan, on an acutely injured intervertebral disc (IVD) in a rabbit model. METHODS: After conducting an in vitro analysis of the chondrogenic capacity of the biomolecule cocktail use (ie, TGF-β(3), BMP-4, and TIMP-2) and confirming stem cell viability in chitosan hydrogel, 15 New Zealand white rabbits underwent a lateral approach of the L1 to L4 IVDs. In each rabbit, the L2 to L3 IVD was left pristine, whereas the L1 to L2 and the L3 to L4 IVDs in each rabbit underwent nucleotomy via a 25-G needle, and the animal was subsequently randomized to no further treatment (defect only), chitosan alone, Chitosan + TGF-β(3) + BMP-4, or chitosan + TGF-β(3) + BMP-4 + TIMP-2. At 6 weeks after injury and intervention, the rabbits were killed and spines harvested to undergo quantitative T2 magnetic resonance imaging (MRI) and subsequent histologic analysis. RESULTS: In the in vitro analysis, cells treated with experimental media containing TGF-β(3), BMP-4, and TIMP-2 exhibited staining indicative of GAG production and began to exhibit a chondrocytic morphology. Quantitative T2 MRI mapping demonstrates that discs treated with chitosan, chitosan containing TGF-β(3) and BMP-4, or chitosan containing TGF-β(3), BMP-4, and TIMP-2 had consistently higher T2 relaxation times compared with defect-only discs. When the T2 relaxation times of each treatment group and defect-only discs were normalized to the healthy control disc, it was found that the T2 relaxation time of discs treated with chitosan containing TGF-β(3) and BMP-4 and discs treated with chitosan containing TGF-β(3), BMP-4, and TIMP-2 were significantly greater compared with defect-only discs (P = .048 and P = .013, respectively). Histologically, animals that received chitosan only, or chitosan with TGF-β(3) and BMP-4, showed a significantly higher intensity of Safranin-O staining (P = .016 and P = .02, respectively) compared with control discs, whereas the difference in staining intensity in animals that received chitosan loaded with TGF-β(3), BMP-4, and TIMP-2 failed to achieve significance (P = .161). CONCLUSIONS: A combination of chitosan, TGF-β(3), and BMP-4 was effective at promoting regeneration in an acute disc injury rabbit model, whereas TIMP-2 did not have a significant effect.

ObjectiveAssess acute alterations in bone turnover, microstructure, and histomorphometry following noninvasive anterior cruciate ligament rupture (ACLR).MethodsTwelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading (n=6/group). In vivo μCT was performed at 3, 7, 10, and 14 days post-injury to quantify compartment-dependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near-infrared (NIR) molecular imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo μCT and contrast-enhanced µCT, respectively. Calcein-based dynamic histomorphometry was used to quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number was quantified on TRAP stained-sections.ResultsACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days post-injury, while lateral femoral condyles (LFC) exhibited SCB gains. Trabecular thinning was observed in MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and sustained reduction of bone anabolism (∼15-20%), and a ∼32% increase in bone catabolism at 14 days, compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and increased osteoclast numbers, observed histologically. ACLR-injured femora had significantly elevated OARSI score, cartilage thickness, and cartilage surface deviation.ConclusionACL rupture induces immediate and sustained reduction of bone anabolism and overactivation of bone catabolism, with mild-to-moderate articular cartilage damage at 14 days post-injury.

Objectives: Patients with Femoroacetabular impingement (FAI) have been shown to have elevated circulating biomarkers of inflammation and cartilage catabolism, but little is known about whether corrective surgical intervention improves objective measures of hip strength and inflammation. This study measured several variables including pain, function, quality of life, symptoms, hip strength, and inflammatory and cartilage biomarkers in a cohort of subjects undergoing FAI surgery and postoperative (postop) rehabilitation. We hypothesized that surgical FAI repair and completion of a postop rehabilitation program will significantly improve patient reported outcomes (PROs), increase hip flexion and abduction strength measures, and decrease biomarkers of inflammation and cartilage degradation. Methods: This study was approved by the University of Michigan Medical School IRB (HUM00055335). Male and female patients aged 16-40 years of age, with symptomatic FAI diagnosed by concordant history, physical examination, and imaging findings were eligible for inclusion. Subjects who have undergone previous hip surgery, have a global overcoverage deformity, dysplasia, or degenerative chondral changes greater than Tonnis grade I were excluded. A single, fellowship trained, sports medicine orthopaedic surgeon performed all surgical procedures, and patients underwent a standardized postop rehabilitation program. HOOS questionnaires were assessed at each subject’s preoperative visit (preop), and at 2, 14, 26, and 52 weeks postop. Hip flexion, abduction, and extension were measured at each time point using a BioDex isokinetic dynamometer. High sensitivity C-reactive protein (HS-CRP) and cartilage oligomeric matrix protein (COMP) were measured in plasma using ELISAs. Differences between preop and postop time points were assessed using a mixed-effects model, and data are reported as mean±95% CI. Results: A total of 11 males and 6 females completed the study. Mean age of subjects was 25.2±3.8 years (range 16.0-38.0 years) and BMI of 24.2±2.0 kg/m2 (range 18.1-33.6 kg/m2). For most HOOS subscales, there was a decrease in score at 2 weeks postop, and by 14 weeks activities of daily living (ADL) improved by 18%, pain by 34%, quality of life by 69%, sport and recreation by 36%, and symptoms by 28% compared to preop values (Figure 1A-E). These improvements in HOOS subscales persisted for the duration of the study period (Figure 1A-E). No differences in hip flexion strength were observed, while extension was 20% and 31% significantly higher than preop values at 26 and 52 weeks, and for abduction patients were 34% stronger than preop values at 52 weeks. No differences in HS-CRP or COMP were observed (Figure 1F-J). Conclusion: In support of our hypothesis, we observed significant improvements in PROs of hip function, although changes in PROs preceded improvements in objective measures of hip extension and abduction strength. Despite improvements in other planes, no changes in hip flexion were observed. Plasma biomarkers of hip inflammation and cartilage turnover were not reduced by surgical intervention and rehabilitation. FAI surgery and postop rehabilitation is effective at treating pain, and improving patient reported quality of life and symptoms, with modest improvements in hip strength. However, the surgical correction of pathological hip anatomy and improvements in hip strength did not lead to significant differences in markers of inflammation or cartilage turnover.

Nonbiologic medications (local anesthetics, corticosteroids, and nonsteroidal anti-inflammatory drugs) are commonly administered to athletes for analgesia after injury. However, the risks of nonbiologic injections often are overlooked simply because of their long-term market availability. A thorough understanding of the mechanism of action, the reported benefits, and the potential risks of nonbiologic medications is crucial prior to their use, especially in the treatment of young athletes. Sports medicine physicians and surgeons must be aware of the systemic and local effects of these medications to ensure an appropriate drug choice that minimizes side effects and avoids recently reported toxicity to myocytes, tenocytes, and chondrocytes.

Although numerous spinal biologics are commercially available, a cost-effective and safe bone graft substitute material for spine fusion has yet to be proven. In this study, “3D-Paints” containing varying volumetric ratios of hydroxyapatite (HA) and human demineralized bone matrix (DBM) in a poly(lactide-co-glycolide) elastomer were three-dimensional (3D) printed into scaffolds to promote osteointegration in rats, with an end goal of spine fusion without the need for recombinant growth factor. Spine fusion was evaluated by manual palpation, and osteointegration and de novo bone formation within scaffold struts were evaluated by laboratory and synchrotron microcomputed tomography and histology. The 3:1 HA:DBM composite achieved the highest mean fusion score and fusion rate (92%), which was significantly greater than the 3D printed DBM-only scaffold (42%). New bone was identified extending from the host transverse processes into the scaffold macropores, and osteointegration scores correlated with successful fusion. Strikingly, the combination of HA and DBM resulted in the growth of bone-like spicules within the DBM particles inside scaffold struts. These spicules were not observed in DBM-only scaffolds, suggesting that de novo spicule formation requires both HA and DBM. Collectively, our work suggests that this recombinant growth factor-free composite shows promise to overcome the limitations of currently used bone graft substitutes for spine fusion. IMPACT STATEMENT: Currently, there exists a no safe, yet highly effective, bone graft substitute that is well accepted for use in spine fusion procedures. With this work, we show that a three-dimensional printed scaffold containing osteoconductive hydroxyapatite and osteoinductive demineralized bone matrix that promotes new bone spicule formation, osteointegration, and successful fusion (stabilization) when implemented in a preclinical model of spine fusion. Our study suggests that this material shows promise as a recombinant growth factor-free bone graft substitute that could safely promote high rates of successful fusion and improve patient care.

