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 主要的周围神经损伤（PNI）被归类为长缺陷（≥3cm）或近端发生的损伤 需要长时间的宿主神经与远端结构（远端神经，靶肌等）的再生距离。 这些特征导致功能再生最少，因为远端神经和肌肉通常会退化 由于固有缓慢的再生速率，宿主神经能够重新弥补这些结构。自从 当前的标准临床实践延迟修复神经损伤，直到患者（在多发性疾病的情况下）或 伤害部位稳定，功能恢复通常非常有限。为了维持神经 受伤后神经和肌肉的能力，Axonova Medical的团队已为此建立了代理 退化轴突以维持或“照顾”远端结构，直到宿主轴突能够重新弥补 远端目标。该产品是组织工程的神经肌肉界面（TE-NMI），由轴突区组成 跨越水凝胶柱中的神经元的离散群体。值得注意的是，Te-Nmis的直径是 设计为处于微米的规模，使其易于注射以促进融合到电流中 诊所的护理标准实践。在临床前的啮齿动物研究中，已经看到Te-Nmis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 接受最终的宿主轴突重新连接。 以前，实验室级的Te-NMI已使用原发性大鼠和猪神经元以及 人诱导的多能干细胞（IPSC）衍生的神经元。在这项研究中，将开发临床产品 并以Galsafe®神经元为开始的生物质来表征。 Galsafe®组织是FDA批准的 Revivicor，Inc。生产的异种来源Revivicor具有基因设计的猪以产生组织 缺少碳水性，称为-半乳糖苷酶，已知在引发免疫中起关键作用 人类的反应。 GalSafe®神经元是从Galsafe®猪胚胎的脊髓收获的，并且是 Axonova的其他产品，组织工程神经移植物（Tengs）选择的生物量。对于这个建议， 初始表征和初步体内研究，以确定Te-NMI的效率促进恢复 将在猪中的慢性轴切模型中进行。这些研究的成功执行将加速 临床前的安全性和效率研究将纳入Axonova的IND应用中。总体而言，te-nmis 通过显着增加PNI修复的临床窗口来改变神经修复领域。