Table 3.
List of 3D hiPSC-based cardiac constructs reported in this review.
| Ref. | Scaffold | Cell Types | Physical Stimulation | Disease Modeling | Therapeutic Studies |
|---|---|---|---|---|---|
| [108] | Type I Collagen-based 3D scaffold |
- hESC-/hiPS-CMs (2 × 106) - HUVEC (1 × 106) - human MSCs/MEFs (1 × 106) |
Uniaxal cyclic stress conditioning (mechanical) | N/A | Implantation in athymic rats |
| [93] | 3D cardiac patches (PDMS + fibrinogen, Matrigel, thrombin) |
hESC-CMs (1 × 106) | Patches cultured on a rocking platform | N/A | N/A |
| [116] | Decellularized mouse heart | hiPSC-derived MCPs (CMs, SMCs, ECs) (Tot. 1 × 107) | N/A | N/A | Drug responsiveness |
| [120] | Collagen master mix (Collagen I and Matrigel) | - hESC-CMs - hiPS-derived FBs (Tot. 0.5 × 106) |
Uniaxial mechanical stress and electrical point stimulation | Tachycardic model of arrhythmias | Drug responsiveness |
| [100] | Type I collagen gel | hESC-/hiPS-derived MCPs (CMs, ECs, FBs, SMCs) | Electrical stimulation | N/A | N/A |
| [124] | Elastomers micropatterned with fibronectin lines | hiPS-CMs (1 × 105 cells/cm2) | N/A | Barth syndrome cardiomyopathy caused by TAZ mutations | N/A |
| [147] | 3D Hydrogel platform (Matrigel-based) |
- hESC-CMs (2.5 × 105) - hiPSC-derived ECs (5 × 104) - hAMSCs (5 × 104) |
N/A | N/A | N/A |
| [162] | PDMS substrate + collagen I and human fibrinogen | - hiPS-CMs - Human MSCs (Tot. 1.1 × 106) |
Electrical field stimulation | DCM caused by TTN mutations | N/A |
| [104] | Collagen (I)-based 3D scaffold | hiPS-CMs (2 × 106) | Electric pacing and static stress conditioning | N/A | N/A |
| [130] | Matrigel + collagen type I matrix |
- hiPS-CMs - hiPSC-derived ECs - hiPSC-derived MCs (Tot. 3 × 106) |
N/A | N/A | Implantation in a rat MI model |
| [148] | Fabricated fibronectin and gelatin nanofilms (LbL assembly) | - hiPS-CMs - Human cardiac FBs (Tot. 1–50 × 105) |
N/A | N/A | Responsiveness to cardiotoxic drugs |
| [158] | Micropatterned wells (PDMS substrate + collagen type I and fibrinogen) | - hiPS-CMs - human mesenchymal stem cells (Tot. 1.1 × 106) |
N/A | PRKAG2 cardiomyopathy | N/A |
| [160] | PDMS template + Matrigel/collagen I matrix | - hiPS-CMs - stromal cells (Tot. 1 × 106) |
N/A | HCM caused by BRAF mutation | N/A |
| [163] | PDMS template + Matrigel/collagen I matrix | hiPS-CMs (1 × 106) | N/A | DCM caused by PLN mutation | N/A |
| [169] | PDMS stencils containing rectangular through-holes (hydrogel-free) | - hiPS-CMs - hiPSC-derived FBs (Tot. 2 × 107) |
N/A | N/A | Clinically relevant responsiveness to isoproterenol treatment |
| [95] | Agarose casting molds + fibrin matrix (Matrigel, fibrinogen, thrombin) | hiPS-CMs (1 × 106) | N/A | N/A | N/A |
| [99] | Circular casting molds + Matrigel/collagen matrix | - hESC-/hiPS-CMs - human FBs (Tot. 1 × 104–15 × 106) |
Dynamic stretch conditioning | Model of heart failure | Implantation in athymic rats |
| [102] | Fibrin hydrogel suspension (fibrinogen, thrombin) |
hiPS-CMs (1.7 × 106) | Hydrodynamic drag force fields (Faraday waves) | N/A | N/A |
| [105] | 3D-MPE printed scaffold (methacrylated gelatin-based) | - hiPS-CMs (25 × 103) - hiPSC-derived ECs (12.5 × 103) - hiPSC-derived SMCs (12.5 × 103) |
N/A | N/A | Implantation in a murine model of MI |
| [131] | PDMS template + Matrigel/collagen I matrix | - hiPS-CMs - hiPSC-derived ECs - hiPSC-derived MCs (Tot. 6 × 106) |
N/A | N/A | Implantation in rat model of MI |
