Wharton's jelly and osteoarthritis of the knee.

INTRODUCTION: The existing treatment modalities for knee osteoarthritis (OA) do not actually address the pathology. Biological therapies, including those using material derived from perinatal tissues, represent a ground-breaking approach to alleviating the symptoms of OA of the knee. SOURCE OF DATA: Current scientific literature published in PubMed (MEDLINE), Embase and Scopus databases. Trials registered in various clinical trial databases. AREAS OF AGREEMENT: Perinatal tissues including Wharton's jelly (WJ) and associated mesenchymal stem cells (MSCs) can be used for the management of knee OA. AREAS OF CONTROVERSY: The efficacy of WJ and associated MSCs in the management of knee OA is still controversial. GROWING POINTS: The use of WJ and associated MSCs in the management of knee OA is safe and appears to be effective. AREAS TIMELY FOR DEVELOPING RESEARCH: The present published evidence suggests that WJ tissue and associated MSCs offer an encouraging alternative for the management of knee OA. The published in vitro, preclinical and clinical investigations demonstrate the therapeutic potential of WJ and promote further research in this field to provide symptomatic relief to patients suffering from OA, aiming also to regenerate the osteoarthritic hyaline cartilage, with disease-modifying effects. Future adequately powered randomized controlled trials should be undertaken to establish whether WJ is helpful in the management of OA of the knee.

Artificial Intelligence and Machine Learning in Rotator Cuff Tears.

Rotator cuff tears (RCTs) negatively impacts patient well-being. Artificial intelligence (AI) is emerging as a promising tool in medical decision-making. Within AI, deep learning allows to autonomously solve complex tasks. This review assesses the current and potential applications of AI in the management of RCT, focusing on diagnostic utility, challenges, and future perspectives. AI demonstrates promise in RCT diagnosis, aiding clinicians in interpreting complex imaging data. Deep learning frameworks, particularly convoluted neural networks architectures, exhibit remarkable diagnostic accuracy in detecting RCTs on magnetic resonance imaging. Advanced segmentation algorithms improve anatomic visualization and surgical planning. AI-assisted radiograph interpretation proves effective in ruling out full-thickness tears. Machine learning models predict RCT diagnosis and postoperative outcomes, enhancing personalized patient care. Challenges include small data sets and classification complexities, especially for partial thickness tears. Current applications of AI in RCT management are promising yet experimental. The potential of AI to revolutionize personalized, efficient, and accurate care for RCT patients is evident. The integration of AI with clinical expertise holds potential to redefine treatment strategies and optimize patient outcomes. Further research, larger data sets, and collaborative efforts are essential to unlock the transformative impact of AI in orthopedic surgery and RCT management.

Allogenic Umbilical Cord Tissue for Rotator Cuff Injuries.

Highly prone to injury, the rotator cuff greatly contributes to the stability and mobility of the shoulder. Clinicians prioritize conservative treatment, resorting to surgery only when necessary, although they are hindered by inherent limitations. Biological therapies, including perinatal tissue, such as umbilical cord (UC) tissue, hold promise for treating rotator cuff injuries (RCIs) in the field of regenerative medicine. This article qualitatively presents the in vitro, preclinical, clinical, and ongoing scientific literature exploring the application of UC tissue and associated mesenchymal stem cells in the context of RCIs. Employing the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guidelines, a systematic review was conducted. These studies have presented substantial evidence indicating that UC tissue and UC-derived mesenchymal stem cells are safe and potentially efficacious for managing RCIs, though more adequately powered randomized controlled trials are warranted to further establish efficacy and justify clinical use.

Combination of Platelet-Rich Plasma and Hyaluronic Acid vs. Platelet-Rich Plasma Alone for Treatment of Knee Osteoarthritis.

Knee osteoarthritis (OA) is the most documented form of OA and is accountable for about 80% of total OA cases worldwide [...].

Silver nanoparticle technology in orthopaedic infections.

The irrational and prolonged use of antibiotics in orthopaedic infections poses a major threat to the development of antimicrobial resistance. To combat antimicrobial resistance, researchers have implemented various novel and innovative modalities to curb infections. Nanotechnology involves doping ions/metals onto the scaffolds to reach the target site to eradicate the infective foci. In this connotation, we reviewed silver nanoparticle technology in terms of mechanism of action, clinical applications, toxicity, and regulatory guidelines to treat orthopaedic infections.

Allogenic platelet-rich plasma for treatment of knee and hip osteoarthritis.

