A team at Harvard, which has spent over 10 years working on building a whole synthetic working heart, has announced a major step towards that goal by bioengineering a three-dimensional model of the left ventricle of the human heart.
Relying on techniques from fibre production, the team designed a scaffold of nanofibres that mimic the function of natural fibres in the body, which they then seeded with specialised muscle cells derived from induced stem cells that self-organise onto the scaffold to form a structure that beats in vitro.
"We started by learning how to build cardiac myocytes, then cardiac tissues, then muscular pumps in the form of marine organism mimics, and now a ventricle," said team leader Prof Kit Parker, of Harvard’s John A Paulsen School of Engineering and Applied Sciences. "Along the way we have elucidated some of the fundamental design laws of muscular pumps and developed ideas about how to fix the heart when these laws are broken by disease.”
Parker’s team is hoping to replace or supplement animal models with human models, and specifically patient-specific human models. “In the future, patient stem cells could be collected and used to build tissue models that replicate some of the features of their whole organ,” explained Luke McQueen, first author on a paper the team has published in Nature Biomedical Engineering.
Designing the scaffold was a key part of the project. Heart tissue has a unique structure, and in nature is also built on a scaffold, of parallel myocardial fibres. These guide brick-shaped muscle cells, called cardiomyocytes, to align and assemble end to end into a hollow, cone -shaped structure. When the heart beats, the cells expand and contract.
Prof Parker’s disease biophysics group has devised a nanofibre production method called pull spinning to create fibres that mimic the structure of the myocardial scaffold. This uses a high-speed rotating bristle that dips into a reservoir of liquid polymer – in this case a combination of biodegradable polyester and gelatin – and pulls a droplet from the solution into a jet. As the bristle spins, the fibre travels in a spiral trajectory and solidifies before detaching and moving onto a collector. For the ventricle project, the collector was bullet-shaped and was itself spinning. Because of this, all of the fibres aligned on the collector in the same direction.
"It is important to recapitulate the structure of the natural muscle to obtain ventricles that function like their natural counterparts," said MacQueen. "When the fibres are aligned, the cells will be aligned, which means they will conduct and contract the way that native cells do."
After building several scaffolds, around the size of a rat heart and 1/250 the size of a human heart, the team seeded some with cardiomyocytes from rats and the others with human myocytes derived from induced stem cells, and cultured the resulting assemblages. The cells grew to cover the scaffold within three days, producing a thin wall of tissue whose cells beat in sync with each other. The researchers controlled and monitored propagation of calcium ions in the tissue, which play an important role in the function of heart cells, and inserted a catheter that studied the pressure and volume of the beating ventricle.
The studies also included exposing the cells to isoproterenol, a drug whose function is similar to adrenaline, and observing how the beat rate increased. The researchers also poked holes in the ventricle to mimic a myocardial infarction, and studied the effect of the heart attack in a petri dish that resulted.
The ventricle model made using human cells was cultured for six weeks and studied in a purpose-built, self-contained bioreactor with separate chambers for optional valve inserts, access ports for catheters and the capability to assist the ventricle in beating. “The fact that we can study this ventricle over long periods of time is really good news for studying the progression of diseases in patients as well as drug therapies that take a while to act," said MacQueen.
The team’s ultimate goal is to be able to collect stem cells from patients and use these to build tissue models that replicate the features of their organs including any mutations resulting from their unique DNA. These could then be used to develop and test specific therapies which would work best for them. “We have a long way to go to build a four-chamber heart but our progress is accelerating," Parker said.