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.

项目摘要 心血管疾病是美国人死亡的主要原因。临床疗法 目前可用于心力衰竭的药物是有限的，并且没有提供恢复血液的可行策略 流向一大群患者。因此，该患者人群的生存率严重低于 有限公司实验性疗法试图恢复受威胁的心肌的循环 利用干细胞来再生微循环。虽然这一战略在 实验设置，翻译到临床治疗一直受到缺乏显着的限制， 由于细胞死亡和缺乏保留（<1%），这是有益的。干细胞的治疗益处 似乎在很大程度上与旁分泌机制（细胞分泌的蛋白质）有关， 而不是细胞本身。外泌体似乎是旁分泌信号的中心。 外泌体是由细胞分泌的囊泡，其含有细胞信号分子， 在细胞存活、复制和血管形成中起重要作用。它们特别吸引人 对于治疗，当与细胞相比时，因为它们容易大量收获， 冷冻和无限期储存，并迅速准备治疗。不幸的是，保留 注射外来体是一个挑战为了克服这些限制， 我们已经开发了一种新的剪切稀化水凝胶， 在心脏。这种新型水凝胶能够在剪切力下溶胀，使得能够通过 注射器，并在消除剪切应力后立即重整。的性质 凝胶促进最佳外泌体递送（98%），损失最小。我们假设， 剪切稀化水凝胶内的外来体将能够有效地递送至受损的心脏 肌肉保持力极佳。我们将鉴定外泌体分泌的因子， 了解治疗中涉及的途径。我们还将评估最佳时机，相对 心肌梗塞（心脏病发作）来递送外泌体。此外，我们将翻译 治疗的羊模型的心脏衰竭，作为临床前评估。

项目成果

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

• 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