Micro-computed tomography (μCT) and contrast-enhanced μCT are important tools for preclinical analysis of bone and articular cartilage (AC). Quantitative data from these modalities is highly dependent on the accuracy of tissue segmentations, which are often obtained via time-consuming manual contouring and are prone to inter- and intra-observer variability. Automated segmentation strategies could mitigate these issues, but few such approaches have been described in the context of μCT. Here, we validated a fully-automated strategy for bone and AC segmentation based on registration of an average tissue atlas. Femora from healthy and arthritic rats underwent μCT scanning, and epiphyseal trabecular bone and AC volumes were manually contoured by an expert. Average tissue atlases composed of 1, 3, 5, 10 and 20 pre-contoured training images (n = 10 atlases/group) were generated using iterative shape averaging and registered onto unknown images via affine and non-rigid registration. Atlas-based and expert-defined volumes for bone and AC were compared in terms of shape-based similarity metrics, as well as morphometric and densitometric parameters. Our results demonstrate that atlas-based registrations were capable of highly accurate and consistent segmentation. Atlases built from as few as 3 training images had no incidence of mal-registration and exhibited improved incidence of accurate registration, and higher sensitivity and specificity compared to atlases built from only one training image. Atlas-based segmentation of bone and AC from μCT images is a robust and accurate alternative to manual tissue segmentation, enabling faster, more consistent segmentation of pre-clinical datasets.

Purpose The rat rotator cuff (RC) model is used to study RC pathology and potential treatment; however, native scar-mediated healing allows the rat RC to recover at 4-6 weeks but little is known about acute healing. This study characterized the properties of the repaired and non-repaired rat RC following surgical detachment. Materials and methods Forty-eight rats underwent surgical RC detachment and received surgical repair (Repair) or left unrepaired (Defect) to either 12 or 19 days. Healthy controls were obtained from contralateral limbs. Biomechanical properties were assessed using stress relaxation and failure testing and mechanical modeling performed using quasilinear viscoelastic (QLV) and structurally based elastic models. Histology and micro-magnetic resonance imaging were used to qualitatively grade tendon-to-bone healing. Results Repair and Defect exhibited significantly inferior mechanical properties compared to Healthy at both time points. Repair had significant increases in peak, equilibrium, and ultimate stress, modulus, and stiffness and significant decreases in cross-sectional area, % relaxation, and QLV constant "C" between 12 and 19 days, whereas Defect showed no change. Conclusions This study demonstrates acute differences in mechanical properties of the rat supraspinatus tendon in the presence and absence of surgical repair. Understanding the longitudinal recovery of mechanical properties can facilitate more accurate characterization of RC pathology or future treatments.

Quantitative analyses of bone using micro-computed tomography (μCT) are routinely employed in preclinical research, and virtual image reorientation to a consistent reference frame is a common processing step. The purpose of this study was to quantify error introduced by common reorientation algorithms in μCT-based characterization of bone. Mouse and rat tibial metaphyses underwent μCT scanning at a range of resolutions (6-30 μm). A trabecular volume-of-interest (VOI) was manually selected. Image stacks were analyzed without rotation, following 45° In-Plane axial rotation, and following 45° Triplanar rotation. Interpolation was performed using Nearest-Neighbor, Linear, and Cubic interpolations. Densitometric (bone volume fraction, tissue mineral density, bone mineral density) and morphometric variables (trabecular thickness, trabecular spacing, trabecular number, structural model index) were computed for each combination of voxel size, rotation, and interpolation. Significant reorientation error was measured in all parameters, and was exacerbated at higher voxel sizes, with relatively low error at 6 and 12 μm (max. reorientation error in BV/TV was 2.9% at 6 μm, 7.7% at 12 μm and 36.5% at 30 μm). Considering densitometric parameters, Linear and Cubic interpolations introduced significant error while Nearest-Neighbor interpolation caused minimal error, and In-Plane rotation caused greater error than Triplanar. Morphometric error was strongly and intricately dependent on the combination of rotation and interpolation employed. Reorientation error can be eliminated by avoiding reorientation altogether or by "de-rotating" VOIs from reoriented images back to the original reference frame prior to analysis. When these are infeasible, reorientation error can be minimized through sufficiently high resolution scanning, careful selection of interpolation type, and consistent processing of all images. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2762-2770, 2018.

Mechanical characterization of the intervertebral disc involves labor-intensive and destructive experimental methodology. Contrast-enhanced micro-computed tomography is a nondestructive imaging modality for high-resolution visualization and glycosaminoglycan quantification of cartilaginous tissues. The purpose of this study was to determine whether anionic and cationic contrast-enhanced micro-computed tomography of the intervertebral disc can be used to indirectly assess disc mechanical properties in an ex vivo model of disc degeneration. L3/L4 motion segments were dissected from female Lewis rats. To deplete glycosaminoglycan, samples were treated with 0 U/ml (Control) or 5 U/ml papain. Contrast-enhanced micro-computed tomography was performed following incubation in 40% Hexabrix (anionic) or 30 mg I/ml CA4+ (cationic) for 24 h (n = 10/contrast agent/digestion group). Motion segments underwent cyclic mechanical testing to determine compressive and tensile modulus, stiffness, and hysteresis. Glycosaminoglycan content was determined using the dimethylmethylene blue assay. Correlations between glycosaminoglycan content, contrast-enhanced micro-computed tomography attenuation, and mechanical properties were assessed via the Pearson correlation. The predictive accuracy of attenuation on compressive properties was assessed via repeated random sub-sampling cross validation. Papain digestion produced significant decreases in glycosaminoglycan content and corresponding differences in attenuation and mechanical properties. Attenuation correlated significantly to glycosaminoglycan content and to all compressive mechanical properties using both Hexabrix and CA4+ . Predictive linear regression models demonstrated a predictive accuracy of attenuation on compressive modulus and stiffness of 79.8-86.0%. Contrast-enhanced micro-computed tomography was highly predictive of compressive mechanical properties in an ex vivo simulation of disc degeneration and may represent an effective modality for indirectly assessing disc compressive properties. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2030-2038, 2018.

ACL rupture is a major risk factor for post-traumatic osteoarthritis (PTOA) development. Little information exists on acute systemic metabolic indicators of disease development. Thirty-six female Lewis rats were randomized to Control or noninvasive anterior cruciate ligament rupture (ACLR) and to three post-injury time points: 72 h, 4 weeks, 10 weeks (n = 6). Serum was collected and analyzed by 1 H nuclear magnetic resonance (NMR) spectroscopy and combined direct injection and liquid chromatography (LC)-mass spectrometry (MS)/MS (DI-MS). Univariate and multivariate statistics were used to analyze metabolomic data, and predictive biomarker models were analyzed by receiver operating characteristic (ROC) analysis. Topological pathway analysis was used to identify perturbed pathways. Two hundred twenty-two metabolites were identified by 1 H NMR and DI-MS. Differences in the serum metabolome between ACLR and Control were dominated by medium- and long-chain acylcarnitine species. Further, decreases in several tryptophan metabolites were either found to be significantly different in univariate analysis or to play important contributory roles to multivariate model separation. In addition to acylcarnitines and tryptophan metabolites, glycine, carnosine, and D-mannose were found to differentiate ACLR from Control. Glycine, 9-hexadecenoylcarnitine, trans-2-Dodecenoylcarnitine, linoelaidyl carnitine, hydroxypropionylcarnitine, and D-Mannose were identified as biomarkers with high area under ROC curve values and high predictive accuracies. Our analysis provides new information regarding the potential contribution of inflammatory processes and immune dysregulation to the onset and progression of PTOA following ACL injury. As these processes have most commonly been associated with inflammatory arthropathies, larger-scale studies elucidating their involvement in PTOA development and progression are necessary. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1969-1979, 2018.