Osteoarthritis (OA) induces tremendous amounts of stress and financial burden on patients and healthcare systems worldwide. Current treatments have limitations and do not address the etiopathogenetic cause of OA. Regenerative medicine may circumvent limitations posed by traditional modalities and relies on the utilization of biologics including platelet-rich plasma (PRP). Several peer-reviewed studies have documented the safety and efficacy of autologous PRP in mitigating symptoms in knee and hip OA patients. Nonetheless, only few studies investigated the safety and efficacy of allogenic PRP. This mini review summarizes the outcomes of preclinical and clinical studies using allogenic PRP for treatment of knee or hip OA. We identified 3 preclinical and 1 clinical study using allogenic PRP for treatment of knee OA, and only 1 clinical study using allogenic PRP for treatment of hip OA. Administration of allogenic PRP is safe and probably efficacious in patients with knee or hip OA. However, more pre-clinical studies and high-powered, multi-center, non-randomized and randomized controlled trials with extended follow-up are warranted to further establish the safety and efficacy of allogenic PRP to justify its clinical use.

Dose-Response Meta-Analysis of Corticosteroid Effects in SARS Outbreak: A Model for Risk Stratification and Screening Strategy for Osteonecrosis of Femoral Head Post-Corticosteroid Therapy for COVID-19.

Corticosteroids (CS) have been used in the management regimens for COVID-19 disease to mitigate the cytokine storm and ill effects of the pulmonary inflammatory cascade. With the rampant use of CS, clinicians started reporting the occurrence of osteonecrosis of the femoral head (OFH). In this systematic review, we aim to analyze the literature and identify the definitive cumulative dose and duration of CS needed for the development of OFH based on the SARS model and generate a risk-based screening recommendation for OFH in convalescent COVID-19 patients to facilitate early identification and management. An electronic database search was conducted until December 2022 in PubMed, Web of Science, Embase, and CNKI (China Knowledge Resource Integrated Database). Studies involving CS therapy and osteonecrosis data in SARS patients were included. Three authors independently extracted the data from the included studies and a dose-response meta-analysis was performed for various doses and duration of CS utilized in the included studies. We selected 12 articles with 1728 patients in the analysis. The mean age was 33.41 (±4.93) years. The mean dosage of CS administered was 4.64 (±4.7) g which was administered for a mean duration of 29.91 (±12.3) days. The risk of osteonecrosis increases at pooled OR of 1.16 (95% CI 1.09-1.23, p < 0.001) per 2.0 g increase in the cumulative dose of CS usage. Similarly, the risk increases at pooled OR of 1.02 (95% CI 1.01-1.03, p < 0.001) per 5 days of increase in the cumulative duration of CS usage. A cumulative dosage of 4 g and a duration of 15 days were determined as the critical cut-off for the non-linear dose-response relationship observed. Appropriate and frequent screening of these individuals at regular intervals would help in the identification of the disease at an early stage in order to treat them appropriately.

Approaching Artificial Intelligence in Orthopaedics: Predictive Analytics and Machine Learning to Prognosticate Arthroscopic Rotator Cuff Surgical Outcomes.

Machine learning (ML) has not yet been used to identify factors predictive for post-operative functional outcomes following arthroscopic rotator cuff repair (ARCR). We propose a novel algorithm to predict ARCR outcomes using machine learning. This is a retrospective cohort study from a prospectively collected database. Data were collected from the Surgical Outcome System Global Registry (Arthrex, Naples, FL, USA). Pre-operative and 3-month, 6-month, and 12-month post-operative American Shoulder and Elbow Surgeons (ASES) scores were collected and used to develop a ML model. Pre-operative factors including demography, comorbidities, cuff tear, tissue quality, and fixation implants were fed to the ML model. The algorithm then produced an expected post-operative ASES score for each patient. The ML-produced scores were compared to actual scores using standard test-train machine learning principles. Overall, 631 patients who underwent shoulder arthroscopy from January 2011 to March 2020 met inclusion criteria for final analysis. A substantial number of the test dataset predictions using the XGBoost algorithm were within the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) thresholds: 67% of the 12-month post-operative predictions were within MCID, while 84% were within SCB. Pre-operative ASES score, pre-operative pain score, body mass index (BMI), age, and tendon quality were the most important features in predicting patient recovery as identified using Shapley additive explanations (SHAP). In conclusion, the proposed novel machine learning algorithm can use pre-operative factors to predict post-operative ASES scores accurately. This can further supplement pre-operative counselling, planning, and resource allocation. Level of Evidence: III.

