Table 2.
Nanoengineered Electroconductive Scaffolds for Cardiovascular Tissue Regeneration
| Type of conductive scaffold | Composition | Fabrication techniques | Measurement device | Cellular type | Properties (with a focus on electrical properties and cellular activity) | Ref. |
|---|---|---|---|---|---|---|
| Hydrogels | GelMA–AuNRs | Simple mixing of GelMA with AuNRs, sonication, and UV photocrosslinking | AFM and LCR meter A custom-made electrical field stimulation chamber |
NRVCMs | Embedding AuNRs significantly promoted cellular retention and the expression of cardiac-specific markers, including SAC, cTnI, and Cx43 gap junctions Lower excitation voltage threshold for hydrogels embedded with AuNRs The EIS measurement demonstrated the inclusion of AuNRs and significantly reduced the electrical resistance of GelMA–GNR (2.5 ± 0.03 kΩ at 20 Hz) as compared with both pristine GelMA (5%) (12.65 ± 5.21 kΩ at 20 Hz) and GelMA (20%) (21.58 ± 3.56 kΩ at 20 Hz) hydrogels |
29 |
| Hydrogels/hybrid nanocomposite | GelMA–PANI | Interfacial polymerization Simple blending and crosslinking using Irgacure |
Three electrode system EIS using a custom-made resistance-test-chip Direct current resistance system |
Murine mesenchymal progenitor cells | Can be printed in complex user-defined geometries using digital projection stereolithography Useful in developing next-generation bioelectrical interfaces Significant decrease in resistance (increase in conductivity) by doping PANI. GelMA–PANI showed resistance of 165.56 ± 5.97 Ω compared with pristine GelMA 508.60 ± 6.84 Ω The impedance of GelMA–PANI (2.9 ± 0.3 kΩ) was significantly lower than pure GelMA sample (6.9 ± 0.7 kΩ) |
48 |
| Hydrogels | GelMA-PEDOT:PSS | Filtered, sonicated, blended, crosslinked | EIS workstation | C2C12 myoblasts | In an ex vivo experiment, the threshold voltage to stimulate contraction of abdominal tissue decreased compared with GelMA control Enhanced conductivity and biocompatibility At lower frequencies (similar to electroactive biological tissues, 1 Hz), the resistivity of GelMA:PEDOT:PSS was lower than pure GelMA hydrogel at 1 Hz and impedance decreased from 449.0 kΩ for pure GelMA to 261 kΩ for GelMA:PEDOT:PSS hydrogel |
49 |
| Biohybrid hydrogel arrays | GelMA-CNTs | Encapsulation of microelectrodes into hydrogels, and then UV crosslinking | A custom-made two carbon electrode system | Neonatal rat ventricular CMs | CNT microelectrode-integrated hydrogels exhibited excellent anisotropic electrical conductivity Aligned CNTs provide homogeneous cell organization with improved cell-to-cell coupling and maturation |
45 |
| Hybrid hydrogels | GelMA-rGO | Simple mixing and UV crosslinking | EIS and a custom-made platinum wire electrode system | Neonatal rat ventricular CMs | Significantly enhanced the electrical conductivity and mechanical properties Stronger CM's contractility and faster spontaneous beating rate on rGO–GelMA hydrogels At the same frequency (100 Hz), the GelMA–rGO hydrogels showed significantly lower impedance of 1.2 kΩ than those of pristine GelMA hydrogels (6 kΩ) |
50 |
| Hydrogel | Gelatin (porcine skin)-SWCNTs | Mixing, sonication, and GP crosslinking | Impedance test using a precision LCR meter | H9c2 rat cardiomyoblasts | Enhanced cellular electrical excitability More mature cardiac phenotype in H9c2 Gelatin–SWCNTs showed mechanical strength with low electrical resistance and high thermal conductivity Highest conductivity (at low frequencies) was observed at 0.9% w/w SWCNTs |
51 |
| Injectable hydrogels | CS-AT-PEG | Mixing, and then PEG-DA crosslinking agent | Pocket conductivity meter | C2C12 myoblasts and H9c2 rat cardiomyoblasts | Antibacterial and electroactive injectable hydrogels with self-healing ability High cell viability post injection Tunable release rate, and in vivo cell retention in conductive hydrogels Excellent candidates as cell delivery vehicle for cardiac repair Conductivity of the hydrogels was about 10−3 S/cm, which is quite close to native cardiac tissue 0.1 S/m |
52 |
| Hydrogels | MWCNTs−Collagen (type I) | Mixing and molding | Custom-made electrodes used in impedance test | Neonatal rat CMs | Simultaneous improvements in mechanical strength and electrical performance Increased rhythmic contraction of the infarcted area At lower and more biologically relevant frequencies (<100 Hz), Col–CNTs hydrogels showed lower impedance (3 kΩ vs. 5 kΩ, at 10 Hz) |
53 |
