In situ study on articular cartilage degeneration in simulated microgravity by HOF-ATR-FTIR spectroscopy.

Fourier transform infrared spectroscopy (FTIRS) can provide rich information on the composition and content of samples, enabling the detection of subtle changes in tissue composition and structure. This study represents the first application of FTIRS to investigate cartilage under microgravity. Simulated microgravity cartilage model was firstly established by tail-suspension (TS) for 7, 14 and 21 days, which would be compared to control samples. A self-developed hollow optical fiber attenuated total reflection (HOF-ATR) probe coupled with a FTIR spectrometer was used for the spectral acquisition of cartilage samples in situ, and one-way analysis of variance (ANOVA) was employed to analyze the changes in the contents of cartilage matrix at different stages. The results indicate that cartilage degenerates in microgravity, the collagen content gradually decreases with the TS time, and the structure of collagen fibers changes. The trends of proteoglycan content and collagen integrity show an initial decrease followed by an increase, ultimately significantly decreasing. The findings provide the basis for the cartilage degeneration in microgravity with TS time, which must be of real significance for space science and health detection.

Advancements in hydrogel design for articular cartilage regeneration: A comprehensive review.

This review paper explores the cutting-edge advancements in hydrogel design for articular cartilage regeneration (CR). Articular cartilage (AC) defects are a common occurrence worldwide that can lead to joint breakdown at a later stage of the disease, necessitating immediate intervention to prevent progressive degeneration of cartilage. Decades of research into the biomedical applications of hydrogels have revealed their tremendous potential, particularly in soft tissue engineering, including CR. Hydrogels are highly tunable and can be designed to meet the key criteria needed for a template in CR. This paper aims to identify those criteria, including the hydrogel components, mechanical properties, biodegradability, structural design, and integration capability with the adjacent native tissue and delves into the benefits that CR can obtain through appropriate design. Stratified-structural hydrogels that emulate the native cartilage structure, as well as the impact of environmental stimuli on the regeneration outcome, have also been discussed. By examining recent advances and emerging techniques, this paper offers valuable insights into developing effective hydrogel-based therapies for AC repair.

Advanced therapy with mesenchymal stromal cells for knee osteoarthritis: Systematic review and meta-analysis of randomized controlled trials.

Background: Advanced cell therapies emerged as promising candidates for treatment of knee articular diseases, but robust evidence regarding their clinical applicability is still lacking. Objective: To assess the efficacy and safety of advanced mesenchymal stromal cells (MSC) therapy for knee osteoarthritis (OA) and chondral lesions. Methods: Systematic review of randomized controlled trials conducted in accordance with Cochrane Handbook and reported following PRISMA checklist. GRADE approach was used for assessing the evidence certainty. Results: 25 randomized controlled trials that enrolled 1048 participants were included. Meta-analyses data showed that, compared to viscosupplementation (VS), advanced MSC therapy resulted in a 1.91 lower pain VAS score (95 % CI -3.23 to -0.59; p < 0.00001) for the treatment of knee OA after 12 months. Compared to placebo, the difference was 0.99 lower pain VAS points (95 % CI -1.94 to -0.03; p = 0.76). According to the GRADE approach, the evidence was very uncertain for both comparisons. By excluding studies with high risk of bias, there was a similar size of effect (VAS MD -1.54, 95 % CI -2.09 to -0.98; p = 0.70) with improved (moderate) certainty of evidence, suggesting that MSC therapy probably reduces pain slightly better than VS. Regarding serious adverse events, there was no difference from advanced MSC therapy to placebo or to VS, with very uncertain evidence. Conclusion: Advanced MSC therapy resulted in lower pain compared to placebo or VS for the treatment of knee OA after 12 months, with no difference in adverse events. However, the evidence was considered uncertain. The Translational Potential of this Article: Currently, there is a lack of studies with good methodological structure aiming to evaluate the real clinical impact of advanced cell therapy for knee OA. The present study was well structured and conducted, with Risk of Bias, GRADE certainty assessment and sensitivity analysis. It explores the translational aspect of the benefits and safety of MSC compared with placebo and gold-standard therapy to give practitioners and researchers support to expand this therapy in their practice. PROSPERO registration number: CRD42020158173. Access at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=158173.

