Open access peer-reviewed chapter - ONLINE FIRST

NanoBioSensors: From Electrochemical Sensors Improvement to Theranostic Applications

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Anielle C.A. Silva, Eliete A. Alvin, Lais S. de Jesus, Caio C.L. de França, Marílya P.G. da Silva, Samaysa L. Lins, Diógenes Meneses, Marcela R. Lemes, Rhanoica O. Guerra, Marcos V. da Silva, Carlo J.F. de Oliveira, Virmondes Rodrigues Junior, Renata M. Etchebehere, Fabiane C. de Abreu, Bruno G. Lucca, Sanívia A.L. Pereira, Rodrigo C. Rosa and Noelio O. Dantas

Submitted: December 23rd, 2021Reviewed: January 10th, 2022Published: May 13th, 2022

DOI: 10.5772/intechopen.102552

IntechOpen
Biosignal ProcessingEdited by Vahid Asadpour

From the Edited Volume

Biosignal Processing [Working Title]

Dr. Vahid Asadpour and Dr. Selcan Karakuş

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Abstract

This chapter comments on the advantages of nanobiosensors using nanocrystals in improving electrochemical sensors’ response and their use as theragnostic tools in biomedical applications. The use of nanomaterials to modify electrochemical sensors’ surfaces to increase these devices’ sensitivity and their bio-functionality enables high-quality nanotechnological platforms. Thus, graphene nanostructures and CdSe/CdS magic-sized quantum dots (MSQDs) were shown to improve biosensor’s sensitivity. In addition, the use of CdSe/CdS MSQDs and cobalt ferrite nanocrystals (NCs) as potential tools for drug delivery systems and biocompatible titanium dioxide NCs in osseointegration processes and their bio-location are also demonstrated. So, this chapter shows some impressive results on which the group has been working regarding the applications of nanocrystals to electrochemical sensors and theranostic applications.

Keywords

  • nanocrystals
  • luminescence
  • magnetic nanocrystals
  • magic-sized quantum dots
  • drug delivery systems
  • biosensors
  • biomaterials
  • theranostic applications

1. Introduction

Nanotechnology allows the development of nanomaterials with controllable physical, chemical, and biological properties [1, 2, 3, 4]. These properties are controlled according to the nanomaterials’ size and shape, enabling the development of new innovative technologies, from new device development to tools in the health field [4, 5, 6, 7, 8, 9]. In this context, nanobiotechnology is a recent field emerging from science, which establishes an interface between biology and nanotechnology, evaluating and assigning new functionalized nano biosystems [8]. Thus, this multidisciplinary research field has great potential in developing improved medical engineering [1, 10].

Nanoparticles can be amorphous or crystalline (nanocrystals), and this difference reflects directly on the physical, chemical, and biological properties. Spanó et al. demonstrated that zinc oxide (ZnO) nanocrystals are more biocompatible when compared to amorphous nanoparticles [11]. Amorphous nanoparticles have a long-range disorder of their atoms and are more reactive [12]. On the other hand, nanocrystals show the periodicity of atoms forming crystalline arrangements and consequently fewer defects and less reactivity [13, 14, 15].

Nanocrystals (NCs) are often and successfully applied in several sensors, such as colorimetric, fluorescence, surface plasmon resonance, and electrochemical [16]. Regarding electroanalytical chemistry, conductive nanostructured crystals are interesting for application in electrochemical sensing due to their well-known ability to improve the catalytic activity, the electron transfer speed, and the conductivity of the sensors. Furthermore, the deposition of nanocrystals over electronic surfaces can increase the superficial area and amplify the analytical signal, enhancing the sensitivity regarding the detection of target analytes [17]. Nowadays, nanocrystal-based sensors have been widely explored in various applications and attracted the attention of several researchers [18].

Nanoparticle drug delivery can be used to target the tissue, promote the slow-release, protect against degradation, and diminish toxicity [19, 20]. The pharmacokinetic properties of a compound of biological activity are, among other factors, related to its solubility. The low solubility will result in problems from absorption until elimination. So, it is essential to search for alternatives, and they can increase the solubility of drugs without interfering in their pharmacological activity. Several active compounds are usually poorly soluble in aqueous media [21, 22]. A vast literature reports the possibility of complexation between lipophilic organic molecules appropriately sized, inorganic ions, and other species, with cyclodextrin, dendrimers, and liposomes. Whether for the drug’s application for pharmaceutical use, the nanocrystal compounds are essential on the medical and economic side [23, 24].

The development of biomaterials arouses tremendous scientific and clinical interest, given the possibility of replacing, in part or whole, human bones and/or favoring bone regeneration, both in the craniofacial complex and in other parts of the skeleton. Therefore, it is expected that the materials have osteoconductive properties (materials that function as a support surface for adhesion and proliferation of osteoblastic cells, which promote the formation of mineralized bone tissue), osteoinduction (materials that contain inductive proteins present in the matrix bone tissue and are capable of inducing differentiation of undifferentiated mesenchymal cells into chondroblasts or osteoblasts), osteogenesis (materials that have viable osteoblasts, capable of determining the formation of the new bone when grafted into the host tissue) and/or osteopromotion (materials that constitute physical barriers for the anatomical isolation of the site under repair, aiming at the selection of cells that promote the restoration, while excluding competing for inhibitory cells) [25]. This chapter book will comment specifically on titanium dioxide nanocrystals in dental and orthopedic applications.

Therefore, this chapter shows the innovative results obtained by the group of carbon-based, semiconductor, and magnetic nanocrystals that can be used in biosensors and biomedical applications, further strengthening the development of new tools.

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2. NanoBioSensors and applications

This section shows nanocrystals’ results in improved electrochemical sensors and their use as theranostic tools in biomedical applications. We will demonstrate how graphene nanostructures and CdSe/CdS MSQDs can improve sensors sensitivity. In the biomedical applications, we will show CdSe/CdS MSQDs and cobalt ferrite (CoFe2O4) NCs to drug deliveries and biocompatible titanium dioxide (TiO2) NCs in osseointegration processes and their bio-location.

