Neuronano Research Center, Department of Experimental Medical Science, Faculty of Medicine, Lund University, Medicon Village, Building 404 A2, Scheelevägen 2, 223 81, Lund, Sweden.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00, Lund, Sweden.
J Nanobiotechnology. 2020 Feb 5;18(1):27. doi: 10.1186/s12951-020-0585-9.
Neural interfaces often elicit inflammatory responses and neuronal loss in the surrounding tissue which adversely affect the function and longevity of the implanted device. Minocycline, an anti-inflammatory pharmaceutics with neuroprotective properties, may be used for reducing the acute brain tissue responses after implantation. However, conventional administration routes require high doses which can cause adverse systemic side effects. Therefore, the aim of this study was to develop and evaluate a new drug-delivery-system for local and sustained administration of minocycline in the brain.
Stainless steel needles insulated with Parylene-C were dip-coated with non-crosslinked gelatin and minocycline-loaded PLGA nanoparticles (MC-NPs) were incorporated into the gelatin-coatings by an absorption method and subsequently trapped by drying the gelatin. Parylene-C insulated needles coated only with gelatin were used as controls. The expression of markers for activated microglia (CD68), all microglia (CX3CR1-GFP), reactive astrocytes (GFAP), neurons (NeuN) and all cell nuclei (DAPI) surrounding the implantation sites were quantified at 3 and 7 days after implantation in mice.
MC-NPs were successfully incorporated into gelatin-coatings of neural implants by an absorption method suitable for thermosensitive drug-loads. Immunohistochemical analysis of the in vivo brain tissue responses, showed that MC-NPs significantly attenuate the activation of microglial cells without effecting the overall population of microglial cells around the implantation sites. A delayed but significant reduction of the astrocytic response was also found in comparison to control implants. No effect on neurons or total cell count was found which may suggest that the MC-NPs are non-toxic to the central nervous system.
A novel drug-nanoparticle-delivery-system was developed for neural interfaces and thermosensitive drug-loads. The local delivery of MC-NPs was shown to attenuate the acute brain tissue responses nearby an implant and therefore may be useful for improving biocompatibility of implanted neuro-electronic interfaces. The developed drug-delivery-system may potentially also be used for other pharmaceutics to provide highly localized and therefore more specific effects as compared to systemic administration.
神经接口通常会在周围组织中引发炎症反应和神经元丢失，从而对植入设备的功能和寿命产生不利影响。米诺环素是一种具有神经保护作用的抗炎药物，可用于减少植入后的急性脑组织反应。然而，传统的给药途径需要高剂量，这可能会导致不良的全身副作用。因此，本研究的目的是开发和评估一种新的药物输送系统，用于在大脑中局部和持续给予米诺环素。
用 Parylene-C 绝缘的不锈钢针用非交联明胶浸涂，并用吸收法将载有米诺环素的 PLGA 纳米颗粒（MC-NPs）掺入明胶涂层中，然后通过干燥明胶将其捕获。仅用明胶涂覆的 Parylene-C 绝缘针用作对照。在小鼠植入后 3 天和 7 天，定量分析植入部位周围表达激活小胶质细胞（CD68）、所有小胶质细胞（CX3CR1-GFP）、反应性星形胶质细胞（GFAP）、神经元（NeuN）和所有细胞核（DAPI）的标志物。
通过适用于热敏药物负载的吸收法，成功地将 MC-NPs 掺入神经植入物的明胶涂层中。体内脑组织反应的免疫组织化学分析表明，MC-NPs 可显著抑制小胶质细胞的激活，而对植入部位周围小胶质细胞的总体群体无影响。与对照植入物相比，还发现星形胶质细胞反应延迟但显著减少。未发现对神经元或总细胞计数有影响，这可能表明 MC-NPs 对中枢神经系统无毒。
开发了一种用于神经接口和热敏药物负载的新型药物-纳米颗粒输送系统。局部给予 MC-NPs 可减轻植入物附近的急性脑组织反应，因此可能有助于改善植入神经电子接口的生物相容性。开发的药物输送系统还可能用于其他药物，以提供比全身给药更具局部性和更特异性的作用。