Magnetic Resonance Imaging Features and Functional Score in Patients Requiring Total Knee Arthroplasty.

Introduction Knee osteoarthritis (KOA) is a progressive degenerative disease, with an increasing prevalence among the population. The degenerative changes in KOA affect the cartilage, menisci, synovial tissue, and subchondral bone. The treatment for patients in advanced stages of the disease is total knee arthroplasty (TKA). The purpose of this descriptive study is to identify the MRI features in the case of patients with KOA who did not obtain an improvement in symptoms and joint function after the non-surgical treatments and who applied for surgical treatment, i.e. TKA. Also, we aimed to identify the correlations between the MRI changes and the functional score of the patients, as well as the inter-variable correlations. Materials and methods The study was conducted in the Department of Orthopedics and Traumatology at the University Emergency Hospital of Bucharest between January 1, 2023, and January 31, 2024. It included 50 patients who required TKA. This study is a prospective, observational, and descriptive analysis focusing on patients scheduled for TKA. Results The patients in the study group who required TKA had a Knee Society Score (KSS) ranging from 35 to 70 and a KSS function score between 24 and 60. Among them, 98% had tricompartmental lesions of the articular cartilage, and 100% presented with osteophytes, even when they were not identifiable radiologically. Additionally, 58% of the patients had changes in the infrapatellar fat pad, 66% presented with joint effusion without any traumatic history, and 86% of the patients had partial or complete lesions of the anterior cruciate ligament. Conclusion The MRI pattern of the patient who requires TKA consists of the presence of articular cartilage lesions in more than two compartments with exposure of the subchondral bone and diameter greater than 1 cm, meniscus lesions (>grade 2), meniscus extrusion (>grade 1), the presence of bone marrow lesions (BMLs) in the medial or lateral compartment of the femur or tibia, hyperintense signal of the infrapatellar fat pad, anterior cruciate ligament (ACL) lesions (>grade 2), and the presence of osteophytes together with the presence of effusion in the suprapatellar bursa. BMLs and changes in the infrapatellar fat pad may lead to the opening of new research perspectives explaining the complex changes in KOA in relation to the inflammatory process and gene expression.

Advancing Cartilage Tissue Engineering: A Review of 3D Bioprinting Approaches and Bioink Properties.

Articular cartilage is crucial in human physiology, and its degeneration poses a significant public health challenge. While recent advancements in 3D bioprinting and tissue engineering show promise for cartilage regeneration, there remains a gap between research findings and clinical application. This review critically examines the mechanical and biological properties of hyaline cartilage, along with current 3D manufacturing methods and analysis techniques. Moreover, we provide a quantitative synthesis of bioink properties used in cartilage tissue engineering. After screening 181 initial works, 33 studies using extrusion bioprinting were analyzed and synthesized, presenting results that indicate the main materials, cells, and methods utilized for mechanical and biological evaluation. Altogether, this review motivates the standardization of mechanical analyses and biomaterial assessments of 3D bioprinted constructs to clarify their chondrogenic potential.

Genetic effect of basal metabolic rate on the benign neoplasm of bone and articular cartilage: a Mendelian randomization study.

Background: Previous studies have found an association between basal metabolic rate (BMR) and various malignant neoplasms, including bone tumors. BMR is also associated with bone mineral density, but the causality between BMR and benign neoplasms of bone and articular cartilage remains uncertain. Design: Single nucleotide polymorphisms (SNPs) associated with BMR (p < 5 × 10-8) were used as instrumental variables for Mendelian randomization analysis of neoplasm risk. The inverse variance weighted (IVW) method was the primary approach, with the weighted median and MR-Egger regression serving as supplements. Results: In this MR analysis, the IVW method supported a causal relationship between BMR and benign neoplasms of bone and articular cartilage (OR = 1.417; 95% CI, 1.039 to 1.930; p = 0.027). No evidence of heterogeneity or pleiotropy in the selected SNPs was found in our study. Thus, based on these results, we discovered a possible causal relationship between BMR and benign neoplasms of bone and articular cartilage. Conclusions: In this MR study, evidence suggested a genetic correlation between genetically predicted BMR and the risk of neoplasms in bone and articular cartilage.