2.1 Nanocrystals to biosensors improvement

Graphene has been the nanostructured material most utilized in electroanalytical applications due to its unique features [26]. Graphene consists of a single layer of carbon atoms in the sp2 hybridization organized in a honeycomb structure with six-membered rings, yielding 2D nanocrystals [27]. Some advantages of using graphene in electrochemical sensors are enhanced conductivity, decreased overpotentials, increased electroactive areas, and enhanced charge transfer rate [28]. Graphene is usually synthesized by the chemical reduction of graphene oxide [29, 30].

In this field, the advantages of using graphene-based nanocrystals in electroanalytical sensing have been previously demonstrated by several researchers and our research group [31]. We have reported the modification of a glassy carbon rod electrode (GCRE) with reduced graphene oxide doped with copper nanoparticles (RGO-CuNP). The synthesis of the RGO used in this work was carried out by the modified Hummers’ method [32]. This GCRE modified with RGO-CuNP was coupled, for the first time, to a paper-based electrochemical platform and applied in the electroanalysis of analytes of clinical interest, as illustrated in Figure 1.

Figure 1.

Representation of the modification of the GCRE with RGO-CuNP, coupling of the modified sensor to the paper-based electrochemical platform such as used in work, and voltammetric responses of unmodified and modified electrodes in the simultaneous electroanalysis of paracetamol and caffeine.

The modified sensor was thoroughly studied, optimized, and characterized. The results showed that the modification with RGO-CuNP significantly improved the electrochemical properties of the working electrode. In comparison with the unmodified GCRE, the RGO-CuNP sensor presented lower peak potentials, better sensitivity (ca. two-fold higher), lower electron transfer resistance (857 vs. 21,497 Ω), and larger electroactive area (0.067 vs. 0.040 cm2). These improvements are directly related to the modification with RGO-Cu nanocrystals, which are responsible for enhancing the conductivity and increasing the superficial area of the GCRE. As proof of concept, this modified sensor was employed to determine paracetamol and caffeine in real urine samples simultaneously. These two analytes were successfully quantified in low levels without matrix interferences, and the results showed excellent concordance with high-performance liquid chromatography used to validate the method. So, it evidences some of the advantages of using graphene-based nanocrystal in sensing platforms.

In this context, quantum dots (QDs) are among the most explored nanomaterials nowadays. The synthesis and practical application of QDs are among the main focuses in the development directions of nanotechnology [33]. QDs are semiconductor nanocrystals with optical and electrical properties that are widely employed in sensing applications. Another exciting feature of QDs is that properties such as size, shape, composition, and structure can be controlled and tuned. It allows obtaining QDs with unique properties according to the desired application [34, 35].

Although, promising, conventional QDs have some drawbacks that include moderate stability, limited luminescence spectra, and large size to some applications. At this point, the magic-sized quantum dots (MSQDs) are a class of nanocrystals that show smaller particle sizes, broader spectra, and more excellent stability than conventional QDs [36]. Among other applications, the MSQDs are a promising nanomaterial for electrochemical sensing use. The small size (in nanometric scale) and the electrical properties of these nanocrystals can significantly increase the surface area and the conductivity of the sensors.

Our research group recently explored, for the first time, the application of MSQDs for the modification of electrochemical sensors [37]. This pioneering work proposed a simple and inexpensive paper electrochemical device (PED) whose carbon-based working electrode was modified with CdSe/CdS MSQDs. The three-electrode setup (working, counter, and pseudo-reference) was fabricated on the paper substrate by a simple pencil-drawing method. At the same time, the CdSe/CdS MSQDs were synthesized according to the method described by Silva et al. [36, 38, 39]. This PED was modified with CdSe/CdS MSQDs to demonstrate the analytical feasibility and applied for clinical quantification of dopamine in biological samples, as represented in Figure 2.

Figure 2.

Picture of the paper electrochemical device containing the pencil-drawn carbon electrodes used in work, representing a modification of the working electrode with CdSe/CdS MSQDs, and the voltammetric dopamine response regarding the unmodified and modified electrodes.

Electrochemical and morphological techniques investigated the miniaturized CdSe/CdS MSQDs-based PED. This modified PED presented improved analytical signal (ca. 46% higher), lower charge transfer resistance (32 vs. 169 Ω), and larger superficial area (0.28 vs. 0.14 cm2) in comparison with the unmodified PED. It can be attributed to CdSe/CdS nanocrystals in the sensor, which was also confirmed by microscopy analysis. The electroanalysis of dopamine in real human blood serum samples was successfully carried out, and the limit of detection obtained was lower than other recent reports that utilize more complex electrochemical platforms for detecting the same analyte. In this way, MSQDs have been shown as a promising nanomaterial to be explored in electrochemical sensing.

2.2 Nanocrystals to biomedical applications

In the last decade, several nanostructured systems for the delivery of chemotherapeutic agents have been developed to eliminate tumor cells. However, most of these systems cannot reach specific tumor cells without adequate control of these drug release processes, resulting in serious side effects [40, 41]. It is necessary to direct efforts to improve ideal drug distribution systems to release stimuli and selectively target cancer cells. Thus, quantum dots, liposomes, magnetic nanoparticles, and TiO2 nanocrystals have enormous potential.

Quantum dots have been the subject of extensive investigations in different science and technology areas in the past years [42, 43]. There are few studies of MSQDs, even though they exhibit features such as tiny size, higher fluorescence quantum efficiency, molar absorptivity greater than traditional QDs, and highly stable luminescence in theranostic, which refers to the simultaneous integration of diagnosis and therapy [36, 39, 44, 45].

