Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes

Yanzhao Li; Yeqin Wang; Fangchao Xue; Xuli Feng; Zhaojing Ba; Junjie Chen; Zhenhua Zhou; Yanhong Wang; Ge Guan; Guanyuan Yang; Ziwei Xi; Hao Tian; Yong Liu; Ju Tan; Gang Li; Xiewan Chen; Mingcan Yang; Wen Chen; Chuhong Zhu; Wen Zeng

doi:10.1016/j.bioactmat.2021.05.034

Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes

Bioact Mater. 2021 Jun 25:7:466-477. doi: 10.1016/j.bioactmat.2021.05.034. eCollection 2022 Jan.

Authors

Yanzhao Li¹, Yeqin Wang², Fangchao Xue², Xuli Feng³, Zhaojing Ba², Junjie Chen², Zhenhua Zhou⁴, Yanhong Wang², Ge Guan¹, Guanyuan Yang¹, Ziwei Xi¹, Hao Tian¹, Yong Liu¹, Ju Tan¹, Gang Li¹, Xiewan Chen⁵, Mingcan Yang¹, Wen Chen⁶, Chuhong Zhu^{1

6

7}, Wen Zeng^{2

4

8}

Affiliations

¹ Department of Anatomy, National and Regional Engineering Laboratory of Tissue Engineering, State and Local Joint Engineering Laboratory for Vascular Implants, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Third Military Medical University, Chongqing, 400038, China.
² Department of Cell Biology, Third Military Army Medical University, Chongqing, 400038, China.
³ Innovative Drug Research Centre of Chongqing University, Chongqing, 401331, China.
⁴ Departments of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, China.
⁵ Medical English Department, Third Military Medical University, Chongqing, 400038, China.
⁶ The 8th Medical Center of Chinese PLA General Hospital, Beijing, 100091, China.
⁷ Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
⁸ State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China.

Abstract

Small-diameter tissue-engineered vascular grafts (sdTEVGs) with hyperglycemia resistance have not been constructed. The intimal hyperplasia caused by hyperglycemia remains problem to hinder the patency of sdTEVGs. Here, inspired by bionic regulation of nerve on vascular, we found the released neural exosomes could inhibit the abnormal phenotype transformation of vascular smooth muscle cells (VSMCs). The transformation was a prime culprit causing the intimal hyperplasia of sdTEVGs. To address this concern, sdTEVGs were modified with an on-demand programmable dual-responsive system of ultrathin hydrogels. An external primary Reactive Oxygen Species (ROS)-responsive Netrin-1 system was initially triggered by local inflammation to induce nerve remolding of the sdTEVGs overcoming the difficulty of nerve regeneration under hyperglycemia. Then, the internal secondary ATP-responsive DENND1A (guanine nucleotide exchange factor) system was turned on by the neurotransmitter ATP from the immigrated nerve fibers to stimulate effective release of neural exosomes. The results showed nerve fibers grow into the sdTEVGs in diabetic rats 30 days after transplantation. At day 90, the abnormal VSMCs phenotype was not detected in the sdTEVGs, which maintained long-time patency without intima hyperplasia. Our study provides new insights to construct vascular grafts resisting hyperglycemia damage.

Keywords: Intimal hyperplasia; Nerve reconstruction; Neural exosomes; On-demand programmed responsive systems; sdTEVGs.