Articular Cartilage Defects Research Articles

Stem Cells Promote the Regeneration of Knee Joint Degenerative Bone and Articular Cartilage.

Cartilage damage has a certain ability to spontaneously repair, but the repaired tissue often shows the phenomenon of cartilage terminal differentiation, which causes irreversible damage to its structure and function and seriously affects the quality of life and work of patients. It is of great significance to study the problems encountered in the process of cartilage damage repair. This article mainly studied stem cells to promote the regeneration of knee joint degenerative bone articular cartilage. First, the animal articular cartilage defect is modeled, 10 ml of animal venous blood is drawn, 0.5 ml of PRP is collected by centrifugation, mixed with cartilage fragments, and transplanted into the defect area into a gel. In the BMSCs group, 1 ml of BMSCs with a cell concentration of 107 cells/ml was injected intra-articularly. The histological chromosomes were observed after 6 weeks and 12 weeks, and the effect of cartilage tissue repair was analyzed and evaluated, and the related data were statistically analyzed. We evaluated the spontaneous repair ability of partial cartilage damage, full-thickness cartilage damage, and osteochondral damage. Furthermore, for partial cartilage damage repair, by using the cartilage damage in vitro model and biomaterials to simulate the in vivo microenvironment, the adhesion and cell morphology on the surface of partial- and full-thickness cartilage damage were evaluated, and the experiments were further used to evaluate the exogenous and internal induced migration effect of source on cultured cells in vitro. In the cell concentration study, the cartilage repair effect increased with the increase in concentration within a certain range, and the tissue repair ability remained stable when the concentration exceeded 107 cells/ml. Using ECM-oriented scaffolds to compound autologous BMSCs, tissue-engineered cartilage was successfully constructed, which had the histological and biochemical characteristics of normal cartilage tissue, and better repaired the damaged articular cartilage of large animals.

Effect of silk fibroin microcarrier loaded with clematis total saponins and chondrocytes on promoting rabbit knee articular cartilage defects repair

To prepare the silk fibroin microcarrier loaded with clematis total saponins (CTS) (CTS-silk fibroin microcarrier), and to investigate the effect of microcarrier combined with chondrocytes on promoting rabbit knee articular cartilage defects repair. CTS-silk fibroin microcarrier was prepared by high voltage electrostatic combined with freeze drying method using the mixture of 5% silk fibroin solution, 10 mg/mL CTS solution, and glycerin. The samples were characterized by scanning electron microscope and the cumulative release amount of CTS was detected. Meanwhile, unloaded silk fibroin microcarrier was also prepared. Chondrocytes were isolated from knee cartilage of 4-week-old New Zealand rabbits and cultured. The 3rd generation of chondrocytes were co-cultured with the two microcarriers respectively for 7 days in microgravity environment. During this period, the adhesion of chondrocytes to microcarriers was observed by inverted phase contrast microscope and scanning electron microscope, and the proliferation activity of cells was detected by cell counting kit 8 (CCK-8), and compared with normal cells. Thirty 3-month-old New Zealand rabbits were selected to make bilateral knee cartilage defects models and randomly divided into 3 groups ( n=20). Knee cartilage defects in group A were not treated, and in groups B and C were filled with the unloaded silk fibroin microcarrier-chondrocyte complexes and CTS-silk fibroin microcarrier-chondrocyte complexes, respectively. At 12 weeks after operation, the levels of matrix metalloproteinase 9 (MMP-9), MMP-13, and tissue inhibitor of MMP 1 (TIMP-1) in articular fluid were detected by ELISA. The cartilage defects were collected for gross observation and histological observation (HE staining and toluidine blue staining). Western blot was used to detect the expressions of collagen type Ⅱ and proteoglycan. The inflammatory of joint synovium was observed by histological staining and inducible nitric oxide synthase (iNOS) immunohistochemical staining. The CTS-silk fibroin microcarrier was spherical, with a diameter between 300 and 500 μm, a porous surface, and a porosity of 35.63%±3.51%. CTS could be released slowly in microcarrier for a long time. Under microgravity, the chondrocytes attached to the surface of the two microcarriers increased gradually with the extension of culture time, and the proliferation activity of chondrocytes at 24 hours after co-culture was significantly higher than that of normal chondrocytes ( P<0.05). There was no significant difference in proliferation activity of chondrocytes between the two microcarriers ( P>0.05). In vivo experiment in animals showed that the levels of MMP-9 and MMP-13 in group C were significantly lower than those in groups A and B ( P<0.05), and the level of TIMP-1 in group C was significantly higher ( P<0.05). Compared with group A, the cartilage defects in groups B and C were filled with repaired tissue, and the repaired surface of group C was more complete and better combined with the surrounding cartilage. Histological observation and Western blot analysis showed that the International Cartilage Repair Scoring (ICRS) and the relative expression levels of collagen type Ⅱ and proteoglycan in groups B and C were significantly better than those in group A, and group C was significantly better than group B ( P<0.05). The histological observation showed that the infiltration of synovial inflammatory cells and hyperplasia of small vessels significantly reduced in group C compared with groups A and B. iNOS immunohistochemical staining showed that the expression of iNOS in group C was significantly lower than that in groups A and B ( P<0.05). CTS-silk fibroin microcarrier has good CTS sustained release effect and biocompatibility, and can promote the repair of rabbit cartilage defect by carrying chondrocyte proliferation in microgravity environment.

