Prevention of the foreign body response to implantable medical devices by inflammasome inhibition.
Prevention of the foreign body response to implantable medical devices by inflammasome inhibition.
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DOI：
10.1073/pnas.2115857119
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发表时间：
2022-03-22
影响因子：
11.1
通讯作者：
Bryant CE
中科院分区：
文献类型：
--
作者：
Barone DG;Carnicer-Lombarte A;Tourlomousis P;Hamilton RS;Prater M;Rutz AL;Dimov IB;Malliaras GG;Lacour SP;Robertson AAB;Franze K;Fawcett JW;Bryant CE
植入式电子医疗设备(IEMD)被用于一些临床应用，代表了帕金森氏病、耳聋和瘫痪等顽固性疾病的变革性治疗的令人兴奋的前景。目前IEMD的使用受到限制，因为随着时间的推移，异物反应(FBR)在设备-神经界面上发展，最终IEMD失败，需要移除。在这里，我们证明了在神经损伤模型中，巨噬细胞核苷酸结合的寡聚化结构域样受体家族包含3(NLRP3)的炎症体活性驱动FBR，而将NLRP3抑制剂整合到设备中可以防止FBR，同时允许受损神经组织的完全愈合。继发于异物反应(FBR)的纤维性瘢痕形成了一种物理屏障，阻碍了植入式医疗设备与宿主组织的功能相互作用。FBR的机制基础尚不清楚，限制了目前预防它的治疗选择。在这里，我们表明，在周围神经损伤-植入模型(NI)中，FBR具有失调的先天免疫模式，招募M1样活化的巨噬细胞、未成熟的巨噬细胞、激活的树突状细胞和未成熟的树突状细胞，与仅招募主要招募M2样巨噬细胞的神经损伤相比。FBR的基因特征显示肌成纤维细胞活性增加，这解释了为什么存在胶原和疤痕，但也上调了炎性肌小体成分。通过将核苷酸结合的寡聚化结构域样受体家族含有3(NLRP3)的炎症体抑制剂MCC950整合到植入物的硅胶涂层中，局部传递NLRP3受体家族吡咯结构域，可以减少与NI和皮下植入装置相关的炎症和纤维化。在NI模型中，MCC950不影响神经元修复。因此，抑制NLRP3炎症体可能是预防FBR的一种有前途的治疗方法，从而延长植入式医疗设备和神经植入物的功能寿命。
Implantable electronic medical devices (IEMDs) are used for some clinical applications, representing an exciting prospect for the transformative treatment of intractable conditions such Parkinson’s disease, deafness, and paralysis. The use of IEMDs is limited at the moment because, over time, a foreign body reaction (FBR) develops at the device–neural interface such that ultimately the IEMD fails and needs to be removed. Here, we show that macrophage nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activity drives the FBR in a nerve injury model yet integration of an NLRP3 inhibitor into the device prevents FBR while allowing full healing of damaged neural tissue to occur. Fibrotic scarring secondary to the foreign body reaction (FBR) generates a physical barrier obstructing the functional interaction of implantable medical devices with the host tissue. The mechanistic basis of the FBR is poorly understood, restricting the current therapeutic options to prevent it. Here, we show that in a peripheral nerve injury-implant model (NI) the FBR has a dysregulated innate immune profile recruiting M1-like activated macrophages, immature macrophages, activated dendritic cells, and immature dendritic cells compared with nerve injury alone, which recruits predominantly M2-like macrophages. The gene signature of the FBR shows increased myofibroblast activity, explaining why collagen and scarring are present, but also up-regulation of inflammasome constituents. Local delivery of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome inhibitor MCC950, through its incorporation into the silicone coating of implants, reduced the inflammation and fibrosis associated with both NI and subcutaneous implantable devices. In the NI model, MCC950 did not affect neuronal repair. Inhibition of the NLRP3 inflammasome may, therefore, be a promising therapeutic approach to prevent the FBR, hence prolonging the functional lifespan of implantable medical devices and neural implants.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1146/annurev-pathol-020712-163930
发表时间：
2013-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
Duffield JS;Lupher M;Thannickal VJ;Wynn TA
通讯作者：
Wynn TA
影响因子：
41.2
作者：
Doloff JC;Veiseh O;Vegas AJ;Tam HH;Farah S;Ma M;Li J;Bader A;Chiu A;Sadraei A;Aresta-Dasilva S;Griffin M;Jhunjhunwala S;Webber M;Siebert S;Tang K;Chen M;Langan E;Dholokia N;Thakrar R;Qi M;Oberholzer J;Greiner DL;Langer R;Anderson DG
通讯作者：
Anderson DG
影响因子：
--
作者：
Ewels P;Krueger F;Käller M;Andrews S
通讯作者：
Andrews S
影响因子：
6.7
作者：
Ataide MA;Andrade WA;Zamboni DS;Wang D;Souza Mdo C;Franklin BS;Elian S;Martins FS;Pereira D;Reed G;Fitzgerald KA;Golenbock DT;Gazzinelli RT
通讯作者：
Gazzinelli RT