3D assembly of bidirectional bioelectronic scaffolds towards accelerated tissue repair

Tissue repair and regeneration, as well as 3D cell culture, have received significant attention and benefited from a wealth of advances in biomaterials, cell culture techniques, and bioreactors. These advances have reshaped the landscape for enhanced wound healing, organ transplantation, and model systems for fundamental studies and therapy/toxicological screening. The rise of multimodal (chemical, electrical, physical) and bi-directional (sensing and stimulating) bioelectronic devices, has opened new opportunities in real-time tissue diagnostics as well as responsive actuation of processes implicated in tissue growth or repair. While approaches to 3D-like (often considered “2D+”) bioelectronics provide a useful foundation towards tissue or cell culture integration, their implementation is limited to form factors not readily translatable to true 3D constructs. There is a need to develop a generalizable approach to assemble biomaterial scaffolds with functional, optoelectronically active constructs that can interrogate and affect 3D tissues throughout their bulk in a prescribed, spatiotemporally defined manner. Integration of tissue and bioelectronic elements is often limited to surfaces (i.e. wrapping around the outside of an organ), or otherwise injected/inserted into pre-formed or functional tissue, causing damage or perturbing the system. Recent advances in electroactive materials and fabricated devices present an opportunity for softer, more compliant and flexible bioelectronics that provide an advantageous interface with cells and tissue. The challenge remains, however, to integrate such components (thin-film bioelectronics) with multifunctional, 3D printed elements, to enable a hybrid construct that can both serve as passive and/or bioactive scaffold for tissue growth or regeneration but can also sense tissue state and provide responsive bioelectronic control. In this potential project for the ONR Young Investigators Program, I propose to combine the design freedom of functional 3D printed scaffolds with thin-film bioelectronics through a process of micro continuous liquid interface production (µCLIP) around mesh electronics. This assembled construct will enable bulk tissue stimulation, patterning of structural and/or bioactive components (i.e. vasculature, conduits), and tissue-integrated thin-film electronic sensors. While generalizable to multiple tissue types and applications, we will pursue validation in in-vitro models for bone differentiation and proliferation, and neural conduits for nerve gap repair, through the following objectives: (1) Develop processes and manufacture electroactive 3D printed scaffolds to affect biological function 3D cell culture. (2) Develop assembly processes to achieve truly integrated 3D thin-film bioelectronic sensors with functional scaffolds, and validate functional operation on a benchtop. (3) Apply 3D integrated bioelectronic construct to interrogate and stimulate 3D cell culture model of nerve gap repair, with potential to pilot such constructs in in-vivo nerve gap models. Success will be measured through the delivery of developed protocols and printed constructs, real-time sensing throughout bulk, 3D tissue, and successful stimulation to affect tissue state. The objectives and their sub-tasks will leverage the PI’s expertise in designing electroactive (semi)conducting polymers (NSF CAREER, Alfred P. Sloan fellowship). The PI is well-positioned to accomplish these objectives due to his prior experience fabricating bi-directional bioelectronic platforms for neural interfacing, a