Treatment Of Cartilage Injuries Research Articles

Histological Evaluation of Early-Phase Changes in the Osteochondral Unit After Microfracture in a Full-Thickness Cartilage Defect Rat Model

Background: The microfracture (MF) technique is an established surgical treatment for cartilage injury. However, the early-phase histological changes in full-thickness cartilage defects (FTCDs) after MF and the concomitant changes in the subchondral bone are still unknown. Purpose: To determine the early-phase histological changes in FTCD associated with subchondral bone remodeling after MF in rat model. Study Design: Controlled laboratory study. Methods: Rats were subjected to FTCD, followed by MF at the trochlear groove. For histological analysis, experiment and untreated control rats were sacrificed at 0, 1, 3, 7, 14, 28, and 56 days postoperatively (n = 6 knees per time point). Cartilage healing response was evaluated with the Pineda score. Osteoclast activity was evaluated by counting and locating the number of tartrate-resistant acid phosphatase (TRAP)–positive cells in the subchondral bone. MF hole diameter and bone mineral density in the subchondral bone were measured sequentially in 3 rats (n = 6 knees) by 3-dimensional μ–computed tomography. Results: Pineda score showed no difference in cartilage response from day 0 to day 3 but a significant improvement from day 7 to day 56. Although the MF holes were filled with blood clots in all specimens, the defect sites were not. The number of TRAP-positive cells peaked at day 3, mostly accumulating around the deeper zone of the MF holes. Over time, the number of TRAP-positive cells decreased to preoperative levels, localizing around the aperture of the MF holes where there was active remodeling of the osteochondral unit. The MF hole diameter was largest at day 14, and most holes disappeared by day 28. Bone mineral density was also highest at day 14 and decreased to preoperative levels by day 56. Conclusion: Histological changes in the FTCD after MF were derived from endochondral ossification within the deeper zone of the MF holes. Clinical Relevance: The absence of healing by blood clot in the FTCD should be noted by surgeons performing MF, and indications for MF should be carefully considered not only for maximizing the postoperative clinical outcome but also minimizing potential complications, such as formation of subchondral bone cysts or intralesional osteophytes.

Review of an exploratory phase II FDA regulated clinical trial of a novel surgical innovation: completion of a prospective, randomized, controlled trial to compare NeoCart with the standard-of-care, microfracture, for articular cartilage repair

Background: Full thickness articular cartilage lesions cause significant morbidity, and surgical intervention is frequently applied to restore the joint surface. Current approaches of cartilage restoration have not proven to produce hyaline cartilage and have limited clinical longevity. The objective of the current study was to evaluate a novel autologous cartilage tissue implant, NeoCart, at the conclusion of the FDA-regulated exploratory phase II randomized, prospective clinical trial. The primary surgical standard-of-care, microfracture, was set by the FDA as the control. Objectives included parameter setting for the phase III trial while conducting a preliminary long-term evaluation of safety and efficacy. Methods: Patients were randomized 2:1 to NeoCart (n=21) or microfracture (n=9) surgical intervention at time of arthroscopy. Baseline demographics and patient-reported outcomes were established including: International Knee Documentation Committee (IKDC); Knee Injury and Osteoarthritis Outcome Score (KOOS) components including Pain, Activity of Daily Living, Quality of Life, Symptoms, Sports & Recreation; Short Form 36; and Visual Analog Scale Pain. Adverse events (AEs), range of motion, and patient reported outcomes were assessed annually for 5 years. Results: The treatment and control groups did not significantly differ in age, gender distribution, symptom duration, lesion size, or baseline patient reported outcomes aside from pre-surgical Visual Analog Scale Pain scores and KOOS Sports and Recreation. AE rates did not differ between treatments. The control group had greater loss to follow-up over a 5-year period. Change from baseline was significantly greater for NeoCart than for microfracture for primary end points; IKDC (1, 2 years) and KOOS Pain (1, 3, 4 years), and secondary end points; KOOS Quality of Life, Symptoms, and Sports & Recreation until 4 years. At 5 years, IKDC, KOOS Pain, Activities of Daily Living, and Quality of Life, and Short Form 36 Physical scores for both treatments improved significantly (P<0.05). Improvements for NeoCart were sustained earlier and throughout the entire study period. Conclusions: NeoCart implantation has a safety and efficacy profile supporting further consideration of this therapy in a confirmatory phase III trial for establishment as a primary cartilage injury treatment. While clinical trials for surgical interventions depend on comparison with a standard-of-care, the favorability of the control procedure, microfracture, varied over the study duration. The known short duration of microfracture’s therapeutic effect was likely associated with high loss to follow-up in the small control group. Although adequate for setting phase III parameters, this study is under-powered to clearly attribute differences in longer term efficacy. Nonetheless, preliminary results demonstrate that NeoCart may provide an alternative primary surgical option for cartilage injury with a more rapid onset of action than microfracture.