Decellularized Avian Cartilage, a Promising Alternative for Human Cartilage Tissue Regeneration.

Articular cartilage defects, and subsequent degeneration, are prevalent and account for the poor quality of life of most elderly persons; they are also one of the main predisposing factors to osteoarthritis. Articular cartilage is an avascular tissue and, thus, has limited capacity for healing and self-repair. Damage to the articular cartilage by trauma or pathological causes is irreversible. Many approaches to repair cartilage have been attempted with some potential; however, there is no consensus on any ideal therapy. Tissue engineering holds promise as an approach to regenerate damaged cartilage. Since cell adhesion is a critical step in tissue engineering, providing a 3D microenvironment that recapitulates the cartilage tissue is vital to inducing cartilage regeneration. Decellularized materials have emerged as promising scaffolds for tissue engineering, since this procedure produces scaffolds from native tissues that possess structural and chemical natures that are mimetic of the extracellular matrix (ECM) of the native tissue. In this work, we present, for the first time, a study of decellularized scaffolds, produced from avian articular cartilage (extracted from Gallus Gallus domesticus), reseeded with human chondrocytes, and we demonstrate for the first time that human chondrocytes survived, proliferated and interacted with the scaffolds. Morphological studies of the decellularized scaffolds revealed an interconnected, porous architecture, ideal for cell growth. Mechanical characterization showed that the decellularized scaffolds registered stiffness comparable to the native cartilage tissues. Cell growth inhibition and immunocytochemical analyses showed that the decellularized scaffolds are suitable for cartilage regeneration.

Induction of chondrogenesis with a RANKL-binding peptide, WP9QY, in vitro and in vivo in a rabbit model

WP9QY (W9) is a receptor activator of nuclear factor-κB ligand (RANKL)-binding peptide that inhibits osteoclastogenesis by blunting the RANKL-RANK interaction, and also increases osteoblastogenesis via RANKL reverse signaling. W9 has dual effects on osteoclasts and osteoblasts; however, it is unknown whether the peptide has an effect on chondrocytes. Here, we report that W9 induces proliferation and differentiation of chondrocytes in vitro and repairs full-thickness articular cartilage defects in vivo. W9 stimulated chondrocyte differentiation in a two-dimensional (2D) culture of human mesenchymal stem cells (hMSCs), and transforming growth factor β3 (TGF-β3) showed synergistic effects with W9 on chondrogenesis. W9 enlarged the size of 3D pellet cultures of hMSCs and produced chondrocyte-specific matrices, especially in combined treatment with TGF-β3. The peptide also stimulated proliferation of hMSCs with induction of expression of chondrogenesis-related genes. Several RANKL inhibitors had no effect on chondrocytic differentiation. RANKL-knockdown experiments showed that W9 did not induce chondrogenesis through RANKL, but did induce osteoblastogenesis through RANKL. Intraarticular injection of W9 resulted in significant repair of full-thickness articular cartilage defects in rabbits. Taken together, these results suggest that W9 ameliorates the articular cartilage defects by increasing the volume of cartilaginous matrices with accompanying induction of proliferation and differentiation of chondrocytes via mechanisms independent of RANKL inhibition and RANKL reverse signaling. Since no pharmaceuticals are clinically available for treatment of cartilage damage such as osteoarthritis, our findings demonstrate the potential of W9 to address the unmet medical needs.

