Search Results (550)

Articular cartilage defects affect millions of patients annually and pose one of the most persistent challenges in orthopedic surgery, owing to the tissue’s inherent avascular and alymphatic nature. Current surgical approaches, microfracture, autologous chondrocyte implantation (ACI/MACI), and osteochondral grafting, share a common failure mode: inadequate adhesion between repair constructs and surrounding native cartilage, contributing to deterioration rates of 15–75% at five-year follow-up across all techniques. This review repositions adhesion not as a supplementary material property but as the central determinant of clinical success in cartilage repair. We systematically evaluate the biomechanical demands imposed by the joint environment and define clinically relevant adhesion thresholds. Adhesive hydrogel strategies are categorized by surgical context: microfracture augmentation, ACI/MACI enhancement, osteochondral graft integration, and standalone repair platforms. Material platforms are analyzed across catechol/dopamine systems, NHS ester chemistry, photocrosslinkable hydrogels, supramolecular approaches, and multi-mechanism hybrids. Injectable formulations for arthroscopic delivery are critically examined alongside key translational barriers, including fatigue durability, biocompatibility–adhesion trade-offs, sterilization compatibility, batch variability, and regulatory classification ambiguity. Future directions encompass 4D bioprinting, AI-guided formulation optimization, and stimuli-responsive reversible adhesion systems. Adhesive hydrogels represent the missing link that current cartilage repair paradigms require. Full article

Osteochondral defects of the knee represent a significant clinical challenge due to the limited regenerative capacity of the osteochondral unit. The aim of this study was to evaluate the therapeutic potential of calcium phosphate-based biomaterials combined with honey in a porcine model. Osteochondral defects were surgically induced and treated with a custom-prepared composite material. Tissue regeneration was assessed using integrated macroscopic and microscopic evaluation, supported by multimodal imaging techniques. The outcomes were compared with both a spontaneous healing group and a control site with native cartilage. The composite biomaterial significantly enhanced osteochondral regeneration, with results comparable to healthy cartilage. Notably, improved structural organization and more advanced healing responses were observed in the treated group compared to spontaneous healing. The beneficial effects are attributed to the anti-inflammatory, antimicrobial, antioxidant, and immunomodulatory properties of honey, which may enhance the regenerative microenvironment and support tissue repair. These findings highlight the potential of calcium phosphate-based biomaterials combined with honey as a promising strategy for osteochondral defect treatment, improving structural, biological, and biomechanical aspects of healing. Full article

Articular cartilage is characterized by its avascular, aneural, and alymphatic nature, which confers a limited intrinsic capacity for self-repair. Current regenerative strategies primarily focus on alleviating pain, mitigating symptoms, and restoring joint function. However, their long-term efficacy remains uncertain. Cartilage tissue engineering has emerged as a promising alternative to conventional therapies, offering innovative solutions for articular cartilage regeneration. Central to this approach is the development of functional biomaterials capable of supporting chondrogenic cell adhesion, proliferation, and differentiation, thereby facilitating effective cartilage repair. In this study, we introduce a novel protein-based recombinant spider silk (RSS) as a potential biomaterial for modulating chondrocyte behavior and enabling engineered cartilage formation both in vitro and in vivo. RSS was generated through molecular cloning and processed into silk fibers using biomimetic spinning and acidic coagulation techniques. In micromass cultures of murine chondrocytes, RSS significantly promoted cell aggregation, resulting in increased cell density. Alcian blue and Oil Red O staining demonstrated that RSS-treated cultures produced abundant glycosaminoglycans, a hallmark of chondrogenic activity, while exhibiting minimal lipid accumulation. These findings suggest that RSS supports chondrogenic differentiation and suppresses adipogenic lineage commitment. Real-time PCR analysis revealed upregulation of the chondrogenesis-related gene Sox9 and downregulation of the adipogenic marker PPARγ and the hypertrophic marker Runx2 in RSS-treated micromass cultures. RNA sequencing further corroborated these observations, underscoring the role of RSS in modulating extracellular matrix (ECM) remodeling in chondrocytes. In a subcutaneous transplantation model using severe combined immunodeficiency (SCID) mice, chondrocytes encapsulated in three-dimensional hydrogel scaffolds containing RSS exhibited significantly enhanced ECM accumulation compared to RSS-free controls, indicating that RSS supports the maintenance of the chondrocyte phenotype and promotes cartilage formation in vivo, and underscoring its promising potential as a component of hydrogel composite systems. These findings highlight the potential of RSS as a functional biomaterial to preserve chondrocyte functionality and advance engineered cartilage formation, presenting a promising avenue for cartilage tissue engineering and regeneration. Full article

