Biodegradable amino acid-based poly(ester amine) with tunable immunomodulating properties and their in vitro and in vivo wound healing studies in diabetic rats' wounds
Biodegradable amino acid-based poly(ester amine) with tunable immunomodulating properties and their in vitro and in vivo wound healing studies in diabetic rats' wounds
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DOI：
10.1016/j.actbio.2018.11.053
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发表时间：
2019-01-15
影响因子：
9.7
通讯作者：
Chu, Chih-Chang
中科院分区：
文献类型：
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作者：
He, Mingyu;Sun, Luyao;Chu, Chih-Chang
本研究的目的是设计一种新的可生物降解的合成聚合物生物材料家族，用于提供对巨噬细胞的一氧化氮合酶（NOS）通路的可调抑制。L-精氨酸（Arg）是一氧化氮合酶（NOS）和谷胱甘肽转移酶（GST）的共同底物。两种代谢途径都参与伤口愈合过程。受损的伤口愈合，如糖尿病或其他慢性伤口，通常与巨噬细胞通过NOS途径过度产生NO有关。本研究设计并合成了一类新的基于L-硝基精氨酸（NOArg）的聚酯酰胺（NOArg-PEA）和NOArg-Arg-PEA共聚物（co-PEA）。NOArg-PEA和NOArg-Arg co-PEA是可生物降解的（在37 ℃下4天内体外降解超过50%）、生物相容性的，并且本身不激活静息巨噬细胞免疫应答。NOArg-PEA和NOArg-Arg co-PEA处理经典活化或交替活化的巨噬细胞（CAM/AAM），可降低CAM的NO生成，增加CAM和AAM的β-淀粉酶活性，不同程度地增加CAM的TGF-β 1生成，对TNF-α生成无明显影响。使用糖尿病大鼠模型来评价NOArg-PEA和NOArg-Arg co-PEA对伤口愈合的功效。用2-NOArg-4 PEA、2-NOArg-4-Arg-4 20/80和2-NOArg-4-Arg-4 50/50生物材料治疗的糖尿病大鼠在第7天与对照组相比伤口愈合快40%-80%。来自组织学和免疫组织化学分析的数据显示，2-NOArg-4-Arg-4 20/80和2-NOArg-4-Arg-4 50/50处理导致在前7天内伤口组织中比对照更多的AAM表型（CD 206）和AAM酶I产生，即，表明具有改善的伤口愈合的上皮再形成的促愈合伤口微环境。类似的趋势一直保持到第14天。2-NOArg-4-Arg-4 20/80和2-NOArg-4-Arg-4 50/50处理也增加了第7天和第14天之间愈合伤口中的胶原沉积和血管生成。本研究的体外和体内数据均表明，这种新的NOArg-Arg co-PEA生物材料家族具有作为治疗受损伤口愈合的可行替代品的潜力，例如糖尿病或其他类型的慢性wounds.Statement of Significance糖尿病或其他慢性伤口通常与巨噬细胞过度产生NO和促炎信号有关。精氨酸补充剂或NOS抑制剂给药未能实现预期的伤口愈合改善，因为精氨酸催化剂的动态复杂性、从促炎性转化为促愈合的困难以及短期疗效。我们设计并合成了一个新的水溶性和可降解的硝基精氨酸-精氨酸聚酯酰胺家族，以重新平衡巨噬细胞的NOS/NOS酶代谢途径。它们在体外表现出可调的免疫调节特性。进行体内研究以评价其加速愈合的功效。这些新的生物材料具有作为治疗受损伤口愈合的可行替代品的潜力。《生物材料学报》的普通读者应该对这些发现感兴趣。(C)2018 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
The objective of this study is to design a new family of biodegradable synthetic polymeric biomaterials for providing a tunable inhibition of macrophage's nitric oxide synthase (NOS) pathway. L-Arginine (Arg) is the common substrate for NOS and arginase. Both two metabolic pathways participate in the wound healing process. An impaired wound healing, such as diabetic or other chronic wounds is usually associated with an overproduction of NO by macrophages via the NOS pathway. In this study, a new family of L-nitroarginine (NOArg) based polyester amide (NOArg-PEA) and NOArg-Arg PEA copolymers (co-PEA) were designed and synthesized with different composition ratios. The NOArg-PEA and NOArg-Arg co-PEAs are biodegradable (more than 50% degradation in vitro in 4 days at 37 degrees C), biocompatible and did not activate the resting macrophage immune response per se. When classically activated or alternatively activated macrophages (CAM/AAM) were incubated with NOArg-PEA and NOArg-Arg co-PEAs, the treatments decreased the NO production of CAM, increased the arginase activity in both CAM and AAM, increased TGF-beta 1 production of CAM to various degrees and had no significant effect on TNF-alpha production. Diabetic rat models were used to evaluate the efficacy of NOArg-PEA and NOArg-Arg co-PEAs on wound healing. Diabetic rats treated with 2-NOArg-4 PEA, 2-NOArg-4-Arg-4 20/80, and 2-NOArg-4-Arg-4 50/50 biomaterials achieved 40%-80% faster-wound healing when compared with the control on day 7. The data from the histological and immunohistochemical analysis showed that the 2-NOArg-4-Arg-4 20/80 and 2-NOArg-4-Arg-4 50/50 treatments led to more AAM phenotypes (CD206) and arginase I production in wound tissue than the control during the first 7 days, i.e., suggesting pro-healing wound microenvironment with improved re-epithelialization of wound healing. A similar trend was retained until day 14. The 2-NOArg-4-Arg-4 20/80 and 2-NOArg-4-Arg-4 50/50 treatments also increased the collagen deposition and angiogenesis in the healing wound between day 7 and day 14. Both in vitro and in vivo data of this study showed that this new family of NOArg-Arg co-PEA biomaterials have the potential as viable alternatives for treating impaired wound healing, such as diabetic or other types of chronic wounds.Statement of SignificanceDiabetic or other chronic wounds is usually associated with an overproduction of NO and pro inflammatory signals by macrophages. Arginine supplement or NOS inhibitors administration failed to achieve an expected improved wound healing because of the dynamic complexity of arginine catabolism, the difficulty in transition from pro-inflammatory to pro-healing, and the short-term efficacy. We designed and synthesized a new family of water-soluble and degradable nitroarginine-arginine polyester amides to rebalance NOS/arginase metabolism pathways of macrophages. They showed tunable immunomodulating properties in vitro. The in vivo studies were performed to evaluate their efficacy in accelerating the healing. These new biomaterials have the potential as viable alternatives for treating impaired wound healing. The general audience of Acta Biomaterialia should be interested in these findings. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.