Boosting Chondrocyte Bioactivity with Ultra-Sulfated Glycopeptide Supramolecular Polymers.

Although autologous chondrocyte transplantation can be effective in articular cartilage repair, negative side effects limit the utility of the treatment, such as long recovery times, poor engraftment or chondrogenic dedifferentiation, and cell leakage. Peptide-based supramolecular polymers have emerged as promising bioactive systems to promote tissue regeneration through cell signaling and dynamic behavior. We report here on the development of a series of glycopeptide amphiphile supramolecular nanofibers with chondrogenic bioactivity. These supramolecular polymers were found to have the ability to boost TGFß-1 signaling by displaying galactosamine moieties with differing degrees of sulfation on their surfaces. We were also able to encapsulate chondrocytes with these nanostructures as single cells without affecting viability and proliferation. Among the monomers tested, assemblies of trisulfated glycopeptides led to elevated expression of chondrogenic markers relative to those with lower degrees of sulfation that mimic chondroitin sulfate repeating units. We hypothesize the enhanced bioactivity is rooted in specific interactions of the supramolecular assemblies with TGFß-1 and its consequence on cell signaling, which may involve elevated levels of supramolecular motion as a result of high charge in trisulfated glycopeptide amphiphiles. Our findings suggest that supramolecular polymers formed by the ultra-sulfated glycopeptide amphiphiles could provide better outcomes in chondrocyte transplantation therapies for cartilage regeneration. STATEMENT OF SIGNIFICANCE: : This study prepares glycopeptide amphiphiles conjugated at their termini with chondroitin sulfate mimetic residues with varying degrees of sulfation that self-assemble into supramolecular nanofibers in aqueous solution. These supramolecular polymers encapsulate chondrocytes as single cells through intimate contact with cell surface structures, forming artificial matrix that can localize the growth factor TGFß-1 in the intercellular environment. A high degree of sulfation on the glycopeptide amphiphile is found to be critical in elevating chondrogenic cellular responses that supersede the efficacy of natural chondroitin sulfate. This work demonstrates that supramolecular assembly of a unique molecular structure designed to mimic chondroitin sulfate successfully boosts chondrocyte bioactivity by single cell encapsulation, suggesting a new avenue implementing chondrocyte transplantation with supramolecular nanomaterials for cartilage regeneration.

miR-378a-3p Regulates the BMP2-Smad Pathway to Promote Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells.

This study aims to elucidate the role of miR-378a-3p in facilitating the proliferation and differentiation of synovium-derived mesenchymal stem cells (SMSCs) into chondrocytes. The effects of overexpressing miR-378a-3p on SMSCs were investigated through histological analysis, quantitative PCR, and western blotting. Then we identified binding sites of miR-378a-3p with BMP2 through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and predictions from the RegRNA 2.0 database. Subsequently, BMP2 was confirmed as the target by which miR-378a-3p promotes the chondrogenic differentiation of SMSCs using a luciferase reporter gene assay and an miR-378a-3p RNA interference plasmid. Finally, by constructing a rat model with articular cartilage damage, we detected the reparative effects of miR-378a-3p overexpression on cartilage damage. Additionally, we verified the mechanism by which miR-378a-3p promotes chondrogenic differentiation in SMSCs. MiR-378a-3p enhances the proliferation and differentiation of SMSCs into chondrocytes by modulating the BMP2-Smad signaling pathway, thereby facilitating repair processes for articular cartilage injuries in rats. Notably, knockdown of BMP2 diminished the reparative efficacy of miR-378a-3p on articular cartilage damage. Upregulation of miR-378a-3p promotes chondrogenic differentiation in SMSCs through activation of the BMP2-Smad pathway, positioning it as a potential therapeutic target for osteoarthritis.

