From the Heart
By Kathy Hardy
Radiology Today
Vol. 20 No. 12 P. 10

Collaborative efforts take 3D heart printing from lab to real life.

Replicating the human cardiac landscape in the form of grafts, valves, and full-size hearts is advancing beyond the planning stages and into 3D printing labs. Not only are lifelike models being used as synthetic preplanning surgical tools, actual 3D bioprinting is making way for what could become replacement parts and transplantable organs. Leaders who have partnered in the development of such cutting-edge clinical solutions also see a shift in the role these man-made parts can play in ensuring safe patient outcomes.

“We’re at the point where we want to make 3D printing technology less of a toy and more of a tool,” says Dmitry Levin, associate director and lead research scientist at the University of Washington’s (UW) Center for Cardiovascular Innovation (CCVI). “Our priority is patient safety and how much we can improve on that. We also want to make sure the process is done correctly, so as not to do a disservice to the technology.”

UW Medicine, of which CCVI is a part, is partnering with the VA to develop patient-specific models to help surgeons, cardiologists, and interventional cardiologists plan treatment approaches for complex heart conditions. Participants from UW Medicine and VA Puget Sound Health Care System, both located in Seattle, will work together for the next two years, sharing 3D printers, materials, software, and staff, with a goal of developing new protocols for planning procedures such as the creation of patient-specific 3D-printed models for mitral valve disease.

The CCVI, home to UW Medicine’s 3D printing lab, focuses on accelerating the development of cardiovascular devices for the diagnosis and treatment of coronary and peripheral artery disease, structural heart disease, heart failure, and heart rhythm disorders. Experts in cardiology, cardiac surgery, cardiac anesthesiology, radiology, and engineering collaborate in the development and clinical implementation of cardiovascular devices and tools, including patient-specific 3D models of the heart.

By joining efforts with the VA, Levin says the two institutions can merge their “collective expertise into a unified effort to offer patients personalized cardiac care based on their unique needs.” These 3D-printed heart models allow for a better understanding of the procedure, he says, leading to successful and safer outcomes for patients. Adding presurgery tools such as 3D models can also prove to be cost-effective, reducing procedure times and, ultimately, costs associated with increased surgery time.

“Beyond improving our understanding of a patient’s anatomy, 3D-printed heart models allow us to know which catheters and replacement valves will fit and how best to approach the patient’s particular structure,” Levin says.

A Growing Network
According to Beth Ripley, MD, PhD, a radiologist at VA Puget Sound, the VA and UW Medicine’s Heart Institute were early adopters of 3D printing. The early successes realized from 3D-printed hearts served as a catalyst for the VA’s integrated 3D printing network, which aims to share resources and knowledge across hospitals. In early 2017, only three VA hospitals in the country had 3D printing labs; the network has recently grown to 25 hospitals.

With the VA being the largest integrated health care system in the United States—serving 9 million enrolled patients, many of them with structural heart disease—and UW Medicine’s large geographic base, the belief is that 3D printing innovations developed and fine-tuned within this integrated network, along with the protocols for use, could serve as the launching point for greater 3D printing access outside of these hospital networks. In fact, the two institutions had already been working together informally on several projects.

“UW Medicine has a strong focus on cardiology, with many experts in that medical specialty,” she says. “We looked at what we both do really well and how we could work together to make medical improvements in that area. This collaboration encompasses our knowledge and enthusiasm for improving patient outcomes in this area.”

Also helpful to the partnership is Ripley’s role as an assistant professor of radiology at UW Medicine. In addition, she chairs the Veterans’ Health Administration (VHA) 3D Printing Advisory Committee and is national project lead for the VHA 3D Printing Network Project. Ripley is also a senior fellow with VHA’s Innovation Ecosystem, a group of experts with a goal of cultivating and spreading best practices throughout the VA hospital system.

Model Building
Ripley says the FDA’s recent approval of transcatheter aortic valve replacement devices for low-risk patients, who historically have had to undergo surgery for this procedure, could increase the number of patients who could benefit from 3D heart model printing. Because of this, Ripley says it is important to know the patient’s cardiac landscape.