Leukocyte-Rich vs. Leukocyte-Poor Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis.

Knee osteoarthritis (OA) is a well-established form of OA and accounts for nearly 4/5 of global OA burden […].

Allogenic Perinatal Tissue for Musculoskeletal Regenerative Medicine Applications: A Systematic Review.

Producing tremendous amounts of stress and financial burden on the global patient population and healthcare systems around the world, most current modalities of treatment for musculoskeletal ailments often do not address the etiopathogenetic causes of these disorders. Regenerative medicine for musculoskeletal disorders relies on orthobiologics derived from either allogenic or autologous sources. Multiple drawbacks are associated with autologous sources, including donor-site morbidity, a dearth of studies, and variability in both patient reported and clinical/functional outcomes. On the other hand, allogenic sources address several of these concerns, and continue to be a suitable source of mesenchymal stem cells (MSCs). This review qualitatively reports both the preclinical and clinical outcomes of publications studying the applications of umbilical cord (-derived Wharton's jelly), amniotic suspension allograft, amniotic membrane, and amniotic fluid in musculoskeletal medicine. A systematic review was conducted utilizing the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines on studies published between January 2010 and October 2022 that used allogeneic perinatal tissues. Further randomized controlled clinical studies are necessary to properly evaluate the safety and efficacy of these tissues in orthopedic surgery.

Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Wound Healing.

The well-orchestrated process of wound healing may be negatively impacted from interrupted or incomplete tissue regenerative processes. The healing potential is further compromised in patients with diabetes mellitus, chronic venous insufficiency, critical limb ischemia, and immunocompromised conditions, with a high health care burden and expenditure. Stem cell-based therapy has shown promising results in clinical studies. Mesenchymal stem cell-derived exosomes (MSC Exos) may favorably impact intercellular signaling and immunomodulation, promoting neoangiogenesis, collagen synthesis, and neoepithelization. This article gives an outline of the biogenesis and mechanism of extracellular vesicles (EVs), particularly exosomes, in the process of tissue regeneration and discusses the use of preconditioned exosomes, platelet-rich plasma-derived exosomes, and engineered exosomes in three-dimensional bioscaffolds such as hydrogels (collagen and chitosan) to prolong the contact time of exosomes at the recipient site within the target tissue. An appropriate antibiotic therapy based on culture-specific guidance coupled with the knowledge of biopolymers helps to fabricate nanotherapeutic materials loaded with MSC Exos to effectively deliver drugs locally and promote novel approaches for the management of chronic wounds.

Long noncoding RNAs in mesenchymal stromal/stem cells osteogenic differentiation: Implications in osteoarthritis pathogenesis.

This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling. Specifically, it discusses a novel modality of epigenetic regulation, the long noncoding RNAs (lncRNAs), and provides evidence of their involvement in mesenchymal stromal/stem cells osteo-/adipo-genic differentiation balance. Despite focus on lncRNAs, there is an emerging cross talk between lncRNAs and miRNAs interaction as a novel mechanism in the regulation of the function of the musculoskeletal system, by controlling bone homeostasis and bone regeneration, as well as the osteogenic differentiation of stem cells. Thus, we touched on some examples to demonstrate this interaction. In addition, we believe there is still much to discover from the effects of lncRNAs on progenitor and non-progenitor cell differentiation. We incorporated data from other published articles to review lncRNAs in normal progenitor cell osteogenic differentiation, determined lncRNAs involved in osteoarthritis pathogenesis in progenitor cells, and provided a review of lncRNAs in non-progenitor cells that are differentially regulated in osteoarthritis. In conclusion, we really enjoyed reading this article and with this information we hope to further our under standing of lncRNAs and mesenchymal stromal/stem cells regulation.

Ischiofemoral impingement syndrome: a case report and review of literature.

INTRODUCTION: The etiology of ischiofemoral impingement (IFI) syndrome, an unusual and uncommon form of hip pain, remains uncertain. Some patients demonstrate narrowing of the space between the ischial tuberosity and lesser trochanter from trauma or abnormal morphology of the quadratus femoris muscle. Combined clinical and imaging aid in the diagnosis. CASE REPORT: A 32-year-old female presented with a 3 years history of pain over the lower aspect of the right buttock, aggravated by movements of the right hip, and partially relieved with rest and medications. The right hip showed extreme restriction of abduction and external rotation. MRI of the right hip showed reduced ischiofemoral space and quadratus femoris space when compared to the left hip. The patient underwent endoscopic resection of the right lesser trochanter, with no recurrence of pain at 2 years. CONCLUSION: An unusual cause of hip pain, IFI syndrome, should be suspected when hip pain at extremes of movement is associated with signal abnormality of quadratus femoris muscle. Management is tailored to address the inciting factors that precipitated the IFI syndrome.

