Mechanisms of Foreign Body Response Mitigation by Nitric Oxide Release.
Mechanisms of Foreign Body Response Mitigation by Nitric Oxide Release.
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DOI：
10.3390/ijms231911635
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发表时间：
2022-10-01
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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植入式葡萄糖生物传感器提供关于血糖波动的实时信息，但其实用性和准确性受到时间限制，因为它们插入皮肤下后会产生异物反应(FBR)。一氧化氮(NO)是一种具有炎症调节特性的气体递质，它从传感器表面缓慢释放，已被证明通过降低整体FBR响应来显著提高传感器的分析生物兼容性。事实上，在猪模型中的研究表明，只要植入物(传感器)继续释放NO，即使在低水平，炎症细胞的渗透和由此产生的胶原密度也会减少。虽然这些研究有力地支持了NO释放在缓解FBR方面的好处，但外源性NO作用于周围组织，特别是在高血糖条件下的机制仍然不清楚。这些知识将为改进适当的NO剂量和释放动力学以实现最佳治疗活性的策略提供依据。在这项研究中，我们评估了植入传感器周围局部组织微环境中介质、免疫细胞和mRNA的表达情况，作为NO释放、糖尿病和植入时间的函数。构建了一种用于纳米串条码分析的猪创伤愈合中心复合基因阵列。传感器附近的组织持续释放NO，通过调节组织特异性免疫趋化因子和细胞因子微环境，取消了植入物诱导的急性和慢性FBR，导致FBR急性期(7天)和慢性期(14天)的细胞募集、增殖和激活减少。此外，我们发现持续的NO释放通过调节编码关键免疫信号分子和通路的mRNA，包括STAT1和包括MAPK14、IRAK4、MMP2和CXCL10在内的多个STAT1靶标来消除植入物诱导的急性和慢性异物反应。糖尿病的状况促进了植入物更强大的FBR，这也是由持续的NO释放控制的。
Implantable glucose biosensors provide real-time information about blood glucose fluctuations, but their utility and accuracy are time-limited due to the foreign body response (FBR) following their insertion beneath the skin. The slow release of nitric oxide (NO), a gasotransmitter with inflammation regulatory properties, from a sensor surface has been shown to dramatically improve sensors’ analytical biocompatibility by reducing the overall FBR response. Indeed, work in a porcine model suggests that as long as the implants (sensors) continue to release NO, even at low levels, the inflammatory cell infiltration and resulting collagen density are lessened. While these studies strongly support the benefits of NO release in mitigating the FBR, the mechanisms through which exogenous NO acts on the surrounding tissue, especially under the condition of hyperglycemia, remain vague. Such knowledge would inform strategies to refine appropriate NO dosage and release kinetics for optimal therapeutic activity. In this study, we evaluated mediator, immune cell, and mRNA expression profiles in the local tissue microenvironment surrounding implanted sensors as a function of NO release, diabetes, and implantation duration. A custom porcine wound healing-centric multiplex gene array was developed for nanoString barcoding analysis. Tissues adjacent to sensors with sustained NO release abrogated the implant-induced acute and chronic FBR through modulation of the tissue-specific immune chemokine and cytokine microenvironment, resulting in decreased cellular recruitment, proliferation, and activation at both the acute (7-d) and chronic (14-d) phases of the FBR. Further, we found that sustained NO release abrogated the implant-induced acute and chronic foreign body response through modulation of mRNA encoding for key immunological signaling molecules and pathways, including STAT1 and multiple STAT1 targets including MAPK14, IRAK4, MMP2, and CXCL10. The condition of diabetes promoted a more robust FBR to the implants, which was also controlled by sustained NO release.
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影响因子：
16.6
作者：
Chen Y;Yang S;Lovisa S;Ambrose CG;McAndrews KM;Sugimoto H;Kalluri R
通讯作者：
Kalluri R
影响因子：
3.9
作者：
Hall, Jackson R.;Maloney, Sara E.;Schoenfisch, Mark H.
通讯作者：
Schoenfisch, Mark H.
影响因子：
2.2
作者：
FAHEY, TJ;SADATY, A;SHIRES, GT
通讯作者：
SHIRES, GT
影响因子：
7.4
作者：
Nichols, Scott P.;Le, Nga N.;Schoenfisch, Mark H.
通讯作者：
Schoenfisch, Mark H.
影响因子：
3.7
作者：
Fernando MR;Reyes JL;Iannuzzi J;Leung G;McKay DM
通讯作者：
McKay DM