Conservative Treatment for Ankle Cartilage: Cellular and Acellular Therapies: A Systematic Review.

Biological agents like growth factors (ie, platelet rich plasma) and mesenchymal stem cells are rising in popularity among orthopedics. Orthobiologics therapy aims to fill the gap between conventional conservative therapies like hyaluronic acid and surgery, especially for cartilage disease. Ankle cartilage defects are very symptomatic and could lead to a severe decrease of quality of life in patients, because of pain, swelling, and inability to walk without pain. In this scenario, this paper aims to systematically review the current literature available about biological therapies for ankle cartilage.

Cartilage Injuries: Basic Science Update.

The last several decades have brought about substantial development in our understanding of the biomolecular pathways associated with chondral disease and progression to arthritis. Within domains relevant to foot and ankle, genetic modification of stem cells, augmentation of bone marrow stimulation techniques, and improvement on existing scaffolds for delivery of orthobiologic agents hold promise in improving treatment of chondral injuries. This review summarizes novel developments in the understanding of the molecular pathways underlying chondral damage and some of the recent advancements within related therapeutics.

Minimally invasive treatment for idiopathic chondrolysis of the hip: analysis of forty-one cases.

PURPOSE: Idiopathic chondrolysis of the hip is characterized by the loss of the articular cartilage of the hip joint with spectrum ranging from full recovery to fibrous ankylosis. Study assessed outcomes following intra-articular steroid injections, joint manipulation and traction immobilization. METHODS: Retrospective (2012-2021) review of 41 cases treated for idiopathic chondrolysis of hip, assessed pre-operatively and post-operatively (minimum 2-year follow-up) using Children's Hospital Oakland Hip Evaluation Score (CHOHES), visual analogue scale (VAS) and range of motion measurements. RESULTS: Twenty-five patients (62%) achieved painless mobility, 6 (14%) had hip stiffness without pain and 10 (24%) had painful and stiff hips at final follow-up. They had a mean age of 12.49 ± 2.4 years and a mean follow-up duration of 33.15 ± 13.1 months. Range of motion improved significantly (p < 0.05). VAS improved to 3.93 ± 1.3 from 7.8 ± 0.7. CHOHES improved from 29.12 ± 9.9 to 56.37 ± 17.6. CONCLUSION: Intra-articular steroid injection, manipulation and traction immobilization may effectively treat idiopathic chondrolysis of the hip by enhancing patient function and reducing the need for further surgical intervention.

Advanced Therapeutic Medicinal Products in Bone and Cartilage Defects.

The number of patients with functional loss of bone and cartilage tissue has shown an increasing trend. Insufficient or inappropriate conventional treatments applied for trauma, orthopedic diseases, or other bone and cartilage-related disorders can lead to bone and cartilage damage. This represents a worldwide public health issue and a significant economic burden. Advanced therapeutic medicinal products (ATMPs) proposed promising alternative therapeutic modalities by application of cell-based and tissue engineering approaches. Recently, several ATMPs have been developed to promote bone and cartilage tissue regeneration. Fifteen ATMPs, two related to bone and 13 related to cartilage, have received regulatory approval and marketing authorization. However, four ATMPs were withdrawn from the market for various reasons. However, ATMPs that are still on the market have demonstrated positive results, their broad application faced limitations. The development and standardization of methodologies will be a major challenge in the coming decades. Currently, the number of ATMPs in clinical trials using mesenchymal stromal cells or chondrocytes indicates a growing recognition that current ATMPs can be improved. Research on bone and cartilage tissue regeneration continues to expand. Cell-based therapies are likely to be clinically supported by the new ATMPs, innovative fabrication processes, and enhanced surgical approaches. In this study, we highlighted the available ATMPs that have been used in bone and cartilage defects and discussed their advantages and disadvantages in clinical applications.

Applying additional autologous platelet-rich fibrin matrix or serial platelet-rich plasma to microfracture technique increases the quality of the repaired cartilage.