Isosakuranetin inhibits subchondral osteoclastogenesis for attenuating osteoarthritis via suppressing NF-κB/CXCL2 axis.

As the most predominant form of arthritis, osteoarthritis (OA) is featured with irreversible progress and involvement of the whole joint. Since OA onset, abnormal mechanical load initiates excessive osteoclastogenesis, evolving a rapid turnover of subchondral bone, cyst creation, synovitis, cartilage degradation, and ultimately resulting in joint failure. Additionally, aberrant vascularization and nociceptive pain are invoked by osteoclast-induced angiogenesis and sensory innervation in the subchondral bone. Rhizoma anemarrhenae (Zhimu) has been extensively demonstrated to show multiple pharmacological effects including anti-inflammation, anti-aging, and immunomodulation. Herein, Broussonin a (BRA), Markogein (MAN), and Isosakuranetin (ISN) derived from Rhizoma anemarrhenae, were initially discovered for their affinity with Bone marrow mononuclear cell (BMMC) membranes using the Cell membrane chromatography/Time of flight mass spectrometry (CMC/TOFMS) method, while only ISN exerted a significant inhibitory effect on RANKL-induced osteoclastogenesis in BMMC in vitro. Intriguingly, we disclosed that ISN blunted the overactivation of Tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts in subchondral bone in OA mice, as indicated by enhanced bone volume/total volume (BV/TV), trabecular number (Tb.N), and trabeculae thickness (Tb.Th), as well as diminished trabecular pattern factor (Tb.pf). Treatment with ISN also impaired aberrant angiogenesis and nociceptive reaction in the subchondral bone marrow. Moreover, ISN hindered the loss of articular cartilage proteoglycan and lowered the Osteoarthritis Research Society International (OARSI) grade, boosting the expression amount of Aggrecan (ACAN) and Collagen II (COL II) positive cells while reducing Matrix metalloproteinase 13 (MMP-13) positive cells. For mechanisms, We verified that ISN hampered subchondral osteoclastogenesis by blocking nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 2 (CXCL2) stimulation. Taken together, we reveal that ISN impedes the progression of OA by preventing hyperactivated subchondral osteoclastogenesis via suppressing the NF-κB/CXCL2 axis.

Disuse atrophy of articular cartilage can be restored by mechanical reloading in mice.

BACKGROUND: Moderate mechanical stress generated by normal joint loading and movements helps maintain the health of articular cartilage. Despite growing interest in the pathogenesis of cartilage degeneration caused by reduced mechanical stress, its reversibility by mechanical reloading is less understood. This study aimed to investigate the response of articular cartilage exposed to mechanical reloading after unloading in vivo and in vitro. METHODS AND RESULTS: Disuse atrophy was induced in the knee joint cartilage of adult mice through hindlimb unloading by tail suspension. For in vivo experiments, mice were subjected to reloading with or without daily exercise intervention or surgical destabilization of the knee joint. Microcomputed tomography and histomorphometric analyses were performed on the harvested knee joints. Matrix loss and thinning of articular cartilage due to unloading were fully or partially restored by reloading, and exercise intervention enhanced the restoration. Subchondral bone density decreased by unloading and increased to above-normal levels by reloading. The severity of cartilage damage caused by joint instability was not different even with prior non-weight bearing. For in vitro experiments, articular chondrocytes isolated from the healthy or unloaded joints of the mice were embedded in agarose gel. After dynamic compression loading, the expression levels of anabolic (Sox9, Col2a1, and Acan) and catabolic (Mmp13 and Adamts5) factors of cartilage were analyzed. In chondrocytes isolated from the unloaded joints, similar to those from healthy joints, dynamic compression increased the expression of anabolic factors but suppressed the expression of catabolic factors. CONCLUSION: The results of this study indicate that the morphological changes in articular cartilage exposed to mechanical unloading may be restored in response to mechanical reloading by shifting extracellular matrix metabolism in chondrocytes to anabolism.

