Polymeric Surface Modification of Graphene

CHAPTER

POLYMERIC SURFACE MODIFICATION OF GRAPHENE

14

Renu Geetha Bai*, Ali Hilal-Alnaqbi† Department of Mechanical Engineering, United Arab Emirates University, Al Ain, United Arab Emirates* Electromechanical Technology, Abu Dhabi Polytechnic, Abu Dhabi, United Arab Emirates†

CHAPTER OUTLINE 1 Introduction ................................................................................................................................... 305 2 Graphene and Derivatives Characteristics, Properties and Applications ............................................. 306 3 Graphene Nanomaterials in Nanomedicine ....................................................................................... 306 4 Polymeric Surface Modification of Graphene .................................................................................... 307 5 Current Status of Surface Modified Graphene Biomaterials ............................................................... 310 6 Challenges .................................................................................................................................... 315 7 Conclusion and Future Prospects .................................................................................................... 315 References ........................................................................................................................................ 316

1 INTRODUCTION Carbon nanomaterials play a significant role in the development of advanced biomaterials. Owing to their mechanical stability, structure, and biocompatibility, different forms of carbon materials were successfully employed in advanced medical investigations. Graphene is a two-dimensional allotrope of carbon, which is made of SP2-hybridized single layer of carbon atoms arranged in a honeycomb lattice structure. Exploring the unique physiochemical characteristics of graphene nanomaterials, they were utilized in a variety of applications ranging from medicine, bioengineering, energy storage devices, semiconductors, electronics, automobiles, sensors, etc. Graphene and derivatives possess properties such as excellent electric conductivity, light weight, ease of functionalization, fluorescence quenching ability, surface-enhanced Raman scattering (SERS) property, high mechanical strength, amphiphilicity, and high thermal conductivity. Biomedical applications of graphene materials involve drug delivery, gene therapy, phototherapy, bioimaging, biosensors, theranostics, antibacterial composites, tissue regeneration, etc. The lack of clear understanding of biointeractions and toxicity concerns of graphene-based materials are critical factors that limit the potential of these materials in the biomedical and biological application. In order to overcome the toxicity limitations or to tune the properties, graphene nanomaterials are often surface modified. Despite the different chemical modifications, Biomedical Applications of Graphene and 2D Nanomaterials. https://doi.org/10.1016/B978-0-12-815889-0.00014-3 # 2019 Elsevier Inc. All rights reserved.

305

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polymer-based surface modifications are widely explored for biomedical applications ensuring the biocompatibility/safety concerns. This chapter focuses on the different approaches in the polymer-based surface modification of graphene nanomaterials and its different applications.

2 GRAPHENE AND DERIVATIVES CHARACTERISTICS, PROPERTIES AND APPLICATIONS Being the basic building block of different carbon nanomaterials, graphene is known as “the mother of all graphitic structures.” Graphene has a number of derivatives such as graphene oxide (GO), reduced graphene oxide (rGO), graphene quantum dots (GQDs), graphene nanosheets (GNs), monolayer graphene, and few-layer graphene. Graphene possesses unique physical, chemical, and mechanical properties such as large surface area (2630 m2 g
1), great intrinsic mobility (200,000 cm2 v
1 s
1), exceptional Young’s modulus ( 1.0 TPa), good thermal conductivity ( 5000 Wm
1 K
1), high optical transmittance ( 97.7%), and excellent electric conductivity (1–6). In addition, with ease of modification and functionalization, graphene is an excellent candidate for a variety of biomedical applications (7, 8). Graphene and derivatives are employed as carriers of drug/gene, bioimaging, biosensing, antibacterial/anticancer, and in tissue engineering applications (9–14). Theoretically, graphene is the basic structure of graphite, which is made up of a single layer of carbon atoms. GO is the chemically exfoliated form of oxidized graphite, which is used for the production of rGO through a variety of reduction processes. Owing to its excellent aqueous processability, amphiphilicity, ease of surface functionalization, SERS property, and fluorescence quenching ability, GO is extensively used in nanomedicine (15, 16).rGO is synthesized by the reduction of GO by employing diverse methods such as chemical reduction, photocatalytic reduction, electrochemical reduction, solvothermal reduction, sonochemical reduction, phytochemical (green chemistry) reduction, and multistep reduction. Reduction process involves many physicochemical changes in GO. Changes in the structure, electric conductivity, hydrophilicity, color, and reduction in the side functional groups were observed as a result of the reduction. Thermal deoxygenation, chemical deoxygenation, restoration of long-range conjugated structures, and healing of defects are other changes that occur during the reduction of GO. rGO also possesses higher electric conductivity than GO (17–19). Considering their unique properties, graphene and derivatives are attracting a lot of scientific attention.