“This procedure is highly reliant on imaging,” she says. “We always had 2D images to work with, but with 3D models, cardiologists can physically inspect a replica of the patient’s anatomy before they go into a procedure.”

Establishing protocols for 3D heart printing is a goal of the project and a vital step in achieving any widespread success for the process. Protocols are especially important when dealing with hospital-based 3D printing, where patient safety is a factor. There’s a standard of care when it comes to clinical use of 3D-printed models, and developing protocols will help build that standard.

“Protocols are about quality,” Ripley says. “Having protocols will help us create the best reproducible models every time.”

The model building process includes several quality assurance steps. Model building starts with the patient undergoing a routine CT scan. According to Ripley and Levin, the next steps are “where the magic happens.”

“Once the CT is acquired, that information is translated into a different format,” Levin says. “We extract heart, valve, and vascular data necessary to create the 3D model. Then the physician examines the model to make sure that it is comprised of the same data set as the actual heart.”

As Ripley explains, some of that quality assurance checking includes conducting a CT scan of the model, then doing an overlay of the model’s images with the original heart images to make sure they match. The radiologist and/or cardiologist will conduct that check for accuracy.

“Multiple quality assurance checks are performed on the model before it is ready for use in the patient’s preprocedural plan,” she says.

“As we go through the process, we’re always thinking about ways to verify the data and make sure that it is correct,” Levin adds. “Having a partnership with different facilities and disciplines helps us conduct these deeper dives into the quality checks. This type of analysis leads to protocols and helps establish standards.”

When considering protocols, Levin says it’s also necessary to address differences in heart structure and the various stages of different diseases. Treatment for one condition may require a specific view of the aorta, for example, and a decision needs to be made about how much relational anatomy needs to be included to provide surgeons and interventional cardiologists with the best view of the heart for use in preprocedure planning. It’s a matter of finding the “sweet spot” for every case.

“We need to look at what is the right model for each different procedure related to cardiac care,” he says. “You wouldn’t always want the same model for each procedure. You need a standard operating procedure to create the right models with the right anatomies for the procedure being performed.”

Next Step: Bioprinting
Ripley sees bioprinting tissue and organs as the future of 3D printing, and like-minded experts at Carnegie Mellon University in Pittsburgh are currently working toward that goal. Andrew Lee, BME, PhD, a biomedical engineering student, is cofirst author on a recent Science paper about a technique for bioengineering human hearts called Freeform Reversible Embedding of Suspended Hydrogels (FRESH). The technique allows 3D bioprinting of tissue scaffolds, made from collagen, the major structural protein in the human body.

The development of FRESH in 2015 came from researchers’ attempts to overcome challenges associated with existing 3D bioprinting methods, as well as a need for improved resolution and fidelity when using soft and living materials. Tissue engineering and 3D bioprinting up to that time often resulted in puddles, rather than structures that would form quickly and solidify.

“To print complex geometrics, such as what’s found in organ structures, you need a substance that will move when you apply force, but will solidify when you stop applying force,” Lee says. “By adding collagen, you can control particle sizes and print more uniform parts with greater fidelity.”

As Lee explains, organs such as the heart comprise specialized cells held together by a biological scaffold called the extracellular matrix (ECM). This network of ECM proteins provides the structure and biochemical signals that cells need to carry out their normal functions. Once collagen was introduced to the process, researchers were able to print functioning pieces of the heart, such as valves or ventricles, from cells and collagen.

The FRESH 3D bioprinting method was developed in the lab of Adam Feinberg, PhD, a professor in the biomedical engineering and materials science and engineering department of Carnegie Mellon. It allows collagen to be deposited layer by layer within a support bath of gel. This gives the collagen a chance to solidify in place, while the support gel is melted away after the print is complete. The printed collagen structure remains undamaged.

Lee says this process allows for the printing of collagen scaffolds at the scale needed for human organs, such as the heart.