Allogenic perinatal tissue for musculoskeletal regenerative medicine applications: a systematic review protocol.

BACKGROUND: Musculoskeletal ailments impact the lives of millions of people, and at times necessitate surgery followed by physiotherapy, drug treatments, or immobilization. Regenerative musculoskeletal medicine has undergone enormous progress over the last few decades. Sources of tissues used for regenerative medicine purposes can be grouped into autologous or allogenic. Although autologous sources are promising, there is a wide range of limitations with the treatment, including the lack of randomized controlled studies for orthopaedic conditions, donor site morbidity, and highly variable outcomes for patients. Allogenic sources bypass some of these shortcomings and are a promising source for orthopaedic regenerative medicine applications. METHODS: A systematic search will be performed using PubMed, Elsevier, ScienceDirect, and Google Scholar databases for articles published in English before May 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and guidelines will be used. Studies will be eligible if they apply to acute and chronic orthopaedic musculoskeletal complications or animal or human disease models. Publications must include the use of MSCs and/or tissue obtained from amniotic/chorionic membrane, amniotic fluid, umbilical cord, and/or umbilical cord-derived Wharton's jelly as an intervention. Placebos, noninjury models, acute injury models, non-injury models, and gold standard treatments will be compared. The study selection will be performed by two independent reviewers using a dedicated reference management software. Data synthesis and meta-analysis will be performed separately for preclinical and clinical studies. DISCUSSION: The results will be published in relevant peer-reviewed scientific journals. Investigators will present results at national or international conferences. TRIAL REGISTRATION: The Protocol will be registered on PROSPERO international prospective register of systematic reviews prior to commencement.

Treatment of Knee Osteoarthritis with Intraarticular Umbilical Cord-Derived Wharton's Jelly: A Case Report.

We present the case of a 27-year-old male with grade II knee osteoarthritis (OA) that was intraarticularly injected with a 2 mL umbilical cord-derived Wharton's jelly (UC-derived WJ) formulation. The patients' baseline radiographs were taken and baseline numeric pain rating scale (NPRS), knee injury and osteoarthritis outcome score (KOOS), 7-point Likert scale, and a 36-item short form survey (SF-36) were recorded. The NPRS was re-recorded immediately after the injection, and at 24 h, 48 h, 1 week, 6 weeks, and at 3 months follow-up post-injection. The KOOS and 7-point Likert scale was re-recorded at the patients' 1week, 6 week, and 3month follow-up, and SF-36 was re-recorded at 3 months. A final set of X-rays were also performed at 3 months follow-up post-injection. No adverse effects from the injection were reported over the duration of the study. No significant difference nor progression in OA on X-rays compared to baseline was observed. NPRS decreased by 50% and the 7-point Likert scale increased to Extremely Satisfied. KOOS increased overall by 10% and the SF-36 overall change was 25%. These results indicate the potential application of UC-derived WJ in the treatment of knee OA. Larger, long term, non-randomized and randomized control trials are warranted to adequately assess the safety and efficacy of UC-derived WJ and ultimate clinical use.

Cell-free stem cell-derived extract formulation for treatment of knee osteoarthritis: study protocol for a preliminary non-randomized, open-label, multi-center feasibility and safety study.