Biomarkers for hypertrophic chondrocyte differentiation are associated with spatial cellular organisation and suggest endochondral ossification-like processes in osteoarthritic cartilage: An exploratory study.

Background: In healthy articular cartilage, chondrocytes are found along arcades of collagen fibers as Single Strings. With onset of cartilage degeneration this pattern changes to Double Strings. In the course of osteoarthritis Small Clusters, and finally Big Clusters form. In highly degenerated articular cartilage, another poorly understood pattern is found where chondrocyte morphology differs considerably, and the distribution of cells is diffuse. Progression of osteoarthritis is accompanied by key processes such as chondrocyte proliferation, apoptosis, hypertrophic differentiation, inflammation, and angiogenesis. The aim of this exploratory study was to identify biomarkers for these processes in the context of spatial cellular organizational changes in articular cartilage. Methods: Cartilage explants (n = 166 patients) were sorted according to their predominant cellular pattern. Quantitative or semi-quantitative analysis of 39 biomarkers were performed by multiplex assay (31) or ELISA (8), and qualitative analysis on 12 immunohistochemical markers. Results: Hypertrophic differentiation (e.g. type-X collagen, osteopontin, osteocalcin and interleukin-6) and angiogenesis were associated with changes in chondrocyte organisation. First changes take place already at the transition from Single Strings to Double Strings. Drastic changes in the appearance of numerous biomarkers are found at the transition from Big Clusters to Diffuse. Conclusion: Key processes in osteoarthritis and their biomarkers seem to depend on the spatial distribution of chondrocytes in articular cartilage. Abrupt changes in biomarker occurrence were observed between Big Clusters and Diffuse insinuating that the Diffuse pattern is composed of a different cell population or at least a different form of chondrocyte morphology. The Translational Potential of this Article: In situ identification of the different spatial chondrocyte patterns by fluorescence microscopy has already been established in the recent past. Analysing human in-situ cartilage explants rather than isolated OA chondrocytes closes the gap between in vitro and in vivo studies and as such, stretches a big step towards translation of the observed findings. The direct association between tissue biomarker profile and cellular arrangements representing different states of OA sheds new light on the molecular and cellular physiopathology, especially in the context of larger processes such as angiogenesis, cellular proliferation, differentiation, and apoptosis. This also opens an interesting perspective for future investigation of such biomarkers and processes in clinical studies.

Enhancing Cartilage Repair: Surgical Approaches, Orthobiologics, and the Promise of Exosomes.

Treating cartilage damage is challenging as its ability for self-regeneration is limited. Left untreated, it can progress to osteoarthritis (OA), a joint disorder characterized by the deterioration of articular cartilage and other joint tissues. Surgical options, such as microfracture and cell/tissue transplantation, have shown promise as techniques to harness the body's endogenous regenerative capabilities to promote cartilage repair. Nonetheless, these techniques have been scrutinized due to reported inconsistencies in long-term outcomes and the tendency for the defects to regenerate as fibrocartilage instead of the smooth hyaline cartilage native to joint surfaces. Orthobiologics are medical therapies that utilize biologically derived substances to augment musculoskeletal healing. These treatments are rising in popularity because of their potential to enhance surgical standards of care. More recent developments in orthobiologics have focused on the role of exosomes in articular cartilage repair. Exosomes are nano-sized extracellular vesicles containing cargo such as proteins, lipids, and nucleic acids, and are known to facilitate intercellular communication, though their regenerative potential still needs to be fully understood. This review aims to demonstrate the advancements in cartilage regeneration, highlight surgical and biological treatment options, and discuss the recent strides in understanding the precise mechanisms of action involved.

Metabolic modulation to improve MSC expansion and therapeutic potential for articular cartilage repair.

