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Efficacy of Local Tacrolimus Delivery in Allograft Nerve Transplantation

同种异体神经移植中他克莫司局部给药的疗效

基本信息

批准号：
9137754
负责人：
Jayant Prasad Agarwal
金额：
$ 18.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137754
关键词：
3-Dimensional Adverse effects Affect Allografting Area Autologous Autologous Transplantation Axon Biocompatible Caliber Cellular Structures Clinical Communities Device Designs Devices Diffusion Dimensions Drug Delivery Systems Excision FK506 Fiber Fracture Glycolates Glycolic-Lactic Acid Polyester Gold Graft Rejection Health Histologic Housing Immunosuppression Immunosuppressive Agents In Vitro Injury Kinetics Label Lead Lesion Life Mediating Medical Methods Modeling Morbidity - disease rate Motor Endplate Muscle Muscle function Natural regeneration Nerve Nerve Fibers Nerve Plexus Nerve Regeneration Organ Outcome Patient risk Patients Peripheral Nerves Peripheral nerve injury Pharmaceutical Preparations Polymers Positioning Attribute Prevention Process Property Quality of life Rattus Recovery of Function Research Site Staining method Stains Supporting Cell Tacrolimus Techniques Testing Therapeutic Therapeutic immunosuppression Tissues Transplantation Trauma Trauma patient Walking Weight Withdrawal Work allograft rejection base comparison group density design disability functional outcomes improved improved outcome in vivo injured local drug delivery mathematical model nerve autograft nerve gap nerve injury novel novel therapeutics poly(lactide)prevent prototype relating to nervous system repaired scaffold sciatic nerve success treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Nerve injuries caused by trauma or tumors often require the removal of the injured segment of nerve and subsequent repair with an autologous nerve graft or conduit. Autologous nerve is the current "gold standard" and outperforms conduits. Currently available conduits lack the necessary support cells and structure to allow for nerve regeneration. Despite the advantages of autograft nerve, they still have the problems of donor site morbidity and limited tissue availability. Allografts can overcome these limitations of autografts while maintaining the 3-D scaffold and support cells that are required to enhance nerve regeneration. However, allograft use requires treatment with immunosuppressive drugs, such as tacrolimus, that can have negative side-effects when used systemically. Separately, our group has developed a biodegradable drug delivery conduit that fits concentrically around a nerve graft. This device is made of poly(lactide-co-glycolic acid) (PLGA) and is capable of locally delivering drug in a controlled manner, at the site of nerve graft or direct repair. The gal of this proposal is to combine allograft nerve transplants with our unique drug delivery device that can release tacrolimus locally to the graft to prevent rejection. By delivering the drug locally, we can limit the negative effects of systemic immunosuppressive treatment, while concomitantly preventing graft rejection. Additionally, tacrolimus is known to directly enhance nerve regeneration. We aim to first optimize the device design, reservoir volume and release kinetics to continuously release tacrolimus from the device for 60 days. The drug delivery device is manufactured with bio-compatible and degradable PLGA. Using a combination of mathematical modeling and rapid prototyping the release kinetics of tacrolimus from the drug delivery device will be designed to achieve consistent daily release of tacrolimus (5-10ng/mL). Next, we will investigate the efficacy of our treatment strategy in a 15mm rat sciatic nerve gap model. Using our drug delivery conduit, prevention of allograft rejection and the extent of nerve regeneration with 60 days of local tacrolimus delivery will be evaluated. Comparison groups will include autograft control, allograft with systemic tacr olimus and untreated allograft. Nerve regeneration and functional recovery will be evaluated at 30 and 90 days using walking track analysis, muscle weight comparisons, motor endplate staining and retrograde labelling. Histologic analysis will be performed to evaluate nerve histomorphometry (number of myelinated fibers, fiber diameter) and degree of rejection using standard stereological techniques. We will also evaluate the effects of early withdrawal of immunosuppression (90 day group) on host nerve regeneration and functional outcomes. This aim will allow us to determine if transient local tacrolimus delivery can sufficiently prevent rejection and improve nerve regeneration outcomes. If successful our unique delivery approach can transform the way we treat nerve injuries and allow for the expanded use of allograft nerve transplants.

描述（由申请人提供）：由创伤或肿瘤引起的神经损伤通常需要切除受损的神经节段，随后用自体神经移植物或导管进行修复。自体神经是目前的“黄金标准”，优于管道。目前可用的管道缺乏必要的支撑单元和结构，以允许神经再生尽管自体神经移植有许多优点，但仍存在供区发病率高和组织可用性有限的问题。同种异体移植可以克服这些局限性，自体移植物，同时保持三维支架和支持细胞，需要加强神经再生。然而，使用同种异体移植物需要使用免疫抑制药物（如他克莫司）进行治疗，当全身使用时可能会产生负面副作用。另外，我们的小组已经开发出一种可生物降解的药物输送导管，它可以同心地安装在神经移植物周围。该器械由聚（丙交酯-共-乙醇酸）（PLGA）制成，能够以受控方式在神经移植部位或直接修复部位局部输送药物。这项建议的gal是将联合收割机同种异体神经移植与我们独特的药物输送装置相结合，该装置可以将他克莫司局部释放到移植物中以防止排斥反应。通过局部给药，我们可以限制全身免疫抑制治疗的负面影响，同时防止移植排斥反应。此外，已知他克莫司可直接增强神经再生。我们的目标是首先优化装置设计、储库体积和释放动力学，以从装置连续释放他克莫司60天。药物输送装置由生物相容性和可降解的PLGA制成。使用数学建模和快速原型的组合，他克莫司从药物递送装置的释放动力学将被设计成实现他克莫司的一致的每日释放（5- 10 ng/mL）。接下来，我们将研究我们的治疗策略在15 mm大鼠坐骨神经间隙模型中的疗效。使用我们的药物输送导管，将评估60天局部他克莫司输送对同种异体移植物排斥反应的预防和神经再生的程度。比较组将包括自体移植物对照、全身性他克莫司的同种异体移植物和未处理的同种异体移植物。将在30天和90天时使用步行轨迹分析、肌肉重量比较、运动终板染色和逆行标记评价神经再生和功能恢复。将使用标准体视学技术进行组织学分析，以评价神经组织形态计量学（有髓纤维数量、纤维直径）和排斥程度。我们还将评估早期撤销免疫抑制（90天组）对宿主神经再生和功能结果的影响。这一目标将使我们能够确定，如果短暂的局部他克莫司交付可以充分防止排斥反应和改善神经再生的结果。如果成功，我们独特的输送方法可以改变我们治疗神经损伤的方式，并允许扩大同种异体神经移植的使用。