Articular Cartilage Regeneration Research Articles

Sodium alginate hydrogels co-encapsulated with cell free fat extract-loaded core-shell nanofibers and menstrual blood stem cells derived exosomes for acceleration of articular cartilage regeneration

This study presents a novel scaffold system comprising sodium alginate hydrogels (SAh) co-encapsulated with cell-free fat extract (CEFFE)-loaded core-shell nanofibers (NFs) and menstrual blood stem cell-derived exosomes (EXOs). The scaffold integrates the regenerative potential of EXOs and CFFFE, offering a multifaceted strategy for promoting articular cartilage repair. Coaxially electrospun core-shell NFs exhibited successful encapsulation of CEFFE and seamless integration into the SAh matrix. Structural modifications induced by the incorporation of CEFFE-NFs enhanced hydrogel porosity, mechanical strength, and degradation kinetics, facilitating cell adhesion, proliferation, and tissue ingrowth. The release kinetics of growth factors from the composite scaffold demonstrated sustained and controlled release profiles, essential for optimal tissue regeneration. In vitro studies revealed high cell viability, enhanced chondrocyte proliferation, and migration in the presence of EXOs/CEFFE-NFs@SAh composite scaffolds. Additionally, in vivo experiments demonstrated significant cartilage regeneration, with the composite scaffold outperforming controls in promoting hyaline cartilage formation and defect bridging. Overall, this study underscores the potential of EXOs and CEFFE-NFs integrated into SAh matrices for enhancing chondrocyte viability, proliferation, migration, and ultimately, articular cartilage regeneration. Future research directions may focus on elucidating underlying mechanisms and conducting long-term in vivo studies to validate clinical applicability and scalability.

Key roles of the superficial zone in articular cartilage physiology, pathology, and regeneration.

The superficial zone (SFZ) of articular cartilage is an important interface that isolates deeper zones from the microenvironment of the articular cavity and is directly exposed to various biological and mechanical stimuli. The SFZ is not only a crucial structure for maintaining the normal physiological function of articular cartilage but also the earliest site of osteoarthritis (OA) cartilage degeneration and a major site of cartilage progenitor cells, suggesting that the SFZ might represent a key target for the early diagnosis and treatment of OA. However, to date, SFZ research has not received sufficient attention, accounting for only about 0.58% of cartilage tissue research. The structure, biological composition, function, and related mechanisms of the SFZ in the physiological and pathological processes of articular cartilage remain unclear. This article reviews the key role of the SFZ in articular cartilage physiology and pathology and focuses on the characteristics of SFZ in articular cartilage degeneration and regeneration in OA, aiming to provide researchers with a systematic understanding of the current research status of the SFZ of articular cartilage, hoping that scholars will give more attention to the SFZ of articular cartilage in the future.

Injectable acellular matrix microgel assembly with stem cell recruitment and chondrogenic differentiation functions promotes microfracture-based articular cartilage regeneration

Articular cartilage repair and regeneration is still a significant challenge despite years of research. Although microfracture techniques are commonly used in clinical practice, the newborn cartilage is usually fibrocartilage rather than hyaline cartilage, which is mainly attributed to the inadequate microenvironment for effectively recruiting, anchoring, and inducing bone marrow mesenchymal stem cells (BMSCs) to differentiate into hyaline cartilage. This paper introduces a novel cartilage acellular matrix (CACM) microgel assembly with excellent microporosity, injectability, tissue adhesion, BMSCs recruitment and chondrogenic differentiation capabilities to improve the microfracture-based articular cartilage regeneration. Specifically, the sustained release of simvastatin (SIM) from the SIM@CACM microgel assembly efficiently recruits BMSCs in the early stage of cartilage regeneration, while the abundant interconnected micropores and high specific area assure the quick adhesion, proliferation and infiltration of BMSCs. Additionally, the active factors within the CACM matrix, appropriate mechanical properties of the microgel assembly, and excellent tissue adhesion provide a conductive environment for the continuous chondrogenic differentiation of BMSCs into hyaline cartilage. Owing to the synergistic effect of the above-mentioned factors, good articular cartilage repair and regeneration is achieved.

