Tissue engineers can now build living human tissue in minutes rather than weeks by projecting patterns of light into a vat of gel containing living cells. The core problem is that current methods build tissue layer by slow layer, producing static scaffolds that cells cannot remodel as they do in the body. This leaves large engineered tissues without the blood vessel networks needed to keep them alive. The 3D SPARK project adapts the same mathematics used in CT medical scanners—but in reverse—to project light from multiple angles into a single volume of photoactive gel. This triggers three simultaneous processes: printing the gel into soft vascular structures, releasing growth factors that stimulate cells to form capillaries, and imaging the developing tissue to monitor growth. If successful, this approach could produce transplantable human tissues with working blood vessel networks at scales large enough for clinical use. For patients awaiting organ transplants, that could mean lab-grown kidneys or livers that survive after implantation rather than dying from lack of circulation. For drug developers, it offers realistic human tissue models that replace animal testing.
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Replicating a human organ is a highly complex challenge both structurally and functionally. At the core of this grand challenge lies the critical need for vascularisation and more broadly the need for cellularisation. Cellular systems in our bodies are naturally programmed in a bottom-up fashion where structure is an evolutionary consequence of function. For instance, the need for optimal exchange and transport drives morphogenesis, manifesting itself via dynamic signalling and secretion patterns during vascularisation, alveolarization and the formation of all self-organised tissue compartments. Tissue engineers have attempted the inverse hoping function will also follow form, with a laser focus on the structure problem: the ability to produce acellular architectures such as perfusable networks for transport and microporous scaffolds for cellular aggregation. These top-down engineered matrices are intricate yet static and non-responsive, leaving us with rudimental means of bulk seeding, cellularisation and stimulation, and limiting cell-mediated bottom-up growth and remodelling. Organotypic growth patterns are a dynamic response to physiological needs, driven by the spatiotemporally controlled release of biochemical factors and stimuli, and require extremely soft and degradable cell encapsulated extracellular microenvironments capable of bottom-up remodelling, both of which are currently only afforded at small microfluidic footprints. The 3D SPARK project offers a game-changing solution to large-scale volumetric tissue production via computed axial lithography (CAL) and computed axial stimulation (CAS) - the optical inverses of computed axial tomography (CAT). Volumetric processing challenges conventional wisdom in tissue engineering showing that complex and delicate 3D cellular architectures can be produced all-at-once without relying on slow, sequential processing of biological matter, and that large volumes of manufactured tissue can be accessible at a single cell level without a need for physical manipulation or slow optical scanning. At its core, this revolutionary CAT-inspired method utilises a superposition of 2D angular light projections to construct a 3D spatial distribution of exposure dose, and volumetrically trigger photopolymerization (bioprinting), photorelease (biomodulation) and photoexcitation (imaging) to regulate and monitor key cellular events during tissue development in a photoactive cell-encapsulated hydrogel matrix. With light-mediated volumetric processing and the ability to pattern light intensity in 3D at multiple wavelengths, we introduce a scalable solution to: (1) trigger photopolymerization and manufacture intact vascular structures in such soft (<10 kPa) cell-encapsulated photoactive gels; (2) control the light-induced depletion of chemical species such as oxygen (via radical quenching), and secretion of biochemical factors such as growth factors (via uncaging) directing tissue development across the entire volume; and (3) rapidly image the entire volume to monitor 3D cellularisation concurrent with photomodulation and tissue growth. In our tissue models, larger features such as macrovascular networks are designed and volumetrically printed in a top-down fashion and are internally coated with endothelial cells (ECs). Finer features such as microvascular capillaries are then stimulated with light to emerge and develop from sparsely encapsulated ECs within the printed gel to bridge the macrovascular gaps in a bottom-up fashion. This all-in-one platform goes beyond patterning the physical and chemical properties of the matrix, to enable dynamic manipulation of cellular processes allowing us to accommodate for top-down engineering and bottom-up development simultaneously. Hence, the proposed technology will be the dream tool of tissue engineers giving them spatiotemporal access to large volumes of printed tissue at a single cell level with light in a way never achievable before.
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