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76 Carbon-Based Nanocarriers for Drug Delivery
π-electrons. The non-covalent interactionsare crucial for comprehendingbiomolecular structures, molecular clusters, supramolecular assembly, ionophores,and nanomaterial engineering [3,74]. Since pure graphene nanosheets are hydrophobic and
cannot disperse in polar liquids, conversely, graphene nanosheets may be functionalized to make them dispersible and perhaps soluble in an aqueous medium and organic
solvent [89]. As it is vital to prevent stacking, thenon-covalent functionalization
with organic molecules via π-interactionswould be greatly desired, as demonstrated
by water-soluble fullerenes [90]. In this context, developing new nanomaterials for
designing unique nanodevices depends on the antagonism and collaboration among
individual interactions. Congurations and molecular characteristics of the nanosystems may change signicantly as a result of even slight variations in the electronic
structure of π-electron molecular structures. The non-covalent interactions mainly
comprise π–π, and electrostatic interactions, in addition to hydrogen bonding and
van der Waals interactions.
An understanding of the aromatic complexes is greatly aided by the noncovalent π–π interactions. There are two notably distinct scenarios with these
systems. In the rst scenario, the electron density congurations of the two aromatic moieties are extremely close or identical. Negative and strongly delocalized
π-electron clouds distinguish aromatic systems. Chemical understanding dictates that
such molecular structures should interact adversely. Nonetheless, since the proportion
of electrostatic energy is much inferior to that of dispersion energy, π–π- interactions
are still not governed via electrostatic interaction yet rather by dispersion forces.
To develop novel nanostructures and nanomaterials, a comprehensive investigation
of the energy constituents in π–πinteractions is benecial. Until the H-π interaction
is signicant, aromatic compounds interact with graphene through the π–π interaction [91]. The bonding among graphene and the immobilized molecule is frequently strengthened by the electrostatic interactions induced by charge transfer.
Charge transport is also responsible for shifting the Dirac cone and doping graphene.
Nucleobases on graphene have gained signicant interest due to their potential usage
in DNA sequencing [3,92]. The non-covalent interaction of graphene with aromatic
molecules, polymers, and biomolecules is discussed subsequently.
3.3.2.1 Aromatic molecules
The aromaticity provided by the π-conjugation of graphene made it signicant for
the non-covalent functionalization of graphene through aromatic molecules. These
molecules subsequently position themselves all along graphene’s basal surface and
engage in interactions via π–πstacking. The signicant afnity of pyrene for graphite’s basal plane might be used to improve the properties of a graphite surface. As a
consequence, several research teams have begun to investigate the complexation of
graphene utilizing pyrene derivatives [93,94]. In addition to numerous other characteristics, these functionalizations have yielded graphene that is water-soluble [3,95],
with improvedsolar cell power transmission [96], and also doped with n/p types [97].
It is possible to make graphene/reduced graphene oxide (rGO) water soluble
[74,98]. This aqueousstability can beachieved by sonicating graphite/or rGO in the
vicinity of the pyrene stabilizer. It is interesting to note that even when destabilized
by extremely low pH levels or freeze drying, these kinds of materials have been
demonstrated not to agglomerate [99]. This action is supposed to be induced by the
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residual pyrene stabilizer groups on the surface, thereby preventing the material from
aggregating.
