Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants
Multiple tissue response modifiers to promote angiogenesis and prevent the foreign body reaction around subcutaneous implants
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DOI：
10.1016/j.jconrel.2015.07.021
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发表时间：
2015-09-28
影响因子：
10.8
通讯作者：
Burgess, Diane J.
中科院分区：
文献类型：
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作者：
Kastellorizios, Michail;Papadimitrakopoulos, Fotios;Burgess, Diane J.
地塞米松释放PLGA聚（乳酸-羟基乙酸）微球/PVA（聚乙烯醇）水凝胶复合涂层已经在小型和大型动物模型中被证明可以防止皮下植入物的异物反应（FBR）。开发这种涂层是为了延长植入式生物传感器的使用寿命。然而，由于地塞米松的抗血管生成作用，组织长期暴露于低水平的地塞米松会导致血管密度降低。这种轻微的影响，虽然不会威胁到受试者的健康，但可能会干扰分析物检测和传感器的长期响应时间。目前的工作集中在涂层的开发，提供三种组织反应调节剂（TRMs）的组合：地塞米松，VEGF（血管内皮生长因子）和PDGF（血小板衍生生长因子）。地塞米松、VEGF和PDGF分别阻止FBR、增加血管生成和促进血管成熟（增加血流量）。为了尽量减少这三种trm之间的任何潜在干扰（例如，PDGF增加纤维化），调整地塞米松、VEGF和PDGF的相对剂量。结果表明：a)所有三种TRMs都需要最大限度地促进血管生成、血管成熟和预防FBR；b) VEGF的剂量必须高于PDGF；C)地塞米松剂量的增加必须伴随着生长因子剂量的成比例增加；修改TRM比率可以在整个植入期间实现恒定的毛细密度，这对于生物传感器等应用保持灵敏度和稳定的传感器基线非常重要。此外，开发了一种渗透驱动的蛋白包封工艺，该工艺在低爆发释放的PLGA微球中显示。(C) 2015 Elsevier B.V.版权所有
Dexamethasone-releasing PLGA poly(lactic-co-glycolic acid) microsphere/PVA (polyvinyl alcohol) hydrogel composite coatings have been shown to prevent the foreign body reaction (FBR) to subcutaneous implants in small and large animal models. Such coatings were developed to extend the lifetime of implantable biosensors. However, long-term exposure of tissue to low levels of dexamethasone results in a reduction in blood vessel density due to the anti-angiogenic effect of dexamethasone. This mild effect, while not threatening to the subject's health, may interfere with analyte detection and the sensor response time over the long-term. The present work is focused on the development of coatings that deliver combinations of three tissue response modifiers (TRMs): dexamethasone, VEGF (vascular endothelial growth factor) and PDGF (platelet derived growth factor). Dexamethasone, VEGF and PDGF prevent the FBR, increase angiogenesis and promote blood vessel maturation (which increases blood flow), respectively. To minimize any potential interference among these three TRMs (for example, PDGF increases fibrosis), the relative doses of dexamethasone, VEGF and PDGF were adjusted. It was determined that: a) all three TRMs are required for maximum promotion of angiogenesis, blood vessel maturation and prevention of the FBR; b) VEGF has to be administered at higher doses than PDGF; c) an increase in dexamethasone dosing must be accompanied by a proportional increase in growth factor dosing; and d) modification of the TRM ratio can achieve a constant capillary density throughout the implantation period which is important for applications such as biosensors to maintain sensitivity and a stable sensor baseline. Moreover, an osmosis-driven process for encapsulation of proteins in PLGA microspheres that showed low burst release was developed. (C) 2015 Elsevier B.V. All rights reserved.