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Objective: Meniscus tear is a known risk factor for osteoarthritis (OA). Quantitative assessment of meniscus degeneration, prior to surface break-down, is important to identification of early disease potentially amenable to therapeutic interventions. This work examines the diagnostic potential of ultrashort echo time-enhanced T2∗ (UTE-T2∗) mapping to detect human meniscus degeneration in vitro and in vivo in subjects at risk of developing OA.Design: UTE-T2∗ maps of 16 human cadaver menisci were compared to histological evaluations of meniscal structural integrity and clinical magnetic resonance imaging (MRI) assessment by a musculoskeletal radiologist. In vivo UTE-T2∗ maps were compared in 10 asymptomatic subjects and 25 ACL-injured patients with and without concomitant meniscal tear.Results: In vitro, UTE-T2∗ values tended to be lower in histologically and clinically normal meniscus tissue and higher in torn or degenerate tissue. UTE-T2∗ map heterogeneity reflected collagen disorganization. In vivo, asymptomatic meniscus UTE-T2∗ values were repeatable within 9% (root-mean-square average coefficient of variation). Posteromedial meniscus UTE-T2∗ values in ACL-injured subjects with clinically diagnosed medial meniscus tear (n=10) were 87% higher than asymptomatics (n=10, P<0.001). Posteromedial menisci UTE-T2∗ values of ACL-injured subjects without concomitant medial meniscal tear (n=15) were 33% higher than asymptomatics (P=0.001). Posterolateral menisci UTE-T2∗ values also varied significantly with degree of joint pathology (P=0.001).Conclusion: Significant elevations of UTE-T2∗ values in the menisci of ACL-injured subjects without clinical evidence of subsurface meniscal abnormality suggest that UTE-T2∗ mapping is sensitive to sub-clinical meniscus degeneration. Further study is needed to determine whether elevated subsurface meniscus UTE-T2∗ values predict progression of meniscal degeneration and development of OA. [ABSTRACT FROM AUTHOR]

Introduction: Ultrashort echo-time enhanced T2∗ (UTE-T2∗) mapping of articular cartilage is a novel quantitative MRI technique with the potential to visualize deep cartilage characteristics better than standard T2 mapping. The feasibility and intersession repeatability of UTE-T2∗ mapping of cartilage in vivo has not previously been evaluated.Methods: Eleven asymptomatic subjects underwent repeat UTE-T2∗ imaging on a whole-body 3T MRI scanner on three consecutive days. Full-thickness, superficial and deep regions of interest (ROIs) were evaluated in the central weight-bearing zones of the medial femoral condyle (cMFC) and tibial plateau (cMTP). Intersession precision error across subjects was evaluated by the root-mean-square average coefficients of variation (RMSA-CV) and by the median of intra-subject standard deviations (SDs) of UTE-T2∗ values in each ROI.Results: UTE-T2∗ values in vivo were found to be repeatable with relative (RMSA-CV) intersession precision errors of 8%, 6%, 16% for full-thickness, superficial and deep cMFC ROIs, corresponding to absolute errors (SD) of 1.2, 1.5, 1.5 ms, respectively. In cMTP tissue, UTE-T2∗ relative repeatability was 8%, 8%, 13%, corresponding to absolute repeatability of 1.0, 1.5, 2.1 ms (full-thickness, superficial, deep). UTE-T2∗ values were higher in superficial cartilage compared to deep in both cMFC (P≪0.001) and cMTP (P=0.0004) regions.Conclusion: In vivo 3D UTE-T2∗ mapping at 3T is feasible and can be implemented using a standard clinical MRI scanner and knee coil. Intersession precision error of UTE-T2∗ values in full-thickness ROIs in the weight-bearing regions of asymptomatic subjects is under 1.2 ms or 8% (RMSA-CV). Significant zonal and regional variations of UTE-T2∗ were seen. [ABSTRACT FROM AUTHOR]

The limited repair potential of human articular cartilage contributes to development of debilitating osteoarthritis and remains a great clinical challenge. This has led to evolution of cartilage treatment strategies from palliative to either reconstructive or reparative methods in an attempt to delay or 'bridge the gap' to joint replacement. Further development of tissue engineering-based cartilage repair methods have been pursued to provide a more functional biological tissue. Currently, tissue engineering of articular cartilage has 3 cornerstones; a cell population capable of proliferation and differentiation into mature chondrocytes; a scaffold that can host these cells, provide a suitable environment for cellular functioning, and serve as a sustained-release delivery vehicle of chondrogenic growth factors; and finally, signaling molecules and growth factors that stimulate the cellular response and the production of a hyaline extracellular matrix. The aim of this review is to summarize advances in each of these 3 fields of tissue engineering, with specific relevance to surgical techniques and technical notes. © 2010 Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Objective: To examine the sensitivity of ultra-short echo time (UTE) T(2)* mapping to collagen matrix degeneration in human articular cartilage.Methods: Magnetic resonance imaging (MRI) UTE-T(2)* maps and standard T(2) maps were acquired on four human tibial plateau explants. Thirty-three osteochondral cores were harvested for polarized light microscopy (PLM), and composition analyses. Collagen matrix integrity was evaluated from PLM and histological images. Matrix integrity and composition was compared to standard T(2) values and UTE-T(2)* values on a spatially registered basis.Results: UTE-T(2)* values varied with matrix degeneration (P=0.008) and were lower in severely degraded cartilage compared to healthy tissue (P=0.012). A trend for higher UTE-T(2)* values in healthy tissue compared to mildly degenerate tissue (P=0.051) was detected. Standard T(2) values were not found to vary with matrix degeneration (P=0.13) but tended to be higher in severely degraded cartilage compared to healthy tissue. UTE-T(2)* value variations were independent of type-II collagen and glycosaminoglycan contents. UTE-T(2)* mapping of deep cartilage, adjacent to subchondral bone, was more robust than standard T(2) mapping in this zone.Conclusion: UTE-T(2)* mapping of articular cartilage is sensitive to matrix degeneration and detects short-T(2) signal, particularly in deep tissue, that is not well captured by standard T(2) mapping. Correlation of UTE-T(2)* values and PLM indices supports the hypothesis that both may be sensitive to collagen microstructure. Further exploration of UTE-T(2)* mapping as a non-invasive tool to detect early articular cartilage degeneration is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND: Intra-articular lidocaine is commonly used. PURPOSE: This study was conducted to determine whether short-term exposures to 1% and 2% lidocaine are toxic to articular chondrocytes, whether this is due to pH, and whether an intact articular surface is protective. STUDY DESIGN: Controlled laboratory study. METHODS: Fresh bovine articular chondrocytes in alginate bead cultures were treated with 1% or 2% lidocaine or buffered saline (pH 7.4, 7.0, and 5.0) for 15, 30, or 60 minutes. Chondrocytes were then analyzed for viability by flow cytometry 1 hour, 1 day, and 1 week later. Bovine osteochondral cores with and without the superficial 1 mm of cartilage removed were submerged in either 0.9% saline (pH 7.4) or in 1% or 2% lidocaine for 30 minutes and assessed for viability using fluorescent microscopy. RESULTS: Chondrocyte viability decreased after just 15-minute exposures to 1% lidocaine. Longer exposures to 1% and 2% lidocaine further reduced chondrocyte viability. Chondrotoxicity of 2% lidocaine was greater than 1% lidocaine. There was no difference in chondrocyte viability after exposures to saline solutions of pH 7.4, 7.0, or 5.0. An intact articular surface did not affect lidocaine's chondrotoxic effects. CONCLUSION: Results show dose- and time-dependent cytotoxic effects of lidocaine on bovine articular chondrocytes. Reduction of pH alone did not decrease chondrocyte viability, and the intact articular surface was not protective. CLINICAL RELEVANCE: Although lidocaine chondrotoxicity was less than previously reported with bupivacaine, these observations suggest that local anesthetics as a class of drugs may negatively affect articular cartilage. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether oxygen-dependent activation patterns of hypoxia-inducible factor 1alpha (HIF-1alpha) observed in vascularized tissues are conserved within avascular and hypoxic articular cartilage and whether HIF-1alpha affects cartilage matrix synthesis. METHODS: Explants of bovine articular cartilage and primary chondrocytes were exposed to normoxia (21% O2), hypoxia (2% O2), and simulated hypoxia (21% O2 plus CoCl2). Western blot and immunofluorescence analyses of HIF-1alpha were performed to determine HIF-1alpha activation patterns. To simulate cartilage loss from disease or injury, the top layers of cartilage were removed from osteochondral explants, and the residual cartilage was assessed for HIF-1alpha immunolocalization and proteoglycan synthesis. RESULTS: We demonstrated continuous nuclear translocation of HIF-1alpha in deeper layers of intact articular cartilage. HIF-1alpha was not completely degraded in chondrocytes exposed to normoxia, but rather, colocalized to the Golgi complex, a finding not previously reported for any cell type. Following alteration of the oxygen gradient by removal of the top layers of cartilage, predominantly perinuclear HIF-1alpha was found in the deeper layers. Restoration of intranuclear HIF-1alpha to these areas was achieved by hypoxia and simulated hypoxia. Under conditions in which HIF-1alpha was inactivated, matrix synthetic activity was altered (P < 0.0001) compared with control cartilage. CONCLUSION: These findings demonstrate that hypoxia-dependent activation of HIF-1alpha is highly conserved and that changes in oxygen tensions following cartilage loss from injury or disease alter cartilage metabolism in part by changing HIF-1alpha activity. The discovery of tonic activation of HIF-1alpha within intact articular cartilage underscores its potential importance to cartilage homeostasis. [ABSTRACT FROM AUTHOR]