PURPOSE: The aim of the present study is to investigate and compare the effects of biological adjuvants (platelet-rich plasma, platelet-rich fibrin matrix) and microfracture technique individually and in combination on full thickness chondral defects in a rabbit model. METHODS: A total of 60 New Zealand White rabbits were randomly divided into six groups according to treatment modality as follows: control (C), microfracture (MF), platelet-rich plasma (PRP), platelet-rich fibrin matrix (PRFM), platelet-rich fibrin matrix after microfracture (MF + PRFM) and platelet-rich plasma after microfracture (MF + PRP) groups. The cartilage repair tissue was assessed histologically via International Cartilage Repair Score (ICRS) and macroscopically via ICRS macroscopic assessment scale. RESULTS: It was shown that overall macroscopic scores of the groups with MF were higher than those of the groups without MF. The cell morphology observed in the defect areas was mostly characterized with non-chondrocyte cells in the groups without MF, whereas chondrocyte cells mostly prevailed in the groups with MF. There was a greater integration through the cartilage-like tissue in the MF + PRP and MF + PRFM groups. The control group showed either fissures or fissures partially filled with fibrous tissue. When the groups were individually examined, there were statistically significant differences between the control and MF groups (p = 0.002), between the control and MF + PRFM groups (p = 0.001), between the control and MF + PRP groups (p < 0.001), between the PRFM and MF + PRFM groups (p = 0.014) and between the PRFM and MF + PRP (p = 0.023) groups in terms of histological evaluation scores. CONCLUSION: The application of PRP and PRFM in combination with MF treatment exhibited a positive impact on the repair and restoration of cartilage, and produced better outcomes than the individual use of PRP and PRFM. Nevertheless, in the treatment of full thickness chondral defects, the use of PRFM injection is recommended, which is performed intraoperatively at a single time and with no difficulty of repeating after surgery, instead of serial PRP injections based on the macroscopic and histological results obtained in the present study indicating that there was no significant difference between the use of these two adjuvants.

Orthobiologics: a review.

PURPOSE: The use of biologic materials in orthopaedics (orthobiologics) has gained significant attention over the past years. To enhance the body of the related literature, this review article is aimed at summarizing these novel biologic therapies in orthopaedics and at discussing their multiple clinical implementations and outcomes. METHODS: This review of the literature presents the methods, clinical applications, impact, cost-effectiveness, and outcomes, as well as the current indications and future perspectives of orthobiologics, namely, platelet-rich plasma, mesenchymal stem cells, bone marrow aspirate concentrate, growth factors, and tissue engineering. RESULTS: Currently available studies have used variable methods of research including biologic materials as well as patient populations and outcome measurements, therefore making comparison of studies difficult. Key features for the study and use of orthobiologics include minimal invasiveness, great healing potential, and reasonable cost as a nonoperative treatment option. Their clinical applications have been described for common orthopaedic pathologies such as osteoarthritis, articular cartilage defects, bone defects and fracture nonunions, ligament injuries, and tendinopathies. CONCLUSIONS: Orthobiologics-based therapies have shown noticeable clinical results at the short- and mid-term. It is crucial that these therapies remain effective and stable in the long term. The optimal design for a successful scaffold remains to be further determined.

RNA Extraction from Cartilage: Issues, Methods, Tips.

The increase in degenerative diseases involving articular cartilage has pushed research to focus on their pathogenesis and treatment, exploiting increasingly complex techniques. Gene expression analyses from tissue are representative of the in vivo situation, but the protocols to be applied to obtain a reliable analysis are not completely cleared through customs. Thus, RNA extraction from fresh samples and specifically from musculoskeletal tissue such as cartilage is still a challenging issue. The aim of the review is to provide an overview of the techniques described in the literature for RNA extraction, highlighting limits and possibilities. The research retrieved 65 papers suitable for the purposes. The results highlighted the great difficulty in comparing the different studies, both for the sources of tissue used and for the techniques employed, as well as the details about protocols. Few papers compared different RNA extraction methods or homogenization techniques; the case study reported by authors about RNA extraction from sheep cartilage has not found an analog in the literature, confirming the existence of a relevant blank on studies about RNA extraction from cartilage tissue. However, the state of the art depicted can be used as a starting point to improve and expand studies on this topic.

