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.

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Complete skin reconstruction is a hierarchically physiological assembly involving epidermis, dermis, vasculature, innervation, hair follicles, and sweat glands. Despite various wound dressings having been developed for skin regeneration, few works refer to the complete skin regeneration, particularly lacking for vasculatures and hair follicles. Herein, an instructive wound dressing that integrates the antibacterial property of quaternized chitin and the mechanical strength and biological multifunction of silk fibroin through layer-by-layer electrostatic self-assembly is designed and reported. The resultant dressings exhibit a nanofibrous structure ranging from 471.5 ± 212.1 to 756.9 ± 241.8 nm, suitable flexibility with tensile strength up to 4.47 ± 0.29 MPa, and broad-spectrum antibacterial activity against Escherichia coli and Staphylococcus aureus. More interestingly, the current dressing system remarkably accelerates in vivo vascular reconstruction within 15 days, and the number of regenerated hair follicles reaches up to 22 ± 4 mm −2 , which is comparable to the normal tissue (27 ± 2 mm −2). Those crucial functions might originate from the combination between quaternized chitin and silk fibroin and the hierarchical structure of electrospun nanofiber. This work establishes an easy but effective pathway to design a multifunctional wound dressing for the complete skin regeneration.

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