| Pericardial matrix hydrogels (PMNT gels) | Decellularized cardiac tissue-CDH functionalized MWCNT (CDH-MWCNT) | Decellularization, functionalization, and doping | Custom-made four-point probe electrical station | HL-1 CMs | CMs cultured on a PMNT scaffold triggered proliferation and significantly increased the expression of cardiac gap junctions, connexin 43 The addition of CDH–MWCNT to the gel significantly increased the electrical conductivity from 0.007 to 0.015 S/cm, which is close to the native cardiac tissue conductivity of 0.1 S/cm |
54 |
| Nanoporous scaffolds | Polyurethane containing AP segments (AP-PU), PCL | Salt leaching/compression molding technique | Four-point probe electrical station | Neonatal rat CMs | Scaffolds supported CM's adhesion and growth with more extensive effect on the expression of the cardiac genes involved in muscle contraction and relaxation (troponin-T) and cytoskeleton alignment (actinin-4) The conductivity of the composite scaffold was 10−5 ± 0.09 S/cm (which is in the range of semiconductor materials 10−2–10−6 S/cm) Conductivity preserved for 120 h postfabrication in cell media |
55 |
| Nanofibrous scaffolds | GelMA–Bio–IL | Electrospinning, and then physical conjugation | Two-probe electrical station | Coculture of neonatal rat CMs and CFs | Adhesive and sutureless scaffolds because of the formation of ionic bonding between the Bio-IL and native tissue Overexpression of the gap junction protein connexin 43 in GelMA–Bio-IL scaffolds Minimize cardiac remodeling and preserve normal cardiac function The conductivity of 10% (w/v) GelMA–Bio-IL scaffolds was increased from 0.023 ± 0.002 to 0.138 ± 0.012 S/m by increasing Bio-IL from 33% to 66% |
56 |
| Nanofibrous scaffold | PLGA–PPy | Electrospinning | Cyclic voltammetry measurements | iPS-CMs | The PLGA–PPy fibrous scaffold is capable of delivering direct electrical and mechanical stimulation to iPS Increased expression of cardiac markers No cytotoxic effect on iPS Fiber scaffolds are capable of dynamic mechanical actuation |
57 |
| Electrospun nanofibrous scaffold | PVDF–TrFE | Electrospinning | Deposited gold electrodes to AM systems differential AC amplifier | Neonatal rat left ventricular derived CMs, and hiPSC-CMs | The scaffolds perform as sensors for tissue construction from ∼105 of CMs Contractions of CMs induced mechanical deformations, which resulted in measurable electric voltage |
13 |
| 3D macroporous scaffolds | PEDOT:PSS | Ice-templating method | Custom-made OECTs | Mouse fibroblasts (3T3-L1) | Tunable pore size and morphology Enabled precise control over the conformation of adsorbed proteins (e.g., fibronectin) Electroactive cell adhesion and proangiogenic capability |
58 |
| Hybrid electrospun nanofibrous scaffold | Albumin–AuNRs | Electrospinning, irradiation with IR laser | NA | Neonatal rat left ventricular derived CMs | Suture-free cardiac patch with a high ability to integrate to the native organ AuNRs absorbs the IR light and converts to energy, which provides attachment to the heart Reduce the risk of injury to the myocardium |
36 |
| Hybrid/composite patches | PGS–collagen type I-PPy | Evaporation method | Four-point probe electrical station | H9c2 cardiomyoblast rat cells | High viability of CMs after 1 month seeding on cardiac patches Incorporation of a small molecule (3i-1000) in cardiac patches induced CM proliferation High blood wettability and drug release PGS/Col/5%PPy showed significantly higher conductivity of 0.06 ± 0.14 S/cm |
59 |
| Hybrid polymeric scaffolds | CNTs–PEGDM–124 polymer | Dispersion, molding, UV crosslinking | Ionic conductivity meter | Neonatal rat ventricular CMs | Conductive polyester–CNT scaffolds presented greater tissue maturity 124 polymer–CNT scaffolds demonstrated improved excitation threshold in materials with 0.5% CNT content (3.6 ± 0.8 V/cm) compared with materials with 0% (5.1 ± 0.8 V/cm) and 0.1% (5.0 ± 0.7 V/cm) CNT–porogen mixture had ionic conductivity of 0.08 ± 0.01 mS/m, compared with 0.06 ± 0.01 mS/m for porogen without CNTs and 0.06 ± 0.01 mS/m for DI water |
60 |
| 3D hybrid composite scaffolds (NFYs–NET within a hydrogel shell) | PCL, SF, and CNTs, and GelMA | Weaving technique for fabrication of NFYs–NET, and encapsulation of NFYs–NET layer in GelMA following by crosslinking | Van Der Pauw DC four-probe method | Coculture of CMs (from neonatal rat) and endothelial cells | Mimicking the anisotropic cardiac structure and controlling the cellular alignment and elongation Enhanced CM's maturation in a 3D environment as well as suitable endothelialization The conductivities of these NFYs–NET samples ranging from 6.5 × 10−5 to 8.1 × 10−5 S/m |
61 |