Platelet Rich Plasma in the Repair of Articular Cartilage Injury: A Narrative Review.

OBJECTIVE: This paper reviews the research of platelet-rich plasma (PRP) in articular cartilage injury repair, to assess the mechanism, utilization, and efficacy of PRP in the treatment of articular cartilage injury, hoping to provide a theoretical basis for the clinical application of PRP in the future. MATERIALS AND METHODS: A comprehensive database search on PRP applications in cartilage repair was performed. Among them, the retrieval time range of PRP in clinical trials of repairing knee cartilage injury was from January 1, 2021 to January 1, 2022. Non-clinical trials and studies unrelated to cartilage injury were excluded. RESULT: PRP can affect inflammation, angiogenesis, cartilage protection, and cellular proliferation and differentiation after articular cartilage injury through different pathways. In all, 13 clinical trials were included in the analysis. CONCLUSION: PRP is an emergent therapeutic approach in tissue engineering. Most studies reported that PRP has a positive effect on cartilage injury, improving the joint function, meanwhile there is a lack of standardized standards. The technology of PRP in the repair and treatment of articular cartilage injury is worthy of further research.

Vascular injury of immature epiphyses impair stem cell engraftment in cartilage defects.

The purpose of our study was to investigate if vascular injury in immature epiphyses affects cartilage repair outcomes of matrix-associated stem cell implants (MASI). Porcine bone marrow mesenchymal stromal stem cells (BMSCs) suspended in a fibrin glue scaffold were implanted into 24 full-thickness cartilage defects (5 mm ø) of the bilateral distal femur of six Göttingen minipigs (n = 12 defects in 6 knee joints of 3 immature pigs; age 3.5-4 months; n = 12 defects in 6 knee joints of 3 mature control pigs; age, 21-28 months). All pigs underwent magnetic resonance imaging (MRI) at 2, 4, 12 (n = 24 defects), and 24 weeks (n = 12 defects). After the last imaging study, pigs were sacrificed, joints explanted and evaluated with VEGF, H&E, van Gieson, Mallory, and Safranin O stains. Results of mature and immature cartilage groups were compared using the Wilcoxon signed-rank test. Quantitative scores for subchondral edema at 2 weeks were correlated with quantitative scores for cartilage repair (MOCART score and ICRS score) at 12 weeks as well as Pineda scores at end of the study, using linear regression analysis. On serial MRIs, mature joints demonstrated progressive healing of cartilage defects while immature joints demonstrated incomplete healing and damage of the subchondral bone. The MOCART score at 12 weeks was significantly higher for mature joints (79.583 ± 7.216) compared to immature joints (30.416 ± 10.543, p = 0.002). Immature cartilage demonstrated abundant microvessels while mature cartilage did not contain microvessels. Accordingly, cartilage defects in immature joints showed a significantly higher number of disrupted microvessels, subchondral edema, and angiogenesis compared to mature cartilage. Quantitative scores for subchondral edema at 2 weeks were negatively correlated with MOCART scores (r = - 0.861) and ICRS scores (r = - 0.901) at 12 weeks and positively correlated with Pineda scores at the end of the study (r = 0.782). Injury of epiphyseal blood vessels in immature joints leads to subchondral bone defects and limits cartilage repair after MASI.

Magnetic Hydrogel for Cartilage Tissue Regeneration as well as a Review on Advantages and Disadvantages of Different Cartilage Repair Strategies.

There is a clear clinical need for efficient cartilage healing strategies for treating cartilage defects which burdens millions of patients physically and financially. Different strategies including microfracture technique, osteochondral transfer, and scaffold-based treatments have been suggested for curing cartilage injuries. Although some improvements have been achieved in several facets, current treatments are still less than satisfactory. Recently, different hydrogel-based biomaterials have been suggested as a therapeutic candidate for cartilage tissue regeneration due to their biocompatibility, high water content, and tunability. Specifically, magnetic hydrogels are becoming more attractive due to their smart response to magnetic fields remotely. We seek to outline the context-specific regenerative potential of magnetic hydrogels for cartilage tissue repair. In this review, first, we explained conventional techniques for cartilage repair and then compared them with new scaffold-based approaches. We illustrated various hydrogels used for cartilage regeneration by highlighting the magnetic hydrogels. Also, we gathered in vitro and in vivo studies of how magnetic hydrogels promote chondrogenesis as well as studied the biological mechanism which is responsible for cartilage repair due to the application of magnetic hydrogel.

