Strategies in Electrospun Polymer and Hybrid Scaffolds for Enhanced Cell Integration and Vascularization for Bone Tissue Engineering and Organoids

ABSTRACT Addressing the demand for bone substitutes, tissue engineering responds to the high prevalence of orthopedic surgeries worldwide and the limitations of conventional tissue reconstruction techniques. Materials, cells, and growth factors constitute the core elements in bone tissue engineering, influencing cellular behavior crucial for regenerative treatments. Scaffold design, including architectural features and porosity, significantly impacts cellular penetration, proliferation, differentiation, and vascularization. This review discusses the hierarchical structure of bone and the process of neovascularization in the context of biofabrication of scaffolds. We focus on the role of electrospinning and its modifications in scaffold fabrication to improve scaffold properties to enhance further tissue regeneration, for example, by boosting oxygen and nutrient delivery. We highlight how scaffold design impacts osteogenesis and the overall success of regenerative treatments by mimicking the extracellular matrix (ECM). Additionally, we explore the emerging field of bone organoids—self‐assembled, three‐dimensional (3D) structures derived from stem cells that replicate native bone tissue's architecture and functionality. While bone organoids hold immense potential for modeling bone diseases and facilitating regenerative treatments, their main limitation remains insufficient vascularization. Hence, we evaluate innovative strategies for pre‐vascularization and discuss the latest techniques for assessing and improving vascularization in both scaffolds and organoids presenting the most commonly used cell lines and biological models. Moreover, we analyze cutting‐edge techniques for assessing vascularization, evaluating their advantages and drawbacks to propose complex solutions. Finally, by integrating these approaches, we aim to advance the development of bioactive materials that promote successful bone regeneration.