From Model System to Therapy: Scalable Production of Perfusable Vascularized Liver Spheroids in 'Open-Top' 384-Well Plate

Vasculature is a key component of many biological tissues and helps to regulate a wide range of biological processes. Modeling vascular networks or the vascular interface in organ-on-a-chip systems is an essential aspect of this technology. In many organ-on-a-chip devices, however, the engineered vasculatures are usually designed to be encapsulated inside closed microfluidic channels, making it difficult to physically access or extract the tissues for downstream applications and analysis. One unexploited benefit of tissue extraction is the potential of vascularizing, perfusing, and maturing the tissue in well-controlled, organ-on-a-chip microenvironments and then subsequently extracting that product for in vivo therapeutic implantation. Moreover, for both modeling and therapeutic applications, the scalability of the tissue production process is important. Here we demonstrate the scalable production of perfusable and extractable vascularized tissues in an "open-top" 384-well plate (referred to as IFlowPlate), showing that this system could be used to examine nanoparticle delivery to targeted tissues through the microvascular network and to model vascular angiogenesis. Furthermore, tissue spheroids, such as hepatic spheroids, can be vascularized in a scalable manner and then subsequently extracted for in vivo implantation. This simple multiple-well plate platform could not only improve the experimental throughputs of organ-on-a-chip systems but could potentially help expand the application of model systems to regenerative therapy.