The Role of Mesenchymal Stromal Cells in the Management of Knee Chondral Defects.

➤: Mesenchymal stromal cells (MSCs) are a subset of progenitor cells that help to promote tissue healing and regeneration through the secretion of various cytokines and growth factors. Although technically pluripotent, MSCs in vivo rarely repair damaged tissue through direct differentiation and engraftment. ➤: Augmentation of traditional marrow stimulation techniques with MSCs has been theorized to improve repair tissue quality and defect fill. Clinical trials evaluating this technique are limited but have shown modest improvements compared with isolated marrow stimulation. ➤: Various scaffolds also have been utilized in combination with MSCs to treat focal chondral defects. Although the techniques described are heterogeneous, many have shown promising early clinical outcomes. ➤: Newer techniques involving 3-dimensional bioprinted scaffolds seeded with MSCs allow for the recreation of complex architecture, more closely resembling articular cartilage. These techniques are evolving and have not yet been studied in human clinical trials.

Regenerative Potential of Platelet Concentrate Lysate in Mechanically Injured Cartilage and Matrix-Associated Chondrocyte Implantation In Vitro.

Adjuvant therapy in autologous chondrocyte implantation (ACI) can control the post-traumatic environment and guide graft maturation to support cartilage repair. To investigate both aspects, we examined potential chondro-regenerative effects of lysed platelet concentrate (PC) and supplementary interleukin 10 (IL-10) on mechanically injured cartilage and on clinically used ACI scaffolds. ACI remnants and human cartilage explants, which were applied to an uniaxial unconfined compression as injury model, were treated with human IL-10 and/or PC from thrombocyte concentrates. We analyzed nuclear blebbing/TUNEL, sGAG content, immunohistochemistry, and the expression of COL1A1, COL2A1, COL10A1, SOX9, and ACAN. Post-injuriously, PC was associated with less cell death, increased COL2A1 expression, and decreased COL10A1 expression and, interestingly, the combination with Il-10 or Il-10 alone had no additional effects, except on COL10A1, which was most effectively decreased by the combination of PC and Il-10. The expression of COL2A1 or SOX9 was statistically not modulated by these substances. In contrast, in chondrocytes in ACI grafts the combination of PC and IL-10 had the most pronounced effects on all parameters except ACAN. Thus, using adjuvants such as PC and IL-10, preferably in combination, is a promising strategy for enhancing repair and graft maturation of autologous transplanted chondrocytes after cartilage injury.

A Review of the Use of Microparticles for Cartilage Tissue Engineering.

Tissue and organ failure has induced immense economic and healthcare concerns across the world. Tissue engineering is an interdisciplinary biomedical approach which aims to address the issues intrinsic to organ donation by providing an alternative strategy to tissue and organ transplantation. This review is specifically focused on cartilage tissue. Cartilage defects cannot readily regenerate, and thus research into tissue engineering approaches is relevant as a potential treatment option. Cells, scaffolds, and growth factors are three components that can be utilized to regenerate new tissue, and in particular recent advances in microparticle technology have excellent potential to revolutionize cartilage tissue regeneration. First, microspheres can be used for drug delivery by injecting them into the cartilage tissue or joint space to reduce pain and stimulate regeneration. They can also be used as controlled release systems within tissue engineering constructs. Additionally, microcarriers can act as a surface for stem cells or chondrocytes to adhere to and expand, generating large amounts of cells, which are necessary for clinically relevant cell therapies. Finally, a newer application of microparticles is to form them together into granular hydrogels to act as scaffolds for tissue engineering or to use in bioprinting. Tissue engineering has the potential to revolutionize the space of cartilage regeneration, but additional research is needed to allow for clinical translation. Microparticles are a key enabling technology in this regard.

