Biomimetic scaffolds for targeted peripheral nerve regeneration

用于靶向周围神经再生的仿生支架

• 批准号: 7532317
• 负责人: DAVID IRA SHREIBER
• 金额: $ 18.69万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532317
• 关键词: Axon; Biocompatible Materials; Biomimetics; Carbohydrates; Clinical; Collagen; Coupling; Cues; Cutaneous; Development; Distal; Engineering; Epitopes; Fibrillar Collagen; Gel; Generations; Goals; Growth; Horns; Human; In Vitro; Individual; Lead; Modeling; Motor; Mus; Muscle; Natural Killer Cells; Natural regeneration; Nerve; Nerve Regeneration; Neural Cell Adhesion Molecules; Neurites; Neurons; Outcome; Peptides; Peripheral; Peripheral Nerves; Peripheral nerve injury; Polysialic Acid; Public Health; Recovery; Recovery of Function; Research; Research Personnel; Skin; Sorting - Cell Movement; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Time; Translations; Trauma; United States Food and Drug Administration; Vertebral column; axon regeneration; femoral nerve; improved; in vivo; man; mouse model; nerve injury; nerve supply; neurite growth; performance tests; reinnervation; relating to nervous system; repaired; response; scaffold

DESCRIPTION (provided by investigator): The broad, long-term objective of this research is to develop an implantable construct for peripheral nerve regeneration following nerve trauma. Peripheral neurons can regenerate their axons after nerve injury and reinnervate peripheral targets. Despite the robust regenerative potential, the clinical outcome of nerve repair is often disappointing, and regrowth of severed peripheral motor axons to improper targets is considered a major reason for poor functional recovery. We have developed peptide mimics of two carbohydrates carried by neural cell adhesion molecules that are important in targeted innervation during development and that promote neuron survival and neurite growth in vitro and in vivo: the human natural killer cell epitope HNK-1, and 2,8 Polysialic acid (PSA). These carbohydrates and peptide mimics appear to induce preferential motor reinnervation in regenerating motor axons, thereby making them receptive to distal cues that sort the axons into their function-appropriate tracts. We have demonstrated that a soluble mimic of HNK-1 increases the accuracy of regenerating motor neurites into the muscle branch of the femoral nerve and enhances recovery of motor function following peripheral nerve injury, and that soluble mimics of HNK-1 and PSA together improve motor function recovery follow spinal cord injury. The goal of this proposal is to enhance the clinical potential of these peptides by incorporating them on to a biomaterial scaffold for peripheral nerve regeneration, rather than have them introduced in a soluble form, which limits their resident time within the graft. We will graft the peptide mimics on to a three-dimensional fibrillar collagen scaffold, which is ideal as a supporting scaffold for a bioartificial entubulation graft. We will evaluate neurite growth from isolated mouse spinal cord neurons through gels grafted with either HNK-1 or PSA mimics, and then optimize the dual presentation of the mimics in vitro. We will then test the performance of the optimum biomaterial in vivo in a mouse peripheral nerve injury model. In Specific Aim 1, we evaluate the ability of individual HNK-1 or PSA grafted peptide mimics to accelerate axon regeneration and improve the accuracy of regeneration in vitro in 3D collagen gels. In Specific Aim 2, we optimize combinations of grafted HNK-1 and PSA mimics for accurate and accelerated regeneration in vitro. In Specific Aim 3, we test the promising combinations in vivo in a mouse model of peripheral nerve injury. Following completion of these aims we will have identified promising combinations of immobilized peptide mimics of growth-promoting carbohydrates in an implantable collagen matrix. We will have tested the collagen matrix in vitro and in vivo in a mouse model of femoral nerve injury. The collagen matrix is essentially identical to FDA approved substrates for bioartificial skin and peripheral nerve grafts, and could therefore fast-track the translation of the results to clinical practice. PUBLIC HEALTH RELEVANCE: Despite the robust regenerative potential of peripheral nerves, the clinical outcome of nerve repair is often disappointing. Regrowth of severed peripheral motor axons to improper targets is considered a major reason for poor functional recovery. We have developed peptide mimics of two carbohydrates carried by neural cell adhesion molecules that are improve the accuracy of regenerating motor axons at the decision point between entry into the muscle branch vs. cutaneous branch of a peripheral nerve: HNK-1, and 2,8 polysialic acid (PSA). We propose to incorporate these peptide mimics into a biomaterial therapy for peripheral nerve regeneration by covalently grafting the peptides on to collagen to improve the bioactivity of the scaffold. The peptide mimic- grafted collagen biomaterial would be the first engineered grafting therapy to specifically induce preferential motor reinnervation, and would provide a major step forward towards the successful clinical translation of these guidance molecules.

