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Living cells need oxygen to survive. Since the advent of 3D bioprinting, doctors and scientists have been asked, “When can we transplant a 3D bioprinted heart, a kidney, or a lung?”
It is tantalizing and exciting for the human race to dream of using a straightforward technology to address pressing medical problems for the millions of people suffering from organ failure. It is so exciting that mock-ups of heart and lung structures are printed as examples of the power of bioprinting to re-create any structure–well, almost any structure.
There has been a technical problem, a tiny one: capillaries. Capillaries are the 5-10 micrometer blood vessels (1/10th the size of a human hair) that are the primary place of oxygen exchange throughout our bodies. Capillaries are so small that sometimes single red blood cells fold sideways to make it through. All organisms that rely on oxygen and have bodies larger than 300 micrometers have some version of capillaries.
Nozzle-based printers are the standard in bioprinting. The problem is that no nozzle-based printing system can print at a high enough resolution to build capillaries.
Every tissue in the human body is supplied with oxygen by capillaries; in our lungs, capillaries are where oxygen is absorbed when we breathe.
Capillaries are ubiquitous but are distributed at different densities in different tissues. The maximum spacing of a capillary is dependent on oxygen diffusion, which is about 250 to 300 micrometers through living tissues. Without oxygen cells simply begin to die off, sometimes in a matter of minutes. In your heart, which is always beating and requires quite a bit of oxygen, capillaries are only 20 micrometers apart. In the brain, it is estimated that each neuron has it’s own capillary to ensure it has plenty of oxygen to function properly. In low metabolic activity tissues, capillaries are spaced further apart, as far as 250-300 microns apart in fat tissue.
The oxygen diffusion limits are evolutionarily conserved, and though researchers have experimented with alternatives to capillaries in bioprinted tissue–larger structures that can be printed at around 50 micrometers–none of them have worked. These larger blood vessels have fallen short because the surface area to volume ratio is not sufficient for oxygen delivery without disrupting the function of the tissue. In short, you can build larger tubes, but those larger tubes take up most of the room in the tissue and don’t allow for tissue function. Even more importantly, kidneys, lungs, and livers require the large surface area to volume ratios provided by numerous capillaries to function: for filtration, oxygen absorption, and removal of toxins.
3D bioprinting hit a technical wall when applied to bioprinting organ. The resolution of even the best 3D bioprinting systems is too low (by about 100-fold) to create capillaries, leaving the dream of true organ replacement out of reach—until now.
Even with resolution and speed limitations, human tissue engineering and 3D bioprinting have produced fantastic biological replacements for cartilage and bone, demonstrating that 3D bioprinting for non-metabolically active tissues works well for human transplantation. The technology can yield real medical solutions.
Patients have had 3D printed tissue successfully transplanted: their bodies have adapted and incorporated the engineered tissue as their own and even developed vasculature post-transplantation. The engineered tissue has become a living tissue.
In my career as a Physiologist and Biophysicist studying immune responses and cell-cell interactions, I found the resolution problem and the associated limits in biological fabrication fascinating. Routinely in the laboratory, we used a laser-based method to image cell-cell interactions in real time, in living tissues. It was common-place to take full 3D videos of tissues and tiny capillaries at resolutions much higher than what was necessary to print a human capillary.
In thinking about the millions of people that could benefit from organ and tissue replacement, a single burning question stuck with me: if we can see these blood vessels, why can’t we build them?
Laser-based printing has been utilized in numerous fields to achieve high-resolution structures, from semiconductors to drug delivery devices. However, this printing method has been slow, and the complexity of human capillary structures made the speed of laser-based printing prohibitive for building much beyond a few small structures. The manufacturing method was not scalable to anything much larger than a millimeter. Millimeter-sized kidneys weren’t going to solve the world’s human organ shortage problem.
I left academia with this burning question in mind, and I spent months researching a way to make a high-resolution, high-speed bioprinting system. These were the scary times when people talk about in an entrepreneur’s life: I turned down good job offers, and I didn’t take a paycheck for 8 months. To support myself, I sold the condo I had scraped together enough savings to buy while in grad school.
But I found the solution.
By combining methods from several fields of imaging and changing a few parameters, I had an idea on paper that looked like we could solve the final major engineering problem in building human organs. Prellis Biologics was founded (Prellis originated from the words “printed trellis”). Patents were filed, we brought in some initial capital, and we started building. And physics and technology worked! It was in the summer of 2017, as part of IndieBio Class 5, and my team was overjoyed.
We can print with or without cells present as we use a far-red non-toxic laser-based system, lending the technology to high-resolution cell deposition as well as a generation of vascular tissue structures that can be seeded with any cell type. These are key steps toward full organ development, but these structures are a solution in and of themselves too. Vascularized tissue allows pharmaceutical companies to push the boundaries for human tissue testing and develops better therapeutics faster, and researchers in many sectors are in desperate need of larger tissue models.
I believe in the democratization of science and research. I believe that not one team but many will be able to make deeply important advances for human health with this technology in hand.
Today, we are producing Vascularized Tissue Blanks™ for researchers whose cells of choice can be cultured alone or with other cells of interest. More than eight distinct primary and human cell lines have been tested with our large format structures, and not only do the cells grow, they seem to grow better than they do in two-dimensional tissue culture dishes. We are allowing researchers to grow their own cells, transplant, and test therapeutics in ways that were not previously possible.
And to support innovation in this field, Prellis Biologics has partnered with Cellink to provide dedicated tissue engineering and regenerative medicine researchers access to our technology. We have released a printing system that allows researchers to design and build their own vascularized structures in a CAD program, print them, and use them for cell culture, transplantation, therapeutics, and complex in vitro culture studies.
The future of human tissue bioprinting is bright–nearly as bright as our lasers. Having solved the vascularization problem, we believe it is only a matter of time before viable human tissues and organs are available for the millions in need of a life-saving tissue transplant.
About the Author:
Dr. Matheu founded Prellis Biologics in October 2016 with a design for an optical-based printing system on paper and a vision to create fully vascularized human tissues and organs for transplantation. Melanie’s combined PhD-level specialties in laser-based microscopy, Immunology, Chemistry, Physiology, and Biophysics have allowed her to bridge the gap between seemingly disparate fields to make real human organ engineering a reality. During her academic career, Dr. Matheu authored numerous peer-reviewed publications and a book chapter detailing methods and approaches for high-resolution imaging in tissues. Melanie was inspired to find a way to reverse-engineer laser-based imaging systems into a printer when she realized that the final roadblock in building human organs for transplant was a well-defined engineering problem: How can microvasculature be printed fast enough to build human tissues? Prellis Biologics technology solves this problem by partially decoupling printing speed from resolution with a novel patent-pending laser-based projection system.
Dr. Matheu’s vision is to shift the focus of health and medicine from palliative care to curative solutions, giving patients their lives back.
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