BACKGROUND: Articular cartilage degeneration can result from injury, age, or arthritis, causing significant joint pain and disability without surgical intervention. Currently, the only FDA cell-based therapy for articular cartilage injury is Autologous Chondrocyte Implantation (ACI); however, this procedure is costly, time-intensive, and requires multiple treatments. Mesenchymal stromal cells (MSCs) are an attractive alternative autologous therapy due to their availability and ability to robustly differentiate into chondrocytes for transplantation with good safety profiles. However, treatment outcomes are variable due to donor-to-donor variability as well as intrapopulation heterogeneity and unstandardized MSC manufacturing protocols. Process improvements that reduce cell heterogeneity while increasing donor cell numbers with improved chondrogenic potential during expansion culture are needed to realize the full potential of MSC therapy. METHODS: In this study, we investigated the potential of MSC metabolic modulation during expansion to enhance their chondrogenic commitment by varying the nutrient composition, including glucose, pyruvate, glutamine, and ascorbic acid in culture media. We tested the effect of metabolic modulation in short-term (one passage) and long-term (up to seven passages). We measured metabolic state, cell size, population doubling time, and senescence and employed novel tools including micro-magnetic resonance relaxometry (µMRR) relaxation time (T2) to characterize the effects of AA on improved MSC expansion and chondrogenic potential. RESULTS: Our data show that the addition of 1 mM L-ascorbic acid-2-phosphate (AA) to cultures for one passage during MSC expansion prior to initiation of differentiation improves chondrogenic differentiation. We further demonstrate that AA treatment reduced the proportion of senescent cells and cell heterogeneity also allowing for long-term expansion that led to a > 300-fold increase in yield of MSCs with enhanced chondrogenic potential compared to untreated cells. AA-treated MSCs with improved chondrogenic potential showed a robust shift in metabolic profile to OXPHOS and higher µMRR T2 values, identifying critical quality attributes that could be implemented in MSC manufacturing for articular cartilage repair. CONCLUSIONS: Our results suggest an improved MSC manufacturing process that can enhance chondrogenic potential by targeting MSC metabolism and integrating process analytic tools during expansion.

SHP2 ablation mitigates osteoarthritic cartilage degeneration by promoting chondrocyte anabolism through SOX9.

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4+ AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan+ pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.

A Prospective, Randomized, Double-Blind Clinical Trial to Investigate the Efficacy of Autologous Bone Marrow Aspirate Concentrate During Arthroscopic Meniscectomy in Patients With Early Knee Osteoarthritis.

BACKGROUND: Despite being recognized as a safe procedure with minimal reported complications, injecting autologous bone marrow aspirate concentrate (BMAC) as an adjuvant to arthroscopic partial meniscectomy (APM) for symptomatic patients with meniscal tears and concomitant knee osteoarthritis (OA) has not been studied in randomized controlled trials. PURPOSE: To compare patient-reported outcome measure (PROM) scores and radiographic outcomes in symptomatic patients with meniscal tears and concomitant mild knee OA who underwent APM with and without an autologous BMAC injection administered at the time of surgery. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Enrolled patients aged ≥18 years determined to have a symptomatic meniscal tear with concomitant mild knee OA suitable for APM and meeting inclusion and exclusion criteria were randomized into 2 groups: BMAC and control (no BMAC). The primary endpoint of the study was the International Knee Documentation Committee (IKDC) score at 1 year postoperatively. Secondary endpoints included radiographic outcomes (Kellgren-Lawrence grade) at 1 year postoperatively and various PROM scores, including those for the IKDC, Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale, and Veterans RAND 12-Item Health Survey, at 3 months, 6 months, 1 year, and 2 years after meniscectomy. RESULTS: Of the 95 enrolled patients, 83 (87.4%) were included for final analysis. No significant differences were found between the groups with regard to patient characteristics, intraoperative variables, concomitant procedures, preoperative PROM scores, or preoperative radiographic findings. At 1 year postoperatively, the BMAC group failed to demonstrate significantly better IKDC scores (P = .687) or radiographic outcomes (P > .05 for all radiographic measures) compared with the control group. Secondary PROM scores also did not significantly differ between the groups (P > .05 for all PROMs). However, there were higher achievement rates of the minimal clinically important difference for the KOOS Sport (100.0% vs 80.0%, respectively; P = .023) and KOOS Symptoms (92.3% vs 68.0%, respectively; P = .038) at 1 year postoperatively in the BMAC group than in the control group. All PROMs, excluding the VR-12 mental score, showed significant improvements compared with baseline at all postoperative time points for both the BMAC and control groups. CONCLUSION: The addition of an autologous BMAC injection during APM did not result in significant changes in IKDC scores or radiographic outcomes at the 1-year postoperative mark. Secondary PROM scores were generally comparable between the 2 groups, but there was higher minimal clinically important difference achievement for the KOOS Sport and KOOS Symptoms at 1 year postoperatively in the BMAC group. In patients with symptoms consistent with a meniscal tear who had concomitant mild OA, the addition of BMAC to arthroscopic debridement did not affect the outcome. REGISTRATION: NCT02582489 (ClinicalTrials.gov).

