UC Irvine

The architectural matrices that house cells under natural physiological conditions are ubiquitously observed with spatially defined properties such as physiochemical gradients or stiffness heterogeneity, mainly due to their critical roles in enabling biological processes like tissue morphogenesis. Recapitulating these characteristics in engineered in vitro models is often limited by the resolution afforded by currently available material platforms or three-dimensional (3-D) manufacturing tools. This work is centered on developing biomaterial systems and approaches that present chemical, mechanical, and electrical cues related to 3-D brain models in a spatially engineered manner. Through our collaborative efforts, central to this work is the utility of cortical organoids as a model system, as they are established as transcriptionally and functionally better mimics of the primary human fetal cortex than two-dimensional (2-D) adherent cultures. We addressed the lack of high-fidelity cell diversity and topographic organization (or ‘arealization’) as the in vivo conditions for the cortical organoids produced via conventional protocols. In particular, we pioneered two biomaterial-based platforms relevant to spatial engineering of cortical organoids: (i) a multi-material hydrogel system with stiffness gradient-controlled diffusion of morphogens towards where the organoids are embedded; and (ii) a biopolymeric hydrogel system doped with π-conjugated supramolecular assemblies that provide a pathway for energy transport and mechanical dissipation, making an electroactive and viscoelastic material at the same time. Both systems are processable via photopolymerization/photocrosslinking routes, making them compatible with digital light processing (DLP) for creating 3-D bioprinted constructs with micron-scale resolution. For the first system, we mimicked morphogen gradients secreted by neural signaling centers, such as the anterior neural ridge and roof plate of the telencephalon, in order to generate cortical organoids as in vitro models that express different cortical areas in organoids. We utilized DLP as a high-throughput and -precision 3-D printing approach to produce micro-architectured hydrogels with spatially defined distribution of antagonistic morphogens for cortical organoids. For the second system, we developed a synthetic hydrogel matrix with conductive characteristics relevant to late-stage organoids. We showed how peptide sequence and molecular assembly triggers influenced the assemblies formed and their printability via DLP. In summary, this work offers new engineered platforms that showcase the advantages of utilizing 3-D bioprinting and biomaterials to enable more spatially accurate studies of neurodevelopmental diseases and regenerative tissue engineering.