Utilizing aromatic macrocycles like phthalocyanines and porphyrins, graphene
may also be functionalized through non-covalent interactions [3,100]. Noncovalently functionalizing with water-soluble porphyrins makes it possible to provide
desired water solubility to graphene. Using a vacuum ltering procedure coupled
with thermal annealing, those solutions are then employed to generate extremely
conductive and transparent graphene sheets. Through functionalizing graphene
sheets with porphyrin or phthalocyanine, it is possible to develop light-harvesting
sheets that may be utilized to analyze a variety of proteins [101]. The synthesis of a
hemin-graphene hybrid composite viaπ–π interactions may be accomplished with
a conventional wet-chemical method [102]. This novel nanomaterial was employed
to distinguish between single-stranded (ss) and double-stranded (ds) DNA due to its
peroxidase-like activity, good solubility, as well asstability in aqueous media. Based
on this understanding, an assay for precise visual assessment of single-nucleotide
polymorphisms at room temperature was designed. It was estimated that once the
hemin-graphene compound was complexed with streptavidin and paired with a biotinylated molecular beacon, DNA could be electrochemically detected at the molar
level [74]. Ahighly precise and selective electrochemical detector for dopamine was
developed using an analogous wet-chemistry method [103]. The ascorbic acid and
uric acid inhibition typically accompanied with dopamine detection could not be
recognized using a glassy carbon electrode covered with the graphene/meso-tetra
(4-carboxyphenyl) porphyrin composite. This is supposed to result from preferred
π–πinteractions between negatively charged porphyrin and positively charged dopamine. The non-covalent coupling of meso-tetrakis(4-methoxyl-3-sulfonate phenyl)
porphyrin with graphene resulted in a robust and efcient label-free adenosine triphosphate sensing platform [104]. With a limit of detection of 0.7 nM for photosensitizers, this substance might be utilized to distinguish among adenosine triphosphate
and cytidine/guanosine/uridine triphosphate nucleosides [100].
3.3.2.2 Polymers
Graphene may be functionalized with polymers through non-covalent interactionsto
provide materials for electronics, biomedical,green chemistry, capacitors,and other
applications. Due to the π–πinteractionsbetween the aromatic framework of sulfonated polyaniline and the graphene basal plane, it was possible to make graphene water
stable by utilizing these substances[105]. These substances also demonstrated signicant electrocatalytic activity, conductance, and stability. Apolystyrene/graphene
nanocomposite may be developed by in situ stripping of graphite nanoplates in the
vicinity of a polystyrene solution [106]. Due to the equal distribution of graphene
throughout the matrix, the resulting composites were demonstrated to be conductive; surprisingly, the polystyrene segments prevented the graphene nanoplates from
aggregation due to signicant π–πinteractions.
These signicant non-covalent interactions among both the graphene carboxylic as
well as the polyimide substrate prevent emulsication throughout thermal imidization,
resulting in a clear polyimide/graphene polymer composite with superior mechanical
strength [107]. It is considered that the 2D conguration of the graphene nanosheets
transverse to the polyimide lms and the uniform distribution of graphene all across
78 Carbon-Based Nanocarriers for Drug Delivery
the polymer matrices are the sources of the specimens’ improved mechanical resilience. The inclusion of graphene increased the shape memory of the polyimide/
graphene composite well beyond theglass transition temperature (GT)(250 °C). It is
possible to developpH-dependent soluble composites such asrGO/chitosan through
the reduction ofGOwith anatural polymer,chitosan [108]. This substance exhibited
pH-dependent solubility in water, which is likely to be mediated by electrostatic interaction and h-bonding between functional entities of chitosan and graphene. It was
demonstrated in a subsequent investigation that this compound might function as a pH
sensor due to its reversible pH switching across dispersion and agglomeration [109].
Similar methods exist for stabilizing graphene in the aqueous phase, including the use
of biopolymers likecellulose and lignin compounds [110].
Through the straightforward process of sonication of the substrates, a thermoresponsive graphene/poly-(N-isopropyl acrylamide) composite can be developed.
The compound was demonstrated to have a reduced critical solution temperature of
24 oC, under which it would be distributed in an aqueous system. Graphene was successfullydispersed in water using the π–πstacking phenomenon that occurred among
poly-(2,5-bis(3-sulfonatopropoxy)-1,4-ethynyl-phenylene-alt-1,4-ethynyl phenylene)
sodium salt (PPE-SO3Na+) and graphene [111]. The (PPE-SO3) sodium salt offers the
substance with extra negative charges, which presents a unique technique to functionalize the graphene-based substance effectively. Utilizing poly oxy-ethylene sorbitan laurate, graphene may be stabilized in an aqueous system [112]. This approach
allowed for the synthesis of a lm that demonstrated resilience in water and biocompatibility to mammalian cell lines, making it suitable for use in biological applications such as tissue engineering,whereinexcellent mechanical strength is required.