Our group investigated the first study about the core-shell MSQDs by analyzing the electrochemical behavior of CdSe/CdS MSQDs immobilized on a gold electrode modified with a self-assembled cyclodextrin monolayer using cyclic voltammetry and electrochemical impedance spectroscopy techniques [46]. The work showed a good interaction between the thiol group from thiolated cyclodextrin and CdSe/CdS MSQDs (Figure 3a). The proposed method was successfully applied to encapsulation studies of Mangiferin, a natural antioxidant compound, and cyclodextrin associated with the CdSe/CdS MSQDs, and the response was compared with that of the modified electrode without MSQDs. The fluorescence study revealed that CdSe/CdS MSQDs emit blue light when excited by an optical source of the wavelength of 350 nm, and a significant increase in fluorescence and absorbance intensity is observed from the core-shell CdSe/CdS MSQDs when quantities of Mangiferin are added to the solution containing thiolated cyclodextrin. CdSe/CdS MSQDs are optically and electrochemically sensitive and can be used to detect and interact with compounds encapsulated in cyclodextrin and can be applied in theranostic.

Figure 3.

(a) CdSe/CdS MSQDs immobilized on a gold electrode modified with a self-assembled cyclodextrin to encapsulation studies of Mangiferin, and (b) illustration of liposome with MSQDs (top panel) when MSQDs are (i) inside or (ii) outside and optical image the scale bar is 1 mm (bottom panel).

Because of their reduced size, lipophilic nanoparticles of less than 100 nm can cross the brain-blood barrier by diffusion, allowing the drug delivery directly to the Central Nervous System (CNS) [47]. Neurodegenerative diseases (ND) such as Alzheimer’s, Parkinson’s, strokes, glioblastoma, Huntington’s, amyotrophic lateral sclerosis may be treated differently with this approach [19]. Just like liposomes, polymeric nanoparticles may be environmentally sensitive to drug release, such as temperature change, pH change, among others. These systems may be combined therapy, delivering two or more drugs, allowing different therapy combinations.

The group has also been developing liposomes containing CdSe/CdS MSQDs aiming at a new luminescent tool for drug delivery. Figure 3b shows the illustration of liposomes with MSQDs (top panel); when MSQDs are (i) inside or (ii) outside and optical image, the scale bar is 1 mm (bottom panel). Therefore, we demonstrate that CdSe/CdS MSQDs can be used in drug delivery systems, which serve as photostable fluorescent reporters. A combination of MSQDs with liposomes is a powerful theranostic tool since it is possible to monitor their location via luminescence in addition to drug delivery.

Since the 1990’s Liposomal Amphotericin B has been available in the market, being one of the oldest and most clinical used nanoparticle formulations in the treatment of leishmaniasis. In 1978, Alvin et al. proved that the use of liposomal leishmanicidal drugs could enhance 700 times the efficacy [48]. Liposome functionalization is another advance that can enhance circulation time and release drugs according to temperature change and pH change; magnetic prepared liposomes can be target-directed by applying a magnetic field, and ligands in the lipidic bilayer can actively target cellular types [49]. Thus, the group has been working to develop drug systems containing liposomes and nanocrystals.

The study of bioactive substances by electrochemical and UV-visible spectroscopic methods is already very conceptual. The association of magnetic nanoparticles has emerged as a new bias of these techniques. We group reported the interaction between the molecule LQM10, a derivative of guanylhydrazone, with the CoFe2O4 NCs coated with polyamidoamine dendrimer (PAMAM), generating a nanocarrier to benefit LQM10 (Figure 4). The PAMAM dendrimer has empty spaces that change according to its generation. In these places, as well as cyclodextrins, “guest-host” interactions can occur, where the hydrophobic molecule can interact with dendrimers by hydrogen bonds, ionic bonding, or hydrophobic interactions, being possible interaction with LQM10 due to the tert-butyl group attached to its ring, which gives it a hydrophobic character, as well as with CoFe2O4 NCs. In addition to this type of interaction. PAMAM can make covalent and non-covalent bonds through its primary and tertiary amine groups, which would also be possible by observing the structure of LQM10. Both interactions can occur in an isolated or simultaneous way, making it possible for a single molecule of PAMAM to interact with several other substances, which enables its association with CoFe2O4 NCs, producing a better nanocarrier for LQM10 [50].

Figure 4.

Illustrative scheme of the nanocarrier composed by the PAMAN molecule, the black spheres represent the CoFe2O4 NCs and the LQM10 molecule.

The magnetic properties of CoFe2O4 NCs and each nanocarrier were confirmed by a vibrating sample magnetometer and field-effect calorimetry. LQM10 showed good interaction corroborating with the results of UV-visible and electrochemistry data. The heat generation by magnetic hyperthermia of CoFe2O4 NCs in the presence of PAMAM G3 and LQM10 was observed, demonstrating the association of promising nanocarriers (PAMAM G3 and CoFe2O4 NCs) with anticancer substances and their applicability as magnetic hyperthermia [50].

The implantation of material inside biological tissues must meet a minimum requirement, called biocompatibility, defined as a biomaterial’s ability to perform the desired therapeutic function without triggering any undesirable local or systemic effect, generating the most cellular or tissue response. Therefore, optimizing clinical therapeutic performance should be as beneficial as possible [51]. After application, an interaction occurs between the host’s immune system and the implanted biomaterial, leading to a specific cellular reaction to the biomaterial [52]. Proteins play a crucial role in the interaction between biomaterials and cells or tissues. Thus, the absorption of proteins on the material surface is the first event of this interaction, which is decisive for the subsequent cell growth processes, differentiation, and extracellular matrix formation [53].

The deliberate, accidental implantation of any foreign material into living tissues causes a response, and it is not the response itself but the extent, intensity, and duration that define biocompatibility. The ideal response of biological tissues to a biomaterial is when the initial inflammatory response resulting from the surgical procedure is quickly resolved, without the presence of a chronic inflammatory infiltrate or the development of an immune response. Thus, the biomaterial must be biocompatible and have characteristics that include predictability, clinical applicability, absence of transoperative risks and minimal postoperative sequelae, and acceptance by the patient. It is also expected that this biomaterial is not carcinogenic, that it presents adequate chemical and biological stability, mechanical and elastic resistance, and has low cost [54].

The biomaterial is a natural or synthetic material intended to interact with biological systems to assess, treat, augment, or replace an organism’s organ, tissue, or function [51]. The primary function of biomaterials is to replace damaged tissue and passively assume its function, selection, and manufacture, based on the imitation of the chemical and physical properties of natural tissue, causing minimal response as a foreign body [53].

