Long distance nerve regeneration via processed allografts in a caprine model

描述（由申请人提供）：在美国，每年有数百万人遭受严重的周围神经损伤。周围神经系统（PNS）的损伤是残疾的主要原因，损害了运动肌肉或感觉正常感觉的能力。为了治疗这些问题，2002年美国进行了100多万次手术，医疗费用总额超过100亿美元。周围神经损伤的治疗主要是因为修复选择有限和无效。修复不能直接修复的PNS损伤的临床金标准是使用自体神经移植物，然而，许多临床并发症以及有限数量的可消耗神经节段，需要寻找替代方法。同种异体神经移植有希望的临床结果促使人们研究各种制备同种异体神经移植的方法，使其成为更可行的临床选择。同种异体神经移植已经在小动物模型（如大鼠）中进行了研究，移植的长度从1到4厘米不等。大型动物模型将允许产生更大的间隙，并包含更长的再生距离，这将更接近模拟人类神经移植对严重创伤或医源性损伤的挑战。这个一期项目的总体目标是确定在一种新的山羊动物模型中测试同种异体神经移植物的可行性，该模型允许通过大的神经间隙和较长的肌肉目标组织再生距离对轴突再生功效进行功能和组织形态测定。我们提出的运动轴突再生功能试验在其他先前开发的模型系统中是不可用的。将利用一种专有的多步骤同种异体移植制备方法（已经开发用于大鼠组织）来评估处理长多束神经的可行性，该方法更接近于模拟人类神经的大小和复杂结构。移植物制备方法的成功转移将通过免疫学分析和组织学分析来确定(i)移植物的结构保存和（ii）细胞去除和CSPG神经生长抑制剂的完全降解。山羊的再生成功将取决于：(i)使用一种新的功能评估范式（包括触觉刺激激活的多突触脊髓反射）再生成肌肉目标肌肉收缩水平的证据，以及（ii）对受体远端神经段健康再生轴突的组织形态计量学分析。在美国，每年有数百万人遭受严重的周围神经损伤。周围神经系统（PNS）的损伤是残疾的主要原因，损害了运动肌肉或感觉正常感觉的能力。[如果项目成功，该产品将成为这些患者无与伦比的治疗选择，并将成为唯一可替代自体神经移植的商业长移植物。]

DESCRIPTION (provided by applicant): Every year in the US, several million people suffer serious peripheral nerve injury. Injuries to the peripheral nervous system (PNS) are a major source of disability, impairing the ability to move muscles or to feel normal sensations. To treat these problems, more than one million procedures were performed in the US in 2002, totaling more than $10 billion in medical costs. Peripheral nerve injuries are under treated primarily because repair options are limited and ineffective. The clinical gold standard for repairing PNS injuries that cannot be repaired by direct coaptation is the use of nerve autograft, however, numerous clinical complications as well as a limited amount of expendable nerve segments, have necessitated a search for an alternative approach. Promising clinical results with nerve allografts has prompted research into various methods of preparing allografts to enable them to be more viable clinical options. Nerve allografts have been studied in small animal models (e.g. rat) for grafts ranging in length from 1 to 4cm. A large animal model would allow larger gaps to be created and incorporate long regeneration distances that would more closely model the challenge of human nerve grafting for severe traumatic or iatrogenic injuries. The overall aim of this Phase I project is to determine the feasibility of testing nerve allografts in a novel goat animal model which allows for functional and histomorphometric assays of axon regeneration efficacy though a large nerve gap and long regeneration distance to the muscle target tissue. Our proposed functional assay for motor axon regeneration is not available in other previously developed model systems. Feasibility of processing long multi-fasciculated nerves will be evaluated by applying a proprietary multistep allograft preparation method (already developed for rat tissue) to goat nerves which more closely mimic the size and complex structure of human nerves. Successful transfer of the graft preparation method will be determined by immunological analysis and histological analysis verifying (i) structural preservation of the graft and (ii) cellular removal and complete degradation of CSPG nerve growth inhibitors post-processing. Regeneration success in the goat will be determined by (i) evidence of regeneration into a muscle target to the level of muscle contraction using a novel functional assessment paradigm involving a tactile stimulus-activated polysynaptic spinal reflex and by (ii) a histomorphometric analysis of healthy regenerated axons in the distal nerve segment of the recipient. Every year in the US, several million people suffer serious peripheral nerve injury. Injuries to the peripheral nervous system (PNS) are a major source of disability, impairing the ability to move muscles or to feel normal sensations. [The product that would result from a successful project would be an unmatched treatment option for these patients and would be the only commercially available long graft alternative to nerve autograft.]