Background: Cartilage T 2 can detect joints at risk of developing osteoarthritis. The quantitative double-echo steady state (qDESS) sequence is attractive for knee cartilage T 2 mapping because of its acquisition time of under 5 minutes. Understanding the reproducibility errors associated with qDESS T 2 is essential to profiling the technical performance of this biomarker., Purpose: To examine the combined acquisition and segmentation reproducibility of knee cartilage qDESS T 2 using two different regional analysis schemes: 1) manual segmentation of subregions loaded during common activities and 2) automatic subregional segmentation., Study Type: Prospective., Subjects: 11 uninjured participants (age: 28 ± 3 years; 8 (73%) female)., Field Strength/sequence: 3-T, qDESS., Assessment: Test-retest T 2 maps were acquired twice on the same day and with a 1-week interval between scans. For each acquisition, average cartilage T 2 was calculated in four manually segmented regions encompassing tibiofemoral contact areas during common activities and 12 automatically segmented regions from the deep-learning open-source framework for musculoskeletal MRI analysis (DOSMA) encompassing medial and lateral anterior, central, and posterior tibiofemoral regions. Test-retest T 2 values from matching regions were used to evaluate reproducibility., Statistical Tests: Coefficients of variation (%CV), root-mean-square-average-CV (%RMSA-CV), and intraclass correlation coefficients (ICCs) assessed test-retest T 2 reproducibility. The median of test-retest standard deviations was used for T 2 precision. Bland-Altman (BA) analyses examined test-retest biases. The smallest detectable difference (SDD) was defined as the BA limit of agreement of largest magnitude. Significance was accepted for P < 0.05., Results: All cartilage regions across both segmentation schemes demonstrated intraday and interday qDESS T 2 CVs and RMSA-CVs of ≤5%. T 2 ICC values >0.75 were observed in the majority of regions but were more variable in interday tibial comparisons. Test-retest T 2 precision was <1.3 msec. The T 2 SDD was 3.8 msec., Data Conclusion: Excellent CV and RMSA-CV reproducibility may suggest that qDESS T 2 increases or decreases >5% (3.8 msec) could represent changes to cartilage composition., Technical Efficacy: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

The United States is a nation of diverse racial and ethnic origins. Athletes represent the full spectrum of the nation's population. However, the orthopedic surgeons who serve as team physicians are Caucasian and male with staggeringly few exceptions. This manuscript provides an overview of the current status and barriers to diversity among orthopedic team physicians, along with strategies to address the issue. Specifically, pipeline initiatives implemented at one academic medical school and orthopedic surgery department are summarized as potential models that can be further developed by other institutions to enhance diversity in orthopedic surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

Abstract: Improving the performance and impact of orthopaedic research is a critical leadership challenge. Musculoskeletal (MSK) conditions are a leading cause of disability worldwide, for which research investment and performance lags far behind the burden of disease. In the United States, MSK disorders account for the highest health care costs, have increased in incidence at the fastest rate, and exceed the combined costs of cardiovascular diseases and neoplasms. Despite the cost to society, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), with primary responsibility for MSK research, receives <1.4% of the funds allocated to the National Institutes of Health (NIH). Although orthopaedic surgeons are leading providers of MSK clinical care, the dearth of orthopaedic clinician-scientists also greatly reduces representation of MSK scientific and clinical expertise among academic and scientific leaders. The goals of this symposium were to highlight the critical need for greater prioritization and investment in orthopaedic research and to engage orthopaedic leaders in addressing these needs. Compelling stories of research success from 3 orthopaedic chairs were featured to highlight how orthopaedic surgeon leadership in bench-to-bedside research substantially advances MSK clinical care. Seminar participants also emphasized the need to improve evidence-based clinical practice for which multicenter prospective cohort and registry studies represent opportunities for broader involvement. Prioritization of orthopaedic clinician-scientist development and formation of multidisciplinary partnerships with basic and translational scientists were emphasized as critical needs to advance MSK health. It is critical for orthopaedic chairs to "be invested in" and to "invest in" the success of orthopaedic research. This investment includes developing a professional climate that values research achievement and collaboration as well as implementing strategies to support and sustain research success. Finally, orthopaedic leaders need to advocate for federal research funding to be proportional to the economic burden of disease for which MSK conditions carry the highest current and projected costs. With health-care costs accounting for nearly one-fifth of the U.S. economy, increasing the investment in orthopaedic research to reduce the prevalence, disability, and morbidity from MSK disease needs to be a top orthopaedic and national leadership priority., Competing Interests: Disclosure: No external funding was received for this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H796 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Anterior cruciate ligament (ACL) injury increases risks for osteoarthritis (OA), a poorly modifiable and disabling condition. Joint changes of potentially reversible pre-OA have been described just 2 years after ACL reconstruction (ACLR) when early bone shape changes have also been reported., Purpose: This study evaluates relationships between interlimb differences in tibiofemoral bone shape derived from statistical shape modeling (SSM) of magnetic resonance imaging (MRI) and participant factors on patient-reported outcomes 2 years after unilateral ACLR., Study Design: Cross-sectional study; Level of evidence, 3., Methods: SSM-derived tibiofemoral bone shape and subchondral bone area were assessed from bilateral knee MRI scans of 72 participants with unilateral ACLR (mean age, 34 ± 11 years; 32 women) and compared with a reference cohort of 398 older individuals without OA (mean age, 50 ± 3 years; 213 women). Multivariable logistic regression models examined relationships between participant and surgical factors with interlimb differences in bone shapes or subchondral bone areas. Relationships between patient-reported outcomes and the interlimb differences in bone shape and subchondral area were examined using similar models., Results: Bone shape scores and subchondral bone areas were greater (more OA-like) in ACLR knees than uninjured contralateral knees in every bone metric tested ( P ≤ .001). Interlimb differences in femur shape scores of participants with ACLR were 65% greater ( P < .001) than those of the significantly older reference cohort. Taller height, medial meniscal tears, and decreasing age were associated with larger interlimb differences in shape scores and subchondral areas ( P < .05). Bone-patellar tendon-bone (BPTB) autograft recipients demonstrated greater interlimb subchondral area differences compared with allograft recipients ( P < .05). Interlimb differences for hamstring autograft recipients did not differ from those with BPTB or allograft. Greater interlimb differences in medial femur subchondral areas were associated with worse patient-reported Knee injury and Osteoarthritis Outcome Score Symptoms ( R = 0.27; P = .040)., Conclusion: Even in the absence of radiographic OA, just 2 years after unilateral ACLR patients showed greater bone shape scores and subchondral areas consistent with pre-OA in their ACLR knees. Furthermore, greater medial femur bone areas were weakly associated with worse symptoms. Patients who are younger, are taller, have meniscal tears, or have BPTB grafts may be at increased risk for bony asymmetries 2 years after ACLR., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: Funding for this work was provided by NIH RO1 AR052784 (PI: C.R.C.) and DOD W81XWH-18-1-0590 (PI: C.R.C.). A.B. is employed by and holds stocks and options in Stryker Corporation. C.R.C. has received support for education from Evolution Surgical Inc. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Gene therapy approaches using adeno-associated viral vectors have been successfully tested in the equine post-traumatic osteoarthritis (PTOA) model. Owing to differences in the levels of transgene expression and adverse tissue reactions observed in published studies, we sought to identify a safe therapeutic dose of scAAVIL-1ra in an inflamed and injured joint that would result in improved functional outcomes without any adverse events. scAAVIL-1ra was delivered intra-articularly over a 100-fold range, and horses were evaluated throughout and at the end of the 10-week study. A dose-related increase in IL-1ra levels with a decrease in PGE 2 levels was observed, with the peak IL-1ra concentration being observed 7 days post-treatment in all groups. Perivascular infiltration with mononuclear cells was observed within the synovial membrane of the joint treated with the highest viral dose of 5 × 10 12 vg, but this was absent in the lower-dosed joints. The second-highest dose of scAAVeqIL-1ra 5 × 10 11 vg demonstrated elevated IL-1ra levels without any cellular response in the synovium. Taken together, the data suggest that the 10-fold lower dose of 5 × 10 11 vg scAAVIL-1ra would be a safe therapeutic dose in an equine model of PTOA., (© 2023. The Author(s).)

