Hydrogel Implementing Drug Delivery in Cranial Bone Tissue Engineering.

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.