Abstract
As a 3D bioprinting technique, hydrogel stereolithography has historically been limited in its ability to capture the spatial heterogeneity that permeates mammalian tissues and dictates structure–function relationships. This limitation stems directly from the difficulty of preventing unwanted material mixing when switching between different liquid bioinks. Accordingly, we present the development, characterization, and application of a multi-material stereolithography bioprinter that provides controlled material selection, yields precise regional feature alignment, and minimizes bioink mixing. Fluorescent tracers were first used to highlight the broad design freedoms afforded by this fabrication strategy, complemented by morphometric image analysis to validate architectural fidelity. To evaluate the bioactivity of printed gels, 344SQ lung adenocarcinoma cells were printed in a 3D core/shell architecture. These cells exhibited native phenotypic behavior as evidenced by apparent proliferation and formation of spherical multicellular aggregates. Cells were also printed as pre-formed multicellular aggregates, which appropriately developed invasive protrusions in response to hTGF-β1. Finally, we constructed a simplified model of intratumoral heterogeneity with two separate sub-populations of 344SQ cells, which together grew over 14 days to form a dense regional interface. Together, these studies highlight the potential of multi-material stereolithography to probe heterotypic interactions between distinct cell types in tissue-specific microenvironments.
Highlights
As a 3D bioprinting technique, hydrogel stereolithography has historically been limited in its ability to capture the spatial heterogeneity that permeates mammalian tissues and dictates structure–function relationships
When encapsulated in multi-material core/shell architectures, we found that populations of dispersed cancer cells underwent considerable proliferation and that pre-formed multicellular aggregates exhibited phenotypically appropriate invasive morphologies in response to hTGF-β1
The difficulty of modifying proprietary hardware/software to accommodate soft biological materials—such as hydrogels—has impeded widespread adoption by the bioprinting community. To address this gap in technology, we have developed a fully open-source multi-material stereolithography (MMSLA) bioprinter consisting of inexpensive, readily available components that allow for multi-material fabrication of spatially heterogeneous hydrogel structures (Fig. 1a)
Summary
As a 3D bioprinting technique, hydrogel stereolithography has historically been limited in its ability to capture the spatial heterogeneity that permeates mammalian tissues and dictates structure–function relationships. We constructed a simplified model of intratumoral heterogeneity with two separate sub-populations of 344SQ cells, which together grew over 14 days to form a dense regional interface. Together, these studies highlight the potential of multi-material stereolithography to probe heterotypic interactions between distinct cell types in tissue-specific microenvironments. Mammalian organ function relies on controlled interactions between discrete tissue domains that are physically separate yet biochemically linked These interfaces are exemplified by vascular capillaries, with which parenchymal and stromal tissues exchange gases, small molecules, and proteins, without transferring larger components such as albumin, fibrinogen, or red and white blood cells. The need for biaxial heterogeneity can be addressed with inkjet p rinting[4,5], microcontact p rinting[6], or p hotolithography[7], but these strategies do not scale to full 3D control
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