Hyaluronic acid (HA), a native non-sulfated glycosaminoglycan of the extracellular matrix, has emerged as a central biomaterial in tissue engineering due to its biocompatibility, hydration capacity, and receptor-mediated bioactivity. Beyond its structural role, HA actively regulates cellular behaviors through interactions with receptors such as CD44 and RHAMM, with outcomes highly dependent on molecular weight, degradation state, and matrix context. Recent advances in chemical modification and crosslinking strategies have enabled the development of HA-based hydrogels, nanofibers, and composite systems with tunable mechanics and degradation profiles, supporting applications in bone, cartilage, vascular, and skin regeneration, as well as in emerging platforms such as 3D bioprinting and nanomedicine. However, inconsistent biological responses and limited clinical translation remain key challenges. This review integrates current understanding of HA synthesis, physicochemical properties, degradation, and receptor-mediated signaling, and establishes a mechanistic framework linking molecular characteristics, matrix mechanics, and cell responses. Building on this framework, we outline design strategies for multifunctional HA composites, advanced biofabrication approaches, and receptor-targeted systems, providing a basis for the rational engineering of next-generation HA-based biomaterials with improved translational potential. Full article

Hydrogel scaffolds have emerged as a central platform in tissue engineering due to their ability to mimic the extracellular matrix and support cellular functions. Among natural polymers, chitin and its derivative chitosan have emerged as valuable candidates for hydrogel scaffold development because of their biodegradability, compatibility with living tissues, and inherent biological functionality; however, their distinct and complementary roles in hydrogel scaffold design are often insufficiently differentiated in the literature. This review provides a comprehensive and mechanism-driven analysis of chitin- and chitosan-based hydrogel scaffolds, emphasising how their molecular structure governs network formation, mechanical performance, and biological functionality. Chitin is highlighted primarily as a structurally robust and crystalline component suitable for reinforcement. In contrast, chitosan serves as a versatile, soluble, and chemically reactive matrix enabling various crosslinking and functionalization strategies. Recent advances in physical, ionic, and covalent crosslinking as well as composite scaffold engineering, biofunctionalization, and emerging fabrication approaches such as injectable systems and three-dimensional bioprinting are systematically examined. The relationships between scaffold architecture, degradation behaviour, and cellular responses are discussed in key tissue engineering applications, including bone, cartilage, skin, and nerve regeneration. Importantly, this review introduces a unified structure–property–function framework that distinguishes the roles of chitin and chitosan within hydrogel systems and links crosslinking mechanisms to application-specific performance requirements, an aspect not comprehensively addressed in previous studies. Current challenges related to mechanical limitations, material variability, and clinical translation are critically evaluated, and future perspectives for the rational design of next-generation biomimetic hydrogel scaffolds are proposed. Full article

