A variety of engineered scaffolds have been created for tissue engineering using polymers, ceramics and their composites. Biomimicry has been adopted for majority of the three-dimensional (3D) scaffold design both in terms of physicochemical properties, as well as bioactivity for superior tissue regeneration. Scaffolds fabricated via salt leaching, particle sintering, hydrogels and lithography have been successful in promoting cell growth in vitro and tissue regeneration in vivo. Scaffold systems derived from decellularization of whole organs or tissues has been popular due to their assured biocompatibility and bioactivity. Traditional scaffold fabrication techniques often failed to create intricate structures with greater resolution, not reproducible and involved multiple steps. The 3D printing technology overcome several limitations of the traditional techniques and made it easier to adopt several thermoplastics and hydrogels to create micro-nanostructured scaffolds and devices for tissue engineering and drug delivery. This review highlights scaffold fabrication methodologies with a focus on optimizing scaffold performance through the matrix pores, bioactivity and degradation rate to enable tissue regeneration. Review highlights few examples of bioactive scaffold mediated nerve, muscle, tendon/ligament and bone regeneration. Regardless of the efforts required for optimization, a shift in 3D scaffold uses from the laboratory into everyday life is expected in the near future as some of the methods discussed in this review become more streamlined.

Electrical stimulation (ES) is predominantly used as a physical therapy modality to promote tissue healing and functional recovery. Research efforts in both laboratory and clinical settings have shown the beneficial effects of this technique for the repair and regeneration of damaged tissues, which include muscle, bone, skin, nerve, tendons, and ligaments. The collective findings of these studies suggest ES enhances cell proliferation, extracellular matrix (ECM) production, secretion of several cytokines, and vasculature development leading to better tissue regeneration in multiple tissues. However, there is still a gap in the clinical relevance for ES to better repair tissue interfaces, as ES applied clinically is ineffective on deeper tissue. The use of a conducting material can transmit the stimulation applied from skin electrodes to the desired tissue and lead to an increased function on the repair of that tissue. Ionically conductive (IC) polymeric scaffolds in conjunction with ES may provide solutions to utilize this approach effectively. Injectable IC formulations and their scaffolds may provide solutions for applying ES into difficult to reach tissue types to enable tissue repair and regeneration. A better understanding of ES-mediated cell differentiation and associated molecular mechanisms including the immune response will allow standardization of procedures applicable for the next generation of regenerative medicine. ES, along with the use of IC scaffolds is more than sufficient for use as a treatment option for single tissue healing and may fulfill a role in interfacing multiple tissue types during the repair process.

Tissue engineering often utilizes biodegradable polymers in the form of porous scaffolds for regenerating de novo tissues. There is an ever-increasing need for biodegradable polymers as temporary substrates for facilitating tissue regeneration. Compared to the widely used polyesters, polyorthoesters, poly(α-amino acids), and poly(anhydrides), biodegradable polyphosphazenes form a unique class of polymers that has vast potential for tissue engineering applications. Polyphosphazenes are linear high molecular weight polymers with an inorganic backbone consisting of alternating phosphorous and nitrogen atoms with two organic side groups attached to each phosphorous atom. The synthetic flexibility of polyphosphazenes has enabled the development of a wide range of polymers with a variety of physical, chemical and biological properties. These biodegradable polyphosphazenes undergo hydrolytic degradation yielding non-toxic and neutral pH degradation products due to the buffering capacity of phosphates and ammonia that are produced simultaneously during polyphosphazene degradation. This review focuses on synthesis of biodegradable polyphosphazenes, their degradation characteristics, biocompatibility, and their applications as tissue regeneration and controlled delivery matrices with a particular emphasis on systems based on polyphosphazenes alone, polyphosphazene blends and polyphosphazene composites.

Peptide molecules have design flexibility, self-assembly ability, high biocompatibility, good biodegradability, and easy functionalization, which promote their applications as versatile biomaterials for tissue engineering and biomedicine. In addition, the functionalization of self-assembled peptide nanomaterials with other additive components enhances their stimuli-responsive functions, promoting function-specific applications that induced by both internal and external stimulations. In this review, we demonstrate recent advance in the peptide molecular design, self-assembly, functional tailoring, and biomedical applications of peptide-based nanomaterials. The strategies on the design and synthesis of single, dual, and multiple stimuli-responsive peptide-based nanomaterials with various dimensions are analyzed, and the functional regulation of peptide nanomaterials with active components such as metal/metal oxide, DNA/RNA, polysaccharides, photosensitizers, 2D materials, and others are discussed. In addition, the designed peptide-based nanomaterials with temperature-, pH-, ion-, light-, enzyme-, and ROS-responsive abilities for drug delivery, bioimaging, cancer therapy, gene therapy, antibacterial, as well as wound healing and dressing applications are presented and discussed. This comprehensive review provides detailed methodologies and advanced techniques on the synthesis of peptide nanomaterials from molecular biology, materials science, and nanotechnology, which will guide and inspire the molecular level design of peptides with specific and multiple functions for function-specific applications.