Full-thickness Cartilage Injuries Research Articles

Response of Articular Cartilage to Hyperosmolar Stress: Report of an Ex Vivo Injury Model

Background: Physiological 0.9% saline is commonly used as an irrigation fluid in modern arthroscopy. There is a growing body of evidence that a hyperosmolar saline solution has chondroprotective effects, especially if iatrogenic injury occurs. Purpose: To (1) corroborate the superiority of a hyperosmolar saline solution regarding chondrocyte survival after mechanical injury and (2) observe the modulatory response of articular cartilage to osmotic stress and injury. Study Design: Controlled laboratory study. Methods: Osteochondral explants were isolated from bovine stifle joints and exposed to either 0.9% saline (308 mOsm) or hyperosmolar saline (600 mOsm) and then damaged with a sharp dermatome blade to attain a confined full-thickness cartilage injury site, incubated in the same fluids for another 3 hours, and transferred to chondropermissive medium for further culture for 1 week. Chondrocyte survival was assessed by confocal imaging, while the cellular response was evaluated over 1 week by relative gene expression for apoptotic and inflammatory markers and mediator release into the medium. Results: The full-thickness cartilage cut resulted in a confined zone of cell death that mainly affected superficial zone chondrocytes. Injured samples that were exposed to hyperosmolar saline showed less expansion of cell death in both the axial (P < .007) and the coronal (P < .004) plane. There was no progression of cell death during the following week of culture. Histological assessment revealed an intact cartilage matrix and normal chondrocyte morphology. Inflammatory and proapoptotic genes were upregulated on the first days postexposure with a notable downregulation toward day 7. Mediator release into the medium was concentrated on day 3. Conclusion: This in vitro cartilage injury model provides further evidence for the chondroprotective effect of a hyperosmolar saline irrigation fluid, as well as novel data on the capability of articular cartilage to quickly regain joint homeostasis after osmotic stress and injury. Clinical Relevance: Raising the osmolarity of an irrigating solution may be a simple and safe strategy to protect articular cartilage during arthroscopic surgery.

Interferon-gamma signaling promotes cartilage regeneration after injury

Osteoarthritis is a common chronic disease and major cause of disability and chronic pain in ageing populations. In this pathology, the entire joint is involved, and the regeneration of articular cartilage still remains one of the main challenges. Here, we investigated the molecular mechanisms underlying cartilage regeneration in young mice using a full-thickness cartilage injury (FTCI) model. FTCI-induced cartilage defects were created in the femoral trochlea of young and adult C57BL/6 mice. To identify key molecules and pathways involved in the early response to cartilage injury, we performed RNA sequencing (RNA-seq) analysis of cartilage RNA at 3 days after injury. Young mice showed superior cartilage regeneration compared to adult mice after cartilage injury. RNA-seq analysis revealed significant upregulation of genes associated with the immune response, particularly in the IFN-γ signaling pathway and qRT-PCR analysis showed macrophage polarization in the early phase of cartilage regeneration (3 days) in young mice after injury, which might promote the removal of damaged or necrotic cells and initiate cartilage regeneration in response to injury. IFN-γR1- and IFN-γ-deficient mice exhibited impaired cartilage regeneration following cartilage injury. DMM-induced and spontaneous OA phenotypes were exacerbated in IFN-γR1−/− mice than in wild-type mice. Our data support the hypothesis that IFN-γ signaling is necessary for cartilage regeneration, as well as for the amelioration of post-traumatic and age-induced OA.

Application of 3D Modeling Software to Preoperative MRI for Prediction of Surface Area of Tissue Applied During Osteochondral Allograft Reconstruction of the Knee.