3 GRAPHENE NANOMATERIALS IN NANOMEDICINE The ideal therapeutic design of graphene-based biomaterials requires several modifications prior to introduction to a living organism. There are diverse modes of interaction between graphene nanomaterial and biomolecules such as nucleic acids, lipid bilayers, proteins, and small molecule drugs, and the biointeractions are varied based on the material properties such as layer number, lateral size, stiffness, hydrophobicity, surface functionalization, and dose (20). In advanced medicine, graphene nanomaterials are explored mainly in fields as listed in Fig. 1 of cancer drug delivery, gene/protein therapy, tissue engineering, biosensing, bioimaging, photo/sonotherapy, regenerating scaffolds, antibacterial effects, and biomaterial implants. Being an excellent carrier with huge loading capacity, graphene nanomaterials act as a cargo for DNA, antibodies, proteins, genes, and small drug molecules that could be smartly

4 POLYMERIC SURFACE MODIFICATION OF GRAPHENE

307

FIG. 1 Major applications of graphene nanomaterials in nanomedicine.

delivered on the targeted locations by the change in temperature, pH, or other external stimuli such as magnetic field, sound, and radiation (21). Considering the biocompatibility, efficiency of carrier, and preclinical evaluation results, a huge number of graphene-based biomaterials are introduced in the last decade that strongly support the role of graphene in modern medicine (22). Graphene nanomaterials are excellent nonviral gene transfer agents with high gene transfection efficiency. In tissue engineering, graphene and derivatives are contributing to the attachment, proliferation, and differentiation of the cell lines. In the case of stem cells, graphene nanomaterials encouraged the differentiation into osteogenic, cardio, neuronal, and adipogenic lineages (23). Sensing potential of graphene nanomaterials is highly explored due to its excellent electric conducting characteristic. Moreover, the electrocatalytic potential of graphene-associated nanocomposites is also highly explored for the determination of biomarkers associated with different diseases (14, 18). Graphene could be employed as field-effect transistor biosensor, electrochemical impedance biosensor, electrochemical sensor, and fluorescence-based sensor (24).

4 POLYMERIC SURFACE MODIFICATION OF GRAPHENE Surface modification of graphene nanomaterials tunes its specific features and thus enables a safe utilization of them for drug delivery, gene delivery, imaging, biosensing, tissue engineering, etc. (25, 26). For biomedical applications, the compatibility of the material is a critical factor; thus, suitable surface