It is also conceivable to develop amphiphilic graphene compounds parallel to
the water-soluble varieties. The rGO can be made soluble in a wide range of polar
and nonpolar organic media by functionalizing it with polyethylene glycol (PEG)
andpolyethylene oxide (OPE) triblock copolymer. By functionalizing graphene with
ionic liquid molecules, it is possible to induce phase transition between immiscible
liquids [113].
3.3.2.3 Biomolecules
Graphene nanostructure can eventually be functionalized non-covalently with the
biomolecules like peptides, enzymes, and nucleic acids for their application in
drug and gene delivery. Liu etal. (2010) demonstrated the non-covalent functionalization of graphene through thiolated DNA (Figure 3.7). The gold NPsthat are
subsequently attached to such water-soluble DNA/graphene combination may enable
the application of these compounds in systems for bio-detection, catalysis, and eld
effects [114]. Graphene oxide/DNA material may be employed through a selfassembly procedure to produce a 3D hydrogel [115]. The process of self- assembly is
initiated by putting the material in solution at90 °C, which causes the DNA segments
to unfold and enable a connection of distinct GOsheets as ss-DNA. This substance
was demonstrated to have a high dye-adsorption capacity, self-healing properties
after heating, chemical stability, and strong mechanical properties. Additionally,
< 2 nm Pt nanostructures have been uniformly grown on the graphene surface
under the direct inuence of DNA-functionalized graphene [116]. In addition, this
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FIGURE 3.7 Non-covalent Functionalization of GO and rGO through Thiolated DNA and
Gold NPs. [Reproduced with permission from Liu et al. (2010)] [114].
approach provides an electrochemically active surface area that is multiple times
larger than that of Pt-graphene without DNA functionalization. It was discovered
that when this substance was used in the oxygen reduction reaction (ORR), it displayed greater ORR half-wave current and potentialascompared to the Pt-graphene
and standard Pt/C catalyst.
The non-covalent interactions among a graphene nanosheet and a lipids backbone make it simple to form a monolayer of phospholipids over it, forming a
distinctplanar mimic of the biological membranes. Through reactivating the uorescence of a uorescein-labeled phospholipid that has been incorporated into
the monolayer, a potential biosensor can be developed to monitorthe functioning
of the phospholipase D-enzyme. Enzymes may also be immobilized on graphene
covered with a lipid monolayer, and this kind of substance can potentially be
employed as abiosensor [74]. Encapsulated in the lipid/graphene framework, the
enzyme Microperoxidase-11 demonstrated exceptionalsensitivity and reproducibility for hydrogen peroxide detection with a limit of detection of 7.2 10–7 M.
The advantage of adopting these particular lipid/graphene compounds is that they
80 Carbon-Based Nanocarriers for Drug Delivery
are biocompatible, which results in the development of an ideal situation for the
immobilization of enzymes that are procient in preserving their structure and
bioavailability. Additionally, enzymes may directly functionalize graphene monolayers. Lu etal. (2012) demonstrated in their investigation that pH-dependentand
water-solublegraphene could be obtained through the non-covalent functionalization of rGO with β-lactoglobulin. Surprisingly, the connected β-lactoglobulin
not only provides anchoring sulfhydryl groups that may be utilized to hold gold
NPs but also aids in the reduction of GO. Furthermore, it was demonstrated that
the Au-functionalized-lactoglobulin/graphene compound exhibited a surfaceenhanced Raman spectroscopic effect [117].
Additionally, agraphene surface was functionalized by the anticoagulant heparin, making the compound more biocompatible and water-soluble. Compared to pure
herapin, which utilized 85.6 IU mL-1 of anticoagulant anti-factor Xa activity, the
herapin/graphene composite consumed just 29.6 IU mL-1. Given that the herapin can
maintain its reactivity even after being functionalized to graphene, this is encouraging for biological applications. Herapin is a reducing agent that may be used to
functionalize graphene by reducing the substratescomposed of GO[118].