Current imaging-based morphometric indicators of osteoarthritis (OA) using whole-compartment mean cartilage thickness (MCT) and volume changes can be insensitive to mild degenerative changes of articular cartilage (AC) due to areas of adjacent thickening and thinning. The purpose of this preliminary study was to evaluate cartilage thickness-based surface roughness as a morphometric indicator of OA. 3D magnetic resonance imaging (MRI) datasets were collected from osteoarthritis initiative (OAI) subjects with Kellgren-Lawrence (KL) OA grades of 0, 2, and 4 (n = 10/group). Femoral and tibial AC volumes were converted to two-dimensional thickness maps, and MCT, arithmetic surface roughness (Sa ), and anatomically normalized Sa (normSa ) were calculated. Thickness maps enabled visualization of degenerative changes with increasing KL grade, including adjacent thinning and thickening on the femoral condyles. No significant differences were observed in MCT between KL grades. Sa was significantly higher in KL4 compared to KL0 and KL2 in the whole femur (KL0: 0.55 ± 0.10 mm, KL2: 0.53 ± 0.09 mm, KL4: 0.79 ± 0.18 mm), medial femoral condyle (KL0: 0.42 ± 0.07 mm, KL2: 0.48 ± 0.07 mm, KL4: 0.76 ± 0.22 mm), and medial tibial plateau (KL0: 0.42 ± 0.07 mm, KL2: 0.43 ± 0.09 mm, KL4: 0.68 ± 0.27 mm). normSa was significantly higher in KL4 compared to KL0 and KL2 in the whole femur (KL0: 0.22 ± 0.02, KL2: 0.22 ± 0.02, KL4: 0.30 ± 0.03), medial condyle (KL0: 0.17 ± 0.02, KL2: 0.20 ± 0.03, KL4: 0.29 ± 0.06), whole tibia (KL0: 0.34 ± 0.04, KL2: 0.33 ± 0.05, KL4: 0.48 ± 0.11) and medial plateau (KL0: 0.23 ± 0.03, KL2: 0.24 ± 0.04, KL4: 0.40 ± 0.10), and significantly higher in KL2 compared to KL0 in the medial femoral condyle. Surface roughness metrics were sensitive to degenerative morphologic changes, and may be useful in OA characterization and early diagnosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2755-2764, 2017.

Background The management of glenoid deformity during anatomic total shoulder arthroplasty remains controversial. In this study, we evaluate variable correction of glenoid deformity by eccentric reaming. We hypothesize that partial correction of modified Walch B/C-type glenoid deformities can achieve 75% bone-implant contact area (BICA) with a reduced vault perforation risk compared with complete correction. Methods Fifty shoulder computed tomographic scans with glenohumeral osteoarthritis were retrospectively evaluated. The Tornier BluePrint v2.1.5 software simulated 3 eccentric reaming scenarios including no, partial, and complete deformity correction. Each scenario was evaluated at 4 BICAs and using 3 implant fixation types. Three-dimensional surface representations were used to evaluate medialization and vault perforation. Results The patients had mean glenoid retroversion and inclination of 18.5° and 8.8°, respectively, and mean posterior humeral head subluxation of 76%. With 75% BICA, the 3 fixation types had glenoid vault perforation in 6%-26% and 26%-54% of cases for partial and complete glenoid deformity correction, respectively. The central and posterior-inferior implant components were most likely to perforate across all scenarios. Discussion Eccentric reaming for glenoid deformity correction increases the risk of vault perforation. Severe glenoid deformity required increased medialization to achieve 75% BICA. Pegged implants have increased chances of perforation compared with a keeled design; the central and posterior-inferior components were most likely to perforate during deformity correction. Conclusion Partial deformity correction of modified Walch B/C-type glenoid deformities can achieve 75% BICA while reducing the risk of vault perforation compared with complete correction at the time of anatomic total shoulder arthroplasty.

Objective: Characterize 3D remodeling of the rat intervertebral disc (IVD) following acute annular injury via in vivo micro-computed tomography (µCT), ex vivo contrast-enhanced (CE)-µCT, and histology. Design: Female Lewis rats (N = 4/group) underwent either sham surgery or anterior annular puncture to L3-L4 and L5-L6 (n = 8 IVDs/group) to induce IVD degeneration. Rats were allowed ad libidum cage activity before and after surgery and underwent in vivo µCT scanning at baseline and every 2 weeks post-op for 12 weeks to characterize longitudinal changes in IVD height. At 12 weeks, lumbar spines were dissected and underwent CE-µCT scanning to characterize endpoint glycosaminoglycan distribution and nucleus pulposus (NP) volume ratio. Spines were processed for safranin-O-stained sagittal histology, and IVD degeneration was graded via the Rutges scale. Results: Puncture IVDs exhibited loss of IVD height at all time points from 4 weeks onward compared to Sham-the most severe height loss occurred posteriorly, with significant changes also occurring in the NP and laterally. Puncture IVDs exhibited higher CE-µCT attenuation, indicative of lower glycosaminoglycan content, and reduced NP volume ratio compared to Sham. Histologically, Puncture IVDs had higher Rutges damage scores and exhibited reduced NP cellularity and hydration, disorganized annulus fibrosus (AF) lamellae with evidence of the stab tract, and indistinct AF-NP border compared to Sham. Conclusions: Characterization of the complex, 3D alterations involved in the onset and early progression of IVD degeneration can foster greater understanding of the pathoetiology of IVD degeneration and may inform future studies assessing more sensitive diagnostic techniques or novel therapies.

Background: Professional basketball players are at increased risk of hip and groin pain. Epidemiologic data exist on the prevalence of hip and groin issues among players in the National Basketball Association (NBA), but little is known about how these injuries affect athletes after retirement. Hypothesis: A high proportion of retired NBA athletes would have hip and/or groin pain. Study Design: Cross-sectional survey. Level of Evidence: Level 4. Methods: A survey was developed through an interdisciplinary focus group. The survey was developed to capture data regarding demographics, collegiate and professional athletic injuries, and current quality of life and musculoskeletal health. The questionnaire was electronically distributed to all members of the National Basketball Players Association using SurveyMonkey (N = 900). Results: A total of 108 (12%) retired NBA players completed the survey. More than one-third (36.3%) of athletes report currently experiencing hip and/or groin pain, and 17.6% had received injections for hip or groin conditions since retiring from the NBA. Since retiring, 14.7% of respondents had undergone total hip arthroplasty. The median Tegner activity level scale was 3 out of 10. Nearly one-third (32.4%) of athletes report moderate to severe problems with mobility, and close to half (48%) had moderate to extreme pain/discomfort. Conclusion: Hip and groin injuries are common among NBA athletes, affecting players throughout their careers and into retirement. A subset of athletes may exist in whom intra-articular hip pathology is not appropriately identified and treated while playing in the NBA. Clinical Relevance: Retired NBA athletes are at high risk of hip and groin pain after retirement and are more likely to require total hip arthroplasty compared with the general population.

