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: 7631440
• 负责人: DAVID IRA SHREIBER
• 金额: $ 22.51万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631440
• 关键词: Axon; Biocompatible Materials; Biomimetics; Carbohydrates; Clinical; Collagen; Coupling; Cues; Cutaneous; Development; Distal; Engineering; Epitopes; FDA approved; 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; Recovery; Recovery of Function; Research; Research Personnel; Skin; Sorting - Cell Movement; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Time; Translations; Trauma; Vertebral column; axon regeneration; clinical practice; femoral nerve; improved; in vivo; man; mouse model; nerve injury; nerve supply; neurite growth; performance tests; public health relevance; regenerative; 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（由研究者提供）：本研究的广泛、长期目标是开发一种用于神经创伤后周围神经再生的植入式结构。 周围神经元在神经损伤后可以再生轴突并重新支配周围靶点。 尽管有强大的再生潜力，神经修复的临床结果往往是令人失望的，切断的外周运动轴突再生长到不适当的目标被认为是功能恢复差的主要原因。 我们已经开发了神经细胞粘附分子所携带的两种碳水化合物的肽模拟物，这两种碳水化合物在发育过程中对靶向神经支配很重要，并在体外和体内促进神经元存活和神经突生长：人类自然杀伤细胞表位HNK-1和2，8聚唾液酸（PSA）。 这些碳水化合物和肽模拟物似乎在再生运动轴突中诱导优先运动神经再支配，从而使它们接受将轴突分类到其功能适当的区域中的远端线索。 我们已经证明，HNK-1的可溶性模拟物增加了将运动神经突再生到股神经的肌肉分支中的准确性，并增强了外周神经损伤后运动功能的恢复，并且HNK-1和PSA的可溶性模拟物一起改善了脊髓损伤后运动功能的恢复。 该提案的目标是通过将这些肽结合到用于外周神经再生的生物材料支架上来增强这些肽的临床潜力，而不是将它们以可溶性形式引入，这限制了它们在移植物内的停留时间。 我们将肽模拟物移植到三维纤维状胶原支架上，这是生物人工血管移植的理想支撑支架。 我们将评估神经突起的生长，从分离的小鼠脊髓神经元通过凝胶移植HNK-1或PSA模拟物，然后优化的模拟物在体外的双重介绍。 然后，我们将在小鼠周围神经损伤模型中测试最佳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胶原凝胶中加速轴突再生和提高体外再生准确性的能力。 在具体目标2中，我们优化了移植HNK-1和PSA模拟物的组合，以实现体外准确和加速再生。 在具体目标3中，我们在周围神经损伤的小鼠模型中体内测试了有希望的组合。 在完成这些目标之后，我们将确定在可植入胶原基质中的促生长碳水化合物的固定化肽模拟物的有前途的组合。 我们将在股神经损伤的小鼠模型中在体外和体内测试胶原基质。 胶原蛋白基质与FDA批准的生物人工皮肤和外周神经移植物基质基本相同，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。 被切断的外周运动轴突向不适当的目标再生长被认为是功能恢复不良的主要原因。 我们已经开发了神经细胞粘附分子携带的两种碳水化合物的肽模拟物，其提高了在进入周围神经的肌肉分支与皮肤分支之间的决定点处再生运动轴突的准确性：HNK-1和2，8聚唾液酸（PSA）。 我们建议将这些肽模拟物结合到周围神经再生的生物材料治疗中，通过将肽共价接枝到胶原蛋白上来提高支架的生物活性。 肽模拟物移植的胶原蛋白生物材料将是第一种特异性诱导优先运动神经再支配的工程化移植疗法，并且将向这些指导分子的成功临床转化迈出重要一步。