Robust, self-lubricating and injectable dECM-loaded hydrogels based on rapid photo-crosslinking for articular cartilage regeneration

The restoration of articular cartilage poses a significant clinical challenge due to its avascular nature and the limited presence of chondrocytes. Recently, there has been a growing emphasis on developing materials that emulate the properties of cartilage to facilitate high-quality repair. Here, an injectable dECM-loaded hydrogel (HS-dECM) with potent compressive strength and self-lubricating ability was prepared by photo-crosslinking for cartilage regeneration. The HS-dECM hydrogel was formed by integrating cartilage decellularized extracellular matrix (dECM) with hyaluronic acid methacrylate (HAMA) and sulfobetaine methacrylate (SBMA). Once injected into irregular defects, a robust hydrogel was rapidly formed in situ by UV irradiation with negligible heat release. The HS-dECM hydrogel exhibited robust compressive strength (898 ± 86 kPa), excellent fatigue resistance and a low friction coefficient, and had the feasibility of minimally invasive implantation. Besides, HS-dECM hydrogel promoted chondrogenic differentiation of BMSCs in vitro and repaired articular cartilage defects in rats. Therefore, the high-performance injectable HS-dECM hydrogel represents a novel minimally invasive strategy that significantly promote the cartilage injuries repair and regeneration.

Mechanical properties and biocompatibility characterization of 3D printed collagen type II/silk fibroin/hyaluronic acid scaffold

Damage to articular cartilage is irreversible and its ability to heal is minimal. The development of articular cartilage in tissue engineering requires suitable biomaterials as scaffolds that provide a 3D natural microenvironment for the development and growth of articular cartilage. This study aims to investigate the applicability of a 3D printed CSH (collagen type II/silk fibroin/hyaluronic acid) scaffold for constructing cartilage tissue engineering. The results showed that the composite scaffold had a three-dimensional porous network structure with uniform pore sizes and good connectivity. The hydrophilicity of the composite scaffold was 1071.7 ± 131.6%, the porosity was 85.12 ± 1.6%, and the compressive elastic modulus was 36.54 ± 2.28 kPa. The creep and stress relaxation constitutive models were also established, which could well describe the visco-elastic mechanical behavior of the scaffold. The biocompatibility experiments showed that the CSH scaffold was very suitable for the adhesion and proliferation of chondrocytes. Under dynamic compressive loading conditions, it was able to promote cell adhesion and proliferation on the scaffold surface. The 3D printed CSH scaffold is expected to be ideal for promoting articular cartilage regeneration.

Three-Dimensional Printed Silk Fibroin/Hyaluronic Acid Scaffold with Functionalized Modification Results in Excellent Mechanical Strength and Efficient Endogenous Cell Recruitment for Articular Cartilage Regeneration.

Treatment of articular cartilage remains a great challenge due to its limited self-repair capability. In tissue engineering, a scaffold with both mechanical strength and regenerative capacity has been highly desired. This study developed a double-network scaffold based on natural biomaterials of silk fibroin (SF) and methacrylated hyaluronic acid (MAHA) using three-dimensional (3D) printing technology. Structural and mechanical characteristics of the scaffold was first investigated. To enhance its ability of recruiting endogenous bone marrow mesenchymal stem cells (BMSCs), the scaffold was conjugated with a proven BMSC-specific-affinity peptide E7, and its biocompatibility and capacity of cell recruitment were assessed in vitro. Animal experiments were conducted to evaluate cartilage regeneration after transplantation of the described scaffolds. The SF/HA scaffolds exhibited a hierarchical macro-microporous structure with ideal mechanical properties, and offered a 3D spatial microenvironment for cell migration and proliferation. In vitro experiments demonstrated excellent biocompatibility of the scaffolds to support BMSCs proliferation, differentiation, and extracellular matrix production. In vivo, superior capacity of cartilage regeneration was displayed by the SF/MAHA + E7 scaffold as compared with microfracture and unconjugated SF/MAHA scaffold based on macroscopic, histologic and imaging evaluation. In conclusion, this structurally and functionally optimized SF/MAHA + E7 scaffold may provide a promising approach to repair articular cartilage lesions in situ.