Since the early 1970s, various synthetic bone substitutes have been developed to minimize the difficulties inherent in using autogenous bone grafts and homogeneous and heterogeneous bone implants [25]. The main advantages of grafts created from synthetic materials through bioengineering are biocompatibility and good reabsorption [55]. The alloplastic materials most commonly used in the medical-dental field are metals or metal alloys, ceramics, polymers, composites, and bioactive glasses [25]. Despite the wide variety of organic and synthetic materials capable of replacing bone tissue or stimulating reparational osteogenesis, there is still no material that meets all the desired requirements.

Titanium dioxide (TiO2) is a semiconductor that absorbs and emits in the ultraviolet region with numerous applications in biomedical fields such as cosmetics, medicines, and pharmaceutical products [56, 57, 58]. This material has three crystalline phases: anatase, brookite, rutile, and physical and biological properties [59]. The anatase phase is more electroactive than the rutile phase, having greater genotoxicity and photocatalytic effects [60, 61, 62, 63]. The TiO2 NCs have shown great potential for use in implants due to their excellent physical, chemical, and biological properties, such as high specific surface area, ability to provoke positive cellular response and stability in body fluids, is suitable for the propagation, proliferation, and differentiation of osteoblast cells [56, 64]. Thus, will show exciting results obtained by the group using TiO2 nanocrystals as well as their luminescence bio-location.

The porous structure of TiO2 nanotubes increases bone regeneration and repair, presenting good osteointegration, being used as a graft and biological fixation element for implants [57, 65, 66, 67, 68, 69, 70]. In an experimental study carried out by our research group using TiO2 NCs, adequate osteointegration in bone failure in the calvary of rats was evidenced, with the presence of a large amount of newly formed tissue, suggesting effective osteoinductive action, as can be seen in Figure 5.

Figure 5.

Histological section of rats’ calvaria: (a) fibrous connective tissue (asterisk); bone tissue (arrow); and (b) TiO2 NCs (arrows), bone tissue (arrow), and neoformed fibrous connective tissue (asterisk) (hematoxylin and eosin staining, 400×).

Despite the promising findings with TiO2 NCs, it is essential to report that there may be a high contamination rate and post-surgical infection since, currently, the spread of antibiotic-resistant bacteria is a worrying threat to human health.

In this context, it is essential to establish new antimicrobial strategies, in which the idea of coating device surfaces with active antimicrobial metals is considered one of the essential strategies. Therefore, bimetallic corrosion is inevitable, in which TiO2 photocatalytic nanomaterials, in the anatase form, offer more significant advantages for antimicrobial purposes [71]. Still, the photocatalytic activity of TiO2 under exposure to ultraviolet radiation results in disinfectant properties, mainly related to the generation of reactive oxygen species [72].

In this perspective, the sensitive and accurate detection of biological analytes in low concentrations is another application of TiO2 nanostructures that is beneficial for biomedical research and clinical diagnosis. There has been significant interest in applying TiO2 detection in biosensors [57, 67]. Therefore, those reported in the literature point out that TiO2 nanocrystals are inert and safe structures when exposed to the human organism, thus contributing to new promising nanotechnologies with the biomedical application.

Luminescence is related to some materials’ ability to light emissions. This excitation energy (absorbed energy) can be obtained from different sources: photons usually in the ultraviolet region of the electromagnetic spectrum (emission called photoluminescence), electrical energy (electroluminescence), electron beam (cathodoluminescence), physical impact (gives rise to triboluminescence) and heating the luminophore (results in thermoluminescence) [73, 74]. Photoluminescent materials are often called phosphors or luminophores [73]. Efficient luminophore requirements are efficient absorption of light in a suitable spectral region; chemical stability of the excited electronic state populated after light absorption; high conversion efficiency to the excited luminescent state; a long lifetime of excited state luminescence; high luminescent efficiency [75].

Photoluminescent materials require a host crystalline matrix, such as TiO2, as well as an activating ion, such as lanthanides. Lanthanide ions are known to have characteristic luminescence (high color purity). Among lanthanides, the europium ion (Eu3+) is one of the most used for biomarking due to its intrinsic electronic spectroscopic properties in the visible region under excitation in the ultraviolet region [76, 77].

Compounds with trivalent europium ions emit red light, with emission spectra of thin bands of approximately 614 nm. Therefore, it has been applied to investigate the properties and functions of biochemical systems and the determination of biologically active substances. In this context, we find reports of its application mainly as spectroscopic probes in the study of biomolecules [78]; in biological tracers to follow the path taken by medicines in the human organism and animals; as markers in immunology (fluoroimmunoassays) [79], as well as contrast agents in non-invasive diagnosis of pathologies in tissues by nuclear magnetic resonance imaging [80].

In a study carried out by our research group with TiO2 NCs doped with Eu3+, in the culture of mesenchymal stem cells, isolated from bone marrow cells, the presence of these nanocrystals was observed in the cytoplasm of the cells after 24 hours of incubation, not being found in the cell nucleus, suggesting the absence of cytotoxicity and genotoxicity (Figure 6).

Figure 6.

Fluorescence microscopy of mesenchymal stem cells treated with europium doped TiO2 NCs: (a) culture medium with 50 μg of mesenchymal stem cells; and (b) culture medium with 100 μg of mesenchymal stem cells.

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3. Conclusion

Therefore, this chapter showed nanocrystals inserted in biosensors and their use in drug delivery tools or biomaterials. Graphene and magic-sized quantum dots into biosensors enable an increase in sensitivity and specificity, making the development of nanotechnological platforms in biological diagnosis possible. In theranostic applications, magic-sized quantum dots, magnetic nanoparticles, and TiO2 nanocrystals can be innovative drug delivery tools and dental and orthopedic applications. Thus, the fabrication of nanomaterials with interesting properties makes it possible to generate several potential tools to improve electrochemical sensors and in theranostic applications.

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Acknowledgments

This work was supported by CNPq, CAPES, FAPEAL, and FAPEMIG.

