A Cell-Based Drug Factory with Sense and Respond Peptide Production via a Bioelectric Device Interface

Interfacing cell-based therapeutics with bioelectronic devices can enable sense and respond capabilities to regulate therapeutic dosing. Herein, we present an implantable cell-based drug factory platform that interfaces with a bioelectric device to enable closed-loop, inducible and traceable protein production for <i>in situ</i> therapeutic dose regulation. For this system we engineered a clinically relevant cell line (ARPE-19) to co-express hormones which regulate circadian rhythms and EGFP under the control of a light-responsive optogenetic system. Engineered cells produced physiologically relevant peptides (leptin, glucagon-like peptide-1 and adrenocorticotropic hormone) and regulated their production by 16-fold in response to light actuation. We encapsulated engineered cells in an immunomodulatory hydrogel to facilitate implantation and demonstrated that a millimeter-scale implantable device could sense the produced EGFP fluorescence. By genetically linking the production of EGFP to the therapeutic peptide we have shown that this fluorescence reading can be used to calculate the dose of peptide produced by the cell factories. In combining the sense and actuate capabilities, we can create a cell therapy-bioelectric hybrid device capable of tracking and adjusting therapeutic dosing <i>in situ. </i>This technology will enable therapeutic modulation of precisely regulated biological processes including the circadian rhythm.