Biochemical Aspects of Scaffolds for Cartilage Tissue Engineering; from Basic Science to Regenerative Medicine.

Chondral defects are frequent and important causes of pain and disability. Cartilage has limited self-repair and regeneration capacity. The ideal approach for articular cartilage defects is the regeneration of hyaline cartilage with sustainable symptom-free constructs. Tissue engineering provides new strategies for the regeneration of functional cartilage tissue through optimized scaffolds with architectural, mechanical, and biochemical properties similar to the native cartilage tissue. In this review, the basic science of cartilage structure, interactions between proteins, stem cells, as well as biomaterials, scaffold characteristics and fabrication methods, as well as current and potential therapies in regenerative medicine will be discussed mostly from a biochemical point of view. Furthermore, the recent trends in scaffold-based therapies and supplementary factors in cartilage tissue engineering will be considered.

Consequences of Progressive Full-Thickness Focal Chondral Defects Involving the Medial and Lateral Femoral Condyles After Meniscectomy: A Biomechanical Study Using a Goat Model.

Background:Full-thickness chondral defects alter tibiofemoral joint homeostasis and, if left untreated, have the potential to progress to osteoarthritis.Purpose:To assess the effects of isolated and dual full-thickness chondral defect size and location on the biomechanical properties of the lateral femoral condyle (LFC) and medial femoral condyle (MFC) during dynamic knee flexion in goat knees without menisci.Methods:In 12 goat knees, we created progressively increasing full-thickness circular chondral defects (3-, 5-, and 7.5-mm diameter) in the weightbearing contact area of flexion and extension in the MFC, the LFC, or both. Each knee was fixed into a custom steel frame and attached to a motor with sensors inserted intra-articularly. For each testing condition, the knee was loaded to 100 N and underwent a dynamic range of motion between 90° of flexion and 30° of extension. The following parameters were collected: contact area, contact pressure, contact force, peak area, and peak pressure.Study Design:Controlled laboratory study.Results:The peak pressure at the defect rim of the MFC at full extension increased by 51.51% from no defect (1.887 MPa) to a 7.5-mm defect (2.859 MPa) (P < .001), and the peak pressure at the defect rim of the LFC at full extension increased by 139.14% from no defect (1.704 MPa) to a 7.5-mm defect (4.075 MPa) (P < .001). The peak pressures for LFC defects at all 3 diameters were significantly greater when compared with dual defects consisting of increasing LFC defect diameter and constant MFC defect diameter (P < .001 for all).Conclusion:Extremely large increases in peak pressure were seen at the rim of articular cartilage defects when evaluated under dynamic loading conditions. Isolated LFC defects experienced a greater increase in defect rim stress concentrations when compared with isolated MFC defects for equivalent increases in defect size. Defect size played a significant role independent of location for peak pressures on the MFC and LFC.Clinical Relevance:Significant rim-loading effects increase with defect size under dynamic loading and may result in increasingly rapid progression of articular cartilage lesions. Within the context of this goat model, findings suggest that lateral compartment chondral lesions are more likely to progress than medial compartment lesions of equivalent size.

Injectable adipose-derived stem cells-embedded alginate-gelatin microspheres prepared by electrospray for cartilage tissue regeneration.