A lab-fabricated ocean bottom seismometer was modified and deployed terrestrially to detect low-frequency (<10 Hz) ground vibrations produced by debris flows. A frequency−response test of the new seismometer revealed that it can detect seismic signals at frequencies of 0.3−120 Hz. Its seismic ground motion detection ability was investigated by comparing its measurements of seismic signals produced by rockfalls with those of a geophone. Two new seismometers were deployed at the Aiyuzi Stream, Nantou County, Taiwan, in September 2012. Seismic signals produced by two local earthquakes, two teleseisms, and three debris flows detected by the seismometer in 2013 and 2014 were discussed. The seismic signal frequencies of the local earthquakes and teleseisms (both approximately 1800 km apart) were 0.3−30 and <1 Hz, respectively. Moreover, seismometer measurements revealed that seismic signals generated by debris flows can have minimum frequencies as low as 2 Hz. Time-matched CCD camera images revealed that debris flow surge fronts with larger rocks have lower minimum frequencies. Finally, because the seismometer can detect low-frequency seismic waves with low spatial decay rates, it was able to detect one debris flow approximately 3 min and 40 s before it arrived.

Mechanical factors have been implicated in the development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction. This study tested for associations between ambulatory joint loading (total joint moment [TJM] and vertical ground reaction force [vGRF]) and changes in serum levels of cartilage oligomeric matrix protein (COMP) in response to a mechanical stimulus (30-min walk) in individuals with ACL reconstruction. Twenty-five subjects (mean age: 34.5 ± 9.8 years; 2.2 ± 0.2 years post-surgery) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and TJM first (TJM1) and second (TJM2) peaks. Serum COMP concentrations were measured by enzyme-linked immunosorbent assay immediately before, 3.5 h, and 5.5 h after a 30-min walk. Pearson correlation coefficients and backward stepwise multiple linear regression analysis, with adjustments for age, sex, body mass index, and between-limb speed difference, assessed associations between changes in COMP and between-limb differences in joint loading parameters. Greater TJM1 (R = 0.542, p = 0.005), TJM2 (R = 0.460, p = 0.021), and vGRF (R = 0.577, p = 0.003) in the ACL-reconstructed limb as compared to the contralateral limb were associated with higher COMP values 3.5 h following the 30-min walk. Change in COMP at 5.5 h became a significant predictor of the between-limb difference in TJM1 and vGRF in multivariate analyses after accounting for the between-limb speed difference. These results demonstrate that higher TJM and vGRF in the ACLR limb as compared to the contralateral limb are associated with higher relative COMP levels 3.5 and 5.5 h after a 30-min walk. Future work should investigate the effect of therapies to alter joint loading on the biological response in individuals after ACL reconstruction., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Disruptions in knee biomechanics during walking following anterior cruciate ligament (ACL) injury have been suggested to lead to the development of premature knee osteoarthritis (OA) and to be potential markers of OA risk and targets for intervention. This study investigated if side-to-side differences in early stance peak vertical ground reaction force (vGRF) during walking 2 years after ACL reconstruction are associated with longer-term (10 years post-reconstruction) changes in patient-reported outcomes. Twenty-eight participants (mean age: 28.7 ± 6.4 years) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and completed Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) surveys at 2 years post-surgery (2.2 ± 0.3 years) and completed surveys at follow-up 10 years post-surgery (10.5 ± 0.9 years). Associations between changes (10-2 years) in patient-reported outcomes and between limb-differences in vGRF were assessed with Pearson or Spearman's ρ correlation coefficients and exploratory backwards elimination multiple linear regression analyses. Differences in vGRF between symptomatic progressors and non-progressors were also assessed. The side-to-side difference in vGRF was related to the variability in longer-term changes in patient-reported outcome metrics and distinguished symptomatic progressors from non-progressors. Participants with higher vGRF in the reconstructed (ACLR) limb versus the contralateral limb had worsening of IKDC (R = -0.391, p = 0.040), KOOS pain (ρ = -0.396, p = 0.037), KOOS symptoms (ρ = -0.572, p = 0.001), and KOOS quality of life (R = -0.458, p = 0.014) scores at follow-up. Symptomatic progressors had greater vGRF in the ACLR limb as compared to the contralateral limb at baseline than non-progressors (p = 0.023). These data highlight associations between a simple-to-measure gait metric and the development of long-term clinical symptoms after an ACL injury., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Anterior cruciate ligament (ACL) reconstruction is successful at restoring stability to return ACL injured patients to high-demand work, sports, and recreational activities. The development of posttraumatic osteoarthritis (OA) in roughly half of patients just 10-15 years after ACLR highlight the need to improve clinical care pathways. Graft failure and reinjury rates, which further increase OA risk, also remain high for younger and more active patients. The biological components of joint recovery and graft incorporation, therefore, impact short- and long-term clinical outcomes. Biochemical and magnetic resonance imaging (MRI) data show substantial compromise of articular cartilage metabolism and matrix composition after ACL injury and reconstructive surgery suggesting a potential need for activity modulation in early recovery. Furthermore, joint recovery is variable with compositional MRI studies showing progressive cartilage degeneration 1 and 2 years after ACLR. Biopsy and MRI studies also show high variability in ACL graft characteristics within the 1st year after ACLR followed by continued graft maturation into the 2nd year and beyond. To improve the care of ACL injured patients, there is a critical need for clinical attention and scientific inquiry into timing the reintroduction of higher load activities in relationship to neuromuscular recovery, joint biology, and graft maturation. In addition to symptomatic and mechanical recovery, development and validation of biological markers for joint and cartilage homeostasis as well as ACL graft healing are needed for personalized decision making on rehabilitation needs, reduction of OA risk, and resumption of athletic, recreational, and vocational activities., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Purpose: To compare subjective outcomes and complications of anterior cruciate ligament reconstruction (ACLR) using either bone-patellar tendon-bone (BPTB) or quadriceps tendon (QT) autograft., Methods: A retrospective analysis of prospectively collected data identified consecutive cohorts of patients undergoing ACLR with either BPTB or QT autograft. Patients with less than 12-month follow-up and those undergoing concomitant osteotomies, cartilage restoration, and/or other ligament reconstruction procedures were excluded. Pre- and postsurgical patient-reported outcomes including International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome Score, Patient-Reported Outcomes Measurement Information System (PROMIS), Single Assessment Numeric Evaluation, Tegner, and Marx were compared between groups. Complications requiring reoperation were recorded., Results: One hundred nineteen patients met inclusion criteria, including 39 QT autografts and 80 BPTB autografts. Demographic information was comparable between groups. Mean follow-up was comparable between groups (QT 22.4 ± 10.6 months vs BPTB 28.5 ± 18.5 months, P  = .06). At minimum 12-month follow-up (range 12.0-100.8 months), patients in both groups demonstrated statistically significant improvements in International Knee Documentation Committee (QT 60.0%, P < .0001; BPTB 57.7%, P < .0001), all Knee Injury and Osteoarthritis Outcome Score domains, PROMIS Mobility T-Score (QT 27.2%, P  = .0001; BPTB 23.2%, P < .0001), PROMIS Global Physical Health (QT 14.4%, P  = .002; BPTB 13.4%, P  = .001), PROMIS Physical Function (QT 29.6%, P < .0001; BPTB 37.1%, P < .0001), PROMIS Pain Interference (QT -16.5%, P < .0001; BPTB -20.8%, P < .0001), Single Assessment Numeric Evaluation, (QT 76.9%, P  < .0001; BPTB 73.3%, P < .0001), Tegner (QT 92.9%, P  = .0002; BPTB 101.4%, P < .0001), and Marx (QT -26.6%, P  = .02; BPTB -32.0%, P  = .0002) with no statistically significant differences between the 2 groups. Overall postoperative reoperation rate did not differ between groups (QT 12.8% vs BPTB 23.8%, P  = .2). Revision ACL reconstruction rate did not differ between groups (QT 5.1% vs BPTB 7.5%, P  = .6)., Conclusions: Patients undergoing autograft ACLR with either BPTB or QT demonstrated significant subjective improvements in patient-reported outcomes from preoperative values and no statistically significant differences in outcomes between the groups. Complication and revision ACLR rates were similar between the 2 groups., Level of Evidence: III, retrospective cohort study., (© 2021 The Authors.)