Preoperative magnetic resonance imaging (MRI) is used to estimate the quantity of tissue provided for fresh osteochondral allograft (FOCA) in the knee. Use of 3-dimensional (3D) MRI modeling software for this purpose may improve defect assessment, providing a more accurate estimate of osteochondral allograft tissue required and eliminating the possibility of acquiring an inadequate quantity of tissue for transplant surgery. To evaluate the capacity of damage assessment (DA) 3D MRI modeling software to preoperatively estimate the osteochondral allograft surface area used in surgery. Cohort study (diagnosis); Level of evidence, 2. Included were 36 patients who had undergone FOCA surgery to the distal femur. Based on the preoperative MRI scans, the DA software estimated the total surface area of the lesion as well as the surface areas of each subarea of injury: full-thickness cartilage injury (International Cartilage Repair Society [ICRS] grade 4), partial-thickness cartilage injury (ICRS grade 2-3), bone marrow edema, bone loss, and bone cyst. The probability of overestimation of graft tissue areas by the DA software was calculated using a Bayes-moderated proportion, and the relationship between the prediction discrepancy (ie, over- or underestimation) and the magnitude of the DA estimate was assessed using nonparametric local-linear regression. The DA total surface area measurement overestimated the actual area of FOCA tissue transplanted 81.6% (95% CI, 67.2%-91.4%) of the time, corresponding to a median overestimation of 3.14 cm2, or 1.78 times the area of FOCA transplanted. The DA software overestimated the area of FOCA transplanted 100% of the time for defect areas measuring >4.52 cm2. For defects <4.21 cm2, the maximum-magnitude underestimation of tissue area was 1.45 cm2 (on a fold scale, 0.63 times the transplanted area); a plausible heuristic is that multiplying small DA-measured areas of injury by a factor of ∼1.5 would yield an overestimation of the tissue area transplanted most of the time. The DA 3D modeling software overestimated osteochondral defect size >80% of the time in 36 distal femoral FOCA cases. A policy of consistent but limited overestimation of osteochondral defect size may provide a more reliable basis for predicting the minimum safe amount of allograft tissue to acquire for transplantation.

Management strategies in the treatment of osteochondral lesions of the talus

Osteochondral defects of the talus are a common occurrence and remain a challenge to the orthopaedic surgeon. Commonly found on the medial talar dome, they are usually the sequelae from traumatic injuries and often are delayed in their presentation to the outpatient setting. They can occur after ankle trauma, such as sprains or fractures, but they usually present as a continued ankle pain after the initial injury has resolved. Management of these full-thickness cartilage injuries is usually guided by the size, as well as position on the talar dome surface. Arthroscopic microfracture has been the mainstay of first-line surgical treatment as well as for smaller lesions. Larger lesions may need more novel procedures which include scaffold-based therapies or osteochondral transplantation.

Glenoid microfracture in active-duty military patients: minimum 5-year follow-up demonstrates 75% survival.

To present midterm patient-reported outcomes and survivorship data of active-duty military patients undergoing microfracture for full-thickness cartilage defects of the glenoid. All consecutive patients from January 2013 through December 2016 who underwent glenoid microfracture for full-thickness cartilage injuries with complete outcome scores were identified. Twenty patients met the final inclusion criteria for the study, and all were active-duty military at the time of surgery. A separate subgroup analysis was performed to determine if dominant-shoulder involvement portends worse outcomes. The mean follow-up was 81.45±19.43 months (range, 60-108). Of the 20 patients, 5 required a secondary surgical procedure within 5 years of their index procedure, with an average time to failure of 45.6±13.15 months. For the 15 patients who did not fail, there was a statistically significant increase in the mean American Shoulder and Elbow Surgeons score (57.20 vs. 88.27, P<.0001) and Single Assessment Numeric Evaluation (45.00 vs. 86.33, P<.0001). Mean pain decreased significantly as measured by the pain visual analog scale (5.40 vs. 1.37, P<.0001). Range of motion in forward elevation, external rotation, and internal rotation did not change significantly postoperatively (P=.4528, .4810, and .1919, respectively). Concomitant procedures did not predict changes in pain, American Shoulder and Elbow Surgeons, or Single Assessment Numeric Evaluation scores. A majority of patients (13/20, 65%) were able to remain on unrestricted military active-duty service, but 7 (35%) underwent medical discharge, including the 5 patients who had experienced treatment failure, plus 2 additional patients. Glenoid microfracture can result in pain relief and symptomatic improvement for a select group of active-duty military patients, with 75% survivorship at 5 years. Approximately one in three (35%) patients, however, were unable to remain on active-duty military service.