Biomimetic microgels for articular cartilage regeneration. A minipig knee model

The aim of this study is to explore, with an in vivo model, the regeneration of articular cartilage that can be obtained with a strategy that combines the stimulation of the subchondral bone with the implantation of a biomimetic microgel at the site of the cartilage defect. The microgel consists of an agglomerate of two types of microspheres: ones rigid, made of a biodegradable polyester, and the other ones composed of a polymeric network of gelatin and hyaluronic acid that encapsulate platelet-rich plasma (PRP) obtained from circulating autologous blood. A defect of 7 mm in diameter and full depth was performed in the in the articular cartilage at the trochlea of the animal knee, using a minipig model. Microdrilling was performed in the underlying bone and the defect was filled with the microgel in which the platelets it contains were previously activated with calcium chloride. The whole defect containing the microgel was covered with a synthetic membrane to avoid the release of microspheres. The results of the in vivo follow-up of the experiment, the histological analysis and the mechanical measurements of the regenerated tissue 9 months after implantation were compared with those of a group of animals in which only microdrilling was performed and the defect was covered with the membrane and with another group in which a clinical use commercial collagen mesh was implanted. The mean value of the elastic modulus of the newly formed tissue was not significantly different from that of the native tissue in the case of microgel implantation while its content of GAGs, was significantly better than in the other groups.

Osteochondral regeneration with a tri-layered biomimetic resorbable scaffold: In vivo study in a sheep model up to 12 months of follow-up

The treatment of osteochondral joint lesions requires the regeneration of both articular cartilage and subchondral bone tissue. Scaffold-based strategies aimed at mimicking the native osteochondral structure have been explored with mixed results. The aim of this study was to evaluate the regenerative potential of a tri-layered osteochondral cell-free scaffold in a large animal model at both 6 and 12 months of follow-up. Bilateral critical-sized osteochondral defects were created in 22 sheep. One defect was filled with the scaffold, whereas the contralateral was left empty. The repair tissue quality was evaluated at 6 and 12 months of follow-up in terms of macroscopic appearance, histology, trabecular bone formation, and inflammation grade. The mean global ICRS II score in the scaffold and control groups was 41 ± 11 vs 30 ± 6 at 6 months (p = 0.004) and 54 ± 13 vs 37 ± 11 at 12 months (p = 0.002), respectively. A higher percentage of bone was found in the treatment group compared to controls both at 6 (BV/TV 48.8 ± 8.6 % vs 37.4 ± 9.5 %, respectively; p < 0.001) and 12 months (BV/TV 51.8 ± 8.8 % vs 42.1 ± 12.6 %, respectively; p = 0.023). No significant levels of inflammation were seen. These results demonstrated the scaffold safety and potential to regenerate both cartilage and subchondral tissues in a large animal model of knee osteochondral lesions.

