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4D Bioprinting Smart Constructs for the Heart

Maryland researchers investigate new 4D printing techniques to control stem cell cardiomyogenesis

3 min read
University of Maryland

Cardiovascular disease is the leading cause of mortality worldwide, accounting for nearly 18 million deaths each year, according to the World Health Organization. In recent years, scientists have looked to regenerative therapies – including those that use 3D-printed tissue – to repair damage done to the heart and restore cardiac function.

Thanks to advancements in 3D-printing technology, engineers have applied cutting-edge bioprinting techniques to create scaffolds and cardiac tissue that, once implanted, can quickly integrate with native tissues in the body. While 3D bioprinting can create 3D structures made of living cells, the final product is static – it cannot grow or change in response to changes in its environment.

Conversely, in 4D bioprinting, time is the fourth dimension. Engineers apply 4D printing strategies to create constructs using biocompatible, responsive materials or cells that can grow or even change functionalities over time and in response to their environment. This technology could be a game-changer for human health, particularly in pediatrics, where 4D-printed constructs could grow and change as children age, eliminating the need for future surgeries to replace tissues or scaffolds that fail to do the same.

U Maryland

But, 4D bioprinting technology is still young. One of the critical challenges impacting the field is the lack of advanced 4D-printable bioinks – material used to produce engineered live tissue using printing technology – that not only meet the requirements of 3D bioprinting, but also feature smart, dynamic capabilities to regulate cell behaviors and respond to changes in the environment wherever they're implanted in the body.

Recognizing this, researchers at George Washington University (GWU) and the University of Maryland's A. James Clark School of Engineering are working together to shed new light on this burgeoning field. GWU Department of Mechanical and Aerospace Engineering Associate Professor Lijie Grace Zhang and UMD Fischell Department of Bioengineering Professor and Chair John Fisher were recently awarded a joint $550,000 grant from the National Science Foundation to investigate 4D bioprinting of smart constructs for cardiovascular study.

U Maryland

Their main goal is to design novel and reprogrammable smart bioinks that can create dynamic 4D-bioprinted constructs to repair and control the muscle cells that make up the heart and pump blood throughout the body. The muscle cells they're working with – human induced pluripotent stem cell (iPSC) derived cardiomyocytes – represent a promising stem cell source for cardiovascular regeneration.

In this study, the bioinks, and the 4D structures they're used to create, are considered “reprogrammable" because they can be precisely controlled by external stimuli – in this case, by light – to contract and elongate on command in the same way that native heart muscle cells do with each and every heartbeat.

The research duo will use long-wavelength near-infrared (NIR) light to serve as the stimulus that prompts the 4D bioprinted structures into action. Unlike ultraviolet or visible light, long-wavelength NIR light could efficiently penetrate the bioprinted structures without causing harm to surrounding cells.

Images of 4D bioprinted heart-shaped structure and its 4D transformation process

"4D bioprinting is at the frontier of the field of bioprinting," Zhang said. "This collaborative research will expand our fundamental understanding of iPSC cardiomyocyte development in a dynamic microenvironment for cardiac applications. We are looking forward to a fruitful collaboration between our labs in the coming years."

"We are thrilled to work with Dr. Zhang and her lab to continue to develop novel bioinks for 3D- and 4D- printing," Fisher said. "We are confident that the collaborative research team will continue to bring to light untapped printing strategies, particularly in regards to stem cell biology."

Moving forward, Zhang and Fisher hope to apply their 4D bioprinting technique to further study of the fundamental interactions between 4D structures and cardiomyocyte behaviors.

“The very concept of 4D bioprinting is so new that it opens up a realm of possibilities in tissue engineering that few had ever imagined," Fisher said. “While scientists and engineers have a lot of ground to cover, 4D bioprinted tissue could one day change how we treat pediatric heart disease, or even pave the way to alternatives to donor organs."

At GWU, Zhang leads the Bioengineering Laboratory for Nanomedicine and Tissue Engineering. At UMD, Fisher leads the Center for Engineering Complex Tissues, a joint research collaboration between UMD, Rice University, and the Wake Forest Institute for Regenerative Medicine. Fisher is also the principal investigator of the Tissue Engineering and Biomaterials Lab, housed within the UMD Fischell Department of Bioengineering.

The Conversation (0)
A photo showing machinery in a lab

Foundries such as the Edinburgh Genome Foundry assemble fragments of synthetic DNA and send them to labs for testing in cells.

Edinburgh Genome Foundry, University of Edinburgh

In the next decade, medical science may finally advance cures for some of the most complex diseases that plague humanity. Many diseases are caused by mutations in the human genome, which can either be inherited from our parents (such as in cystic fibrosis), or acquired during life, such as most types of cancer. For some of these conditions, medical researchers have identified the exact mutations that lead to disease; but in many more, they're still seeking answers. And without understanding the cause of a problem, it's pretty tough to find a cure.

We believe that a key enabling technology in this quest is a computer-aided design (CAD) program for genome editing, which our organization is launching this week at the Genome Project-write (GP-write) conference.

With this CAD program, medical researchers will be able to quickly design hundreds of different genomes with any combination of mutations and send the genetic code to a company that manufactures strings of DNA. Those fragments of synthesized DNA can then be sent to a foundry for assembly, and finally to a lab where the designed genomes can be tested in cells. Based on how the cells grow, researchers can use the CAD program to iterate with a new batch of redesigned genomes, sharing data for collaborative efforts. Enabling fast redesign of thousands of variants can only be achieved through automation; at that scale, researchers just might identify the combinations of mutations that are causing genetic diseases. This is the first critical R&D step toward finding cures.

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