Long distance nerve regeneration via processed allografts in a caprine model

在山羊模型中通过处理后的同种异体移植物进行长距离神经再生

• 批准号: 7218849
• 负责人: RICHARD David JOHNSON
• 金额: $ 10.27万
• 依托单位: AXOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2009-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218849
• 关键词: Adult; Allografting; Animal Model; Autologous Transplantation; Axon; Behavioral; Biological Assay; Biological Models; Biological Preservation; Body part; Characteristics; Chondroitin Sulfate Proteoglycan; Cicatrix; Clinical; Complex; Data; Depth; Distal; Esthesia; Evaluation; Excision; Extracellular Matrix; Future; Genus Capra; Goat; Gold; Government; Growth; Growth Inhibitors; Harvest; Human; Immunosuppression; Injury; Laminin; Lateral; Length; Mediating; Medical; Methods; Modeling; Motor; Mus; Muscle; Muscle Contraction; Natural regeneration; Nerve; Nerve Regeneration; Nerve Tissue; Nervous System Trauma; Neuroma; Oryctolagus cuniculus; Pain; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Persons; Phase; Phase I Clinical Trials; Physiological; Pre-Clinical Model; Preparation; Procedures; Process; Purpose; Range; Rattus; Recovery of Function; Research; Site; Source; Standards of Weights and Measures; Stimulus; Structure; Structure of thoracic nerve; Surgeon; Surgical sutures; Tactile; Testing; Therapeutic immunosuppression; Tissues; afferent nerve; axon regeneration; base; commercialization; cost; design; desire; disability; functional loss; injured; injury and repair; interest; nerve autograft; nerve gap; novel; promoter; repaired; research study; size; spinal reflex; success

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.]

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）损伤是残疾的主要来源，损害了肌肉运动或感觉正常感觉的能力。为了治疗这些问题，2002年在美国进行了100多万次手术，总计超过100亿美元的医疗费用。周围神经损伤治疗不足主要是因为修复选择有限且无效。修复不能通过直接接合修复的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的消耗性神经节段，需要寻找替代方法。神经同种异体移植物的临床结果令人鼓舞，这促使人们研究各种制备同种异体移植物的方法，使其成为更可行的临床选择。已经在小动物模型（例如大鼠）中研究了神经同种异体移植物，移植物长度范围为1至4 cm。大型动物模型将允许创建更大的间隙，并包含长的再生距离，这将更接近模拟人类神经移植治疗严重创伤或医源性损伤的挑战。该I期项目的总体目标是确定在新型山羊动物模型中测试神经同种异体移植物的可行性，该模型允许通过大的神经间隙和长的肌肉靶组织再生距离来进行轴突再生功效的功能和组织形态测定。我们提出的运动轴突再生的功能测定是不可用的，在其他以前开发的模型系统。将通过将专有的多步同种异体移植物制备方法（已开发用于大鼠组织）应用于山羊神经（更接近模拟人类神经的大小和复杂结构），评价处理长多束神经的可行性。将通过免疫学分析和组织学分析确定移植物制备方法的成功转移，以验证（i）移植物的结构保留和（ii）处理后CSPG神经生长抑制剂的细胞去除和完全降解。山羊中的再生成功将通过（i）使用涉及触觉刺激激活的多突触脊髓反射的新型功能评估范例再生到肌肉收缩水平的肌肉靶点的证据和（ii）受体远端神经节段中健康再生轴突的组织形态计量学分析来确定。在美国，每年有数百万人遭受严重的外周神经损伤。周围神经系统（PNS）损伤是残疾的主要来源，损害了肌肉运动或感觉正常感觉的能力。[The一个成功的项目所产生的产品将是这些患者无与伦比的治疗选择，并且将是唯一可商业化的长移植物替代自体神经移植物。