Polymeric electron paramagnetic resonance probes for real-time monitoring of tissue vascularization

项目主任/首席调查员(末位、第一位、中位)：关建军 项目摘要 这项提议的目标是创造生物可消除和可注射的基于水凝胶的电子顺磁 可植入的共振(EPR)探头，用于组织氧(O2)的实时和长期测量 集中精神。目的是在治疗过程中监测缺血组织的血管形成过程。缺血型 由于血液供应减少而导致的疾病会导致各种组织和器官的严重损害和损伤。 缺血性疾病的主要治疗目标是使缺血组织血管化，以恢复血液流动。至 快速、方便、准确地评估治疗效果，实时和可重复地监测 用微创或非侵入性光谱分析同一组织位置的组织氧浓度变化 这种方法代表了一种引人注目的战略。然而，这不能通过任何临床可用的方法实现。 接近了。当前的方法要么无法在以下情况下提供实时和长期测量 缺血型或侵袭型。 在组织氧气浓度测量的不同技术中，EPR具有实现这一点的潜力 进球。与其他技术相比，EPR具有明显的优势，例如能够测量组织中的氧气浓度 不消耗氧气，即使在低氧气浓度环境下也能提供绝对值。然而，直到 现在缺乏合适的EPR探针，可以在组织中长期保持一致的浓度 期间(≥4周)，并可通过微创途径植入和/或取回。 拟议的工作满足了对可生物消除、无毒和长效EPR探针的迫切需求 可以通过微创方法植入，用于长期监测组织中的氧气浓度。这是 以前还没有开发出高度新颖和类似的EPR探针。提出的基于水凝胶的EPR 探针不仅是可注射的和可生物消除的，而且还具有快速胶凝速度，缓慢的减重速度， 高透氧性，高EPR灵敏度。该可注射水凝胶可以通过一种 微创注射方法。基于水凝胶的EPR探针将具有高分子量，这将 克服常用小分子EPR探针的毒性问题。此外，它们还可以从 身体后通过侧基的水解变得可溶，从而消除了回收的需要。这个 水凝胶将被设计成具有高凝胶率，以实现在组织中的高保留率。慢速的探头 减重率将在较长时间内保持EPR信号强度，同时保持在一定范围内 组织定位，允许长期监测氧气浓度。高透氧性和EPR敏感性 将确保可以实时监测氧气浓度的微小变化。 目标1将创造可生物消除和可注射的基于水凝胶的EPR探针，具有快速的凝胶速度，缓慢的 失重率、高透氧性和高EPR灵敏度。 Aim#2将测试所开发的基于水凝胶的EPR探头将允许持续监测的假设 使用缺血肢体模型计算组织氧浓度。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): GUAN, JIANJUN Project Summary The objective of this proposal is to create bioeliminable and injectable hydrogel-based electron paramagnetic resonance (EPR) probes that can be implanted for the real-time and long-term measurement of tissue oxygen (O2) concentration. The purpose is to monitor the ischemic tissue vascularization process during therapy. Ischemic diseases, resulting from reduced blood supply, lead to serious damage and injury of various tissues and organs. The primary therapeutic goal for ischemic diseases is to vascularize the ischemic tissues to restore blood flow. To quickly, conveniently, and accurately evaluate the efficacy of the therapy, real-time and reproducible monitoring of tissue O2 concentration changes at the same tissue location by a minimally invasive or non-invasive spectroscopic approach represents a compelling strategy. However, this cannot be achieved by any clinically available approaches. Current approaches are either unable to provide real-time and long-term measurements under ischemic conditions or invasive. Among the different techniques for tissue O2 concentration measurement, EPR has the potential to achieve this goal. EPR has distinct advantages over other techniques, such as the ability to measure tissue O2 concentration without consuming O2, and to provide absolute values even at low O2 concentration environment. However, until now there is a lack of suitable EPR probes that can maintain a consistent concentration in tissues for an extended period (≥ 4 weeks), and can be implanted and/or retrieved by a minimally invasive approach. The proposed work addresses the critical need for bioeliminable, non-toxic, and long-lasting EPR probes that can be implanted by a minimally invasive approach for the long-term monitoring of tissue O2 concentration. This is highly novel and similar EPR probes have not been developed previously. The proposed hydrogel-based EPR probes will not only be injectable and bioeliminable, but also feature a fast gelation rate, a slow weight loss rate, high O2 permeability, and high EPR sensitivity. The injectable hydrogels can be implanted into tissues by a minimally invasive injection approach. The hydrogel-based EPR probes will have high molecular weight, and this will overcome the toxicity issue of commonly used small molecule EPR probes. Furthermore, they can be removed from the body after becoming water soluble by hydrolysis of side groups, thereby eliminating the need for retrieval. The hydrogels will be designed to have high gelation rate to achieve high retention in tissues. The probes with slow weight loss rate will maintain the EPR signal intensity for an extended period of time while retaining in a certain tissue location, allowing for long-term monitoring of O2 concentration. The high O2 permeability and EPR sensitivity will ensure that a small change in O2 concentration can be monitored in real-time. AIM #1 will create bioeliminable and injectable hydrogel-based EPR probes with a fast gelation rate, a slow weight loss rate, high oxygen permeability, and high EPR sensitivity. AIM #2 will test the hypothesis that the developed hydrogel-based EPR probe will allow continuous monitoring of tissue oxygen concentration using an ischemic limb model. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page