With the increasing worldwide prevalence of tissue damage, there is an urgent, growing demand for tissue engineering materials to mimic autologous tissue for surgical repair. Many attempts have been made to produce long-lasting, biocompatible implants. To overcome the mechanical and biological limitations of synthetic implants, the development of native macromolecule-based 3D substitutes as alternatives has been the latest focus. Advances in nanofabrication and controlled-release technology have vastly improved the potential of such 3D substitutes in influencing cell and tissue performance. This book is an overview of the current state of knowledge in the field of native macromolecule-based 3D substitutes for the repair of several tissue types, including bone, cartilage, vascular, and many more.