Multi-crosslinked hydrogels composed of hyaluronic acid, silk fibroin and chitosan nanoparticles with capacity of bioactive molecule delivery and degradation tolerance for cartilage tissue engineering

Polymer hydrogels intended for cartilage repair applications need to be mechanically competent and degradation-endurable. Combining these essential properties jointly into the natural polymer hydrogels is an ongoing challenge. Here, a new type of multi-crosslinked composite hydrogel with enhanced mechanical and degradation-resistant properties has been developed using thiolated hyaluronic acid (THA), silk fibroin (SF), and thiolated chitosan (TCH) nanoparticles (NPs). In addition, kartogenin is loaded into TCH NPs, and meanwhile, platelet-derived growth factor-BB is incorporated into the gel matrix in combination with fucoidan for bestowing collaborative biofunctions upon the composite hydrogels. The optimally achieved THA/SF/TCH hydrogels exhibit strong, elastic, and tough characteristics and enhanced degradation tolerance. The THA/SF/TCH hydrogels also show a confirmative ability to stimulate the migration of bone marrow mesenchymal stem cells and induce their chondrogenic differentiation. These results suggest that these composite gels have promising potential as an injective material for endogenous articular cartilage repair and regeneration.

A novel mesenchymal stem cell-targeting dual-miRNA delivery system based on aptamer-functionalized tetrahedral framework nucleic acids: Application to endogenous regeneration of articular cartilage

Articular cartilage injury (ACI) remains one of the key challenges in regenerative medicine, as current treatment strategies do not result in ideal regeneration of hyaline-like cartilage. Enhancing endogenous repair via microRNAs (miRNAs) shows promise as a regenerative therapy. miRNA-140 and miRNA-455 are two key and promising candidates for regulating the chondrogenic differentiation of mesenchymal stem cells (MSCs). In this study, we innovatively synthesized a multifunctional tetrahedral framework in which a nucleic acid (tFNA)-based targeting miRNA codelivery system, named A-T-M, was used. With tFNAs as vehicles, miR-140 and miR-455 were connected to and modified on tFNAs, while Apt19S (a DNA aptamer targeting MSCs) was directly integrated into the nanocomplex. The relevant results showed that A-T-M efficiently delivered miR-140 and miR-455 into MSCs and subsequently regulated MSC chondrogenic differentiation through corresponding mechanisms. Interestingly, a synergistic effect between miR-140 and miR-455 was revealed. Furthermore, A-T-M successfully enhanced the endogenous repair capacity of articular cartilage in vivo and effectively inhibited hypertrophic chondrocyte formation. A-T-M provides a new perspective and strategy for the regeneration of articular cartilage, showing strong clinical application value in the future treatment of ACI.

Cell Proliferation, Chondrogenic Differentiation, and Cartilaginous Tissue Formation in Recombinant Silk Fibroin with Basic Fibroblast Growth Factor Binding Peptide.

Regeneration of articular cartilage remains a challenge for patients who have undergone cartilage injury, osteochondritis dissecans and osteoarthritis. Here, we describe a new recombinant silk fibroin with basic fibroblast growth factor (bFGF) binding peptide, which has a genetically introduced sequence PLLQATLGGGS, named P7. In this study, we cultured a human mesenchymal cell line derived from bone marrow, UE6E7-16, in wild-type fibroin sponge (FS) and recombinant silk fibroin sponge with P7 peptide (P7 FS). We compared cell proliferation, chondrogenic differentiation and cartilaginous tissue formation between the two types of sponge. After stimulation with bFGF at 3 ng/mL, P7 FS showed significantly higher cell growth (1.2-fold) and higher cellular DNA content (5.6-fold) than did wild-type FS. To promote chondrogenic differentiation, cells were cultured in the presence of TGF-β at 10 ng/mL for 28 days. Immunostaining of P7 FS showed SOX9-positive cells comparable to wild-type FS. Alcian-Blue staining of P7 FS also showed cartilaginous tissue formation equivalent to wild-type FS. A significant increase in cell proliferation in P7 FS implies future clinical application of this transgenic fibroin for regeneration of articular cartilage. To produce cartilaginous tissue efficiently, transgenic fibroin sponges and culture conditions must be improved. Such changes should include the selection of growth factors involved in chondrogenic differentiation and cartilage formation.