ObjectiveTo prepare adipose-derived stem cells (ADSCs)-embedded alginate-gelatinemicrospheres (Alg-Gel-ADSCs MSs) by electrospray and evaluate their feasibility for cartilage tissue engineering. To observe the efficacy of Alg-Gel-ADSCs MSs in repairing articular cartilage defects in SD rats.MethodsADSCs were isolated and characterized by performing induced differentiation and flow cytometry assays. Alginate-gelatine microspheres with different gelatine concentrations were manufactured by electrospraying, and the appropriate alginate-gelatine concentration and ratio were determined by evaluating microsphere formation. Alg-Gel-ADSCs MSs were compared with Alg-ADSCs MSs through the induction of chondrogenic differentiation and culture. Their feasibility for cartilage tissue engineering was analysed by performing Live/Dead staining, cell proliferation analysis, toluidine blue staining and a glycosaminoglycan (GAG) content analysis. Alg-Gel-ADSCs MSs were implanted in the cartilage defects of SD rats, and the cartilage repair effect was evaluated at different time points. The evaluation included gross observations and histological evaluations, fluorescence imaging tracking, immunohistochemical staining, microcomputed tomography (micro-CT) and a CatWalk evaluation.ResultsThe isolated ADSCs showed multidirectional differentiation and were used for cartilage tissue engineering. Using 1.5 w:v% alginate and 0.5 w:v% gelatine (Type B), we successfully prepared nearly spherical microspheres. Compared with alginate microspheres, alginate gel increased the viability of ADSCs and promoted the proliferation and chondrogenesis of ADSCs. In our experiments on knee cartilage defects in SD rats in vivo, the Alg-Gel-ADSCs MSs showed superior cartilage repair in cell resides, histology evaluation, micro-CT imaging and gait analysis.ConclusionsMicrospheres composed of 1.5 w:v% alginate-0.5 w:v% gelatine increase the viability of ADSCs and supported their proliferation and deposition of cartilage matrix components. ADSCs embedded in 1.5 w:v% alginate-0.5 w:v% gelatine microspheres show superior repair efficacy and prospective applications in cartilage tissue repair.The translational potential of this articleIn this study, injectable adipose-derived stem cells-embedded alginate-gelatin microspheres (Alg-Gel-ADSCs MSs) were prepared by the electrospray . Compared with the traditional alginate microspheres, its support ability for ADSCs is better and shows a better repair effect. This study provides a promising strategy for cartilage tissue regeneration.

Implication of Mesenchymal Stem Cells and Their Derivates for Osteochondral Regeneration.

Healing of articular cartilage defects presents a challenging issue, due to its regenerative shortcomings. Lacking vascularity and innervation of cartilage and low proliferative potential of chondrocytes are the main reasons for the limited healing potential of articular cartilage. Traditional reparative approaches are limited in their efficiency, hence there is a demand for novel reparative treatments. Mesenchymal stromal cells, preferred for clinical uses, can be readily derived from various sources and have been proven to have a therapeutic effect on cartilage and subchondral bone. Therefore, mesenchymal stromal cells, their derivates, and scaffolds have been utilized in research targeting osteochondral regeneration. The present review aims to comprehensively outline and discuss literature considering this topic published within last 5 years.

High-Density Horizontal Stacking of Chondrocytes via the Synergy of Biocompatible Magnetic Gelatin Nanocarriers and Internal Magnetic Navigation for Enhancing Cartilage Repair.

Osteoarthritis (OA) is a globally occurring articular cartilage degeneration disease that adversely affects both the physical and mental well-being of the patient, including limited mobility. One major pathological characteristic of OA is primarily related to articular cartilage defects resulting from abrasion and catabolic and proinflammatory mediators in OA joints. Although cell therapy has hitherto been regarded as a promising treatment for OA, the therapeutic effects did not meet expectations due to the outflow of implanted cells. Here, we aimed to explore the repair effect of magnetized chondrocytes using magnetic amphiphilic-gelatin nanocarrier (MAGNC) to enhance cellular anchored efficiency and cellular magnetic guidance (MG) toward the superficial zone of damaged cartilage. The results of in vitro experiments showed that magnetized chondrocytes could be rapidly guided along the magnetic force line to form cellular amassment. Furthermore, the Arg-Gly-Asp (RGD) motif of gelatin in MAGNC could integrate the interaction among cells to form cellular stacking. In addition, MAGNCs upregulated the gene expression of collagen II (Col II), aggrecan, and downregulated that of collagen I (Col I) to reduce cell dedifferentiation. In animal models, the magnetized chondrocytes can be guided into the superficial zone with the interaction between the internal magnetic field and MAGNC to form cellular stacking. In vivo results showed that the intensity of N-sulfated-glycosaminoglycans (sGAG) and Col II in the group of magnetized cells with magnetic guiding was higher than that in the other groups. Furthermore, smooth closure of OA cartilage defects was observed in the superficial zone after 8 weeks of implantation. The study revealed the significant potential of MAGNC in promoting the high-density stacking of chondrocytes into the cartilage surface and retaining the biological functions of implanted chondrocytes for OA cartilage repair.

Differences in Clinical and Functional Outcomes Between Osteochondral Allograft Transplantation and Autologous Chondrocyte Implantation for the Treatment of Focal Articular Cartilage Defects.

