Development of Tissue Engineered Neuromuscular Interfaces from GalSafe Neurons.

从 GalSafe 神经元开发组织工程神经肌肉接口。

• 批准号: 10385405
• 负责人: Kritika Katiyar
• 金额: $ 25.04万
• 依托单位: AXONOVA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385405
• 关键词: Address; Afferent Neurons; Animals; Architecture; Autologous Transplantation; Axon; Axotomy; Biological Assay; Biological Products; Biomass; Bungarotoxins; Caliber; Carbohydrates; Cell Differentiation process; Cell Survival; Cells; Chronic; Clinic; Clinical; Clinical Trials; Control Groups; Cyclic GMP; Defect; Development; Distal; Embryo; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; FDA approved; Family suidae; Functional Regeneration; Galactosidase; Genetic Engineering; Harvest; Human; Hydrogels; Immune response; Implant; In Vitro; Induced pluripotent stem cell derived neurons; Injectable; Injury; Label; Laboratories; Lactate Dehydrogenase; Lesion; Licensing; Maintenance; Medical; Modeling; Motor; Motor Neurons; Multiple Trauma; Muscle; Muscle Cells; Muscle function; Natural regeneration; Nerve; Nervous system structure; Neuromuscular Junction; Neurons; Operative Surgical Procedures; Organ; Outcome; Patients; Pennsylvania; Peripheral nerve injury; Phase; Play; Population; Process; Protocols documentation; Proxy; Quality of life; Rattus; Recovery; Recovery of Function; Risk; Rodent; Schwann Cells; Sensory; Site; Small Business Innovation Research Grant; Source; Spinal Cord; Structure; Synaptophysin; Techniques; Testing; Time; Tissue Engineering; Tissue Transplantation; Tissues; Trauma; Tumorigenicity; Universities; axon regeneration; biofabrication; clinical practice; design; efficacy study; experience; human stem cells; immunocytochemistry; implantation; in vivo; in vivo evaluation; injury and repair; limb injury; manufacturing process; meetings; minimally invasive; nerve damage; nerve injury; nerve repair; nerve supply; neural network; neuromuscular; peroneal nerve; phase 2 study; porcine model; pre-clinical; preclinical safety; preservation; product development; programs; regenerative; reinnervation; repair strategy; repaired; safety study; standard of care

PROJECT SUMMARY Major peripheral nerve injury (PNI) is classified as an injury with a long defect (≥3cm) or occurring proximally, requiring long regenerative distances of the host nerve to distal structures (distal nerve, target muscle, etc.). These features result in minimal, if any, functional regeneration as the distal nerve and muscle often degenerate before the host nerve is able to reinnervate these structures due to inherently slow regeneration rates. Since current standard clinical practices delay repairing nerve injuries until the patient (in cases of polytrauma) or the injury site is stabilized, functional recovery is often extremely limited. In order to maintain the innervation capability of nerves and muscles following injury, the team at Axonova Medical has developed a proxy for these degenerating axons to maintain or “babysit” the distal structures until the host axons are able to reinnervate the distal targets. This product, the tissue engineered neuromuscular interface (TE-NMI), consists of axon tracts spanning a discrete population of neurons within a hydrogel column. Notably, the diameter of TE-NMIs is designed to be on the scale of micrometers, making them easily injectable to facilitate incorporation into current standard of care practices in the clinic. In pre-clinical rodent studies, TE-NMIs have been seen to extend axons into distal structures post implantation, resulting in babysitting of distal nerve and muscle, therefore keeping it receptive to eventual host axon reinnervation. Previously, laboratory-grade TE-NMIs have been fabricated using primary rat and porcine neurons as well as human induced pluripotent stem cell (iPSC)-derived neurons. In this study, a clinical product will be developed and characterized using GalSafe® neurons as the starting biomass. GalSafe® tissue is an FDA-approved xenogeneic source produced by Revivicor, Inc. Revivicor has genetically engineered swine to produce tissue lacking a carbohydrate, known as -galactosidase, that is known to play a key role in eliciting an immune response in humans. GalSafe® neurons are harvested from the spinal cords of GalSafe® swine embryo, and is the chosen biomass for Axonova’s other product, tissue engineered nerve grafts (TENGs). For this proposal, initial characterization and a preliminary in vivo study to determine the efficacy of TE-NMIs to promote recovery in a chronic axotomy model in swine will be carried out. Successful execution of these studies will accelerate preclinical safety and efficacy studies and will be incorporated in Axonova’s IND application. Overall, TE-NMIs hold promise in transforming the field of nerve repair by significantly increasing the clinical window for PNI repair.

项目摘要 主要周围神经损伤（PNI）被分类为具有长缺损（≥3cm）或发生在近端的损伤， 需要宿主神经到远端结构（远端神经、目标肌肉等）的长再生距离。 这些特征导致最小的，如果有的话，功能性再生，因为远端神经和肌肉经常退化 在宿主神经能够重新支配这些结构之前，由于固有的缓慢再生速率。以来 目前的标准临床实践延迟了神经损伤的修复，直到患者（在多发性创伤的情况下）或 受伤部位稳定后，功能恢复往往极其有限。为了维持神经支配 由于神经和肌肉在受伤后的能力，Axonova Medical的团队已经开发了一种替代品， 退化的轴突以维持或“照看”远端结构，直到宿主轴突能够重新神经支配远端结构。 远端目标该产品，组织工程神经肌肉接口（TE-NMI），由轴突束 跨越水凝胶柱内离散的神经元群体。值得注意的是，TE-NMI的直径为 设计为微米级，使其易于注射，以促进纳入电流 临床护理实践标准。在临床前啮齿动物研究中，TE-NMIs已经被发现延伸轴突 植入后进入远端结构，导致远端神经和肌肉的保姆，因此保持其 接受最终的宿主轴突再神经支配。 以前，实验室级TE-NMI已经使用原代大鼠和猪神经元以及 人诱导多能干细胞（iPSC）衍生的神经元。本研究将开发一种临床产品 并使用GalSafe®神经元作为起始生物质进行表征。GalSafe®组织是FDA批准的 Revivicor，Inc.生产的异种源Revivicor已经对猪进行了基因工程改造， 缺乏一种称为β-半乳糖苷酶的碳水化合物，这种碳水化合物在引发免疫反应中起着关键作用。 人类的反应。GalSafe®神经元从GalSafe®猪胚胎的脊髓收获，并且 Axonova的另一种产品组织工程神经移植物（TENGs）的选择生物质。对于这一提议， 初步表征和初步体内研究，以确定TE-NMIs促进恢复的功效 在猪的慢性轴突切断模型中进行。这些研究的成功实施将加速 临床前安全性和有效性研究，并将纳入Axonova的IND申请。总体而言， 通过显著增加PNI修复的临床窗口，有望改变神经修复领域。