A bioactive composite scaffold enhances osteochondral repair by using thermosensitive chitosan hydrogel and endothelial lineage cell-derived chondrogenic cell

Articular cartilage regeneration is a major challenge in orthopedic medicine. Endothelial progenitor cells (EPCs) are a promising cell source for regenerative medicine applications. However, their roles and functions in cartilage regeneration are not well understood. Additionally, thermosensitive chitosan hydrogels have been widely used in tissue engineering, but further development of these hydrogels incorporating vascular lineage cells for cartilage repair is insufficient. Thus, this study aimed to characterize the ability of EPCs to undergo endothelial–mesenchymal stem cell transdifferentiation and chondrogenic differentiation and investigate the ability of chondrogenic EPC-seeded thermosensitive chitosan-graft-poly (N-isopropylacrylamide) (CEPC-CSPN) scaffolds to improve healing in a rabbit osteochondral defect (OCD) model. EPCs were isolated and endothelial-to-mesenchymal transition (EndMT) was induced by transforming growth factor-β1 (TGF-β1); these EPCs are subsequently termed transdifferentiated EPCs (tEPCs). The stem cell-like properties and chondrogenic potential of tEPCs were evaluated by a series of in vitro assays. Furthermore, the effect of CEPC-CSPN scaffolds on OCD repair was evaluated. Our in vitro results confirmed that treatment of EPC with TGF-β1 induced EndMT and the acquisition of stem cell-like properties, producing tEPCs. Upon inducing chondrogenic differentiation of tEPCs (CEPCs), the cells exhibited significantly enhanced chondrogenesis and chondrocyte surface markers after 25 days. The TGF-β1-induced differentiation of EPCs is mediated by both the TGF-β/Smad and extracellular signal-regulated kinase (Erk) pathways. The CEPC-CSPN scaffold reconstructed well-integrated translucent cartilage and repaired subchondral bone in vivo, exhibiting regenerative capacity. Collectively, our results suggest that the CEPC-CSPN scaffold induces OCD repair, representing a promising approach to articular cartilage regeneration.

Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms.

Increasing attention has been paid to the development of effective strategies for articular cartilage (AC) and osteochondral (OC) regeneration due to their limited self-reparative capacities and the shortage of timely and appropriate clinical treatments. Traditional cell-dependent tissue engineering faces various challenges such as restricted cell sources, phenotypic alterations, and immune rejection. In contrast, endogenous tissue engineering represents a promising alternative, leveraging acellular biomaterials to guide endogenous cells to the injury site and stimulate their intrinsic regenerative potential. This review provides a comprehensive overview of recent advancements in endogenous tissue engineering strategies for AC and OC regeneration, with a focus on the tissue engineering triad comprising endogenous stem/progenitor cells (ESPCs), scaffolds, and biomolecules. Multiple types of ESPCs present within the AC and OC microenvironment, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AD-MSCs), synovial membrane-derived mesenchymal stem cells (SM-MSCs), and AC-derived stem/progenitor cells (CSPCs), exhibit the ability to migrate toward injury sites and demonstrate pro-regenerative properties. The fabrication and characteristics of scaffolds in various formats including hydrogels, porous sponges, electrospun fibers, particles, films, multilayer scaffolds, bioceramics, and bioglass, highlighting their suitability for AC and OC repair, are systemically summarized. Furthermore, the review emphasizes the pivotal role of biomolecules in facilitating ESPCs migration, adhesion, chondrogenesis, osteogenesis, as well as regulating inflammation, aging, and hypertrophy-critical processes for endogenous AC and OC regeneration. Insights into the applications of endogenous tissue engineering strategies for in vivo AC and OC regeneration are provided along with a discussion on future perspectives to enhance regenerative outcomes.

Comparative Efficacy of Endogenous Stem Cells Recruiting Hydrogels and Stem Cell-loaded Hydrogels in Knee Cartilage Regeneration: A Meta- analysis.