Background:Articular cartilage pathology can result from a spectrum of origins, including trauma, osteochondritis dissecans, avascular necrosis, or degenerative joint disease.Purpose:To compare the differences in clinical and patient-reported outcomes after autologous chondrocyte implantation (ACI) versus osteochondral allograft transplantation (OCA) in patients with focal articular cartilage defects without underlying bone loss.Study Design:Cohort study; Level of evidence, 3.Methods:A retrospective review identified patients who underwent ACI or OCA between 2008 and 2016 for isolated grades 3 and 4 articular cartilage defects without underlying bone loss. Outcome measures included the Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR), International Knee Documentation Committee (IKDC) evaluation, and 12-Item Short Form Health Survey–Physical Component (SF-12-P) scores. Defect location, size, complications, and rate of subsequent surgery were determined.Results:Overall, 148 patients were included: 82 (55%) underwent ACI and 66 (45%) underwent OCA. The mean age at the time of surgery was 31.2 years within the ACI cohort and 37.7 years within the OCA cohort (P < .001); the mean follow-up for both cohorts was 6.7 years (P = .902). Within the ACI group, 28 (34%) patients had multifocal defects, 21 (26%) had defects confined to the femoral condyles, and 33 (40%) had defects in the patellofemoral region. Within the OCA group, 23 (35%) patients had multifocal defects, 30 (46%) had confined femoral condyle lesions, and 13 (20%) had patellofemoral defects. When comparing by lesion location, there were no significant differences in KOOS JR, and IKDC scores between the ACI and OCA cohorts (P < .05). There was, however, a significant difference for SF-12-P scores for FDD trochlear lesions. In both cohorts, traumatic patellofemoral pathology demonstrated lower patient-reported outcomes and higher failure rates than degenerative lesions. The overall rate of failure, defined as graft failure with revision surgery and/or conversion to arthroplasty, was significantly greater in the OCA group (21% vs 4%; P = .002).Conclusion:Study results indicated that ACI provides similar outcomes to OCA with or without concomitant procedures for the treatment of symptomatic articular cartilage defects in all lesion locations and may have a lower revision rate for multifocal and condylar lesions.

Application of Biological Composite Materials in the Regeneration of Subchondral Defects and Articular Cartilage in a Synovial Joint: An Experimental Model.

Objective: Since the benefits of Nano-material usage have been well documented in orthopedic surgery, this study was conducted to explore the effect of polyvinyl alcohol/nano-hydroxyapatite/polyamide 66 (PVA/n-HA/P66) on repairing of traumatic cartilage defects in rabbit knee joint. Methods: New Zealand white rabbits were used to make a rabbit knee traumatic cartilage defect animal model. All rabbits were randomly located in three groups. Group-A (PVA/n-HA+PA66 implanted in cartilage defects); Group-B (HA nanospheres implanted in cartilage defects)/Gelatin sponge composite scaffold); Group-C (only cartilage defect without implant). The repairment of articular cartilage defects and the general observation were studied by using pathological staining and gene expression of collagen using RT-PCR after 12 weeks. Results: After 12 weeks, we observed a small amount of fibrous tissue growth in group C without soft cell filling. The repaired tissue in group B was stained with immunohistochemical and toluidine blue staining for collagen and type II collagen is positive, but chondrocyte structure is more visible. The relative mRNA expression of type II collagen was higher in group B in comparison to other groups. The results of the Wakitani score were 5.50±2.59 for group A, 8.83±2.79 for group B, 11.50±1.05 for group C. Results showed no significant difference between group B and C; however, significant differences were found in the scoring results between groups A and B, and between-group A and C. Conclusion: This study showed the high effectiveness of PVA/n-HA+PA66 in the treatment of cartilage defects through increasing the expression of type II collagen.

