A Novel Shear Thinning Hydrogel System for Advanced Cellular Therapy in Ischemic Heart Disease

用于缺血性心脏病先进细胞疗法的新型剪切稀化水凝胶系统

• 批准号: 10171608
• 负责人: PAVAN ATLURI
• 金额: $ 48.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171608
• 关键词: Acute; Adamantane; Address; Animal Model; Animals; Apoptotic; Biochemical; Blood Circulation; Blood flow; Cardiovascular Diseases; Catheters; Cause of Death; Cell Death; Cell Survival; Cell Therapy; Cell Transplantation; Cell membrane; Cell physiology; Cells; Clinical; Complex; Coronary Arteriosclerosis; Coronary Artery Bypass; Coronary artery; Event; Exposure to; Fibrosis; Freezing; Gel; Geometry; Guidelines; Harvest; Heart; Heart Diseases; Heart failure; Histologic; Hyaluronic Acid; Hydrogels; Infarction; Inflammatory; Injectable; Injections; Intervention; Investigation; Investigational Therapies; Literature; Magnetic Resonance Imaging; Mass Spectrum Analysis; Mediating; Medicine; Microcirculation; Molecular; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Operative Surgical Procedures; Paracrine Communication; Pathway interactions; Patients; Phase; Plasma Cells; Play; Property; Proteins; Prunella vulgaris; Role; Secondary to; Signal Transduction; Signaling Molecule; Structure; Syringes; Techniques; Therapeutic; Therapeutic Uses; Thinness; Time; Translating; Translations; United States; Ventricular Remodeling; Vesicle; Work; advanced system; angiogenesis; base; beta-Cyclodextrins; cytokine; endothelial stem cell; exosome; global health; mortality; myocardial hypoxia; nanovesicle; novel; novel strategies; paracrine; patient population; percutaneous coronary intervention; pre-clinical; pre-clinical assessment; preservation; regenerative; shear stress; sheep model; stem cell therapy; stem cells; therapeutic target

Project Summary Cardiovascular disease is the leading cause of death in the United States. Clinical therapies currently available for heart failure are limited and do not provide a viable strategy to restore blood flow to a large group of patients. Consequently, the survival in this patient population is severely limited. Experimental therapies have attempted to restore circulation to threatened heart muscle using stem cells to regenerate micro-circulation. While this strategy demonstrated promise in experimental settings, translation to clinical therapy has been limited by a lack of significant benefit, due to cell death and a lack of retention (<1%). The therapeutic benefit of stem cells appears to be largely related to paracrine mechanisms (the proteins secreted by the cells) rather than the cells themselves. Exosomes appear to be at the center of paracrine signaling. Exosomes are vesicles secreted by the cells that contain cell signaling molecules that play an important role in cell survival, replication, and formation of vessels. They are particularly attractive for therapy, when compared to cells, in that they are easily harvested in large quantities, can be frozen and stored indefinitely, and rapidly prepared for therapy. Unfortunately, retaining the exosomes in the heart with just injection is a challenge. In order to overcome these limitations, we have developed a novel shear thinning hydrogel to allow delivery and retention of exosomes in the heart. This novel hydrogel is able to liquefy under shear forces, enabling injection through a syringe, and immediately reforming upon elimination of the shear stress. The properties of the gel facilitate optimal exosome delivery (98%) with minimal loss. We hypothesize that delivery of exosomes within the shear thinning hydrogel will enable efficient delivery to compromised heart muscle with excellent retention. We will identify factors secreted by the exosomes and gain an understanding of the pathways involved in therapy. We will also evaluate optimal timing, relative to myocardial infarction (heart attack) for delivery of the exosomes. Additionally, we will translate therapy to a sheep model of heart failure, as a preclinical assessment.

项目概要 心血管疾病是美国的首要死因。临床治疗 目前可用于心力衰竭的药物有限，并且没有提供可行的恢复血液策略 流向一大群患者。因此，该患者群体的生存受到严重影响 有限的。实验疗法试图恢复受威胁心肌的循环 使用干细胞再生微循环。虽然这一战略在 由于缺乏显着的实验设置，临床治疗的转化受到限制 由于细胞死亡和缺乏保留（<1%）而受益。干细胞的治疗益处 似乎很大程度上与旁分泌机制（细胞分泌的蛋白质）有关，而不是 比细胞本身。外泌体似乎处于旁分泌信号传导的中心。 外泌体是由细胞分泌的囊泡，含有细胞信号分子，可发挥 在细胞存活、复制和血管形成中发挥重要作用。他们特别有吸引力 与细胞相比，它们易于大量收获，因此可用于治疗 无限期冷冻和储存，并迅速为治疗做好准备。不幸的是，保留 仅通过注射将外泌体注入心脏是一个挑战。为了克服这些限制， 我们开发了一种新型剪切稀化水凝胶，可以递送和保留外泌体 在心里。这种新型水凝胶能够在剪切力下液化，从而能够通过注射 注射器，并在消除剪切应力后立即重整。的属性 凝胶有利于最佳外泌体递送（98%）且损失最小。我们假设交付 剪切稀化水凝胶内的外泌体将能够有效输送到受损的心脏 肌肉具有出色的保持力。我们将鉴定外泌体分泌的因子并获得 了解治疗所涉及的途径。我们还将评估最佳时机、相对 用于心肌梗塞（心脏病发作）的外泌体递送。另外，我们会翻译 对心力衰竭绵羊模型的治疗，作为临床前评估。

项目成果

Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics.

通过剪切稀化凝胶延迟递送内皮祖细胞来源的细胞外囊泡可改善梗塞后血流动力学。

• DOI: 10.1016/j.jtcvs.2019.06.017
• 发表时间: 2020-05-01
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: Jennifer J. Chung;Jason J. Han;Leo L. Wang;M. Arisi;Samir Zaman;Jonathan S. Gordon;Elizabeth C Li;Samuel T. Kim;Zoe Tran;Carol W. Chen;A. Gaffey;J. Burdick;P. Atluri
• 通讯作者: P. Atluri

Therapeutic Efficacy of Cryopreserved, Allogeneic Extracellular Vesicles for Treatment of Acute Myocardial Infarction.

冷冻保存的同种异体细胞外囊泡治疗急性心肌梗死的疗效。

• DOI: 10.1536/ihj.20-224
• 发表时间: 2021-03-30
• 期刊: International heart journal
• 影响因子: 1.5
• 作者: Chung JJ;Kim ST;Zaman S;Helmers MR;Arisi MF;Li EC;Tran Z;Chen CW;Altshuler P;Chen M;Burdick JA;Atluri P
• 通讯作者: Atluri P