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. 2022 May 8;10(5):1095. doi: 10.3390/biomedicines10051095

Table 3.

Overview of cell sources and scaffold materials used for aortic valve replacement.

HVTE Cell Sources Study Conditions Main Results Ref.
In vitro Human aortic valve interstitial cells
(HAVICs)
  • -

    time: 7 days;

  • -

    scaffold: Me-HA/Me-Gel bioactive hydrogel
  • -

    hydrogels’ stiffness regulates the cellular response (the best 4%Me-HA/12%Me-Gel); high cell viability (>90%) for all hydrogels;

  • -

    GAG deposition markedly higher on day 7 (p < 0.01);

  • -

    the more spreading cells within hydrogels had more expression of genes (α-SMA, vimentin, periostin and collagen I);

  • -

    the heart valve conduit was successfully printed (4%Me-HA/10%Me-Gel) with acellular root and HAVICs encapsulated leaflets.

 [131]
  • -

    time: 14 days;

  • -

    scaffold: embedded PAN nano-micro fibrous woven fabric into Me-HA/Me-Gel bioactive hydrogel (composite hydrogel)
  • -

    HAVICs homogeneously distributed; high cell viability (>90%); improved cell proliferation rate at day 14 (406.4 ± 33.0 ng, p < 0.01).

  • -

    highest levels of α-SMA in hydrogels; collagen content in composite scaffolds lower than hydrogels (p < 0.05);

  • -

    the composite scaffold suppressed transdifferentiation into myofibroblasts and restrains differentiation towards osteoblastic phenotype.

 [132]
HHghHuman aortic root smooth muscle cells (HAoSMCs)
  • -

    time: 7 days;

  • -

    scaffold: alginate/gelatin hydrogels
  • -

    viable SMCs encapsulated within alginate/gelatin hydrogel for 7 days;

  • -

    cell viability after 7 days: 84.6 ± 63.1%;

  • -

    SMCs expressed α-SMA and vimentin after 7 days.

 [133]
Human umbilical cord vein endothelial cells (HUVECs)
  • -

    time: 28 days;

  • -

    scaffold: fibrin hydrogel in PET warp knitted mesh
  • -

    before and after crimping: MPG: 7.3 ± 1.5 mmHg and 6.8 ± 1.7 mmHg; regurgitation: 15.1 ± 2.5% and 15.3 ± 3.6%;

  • -

    deposition of collagen types I and III orientated along the longitudinal direction; longitudinally aligned α-SMA;

  • -

    homogeneous cell distribution throughout the valve’s thickness.

 [120]
  • -

    time: 21 days;

  • -

    scaffold: single multifilament PLDL fibers with e-spun PLGA sheet embedded in fibrin hydrogel
  • -

    hydrodynamic performance: MPG: 10.7 ± 0.7 mm Hg; the regurgitation fraction: 4.0 ± 1.0%; EOA: 1.4 ± 0.1 cm2;

  • -

    PLDL presence increased the Young’s modulus of the e-spun layer from 2.1 to 7.4 MPa;

  • -

    α-SMA aligned with the longitudinal direction (wall and leaflet); deposition of collagen types I and III; fibronectin in wall and leaflet.

 [134]
Human umbilical cord blood cells (HUCBs)
  • -

    time: 27 days;

  • -

    scaffold: PGA-P4HB
  • -

    good ingrowth of myofibroblasts into the PGA-P4HB scaffolds under cyclic strain;

  • -

    organized tissue-formation with good ECM formed by myofibroblasts in the inner part of the patches;

  • -

    collagen: strained 4.06 ± 1.92 mg/mg, perfused 4.21 ± 0.44 mg/mg; GAG: strained 6.44 ± 1.45 mg/mg, patches: 4.65 ± 0.61 mg/mg; cell number was higher in the strained patches.

[135]
  • -

    time: 25 days;

  • -

    scaffold: P4HB
  • -

    cells differentiated into endothelial-like and myofibroblast-like cells; it was formed a confluent monolayer and stained positive for fibroblast, α-SMA and desmin;

  • -

    the endothelial cell layer, α-SMA (the whole construct); collagen and β1-integrin (leaflets and vascular wall).

