An Intercalcated-Spiral Dual Circuit Hollow Fiber Bioreactorfor the Culture of Human Hybridomas

本工作的目的是开发一种中空纤维生物反应器，该反应器利用嵌入式螺旋缠绕双回路结构。中空纤维系统被用来生产针对肿瘤相关抗原的人类单克隆抗体。作为体内诊断和治疗试剂，人单克隆抗体应优于单克隆抗体。许多人杂交瘤分泌单克隆抗体的速度比小鼠杂交瘤低得多。因此，开发能够有效生产人单克隆抗体的工艺至关重要。研究了连续生产中存在的问题。数据和系统分析辅以数学模型，其中包括流体动力学，膜运输和细胞动力学。本项目将生物反应器工程原理应用于群体细胞培养。随着对哺乳动物细胞培养生物化学物质需求的增加，相应地需要开发先进的生物反应器技术，不仅要大量生产，而且要有效地生产生物化合物。一个重要的例子是单克隆抗体的制造。单克隆抗体纯度高，具有特异性生化反应。它们已被证明在许多诊断和治疗应用中非常有用。抗体是大而复杂的蛋白质分子，最适合通过在先进的中空纤维生物反应器中培养的哺乳动物细胞（融合）来合成，这种生物反应器具有非常均匀分布的动脉和静脉毛细血管网络。这是一个试图了解流体力学，营养运输和细胞生理学的基本方面。有必要合并来自这些不同领域的信息来解决一般问题。

The objective of this work is to develop a hollow fiber bioreactor which makes use of an intercalated-spiral wound dual circuit construction. The hollow fiber system is used to produce human monoclonal antibodies specific to tumor-associated antigens. Human monoclonal antibodies should be superior to monoclonal antibodies as in vivo diagnostic and therapeutic reagents. Many human hybridomas secrete monoclonal antibodies at a much lower rate than murine hybridomas. Hence it is crucial to develop processes which can produce human monoclonal antibodies effectively. Problems in continuous production are investigated. Data and system analyses are complemented by mathematical models which incorporate hydrodynamics, membrane transport and cellular kinetics. This project applies the principles of bioreactor engineering to mass cell culture. As demand for biochemicals from mammalian cell cultures increases, there is a corresponding need to develop advanced bioreactor technology to produce not only in large quantitie, but also effectively, biological compounds. One important example is the making of monoclonal antibodies. Monoclonal antibodies are very pure and have specific biochemical reactivities. They have proven to be very useful in many diagnostic and therapeutic applications. Antibodies are big and complex protein molecules which can best be synthesized by (fusion) mammalian cells cultured in an advanced hollow fiber bioreactor which mimics an artificial organ in the sense that the bioreactor has a very uniform distribution of arterial and venous capillary networks. This is an attempt to understand the fundamental aspects of fluid mechanics, nutrient transport, and cell physiology. It is necessary to merge information from these different areas to solve the general problem.