A hop testing alternative for functional performance following anterior cruciate ligament reconstruction.

The purpose of this work was to provide a simple method to determine reactive strength during the 6-meter timed hop test (6mTH) and evaluate its association with isokinetic peak torque in patients following anterior cruciate ligament reconstruction (ACLR). Twenty-nine ACLR patients who were at least four months from surgery were included in this analysis. Participants were brought into the laboratory on one occasion to complete functional testing. Quadriceps and hamstring isokinetic testing was completed bilaterally at 60, 180, and 300 deg∙s-1, using extension peak torque from each speed as the outcome measure. The 6mTH was completed bilaterally using a marker-based motion capture system, and reactive strength ratio (RSR) was calculated from the vertical velocity of the pelvis during the test. An adjustment in RSR was made using the velocity of the 6mTH test to account for different strategies employed across participants. Repeated measures correlations were used to determine associations among isokinetic and hop testing variables. A two-way mixed analysis of variance was used to determine differences in isokinetic and hop testing variables between operated and non-operated legs and across male and female participants. Moderate positive associations were found between RSR (and adjusted RSR) and isokinetic peak torque at all speeds (r = .527 to .577). Mean comparisons showed significant main effects for leg and sex. Patients showed significant deficits in their operated versus non-operated legs in all isokinetic and hop testing variables, yet only isokinetic peak torque and timed hop time showed significant differences across male and female groups. Preliminary results are promising but further development is needed to validate other accessible technologies available to calculate reactive strength during functional testing after ACLR. Pending these developments, the effects of movement strategies, demographics, and levels of participation on RSR can then be explored to translate this simple method to clinical environments.

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal.

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.

Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients.

Osteosarcoma (OS) is a type of bone cancer that is derived from primitive mesenchymal cells typically affecting children and young adults. The current standard of treatment is a combination of neoadjuvant chemotherapy and surgical resection of the cancerous bone. Post-resection challenges in bone regeneration arise. To determine the appropriate amount of bone to be removed, preoperative imaging techniques such as bone and CT scans are employed. To prevent local recurrence, the current standard of care suggests maintaining bony and soft tissue margins from 3 to 7 cm beyond the tumor. The amount of bone removed in an OS patient leaves too large of a deficit for bone to form on its own and requires reconstruction with metal implants or allografts. Both methods require the bone to heal, either to the implant or across the allograft junction, often in the setting of marrow-killing chemotherapy. Therefore, the issue of bone regeneration within the surgically resected margins remains an important challenge for the patient, family, and treating providers. Mesenchymal stem/stromal cells (MSCs) are potential agents for enhancing bone regeneration post tumor resection. MSCs, used with scaffolds and growth factors, show promise in fostering bone regeneration in OS cases. We spotlight two MSC types-bone marrow-derived (BM-MSCs) and adipose tissue-derived (ASCs)-highlighting their bone regrowth facilitation and immunomodulatory effects on immune cells like macrophages and T cells, enhancing therapeutic outcomes. The objective of this review is two-fold: review work demonstrating any ability of MSCs to target the deranged immune system in the OS microenvironment, and synthesize the available literature on the use of MSCs as a therapeutic option for stimulating bone regrowth in OS patients post bone resection. When it comes to repairing bone defects, both MB-MSCs and ASCs hold great potential for stimulating bone regeneration. Research has showcased their effectiveness in reconstructing bone defects while maintaining a non-tumorigenic role following wide resection of bone tumors, underscoring their capability to enhance bone healing and regeneration following tumor excisions.

Therapeutic Perspectives for Inflammation and Senescence in Osteoarthritis Using Mesenchymal Stem Cells, Mesenchymal Stem Cell-Derived Extracellular Vesicles and Senolytic Agents.

Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.

CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions.

The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC sEVs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their sEV miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low sEVs on stimulated by inflammatory/fibrotic cues synoviocyte monocultures and cocultures with IFP-MSC-derived chondropellets. Finally, CD10High sEVs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low sEVs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in sEVs showed their involvement in the regulation of six gene groups, particularly those involving the immune system. Stimulated synoviocytes exposed to IFP-MSC sEVs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High sEV treatment of stimulated chondropellets/synoviocyte cocultures indicated significant chondroprotective effects. Therapeutically, CD10High sEV treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High sEVs possess immunomodulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for sEV-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).

