University of Minnesota uses biological 3D printing to create a beating human heart

China3D printingNet July 8th, researchers at the University of Minnesota have developed a new type of bio-ink that enables them to create functional3D printingBeatingofHuman heart.
Cell-filled biomaterials produced using pluripotent stem cells enable the research team to3D printingA replica of the aorta with more chambers, ventricles and higher cell wall thickness than before. In the future, organs replicated using this process can provide test beds for various drugs and equipment, and provide models for genetic diseases.

The research team said: “This method can be applied to many other cell types that have poor proliferation and migration ability after differentiation. The living pump shown here and future design iterations will be used in multi-scale in vitro cardiology determination, injury and disease modeling. It should be easier to transfer to clinically relevant results if they find practicality in models, medical device testing, and regenerative medicine research.”


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The heart is proven to be able to run for more than six weeks” alt=” Created by researchers
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The heart is proven to be able to run for more than six weeks” width=”600″ height=”480″ />

Created by researchers3D printingThe heart proved to be able to run for more than six weeks. The picture comes from Hnet, the magazine “Circular Research”.

3D printingVascular applications

Early work to replicate heart tissue included simple geometric structures made by casting cardiomyocytes in ECM-based gels. Although these tissues can be attached to the pillars, allowing them to contract and adjust the mechanical load, their lack of complexity has limited their use in in vitro applications. In addition, such tissues can generate force but cannot pump fluid, which further limits their ability to mimic the structure of blood vessels.

To solve this problem, researchers have recently developed a tissue model that can replicate the pressure-volume dynamics of the heart. Nevertheless, these are usually single-ventricular solutions and cannot be perfused, which is an important feature of real blood vessels and organs. In addition, in order to be able to cast ECM gel or implant cardiomyocytes after manufacturing, many existing single-ventricle models rely on a simple cup-shaped design. These methods are suitable for open single-chamber structures with a wider top than the bottom; however, to generate a closed, fillable model requires more advanced manufacturing technology. “The researcher said.

In addition, more and more studies have demonstrated the ability of using biological materials to print models of the entire heart organ, but these structures lack the cellular or electromechanical functions to replicate the authentic ones. This is due to the challenges associated with handling mature cardiomyocytes that are not prone to proliferation or migration, which prevents researchers from achieving the high cell density required.
It has not yet included continuous muscle activation to support the pump function. This is mainly due to the challenge of obtaining high-density cardiomyocytes (a well-known non-proliferating cell type),” the research team explained. “Another strategy is to print with human induced pluripotent stem cells, which can proliferate. To high density and fill the tissue space, and then differentiate them into cardiomyocytes in situ. “

Contrary to traditional casting methods,3D bioprintingProvide researchers with an easy way to produce more complex tissues from scratch. The Minnesota research team used highly proliferating stem cells to induce the differentiation of cardiomyocytes in situ, thereby customizing tissues for cardiac applications.
In order for this method to succeed, the team will need to develop a bio-ink formulation that can increase cell viability and allow hiPSCs to proliferate and then differentiate into cardiomyocytes. The researchers achieved this goal by modifying the ECM formula used in previous studies to promote the differentiation of cardiomyocytes, and created a new type of bio-ink that can be deposited with fidelity in space.





This figure shows the evolution of cell proliferation within 24 days after the bioprinting process. Picture from “Circular Research” magazine.

3D printingHuman heart

The process of creating a new bio-ink starts with a base material of gelatin methacrylate (GelMA), which is then cross-linked by light activation to make the bio-ink printable. It was found that further addition of chemical fibronectin and laminin-111, as well as stem cells and ECM proteins, can support cardiomyocyte differentiation and structural integrity. The cell density of this preparation is 0.1 mg DNA/g gel, which is the same order of magnitude as natural heart tissue, so it is very suitable for experiments.

By performing magnetic resonance imaging scans of the human heart and newly designed bio-ink, the team3D printingA structure filled with stem cells with two chambers and a blood vessel inlet and outlet. After the cells multiply to a sufficient density, the research team differentiated the cells within the structure, giving them different roles in the heart. Although the diaphragm between the ventricles is partially removed to provide nutrient input, and the structure is limited to the connection of two blood vessels, the function of the heart has been proven to be flexible and functional.

To test the accuracy of its creation, the research team used magnetic resonance imaging scans to compare its aortic structure with 3D digital reconstructions. It is found that not only 86% of the printed structures are within 0.5 mm of the template, but also the cross-sectional comparison shows that the fidelity in the internal cavity is very high. After 14 days, cells from both single and large colonies occupied 90% of the bio-ink, and by six weeks, very limited cell death was observed, indicating that the cell health in the aortic structure of the replica continued.
3D printingHeart accuracy” alt=”The figure shows the production process and the overlay (top) shows3D printingThe accuracy of the heart” width=”620″ height=”528″ />
The figure shows the production process and the overlay (top) shows3D printingThe accuracy of the heart. Picture from “Circular Research” magazine.
In addition, the conventional manufacture of heart cells means that it can pump blood or “beat.” In order to determine the degree of preservation of the electromechanical function in the entire blood vessel, the electrical function was measured by randomly selecting the calcium transient in the area. Six weeks. The peak amplitude has not changed during this time, and the beating frequency has not changed. The artificial organ shows the potential to last more than six weeks. Then use optical mapping to measure the voltage change across the structure. The final action potential detected on the surface of the heart reflects the researchers’ expected response to changes in pacing frequency and drug stimulation.

As a result, the Minnesota research team concluded that they have successfully created the first powerful electromechanical function in a perfusible chamber heart pump. After six weeks, the heart exhibited the same behavior. In the densest area, the wall thickness of the organ exceeded 500 μm. Not only was the team larger than the single-ventricle model showed, but the team found that a higher cell layer thickness would increase the volume output of the replicated heart, making the pump more powerful. The resulting macroscopic human heart structure can be examined on multiple scales, thereby providing a large number of potential drug benefits in the future. This can greatly support medical device testing and preclinical cardiology, and bring research closer to clinical transplantation.

The research team concluded: “This progress represents a key step towards the generation of large-scale tissues similar to aggregate organoids, but has the key advantage of preserving the geometric structure essential for myocardial pump function. Looking to the future, this type of Human ventricle organoids may also be used as test beds for cardiac medical equipment and eventually lead to therapeutic tissue transplantation.”

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