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.

项目概要 主要周围神经损伤（PNI）被归类为具有长缺损（≥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。 由于远端神经和肌肉经常退化，这些特征导致功能再生即使有也极少 由于固有的再生速度缓慢，宿主神经能够重新支配这些结构。 当前的标准临床实践延迟修复神经损伤，直到患者（在多发伤的情况下）或 损伤部位稳定后，功能恢复往往极其有限，以维持神经支配。 为了评估受伤后神经和肌肉的能力，Axonova Medical 的团队开发了一种替代品 退化轴突以维持或“照顾”远端结构，直到宿主轴突能够重新支配远端结构 该产品是组织工程神经肌肉接口 (TE-NMI)，由轴突束组成。 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，使其易于注入，以便于融入电流中 在临床前啮齿动物研究中，TE-NMI 被发现可以延长轴突。 植入后进入远端结构，导致远端神经和肌肉的保姆，因此保留它 接受最终宿主轴突神经支配。 此前，实验室级 TE-NMI 已使用原代大鼠和猪神经元以及 在这项研究中，将开发一种人类诱导多能干细胞 (iPSC) 衍生的神经元。 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。 由 Revivicor, Inc. 生产的异种来源。Revivicor 对猪进行基因改造以生产组织 缺乏一种称为α-半乳糖苷酶的碳水化合物，众所周知，这种酶在引发免疫方面发挥着关键作用 GalSafe® 神经元是从 GalSafe® 猪胚胎的脊髓中获取的。 对于该提案，Axonova 的其他产品组织工程神经移植物 (TENG) 所选择的生物质， 初步表征和初步体内研究以确定 TE-NMI 促进康复的功效 将在猪的慢性轴突切除术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将纳入 Axonova 的 IND 申请中。 通过显着增加 PNI 修复的临床窗口，有望改变神经修复领域。