Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial.

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043-a derivative of angiopoietin-like 3 (ANGPTL3)-as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α5ß1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA.

Test-retest reliability of wireless inertial-sensor derived measurements of knee joint kinematics.

Advances in sensor technology have provided an opportunity to measure gait characteristics using body-worn inertial measurement units (IMUs). Whilst research investigating the validity of IMUs in reporting gait characteristics is extensive, research investigating the reliability of IMUs is limited. This study aimed to investigate the inter-session reliability of wireless IMU derived measures of gait (i.e., knee angle, range of motion) taking multiple test administrators into account. Fifteen healthy volunteers (43 ± 15 years) completed two visits. Within each visit, participants were required to perform two sets of 6 gait trials (6-metre walk tests). IMUs were placed on the participant in 7 locations on the lower limbs and waist. A different test administrator (n = 3) applied the IMUs at each set. At visit 2, this procedure was repeated with the same test administrators as visit 1. Kinematic measures of maximum angle (Knee_Max), minimum angle (Knee_Min), and range of motion (RoM) are reported for the left and right knee. The intraclass correlation coefficients (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) are reported to determine IMU reliability. The results confirmed moderate to good inter-session reliability across all features (0.73-0.87). SEM values ranged from 1.21-3.32° and MDC values ranged from 3.37 - 9.21°. Therefore, IMUs appear to be a reliable method to determine inter-session gait characteristics across multiple test administrators.

An Automatic Foot and Shank IMU Synchronization Algorithm: Proof-of-concept.

When using wearable sensors for measurement and analysis of human performance, it is often necessary to integrate and synchronise data from separate sensor systems. This paper describes a synchronization technique between IMUs attached to the shanks and insoles attached at the feet and aims to solve the need to compute the ankle joint angle, which relies on synchronized sensor data. This will additionally enable concurrent analysis using gait kinematic and kinetic features. A proof-of-concept of the algorithm, which relies on cross-correlation of gyroscope sensor data from the shank and foot, to align the sensor systems is demonstrated. The algorithm output is validated against those signals synchronized using manually annotated heel-strike and toe-off ground-truth signal landmarks, identified in both the shank and feet signals using previously published definitions. Results demonstrate that the developed algorithm is capable of synchronizing both sensor systems, based on IMU data from both healthy participants and participants suffering from knee osteoarthritis, with a mean lag time bias of 25.56ms when compared to the ground truth. A proof-of-concept of technique to synchronise IMUs attached to the shanks and insoles attached at the feet is demonstrated and offers an alternative approach to sensor system synchronisation.

Orthotopic Bone Formation by Streamlined Engineering and Devitalization of Human Hypertrophic Cartilage.

Most bones of the human body form and heal through endochondral ossification, whereby hypertrophic cartilage (HyC) is formed and subsequently remodeled into bone. We previously demonstrated that HyC can be engineered from human mesenchymal stromal cells (hMSC), and subsequently devitalized by apoptosis induction. The resulting extracellular matrix (ECM) tissue retained osteoinductive properties, leading to ectopic bone formation. In this study, we aimed at engineering and devitalizing upscaled quantities of HyC ECM within a perfusion bioreactor, followed by in vivo assessment in an orthotopic bone repair model. We hypothesized that the devitalized HyC ECM would outperform a clinical product currently used for bone reconstructive surgery. Human MSC were genetically engineered with a gene cassette enabling apoptosis induction upon addition of an adjuvant. Engineered hMSC were seeded, differentiated, and devitalized within a perfusion bioreactor. The resulting HyC ECM was subsequently implanted in a 10-mm rabbit calvarial defect model, with processed human bone (Maxgraft®) as control. Human MSC cultured in the perfusion bioreactor generated a homogenous HyC ECM and were efficiently induced towards apoptosis. Following six weeks of in vivo implantation, microcomputed tomography and histological analyses of the defects revealed an increased bone formation in the defects filled with HyC ECM as compared to Maxgraft®. This work demonstrates the suitability of engineered devitalized HyC ECM as a bone substitute material, with a performance superior to a state-of-the-art commercial graft. Streamlined generation of the devitalized tissue transplant within a perfusion bioreactor is relevant towards standardized and automated manufacturing of a clinical product.

