Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects

Abstract

Large segmental bone regeneration remains a great challenge due to the lack of vascularization in newly formed bone. Conventional strategies primarily combine bone scaffolds with seed cells and growth factors to modulate osteogenesis and angiogenesis. Nevertheless, cell-based therapies have some intrinsic issues regarding immunogenicity, tumorigenesis, bioactivity and off-the-shelf transplantation. Exosomes are nano-sized (50-200 nm) extracellular vesicles with a complex composition of proteins, nucleic acids and lipids, which are attractive as therapeutic nanoparticles for disease treatment. Exosomes also have huge potential as desirable drug/gene delivery vectors in the field of regenerative medicine due to their excellent biocompatibility and efficient cellular internalization. Methods: We developed a cell-free tissue engineering system using functional exosomes in place of seed cells. Gene-activated engineered exosomes were constructed by using ATDC5-derived exosomes to encapsulate the VEGF gene. The specific exosomal anchor peptide CP05 acted as a flexible linker and effectively combined the engineered exosome nanoparticles with 3D-printed porous bone scaffolds. Results: Our findings demonstrated that engineered exosomes play dual roles as an osteogenic matrix to induce the osteogenic differentiation of mesenchymal stem cells and as a gene vector to controllably release the VEGF gene to remodel the vascular system. In vivo evaluation further verified that the engineered exosome-mediated bone scaffolds could effectively induce the bulk of vascularized bone regeneration. Conclusion: In our current work, we designed specifically engineered exosomes based on the requirements of vascularized bone repair in segmental bone defects. This work simultaneously illuminates the potential of functional exosomes in acellular tissue engineering.

A Comprehensive Review on the Applications of Exosomes and Liposomes in Regenerative Medicine and Tissue Engineering

“…However, to fully understand the possibilities of exosomes as cancer treatments, more research is needed. Exosomes generated by stem cells have also been effectively utilized to promote osteogenesis in vivo, allowing for both development of new blood vessels and the formation of bone [ 227 , 229 ].…”

3D Printing of Dual-cell Delivery Titanium Alloy Scaffolds for Improving Osseointegration Through Enhancing Angiogenesis and Osteogenesis

“…It is known that HIF-1α and VEGF is an effective factor to improve the scaffold vascularization via angiogenesis [15,49]. The levels of angiogenesis-related gene, HIF-1α, was increased signi cantly in the EPC/hTi Group compared with eTi Group, hTi Group, and BMSC/hTi Group (p < 0.05).…”

“…In addition, a series of surface modi cation strategies have also been used to induce osteogenesis and osseointegration of the porous titanium scaffolds [12,13]. Although it is recognized that the use of additional BMSC incorporation or prosthetic surface modi cation to treat bone defects can effectively accelerate bone formation, the size of the regenerated bone has always been a restriction for su cient bone repair, mainly because of the absence of blood vessels in the grafts [14,15]. Since abundant angiogenesis is critical to provide su cient nutritional support, active osteoblast function, and accelerate new bone formation.…”

Cell-free exosome-laden scaffolds for tissue repair

“…59 Recent research has shown that modified exosomes combined with a 3D printed porous bone scaffold through a specific linker (exosomal anchor peptide CP05) can effectively increase the osteogenesis and angiogenesis by exosomes encapsulating the VEGF gene. 60…”