Prevalence of Abnormalities and Normal Variants in the Adolescent Knee on MRI in a Population-Based Cohort of 3800 Knees.

BACKGROUND: Many adolescents experience knee pain, and only some undergo detailed imaging. In this population, the prevalence of abnormalities and normal variants on magnetic resonance imaging (MRI) scans is unknown. PURPOSE: To investigate the prevalence of abnormalities and normal variants of the knee on MRI scans and their relationship with participant characteristics in the general young adolescent population. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: This study was part of an open population-based cohort study that focuses on health, growth, and development from fetal life until adulthood. Between 2017 and 2020, adolescents aged 12 to 15 years underwent MRI of both knees. These MRI scans were assessed in a standardized way for abnormalities and normal variants to determine their prevalence. Logistic regression was used to analyze the presence of abnormalities and normal variants in relation to sex, height, weight, body mass index-standard deviation (BMI-SD), and ethnicity. RESULTS: A total of 1910 participants (median age, 13.5 years; interquartile range, 13.4-13.7 years; 52% girls) were included in this study. Of them, 370 (19.4%) participants had at least 1 abnormality or normal variant. Bone marrow edema around the knee was the most prevalent finding, affecting 140 (7.3%) participants. In 107 (5.6%) participants, nonossifying fibromas were found. A total of 43 (2.3%) participants had characteristics of Osgood-Schlatter disease, 16 (0.8%) showed characteristics of Sinding-Larsen-Johansson syndrome, and osteochondritis dissecans was found in 13 (0.7%) participants. Variants such as discoid menisci were found in 40 (2.1%) participants and a bipartite patella in 21 (1.1%) participants. There were multiple associations between abnormalities or variants and participant characteristics, including bone marrow edema being more often present in boys (odds ratio [OR], 2.44; 95% CI, 1.69-3.52) and those with a lower BMI-SD (OR, 0.85; 95% CI, 0.73-0.98). Osgood-Schlatter and osteochondritis dissecans were more often present in boys (OR, 4.21 [95% CI, 2.01-8.85] and OR, 13.18 [95% CI, 1.71-101.58], respectively). Discoid menisci were associated with a non-Western ethnicity (OR, 2.06; 95% CI, 1.07-3.96) and higher BMI-SD (OR, 2.34; 95% CI, 1.76-3.11). CONCLUSION: Abnormalities and normal variants on MRI scans of the knees are common in adolescents. Physicians who are involved in the treatment of adolescents with knee pain need to be aware of this prevalence so that these children will not be overtreated or misdiagnosed.

Bidirectionally validated in silico and in vitro formation of specific depth zone-derived chondrocyte spheroids and clusters.

3D multicellular self-organized cluster models, e.g., organoids are promising tools for developing new therapeutic modalities including gene and cell therapies, pharmacological mechanistic and screening assays. Various applications of these models have been used extensively for decades, however, the mechanisms of cluster formation, maintenance, and degradation of these models are not even known over in-vitro-life-time. To explore such advantageous models mimicking native tissues or organs, it is necessary to understand aforementioned mechanisms. Herein, we intend to clarify the mechanisms of the formation of cell clusters. We previously demonstrated that primary chondrocytes isolated from distinct longitudinal depth zones in articular cartilage formed zone-specific spherical multicellular clusters in vitro. To elucidate the mechanisms of such cluster formation, we simulated it using the computational Cellular Potts Model with parameters were translated from gene expression levels and histological characteristics corresponding to interactions between cell and extracellular matrix. This simulation in silico was validated morphologically with cluster formation in vitro and vice versa. Since zone specific chondrocyte cluster models in silico showed similarity with corresponding in vitro model, the in silico has a potential to be used for prediction of the 3D multicellular in vitro models used for development, disease, and therapeutic models.

