Biomaterials and extracellular vesicles in cell-free therapy for bone repair and regeneration: Future line of treatment in regenerative medicine

The conventional treatments for critical-sized bone defect repairs, such as autograft or allograft of bone are expensive procedures. Hence, developing better and economically feasible biomaterial-based alternatives for bone tissue engineering (BTE) becomes imperative. The mesenchymal stem cells (MSCs) are used for injured or damaged bone repairs and regeneration, due to their ability to proliferate, self-renew and differentiate into several cell lineages. This regenerative potential of MSCs happens through paracrine mode via their secretome comprising both, extracellular vesicles (EVs) and soluble factors. The recent trend shows that the cells could be replaced by MSC-derived EVs, including microvesicles and exosomes, as a “cell-free therapy”. Using EVs as a cell-free biologic could reduce complications associated with MSC transplantation. To retain at the site of injury, EVs could be encapsulated in suitable biomaterials and effectively used for bone repair and regeneration, as the EV-functionalized biomaterials provide a sustained delivery of EVs at the site of injury throughout the regenerative process. This review compiles the most frequently used biomaterial-based 3D approaches [β-tricalcium phosphate (β-TCP)-modified scaffolds, EV-encapsulated hydrogels, 3D-bioprinting, PEI-engineered-EVs coated PLA scaffold, injectable chitosan hydrogels] for bone tissue engineering and angiogenesis using MSC-derived EVs. In addition, this review highlighs the importance of imitating the bone tissue micro-environment in vivo and discusses the promising future of EVs as a cell-free therapy in bone tissue regeneration in defect/fractures resulting from accidental injuries and diseases like osteoporosis and osteoarthritis. Accumulating evidence suggests that EV-based cell-free therapy could be a convincing alternative to the use of MSCs themselves because of its advantages over the respective MSCs. These EVs-based cell-free approaches could form a cutting-edge science, however, they are still in their preliminary stages and suffer from lack of evidence from clinical studies. Further, this review suggests the use of the biomaterial-based interpenetrating network (IPN) hydrogel-based approach, comprising both, natural and synthetic polymer networks which are physically interlocked, as a promising technique as this system provides superior mechanical strength and biological acceptability for augmenting encapsulation performance and the delivery of EVs.