Research ArticleTissue Engineering

Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model

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Science Translational Medicine  09 May 2018:
Vol. 10, Issue 440, eaan4587
DOI: 10.1126/scitranslmed.aan4587
  • Fig. 1 TEHV manufacturing and characterization.

    (A) Macroscopic appearance of the distal and (B) proximal view of a representative TEHV after 4 weeks of in vitro culturing using geometrical constraints. (C) Representative flow and pressure curves of in vitro measurements, with representative images of the opening and closure behavior of the TEHV during the cardiac cycle. (D) Graphical representations of the initial in vivo circumferential (circ. strains) and radial (rad. strains) deformations as predicted by the computational model. (E) Average biaxial tensile test results of the control valves (n = 4) and fits of the material parameters (k1, k2, and σ) in the computational model (left) and predictions of the initial in vivo circumferential and radial strains in the belly center as a function leaflet thickness (right). The R2 value (left) indicates to what extent the model can predict the experimental data (with a maximum of 1).

  • Fig. 2 Preserved long-term functionality of the TEHVs over 1-year follow-up as assessed by ICE and cardiac MRI flow measurements.

    (A to C) ICE evaluation on valve morphology, insufficiency grade (regurgitation), and leaflet coaptation. Exemplary imagery of valve I is shown. (D) Longitudinal cardiac MRI flow analysis of valve regurgitation of all valves at weeks 1, 24, and 52 after TEHV implantation (see also fig. S5).

  • Fig. 3 Computational predictions of valve remodeling based on initial tissue properties.

    (A) Circumferential (circ.) and radial (rad.) strains in the loaded configuration upon variations in cell contractility. Results shown with the average leaflet thickness. If present, the central opening of the valve during diastole serves as an indirect measure of valvular insufficiency. (B) The predicted valve opening (percentage of the total orifice area and top views of the corresponding valves with average leaflet thickness during diastole) as a function of contractility. The effects of variations in leaflet thickness from the average value are reported in fig. S7B. (C) Predictions of collagen alignment for different leaflet thicknesses and low cell contractility (colored lines) compared to the collagen distributions measured in the explants (gray lines).

  • Fig. 4 Computational predictions of valve remodeling based on valve-specific tissue properties at explantation.

    (A) Circumferential and (B) radial strains predicted for the different valves during hemodynamic loading. (C) Measured (red) and predicted (blue) collagen architecture for each valve.

  • Fig. 5 Postmortem histological analyses of an exemplary TEHV explant after 1 year in vivo (valve N).

    (A) Gross images of the valve after harvest with distal and proximal views of the fully expanded unloaded valve and (B) of the three leaflets after the valve was cut open longitudinally through one of the commissural points. (C) Hematoxylin and eosin (H&E) staining of the longitudinal transection of entire valve and (D) of the higher magnification of the insets (black boxes) from the wall, leaflet, and hinge areas (scale bars, 100 μm). (E to H) Stainings for Elastica van Gieson (ELVG), αSMA, vimentin, and CD31 (arrows indicate endothelial cells) in the wall, leaflet, and hinge areas (scale bars, 100 μm). (I) Scanning electron microscopy (SEM) analysis of the wall, leaflet, and hinge surfaces of the explanted TEHV (scale bars, 20 μm).

  • Fig. 6 Biochemical tissue remodeling analysis.

    (A to C) HYP, sGAGs, and DNA content in the nonimplanted control valves and explants. Data are median with the IQR. Groups were compared using unpaired, two-tailed Mann-Whitney tests.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/10/440/eaan4587/DC1

    Materials and Methods

    Fig. S1. Schematic overview of study concept.

    Fig. S2. Gross and histological characterization of a control TEHV.

    Fig. S3. Overview of the clinical-grade percutaneous implantation system and the multimodality imaging protocols to assess TEHV positioning, functionality, and performance throughout the study.

    Fig. S4. Computational predictions of valve remodeling and postmortem analysis of valve G, which was malpositioned upon implantation.

    Fig. S5. Longitudinal cardiac MRI flow measurements for the assessment of TEHV function and regurgitation fraction over 1 year.

    Fig. S6. Postmortem analyses of valve E explanted after 6 months in vivo.

    Fig. S7. Additional results on the computational predictions of in vivo strains and valve remodeling based on initial tissue properties.

    Fig. S8. Analysis of collagen alignment.

    Fig. S9. Histological evaluation of cellular infiltration in a representative valve (valve N) using Masson Goldner staining.

    Fig. S10. Evaluation of elastogenesis and neosinus formation.

    Fig. S11. Assessment of leaflet length and position.

    Fig. S12. Evaluation of calcification in different explants with von Kossa staining.

    Fig. S13. Histological evaluation of the inflammatory response using H&E staining.

