Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes.
Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes.
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可编程双响应系统重建神经与小直径组织工程血管移植物的相互作用并抑制糖尿病患者的内膜增生
DOI：
10.1016/j.bioactmat.2021.05.034
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发表时间：
2022-01
影响因子：
18.9
通讯作者：
Zeng W
中科院分区：
文献类型：
--
作者：
Li Y;Wang Y;Xue F;Feng X;Ba Z;Chen J;Zhou Z;Wang Y;Guan G;Yang G;Xi Z;Tian H;Liu Y;Tan J;Li G;Chen X;Yang M;Chen W;Zhu C;Zeng W
具有高血糖抵抗性的小直径组织工程血管移植物（sdTEVGs）尚未被构建。高血糖引起的内膜增生仍然是阻碍sdTEVGs通畅的问题。受神经对血管的仿生调节的启发，我们发现释放的神经外泌体可以抑制血管平滑肌细胞（VSMCs）的异常表型转化。这种转化是导致sdTEVGs内膜增生的罪魁祸首。为了解决这个问题，sdtevg采用了一种按需可编程的超薄水凝胶双响应系统。首先通过局部炎症触发外源性活性氧（ROS）应答的Netrin-1系统，诱导sdTEVGs的神经重塑，克服高血糖下神经再生的困难。然后，内部次级ATP反应的DENND1A（鸟嘌呤核苷酸交换因子）系统被来自移入神经纤维的神经递质ATP打开，刺激神经外泌体的有效释放。结果显示，糖尿病大鼠的神经纤维在移植后30天内发育为sdTEVGs。在第90天，在sdtevg中未检测到异常的VSMCs表型，维持了长时间的通畅，没有内膜增生。本研究为构建抗高血糖损伤血管移植提供了新的思路。在高糖条件下，VSMCs发生表型转变，导致sdtevg的内膜增生。神经外泌体可以抑制VSMCs由收缩型向合成型的异常表型转化。具有按需可编程双反应系统的SdTEVGs抑制糖尿病内膜增生。
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. VSMCs undergo a phenotypic transformation under high glucose, which lead to intimal hyperplasia in sdTEVGs. Neural exosomes could inhibit the abnormal phenotype transformation of VSMCs from contractile to synthetic. SdTEVGs with on-demand programmable dual responsive system inhibited intimal hyperplasia in diabetes.
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