Carbon as a Biomaterial for Scaffold Development: Comparison
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A scaffold is a crucial biological substitute designed to aid the treatment of damaged tissue caused by trauma and disease. Various scaffolds are developed with different materials, known as biomaterials, and have shown to be a potential tool to facilitate in vitro cell growth, proliferation, and differentiation. Among the materials studied, carbon materials are potential biomaterials that can be used to develop scaffolds for cell growth. Many researchers have attempted to build a scaffold following the origin of the tissue cell by mimicking the pattern of their extracellular matrix (ECM). In addition, extensive studies were performed on the various parameters that could influence cell behaviour. Previous studies have shown that various factors should be considered in scaffold production, including the porosity, pore size, topography, mechanical properties, wettability, and electroconductivity, which are essential in facilitating cellular response on the scaffold. These interferential factors will help determine the appropriate architecture of the carbon-based scaffold, influencing stem cell (SC) response.

  • carbon-based
  • scaffold
  • biomaterial
  • biophysical factors
  • stem cells
  • tissue engineering

1. Carbon as Scaffold Biomaterials for SC Applications

Carbon exists naturally as allotropes with distinct physicochemical properties. It is among one of the most abundant elements in the universe and is widely distributed in nature. Additionally, the human body is composed of carbon elements, where carbon is the second most abundant element after oxygen. Thus, carbon materials have become a more desirable choice in the applications of various research areas, including microscience and nanoscience, engineering, technology, material sciences, and even biomedical applications [1][2]. Current carbon materials include graphene [3], graphite [4], carbon nanotube (CNT) [5], diamond [6], fullerene [7], amorphous carbon [8], and glassy carbon [9]. Various carbon allotropes have been investigated concerning their viability as a scaffold for SCs, other biological cell applications are shown in Table 1.
Table 1. Carbon materials application in SCs and other biological cells research.
Types of Carbon Dimensions Composite