The objective of this study was to quantify and compare the contrast-enhancing properties of the anionic contrast agent ioxaglate/Hexabrix, and cationic contrast agent CA4+ for biochemical and morphological characterization of the intervertebral disc (IVD) via μCT. Optimal contrast agent concentrations were determined by incubating rat lumbar IVDs in dilutions of Hexabrix-320 (20%, 30%, 40%, and 50%) and CA4+ (10, 20, 30, and 40 mg I/ml). μCT imaging was performed at 70 kVp, 114 μA, and 250 ms integration time, 12 μm voxel size. The kinetics of contrast enhancement were quantified with cumulative incubations for 0.5, 1, 2, 12, 16, 20, and 24 h using both agents. Agreement in morphological quantification was assessed via serial scans of the same IVDs. Correlation of attenuation to glycosaminoglycan (GAG) content was determined by enzymatic digestion of IVDs, subsequent μCT imaging, and GAG quantification via dimethylmethylene blue assay. Forty percent Hexabrix and 30 mg I/ml CA4+ were chosen as optimal concentrations. Hexabrix enabled greater delineation of the IVD from surrounding tissues, and CA4+ had the lowest uptake in surrounding soft tissue. Twenty-four hour incubation was sufficient for >99% equilibration of both agents. A high level of agreement was observed in the quantification of IVD volume (ICC = 0.951, r = 0.997) and height (ICC = 0.947, r = 0.991). Both agents exhibited strong linear correlations between μCT attenuation and GAG content (Hexabrix: r = -0.940; CA4+ : r = 0.887). Both agents enable biochemical and morphological quantification of the IVD via contrast-enhanced μCT and are effective tools for preclinical characterization. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1067-1075, 2017.

Summary Objective Animal models are frequently used to study post-traumatic osteoarthritis (PTOA). A common anterior cruciate ligament (ACL) injury model is surgical transection, which may introduce confounding factors from surgery. Noninvasive models could model human injury more closely. The purpose of this study was to compare subchondral and epiphyseal trabecular bone remodeling after surgical transection and noninvasive rupture of the ACL. Methods Thirty-six rats were randomized to an uninjured control, surgical transection (Transection), or noninvasive rupture (Rupture). Animals were randomized to 4 or 10 week time points ( n = 6 per group). Micro computed tomography (μCT) imaging was performed with an isotropic voxel size of 12 μm. Subchondral and epiphyseal bone was segmented semi-automatically, and morphometric analysis was performed. Results Transection caused a greater decrease in subchondral bone volume fraction (BV/TV) than Rupture in the femur and tibia. Rupture had greater subchondral bone tissue mineral density (TMD) at 4 and 10 weeks in the femur and tibia. Subchondral bone thickness (SCB.Th) was decreased in the femur in Transection only. Epiphyseal BV/TV was decreased in Transection only, and Rupture exhibited increased femoral epiphyseal TMD compared to both Control and Transection. Rupture exhibited greater femoral epiphyseal trabecular thickness (Tb.Th.) compared to Control and Transection at 4 weeks, and both Rupture and Transection had increased femoral epiphyseal Tb.Th. at 10 weeks. Epiphyseal trabecular number (Tb.N) was decreased in both injury groups at both time points. Femoral and tibial epiphyseal structure model index (SMI) increased in both groups. Conclusions The two injury models cause differences in post-injury bone morphometry, and surgical transection may be introducing confounding factors that affect downstream bony remodeling.

To assess the retear rate, retear size and location, the clinical impact of a retear, and preoperative patient factors related to postoperative outcome after arthroscopic suture bridge rotator cuff repair.Fifty six patients with an isolated, full-thickness supraspinatus tendon tear who underwent arthroscopic suture bridge rotator cuff repair were retrospectively identified. Patients were evaluated and rotator cuff integrity was assessed using ultrasonography. Visual analog score (VAS), the American Shoulder and Elbow Surgeon (ASES) score, shoulder range of motion and strength were used for clinical evaluation. Retears were assessed for size and location on ultrasonography.Forty two patients (75%) aged a mean 59.7 ± 8.6 years (range 41-79 years) were available for follow-up at a mean 13.5 months. Postoperative evaluation indicated significant improvements in ASES score (49.76 ± 18.2 to 86.57 ± 13.4, P0.001), VAS pain score (4.69 ± 2.17 to 0.63 ± 1.29, P0.001), forward elevation range of motion (144.1° ± 29.9 to 159.69° ± 13.9, P = 0.002), and internal rotation ROM (44.13° ± 12.0 to 52.09° ± 12.0, P = 0.003). The retear rate was 14.28% (6/42). Patients with retears were not older (P = 0.526) but had a larger preoperative tear size (3.25 cm ± 0.5 vs. 2.05 cm ± 0.48, P0.001). Preoperative tear size was significantly associated with a postoperative retear (P0.001). The duration of preoperative symptoms was significantly associated with pain (P = 0.029), pain improvement (P = 0.013), internal rotation ROM (P = 0.002), and internal rotation strength (P = 0.004).Arthroscopic suture bridge repair provides good clinical results with a low retear rate. The duration of preoperative symptoms was associated with postoperative outcome, indicating that delaying surgery may result in inferior outcomes.IV, Case Series.

Background Context Degenerative disc disease (DDD) is associated with longitudinal remodeling of paravertebral tissues. Although chronic vertebral changes in advanced stages of DDD are well-studied, very little data exists on acute vertebral bone remodeling at the onset and progression of DDD. Purpose To longitudinally characterize bony remodeling in a rodent model of disc injury-induced DDD. Study Design In vivo animal study involving a rat annulus fibrosus injury model of DDD. Methods Eight female Lewis rats were assigned to intervertebral disc (IVD) injury (Puncture) or sham surgery (Sham). All rats underwent anterior, transperitoneal approach to the lumbar spine, and Puncture rats underwent annulus fibrosus injury at the L3-L4 and L5-L6 IVDs (n = 8 per group). Live micro computed tomography imaging (10-μm voxel size) was performed 1 week before surgery and postoperatively at 2-week intervals up to a 12-week endpoint. Bone morphology and densitometry of the cranial vertebral body and bony endplate were analyzed and reported with respect to the preoperative baseline scan. Sagittal Safranin-O/Fast-Green and Toluidine Blue histology evaluated using the Rutges IVD score and a custom vertebral endplate score. Results Vertebral trabecular tissue mineral density (TMD), vertebral trabecular spacing, endplate TMD, and endplate apparent bone mineral density were all significantly greater in Puncture compared with Sham at 4 weeks and each subsequent timepoint. Puncture rats exhibited marginally lower endplate total volume. Anterior endplate osteophyte formation and central physeal ossification were observed in Puncture rats. Endpoint histological analysis demonstrated moderate evidence of IVD degeneration, indicating that vertebral bone adaptation occurs in the acute phases of DDD onset and progression. Conclusions Annulus injury-induced DDD leads to acute and progressive changes to the morphology and densitometry of bone in the adjacent vertebral bodies and endplates.

The onset of post-traumatic osteoarthritis (PTOA) remains prevalent following traumatic joint injury such as anterior cruciate ligament (ACL) rupture, and animal models are important for studying the pathomechanisms of PTOA. Noninvasive ACL injury using the tibial compression model in the rat has not been characterized, and it may represent a more clinically relevant model than the common surgical ACL transection model. This study employed four loading profiles to induce ACL injury, in which motion capture analysis was performed, followed by quantitative joint laxity testing. High-speed, high-displacement loading repeatedly induces complete ACL injury, which causes significant increases in anterior-posterior and varus laxity. No loading protocol induced valgus laxity. Tibial internal rotation and anterior subluxation occurs up to the point of ACL failure, after which the tibia rotates externally as it subluxes over the femoral condyles. High displacement was more determinative of ACL injury compared to high speed. Low-speed protocols induced ACL avulsion from the femoral footprint whereas high-speed protocols caused either midsubstance rupture, avulsion, or a combination injury of avulsion and midsubstance rupture. This repeatable, noninvasive ACL injury protocol can be utilized in studies assessing PTOA or ACL reconstruction in the rat.