The roles and therapeutic potentialof mesenchymal stem/stromal cells and their extracellular vesicles in tendinopathies.

Tendinopathies encompass a highly prevalent, multi-faceted spectrum of disorders, characterized by activity-related pain, compromised function, and propensity for an extended absence from sport and the workplace. The pathophysiology of tendinopathy continues to evolve. For decades, it has been related primarily to repetitive overload trauma but more recently, the onset of tendinopathy has been attributed to the tissue's failed attempt to heal after subclinical inflammatory and immune challenges (failed healing model). Conventional tendinopathy management produces only short-term symptomatic relief and often results in incomplete repair or healing leading to compromised tendon function. For this reason, there has been increased effort to develop therapeutics to overcome the tissue's failed healing response by targeting the cellular metaplasia and pro-inflammatory extra-cellular environment. On this basis, stem cell-based therapies have been proposed as an alternative therapeutic approach designed to modify the course of the various tendon pathologies. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells often referred to as "medicinal signaling cells" due to their immunomodulatory and anti-inflammatory properties that can produce a pro-regenerative microenvironment in pathological tendons. However, the adoption of MSCs into clinical practice has been limited by FDA regulations and perceived risk of adverse events upon infusion in vivo. The introduction of cell-free approaches, such as the extracellular vesicles of MSCs, has encouraged new perspectives for the treatment of tendinopathies, showing promising short-term results. In this article, we review the most recent advances in MSC-based and MSC-derived therapies for tendinopathies. Preclinical and clinical studies are included with comment on future directions of this rapidly developing therapeutic modality, including the importance of understanding tissue loading and its relationship to any treatment regimen.

Analysis of Questions in Sections of the Orthopaedic In-Training Examination: A Scoping Review.

PURPOSE: The purpose of this review was to assess all available studies that analyzed the types of questions in individual sections of the Orthopaedic In-Training Examination, which may be used as a reference for residents studying for their examination. METHODS: Following the Providing Innovative Service Models and Assessment extension for Scoping Reviews guidelines, a systematic review was conducted on studies that report on sections or question categories of the Orthopaedic In-Training Examination using PubMed, MEDLINE, and Web of Science databases. Two reviewers and an arbitrator reviewed and extracted relevant data from 20 included studies which made up the systematic review. RESULTS: All 20 studies in the review reported the mean number of questions per section, with the highest coming from musculoskeletal trauma (18.9% to 19.0%). 18 studies reported the Buckwalter taxonomic classification; 42.0% of questions were T1, 18.2% were T2, and 39.5% were T3 with a wide range from section to section. Primary sources were nearly three times more likely to be cited when compared with textbook sources. There were 12 journals that were commonly cited with the most being the Journal of Bone and Joint Surgery: American Volume (17/18). DISCUSSION: This study accurately portrays the characteristics of each section of the Orthopaedic In-Training Examination over the past 10 years. These data suggest that orthopaedic residents may be inclined to focus on musculoskeletal trauma, topics related to clinical management, and primary journal sources for studying. In addition, residency programs may choose to focus on higher yield sources or material to prepare their residents for the examination.

CD146+ Endometrial-Derived Mesenchymal Stem/Stromal Cell Subpopulation Possesses Exosomal Secretomes with Strong Immunomodulatory miRNA Attributes.