Material		 Fabrication Methods Types of Cells Ref.
Carbon Nanocage 3D nanoscale - - HUC-MSCs [10]
Fullerene Aligned fullerene nanowhisker nanopatterned - Langmuir–Blodgett Human MSCs [11]
Aligned fullerene nanowhiskers - Modified liquid–liquid interfacial precipitation method NSCs [12]
Graphene rGONRs grids polydimethylsiloxane (PDMS) Drop casting method Human MSCs [13]
2D graphene (GNOs, GONRs, GONPs) distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)] (DSPE-PEG) GONRs synthesis by using modified longitudinal unzipping method; GONPs synthesis by using modified Hummer’s method AMSCs, BMSCs [14]
3D matrix Polycaprolactone (PCL) Extrusion-based additive manufacturing AMSCs [3]
3D foams and 2D films - chemical vapor deposition (CVD) NSCs [15]
Fibres Poly-L-lactic-acid (PLLA) Thermal-induced phase separation BMSCs [16]
Nanosheets PCL Water-assisted liquid phase exfoliation AMSCs [17]
3D graphene oxide Polypeptide thermogel Temperature-sensitive sol to gel transition Tonsil-derived MSCs [18]
3D graphene Nickel foam CVD Mouse NSCs [19]
3D Graphene/SWCNT - CVD Mouse MSCs [20]
Carbon Nanotube COOH-SWCNT and -MWCNT, PEG-SWCNT Ethanol, polyethylene Glycol (PEG) Air brush spraying on a coverslip Canine MSCs [5]
CNT fibres PLLA Thermal-induced phase separation BMSCs [16]
CNT PCL CVD AMSCs [17]
MWCNT PCL Electrospinning Human Dental Pulp Stem Cell [21]
MWCNT Thermoplastic polyurethane Electrospinning Rat AMSCs [22]
MWCNT PLLA Electrospinning Mouse ESCs [23]
MWCNT Collagen hydrogel Gelation Rat MSCs [24]
MWCNT Polyion complex hydrogel Extrusion-based 3D printing Rat BMSCs [25]
MWCNT PEG Drop-drying method Human MSCs [26]
MWCNT Poly-lactic acid (PLA), alginate, gelatine Layer-by-layer assembly method Wharton’s Jelly-derived mesenchymal stem cells (WJMSCs) [27]
Nanodiamond Monolayer - Ultrasonication Human NSCs [28]
Reticulated vitreous carbon 3D Foam - Etching and Pyrolysis BMSCs [29]
Carbon Nano-onions Poly 4-mercaptophenyl methacrylate-carbon nano-onions PCL Probe sonication, hydraulic pressing Human osteoblast cells [30]
Oxidized CNOs Chitosan, poly(vinyl-alcohol) Cure on acetate molds In vivo study on Wistar rat [31]
Poly 4-mercaptophenyl methacrylate-carbon nano-onions Bovine serum albumin, trifluoroacetic acid Force spinning Human fibroblast cells [32]
Poly 4-mercaptophenyl methacrylate-carbon nano-onions Gelatin Probe sonication, freeze drying Human osteoblast cells [33]
Carbon black nanoparticle Nanoparticles - Probe sonication In vivo study on mouse brains astrocyte [34]
Carbon dots Citric acid-derived nanodots - Hydrothermal Rat BMSCs [35]
Porphyra polysaccharide-derived carbon dots - Hydrothermal Ectodermal MSCs [36]
Cellulose-derived reduced nanographene oxide carbon nanodots PCL Microwave MG63 [37]
Onion-derived carbon nanodots - Microwave Human foreskin fibroblast, MG63, red blood cells [38]
Human fingernail-derived carbon nanodots - Pyrolysis HEK-293 [39]
Food-derived carbon nanodots Glass beads Hydrothermal Prostate cancer (PC3) cells, NRK cells [40]
Carbon, as a scaffold material for SC application, has shown promising results. However, the fabrication of a suitable external ECM as a scaffold for the cells to grow and differentiate, is still a significant challenge. The optimal architecture and properties of the scaffold, that can enhance SC survivability and differentiation into the desired functional cells, is still lacking [41]. Hence, besides biocompatibility factors, the ideal parameters for creating the scaffold, that mimic the natural ECM of SCs, are also important. Scaffolds mimicking the natural tissue ECM for SC culture may provide a more closely resembling microenvironment, similar to that of the human body, providing a better understanding of cellular response and development [42]. Therefore, the fabrication of the in vitro cell microenvironment, as in the living organism, will give a more predictive in vivo system. Hence, suitable materials, designs, and fabrication methods of microstructures for specific SCs applications, has become essential. A schematic illustration of carbon material application is presented in Figure 1.
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Figure 1. Schematic illustration of carbon material application.

2. Carbon Precursors as Scaffold Biomaterials for SCs Applications

The use of carbon precursors as an alternative to carbon has shown more advantages and has received much attention in the production of carbon-based microstructures. In the last few years, the fabrication of carbon precursors, in various studies due to their manufacturing flexibility and customizable properties, has been employed [43]. Carbon precursor materials can be converted into high-percentage carbon materials when subjected to high temperatures or chemicals. The tuneability properties of carbon precursors have allowed the production of different patterns (i.e., organised or random alignment) that mimic the microenvironment niche of cells by using a simple method with good reproducibility and low cost. Plus, carbon precursors can be tailored to produce conductive carbon-based scaffolds through modifications to their chemical composition and pyrolysis process (Table 2). Every scaffold should exhibit mechanically and biologically suitable qualities, mimicking the ECM of SCs to support the adhesion and development of cells, something which carbon precursors can provide [44][52].

Table 2.

Carbon precursor in biological applications.

Type of Precursor

Fabrication Method

Structure

Application

Ref.