Objective: Anterior cruciate ligament reconstruction (ACLR) has not been shown to decrease the risk for development of post-traumatic osteoarthritis. Magnetic resonance imaging (MRI) T2 mapping can be used to assess cartilage compositional changes. This study tests whether (1) worse cartilage arthroscopic status at ACLR is reflected by higher cartilage T2 values in matched study regions 6 weeks and 1 year after ACLR, and (2) increasing cartilage T2 values between 6 weeks and 1 year after ACLR are associated with worsening patient-reported outcomes., Design: Twenty-two participants with ACLR and 26 controls underwent 3T MRI. T2 values in medial and lateral femoral and tibial cartilage were measured at 6 weeks and 1 year after ACLR and compared with arthroscopic grades, Knee injury and Osteoarthritis Outcome Scores (KOOS), and control T2 values., Results: Most (59%-86%) cartilage study regions examined by arthroscopy demonstrated intact articular surfaces. Average T2 value increased in 3 of 4 study regions between 6 weeks and 1 year after ACLR ( P = .001-.011). T2 value increased ( P < .013) even for participants whose cartilage had intact articular surfaces at ACLR. Participants with ACLR who showed greater increases in cartilage T2 values had less improvement to KOOS Quality of Life ( P = .009, ρ = -0.62)., Discussion: Cartilage status assessed arthroscopically at ACLR and by MRI T2 maps 6 weeks later was healthier than cartilage status assessed by MRI T2 maps at 1-year follow-up. Progressive T2 elevations were observed over the first year after ACLR even in patients with arthroscopically intact cartilage at the time of surgery and were associated with reduced improvement in knee quality of life suggesting preosteoarthritis.