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Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.Darvishi MH, Nomani A, Hashemzadeh H, Amini M, Shokrgozar MA, Dinarvand R. Targeted DNA delivery to cancer cells using a biotinylated chitosan carrier. Biotechnology and Applied Biochemistry. 2017;64:423-432. DOI: 10.1002/bab.1497
  2. 2.Razavi H, Janfaza S. Ethosome: A nanocarrier for transdermal drug delivery. Archives of Advances in Biosciences. 2015;6:38-43. DOI: 10.22037/jps.v6i2.8856
  3. 3.Hashemzadeh H, Allahverdi A, Sedghi M, Vaezi Z, Moghadam TT, Rothbauer M, et al. PDMS nano-modified scaffolds for improvement of stem cells proliferation and differentiation in microfluidic platform. Nanomaterials. 2020;10:668. DOI: 10.3390/nano10040668
  4. 4.Esfandyari J, Shojaedin-Givi B, Hashemzadeh H, Mozafari-Nia M, Vaezi Z, Naderi-Manesh H. Capture and detection of rare cancer cells in blood by intrinsic fluorescence of a novel functionalized diatom. Photodiagnosis and Photodynamic Therapy. 2020;30:101753. DOI: 10.1016/j.pdpdt.2020.101753
  5. 5.Garimella R, Eltorai AEM. Nanotechnology in orthopedics. Journal of Orthopaedics. 2017;14:30-33. DOI: 10.1016/j.jor.2016.10.026
  6. 6.Janfaza S, Banan Nojavani M, Nikkhah M, Alizadeh T, Esfandiar A, Ganjali MR. A selective chemiresistive sensor for the cancer-related volatile organic compound hexanal by using molecularly imprinted polymers and multiwalled carbon nanotubes. Microchimica Acta. 2019;186:137. DOI: 10.1007/s00604-019-3241-z
  7. 7.Razavi H, Darvishi MH, Janfaza S. Silver sulfadiazine encapsulated in lipid-based nanocarriers for burn treatment. Journal of Burn Care & Research. 2018;39:319-325. DOI: 10.1097/BCR.0000000000000602
  8. 8.Hashemzadeh H, Allahverdi A, Ghorbani M, Soleymani H, Kocsis Á, Fischer MB, et al. Gold nanowires/fibrin nanostructure as microfluidics platforms for enhancing stem cell differentiation: Bio-AFM study. Micromachines. 2020;11:50. DOI: 10.3390/mi11010050
  9. 9.Hashemzadeh H, Javadi H, Darvishi MH. Study of structural stability and formation mechanisms in DSPC and DPSM liposomes: A coarse-grained molecular dynamics simulation. Scientific Reports. 2020;10:1-10. DOI: 10.1038/s41598-020-58730-z
  10. 10.Jha RK, Jha PK, Chaudhury K, Rana SVS, Guha SK. An emerging interface between life science and nanotechnology: Present status and prospects of reproductive healthcare aided by nano-biotechnology. Nano Reviews. 2014;5:22762. DOI: 10.3402/nano.v5.22762
  11. 11.de Reis ÉM, de Rezende AAA, Santos DV, de Oliveria PF, Nicolella HD, Tavares DC, et al. Assessment of the genotoxic potential of two zinc oxide sources (amorphous and nanoparticles) using the in vitro micronucleus test and the in vivo wing somatic mutation and recombination test. Food and Chemical Toxicology. 2015;84:55-63. DOI: 10.1016/j.fct.2015.07.008
  12. 12.Hoang V, Ganguli D. Amorphous nanoparticles—Experiments and computer simulations. Physics Reports. 2012;518:81-140. DOI: 10.1016/j.physrep.2012.07.004
  13. 13.Chen Y, Lai Z, Zhang X, Fan Z, He Q , Tan C, et al. Phase engineering of nanomaterials. Nature Reviews Chemistry. 2020;4:243-256. DOI: 10.1038/s41570-020-0173-4
  14. 14.Jiang J, Oberdörster G, Elder A, Gelein R, Mercer P, Biswas P. Does nanoparticle activity depend upon size and crystal phase? Nanotoxicology. 2008;2:33-42. DOI: 10.1080/17435390701882478
  15. 15.Moreau LM, Ha DH, Zhang H, Hovden R, Muller DA, Robinson RD. Defining crystalline/amorphous phases of nanoparticles through X-ray absorption spectroscopy and X-ray diffraction: The case of nickel phosphide. Chemistry of Materials. 2013;25:2394-2403. DOI: 10.1021/cm303490y
  16. 16.Geetha Bai R, Muthoosamy K, Zhou M, Ashokkumar M, Huang NM, Manickam S. Sonochemical and sustainable synthesis of graphene-gold (G-Au) nanocomposites for enzymeless and selective electrochemical detection of nitric oxide. Biosensors & Bioelectronics. 2017;87:622-629. DOI: 10.1016/j.bios.2016.09.003
  17. 17.Song BB, Zhen YF, Yin HY, Song XC. Electrochemical sensor based on platinum nanoparticles modified graphite-like carbon nitride for detection of phenol. Journal of Nanoscience and Nanotechnology. 2019;19:4020-4025. DOI: 10.1166/jnn.2019.16297
  18. 18.Yin HY, Zheng YF, Wang L. Au/CeO 2/g-C 3 N 4 nanocomposite modified electrode as electrochemical sensor for the determination of phenol. Journal of Nanoscience and Nanotechnology. 2020;20:5539-5545. DOI: 10.1166/jnn.2020.17857
  19. 19.Gondim BLC, da Silva Catarino J, de Sousa MAD, de Oliveira Silva M, Lemes MR, de Carvalho-Costa TM, et al. Nanoparticle-mediated drug delivery: Blood-brain barrier as the main obstacle to treating infectious diseases in CNS. Current Pharmaceutical Design. 2019;25:3983-3996. DOI: 10.2174/1381612825666191014171354
