A Therapeutic Tool for Ultrasound-Guided Stem Cell Therapy

超声引导干细胞治疗的治疗工具

• 批准号: 9303431
• 负责人: Jesse Vincent Jokerst
• 金额: $ 24.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303431
• 关键词: Adverse event; Animal Model; Animals; Area; Autologous; BCL2 gene; Biodegradation; Biodistribution; Biological Phenomena; Cardiac; Cardiac Output; Cardiology; Cardiovascular system; Cause of Death; Cell Death; Cell Proliferation; Cell Survival; Cells; Chemicals; Chemistry; Clinical; Contrast Media; Coronary; Data; Development; Disease; Drops; Drug Delivery Systems; EFRAC; Echocardiography; Ensure; Faculty; Fibrosis; Five-Year Plans; Funding; Goals; Grant; Growth; Growth Factor; Heart; Heart Diseases; Histology; Human; Hypoxia; Image; Image-Guided Surgery; Imaging Device; Imaging Techniques; Implant; In Vitro; Infarction; Inflammation; Injectable; Injection of therapeutic agent; International; Ischemia; Label; Left ventricular structure; Magnetic Resonance Imaging; Measures; Medicine; Mentors; Modeling; Monitor; Mus; Myocardial Ischemia; Patients; Physicians; Porifera; Porosity; Proteins; Quality of life; Regenerative Medicine; Research; Resolution; Resources; Rodent Model; Serum-Free Culture Media; Shortness of Breath; Silicon Dioxide; Somatomedins; Stem cells; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Translational Research; Transplantation; Treatment Efficacy; Ultrasonography; Validation; Visualization software; Work; base; caprolactone; career; cell growth; cellular imaging; combat; contrast imaging; cost; follow-up; heart function; hemodynamics; image guided; imaging agent; implantation; improved; innovation; member; monomer; nanoparticle; novel; novel strategies; quantitative imaging; small molecule; stem cell therapy; tenure track; tissue regeneration; tool; translational medicine

DESCRIPTION (provided by applicant): Ischemic heart disease is the leading cause of death in the U.S.A., and stem cell therapy can improve the ejection fraction of damaged cardiac tissue by over 10%. Unfortunately, many stem cells days after implantation and those that do survive are often located in hypoxic or fibrotic tissue that are unreceptive to tissue regeneration-my near term goal is to improve the efficacy of cardiac stem cells therapy. Exciting preliminary data suggests that silica nanoparticles can be used to both study stem cells and ensure their survival after transplant. These nanoparticles have ultrasound contrast for image-guided delivery away from fibrosis as opposed to the existing paradigm of imaging only after injection. The multifunctional nanoparticle also has MRI contrast for high resolution follow-up. Finally, the same nanoparticle offers sustained release of growth factors to encourage cell proliferation. This nanoparticle is the ideal vehicle to facilitate my long-term objective of improving heart function with stem cell therapy, but this approach requires the additional refinement and validation proposed here. The workflow is divided into three main components to test my hypothesis that combining a sustained release delivery vehicle for prosurvival agents with a real time imaging agent can overcome challenges with both cell delivery and poor cell survival. 1) I will improve the biodegradation and porosity (for loading prosurvival agents) of the nanoparticle with materials chemistry. The nanoparticle will then be evaluated with cell and animal toxicity studies and refined if needed. 2) Prosurvival agents will be loaded into nanoparticles and used to treat stem cells under challenging growth conditions ex vivo. The agents will be iteratively optimized to improve therapy. 3) Finally, I will use animal models of ischemic disease and imaging to determine the efficacy of nanoparticle-enabled stem cell therapy. The innovation lies in real-time, quantitative imaging, which allows a transition to intra-cardiac injection rather tha intra-coronary delivery and thus implantation into the most receptive tissue in the heart. Sustained release of prosurvival agents from the sponge-like nanoparticle will combat the cell death that plagues this field. This proposal advances a fundamentally new tool and approach to stem cell therapy, which will have broad applications well beyond cardiovascular medicine. Finally, the research and professional training facilitated by this grant comprise an ideal stepping-stone to my career goal of an independent career with guidance and mentoring from Stanford Profs. Sanjiv Sam Gambhir and Joseph Wu-internationally renowned experts in cell imaging and cardiovascular research.