Results of Acetabular Microfracture in Patients undergoing FAI surgery are Strongly Correlated with Age (142)

Objectives:Full-thickness cartilage injury is not uncommon in patients undergoing primary treatment of Femoroacetabular impingement (FAI). Treatment of these lesions with microfracture is commonly performed. However, the outcomes of these procedures relative to other patients undergoing FAI surgery is not well established and the literature on this topic is limited to small, retrospective single surgeon studies. The purpose of the present study was to evaluate outcomes of patients who underwent concurrent FAI correction and acetabular microfracture and to identify predictors treatment failure.Methods:A prospective multicenter cohort study of the treatment of FAI was performed. A total of 760 hips undergoing primary FAI surgery were enrolled. Inclusion criteria were primary FAI surgery, Tonnis 0 or 1 osteoarthritis grade, and age between 16 and 55 years. A total of 61 hips underwent treatment of full-thickness acetabular cartilage lesions with microfracture, with 55 (90.2%) having follow-up greater than 1 year (mean 4.0 years). This group had a mean age of 35.0+10.1 years, BMI of 27.2+4.2, and included 81.8% (45/55) males. A comparison cohort of 492 hips undergoing primary FAI surgery without treatment of acetabular full-thickness cartilage was utilized. Baseline, intraoperative, and follow-up data was recorded including the modified Harris hip score (mHHS) and HOOS domains of pain, ADLs, sports and recreation, symptoms, and quality of life. Composite failure was characterized by reoperation [total hip arthroplasty (THA) or revision surgery] or clinical failure (failure to meet either MCID or PASS for mHHS). Age was assessed in 5 year intervals. Students t-test was used for continuous variables and chi squared were used for categorical variables. A p value less than 0.05 was considering significant.Results:Hips undergoing acetabular microfracture were more likely (compared to comparison cohort) to be male (81.8% vs. 40.9%, p<.001) older (35.0 vs. 29.9 years, p=0.001), had higher BMI (27.2 vs. 25.0, p=.001), and greater alpha angle (69.6 vs. 62.3, p<.001). In the microfracture cohort, 12.7% of patients progressed to THA (compared to 3.0% in comparison cohort, p=.001), while the rate of composite failure was similar to the comparison cohort (29.1% vs. 26.0%, p=.618). Age was highly correlated with the risk of THA and composite failure. The rate of THA for patients <35, 35-40*, and >40 years* of age was 0%, 20.0%, and 22.7% p=.016*), while the rate of composite failure in these groups was 17.4%, 20.0% and 45.5%, respectively (p=.029*). Hips greater than 35 years of age demonstrated inferior HOOS outcomes for domains of pain, ADLs, sports and recreation, QOL, and symptoms and SF-12 physical component scores(Table 1).Conclusions:The results of acetabular microfracture in patients undergoing FAI surgery at a mean follow-up of 4.0 years postoperatively are strongly correlated with age. Patients under 35 years of age demonstrate excellent outcomes with low rates of revision or progression to THA. Acetabular microfracture should have a limited to absent role in patients over the age of 40.

Repair of full-thickness articular cartilage defects using IEIK13 self-assembling peptide hydrogel in a non-human primate model

Articular cartilage is built by chondrocytes which become less active with age. This declining function of the chondrocytes, together with the avascular nature of the cartilage, impedes the spontaneous healing of chondral injuries. These lesions can progress to more serious degenerative articular conditions as in the case of osteoarthritis. As no efficient cure for cartilage lesions exist yet, cartilage tissue engineering has emerged as a promising method aiming at repairing joint defects and restoring articular function. In the present work, we investigated if a new self-assembling peptide (referred as IEIK13), combined with articular chondrocytes treated with a chondrogenic cocktail (BMP-2, insulin and T3, designated BIT) could be efficient to restore full-thickness cartilage defects induced in the femoral condyles of a non-human primate model, the cynomolgus monkey. First, in vitro molecular studies indicated that IEIK13 was efficient to support production of cartilage by monkey articular chondrocytes treated with BIT. In vivo, cartilage implant integration was monitored non-invasively by contrast-enhanced micro-computed tomography, and then by post-mortem histological analysis and immunohistochemical staining of the condyles collected 3 months post-implantation. Our results revealed that the full-thickness cartilage injuries treated with either IEIK13 implants loaded with or devoid of chondrocytes showed similar cartilage-characteristic regeneration. This pilot study demonstrates that IEIK13 can be used as a valuable scaffold to support the in vitro activity of articular chondrocytes and the repair of articular cartilage defects, when implanted alone or with chondrocytes.

Allogeneic umbilical cord blood-derived mesenchymal stem cells combined with high tibial osteotomy: a retrospective study on safety and early results.

Cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use. To investigate the short-term outcomes and cartilage regeneration after implantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in patients who received high tibial osteotomy (HTO) for symptomatic medial knee osteoarthritis. Patients underwent treatment of full-thickness chondral injury in the osteoarthritic knee with HTO and implantation of hUCB-MSCs and were followed prospectively for a minimum of oneyear. Ninety-three patients were followed for a mean 1.7years (range, 1.0-3.5). Median cartilage lesion size was 6.5cm2 (range, 2.0-12.8). Clinical outcomes were examined with patient-reported scoring instruments that consisted of the International Knee Documentation Committee (IKDC) subjective score, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, Knee Society Score (KSS), and Hospital for Special Surgery (HSS) score. Cartilage regeneration was evaluated using the International Cartilage Repair Society (ICRS) cartilage repair assessment grading (CRA) system and the Koshino regeneration staging system in 49 patients who underwent secondlook arthroscopic assessment when their HTO plates were removed. At final follow-up, the median IKDC subjective score had significantly improved from 39.0 to 71.3; the WOMAC score from 44.5 to 11.0; the KSS pain and function scores from 29.8 to 43.2 and 61.0 to 81.2, respectively; and the HSS from 61.6 to 82.7 (p < 0.05). Pre-operative examination showed ICRS grade IV cartilage injury in all knees, and cartilage regeneration at 2nd look arthroscopy showed improvements (8.2% of patients improved to ICRS grade I, 69.3% to grade II, and 22.5% to grade III). Moreover, Koshino stage was B in 24.5% and C in 75.5% of patients (p < 0.05). Allogeneic hUCB-MSC implantation combined with HTO for medial knee osteoarthritis was safe and showed signs of cartilage status improvement. Furthermore, randomized controlled studies with a control group are necessary to determine the real effectiveness and indications of this new combined procedure for patients with osteoarthritis.

Mesenchymal Stem Cell Therapy in Cartilage Injuries of Knee – Review

Full-thickness cartilage injuries when left alone would increase the risk of osteoarthritis (OA) with severe associated pain and functional disability. The capability of the mesenchymal stem cells (MSCs) to repair and regenerate cartilage has been widely investigated. Articular cartilage defect may result from direct trauma or chronic degeneration. The subchondral bone plays an important role in healing through the presence of mesenchymal elements. MSCs are the most representative adult stem cells. It was observed that BM-MSCs (Bone Marrow derived MSCs) had superior chondrogenic differentiation capacity as compared to MSCs from other origins. It has been observed that a MSC density of 5 × 107 or 5 × 108 cells per milliliter embedded in a collagen gel had more proteoglycans than lower cell densities, better facilitating cartilage defect healing. The most potent chondrogenic differentiation inducers are transforming growth factor β, bone morphogenic protein, fibroblast growth factor, and insulin-like growth factor 1. Most commonly used delivery system for MSCs are either sealant or scaffold based. Ideal scaffold should have similar characteristics to the native tissue. The scaffold has the advantage of withstanding the in-vivo loading environment and protects the embedded cells. There is contradictory evidence regarding injectable treatment with BM-MSCs suggesting scaffolds may be required for the regeneration of cartilage. There is high quality of evidence to support MSC therapy but further refinement of methodology will be required to support its routine clinical use. There are few options to be explored e.g. MSC exosomes, genetic engineering and epigenetic regulatory mechanisms governing MSC biology

No effect of platelet-rich plasma as adjuvant to bone marrow stimulation for the treatment of chondral defects in a large animal model.

Bone marrow stimulation (BMS) remains a dominant treatment strategy for symptomatic full thickness articular cartilage defects. Autologous platelet-rich plasma (PRP), may improve biological cartilage repair as an adjunct to BMS. To assess the histological quality of cartilage repair after BMS with and without repeated local injections of PRP for the treatment of full-thickness focal chondral defects of the knee. Two full-thickness chondral defects (Ø = 6mm) were surgically performed in the medial and lateral trochlea of each knee in skeletally mature Göttingen minipigs. The two treatment groups with 12 defect for each groups were (1) BMS with one weekly PRP injection for 4weeks, and (2) BMS alone. The animals were euthanized after 6months. Samples of both whole blood and PRP were analysed with an automated hematology analyzer to determine the concentrations of platelets and nucleated cells. The composition of cartilage repair tissue was assessed using gross appearance assessment, histomorphometry and semi-quantitative scoring (ICRS II). The average fold increase in platelets was 10.2 ± 2.2. Leukocyte concentration increased in PRP samples by an average fold change of 7.2 ± 1.3. Our macroscopic findings showed that the defects in the BMS + PRP-treated group, were filled with an irregular, partially rough tissue similar to the BMS-treated group. No significant difference in amount of hyalin cartilage, fibrocartilage or fibrous tissue content and ICRS II scores was found between the groups. Four repeated local injections of leukocyte-rich PRP after BMS in the treatment of full-thickness cartilage injuries demonstrated no beneficial effects in terms of macroscopic and histological cartilage repair tissue quality.