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modifications are done before the introduction of any graphene nanomaterials into a living organism. The polymeric surface modification is an easy way of modifying graphene nanomaterials, to obtain desired surface characteristics, to make it compatible with different diagnostic and therapeutic applications. Polymer surface modification is an efficient way of creating stable graphene dispersion to avoid agglomeration due to its high surface energy. Surface modification of graphene could be done either by small molecules or by polymers (27–30). The surface modification of graphene is done in chemical and physical methods in the presence of different modifying agents and suitable dispersing medium. The important surface modification methods are the covalent modification, noncovalent modification, π-π interaction, electrochemical modification, chemical-induced reduction, nucleophilic substitution, thermal treatment, diazonium salt coupling, etc. (30–32). As a result of the surface modification, polymer-graphene nanocomposites and graphene-filled polymers were developed. Polymer-graphene nanocomposites are formed by in situ intercalative polymerization (graphene is dispersed in liquid monomer, and polymerization is initiated by heat/radiation), solution intercalation (polymer in solvent and graphene is introduced to the solvent), and melt intercalation (thermostatic polymer mixed with graphene in molten stage). Another type of polymeric modification is graphene-filled polymer composites. Graphene as a filler material is successfully tested in different polymeric systems, such as epoxy, polystyrene (PS), polyaniline (PANI), polyurethane (PU), polyvinylidene fluoride (PVDF), Nafion, polycarbonate (PC), and polyethylene terephthalate (PET) (33). Among the different graphene derivatives, GO is one of the extensively investigated graphene nanomaterials. Due to the presence of surface and edge functional groups (hydroxyl, carboxyl, and epoxy groups), vast surface area, and structural defects, GO is subjected to easy functionalization with polymers to obtain polymeric composites with altered physiochemical properties. For example, the GO is surface modified with polymethyl methacrylate chains utilizing atom transfer radical polymerization that resulted in a novel nanocomposite with significant improvement in mechanical properties, that is, improvement of the elongation at break, more ductility, and tougher material. In addition to the mechanical properties, the new nanocomposite exhibited enhanced thermal stability also (34). Similarly, polymer-modified GO nanocomposite films showed altered dielectric properties modified with poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) incorporating polyethyleneimine (PEI) by a solution-cast method (35). Introduction of GO as a conductive filler in polymeric materials facilitated the preparation of epoxy nanocomposites with light weight, high thermal stability, and outstanding dielectric performance (36). GO when covalently grafted with polymer (triphenylamine-based polyazomethine) displayed bistable electric switching and a nonvolatile rewritable memory effect (37). GO is a promising biomaterial in therapeutics. Suitable surface modifications enable the use of GO in new drug delivery concepts based on smart delivery systems for targeting and stimulation with pH, temperature, chemical interactions, photoinduction, magnetic induction, etc. (22). Several studies showed the toxicity responses of GO in terms of damage to cell membrane integrity and abnormality in cellular functions, platelet depletion, pro-inflammatory response, and pathological changes. In order to improve the cytocompatibility of GO, several modifications were made such as addition of amino group, poly(acrylamide), poly(acrylic acid), and poly(ethylene glycol) to form aminated GO (GO-NH2), poly(acrylamide)-functionalized GO (GO-PAM), poly(acrylic acid)functionalized GO (GO-PAA), and poly(ethylene glycol)-functionalized GO (GO-PEG), respectively. When comparing the in vitro and in vivo toxicity with pristine GO, GO-PAA found to be the most biocompatible modified form where the GO-PEG and GO-PAA displayed less toxicity than pristine GO (38). Similarly, PEG-modified GO (PEG-GO) displayed selective inhibition to cancer cell

