Biodegradable Natural Polymer-Based Drug Delivery Systems for Bone Tissue Engineering

The increasing incidence of bone diseases and injuries, especially among aging populations, has underscored the shortcomings of traditional treatments such as bone grafts and metal implants, which often face complications including immune rejection, mechanical failure, and delayed healing. In response, drug delivery systems incorporated into biomaterial scaffolds have emerged as a promising strategy to enhance therapeutic efficacy and promote bone regeneration. This review provides a comprehensive overview of biodegradable natural polymer-based scaffolds, focusing on their structural characteristics and drug delivery capabilities in bone tissue engineering. Four principal scaffold architectures-sponges, nanofibers, hydrogels, and microspheres-are examined with respect to their regenerative functionality, associated limitations, and recent engineering advancements. In particular, we discuss the use of four representative natural polymers-collagen, cellulose, chitosan, and hyaluronic acid-and their physicochemical properties that contribute to osteogenesis. Furthermore, recent strategies for enhancing scaffold performance can be broadly divided into two categories. First, nanostructured approaches that reinforce the intrinsic functionality of natural polymers, such as MXene-polymer nanocomposites, halloysite nanotube-loaded hydrogels, and nanocrystalline cellulose systems, have improved drug delivery efficiency and mechanical resilience. Second, advances in three-dimensional (3D) scaffold fabrication-including electrospinning, freeze-drying, 3D printing, bioplotting, photolithography, and microfluidics-have enabled precise control over scaffold architecture, porosity, and biomolecule positioning. Together, these strategies represent critical developments for designing next-generation bone tissue engineering platforms.