Relationship between depth-wise refractive index and biomechanical properties of human articular cartilage.

Significance: Optical properties of biological tissues, such as refractive index (RI), are fundamental properties, intrinsically linked to the tissue's composition and structure. We hypothesize that, as the RI and the functional properties of articular cartilage (AC) are dependent on the tissue's structure and composition, the RI of AC is related to its biomechanical properties. Aim: This study aims to investigate the relationship between RI of human AC and its biomechanical properties. Approach: Human cartilage samples ( n = 22 ) were extracted from the right knee joint of three cadaver donors (one female, aged 47 years, and two males, aged 64 and 68 years) obtained from a commercial biobank (Science Care, Phoenix, Arizona, United States). The samples were initially subjected to mechanical indentation testing to determine elastic [equilibrium modulus (EM) and instantaneous modulus (IM)] and dynamic [dynamic modulus (DM)] viscoelastic properties. An Abbemat 3200 automatic one-wavelength refractometer operating at 600 nm was used to measure the RI of the extracted sections. Similarly, Spearman's and Pearson's correlation coefficients were employed for non-normal and normal datasets, respectively, to determine the correlation between the depth-wise RI and biomechanical properties of the cartilage samples as a function of the collagen fibril orientation. Results: A positive correlation with statistically significant relations ( p - values < 0.05 ) was observed between the RI and the biomechanical properties (EM, IM, and DM) along the tissue depth for each zone, e.g., superficial, middle, and deep zones. Likewise, a lower positive correlation with statistically significant relations ( p - values < 0.05 ) was also observed for collagen fibril orientation of all zones with the biomechanical properties. Conclusions: The results indicate that, although the RI exhibits different levels of correlation with different biomechanical properties, the relationship varies as a function of the tissue depth. This knowledge paves the way for optically monitoring changes in AC biomechanical properties nondestructively via changes in the RI. Thus, the RI could be a potential biomarker for assessing the mechanical competency of AC, particularly in degenerative diseases, such as osteoarthritis.

Loss of collagen content is localized near cartilage lesions on the day of injurious loading and intensified on day 12.

Joint injury can lead to articular cartilage damage, excessive inflammation, and post-traumatic osteoarthritis (PTOA). Collagen is an essential component for cartilage function, yet current literature has limited understanding of how biochemical and biomechanical factors contribute to collagen loss in injured cartilage. Our aim was to investigate spatially dependent changes in collagen content and collagen integrity of injured cartilage, with an explant model of early-stage PTOA. We subjected calf knee cartilage explants to combinations of injurious loading (INJ), interleukin-1α-challenge (IL) and physiological cyclic loading (CL). Using Fourier transform infrared microspectroscopy, collagen content (Amide I band) and collagen integrity (Amide II/1338 cm-1 ratio) were estimated on days 0 and 12 post-injury. We found that INJ led to lower collagen content near lesions compared to intact regions on day 0 (p < 0.001). On day 12, near-lesion collagen content was lower compared to day 0 (p < 0.05). Additionally, on day 12, INJ, IL, and INJ + IL groups exhibited lower collagen content along most of tissue depth compared to free-swelling control group (p < 0.05). CL groups showed higher collagen content along most of tissue depth compared to corresponding groups without CL (p < 0.05). Immunohistochemical analysis revealed higher MMP-1 and MMP-3 staining intensities localized within cell lacunae in INJ group compared to CTRL group on day 0. Our results suggest that INJ causes rapid loss of collagen content near lesions, which is intensified on day 12. Additionally, CL could mitigate the loss of collagen content at intact regions after 12 days.