4 POLYMERIC SURFACE MODIFICATION OF GRAPHENE

309

migration in vitro and in vivo by impaired mitochondrial oxidative phosphorylation (OXPHOS) in MDA-MB-231 breast cancer cells and no effects on noncancerous cells. The inhibition of OXPHOS resulted in reduced ATP production and impaired assembly of the structural proteins in breast cancer cells, which is required for the migratory and invasive phenotype of cancer cells, which offers a new therapeutic approach to treat metastatic breast cancer (39). Moreover, the excellent drug-loading capacity of GO is utilized in the design of heparin and heparin-mimicking polymer-based hydrogels for antithrombogenic materials, growth factor carriers, and scaffolds for tissue engineering and regeneration medicine. Poly(ethylene glycol) methyl ether methacrylate (PEGMA) and 2-hydroxyethyl methacrylate (HEMA) hydrogels, when incorporated with GO, showed excellent porosity, high drug-loading efficiency, and controlled drug release profile (40). Polyethylene oxide (PEO)/chitosan-modified GO was prepared as DOX-loaded electrospun nanofibrous scaffolds for the PH-controlled drug delivery of DOX for lung cancer treatment (41). For tissue engineering applications, poly(propylene fumarate)/polyethylene glycol-modified GO nanocomposites were used, which had improved hydrophilicity, water uptake, biodegradation rate, surface roughness, protein absorption capability, mechanical stability, and thermal stability based on the GO concentration in the composite. Moreover, these nanocomposites provided effective support for bone tissue formation with excellent biocompatibility and good antibacterial activity (42). Similarly, chitosan-modified GO scaffolds also successfully employed stimulated growth of osteoblasts in tissue engineering (43). One of the major graphene synthesis methods involves the reduction of GO, which results in rGO (44). Owing to its high-conductance nature, rGO is an ideal material utilized for high-performance molecular sensors (45). For the electrocatalytic nonenzymatic sensing of glucose in human serum samples, rGO is modified with conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) decorated with nickel nanoparticles. The glassy carbon electrode is electropolymerized through cyclic voltammetry with GO-doped PEDOT composite for the electrode preparation. Ultimately, the modified rGO resulted in an enhanced electrocatalytic sensing potential toward glucose detection with a detection limit of 0.8 μM having exceptional stability, high reproducibility, and specific selectivity against similar interference with promising potential toward the clinical application (46). Similarly, the fabrication of a Whatman paper-based rGO biosensor is modified with poly(3,4-ethylenedioxythiophene)/poly (styrenesulfonate) (PEDOT/PSS) and analyzed its electrocatalytic potential in various solvents like methanol, ethylene glycol, and sulfuric acid. When treated with ethylene glycol, the conductivity of this solution processed conducting paper considerably increases up to 300 times. This change in conductivity is due to conformational rearrangement in the polymer and is due to strong noncovalent cooperative interaction between PEDOT and the cellulose molecules in the paper. This economical, stable, flexible, and eco-friendly biosensor is utilized for the detection of carcinoembryonic antigen, a cancer biomarker with high sensitivity of 25.8 μA ng
1 mL cm
2 in the physiological range, 1–10 ng mL
1 (47). A pyrrole-3-carboxylic acid-modified rGO genosensor was also developed, where the conductive polymer enhanced the electrocatalytic activity of rGO. Breast cancer-associated BRCA1 gene is detected using the DNA-immobilized polymer-coated rGO by voltammetric techniques with a limit of detection as low as 3 fM. Moreover, the proposed genosensor showed a perfect differentiating nature toward the complementary, noncomplementary, and mismatched DNA sequences. This polymer-coated rGO genosensor displayed excellent selectivity, sensitivity, repeatability, reproducibility, and remarkable reusability. Furthermore, this sensor is utilized for accurate determination of trace amounts of DNA target in blood plasma samples (48). Similarly, polypyrrole (PPy) and PEG-modified rGO are used for electrochemical detection of didanosine—a nucleoside

310

CHAPTER 14 POLYMERIC SURFACE MODIFICATION OF GRAPHENE

analogue reverse transcriptase inhibitor, in real samples in the range of 0.02–50.0 μM—and this electrode provided a low limit of detection (LOD ¼ 8.0 nM) (49). A polydopamine (PDA)-modified superparamagnetic rGO nanocomposite was developed by mussel-inspired chemistry via one-pot chemical functionalization method for various industrial catalytic applications. When modified with thermoresponsive polymer of poly(N-isopropylacrylamide-co-2,3-epithiopropyl methacrylate) P(NIPAMco-ETMA), an improved temperature-responsive behavior for the catalytic reduction of nitrophenol is exhibited by the gold nanoparticle-functionalized rGO nanocomposites (50). Combination of multiple therapeutic systems in a single platform introduces the concept of synergistic therapy. Herein, rGO is modified with mesoporous silica (MS)-coated polydopamine and hyaluronic acid (HA) to be used as a chemotherapy-photothermal therapy agent pRGO@MS(DOX)-HA against HeLa cancer cells. The noncovalent functionalization of rGO by using mussel-inspired dopamine enhanced the biocompatibility and the photothermal effect of rGO nanocomposite, where the MS coating and HA modification improved doxorubicin (DOX) loading and specific targeting, respectively. The in vitro evaluation of pH-dependent and near-infrared (NIR) laser irradiation-triggered DOX release from the rGO complex resulted in excellent dispersibility, good photothermal property, significant tumor cell killing efficiency, and specific tumor targeting. Further in vivo antitumor investigation on mice models validated the excellent synergistic antitumor efficacy of light-mediated photothermal cancer therapy as shown in Fig. 2 (51). Owing to the significance in bioimaging, biosensing, and catalysis, GQDs are a prominent derivative of graphene family. In addition to the excellent optical properties, the small size, chemical inertness, biocompatibility, and low toxicity enable its potential uses in nanomedicine (52, 53). GQD-based bioimaging has the advantages including tunable photoluminescence, excellent photostability, and biocompatibility. Moreover, they could be specifically labeled and used for tracking molecular targets as fluorotags involved in dynamic cellular processes in live cells (54). In a GQD-based photodynamic therapy (PDT) system, the GQDs are modified with a disulfide linkage and coated with a redoxsensitive PEG shell. When compared with a GO-based system, the GQD-based photodynamic system showed enhanced tumor update and intense fluorescence response (55). PEG modification is utilized as a major step in GQD preparation to enhance the stability and improve the biocompatibility for both in vitro and in vivo applications (56). In addition to reduced toxicity, PEGylation supports the low intracellular ROS production of GQDs for the bioimaging and drug delivery applications (57). Dopamine-conjugated HA is used for the preparation of HA-modified GQD for testing the DOX delivering and bioimaging potential of GQDs (58) (Table 1).