Effects of mechanical injury on the tribological rehydration and lubrication of articular cartilage

Healthy articular cartilage is crucial to joint function, as it provides the low friction and load bearing surface necessary for joint articulation. Nonetheless, joint injury places patients at increased risk of experiencing both accelerated cartilage degeneration and wear, and joint dysfunction due to post-traumatic osteoarthritis (PTOA). In this study, we used our ex vivo convergent stationary contact area (cSCA) explant testing configuration to demonstrate that high-speed sliding of healthy tissues against glass could drive consistent and reproducible recovery of compression-induced cartilage deformation, through the mechanism of ‘tribological rehydration’. In contrast, the presence of physical cartilage damage, mimicking those injuries known to precipitate PTOA, could compromise tribological rehydration and the sliding-driven recovery of cartilage function. Full-thickness cartilage injuries (i.e. fissures and chondral defects) markedly suppressed sliding-driven tribological rehydration. In contrast, impaction to cartilage, which caused surface associated damage, had little effect on the immediate tribomechanical response of explants to sliding (deformation/strain, tribological rehydration, and friction/lubricity). By leveraging the unique ability of the cSCA configuration to support tribological rehydration, this study permitted the first direct ex vivo investigation of injury-dependent strain and friction outcomes in cartilage under testing conditions that replicate and maintain physiologically-relevant levels of fluid load support and frictional outcomes under high sliding speeds (80 mm/s) and moderate compressive stresses (~0.3 MPa). Understanding how injury alters cartilage tribomechanics during sliding sheds light on mechanisms by which cartilage's long-term resilience and low frictional properties are maintained, and can guide studies investigating the functional consequences of physical injury and joint articulation on cartilage health, disease, and rehabilitation.

No Effect of Platelet-Rich Plasma Injections as an Adjuvant to Autologous Cartilage Chips Implantation for the Treatment of Chondral Defects.

Repair of chondral injuries using cartilage chips has recently demonstrated clinical feasibility. Autologous platelet-rich plasma (PRP) is a potential promising technique for improving healing response during cartilage repair. To assess the cartilage repair tissue quality after autologous cartilage chips treatment (CC) with and without repeated local injections of PRP for the treatment of full-thickness focal chondral defects of the knee. Two full-thickness chondral defects (Ø = 6 mm) were created in the medial and lateral trochlea facets of each knee in 6 skeletally mature Göttingen minipigs. The 2 treatment groups were (1) CC with 1 weekly PRP injection for 3 weeks (n = 12) and (2) CC alone (n = 12). The animals were euthanized after 6 months. Samples of whole blood and PRP were analyzed for concentrations of platelets and nucleated cells. The composition of the cartilage repair tissue was assessed using gross appearance assessment, histomorphometry, and semiquantitative scoring (ICRS II). Histological evaluation demonstrated no significant difference in the content of hyaline cartilage (CC + PRP: 18.7% vs. CC: 19.6%), fibrocartilage (CC + PRP: 48.1% vs. CC: 51.8%), or fibrous tissue (CC + PRP: 22.7% vs. CC: 21.8%) between the treatment groups. Macroscopic evaluation did not demonstrate any difference between groups. PRP injections after CC in the treatment of full-thickness cartilage injuries demonstrated no beneficial effects in terms of macroscopic and histologic composition of cartilage repair tissue.

Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid–Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate

Background: Cell-based cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use. Purpose: To investigate the long-term clinical outcomes of cartilage repair in the knee with a hyaluronic acid–based scaffold embedded with bone marrow aspirate concentrate (HA-BMAC) for the treatment of full-thickness cartilage injury. Study Design: Case series; Level of evidence, 4. Methods: Patients underwent treatment of full-thickness chondral injury in the knee with HA-BMAC and were followed prospectively for a minimum of 6 years. Clinical outcomes were examined with patient-reported scoring instruments that consisted of the Tegner Activity Scale, International Knee Documentation Committee (IKDC) subjective score, visual analog scale, and Knee injury and Osteoarthritis Outcome Score (KOOS). Comparative analysis of pre- and postoperative scores was performed, and the effects of patient age, body mass index, lesion size, number of treated lesions, and concurrent treatment with associated procedures were examined. Results: Twenty-three patients (mean age, 48.5 years) were followed prospectively for a mean 8 years (range, 6-10 years). Median cartilage lesion size was 6.5 cm2 (range, 2-27 cm2). At final follow-up, median Tegner, visual analog scale, and IKDC subjective scores were 4, 0.3, and 85, respectively. Final median KOOS subset scores were as follows: Pain, 94; Symptoms, 89; Activities of Daily Living, 99; Sports/Recreation, 85; and Quality of Life, 85. All scores were significantly increased at final follow-up (P < .001). Comparable median outcome scores were demonstrated after categorization of patients by age, lesion size, treatment of multiple lesions, treatment of multiple knee compartments, and treatment by associated procedures. Rank correlation analysis demonstrated a negative correlation between patient age and final outcome scores of the IKDC, Tegner, and KOOS subsets of Pain, Activities of Daily Living, and Sports/Recreation. No associations were identified between body mass index or lesion size and outcome scores. Conclusion: Repair of full-thickness cartilage injury in the knee with a HA-BMAC provides good to excellent clinical outcomes at long-term follow-up in the treatment of small to large lesions. Cartilage repair with HA-BMAC leads to comparatively successful long-term outcomes in the treatment of small or large lesions, single or multiple lesions, and lesions in 1 or 2 compartments, as well as in cases of associated lesion treatment. While good outcomes can be expected among treated patients >45 years of age, outcomes may be comparatively more successful in younger patients.

Genetic correlations in recombinant inbred mouse strains suggest that cartilage repair is positively correlated with protection from osteoarthritis

Purpose: The etiology of osteoarthritis (OA) is unknown, however, there appears to be a significant contribution from genetics. We have identified recombinant inbred strains of mice derived from LG/J (large) and SM/J (small) that vary significantly in their susceptibility to post-traumatic OA due to their genetic composition. While in the past, it was considered that articular cartilage could not undergo repair, we have demonstrated that a number of mouse strains, considered “healer” mice, are able to repair articular cartilage. Here we report cartilage repair phenotypes in the same strains of mice in which OA susceptibility was analyzed. We demonstrate that protection from OA is positively correlated with the ability to repair cartilage. These results suggest a shift in the risk paradigm for OA from degeneration to regeneration. Methods: All procedures were approved by the Institutional Animal Care and Use Committee. We used 12 recombinant inbred (RI) strains of mice generated from LG/J by SM/J intercross to test three phenotypes: ear wound healing, articular cartilage repair, and post-traumatic OA. (1) A 2 mm hole was created in the external ears using a biopsy punch (n = 263) at 6 weeks of age and healing outcome was measured at 30-day post-punch. (2) An acute full-thickness articular cartilage injury was introduced in the trochlear groove of 8-week-old mice (n = 126) through microsurgery and healing outcomes were measured at 16 weeks after surgery. (3) OA was induced in 10-week-old mice (n = 53) by destabilization of medial meniscus (DMM). Maximum OARSI score (representing the highest score within all sectioned levels of the knee), summed OARSI score (representing whole joint changes) and synovitis score (representing synovial cell proliferation) were measured 8 weeks post-DMM. Genetic correlations between various traits were calculated as Pearson correlation coefficients of strain means using GraphPad Prism. Results: We found a significant positive correlation between ear wound healing and knee articular cartilage regeneration (r = 0.74, P = 0.006) (Fig. 1A). We observed a strong linear correlation between cartilage regeneration and protection from OA based on summed OARSI (r = 0.49, P = 0.106) as well as maximum OARSI scores (r = 0.50, P = 0.097) (Fig. 1B). Summed and maximum OARSI scores were also significantly associated with each other (r = 0.92, P < 0.0001) (Fig. 1C). While synovitis was not significantly correlated with knee cartilage healing, it showed highly significant positive correlation with maximum OARSI score (r = 0.63, P = 0.028) and summed OARSI score (r = 0.70, P = 0.011) (Fig. 1D). Despite strong significant correlation between ear wound healing and knee cartilage regeneration, there was a weak correlation between ear wound healing and OA. Conclusions: Our study allows, for the first time, the measurement of genetic correlations of regeneration phenotypes with the degeneration phenotypes that are characteristics of PTOA. These results demonstrate a linear relationship between the resistance to OA after DMM surgery in mouse strains of different genotypes in recombinant inbred strains of a “healer” mouse, LG/J and a “non-healer” mouse, SM/J and the ability to heal an articular cartilage defect in the same mouse strains. While cartilage degeneration and regeneration were the phenotypes of primary interest in these studies, we also assessed synovitis in the OA study and thus could correlate synovitis with OA. The correlation between synovitis and OA ranged from 0.63-0.70, which is consistent with reports of patients with OA. Consequently, we have confidence that our correlation of OA with cartilage repair of 0.5 will be reflective of human cartilage degeneration and repair. We predict that the human population will also demonstrate this genetic variability in cartilage repair for which there is already some data derived from the ability to differentiate cartilage from stem cells. Thus, in the future the ability to repair cartilage may be a powerful indicator of the future susceptibility to OA after injury. Lastly, gene variants involved in cartilage repair may be informative as potential treatments for OA.