| [146] | Scaffold-free (spheroids) | - hESC-/hiPS-CMs - hESC-/hiPSC-derived ECs (Tot. 5 × 103) |
N/A | N/A | Drug responsiveness |
| [164] | Circular casting molds + Matrigel/collagen matrix | hiPS-CMs (1 × 106) | Mechanical stress conditioning | DCM caused by RBM20 mutation | N/A |
| [170] | PDMS elastomer molds + Matrigel/collagen I matrix | - hESC-CMs (1 × 105) - human FBs (1 × 105) |
N/A | N/A | Responsiveness to cardioactive drugs |
| [171] | PDMS square molds + Hydrogel matrix (fibrinogen, Matrigel, thrombin) | hiPS-CMs (0.5–1 × 106) | Patches cultured on a rocking platform | N/A | Implantation in nude mice (skin) and nude rats (epicardium) |
| [172] | Fabricated fibronectin and gelatin nanofilms (LbL assembly) | - hiPS-CMs - human cardiac FBs - HCMVECs (Tot. 1.1–3.7 × 106) |
N/A | N/A | Implantation in rat infarcted hearts |
| [97] | PDMS elastomeric pillars + fibrin hydrogel (fibrinogen, thrombin) | - hiPS-CMs - human dermal FBs (Tot. 2 × 106) |
Mechanical loading and electrical conditioning | N/A | Responsiveness to isoproterenol treatment |
| [123] | PDMS elastomer molds + collagen I matrix | - hiPS-CMs (1 × 106) - human MSCs (0.2 × 106) |
Static stress conditioning | Systolic cardiomyopathy (MYH7 mutation) | N/A |
| [129] | Rectangular agarose/PDMS casting molds + fibrinogen/thrombin matrix | - hiPS-CMs (5 × 105) - human MSCs (5 × 104) |
Mechanical loading (afterload) | N/A | N/A |
| [161] | Cell-encapsulation gel-free filamentous matrix (OrmoClear®polymer) | - hiPS-CMs - hiPSC-derived FBs - hiPSC-derived stromal cells (Tot. 3 × 106) |
Mechanical conditioning | Contractile dysfunctions caused by MYBPC3 deficit | N/A |
| [173] | Fibronectin/gelatin nanofilms (LbL assembly) | - hiPS-CMs - hiPSC-derived FBs - hiPSC-derived SMCs (Tot. 5 × 105) |
N/A | N/A | Drug-induced cardiotoxicity assay |
| [113] | Scaffold-free (organoids) | - hiPS-CMs - human cardiac FBs (Tot. 1 × 103) |
N/A | N/A | Environmental toxin screening |
| [174] | Fibrin matrix (patch) containing spheroids (spheroid fusions) | hiPS-CMs (2.5 × 103–3 × 105) | N/A | N/A | Implantation in a murine model of MI |
| [112] | Cell sheets wrapped around a hollow octagonal tubular column (fibrin and collagen gels to seal the extremities) | - hiPS-CMs (6 × 106 cells/sheet) - human dermal FBs (6 × 106 cells/sheet) |
Electrical stimulation and mechanical stretch (provided by a circulation system) | N/A | N/A |
| [114] | Personalized hydrogel from decellularized human ECM | - hiPS-CMs (1 × 108) - hiPSC-derived ECs (1.5 × 107) - human neonatal dermal FBs (3 × 106) |
N/A | N/A | N/A |
| [128] | Parallel POMaC wires + hydrogel matrix (collagen, Matrigel, fibrin) | - hiPS-CMs (1 × 105) - human cardiac FBs (1 × 104) |
Long-term electrical field stimulation | N/A | Canonical responses to cardiotherapeutic and cardiotoxic agents |
| [111] | Flexible POMaC wires + hydrogel matrix (collagen, Matrigel) | - hESC-/hiPS-CMs (7.47 × 104) - human cardiac FBs (3.5 × 104) |
Electrical field stimulation | Left ventricular hypertrophy | Chamber-specific responsiveness to serotonin and ranolazine |
| [159] | Micromolded gelatin muscular thin film substrate + fibronectin and gelatin matrix | hiPS-CMs (1 × 106) | N/A | CPVT caused by RYR2 mutation | N/A |
| [165] | Flexible PDMS posts + fibrin matrix (Matrigel, fibrinogen, thrombin) | hiPS-CMs (8 × 105) | N/A | HCM caused by ACTN2 mutation | Ameliorated phenotype upon diltiazem treatment |
