Therapeutic delivery to the brain is limited by the blood-brain barrier and is exacerbated by off-target effects associated with systemic delivery, thereby precluding many potential therapies from even being tested. Given the systemic side effects of cyclosporine and erythropoietin, systemic administration would be precluded in the context of stroke, leaving only the possibility of local delivery. We wondered if direct delivery to the brain would allow new reparative therapeutics, such as these, to be identified for stroke. Using a rodent model of stroke, we employed an injectable drug delivery hydrogel strategy to circumvent the blood-brain barrier and thereby achieved, for the first time, local and sustained co-release to the brain of cyclosporine and erythropoietin. Both drugs diffused to the sub-cortical neural stem and progenitor cell (NSPC) niche and were present in the brain for at least 32 days post-stroke. Each drug had a different outcome on brain tissue: cyclosporine increased plasticity in the striatum while erythropoietin stimulated endogenous NSPCs. Only their co-delivery, but not either drug alone, accelerated functional recovery and improved tissue repair. This platform opens avenues for hitherto untested therapeutic combinations to promote regeneration and repair after stroke.

中文翻译：

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注射式水凝胶可实现局部和持续向大脑的共同递送：两种临床批准的生物分子，环孢素和促红细胞生成素，可加速中风大鼠模型的功能恢复。

脑血的治疗受到血脑屏障的限制，与全身性转移相关的脱靶效应加剧了这种情况，从而甚至无法测试许多潜在的治疗方法。考虑到环孢霉素和促红细胞生成素的全身性副作用，在中风的情况下将不进行全身性给药，仅留下局部给药的可能性。我们想知道直接递送至大脑是否可以识别出针对中风的新型修复疗法。使用中风的啮齿动物模型，我们采用了可注射药物输送水凝胶策略来规避血脑屏障，从而首次实现了环孢素和促红细胞生成素向大脑局部和持续的共释放。两种药物均扩散至皮层下神经干细胞和祖细胞（NSPC）小生境，并在中风后至少存在32天。每种药物在脑组织上都有不同的结局：环孢霉素增加纹状体的可塑性，而促红细胞生成素刺激内源性NSPC。仅它们的共同递送，而不是单独的一种药物，可以加速功能恢复并改善组织修复。该平台为迄今为止未经测试的治疗组合打开了途径，以促进中风后的再生和修复。加快功能恢复并改善组织修复。该平台为迄今为止未经测试的治疗组合打开了途径，以促进中风后的再生和修复。加快功能恢复并改善组织修复。该平台为迄今为止未经测试的治疗组合打开了途径，以促进中风后的再生和修复。