Mutations in COMP (cartilage oligomeric matrix protein) cause severe long bone shortening in mice and humans. Previously, we showed that massive accumulation of misfolded COMP in the ER of growth plate chondrocytes in our MT-COMP mouse model of pseudoachondroplasia (PSACH) causes premature chondrocyte death and loss of linear growth. Premature chondrocyte death results from activation of oxidative stress and inflammation through the CHOP-ER pathway and is reduced by removing CHOP or by anti-inflammatory or antioxidant therapies. Although the mutant COMP chondrocyte pathologic mechanism is now recognized, the effect of mutant COMP on bone quality and joint health (laxity) is largely unknown. Applying multiple analytic approaches, we describe a novel mechanism by which the deleterious consequences of mutant COMP retention results in upregulation of miR-223 disturbing the adipogenesis - osteogenesis balance. This results in reduction in bone mineral density, bone quality, mechanical strength and subchondral bone thickness. These, in addition to abnormal patterns of ossification at the ends of the femoral bones likely contribute to precocious osteoarthritis (OA) of the hips and knees in the MT-COMP mouse and PSACH. Moreover, joint laxity is compromised by abnormally thin ligaments. Altogether, these novel findings align with the PSACH phenotype of delayed ossification and bone age, extreme joint laxity and joint erosion, and extend our understanding of the underlying processes that affect bone in PSACH. These results introduce a novel finding that miR-223 is involved in the ossification defect in MT-COMP mice making it a therapeutic target.

The production of wear debris particulate remains a concern due to its association with implant failure through complex biologic interactions. In the setting of unicompartmental knee arthroplasty (UKA), damage and wear of the components may introduce debris particulate into the adjacent, otherwise, healthy compartment. The purpose of this study was to investigate the in vitro effect of polymeric and metallic wear debris particles on cell proliferation, extracellular matrix regulation, and phagocytosis index of normal human articular chondrocytes (nHACs). In culture, nHACs were exposed to both cobalt-chromium-molybdenum (CoCrMo) and polymethyl-methacrylate (PMMA) wear debris particulate for 3 and 10 days. At 3 days, no significant difference in cell proliferation was found between control cells and cells exposed to both CoCrMo or PMMA particles. However, cell proliferation was significantly decreased for CoCrMo exposed nHACs at both 6 (P

Background:Numerous variations of ulnar collateral ligament (UCL) reconstruction have been described since the original technique by Jobe et al.Purpose/Hypothesis:To biomechanically compare the new TightRope technique and the traditional ulnar bone tunnels as used in the docking technique. The hypothesis was that the TightRope technique would exhibit improved kinematics and comparable failure properties.Study Design:Controlled laboratory study.Methods:Seven matched pairs of cadaveric arms (mean age, 44.71 years) were tested in both the native state and reconstructed state. Kinematics were assessed at 15° to 90° of flexion by applying a 1.5-N·m valgus torque and measuring the resultant angular displacement. Failure testing was performed by loading to failure at 4.5 deg/s in 70° of flexion. Sides of a matched pair were randomized to the TightRope (TR) and docking (DO) techniques after testing the native state.Results:There was no significant difference in kinematic results between the native state and reconstructed state in either the TR or DO group at 15° to 75° of flexion. At 90°, the TR group had significantly higher angular displacement (2.23° ± 1.0°) compared with the native state (1.31° ± 0.7°) ( P = .020). The TR-reconstructed specimens had significantly lower initial stiffness (49.34 ± 19.3 N·m/rad vs 82.47 ± 36.0 N·m/rad, respectively; P = .007) and total stiffness (53.81 ± 27.8 N·m/rad vs 101.06 ± 34.4 N·m/rad, respectively; P < .001) than did the paired native specimens. In addition, the TR-reconstructed specimens had significantly lower torsional torque at 5° of valgus rotation (mean, 4.61 ± 2.2 N·m vs 7.62 ± 3.7 N·m, respectively; P = .010), at 15° of valgus rotation (12.24 ± 4.4 N·m vs 20.65 ± 6.8 N·m, respectively; P = .002), and at ultimate failure (19.18 ± 7.5 N·m vs 25.42 ± 7.1 N·m, respectively; P = .025) than did the paired native specimens. There was no significant difference in torsional torque between the TR and DO groups at 5° of valgus rotation (4.61 ± 2.2 N·m vs 4.09 ± 1.7 N·m, respectively; P = .644), at 15° of valgus rotation (12.24 ± 4.4 N·m vs 17.94 ± 7.23 N·m, respectively; P = .178), or at failure (19.18 ± 7.5 N·m vs 23.19 ± 10.6 N·m, respectively; P = .444). The DO group exhibited significantly higher angular displacement at failure than did the native state (28.12° ± 8.5° vs 18.04° ± 4.8°, respectively; P = .009), but there was no difference at 3 N·m of loading. There was no significant difference in angular displacement either at 3 N·m or at failure between the native state and reconstructed state in the TR group.Conclusion:Both the TR and DO techniques restored native joint kinematics from 15° to 75° of flexion under low loading conditions. While the TR technique exhibited inferior failure torque compared with the native state, the DO technique did not differ from the native state. No differences were found between the TR and DO groups when compared directly. The DO technique restored valgus stability under high loading to a greater extent than did the TR technique but also failed at higher angular displacement.Clinical Relevance:Strong postoperative UCL reconstruction fixation is important to restore ulnotrochlear joint stability. Our study demonstrates that the new TR technique has comparable kinematic and failure properties to the traditional DO technique.

Background: Owing to the debilitating nature of degenerative disc disease (DDD) and other spine pathologies, significant research has been performed with the goal of healing or regenerating the intervertebral disc (IVD). Structural complexity, coupled with low vascularity and cellularity, make IVD regeneration an extremely challenging task. Methods: Tissue engineering-based strategies utilize three components to enhance tissue regeneration; scaffold materials to guide cell growth, biomolecules to enhance cell migration and differentiation, and cells (autologous, or allogeneic) to initiate the process of tissue formation. Significant advances in IVD regeneration have been made utilizing these tissue engineering strategies. Results: The current literature demonstrates that members of the transforming growth factor beta (TGF-β) superfamily are efficacious in the regeneration of an anabolic response in the IVD and to facilitate chondrogenic differentiation. Gene therapy, though thwarted by safety concerns and the risk of ectopic transfection, has significant potential for a targeted and sustained regenerative response. Stem cells in combination with injectable, biocompatible, and biodegradable scaffolds in the form of hydrogels can differentiate into de novo IVD tissue and facilitate regeneration of the existing matrix. Therapies that address both anabolism and the inherent catabolic state of the IVD using either direct inhibitors or broad-spectrum inhibitors show extensive promise. Conclusion: This review article summarizes the genetic and molecular advances that promise to play an integral role in the development of new strategies to combat DDD and promote healing of injured discs.

Summary Objective Little is known regarding acute local and systemic processes following anterior cruciate ligament (ACL) rupture. No study has elucidated whether bone marrow-derived mesenchymal stem cells (MSCs) are mobilized into circulation and recruited to the injured joint. Methods In Part 1, Lewis rats were randomized to noninvasive ACL rupture (Rupture) or non-injured (Control) (n = 6/group). After 72 h, whole blood MSC concentration was assessed using flow cytometry. Synovial fluid and serum were assayed for stromal cell-derived factor (SDF)-1α and cartilage degeneration biomarkers, respectively. In Part 2, 12 additional rats were randomized and intravenously-injected with fluorescently-labeled allogenic MSCs. Cell tracking was performed using longitudinal, in vivo and ex vivo near-infrared (NIR) imaging and histology. Synovium SDF-1α and interleukin (IL)-17A immunostaining was performed. Serum was assayed for SDF-1α and 29 other cytokines. Results In Part 1, there was a significant increase in MSC concentration and synovial fluid SDF-1α in Rupture. No differences in cartilage biomarkers were observed. In Part 2, Rupture had significantly higher NIR signal at 24, 48, and 72 h, indicating active recruitment of MSCs to the injured joint. Ex vivo cell tracking demonstrated MSC localization in the synovium and myotendinous junction (MTJ) of the quadriceps. Injured synovia exhibited increased synovitis grade and higher degree of IL-17A and SDF-1α immunostaining. Conclusion ACL rupture induced peripheral blood mobilization of MSCs and migration of intravenously-injected allogenic MSCs to the injured joint, where they localized in the synovium and quadriceps MTJ.