| [168] | Agarose/PDMS-casting molds + fibrin matrix (Matrigel, fibrinogen, thrombin) | hiPS-CMs (1 × 106) | Chronic optical tachypacing | Ventricular tachycardia | Responsiveness to antiarrhythmic compounds |
| [175] | PDMS molds + Matrigel/Collagen I mixture (to form cardiac organoids) |
- hESC-CMs - hESC-derived stromal cells (Tot. 5 × 104) |
N/A | N/A | Functional screening of 105 compounds with pro-regenerative potential |
| [176] | Circular microfibrous polycaprolactone sheets + Geltrex |
- hiPS-CMs (1 × 106) - hiPSC-derived ECs (4 × 104) |
N/A | N/A | Subcutaneous transplantation in SCID mice and epicardial transplantation onto rat MI model |
| [109] | Ring-shaped casting molds + Collagen-based hydrogel matrix | - hESC-CMs (atrial and ventricular differentiation) (Tot. 2 × 106) |
Passive stretch conditioning | Atrial arrhythmia model (AF-like) | Arrhythmic phenotype rescued after electrical cardioversion or after treatment with anti-arrhythmic agents |
| [125] | Polystrene chip with two parallel POMaC wires + collagen hydrogel (with Matrigel) or collagen/fibrin hydrogel (with fibrinogen) | - hESC-/hiPS-CMs (atrial and ventricular) - mesenchymal stem cells - human cardiac FBs (Tot. 25–150 × 106) |
Electrical conditioning | N/A | N/A |
| [103] | 3D-printed cuboids and hexagons micro-scaffolds (PETA monomer) | -iPSC-derived CMs (murine) (2 × 104) | N/A | N/A | N/A |
| [145] | PDMS support + collagen I mixture (LbL assembly) | - hESC-/hiPS-CMs (1 × 106) - human cardiac FBs (2 × 105) |
N/A | N/A | N/A |
| [149] | Scaffold-free (3D-bioprinted spheroids) | - hiPS-CMs - human cardiac FBs - HUVEC or hiPSC-derived vascular cells (Tot. 3.3 × 104) |
N/A | N/A | N/A |
| [166] | Scaffold-free aggregates (3D self-organization) | hiPS-CMs (1.5 × 103) | 3D aggregates cultured with controlled pO2 and pH in stirred-tank bioreactors | Myocardial ischemia-reperfusion injury model | N/A |
| [167] | Scaffold-free self-assembled organoids | - hiPS-CMs - human cardiac FBs - HUVEC - human adipose-derived stem cells (Tot. 1.5 × 105) |
Oxygen-diffusion gradient | Model of MI | Fibrotic phenotype ameliorated upon treatment with HF drug candidate and canonical cardiotoxic response to doxorubicin |
+, combined with; 3D, three-dimensional; ACTN2, alpha actinin 2; AF, atrial fibrillation; CM, cardiomyocyte; CMPC, cardiomyocyte progenitor cell; DCM, dilated cardiomyopathy; EC, endothelial cell; ESC, embryonic stem cell; FB, fibroblast; hAMSC, human amniotic mesenchymal stem cell; HCMVEC, human cardiac microvascular endothelial cells; hESC-CM, human ESC-derived cardiomyocyte; HCM, hypertrophic cardiomyopathy; HF, heart failure; hiPSC, human induced pluripotent stem cell; hiPS-CM, human induced pluripotent stem cell-derived cardiomyocytes; HUVEC, human umbilical vein endothelial cell; LbL, Layer-by-Layer; MC, mural cell; MCP, multipotential cardiovascular progenitor; MEF, mouse embryonic fibroblast; MI, myocardial infraction; MPE, multiphoton excited; MSC, marrow stromal cells; MYBPC3, myosin binding protein C3; MYH7, myosin heavy chain 7; PDMS, polydimethylsiloxane; PETA, pentaerythritol triacrylate; pO2, partial pressure of oxygen; PLN, phospholamban; POMaC, poly (octa-methylene maleate (anhydride) citrate); PRKAG2, protein kinase AMP-activated non-catalytic subunit Gamma 2; RBM20, RNA-binding motif protein 20; RYR2, ryanodine receptor 2; SCID, severe combined immunodeficiency; SMC, smooth muscle cell; TAZ, tafazzin; Tot., total number of cells; TTN, titin.