  20. 20.Téllez J, Echeverry MC, Romero I, Guatibonza A, Santos Ramos G, Borges De Oliveira AC, et al. Use of liposomal nanoformulations in antileishmania therapy: Challenges and perspectives. Journal of Liposome Research. 2020;31:169-176. DOI: 10.1080/08982104.2020.1749067
  21. 21.Feitosa RC, Geraldes DC, Beraldo-de-Araújo VL, Costa JSR, Oliveira-Nascimento L. Pharmacokinetic aspects of nanoparticle-in-matrix drug delivery systems for oral/buccal delivery. Frontiers in Pharmacology. 2019;10:1057. DOI: 10.3389/fphar.2019.01057
  22. 22.Raza K, Kumar P, Kumar N, Malik R. Pharmacokinetics and biodistribution of the nanoparticles. In: Advances in Nanomedicine for the Delivery of Therapeutic Nucleic Acids. Amsterdam, Netherlands: Elsevier Inc; 2017. pp. 166-186
  23. 23.Abdifetah O, Na-Bangchang K. Pharmacokinetic studies of nanoparticles as a delivery system for conventional drugs and herb-derived compounds for cancer therapy: A systematic review. International journal of Nanomedicine. 2019;14:5659-5677. DOI: 10.2147/IJN.S213229
  24. 24.Rodallec A, Benzekry S, Lacarelle B, Ciccolini J, Fanciullino R, Benzekry S. Pharmacokinetics variability: Why nanoparticles are not magic bullets in oncology. Critical Reviews in Oncology/Hematology. 2018;129:1-12. DOI: 10.1016/j.critrevonc.2018.06.008ï
  25. 25.Moore WR, Graves SE, Bain GI. Synthetic bone graft substitutes. ANZ Journal of Surgery. 2001;71:354-361. DOI: 10.1046/j.1440-1622.2001.02128.x
  26. 26.Hong J, Wang Y, Zhu L, Jiang L. An electrochemical sensor based on gold-nanocluster-modified graphene screen-printed electrodes for the detection of β-lactoglobulin in milk. Sensors. 2020;20:3956. DOI: 10.3390/s20143956
  27. 27.Chen D, Tang L, Reviews JL-CS. undefined graphene-based materials in electrochemistry. Chemical Society Reviews. 2010;8:3157-3180. DOI: 10.1039/b923596e
  28. 28.Zhang X, Wang KP, Zhang LN, Zhang YC, Shen L. Phosphorus-doped graphene-based electrochemical sensor for sensitive detection of acetaminophen. Analytica Chimica Acta. 2018;1036:26-32. DOI: 10.1016/j.aca.2018.06.079
  29. 29.Wang X, Sun G, Routh P, Kim DH, Huang W, Chen P. Heteroatom-doped graphene materials: Syntheses, properties and applications. Chemical Society Reviews. 2014;43:7067-7098. DOI: 10.1039/c4cs00141a
  30. 30.Yu X, Feng L, Park HS. Highly flexible pseudocapacitors of phosphorus-incorporated porous reduced graphene oxide films. Journal of Power Sources. 2018;390:93-99. DOI: 10.1016/j.jpowsour.2018.04.032
  31. 31.Petroni JM, Lucca BG, da Silva Júnior LC, Barbosa Alves DC, Souza Ferreira V. Paper-based electrochemical devices coupled to external graphene-Cu nanoparticles modified solid electrode through meniscus configuration and their use in biological analysis. Electroanalysis. 2017;29:2628-2637. DOI: 10.1002/elan.201700398
  32. 32.Hummers WS, Offeman RE. Preparation of graphitic oxide. Journal of the American Chemical Society. 1958;80:1339. DOI: 10.1021/ja01539a017
  33. 33.Saquib Q , Faisal M, Al-Khedhairy AA, Alatar AA, editors. Cellular and Molecular Toxicology of Nanoparticles. Vol. 1048. Cham: Springer International Publishing; 2018
  34. 34.Rezaei B, Jamei HR, Ensafi AA. Lysozyme aptasensor based on a glassy carbon electrode modified with a nanocomposite consisting of multi-walled carbon nanotubes, poly(diallyl dimethyl ammonium chloride) and carbon quantum dots. Microchimica Acta. 2018;185:1-10. DOI: 10.1007/s00604-017-2656-7
  35. 35.Jasieniak J, Smith L, Van Embden J, Mulvaney P, Califano M. Re-examination of the size-dependent absorption properties of CdSe quantum dots. Journal of Physical Chemistry C. 2009;113:19468-19474. DOI: 10.1021/jp906827m
  36. 36.Silva ACA, de Deus SLV, Silva MJB, Dantas NO. Highly stable luminescence of CdSe magic-sized quantum dots in HeLa cells. Sensors and Actuators B: Chemical. 2014;191:108-114. DOI: 10.1016/j.snb.2013.09.063
  37. 37.de França CCL, Meneses D, Silva ACA, Dantas NO, de Abreu FC, Petroni JM, et al. Development of novel paper-based electrochemical device modified with CdSe/CdS magic-sized quantum dots and application for the sensing of dopamine. Electrochimica Acta. 2021;367:137486. DOI: 10.1016/j.electacta.2020.137486
  38. 38.Silva ACA, Da Silva SW, Morais PC, Dantas NO. Shell thickness modulation in ultrasmall CdSe/CdSxSe 1-x/CdS core/shell quantum dots via 1-thioglycerol. ACS Nano. 2014:8, 1913-1922. DOI: 10.1021/nn406478f
  39. 39.Almeida Silva A, Silva MJ, da Luz FA, Silva D, de Deus S, Dantas N. Controlling the cytotoxicity of CdSe magic-sized quantum dots as a function of surface defect density. Nano Letters;14:5452-5457. DOI: 10.1021/nl5028028
  40. 40.Lammers T, Subr V, Ulbrich K, Hennink WE, Storm G, Kiessling F. Polymeric nanomedicines for image-guided drug delivery and tumor-targeted combination therapy. Nano Today. 2010;5:197-212. DOI: 10.1016/j.nantod.2010.05.001