Effects of Interleukin-1ß Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1ß (IL-1ß) can reduce the consequences of large joint osteoarthritis is unclear. OBJECTIVE: To determine whether IL-1ß inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). DESIGN: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846). SETTING: 1091 clinical sites in 39 countries. PARTICIPANTS: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. INTERVENTION: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. MEASUREMENTS: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. RESULTS: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. LIMITATION: Because the parent trial was not designed to examine the efficacy of IL-1ß inhibitors in osteoarthritis, information on structural joint outcomes was not collected. CONCLUSION: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1ß inhibition for treatment of large joint osteoarthritis. PRIMARY FUNDING SOURCE: Novartis Pharmaceuticals.

VEGF Over-Expression by Engineered BMSC Accelerates Functional Perfusion, Improving Tissue Density and In-Growth in Clinical-Size Osteogenic Grafts.

The first choice for reconstruction of clinical-size bone defects consists of autologous bone flaps, which often lack the required mechanical strength and cause significant donor-site morbidity. We have previously developed biological substitutes in a rabbit model by combining bone tissue engineering and flap pre-fabrication. However, spontaneous vascularization was insufficient to ensure progenitor survival in the core of the constructs. Here, we hypothesized that increased angiogenic stimulation within constructs by exogenous VEGF can significantly accelerate early vascularization and tissue in-growth. Bone marrow stromal cells from NZW rabbits (rBMSC) were transduced with a retroviral vector to express rabbit VEGF linked to a truncated version of rabbit CD4 as a cell-surface marker. Autologous cells were seeded in clinical-size 5.5 cm3 HA scaffolds wrapped in a panniculus carnosus flap to provide an ample vascular supply, and implanted ectopically. Constructs seeded with VEGF-expressing rBMSC showed significantly increased progenitor survivival, depth of tissue ingrowth and amount of mineralized tissue. Contrast-enhanced MRI after 1 week in vivo showed significantly improved tissue perfusion in the inner layer of the grafts compared to controls. Interestingly, grafts containing VEGF-expressing rBMSC displayed a hierarchically organized functional vascular tree, composed of dense capillary networks in the inner layers connected to large-caliber feeding vessels entering the constructs at the periphery. These data constitute proof of principle that providing sustained VEGF signaling, independently of cells experiencing hypoxia, is effective to drive rapid vascularization and increase early perfusion in clinical-size osteogenic grafts, leading to improved tissue formation deeper in the constructs.

Assessment of Low-Grade Focal Cartilage Lesions in the Knee With Sodium MRI at 7 T: Reproducibility and Short-Term, 6-Month Follow-up Data.

OBJECTIVES: Several articles have investigated potential of sodium (Na) magnetic resonance imaging (MRI) for the in vivo evaluation of cartilage health, but so far no study tested its feasibility for the evaluation of focal cartilage lesions of grade 1 or 2 as defined by the International Cartilage Repair Society. The aims of this study were to evaluate the ability of Na-MRI to differentiate between early focal lesions and normal-appearing cartilage, to evaluate within-subject reproducibility of Na-MRI, and to monitor longitudinal changes in participants with low-grade, focal chondral lesions. MATERIALS AND METHODS: Thirteen participants (mean age, 50.1 ± 10.9 years; 7 women, 6 men) with low-grade, focal cartilage lesions in the weight-bearing region of femoral cartilage were included in this prospective cohort study. Participants were assessed at baseline, 1 week, 3 months, and 6 months using morphological MRI at 3 T and 7 T, compositional Na-MRI at 7 T, and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Na signal intensities corrected for coil sensitivity and partial volume effect (Na-cSI) were calculated in the lesion, and in weight-bearing and non-weight-bearing regions of healthy femoral cartilage. Coefficients of variation, repeated measures analysis of covariance models, and Pearson correlation coefficients were calculated to evaluate within-subject reproducibility as well as cross-sectional and longitudinal changes in Na-cSI values. RESULTS: The mean coefficients of variation of Na-cSI values between the baseline and 1-week follow-up were 5.1% or less in all cartilage regions. Significantly lower Na-cSI values were observed in lesion than in weight-bearing and non-weight-bearing regions at all time points (all P values ≤ 0.002). Although a significant decrease from baseline Na-cSI values in lesion was found at 3-month visit (P = 0.015), no substantial change was observed at 6 months. KOOS scores have improved in all subscales at 3 months and 6 months visit, with a significant increase observed only in the quality of life subscale (P = 0.004). CONCLUSIONS: In vivo Na-MRI is a robust and reproducible method that allows to differentiate between low-grade, focal cartilage lesions and normal-appearing articular cartilage, which supports the concept that compositional cartilage changes can be found early, before the development of advanced morphological changes visible at clinical 3-T MRI.