5 CURRENT STATUS OF SURFACE MODIFIED GRAPHENE BIOMATERIALS Past few decades witnessed the enormous potential of graphene materials and its applications in the field of advanced medicine. A large number of graphene-based biomaterials are investigated for the purpose of diagnosis, therapy, tissue engineering, and regenerative purposes. Polymer-based modification enables the graphene nanomaterials to act as smart biomaterials and stimuli-responsive triggering systems using such as pH, temperature, and external signals (82, 83). Introduction of specific targeting moieties and on time response analysis devices have encouraged the use of nanomedical devices in modern medicine. The polymer-modified graphene nanoscaffolds are popular in tissue engineering because of their biocompatibility and adjustable biodegradation kinetics. Surface-modified

30 s

60 s

120 s

180 s

240 s

0 day

300 s 60°C

5 day

9 day

15 day

19 day

Saline

Saline DOX

pRGO@MS-HA

pRGO@MS pRGO@MS(DOX)-HA

pRGO@MS-HA +NIR

pRGO@MS(DOX)-HA pRGO@MS(DOX)-HA

1600

Tumor volume (mm3)

Temperature (°C)

70 60 50 40 30

Saline

20

DOX pRGO@MS-HA

10

pRGO@MS(DOX)-HA

1400 1200 1000

0

(C)

(B)

25°C

0

60

120 180 240 300 Time (s)

Saline

(D)

pRGO@MS-HA

+NIR

25

Saline pRGO@MS-HA DOX pRGO@MS(DOX)-HA pRGO@MS-HA+NIR pRGO@MS(DOX)-HA+NIR

800 600 400

*** ***

200

Body weight (g)

(A)

0

20 15

Saline DOX pRGO@MS-HA pRGO@MS-HA+NIR pRGO@MS(DOX)-HA pRGO@MS(DOX)-HA+NIR

10 5

0

5

10

15

20

25

Time (day) DOX

pRGO@MS(DOX)-HA

(E)

0

5

10

15

20

Time (day)

pRGO@MS-HA +NIR

pRGO@MS(DOX)-HA +NIR

(F) FIG. 2 In vivo antitumor activity of pRGO@MS(DOX)-HA composite. (A) IR images of mouse models on 808 nm laser at different time periods. (B) Pictures of HeLa tumorbearing mice at different time periods. (C) IR thermal images respond to the NIR exposure and temperature-time curve. (D) Tumor growth curve responds to different treatments at time. (E) Average body weight evaluation versus time for different treatments. (F) Images of H&E sections of tumors versus treatment agents (listed in picture). Data presented as mean  SD (n ¼ 5). P values in (D) were calculated by the two-tailed student’s t-test (***P < .001, **P < .01, or *P < .05). From Shao, L.; Zhang, R.; Lu, J.; Zhao, C.; Deng, X.; Wu, Y. Mesoporous Silica Coated Polydopamine Functionalized Reduced Graphene Oxide for Synergistic Targeted Chemo-Photothermal Therapy. ACS Appl. Mater. Interfaces 2017, 9 (2), 1226–36, with permission.