3.4 APPLICATION OF GRAPHENE IN DRUG DELIVERY
The signicant advancements in the eld of nanotechnology have driven the recent
advancements for its application in numerous biomedical applications. Nanomaterials, with their distinct characteristics like a smaller size, higher reactivity,
larger surface area, and controllable surface chemistry, have provided signicant advantages for their application incancer diagnosisand therapeutics as well
as in DDS and tissue engineering. The application of nanomaterial-based DDS
potentiallyleads to 1.extended systemic circulation [119], 2. regulated administration of chemotherapy drugs to the target cells/tissue, and, therefore, 3. enhanced
pharmacokinetic and pharmacodynamic proles [120]. Nanoscale-targeted DDSs
have the potential to concentrate in the tumor microenvironment using a
“ passive-targeting” mechanism based on the enhanced permeability and retention
(EPR) effect and to target cancerous cells using an “active-targeting” approach
that involves expressing oncomarkers [121]. Furthermore, smart stimuli- responsive
nanocarriers could react to physicochemical and biological disturbances in the
tumor microenvironment, such as low pH, elevated temp, reduced oxygen level,
and highly expressed proteases [122].
In addition to other nanomaterials, graphene-based nanocarriers have received
prodigious attention in the DDS eld since they are known to be excellent drug
carriers for a plethora of drugs, such as chemotherapeutic agents, genes, and small
interfering RNAs (siRNAs) [123]. The unique physicochemical features of graphene
and its oxidized derivative, GO, have been extensively employed for numerous biomedical applications (Figure 3.8) [124]. Graphene derivatives like GO and rGO
have been widely employed as effective photosensitizing agents in photodynamic
(PDT)and photothermal (PTT)treatment due to inherent optical absorption in the
NIR range. The applications of graphene-based nanocarriers in drug delivery for
cancer therapeutics and tissue engineering are presented subsequently.
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FIGURE 3.8 Biomedical Applications of Graphene-Based Nanomaterials. [Reprinted with
permission from Shin et al. (2016)] [124].
3.4.1 chemoTherapy
Graphene, with its high degree of hydrophobicity and absence of an oxygencontaining functional group,exhibits poor aqueous stability and dispersion. However, it provides suitable functionalization ability through covalent and non-covalent
interactions for improving its physicochemical characteristics. As a result, GO can
be readily synthesized using graphene functionalization, a covalent functionalization technique wherein theoxygenated groups such as epoxy, hydroxyl,and carboxyl
can beimpregnated on the edges and basal planes of the graphene nanosheetsto
augment its water solubility [125,126]. However, GO has the propensity to agglomeratein physiological solutions in the vicinity of salts and proteins due to electrostatic charge shielding and the establishment of nonspecic interaction with proteins
[127]. Furthermore, two major techniques, comprising covalent and non-covalent
alterations by various modiers, have been used to improve the physiological stability, cellular absorption, and transfection effectiveness ofgraphene-based nanocarriers [128]. Covalent functionalizationtechniques were employed when the modied
graphene must have stability and superior mechanical characteristics, whereas
non-covalent functionalization is favored when the graphene’s dielectric properties
and wide surface area are required. Both techniques of modication can provide
higher drug loading capacity andDNA/RNA condensation,making them favorable
for drug delivery andintracellular gene delivery applications [17]. The aqueous stability of graphene-based nanocarriers also leads to biocompatibility-related issues
for their application in DDS. It was observed that the conjugation and modication
82 Carbon-Based Nanocarriers for Drug Delivery
with the protecting polymers might improve their biocompatibility as well as circulation time in the bloodstream [129].
In recent times, several investigations have been conducted on the aptitude of
graphene-based nanocarriersfor the delivery of anticancer agents and genes. The
discoveries have established graphene as a prospective drug delivery vehicle, largely
because of its signicant surface area, tiny size, electrostatic or hydrophobic interaction, andπ-π stacking. As an illustration, it has been effectively employed to load
hydrophobic drugs like doxorubicin (DOX) and docetaxel with a targeting ligand for
the selective eradication of cancer cells [130–132]. The graphene-based nanocarriers
were successfully employed for the chemotherapy application by delivering conventional chemotherapeutic drugs such as DOX [133] and Paclitaxel (PTX) [134] and
natural chemotherapeutic agents like gallic acid (GA) [135], caffeic acid (CA) [136],
and chlorogenic acid [137]. Quagliarini etal. (2020) studied the anticancer mechanism of GO-DOX on MCF-7 and MDA-MB 231 (breast cancer cells) and compared
its performance with liposomal-doxorubicin (L-DOX), another commonly used drug
for breast cancer. They reported that the GO-DOX complex had higher efciency
than L-DOX. Encapsulating drugs with nanocarriers increases their bioavailability
and cellular uptake. GO provides higher cell internalization by binding with integrins at the plasma membrane of cells, which creates a pathway for conjugated drugs.
