Red Blood Cell Mimics

描述（由申请人提供）：尽管投入了大量资金，但开发和制造血液替代品的尝试多次失败。目前在北美或欧洲还没有被批准用作血液替代品的产品。在这个应用程序中，我们建议采用一种仿生方法来设计红细胞（RBC），使用由北卡罗来纳大学教堂山分校开发的一种强大的成型技术，称为PRINT(R)（非润湿模板中的颗粒复制）。PRINT将用于合成具有形状特异性、胶体稳定性的水凝胶颗粒，其尺寸和机械特性类似于红细胞，并且可以单独变形，从而使它们能够通过脾脏中3微米大小的窦。以前设计合成血液的方法主要集中在i)可以溶解大量血气的氟碳乳液；ii)聚乙二醇化血红蛋白；iii)血红蛋白的脂质体递送。到目前为止，还没有人报道直接成型的红细胞模拟具有相同的进化设计的形状和变形能力或模量的红细胞。PRINT成型技术使我们能够独立设计和研究真正替代血液所需的关键标准，包括：形状控制、颗粒模量或灵活性、表面化学和表面配体，包括自我标记、流动特性和气体输送特性。模塑颗粒将被设计成隔离血红蛋白和变构效应器作为货物，防止自由血红蛋白的释放和循环。红细胞模拟物促进了类似生命的氧气携带能力，但以一种将其与各种器官的物理接触隔离开来的形式存在，以避免与游离血红蛋白及其交联衍生物相关的副作用。此外，我们还建议将“自我标记”结合到这些可变形的模塑RBC模拟物上，以最大限度地减少网状内皮系统（RES）的消除。该项目的主要目标是开发和测试一种长循环红细胞模拟物，该模拟物具有经典的氧平衡曲线的s形形状，其表面体积比与真正的红细胞相关，可通过体外和体内研究证明具有最佳的氧携带和释放能力。

DESCRIPTION (provided by applicant): Despite substantial investment, there are many failed attempts to develop and manufacture a blood substitute. At this time there are no currently approved products for use as blood substitutes in North America or Europe. We propose in this application to take a biomimetic approach to the design of red blood cells (RBC) using a powerful molding technique called PRINT(R) (Particle Replication in Non-wetting Templates) developed at the University of North Carolina at Chapel Hill. PRINT will be used synthesize shape-specific, colloidally stable, hydrogel particles with dimensions and mechanical properties which resemble red blood cells and that are individually deformable in a manner to allow them to pass through the 3 micron sized sinusoids in the spleen. Previous approaches for the design of synthetic blood have focused on i) fluorocarbon emulsions which can dissolve large amounts of blood gases; ii) PEGylated hemoglobin; and iii) liposomal delivery of hemoglobin. Heretofore, no one has reported direct molding of RBC mimics which have the same evolutionarily designed shapes and deformability or modulus as RBCs. The PRINT molding technique allows us to independently design and investigate the key criteria necessary for a true replacement for blood, including: shape control, particle modulus or flexibility, surface chemistry and surface ligands including markers of self, flow characteristics and gas transport characteristics. The molded particles will be designed to sequester hemoglobin and allosteric effectors as a cargo, preventing the release and circulation of free-hemoglobin. The RBC mimics facilitate life-like oxygen carrying capacity, but have it in a form that isolates it from physical contact with various organs to avoid the documented side effects associated with free hemoglobin and its cross-linked derivatives. In addition, we also propose to conjugate "markers of self" onto these deformable molded RBC mimics to minimize elimination by the reticuloendothelial system (RES). Key goals of the program will be to develop and test a long circulating red blood cell mimic that has the classical sigmoidal shape of the oxygen equilibrium curve with a surface to volume ratio associated with a true RBC for optimal oxygen carrying and release capacity as demonstrated by in vitro and in vivo studies. PUBLIC HEALTH RELEVANCE: The need to develop safe and effective synthetic blood substitutes for civilian and military uses is immediate, particularly shelf-stable supplies that don't require blood antigen type matching. There will be an estimated shortage of as much as 4 million units of donor blood in the United States alone by 2030. In addition, there is increasing risk of disease transmission from current blood supplies including HIV, Hepatitis A virus, B19 parvovirus, Hepatitis C virus, and infectious prion proteins - the agents associated with variant Creutzfeldt- Jakob disease, mad cow disease and scrapie. A biomimetic approach will be taken to design red blood cells mimics with the same evolutionarily designed shapes and deformability or modulus as RBCs using a powerful molding technique called PRINT(R) (Particle Replication in Non-wetting Templates), which allows for control over shape, particle modulus, surface chemistry and surface ligands, flow characteristics and gas transport characteristics.