Polymer

Application

Impacts

References

GO

Dextran

Drug delivery

(59)

GO

BC

Drug delivery

GO

HA

Drug delivery

GO

ALG

Drug delivery

Graphene

Chitosan

Drug delivery

GQD

CMC

Drug delivery

GO

PEG

Drug delivery

GO

PEG

Drug delivery

GO

Chitosan and PEG

Drug delivery

GO

PEG and PLGA

Drug delivery

AS1411 aptamer used for the specific targeting of curcumin-loaded dextran-GO complex. The nanocomplex showed significantly higher cytotoxicity The ibuprofen loaded on 3D nanoscaffold In vitro cell viability evaluation revealed its potential as drug delivery system In vivo and in vitro results indicated selective delivery of DOX to HA receptor overexpressing tumors through passive and active targeting. Cytoplasm-specific DOX delivery through NIR-controlled endo/ lysosome disruption and redox-triggered release of DOX The in vivo investigation of 5-fluorouracil-loaded GO-ALG nanocomposite displayed inhibited tumor growth and liver metastasis, thus prolonging the survival duration of mice Thermosensitive chitosan-graphene hybrid hydrogels exhibited a slow and controllable release of MTX. The antitumor effect on breast cancer cells expressed as inhibition to the growth of MCF-7 breast cancer cells The CMC/GQD hydrogel films showed excellent pH-sensitive DOX delivery. This hydrogel films could be used as an anticancer film and drug delivery system GO-PEG-DOX complex showed enhanced water solubility, targeting sensitivity of DOX, and DOX-induced tumor cell apoptosis Camptothecin-loaded GO functionalized with PEG and folic acid showed a pH-dependent drug release. The anticancer drug activity by MTT assay using MCF-7 breast cancer cell lines showed enhanced anticancer activity DOX-loaded Fe3O4 magnetic nanoparticles on GO nanoplatelets were investigated for pH-dependent drug release at different pHs. In vitro cytotoxicity tests on U87 human glioblastoma cell line exhibited pH-dependent drug release properties, for targeted delivery of chemotherapy drugs In vitro and in vivo experiments of DOX delivery showed successful antitumor effect. No systemic adverse toxicity was observed on B16 tumor-bearing mice models

(60)

(61)

(62)

(63)

(64)

(65) (66)

(67)

(68)

CHAPTER 14 POLYMERIC SURFACE MODIFICATION OF GRAPHENE

Graphene Material

312

Table 1 The Recent Reports of Polymeric Surface-Modified Graphene Nanomaterials and Their Applications Are Listed in the Table

PEG

Radioisotope therapy, bioimaging

Graphene

PEG

Drug delivery

Graphene

Pluronic F127

Hyperthermia, stimuli-responsive drug release

GO

PEI and PLGA

Gene delivery

Graphene

Heparindopamine

Protein delivery

GO

Alginate, chitosan, and collagen PGS and PCL

Tissue engineering

Graphene

Graphene

Bioactive glass and PCL

Tissue engineering

Tissue engineering

(69)

(70)

(71)

(71)

(72)

(73)

(74)

(75)