Sprifermin treatment enhances cartilage integration in an in vitro repair model.

Cartilage integration remains a clinical challenge for treatment of focal articular defects. Cartilage exhibits limited healing capacity that declines with tissue maturation. Many approaches have been investigated for their ability to stimulate healing of mature cartilage or integration of repair tissue or tissue-engineered constructs with native cartilage. Growth factors present in immature tissue may enhance chondrogenesis and promote integrative repair of cartilage defects. In this study, we assessed the role of one such factor, fibroblast growth factor 18 (FGF18). Studies using FGF18 have shown a variety of positive effects on cartilage, including stimulation of chondrocyte proliferation, matrix biosynthesis, and suppression of proteinase activity. To explore the role of FGF18 on cartilage defect repair, we hypothesized that treatment with recombinant human FGF18 (sprifermin) would increase matrix synthesis in a defect model, thus improving integration strength. To test this hypothesis, 6 mm cartilage cylinders were harvested from juvenile bovine knees. A central 3 mm defect was created in each explant, and this core was removed and replaced. Resulting constructs were cultured in control or sprifermin-containing medium (weekly 24-h exposure of 100 ng/ml sprifermin) for 4 weeks. Mechanical testing, biochemical analysis, micro-CT, scanning electron microscopy, and histology were used to assess matrix production, adhesive strength, and structural properties of the cartilage-cartilage interface. Results showed greater adhesive strength, increased collagen content, and larger contact areas between core and annular cartilage in the sprifermin-treated group. These findings present a novel treatment for cartilage injuries that have potential to enhance defect healing and lateral cartilage-cartilage integration. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2648-2656, 2018.

Evaluation of articular cartilage injury using computed tomography with axial traction in ankle joint

Category: Ankle Introduction/Purpose: Although chondral or osteochondral injuries are usually assessed by MRI, its accuracy is reportedly low because of the relatively thin cartilage layer and its close apposition to the cartilage talus and tibial plafond. The subchondral bone plays a role in cartilage metabolism, therefore the evaluation of subchondral bone is crucial for cartilage treatment. A method which enables the simultaneous evaluation of cartilage and subchondral bone is useful for the treatment of cartilage injury. The purpose of this study was to assess the feasibility of CT imaging with axial traction for the diagnosis of articular cartilage injuries. Methods: Chondral lesion in 18 ankles of 17 patients were evaluated. These 18 ankles consisted of 11 ankles of osteochondral lesion of the talar dome (OLT), 5 ankles of osteoarthritis of ankle joints and 2 ankles of anterior impingement syndrome. Twelve males and 5 women were included, with a mean age of 33.7 years (range, 15 -70 years). An ankle distractor foot strap was placed on the ankle with 30 degrees flexion of the knee joint, and a traction force of 80 N was applied during CT scanning. Gray scale CT images were allocated colors to make it easier to evaluate the cartilage layer. The international Cartilage Repair Society (ICRS) grades on CT were compared with those in arthroscopic findings. Results: The respective sensitivity and specificity of CT imaging with traction compared to ICRS grading were 74.4%, and 96.3%. The level of agreement of the ICRS grading between CT images and arthroscopic findings showed moderate (kappa coefficient; 0.547). The diagnosis of grade 3 or 4 lesions had 80.0% sensitivity. Axial traction to CT enabled the delineation of the cartilage surface including chondral thinning, defect and cartilage separation more visible (Figure 1). Conclusion: CT with axial traction could obtain acceptable levels of sensitivity and specificity for the evaluation of articular cartilage injuries in addition to the assessment of subchondral bone.

