This review critically examines recent advances in the development and application of HAp–hydrogel composites for cartilage regeneration, highlighting material design principles, fabrication strategies, healing mechanisms, and the key challenges that continue to influence their clinical translation.
Abstract
Articular cartilage defects remain a significant clinical challenge due to the limited intrinsic regenerative capacity of cartilage and the inability of many current therapeutic approaches to restore the structure and function of native hyaline tissue. As a result, considerable research efforts have been directed toward the development of tissue-engineering and biomaterial-based strategies capable of promoting more effective regeneration. Among these, hydroxyapatite–hydrogel (HAp–hydrogel) composites have emerged as particularly promising candidates because they combine the biological functionality of HAp with the structural versatility of hydrogel networks. Hydrogels provide a highly hydrated, extracellular matrix-like environment that supports cell survival, facilitates matrix deposition, and enables the localized delivery of therapeutic agents. At the same time, their physicochemical properties can be tailored through a variety of crosslinking approaches and advanced responsive design strategies. The incorporation of HAp, either in nano- or microscale form, contributes to mechanical reinforcement, supports subchondral bone regeneration, and influences cellular behavior through both biochemical and mechanotransductive mechanisms. Beyond promoting chondrogenic differentiation, HAp–hydrogel composites have also been investigated for their capacity to modulate inflammation, stimulate angiogenesis within the subchondral region, provide antibacterial protection, and maintain a microenvironment conducive to tissue repair. This review critically examines recent advances in the development and application of HAp–hydrogel composites for cartilage regeneration, highlighting material design principles, fabrication strategies, healing mechanisms, and the key challenges that continue to influence their clinical translation.
Due to the extremely limited intrinsic regenerative ability of cartilage, the repair of articular cartilage defects remains a major clinical challenge at present. Here, through the Schiff-base crosslinking between chitosan and gelatin, reinforced with Sr2+, an injectable and rapidly gelling composite hydrogel - loaded coaxial electrospun staple fiber was developed. The embedded fibers bridge adjacent pores to form a layered ECM simulation structure, enhancing structural stability, cell adhesion, and local microenvironment regulation. The hydrogel exhibited rapid gelation and obvious shear thinning behavior within 30 s, realizing minimally invasive injection. The encapsulation of Sr2+ within coaxial fibers effectively suppressed initial burst release and achieved sustained ion release for 30 days, with a cumulative release of approximately 60%. In vitro, the composite hydrogel showed good biocompatibility, promoted the proliferation and migration of bone marrow mesenchymal stem cells, enhanced the early cartilage related matrix deposition, and reduced the expression of pro-inflammatory cytokines in LPS stimulated macrophages. In the rat full-thickness cartilage defect model, the sustained release hydrogel showed improved defect filling and hyaline-like cartilage repair at 8 weeks, accompanied by Safranin O staining and significantly increased COL-II and SOX-9 expression. This work may provide an effective strategy for promoting cartilage repair in vivo through the long-term release of biological factors using functional biomass materials.
Jiyang Zeng, Wei Li, Yuliang Dai et al.· International Journal of Bio...· 0 citations
Articular cartilage possesses a very limited intrinsic capacity for repair due to its avascularity, low cellularity, and poor extracellular matrix turnover, making effective regeneration after injury-induced osteoarthritis particularly challenging. In recent years, hydrogel-based electroactive platforms, particularly self-powered hydrogels, have emerged as promising strategies for cartilage repair by integrating extracellular matrix mimetic hydration, mechanical compliance, and localized bioelectrical stimulation within a unified regenerative system. This review summarizes current advances of self-powered hydrogels for cartilage tissue engineering, with a focus on their material classification, underlying mechanisms, and translational potential. The fundamental concept of self-powered hydrogels is first outlined, and hydrogel-native electroactive systems are distinguished from hydrogel-enabled self-powered platforms. The major mechanistic categories are then discussed, including piezoelectric hydrogels, hydrogel-based triboelectric platforms, mechano-iontronic hydrogels, and other emerging self-powered systems such as thermoelectric, hydrovoltaic, and biofuel cell-based constructs. Particular emphasis is placed on the material basis, structural design, mechanoelectrical transduction pathways, and the current in vitro and in vivo evidence supporting their application in cartilage and osteochondral regeneration. This review also analyzes the major barriers to clinical translation, including insufficient mechanistic decoupling, lack of standardized electrical dose evaluation, signal attenuation in the hydrated joint environment, degradation-performance mismatch, and the limited availability of long-term, larger animal, and clinically relevant validation studies. Overall, self-powered hydrogels represent a rapidly evolving class of bioelectronic biomaterials capable of recapitulating the coupled mechanical, electrical, and ionic microenvironment of native cartilage. Future advances will depend on coordinated progress in material design, quantitative bioelectrical characterization, and translational evaluation.