The perivascular localization of endometrial mesenchymal stem/stromal cells (eMSC) allows them to sense local and distant tissue damage, promoting tissue repair and healing. Our hypothesis is that eMSC therapeutic effects are largely exerted via their exosomal secretome (eMSC EXOs) by targeting the immune system and angiogenic modulation. For this purpose, EXOs isolated from Crude and CD146+ eMSC populations were compared for their miRNA therapeutic signatures and immunomodulatory functionality under inflammatory conditions. eMSC EXOs profiling revealed 121 in Crude and 88 in CD146+ miRNAs, with 82 commonly present in both populations. Reactome and KEGG analysis of miRNAs highly present in eMSC EXOs indicated their involvement among others in immune system regulation. From the commonly present miRNAs, four miRNAs (hsa-miR-320e, hsa-miR-182-3p, hsa-miR-378g, hsa-let-7e-5p) were more enriched in CD146+ eMSC EXOs. These miRNAs are involved in macrophage polarization, T cell activation, and regulation of inflammatory cytokine transcription (i.e., TNF-α, IL-1ß, and IL-6). Functionally, stimulated macrophages exposed to eMSC EXOs demonstrated a switch towards an alternate M2 status and reduced phagocytic capacity compared to stimulated alone. However, eMSC EXOs did not suppress stimulated human peripheral blood mononuclear cell proliferation, but significantly reduced secretion of 13 pro-inflammatory molecules compared to stimulated alone. In parallel, two anti-inflammatory proteins, IL-10 and IL-13, showed higher secretion, especially upon CD146+ eMSC EXO exposure. Our study suggests that eMSC, and even more, the CD146+ subpopulation, possess exosomal secretomes with strong immunomodulatory miRNA attributes. The resulting evidence could serve as a foundation for eMSC EXO-based therapeutics for the resolution of detrimental aspects of tissue inflammation.

Monitoring joint mechanics in anterior cruciate ligament reconstruction using depth sensor-driven musculoskeletal modeling and statistical parametric mapping.

The incidence of anterior cruciate ligament injury and reconstruction (ACLR) may set the stage for the development of early onset osteoarthritis in these patients. Development of accessible quantitative motion capture methodologies for recurrent monitoring of knee joint loading during daily activities following ACLR is necessary. This study aimed to compare lower extremity kinetics between ACLR affected limbs, ACLR unaffected limbs, and dominant limbs of healthy control subjects during over-ground gait and stair ascent using a single depth sensor-driven musculoskeletal modeling approach. No meaningful differences were found between groups during over-ground gait in any kinetic variables. When subjected to a stair ascent task, both ACLR limbs showed greater hip extension and internal rotation moments compared to control subjects at approximately 72-79% stance. This was coincident with greater knee flexion moments in both ALCR limbs compared to control. The absence of differences during over-ground gait but presence of compensatory strategies during stair ascent, suggests task dependent recovery in this cohort who were tested at least 1-year following surgery. Importantly, this was determined using a portable low-cost motion capture method which may be attractive to professionals in sports medicine for recurrent monitoring following ACLR.

Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures.

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases. Our hypothesis is that IFP-derived mesenchymal stem cells (IFP-MSC) robust immunomodulatory therapeutic effects are largely exerted via their exosomal (IFP-MSC EXOs) secretome by attenuating synoviocytes and macrophages pro-inflammatory activation. IFP-MSC EXOs showed distinct miRNA and protein immunomodulatory profiles. Reactome analysis of 24 miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, including immune system. Exosomes were enriched for immunomodulatory and reparative proteins that are involved in positive regulation of cell proliferation, response to stimulus, signal transduction, signal receptor activity, and protein phosphorylation. Stimulated synoviocytes or macrophages exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation, altered inflammation-related molecular profiles, and reduced secretion of pro-inflammatory molecules compared to stimulated alone. In an acute synovial/IFP inflammation rat model, IFP-MSC EXOs therapeutic treatment resulted in robust macrophage polarization towards an anti-inflammatory therapeutic M2 phenotype within the synovium/IFP tissues. Based on these findings, we propose a viable cell-free alternative to MSC-based therapeutics as an alternative approach to treating synovitis and IFP fibrosis.

Training, Injury, and Lifestyle Characteristics of Recreational Triathletes.

ABSTRACT: Triathlon is a popular sport among recreational and competitive athletes. As triathletes compete in races ranging from 16 to 140.6 miles and train in three disciplines simultaneously, it is difficult to identify injury risk factors. The aim of this study was to evaluate characteristics of a group of recreational triathletes regarding their medical history, training regimen, and injuries. Thirty-four triathletes completed this survey. We found a wide range of body types, training habits, and lifestyle characteristics. As in previous studies, we found a high rate of injuries in our surveyed triathletes. Injury rates were higher in athletes who had completed a longer race and those who reported higher training times per week. Additionally, many individuals have medical problems, use a variety of supplements, and follow specific dietary restrictions, which need to be considered in addition to training when assessing injury risk and recovery from injury.

