Bioprinting Engineered Tissues Containing Intricate Small-Scale Vascular Networks

The generation of appropriately dense and small-scale capillary networks remains the major roadblock in the progression of tissue engineering, and this has been the case for many years now. Researchers have established the recipes needed to generate functional tissue structures for many organs, from lungs to liver, but in order to grow more than millimeter-thick tissue sections, blood vessels are needed to carry nutrients and oxygen to the inner cells. Unfortunately, growing blood vessels is a very challenging problem, and up until quite recently no-one was even getting close to a viable solution that didn’t involve taking existing tissues and decellularizing them to obtain a preexisting extracellular matrix structure with a capillary network. This matrix can then be repopulated with the required cell types to reform a working tissue.

The decellularization approach is a potentially useful bridging technology, but it doesn’t scale up very well for widespread use, even in the scenario in which genetically engineered animals can be farmed for their organs. What is needed is the ability to rapidly grow or bioprint suitably vascularized tissue from a patient cell sample. Bioprinting is certainly a going concern, an evolution of rapid prototyping as applied to living cells and tissue structure. Using it to print very fine scale detail in tissue has been a challenging capability to realize, however. Much of the focus of the research community has instead been on finding ways to convince cells to vascularize their own tissue, which turns out to be far from trivial even for larger blood vessels, never mind a very dense network of hundreds of capillaries passing through every square millimeter cross-section of tissue.

In the line of research noted here, scientists working on bioprinter technology have now reached the point at which they can demonstrate the ability to bioprint very small-scale features in tissue. This allows for the generation of equally small scale and complex vascular networks, much further along the road towards mimicking natural capillary networks. Fortunately, it is probably not necessary to achieve complete fidelity with nature in order produce larger, functional tissue sections. That will advance the state of the art considerably, as progress continues towards the bioprinting of full-sized patient-matched organs.

Organ bioprinting gets a breath of fresh air

Bioengineers have cleared a major hurdle on the path to 3D printing replacement organs with a breakthrough technique for bioprinting tissues. The new innovation allows scientists to create exquisitely entangled vascular networks that mimic the body’s natural passageways for blood, air, lymph and other vital fluids. “One of the biggest road blocks to generating functional tissue replacements has been our inability to print the complex vasculature that can supply nutrients to densely populated tissues. Further, our organs actually contain independent vascular networks – like the airways and blood vessels of the lung or the bile ducts and blood vessels in the liver. These interpenetrating networks are physically and biochemically entangled, and the architecture itself is intimately related to tissue function. Ours is the first bioprinting technology that addresses the challenge of multivascularization in a direct and comprehensive way.”

Layers are printed from a liquid pre-hydrogel solution that becomes a solid when exposed to blue light. A digital light processing projector shines light from below, displaying sequential 2D slices of the structure at high resolution, with pixel sizes ranging from 10-50 microns. With each layer solidified in turn, an overhead arm raises the growing 3D gel just enough to expose liquid to the next image from the projector. The key insight was the addition of food dyes that absorb blue light. These photoabsorbers confine the solidification to a very fine layer. In this way, the system can produce soft, water-based, biocompatible gels with intricate internal architecture in a matter of minutes.

Tests of the lung-mimicking structure showed that the tissues were sturdy enough to avoid bursting during blood flow and pulsatile “breathing,” a rhythmic intake and outflow of air that simulated the pressures and frequencies of human breathing. Tests found that red blood cells could take up oxygen as they flowed through a network of blood vessels surrounding the “breathing” air sac. This movement of oxygen is similar to the gas exchange that occurs in the lung’s alveolar air sacs.

Multivascular networks and functional intravascular topologies within biocompatible hydrogels

Solid organs transport fluids through distinct vascular networks that are biophysically and biochemically entangled, creating complex three-dimensional (3D) transport regimes that have remained difficult to produce and study. We establish intravascular and multivascular design freedoms with photopolymerizable hydrogels by using food dye additives as biocompatible yet potent photoabsorbers for projection stereolithography. We demonstrate monolithic transparent hydrogels, produced in minutes, comprising efficient intravascular 3D fluid mixers and functional bicuspid valves. We further elaborate entangled vascular networks from space-filling mathematical topologies and explore the oxygenation and flow of human red blood cells during tidal ventilation and distension of a proximate airway. In addition, we deploy structured biodegradable hydrogel carriers in a rodent model of chronic liver injury to highlight the potential translational utility of this materials innovation.

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