Fibronectin Enhances Cartilage Repair by Activating Progenitor Cells Through Integrin α5β1 Receptor.

This study aimed to determine the effect of fibronectin (FN) on cartilage regeneration through the activation of chondrogenic progenitor cells (CPCs). Cells were isolated from the knee cartilage of mice and cultured in the presence of various concentrations of FN. Proliferation, migration, and chondrogenic differentiation assays were performed in vitro. In some experiments, CPCs were preincubated with anti-integrin α5β1 antibody for 60 min before FN treatment to block the integrin α5β1 receptor. Soluble FN was mixed with Pluronic F-127 and injected into the joint cavity in an early-stage osteoarthritis model. Cartilage repair was evaluated histologically, biochemically, and biomechanically. In vitro, we observed that the isolated CPCs, which exhibited stem cell-relevant markers, proliferated most at a concentration of 20 μg/mL FN (p < 0.05). In addition, FN enhanced the proliferation, migration, and chondrogenic differentiation capacity of CPCs, and the enhancement was significantly decreased by blockade of the integrin α5β1 receptor (p < 0.05). In vivo, FN also significantly promoted cartilage repair along with increased CPC activation and integrin α5β1 expression (p < 0.05). These findings suggest that FN enhances CPC proliferation, migration, and chondrogenic differentiation through the integrin α5β1-dependent signaling pathway. Based on these results, a novel and promising therapy focused on targeted activation of CPCs by FN could be developed for the treatment of cartilage injuries in a clinical setting.

Neuralgic and Nociceptive Pain in the Knee as a Cause of the Treatment Failure after Cartilage Repair Surgery: Two Case Reports

Objective: Cartilage injuries are one of the most frequent causes of knee pain. Other causes such as meniscus tears, synovial plica, synovitis, partial and total ligament ruptures are rather easy to identify by standard diagnostic methods and diagnostic arthroscopy. In this study we are describing two other clinical states, which could be the cause of the knee pain and should be addressed before a decision for operative treatment of cartilage injury has been made by a surgeon. Materials and Methods: Two patients with isolated focal defects due to previous trauma to the knee were diagnosed both using magnetic resonance imaging preoperatively and intraoperatively during arthroscopy. These were operated arthroscopically with standard procedure for microfracture. Both patients had treatment failure without a sign of significant improvement after six and twelve months. Results: Second look arthroscopy was performed in both cases due to the treatment failure and close to normal cartilage was found in the patella in first case and both in trochlea and medial femoral condyle in other case. No other cause of pain could be identified both with second look arthroscopy and magnetic resonance imaging done 6-12 months postoperatively. The patients were diagnosed with neuralgic pain in one case, and nociceptive pain in other case. Conclusion: These states are rare, but have to be addressed by the surgeon before making the decision about the operative treatment. By doing so, one could avoid eventual treatment failure and exposition of the patient to an unnecessary risk of complications during the surgery.

Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)