The limited regenerative capacity of articular cartilage (AC) following injury has led to a high prevalence of degenerative AC-related disorders, including osteoarthritis (OA). Current clinical treatments for OA have failed to halt disease progression, driving growing interest in cartilage tissue engineering (CTE) strategies aimed at developing biomimetic substitutes to regenerate damaged AC tissue. Among the available biofabrication techniques, electrospinning has gained attention due to its ability to generate fibrous scaffolds that closely mimic the architecture of the native AC extracellular matrix, while also serving as versatile drug delivery platforms with high surface area and elevated drug loading efficiency. Small molecules, low-molecular-weight therapeutic agents capable of interacting with both cell membrane and intracellular components, can be incorporated into these scaffold systems to target the underlying mechanisms of OA. This review examines the current state of the art of small molecule-loaded electrospun scaffolds for CTE applications. Small molecules targeting pain, inflammation, and cartilage function restoration show considerable therapeutic potential, and their incorporation into coaxial and other advanced electrospinning setups enables controlled and sustained drug release. Recent examples of small molecule-loaded electrospun scaffolds for AC repair demonstrate enhanced chondrogenic differentiation and neo-cartilage formation, supporting their potential as viable CTE strategies. Nevertheless, challenges related to drug release kinetics, scaffold load-bearing properties, manufacturing scalability, reproducibility, and regulatory approval remain critical barriers to clinical translation. Emerging fabrication strategies, AI-assisted optimization, personalized medicine approaches, and stimuli-responsive drug delivery systems offer promising avenues to overcome these limitations and advance the clinical adoption of these platforms. Full article

The increase in older adults and active lifestyles has made chondral and osteochondral lesions common in the population, making them one of the central challenges in orthopedics. Although hydrogel-based regenerative medicine offers an encouraging therapeutic option for these lesions, important obstacles still prevent these therapies from reaching the clinic. In view of these factors, we adopted a risk-based approach for this review, in line with the current legislative requirements in clinical translation and clinical trials. We identified the factors that could undermine patient safety or lead to poor outcomes. Then, we outlined solutions to remedy these problems that integrate hydrogel technology, clinical/pharmaceutical/surgical protocols, and post-operative follow-up. Upcoming studies should give priority to the development of hydrogel scaffolds modified to mimic cartilage’s mechanical and physicochemical properties, together with patient-specific features. Other crucial characteristics are host-tissue integration, long-lasting cartilage tissue regeneration, and a positive outcome. In parallel, to scale complex and costly innovations, efforts should focus on a harmonized, simplified legislative landscape, optimized standards, and established follow-up protocols. Getting through this “valley of death” between research and innovation is strategic for reaching the clinics and the largest number of patients. Full article

Articular cartilage has a limited capacity for self-repair, and effective strategies for its regeneration remain a major clinical challenge. Full-thickness cartilage defects extending to the subchondral bone induce an enhanced inflammatory response and impair spontaneous healing. This study aimed to evaluate the regenerative potential of autologous chondrocyte transplantation using an insoluble polyethersulfone (PES) scaffold in a rabbit model of grade III articular cartilage lesions. Chondrocytes were isolated and expanded in vitro and subsequently seeded onto PES membranes. Sixty-two rabbit knees with defects extending to the subchondral bone were divided into three groups: group I received chondrocyte-seeded PES scaffolds (n = 25), group II received cell-free PES scaffolds (n = 25), and group III served as an untreated control (n = 12). Cartilage regeneration was evaluated macroscopically and histologically over 52 weeks. In addition, the chondrogenic differentiation potential of cells cultured on PES scaffolds was assessed. This study extends our previous investigations of PES scaffolds in grade IV cartilage defects to a clinically relevant grade III lesion model, enabling evaluation of regenerative outcomes at an earlier stage of cartilage degeneration. The results demonstrated superior tissue regeneration in defects treated with chondrocyte-seeded PES scaffolds compared to both control groups. These findings indicate that synthetic PES scaffolds support cartilage repair and represent a promising biomaterial for the development of cell-based therapies in articular cartilage regeneration. Full article

Tissue engineering integrates concepts from medicine, biology, and engineering to create living constructs capable of repairing, replacing, or supporting damaged tissues. This multidisciplinary field relies on the interplay between biomaterials, cellular sources, and bioactive signaling to achieve functional tissue regeneration. This review provides a comprehensive overview of recent advances in scaffold design, highlighting natural, synthetic, and hybrid materials, as well as innovative fabrication techniques such as electrospinning, 3D bioprinting, and smart biomaterials. It discusses the role of stem cells and growth factors in directing regeneration and examines a wide range of clinical applications, including skin regeneration, cartilage repair, bone tissue engineering, dental and periodontal regeneration, nerve repair, cardiac tissue engineering, liver tissue models, and ophthalmic applications. Current challenges, such as immune responses, limited vascularization, scalability, and regulatory barriers, are addressed alongside emerging strategies aimed at improving clinical translation. By integrating diverse tissue types and engineering approaches within a unified framework, this review offers a broad yet detailed perspective on the current state and future directions of regenerative medicine. Full article

