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

Table 4.

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

HVTE Cell Sources Study Conditions Main Results Ref.
In vitro Human chorionic villous mesenchymal stem cells
(CV-MSCs)
  • -

    time: 28 days;

  • -

    scaffold: PGA-P4HB.

  • -

    in strained leaflets: GAG: 5.5 ± 0.73 μm/mg;

  • -

    hydroxyproline: 4.62 ± 2.11 μm/mg; DNA content: 2.78 ± 0.72 μm/mg;

  • -

    cells expressed vimentin, but lacked α-SMA expression;

  • -

    after differentiation EPC expressed CD31.

 [142]
Human amniotic fluid cells
(H-AFCs)
  • -

    time: 28 days;

  • -

    scaffold: PGA-P4HB.
  • -

    immunohistochemistry revealed expression of CD44 and vimentin;

  • -

    cells started to express eNOS, but no expression of CD31 (28 days);

  • -

    in strained leaflets: GAG: 12.5 ± 0.81 μg/mg;

  • -

    hydroxyproline: 2.51 ± 0.79 μg/mg;

  • -

    DNA content: 4.12 ± 0.77 μg/mg.

 [143]
Cardiac Stem Cells (eCSCs) from Adult Mouse Heart
  • -

    time: 15 days;

  • -

    scaffold: PCL-PLLA nano-micro fiber.
  • -

    cells exhibited strong metabolic activities;

  • -

    stem cells were able to deposited between the fibers.

 [144]
Porcine aortic valve interstitial cells (PAVICs)
  • -

    time: 15 days;

  • -

    scaffold: PCL-PLLA nano-micro fiber.
  • -

    improved proliferation with the increase PLLA content;

  • -

    rotary seeding: better scaffolds penetration of PAVICs;

  • -

    static seeding: formation of a monolayer of cells.

 [144]
Ovine vascular-derived cells
  • -

    time: 28 days;

  • -

    scaffold: fibrin hydrogel.
  • -

    cells expressed vimentin; fewer cells express α-SMA (leaflets and valve wall); cells expressed α-SMA positive (valve conduits).

  • -

    hydroxyproline: (walls): 20.8 ± 5.5 μg/mg (n = 4);

  • -

    (leaflets): 18.4 ± 6.4 μg/mg (n = 4).

 [145]
  • -

    time: 20 days;

  • -

    scaffold: PGA-P4HB.
  • -

    regurgitation: 8 ± 3%; orifice area: 1.9 ± 0.1 cm2; mean pressure gradient: 5.1 ± 0.3 mmHg;

  • -

    deposition of collagen: in leaflets and in the outer tissue layers (wall);

  • -

    DNA: 3.4 ± 0.2 μg/mg; GAG: 12.3 ± 0.8 μg/mg;

  • -

    hydroxyproline: 9.7 ± 0.6 μg/mg.

 [146]
Ovine bone marrow-derived mesenchymal stromal cells (oBM-MSCs)
  • -

    time: 4 weeks;

  • -

    scaffold: PGA-PLLA.
  • -

    tensile strength decreased rapidly in 4 weeks;

  • -

    diffuse cells expressed of α-SMA throughout the scaffold; cells expressing vimentin evenly distributed.

 [147]
  • -

    time: 1 month;

  • -

    scaffold: PGA-PLLA.

  • -

    cusp length decreased: 3.0 ± 0.10 cm (assembly); 2.5 ± 0.16 cm (implantation);

  • -

    cusp width decreased: 2.8 ± 0.05 cm (assembly);

  • -

    1.62 ± 0.23 cm (implantation);

  • valved conduit stable: 2.3 ± 0.07 cm.

  • -

    cells infiltration in outer layers of scaffold.

 [148]
In situ Human dermal fibroblasts, neonatal (HDFn)
  • -

    time: 5 weeks;

  • -

    scaffold: non-woven PLA mesh; woven Dacron;

  • -

    implanted in sheep.

  • -

    collagen: 24 ± 2 mg/mL (4 weeks), 31 ± 2 mg/mL (8 weeks); elastin: 0.11 mg/mL;

  • -

    cell concentration: >122% higher compared to implant leaflets (8 weeks);

  • -

    mean pressure gradient: 2.1 ± 0.8 mm Hg; mean flow velocity: 159 ± 36 cm/s; orifice area: 2.8 ± 0.2 cm2.

 [149]
  • -

    time: 4 weeks;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    neo-tissue formation and homogeneous ECM deposition;

  • -

    GAG: 3.65 ± 1.68 μg/mg; hydroxyproline: 18.30 ± 6.34 μg/mg;

  • -

    deposition of collagen types I and III;

  • -

    no evidence of regurgitation; no paravalvular leakage.

