3D bioprinting of engineered exosomes secreted from M2-polarized macrophages through immunomodulatory biomaterial promotes in vivo wound healing and angiogenesis

IF 18 1区医学 Q1 ENGINEERING, BIOMEDICAL

Bioactive Materials Pub Date : 2024-11-27 DOI:10.1016/j.bioactmat.2024.11.026

Sayan Deb Dutta , Jeong Man An , Jin Hexiu , Aayushi Randhawa , Keya Ganguly , Tejal V. Patil , Thavasyappan Thambi , Jangho Kim , Yong-kyu Lee , Ki-Taek Lim

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引用次数: 0

Abstract

Biomaterial composition and surface charge play a critical role in macrophage polarization, providing a molecular cue for immunomodulation and tissue regeneration. In this study, we developed bifunctional hydrogel inks for accelerating M2 macrophage polarization and exosome (Exo) cultivation for wound healing applications. For this, we first fabricated polyamine-modified three-dimensional (3D) printable hydrogels consisting of alginate/gelatin/polydopamine nanospheres (AG/NSPs) to boost M2-exosome (M2-Exo) secretion. The cultivated M2-Exo were finally encapsulated into a biocompatible collagen/decellularized extracellular matrix (COL@d-ECM) bioink for studying angiogenesis and in vivo wound healing study. Our findings show that 3D-printed AGP hydrogel promoted M2 macrophage polarization by Janus kinase/signal transducer of activation (JAK/STAT), peroxisome proliferator-activated receptor (PPAR) signaling pathways and facilitated the M2-Exo secretion. Moreover, the COL@d-ECM/M2-Exo was found to be biocompatible with skin cells. Transcriptomic (RNA-Seq) and real-time PCR (qRT-PCR) study revealed that co-culture of fibroblast/keratinocyte/stem cells/endothelial cells in a 3D bioprinted COL@d-ECM/M2-Exo hydrogel upregulated the skin-associated signature biomarkers through various regulatory pathways during epidermis remodeling and downregulated the mitogen-activated protein kinase (MAPK) signaling pathway after 7 days. In a subcutaneous wound model, the 3D bioprinted COL@d-ECM/M2-Exo hydrogel displayed robust wound remodeling and hair follicle (HF) induction while reducing canonical pro-inflammatory activation after 14 days, presenting a viable therapeutic strategy for skin-related disorders.

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通过免疫调节生物材料对 M2 极化巨噬细胞分泌的工程外泌体进行三维生物打印，促进体内伤口愈合和血管生成

生物材料的成分和表面电荷在巨噬细胞极化中起着关键作用，为免疫调节和组织再生提供了分子线索。在这项研究中，我们开发了双功能水凝胶墨，用于加速 M2 巨噬细胞极化和外泌体（Exo）培养，以促进伤口愈合。为此，我们首先制作了由海藻酸盐/明胶/多巴胺纳米球（AG/NSPs）组成的聚胺改性三维（3D）可打印水凝胶，以促进M2-外泌体（M2-Exo）的分泌。培养的M2-外泌体最后被封装到生物相容性胶原/脱细胞细胞外基质（COL@d-ECM）生物墨水中，用于研究血管生成和体内伤口愈合。我们的研究结果表明，三维打印的 AGP 水凝胶通过 Janus 激酶/活化信号转导因子（JAK/STAT）、过氧化物酶体增殖激活受体（PPAR）信号通路促进了 M2 巨噬细胞的极化，并促进了 M2-Exo 的分泌。此外，研究还发现 COL@d-ECM/M2-Exo 与皮肤细胞具有生物相容性。转录组（RNA-Seq）和实时 PCR（qRT-PCR）研究表明，成纤维细胞/角质形成细胞/干细胞/内皮细胞在三维生物打印的 COL@d-ECM/M2-Exo 水凝胶中共同培养 7 天后，在表皮重塑过程中通过各种调控途径上调与皮肤相关的标志性生物标志物，并下调丝裂原活化蛋白激酶（MAPK）信号通路。在皮下伤口模型中，三维生物打印的 COL@d-ECM/M2-Exo 水凝胶在 14 天后显示出强大的伤口重塑和毛囊（HF）诱导能力，同时降低了典型的促炎激活，为皮肤相关疾病提供了一种可行的治疗策略。

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来源期刊

Bioactive Materials Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

28.00

自引率

6.30%

发文量

436

审稿时长

20 days

期刊介绍： Bioactive Materials is a peer-reviewed research publication that focuses on advancements in bioactive materials. The journal accepts research papers, reviews, and rapid communications in the field of next-generation biomaterials that interact with cells, tissues, and organs in various living organisms. The primary goal of Bioactive Materials is to promote the science and engineering of biomaterials that exhibit adaptiveness to the biological environment. These materials are specifically designed to stimulate or direct appropriate cell and tissue responses or regulate interactions with microorganisms. The journal covers a wide range of bioactive materials, including those that are engineered or designed in terms of their physical form (e.g. particulate, fiber), topology (e.g. porosity, surface roughness), or dimensions (ranging from macro to nano-scales). Contributions are sought from the following categories of bioactive materials: Bioactive metals and alloys Bioactive inorganics: ceramics, glasses, and carbon-based materials Bioactive polymers and gels Bioactive materials derived from natural sources Bioactive composites These materials find applications in human and veterinary medicine, such as implants, tissue engineering scaffolds, cell/drug/gene carriers, as well as imaging and sensing devices.