 [121]
Human dermal fibroblasts
(HDFn)
and
Ovine dermal fibroblast (ODF)
  • -

    time: 24 weeks;

  • -

    scaffold: fibrin hydrogel
  • -

    collagen (24 weeks): 48 ± 8 mg/mL; total protein conc. (24 weeks): 76 ± 14 mg/mL;

  • -

    cells were positive for an interstitial phenotype (α-SMA and vimentin); laminin and collagen IV (the endothelialized surface);

  • -

    no evidence of calcification.

 [136]
Porcine aortic valve interstitial cells
(PAVICs)
  • -

    time: 21 days;

  • -

    scaffold: PEG-DA with alginate.
  • -

    cells viability: 91.3 ± 10.7% (day 1), 100% (day 7 and 21);

  • -

    viable cells disperse on entire surface; few cells on root and leaflet.

 [137]
  • -

    time: 7 days;

  • -

    scaffold: alginate/gelatin hydrogel.
  • -

    viable VICs encapsulated within alginate/gelatin hydrogel for 7 days;

  • -

    cell viability (day 7): 84.6 ± 63.1%;

  • -

    VICs expressed α-SMA and vimentin after 7 days; VICs showed higher vimentin expression than α-SMA.

 [133]
  • -

    time: 1 month;

  • -

    scaffold: PCL.
  • -

    tensile moduli (aortic valve leaflet): 7.25 ± 2.10 MPa;

  • -

    VICs demonstrated active fibroblast phenotype (high vimentin, high collagen type I and low α-SMA expression).

 [138]
  • -

    time: 28 days;

  • -

    scaffold: BPUR/PEG.
  • -

    heterogeneous distribution of cells; fewer cells along the edges of the scaffold;

  • -

    compacted cell layers aligned parallel to BPUR; strongly expressed α-SMA and secreted collagen type I;

  • -

    quiescent VICs growing in PEG; no expression of α-SMA and collagen type I.

 [139]
Ovine umbilical vein endothelial cells (OUVECs)
  • -

    time: 21 days;

  • -

    scaffold: fibrin hydrogel in PET warp-knitted mesh and fibrin hydrogel.
  • -

    for PET-fibrin hydrogel, the cells are homogeneously distributed throughout the whole thickness; for fibrin hydrogel, cells appear to be less densely distributed in center;

  • -

    deposition of collagen types I and III (dynamic conditions).

 [140]
Ovine carotid arteries cells
and
Ovine umbilical arteries cells
  • -

    time: 4 weeks;

  • -

    scaffold: ELR-fibrin hybrid hydrogel and fibrin hydrogel.
  • -

    deposition of collagen I near lumen (TEHV) and homogenous distribution of collagen I in leaflets (native aortic wall);

  • -

    in TEHV, α-SMA found in conduit wall; α-SMA negative in the leaflet and the density of cells was lower.

[32]
In situ Ovine dermal fibroblast (oDF)
  • -

    time: 4 weeks;

  • -

    scaffold: fibrin hydrogel.

  • -

    collagen aligned circumferentially;

  • -

    systolic pressure drop: 25 mmHg; EOA: 1.1 cm2;

  • -

    regurgitant fraction: 5% (aortic conditions);

 [141]
  • -

    time: 24 weeks;

  • -

    scaffold: fibrin hydrogel,

  • -

    implanted in sheep.
  • -

    collagen: 48 ± 8 mg/mL (24 weeks); total protein: 76 ± 14 mg/mL; total DNA content: 141 ± 121 mg/mL (24 weeks);

  • -

    mean systolic pressure drop: (12 weeks) 48 ± 16 mmHg (n = 4) and (24 weeks) 45 ± 16 mmHg at (n = 3);

  • -

    measured aorta size (24 weeks): 27 ± 1 mm.

 [136]

Abbreviations: BPUR—biodegradable poly(ether ester urethane) urea; DNA—deoxyribonucleic acid; ELR—elastin like recombinamer; EOA—effective orifice area; GAG—glycosaminoglycans; Me-Gel—methacrylate gelatin; Me-HA—methacrylated hyaluronic acid; MPG—mean pressure gradient; P4HB—poly-4-Hydroxybutyric acid; PAN—polyacrylonitrile; PCL—polycaprolactone; PEG—poly(ethylene glycol); PEG-DA—poly(ethylene glycol) diacrylate; PET—polyethylene terephthalate; PGA—polyglycolic acid; PLDL—poly(L/D,L-lactide); PLGA—poly(lactic-co-glycolic acid); SMC—aortic root sinus smooth muscle cells; α-SMA—α-smooth muscle actin.