Davis Brett, Wojtalewicz Susan, Labroo Pratima, Shea Jill, Sant Himanshu, Gale Bruce, Agarwal Jayant
Department of Bioengineering, University of Utah; Department of Surgery, University of Utah, Salt Lake City, UT, USA.
Department of Bioengineering, University of Utah, Salt Lake City, UT, USA.
Neural Regen Res. 2018 Jul;13(7):1247-1252. doi: 10.4103/1673-5374.235063.
After decades of research, peripheral nerve injury and repair still frequently results in paralysis, chronic pain and neuropathies leading to severe disability in patients. Current clinically available nerve conduits only provide crude guidance of regenerating axons across nerve gap without additional functionality. FK506 (Tacrolimus), an FDA approved immunosuppressant, has been shown to enhance peripheral nerve regeneration but carries harsh side-effects when delivered systemically. The objective of this study was to develop and evaluate a bioresorbable drug delivery system capable of local extended delivery of FK506 that also provides topological guidance cues to guide axon growth via microgrooves. Photolithography was used to create micropatterned poly(lactide-co-glycolic acid) (PLGA) films embedded with FK506. Non-patterned, 10/10 μm (ridge/groove width), and 30/30 μm patterned films loaded with 0, 1, and 3 μg/cm FK506 were manufactured and characterized. In vitro FK506 rate of release testing indicated that the films are capable of an extended (at least 56 days), controlled, and scalable release of FK506. Neurite extension bioactivity assay indicated that FK506 released from the films (concentration of samples tested ranged between 8.46-19.7 ng/mL) maintained its neural bioactivity and promoted neurite extension similar to control FK506 dosages (10 ng/mL FK506). The multi-functional FK506 embedded, micropatterned poly(lactide-co-glycolic acid) films developed in this study have potential to be used in the construction of peripheral nerve repair devices.
经过数十年的研究，周围神经损伤与修复仍常常导致患者出现瘫痪、慢性疼痛和神经病变，进而造成严重残疾。目前临床上可用的神经导管仅能为再生轴突跨越神经间隙提供粗略的引导，并无其他附加功能。FK506（他克莫司）是一种经美国食品药品监督管理局（FDA）批准的免疫抑制剂，已被证明可促进周围神经再生，但全身给药时会产生严重的副作用。本研究的目的是开发并评估一种可生物降解的药物递送系统，该系统能够局部延长递送FK506，同时还能通过微槽提供拓扑引导线索以引导轴突生长。采用光刻技术制备了嵌入FK506的微图案化聚乳酸-乙醇酸共聚物（PLGA）薄膜。制备并表征了加载0、1和3μg/cm FK506的无图案、10/10μm（脊/槽宽度）和30/30μm图案化薄膜。体外FK506释放速率测试表明，这些薄膜能够实现FK506的延长（至少56天）、可控且可扩展的释放。神经突延伸生物活性测定表明，从薄膜中释放的FK506（测试样品的浓度范围为8.46 - 19.7 ng/mL）保持了其神经生物活性，并促进了神经突延伸，类似于对照FK506剂量（10 ng/mL FK506）。本研究中开发的嵌入多功能FK506的微图案化聚乳酸-乙醇酸共聚物薄膜有潜力用于构建周围神经修复装置。
