Stem Cell Implantable Bioreactor for In Vivo Production and Delivery of Paracrine Factors

项目摘要 尽管急性心肌梗死（MI）的治疗取得了进展，但许多患者仍会发生损失 心脏重塑和心力衰竭。干细胞治疗 心肌梗死后早期应用，旨在通过减少细胞死亡和增加心肌再生来减少心力衰竭。 新的心肌和血管细胞。然而，大多数试验仅获得了适度的临床益处。 越来越多的证据表明，干细胞的许多有益作用是由于外泌体， 它们分泌的其他旁分泌因子（PFs）。这些因子增加血管生成，减少细胞凋亡，增强 细胞增殖，促进细胞迁移，结果，"打开"和"打开"身体的内在修复卡帕克- ity。这些干细胞因子的输送及其在损伤部位的持续存在可以限制损伤， 修复，并产生显著和持久的临床益处。然而，能够感知到 不断变化的需求，并作为响应，提供大量和不同的所需因素， 无法使用。我们创造了干细胞植入式生物反应器（SCIB），这是一种新型的可移动平台， 干细胞PF的体内生产和递送，以实现这一目标。 SCIB在急性MI的再灌注治疗后放置在中央静脉中，并在其中庇护干细胞。 一个保护性的半渗透袋，保护他们免受冲刷和免疫攻击，但允许营养素， 进入和PF自由地进入循环并到达受伤的组织。SCIB中的干细胞充当"工厂" 它能感知宿主信号，并作为回应，在右边产生可能有数百个PF的整个库， 治疗所需的顺序、浓度、组合和持续时间。第一代SCIB 减少猪前壁心肌梗死后的不良心脏重塑，但不渗透外来体， 有限的干细胞能力，并且不是使用临床级材料制造的。 我们成立了Domicell LLC，以开发用于人体测试的精致SCIB并将该技术商业化。 在SBIR第1阶段申请中，我们提出了关键的体外和体内研究，以支持开发 第二代SCIB使用临床级材料，具有更高的干细胞容量和渗透性， 所有的PF包括外来体。在拟议的SBIR 1期研究结束时，Domicell LLC将有一个 临床级SCIB产品，将支持SBIR II期的关键临床前大型动物研究，结果 其中一部分将用于向FDA申请首次人体临床试验。从长远来看，Domicell LLC设想 基于可植入生物反应器的细胞治疗将成为一种全新的方法， 需要，细胞衍生的PF用于治疗心脏和非心脏疾病。

Project Summary Despite advances in the treatment of acute myocardial infarction (MI), many patients still experience loss of cardiac muscle with subsequent adverse cardiac remodeling and heart failure. Stem cell therapy administered early after MI was designed to reduce heart failure by decreasing cell death and increasing the regeneration of new cardiac muscle and vascular cells. However, most trials achieved only modest clinical benefits. Growing evidence suggests that many of the beneficial effects of stem cells are due to exosomes and other paracrine factors (PFs) they secrete. These factors increase angiogenesis, decrease apoptosis, potentiate cell proliferation, promote cell migration, and as a result, "turn on" and "turn up" the body's intrinsic repair capac- ity. Delivery of these stem cell factors and their sustained presence at the injured site could limit damage, effect repair, and produce a significant and lasting clinical benefit. However, delivery vehicles that can sense the evolving needs of injured tissue and, in response, deliver the large and varying array of required factors have not been available. We created the Stem Cell Implantable Bioreactor (SCIB), a novel removable platform for in vivo production and delivery of stem cell PFs, to achieve this objective. The SCIB is placed in a central vein after reperfusion therapy for acute MI, and shelters stem cells within a protective semi-permeable pouch, shielding them from washout and immune attack, but allowing nutrients to enter and PFs to pass freely into the circulation and to the injured tissue. Stem cells in the SCIB act as "factories" that sense host signals and, in response, produce the entire library of potentially hundreds of PFs in the right sequence, concentration, combination, and duration required for healing. The first generation SCIB favorably reduced adverse cardiac remodeling after an anterior MI in pigs, but was impermeable to exosomes, had a limited stem cell capacity, and was not manufactured using clinical-grade materials. We formed Domicell LLC to develop a refined SCIB for human testing and commercialize the technology. In this SBIR Phase 1 application, we propose critical in vitro and in vivo studies that will support the development of a second generation SCIB using clinical-grade materials, with a higher stem cell capacity and permeability to all PFs including exosomes. At the conclusion of the proposed SBIR Phase 1 studies, Domicell LLC will have a clinical-grade SCIB product that will support a pivotal pre-clinical large animal study in SBIR Phase 2, the results of which will be used to apply to the FDA for first-in-man clinical trials. In the long term, Domicell LLC envisions that cell therapy based on implantable bioreactors will become a fundamentally new approach to deliver, on demand, cell-derived PFs for the treatment of both cardiac and non-cardiac diseases.