Rotator cuff tears are a common shoulder pathology. The rat supraspinatus tendon model is commonly employed for preclinical assessment of rotator cuff pathology or regeneration. However, there is a lack of a standardized biomechanical testing protocol; previous studies have tested the tendon at abduction angles ranging from -15° to 90°. This study aimed to assess the effect of abduction/testing angle on the biomechanical properties of the rat supraspinatus tendon. Fourty-eight shoulders (n=12/group) from healthy Sprague-Dawley rats were randomized to 4 testing angle groups: 0° (corresponding to 90° abduction), 30°, 60°, and 90° (0° abduction). Biomechanical testing of the supraspinatus was performed, consisting of stress-relaxation and load-to-failure. Mechanical properties were calculated, and nonlinear tensile modeling was performed via the Quasilinear Viscoelastic (QLV) and Structurally Based Elastic (SBE) models. Results indicate that testing angle significantly affects supraspinatus tendon biomechanics. Stiffness and modulus significantly decreased with increasing testing angle (stiffness: 20.93±5.8N/mm at 0° vs. 6.12±1.0N/mm at 90°, P.001; modulus: 59.51±34.0MPa at 0° vs. 22.37±7.4MPa at 90°, P=.002). Testing angle correlated significantly to ultimate strain, yield strain, and all coefficients of the SBE and QLV models, implying differences in collagen fiber crimp patterns and viscoelastic behavior as a function of testing angle. These results suggest that differences in testing methodology, in particular testing angle, significantly affect the measured mechanical properties of the supraspinatus tendon. Future studies may consider utilizing testing angles of 0°-30°, at which tendon stiffness is maximized, and full standardization of rat rotator cuff testing protocols is necessary.

Summary Objective Post-traumatic osteoarthritis (PTOA) is commonly studied using animal models. Surgical ACL transection is an established model, but noninvasive models may mimic human injury more closely. The purpose of this study was to quantify and compare changes in 3D articular cartilage (AC) morphology following noninvasive ACL rupture and surgical ACL transection. Methods Thirty-six rats were randomized to uninjured control, noninvasive ACL rupture (Rupture), and surgical ACL transection (Transection), and 4 and 10 week time points ( n = 6 per group). Contrast-enhanced micro-computed tomography (CE-μCT) was employed for AC imaging. Femoral and tibial AC were segmented and converted into thickness maps. Compartmental and sub-compartmental AC thickness and surface roughness (S a ) were computed. OARSI histologic scoring was performed. Results In both injury groups, zones of adjacent thickening and thinning were evident on the medial femoral condyle, along with general thickening and roughening of femoral and tibial AC. The posterior tibia exhibited drastic thickening and surface degeneration, and this was worse in Transection. Both injury groups had increased AC thickness and S a compared to Control at both time points, and Transection exhibited significantly higher S a in every tibial compartment compared to Rupture. Histologic score was elevated in both groups, and the medial femur exhibited the most severe histologic degeneration. Conclusions This is the first 3D quantification of preclinical AC remodeling after ACL injury. Both injury models induced similar changes in AC morphology, but Transection exhibited higher tibial S a and a greater degree of posterior tibial degeneration. We conclude that AC degeneration is a time-, compartment-, and injury-dependent cascade.

Degenerative disk disease is an accelerating cascade of tissue degeneration in the intervertebral disk. A harsh catabolic environment perpetuates the degeneration of the intervertebral disk. Tissue engineering-based techniques offer effective treatment to slow the progression of degenerative disk disease and regenerate intervertebral disk tissue. The purpose of this study was to assess the efficacy of a regenerative therapy for degenerative disk disease by treating human chondrocytes with anabolic growth factors and a proteinase inhibitor. The use of both proved effective in upregulating important extracellular matrix markers of human chondrocytes. These successful in vitro results have implications for the regeneration of the intervertebral disk.

Background The underlying cause of glenohumeral arthritis is poorly understood. Glenohumeral arthrosis patterns have been classified and described, and differential contact stresses within the joint have been implicated as a cause of joint degeneration, but the intrinsic cause of degeneration patterns in the glenohumeral joint (GHJ) remains largely unknown. Purpose/hypothesis The purpose of this study was to assess morphological and mechanical differences in articular cartilage (AC) and subchondral bone (SCB) of the glenoid and humeral head in matched cadaveric specimens. We hypothesized that there would be significant zone-dependent differences between the intrinsic characteristics (AC thickness, SCB thickness, compressive forces) of the glenoid and humeral head. Study design Descriptive laboratory study. Methods Ten human cadaveric GHJs (mean age, 60.2 years) were dissected to expose articular surfaces to facilitate biomechanical testing. A 2-mm and 6-mm osteochondral plug was harvested at 5 zones (central, anterior, posterior, inferior, superior) on the glenoid and humeral head (N = 200 plugs). Each 2-mm core was histologically sectioned and stained with hematoxylin and eosin. AC thickness measurements were taken using light microscopy. The 6-mm plugs were imaged using micro-computed tomography to measure SCB thickness. After imaging, AC specimens were removed from the SCB and tested in confined compression. The compressive aggregate modulus (HA0), compressive stiffening coefficient (β), and compressive modulus at 16% strain (HA0.16) and at 50% strain (HA0.50) were calculated. Results The overall AC thickness was significantly greater on the glenoid. The glenoid also had significantly thicker AC at the inferior, posterior, and superior zones as well as significantly higher SCB thickness overall and significantly greater SCB thickness at the anterior and central zones. The glenoid had significantly greater overall HA0.50 and HA0.50 values at the superior zone and had a significantly greater overall compressive stiffening coefficient (β). Conclusion The glenoid had thicker AC, thicker SCB, and greater compressive stiffness at high strain. Clinical relevance These intrinsic differences may help better elucidate the cause of differential degeneration patterns between the glenoid and humeral head.

Background:Although recent evidence suggests that any prior shoulder surgery may cause inferior shoulder arthroplasty outcomes, there is no consensus on whether previous rotator cuff repair (RCR) is associated with inferior outcomes after reverse total shoulder arthroplasty (RTSA).Purpose:To retrospectively compare outcomes in patients who underwent RTSA with and without previous RCR.Study Design:Cohort study; Level of evidence, 3.Methods:Patients with prior RCR and those without previous shoulder surgery (control) who underwent RTSA for cuff tear arthropathy or irreparable cuff tear were retrospectively identified from a prospective database. Exclusion criteria included revision arthroplasty, fractures, rheumatoid arthritis, dislocations, infection, prior non-RCR procedures, less than 12 months of follow-up, and latissimus dorsi tendon transfer. The American Shoulder and Elbow Surgeons (ASES) score, ASES Activities of Daily Living (ADL) score, visual analog scale (VAS) score for pain, Subjective Shoulder Value (SSV), and range of motion (ROM) were compared between groups.Results:Patients with previous RCR (n = 83 shoulders) were younger (mean ± SD, 67 ± 10 vs 72 ± 8 years; P < .001) and more likely to be male (46% vs 32%, P = .033) than controls (n = 189 shoulders). No differences were found in follow-up duration (25 ± 13 vs 26 ± 13 months, P = .734), body mass index, or any preoperative outcome variable or ROM measure. At final follow-up, patients with previous RCR had significantly lower ASES (76.5 [95% CI, 71.2-81.7] vs 85.0 [82.6-87.5], P = .015), lower SSV (76 [72-81] vs 86 [83-88], P < .001), worse pain (2.0 [1.4-2.6] vs 0.9 [0.6-1.1], P < .001), and less improvement in the ASES, ASES ADL, VAS, SSV, and forward elevation measures than controls. Multivariable linear regression analysis demonstrated that previous RCR was significantly associated with lower postoperative ASES score ( B = –9.5, P < .001), lower ASES improvement ( B = –7.9, P = .012), worse postoperative pain ( B = 0.9, P = .001), worse improvement in pain ( B = –1.0, P = .011), lower postoperative SSV ( B = –9.2, P < .001), lower SSV improvement ( B = –11.1, P = .003), and lower forward elevation ROM improvement ( B = –12.7, P = .008).Conclusion:Patients with previous RCR attempts may experience fewer short-term gains in functional and subjective outcome scores after RTSA compared with patients with no history of shoulder surgery who undergo RTSA. However, the differences between groups were small and below the minimal clinically important differences for the outcome measures analyzed.