Cartilage injuries caused by arthritis or trauma pose formidable challenges for effective clinical management due to the limited intrinsic proliferative capability of chondrocytes. Autologous stem cell-based therapies and transgene-enhanced cartilage tissue engineering may open new avenues for the treatment of cartilage injuries. Bone morphogenetic protein 2 (BMP2) induces effective chondrogenesis of mesenchymal stem cells (MSCs) and can thus be explored as a potential therapeutic agent for cartilage defect repair. However, BMP2 also induces robust endochondral ossification. Although the precise mechanisms through which BMP2 governs the divergence of chondrogenesis and osteogenesis remain to be fully understood, blocking endochondral ossification during BMP2-induced cartilage formation may have practical significance for cartilage tissue engineering. Here, we investigate the role of Sox9-donwregulated Smad7 in BMP2-induced chondrogenic differentiation of MSCs. We find that overexpression of Sox9 leads to a decrease in BMP2-induced Smad7 expression in MSCs. Sox9 inhibits BMP2-induced expression of osteopontin while enhancing the expression of chondrogenic marker Col2a1 in MSCs. Forced expression of Sox9 in MSCs promotes BMP2-induced chondrogenesis and suppresses BMP2-induced endochondral ossification. Constitutive Smad7 expression inhibits BMP2-induced chondrogenesis in stem cell implantation assay. Mouse limb explant assay reveals that Sox9 expands BMP2-stimulated chondrocyte proliferating zone while Smad7 promotes BMP2-intitated hypertrophic zone of the growth plate. Cell cycle analysis indicates that Smad7 induces significant early apoptosis in BMP2-stimulated MSCs. Taken together, our results strongly suggest that Sox9 may facilitate BMP2-induced chondrogenesis by downregulating Smad7, which can be exploited for effective cartilage tissue engineering.

Effects of insulin-like growth factor 1 and basic fibroblast growth factor on the morphology and proliferation of chondrocytes embedded in Matrigel in a microfluidic platform.

An integrated microfluidic device was utilized in the present study to investigate the morphology and proliferation of rabbit articular chondrocytes embedded in Matrigel in the presence of insulin-like growth factor 1 (IGF-1) and/or basic fibroblast growth factor (bFGF). The microfluidic device was composed of two parallel channels and a central perfusion-based three-dimensional cell culture module. The rabbit chondrocytes were cultured for 2 weeks at series of concentration gradients of IGF-1 and/or bFGF, which were generated through a diffusion process. At the end of the experiment, the morphology and quantity of cells were measured. Since high expression of collagen II is essential to the function of hyaline cartilage, immunofluorescent images of collagen II expression prior to and after the experiments were gathered for each group. The mean fluorescence intensity ratio (MIR) of collagen II in each group was calculated. The MIRs of collagen II in chondrocytes treated with IGF-1 ranged from 0.6-0.81, those in the cells treated with bFGF ranged from 0.47-0.52, and those in cells treated with a combination of IGF-1 and bFGF ranged from 0.63-0.83. Chondrocyte aggregations were observed in the group treated with 75-100 ng/ml IGF-1 (3.46-fold proliferation ratio). Similarly, a 3.83-fold proliferation ratio was identified in chondrocytes treated with 2.5-5.0 ng/ml bFGF. The group treated with 50-75 ng/ml IGF-1 and 2.5-5.0 ng/ml bFGF exhibited the optimum increase in proliferation (4.83-fold proliferation ratio). The microfluidic device used in the present study can be easily adapted to investigate other growth factors at any concentration gradient. In addition, parallel experiments can be performed simultaneously with a small quantity of cells, making it an attractive platform for the high-throughput screening of cell culture parameters. This platform will aid in the optimization of culture conditions for the in vitro expansion of chondrocytes while maintaining their in vivo morphology, which will improve autologous chondrocyte implantation capabilities for the treatment of cartilage injury.

Regeneration of hyaline-like cartilage in situ with SOX9 stimulation of bone marrow-derived mesenchymal stem cells.

Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.

In Vitro and In Vivo Studies of Alar-Nasal Cartilage Using Autologous Micro-Grafts: The Use of the Rigenera® Protocol in the Treatment of an Osteochondral Lesion of the Nose.