Thus, GO-DOX exhibits superior performance as it delivers DOX by attaching it
to the cell membrane and destroying the DNA [138]. Recently, Guo etal. (2021)
established a drug delivery system with PEG-modied and oxidized sodium alginate functionalized GO nanosheets to deliver PTX and treat gastric cancer. PTX@
GO-PEG-OSA was designed to overwhelm the drug resistance faced by PTX in gastric cancer cells due to P-glycoprotein (P-gp). When exposed to NIR radiations, the
PTX@GO-PEG-OSA NSs exhibit a photo-thermal effect that generates ROS, limits
mitochondrial respiratory chain complex enzyme activity, and diminishes ATP supplement to P-gp. Thus, this nanocarrier system provides better efciency than free
PTX [139].
Gu etal. (2018) reported that GA exerts an anticancer effect by inhibiting mitochondrial respiration in cancer cells [140]. Zhang (2019) studied the effect of GA on
NSCLC A549 cells with and without cisplatin, another chemotherapeutic. The ndings showed that GA controlled the proliferation and persuaded apoptosis of cancerous cells. Also, GA enhanced the effect of cisplatin [141]. Recently, Sontakke etal.
(2022) developed a novel GO nanoscrolls (GONS)-based nano delivery system for
the sustained release of GA. The nanoscrolls were fabricated via the low- frequency
ultrasonication method and further loaded with GA. The loading capacity for the
presented nanocarrier was ~30%. The GONS-GA nanocomposite demonstrated suitableanticancer efcacy against A549 lung cancer cells (IC50=60.7 µg/mL) [142].
Dorniani etal. (2016) loaded GA on GO nanocarriers. The application of the GO/GA
system was studied on normal broblast and liver cancer cells at different concentrations. It was conveyed that the complex hindered the growth of cancer cells and had
no side effects on normal cells [135].
Meanwhile, traditional drug delivery methods have some drawbacks, such as the
release of the drug before reaching the targeted site, low efciency, low drug retention, poor solubility in the physiological medium, and side effects on healthy cells
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[143]. The advantages of smart drug systems, as summarized by Shah etal. (2021),
are improved utilization of the drug and lowered administration frequency, drug protection from degradation, and reduced side effects [144]. The advances in nanotechnology have led to the advancement in nanocarrier-based targeted DDS. The DDSs,
which are target-specic, lead to the proper distribution of the drug in the patient’s
body as the nano-structures have the required size and display excellent drug loading and release behavior [144]. Graphene and graphene oxide (GO) have exceptional
physicochemical qualities, which have sparked interest in research for its biomedical applications. Meanwhile, the targetability of the GO-based nanocarriers can be
enhanced by its functionalization with the targeting ligands such as folic acid, aptamers, and lactoferrin. As the cancer cells are overexpressed to folate receptors, the
FA functionalized nanocarriers loaded drug conjugates accumulate over the tumor
cell, henceforth increasing their local concentration and enhancing the therapeutic
efciency in chemotherapy.
Fong etal. (2017) recently developed a folic acid (FA) conjugated GO nanocarrier
(GO-FA) for the targeted delivery of DOX. For intratumoral drug administration,
the drug-loaded nanocomposite (GO-FA-DOX) was encapsulated with the injectable and thermosensitive hyaluronic acid-chitosan-g-poly(N-isopropyl acrylamide)
(HACPN) hydrogel. The breakdown duration of HACPN hydrogel may be modulated, potentially resulting in a controlled distribution of DOX from the GO-FA
nanocarrier. Furthermore, biopsies of major organs and blood analysis indicated
no adverse effects of the medication, conrming its safety [145]. Pourjavadi etal.