Infrapatellar fat pad-derived mesenchymal stem cell-based spheroids enhance their therapeutic efficacy to reverse synovitis and fat pad fibrosis.

BACKGROUND: To investigate the in vitro and in vivo anti-inflammatory/anti-fibrotic capacity of IFP-MSC manufactured as 3D spheroids. Our hypothesis is that IFP-MSC do not require prior cell priming to acquire a robust immunomodulatory phenotype in vitro in order to efficiently reverse synovitis and IFP fibrosis, and secondarily delay articular cartilage damage in vivo. METHODS: Human IFP-MSC immunophenotype, tripotentiality, and transcriptional profiles were assessed in 3D settings. Multiplex secretomes were assessed in IFP-MSC spheroids [Crude (non-immunoselected), CD146+ or CD146- immunoselected cells] and compared with 2D cultures with and without prior inflammatory/fibrotic cell priming. Functionally, IFP-MSC spheroids were assessed for their immunopotency on human PBMC proliferation and their effect on stimulated synoviocytes with inflammation and fibrotic cues. The anti-inflammatory and anti-fibrotic spheroid properties were further evaluated in vivo in a rat model of acute synovitis/fat pad fibrosis. RESULTS: Spheroids enhanced IFP-MSC phenotypic, transcriptional, and secretory immunomodulatory profiles compared to 2D cultures. Further, CD146+ IFP-MSC spheroids showed enhanced secretory and transcriptional profiles; however, these attributes were not reflected in a superior capacity to suppress activated PBMC. This suggests that 3D culturing settings are sufficient to induce an enhanced immunomodulatory phenotype in both Crude and CD146-immunoselected IFP-MSC. Crude IFP-MSC spheroids modulated the molecular response of synoviocytes previously exposed to inflammatory cues. Therapeutically, IFP-MSC spheroids retained substance P degradation potential in vivo, while effectively inducing resolution of inflammation/fibrosis of the synovium and fat pad. Furthermore, their presence resulted in arrest of articular cartilage degradation in a rat model of progressive synovitis and fat pad fibrosis. CONCLUSIONS: 3D spheroids confer IFP-MSC a reproducible and enhanced immunomodulatory effect in vitro and in vivo, circumventing the requirement of non-compliant cell priming or selection before administration and thereby streamlining cell products manufacturing protocols.

Estimation of ground reaction forces during stair climbing in patients with ACL reconstruction using a depth sensor-driven musculoskeletal model.

BACKGROUND: Although stair ambulation should be included in the rehabilitation of the long-term effects of ACL injury on knee function, the assessment of kinetic parameter in the situation where stair gait can only be established using costly and cumbersome force platforms via conventional inverse dynamic analysis. Therefore, there is a need to develop a practical laboratory setup as an assessment tool of the stair gait abnormalities in lower extremity that arise from an ACL deficiency. RESEARCH QUESTION: Can the use of a single depth sensor-driven full-body musculoskeletal gait model be considered an accurate assessment tool of the ground reaction forces (GRFs) during stair climbing for patients following ACL reconstruction (ACLR) surgery? METHODS: A total of 15 patients who underwent ACLR participated in this study. GRFs data during stair climbing was collected using a custom-built 3-step staircase with two embedded force platforms. A single depth sensor, commercially available and cost effective, was used to obtain participants' depth map information to extract the full-body skeleton information. The AnyBody TM GaitFullBody model was utilized to estimate GRFs attained by 25 artificial muscle-like actuators placed under each foot. Mean differences between the measured and estimated GRFs were compared using paired samples t-tests. The ensemble curves of the GRFs were compared between both approaches during stance phase of the gait cycle. RESULTS: The findings of this study showed that the estimation of the GRFs produced during staircase gait using a depth sensor-driven musculoskeletal model can produce acceptable results when compared to the traditional inverse dynamics modelling approach as an alternative tool in clinical settings for individuals who had undergone ACLR. SIGNIFICANCE: The introduced approach of full-body musculoskeletal modelling driven by a single depth sensor has the potential to be a cost-effective stair gait analysis tool for patients with ACL injury.

High kinesiophobia and pain catastrophizing in people with articular cartilage defects in the knee and associations with knee function.

