3D microprinting-enabled microinjection needle arrays for enhanced therapeutics delivery into the brain

支持 3D 微打印的显微注射针阵列可增强向大脑的治疗输送

基本信息

批准号：
10761073
负责人：
Kinneret Rand
金额：
$ 40.38万
依托单位：
SEETRUE TECHNOLOGY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-10 至 2024-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761073
关键词：
3-Dimensional 3D Print Address Architecture Brain Cells Diffusion Dimensions Embryo Extravasation Fluorescence Gel Genes Goals Health Histologic Human In Vitro Individual Industry Industry Standard Injections Lasers Lateral Legal patent Lentivirus Malignant Neoplasms Marketing Measures Mediating Medical Microfluidics Microinjections Modulus Mus Needles Neurodegenerative Disorders Neuroglia Neurologic Outcome Output Pain Penetration Performance Printing Protocols documentation Puncture procedure Research Retrieval Sepharose Shapes Side Site Solid Stainless Steel Survival Rate Suspensions Technology Therapeutic Tissues Traumatic Brain Injury Viral Vector Writing Zebrafish brain parenchyma brain tissue clinical application design efficacy evaluation improved in vivo innovation manufacture nanoparticle nerve stem cell novel operation particle pressure prototype spinal cord and brain injury stem cell delivery stem cell survival stem cells tissue injury tool two photon microscopy two-photon

项目摘要

PROJECT SUMMARY Microinjection technologies underlie many research and clinical applications that require gene and cell delivery, including studies and emerging treatments of neurological conditions (e.g., neurodegenerative diseases, traumatic brain injury, and cancer). Unfortunately, challenges associated with the microinjection tools by which the viral vectors and cells inherent in these applications are delivered into brain tissues remain major barriers in these rapidly growing fields. Although widely used, the currently used industry standard needles (ISNs) comprise one needle with a single output port at the tip and are associated with a variety of validated customer pain points. In particular, (1) the physical size of therapeutics such as lentiviral particles (80–100 nm) and stem cells (>10 μm) restricts ISN-mediated delivery into a single injection site inherently restricts the effective coverage range; (2) the single injection site for ISNs can also result in inhomogeneous distributions of delivered therapeutics, which can be detrimental to efficacy; and (3) the shape and size of ISNs can lead to brain tissue injury. Consequently, alternative, novel microinjection tools for both gene and cell delivery are in critical demand. The objective of this proposal is to develop an entirely new class of microneedle arrays (MNAs) that can be realized to simultaneously address all three aforementioned pain points of ISNs. The working hypothesis is that the minimal viable product (MVP) will transform microinjection outcomes via unparalleled versatility in realizing geometrically sophisticated MNAs innovations, improve the efficacy of delivering therapeutics to the brain and reducing microinjection-associated tissue damage. Preliminary studies demonstrated the ability of 3D microprinting-enabled microneedle arrays (MNAs) delivery strategy to penetrate and deliver microfluidic payloads into mouse brains. In addition, 3D-printed multi-side-port microneedles showed reduced penetration and retrieval-associated damage to zebrafish embryos during microinjection protocols. This proposal will examine the efficacy of this innovation to enhance fundamental performance metrics underlying both gene and cell delivery into brain tissue. To effectively accomplish this goal, we will: 1) establish and characterize MNA additive manufacturing protocols for novel 3D microneedle designs, 2) assess microfluidic and cell delivery efficacy of our innovative delivery strategy versus ISNs in vitro, and 3) evaluate gene and stem cell delivery into mouse brains mediated by our MNA innovation versus ISNs in vivo. This proposal to prototype MNA MVPs that improve penetration, injection, and retrieval efficacy versus ISNs bridges an important need in the biomedical industry, which will positively impact foundational human health-related research and medical applications.

项目概要显微注射技术是许多需要基因和细胞输送的研究和临床应用的基础，包括神经系统疾病的研究和新兴治疗方法（例如神经退行性疾病、不幸的是，与显微注射工具相关的挑战。这些应用中固有的病毒载体和细胞被输送到脑组织中仍然是主要障碍这些快速增长的领域虽然得到了广泛应用，但目前使用的行业标准针 (ISN) 包括在内。一根针头在尖端有一个输出端口，并与各种经过验证的客户痛点相关联。特别是，(1) 慢病毒颗粒 (80–100 nm) 和干细胞 (>10 μm) 限制了 ISN 介导的递送到单个注射部位，本质上限制了有效覆盖范围； (2) ISN 的单一注射部位也会导致所递送治疗药物的分布不均匀，这可能会影响疗效；(3) ISN 的形状和大小可能导致脑组织损伤。迫切需要用于基因和细胞递送的经过测试的替代性新型显微注射工具。该提案的目标是开发一类全新的微针阵列 (MNA)，实现同时解决 ISN 的所有三个痛点。工作假设是：最小可行产品（MVP）将通过无与伦比的多功能性来改变显微注射结果几何复杂的 MNA 创新，提高了向大脑提供治疗的功效，初步研究证明了 3D 的能力。支持微打印的微针阵列 (MNA) 传递策略，用于渗透和传递微流体此外，3D 打印的多侧端口微针的穿透力降低。该提案将在显微注射过程中对斑马鱼胚胎进行修复和修复相关的损伤。检查这项创新的功效，以增强基因和基础性能指标为了有效地实现这一目标，我们将：1）建立并表征 MNA。用于新型 3D 微针设计的增材制造方案，2) 评估微流体和细胞输送我们的创新递送策略相对于体外 ISN 的功效，以及 3) 评估基因和干细胞递送到由我们的 MNA 创新介导的小鼠大脑与体内 ISN 的对比该提案对 MNA MVP 进行了原型设计。与 ISN 相比，提高渗透、注射和回收功效，满足了生物医学领域的重要需求行业，这将对人类健康相关的基础研究和医疗应用产生积极影响。