The comparison of the performance of 3 T and 7 T T2 mapping for untreated low-grade cartilage lesions.

OBJECTIVE: To investigate T2 mapping as a possible marker for low-grade human articular cartilage lesions during a one-year follow-up, possible changes during the follow-up and compare the reliability and sensitivity of these measurements on high-field (3 T) and ultra-high-field (7 T) MRI scanners. DESIGN: Twenty-one patients with femoral, tibial and patellar cartilage defect in the knee joint participated in the study. The MRI protocol consisted of morphological, as well as three-dimensional triple-echo steady-state (3D-TESS) T2 mapping sequences with similar parameters at 3T and 7T. Patients were scanned at five time-points up to 12 months. T2 values were evaluated in the lesion and healthy-appearing regions for superficial and deep cartilage zone. The repeated ANOVA was used to determine differences in T2 values at various time points. RESULTS: A significant decrease in T2 values was observed between baseline and six months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 ±â€¯9.3 ms to 31.21 ±â€¯7.2 ms, which is a difference of -5.67 ±â€¯2.2 ms (p = 0.031)), and at 12 months in the superficial layer of the lesion in patients at 3 T (decrease from 41.89 ±â€¯9.3 ms to 35.28 ±â€¯4.9 ms, which is a difference of -6.60 ±â€¯4.4 ms (p = 0.044). No significant differences were recorded at 7 T. CONCLUSION: The change in T2 values acquired with 3 T 3D-TESS appears to be reflecting subtle changes of cartilage composition in the course of low-grade lesion development. 7 T T2 mapping does not reflect these changes probably due to completely decayed short T2 component.

Monocytes Seeded on Engineered Hypertrophic Cartilage Do Not Enhance Endochondral Ossification Capacity.

Engineered hypertrophic cartilage (HC) represents an attractive bone substitute material, capable to induce bone formation by endochondral ossification. Since bone formation by HC depends on factors released from the extracellular matrix, in this study, we hypothesized that HC seeding with monocytes committed to osteoclastogenesis could enhance its remodeling, improve chemotaxis of skeletal and vascular cells, and consequently enhance bone formation. This would be particularly relevant for devitalized HC, which currently exhibits only limited osteoinductivity. Living or devitalized HC engineered from human bone marrow-derived mesenchymal stromal cells (MSCs) was seeded or not with human monocytes in the presence of macrophage colony-stimulating factor and RANK-ligand, cultured for up to 15 days, or implanted ectopically in nude mice. Monocytes seeded on devitalized, but not living, HC induced its in vitro resorption, resulting in 30-fold higher release and 2.7-fold lower content of glycosaminoglycans compared with unseeded samples. In vitro, supernatants from monocyte-seeded devitalized HC attracted more monocytes compared with unseeded samples, but did not enhance chemotaxis of MSCs or human umbilical vein endothelial cells. In vivo, however, neither remodeling nor invasion by osteoclasts, endothelial cells, and mouse MSCs were significantly affected by the seeding with monocytes. Finally, in vitro priming of living or devitalized HC by monocytes did not enhance their bone-forming capacity. Further investigations should test the proposed approach on HC engineered to prevent rapid degradation and support osteoclastogenesis, or identify alternative strategies to enhance engineered HC remodeling and bone-forming capacity.

