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

项目负责人/主要研究者（末、首、中）：关健军 项目摘要 该提案的目的是创建生物可消除的和可注射的基于水凝胶的电子顺磁 可植入用于实时和长期测量组织氧（O2）的EPR探头 浓度.目的是监测治疗过程中缺血组织血管化过程。缺血性 由于血液供应减少而引起的疾病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流。到 快速、方便、准确地评估治疗效果，实时、可重复地监测 通过微创或非侵入性光谱分析， 这是一个令人信服的战略。然而，这不能通过任何临床可用的方法来实现。 接近。目前的方法要么无法提供实时和长期的测量下， 局部缺血或侵入性。 在用于组织O2浓度测量的不同技术中，EPR具有实现这一点的潜力 目标. EPR与其他技术相比具有明显的优势，例如能够测量组织O2浓度 而不消耗O2，并且即使在低O2浓度环境下也提供绝对值。然而直到 现在缺乏合适的EPR探针，其可以在组织中保持一致的浓度， 时间（≥ 4周），并且可以通过微创方法植入和/或取出。 拟议的工作解决了对生物可消除，无毒和持久的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O2浓度。这是 以前还没有开发出非常新颖和类似的EPR探针。水凝胶EPR 探针将不仅是可注射的和可生物消除的，而且还具有快速凝胶化速率，缓慢的重量损失速率， 高透氧性和高EPR灵敏度。可注射的水凝胶可以通过微生物学方法植入组织中。 微创注射方法。基于水凝胶的EPR探针将具有高分子量，并且这将 克服了常用小分子EPR探针的毒性问题。此外，它们可以从 在通过侧基的水解而变成水溶性之后，该主体由此消除了回收的需要。的 将水凝胶设计成具有高胶凝速率以实现在组织中的高保留。探针缓慢 重量损失率将在延长的时间段内保持EPR信号强度，同时保持一定的 组织定位，允许长期监测O2浓度。高氧渗透率和EPR灵敏度 将确保可以实时监测O2浓度的微小变化。 AIM#1将创建生物可消除和可注射的基于水凝胶的EPR探针，其具有快速的凝胶化速率，缓慢的 失重率高，透氧性好，EPR灵敏度高。 AIM #2将测试开发的水凝胶EPR探头将允许连续监测的假设 使用缺血肢体模型测量组织氧浓度。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码

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