Aug 2026· Journal of Functional Biomaterials· Vol 17, pp. 401· 0 citations· 295 references
Medicine
TL;DR
This review provides a comprehensive overview of hydrogel-based delivery strategies designed to regulate the spatiotemporal presentation of bioactive agents within cranial defects and places particular emphasis on how hydrogel design parameters, including crosslinking density, degradation kinetics, and responsiveness to microenvironmental cues, govern therapeutic release and influence regenerative outcomes.
Abstract
Cranial bone defects remain a significant clinical challenge due to their limited intrinsic regenerative capacity and the complexity of coordinating osteogenesis, angiogenesis, and immune responses within a confined and poorly vascularised environment. Conventional approaches, including autologous grafts and synthetic implants, provide structural support but fail to actively modulate the biological processes required for effective bone regeneration. In this context, hydrogel-based systems have emerged as versatile platforms for localized and controlled drug delivery in cranial bone tissue engineering (BTE). This review provides a comprehensive overview of hydrogel-based delivery strategies designed to regulate the spatiotemporal presentation of bioactive agents within cranial defects. The main classes of hydrogels, natural, synthetic, semi-synthetic, and hybrid systems, are discussed in relation to their physicochemical properties and suitability for drug delivery applications. Current delivery approaches are analysed, including cell-free systems (growth factors, peptides, bioactive ions, nucleic acids, and small molecules drugs), cell-based platforms, and multifunctional systems integrating secondary carriers such as nanoparticles (NPs), microparticles (MPs), and extracellular vesicles (EVs). Particular emphasis is placed on how hydrogel design parameters, including crosslinking density, degradation kinetics, and responsiveness to microenvironmental cues, govern therapeutic release and influence regenerative outcomes. Emerging strategies and key translational challenges are also highlighted.
Clinical repair of bone defects has long faced challenges including the limited availability of autografts, immunological rejection of allografts, and mechanical mismatch of traditional implants. Injectable hydrogels have emerged as highly promising strategies in bone tissue engineering due to their unique advantages: minimally invasive implantation, the ability to conform to irregular defect cavities, excellent biocompatibility, and high functional tunability. This review systematically outlines recent advances in injectable hydrogels for bone regeneration. It comprehensively outlines material classifications and fundamental properties. Specifically, it analyzes key design strategies, including enhancing mechanical support through cross-linking optimization and the incorporation of reinforcing phases, reconstructing the regenerative microenvironment via bioactive factor loading, and enabling synchronized degradation and tissue regeneration. Furthermore, this review summarizes current applications for different bone defect types, identifies current technical bottlenecks such as balancing mechanical strength with minimally invasive delivery, and anticipates future directions, including stimuli-responsive design and multifunctional integration.
Xin-Yue Zhang, Zhen-Shun Zhuang, Bo Liu et al.· RSC Advances· 0 citations
The functional reconstruction of bone defects caused by trauma, infection, surgical resection and degenerative diseases poses substantial clinical challenges. Bone tissue engineering (BTE) holds immense potential for treating bone defects while avoiding complications commonly associated with conventional autografts, allografts and internal fixation. Bioactive hydrogels with exceptional drug delivery capabilities, excellent biocompatibility and tunable physicochemical properties have emerged as promising biomaterial scaffolds for BTE. This review provides a comprehensive overview of recent advancements in bioactive hydrogel–based strategies for BTE applications. An initial introduction to bone physiology is followed by a critical discussion of the design considerations for hydrogel platforms, specifically biomaterial selection, innovative crosslinking mechanisms and bioactive functionalization. Furthermore, hydrogel engineering for the controlled delivery of bioactive cargo is critically examined, with an emphasis on spatiotemporally programmable release behaviors that coordinate osteogenesis, angiogenesis and immunomodulation. Finally, key translational challenges are discussed, and the emerging role of artificial intelligence–assisted design is explored as a transformative approach for facilitating the clinical translation of next-generation bioactive hydrogels for BTE.
Chongzheng Yan, Yuxue Pan, Yu Tian et al.· Asian Journal of Pharmaceuti...· 0 citations
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.