PURPOSE: The purpose of this study was to evaluate the extent to which individuals with knee articular cartilage defects (ACDs) have kinesiophobia and pain catastrophizing, and how these psychological factors relate to self-reported knee outcomes. METHODS: Thirty-five individuals seeking surgical consultation for an ACD in the knee confirmed with 3.0T MRI and 18 controls without history of knee injury participated in the study. Kinesiophobia was measured with the Tampa Scale of Kinesiophobia (TSK), and scored using the modified 11-item (TSK-11) methods. Pain catastrophizing was measured with the Pain Catastrophizing Scale (PCS). Data were analyzed using descriptive statistics, independent t-tests, chi-squared tests and Spearman's correlation coefficients, as appropriate (α = 0.05). RESULTS: Participants with ACDs reported higher TSK-11 scores (median 27 [IQR 25-29]) and higher PCS scores (median 10 [IQR 4-18]) than controls (median TSK-11 16 [IQR 14-17], p < 0.001; median PCS 0 [IQR 0-9], p < 0.001). Within those with knee ACDs, higher TSK-11 scores were associated with worse knee pain, function on activities of daily living, sports/recreation, and knee-related quality of life scores (rho = -0.38 to -0.61). Higher pain catastrophizing was associated with worse function with activities of daily living and knee-related quality of life (rho = -0.37 to -0.40). CONCLUSIONS: Kinesiophobia and pain catastrophizing in people with knee ACDs were higher than controls. Higher kinesiophobia and pain catastrophizing were associated with worse function and quality of life. Further study of the impact of these psychological factors on outcomes and prognosis in people with knee ACDs is warranted.

Accuracy of the Region of Limb Stability in Predicting Risk for Lower Limb Injury.

PURPOSE: This study aimed to determine whether a measure of lower limb segment stability derived from body-worn inertial measurement units can predict risk for lower limb musculoskeletal injury in Division I Collegiate Football Players (D1CFP). METHODS: The region of limb stability (ROLS) values were collected in a cohort of D1CFP during preseason. ROLS is a measure of knee joint stability, defined by thigh and shank excursion (cm) in the anterior-posterior and medial-lateral direction during single limb stance. The ROLS symmetry index (SI) (%) is the ratio between lower limb ROLS values where 100% suggests absolute symmetry. RESULTS: One-hundred and four D1CFP participated in this study and were divided into two groups: 1) no previous lower limb injury or no in-season injury (n = 70, "noninjured group") and 2) no previous lower limb injury, but in-season injury requiring surgery (n = 34, "injured group" group). The mean ± SD ROLS SI was 82.86% ± 14.75% and 65.58% ± 16.46% for the noninjured and injured group, respectively. Significant differences in ROLS SI were found between groups (P < 0.001). The ROLS SI demonstrated an area under the curve of 0.8 (P < 0.001; 95% confidence interval = 0.71-0.88) with an SE of 0.04, indicating that the ROLS SI has good predictive accuracy in detecting those healthy D1CFP at risk for lower limb injury resulting in surgery. CONCLUSION: The ROLS SI was found to have good predictive accuracy in detecting individuals at risk for injury that were healthy and asymptomatic during preseason testing. Increase in thigh and shank excursions and/or decrease in SI between lower limbs may be a predictor of risk for future injury.

Correction to: Clinical Characteristics and Multisystem Imaging Findings of COVID-19: An Overview for Orthopedic Surgeons.

[This corrects the article DOI: 10.1007/s11420-020-09775-3.].

Sustained acoustic medicine as a non-surgical and non-opioid knee osteoarthritis treatment option: a health economic cost-effectiveness analysis for symptom management.