描述(由研究人员提供)：这项研究的广泛、长期目标是开发一种可植入的结构，用于神经损伤后的周围神经再生。外周神经元可以在神经损伤后再生轴突，并重新支配外周靶点。尽管有强大的再生潜力，但神经修复的临床结果往往令人失望，被切断的周围运动神经轴突再生到不适当的靶点被认为是功能恢复不良的主要原因。我们已经开发了两种碳水化合物的多肽模拟物，这两种碳水化合物由神经细胞黏附分子携带，在发育过程中对靶向神经支配非常重要，并在体外和体内促进神经元存活和轴突生长：人类自然杀伤细胞表位HNK-1和2，8聚唾液酸(PSA)。这些碳水化合物和多肽类似物似乎在再生运动轴突时诱导优先的运动神经再支配，从而使它们接受将轴突分类到其功能适当的束的远端线索。我们已经证明，HNK-1的可溶性模拟物提高了周围神经损伤后运动神经元再生为股神经肌支的准确性，促进了运动功能的恢复，并且HNK-1和PSA的可溶性模拟物共同促进了脊髓损伤后的运动功能恢复。这项提议的目标是通过将这些多肽结合到用于周围神经再生的生物材料支架上来增强它们的临床潜力，而不是以可溶性的形式引入它们，这限制了它们在移植物中的停留时间。我们将把模拟的多肽移植到三维纤维状胶原支架上，这是生物人工植入移植物的理想支架。我们将通过移植HNK-1或PSA模拟物的凝胶来评估分离的小鼠脊髓神经元的轴突生长，然后优化模拟物的体外双重呈现。然后，我们将在小鼠周围神经损伤模型中测试最优生物材料的体内性能。在具体目标1中，我们评估了单个HNK-1或PSA接枝肽模拟物在3D胶原凝胶中促进轴突再生和提高体外再生准确性的能力。在特定目标2中，我们优化了嫁接的HNK-1和PSA模拟物的组合，以实现准确和加速体外再生。在特定的目标3中，我们在周围神经损伤的小鼠模型中测试了有希望的组合。随着这些目标的完成，我们将在可植入的胶原基质中确定有希望的促进生长的碳水化合物的固定化多肽模拟物的组合。我们将在股神经损伤的小鼠模型上进行体外和体内的胶原基质测试。胶原蛋白基质基本上与FDA批准的生物人工皮肤和周围神经移植物的基质相同，因此可以快速将结果转化为临床实践。公共卫生相关性：尽管周围神经具有强大的再生潜力，但神经修复的临床结果往往令人失望。切断的外周运动轴突重长到不正确的靶点被认为是功能恢复不佳的主要原因。我们已经开发了由神经细胞黏附分子携带的两种碳水化合物的多肽模拟物，这两种多肽可以提高周围神经进入肌支和皮支之间的决策点再生运动轴突的准确性：HNK-1和2，8多唾液酸(PSA)。我们建议将这些多肽模拟物加入到周围神经再生的生物材料治疗中，通过将这些多肽共价嫁接到胶原上来提高支架的生物活性。这种模拟多肽的胶原生物材料将是第一个专门诱导优先运动神经再支配的工程化移植疗法，并将朝着这些指导分子的成功临床翻译向前迈进一大步。