Chondroitin sulfate cross-linked three-dimensional tailored electrospun scaffolds for cartilage regeneration

Degenerated cartilage tissues remain a burgeoning issue to be tackled, while bioactive engineering products available for optimal cartilage regeneration are scarce. In the present study, two-dimensional (2DS) poly(l-lactide-co-ε-caprolactone)/silk fibroin (PLCL/SF)-based scaffolds were fabricated by conjugate electrospinning method, which were then cross-linked with chondroitin sulfate (CS) to further enhance their mechanical and biological performance. Afterwards, three-dimensional (3D) PLCL/SF scaffolds (3DS) and CS-crosslinked 3D scaffolds (3DCSS) with tailored size were successfully fabricated by an in-situ gas foaming in a confined mold followed by freeze-dried. Gas-foamed scaffolds displayed high porosity, rapid water uptake, and stable mechanical properties. While all of the scaffolds exhibited good cytocompatibility in vitro; 3DCSS showed better cell seeding efficiency and chondro-protective effect compared to other scaffolds. Besides, 3DCSS scaffolds supported the formation of more mature cartilage-like tissues along with the best repair outcome in a rabbit articular cartilage defect model in vivo, as well as less expression level of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α than that of the other groups. Taken together, 3DCSS may provide an alternative therapeutic option for cartilage tissue repair.

Cartilage Repair Using Clematis Triterpenoid Saponin Delivery Microcarrier, Cultured in a Microgravity Bioreactor Prior to Application in Rabbit Model.

Cartilage tissue engineering provides a promising method for the repair of articular cartilage defects, requiring appropriate biological scaffolds and necessary growth factors to enhance the efficiency of cartilage regeneration. Here, a silk fibroin (SF) microcarrier and a clematis triterpenoid saponin delivery SF (CTS-SF) microcarrier were prepared by the high-voltage electrostatic differentiation and lyophilization method, and chondrocytes were carried under the simulated microgravity condition by a rotating cell culture system. SF and CTS-SF microspheres were relatively uniform in size and had a porous structure with good swelling and cytocompatibility. Further, CTS-SF microcarriers could sustainably release CTSs in the monitored 10 days. Compared with the monolayer culture, chondrocytes under the microgravity condition maintained a better chondrogenic phenotype and showed better proliferation ability after culture on microcarriers. Moreover, the sustained release of CTS from CTS-SF microcarriers upregulated transforming growth factor-β, Smad2, and Smad3 signals, contributing to promote chondrogenesis. Hence, the biophysical effects of microgravity and bioactivities of CTS-ST were used for chondrocyte expansion and phenotype maintenance in vitro. With prolonged expansion, SF- and CTS-SF-based microcarrier-cell composites were directly implanted in vivo to repair rabbit articular defects. Gross evaluations, histopathological examinations, and biochemical analysis indicated that SF- and CTS-SF-based composites exhibited cartilage-like tissue repair compared with the nontreated group. Further, CTS-SF-based composites displayed superior hyaline cartilage-like repair that integrated with the surrounding cartilage better and higher cartilage extracellular matrix content. In conclusion, these results provide an alternative preparation method for drug-delivered SF microcarrier and a culture method for maintaining the chondrogenic phenotype of seed cells based on the microgravity environment. CTS showed its bioactive function, and the application of CTS-SF microcarriers can help repair and regenerate cartilage defects.

Dendrimer-modified gelatin methacrylate hydrogels carrying adipose-derived stromal/stem cells promote cartilage regeneration

BackgroundCartilage defects pose a significant burden on medical treatment, leading to an urgent need to develop regenerative medicine approaches for cartilage repair, such as stem cell therapy. However, the direct injection of stem cells can result in insufficient delivery or inaccurate differentiation. Hence, it is necessary to choose appropriate stem cell delivery scaffolds with high biocompatibility, injectability and chondral differentiation induction ability for cartilage regeneration.MethodsIn this study, the photocrosslinked gelatin methacrylate (GelMA) hydrogel with high cell affinity and plasticity was selected and strengthened by incorporating methacrylic anhydride-modified poly(amidoamine) (PAMAM-MA) to fabricate an adipose-derived stromal/stem cells (ASCs) delivery scaffold for cartilage repair. The physiochemical properties of the GelMA/PAMAM-MA hydrogel, including the internal structure, stability and mechanical properties, were tested. Then, ASCs were encapsulated into the hydrogels to determine the in vitro and in vivo chondrogenic differentiation induction abilities of the GelMA/PAMAM-MA hydrogel.ResultsCompared with the GelMA hydrogel, the GelMA/PAMAM-MA hydrogel exhibited more uniform structure, stability and mechanical properties. Moreover, on the basis of good biocompatibility, the hybrid hydrogel was proven to exert a sufficient ability to promote cartilage regeneration by in vitro three-dimensional (3D) culture of rASCs and in vivo articular cartilage defect repair.ConclusionsThe injectable photocrosslinked GelMA/PAMAM-MA hydrogel was proven to be a capable stem cell carrier for cartilage repair and provides new insight into the design strategy of stem cell delivery scaffolds.