Cartilage defects remain a challenge in diseases such as osteoarthritis (OA) and fractures. Scientists have explored the use of hydrogels in conjunction with stem cell technology as a tissue engineering method to treat cartilage defects in joints. In recent years, research into hydrogels containing stem cell technology for cartilage repair has mainly focused on two categories: stem cell-loaded hydrogels and endogenous stem cell recruiting hydrogels. The latter, utilizing cell-free products, represents a novel concept with several advantages, including easier dose standardization, wider sources, and simpler storage. This meta-analysis aims to assess and compare the therapeutic effects of endogenous stem cell recruiting hydrogels and stem cell-loaded hydrogels in promoting articular cartilage regeneration in animal models, with the goal of exploring endogenous stem cell recruiting hydrogels as a promising replacement therapy for knee cartilage regeneration in preclinical animal studies. We systematically searched PubMed, Web of Science, Cochrane Library, and Embase until January 2023 using key words related to stem cells, cartilage regeneration and hydrogel. A random-effects meta-analysis was performed to evaluate the therapeutic effect on newborn cartilage formation. Stratified analyses were also carried out by independently classifying trials according to similar characteristics. The level of evidence was determined using the GRADE method. Twenty-eight studies satisfied the inclusion criteria. Comprehensive analyses revealed that the use of endogenous stem cell recruiting hydrogels significantly promoted the formation of new cartilage in the knee joint, as evidenced by the histological score (3.77, 95% CI 2.40, 5.15; p < 0.0001) and the International Cartilage Repair Society (ICRS) macroscopic score (3.00, 95% CI 1.83, 4.18; p = 0.04), compared with the control group. The stem cell-loaded hydrogels also increased cartilage regeneration in the knee with the histological score (3.13, 95% CI 2.22, 4.04; p = 0.02) and the ICRS macroscopic score (2.49, 95% CI 1.16, 3.82; p = 0.03) in comparison to the control. Significant heterogeneity between studies was observed, and further stratified and sensitivity analyses identified the transplant site and modelling method as the sources of heterogeneity. The current study indicates that both endogenous stem cell recruiting hydrogels and stem cell loaded hydrogels can effectively promote knee joint cartilage regeneration in animal trials.

Evaluation of Articular Cartilage Regeneration Properties of Decellularized Cartilage Powder/Modified Hyaluronic Acid Hydrogel Scaffolds.

The articular cartilage has poor intrinsic healing potential, hence, imposing a great challenge for articular cartilage regeneration in osteoarthritis. Tissue regeneration by scaffolds and bioactive materials has provided a healing potential for degenerated cartilage. In this study, decellularized cartilage powder (DCP) and hyaluronic acid hydrogel modified by aldehyde groups and methacrylate (AHAMA) were fabricated and evaluated in vitro for efficacy in articular cartilage regeneration. In vitro tests such as cell proliferation, cell viability, and cell migration showed that DCP/AHAMA has negligible cytotoxic effects. Furthermore, it could provide an enhanced microenvironment for infrapatellar fat pad stem cells (IFPSCs). Mechanical property tests of DCP/AHAMA showed suitable adhesive and compressive strength. IFPSCs under three-dimensional (3D) culture in DCP/AMAHA were used to assess their ability to proliferate and differentiate into chondrocytes using normal and chondroinductive media. Results exhibited increased gene expression of COL2 and ACN and decreased COL1 expression. DCP/AHAMA provides a microenvironment that recapitulates the biomechanical properties of the native cartilage, promotes chondrogenic differentiation, blocks hypertrophy, and demonstrates applicability for cartilage tissue engineering and the potential for clinical biomedical applications.

Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration

Despite numerous studies on chondrogenesis, the repair of cartilage—particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited. In this study, we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals, enabling sequential immunomodulation and endogenous articular cartilage regeneration. We first integrated the chondrogenic growth factor transforming growth factor-β3 (TGF-β3) into mesoporous silica nanoparticles (MSNs). Then, TGF-β3@MSNs and insulin-like growth factor 1 (IGF-1) were encapsulated within microspheres made of polydopamine (pDA). In the final step, growth factor-loaded MSN@pDA and a chitosan (CS) hydrogel containing platelet-derived growth factor-BB (PDGF-BB) were blended to produce growth factors loaded composite microspheres (GFs@μS) using microfluidic technology. The presence of pDA reduced the initial acute inflammatory response, and the early, robust release of PDGF-BB aided in attracting endogenous stem cells. Over the subsequent weeks, the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation. μS were incorporated into an acellular cartilage extracellular matrix (ACECM) and combined with a polydopamine-modified polycaprolactone (PCL) structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix, resulting in enhanced cartilage repair and patellar cartilage protection. This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling, leading to efficient articular cartilage regeneration.

Enhancement of hyaline cartilage and subchondral bone regeneration in a rat osteochondral defect model through focused extracorporeal shockwave therapy.

To explore the efficacy of extracorporeal shockwave therapy (ESWT) in the treatment of osteochondral defect (OCD), and its effects on the levels of transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, -3, -4, -5, and -7 in terms of cartilage and bone regeneration. The OCD lesion was created on the trochlear groove of left articular cartilage of femur per rat (40 rats in total). The experimental groups were Sham, OCD, and ESWT (0.25 mJ/mm2, 800 impulses, 4 Hz). The animals were euthanized at 2, 4, 8, and 12 weeks post-treatment, and histopathological analysis, micro-CT scanning, and immunohistochemical staining were performed for the specimens. In the histopathological analysis, the macro-morphological grading scale showed a significant increase, while the histological score and cartilage repair scale of ESWT exhibited a significant decrease compared to OCD at the 8- and 12-week timepoints. At the 12-week follow-up, ESWT exhibited a significant improvement in the volume of damaged bone compared to OCD. Furthermore, immunohistochemistry analysis revealed a significant decrease in type I collagen and a significant increase in type II collagen within the newly formed hyaline cartilage following ESWT, compared to OCD. Finally, SRY-box transcription factor 9 (SOX9), aggrecan, and TGF-β, BMP-2, -3, -4, -5, and -7 were significantly higher in ESWT than in OCD at 12 weeks. ESWT promoted the effect of TGF-β/BMPs, thereby modulating the production of extracellular matrix proteins and transcription factor involved in the regeneration of articular cartilage and subchondral bone in an OCD rat model.

Chondral regeneration in femoroacetabular lesions is favoured using peripheral blood stem cells with hyaluronan-based scaffold and micro-drilling: A prospective cohort study.

To determine whether intra-articular injections of peripheral blood stem cells (PBSC) with hyaluronan (HA)-based scaffold improve articular cartilage regeneration in chondral injuries caused by mixed-femoroacetabular impingement syndrome (FAIS) over a period longer than 24 months post-hip arthroscopy. In this prospective cohort study, patients with mixed-FAIS and chondral injury ≥ IIIB according to the International Cartilage Regeneration and Joint Preservation Society grade or III/IV of Konan/Haddad classification underwent intra-articular injection of PBSC with an HA-based scaffold and micro-drillings during hip arthroscopy. The degree of chondral repair was measured at baseline and 5 years using the International Cartilage Repair Society morphologic score system (MSS) as the primary outcome. Pain was measured at baseline and 5 years using the Visual Analogue Scale for Pain (VAS Pain), and hip functionality was measured at baseline (presurgery), 6 months, 1 year, and 5 years using the Hip Outcome Score (HOS). The largest diameter of injury, median follow-up, side effects, complications, and improvements were described. T-test, ANOVA with multiple comparisons, and statistical power were estimated. From initially 34 cases, 25 patients were enrolled. The median follow-up was 5.1 ± 0.3 years. One patient (4%) reported a few side effects with filgrastim administration. No infection, tumours, or synovitis was reported. The largest diameters in zones two, three, and four were 12.4 ± 3.1 mm (n = 8), 13.5 ± 2.8 mm (n = 14), and 11.4 ± 1.9 mm (n = 3), respectively. Ninety-two percent (23/25) of patients improved their outcomes. The MSS and HOS increased from 3.8 ± 1.1 to 9.6 ± 1.5 pts (p < 0.001) and from 65.5 ± 13.0 to 93.9 ± 2.4 pts (p < 0.001), respectively. The VAS-Pain decreased from 5.3 ± 0.7 to 1.3 ± 0.6 mm (p < 0.001). The obtained a posteriori power-size was 0.99. The intervention suggests a favourable impact on articular cartilage regeneration and clinical outcomes for hip chondral lesions in mixed-FAIS injuries after a median follow-up of 5.1 ± 0.3 years. Level IV.

