Bone grafting, as the current gold-standard for large scaled bone damage of various causes, has faced challenges from both the source and appliance. Emerging new tissue engineering substitutes are demonstrating more options and possibilities, with their improved biocompatibility, accessibility, and customizable function. Amongst them, injectable gels (IGs) are a class of gel material displaying astonishing non-invasive properties and surgical viability. While possessing responsiveness toward specific stimuli, they change their physical form in vivo, thus serving as wonderful biomaterials and drug delivery systems. In this review, the mechanics of stimuli-responsive IGs developed during the past decade are illustrated. Two branches of crosslinked gels -co-valent and non-covalent crosslinked IGs and their composition and customization are introduced. In conclusion, the present trend in bone tissue engineering research is summarized and made an outlook for future. It is hoped that this comprehensive review can provide a proper reference for the development of new IGs.
The repair of critical bone defects remains challenging worldwide. Three canonical pillars (biomaterial scaffolds, bioactive molecules, and stem cells) of bone tissue engineering have been widely used for bone regeneration in separate or combined strategies, but the delivery of bioactive molecules has several obvious drawbacks. Biophysical stimuli have great potential to become the fourth pillar of bone tissue engineering, which can be categorized into three groups depending on their physical properties: internal structural stimuli, external mechanical stimuli, and electromagnetic stimuli. In this review, distinctive biophysical stimuli coupled with their osteoinductive windows or parameters are initially presented to induce the osteogenesis of mesenchymal stem cells (MSCs). Then, osteoinductive mechanisms of biophysical transduction (a combination of mechanotransduction and electrocoupling) are reviewed to direct the osteogenic differentiation of MSCs. These mechanisms include biophysical sensing, transmission, and regulation. Furthermore, distinctive application strategies of biophysical stimuli are presented for bone tissue engineering, including predesigned biomaterials, tissue-engineered bone grafts, and postoperative biophysical stimuli loading strategies. Finally, ongoing challenges and future perspectives are discussed.
Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.
Exosomes, as messengers of cell-to-cell communication, have many functional properties similar to those of their derived cells. Because they contain a large number of bioactive components that regulate recipient cell behavior, they are inanimate and do not require external maintenance or assistance. Various cell-derived exosomes are involved in many physiological processes of bone tissue repair. Hydrogels are widely used as scaffolding materials for bone tissue repair because their 3D network structure resembles the natural extracellular matrix. Moreover, their material properties and biological functions are adjustable. Exosomes can be delivered directly to the bone tissue damage site by hydrogel, and their duration of action in vivo can be prolonged by slow release. Therefore, the exosome-loaded hydrogel (Exo-Gel) system is a promising material for bone tissue engineering. In this study, the progress of the application of Exo-Gel in bone tissue repair and the improvement strategies, problems and research prospects of the current exosomes and hydrogels that have been applied to the Exo-Gel system for bone tissue repair are reviewed.
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