Computationally Modeling Tissue-Engineered Heart Valves

By Karthika Swamy Cohen

While mechanical or bioprosthetic insertion is one of the most common interventions for valvular disease, they have limitations. Their lack of growth, and inability to repair and remodel once implanted into the body makes them inappropriate for long-term functionality. Moreover, the likelihood of reoperation with valvular prosthetics is very high, especially in younger patients.

Tissue engineering of living heart valves shows promise as valvular substitutes that can potentially grow and remodel. The functionality of an engineered valve depends on the strength and anisotropic properties of its leaflets; in particular, mature heart valves have distinct anisotropic collagen architecture, which provides flexibility. One of the challenges in tissue engineering is mimicking this anisotropic collagen structure. 

 A predominant problem in heart valve tissue engineering is progressive valvular insufficiency developed due to leaflet retraction. At the SIAM Conference on the Life Sciences being held in Boston this week, Frank Baaijens (Technische Universiteit Eindhoven) described computational approaches using tissue-engineered heart valves in his invited talk, “Rational Design of Tissue Engineered Heart Valves.”  

In their computational simulations, Baaijens and his group subjected tissue-engineered valves (TEHVs) to dynamic pulmonary and aortic pressure conditions, in order to predict the remodeling process and assess the risk of valvular insufficiency. As Baaijens recounted his group’s experience with design and modeling, the importance of computational approaches in determining the long-term stability and functionality of TEHVs became evident. 

The group’s initial experiments resulted TEHVs that displayed leaflet thickening and slight retraction. They then decellularized TEHVs for over a year. After this, the TEHVs were repopulated with endogenous cells at 8 weeks. No thickening or retraction was observed at this point. 

The polymer residue in the scaffolding elicited a controlled inflammatory response, with leukocytes then differentiated into macrophages, secreting cytokines. However after degradation of macrophages, the immune response subsided. Still development of regurgitation was seen over time. 

With this design not successful, the researchers had to go back to the designing board. They next incorporated mechanical properties into the computational model to, which were measured using indentation experiments. This allowed them to mimic mechanics of native valves and addressed the question: what is driving homeostasis in these valves? 

The new design included new biometric curved geometry including coaption. They next incorporated the mechanics of collagen in the model. Cells not only synthesize collagen; they also have enzymes that degrade it. Stretching collagen makes it less susceptible to enzymatic activity. Cells exert forces by actin stress fibers. 

The group developed an open model incorporating orientation of actin stress fibers and collagen modeling. The TEHVs in this case showed no retraction or regurgitation. Computational modeling, in this case, proved crucial in the design of functional TEHVs. “We are no longer afraid that we'll have retraction because of the stability of the modeling process,” concluded Baaijens.

Karthika Swamy Cohen is the managing editor of SIAM News.