Reliability of the MOCART score: a systematic review.

BACKGROUND: The present systematic review analysed the available literature to assess reliability of the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score in the evaluation of knee and ankle osteochondral lesions. METHODS: All the studies using the MOCART score for knee and/or talus chondral defects were accessed in March 2021. A multivariate analysis was performed to assess associations between the MOCART score at last follow-up and data of patients at baseline, clinical scores and complications. A multiple linear model regression analysis was used. RESULTS: The MOCART score evidenced no association with patient age (P = 0.6), sex (P = 0.1), body mass index (P = 0.06), defect size (P = 0.9), prior length of symptoms (P = 0.9) or visual analogue scale (P = 0.07). For chondral defects of the knee, no statistically significant association was found between the MOCART score and the International Knee Documentation Committee (P = 0.9) and with the Lysholm Knee Scoring Scales (P = 0.2), Tegner Activity Scale (P = 0.2), visual analogue scale P = 0.07), rate of failure (P = 0.2) and revision (P = 0.9). For chondral defect of the talus, no statistically significant associations were found between the MOCART score and the American Orthopedic Foot and Ankle Score (P = 0.3), Tegner Activity Scale (P = 0.4), visual analogue scale (P = 0.1), rate of failure (P = 0.1) and revision (P = 0.7). CONCLUSION: The MOCART score demonstrated no association with patient characteristics and with the surgical outcome in patients who underwent surgical management for knee and talus chondral defects. LEVEL OF EVIDENCE: Level IV.

[Chondrodermatitis nodularis helicis: a practical overview with treatment recommendations for the primary and secondary care]. / Chondrodermatitis nodularis helicis.

Chondrodermatitisnodularishelicis is characterized by a sore nodule of the helix or antihelix of the ear. Pressure plays an important role in the pathogenesis of the benign inflammatory condition. Pressure relieving is a rational first-line treatment modality and could be applied in combination with or followed by intralesional steroid injections. If the condition remains, a surgical procedure is warranted. Cartilage removal without skin excision is the procedure of choice. Particular attention should be paid to the complete removal of all defective cartilage. This procedure is elegant and simple compared to the conventional wedge excision and has a lower risk of recurrence. Because of high recurrence rates of non-surgical treatments, early surgical treatment is recommended.

Gellan gum/alginate-based Ca-enriched acellular bilayer hydrogel with robust interface bonding for effective osteochondral repair.

The treatment of osteochondral (OC) defects remains challenging because of the lack of economical and feasible therapeutic strategies for OC repair and reconstruction. In this study, we report an integrated bilayer hydrogel with robust interface binding force (40 kPa) by facilitating the diffusion of calcium ions to the secondary crosslink of the bilayer hydrogel, in which gellan gum and sodium alginate acted as the chondral layer, gellan gum and hydroxyapatite acted as subchondral layer. This integrated construct has high cytocompatibility, and can seed with mesenchymal stem cells (MSCs) related to different functional protein expression for cartilage and bone formation, respectively. Furthermore, in the rabbit critical-sized osteochondral defect model (4.0 mm in diameter and 8.0 mm in depth), the calcium enriched hydrogel act as a calcium reservoir, promote neovascularization at week 4, and repair the critical defect at week 8, demonstrating the feasible preparation of an acellular hydrogel for OC repair.

Editorial Commentary: Risks of Biologic Therapies in Sports Medicine: Landmines on the Road to the Holy Grail.

Biologic therapies hold great promise in the treatment of a variety of sports medicine conditions, including cartilage injuries, osteoarthritis, and tendon or ligament tears. Cell-based therapies currently under investigation include autologous products such as platelet-rich plasma, bone marrow aspirate concentrate, other adipose and mesenchymal stem cell products, and allogeneic products such as umbilical cord and placenta-derived products. However, their use does not come without risk, and the complications of these treatments can be underreported. Risks include infection, sterile inflammatory response, or a combination. Many times, when offering injection therapy, we consider the greatest risk a lack of efficacy. A "no harm, no foul" attitude is taken. Many of us think that the biggest risk of such injections, due to out-of-pocket expense, would be damage to someone's checkbook more than damage to their health. However, there are real medical risks to our treatments. Regulatory efforts around the use of biologics are needed to track both efficacy and side effects, as we advance this technology and expand its use in the future.