Cartilage defects represent a serious problem due to the poor regenerative properties of this tissue. Regarding the nose, nasal valve collapse is associated with nasal blockage and persistent airway obstruction associated with a significant drop in the quality of life for patients. In addition to surgical techniques, several cell-based tissue-engineering strategies are studied to improve cartilage support in the nasal wall, that is, to ameliorate wall insufficiency. Nevertheless, there are no congruent data available on the benefit for patients during the follow-up time. In this manuscript, we propose an innovative approach in the treatment of cartilage defects in the nose (nasal valve collapse) based on autologous micro-grafts obtained by mechanical disaggregation of a small portion of cartilage tissue (Rigenera® protocol). In particular, we first analyzed in vitro murine and human cartilage micro-grafts; secondly, we analyzed the clinical results of a patient with pinched nose deformity treated with autologous micro-grafts of chondrocytes obtained by Rigenera® protocol. The use of autologous micro-graft produced promising results in surgery treatment of cartilage injuries and could be safely and easily administrated to patients with cartilage tissue defects.

Minicircle Mediated Gene Delivery to Canine and Equine Mesenchymal Stem Cells.

Gene-directed tissue repair offers the clinician, human or veterinary, the chance to enhance cartilage regeneration and repair at a molecular level. Non-viral plasmid vectors have key biosafety advantages over viral vector systems for regenerative therapies due to their episomal integration however, conventional non-viral vectors can suffer from low transfection efficiency. Our objective was to identify and validate in vitro a novel non-viral gene expression vector that could be utilized for ex vivo and in vivo delivery to stromal-derived mesenchymal stem cells (MSCs). Minicircle plasmid DNA vector containing green fluorescent protein (GFP) was generated and transfected into adipose-derived MSCs from three species: canine, equine and rodent and transfection efficiency was determined. Both canine and rat cells showed transfection efficiencies of approximately 40% using minicircle vectors with equine cells exhibiting lower transfection efficiency. A Sox9-expressing minicircle vector was generated and transfected into canine MSCs. Successful transfection of the minicircle-Sox9 vector was confirmed in canine cells by Sox9 immunostaining. This study demonstrate the application and efficacy of a novel non-viral expression vector in canine and equine MSCs. Minicircle vectors have potential use in gene-directed regenerative therapies in non-rodent animal models for treatment of cartilage injury and repair.

Characterisation of synovial fluid and infrapatellar fat pad derived mesenchymal stromal cells: The influence of tissue source and inflammatory stimulus

The infrapatellar fat pad (FP) and synovial fluid (SF) in the knee serve as reservoirs of mesenchymal stromal cells (MSCs) with potential therapeutic benefit. We determined the influence of the donor on the phenotype of donor matched FP and SF derived MSCs and examined their immunogenic and immunomodulatory properties before and after stimulation with the pro-inflammatory cytokine interferon-gamma (IFN-γ). Both cell populations were positive for MSC markers CD73, CD90 and CD105, and displayed multipotency. FP-MSCs had a significantly faster proliferation rate than SF-MSCs. CD14 positivity was seen in both FP-MSCs and SF-MSCs, and was positively correlated to donor age but only for SF-MSCs. Neither cell population was positive for the co-stimulatory markers CD40, CD80 and CD86, but both demonstrated increased levels of human leukocyte antigen-DR (HLA-DR) following IFN-γ stimulation. HLA-DR production was positively correlated with donor age for FP-MSCs but not SF-MSCs. The immunomodulatory molecule, HLA-G, was constitutively produced by both cell populations, unlike indoleamine 2, 3-dioxygenase which was only produced following IFN-γ stimulation. FP and SF are accessible cell sources which could be utilised in the treatment of cartilage injuries, either by transplantation following ex-vivo expansion or endogenous targeting and mobilisation of cells close to the site of injury.

Chondrogenic Potency Analyses of Donor-Matched Chondrocytes and Mesenchymal Stem Cells Derived from Bone Marrow, Infrapatellar Fat Pad, and Subcutaneous Fat.