“The goal is to build patient-specific tissues and organs for use in surgical planning or, eventually, implantation,” he says. “We just use MRI to image the heart and develop a 3D model from that, using the FRESH 3D bioprinting method.”

On the hardware side, Lee says the actual 3D printing is performed on a commercial thermal plastic printer modified to print with the collagen substance.

 “The 3D printer is a simple machine that moves in three axes and deposits material as it moves,” he says.

With expertise in hearts and cardiac issues, bioprinted 3D hearts were the logical first step for Carnegie Mellon. Lee says that future projects could include branching out to other organs. Future plans also include replicating the heart’s complex weave of fibers and the role they play in efficiently “squeezing” blood through the body. “Being able to re-create that is important,” he says.

Commercial Printing
Research in 3D printing is spawning commercial bioprinting efforts, such as BIOLIFE4D, a startup life sciences and tissue engineering biotech company. Founder and CEO Steven Morris applied his experiences in the medical device field to work in life sciences and printing, compiling a multidisciplinary team of medical experts, scientists, and engineers who could bring all the pieces together and into the bioprinting marketplace. The team at BIOLIFE4D is working to develop a patient-specific, fully functioning heart through 3D bioprinting, using a patient’s own cells.

“Our process simulates organ development that naturally occurs in vivo, but we’re conducting that process outside the body,” he says.

As Morris describes BIOLIFE4D’s bioengineering process, work begins with the patient’s own blood and an MRI of their heart. White blood cells are separated out and induced to “go back to their stem cell state.” The cells are then reprogrammed to differentiate between the various types of cells that make up the heart, including cardio, electrical transmission, and smooth muscle cells. Using the MRI for sizing purposes, the bioprinter puts the cells back in place, along with a bioprinted scaffolding that holds everything in place. The entire process takes about six weeks, with the cell development being the most time-consuming stage.

Hearts and Their Parts
BIOLIFE4D’s first milestone, in June 2018, was printing a cardiac patch of viable heart tissue comprising all of the cells that make up the heart. Once printed, this patch could be applied anywhere to the heart.

The company also reached proof of concept in April 2019 for a “mini-heart,” about the size of a mouse heart. This scaled-down version of a human heart could be used by pharmaceutical companies as a toxicity model for cardiac drug testing.

“The mini-heart should provide a better predictor of what the drug would do in a human,” Morris says. “Also, with the mini-heart, you don’t need full vascularization to make it functional as a predictive tool. You just need to keep it alive long enough for toxicity testing to be completed. As we scale up to a heart viable for human transplantation, however, the vascularization will be more complicated, in order to provide the fully functional vascular network required to keep a transplanted organ viable.”

Morris says there is no FDA approval necessary for the mini-heart. Its use in toxicity testing requires a different approval process, he says. Valves, grafts, and patches will need FDA approval before going to market. Approval of a full-size heart, however, could take less time due to the “compassionate exception” rule.

“The FDA path could go faster for the full heart than for valves and grafts,” Morris says. “There are an estimated 200,000 individuals in the United States with late-stage heart failure who don’t make it onto the waiting list for a heart transplant. If we can show that our data are good for a 3D-bioprinted human heart, some of those 200,000 could decide to accept one of our hearts. They know the heart hasn’t gone through the entire FDA approval process, but they are at risk of dying without any alternative at all.”

BIOLIFE4D is benefitting from partnerships with other experts in the field, sharing knowledge and equipment. While BIOLIFE4D’s headquarters is in Chicago, their lab is located at Texas Medical Center in Houston. Morris says the company partners with other research institutions and hospitals in the Houston area, due primarily to the cardiac and bioprinting expertise at those locations. Through those partnerships, the company is also able to access bioprinters in various labs, with BIOLIFE4D’s CMO and chief science officer on site when printing takes place.

Collaborative efforts among experts in academia, health care, and commercial medical development are taking 3D heart printing from concept to production. Shared knowledge is resulting in the development of effective tools that can turn models to reality.

— Kathy Hardy is a freelance writer based in Phoenixville, Pennsylvania. She is a frequent contributor to Radiology Today.