Thoracic Outlet Syndrome in the Overhead Athlete: A Report of 2 Cases of Subclavius Posticus Muscle.

Subclavius posticus muscle is a supernumerary anatomical variation of the subclavius muscle. The aim of this study was to show the possible contribution of the posticus muscle in the development of unilateral thoracic outlet syndrome (TOS) in overhead athletes, presenting hypertrophy of the dominant arm due to their sport activity. Reported here are 2 young overhead athletes complaining pain, paresthesia, weakness in the dominant upper limb, although presenting none of the main shoulder and neurological disorders. After developing subclavian vein thrombosis, TOS was suspected and finally diagnosed by dynamic magnetic resonance angiography, which also showed bilateral subclavius posticus muscle in both patients. Despite bilateral subclavius posticus, TOS was only evident in the dominant limb in which the association of hypertrophy of lateral cervical muscles, resulting from the overhead sport activity, to the subclavius posticus likely led to a significant reduction of the upper thoracic outlet space.

One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.

PURPOSE: The aim of this study is to prospectively evaluate the medium-term effectiveness and regenerative capability of autologous adult mesenchymal stem cells, harvested as bone marrow aspirate concentrate (BMAC), along with a hyaluronan-based scaffold (Hyalofast) in the treatment of ICRS grade 4 chondral lesions of the knee joint, in patients older than 45 years. METHODS: A study group of 20 patients with an age >45 years (mean 50.0 ± 4.1 years) was compared to a control group of 20 patients with an age <45 years (mean 36.6 ± 5.0). Patients were prospectively evaluated for 4 years. All patients were evaluated with MRI, KOOS, IKDC, VAS and Tegner scores preoperatively and at two-year and final follow-up. RESULTS: At final follow-up, all scores significantly improved (P < 0.001) as follows: all KOOS score categories; Tegner 2 (range 0-4) to 6 (range 4-8) and 3 (range 0-6) to 6 (range 3-10); IKDC subjective (39.2 ± 16.5 to 82.2 ± 8.9) and (40.8 ± 13.9 to 79.4 ± 14.6), in the study and control group respectively. In addition, we show that results are affected by lesion size and number but not from concomitant surgical procedures. MRI showed complete filling in 80 % of patients in the study group and 71 % of patients in the control group. Histological analysis conducted in three patients from the study and two patients from the control group revealed good tissue repair with a variable amount of hyaline-like tissue. CONCLUSION: Treatment of cartilage lesions with BMAC and Hyalofast is a viable and effective option that is mainly affected by lesion size and number and not by age. In particular, it allows to address the >45 years population with functional outcomes that are comparable to younger patients at final follow-up. LEVEL OF EVIDENCE: Prospective cohort study, Level II.

Fat-Derived Stromal Vascular Fraction Cells Enhance the Bone-Forming Capacity of Devitalized Engineered Hypertrophic Cartilage Matrix.

