Autologous Versatile Vesicles‐Incorporated Biomimetic Extracellular Matrix Induces Biomineralization

Abstract

Restoring extracellular matrix (ECM) with supportive and osteoinductive abilities is of great significance for bone tissue regeneration. Current approaches involving cell-based scaffolds or nanoparticle-modified biomimic-ECM have been met with additional biosafety concerns. Herein, the natural biomineralization process is first analyzed and is found that mesenchymal stem cells-derived extracellular vesicles (EVs) from early and late stages of osteoinduction play different roles during the mineralization process. The functional EVs hierarchically with blood-derived autohydrogel (AH) are then incorporated to form an osteoinductive biomimetic extracellular matrix (BECM). The alkaline phosphatase-rich EVs are released from the outer layers to induce osteoblast differentiation during early stages. Thereafter, as the degradation of AH occurred, calcium/phosphorus (Ca/P)rich EVs are liberated to promote the nucleation of extracellular mineral crystals. Additionally, BECM contains considerable collagen fibrils that provide additional nucleation sites for crystallites deposition, thus reaching self-mineralization in situ. In conclusion, this research provides a promising, versatile mineralization-instructive platform to tackle the challenges faced in bone-tissue engineering. Scheme 1. Illustration of the BECM induced osteogenesis and biomineralization. In the early stage of mineralization, BECM secreted ALP-rich E-EVs. The E-EVs moved to intracellular mitochondria and provided ALP for phosphate metabolism, contributing to the formation of Ca/P-rich vesicles. Later, with the degradation of BECM, Ca/P-rich L-EVs were released gradually. The L-EVs aligned to extracellular collagen and promoted the nucleation of extracellular mineral crystals. Besides, L-EVs inside BECM aggregate around the internally collagen fibrils and initiated in situ mineralization. Finally, with the complete degradation of BECM, the internal mineralized components were released to the extracellular matrix, promoting the deposition formation together to realize an ideal self-mineralization process for bone tissue regeneration.www.afm-journal.de www.advancedsciencenews.com (3 of 15)

A Novel Dual‐Crosslinked Functional Hydrogel Activated by POSS for Accelerating Wound Healing

“…This may be related to the sustained release of Ag + from the PEGDA/TCS/POSSP@Ag system could effectively inhibit inflammation and to the Si in the POSSP nanoparticles, which enhance angiogenesis and synergistically accelerate wound regeneration in vivo. [ 41,42 ]…”

Bioinspired mineralized collagen scaffolds for bone tissue engineering

“…In order to simulate the mineralization process in nature, some researchers proposed to encapsulate calcium and phosphate ions in vesicles. These liposomes vesicles were embedded in ECM and mainly composed of COL [ 104 , 105 ]. Different driving strategies were then used to release mineral ions and mineralize them in the matrix.…”

Emerging biogenesis technologies of extracellular vesicles for tissue regenerative therapeutics

“…Increasing the quantity (mass production) of EVs is considered a significant challenge for their in vivo application and clinical translation. The strategies for mass-production of EVs include modulating the components or secretary machinery proteins of EVs, [38][39][40] increasing the intracellular Ca ions, 41,42 adjusting biochemical cues such as extracellular DNA, liposomes, and proton concentration, [43][44][45] and Adapted from Wei et al 30 in Adv Funt Mater, by Rocha et al 34 in Adv Sci, and by Yu et al 37 in Chem Eng J.…”

“…Studies have been focused on modulating the culture microenvironments of EVs-secreting donor cells, such as altering ingredients, oxidative stress, and physical cues. Specifically, EVs have been generated under different conditions, involving differentiation medium, 30 , 31 hypoxia, 32 , 33 3D culture, 34 mechanical force, 35 , 63 and their combinations (e.g. 3D culture + mechanical force).…”

“…The EVs secreted at an early stage of osteogenesis (at day 5) were shown to highly express the early osteogenic marker alkaline phosphatase (ALP). In contrast, those from a late-stage (at day 11) were rich in calcium phosphate crystals, implying the possibility of loading distinct cargo molecules within EVs by controlling the differentiation stage/period 30 ( Figure 3(a) ). In another study with human adipose-derived stem cells (ASCs), the endothelial differentiation medium generated the EVs with higher miRNA-31 levels compared to the normal growth medium, which ultimately contributed to the increased endothelial cell migration, tubule formation, and aortic ring outgrowth.…”