Integration concepts for multi-organ chips: how to maintain flexibility?!

Abstract

Multi-organ platforms have an enormous potential to lead to a paradigm shift in a multitude of research domains including drug development, toxicological screening, personalized medicine as well as disease modeling. Integrating multiple organ-tissues into one microfluidic circulation merges the advantages of cell lines (human genetic background) and animal models (complex physiology) and enables the creation of more in vivo-like in vitro models. In recent years, a variety of design concepts for multi-organ platforms have been introduced, categorizable into static, semistatic and flexible systems. The most promising approach seems to be flexible interconnection of single-organ platforms to application-specific multi-organ systems. This perspective elucidates the concept of 'mix-and-match' toolboxes and discusses the numerous advantages compared with static/semistatic platforms as well as remaining challenges.

Keywords: drug development; flexible multi-organ toolbox; microfluidics; multi-organ chip; organs-on-a-chip; personalized medicine.

Figure 1.. The general concept of the organ-on-a-chip technology.

(A) Current organ-on-a-chip systems can be categorized into two fundamental concepts: single-organ chips integrating one type of tissue or organ only and multi-organ chips featuring at least two different types of tissue or organ compartments. Single-organ systems, in turn, can be subdivided into tissue-specific (B) and generic (C) single-organ chips. While the geometry of organ/tissue-specific chips is precisely tailored to the needs of a certain type of tissue, a generic one-geometry-fits-all-tissues approach allows a rapid commercialization.

Figure 2.. General approaches for the integration to multi-organ devices.

(A) Static systems: multiple tissues are integrated into a single device connected to each other. (B) Semistatic systems: tissues are interconnected via a fluidic network with Transwell^®-based tissue inserts. (C) Flexible systems: individual organ/tissue specific platforms are joined together using flexible microconnectors. (A) Reproduced with permission from the Royal Society of Chemistry [38]; (B) Reproduced with permission from the Royal Society of Chemistry [41].

Figure 3.. The concept of flexible multi-organ systems.

(A) A comparison of the success rates of multi-organ networks set up according to the three different multi-organ integration concepts. Flexible multi-organ devices theoretically achieve a 100% functionality, irrespective of an increasing number of interconnected organs. In reality, however, we suspect the connectors in between the single-organ compartments to be a minor source of error. Hence, the slight decrease of flexible multi-organ functionality will be caused by the quality and the number of connectors in between the individual organ compartments. In comparison, the success rates of static and semistatic multi-organ systems are significantly lower and diminish with increasing number of interconnected organs. (B) The concept of the proposed flexible ‘mix-and-match’ multi-organ tool box intends on preculturing the required single-organ systems separately, and in a parallelized, redundant manner. Upon maturity of all systems, the single units will be connected. By bypassing defective single-organ systems, the performance of the resulting multi-organ system is maintained at its highest level.

Figure 4.. The future potential of the flexible ‘mix-and-match’ multiorgan toolbox.

In combination with the technology of iPSCs, flexible multi-organ systems will significantly contribute to future advances in a variety of domains of research. The multifarious application areas of the multi-organ system will include drug development and toxicity screening, disease modeling and mechanistic studies, as well as personalized medicine and research on the human microbiome. iPSC: Induced pluripotent stem cell.