313

PEG-modified 131I labeled and rGO-MnO2 nanocomposites improve the oxygen formation in the solid tumor sites in the presence of H2O2, thus overcoming hypoxic microenvironments and enhanced RIT of cancer. In vivo treatment showed long-time blood circulation and high tumor accumulation of nanocomposite. MnO2 supports the MR imaging ensuring bioimaging-guided cancer therapy Transferrin-loaded PEGylated graphene is used for the DOX delivery. The 3D in vitro tumor model and in vivo mouse model with choroidal melanoma demonstrated the targeted delivery and controlled release of antitumor drugs from the nanocomposite DOX-loaded multifunctional graphene-based magnetic nanoparticles displayed both exogenous electric field and endogenous pHresponsive targeted thermo-/chemotherapy, combining magnetic hyperthermia and controlled drug release triggered by the abnormal tumor environment Electrospun GO-doped PLGA nanofibers exhibited good biocompatibility and improvement in DNA transfection efficiency in embryonic kidney 293 cells and human umbilical cord-derived mesenchymal stem cells by regulating their proliferation and differentiation Heparin-dopamine modification of graphene foam showed significant enhancement in BMP2 binding ability and longer release capacity. The exogenous BMP2-induced osteogenic differentiation displays a new multifunctional carrier for therapeutic proteins and stem cells in bone tissue engineering In vitro studies on mouse osteoblast cells on various scaffolds showed cell proliferation, mineralization, and differentiation supporting bone tissue engineering Mixing PGS with PCL significantly improved the hydrophilicity and cell attachment. Addition of graphene improved conductivity, elastic modulus, and tensile strength. Graphene polymeric films resulted in superior mechanical properties, high aspect of ratio, improved cell survival, and cell attachment and thus suitable for nerve tissue engineering Graphene-containing bilayered scaffolds were investigated on osteoblastic and chondrogenic cells for osteochondral tissue engineering applications. Biological response was assessed using three-dimensional monoculture and coculture systems. Osteoblastic and chondrogenic cells expressed higher cell viability rates under coculture conditions with mineralization and calcium deposition. Monoculture electrostimulation revealed that applied electric field suppressed the MC3T3-E1 cell viability whereas it enhanced the ATDC5 cell viability rates

5 CURRENT STATUS OF SURFACE MODIFIED GRAPHENE BIOMATERIALS

rGO

Continued

Table 1 The Recent Reports of Polymeric Surface-Modified Graphene Nanomaterials and Their Applications Are Listed in the Table—cont’d Application

Impacts

References

Graphene

PEG

Biosensing

(76)

GO

PEG

Bioimaging, photodynamic therapy

GO

PEG

Bioimaging, photothermal therapy, photodynamic therapy

GO

PEG

Drug delivery, tissue engineering, and regenerative stem cell therapy

GO

PEG

Drug delivery, bioimaging, photothermal therapy

GO

PEG

Drug delivery, bioimaging, photothermal therapy

PEGylated graphene-gold nanoparticle composites are a highly sensitive biosensing material with stable, reproducible, and highly sensitive SERS nanotags for biosensing, with a limit of detection lower than 31.0 fM for IgG detection GO-PEG composite is used as an AIE nanosystem for fluorescence bioimaging and photodynamic therapy. The dual-functional AIE molecule two-photon fluorescence imaging of both mouse ear blood vessels and UMUC3 cells. The in vitro and in vivo PDT effects at 450 nm laser irradiation displayed inhibition to the tumor growth. Thus, it acts as a multiple therapeutic system enabling imaging and therapy The GO nanocomposites acted as an UCL imaging probes of cells and whole-body animals with high contrast and also can generate ROS under 808 nm light excitation for PDT; moreover, they proficiently translate the 800 nm photon into thermal energy for PTT A novel collagen-nanomaterial-drug hybrid scaffold was constructed from GO-PEG-mediated quercetin-modified acellular dermal matrix. This biocompatible scaffold exhibited MSC attachment and proliferation. Quercetin-induced differentiation of MSCs into adipocytes and osteoblasts and the biodegradable nanofiber interface stimulated collagen deposition and angiogenesis in diabetic wound repair. In the in vivo studies, hybrid scaffold was implanted in diabetic wound, which exhibited wound healing via collagen deposition and capillary construction Multifunctional theranostic nanoplatform displayed NIR absorbance of the nanocomposite for photothermal conversion for PA imaging. In vivo magnetic resonance and PA imaging proved an efficient bimodal contrast agent. The nanocomposite showed a high loading capacity for DOX and pH-triggered release by external NIR light. The synergistic photothermal therapy-chemotherapy is tested in xenograft 4T1 tumor models The in vivo tests of nanocomposite exhibited multimodal imaging by fluorescent, MR, and photothermal imaging. The magnetic GO nanocomposite displayed superior inhibition (in vitro and in vivo) for tumor by the synergistic therapeutic effect. The intense heating effect and improved DOX release upon 808 nm NIR light exposure result in multimodal imaging-assisted chemo-/photothermal synergistic cancer therapy

