Modeling of tissue-engineered heart valves. Image credit: Frank Baaijens, AN16 presentation.
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
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.
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.
Cell-mediated retraction and remodeling in TEHVs. Image credit: Frank Baaijens, AN16 presentation.
initial experiments resulted TEHVs that displayed leaflet thickening and slight
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,”
||Karthika Swamy Cohen is the managing editor of SIAM News.