Background: Various surgical treatment options exist for repairing, replacing, or regenerating tissue to fill osteochondral defects. Biologic augmentation has been increasingly studied as an adjunct in the surgical treatment of osteochondral defects of the knee in animal and human models., Purpose/hypothesis: The purpose of the study was to systematically review use of platelet-rich plasma (PRP) and bone marrow concentrate (BMC) augmentation in the surgical treatment of osteochondral knee defects and to describe the outcomes. It was hypothesized that both PRP and BMC augmentation will result in improved outcomes in osteochondral knee surgery in both animal and human models., Study Design: Systematic review., Methods: PubMed, MEDLINE, and Embase were searched for studies relating to PRP or BMC and treatment of osteochondral defects of the knee, from database inception to February 1, 2020. Included were articles that (1) studied PRP or BMC augmentation; (2) used osteochondral autograft, allograft, or biologic scaffold; and (3) treated osteochondral defects in the knee. Data on use of PRP or BMC, outcomes assessed, and results were recorded for each publication., Results: Of the 541 articles identified initially, 17 were included in the final review. Five articles studied osteochondral grafts in animals, 5 studied biologic scaffolds in animals, and 7 studied scaffolds or allografts in humans; the combined sample size was 202 patients. Of 4 histologic scaffold studies, 3 PRP-augmented scaffold studies identified histologic improvements in regenerated cartilage in animal models, while 1 BMC study demonstrated similar improvement in histologic scores of BMC-augmented scaffolds compared with controls. Three studies associated greater collagen type 2 and glycosaminoglycan content with PRP treatment. Comparative studies found that both augments increase osteogenic proteins, including bone morphogenetic protein-2 and osteoprotegerin. Two of 3 studies on BMC-augmented osteochondral allografts reported no difference in radiographic features postoperatively. Long-term improvement in clinical and radiographic outcomes of PRP-augmented scaffolds was demonstrated in 1 human study., Conclusion: Animal studies suggest that biologics possess potential as adjuncts to surgical treatment of osteochondral knee defects; however, clinical data remain limited., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: D.V.C. has received education payments from Evolution Surgical. C.R.C. has received honoraria from Fidia Pharma. G.D.A. has received education payments from Evolution Surgical and royalties from Orthofix Medical. M.R.S. has received consulting fees from Anika Therapeutics, Linvatec, Medacta, and Smith & Nephew; speaking fees from Linvatec and Smith & Nephew; royalties from Smith & Nephew; and honoraria from Medacta. S.L.S. has received grant support from DJO; education payments from Elite Orthopedics and Evolution Surgical; consulting fees from Ceterix, Flexion Therapeutics, JRF Ortho, Linvatec, Vericel, Olympus America, and Smith & Nephew; nonconsulting fees from Arthrex and Vericel; honoraria from Vericel; royalties from Linvatec; and hospitality payments from Aesculap Biologics. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Osteoarthritis (OA) is a leading cause of pain and disability for which disease-modifying treatments remain lacking. This is because the symptoms and radiographic changes of OA occur after the onset of likely irreversible changes. Defining and treating earlier disease states are therefore needed to delay or to halt OA progression. Taking this concept a step further, studying OA pathogenesis before disease onset by characterizing potentially reversible markers of increased OA risk to identify a state of "pre-osteoarthritis (pre-OA)" shifts the paradigm towards OA prevention. The purpose of this review is to summarize the 42 studies comprising the 2019 Kappa Delta Elizabeth Lanier Award where conceptualization of a systems-based definition for "pre-osteoarthritis (pre-OA)" was followed by demonstration of potentially reversible markers of heightened OA risk in patients after anterior cruciate ligament (ACL) injury and reconstruction. In the process, these efforts contributed a new magnetic resonance imaging method of ultrashort echo time (UTE) enhanced T2* mapping to visualize joint tissue damage before the development of irreversible changes. The studies presented here support a transformative approach to OA that accounts for interactions between mechanical, biological, and structural markers of OA risk to develop and evaluate new treatment strategies that can delay or prevent the onset of clinical disease. This body of work was inspired by and performed for patients. Shifting the paradigm from attempting to modify symptomatic radiographic OA towards monitoring and reversing markers of "pre-OA" opens the door for transforming the clinical approach to OA from palliation to prevention., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Rather than using wooden sticks to simulate the breakage of trees in high winds as in most research, we employ fresh samples from camphor and Formosa gum with branches and leaves to certify the crucial role of the tree crown. By using a blowdown wind tunnel with a maximum wind speed of 50 m/s, we purposely reduce the number of leaves and show that the drag force will drop by as much as two thirds when half pruned. Based on real observations, we model the leaf by an open and full cone in the presence of light and strong winds, and calculate how their corresponding cross-sectional area A and drag force F vary with wind speed v. Different slopes before and after the formation of a full cone are predicted and confirmed when these two quantities are plotted in full-log scale. Compared to the empirical value, our simple model gave α=2/5 and 2/3 for A∝v^{-α} and β=4/5 and 2/3 for F∝v^{β} at low and high winds. Discrepancies can be accounted for by including further details, such as the reorientation of open cones and the movement of branches.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA., Competing Interests: One or more of the authors has declared a potential conflict of interest or source of funding: see supplemental material for details. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Objective: To address the need for early knee osteoarthritis (OA) markers by testing if longitudinal cartilage thickness changes are associated with specific biomechanical and biological measures acquired at a baseline test in asymptomatic aging subjects., Design: Thirty-eight asymptomatic subjects over age 45 years were studied at baseline and at an average of 7-9 year follow-up. Gait mechanics and knee MRI were measured at baseline and MRI was obtained at follow-up to assess cartilage thickness changes. A subset of the subjects (n = 12) also had serum cartilage oligomeric matrix protein measured at baseline in response to a mechanical stimulus (30-min walk) (mCOMP). Baseline measures, including the knee extension (KEM), flexion (KFM), adduction (KAM) moments and mCOMP, were tested for associations with cartilage thickness changes in specific regions of the knee., Results: Cartilage change in the full medial femoral condyle (p = 0.005) and external medial femoral region (p = 0.041) was negatively associated with larger early stance peak KEM. Similarly, cartilage change in the full medial femoral region (p = 0.009) and medial femoral external region (p = 0.043) was negatively associated with larger first peak KAM, while cartilage change in the anterior medial tibia was positively associated with larger first peak KAM (p = 0.003). Cartilage change in the anterior medial tibia was also significantly associated (p = 0.011) with mCOMP levels 5.5-h post-activity (percentage of pre-activity levels)., Conclusions: Interactions found between gait, mechanically-stimulated serum biomarkers, and cartilage thickness in an at-risk aging asymptomatic population suggest the opportunity for early detection of OA with new approaches that bridge across disciplines and scales., Competing Interests: Declaration of competing interest There are no conflicts of interest for any of the authors., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Patellofemoral joint degeneration and dysfunction after anterior cruciate ligament reconstruction (ACLR) are increasingly recognized as contributors to poor clinical outcomes., Purpose: To determine if greater deep cartilage matrix disruption at 2 years after ACLR, as assessed by elevated patellofemoral magnetic resonance imaging (MRI) ultrashort echo time-enhanced T2* (UTE-T2*), is correlated with (1) worse patient-reported knee function and pain and (2) gait metrics related to patellofemoral tracking and loading, such as greater external rotation of the tibia at heel strike, reduced knee flexion moment (as a surrogate of quadriceps function), and greater knee flexion angle at heel strike., Study Design: Cross-sectional study; Level of evidence, 3., Methods: MRI UTE-T2* relaxation times in patellar and trochlear deep cartilage were compared with patient-reported outcomes and ambulatory gait metrics in 60 patients with ACLR at 2 years after reconstruction. ACLR gait metrics were compared with those of 60 uninjured reference patients matched by age, body mass index, and sex. ACLR UTE-T2* values were compared with those of 20 uninjured reference patients., Results: Higher trochlear UTE-T2* values were associated with worse Knee injury and Osteoarthritis Outcome Scores (KOOS) Sport/Recreation subscale scores (rho = -0.32; P = .015), and showed a trend for association with worse KOOS Pain subscale scores (rho = -0.26; P = .045). At 2 years after ACLR, greater external rotation of the tibia at heel strike was associated with higher patellar UTE-T2* values ( R = 0.40; P = .002); greater knee flexion angle at heel strike was associated with higher trochlear UTE-T2* values (rho = 0.39; P = .002); and greater knee flexion moment showed a trend for association with higher trochlear UTE-T2* values (rho = 0.30; P = .019). Patellar cartilage UTE-T2* values, knee flexion angle at heel strike, and external rotation of the tibia at heel strike were all elevated in ACLR knees as compared with reference knees ( P = .029, .001, and .044, respectively)., Conclusion: Patellofemoral deep cartilage matrix disruption, as assessed by MRI UTE-T2*, was associated with reduced sports and recreational function and with gait metrics reflective of altered patellofemoral loading. As such, the findings provide new mechanistic information important to improving clinical outcomes related to patellofemoral dysfunction after ACLR.

This study aimed to determine if changes in knee adduction moment (KAM) after 6 months of variable-stiffness shoe wear are associated with changes in symptoms or serum levels of cartilage oligomeric matrix protein (COMP) following a mechanical stimulus in subjects with medial knee osteoarthritis (OA). Twenty-five subjects were enrolled in the study and assigned a variable-stiffness shoe, and 19 subjects completed the 6-month follow-up. At baseline and follow-up subjects underwent gait analysis in control and variable-stiffness shoes, completed Western Ontario and McMaster Universities (WOMAC) questionnaires, and serum COMP concentrations were measured immediately before, 3.5 and 5.5 hours after a 30-minute walking activity. Relationships between changes in KAM (first peak and impulse) and changes in (a) COMP levels in response to the 30-minute walking activity and (b) WOMAC scores from baseline to 6-month follow-up were assessed by Pearson correlation coefficients. Changes in first peak KAM were associated with changes in COMP levels 5.5 hours postactivity from baseline to follow-up (R = .564, P = .045). Subjects with greater reductions in KAM had larger decreases in COMP (expressed as a percent of preactivity levels) at follow-up. Subjects with greater reductions in KAM impulse had significantly greater improvements in WOMAC Pain (R = -.56, P = .015) and Function (R = -.52, P = .028) scores at follow-up. The study results demonstrated the magnitude of reduction in the KAM wearing a variable-stiffness shoe is associated with decreases in mechanically stimulated COMP levels and pain/function. This work suggests that interactions between COMP and joint loading during walking should be further investigated in future studies of treatment outcomes in OA., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Pain and proprioception deficits are often associated with knee pathologies and resultant quadriceps muscle inhibition. There is a need for new approaches to mitigate active knee pain and restore muscle function during walking. Activating properties of the somatosensory system with common pain and sensory pathways offers a novel opportunity to enhance quadriceps function during walking., Research Question: Conduct a controlled clinical trial that investigates the effects of applying intermittent vibrational cutaneous stimulation during walking on knee pain and symptoms and their correlations to gait parameters., Methods: This longitudinal controlled cross-over clinical study included thirty-two patients randomly and blindly assigned to active Treatment A and passive Treatment B for 4 weeks with a 2-week washout period between treatments., Results: Subjects when wearing active Treatment A for 4 weeks had significant (p = 0.04) improvement in patient reported outcomes, while they had no significant differences with passive Treatment B (p > 0.7) compared to the no treatment condition. For Treatment A, subjects with low knee flexion moment and knee flexion angle in no-treatment condition exhibited the greatest increase in knee flexion moment/angle in the active treatment condition (R > 0.57, p < 0.001). These changes in gait measures were correlated significantly to changes in pain., Significance: This clinical trial indicates that knee pain can be reduced, and gait improved in a manner that enhances quadriceps function by applying intermittent cutaneous stimulation during gait in patients following knee injury or disease. The correlation between decreased pain and improved gait suggests that rehabilitation and exercise therapy may benefit from this treatment., Competing Interests: Declaration of Competing Interest On behalf of my co-authors, I declare that this manuscript “Utilizing the Somatosensory System via Vibratory Stimulation to Mitigate Knee Pain during Walking: Randomized Clinical Trial” is original work, has not been published before and is not currently being considered for publication elsewhere. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.

