Toward a Functional Biomimetic Extracellular Matrix: Advances in Electrospun Scaffolds

The extracellular matrix (ECM) is a dynamic and highly organized network that provides structural support while regulating cellular behavior and tissue homeostasis. Its tissue- and organ-specific architecture, comprising fibrous proteins, glycoproteins, and proteoglycans, presents a major challenge for reproducing the structural and functional complexity of native ECM. Electrospinning offers a versatile approach for fabricating fibrous scaffolds that recapitulate key ECM features, including submicron-scale fibers, high surface area, porosity, and tunable physicochemical properties. Despite extensive investigation of electrospun scaffolds for skin, bone, cardiac, and vascular regeneration, tissue-specific strategies for several clinically important anatomical targets remain comparatively underexplored. This review focuses specifically on electrospun ECM-mimicking scaffolds for the salivary gland, eardrum, small intestine, proximal tubule, cornea, thymus, and fetal/pediatric tissues, emphasizing how tissue- and organ-specific ECM architecture and function can guide the development of biomimetic scaffolds tailored to cellular regeneration and tissue-specific requirements. We further discuss the emerging integration of artificial intelligence (AI) with electrospinning for predictive optimization of fiber morphology, porosity, composition, mechanical properties, cell-material interactions, drug delivery, and tissue- and disease-specific scaffold design. These approaches have the potential to reduce conventional trial-and-error experimentation and improve scaffold development. However, limited and heterogeneous datasets, model bias and hallucinations, source verification, reproducibility, scalability, and biological validation remain significant barriers to reliable translation. Overall, integrating tissue-specific ECM mimicry, electrospinning, and AI provides a promising framework for advancing precision scaffold design and personalized regenerative medicine.