(2020) designed a GO-based DDS for the loading and controlled release of both
hydrophobic and hydrophilic anticancer drugs [146]. The hydrophobic drug (curcumin) was loaded by π-π interaction and hydrophilic (DOX) by covalent bonding.
Also, GO was modied with oxygen-rich polymers to enhance its aqueous solubility. The system displayed pH-triggered release behavior, and dual-loading resulted
in better drug internalization. Zhou etal. (2014) developed nanocarriers based on
GO and polyelectrolytes that showed charge-reversal and pH-responsive behavior
[147]. The system could release the loaded DOX under an acidic environment. The
surface charge alternated when GO-Abs/PEI/PAH-Cit/DOX entered the cell resulting in the release of the drug, which reached the cytoplasm and then the nucleus of
cancer cells.
For developing the GO-based electrically controlled DDS, Weaver etal. (2014)
incorporated GO nanosheets into a conducting polymer. The poly(pyrrole) (PPy)/
GO composite was developed to deliver dexamethasone, and the system could be
simulated electrically [148]. The nanocomposite demonstrated a linear release prole that was stable for a large number of simulations. Wang etal. (2017) designed
a magnetically controlled drug delivery system, Fe
/GO nanocarriers, to deliver
3O4
5-uorouracil [149]. The composite had combined properties of GO and Fe3O4 and
could release the drug under externally applied magnetism. They also concluded
that the drug loading of Fe3O4/GO was higher than Fe3O4, and it had good dispersity in water. Recently, Liang etal. (2019) have employed a modied Hummers’s
method to synthesize targeted NCGO-FA nanocomplexes effectively. The carboxyl
functional groups of the nanoscale GO were activated to obtain NCGO prior to
its functionalization with FA. The resultant nanocomplex was further loaded with
84 Carbon-Based Nanocarriers for Drug Delivery
the photosensitizer MB dyes and anticancer agent DOX via non-covalent interactions to develop a dual responsive, namely, thermal and pH-responsive NCGO@
DOX-FA and NCGO@MB-FA nanoplatform for combined chemo-photothermal
therapy. The NCGO-FA nanocomplexes demonstrate outstanding photothermal
conversion efciency and photo-stability in addition to a signicant drug loading
capacity and dual-responsive drug release properties to temperature and pH. More
signicantly, compared to separately administered photothermal treatment or
chemotherapy, the photothermal-photodynamic or photothermal-chemo simultaneous therapies using the NCGO@DOX-FA or NCGO@MB-FA nanoplatform
demonstrated an exceptional synergistic impact, resulting in a distinct anticancer
efciency [150].
Imani et al. (2022) recently investigated the prospect of siRNA-based gene
delivery using a PEG/R8/FA multifunctionalized GO loaded via chloroquine (CQ).
By using physical and chemical step-by-step conjugation, the FA was effectively
attached to the GO-PEG-R8 (GPP) nanocarrier, and the efciency of FA encapsulation was improved. The rate of MCF-7 cellular internalization through receptormediated endocytosis was substantially increased by incorporating FA into the
R8/PEG-functionalized nanocarrier. Due to CQ’s lysosomotropic action, incorporating CQ at an optimum concentration of 10 μM throughπ-π interactions allowed the
GPPF nanocarrier to discharge from the lysosomal partition. Additionally, compared
to free CQ therapy, the pH-dependent release of CQ through nanocarriers (95.3%
at pH 4.5) was safer and more effective. In addition, the antimalarial drug CQ was
unanimously implemented as an anticancer agent. Itis a lysosomotropic substance
that predominantly deposits in lysosomal regions. As a result, it has frequently been
employed to improve the efciency of gene delivery. The presented study also delivers its signicance for combined gene-chemo therapy [151,152]. Similarly, Chen
etal. (2022) have designed a GO-PEI-DTX-anti-miRNA21-based DDS for combined
chemo-gene-photothermal therapy [153].
