Reproducibility of Quantitative Double-Echo Steady-State T2 Mapping of Knee Cartilage.

BACKGROUND: Cartilage T2 can detect joints at risk of developing osteoarthritis. The quantitative double-echo steady state (qDESS) sequence is attractive for knee cartilage T2 mapping because of its acquisition time of under 5 minutes. Understanding the reproducibility errors associated with qDESS T2 is essential to profiling the technical performance of this biomarker. PURPOSE: To examine the combined acquisition and segmentation reproducibility of knee cartilage qDESS T2 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 T2 maps were acquired twice on the same day and with a 1-week interval between scans. For each acquisition, average cartilage T2 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 T2 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 T2 reproducibility. The median of test-retest standard deviations was used for T2 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 T2 CVs and RMSA-CVs of ≤5%. T2 ICC values >0.75 were observed in the majority of regions but were more variable in interday tibial comparisons. Test-retest T2 precision was <1.3 msec. The T2 SDD was 3.8 msec. DATA CONCLUSION: Excellent CV and RMSA-CV reproducibility may suggest that qDESS T2 increases or decreases >5% (3.8 msec) could represent changes to cartilage composition. TECHNICAL EFFICACY: Stage 2.

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

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.

Strengthening the Pipeline: Promoting Diversity into Orthopedic Surgery.

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.

Optimizing Tissue Engineering for Clinical Relevance in Rotator Cuff Repair.

Rotator cuff tear (RCT) is the most common cause of disability in the upper extremity. It results in 4.5 million physician visits in the United States every year and is the most common etiology of shoulder conditions evaluated by orthopedic surgeons. Over 460,000 RCT repair surgeries are performed in the United States annually. Rotator cuff (RC) retear and failure to heal remain significant postoperative complications. Literature suggests that the retear rates can range from 29.5% to as high as 94%. Weakened and irregular enthesis regeneration is a crucial factor in postsurgical failure. Although commercially available RC repair grafts have been introduced to augment RC enthesis repair, they have been associated with mixed clinical outcomes. These grafts lack appropriate biological cues such as stem cells and signaling molecules at the bone-tendon interface. In addition, they do little to prevent fibrovascular scar tissue formation, which causes the RC to be susceptible to retear. Advances in tissue engineering have demonstrated that mesenchymal stem cells (MSCs) and growth factors (GFs) enhance RC enthesis regeneration in animal models. These models show that delivering MSCs and GFs to the site of RCT enhances native enthesis repair and leads to greater mechanical strength. In addition, these models demonstrate that MSCs and GFs may be delivered through a variety of methods including direct injection, saturation of repair materials, and loaded microspheres. Grafts that incorporate MSCs and GFs enhance anti-inflammation, osteogenesis, angiogenesis, and chondrogenesis in the RC repair process. It is crucial that the techniques that have shown success in animal models are incorporated into the clinical setting. A gap currently exists between the promising biological factors that have been investigated in animal models and the RC repair grafts that can be used in the clinical setting. Future RC repair grafts must allow for stable implantation and fixation, be compatible with current arthroscopic techniques, and have the capability to deliver MSCs and/or GFs.

How Research Improves Clinical Care: The Case for Orthopaedic Surgeon Research Leadership and Collaboration: AOA Critical Issues Symposium.

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.

Using 3D MRI Bone Shape to Predict Pre-Osteoarthritis of the Knee 2 Years After Anterior Cruciate Ligament Reconstruction.

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.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

No Difference in Complication Rates or Patient-Reported Outcomes Between Bone-Patella Tendon-Bone and Quadriceps Tendon Autograft for Anterior Cruciate Ligament Reconstruction.

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.

Vertical ground reaction force 2 years after anterior cruciate ligament reconstruction predicts 10-year patient-reported outcomes.

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.

A Quick and Efficient Method for the Generation of Immunomodulatory Mesenchymal Stromal Cell from Human Induced Pluripotent Stem Cell.

Mesenchymal stromal cells (MSCs) have been widely investigated for their regenerative capacity, anti-inflammatory properties and beneficial immunomodulatory effects across multiple clinical indications. Nevertheless, their widespread clinical utilization is limited by the variability in MSC quality, impacted by donor age, metabolism, and disease. Human induced pluripotent stem cells (hiPSCs) generated from readily accessible donor tissues, are a promising source of stable and rejuvenated MSC but differentiation methods generally require prolonged culture and result in low frequencies of stable MSCs. To overcome this limitation, we have optimized a quick and efficient method for hiPSC differentiation into footprint-free MSCs (human induced MSCs [hiMSCs]) in this study. This method capitalizes on the synergistic action of growth factors Wnt3a and Activin A with bone morphogenetic protein-4 (BMP4), leading to an enrichment of MSC after only 4 days of treatment. These hiMSCs demonstrate a significant upregulation of mesenchymal stromal markers (CD105+, CD90+, CD73, and cadherin 11) compared with bone marrow-derived MSCs (bmMSCs), with reduced expression of the pluripotency genes (octamer-binding transcription factor [Oct-4], cellular myelocytomatosis oncogene [c-Myc], Klf4, and Nanog homebox [Nanog]) compared with hiPSC. Moreover, they show improved proliferation capacity in culture without inducing any teratoma formation in vivo. Osteogenesis, chondrogenesis, and adipogenesis assays confirmed the ability of hiMSCs to differentiate into the three different lineages. Secretome analyses showed cytokine profiles compared with bmMSCs. Encapsulated hiMSCs in alginate beads cocultured with osteoarthritic (OA) cartilage explants showed robust immunomodulation, with stimulation of cell growth and proteoglycan production in OA cartilage. Our quick and efficient protocol for derivation of hiMSC from hiPSC, and their encapsulation in microbeads, therefore, presents a reliable and reproducible method to boost the clinical applications of MSCs.

Can we afford to ignore the biology of joint healing and graft incorporation after ACL reconstruction?

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.

Cartilage oligomeric matrix protein responses to a mechanical stimulus associate with ambulatory loading in individuals with anterior cruciate ligament reconstruction.

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.

Cartilage Matrix Degeneration Occurs within the First Year after ACLR and Is Associated with Impaired Clinical Outcome.

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.

Biologic Augmentation for the Operative Treatment of Osteochondral Defects of the Knee: A Systematic Review.

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.

Biologic Association Annual Summit: 2020 Report.

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.

Visualizing pre-osteoarthritis: Integrating MRI UTE-T2* with mechanics and biology to combat osteoarthritis-The 2019 Elizabeth Winston Lanier Kappa Delta Award.

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.

Patient-Reported Outcomes and Knee Mechanics Correlate With Patellofemoral Deep Cartilage UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction.

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.

Changes in knee adduction moment wearing a variable-stiffness shoe correlate with changes in pain and mechanically stimulated cartilage oligomeric matrix levels.

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.