Autologous chondrocyte implantation (ACI) is a cell-based therapy that has been used clinically for over 20 years to treat cartilage injuries more efficiently in order to negate or delay the need for joint replacement surgery. In this time, very little has changed in the ACI procedure, but now many centres are considering or using alternative cell sources for cartilage repair, in particular mesenchymal stem cells (MSCs). In this study, we have tested the chondrogenic potential of donor-matched MSCs derived from bone marrow (BM), infrapatellar fat pad (FP), and subcutaneous fat (SCF), compared to chondrocytes. We have confirmed that there is a chondrogenic potency hierarchy ranging across these cell types, with the most potent being chondrocytes, followed by FP-MSCs, BM-MSCs, and lastly SCF-MSCs. We have also examined gene expression and surface marker profiles in a predictive model to identify cells with enhanced chondrogenic potential. In doing so, we have shown that Sox-9, Alk-1, and Coll X expressions, as well as immunopositivity for CD49c and CD39, have predictive value for all of the cell types tested in indicating chondrogenic potency. The findings from this study have significant clinical implications for the refinement and development of novel cell-based cartilage repair strategies.

From gristle to chondrocyte transplantation: treatment of cartilage injuries.

This review addresses the progress in cartilage repair technology over the decades with an emphasis on cartilage regeneration with cell therapy. The most abundant cartilage is the hyaline cartilage that covers the surface of our joints and, due to avascularity, this tissue is unable to repair itself. The cartilage degeneration seen in osteoarthritis causes patient suffering and is a huge burden to society. The surgical approach to cartilage repair was non-existing until the 1950s when new surgical techniques emerged. The use of cultured cells for cell therapy started as experimental studies in the 1970s that developed over the years to a clinical application in 1994 with the introduction of the autologous chondrocyte transplantation technique (ACT). The technology is now spread worldwide and has been further refined by combining arthroscopic techniques with cells cultured on matrix (MACI technology). The non-regenerating hypothesis of cartilage has been revisited and we are now able to demonstrate cell divisions and presence of stem-cell niches in the joint. Furthermore, cartilage derived from human embryonic stem cells and induced pluripotent stem cells could be the base for new broader cell treatments for cartilage injuries and the future technology base for prevention and cure of osteoarthritis.

Surgical techniques of mesenchymal stimulation of hyaline cartilage reparative chondrogenesis

The main direction of surgical treatment of cartilage injuries are the surgeries that create conditions for chondrogenesis stimulation by the method of perforation of subchondral bone plate – osteoperforative methods. The modern osteoperforative method is a microfracturization of the fundus of cartilage defect. The aim. of experimental research was the study of features of clinical course of reparative chondrogenesis on the background of chondromalacia using two osteoperforative methods. Methods. Experimental researches were carried out on 45 sexually mature male rats that underwent modeling of knee joint chondromalacia. There were carried out histological examinations of cartilaginous tissue of the joint. For study of the source of oligopotent cells of mesenchymal nature immunohistochemical research was carried out. Results. The most significant advantages of joint cartilage regeneration were observed at tunnelization to the medullary cavity. The most cells-precursors of chondroblasts were localized on the border of endosteum and medullary cavity. An access of stem cells of mesenchymal nature to an injured cartilage can be ensured by tunnelization to the medullary cavity. Conclusions. Subchondral tunnalization of the defect area in conditions of chondromalacia is less effective that tunnelization of medullary cavity. Arthroscopic surgical technology of the treatment of patients with chondromalacia of articular cartilage was grounded.

The Use of Osteochondral Allograft Transplantation for Primary Treatment of Cartilage Lesions in the Knee.