(77)

(78)

(79)

(80)

(81)

BC, bacterial cellulose; HA, hyaluronic acid; DOX, doxorubicin; NIR, near-infrared; ALG, sodium alginate; MTX, methotrexate; CMC, carboxymethyl cellulose; PEG, polyethylene glycol; Fe3O4, iron oxide; PLGA, poly(lactic-co-glycolic acid); 131I, iodine-131isotope; RIT, radioisotope therapy; MnO2, manganese dioxide; MR, magnetic resonance; DNA, deoxyribonucleic acid; BMP2, bone morphogenetic protein-2; PGS, poly(glycerol sebacate); PCL, polycaprolactone; SERS, surface-enhanced Raman spectroscopy; IgG, immunoglobulin G; AIE, aggregation-induced emission; PDT, photodynamic therapy; UCL, upconversion luminescence; ROS, reactive oxygen species; PTT, photothermal therapy; MSCs, mesenchymal stem cells; PA, photoacoustic.

CHAPTER 14 POLYMERIC SURFACE MODIFICATION OF GRAPHENE

Polymer

314

Graphene Material

7 CONCLUSION AND FUTURE PROSPECTS

315

graphene-based nanotheranostic agents have displayed an excellent promise to the future cancer diagnosis and management, and their synergistic action could significantly enhance the therapeutic efficiency. The integration of multimodality imaging techniques with advanced therapeutic approaches enables the early diagnosis and thus controls the progression of the diseases, to improve the life quality of the patient (84, 85).

6 CHALLENGES Though the surface modification enables the tuning of graphene material properties, the design and fabrication of graphene-based diagnosis and nanotherapeutics still face many challenges, including biocompatibility, long duration in the development of the nanosystems, pharmacokinetics, clearance, in vivo targeting efficacy, and cost-effectiveness. The lack of clarity in the long-term effects of nanomaterials is still a critical factor to be considered (86, 87). Ensuring the long-term effects in human volunteers is a critical step in the development of these systems. The major limitations of bench-tobed translation of these new nanotherapeutic systems include the absence of information about preclinical investigations such as long-term exposure effects, fate of nanomaterials, and ultimately safety concerns regarding clinical trials. Overcoming these hurdles will ensure the effective utilization of graphene-based nanotherapeutics for future health-care applications.

7 CONCLUSION AND FUTURE PROSPECTS Current advancements in graphene-based nanomaterials enable utilization in modern medicine for drug delivery, gene delivery, tissue engineering, stem cell therapy, cancer treatment, biosensing, bioimaging, phototherapy, etc. Graphene materials continue to be the research focus due to the outstanding properties and unlimited applications. Considering the potential of surface-modified graphene-based nanomaterials, more investigations should be devoted to developing facile strategies for wellregulated, reproducible, and scalable synthesis and modification of graphene nanomaterials for their application. The polymeric surface modifications have influenced the biocompatibility, stability, and tissue regenerative properties of graphene nanomaterials where the size, charge, structure, surface state, and wettability of nanomaterials are influenced by the modification. Exploiting the surface modification of graphene biomaterials via covalent or noncovalent interactions should be of high interests for nanomedicine fields to evaluate more about the material characteristics and biological applications. To expand the scope of the bioapplications of the graphene nanomaterials, more research has to be performed on the surface modifications and its results on preclinical and clinical investigations. The critical factor limiting the exploration of nanomedicine is the ambiguity in the actual interaction between the nanomaterials and the biological entities. A clear understanding on the nanomaterial action, biological interactions, and clearance mechanism could facilitate its safer use in the near future. Furthermore, the concerns about their long-term toxicity, cellular-uptake mechanism, and influence on metabolic pathways have to be considered and strictly inspected. Solving the current concerns about the graphene-based nanomaterials could introduce a promising future toward the modern medicine with early diagnosis and effective treatments for a healthier generation.

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