Articular cartilage (AC) morphology is an important metric for characterizing degeneration. We propose a novel morphologic analysis using mesh parameterization, enabling the use of surface roughness and thickness metrics to characterize degeneration in a rodent model of post-traumatic osteoarthritis.Six rats underwent anterior cruciate ligament transection (ACL-T) and six were controls (Control). At 4-weeks, femora and tibiae were harvested and imaged using contrast-enhanced micro-computed tomography (μCT). Cartilage surfaces were manually outlined, and 2-dimensional thickness maps were generated using mesh parameterization and analyzed by thickness and surface roughness (Sa). The parameterization technique was validated against the direct distance transform (DDT) and histologic AC thickness from sagittal Safranin-O/Fast-Green sections. Parameterization and DDT measurements were also validated using known, virtual shapes with zero, one, and two planes of curvature.Parameterization had 0.00-6.26% error and DDT had 5.06-12.02% error in determining thicknesses of known shapes. Parameterization thickness correlated highly to DDT thickness (femur: r = 0.978, P 0.001; tibia: r = 0.992, P 0.001) and histologic thickness (femur: r = 0.952, P 0.001; tibia: r = 0.959, P 0.001). Thickness maps enabled visualization and quantification of AC degeneration. ACL-T samples displayed general thickening of cartilage, with adjacent regions of thickening and thinning on the medial femoral condyle. Compared to Control, ACL-T thickness was higher in the whole femur, whole tibia, and all compartments and sub-compartments. Sa was higher in the whole femur and medial and lateral condyle, and the whole tibia and medial and lateral plateau. The largest increases in Sa were observed on the medial femoral condyle.Cartilage analysis using parameterization effectively characterized early degeneration in AC, including sub-compartmental thickening/thinning, and is a powerful tool for assessing degeneration in preclinical osteoarthritis.

The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF).We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing?After creation of full-thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses.G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 ± 1.14 [confidence interval {CI}, 5.98-8.81] versus 4.50 ± 0.57 [CI, 3.58-5.41], p = 0.038; 19 days: 8.00 ± 1.00 [CI, 6.75-9.24] versus 5.40 ± 0.89 [CI, 4.28-6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0.999, p = 0.964, p = 1.000, p = 0.988, and p = 0.904, respectively). There was no difference in MRI score between G-CSF and control animals at either 12 days (2.7 ± 1.8 [CI, 1.08-4.24] versus 2.3 ± 1.8 [CI, 0.49-4.17], p = 0.623) or 19 days (2.5 ± 1.4 [CI, 1.05-3.94] versus 2.3 ± 1.5 [CI, 0.75-3.91], p = 0.737). G-CSF-treated animals exhibited significantly lower relative bone volume compared with normal animals in the entire humeral head (24.89 ± 3.80 [CI, 20.17-29.60) versus 32.50 ± 2.38 [CI, 29.99-35.01], p = 0.009) and at the supraspinatus insertion (25.67 ± 5.33 [CI, 19.04-32.29] versus 33.36 ± 1.69 [CI, 31.58-35.14], p = 0.027) at 12 days. Further analysis did not reveal any additional significant relationships with respect to regional bone volume or trabecular thickness between groups and time points (p0.05).Postoperative stem cell mobilization agents may be an effective way to enhance rotator cuff repair. Future studies regarding the kinetics of mobilization, the homing capacity of mobilized cells to injured tissues, and the ability of homing cells to participate in regenerative pathways are necessary.

Reverse total shoulder arthroplasty (RTSA) allows the deltoid to substitute for the nonfunctioning rotator cuff. To date, it is unknown whether preoperative deltoid and rotator cuff parameters correlate with clinical outcomes.We asked whether associations exist between 2-year postoperative results (ROM, strength, and outcomes scores) and preoperative (1) deltoid size; (2) fatty infiltration of the deltoid; and/or (3) fatty infiltration of the rotator cuff.A prospective RTSA registry was reviewed for patients with cuff tear arthropathy or massive rotator cuff tears, minimum 2-year followup, and preoperative shoulder MRI. Final analysis included 30 patients (average age, 71±10 years; eight males, 22 females). Only a small proportion of patients who received an RTSA at our center met inclusion and minimum followup requirements (30 of 222; 14%); however, these patients were found to be similar at baseline to the overall group of patients who underwent surgery in terms of age, gender, and preoperative outcomes scores. The cross-sectional area of the anterior, middle, and posterior deltoid was measured on axial proton density-weighted MRI. Fatty infiltration of the deltoid, supraspinatus, infraspinatus, teres minor, and subscapularis were quantitatively assessed on sagittal T1-weighted MR images. Patients were followed for Constant-Murley score, American Shoulder and Elbow Surgeons (ASES) scores, subjective shoulder value, pain, ROM, and strength. Correlations of muscle parameters with all outcomes measures were calculated.Preoperative deltoid size correlated positively with postoperative Constant-Murley score (67.27±13.07) (ρ=0.432, p=0.017), ASES (82.64±14.25) (ρ=0.377; p=0.40), subjective shoulder value (82.67±17.89) (ρ=0.427; p=0.019), and strength (3.72 pounds±2.99 pounds) (ρ=0.454; p=0.015). Quantitative deltoid fatty infiltration (7.91%±4.32%) correlated with decreased postoperative ASES scores (ρ=-0.401; p=0.047). Quantitative fatty infiltration of the infraspinatus (30.47%±15.01%) correlated with decreased postoperative external rotation (34.13°±16.80°) (ρ=-0.494; p=0.037).Larger preoperative deltoid size correlates with improved validated outcomes scores, whereas fatty infiltration of the deltoid and infraspinatus may have deleterious effects on validated outcomes scores and ROM after RTSA. The current study is a preliminary exploration of this topic; future studies should include prospective enrollment and standardized MRI with a multivariate statistical approach. Quantitative information attained from preoperative imaging not only holds diagnostic value, but, should future studies confirm our findings, also might provide prognostic value. This information may prove beneficial in preoperative patient counseling and might aid preoperative and postoperative decision-making by identifying subpopulations of patients who may benefit by therapy aimed at improving muscle properties.Level III, prognostic study.

The long head of the biceps tendon (LHBT) occupies a unique proximal intra-articular and distal extra-articular position within the human shoulder. In the presence of a rotator cuff (RC) tear, the LHBT is recruited into an accelerated role undergoing potential mechanical and biochemical degeneration. Intra-articular sections of the LHBT were harvested during primary shoulder arthroplasty from patients with an intact or deficient RC. LHBTs were stained (H&E, Alcian Blue) and subjected to histologic analysis using the semiquantitative Bonar scale and measurement of collagen orientation. LHBTs (n = 12 per group) were also subjected to gene-expression analyses via an RT(2) -PCR Profiler Array quantifying 84 genes associated with cell-cell and cell-matrix interactions. LHBTs (n = 18 per group) were biomechanically tested with both stress-relaxation and load-to-failure protocols and subsequently modeled with the Quasilinear Viscoelastic (QLV) and Structural-Based Elastic (SBE) models. While no histologic differences were observed, significant differences in mechanical testing, and viscoelastic modeling parameters were found. PCR arrays identified five genes that were differentially expressed between RC-intact and RC-deficient LHBT groups. LHBTs display signs of pathology regardless of RC status in the arthroplasty population, which may be secondary to both glenohumeral joint arthritis and the additional mechanical role of the LHBT in this population.

