3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Barco, Guimarães, Portugal.
ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal.
Adv Exp Med Biol. 2020;1230:137-159. doi: 10.1007/978-3-030-36588-2_9.
The mass use of biological agents for pharmaceutical purposes started with the development and distribution of vaccines, followed by the industrial production of antibiotics. The use of dynamic systems, such as bioreactors, had been already applied in the food industry in fermentation processes and started being used for the development of pharmaceutical agents from this point on. In the last decades, the use of bioreactors and microfluidic systems has been expanded in different fields. The emergence of the tissue engineering led to the development of in vitro models cultured in dynamic systems. This is particularly relevant considering the urgent reduction of the total dependence on animal disease models that is undermining the development of novel drugs, using alternatively human-based models to make the drug discovery process more reliable. The failure out coming from animal models has been more prevalent in certain types of cancer, such as glioblastoma multiform and in high-grade metastatic cancers like bone metastasis of breast or prostatic cancer. The difficulty in obtaining novel drugs for these purposes is mostly linked to the barriers around the tumors, which these bioactive molecules have to overcome to become effective. For that reason, the individualized study of each interface is paramount and is only realistic once applying human-based samples (e.g. cells or tissues) in three-dimensions for in vitro modeling under dynamic conditions. In this chapter, the most recent approaches to model these interfaces in 3D systems will be explored, highlighting their major contributions to the field. In this section, these systems' impact on increased knowledge in relevant aspects of cancer aggressiveness as invasive or motile cellular capacity, or even resistance to chemotherapeutic agents will have particular focus. The last section of this chapter will focus on the integration of the tumor interfaces in dynamic systems, particularly its application on high-throughput drug screening. The industrial translation of such platforms will be discussed, as well as the main upcoming challenges and future perspectives.
大规模将生物制剂用于制药目的始于疫苗的开发和分发，随后是抗生素的工业化生产。从那时起，生物反应器等动态系统已在食品工业的发酵过程中得到应用，并开始用于开发药物制剂。在过去的几十年中，生物反应器和微流控系统在不同领域的应用得到了扩展。组织工程的出现导致了在动态系统中培养的体外模型的发展。考虑到迫切需要减少对动物疾病模型的全面依赖，这一点尤其重要，动物疾病模型正在破坏新型药物的开发，转而使用基于人类的模型来使药物发现过程更加可靠。动物模型的失败在某些类型的癌症中更为普遍，例如多形性胶质母细胞瘤和高级转移性癌症，如乳腺癌或前列腺癌的骨转移。出于这些目的，难以获得新型药物主要与肿瘤周围的障碍有关，这些生物活性分子必须克服这些障碍才能发挥作用。因此，对每个界面的个体化研究至关重要，只有在应用基于人类的样本（例如细胞或组织）在三维空间中进行动态条件下的体外建模时，才能实现这一目标。在本章中，将探讨在 3D 系统中建模这些界面的最新方法，强调它们对该领域的主要贡献。在这一节中，将特别关注这些系统对增加癌症侵袭性或运动细胞能力等相关方面的知识的影响，甚至对化疗药物的耐药性。本章的最后一部分将重点介绍肿瘤界面在动态系统中的整合，特别是其在高通量药物筛选中的应用。还将讨论这些平台的工业转化，以及主要的未来挑战和未来展望。
