I-Corps: Developing polymerized hemoglobin using enzymatic ligation

I-Corps项目的更广泛影响/商业潜力是开发用于兽医和人类应用的血液替代品。 由于战争、自然灾害和流行病/地方病等全球性灾难，对献血的需求正在上升。此外，军方可能对野战氧气（O2）载体感兴趣，这种载体可以为可能导致严重失血的失血性休克病例提供不切实际的输血替代方案。目前用于创伤和无血复苏的临床标准是使用晶体，如乳酸林格氏溶液。类晶体广泛可用，安全且便宜。 这些溶液用于恢复血容量和血压，使血流继续，但不具有（O2）携带能力，对血流和O2输送有不同的负面影响。 理想的复苏液需要能够维持血容量和血压，而不会过度稀释O2携带能力和血浆蛋白，或降低血液粘度。 这项技术提供了一种替代血液替代品的方法，称为“O2桥”或血红蛋白氧载体（HBOC）。HBOCs有可能被改造成复制，甚至优化循环血液的关键生物物理参数，从而能够生产维持生命的产品。 所提出的技术旨在将O2有效地输送到组织中，就像全血或浓缩红细胞一样。此外，这种HBOC解决方案可以执行此功能，而没有疾病传播，输血反应或其他输血相关并发症的风险。这个I-Corps项目是基于血红蛋白基氧载体的开发，该氧载体是从过期的捐献人类血液中产生的。所提出的技术使用酶连接（转氨酶）来产生大尺寸聚合的人血红蛋白（PolyhHb）。 在这个过程中，红细胞从其膜上剥离，留下血红蛋白蛋白进行纯化并加工成功能性生物相容性溶液。大的聚合血红蛋白基氧载体（HBOC）溶液具有更长的循环半衰期的优势，这表明全身和网状内皮铁转运标志物的差异。 这项技术已经在小动物身上进行了测试，并在贫血状况下显示出有希望的结果。此外，它还针对其他HBOC设计和其他血液制品进行了测试。所提出的技术可用于创建一个功能HBOC解决方案，在不可控的出血环境中具有实际用途。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

The broader impact/commercial potential of this I-Corps project is the development of a blood substitute for use in veterinary and human applications. The demand for donated blood is rising due to global catastrophes such as war, natural disasters, and pandemics/endemics. Additionally, the military may have interest in field-ready oxygen (O2) carriers that can provide an alternative solution to impractical blood transfusions for cases of hemorrhagic shock in the field that may lead to severe blood loss. The current clinical standard for resuscitation from trauma and the absence of blood is the use of crystalloids, such as lactated Ringer’s solution. Crystalloids are widely available, safe, and inexpensive. These solutions are used to restore blood volume and blood pressure, allowing blood flow to continue, but do not have (O2)-carrying capacity and have varying negative effects on blood flow and O2 delivery. The ideal resuscitation fluid needs to be able to maintain blood volume and blood pressure, without excessively diluting O2-carrying capacity, and plasma proteins, or reducing blood viscosity. The proposed technology offers an alternative approach to blood substitutes, termed “O2 bridges”, or hemoglobin-based oxygen carrier (HBOC). HBOCs have the potential to be engineered to replicate, or even optimize the critical biophysical parameters of circulating blood, enabling the production of a life-sustaining product. The proposed technology is designed to transport O2 to tissues as effectively as whole blood or packed red blood cells. In addition, this HBOC solution may perform this function without the risk of disease transmission, transfusion reactions, or other transfusion-related complications.This I-Corps project is based on the development of a hemoglobin-based oxygen carrier that is produced from expired donated human blood. The proposed technology uses enzymatic ligation (transglutaminase) to produce large-size polymerized human hemoglobin (PolyhHb). In this process, red blood cells are stripped from their membrane leaving the hemoglobin protein to be purified and processed into a functional biocompatible solution. Large, polymerized hemoglobin-based oxygen carrier (HBOC) solutions have the advantage of longer circulatory half-life indicative of the difference in markers of systemic and reticuloendothelial iron transport. This technology has been tested in small animals and has shown promising results in anemic conditions. In addition, it has been tested against other HBOC designs and other blood products. The proposed technology may be used to create a functional HBOC solution that has practical use in uncontrollable hemorrhage environments.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.