Collagen, the most abundant extracellular matrix (ECM) protein, has emerged as a cornerstone biomaterial in drug delivery and regenerative medicine due to its intrinsic biocompatibility, biodegradability, and low immunogenicity. Engineering collagen into microspheres transforms its functionality beyond bulk scaffolds by increasing surface area, enabling minimally invasive delivery, and providing precise control over degradation, mechanical properties, and therapeutic release. This review provides a comprehensive analysis of collagen-based microspheres, with a particular focus on their dual role as biomimetic microenvironments and delivery systems. Recent advances in fabrication strategies, including emulsification, microfluidics, spray-drying, and electrospraying, are discussed in the context of scalability, size control, and payload encapsulation. Composite approaches that incorporate bioactive minerals, polysaccharides, or synthetic polymers are highlighted for their ability to enhance mechanical performance and biological function. We further examine characterization frameworks that link microscale structure and physicochemical properties to biological outcomes, with emphasis on how collagen microspheres replicate key structural, mechanical, and signaling features of native tissue microenvironments. Collagen microspheres have demonstrated broad utility as controlled delivery platforms, cell-instructive microcarriers, and injectable systems for tissue regeneration, including applications in bone, cartilage, skin, and nerve repair, as well as advanced wound care and localized cancer therapy. Finally, we critically assess current challenges related to scalable manufacturing, sterilization compatibility, and batch reproducibility, and outline emerging solutions such as recombinant collagen, advanced biofabrication, and stimuli-responsive systems. Collectively, collagen microspheres represent a powerful and adaptable platform poised to advance next-generation regenerative and therapeutic technologies. Full article

Piezoelectric biomaterials have attracted considerable interest in osteochondral tissue engineering owing to their inherent ability to produce electrical signals in response to mechanical stimuli without external power, thereby closely mimicking the physiological electrical microenvironment required for tissue regeneration. This review comprehensively summarizes recent insights into biological piezoelectricity from the molecular to the macroscopic level, highlighting its interplay with streaming potentials and its regulatory roles in bone and cartilage regeneration. We critically analyze recent advances in major piezoelectric material systems, including ceramics, polymers, and composite scaffolds, with emphasis on their structural characteristics, bioactive performance, and suitability for tissue-specific repair. Among them, polymer-based composite and hybrid piezoelectric scaffolds appear particularly promising for the development of flexible, high-performance osteochondral repair platforms, as they offer a more favorable balance between mechanical compliance, electromechanical output, and biological adaptability. Despite encouraging preclinical findings, significant challenges remain, including biocompatibility, controlled degradation kinetics, and the precise modulation of electrical cues for specific biological contexts. To address these barriers, future research should focus on optimizing scaffold design, integrating responsive and multimodal stimulation strategies, and establishing standardized protocols for preclinical evaluation and clinical translation. Overall, piezoelectric biomaterials hold substantial potential for the development of innovative regenerative therapies for complex osteochondral defects. Full article

Musculoskeletal disorders and injuries are highly prevalent and encompass a broad range of conditions, including bone fractures and segmental defects, tendinopathies and tendon injury, and cartilage disorders such as osteoarthritis, cartilage defects, and intervertebral disc disease. These conditions can arise from diverse causes including trauma and injury, tumor resection, congenital abnormalities, and age-related degeneration. In the past decades, administration of chemically modified mRNA (cmRNA) encoding growth factors and transcriptional regulators has demonstrated effectiveness in repairing musculoskeletal tissues in preclinical studies. This review summarizes recent advancements in bone, tendon, cartilage, intervertebral disc, and muscle regeneration achieved through the localized delivery of protein-encoding mRNAs to express therapeutic target proteins. Delivery of cmRNA encoding growth factors such as BMP-2, BMP-9, VEGF, FGF-18, and IGF-1, or transcriptional regulators including Runx1, to various animal models has shown beneficial effects on bone, tendon, cartilage, and muscle injury repair in preclinical models. Alongside these progresses, the advantages and disadvantages of applying chemically modified mRNA for musculoskeletal tissue regeneration are also discussed. While studies show the promise of cmRNA for therapeutic applications in orthopedic tissue regeneration, more research is required to optimize growth factors and delivery methods, as well as validate long-term safety and efficacy prior to successful translation into new therapies to benefit patients. Full article