Biodegradable hydrogels are injected in situ to create scaffolds in complex tissue defects with a minimally invasive approach. The current narrative review critically discusses their design principles such as polymer type (natural, synthetic and hybrid systems), crosslinking processes (physical, chemical, and self-crosslinking strategies), and optimization of their rheological properties for clinical injectability. Various advanced biofunctionalization strategies such as cell encapsulation, spatiotemporal delivery of growth factors, extracellular matrix mimicry via fiber-reinforced composites, and active immunomodulation are assessed for their application in tissue-specific regeneration in cartilage, bone, cardiac, neural, skin, and dental applications. While there has been significant progress in preclinical work, there are significant translational challenges that remain: mechanical mismatch with load-bearing native tissues, natural polymer batch-to-batch variability, unpredictable degradation rates, and a complex regulatory pathway for combination products. We explore under-explored areas such as 4D bioprinting for dynamic shape morphing, the design of materials through artificial intelligence, and closed-loop theranostic platforms that combine real-time biosensing with on-demand therapeutic release. This review suggests that the interdisciplinary convergence of materials science, bioengineering, and regulatory science is necessary to tackle these challenges and make injectable hydrogels a standard-of-care regenerative therapeutic.
Elnaz Abedini, Daver Ali· Exploration of BioMat-X· 0 citations
Orthopedic diseases impose heterogeneous therapeutic demands, ranging from symptomatic control of inflammation and pain to intra-articular drug delivery, cartilage repair, bone regeneration, and prevention of implant-associated infection. Although hydrogels are widely investigated as tunable biomaterials for these applications, their translational potential is often discussed primarily in terms of polymer composition or crosslinking chemistry. This review argues that delivery modality provides a clinically useful framework for evaluating orthopedic hydrogel systems, but translational success depends on the combined influence of material properties, mechanical requirements, degradation behavior, biological integration, manufacturability, and regulatory feasibility. Hydrogel patches, injectable hydrogels, and implantable hydrogels differ in tissue access, mechanical competence, payload capacity, residence time, invasiveness, and regulatory feasibility. Here, we critically compare these three delivery paradigms across major orthopedic indications. Hydrogel patches are best positioned for localized analgesic and anti-inflammatory therapy but remain poorly suited for deep regenerative delivery because of skin-barrier limitations. Injectable hydrogels can offer a strong balance between minimally invasive administration and localized therapeutic control, particularly for intra-articular disease and irregular defects, but require improved retention, mechanical stability, and predictable gelation. Implantable hydrogels can provide architectural and mechanical control for focal bone and osteochondral repair when designed as structural or composite systems, yet their clinical adoption is constrained by surgical burden, manufacturing complexity, and long-term durability requirements. By shifting the discussion from material cataloguing to indication- and delivery-modality-driven design, this review provides a balanced framework for evaluating orthopedic hydrogel technologies and identifies practical translational priorities related to tissue access, mechanical durability, biological response, manufacturing, and clinical feasibility.
A. Martino, J. Moskow, Jason Shenoi et al.· Biomaterials Science· 0 citations
Tissue repair following disease or injury remains a major clinical challenge, driving the search for advanced biomaterials that can effectively support tissue regeneration. Injectable hydrogels have recently gained significant attention as promising candidates in regenerative medicine due to their minimally invasive administration, ability to conform to irregular defects, and precise spatial localization, overcoming the limitations of conventional pre‐formed hydrogels. Among natural polymers, silk fibroin (SF) has attracted considerable attention owing to its unique chemical structure, outstanding mechanical properties, versatile processability, biocompatibility, cost‐effectiveness, and large‐scale availability. Consequently, a wide variety of SF‐based injectable hydrogels have been developed, either alone or in combination with other biomaterials, for diverse tissue engineering applications. This review provides an in‐depth discussion of their injectability, underlying gelation mechanisms, and therapeutic advantages, including roles in tissue regeneration, drug delivery, cell therapy, immunomodulation, and angiogenesis. Furthermore, the current challenges, recent advances, and future directions for the clinical translation of SF‐based injectable hydrogels are critically assessed, highlighting their potential as next‐generation biomaterials for regenerative medicine.
M. Farokhi, F. Mottaghitalab, Baolin Guo· Advanced Healthcare Material...· 0 citations
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