Tissue regeneration is a central frontier in biomedicine, yet articular cartilage defect repair in osteoarthritis (OA) remains a formidable challenge. Although mesenchymal stem cell (MSC)-based therapies show great potential for cartilage regeneration, their clinical translation is hindered by sequential barriers: low cell retention, oxidative stress-induced apoptosis, and inefficient MSC homing to defect sites and subsequent integration. Herein, we fabricate chondrogenic niche hydrogel microspheres (Chonichspheres) via microfluidics. These HMs are composed of gelatin methacryloyl (GelMA)/aldehyde-hyaluronic acid methacrylate (AHAMA) composite matrices loaded with amino fullerenes (AF) and transforming growth factor-β3 (TGF-β3). Chonichspheres exert four synergistic functions: GelMA acts as a structural scaffold to promote MSC adhesion; AF exert sustained antioxidant effects to regulate redox homeostasis in MSCs and OA chondrocytes; AHAMA enables precise targeted homing and tissue integration; and TGF-β3 induces MSC chondrogenic differentiation. Validated by an HM-adapted custom microphysiological system (MPS) and in vivo experiments, Chonichspheres activate the integrin–PI3K–AKT–mTOR axis, protecting MSCs and facilitating chondrogenic differentiation under OA-mimicking dynamic culture conditions. By synergizing active covalent tissue integration with durable, non-sacrificial antioxidant defense, this programmatic platform provides a robust precision regenerative strategy for OA cartilage repair.
Jinping Chen, pengcheng xiao, Xingkuan Wang et al.· Bioactive Materials· 0 citations
Critical-sized bone defects (CSDs) fail to undergo spontaneous regeneration. Conventional treatment methods, including bone grafts, as well as therapies based on growth factors and cytokines often face serious limitations, including limited availability, immune rejection, high cost, and safety concerns. Although tissue engineering using scaffolds has emerged as a promising alternative, many scaffold-based approaches still rely on the incorporation of exogenous growth factors or cytokines to achieve adequate osteoinductive performance, adding complexity, cost, and potential safety concerns to the treatment. Moreover, invasive implantation techniques and use of toxic crosslinkers during scaffold fabrication present additional challenges. Herein, we report the development of a minimally invasive, injectable, and fully biocompatible hydrogel (CCD@HapSi). The hydrogel, formed via a simple Schiff-base reaction between carboxymethyl chitosan and oxidized dextran, incorporates nanohydroxyapatite and silica nanoparticles to impart osteoinductive, osteoconductive, and antibacterial functionality without the need for external crosslinkers or growth factors. CCD@HapSi exhibited ultrafast gelation, optimal mechanical strength, and controlled degradation, while supporting stem cell adhesion, proliferation, and upregulation of osteogenic genes. In vivo, the hydrogel promoted substantial bone regeneration in a critical sized calvarial defect, significantly outperforming control groups. These findings highlight CCD@HapSi as a safe, cost-effective, and clinically translatable platform for bone regeneration.
Malika Arora, Satish Kumar, Jijo Thomas et al.· International Journal of Bio...· 2 citations
Multifunctional integrated hydrogels have emerged as advanced biomaterials that integrate diverse functional properties, including bioactivity, mechanical adaptability, controlled drug release, and electrical/magnetic responsiveness, exhibiting substantial potential in tissue regeneration and repair. These hydrogels provide a versatile platform to mimic the complex microenvironment of native tissues, thereby facilitating cell proliferation, differentiation, and tissue remodeling. Despite rapid progress in their design and development, optimizing performance for specific tissues (e.g., bone, cartilage, skin, nerve, myocardium) remains challenging. Current research focuses on innovative design strategies and the incorporation of key functional modules to tailor hydrogels for targeted regenerative applications. Moreover, translating these materials from bench to bedside requires overcoming barriers related to biocompatibility, scalability, regulatory approval, and long-term functional stability. This review comprehensively summarizes recent advances in multifunctional integrated hydrogels, highlights their applications across different tissue regeneration scenarios, and critically evaluates translational challenges. By synthesizing cutting-edge findings, this work aims to guide the development of next-generation smart tissue engineering scaffolds and accelerate their clinical adoption, ultimately advancing regenerative medicine.
Ying Liu· Tissue engineering. Part B,...· 0 citations
Hydrogels have emerged as one of the most versatile classes of biomaterials for tissue engineering and regenerative medicine (TERM) due to their striking structural and functional similarities to the native extracellular matrix high water content, tunable physicochemical properties, and excellent biocompatibility. This comprehensive review provides a systematic synthesis of hydrogel-based biomaterials, examining their evolving role in regenerative medicine through a critical analysis of literature published between 2020 and 2026. The fundamental design requirements for regenerative scaffolds, namely biocompatibility, biodegradability, mechanical tunability, and extracellular matrix (ECM) biomimicry, are first established. Subsequently, natural polymers (alginate, chitosan, collagen, gelatin, and hyaluronic acid (HA) and synthetic polymers (polyethylene glycol, PLA, polycaprolactone, PNIPAM) are critically evaluated as hydrogel building blocks, with their advantages, limitations, and representative applications systematically compared. Recent advances in hydrogel fabrication technologies including injectable systems, nanocomposite hydrogels, stimuli-responsive “smart” hydrogels, self-healing formulations, and conductive platforms, are systematically reviewed with specific focus on applications in bone, cartilage, skin, cardiac, neural, and oral tissue engineering. We then examine emerging therapeutic applications beyond traditional scaffolding, including controlled drug/gene delivery, biosensing, and personalized medicine. A critical analysis of translational barriers addresses preclinical model relevance, scalability challenges, sterilization requirements, and evolving regulatory frameworks including the FDA Modernization Act 2.0. Finally, we explore future directions including AI-assisted hydrogel design, patient-specific biofabrication, and “living” hydrogel systems incorporating engineered cells. By identifying evidence-based design principles and persistent knowledge gaps, this review provides a roadmap for accelerating the clinical adoption of next-generation hydrogel-based regenerative therapies.
Jigar Vyas, Nensi Raytthatha, Puja Vyas et al.· Frontiers in Biomaterials Sc...· 0 citations