Objective: To stimulate future research directions that seek solutions for osteoarthritis (OA) at the interface between diverse disciplines and address osteoarthritis (OA) as a serious disease with a complexity that has presented a barrier to finding safe effective solutions., Methods: Sessions were conducted at the 2019 meetings of the Orthopaedic Research Society (ORS) and Osteoarthritis Research Society International (OARSI) that included presentations and questions/comments submitted from leading OA researchers representing imaging, mechanics, biomarkers, phenotyping, clinical, epidemiology, inflammation and exercise., Results: Solutions for OA require a paradigm shift in research and clinical methods in which OA is contextualized as a complex whole-body/person disease. New OA definition(s)/phenotype(s) and OA markers/signals are needed to address the interplay between genetic and environmental factors of the disease as well as capture the mechanosensitivity of the disease. The term "Mechanokines" was proposed to highlight the importance of incorporating whole body mechanics as a marker of early OA. New interventions and apparent paradoxical observations/questions (e.g. exercise vs. load modification) were also discussed in the context of considering OA as a complex system., Conclusion: To advance new OA treatments that are safe and effective, OA should be considered as a "Whole Person" disease. This approach requires a concerted effort to bridge disciplines and include interactions across scales from the molecule to the whole body, including psychosocial aspects., Competing Interests: The authors have nothing to disclose regarding the content of this manuscript., (© 2020 The Authors.)

Juvenile chondrocytes are robust in regenerating articular cartilage, but their clinical application is hindered by donor scarcity. Stem cells offer an abundant autologous cell source but are limited by slow cartilage deposition with poor mechanical properties. Using 3D co-culture models, mixing stem cells and chondrocytes can induce synergistic cartilage regeneration. However, the resulting cartilage tissue still suffers from poor mechanical properties after prolonged culture. Here we report a microribbon/hydrogel composite scaffold that supports synergistic interactions using co-culture of adipose-derived stem cells (ADSCs) and neonatal chondrocytes (NChons). The composite scaffold is comprised of a macroporous, gelatin microribbon (μRB) scaffolds filled with degradable nanoporous chondroitin sulfate (CS) hydrogel. We identified an optimal CS concentration (6%) that best supported co-culture synergy in vitro. Furthermore, 7 days of TGF-β3 exposure was sufficient to induce catalyzed cartilage formation. When implanted in vivo, μRB/CS composite scaffold supported over a 40-fold increase in compressive moduli of cartilage produced by mixed ADSCs/NChons to ~330 kPa, which surpassed even the quality of cartilage produced by 100% NChons. Together, these results validate μRB/CS composite as a promising scaffold for cartilage regeneration using mixed populations of stem cells and chondrocytes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of αVβ3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVβ3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVβ3 and CD47 signaling in OA pathogenesis and suggest that activation of αVβ3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting αVβ3, CD47, and their signaling pathways as a disease-modifying therapy.

Background: Noninvasive quantitative magnetic resonance imaging (MRI) measures to assess anterior cruciate ligament (ACL) graft maturity are needed to help inform return to high-demand activities and to evaluate the effectiveness of new treatments to accelerate ACL graft maturation. Quantitative MRI ultrashort echo time T2* (UTE-T2*) and T2* mapping captures short T2 signals arising from collagen-associated water in dense regular connective tissues, such as tendon, ligament, and maturing grafts, which are invisible to conventional MRI., Hypothesis: Quantitative MRI UTE-T2* and T2* mapping is sensitive to ACL graft changes over the first 2 years after ACL reconstruction (ACLR)., Study Design: Case series; Level of evidence, 4., Methods: A total of 32 patients (18 men; mean ± SD age, 30 ± 9 years) undergoing unilateral ACLR and 30 uninjured age-matched controls (18 men; age, 30 ± 9 years) underwent 3-T MRI examination. Patients who underwent ACLR were imaged at 6 weeks, 6 months, and 1 and 2 years postoperatively. Two separate ACLR cohorts were scanned with 2 MRI platforms at 2 institutions. Twelve ACLR knees were scanned with a 3-dimensional acquisition-weighted stack of spirals UTE sequence on a Siemens scanner, and 20 ACLR knees were scanned with a 3-dimensional Cones UTE sequence on a GE scanner. UTE-T2* or T2* maps were calculated for the intra-articular portion of the ACL graft., Results: Mean ACL graft UTE-T2* and T2* decreased from 1 to 2 years after ACLR. ACL graft T2* increased 25% to 30% during the first 6 months ( P < .013) to a level not different from that of uninjured native ACL ( P > .4), stabilized between 6 months and 1 year ( P ≥ .999), and then decreased 19% between 1 and 2 years after ACLR ( P = .027). At 6-month follow-up, ACL graft UTE-T2* differed from that of tendon ( P < .02) but not uninjured native ACL ( P > .7) and showed the greatest variability among patients., Conclusion: UTE-T2* mapping suggested substantial changes within the graft during the first 6 months postsurgery. T2* and UTE-T2* mapping showed relatively stable graft composition from 6 months to 1 year, consistent with remodeling, followed by decreases from 1 to 2 years, suggestive of continuing maturation. MRI UTE-T2* and T2* mapping demonstrated potential clinical utility as noninvasive quantitative imaging metrics for evaluation of human ACL grafts., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was funded by the National Institutes of Health (AR052784, to C.R.C.). GE Healthcare provided the Cones sequence and sequence support with access to its research magnet installed at Stanford University. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

There is good scientific rationale to support the use of growth factors to promote musculoskeletal tissue regeneration. However, the clinical effectiveness of platelet-rich plasma (PRP) and other blood-derived products has yet to be proven. Characterization and reporting of PRP preparation protocols utilized in clinical trials for the treatment of musculoskeletal disease is highly inconsistent, and the majority of studies do not provide sufficient information to allow the protocols to be reproduced. Furthermore, the reporting of blood-derived products in orthopaedics is limited by the multiple PRP classification systems available, which makes comparison of results between studies challenging. Several attempts have been made to characterize and classify PRP; however, no consensus has been reached, and there is lack of a comprehensive and validated classification. In this annotation, we outline existing systems used to classify preparations of PRP, highlighting their advantages and limitations. There remains a need for standardized universal nomenclature to describe biological therapies, as well as a comprehensive and reproducible classification system for autologous blood-derived products. Cite this article: Bone Joint J 2019;101-B:891-896.

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: QW, CL, HR, LR, MT, HW, Ev, NL, MB, NH, EE, FO, LP, NG, SG, CC, JS, YF, SG, WR No competing interests declared, LS Virginia Commonwealth University collects royalties for the tryptase assay licensed to Thermofisher and for tryptase antibodies licensed to Millipore and Santa Cruz, which are shared with Lawrence B Schwartz, who also is a paid consultant for Genentech., (© 2019, Wang et al.)