Citric acid

Hydrothermal

Carbon nanodots

Rat BMSCs

[45]

Porphyra polysaccharide

Hydrothermal

Carbon nanodots

Ectodermal MSCs

[46]

Polyacrylonitrile

(PAN)

Electrospun, pyrolysis

Electrospun carbon nanofibres

Mouse NSCs culture

[47]

Electrospun, pyrolysis

Electrospun carbon nanofibres

Human endometrial stem cells (hEnSCs)

[48]

Cryogel (chitosan/agarose/gelatin)

Pyrolysis

3D carbon-based scaffold

NSCs

[49]

Sucrose

Sugar blowing technique, Pyrolysis

3D glassy carbon

SH-SY5Y, HEK-293

[50]

Polydopamine

Electrospun, pyrolysis

Microfibre scaffold

NSCs

[51]

SU-8

Photolithography, pyrolysis

3D carbon-based scaffold

Human NSCs, PC12

[52]

photolithography, Pyrolysis

Gold nanoparticles glassy carbon

Primary dermal

fibroblast

[53]

Zif-8

Pyrolysis

C-ZnO nanoparticles

MSCs

[54]

Cotton

Pyrolysis

Pyrolysed cotton microfibres

PC12

[55]

Epoxy resin

Stereolithography, pyrolysis

Carbon microlattices

MC3E3-E1

[56]

3. Application of Carbon-Based Scaffold in Tissue Engineering

The biocompatibility of carbon-based scaffolds with a variety of stem cells, including other biological cells, were positively significant. Numerous studies have also reported the potential of the carbon-based scaffolds in supporting and/or directing stem cells to differentiate into a variety of cell lineages.

3.1. Neural Tissue

Carbon-based scaffold in neural tissue engineering applications has shown significant potential in numerous studies. As such, Shin et al. has developed a scaffold incorporated with CNTs for neural tissue regeneration. They reported that the addition of CNTs improved the scaffold’s mechanical properties, swelling ability, and degradation rate. The scaffolds also enhanced the neuronal differentiation of human foetal neural stem cells (hfNSCs) and hiPSC-NPCs. However, an increase in CNT concentration led to significant cytotoxicity. Therefore, low CNT concentration is preferable to reduce the cytotoxicity effect and ensure cell viability [57].
Similarly, Hasanzadeh et al. developed a scaffold containing MWCNT for neural tissue engineering. The incorporation of MWCNT improved the electrical conductivity and mechanical properties of the scaffold in addition to, enhanced cell adhesion, proliferation, and the viability of human endometrial stem cells (hEnSCs) [58].
Meanwhile, Lee et al. developed a 3D printed scaffold incorporating amine-functionalized multi-walled carbon nanotubes (MWCNT) for neural tissue engineering. They reported that the addition of MWCNTs provided good electrical conductivity properties and improved the elastic modulus of the scaffold. The scaffold also supports cell adhesion and growth, as well as promotes the neuronal differentiation of NSCs. Furthermore, the electrical stimulation of cells enhanced the cells’ viability and neural differentiation by upregulating the neural marker of TUJ1 and GFAP [59].
In contrast, Chen et al. developed a Porphyra polysaccharide-based CD via one-pot hydrothermal treatment for non-viral gene carrier and neural induction. The resulting CDs were able to condense macromolecular plasmid DNA (CDs/pDNA). The CDs/pDNA nanoparticles enhanced the neural differentiation of ectodermal MSCs better than CDs alone. They also reported that the cellular uptake of CDs/pDNA occurred in multiple pathways, including clathrin and caveolae-dependent endocytosis. The multiple pathways of CDs/pDNA cellular uptake may improve the transfection efficiency of CDs/pDNA, thus enhancing the neural differentiation of ectodermal MSCs [36].

3.2. Cardiac Tissue

Other than neural tissue application, the carbon-based scaffold also significantly influenced cardiac tissue regeneration. For instance, Mombini et al. developed an electrically conductive chitosan-PVA-CNT nanofibers scaffold by using the electrospun technique for cardiac tissue engineering application. They reported that the addition of CNT improved the electrical conductivity, mechanical properties, and chemical stability of the resulting scaffold. It also improved the adhesion, growth, and viability of MSCs, as well as enhanced cardiac differentiation of MSCs on the scaffold [60].
Meanwhile, Yan et al. (2020) developed scaffolds containing P-phenylenediamine surface functionalised carbon quantum dots (CQDs) from graphite rods. The addition of CQDs improved the compressive modulus and swelling properties of the scaffold. It also enhanced the metabolic activity and viability of rat cardiomyocytes. Plus, it upregulated the cardiac-marker gene [61].
Moreover, Martinelli et al. developed a3D carbon nanotube composites scaffold by incorporating MWCNTs into the scaffold. They reported that the scaffold improved the neonatal rat ventricular cardiomyocytes (NRVM) viability, proliferation, and maturation to cardiac myocytes, while subduing the proliferation of cardiac fibroblast [62].

