Trimodal vitality imaging of neural progenitor cells in the spinal cord

脊髓神经祖细胞的三模态活力成像

• 批准号: 10221069
• 负责人: STANISLAV Y EMELIANOV
• 金额: $ 60.63万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221069
• 关键词: 3-Dimensional; Abbreviations; Address; Affect; Amyotrophic Lateral Sclerosis; Anatomy; Apoptosis; Apoptotic; Area; Autopsy; Behavior; Biological; CASP3 gene; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Clinic; Clinical; Clinical Protocols; Clinical Trials; Contrast Media; Cytosol; Data; Development; Disease; Dyes; Engineering; Engraftment; Excision; Failure; Family suidae; Foundations; Future; Glossary; Histologic; Histology; Image; Imaging Techniques; Imaging technology; Implant; In Vitro; Injections; Label; Laminectomy; Lasers; Lead; Light; Location; Magnetic Resonance Imaging; Magnetic nanoparticles; Methods; Monitor; Nature; Needles; Penetration; Performance; Physiologic pulse; Postoperative Period; Procedures; Property; Protocols documentation; Quality of life; Rattus; Reporter; Risk; Rodent; Sampling; Scientist; Signal Transduction; Source; Spinal Cord; Spinal Cord Diseases; Spinal cord injury; Stem cell transplant; System; Techniques; Testing; Therapeutic; Time; Tissue Model; Tissues; Toxic effect; Translations; Transplantation; Ultrasonography; Visualization; Work; base; bone; cell behavior; cellular imaging; clinical imaging; clinical translation; cost effective; effective therapy; image guided; imaging modality; imaging platform; imaging system; implantation; improved; in vivo; in vivo imaging; migration; multimodality; nanomagnetic; nanoparticle; nerve stem cell; non-invasive imaging; novel; optical fiber; photoacoustic imaging; portability; post-transplant; pre-clinical; preclinical study; programs; real-time images; serial imaging; spinal cord imaging; stem cell delivery; stem cell therapy; tool

ABSTRACT Spinal cord diseases and disorders such as spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS) are debilitating, often resulting in loss of mobility and decreased quality of life for those affected. One promising treatment involves the transplantation of neural progenitor cells (NPC) into the spinal cord, which has been shown to have neuroprotective properties. However, most NPC-based therapies fail after reaching clinical trials, and without a method to monitor the injected cells and viability, locating injected NPCs is limited to postmortem histology. The ability to track and assess the viability of transplanted cells could be crucial in understanding whether the failure is technical or biological in nature, such as whether the injected cells were delivered to and remain at the correct location or survived transplantation. We propose the development of multi-modal contrast agents and a clinical ultrasound and photoacoustic (US/PA) imaging system for image guided delivery of trans- planted cells and longitudinal monitoring. Together with clinical magnetic resonance imaging (MRI), the use of US/PA imaging can allow for pre-, intra- and post-operative visualization of the cells. The MRI and US imaging modalities are well established in the clinic, and PA can be easily integrated with existing clinical US imaging systems. We hypothesize that visualizing the location and viability of injected neural progenitor cells obtained through the labeling of NPCs with contrast agents will allow for better understanding of transplanted cell behavior and improved translation of cell based therapies. Two contrast agents will be developed: photo-magnetic nano- particles, which will allow for photoacoustic and MRI tracking, and a dye-based apoptosis reporter, which will provide photoacoustic contrast upon apoptotic activity. These will be delivered to the cytosol of the neural pro- genitor cells and assessed for labeling efficiency and toxicity. Once optimized, labeled NPCs in different ratios of live to dead will be injected into the spinal cords of rats to assess the feasibility of distinguishing live and dead cells in vivo. After injection, the NPCs will be monitored longitudinally using trimodal US/PA/MR imaging. After validating the performance of the contrast agents in vivo, a clinical US/PA imaging system will be developed to demonstrate real-time image guided-delivery, US/PA/MRI longitudinal tracking, and PA viability assessment of the labeled cells. The ability to monitor the transplanted cells at every point during and after the procedure will allow for more accurate delivery of the cells and could elucidate common issues and behaviors of injected NPCs that could lead to therapeutic improvements. Furthermore, if successful, it will validate both the contrast agents and US/PA as a valuable tool for tracking and monitoring cell-based therapies to improve clinical translation.

抽象的 脊髓疾病和病症，例如脊髓损伤 (SCI) 和肌萎缩侧索硬化症 (ALS) 使人衰弱，常常导致受影响者失去行动能力并降低生活质量。一位有前途的 治疗方法包括将神经祖细胞（NPC）移植到脊髓中，这种方法已被证实 显示具有神经保护特性。然而，大多数基于鼻咽癌的疗法在达到临床试验后都失败了， 由于没有监测注射细胞和活力的方法，只能通过尸检来定位注射的 NPC 组织学。跟踪和评估移植细胞活力的能力对于理解移植细胞的活力至关重要 失败是否是技术性的或生物性的，例如注射的细胞是否被输送到和 保留在正确的位置或在移植后存活。我们建议开发多模态对比 代理和临床超声和光声（US/PA）成像系统，用于图像引导传输反式 种植细胞和纵向监测。与临床磁共振成像 (MRI) 一起使用 US/PA 成像可以实现术前、术中和术后细胞的可视化。 MRI 和 US 成像 模式在临床中已得到很好的确立，PA 可以轻松地与现有的临床超声成像相集成 系统。我们假设通过可视化所获得的注射神经祖细胞的位置和活力 通过用造影剂标记 NPC 将有助于更好地了解移植细胞的行为 并改进细胞疗法的转化。将开发两种造影剂：光磁纳米造影剂 粒子，这将允许光声和 MRI 跟踪，以及基于染料的细胞凋亡报告器，这将 提供细胞凋亡活性的光声对比。这些将被传递到神经亲细胞的细胞质中 生殖细胞并评估标记效率和毒性。优化后，以不同比例标记 NPC 的活与死将被注射到大鼠的脊髓中，以评估区分活与死的可行性 体内的细胞。注射后，将使用三模态 US/PA/MR 成像对 NPC 进行纵向监测。后 为了验证造影剂的体内性能，将开发临床 US/PA 成像系统 展示实时图像引导递送、US/PA/MRI 纵向跟踪以及 PA 生存能力评估 标记的细胞。在手术过程中和手术后的每个时间点监测移植细胞的能力将 允许更准确地输送细胞，并可以阐明注射 NPC 的常见问题和行为 这可能会导致治疗的改善。此外，如果成功，它将验证两种造影剂 US/PA 作为跟踪和监测细胞疗法以改善临床转化的宝贵工具。