Traumatic injury, stenosis, and malignancy involving large segments of the airway are difficult to reconstruct and require novel solutions. Despite advances in surgical techniques, the reconstruction of long-segment tracheal defects remains a significant challenge. Several bioengineering approaches have been explored for tracheal regeneration in vitro and in vivo, using cells in combination with three dimentional (3D) biological or synthetic scaffolds. This paper reviews recent advances in developing bioengineered trachea and the technologies utilized toward generating transplantable tracheal grafts. Specifically, the review will focus on the recellularization of tissue-engineered grafts using natural or synthetic scaffolds, highlighting relevant cell types used to reconstitute tracheal epithelium and cartilage. The promise of newly explored paradigms, including the application of pluripotent stem cells, will be discussed with an overview of associated challenges and necessary steps for future translation. Overall, these advances provide a foundation for the development of clinically viable tracheal grafts, bringing engineered tracheal reconstruction closer to reality. Full article

Cartilage regeneration remains an unmet clinical challenge. Despite the great advances in the production of hydrogels as support matrices for cartilage regeneration, the resulting mechanical properties remain low. Granular composite hydrogels appear as ideal candidates due to their injectability and modularity in design. Here, we report on the fabrication and characterization of heterogeneous composite granular hydrogels based on methacrylated chitosan (CHIMA) and gelatin (GelMA) microparticles supported by an interstitial methacrylated alginate (ALMA) matrix. Microparticles were prepared by an oil-emulsion method and their size and morphology optimized, resulting in CHIMA and GelMA microparticles of 10.8 µm (95% CI 9.2, 13.1) and 115.8 µm (95% CI 107.5, 137.6) in diameter, respectively. The microparticles were mixed with ALMA and crosslinked to form granular hydrogels that demonstrated reduced swelling and weight loss. The storage modulus increased from 33 to 66.4 kPa for CHIMA/ALMA hydrogels and from 11.5 to 19.5 kPa for GelMA/ALMA hydrogels when the particle concentration increased from 10 to 50%, and was higher than traditional ALMA hydrogels. Hydrogels of 50:50 CHIMA:GelMA permitted a 6.6-fold increase in cell number after 28 days of culture, and promoted the chondrogenic differentiation of embedded mouse mesenchymal stem cells with a glycosaminoglycan deposition of over 15 µg and the expression of chondrogenic markers. Full article

The development of inks with suitable rheological, physicochemical, mechanical, and biological properties is crucial for the successful fabrication of functional scaffolds via extrusion-based 3D printing. In this study, collagen/chitosan hydrogels with varying polymer ratios were developed and characterized to evaluate their printability and suitability for cartilage tissue engineering. Rheological analyses revealed that all samples exhibited shear-thinning behavior and solid-like viscoelasticity, with the formulation of an 80:20 COL/CHI ratio (20CHI) demonstrating optimal filament formation and dimensional stability. Physicochemical analyses confirmed the preservation of the collagen triple helix and the formation of hydrogen bonding between chitosan and collagen. 20CHI scaffolds showed swelling capacity and high cohesiveness. In vitro studies confirmed the cytocompatibility of the scaffolds with murine fibroblasts and the ability of the scaffolds to promote adhesion, proliferation, and extracellular matrix production of both chondrocytes and adipogenic mesenchymal stem cells (aMSCs). Quantification of sulfated glycosaminoglycan (sGAG) indicated sustained matrix deposition over 28 days, particularly by chondrocytes. These findings demonstrate that 20CHI hydrogel is a promising candidate for 3D printing of biomimetic scaffolds for cartilage regeneration. Full article