Replacement Heart Valve Structures that Mimic Natural Extracellular Matrix

Over the past few years, there have been a number of important advances in the infrastructure technologies needed for tissue engineering and related fields such as the construction of scaffolds to support and guide cell growth. Along these lines, researchers have recently demonstrated a rapid jet spinning approach to the construction of scaffold materials that mimic the properties of natural extracellular matrix. This allows for the construction of - to pick one example - heart valve implants, structures that will be populated by cells to form living tissue, capable of regeneration and growth, after implantation in a patient. This has been tested in animal models, and represents an improvement in cost and time over the prior standard approaches to constructing scaffolds.

Implanting scaffolds that carry chemical cues similar to those of the extracellular matrix, but lack any cells, is one of many different approaches to tissue engineering that chiefly differ from one another in where the tissue growth is expected to occur. There is a lot to be said for pushing the tissue growth stage into the body, as this works around many of the challenges inherent in trying to grow tissues outside the body: establishing all of the correct signals and environmental factors; growing blood vessel networks needed to support larger tissue sections; designing and maintaining a suitable custom bioreactor for the time it takes tissue to assemble itself; that intrusive rather than minimal surgery is required to transplant new tissue; and so on. Ultimately, I think it likely that the end goal for the tissue engineering field is to attain sufficient control over cells and cell signaling to direct the desired behavior inside the body without the need for scaffolds, bioreactors, transplantation, and other related technologies. That lies some way in the future, however. At the present time, all viable approaches that enable creation of tissue without the need for donors represent a great leap forward, a dramatic improvement over current limitations.

Engineering heart valves for the many

The human heart beats approximately 35 million times every year, effectively pumping blood into the circulation via four different heart valves. Unfortunately, in over four million people each year, these delicate tissues malfunction due to birth defects, age-related deteriorations, and infections, causing cardiac valve disease. Today, clinicians use either artificial prostheses or fixed animal and cadaver-sourced tissues to replace defective valves. While these prostheses can restore the function of the heart for a while, they are associated with adverse comorbidity and wear down and need to be replaced during invasive and expensive surgeries.

A team lead recently developed a nanofiber fabrication technique to rapidly manufacture heart valves with regenerative and growth potential. The researchers fabricated a valve-shaped nanofiber network that mimics the mechanical and chemical properties of the native valve extracellular matrix (ECM). To achieve this, the team used a rotary jet spinning technology in which a rotating nozzle extrudes an ECM solution into nanofibers that wrap themselves around heart-valve-shaped mandrels. "Our setup is like a very fast cotton candy machine that can spin a range of synthetic and natural occurring materials. In this study, we used a combination of synthetic polymers and ECM proteins to fabricate biocompatible JetValves that are hemodynamically competent upon implantation and support cell migration and re-population in vitro. Importantly, we can make human-sized JetValves in minutes - much faster than possible for other regenerative prostheses."

Another group of researchers have previously developed regenerative, tissue-engineered heart valves to replace mechanical and fixed-tissue heart valves. In their approach, human cells directly deposit a regenerative layer of complex ECM on biodegradable scaffolds shaped as heart valves and vessels. The living cells are then eliminated from the scaffolds resulting in an "off-the-shelf" human matrix-based prostheses ready for implantation. In collaboration the two teams successfully implanted JetValves in sheep using a minimally invasive technique and demonstrated that the valves functioned properly in the circulation and regenerated new tissue. "In our previous studies, the cell-derived ECM-coated scaffolds could recruit cells from the receiving animal's heart and support cell proliferation, matrix remodeling, tissue regeneration, and even animal growth. While these valves are safe and effective, their manufacturing remains complex and expensive as human cells must be cultured for a long time under heavily regulated conditions. The JetValve's much faster manufacturing process can be a game-changer in this respect."

In support of these translational efforts, a larger initiative will commence to generate a functional heart valve replacement with the capacity for repair, regeneration, and growth. The team is also working towards a GMP-grade version of their customizable, scalable, and cost-effective manufacturing process that would enable deployment to a large patient population. In addition, the new heart valve would be compatible with minimally invasive procedures to serve both pediatric and adult patients.

JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement

Tissue engineered scaffolds have emerged as a promising solution for heart valve replacement because of their potential for regeneration. However, traditional heart valve tissue engineering has relied on resource-intensive, cell-based manufacturing, which increases cost and hinders clinical translation. To overcome these limitations, in situ tissue engineering approaches aim to develop scaffold materials and manufacturing processes that elicit endogenous tissue remodeling and repair. Yet despite recent advances in synthetic materials manufacturing, there remains a lack of cell-free, automated approaches for rapidly producing biomimetic heart valve scaffolds.

Here, we designed a jet spinning process for the rapid and automated fabrication of fibrous heart valve scaffolds. The composition, multiscale architecture, and mechanical properties of the scaffolds were tailored to mimic that of the native leaflet fibrosa and assembled into three dimensional, semilunar valve structures. We demonstrated controlled modulation of these scaffold parameters and show initial biocompatibility and functionality in vitro. Valves were minimally-invasively deployed via transapical access to the pulmonary valve position in an ovine model and shown to be functional for 15 h.

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