  41. 41.Zahednezhad F, Zakeri-Milani P, Shahbazi Mojarrad J, Valizadeh H. The latest advances of cisplatin liposomal formulations: Essentials for preparation and analysis. Expert Opinion on Drug Delivery. 2020;17:523-541. DOI: 10.1080/17425247.2020.1737672
  42. 42.Kargozar S, Hoseini SJ, Milan PB, Hooshmand S, Kim HW, Mozafari M. Quantum dots: A review from concept to clinic. Biotechnology Journal. 2020;15:e2000117. DOI: 10.1002/biot.202000117
  43. 43.Wagner AM, Knipe JM, Orive G, Peppas NA. Quantum dots in biomedical applications. Acta Biomaterialia. 2019;94:44-63. DOI: 10.1016/j.actbio.2019.05.022
  44. 44.Silva ACA, Correia LIV, Silva MJB, Zóia MAP, Azevedo FVPV, Rodrigues JP, et al. Biocompatible magic sized quantum dots: Luminescent markers and probes. In: State of the Art in Nano-Bioimaging. Vol. 1. 2017. pp. 95-104
  45. 45.Silva ACA, Azevedo FVPV, Zóia MAP, Rodrigues JP, Dantas NO, Melo VRÁ, et al. Magic sized quantum dots as a theranostic tool for breast cancer. In: Recent Studies & Advances in Breast Cancer. Wilmington: Open Access eBooks; 2017. pp. 1-10
  46. 46.de Lima França CC, da Silva Terto EG, Dias-Vermelho MV, Silva ACA, Dantas NO, de Abreu FC. The electrochemical behavior of core-shell CdSe/CdS magic-sized quantum dots linked to cyclodextrin for studies of the encapsulation of bioactive compounds. Journal of Solid State Electrochemistry. 2016;20:2533-2540. DOI: 10.1007/s10008-016-3221-8
  47. 47.Mansoor KR, Sima KR, Soheila KR. Advancement of polymer–based nanoparticles as smart drug delivery systems in neurodegenerative medicine. Journal of Nanomedicine Reseasrch. 2019;8:277-280. DOI: 10.15406/jnmr.2019.08.00198
  48. 48.Alving CR, Steck EA, Chapman WL, Waits VB, Hendricks LD, Swartz GM, et al. Therapy of leishmaniasis: Superior efficacies of liposome encapsulated drugs. Proceedings of the National Academy of Sciences of the United States of America. 1978;75:2959-2963. DOI: 10.1073/pnas.75.6.2959
  49. 49.Cheng R, Liu L, Xiang Y, Lu Y, Deng L, Zhang H, et al. Advanced liposome-loaded scaffolds for therapeutic and tissue engineering applications. Biomaterials. 2020;232:119706. DOI: 10.1016/j.biomaterials.2019.119706
  50. 50.da Silva MPG, Candido ACL, de Araújo-Júnior JX, Silva ACA, Dantas NO, de Aquino TM, et al. Evaluation of the interaction of a guanylhydrazone derivative with cobalt ferrite nanoparticles and PAMAM electrochemical and UV/visible spectroscopic techniques. Journal of Solid State Electrochemistry. 2020;25:743-752. DOI: 10.1007/s10008-020-04848-z
  51. 51.Williams DF. On the mechanisms of biocompatibility. Biomaterials. 2008;29:2941-2953. DOI: 10.1016/j.biomaterials.2008.04.023
  52. 52.Al-Maawi S, Orlowska A, Sader R, James Kirkpatrick C, Ghanaati S. In vivo cellular reactions to different biomaterials—Physiological and pathological aspects and their consequences. Seminars in Immunology. 2017;29:49-61. DOI: 10.1016/j.smim.2017.06.001
  53. 53.Othman Z, Cillero Pastor B, van Rijt S, Habibovic P. Understanding interactions between biomaterials and biological systems using proteomics. Biomaterials. 2018;167:191-204. DOI: 10.1016/j.biomaterials.2018.03.020
  54. 54.Boss JH, Shajrawi I, Aunullah J, Mendes DG. The relativity of biocompatibility. A critique of the concept of biocompatibility. Israel Journal of Medical Sciences. 1995;31:203-209
  55. 55.Karalashvili L, Kakabadze A, Uhryn M, Vyshnevska H, Ediberidze K, Kakabadze Z. Bone grafts for reconstruction of bone defects (review). Georgian Medical News. 2018;282:44-49
  56. 56.Hasanzadeh Kafshgari M, Goldmann WH. Insights into Theranostic Properties of Titanium Dioxide for Nanomedicine. Nano-Micro Letters. 2020;12:1-35. DOI: 10.1007/s40820-019-0362-1
  57. 57.Molaeirad A, Janfaza S, Karimi-Fard A, Mahyad B. Photocurrent generation by adsorption of two main pigments of halobacterium salinarum on TiO2 nanostructured electrode. Biotechnology and Applied Biochemistry. 2015;62:121-125. DOI: 10.1002/bab.1244
  58. 58.Naseri N, Janfaza S, Irani R. Visible light switchable bR/TiO2 nanostructured photoanodes for bio-inspired solar energy conversion. RSC Advances. 2015;5:18642-18646. DOI: 10.1039/c4ra16188b
  59. 59.Chen X, Selloni A. Introduction: Titanium dioxide (TiO2) nanomaterials. Chemical Reviews. 2014;114:9281-9282. DOI: 10.1021/cr500422r
  60. 60.de Melo Reis É, de Rezende AAA, de Oliveira PF, Nicolella HD, Tavares DC, Silva ACA, et al. Evaluation of titanium dioxide nanocrystal-induced genotoxicity by the cytokinesis-block micronucleus assay and the Drosophila wing spot test. Food and Chemical Toxicology. 2016;96:309-319. DOI: 10.1016/j.fct.2016.08.023
  61. 61.Carvalho Naves MP, de Morais CR, Silva ACA, Dantas NO, Spanó MA, de Rezende AAA. Assessment of mutagenic, recombinogenic and carcinogenic potential of titanium dioxide nanocristals in somatic cells of drosophila melanogaster. Food and Chemical Toxicology. 2018;112:273-228. DOI: 10.1016/j.fct.2017.12.040
