Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis

Limei Li; Qing Li; Li Gui; Yi Deng; Lu Wang; Jianlin Jiao; Yingrui Hu; Xiaoqian Lan; Jianhong Hou; Yao Li; Di Lu

doi:10.1016/j.bioactmat.2022.03.037

Sequential gastrodin release PU/n-HA composite scaffolds reprogram macrophages for improved osteogenesis and angiogenesis

Bioact Mater. 2022 Apr 1:19:24-37. doi: 10.1016/j.bioactmat.2022.03.037. eCollection 2023 Jan.

Authors

Limei Li¹, Qing Li¹, Li Gui², Yi Deng³, Lu Wang¹, Jianlin Jiao¹, Yingrui Hu¹, Xiaoqian Lan⁴, Jianhong Hou⁵, Yao Li⁶, Di Lu¹

Affiliations

¹ Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, 650500, China.
² Department of Endocrinology, The Third People's Hospital of Yunnan Province, Kunming, 650011, China.
³ School of Chemical Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China.
⁴ Department of Neurology, The First Affiliated Hospital, Kunming Medical University, Kunming, 650000, China.
⁵ Department of Orthopaedics, The Third People's Hospital of Yunnan Province, Kunming, 650011, China.
⁶ Department of Stomatology, The First People's Hospital of Yunnan Province, Kunming, 650032, China.

Abstract

Wound healing is a highly orchestrated process involving a variety of cells, including immune cells. Developing immunomodulatory biomaterials for regenerative engineering applications, such as bone regeneration, is an appealing strategy. Herein, inspired by the immunomodulatory effects of gastrodin (a bioactive component in traditional Chinese herbal medicine), a series of new immunomodulatory gastrodin-comprising biodegradable polyurethane (gastrodin-PU) and nano-hydroxyapatite (n-HA) (gastrodin-PU/n-HA) composites were developed. RAW 264.7 macrophages, rat bone marrow mesenchymal stem cells (rBMSCs), and human umbilical vein endothelial cells (HUVECs) were cultured with gastrodin-PU/n-HA containing different concentrations of gastrodin (0.5%, 1%, and 2%) to decipher their immunomodulatory effects on osteogenesis and angiogenesis in vitro. Results demonstrated that, compared with PU/n-HA, gastrodin-PU/n-HA induced macrophage polarization toward the M2 phenotype, as evidenced by the higher expression level of pro-regenerative cytokines (CD206, Arg-1) and the lower expression of pro-inflammatory cytokines (iNOS). The expression levels of osteogenesis-related factors (BMP-2 and ALP) in the rBMSCs and angiogenesis-related factors (VEGF and BFGF) in the HUVECs were significantly up-regulated in gastrodin-PU/n-HA/macrophage-conditioned medium. The immunomodulatory effects of gastrodin-PU/n-HA to reprogram macrophages from a pro-inflammatory (M1) phenotype to an anti-inflammatory and pro-healing (M2) phenotype were validated in a rat subcutaneous implantation model. And the 2% gastrodin-PU/n-HA significantly decreased fibrous capsule formation and enhanced angiogenesis. Additionally, 2% gastrodin-PU/n-HA scaffolds implanted in the rat femoral condyle defect model showed accelerated osteogenesis and angiogenesis. Thus, the novel gastrodin-PU/n-HA scaffold may represent a new and promising immunomodulatory biomaterial for bone repair and regeneration.

Keywords: Angiogenesis; Gastrodin-delivery; Immune/inflammatory response; Osteogenesis; Tissue repair.