Injectable porous microspheres for articular cartilage regeneration through in situ stem cell recruitment and macrophage polarization

In situ mesenchymal stem cells (MSCs) regenerative therapy holds promising potential for treating osteoarthritis. However, MSCs engraftment and intra-articular inflammation limit the therapeutic efficacy of this approach. This study introduces porous microspheres (PMs) composed of aldehyde-modified poly(lactic-co-glycolic acid), that encapsulate platelet derived growth factor-AB and kartogenin. Metformin (Met) is also incorporated onto the microsphere through a Schiff base reaction to create PMs@Met. In vitro, in vivo and ex experiments revealed that PMs@Met can be injected into the joint cavity, effectively recruiting endogenous MSCs in situ. This approach creates a favorable environment for MSCs proliferation. It also controls the intra-articular inflammatory environment by modulating the polarization of synovial macrophages, ultimately promoting cartilage repair. In summary, our study presents an innovative tissue engineering strategy for the treatment of osteoarthritis-induced articular cartilage injuries. Statement of significanceCell therapy using autologous mesenchymal stem cells (MSCs) has potential to slow the progression of osteoarthritis (OA). Nonetheless, there are some disadvantages to adopting in situ MSCs therapy, including difficulties with MSC engraftment into cartilage-deficient regions, the effect of intra-articular inflammation on MSC therapeutic efficacy, and attaining selective chondrogenic MSC differentiation. We created injectable PLGA microspheres (PMs) that were loaded with PDGF-AB and KGN. Metformin was bonded to the surface of microspheres using a Schiff base reaction. The microspheres can recruit intra-articular MSCs and encourage their development into chondrocytes. The microspheres actively modulate the inflammatory joint environment by altering synovial macrophage polarization, thereby supporting MSCs in effective cartilage treatment. To summarize, microspheres hold great potential in the treatment of OA.

Hydrogel-Based 3D Bioprinting Technology for Articular Cartilage Regenerative Engineering.

Articular cartilage is an avascular tissue with very limited capacity of self-regeneration. Trauma or injury-related defects, inflammation, or aging in articular cartilage can induce progressive degenerative joint diseases such as osteoarthritis. There are significant clinical demands for the development of effective therapeutic approaches to promote articular cartilage repair or regeneration. The current treatment modalities used for the repair of cartilage lesions mainly include cell-based therapy, small molecules, surgical approaches, and tissue engineering. However, these approaches remain unsatisfactory. With the advent of three-dimensional (3D) bioprinting technology, tissue engineering provides an opportunity to repair articular cartilage defects or degeneration through the construction of organized, living structures composed of biomaterials, chondrogenic cells, and bioactive factors. The bioprinted cartilage-like structures can mimic native articular cartilage, as opposed to traditional approaches, by allowing excellent control of chondrogenic cell distribution and the modulation of biomechanical and biochemical properties with high precision. This review focuses on various hydrogels, including natural and synthetic hydrogels, and their current developments as bioinks in 3D bioprinting for cartilage tissue engineering. In addition, the challenges and prospects of these hydrogels in cartilage tissue engineering applications are also discussed.