Background: Anterior cruciate ligament (ACL) injury is often followed by quadriceps deficits that are apparent with gait analysis. The deficit frequently remains after ACL reconstruction (ACLR). As such, evaluation of ACLR patients could be enhanced by a simple method to detect quadriceps deficits. Analyzing forward trunk flexion during stair ascent has been suggested as an assessment of quadriceps function that can be visualized with relatively simple instrumentation., Aim: The purpose of this study was to determine if trunk flexion angle (TFA) during stair ascent is associated with quadriceps function (as measured by the peak knee flexion moment (KFM)) at 2 and 8 years post-ACLR and if changes are associated with patient-reported outcomes (PRO)., Methods: Fourteen subjects with unilateral primary ACLR performed three stair-ascending trials at two-time periods: 2 years (baseline) and 8 years (follow-up) post-ACLR. Paired Student t-tests determined differences in KFM and TFA. Associations between KFM, TFA, and PRO were determined through Pearson correlations., Results: Peak KFM during stair ascent significantly increased from baseline to follow-up (p = 0.01). Though there was no significant difference in TFA (p = 0.84) compared to baseline, 50% of subjects showed decreases in TFA. Further, subjects with reduced TFA during stair ascent at follow-up had significantly increased peak KFM (p = 0.029) and improvements in PRO (p = 0.001)., Discussion: The results suggest that TFA during stair ascent can provide a simple method to assess changes in quadriceps function and pain over time following ACLR. Further analysis is needed to draw conclusions between knee osteoarthritis development and increases in TFA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alteration of deep cartilage matrix has been observed following anterior cruciate ligament (ACL) injury, evidenced by elevated MRI UTE-T2* values measured in small, 2-D cartilage regions of interest. This Level I diagnostic study seeks to more thoroughly evaluate deep cartilage matrix changes to medial tibiofemoral UTE-T2* maps 2 years after ACL reconstruction and examine the relative utilities of 3-D compared to 2-D assessments of cartilage UTE-T2* maps. Thirty-eight ACL-reconstructed and 20 uninjured subjects underwent MRI UTE-T2* mapping. "Small" single mid-sagittal 2-D and larger 3-D "tread mark" regions of interest were manually segmented and found to be correlated in medial cartilage (r > 0.58, p < 0.005). 3-D analyses of UTE-T2* maps showed differences to medial tibial cartilage between ACL-reconstructed and uninjured subjects (p = 0.007) that were not detected by smaller 2-D regions (p > 0.46). Quantitative comparisons show 14/38 (37%) ACL-reconstructed subjects have values >2 standard deviations higher than uninjured controls. Among a subset of ACL-reconstructed subjects with no morphologic MRI evidence of medial tibiofemoral cartilage or meniscal pathology (n = 12), elevated UTE-T2* values in "small" 2-D femoral (p = 0.011), but not larger 3-D tread mark regions of interest (p > 0.13), were observed. These data show the utility of 2-D UTE-T2* assessments of mid-sagittal weight-bearing regions of medial femoral cartilage for identifying subclinical deep cartilage matrix changes 2 years after ACLR. Clinical Significance: Mid-sagittal single slice 2-D UTE-T2* mapping may be an efficient means to assess medial femoral cartilage for subsurface matrix changes early after ACL reconstruction while 3-D assessments provide additional sensitivity to changes in the medial tibial plateau. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:370-377, 2019., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Concern that misinformation from direct-to-consumer marketing of largely unproven "biologic" treatments such as platelet-rich plasma and cell-based therapies may erode the public trust and the responsible investment needed to bring legitimate biological therapies to patients have resulted in calls to action from professional organizations and governing bodies. In response to substantial patient demand for biologic treatment of orthopaedic conditions, the American Academy of Orthopaedic Surgeons convened a collaborative symposium and established a consensus framework for improving and accelerating the clinical evaluation, use, and optimization of biologic therapies for musculoskeletal diseases. The economic and disease burden of musculoskeletal conditions is high. Of the various conditions discussed, knee osteoarthritis was identified as a "serious condition" associated with substantial and progressive morbidity and emerged as the condition with the most urgent need for clinical trial development. It was also recognized that stem cells have unique characteristics that are not met by minimally manipulated mixed cell preparations. The work group recommended that minimally manipulated cell products be referred to as cell therapy and that the untested and uncharacterized nature of these treatments be clearly communicated within the profession, to patients, and to the public. Minimum standards for product characterization and clinical research should also be followed. A framework for developing clinical trials related to knee OA was agreed upon. In addition to recommendations for development of high-quality multicenter clinical trials, another important recommendation was that physicians and institutions offering biologic therapies commit to establishing high-quality patient registries and biorepository-linked registries that can be used for postmarket surveillance and quality assessments.

Quadriceps muscle rehabilitation following knee injury or disease is often hampered by pain, proprioception deficits or instability associated with inhibition of quadriceps activation during walking. The cross-modal plasticity of the somatosensory system with common sensory pathways including pain, pressure and vibration offers a novel opportunity to enhance quadriceps function during walking. This study explores the effectiveness of an active knee brace that used intermittent cutaneous vibration during walking to enhance the peak knee flexion moment (KFM) during early stance phase as a surrogate for net quadriceps moment (balance between knee extensor and flexor muscle moments). The stimulus was turned on prior to heel strike and turned off at mid-stance of the gait cycle. Twenty-one subjects with knee pathologies known to inhibit quadriceps function were tested walking under three conditions: control (no brace), a passive brace, and an active brace. Findings show that compared to the control, subjects wearing an active brace during gait exhibited a significant (p < 0.001) increase in peak KFM and no significant difference when wearing a passive brace (p = 0.17). Furthermore, subjects with low KFM and knee flexion angle (KFA) in control exhibited the greatest increase in KFA at loading response in the active brace condition (R = 0.47, p < 0.05). Intermittent cutaneous stimulation during gait, therefore, provides an efficient method for increasing the KFM in patients with knee pathologies. This study's results suggest that intermittent vibration stimulus can activate the cross-modalities of the somatosensory system in a manner that gates pain stimulus and possibly restores quadriceps function in patients with knee pain., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The purpose of this study was to longitudinally investigate changes in knee joint kinematics and kinetics from 2 to 8 years post-ACLR. Seventeen subjects with primary unilateral transtibial ACLR performed bilateral gait analysis approximately 2 years and 8 years post-ACLR. Seventeen matched healthy control subjects were also analyzed. Kinematic and kinetic comparisons between the ACLR and contralateral limbs over time were completed using a 2 × 2 (time, limb) repeated-measures ANOVA. Unpaired Student's t-tests were used to compare the ACLR and contralateral kinematics and kinetics to the control group. The ACLR and contralateral limbs had similar gait changes over time. Kinetic changes over time included a reduction in first (p = 0.048) and second (p < 0.001) peak extension moments, internal rotation moment (p < 0.001), adduction moment (first peak: p = 0.002, second peak: p = 0.009, impulse: p = 0.004) and an increase in peak knee flexion moment (p = 0.002). Kinematic changes over time included increases in peak knee flexion angle in the first half of stance (p = 0.026), minimum knee flexion angle in the second half of stance (p < 0.001), and average external rotation angle during stance (p = 0.007), and a reduction in average anterior femoral displacement during stance (p = 0.006). Comparison to healthy controls demonstrated improvement in some gait metrics over time. The results demonstrated longitudinal changes from 2 to 8 years after ACLR in knee joint kinetics and kinematics that have been related to clinical outcome after ACLR and the progression of knee OA, and support future larger and comprehensive investigations into long-term changes in joint mechanics in the ACLR population. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1478-1486, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: Quantitative magnetic resonance imaging (MRI) ultrashort echo time (UTE) T2* is sensitive to cartilage deep tissue matrix changes after anterior cruciate ligament reconstruction (ACLR). This study was performed to determine whether UTE-T2* profile analysis is a useful clinical metric for assessing cartilage matrix degeneration. This work tests the hypotheses that UTE-T2* depthwise rates of change (profile slopes) correlate with clinical outcome metrics of walking mechanics and patient reported outcomes (PRO) in patients 2 years after ACLR., Design: Thirty-six patients 2 years after ACLR completed knee MRI, gait analysis, and PRO. UTE-T2* maps were generated from MRI images and depthwise UTE-T2* profiles were calculated for weight-bearing cartilage in the medial compartment. UTE-T2* profiles from 14 uninjured subjects provided reference values. UTE-T2* profile characteristics, including several different measures of profile slope, were tested for correlation to kinetic and kinematic measures of gait and also to PRO., Results: Decreasing UTE-T2* profile slopes in ACLR knees moderately correlated with increasing knee adduction moments (r = 0.41, P < 0.015), greater external tibial rotation (r = 0.44, P = 0.007), and moderately negatively correlated with PRO (r = -0.36, P = 0.032). UTE-T2* profiles from both ACLR and contralateral knees of ACLR subjects differed from that of uninjured controls (P < 0.015)., Conclusions: The results of this study suggest that decreasing UTE-T2* profile slopes reflect cartilage deep tissue collagen matrix disruption in a population at increased risk for knee osteoarthritis (OA). That UTE-T2* profiles were associated with mechanical and patient reported measures of clinical outcomes support further study into a potential mechanistic relationship between these factors and OA development., (Copyright © 2018. Published by Elsevier Ltd.)