: Engineered and devitalized hypertrophic cartilage (HC) has been proposed as bone substitute material, potentially combining the features of osteoinductivity, resistance to hypoxia, capacity to attract blood vessels, and customization potential for specific indications. However, in comparison with vital tissues, devitalized HC grafts have reduced efficiency of bone formation and longer remodeling times. We tested the hypothesis that freshly harvested stromal vascular fraction (SVF) cells from human adipose tissue-which include mesenchymal, endothelial, and osteoclastic progenitors-enhance devitalized HC remodeling into bone tissue. Human SVF cells isolated from abdominal lipoaspirates were characterized cytofluorimetrically. HC pellets, previously generated by human bone marrow-derived stromal cells and devitalized by freeze/thaw, were embedded in fibrin gel with or without different amounts of SVF cells and implanted either ectopically in nude mice or in 4-mm-diameter calvarial defects in nude rats. In the ectopic model, SVF cells added to devitalized HC directly contributed to endothelial, osteoblastic, and osteoclastic populations. After 12 weeks, the extent of graft vascularization and amount of bone formation increased in a cell-number-dependent fashion (up to, respectively, 2.0-fold and 2.9-fold using 12 million cells per milliliter of gel). Mineralized tissue volume correlated with the number of implanted, SVF-derived endothelial cells (CD31+ CD34+ CD146+). In the calvarial model, SVF activation of HC using 12 million cells per milliliter of gel induced efficient merging among implanted pellets and strongly enhanced (7.3-fold) de novo bone tissue formation within the defects. Our findings outline a bone augmentation strategy based on off-the-shelf devitalized allogeneic HC, intraoperatively activated with autologous SVF cells. SIGNIFICANCE: This study validates an innovative bone substitute material based on allogeneic hypertrophic cartilage that is engineered, devitalized, stored, and clinically used, together with autologous cells, intraoperatively derived from a lipoaspirate. The strategy was tested using human cells in an ectopic model and an orthotopic implantation model, in immunocompromised animals.

Engineering Small-Scale and Scaffold-Based Bone Organs via Endochondral Ossification Using Adult Progenitor Cells.

Bone development, growth, and repair predominantly occur through the process of endochondral ossification, characterized by remodelling of cartilaginous templates. The same route efficiently supports engineering of bone marrow as a niche for hematopoietic stem cells (HSC). Here we describe a combined in vitro/in vivo system based on bone marrow-derived Mesenchymal Stem/Stromal Cells (MSC) that duplicates the hallmark cellular and molecular events of endochondral ossification during development. The model requires MSC culture with instructive molecules to generate hypertrophic cartilage tissues. The resulting constructs complete the endochondral route upon in vivo implantation, in the timeframe of up to 12 weeks. The described protocol is clearly distinct from the direct ossification approach typically used to drive MSC towards osteogenesis. Recapitulation of endochondral ossification allows modelling of stromal-HSC interactions in physiology and pathology and allows engineering processes underlying bone regeneration.

Stem Cells for Bone Regeneration: From Cell-Based Therapies to Decellularised Engineered Extracellular Matrices.

Currently, autologous bone grafting represents the clinical gold standard in orthopaedic surgery. In certain cases, however, alternative techniques are required. The clinical utility of stem and stromal cells has been demonstrated for the repair and regeneration of craniomaxillofacial and long bone defects although clinical adoption of bone tissue engineering protocols has been very limited. Initial tissue engineering studies focused on the bone marrow as a source of cells for bone regeneration, and while a number of promising results continue to emerge, limitations to this technique have prompted the exploration of alternative cell sources, including adipose and muscle tissue. In this review paper we discuss the advantages and disadvantages of cell sources with a focus on adipose tissue and the bone marrow. Additionally, we highlight the relatively recent paradigm of developmental engineering, which promotes the recapitulation of naturally occurring developmental processes to allow the implant to optimally respond to endogenous cues. Finally we examine efforts to apply lessons from studies into different cell sources and developmental approaches to stimulate bone growth by use of decellularised hypertrophic cartilage templates.

Cartilage Repair in the Inflamed Joint: Considerations for Biological Augmentation Toward Tissue Regeneration.