BACKGROUND: Patients diagnosed with osteoarthritis (OA) and presenting with symptoms are seeking conservative treatment options to reduce pain, improve function, and avoid surgery. Sustained acoustic medicine (SAM), a multi-hour treatment has demonstrated improved clinical outcomes for patients with knee OA. The purpose of this analysis was to compare the costs and effectiveness of multi-hour SAM treatment versus the standard of care (SOC) over a 6-month timeframe for OA symptom management. METHODS: A decision tree analysis was used to compare the costs and effectiveness of SAM treatment versus SOC in patients with OA. Probabilities of success for OA treatment and effectiveness were derived from the literature using systematic reviews and meta-analyses. Costs were derived from Medicare payment rates and manufacturer prices. Functional effectiveness was measured as the effect size of a therapy and treatment pathways compared to a SOC treatment pathway. A sensitivity analysis was performed to determine which cost variables had the greatest effect on deciding which option was the least costly. An incremental cost-effectiveness plot comparing SAM treatment vs. SOC was also generated using 1000 iterations of the model. Lastly, the incremental cost-effectiveness ratio (ICER) was calculated as the (cost of SAM minus cost of SOC) divided by (functional effectiveness of SAM minus functional effectiveness of SOC). RESULTS: Base case demonstrated that over 6 months, the cost and functional effectiveness of SAM was $8641 and 0.52 versus SOC at: $6281 and 0.39, respectively. Sensitivity analysis demonstrated that in order for SAM to be the less expensive option, the cost per 15-min session of PT would need to be greater than $88, or SAM would need to be priced at less than or equal to $2276. Incremental cost-effectiveness demonstrated that most of the time (84%) SAM treatment resulted in improved functional effectiveness but at a higher cost than SOC. CONCLUSION: In patients with osteoarthritis, SAM treatment demonstrated improved pain and functional gains compared to SOC but at an increased cost. Based on the SAM treatment ICER score being ≤ $50,000, it appears that SAM is a cost-effective treatment for knee OA.

Clinical Characteristics and Multisystem Imaging Findings of COVID-19: An Overview for Orthopedic Surgeons.

The COVID-19 pandemic holds widespread implications for global public health, economies, societies, and the practice of orthopedic surgery. As our knowledge of the transmissibility of SARS-CoV-2 and the symptomatology and management of COVID-19 expands, orthopedic surgeons must remain up to date on the latest medical evidence and surgical perspectives. While COVID-19 primarily manifests with pulmonary symptoms, cardiovascular, neurologic, and other major organ systems may also be affected and present with hallmark imaging findings. This article reviews initial and emerging literature on clinical characteristics and imaging findings of COVID-19.

Regulatory-compliant conditions during cell product manufacturing enhance in vitro immunomodulatory properties of infrapatellar fat pad-derived mesenchymal stem/stromal cells.

BACKGROUND AIMS: Mesenchymal stem/stromal cell (MSC)-based therapies have gained attention as potential alternatives for multiple musculoskeletal indications based on their trophic and immunomodulatory properties. The infrapatellar fat pad (IFP) serves as a reservoir of MSCs, which play crucial roles modulating inflammatory and fibrotic events at the IFP and its neighboring tissue, the synovium. In an effort to comply with the existing regulatory framework regarding cell-based product manufacturing, we interrogated the in vitro immunomodulatory capacity of human-derived IFP-MSCs processed under different conditions, including a regulatory-compliant protocol, in addition to their response to the inflammatory and fibrotic environments often present in joint disease. METHODS: Immunophenotype, telomere length, transcriptional and secretory immunomodulatory profiles and functional immunopotency assay were assessed in IFP-MSCs expanded in regular fetal bovine serum (FBS)-supplemented medium and side-by-side compared with same-donor cells processed with two media alternatives (i.e., regulatory-compliant pooled human platelet lysate [hPL] and a chemically reinforced/serum-reduced [Ch-R] formulation). Finally, to assess the effects of such formulations on the ability of the cells to respond to pro-inflammatory and pro-fibrotic conditions, all three groups were stimulated ex vivo (i.e., cell priming) with a cocktail containing TNFα, IFNγ and connective tissue growth factor (tumor-initiating cells) and compared with non-induced cohorts assessing the same outcomes. RESULTS: Non-induced and primed IFP-MSCs expanded in either hPL or Ch-R showed distinct morphology in vitro, similar telomere dynamics and distinct phenotypical and molecular profiles when compared with cohorts grown in FBS. Gene expression of IL-8, CD10 and granulocyte colony-stimulating factor was highly enriched in similarly processed IFP-MSCs. Cell surface markers related to the immunomodulatory capacity, including CD146 and CD10, were highly expressed, and secretion of immunomodulatory and pro-angiogenic factors was significantly enhanced with both hPL and Ch-R formulations. Upon priming, the immunomodulatory phenotype was enhanced, resulting in further increase in CD146 and CD10, significant CXCR4 presence and reduction in TLR3. Similarly, transcriptional and secretory profiles were enriched and more pronounced in IFP-MSCs expanded in either hPL or Ch-R, suggesting a synergistic effect between these formulations and inflammatory/fibrotic priming conditions. Collectively, increased indoleamine-2,3-dioxygenase activity and prostaglandin E2 secretion for hPL- and Ch-R-expanded IFP-MSCs were functionally reflected by their robust T-cell proliferation suppression capacity in vitro compared with IFP-MSCs expanded in FBS, even after priming. CONCLUSIONS: Compared with processing using an FBS-supplemented medium, processing IFP-MSCs with either hPL or Ch-R similarly enhances their immunomodulatory properties, which are further increased after exposure to an inflammatory/fibrotic priming environment. This evidence supports the adoption of regulatory-compliant practices during the manufacturing of a cell-based product based on IFP-MSCs and anticipates a further enhanced response once the cells face the pathological environment after intra-articular administration. Mechanistically, the resulting functionally enhanced cell-based product has potential utilization as a novel, minimally invasive cell therapy for joint disease through modulation of local immune and inflammatory events.

