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Injectable MMP1-sensitive microspheres with spatiotemporally controlled exosome release promote neovascularized bone healing

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机构: [1]The Third Affiliated Hospital of Southern Medical University, Guangdong Medical Innovation Platform for Translation of 3D Printing Application, Southern Medical University, Guangzhou 510630, China [2]Department of Anatomy, Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China [3]Department of Pediatric Orthopedic, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou 510630, China [4]Department of Urology and Andrology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 20 0 0 01, China [5]Department of Stomatology, Guangdong Key Laboratory of Traditional Chinese Medicine Research and Development, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou 510095, China [6]Department of orthopedic, Dongguan People’s Hospital, Dongguan 523058, China
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关键词: Exosome Injectable microsphere Microfluidic chip Self-assembling peptide MMP1 Spatiotemporally controlled Neovascularized bone healing

摘要:
Bone marrow mesenchymal stromal cell-derived exosomes (BMSC-Exos) can recruit stem cells for bone repair, with neovessels serving as the main migratory channel for stem cells to the injury site. However, existing exosome (Exo) delivery strategies cannot reach the angiogenesis phase following bone injury. To that end, an enzyme-sensitive Exo delivery material that responds to neovessel formation during the angiogenesis phase was designed in the present study to achieve spatiotemporally controlled Exo release. Herein, matrix metalloproteinase-1 (MMP1) was found to be highly expressed in neovascularized bone; as a result, we proposed an injectable MMP1-sensitive hydrogel microspheres (KGE) made using a microfluidic chip prepared by mixing self-assembling peptide (KLDL-MMP1), GelMA, and BMSC-Exos. The results revealed that KGE microspheres had a uniform diameter of 50-70 µm, ideal for minimally invasive injection and could release exosomes in response to MMP1 expression. In vitro experiments demonstrated that KGE had less cytotoxicity and could promote the migration and osteodifferentiation of BMSCs. Furthermore, in vivo experiments confirmed that KGE could promote bone repair during angiogenesis by recruiting CD90+ stem cells via neovessels. Collectively, our results suggest that injectable enzyme-responsive KGE microspheres could be a promising Exo-secreting material for accelerating neovascularized bone healing. STATEMENT OF SIGNIFICANCE: Exosomes can spread through blood vessels and activate stem cells to participate in bone repair, but under normal circumstances, exosomes lacking sustained-release delivery materials cannot be maintained until the angiogenesis phase. In this study, we found that MMP1 was highly expressed in neovascularized bone, then we proposed an MMP1-sensitive injectable microsphere that carries exosomes and responds temporally and spatially to neovascularization, which maximizes the ability of exosomes to recruit stem cells. Different from previous strategies that focus on promoting angiogenesis to accelerate bone healing, this is a brand new delivery strategy that is stimuli-responsive to neovessel formation. In addition, the preparation of self-assembled peptide microspheres by a microfluidic chip is also proposed for the first time.Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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出版当年[2021]版:
大类 | 1 区 工程技术
小类 | 1 区 工程:生物医学 1 区 材料科学:生物材料
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 工程:生物医学 1 区 材料科学:生物材料
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第一作者机构: [1]The Third Affiliated Hospital of Southern Medical University, Guangdong Medical Innovation Platform for Translation of 3D Printing Application, Southern Medical University, Guangzhou 510630, China [2]Department of Anatomy, Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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通讯机构: [1]The Third Affiliated Hospital of Southern Medical University, Guangdong Medical Innovation Platform for Translation of 3D Printing Application, Southern Medical University, Guangzhou 510630, China [2]Department of Anatomy, Guangdong Provincial Key Laboratory of Medical Biomechanics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
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