Modification of PLGA Scaffold by MSC‐Derived Extracellular Matrix Combats Macrophage Inflammation to Initiate Bone Regeneration via TGF‐β‐Induced Protein

Abstract

The immunologic response toward chronic inflammation or bone regeneration via the accumulation of M1 or M2 macrophages after injury could determine the fate of biomaterial. Human umbilical cord mesenchymal stem cells (hUCMSCs) have a pivotal immunomodulatory property on directing macrophage behaviors. Herein, for the first time, 3D‐printed poly(lactide‐co‐glycolide) (PLGA) scaffolds modified with hUCMSC‐derived extracellular matrix (PLGA‐ECM) are prepared by a facile tissue engineering technique with physical decellularization and 2.44 ± 0.29 mg cm−3 proteins immobilized on the PLGA‐ECM contain multiple soluble cytokines with a sustainable release profile. The PLGA‐ECM not only attenuates the foreign body response, but also improves bone regeneration by increasing the accumulation of M2 macrophages in an improved heterotopic transplantation model of SCID mice. Furthermore, the PLGA‐ECM scaffolds with the knockdown of transforming growth factor‐β‐induced protein (TGFβI/βig‐H3) demonstrate that M2 macrophage accumulation improved by the PLGA‐ECM could be attributed to increasing the migration of M2 macrophages and the repolarization of M1 macrophages to M2 phenotype, which are mediated by multiple integrin signaling pathways involving in integrin β7, integrin α9, and integrin β1 in a TGFβI‐dependent manner. This study presents an effective surface modification strategy of polymeric scaffolds to initiate tissue regeneration and combat inflammatory response by increasing M2 macrophage accumulation.

Host Response to Biomaterials for Cartilage Tissue Engineering: Key to Remodeling

“…M1 macrophages can drive the inflammatory response, causing the scaffold to be wrapped in fibrous tissue, separating it from the surrounding tissue ( Fujihara et al, 2020 ). In contrast, M2 macrophages have anti-inflammatory properties and promote repair ( Ma et al, 2014 ; Hotchkiss et al, 2018 ; Deng et al, 2020 ).…”

Mesenchymal Stem Cell-Macrophage Crosstalk and Maintenance of Inflammatory Microenvironment Homeostasis

“…Promote lung cancer development Gazdic et al, 2017;Ren et al, 2019 (Continued) Frontiers in Cell and Developmental Biology | www.frontiersin.org Gong et al, 2016;Zhang et al, 2017;Deng et al, 2020; In vitro M2 macrophages, thereby forming a feedback pathway that enables MSC therapy improvement in hepatic injury (Bartosh et al, 2013;Lee et al, 2015;Reading et al, 2015;Luz-Crawford et al, 2016). Ko et al (2020) reported that macrophagederived amphiregulin is essential for MSC-mediated CD4+ T cell suppression and preserves epithelial stem cells to alleviate autoimmune uveoretinitis.…”

“…Gong et al (2016) also found that macrophage polarization plays an extremely important role in regulating MSC osteogenic differentiation to maintain bone homeostasis and bone regeneration. In addition, the MSCderived extracellular matrix alleviates macrophage inflammation to promote bone regeneration (Deng et al, 2020). Other studies have shown that for certain materials, the interaction between MSCs and macrophages includes the MSC-induced transformation macrophage phenotypes and macrophageinduced promotion of MSC differentiation; therefore, the physiological functions of MSCs and macrophages are regulated to improve osseointegration and promote bone repair (He et al, 2019;Mahon et al, 2020).…”

Current Advances in 3D Bioprinting Technology and Its Applications for Tissue Engineering

“…However, surface coating and plasma treatment can improve protein adsorption and enhance cell affinity [125]. Surface-modified bioprinted PLA and PLGA can provide a 3D cell culture environment for building various types of tissues [126][127][128].…”