Role of Matrix-Associated Autologous Chondrocyte Implantation with Spheroids in the Treatment of Large Chondral Defects in the Knee: A Systematic Review.

Autologous chondrocyte implantation (ACI) is a cell therapy for the treatment of focal cartilage defects. The ACI product that is currently approved for use in the European Union (EU) consists of spheroids of autologous matrix-associated chondrocytes. These spheroids are spherical aggregates of ex vivo expanded human autologous chondrocytes and their self-synthesized extracellular matrix. The aim is to provide an overview of the preclinical and nonclinical studies that have been performed to ensure reproducible quality, safety, and efficacy of the cell therapy, and to evaluate the clinical data on ACI with spheroids. A systematic review was performed to include all English publications on self-aggregated spheroids of chondrocytes cultured in autologous serum without other supplements. A total of 20 publications were included, 7 pre- and nonclinical and 13 clinical research publications. The pre- and nonclinical research publications describe the development from concept to in vivo efficacy and quality- and safety-related aspects such as biodistribution, tumorigenicity, genetic stability, and potency. The evaluation of clinical research shows short- to mid-term safety and efficacy for the ACI with spheroid-based treatment of cartilage defects in both randomized clinical trials with selected patients, as well as in routine treatment providing real-world data in more complex patients.

Differences in the Demographics and Preferred Management of Knee Cartilage Injuries in Soccer Players Across FIFA Centers of Excellence.

OBJECTIVE: We sought to report on the demographics and epidemiology of knee cartilage injuries and preferred management in soccer players, across FIFA Medical Centers of Excellence (FMCE). DESIGN: A descriptive questionnaire focusing on characteristics of knee cartilage injuries and their management in soccer players during the 10-year period prior to the distribution of the questionnaire was sent to all FMCE around the world in September 2019 via an online platform. Voluntary responses from centers were processed and analyzed. Descriptive characteristics were reported using median and interquartile ranges (IQR) for continuous variables and frequencies and percentages (%) for discrete variables. RESULTS: A total of 15 centers from 5 continents responded to the questionnaire and reported on a total of 4526 soccer players. Among centers, the median age was 27 years (IQR: 23-38), the median rate of male players was 75% (IQR: 68-90), and the median rate of professional players was 10% (IQR: 5-23). The most common reported etiology for cartilage injury was traumatic (median 40%, IQR: 13-73). The most common nonoperative treatment utilized was physical therapy (median 90%, IQR: 51%-100%) and the most common operative treatment utilized was bone marrow stimulation/micro-fracture (median 40%, IQR: 19-54%). The utilization of other cartilage restoration procedures varied across centers. CONCLUSIONS: Our findings highlight different tendencies in the management of these injuries across FMCE and emphasize the need for collaborative efforts focusing on establishing consensus guidelines for the optimal management of these challenging injuries in soccer players.

Promising diagnostic and therapeutic circRNAs for skeletal and chondral disorders.

Circular RNAs (circRNAs) belong to a highly conserved subtype of non-coding RNAs, produced by the back-splicing of specific regions of pre-mRNA. CircRNAs have wide-ranging effects on eukaryotic physiology and pathology by acting as transcription regulators, miRNA sponges, protein sponges, and templates for translation. Skeletal and chondral disorders are the leading causes of pain and disability, especially for elders, affecting hundreds of millions of people worldwide. Plenty of evidence have shown that circRNAs are dysregulated and play vital roles in the occurrence and progression of skeletal and chondral disorders. Herein, we systematically summarize the emerging roles and underlying molecular mechanisms of hub circRNAs in the pathogenesis of several representative skeletal and chondral disorders. Our findings may provide further insight into the mechanistic details of the role of circRNA in bone or cartilage metabolism, and highlight the promising application of circRNAs in serving as potential diagnostic or therapeutic targets for the prevention and treatment of skeletal and chondral disorders.