In the last thirty years, tissue engineering (TI) has emerged as an alternative method to regenerate tissues and organs and restore their function by implanting specific lineage cells, growth factors, or biomolecules functionalizing a matrix scaffold. Recently, several pathologies have led to bone loss or damage, such as malformations, bone resorption associated with benign or malignant tumors, periodontal disease, traumas, and others in which a discontinuity in tissue integrity is observed. Bone tissue is characterized by different stiffness, mechanical traction, and compression resistance as a function of the different compartments, which can influence susceptibility to injury or destruction. For this reason, research into repairing bone defects began several years ago to find a scaffold to improve bone regeneration. Different techniques can be used to manufacture 3D scaffolds for bone tissue regeneration based on optimizing reproducible scaffolds with a controlled hierarchical porous structure like the extracellular matrix of bone. Additionally, the scaffolds synthesized can facilitate the inclusion of bone or mesenchymal stem cells with growth factors that improve bone osteogenesis, recruiting new cells for the neighborhood to generate an optimal environment for tissue regeneration. In this review, current state-of-the-art scaffold manufacturing based on the use of polycaprolactone (PCL) as a biomaterial for bone tissue regeneration will be described by reporting relevant studies focusing on processing techniques, from traditional—i.e., freeze casting, thermally induced phase separation, gas foaming, solvent casting, and particle leaching—to more recent approaches, such as 3D additive manufacturing (i.e., 3D printing/bioprinting, electrofluid dynamics/electrospinning), as well as integrated techniques. As a function of the used technique, this work aims to offer a comprehensive overview of the benefits/limitations of PCL-based scaffolds in order to establish a relationship between scaffold composition, namely integration of other biomaterial phases’ structural properties (i.e., pore morphology and mechanical properties) and in vivo response.

The integration of biomaterials in tissue engineering faces challenges due to the host's inflammatory response, which can compromise scaffold biocompatibility. Polycaprolactone (PCL) is approved by the Food and Drug Administration (FDA) for certain medical devices but lacks universal acceptance as a standalone biomaterial due to its hydrophobic nature and low bioactivity. Combining PCL with natural polymers like gelatin has been shown to improve hydrophilicity, biocompatibility, and cellular interactions. However, gelatin's instability in aqueous environments requires crosslinking for sustained performance. In this study, three‐dimensional (3D) porous PCL scaffolds were fabricated using the solvent casting and particle leaching (SCPL) technique, then functionalized with gelatin. Stabilization was achieved through chemical crosslinking (EDC/NHS) and physical crosslinking (UV radiation). The scaffolds were characterized in terms of morphology, porosity, wettability, and microhardness, and biologically evaluated in vitro with human fetal osteoblasts (hFOB) and in vivo in a subcutaneous implantation model in Wistar rats. Results confirmed stable gelatin incorporation without compromising porosity. Enhanced hydrophilicity, surface resistance, and improved cellular adhesion, viability, and proliferation were observed in vitro. Histological analysis in vivo showed no adverse inflammatory responses. These findings suggest that functionalizing PCL scaffolds with crosslinked gelatin is a promising strategy for regenerative medicine applications.