OBJECTIVE: To determine if T1ρ magnetic resonance imaging (T1ρ MRI) could assess early articular cartilage changes in knees of asymptomatic female collegiate athletes. It was hypothesized that impact cohort would demonstrate greater changes than nonimpact cohort. DESIGN: An institutional review board–approved prospective cohort study. Blinded MRI analyses. SETTING: Participants from collegiate athletic program. Imaging at university hospital, February 2008 to July 2009. PARTICIPANTS: Inclusion criteria were female collegiate athletes in athletic season and asymptomatic. Exclusion criteria were previous/current knee injuries/surgeries. Twenty-one female NCAA Division I athletes, 11 impact (basketball players) and 10 nonimpact (swimmers) participants were consented and imaged with 3.0-T MRI (Siemens) and T1ρ sequence (University of Pennsylvania). One patient was removed (injury diagnosis). Final roster was 10 impact and 10 nonimpact participants. No difference in cohort body mass index, height, or weight. MAIN OUTCOME MEASURES: Average T1ρ relaxation times (ART) for patellar and femoral cartilage to analyze defined regions and depth and modified International Cartilage Repair Society classification. RESULTS: Statistical analyses showed that ART of radial zone of central third weight-bearing region of cartilage in basketball players was significantly greater (P = 0.041) than swimmers and ART of the superficial zone in basketball players was significantly less (P = 0.003) than that of swimmers. For both groups, the ART of super-ficial zones were significantly greater than that of radial zones (P < 0.001). Four impact athletes showed macroscopic changes (none in nonimpact cohort). CONCLUSIONS: T1ρ MRI detected early changes in articular cartilage of asymptomatic collegiate female impact athletes, with significant differences between cohorts in radial zone of central third weight-bearing region and superficial zones ART. Both cohorts showed increased ART in superficial zone. Four impact athletes showed macroscopic changes. CLINICAL RELEVANCE: This study demonstrates a quantitative MRI sequence able to detect signal differences in articular cartilage in asymptomatic athletes.

Purpose To systematically review current literature on the anterolateral ligament (ALL) of the knee. Methods We searched the PubMed/Medline database for publications specifically addressing the ALL. We excluded studies not written in English, studies not using human cadavers or subjects, and studies not specifically addressing the ALL. Data extraction related to the incidence, anatomy, morphometry, biomechanics, and histology of the ALL and its relation to the Segond fracture was performed. Results The incidence of the ALL ranged from 83% to 100%, and this range occurs because of small discrepancies in the definition of the ALL's bony insertions. The ALL originates anterior and distal to the femoral attachment of the lateral collateral ligament. It spans the joint in an oblique fashion and inserts between the fibular head and Gerdy tubercle on the tibia. Exact anatomic and morphometric descriptions vary in the literature, and there are discrepancies regarding the ALL's attachment to the capsule and lateral meniscus. The ALL is a contributor to tibial internal rotation stability, and histologically, it exhibits parallel, crimped fibers consistent with a ligamentous microstructure. The footprint of the ALL has been shown to be at the exact location of the Segond fracture. Conclusions The ALL is a distinct ligamentous structure at the anterolateral aspect of the knee, and it is likely involved in tibial internal rotation stability and the Segond fracture. Level of Evidence Level IV, systematic review of anatomic and imaging studies.

Background: Recent work has shown the presence of catabolic cytokines in platelet-rich plasma (PRP), but little is known about endogenous catabolic proteases such as matrix metalloproteinases (MMPs). Hypothesis/Purpose: To quantify MMP content in 2 commercially available PRP preparation systems: Arthrex Double Syringe System autologous conditioned plasma (ACP) and Biomet GPS (GPS). The hypothesis was that MMPs are actively secreted from PRP immediately after preparation. Study Design: Controlled laboratory study. Methods: PRP was prepared using either ACP (low platelet, low leukocyte) or GPS (high platelet, high leukocyte). MMP-2, MMP-3, and MMP-9 concentrations were measured using multiplex enzyme-linked immunosorbent assays for up to 6 days in 2 donors, and MMP activity was measured in 3 donors using kinetic activity kits able to detect the enzymatic cleavage of a fluorogenic peptide. Human ligament fibroblasts were cultured and exposed to both ACP and GPS from 1 donor each. MMP-2, -3, and -9 concentrations were assayed in culture media at 24 and 48 hours after exposure. Results: GPS exhibited higher total MMP-2, -3, and -9 concentrations for up to 144 hours of release, while ACP had higher platelet-normalized MMP-2 and MMP-3 concentrations. GPS had significantly higher total and endogenous MMP-2 activity ( P = .004 and .014, respectively), MMP-3 activity ( P = .020 and .015, respectively), and MMP-9 activity ( P = .004 and .002, respectively) compared with ACP. Once normalized to platelet count, differences in MMP activity were not significant between ACP and GPS. Compared with controls, cells stimulated with interleukin-1 beta (IL-1β) and treated with ACP showed significantly higher fold changes of MMP-2 ( P = .001) and MMP-3 ( P = .003) concentrations at 24 hours than did cells treated with GPS. Total MMP-9 content was higher in the media of GPS-treated, IL-1β–stimulated cells compared with ACP-treated cells ( P = .001). At 48 hours, IL-1β–stimulated cells treated with GPS exhibited higher fold changes of MMP-2 concentration ( P = .002) compared with controls, but no difference in MMP-3 concentration was found. At 48 hours, there was a significantly higher concentration of MMP-9 in the cell culture media of ACP-treated cells compared with GPS-treated cells ( P = .003). Conclusion: PRP prepared as both ACP and GPS contains MMP-2, -3, and -9, which is released over a period of at least 6 days. Furthermore, a large proportion of these MMPs are in their active form, and MMP activity is dependent on platelet count within the PRP preparation. Once exposed to ligament fibroblasts, both ACP and GPS cause the fibroblasts to release MMPs, most notably 24 hours after PRP exposure, and this release is dependent on prior IL-1β stimulation. Clinical Relevance: The results of this study demonstrate that PRP therapy delivers ng/mL-range concentrations of catabolic proteases, which could perpetuate inflammation and inhibit tissue healing.

Physical rehabilitation following arthroscopic rotator cuff repair has conventionally involved a 4- to 6-week period of immobilization; there are two schools of thought regarding activity level during this period. Some authors encourage early, more aggressive rehabilitation along with the use of a continuous passive motion device; others propose later, more conservative rehabilitation. Although some studies report trends in improved early range of motion, pain relief, and outcomes scores with aggressive rehabilitation following rotator cuff repair, no definitive consensus exists supporting a clinical difference resulting from rehabilitation timing in the early stages of healing. Rehabilitation timing does not affect outcomes after 6 to 12 months postoperatively. Given the lack of information regarding which patient groups benefit from aggressive rehabilitation, individualized patient care is warranted.

Acromioclavicular (AC) joint dislocation is a common injury observed and treated by physicians from several disciplines; proper classification and communication of the diagnosis between physicians is essential to manage injuries properly. This study assessed inter- and intradepartmental agreement in the rating of AC joint dislocations and compared departments of orthopedic surgery, musculoskeletal (MSK) radiology, and emergency medicine (EM).Fifty radiographs indicating a random distribution of AC dislocations (Rockwood types I, II, III, and V) were sent to 25 resident, fellow, and attending physicians; the study group consisted of orthopedic surgeons (n = 9), MSK radiologists (n = 7), and EM physicians (n = 9). Dislocations were rated by physicians using the Rockwood classification (excluding type IV) and rating agreement was derived using the multirater κ statistic.Moderate rating agreement was found among orthopedic surgeons (κ = 0.5147), which was higher than among radiologists (κ = 0.3628) or EM physicians (κ = 0.1894). Interdisciplinary rating agreement was highest between orthopedic surgeons and MSK radiologists and lowest between MSK radiologists and EM physicians. Attending orthopedic surgeons showed the highest rating agreement (κ = 0.5167) compared with attending MSK radiologists (κ = 0.3585) and attending EM physicians (κ = 0.2612). In-training orthopedic surgeons had higher rating agreement (κ = 0.4918) than in-training MSK radiologists (κ = 0.4218) and in-training EM physicians (κ = 0.1410).Orthopedic surgeons exhibited the highest intradepartmental rating agreement in assessing AC joint injuries, but interdepartmental rating agreement was low. It is unclear if low interdepartmental rating agreement reflects classification or training weaknesses; recognition of these differences may help develop a more standardized education for physicians to improve the management of AC joint injuries.Interdisciplinary rating agreement of AC joint injuries is low. Further study may help improve education and communication about AC joint injuries among physicians.