Long-term cost-effectiveness of matrix-associated chondrocyte implantation in the German health care system: a discrete event simulation

IntroductionCartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR.Materials and methodsWe developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance.ResultsThe majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost‐effectiveness ratio (ICER) of 3376 € /QALY.ConclusionM-ACI is projected to be a highly cost‐effective treatment for chondral defects of the knee in the German healthcare setting.

Generation of hybrid tissue engineered construct through embedding autologous chondrocyte loaded platelet rich plasma/alginate based hydrogel in porous scaffold for cartilage regeneration

Over the past decades, various attempts have been made to develop suitable tissue-engineered constructs to repair or regenerate the damaged or diseased articular cartilage. In the present study, we embedded Platelet rich plasma (PRP)/Sodium Alginate (SA) based hydrogel in porous 3D scaffold of chitosan (CH)/chondroitin sulfate (CS)/silk fibroin (SF) to develop hybrid scaffold for cartilage tissue construct generation with abilities to support shape recovery potential, facilitate uniform cells distribution and mimic gel like cartilage tissue extracellular matrix.The developed hybrid matrix shows suitable pore size (55–261 μm), porosity (77 ± 4.3%) and compressive strength (0.13 ± 0.04 MPa) for cartilage tissue construct generation and its applications. The developed SA/PRP-based cartilage construct exhibits higher metabolic activity, glycosaminoglycan deposition, expression of collagen type II, and aggrecan in comparison to SA based cell-scaffold construct. In-vivo animal study was also performed to investigate the biocompatibility and cartilage tissue regeneration potential of the developed construct. The obtained gross analysis of knee sample, micro-computed tomography, and histological analysis suggest that implanted tissue construct possess the superior potential to regenerate hyaline cartilage defect of thickness around 1.10 ± 0.36 mm and integrate with surrounding tissue at the defect site. Thus, the proposed strategy for the development of cartilage tissue constructs might be beneficial for the repair of full-thickness knee articular cartilage defects.

Premature cellular senescence in isolated chondrocytes from polydactyl cartilage in FBS containing serum in comparison to human serum

Background. Transplantation of chondrocytes is one of the methods for treatment of articular cartilage defects. For this purpose, it is necessary to isolate these chondrocytes and expand in serum containing culture medium. Sera contain growth factors that are added to medium. Fetal bovine serum (FBS) is used for standard cell culture. However bovine proteins of FBS are accompanied with risk of host immune system reactions. Therefore, it is necessary to replace FBS with human serum for clinical cases. In addition, infants have chondrocytes with high proliferation potency versus adults. In this study, the effects of FBS and human placental serum was investigated on morphology and cellular senescence related genes expression of chondrocytes of infants. Methods. Chondrocytes after isolation of from polydactyly cartilage tissue samples, were cultured in 10% FBS and human serum up to passage 5. Human placental serum was obtained from venous blood of embryonic surface of human placenta. Chondrocytes in two culture medium were compared morphologically by inverted microscope. For cellular senescence evaluation, relative expression of IGF1 and P16 genes were assessed by quantitative real-time RT PCR. Results. Proliferation of chondrocytes is markedly decreased in FBS groups in comparison with human serum. In FBS containing medium, phenotypes of cells were changed from spindle shape to flat appearance after five passages. The expression IGF1 and P16 genes are increased in chondrocytes grown in FBS containing medium and it was significant about P16. Morphologic results were in agreement with Real-time RT PCR results. Conclusion. Human placental serum has advantages such as high proliferation rate on human chondrocytes, prevention from cellular senescence and immunological problems in using cultured chondrocytes for cartilage tissue engineering.

Long-Term Recruitment of Endogenous M2 Macrophages by Platelet Lysate-Rich Plasma Macroporous Hydrogel Scaffold for Articular Cartilage Defect Repair.