3.3. Bone Tissue

Interestingly, the carbon-based scaffold was able to support and promote bone tissue regeneration. For instance, Tohidlou et al. developed a scaffold incorporated with amine-functionalised single-walled carbon nanotube (aSWCNT) for bone tissue engineering. They reported that the addition of aSWCNT improved the scaffold’s tensile strength, electrical conductivity, bioactivity, and degradation rate. Furthermore, it also enhanced the attachment, proliferation, and differentiation of rat BMSCs [63].
In contrast, Nie et al. developed a 3D scaffold containing reduced graphene oxide (RGO) for bone tissue engineering. They reported that the scaffold with RGO improved the in vitro rat BMSCs adhesion, proliferation, and osteogenic differentiation. Additionally, in vivo study showed that the scaffold positively promoted the healing of circular calvarial defects in rabbits in 6 weeks with enhanced collagen deposition, cell proliferation, and mineralisation of new bone formation [64].
Meanwhile, Shafiei et al. (2019) developed a scaffold incorporated with carbon dots (CDs) by electrospun techniques. They reported that the synergetic effect of CDs and calcium phosphate on the scaffold enhanced the metabolic activity and proliferation of human buccal fat pad-derived stem cells (hBFPSCs). It also promoted a higher osteogenic differentiation and proliferation rate of hBFPSCs [65].
In addition, Amiryaghoubi et al. developed an injectable thermosensitive scaffold containing graphene oxide for bone tissue engineering. They reported that the addition of graphene oxide improved the scaffold’s mechanical properties, swelling abilities, and degradation rate. Additionally, the scaffold was haemocompatible and promoted the growth and viability of human dental pulp stem cells (hDPSCs). This also supports and enhances the osteogenic differentiation of hDPSCs [66].
Moreover, Dai et al. developed a 3D chitosan/honeycomb porous carbon/hydroxyapatite (CS/HPC/nHA) for bone tissue engineering (Figure 19). They showed that the addition of HPC improved the swelling abilities and mechanical properties of the scaffold. The resulting scaffold also promotes the growth, proliferation, viability, and osteogenic differentiation of mouse BMSCs. Meanwhile, the in vivo study of the scaffold has significantly promoted bone regeneration on distal femoral condyle defects of the rabbit model [67].
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Figure 19. Example of carbon biomaterials effect on scaffold characteristics and BMSCs behaviours. (1) SEM images of (A,D) CS scaffold, (B,E) CS/nHA scaffold, and (C,F) CS/HPC/nHA scaffold, respectively; SEM images of (G) CS scaffold, (H) CS/nHA scaffold, (I) CS/HPC/nHA scaffold after 4 days immersion in simulated body fluid. (2) Scaffold characterisation: (A) Porosity, (B) uptake-water capacity, (C) elastic modulus, (D) typical stress–strain curves of the different scaffolds. (3) (A) CT images of the cross-section, coronal, sagittal, and three-dimensional reconstruction of the distal femoral defect area of the rabbit femur after 4 weeks of implantation of three different scaffolds. (B) 12 weeks postoperatively. (C) Morphometric analysis of the percentage of newly formed bone mass (BV/TV) at 4 and 12 weeks postoperatively. (D) Intraoperative photograph of the distal femoral condyle of the rabbit. (4) (A) Percentage of new bone area in the defects; (B) the cross-sectional morphology of the distal femoral defect area of the femur; tissue brace of the distal femoral defect area of the rabbit femur implanted with (C) CS, (D) CS/nHA and (E) CS/HPC/nHA scaffolds, (* p < 0.05, ** p < 0.03, *** p < 0.01). Reproduced with permission from Ref. [67]; Copyright 2020, America Chemical Society.

