Innovations in cardiac technology

Cardiovascular-related technology is an exciting field as new devices and biotech products continue to emerge from research labs with rapid succession propelled by a vigorous stream of innovation. In this focus on smart tech for cardiology we look at some of the latest developments in this extremely dynamic arena – from 3D bioprinted cardiovascular tissue to a new bionic heart and synthetic blood.

Engineers at MIT have recently developed a bionic heart, not for transplant or a bridge to transplant, but for research. The demand for prosthetic heart valves and other cardiac devices is expected to grow significantly in the coming years driven by a growing geriatric population.

Prosthetic valves are designed to mimic a real, healthy heart valve in helping to circulate blood through the body. However, many of them have issues, such as leakage around the valve. Engineers working to improve these designs must test them repeatedly, first in simple benchtop simulators, then in animal subjects, before reaching human trials – a long and expensive process. This is where the bionic heart comes in. The bionic heart offers a more realistic model for testing artificial valves and other cardiac devices.

The device is a real biological heart in which the tough muscle tissue has been replaced with a soft matrix of artificial heart muscles, resembling bubble wrap. The orientation of the artificial muscles mimics the pattern of the heart’s natural muscle fibres, in such a way that when the researchers remotely inflate the bubbles, they act together to squeeze and twist the inner heart, similar to the way a real, whole heart twists when it beats and pumps blood.

With this new design, which the researchers call a “biorobotic hybrid heart”, they envision that device designers and engineers could iterate and fine-tune designs more quickly by testing on the biohybrid heart, significantly reducing the cost of cardiac device development. Ellen Roche, assistant professor of mechanical engineering at MIT, explains: “Regulatory testing of cardiac devices requires many fatigue tests and animal tests. The biorobotic hybrid heart could realistically represent what happens in a real heart, to reduce the amount of animal testing or iterate the design more quickly.”

Roche and her colleagues published their results January 29, 2020 in the journal Science Robotics.

Inspired design
The heart normally pumps blood by squeezing and twisting, a complex combination of motions that is a result of the alignment of muscle fibres along the outer myocardium that covers each of the heart’s ventricles. The team planned to fabricate a matrix of artificial muscles resembling inflatable bubbles, aligned in the orientations of the natural cardiac muscle. But copying these patterns by studying a ventricle’s three-dimensional geometry proved extremely challenging.

They eventually came across the helical ventricular myocardial band theory, the idea that cardiac muscle is essentially a large helical band that wraps around each of the heart’s ventricles. This theory is still a subject of debate by some researchers, but Roche and her colleagues took it as inspiration for their design. Instead of trying to copy the left ventricle’s muscle fibre orientation from a 3D perspective, the team decided to remove the ventricle’s outer muscle tissue and unwrap it to form a long, flat band – a geometry that should be far easier to recreate. In this case, they used the cardiac tissue from an explanted pig heart.

In collaboration with co-lead author Chris Nguyen at Massachusetts General Hospital, the researchers used diffusion tensor imaging, an advanced technique that typically tracks how water flows through white matter in the brain, to map the microscopic fibre orientations of a left ventricle’s unfurled, two-dimensional muscle band. They then fabricated a matrix of artificial muscle fibres made from thin air tubes, each connected to a series of inflatable pockets, or bubbles, the orientation of which they patterned after the imaged muscle fibres.

The soft matrix consists of two layers of silicone, with a watersoluble layer between them to prevent the layers from sticking, as well as two layers of laser-cut paper, which ensures that the bubbles inflate in a specific orientation.

Finally, the researchers placed the entire hybrid heart in a mould that they had previously cast of the original, whole heart, and filled the mould with silicone to encase the hybrid heart in a uniform covering – a step that produced a form similar to a real heart and ensured to a real heart and ensured that the robotic bubble wrap fitted snugly around the real ventricle.

“That way, you don’t lose transmission of motion from the synthetic muscle to the biological tissue,” Roche explained.

When the researchers pumped air into the bubble wrap at frequencies resembling a naturally beating heart, and imaged the bionic heart’s response, it contracted in a manner similar to the way a real heart moves to pump blood through the body.

Ultimately, the researchers hope to use the bionic heart as a realistic environment to help designers test cardiac devices, such as prosthetic heart valves.

3D bioprinted cardiovascular tissue

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, with over 17 million deaths per year, according to the World Health Organisation.

The ideal treatment for some forms of severe CVD, such as chronic heart failure or extensive myocardial injury, is cardiac transplantation. Due to shortages in available donor tissue, this cannot be given to all patients. The average waiting time for a suitable donor is six to twelve months in the United States and around one in six people die before they can receive a transplant. There is a clear need for a more abundant supply of hearts suitable for transplantation.