    Fig. S14. Evaluation of leaflet remodeling using Elastica van Gieson staining.

    Fig. S15. Postmortem analyses of valve J explanted after 1 year in vivo.

    Fig. S16. Immunohistochemical analysis for presence and distribution of αSMA-positive cells in valve G.

    Fig. S17. Schematic representation depicting the functional remodeling process within the TEHV.

    Table S1. In vitro TEHV functionality before implantation.

    Table S2. Animal characteristics.

    Table S3. Pulmonary dimensions and hemodynamics before and after implantation.

    Table S4. Functional long-term catheter data (invasive hemodynamic measurements) of TEHVs at baseline and after 1 year.

    Table S5. Functional ICE data of TEHVs at baseline and after 1 year.

    Table S6. Functional MRI data of TEHV insufficiency at baseline and after 1 year.

    Table S7. Leaflet thickness in the explants.

    Movie S1. In vitro TEHV testing.

    Movie S2. Angiography after TEHV implantation.

    Movie S3. ICE after implantation.

    Movie S4. Color-coded ICE after implantation.

    Movie S5. ICE at 6-month follow-up.

    Movie S6. Color-coded ICE at 6-month follow-up.

    Movie S7. ICE at 12-month follow-up.

    Movie S8. Color-coded ICE at 12-month follow-up.

    References (5052)

  • Supplementary Material for:

    Computational modeling guides tissue-engineered heart valve design for long-term in vivo performance in a translational sheep model

    Maximilian Y. Emmert, Boris A. Schmitt, Sandra Loerakker, Bart Sanders, Hendrik Spriestersbach, Emanuela S. Fioretta, Leon Bruder, Kerstin Brakmann, Sarah E. Motta, Valentina Lintas, Petra E. Dijkman, Laura Frese, Felix Berger, Frank P. T. Baaijens, Simon P. Hoerstrup*

    *Corresponding author. Email: simon.hoerstrup{at}irem.uzh.ch

    Published 9 May 2018, Sci. Transl. Med. 10, eaan4587 (2018)
    DOI: 10.1126/scitranslmed.aan4587

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Schematic overview of study concept.
    • Fig. S2. Gross and histological characterization of a control TEHV.
    • Fig. S3. Overview of the clinical-grade percutaneous implantation system and the multimodality imaging protocols to assess TEHV positioning, functionality, and performance throughout the study.
    • Fig. S4. Computational predictions of valve remodeling and postmortem analysis of valve G, which was malpositioned upon implantation.
    • Fig. S5. Longitudinal cardiac MRI flow measurements for the assessment of TEHV function and regurgitation fraction over 1 year.
    • Fig. S6. Postmortem analyses of valve E explanted after 6 months in vivo.
    • Fig. S7. Additional results on the computational predictions of in vivo strains and valve remodeling based on initial tissue properties.
    • Fig. S8. Analysis of collagen alignment.
    • Fig. S9. Histological evaluation of cellular infiltration in a representative valve (valve N) using Masson Goldner staining.
    • Fig. S10. Evaluation of elastogenesis and neosinus formation.
    • Fig. S11. Assessment of leaflet length and position.
    • Fig. S12. Evaluation of calcification in different explants with von Kossa staining.
    • Fig. S13. Histological evaluation of the inflammatory response using H&E staining.
    • Fig. S14. Evaluation of leaflet remodeling using Elastica van Gieson staining.
    • Fig. S15. Postmortem analyses of valve J explanted after 1 year in vivo.
    • Fig. S16. Immunohistochemical analysis for presence and distribution of αSMA-positive cells in valve G.
    • Fig. S17. Schematic representation depicting the functional remodeling process within the TEHV.
    • Table S1. In vitro TEHV functionality before implantation.
    • Table S2. Animal characteristics.
    • Table S3. Pulmonary dimensions and hemodynamics before and after implantation.
    • Table S4. Functional long-term catheter data (invasive hemodynamic measurements) of TEHVs at baseline and after 1 year.
    • Table S5. Functional ICE data of TEHVs at baseline and after 1 year.
    • Table S6. Functional MRI data of TEHV insufficiency at baseline and after 1 year.
    • Table S7. Leaflet thickness in the explants.
    • References (5052)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). In vitro TEHV testing.
    • Movie S2 (.avi format). Angiography after TEHV implantation.
    • Movie S3 (.avi format). ICE after implantation.
    • Movie S4 (.avi format). Color-coded ICE after implantation.
    • Movie S5 (.avi format). ICE at 6-month follow-up.
    • Movie S6 (.avi format). Color-coded ICE at 6-month follow-up.
    • Movie S7 (.avi format). ICE at 12-month follow-up.
    • Movie S8 (.avi format). Color-coded ICE at 12-month follow-up.

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