 [150]
Human vascular-derived cells (vena saphena magna, VSM)
  • -

    time: 8 weeks;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in chacma baboons.
  • -

    deposition of collagen throughout leaflet and wall;

  • -

    homogeneous cellular repopulation;

  • -

    α-SMA positive elements (conduit wall); GAG significantly increased after 8 weeks.

[151]
Ovine vascular-derived cells
  • -

    time: 28 days;

  • -

    scaffold: fibrin hydrogel;

  • -

    implanted in sheep.
  • -

    deposition of collagen, types I and III; elastin in granular form (leaflets and wall);

  • -

    hydroxyproline: 28.1 μg/mg (leaflet); 32.7 μg/mg (wall).

 [145]
  • -

    time: 8 weeks;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    deposition of collagen in the outer layers;

  • -

    cells expressed α-SMA and eNOS (wall); cells expressed eNOS and α-SMA (leaflet); cells α-SMA (interstitial);

  • -

    8 weeks (% native leaflets): DNA: 86 ± 54%; GAG: 150 ± 11%; hydroxyproline: 26 ± 6%.

 [146]
  • -

    time: 24 weeks;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    well-developed ECM; homogeneously repopulated (leaflets and wall);

  • -

    increased density of collagen (wall and hinge area); lesser extent in the leaflet;

  • -

    α-SMA negative (leaflet and hinge area); α-SMA positive (wall).

 [152]
  • -

    time: 12 months;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    12 months: mean pressure gradient: 6.1 ± 8.6 mmHg; mean regurgitation fraction: 13.9 ± 5.7%;

  • -

    increased significantly: collagen: 58.98 μg/mg and DNA content: 1.64 μg/mg; GAG: 18.12 μg/mg (no difference);

  • -

    substantial amounts of α-SMA positive cells (wall); very few α-SMA positive cells (leaflets); heterogeneous distribution of vimentin-positive cells (wall, hinge, leaflet).

 [129]
Ovine bone marrow-derived mesenchymal stromal cells (oBM-MSCs)
  • -

    time: 8 months;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    mean systolic gradient: 9.7 ± 1.3 mmHg; orifice area: 1.35 ± 0.17 cm2;

  • -

    α-SMA positive cells were limited to the subendothelial layer;

  • -

    8 months: deposition of collagen (outflow surface); elastin (inflow surface); GAG (valve leaflet).

 [147]
  • -

    time: 20 weeks;

  • -

    scaffold: PGA-PLLA;

  • -

    implanted in sheep.
  • -

    valved conduit diameter stable for > 20 weeks;

  • -

    density of ECM increased after implantation;

  • -

    density of cells increased after implantation.

 [148]
Ovine dermal fibroblast (oDF)
  • -

    time: 4 weeks;

  • -

    scaffold: fibrin hydrogel;

  • -

    implanted in sheep.
  • -

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

  • -

    regurgitant fraction: 5% (pulmonary conditions);

  • -

    fatigue testing (2 weeks): no changes or tissue degeneration (4 weeks);

  • -

    tissue thinning at contacting with the frame struts.

 [141]
  • -

    time: 22 weeks;

  • -

    scaffold: fibrin hydrogel,

  • -

    implanted in lamb.

  • -

    22 weeks: deposition of collagen IV (valve root and leaflets); elastin deposition (root and leaflet);

  • -

    total collagen: 81.2 ± 26.5 mg (explanted root); 49.1 ± 2.04 mg (implant);

  • -

    total collagen content: 15.2 ± 0.5 mg (leaflets); 4.2 ± 1.8 mg (after implantation);

  • -

    calcification was not observed (root or leaflets);

  • -

    22 weeks: α-SMA expressed near the lumenal surface of the root and partially on the leaflet surfaces.

 [153]
Ovine peripheral vein-derived fibroblasts
  • -

    time: 16 weeks;

  • -

    scaffold: PGA-P4HB;

  • -

    implanted in sheep.
  • -

    newly formed tissue at the interface between the nitinol stent and the native tissue;

  • -

    collagen content: 60 μg/mg; GAG: 6.4 μg/mg; DNA content: 4.35 μg/mg;

  • -

    scaffolds demonstrated a high cellular repopulation and ECM remodeling capacity.

 [130]

Abbreviations: CD31—clone JC/70A; CD44—clone G44–26; CD44—fluorescein isothiocyanate [FITC]-conjugated (Clone MEM-85); DNA—deoxyribonucleic acid; eNOS—endothelial nitric oxide synthase type III; GAG—glycosaminoglycans; P4HB—poly-4-hydroxybutyric acid; PCL—polycaprolactone; PGA—polyglycolic acid; PLA—polylactic acid; PLLA—poly L-lactic acid; α-SMA—α-smooth muscle actin.