Objective:To assess the outcome of osteochondral allograft (OCA) transplantation as the primary treatment for cartilage injury in patients with no previous surgical treatment.Study Design:Case series. Patients were identified in our outcomes database. Patients undergoing primary OCA transplantation with no prior surgical treatment and a minimum of 2 years follow-up were selected. Pain and function were evaluated preoperatively and postoperatively. Patient satisfaction was assessed. Reoperations following OCA transplantation were captured. Failure was defined as revision OCA or conversion to arthroplasty.Results:Fifty-five patients (61 knees) were included in the analysis. The study consisted of 30 males and 25 females (mean age = 32.9 years; range = 15.7-67.8 years). The most common diagnoses for the OCA transplantation were osteochondritis dissecans (44.3%) and avascular necrosis (31.1%). Pain and function improved preoperatively to postoperatively on all outcome scales (P < 0.01). The majority of patients (86%) were “extremely satisfied” or “satisfied.” OCA survivorship was 89.5% at 5 years and 74.7% at 10 years. At latest follow-up (mean = 7.6 years; range = 1.9-22.6 years), OCA remained in situ in 50 knees (82%). Eighteen knees (29.5%) had further surgery; 11 OCA failures and 7 other surgical procedure(s). Of the failed knees (mean time to failure = 3.5 years; range = 0.5-13.7 years), 8 were converted to arthroplasty, 2 had OCA revisions, and 1 had a patellectomy.Conclusions:OCA transplantation is an acceptable primary treatment method for some chondral and osteochondral defects of the knee. Failure of previous treatment(s) is not a prerequisite for OCA transplantation.

The Use of Osteochondral Allograft Transplantation for Primary Treatment of Cartilage Injuries in the Knee

Objectives:To assess the clinical outcome of OCA transplantation used as primary treatment for chondral and osteochondral lesions in the knee. In most treatment algorithms, osteochondral allograft (OCA) transplantation is regarded as a salvage procedure when previous treatments have failed. No publications have assessed the outcome of OCA transplantation used as primary treatment for cartilage lesions in the knee.Methods:Our OCA outcomes database was used to identify 61 patients who underwent OCA transplantation as primary treatment for a chondral or osteochondral defect and had a minimum follow-up of two years. None of the patients had previous surgery on the involved knee prior to the OCA. Included in the analysis were 32 males and 29 females with a mean age of 32.9 years (range 15.7-67.8 years). The most common diagnoses were osteochondritis dissecans (44.3%) and avascular necrosis (31.1%), followed by osteoarthritis (8.2%), degenerative chondral lesion (6.6%), traumatic chondral injury (6.6%), and fracture (3.2%). The mean graft area was 9.6 cm2. The majority of grafts were located on the medial (47.5%) and lateral (24.6%) femoral condyles. Thirty-five patients (57.4%) had one graft, 22 (36.2%) had two grafts, and 4 (6.6%) had three grafts. Each patient was evaluated pre- and postoperatively with the International Knee Documentation Committee (IKDC), a modified Merle d’Aubigné-Postel (18-point) scale, and Knee Society function (KS-F) score. Patients came in for a clinical evaluation or were contacted via telephone for follow-up. The number and type of reoperations following the OCA transplantation was captured. Failure was defined as revision OCA or conversion to arthroplasty. Patient satisfaction was assessed.Results:The mean follow-up duration was 7.6 years (range, 1.9 to 22.6 years). Eighteen knees (29.5%) had further surgery following the OCA transplantation. Seven knees (11.5%) had procedures unrelated to the allograft and 11 knees (18%) were considered OCA failures with eight conversions to arthroplasty, two revision OCA, and one patellectomy. The mean time to failure was 5.9 years (range, 0.5-13.7 years). OCA survivorship was 89.5% at 5 years and 74.7% at 10 years. Forty-three (70.5%) knees had their OCA still in situ at latest follow-up. Thirty-eight (84.5%) were rated good/excellent on the 18-point scale. The mean IKDC scores improved from 36.9 preoperatively to 80.4 postoperatively. The KS-F scores improved from 66.5 to 89.7. Eighty-six percent of patients reported being “extremely satisfied” or “satisfied.”Conclusion:OCA transplantation is an acceptable primary treatment method for some chondral and osteochondral defects of the knee. Failure of previous surgical treatment is not a prerequisite for OCA surgery. Outcomes in this group are comparable to other cartilage repair treatment options.