The fundamental problem in treating cancer, like other solid tumors, is the
development of drug resistance. One of the largest contributors to drug resistance
in cancer therapy continues to be the upregulation of multidrug transport machinery, although gene therapy may offer a promising strategy to combat inherent or
developed drug resistance. In this regard, certain genes like pro-apoptotic, carcinogenic transporter genes could be modulated by genetic materials (such as
oligonucleotide antisense, siRNA, etc.) [154,155]. It has been demonstrated that
functionalized graphene-based NSs may effectively transfer nucleic acids into cancer cells while also having the ability to impose PTT/PDT effects [156,157]. For
instance, Zeng et al. (2017) demonstrated FA-conjugated high molecular weight
branching PEI-modied PEGylated nanographene (PPG-FA) asa dual carrier for
the targeted administration of both siRNA and DOX to suppress the development
of efux transporter, P-glycoprotein (P-gp). The PPG-FA carrier was loaded with
DOX and siRNA via electrostatic interaction and π-πstacking. The platform displayed signicant DOX and siRNA loading, and it was discovered that heat and pH
were requisite for their release. Moreover, it was applied as a combination treatment
depending on the photothermal impact of GO under NIR illumination and the anticancer activity of DOX [158].
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3.4.2 TissUe engineering
Tissue engineering is an interdisciplinary area that leverages skills in biology, physiology, medicine,and engineering to design biomimetic tissue structures for regenerative medicine in addition to therapeutic and diagnostic investigations [159,160].
Biomaterials are essential elements in tissue engineering since they can drive cellular
proliferation, promote certain biological activities, and regulate cell-cell interactions
[161]. Furthermore, the biomechanical, electrical, or physical characteristics of various body tissues differ. As solitary materials may not imitate the biological and physical characteristics of native tissue, hybrid composites comprisingmultiple elements
that may accommodate thediverse requirements are commonly employed to build
articial tissues. Researchers have been inspired to employ graphene-based nanomaterials in tissue engineering and regenerative medicine because of their exceptional electrical and mechanical attributes [162–164]. It has been discovered that
graphene may efciently adsorb nucleobases through the π–πinteraction and shield
nucleotides from enzymatic breakage [165]. In tissue regeneration, gene therapy has
lately gained prominence as a treatment for disorders. Protecting DNA from deterioration and delivering high transfection effectiveness are two fundamental needs
of a gene delivery vector[166]. Additionally, both viral and nonviral vectors have
attended immense attention in the eld of gene delivery science [167]. In light of this,
graphene nanosheets would be a good choice for a vector since cells could readily
absorb them. For example, Chen etal. (2011) demonstrated that PEI-GO could augment transfection efciency through a proton-sponge effect by transfecting plasmid
DNA into HeLa cells using a poly(ethylenimine)-GO (PEI-GO) carrier [168].
To develop 2D or 3D graphene-based frameworks, several researchers have used
a range of techniques, including coating, hydrogel mixing, wet/dry spinning operations, and 3D printing. For tissue regeneration applications, graphene and its derivatives may be coupled with additional biomaterials to improve their biomechanical,
electrical, and physicalcharacteristics. Recently, Purohit etal. (2020) used freezedrying to develop gelatin-alginate (GA)-based 3D polymeric scaffolds using graphene
oxide-nanohydroxyapatite (GO-nHAp) nanocomposites as reinforcing agents. The
main physicochemical characteristics of this scaffold and the synergistic effects of all
its constituent parts were established for application in tissue regeneration. Additionally, it demonstrated swelling behavior in water, demonstrating its hydrophilic character and suitability for practice in tissue engineering. The presence of GO-nHAp in
this scaffold increased its compressive strength to 14.72 MPa while lowering its rate
of biodegradation. These characteristics, along with the scaffold’s biocompatibility,
considerably increase its suitability for bone tissue engineering [169].
Similarly, for bone regeneration, Sharma etal. (2022) developed a polydopaminerGO doped 3D printable PLA scaffold with signicant functionalities, including antioxidant, pro-angiogenic, anti-biolm,and osteoinduction. Development of
tissues like bone, which confronts a plethora of biological and physiological constraints leading to declining performance and ultimate rejection of grafts, signicantly requires the assimilation of multifunctionality in a single tailored scaffold. The
presented approachofferedan easy way to develop a multifunctional bone scaffold
that may confront issues like biolm formation brought on by infection, reduced
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