BACKGROUND: Musculoskeletal conditions are highly prevalent, and knee OA is most common. Current treatment modalities have limitations and either fail to solve the underlying pathophysiology or are highly invasive. To address these limitations, attention has focused on the use of biologics. The efficacy of these devices is attributed to presence of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs). With this in mind, we formulated a novel cell-free stem cell-derived extract (CCM) from human progenitor endothelial stem cells (hPESCs). A preliminary study demonstrated the presence of essential components of regenerative medicine, namely GFs, CKs, and EVs, including exosomes, in CCM. The proposed study aims to evaluate the safety and efficacy of intraarticular injection of the novel cell-free stem cell-derived extract (CCM) for the treatment of knee OA. METHODS AND ANALYSIS: This is a non-randomized, open-label, multi-center, prospective study in which the safety and efficacy of intraarticular CCM in patients suffering from grade II/III knee OA will be evaluated. Up to 20 patients with grade II/III OA who meet the inclusion and exclusion criteria will be consented and screened to recruit 12 patients to receive treatment. The study will be conducted at up to 2 sites within the USA, and the 12 participants will be followed for 24 months. The study participants will be monitored for adverse reactions and assessed using Numeric Pain Rating Scale (NPRS), Patient-Reported Outcomes Measurement Information System (PROMIS) Score, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.), 36-ietm short form survey (SF-36), Single Assessment Numeric Evaluation (SANE), physical exams, plain radiography, and magnetic resonance imaging (MRI) with Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for improvements in pain, function, satisfaction, and cartilage regeneration. DISCUSSION: This prospective study will provide valuable information into the safety and efficacy of intraarticular administration of cell-free stem cell-derived extract (CCM) in patients suffering with grade II/III knee OA. The outcomes from this initial study of novel CCM will lay the foundation for a larger randomized, placebo-controlled, multi-center clinical trial of intraarticular CCM for symptomatic knee OA. TRIAL REGISTRATION: Registered on July 21, 2021. ClinicalTrials.gov NCT04971798.

Editorial Commentary: Anterior Shoulder Instability in Adolescent Athletes: "Slaying the Hydra" Is a Subtle Art.

Anterior shoulder instability in adolescent athletes can be cumbersome to identify and treat. An algorithm is to divide the patients into primary and revision cases then to further subdivide patients who have glenoid bone loss <20% and/or an engaging or off-track Hill-Sachs lesion. A bipolar lesion with either of these conditions is an indication for a bone block open Laterjet procedure. In the revision setting, the threshold for Laterjet is lower. Soft-tissue lesions are indications for a Bankart or labral repair. With the proper attention given to concomitant labral, biceps, and rotator cuff pathology, Hill-Sachs lesions less than 1 cm are left alone. However, in situations where lesions are deeper than 1 cm, an arthroscopic remplissage is indicated. An optimal repair aims to create a labral bumper and a bony bed for the soft tissue to heal, whereas inferior quality of soft tissue indicates a segmental labral reconstruction. Reconstructing large capsular rents with torn ligaments with allograft anterior capsular repair is also needed for proper biomechanical restoration.

Immunomodulatory extracellular vesicles: an alternative to cell therapy for COVID-19.

Introduction: SARS-CoV-2 induces a cytokine storm and can cause inflammation, fibrosis and apoptosis in the lungs, leading to acute respiratory distress syndrome (ARDS). ARDS is the leading cause of mortality and morbidity the associated to COVID-19, and the cytokine storm is a prominent etiological factor. Mesenchymal stem cell-derived extracellular vesicles are an alternative therapy for the management of inflammatory and autoimmune conditions due to their immunosuppressive properties. The immunomodulatory and tissue regeneration capabilities of extracellular vesicles may support their application as a prospective therapy for COVID-19.Areas Covered: We explored the clinical evidence on extracellular vesicles as antiviral agents and in mitigating ARDS, and their therapeutic potential in COVID-19.Expert Opinion: Clinical trials using extracellular vesicles are registered against COVID-19 associated complications, with some evidence of safety and efficacy. Extracellular vesicles present an alternative potential for cell therapy for COVID-19 management, but further preclinical and clinical investigations are needed.

Cell-free Stem Cell-Derived Extract Formulation for Regenerative Medicine Applications.

Stem cells for regenerative medicine purposes offer therapeutic benefits, but disadvantages are still ill defined. The benefit of stem cells may be attributed to their secretion of growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs), including exosomes. We present a novel cell-free stem cell-derived extract (CCM), formulated from human progenitor endothelial stem cells (hPESCs), characterized for biologically active factors using ELISA, nanoparticle tracking analysis and single particle interferometric reflectance imaging sensing. The effect on fibroblast proliferation and ability to induce stem cell migration was analyzed using Alamar Blue proliferation and Transwell migration assays, respectively. GFs including IGFBP 1, 2, 3, and 6, insulin, growth hormone, PDGF-AA, TGF-α, TGF-ß1, VEGF, and the anti-inflammatory cytokine, IL-1RA were detected. Membrane enclosed particles within exosome size range and expressing exosome tetraspanins CD81 and CD9 were identified. CCM significantly increased cell proliferation and induced stem cell migration. Analysis of CCM revealed presence of GFs, CKs, and EVs, including exosomes. The presence of multiple factors including exosomes within one formulation, the ability to promote cell proliferation and induce stem cell migration may reduce inflammation and pain, and augment tissue repair.