CD10/Neprilysin Enrichment in Infrapatellar Fat Pad-Derived Mesenchymal Stem Cells Under Regulatory-Compliant Conditions: Implications for Efficient Synovitis and Fat Pad Fibrosis Reversal.

BACKGROUND: Synovitis and infrapatellar fat pad (IFP) fibrosis participate in various conditions of the knee. Substance P (SP), a neurotransmitter secreted within those structures and historically associated with nociception, also modulates local neurogenic inflammatory and fibrotic responses. Exposure of IFP mesenchymal stem cells (IFP-MSCs) to a proinflammatory/profibrotic environment (ex vivo priming with TNFα, IFNγ, and CTGF) induces their expression of CD10/neprilysin, effectively degrading SP in vitro and in vivo. PURPOSE/HYPOTHESIS: The purpose was to test the therapeutic effects of IFP-MSCs processed under regulatory-compliant protocols, comparing them side-by-side with standard fetal bovine serum (FBS)-grown cells. The hypothesis was that when processed under such protocols, IFP-MSCs do not require ex vivo priming to acquire a CD10-rich phenotype efficiently degrading SP and reversing synovitis and IFP fibrosis. STUDY DESIGN: Controlled laboratory study. METHODS: Human IFP-MSCs were processed in FBS or either of 2 alternative conditions-regulatory-compliant pooled human platelet lysate (hPL) and chemically reinforced medium (Ch-R)-and then subjected to proinflammatory/profibrotic priming with TNFα, IFNγ, and CTGF. Cells were assessed for in vitro proliferation, stemness, immunophenotype, differentiation potential, transcriptional and secretory profiles, and SP degradation. Based on a rat model of acute synovitis and IFP fibrosis, the in vivo efficacy of cells degrading SP plus reversing structural signs of inflammation and fibrosis was assessed. RESULTS: When compared with FBS, IFP-MSCs processed with either hPL or Ch-R exhibited a CD10High phenotype and showed enhanced proliferation, differentiation, and immunomodulatory transcriptional and secretory profiles (amplified by priming). Both methods recapitulated and augmented the secretion of growth factors seen with FBS plus priming, with some differences between them. Functionally, in vitro SP degradation was more efficient in hPL and Ch-R, confirmed upon intra-articular injection in vivo where CD10-rich IFP-MSCs also dramatically reversed signs of synovitis and IFP fibrosis even without priming or at significantly lower cell doses. CONCLUSION: hPL and Ch-R formulations can effectively replace FBS plus priming to induce specific therapeutic attributes in IFP-MSCs. The resulting fine-tuned, regulatory-compliant, cell-based product has potential future utilization as a novel minimally invasive cell therapy for the treatment of synovitis and IFP fibrosis. CLINICAL RELEVANCE: The therapeutic enhancement of IFP-MSCs manufactured under regulatory-compliant conditions suggests that such a strategy could accelerate the time from preclinical to clinical phases. The therapeutic efficacy obtained at lower MSC numbers than currently needed and the avoidance of cell priming for efficient results could have a significant effect on the design of clinical protocols to potentially treat conditions involving synovitis and IFP fibrosis.