A common strategy to address heart failure is to use a cardiac pump, such as a left ventricular assist device (LVAD), when a donor heart is not available. Current treatment options are useful to a certain extent, but personalized solutions are required to improve patient outcomes and quality of life. This need is driving the development of cardiovascular 3D bioprinting technologies, which make use of 3D printinglike techniques to combine cells and biomaterials to fabricate biomimetic structures that replicate natural tissue physiology and function.

Developing a dynamic cardiac tissue capable of mimicking the mechanical and electroconductive properties of native myocardium is proving difficult for researchers. Many challenges stand in their way including, among others, re-creating tissue matrix and providing an adequate oxygen supply to each cell.

The success of 3D bioprinting depends on researchers’ ability to vascularise the tissue. For this reason, a lot of focus has recently been placed on the generation of blood vessels. Several promising studies have already been conducted. For instance, researchers at University of California San Diego 3D printed a functional blood vessel network which, once implanted in mice, merged with the animal’s blood vessels and was capable of transporting blood. Similar achievements have been reported by Sichuan Revotek, Rice University and the University of Pennsylvania in the past few years.

Cardiac patches
An important innovation in the we move towards 3D bioprinting cardiac tissue is the development of cell sheets. Terumo, a Japanese conglomerate, has commercialized the Heart Sheet for treatment of heart failure in Japan. To develop Heart Sheet, muscle tissue is harvested from the patient’s leg and cultured in vitro. Terumo has developed a tissue culture plate that allows cells to float off the surface in an intact sheet when the temperature is lowered, thus preserving the extracellular matrix that is lost when cells are removed by other methods.

Cardiac tissue engineering techniques such as this one can be used to create functional constructs capable of re-establishing the structure and function of damaged myocardium following myocardial infarction. The engineered cardiac tissue, which often comes in the form of a “patch”, is implanted directly onto scar tissue. The intention is to compensate for the heart’s reduced function by strengthening its structure and boosting its ability to pump blood. This way, researchers hope to reduce the need for transplants, improve recovery and prevent subsequent events.

Researchers across the world are developing “cardiac patches”. In June 2019, Imperial College London announced the creation of thumbsize patches of heart tissue that start to beat spontaneously after three days and start to mimic mature heart tissue within one month. These patches successfully led to improvements in heart function following a heart attack after only four weeks. Importantly, blood vessels appeared to have formed within the patch after that time. Clinical trials are expected to start this year or 2021.

Once implanted, cardiac patches could do more than just promote cardiac tissue regeneration. For instance, a bionic patch could deliver electrical shocks and act as a pacemaker. Scientists at the University of Tel Aviv also investigated integrating electronic sensors into the patch to enable remote monitoring of cardiac activity.

Although researchers have not yet been able to create a fully functioning artificial heart, an important leap was made in 2019. Researchers from Tel Aviv University unveiled the first 3D bioprinted heart with human tissue including chambers, ventricles and blood vessels. Although the heart is capable of contracting, it remains a long way off from being ready for clinical trials as it cannot yet pump blood.

3D bioprinting has the potential to provide a heart or blood vessels to patients in need of transplants. The tissue would be made from their own cells, thereby considerably reducing the risk of rejection. Despite promising recent innovations, 3D bioprinting technology remains in its early days and is unlikely to become a viable therapeutic option in the near future. This will change once the technology evolves and full-sized hearts and vessels can be constructed efficiently and at scale.

Synthetic blood

For decades scientists have been trying to develop synthetic red blood cells (RBCs) that mimic the favourable properties of natural ones, such as flexibility, oxygen transport and long circulation times. Most have been met with limited success, demonstrating only one or just a few of the key properties. Now, researchers, reporting in the journal ACS Nano [1], have made synthetic RBCs that have all of the cells’ natural abilities, plus a few new ones.

Wei Zhu, C. Jeffrey Brinker and colleagues wanted to make artificial RBCs that had similar properties to natural ones, but that could also perform new jobs such as therapeutic drug delivery, magnetic targeting and toxin detection.

The researchers made the synthetic cells by first coating donated human RBCs with a thin layer of silica. They layered positively and negatively charged polymers over the silica-RBCs, and then etched away the silica, producing flexible replicas. Finally, the team coated the surface of the replicas with natural RBC membranes. The artificial cells were similar in size, shape, charge and surface proteins to natural cells, and they could squeeze through model capillaries without losing their shape. In mice, the synthetic RBCs lasted for more than 48 hours, with no observable toxicity. The researchers loaded the artificial cells with either haemoglobin, an anticancer drug, a toxin sensor or magnetic nanoparticles to demonstrate that they could carry cargoes. They also showed that the new RBCs could act as decoys for a bacterial toxin.

The researchers say future studies will explore the potential of the artificial cells in medical applications, such as cancer therapy and toxin biosensing.

Reference

  1. Biomimetic Rebuilding of Multifunctional Red Blood Cells: Modular Design Using Functional Components https://pubs.acs.org/doi/abs/10.1021/acsnano.9b08714