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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）：由外伤或肿瘤引起的神经损伤通常需要切除受损的神经段，然后用自体神经移植物或导管进行修复。自体神经是当前的“黄金标准”，其性能优于导管。目前可用的导管缺乏必要的支撑单元和结构来允许神经再生。尽管自体移植神经具有优点，但它们仍然存在供体部位发病率和组织可用性有限的问题。同种异体移植可以克服这些限制自体移植物同时保留增强神经再生所需的 3D 支架和支持细胞。然而，同种异体移植的使用需要使用免疫抑制药物（例如他克莫司）治疗，全身使用时可能会产生负面副作用。另外，我们的团队开发了一种可生物降解的药物输送导管，可同心地安装在神经移植物周围。该装置由聚丙交酯乙醇酸 (PLGA) 制成，能够以受控方式在神经移植或直接修复部位局部输送药物。该提案的主要内容是将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上以防止排斥反应。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。此外，已知他克莫司可以直接增强神经再生。我们的目标是首先优化装置设计、储库体积和释放动力学，以从装置中连续释放他克莫司 60 天。该药物输送装置采用生物相容且可降解的 PLGA 制造。通过结合数学模型和快速原型设计，他克莫司从药物输送装置的释放动力学将被设计为实现他克莫司的每日稳定释放（5-10ng/mL）。接下来，我们将在 15mm 大鼠坐骨神经间隙模型中研究我们的治疗策略的疗效。使用我们的药物输送管道，将评估局部他克莫司输送 60 天后同种异体移植排斥的预防和神经再生的程度。比较组包括自体移植物对照、使用全身性tacr olimus的同种异体移植物和未经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来评估神经再生和功能恢复。将进行组织学分析，以使用标准体视技术评估神经组织形态测量（有髓纤维数量、纤维直径）和排斥程度。我们还将评估早期退出免疫抑制（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短暂的局部他克莫司输送是否可以充分防止排斥反应并改善神经再生结果。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。