The Use of Bone Marrow Concentrate in the Treatment of Full-Thickness Chondral Defects

This article is a critical analysis of a study, "Minimally Manipulated Bone Marrow Concentrate Compared with Microfracture Treatment of Full-Thickness Chondral Defects: A One-Year Study in an Equine Model," by Chu et al. (J Bone Joint Surg Am. 100(2):138-146, 2018). The investigation compared two interventions in the management of full-thickness chondral defects in an equine model: autologous bone marrow concentrate without concomitant microfracture treatment versus microfracture treatment alone. This review analyzes the methodology and results of their investigation and examines how their findings may influence the continued development of therapeutic options for full-thickness cartilage injuries. The study utilized in vitro analysis, arthroscopic assessment, magnetic resonance imaging (MRI) evaluation, and histological analysis to compare the treatments and their influence on the quality of cartilage repair. Although Chu et al. reported similar results between groups, their findings offer insight into the role of arthroscopy, MRI, and histology in the evaluation of repair quality. We compare their findings to those of similar investigations, highlighting the limited therapeutic options and variable clinical outcomes related to the treatment of full-thickness articular cartilage defects.

Symptomatic Focal Knee Chondral Injuries in National Football League Combine Players Are Associated With Poorer Performance and Less Volume of Play

To (1) describe the magnetic resonance imaging (MRI) characteristics of knee chondral injuries identified at the National Football League (NFL) Combine and (2) assess in-game performance of prospective NFL players with previously untreated knee chondral injuries and compare it with matched controls. All players with knee chondral injuries identified at the NFL Combine (2009-2015) were retrospectively reviewed. Players with prior knee surgery were excluded. A knee MRI for each player was reviewed; location, modified International Cartilage Repair Society (ICRS) grade (I-IV), and associated compartment subchondral edema were documented. Position, respective NFL Draft pick selection number, games started, played, snap percentage, and position-specific performance metrics during the first 2 NFL seasons were recorded for the injury and injury-free control group composed of players with (1) no prior knee injury, (2) no significant missed time prior to the NFL (≤2 total missed games in college), (3) no history of knee surgery, and (4) drafted in the respective NFL Draft following the NFL Combine. Of the 2,285 players reviewed, 101 (4.4%) had an injury without prior knee surgery. The patella (63.4%) and trochlea (34%) were most commonly affected. Defensive linemen were at highest risk for unrecognized injuries (odds ratio 1.8, P= .015). Players with previously untreated injuries, compared with controls, were picked later (mean pick: 125.8) and played (mean: 23) and started (mean: 10.4) fewer games during the initial 2 NFL seasons (P < .001 for all). Particularly, subchondral bone edema and full-thickness cartilage injuries were associated with fewer games played (P= .003). The patellofemoral joint was most commonly affected in NFL Combine participants. Previously untreated knee articular injuries in players at the NFLCombine are associated with poorer early NFL performance in comparison to uninjured players. Subchondral bone edema and full-thickness cartilage injury on MRI were associated with fewer games played during the initial NFL career. Level III, case-control study.