描述（由申请人提供）：缺血性心脏病是美国的主要死因，而干细胞治疗可以使受损心脏组织的射血分数提高10%以上。不幸的是，许多干细胞在植入后几天以及那些存活下来的干细胞通常位于缺氧或纤维化组织中，这些组织不接受组织再生-我的近 长期目标是提高心脏干细胞治疗的疗效。令人兴奋的初步数据表明，二氧化硅纳米颗粒可用于研究干细胞并确保其移植后的存活。这些纳米颗粒具有超声造影剂，用于远离纤维化的图像引导递送，而不是仅在注射后成像的现有范例。多功能纳米颗粒还具有MRI对比度，用于高分辨率随访。最后，相同的纳米颗粒提供生长因子的持续释放，以促进细胞增殖。这种纳米颗粒是促进我用干细胞治疗改善心脏功能的长期目标的理想载体，但这种方法需要额外的改进和验证。工作流程分为三个主要组成部分，以测试我的假设，即结合缓释输送载体的促生存剂与真实的时间成像剂可以克服挑战与细胞交付和细胞存活率差。1)我将改善生物降解和多孔性（用于装载促生存剂）的纳米粒子与材料化学。然后将通过细胞和动物毒性研究评估纳米颗粒，并在需要时进行改进。2)促存活剂将被加载到纳米颗粒中，并用于在体外挑战性生长条件下处理干细胞。将迭代优化药剂以改善治疗。3)最后，我将使用缺血性疾病的动物模型和成像来确定纳米粒子使能干细胞治疗的功效。创新在于实时定量成像，这允许过渡到心内注射，而不是冠状动脉内输送，从而植入心脏中最易接受的组织。从海绵状纳米颗粒中持续释放促生存剂将对抗困扰这一领域的细胞死亡。这项提议为干细胞治疗提供了一种全新的工具和方法，其应用范围将远远超出心血管医学。最后，这项资助所促进的研究和专业培训是我在斯坦福大学教授的指导和指导下实现独立职业目标的理想垫脚石。 Sanjiv Sam Gambhir和Joseph Wu-细胞成像和心血管研究领域的国际知名专家。

项目成果

What is new in nanoparticle-based photoacoustic imaging?

• DOI: 10.1002/wnan.1404
• 发表时间: 2017-01
• 期刊: WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY
• 影响因子: 8.6
• 作者: Lemaster, Jeanne E.;Jokerst, Jesse V.
• 通讯作者: Jokerst, Jesse V.

Cellular toxicity of silicon carbide nanomaterials as a function of morphology.

碳化硅纳米材料的细胞毒性与形态学的关系。

• DOI: 10.1016/j.biomaterials.2018.06.027
• 发表时间: 2018-10
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Chen F;Li G;Zhao ER;Li J;Hableel G;Lemaster JE;Bai Y;Sen GL;Jokerst JV
• 通讯作者: Jokerst JV

Organosilica Nanoparticles with an Intrinsic Secondary Amine: An Efficient and Reusable Adsorbent for Dyes.

• DOI: 10.1021/acsami.7b04181
• 发表时间: 2017-05-10
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Chen F;Zhao E;Kim T;Wang J;Hableel G;Reardon PJT;Ananthakrishna SJ;Wang T;Arconada-Alvarez S;Knowles JC;Jokerst JV
• 通讯作者: Jokerst JV

A Nanoscale Tool for Photoacoustic-Based Measurements of Clotting Time and Therapeutic Drug Monitoring of Heparin.

• DOI: 10.1021/acs.nanolett.6b02557
• 发表时间: 2016-10-12
• 期刊: Nano letters
• 影响因子: 10.8
• 作者: Wang J;Chen F;Arconada-Alvarez SJ;Hartanto J;Yap LP;Park R;Wang F;Vorobyova I;Dagliyan G;Conti PS;Jokerst JV
• 通讯作者: Jokerst JV

Stem Cell Imaging: Tools to Improve Cell Delivery and Viability.

干细胞成像：改善细胞传递和生存能力的工具。

• DOI: 10.1155/2016/9240652
• 发表时间: 2016
• 期刊: Stem cells international
• 影响因子: 4.3
• 作者: Wang J;Jokerst JV
• 通讯作者: Jokerst JV