| Thin film (patch)/substrate | Single-walled CNTs/collagen substrates | Assembly of IDs through disposition technique | HP 34401A multimeter, and two-probed electrical station | NRVMs | Enhanced CM's adhesion and maturation Addition of CNTs remarkably increased ID-related protein expression and enhanced ID assembly and CNTs remarkably accelerated gap junction formation functionality CNTs enhanced ID assembly Col–CNT (0.1 mg/mL) showed significantly greater conductivity of (1.72 ± 0.31) × 10−9 S compared with the conductivity of pristine collagen as (4.73 ± 0.25) × 10−12 S Conductivity significantly depends on CNT concentration, (1.9 ± 0.1) × 10−11 S for Col–CNT (0.05 mg/mL), while (1.77 ± 0.25) × 10−6 S for Col–CNT (0.2 mg/mL) |
62 |
| Films | PPy–chondroitin sulfate–dodecylbenzene sulfonic–sodium paratoluene–sulfonate | Electrochemical polymerization-doping | Cyclic voltammetry with a potentiostat | CPCs isolated from adult mice hearts | Controlling the surface properties of conductive PPy polymers can greatly influence the viability of CPCs All different dopants demonstrated similar C-V profiles, which showed a capacitive response that is typical for PPy films |
63 |
| 3D printed scaffold | PCL-CNTs | Mixing, sonication, and then 3D printing | Four probe method low Resistivity Meter | H9c2 rat cardiomyoblasts | 1% CNT showed the optimal conductivity and stiffness for the proliferation of H9c2 cells PCL-CNTs are enzymatically biodegradable after cardiac tissue formation Conductivity of PCL-CNTs increased with increasing CNT content, 1.2 × 10−6 S/cm for PCL-5% CNTs (w/w) compared with pure PCL, which is less than 10−15 S/cm |
64 |
| 3D painted hydrogel scaffold | PPy–dopamine–PEGDA–Gelatin | 3D painting | Four-point probe electrical station EIS |
L929 mouse fibroblasts, and BMSCs | HPAE/PPy conductive and adhesive hydrogel can be 3D painted and rapidly bondable onto the surface of the injured heart without adverse liquid leakage Reconstruction and revascularization of the infarcted myocardium was remarkably improved Conductivity of 9.16 ± 0.19 × 10−5 S/cm for HPAE–Py (50%)/Gelatin compared with 8.04 ± 0.28 × 10−6 S/cm for Gelatin |
28 |
| Cryogel | Ppy NPs–GelMA–PEG | Additive component method, then mixing, and finally crosslinking through a muscle-inspired dopamine | Multifunctional digital four-probe tester | Neonatal rat ventricular CMs | Enhanced myocardium regeneration due to the dopamine crosslinker, which facilitates the homogeneous distribution of PPy in cryogel Excellent synchronous contraction by increasing the expression of α-actinin and CX-43 Elevated fractional shortening and ejection fraction, and reduction of infarct size |
44 |
| Injectable shape-memory scaffold | POMAC | Combination of soft-lithography and injection molding | A custom-made EIS workstation | Neonatal rat CMs | Successful minimally invasive delivery of human cell-derived patches to the epicardium of porcine heart was achieved (Fig. 2E) Full recovery of the shape following injection without affecting CM's viability and function |
47 |
124 polymer, poly octamethylene maleate (anhydride) 1,2,4-butanetricarboxylate; 3D, three-dimensional; AFM, atomic force microscopy; AP, aniline pentamer; AuNRs, gold nanorods; Bio-IL, bio-ionic liquid; BMSCs, bone marrow stromal cells; CDH, carbodihydrazide; CFs, cardiac fibroblasts; CMs, cardiomyocytes; CNTs, carbon nanotubes; CPCs, cardiac progenitor cells; CS-AT, chitosan-graft-aniline tetramer; cTnI, cardiac troponin I; Cx43, connexin43; DI, deionized; EIS, electrochemical impedance spectroscopy; e-SiNWs, electrically conductive silicon nanowires; GelMA, gelatin methacryloyl; GP, Genipin; hiPSC-CMs, human induced pluripotent stem cell-derived CMs; HPAE, hyper-branched polyamine-ester; IDs, intercalated discs; iPS-CMs, induced human pluripotent stem cell-derived CMs; IR, infrared; MWCNTs, multiwall carbon nanotubes; NFYs-NET, nanofiber yarns network; NPs, nanoparticles; NRVCMs, neonatal rat ventricular cardiomyocytes; NRVMs, neonatal rat ventricular myocytes; OECTs, organic electrochemical transistors; PANI, polyaniline; PCL, poly(ɛ-caprolactone); PEDOT:PSS, poly(3,4-ethylenedioxythiophene):polystyrenesulfonate; PEG, poly(ethylene glycol); PEG-DA, dibenzaldehyde terminated poly(ethylene glycol); PEGDA, poly(ethylene glycol) diacrylate; PEGDM, poly(ethylene glycol) dimethyl ether; PGS, poly(glycerol sebacate); PLGA, poly(lactic-co-glycolic acid); POMAC, poly(octamethylene maleate (anhydride) citrate); PPy, Polypyrrole; PVDF-TrFE, polyvinylidene fluoride-trifluoroethylene; rGO, reduced graphene oxide; SAC, sarcomeric α-actinin; SWCNTs, single-walled carbon nanotubes; UV, ultraviolet.