Autologous-cell-derived, tissue-engineered cartilage for repairing articular cartilage lesions in the knee: study protocol for a randomized controlled trial

BackgroundSpontaneous recovery from articular cartilage injury is difficult, and the ongoing progression of disease can eventually lead to osteoarthritis. Currently, there is no effective non-surgical treatment for articular cartilage injury. Arthroscopic debridement and microfracture surgery are performed for fibrocartilage repair. But fibrocartilage is different from normal articular cartilage, and functional recovery is not satisfactory. Therefore, it is necessary to develop more effective techniques for articular cartilage repair. Progress in material science, cell biology, biomechanics, and bioreactor technology has allowed the development of biomimetic, tissue-engineered osteochondral composites that have shown potential for the repair of damaged cartilage. We prepared biomimetic, tissue-engineered cartilage scaffolds optimized for biochemical composition and structural characteristics. Based on the experience of our pre-clinical studies on animals, a human articular cartilage acellular matrix scaffold was prepared and is in clinical use. The combination of autologous chondrocytes and scaffolds has shown satisfactory results in repairing cartilage defects in preliminary experiments.MethodsThis is a prospective randomized controlled trial. One hundred patients with full-thickness cartilage injury of the knee will be randomly divided into two groups to receive treatment with either tissue-engineered cartilage constructed using biomimetic cartilage extracellular-matrix-oriented scaffolds combined with autologous chondrocytes, or arthroscopic debridement and microfracture surgery. There will be five visiting time points: at baseline, then at 3, 6, 12, and 18 months postoperatively. The primary outcome will be therapeutic efficacy as assessed by the Lysholm score at 12 months postoperatively. The secondary outcomes will be the International Knee Documentation Committee score, Visual Analog Scale score, and cartilage injury and repair as assessed by magnetic resonance imaging as well as the incidence of postoperative adverse events.DiscussionThis trial will attempt to verify the use of tissue-engineered cartilage constructed using autologous chondrocytes combined with allogeneic, acellular cartilage matrix for the repair of cartilage defects, thereby providing favorable evidence for its use in clinical practice.Trial registrationClinicalTrials.gov, identifier: NCT02770209. Registered on 11 May 2016.

Endogenous PRRX1+ progenitors are present after full thickness cartilage injury but do not directly contribute to fibrocartilage or subchondral bone tissues during the repair process

Endogenous PRRX1+ progenitors are present after full thickness cartilage injury but do not directly contribute to fibrocartilage or subchondral bone tissues during the repair process

Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis

Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury. Rat knee joint models were used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow stromal cells (BMSCs) were used to study the influence of the lipid lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the production of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo. After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state. Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic fibrosis and osteoarthritis.

Hip morphology influences the pattern of articular cartilage damage.

The aim of this study was to obtain data on chondral damage and compare the damage patterns of various hip disorders. Data were collected at 100 consecutive arthroscopies, and chondral lesions were recorded on anatomic articular maps divided into different anatomical zones. This geographic zone method made it possible to analyze the ICRS grade and location in relation to the hip morphology. The distribution and degree of the chondral defects showed a hip morphology-specific pattern. On the acetabular side, there were high incidences of full-thickness defects in the anterior-superior zone and the middle superior zone in patients with femoroacetabular impingement (FAI) (zone 2: 25.4% grade 3, 35.5% grade 4; zone 3: 20.3% grade 3, 37.2% grade 4) and borderline dysplasia (zone 2: 31.2% grade 3, 12.5% grade 4; zone 3: 18.7% grade 3, 25% grade 4). However, in patients with joint laxity, partial-thickness defects were dominant (zone 2: 50% grade 1, 15% grade 2; zone 3: 40% grade 1). In patients with acetabular dysplasia, full-thickness defects extended even to the posterior superior zone (zone 4: 80% grade 4). On the femoral head side, the incidence of full-thickness cartilage injuries was high in patients with FAI and borderline dysplasia compared to those with joint laxity and acetabular dysplasia. Evaluation of chondral damage using the geographic zone method showed that the pattern of cartilage damage was influenced by hip morphology. Understanding of hip disorder-specific chondral damage patterns may be useful for the development of arthroscopic classification of hip disorders and may lead to the establishment of treatment guidelines. Diagnostic study, Level III.