Biomimetic Approach to the Fabrication of Red Blood Cell Mimics

红细胞模拟物的仿生方法

基本信息

批准号：
7845033
负责人：
JOSEPH M. DESIMONE
金额：
$ 36.2万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845033
关键词：
Adverse effects Affect American Animals Antigens Antioxidants Binding Biodistribution Biological Biological Markers Biology Biomimetics Blood Blood Circulation Blood Substitutes Blood Viscosity Blood donor Blood gas Bovine Spongiform Encephalopathy CD 200 CD47 Antigen CD47 gene Caliber Carrying Capacities Characteristics Chemistry Coagulation Process Coronary Creutzfeldt-Jakob Syndrome Development Dimensions Discontinuous Capillary Disease Dose Dose-Limiting Double Stranded DNA Virus Drug Kinetics Electrons Encapsulated Ensure Environment Epitopes Equilibrium Erythrocytes Ethylene Glycols Europe Evaluation Excision Exhibits Extracellular Domain Extravasation Family Fluorocarbon Emulsions Gases Generations Goals HIV Half-Life Height Heme Hemoglobin Hepatic Hepatitis A Virus Hepatitis C virus Hydrogels Immune response In Vitro Individual Integral Membrane Protein Intervention Investments Kidney Laboratories Life Ligands Light Liposomes Malignant - descriptor Marketing Maximum Tolerated Dose Measures Mechanics Mediating Membrane Glycoproteins Methodology Methods Military Personnel Modeling Molds Mus Myocardial Infarction Nephrotoxic Nitric Oxide North America North Carolina Opsin Organ Organ Preservation Oxidants Oxygen Particle Size Parvovirus Performance Perfusion Phagocytes Phagocytosis Phagocytosis Inhibition Phase Play Printing Prions Production Property Proteins Reaction Receptor Signaling Recombinants Reporting Respiratory Transport Reticuloendothelial System Risk Rodent Role SHPS-1 protein Scanning Scrapie Series Serum Shapes Signal Transduction Simulate Solutions Spleen Splenic Red Pulp Stroke Structure Surface System TNFRSF5 gene Techniques Testing Therapeutic Time Tissues Toxic effect Transplantation Treatment Efficacy United States Universities Variant Vascular blood supply Whole Blood Work cell injury cell type crosslink density design disease transmission ethylene glycol flexibility improved in vitro Model in vivo innovation literature survey macrophage member mimetics nano nanoparticle particle prevent programs protein function receptor research study tissue oxygenation

项目摘要

DESCRIPTION (provided by applicant): Despite substantial investment, there are many failed attempts to develop and manufacture a blood substitute and 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 nano-molding technique called PRINT TM (Particle Replication in Non-wetting Templates) developed at the University of North Carolina at Chapel Hill. PRINT TM 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 TM 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 are able to sequester hemoglobin and allosteric effectors as a cargo, preventing the release and circulation of free-hemoglobin, to 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 an oxygen carrier that is long circulating and 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. The need to develop safe and effective synthetic blood substitutes is clear. 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. Military uses of blood supplies are also clear. Especially shelf-stable supplies that don't require blood antigen type matching. Beyond blood supply, there is a significant need for innovative oxygen delivery approaches to treat such conditions as stroke, myocardial infarction, coronary blockage, organ preservation for transplantation, and malignant disease which affect more than 4 million Americans each year.

描述（由申请人提供）：尽管进行了大量投资，但仍有许多未能开发和制造血液替代品的尝试，目前尚无批准的产品用于北美或欧洲的血液替代品。我们建议在此应用中使用一种强大的纳米焊接技术来采用仿生方法来设计红细胞（RBC），称为PRINT TM（颗粒复制中的非润湿模板中的粒子复制），在北卡罗来纳大学教堂山的北卡罗来纳大学开发。印刷TM将用于合成形状特异性的，胶体稳定的水凝胶颗粒，具有尺寸和机械性能，它们类似于红细胞，并且可以单独变形，以使它们通过脾脏中的3微米大小的正弦曲线。合成血液设计的先前方法集中在i）可以溶解大量血液的氟化合物乳液； ii）卵形血红蛋白； iii）血红蛋白的脂质体递送。迄今为止，没有人报道了RBC模拟物的直接成型，后者具有相同的进化设计形状，可变形性或模量与RBC。印刷TM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，颗粒模量或柔韧性，表面化学和表面配体，包括自我，流动特性和气体传输特性的标记。模制颗粒能够将血红蛋白和变构效应子隔离为货物，以防止自由血红蛋白的释放和循环，以促进寿命样的氧气承载能力，但使其以与各种器官的物理接触形式隔离，以避免与自由的副作用相关的自由副作用，与自由的血液蛋白和交叉衍生物相关。此外，我们还建议将“自我标记”结合到这些可变形的模制RBC模拟物上，以最大程度地减少网状内皮系统（RES）的消除。该程序的关键目标是开发长期循环的氧载体，并具有氧气平衡曲线的经典乙状结肠形状，其表面与体积比与真正的RBC相关，以实现最佳的氧气携带和释放能力，如体外和体内研究所证明的。开发安全有效的合成血液替代品的需求是明显的。 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.血液供应的军事用途也很明显。尤其是不需要血液抗原类型匹配的货架稳定供应。除了血液供应之外，还需要进行创新的氧气输送方法来治疗中风，心肌梗塞，冠状动脉阻塞，器官保存的移植和恶性疾病等疾病，每年影响超过400万美国人。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Low modulus biomimetic microgel particles with high loading of hemoglobin.

DOI：
10.1021/bm3007242
发表时间：
2012-09-10
期刊：
BIOMACROMOLECULES
影响因子：
6.2
作者：
Chen, Kai;Merkel, Timothy J.;Pandya, Ashish;Napier, Mary E.;Luft, J. Christopher;Daniel, Will;Sheiko, Sergei;DeSimone, Joseph M.
通讯作者：
DeSimone, Joseph M.

PRINT: a novel platform toward shape and size specific nanoparticle theranostics.

DOI：
10.1021/ar2000315
发表时间：
2011-10-18
期刊：
ACCOUNTS OF CHEMICAL RESEARCH
影响因子：
18.3
作者：
Perry, Jillian L.;Herlihy, Kevin P.;Napier, Mary E.;Desimone, Joseph M.
通讯作者：
Desimone, Joseph M.

The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles.

DOI：
10.1016/j.jconrel.2012.06.009
发表时间：
2012-08-20
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Merkel TJ;Chen K;Jones SW;Pandya AA;Tian S;Napier ME;Zamboni WE;DeSimone JM
通讯作者：
DeSimone JM

Effect of aspect ratio and deformability on nanoparticle extravasation through nanopores.