The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration

The use of stem cells in regenerative medicine offers hope to treat numerous orthopaedic disorders, including articular cartilage defects. Although much research has been carried out on chondrogenesis, this complicated process is still not well understood and much more research is needed. The present review provides an overview of the stages of chondrogenesis and describes the effects of various growth factors, which act during the multiple steps involved in stem cell-directed differentiation towards chondrocytes. The current literature on stem cell-directed chondrogenesis, in particular the role of members of the transforming growth factor-β (TGF-β) superfamily-TGF-βs, bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs)-is reviewed and discussed. Numerous studies have reported the chondrogenic potential of both adult- and embryonic-like stem cells and the role of growth factors in programming differentiation of these cells towards chondrocytes. Mesenchymal stem cells (MSCs) are adult multipotent stem cells, whereas induced pluripotent stem cells (iPSC) are reprogrammed pluripotent cells. Although better understanding of the processes involved in the development of cartilage tissues is necessary, both cell types may be of value in the clinical treatment of cartilage injuries or osteoarthritic cartilage lesions. MSCs and iPSCs both present unique characteristics. However, at present, it is still unclear which cell type is most suitable in the treatment of cartilage injuries.

Enhanced human bone marrow mesenchymal stem cell chondrogenic differentiation in electrospun constructs with carbon nanomaterials

Cartilage as a tissue in the body possesses a low regenerative capacity and is extremely difficult to repair. Today, treatment of cartilage injury, degeneration and defects presents critical clinical challenges, yet none of the currently available cartilage treatments provides a perfect solution. Since natural cartilage extracellular matrix is a nanoscaled structure, the main objective of this study is to design a novel biomimetic nanostructured cartilage construct via electrospinning and carbon nanomaterials for enhancing human bone marrow mesenchymal stem cell chondrogenic differentiation. For this purpose, we synthesized a carbon nanomaterial mixture, using a plasma arc discharge method, consisting of graphene nanoplatelets and single walled carbon nanotubes. This nanomaterial was then incorporated into electrospun polycaprolactone (PCL) microfibrous scaffolds, with and without an additional poly-l-lysine surface coating. Scaffolds were thoroughly characterized for both their biomimetic features and biocompatibility. Our results showed that our scaffolds with carbon nanomaterial have greatly improved mechanical properties and enhanced stem cell adhesion, proliferation and chondrogenic differentiation than PCL controls without carbon nanomaterials, and thus hold promise for improving cartilage formation in future in vivo studies and clinical applications.

Mechanical stimulation enhances integration in an in vitro model of cartilage repair.

(1) To characterize the effects of mechanical stimulation on the integration of a tissue-engineered construct in terms of histology, biochemistry and biomechanical properties; (2) to identify whether cells of the implant or host tissue were critical to implant integration; and (3) to study cells believed to be involved in lateral integration of tissue-engineered cartilage to host cartilage. We hypothesized that mechanical stimulation would enhance the integration of the repair implant with host cartilage in an in vitro integration model. Articular cartilage was harvested from 6- to 9-month-old bovine metacarpal-phalangeal joints. Constructs composed of tissue-engineered cartilage implanted into host cartilage were placed in spinner bioreactors and maintained on a magnetic stir plate at either 0 (static control) or 90 (experimental) rotations per minute (RPM). The constructs from both the static and spinner bioreactors were harvested after either 2 or 4weeks of culture and evaluated histologically, biochemically, biomechanically and for gene expression. The extent and strength of integration between tissue-engineered cartilage and native cartilage improved significantly with both time and mechanical stimulation. Integration did not occur if the implant was not viable. The presence of stimulation led to a significant increase in collagen content in the integration zone between host and implant at 2weeks. The gene profile of cells in the integration zone differs from host cartilage demonstrating an increase in the expression of membrane type 1 matrix metalloproteinase (MT1-MMP), aggrecan and type II collagen. This study shows that the integration of in vitro tissue-engineered implants with host tissue improves with mechanical stimulation. The findings of this study suggests that consideration should be given to implementing early loading (mechanical stimulation) into future in vivo studies investigating the long-term viability and integration of tissue-engineered cartilage for the treatment of cartilage injuries. This could simply be done through the use of continuous passive motion (CPM) in the post-operative period or through a more complex and structured rehabilitation program with a gradual increase in forces across the joint over time.