3.4. Others Tissue

The carbon-based scaffold’s ability to promote stem cell differentiation has motivated another researcher to instigate the ability of the carbon-based scaffold in another area of tissue engineering application. For instance, Tondnevis et al. has developed a scaffold incorporated with SWCNT for dental tissue engineering. They reported that the presence of SWCNT in the scaffold production by electrospun techniques caused bead formation. Also, the incorporation of SWCNT in the scaffold affects the drug’s release rate, allowing the prolonged and continuous release of the drug during regeneration. Moreover, it improved the hDPSC’s adhesion and proliferation on the scaffold [68].
Meanwhile, Gopinathan et al. developed a freeze-dried scaffold incorporated with carbon nanofiber (CNF) for meniscal tissue engineering. The addition of CNF improved the mechanical properties of the scaffold. In vitro study of the scaffold containing CNF also promotes cells adhesion, proliferation, and viability. Meanwhile, the scaffold biotoxicity study on rabbits showed that the scaffold was non-toxic [69]. However, Stocco et al. reported that their scaffold reinforced with CNT improved the mechanical properties, but it does not influence MSC survival [70].
Aspiringly, Yang et al. developed a scaffold incorporated with CNTs for retinal tissue regeneration. They reported that the addition of CNTs improved the scaffold degradation rate and electrical conductivity properties by 16.46%. Furthermore, the increased CNT concentrations, up to 50 µg/mL, do not affect the survivability of the cells. Moreover, in vitro study on the CNT scaffold showed enhanced cell adhesion and migration. It also supported BV2 cells and retinal ganglion cells (RGCs). Plus, the scaffold promoted hiPSCs differentiation into retinal ganglion cells [71].

4. Conclusions and Future Perspective

The interaction between SCs and their environment is quite well-evidenced; however, the extent to which this interaction controls the fate of SCs is still unclear. Moreover, the microenvironment niche and components in SC niches vary for each type of SC [72][73]. Plus, achieving a similar effect of cells in vivo remains a challenge in SCs studies. Furthermore, it is crucial to develop culture conditions that will promote the homogenous and enhanced differentiation ability of SCs into functional and desired tissues. Therefore, understanding the SCs characteristics and regulatory mechanisms is vital in creating a suitable microenvironment niche for SCs. This approach is also essential for SC efficacy and safety in clinical application. Furthermore, the scaffold design plays the most critical role in SC applications, as it regulates the behaviour of SCs, leading to cell lineage differentiation.
However, the development of scaffolds, which mimic the ECM of the SC natural microenvironment niche, is not a simple task. Many parameters should be accounted for when producing a suitable scaffold. These include biophysical and biochemical signals, the extracellular microenvironment, and proper guidance of SC behaviours which are crucial factors that require consideration to achieve a thriving SC culture on the carbon-based scaffold. Thus, patternable and suitable biomaterials should be selected accordingly. The carbon material provides patternable materials (i.e., carbon precursors such as a polymer). Also, carbon materials possess excellent chemical inertness, electroconductivity, mechanical strength, and swelling resistivity. However, carbon still has its limitations that can affect SC response. Thus, further investigation may enhance carbon-based scaffolds as biomaterials for SC application.
Regarding this, technological advancement, such as additive manufacturing methods enabling the fabrication of a complex scaffolds with precise structural designs, is required. Additive manufacturing allows a 3D printing application on a wide range of biomaterials. This method may also allow the fabrication of a scaffold similar to the ECM of SCs, and other biological cells, as it provides a controllable structure production. Currently, various biomaterials, including natural and synthetic polymers, have been investigated as ink for 3D printing and the resulting products are biocompatible to a wide range of cells. Unfortunately, even though manufacturing scaffold with additive manufacturing method is advantageous, the cost of the device and setup remain a challenge. Plus, modification is needed on the natural polymer for it to be suitable as ink for 3D printing. Therefore, additive manufacturing may not be easily accessible due to the cost of the device and materials required to investigate the optimal ink for them to be 3D printable. However, the growing interest in additive manufacturing is increasing due to its potential for modulating the SCs microenvironment and enhancing its development. Hence, the existence of additive manufacturing allows the possibility to develop the most optimal microenvironment specifics to SCs.

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