  62. 62.Abdel Moniem SM, Ali MEM, Gad-Allah TA, Khalil ASG, Ulbricht M, El-Shahat MF, et al. Detoxification of hexavalent chromium in wastewater containing organic substances using simonkolleite-TiO2photocatalyst. Process Safety and Environment Protection. 2015;95:247-254. DOI: 10.1016/j.psep.2015.03.010
  63. 63.Bakbolat B, Daulbayev C, Sultanov F, Beissenov R, Umirzakov A, Mereke A, et al. Recent developments of TiO2-based photocatalysis in the hydrogen evolution and photodegradation: A review. Nanomaterials. 2020;10:1-16. DOI: 10.3390/nano10091790
  64. 64.Bezerra Neta IA, Mota MF, Lira HL, Neves GA, Menezes RR. Nanostructured titanium dioxide for use in bone implants: A short review. Cerâmica. 2020;66:440-450. DOI: 10.1590/0366-69132020663802905
  65. 65.Weetall HH. Biosensor technology what? where? when? and why? Biosensors and Bioelectronics. 1996;11:i-iv. DOI: 10.1016/0956-5663(96)83729-8
  66. 66.Razavi H, Janfaza S. Medical nanobiosensors: A tutorial review. Nanomedicine Journal. 2015;2:74-87
  67. 67.Abdullah M, Kamarudin SK. Titanium dioxide nanotubes (TNT) in energy and environmental applications: An overview. Renewable and Sustainable Energy Reviews. 2017;76:212-225. DOI: 10.1016/j.rser.2017.01.057
  68. 68.Viter R, Tereshchenko A, Smyntyna V, Ogorodniichuk J, Starodub N, Yakimova R, et al. Toward development of optical biosensors based on photoluminescence of TiO2 nanoparticles for the detection of Salmonella. Sensors and Actuators B: Chemical. 2017;252:95-102. DOI: 10.1016/j.snb.2017.05.139
  69. 69.Wang T, Jiang H, Wan L, Zhao Q , Jiang T, Wang B, et al. Potential application of functional porous TiO2 nanoparticles in light-controlled drug release and targeted drug delivery. Acta Biomaterialia. 2015;13:354-363. DOI: 10.1016/j.actbio.2014.11.010
  70. 70.Zhao L, Mei S, Chu PK, Zhang Y, Wu Z. The influence of hierarchical hybrid micro/nano-textured titanium surface with titania nanotubes on osteoblast functions. Biomaterials. 2010;31:5072-5082. DOI: 10.1016/j.biomaterials.2010.03.014
  71. 71.Chung CJ, Lin HI, Tsou HK, Shi ZY, He JL. An antimicrobial TiO2 coating for reducing hospital-acquired infection. Journal of Biomedical Materials Research Part B: Applied Biomaterials: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials. 2008;85:220-224. DOI: 10.1002/jbm.b.30939
  72. 72.Foster HA, Ditta IB, Varghese S, Steele A. Photocatalytic disinfection using titanium dioxide: Spectrum and mechanism of antimicrobial activity. Applied Microbiology and Biotechnology. 2011;90:1847-1868. DOI: 10.1007/s00253-011-3213-7
  73. 73.Parker D. Luminescent lanthanide sensors for pH, p O2 and selected anions. Coordination Chemistry Reviews. 2000;205:109-130. DOI: 10.1016/s0010-8545(00)00241-1
  74. 74.Barth A, Haris P. Advances in biomedical spectroscopy. In: Biological and Biomedical Infrared Spectroscopy. Vol. 2. Amsterdam, Netherlands: IOS Press; 2009
  75. 75.Lima FF, Andrade CT. Synthesis and characterization of aba-type copolymers for encapsulation of bovine hemoglobin. Quimica Nova. 2012;35:956-961. DOI: 10.1590/s0100-40422012000500017
  76. 76.Trotochaud L, Boettcher SW. Synthesis of rutile-phase SnxTi1-xO2 solid-solution and (SnO2)x/(TiO2)1-x core/shell nanoparticles with tunable lattice constants and controlled morphologies. Chemistry of Materials. 2011;23:4920-4930. DOI: 10.1021/cm201737x
  77. 77.Rodrigues LCV, Stefani R, Brito HF, Felinto MCFC, Hls J, Lastusaari M, et al. Thermoluminescence and synchrotron radiation studies on the persistent luminescence of BaAl2O4:Eu2,Dy3. Journal of Solid State Chemistry. 2010;183:2365-2371. DOI: 10.1016/j.jssc.2010.07.044
  78. 78.Richardson FS. Terbium(III) and europium(III) ions as luminescent probes and stains for biomolecular systems. Chemical Reviews. 1982;82:541-552. DOI: 10.1021/cr00051a004
  79. 79.Kodaira CA, Brito HF, Malta OL, Serra OA. Luminescence and energy transfer of the europium (III) tungstate obtained via the Pechini method. Journal of Luminescence. 2003;101:11-21. DOI: 10.1016/S0022-2313(02)00384-8
  80. 80.Silva HRM, Fonseca MG, Espínola JGP, Brito HF, Faustino WM, Teotonio EES. Luminescent Eu III complexes immobilized on a vermiculite clay surface. European Journal of Inorganic Chemistry. 2014;2014:1914-1921. DOI: 10.1002/ejic.201301494

Written By

Anielle C.A. Silva, Eliete A. Alvin, Lais S. de Jesus, Caio C.L. de França, Marílya P.G. da Silva, Samaysa L. Lins, Diógenes Meneses, Marcela R. Lemes, Rhanoica O. Guerra, Marcos V. da Silva, Carlo J.F. de Oliveira, Virmondes Rodrigues Junior, Renata M. Etchebehere, Fabiane C. de Abreu, Bruno G. Lucca, Sanívia A.L. Pereira, Rodrigo C. Rosa and Noelio O. Dantas

Submitted: December 23rd, 2021Reviewed: January 10th, 2022Published: May 13th, 2022