As an important component of the human heart, the heart valve is usually only about 4-6 square centimeters in size. Think of it as a "doorkeeper," preventing blood that has just left the atrium (or ventricle) from flowing back, thus ensuring the body's normal blood circulation. However, if the heart valve malfunctions due to various reasons, is it possible to "replace" it with a new one?
"Currently, people often remove a type of heart valve from a pig or cow, process it by decellularization, and then transplant it into the human body. However, the hemodynamic characteristics and durability of this method are poor, it cannot grow together with the patient, and it is expensive," said Professor Zhao Danyang, professor at the School of Mechanical Engineering at Dalian University of Technology. A better method, he says, is to "print" a heart valve using 3D printing technology.
In recent years, biological 3D printing technology has become one of the most promising technical solutions for realizing the construction of complex human tissues and organs, especially the recently proposed immersion-based ink writing technology, which has attracted attention as a key technical branch of biological 3D printing. However, due to limitations in materials and technical processes, this technology can only "print" relatively small human organs such as the heart valve. Once the organ size exceeds a certain limit, it cannot be printed accurately.
To address this, Zhao Danyang, in collaboration with the team of Professor Jin Yi Fei at the University of Nevada, Reno, and other institutions, after years of research, have proposed a multi-scale immersion printing strategy (MSEP) that can achieve precise printing of tissue and organ structures ranging from millimeters to centimeters, including high-precision corneas, heterogeneous eyeballs, heart valves, and full-size hearts.
Their findings were recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), the official academic journal of the National Academy of Sciences of the United States.
Technical Hurdles Hinder Multi-Scale Organ Printing
According to Zhao Danyang, in simple terms, 3D printing technology is about superimposing "printing materials" layer by layer through computer control, ultimately turning a blueprint on the computer into a physical object. Biological 3D printing technology is a branch of 3D printing technology that can manufacture artificial implants and tissue organs and other biomedical products tailored to the specific anatomical structure, physiological function, and treatment needs of patients.
However, since human organs in the body often have a "suspended" structure, it is necessary to adopt special support methods when 3D printing them. Immersion-based ink writing technology is relatively ideal in this regard.
This technology generally uses a hydrogel material with good yield stress characteristics as the supporting bath material. After the 3D printing needle enters the supporting bath material, it moves along the planned path while extruding the printing ink material. The yield stress characteristics of the supporting bath material make it liquefy when the printing needle passes through it. After the needle extrudes the material and leaves the printing position, it solidifies again, thus firmly "catching" the printing ink material to keep the printing structure stable and ensure the accuracy of the printing structure before the ink solidifies.
"This technology can print relatively complete tissue organs, but it also has an inherent flaw," said Jin Yi Fei. That is, the current traditional supporting bath materials cannot undergo rapid overall "solid-liquid" conversion under simple physical stimulation, so it is difficult to add supporting bath materials on demand during the printing process. This makes it necessary to continuously adjust the printing equipment according to the target printing size when printing tissue organs.
"In other words, when we need to print small tissues, a short small-bore needle and related components must be used, while when printing large organs, a long large-bore needle and its配套组件配套组件are required. Consequently, this method cannot achieve the manufacture of multi-scale tissue organs," said Jin Yi Fei. In fact, at present, this technology can only print tissue and organ structures with functional characteristic dimensions between hundreds of micrometers and tens of millimeters.
Novel Material Capable of "Solid-Liquid" Conversion
The key to solving this problem is to find a material that can freely convert between the solid and liquid states, which has been the goal of Zhao Danyang's team for many years.
Eventually, they achieved this goal.
In the study, Zhao Danyang's team collaborated to develop a stimulus-responsive supporting bath material. This material is composed of a thermoresponsive hydrogel and a yield stress additive nanoclay, and has both yield stress characteristics and thermoresponsiveness. The former enables the material to maintain the rheological properties of the supporting bath material; the latter makes it liquid at low temperatures, allowing it to be easily added to the printing container. At room temperature, it solidifies rapidly, thus meeting the need to add supporting bath materials on demand during printing.
Based on this, the research team successfully developed a multi-scale tissue organ immersion 3D printing strategy. Using this technology, the research team was able to 3D print engineered corneal structures with surface roughness at the micrometer level, as well as millimeter-sized heterogeneous human eyeballs and aortic valve models, and centimeter-sized full-scale human heart models.
It is worth mentioning that in addition to achieving the regeneration and repair of human tissue organs and improving the treatment effect and quality of life of patients, the application prospects of biological 3D printing technology also include preoperative planning (i.e., printing medical models before a patient's operation to provide guidance and simulation for the doctor before the operation), and the use of human models with specific physiological structures and functions to enable researchers to simulate the human physiological environment more accurately and accelerate the new drug development process.
However, regardless of the application prospect, high requirements are placed on the size and printing accuracy of printed tissue organs, which means that the multi-scale tissue organ immersion 3D printing strategy has broad application prospects.
Offering New Methods and Possibilities
Regarding the future, Zhao Danyang said that the ultimate goal of biological 3D printing technology is to manufacture and culture tissue organs that better meet the needs of patients in a short period of time. To this end, in terms of printing materials, future research will focus on developing bioinks with specific bioactivity, artificial and natural polymeric materials with special functions, etc.; in terms of manufacturing precision, it is also necessary to further improve, gradually printing more complex and finer biological structures.
The fusion of AI with bioprinting techniques is on the rise. This integration enables smart design, print parameter optimization, and real-time monitoring, boosting bioprinting efficiency and quality.
Globally, research teams are actively exploring bioprinting advancements. For instance, Harvard University recently developed a cardiac 3D printing technique that mimics the intricate arrangement of heart contraction units, producing cardiac tissue sheets with a complexity akin to human heart muscle layers.
"The convergence of biotechnology and engineering empowers us to ultimately bioprint viable organs," emphasizes Dr. Zhao Danyang. "Our research provides novel approaches and opens possibilities for precise fabrication of multiscale tissues and organs. It lays the groundwork for future tissue engineering and artificial organ transplantation research."
The team plans to delve further into this promising research direction, pushing the boundaries of regenerative medicine and unlocking new frontiers in tissue regeneration.