Cartilage repair/regeneration procedures (e.g., microfracture, autologous chondrocyte implantation [ACI]) typically result in a satisfactory outcome in selected patients. However, the vast majority of patients with chronic symptoms and, in general, a more diseased joint, do not benefit from these surgical techniques. The aims of this work were to (1) review factors negatively influencing the joint environment; (2) review current adjuvant therapies that can be used to improve results of cartilage repair/regeneration procedures in patients with more diseased joints, (3) outline future lines of research and promising experimental approaches. Chronicity of symptoms and advancing patient age appear to be the most relevant factors negatively affecting clinical outcome of cartilage repair/regeneration. Preliminary experience with hyaluronic acid, platelet-rich plasma, and mesenchymal stem cell has been positive but there is no strong evidence supporting the use of these products and this requires further assessment with high-quality, prospective clinical trials. The use of a Tissue Therapy strategy, based on more mature engineered tissues, holds promise to tackle limitations of standard ACI procedures. Current research has highlighted the need for more targeted therapies, and (1) induction of tolerance with granulocyte colony-stimulating factor (G-CSF) or by preventing IL-6 downregulation; (2) combined IL-4 and IL-10 local release; and (3) selective activation of the prostaglandin E2 (PGE2) signaling appear to be the most promising innovative strategies. For older patients and for those with chronic symptoms, adjuvant therapies are needed in combination with microfracture and ACI.

Fresh osteochondral allografts in the knee: only a salvage procedure?

The role of fresh allogeneic osteochondral allograft transplantation (OCA) in the cartilage repair algorithm has been long debated and this procedure is primarily considered as a salvage procedure, to be used when other, simple, techniques have failed. Gracitelli et al. in a retrospective comparison of patients who received OCA as primary treatment or as a salvage procedure, demonstrates that the outcome of this procedure is minimally influenced by a previous failed treatment and that OCA represents an effective solution for both primary and revision surgery of chondral and osteochondral lesions of the knee. In particular, optimal indications for OCA seem to be revision of previously failed bone marrow stimulation techniques with an impaired subchondral bone plate and primary treatment of large osteochondral defects.

Generation and characterization of osteochondral grafts with human nasal chondrocytes.

We investigated whether nasal chondrocytes (NC) can be used to generate composite constructs with properties necessary for the repair of osteochondral (OC) lesions, namely maturation, integration and capacity to recover from inflammatory burst. OC grafts were fabricated by combining engineered cartilage tissues (generated by culturing NC or articular chondrocytes - AC - onto Chondro-Gide® matrices) with devitalized spongiosa cylinders (Tutobone®). OC tissues were then exposed to IL-1ß for three days and cultured for additional 2 weeks in the absence of IL-1ß. Cartilage maturation extent was assessed (immune) histologically, biochemically and by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) while cartilage/bone integration was assessed using a peel-off mechanical test. The use of NC as compared to AC allowed for more efficient cartilage matrix accumulation and superior integration of the cartilage/bone layers. dGEMRIC and biochemical analyzes of the OC constructs showed a reduced glycosaminoglycan (GAG) contents upon IL-1ß administration. Cartilaginous matrix contents and integration forces returned to baseline up on withdrawal of IL-1ß. By having a cartilage layer well developed and strongly integrated to the subchondral layer, OC tissues generated with NC may successfully engraft in an inflammatory post-surgery joint environment.

Engineered decellularized matrices to instruct bone regeneration processes.

Despite the significant progress in the field of bone tissue engineering, cell-based products have not yet reached the stage of clinical adoption. This is due to the uncertain advantages from the standard-of-care, combined with challenging cost-and regulatory-related issues. Novel therapeutic approaches could be based on exploitation of the intrinsic regenerative capacity of bone tissue, provided the development of a deeper understanding of its healing mechanisms. While it is well-established that endogenous progenitors can be activated toward bone formation by overdoses of single morphogens, the challenge to stimulate the healing processes by coordinated and controlled stimulation of specific cell populations remains open. Here, we review the recent approaches to generate osteoinductive materials based on the use of decellularized extracellular matrices (ECM) as reservoirs of multiple factors presented at physiological doses and through the appropriate ligands. We then propose the generation of customized engineered and decellularized ECM (i) as a tool to better understand the processes of bone regeneration and (ii) as safe and effective "off-the-shelf" bone grafts for clinical use. This article is part of a Special Issue entitled Stem Cells and Bone.