After cartilage damage, a large number of monocytes/macrophages infiltrate into adjacent synovium and the resident macrophages in synovial tissue transform to activated macrophages (M1), which secrete pro-inflammatory cytokines to induce sustained inflammation and chondrocyte apoptotic. However, current clinical therapies for cartilage repair can rarely achieve long-term anti-inflammatory regulation and satisfactory outcomes. Herein, a platelet lysate-rich plasma macroporous hydrogel (PLPMH) scaffold with around 100µm pore size and 1.25MPa Young's modulus is developed to sustainedly recruit and polarize endogenous anti-inflammatory macrophages (M2) for improving cartilage defect repair. PLPMH scaffold can steadily release sphingosine1-phosphate and proteins via gradual degradation, thus inducing M2 macrophages migration or resting (M0) macrophages migration and then polarization to M2 phenotype, and improving the secretion of anti-inflammatory cytokines. Furthermore, PLPMH scaffold exhibits negligible inflammatory responses in vivo and promotes endogenous M2 macrophage infiltration in large numbers and long-time duration to provide a local anti-inflammatory microenvironment, which even lasts for 42 d. In a rabbit model of cartilage defect, PLPMH scaffold increases the ratio of M2 macrophages and improves cartilage tissue regeneration. These studies support that PLPMH scaffold may have a great potential in articular cartilage tissue engineering by providing an anti-inflammatory and pro-regenerative microenvironment.

Mapping Thematic Trends and Analysing Hotspots Concerning the Use of Stem Cells for Cartilage Regeneration: A Bibliometric Analysis From 2010 to 2020.

Background: Defects of articular cartilage represent a common condition that usually progresses to osteoarthritis with pain and dysfunction of the joint. Current treatment strategies have yielded limited success in these patients. Stem cells are emerging as a promising option for cartilage regeneration. We aim to summarize the developmental history of stem cells for cartilage regeneration and to analyse the relevant trends and hotspots. Methods: We screened all relevant literature on stem cells for cartilage regeneration from Web of Science during 2010–2020 and analysed the research trends in this field by VOSviewer and CiteSpace. We also summarized previous clinical trials. Results: We screened 1,011 publications. China contributed the largest number of publications (317, 31.36%) and citations (81,376, 48.61%). The United States achieved the highest H-index (39). Shanghai Jiao Tong University had the largest number of publications (34) among all full-time institutions. The Journal of Biomaterials and Stem Cell Research and Therapy published the largest number of studies on stem cells for cartilage regeneration (35). SEKIYA I and YANG F published the majority of articles in this field (14), while TOH WS was cited most frequently (740). Regarding clinical research on stem cells for cartilage regeneration, the keyword “double-blind” emerged in recent years, with an average year of 2018.75. In tissue engineering, the keyword “3D printing” appeared latest, with an average year of 2019.625. In biological studies, the key word “extracellular vesicles” appeared latest, with an average year of 2018.9091. The current research trend indicates that basic research is gradually transforming to tissue engineering. Clinical trials have confirmed the safety and feasibility of stem cells for cartilage regeneration. Conclusion: Multiple scientific methods were employed to reveal productivity, collaborations, and research hotspots related to the use of stem cells for cartilage regeneration. 3D printing, extracellular vesicles, and double-blind clinical trials are research hotspots and are likely to be promising in the near future. Further studies are needed for to improve our understanding of this field, and clinical trials with larger sample sizes and longer follow-up periods are needed for clinical transformation.

Introduction of Innovative Tissue Engineering Technologies into Medical Practice to Restore Damaged Joints

We analyzed the results of surgical treatment of 10 patients with II and III degree osteoarthritis of the knee joint, men = 3, women = 7. The average age was 49.3 years (±28). An arthroscopic revision of the knee joint was performed to determine the location, size and depth of cartilage defects. The synovial membrane was taken (30-50 mg), autologous mesenchymal stem cells were isolated and cultured. Next, arthroscopy of the knee joint was performed, where a heparin-conjugated fibrin hydrogel was implanted into the defect area, containing mesenchymal stem cells of the synovial membrane and growth factors transforming growth factor beta-1 (TGF-β1) and bone morphogenetic protein 4 (BMP-4).None of the patients, heparin-conjugated fibrin hydrogel with mesenchymal stem cells and growth factors caused serious undesirable complications after implantation into articular cartilage defects, which may indicate the safety of the hydrogel.Key words: mesenchymal stem cells, synovia, osteoarthrosis, cell therapy, heparin-conjuged fibrin hydrogel.