Using serum biomarkers to assess osteoarthritis (OA) disease state and risks of progression remain challenging. This study tested the hypothesis that changes to serum biomarkers in response to a mechanical stimulus in patients with medial knee OA signal cartilage thickness changes 5 years later. Specifically, serum concentrations of a collagen degradation marker (C1,2C) and a chondroitin sulfate synthesis marker (CS846) were measured 0.5 and 5.5 hours after a 30-min walk in 16 patients. Regional cartilage thickness changes measured from magnetic resonance images obtained at study entry and at 5-year follow-up were tested for correlations with baseline biomarker changes after mechanical stimulus, and for differences between groups stratified based on whether biomarker levels increased or decreased. Results showed that an increase in the degradation biomarker C1,2C correlated with cartilage thinning of the lateral tibia (R = -0.63, p = 0.009), whereas an increase in the synthesis marker CS846 correlated with cartilage thickening of the lateral femur (R = 0.76, p = 0.001). Changes in C1,2C and CS846 were correlated (R 2  = 0.28, p = 0.037). Subjects with increased C1,2C had greater (p = 0.05) medial tibial cartilage thinning than those with decreased C1,2C. In conclusion, the mechanical stimulus appeared to metabolically link the biomarker responses where biomarker increases signaled more active OA disease states. The findings of medial cartilage thinning for patients with increases in the degradation marker and correlation of cartilage thickening in the less involved lateral femur with increases in the synthetic marker were consistent with progression of medial compartment OA. Thus, the mechanical stimulus facilitated assessing OA disease states using serum biomarkers. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:891-897, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Anterior cruciate ligament (ACL) injury increases risk for posttraumatic knee osteoarthritis (OA). Quantitative ultrashort echo time enhanced T2* (UTE-T2*) mapping shows promise for early detection of potentially reversible subsurface cartilage abnormalities after ACL reconstruction (ACLR) but needs further validation against established clinical metrics of OA risk such as knee adduction moment (KAM) and mechanical alignment., Hypothesis: Elevated UTE-T2* values in medial knee cartilage 2 years after ACLR correlate with varus alignment and higher KAM during walking., Study Design: Cohort study (diagnosis); Level of evidence, 2., Methods: Twenty patients (mean age, 33.1 ± 10.5 years; 11 female) 2 years after ACLR underwent 3.0-T knee magnetic resonance imaging (MRI), radiography, and gait analysis, after which mechanical alignment was measured, KAM during walking was calculated, and UTE-T2* maps were generated. The mechanical axis and the first and second peaks of KAM (KAM1 and KAM2, respectively) were tested using linear regressions for correlations with deep UTE-T2* values in the central and posterior medial femoral condyle (cMFC and pMFC, respectively) and central medial tibial plateau (cMTP). UTE-T2* values from ACL-reconstructed patients were additionally compared with those of 14 uninjured participants (mean age, 30.9 ± 8.9 years; 6 female) using Mann-Whitney U and standard t tests., Results: Central weightbearing medial compartment cartilage of ACL-reconstructed knees was intact on morphological MRI. Mean UTE-T2* values were elevated in both the cMFC and pMFC of ACL-reconstructed knees compared with those of uninjured knees ( P = .003 and P = .012, respectively). In ACL-reconstructed knees, UTE-T2* values of cMFC cartilage positively correlated with increasing varus alignment ( R = 0.568). Higher UTE-T2* values in cMFC and cMTP cartilage of ACL-reconstructed knees also correlated with greater KAM1 ( R = 0.452 and R = 0.463, respectively) and KAM2 ( R = 0.465 and R = 0.764, respectively) and with KAM2 in pMFC cartilage ( R = 0.602)., Conclusion: Elevated deep UTE-T2* values of medial knee cartilage 2 years after ACLR correlate with 2 clinical markers of increased risk of medial knee OA. These results support the clinical utility of MRI UTE-T2* for early diagnosis of subsurface cartilage abnormalities. Longitudinal follow-up of larger cohorts is needed to determine the predictive and staging potential of UTE-T2* for posttraumatic OA.

Background: Autologous platelet-rich plasma (PRP) is widely used for a variety of clinical applications. However, clinical outcome studies have not consistently shown positive effects. The composition of PRP differs based on many factors. An improved understanding of factors influencing the composition of PRP is important for the optimization of PRP use., Hypothesis: Age and sex influence the PRP composition in healthy patients., Study Design: Controlled laboratory study., Methods: Blood from 39 healthy patients was collected at a standardized time and processed into leukocyte-poor PRP within 1 hour of collection using the same laboratory centrifuge protocol and frozen for later analysis. Eleven female and 10 male patients were "young" (aged 18-30 years), while 8 male and 10 female patients were "older" (aged 45-60 years). Thawed PRP samples were assessed for cytokine and growth factor levels using a multiplex assay and enzyme-linked immunosorbent assay. The platelet count and high-sensitivity C-reactive protein levels were measured. Two-way analysis of variance determined age- and sex-based differences., Results: Platelet and high-sensitivity C-reactive protein concentrations were similar in PRP between the groups ( P = .234). Male patients had higher cytokine and growth factor levels in PRP compared with female patients for inflammatory cytokines such as interleukin-1 beta (IL-1β) (9.83 vs 7.71 pg/mL, respectively; P = .008) and tumor necrosis factor-alpha (TNF-α) (131.6 vs 110.5 pg/mL, respectively; P = .048); the anti-inflammatory IL-1 receptor antagonist protein (IRAP) (298.0 vs 218.0 pg/mL, respectively; P < .001); and growth factors such as fibroblast growth factor-basic (FGF-basic) (237.9 vs 194.0 pg/mL, respectively; P = .01), platelet-derived growth factor (PDGF-BB) (3296.2 vs 2579.3 pg/mL, respectively; P = .087), and transforming growth factor-beta 1 (TGF-β1) (118.8 vs 92.8 ng/mL, respectively; P = .002). Age- but not sex-related differences were observed for insulin-like growth factor-1 (IGF-1) ( P < .001). Age and sex interaction terms were not significant. While mean differences were significant, there was also substantial intragroup variability., Conclusion: This study in healthy patients shows differences in the composition of PRP between men and women, with sex being a greater factor than age. There was also proteomic variability within the groups. These data support a personalized approach to PRP treatment and highlight the need for a greater understanding of the relationships between proteomic factors in PRP and clinical outcomes., Clinical Relevance: Variability in the proteomic profile of PRP may affect tissue and clinical responses to treatment. These data suggest that clinical studies should account for the composition of PRP used.