Heart-valve disease has been described as an emerging epidemic1, owing to its worldwide prevalence, its potential to kill, and the lack of therapies for its prevention or treatment. Damaged and defective valves can be replaced with prosthetic ones, but the inability of prostheses to grow or adapt to change makes them a poor solution for young patients2. An alternative is a living replacement made from bioengineered tissue. But, so far, tissue-engineered heart valves (TEHVs) have failed because detrimental valve-tissue remodelling occurs in vivo, impairing normal function. Writing in Science Translational Medicine, Emmert et al.3 address this problem using computational modelling to design a TEHV that remodels favourably after implantation.
A promising strategy for heart-valve tissue engineering is to grow tissues in the shape of a valve in the laboratory using cells and a degradable biomaterial, then remove the cells to leave an empty extracellular-matrix scaffold. After implantation in the heart, the tissue scaffold is populated by the recipient’s cells, presumably from the blood and the adjacent blood-vessel wall. Some of these cells then transform into contractile cells that degrade the scaffold and replace it with new tissue, while pulling on the tissues to hold everything together, and speed up remodelling. In all animal studies so far, however, this process has led to excessive tissue production, which thickens and stiffens the valve’s three leaflets to obstruct blood flow, or to excessive tissue contraction, which causes the leaflets to shorten and retract, preventing proper valve closure and allowing backflow of blood (Fig. 1a).
After valve repair in healthy hearts, the contractile cells typically enter a deactivated state called quiescence, or are cleared from the region by programmed cell death. But certain stimuli, such as biomechanical stresses4, can cause the cells to persist and remain activated. This can lead to excessive collagen production and tissue contraction — a process known as fibrosis4. In the native valve, fibrosis leads to leaflet thickening or retraction, which is similar to the problem seen in TEHVs. Biomechanical activation of fibrosis can be a particular problem in heart valves that are subjected to abnormalities in stretch, compression and pressure changes as they open and close with each heartbeat5.
Using computational modelling, the group behind the current study have previously shown6 that the leaflets of conventional TEHVs are compressed in the radial direction (towards the centre of the valve) by blood pressure when the valve is closed. This type of compression, which does not occur in native valves, acts to shorten the leaflets. It is also associated with contractile-cell activation and fibrotic remodelling.
One way to address this problem would be to directly inhibit fibrosis. But Emmert et al. took an alternative approach, attempting to limit leaflet shortening by minimizing radial compressions, and to guide the remodelling process to prevent persistent contractile-cell activation. The authors used computational modelling to design TEHVs that initially had a non-physiological geometry predicted to minimize radial compression, and a large area of contact between the leaflets when the valve was closed. The computational models predicted that, after implantation, these valves would remodel into a stable geometry that mimicked the shape of native valves (Fig. 1b).
The authors tested this hypothesis by replacing heart valves with computationally inspired TEHVs in ten sheep. They assessed the valves’ performance over one year. As the computational models predicted, the valves adopted a stable tissue architecture in vivo. The valves performed comparably to native valves in nine out of ten animals. The recipient cells that populated the TEHVs produced new collagen without leaflet thickening. Collagen fibres aligned around the circumference of the valve, although not to the same extent as in native valves. The leaflets shortened as the valves remodelled, but shortening stabilized six months after implantation and the leaflets remained in contact with one another, so valve function was not affected. Finally, although many recipient cells infiltrated the valves, few of these were activated contractile cells after one year. Together, these results demonstrate that in vivo TEHV remodelling can be guided towards stable physiological structure and function.
Perhaps the most striking aspect of this study is that the authors’ predictive-modelling approach was successful even though they could not control the cell types that infiltrated the TEHVs. But although this approach worked well in healthy sheep, the cells that repopulate the tissue scaffold in people who have valve diseases or defects might respond differently to mechanical stimuli. Indeed, the authors’ computational model predicted that the TEHVs would work best when cell contractility was low, which may not always be the case in humans. For example, contractile-cell activation is driven by inflammation and immune responses7 that were largely absent in this study, but are often elevated in people with valve disease. In this context, excessive contractile-cell activation could lead to detrimental fibrosis and TEHV failure.
Moving forward, it will therefore be important to determine the robustness of a strategy that involves computational modelling based solely on mechanical influences, given the diversity of pro-fibrotic stimuli that can derail remodelling in patients. Successful TEHV solutions will probably need to combine computationally guided remodelling with complementary strategies to control detrimental fibrosis. For example, native valve cells express anti-fibrotic factors8 that could potentially be delivered alongside a TEHV to help suppress adverse remodelling, particularly in the early post-implantation phase, when inflammation might be heightened.
It is also notable that the remodelled valves showed little development of the trilayered microstructure of native valves, in which the top, middle and underlying sections of each leaflet have different compositions and mechanical properties. This structure is thought to be essential to native-valve mechanics5. Longer-term follow-up will be necessary to determine whether Emmert and colleagues’ TEHVs undergo further remodelling after 12 months to produce this microstructure, as has been observed in other TEHVs9, or if normal function can be maintained without it. Longer-term follow-up will also reveal whether the recipient cells in the TEHVs — which had quiesced and stopped making tissue after one year — can be reactivated to make new tissue and allow the valve to grow, as is required for children.
Ultimately, TEHV cells must be activated to grow and repair as necessary, but then quiesce to prevent fibrosis. Emmert and colleagues’ study clearly demonstrates the potential of a computational strategy to design TEHVs that can achieve this delicate balance on the basis of predicted mechanical and biological outcomes. The work also argues for further development of this approach to account for other factors in remodelling that could be predictably guided.
Nature 559, 42-43 (2018)