Exosome-Functionalized Ceramic Bone Substitute Promotes Critical-Sized Bone Defect Repair in Rats

Abstract

Ceramic biomaterials are promising alternatives to bone autografts. However, limited bioactivity affects their performance. Therefore, bioactive molecules and cells are often added to enhance their performance. Exosomes have emerged as cell-secreted vesicles, delivering proteins, lipids, and nucleic acids in a paracrine/endocrine fashion. We studied two complementary aspects required for exosome activity/therapy using purified exosomes: first, the intracellular uptake of labeled exosomes and second, the influence of delivered exosomes on cell behavior. Origin-specific differences in the characteristics of purified exosomes, quantification of time-dependent intracellular uptake of PKH-26-labeled exosomes by mesenchymal stem cells (MSCs) and preosteoblasts, and influence on cell behavior were evaluated. Furthermore, exosomes from osteoblasts and MSCs cultured under normal and osteogenic environments were isolated. There is little data available on the concentration and dose of exosomes required for bone regeneration. Therefore, equal amounts of quantified exosomes were implanted in vivo in rat tibia critical defects using a calcium sulfate–nano-hydroxyapatite nanocement (NC) bone filler as the carrier. Bone regeneration was quantified using micro-computed tomography and histology. Along with inducing early maturation and mineral deposition by primary preosteoblasts in vitro, exosome treatment also demonstrated a positive effect on bone mineralization in vivo. Our study concludes that providing a local delivery of exosomes loaded onto a slowly resorbing NC bone filler can provide a potential alternate to autografts as a bone substitute.

Exosome-Functionalized, Drug-Laden Bone Substitute along with an Antioxidant Herbal Membrane for Bone and Periosteum Regeneration in Bone Sarcoma

“…We also observed the concentration-dependent effect of CQ on NO production (Figure S3C). MSC exosomes have been reported to have some antioxidant potential due to the presence of active catalases, which are important antioxidant enzymes, and various heat shock proteins (HSP) that can be accounted for its therapeutic effect as observed. ,, The effects of CQ can be attributed to the presence of resveratrol and quercetin as active constituents, which have been reported to alleviate ROS-generated apoptosis in various cells. − The bright-field images (Figure S4G) show the migration of HUVEC cells in the presence and absence of exosomes. As we can see in the figure, the cells readily start migrating toward each other in the exosome-treated group, thereby filling the scratch area; however, most of the wound area in the case of the nontreated group was left open.…”

3D-printed Strontium-Titanium Scaffolds Incorporated with Highly Bioactive Serum Exosomes Promotes Critical Bone Defect Repair by Enhancing Osteogenesis and Angiogenesis

“…Recently, to achieve good osteoinductivity, some research reported that exosomes were obtained from osteogenic differentiation of MSCs that was induced by chemical compounds in vitro, prior to being utilized for treatment of bone defects in vivo [7,31]. However, osteogenic exosomes induced by chemical compounds rather than the natural osteogenic microenvironment, may have limited clinical translation potential due to safety issues and other possible side effects.…”

Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier

“…Indeed, the augmented cartilage formation found in pellet cocultures of MSCs and chondrocytes primarily relies on the trophic effects of the MSCs, leading to promoting chondrocyte growth and matrix deposition rather than MSCs' trans-differentiation into mature and functional chondrocyte [ 77 ]. Like parental MSCs, MSCs-derived exosomes trigger chondrocyte proliferation by inducing Akt and ERK axis in chondrocytes [ 78 , 79 ]. In addition to the supposed growth factors, miR-135b-enriched exosomes can enhance TGF-β1 expression, increase chondrocyte proliferation, and sustain cartilage repair [ 80 ].…”