In the early morning of May 3, 2019, the latest issue of Science magazine published a large-scale work done by a team of scientists from many universities in the United States. The team created a new open source bio-printing technology that can be used within minutes. Produces a soft, water-based, biocompatible gel with a complex internal structure. Through this breakthrough bio-tissue printing technology, researchers can create hydrogel organ replacements that mimic the complex natural vasculature of human blood, air, lymph and other vital fluids.
In the simulated alveolar vesicle hydrogel model demonstrated by the researchers, the exquisite vascular network not only shocks the vision, but also proves that the airway can transport oxygen to the surrounding blood vessels, conquering 3D printing with complex vascular system functional organ replacement. The main obstacle to things. In addition, the researchers successfully implanted bioprintable constructs containing hepatocytes into mice.
Unlike 3D printing of grotesque objects, 3D printing of living organs (even if the thickness exceeds a few millimeters of tissue) without the vasculature as a channel for providing nutrients and eliminating waste, will result in the rapid death of living cells inside the tissue structure. Therefore, for bioengineers, exploring 3D printing involves a large number of methods of living cell prototype organization, facing enormous challenges.
3D printing of living tissue containing complex vasculature
“One of the biggest obstacles to creating functional tissue alternatives is that we can't print complex vasculature that can provide nutrients for dense human tissue.” The main leader of the study, Rice University, Brown School of Engineering Engineering Assistant Professor Jordan Miller said.
Our organs actually contain an independent network of vessels, such as the trachea and blood vessels in the lungs, or the bile ducts and blood vessels in the liver. These complex network of vascular networks are entangled at the physical and biochemical levels, and the structure itself is closely related to the organization. Related. What this research does is the first bioprinting technology to directly and comprehensively address the challenges of complex vascular systems.
“The liver is particularly interesting because it has an incredible more than 500 functions, probably second only to the brain,” says Kelly Stevens, assistant professor of bioengineering and pathology at the University of Washington. “The complexity of the liver means There are currently no machines or therapies that can replace all of its functions when the liver is sick. Bio-printed human organs may one day offer this therapy."
To address this challenge, the research team created a new open source bioprinting technology called the Tissue Engineering Stereo Mirror (SLATE). The system uses laser additive manufacturing technology to print a layer of soft hydrogel at a time.
Each layer is printed from a liquid pre-aqueous gel solution that becomes solid when exposed to blue light. The digital light processing projector emits light from below, displaying a continuous two-dimensional slice of the structure in high resolution ranging from 10-50 microns in pixel size. As each layer solidifies in turn, the top arm lifts the growing 3D gel, exposing the liquid to the next image of the projector.
The key to this is the addition of biocompatible light absorbers that are widely used in the food industry to absorb blue light, which limit solidification to a very fine layer. In this way, the system produces a soft, water-based, biocompatible gel with a complex internal structure in minutes.
Tests on the simulated structure of the lungs show that these tissues are strong enough to avoid rupture during blood flow and pulsation "breathing". Pulsating "breathing" is a rhythmic inspiration and exhalation that simulates the pressure and frequency of human breathing. Tests have found that red blood cells can absorb oxygen as they flow through the network of blood vessels around the "breathing" balloon. This movement of oxygen is similar to the exchange of gases in the alveolar sac.
To validate the biocompatibility of the printed tissue, the team implanted 3D printed tissue loaded with hepatocytes into mice with chronic liver injury with separate compartments for blood vessels and hepatocytes. Experimental results show that hepatocytes can survive after implantation.
According to Kelly Stevens, complex vasculature is important because structures and functions often complement each other. "Organizational engineering has been struggling for a generation in this area. Through this work, we can go a step further. If we can print healthy structures that look more complex in our body, then their functional performance." Would it be more like those organizations? This is an important question because the quality of bioprinting tissue will affect its success as a therapy."
Explore more complex structures of human organs
The huge demand for organ transplantation has driven the development of bioprinting health and functional organs. In the United States alone, more than 100,000 people are waiting for organ transplants, and those who eventually receive organ donation are still treated with life-long immunosuppressive drugs in response to organ immune rejection.
In the past decade, bio-printing technology has attracted great interest, because in theory it can allow doctors to print out replacement organs through the patient's own cells to solve the problems of organ shortage and organ immune rejection. One day, if 3D printing functional organs can be achieved, it will be able to treat millions of patients around the world.
“We expect bioprinting to become an important part of medicine in the next two decades,” Miller said.
In 2015, Miller and the University of Pennsylvania Assistant Professor of Surgery Pavan Atluri led a research team using sugar, silicone and 3D printers to create an implant containing an intricate network of blood vessels that laid the foundation for creating portable alternative tissues and organs.
Although these "works" at the time did not look like blood vessels in organs, they had some key features associated with transplant organs.
In 2016, Miller's Rice University Bioengineering Research team creatively improved the commercial grade CO2 laser cutting machine and created the OpenSLS platform, an open source, selective laser sintering platform that prints complexities from powder plastics and biomaterials. 3D object.
OpenSLS works differently than most traditional extrusion-based 3D printers. Traditional 3D printers use a needle to squeeze a melted plastic to create an object when printing a two-dimensional image, and then construct a three-dimensional object from a continuous two-dimensional layer. In contrast, when the SLS laser is irradiated onto a plastic powder plate, the powder is melted or sintered at the laser focus to form a small volume of solid material. After the first layer is completed, a new layer of powder is applied and the cycle is repeated. Since the sintered object is completely supported by three-dimensional powder, this technology can produce extremely complex structures that other 3D printing technologies cannot produce at all.
In 2017, a team from Miller and Baylor College of Medicine biophysicist Mary Dickinson showed how human endothelial cells and mesenchymal stem cells can be used to initiate vascularization. Studies have confirmed that these endothelial cells differentiated by "induced pluripotent stem cells" have the ability to form capillary-like structures, either in natural materials called fibrin or in semi-synthetic materials called gelatin methacrylate. .
In 2018, Miller and Rice University bioengineer Omid Veiseh attempted to combine cell therapy applications with advanced 3D printing techniques for the treatment of type 1 diabetes. They developed a 3D printed hydrogel that houses islet cells and a network of underlying blood vessels that protect the implanted islet cells from the immune system's packaging materials while allowing cells to grow and respond to environmental changes.
In the latest study, in order to design a complex lung structure, Miller also collaborated with Jessica Rosenkrantz and Jesse Louis-Rosenberg, co-founders of a Massachusetts-based design firm, Nervous System.
“When we started the Nervous System, the goal was to apply algorithms from nature to new ways of designing products,” Rosenkrantz said. "I didn't expect that we have the opportunity to design a living organization now."
According to Miller, the new bioprinting system can also produce intravascular features such as mitral valves that only allow blood to flow in one direction. In the human body, intravascular valves are present in the heart, leg veins, and lymphatic system. "By adding a variety of vascular and intravascular structures, we have introduced a wide range of design freedoms for engineering living tissue," Miller said. "We are now free to build many of the intricate structures found in the body."
The research team is commercializing key aspects of the research through a Houston startup called Volumetric. Miller's labs are also using new design and bioprinting techniques to explore more complex structures. "Our exploration of the human body has just begun, and we still have a lot to learn."
Mille, who has consistently supported open source 3D printing technology, also said that all experimental data published in Science magazine is freely available. In addition, all of the 3D printed files required to construct the stereolithography apparatus, as well as the design files for each hydrogel printed in this study, are available.
“Open hydrogel design documents will allow others to continue exploring our efforts, and even they will use some future 3D printing technologies that do not exist today,” Miller said.
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