Applications of Nano-Ferrites in Medicine

Abstract

Nano-ferrites are elegant and smart nanoparticles. Biomedical implementations of nano-ferrites include cell signaling, hyperthermia, magnetic resonance imaging (MRI), nanorobots, drug delivery, anti-cancer function, anti-fungi, anti-bacteria, biosensors, brain stimulation, wound healing, etc. Nano-ferrites showed anticancer features towards various types of cancer cells, such as breast cancer. They have been used for drug delivery as well as drug release. Magnetic hyperthermia is a successful approach in cancer treatment, where nano-ferrites have been used under the influence of external magnetic fields. Nano-ferrites are used as magnetic resonance imaging (MRI) contrast agents. Furthermore, nano-ferrites have been involved in the magnetic nanorobots and biosensors industries. Superparamagnetic nanocrystals including manganese nano-ferrites have been utilized in the activation of thermos-sensitive transient receptor potential vanilloid 1 (TRPV1) channels to attain further brain stimulation. The chemo-genetic modulation of targeted neural circuits using superparamagnetic nano-ferrite particles provides a novel strategy for brain stimulation so as to investigate brain functions and neurological diseases. Moreover, they have antibacterial and antifungal activity against several types of bacteria and fungi, such as E. coli and Candida albicans. Pr₆O₁₁/Fe₂O₃/GO@PCL film nanocomposites have been used in skin wound healing treatment; thence, these smart new nanocomposites could be utilized in the advancement of wound healing applications.

1. Introduction

Nano-ferrites with their wide variety of types continue to be extremely essential nanocrystals in the recent era from scientific, industrial as well as technological prospects ever since their discovery in 1950s. Specification of such nanocrystals as nano-spinel, nano-hexaferrites, and orthoferrites stems from their tiny nano-particles size as well as their Versatile crystal structures. Recently, ultimate advanced scientific research vistas have essentially focused on promoting and preparing new unique nanocrystals with ultra-fine grain sizes for utilizations in too diverse and spreading technological fields likespintronics, magnetic recording media, shielding technology, and microwave attenuators imputing to their extremely high thermal stability, non-toxic merits, supreme chemical stability and extremely supreme corrosion resistivity [1, 2, 3, 4, 5]. Obviously, Ferrite nanocrystals are vital in industrial vistas such as their uses in wireless networks, Mobile technologies, RADAR, and permanent magnets. The ultimate focus of researchers today is synthesizing these nanocrystals utilizing diverse synthesis procedures and varied characterizing strategies [5, 6, 7, 8].

Early in history, ancient Greeks used lodestone (magnetite Fe₃O₄) to cure many diseases. By precisely advanced nano-biotechnology, utilization of these diverse magnetic ferrite nanocrystals has emerged, which extends to clinical research vistas and modern biomedicine aspects. Since biological tissues are transparent to magnetic fields, in biomedical implementations ferrite nanocrystals could perform various functions synchronized with invisible tissue penetrating magnetic fields. For example, a sort of natural magnetotactic bacteria naturally form Fe oxide nanocrystals in order to generate permanent diodes interior their own natural cells so as to navigate towards the most convenient habitats by the outstanding property of sensing our planet’s magnetic field. These unique ferrite nanocrystals obtain excellent biocompatible features, which in turn used as therapeutic and magnetic resonance imaging agents in clinical scientific research. Then, for the supreme magneto-responsive merits of these nanocrystals, versatile expanding biomedical implementations are created. These wide expanding uses include magnetic resonance imaging (MRI) for various tissues, nanorobots, cell signaling, curing of illnesses via hyperthermia, drug delivery, anti-cancer function, anti-bacterial and anti-fungi function, biosensors, etc. Obviously, ferrite nanocrystals can be delivered to the targeted biological tissues, thus they possess the capability to induce diverse cell responses for modulating biological systems via conversion of external magnetic field energies into bio-sensitive signals, such as heating stimuli, mechanical forces and inducing local field [9, 10, 11, 12, 13, 14, 15]. However, nanocrystal function is highly influenced by the magnetic features of these ferrite ultrafine nanoparticle mediators. Therefore, for efficient transduction of biochemical signals, it is extremely vital to engineer ferrite nanocrystals with enhanced magnetic response. In this respect, biological effects generated by ferrite nanocrystals are extremely influenced by their magnetic merits like saturation magnetization, chemical stability, thermal stability, corrosion resistivity, ultrafine size nature, chemical composition, crystalline structure, and surface morphology, which is closely related to thermal conversion efficiency. Furthermore, several strategies could be taken into consideration in synthesizing assemblies or clusters of magnetic ferrite nanoparticles for improving their performance and merit like saturation magnetization and enhancing their magnetic response for their pioneering biomedical implementations [9, 10, 11, 12, 13, 14, 15].

One of the most recent talented nanostructures is the one-dimensional magnetic nanowire, nanotube, and nanofiber, which possess unique chemical and physical merits. Thus, these magnetic nanofibers have several implementations such as nanoscale magnetic devices industry and biomedical applications like hyperthermia which are extensively attractive and low-cost strategies for cancer treatment. However, magnetic nanocrystals are utilized as supporting material in Radiotherapy and Chemotherapy. Iron oxide nanocrystalline diverse structures have been extensively utilized for hyperthermia application imputing to their ultimate non-toxicity, supreme corrosion resistivity, superior chemical stability, low cost, and echo-friendly habit. As an example, Ni ferrite nanofiber which can be synthesized via electrospinning procedure and also can be annealed to variable annealing temperature degrees in order to obtain various sizes of nanofibers, has been utilized for hyperthermia applications. Their shape enables them to produce extra heat energy at RF alternating magnetic fields. Oleic acid-coated Ni ferrite nanocrystals were utilized for hyperthermia and drug delivery applications. The scarcity of research on the synthesis, structural, magnetic, and hyperthermia of nickel ferrite nanofibers makes them marvelous nanostructures for these studies [16].

Nano-ferrites have diverse nanocrystalline structures and morphological shapes such as one-dimensional (1D) nanoparticles, two-dimensional (2D) nanoparticles, and three-dimensional (3D) nanoparticles. One-dimensional nanoparticles consist of nanorods, nanowires, and nanotubes, and possess obvious interesting biomedical implementations imputing to their unique magnetic merits. Nanorods possess diameters beginning from a few nanometers up to 100 nm in length. Nanotubes have hollow nanorods morphological shapes. Nanowires possess lengths greater than 100 nm. They can be synthesized via diverse preparation routes like hydrothermal, co-precipitation strategies, etc. While two-dimensional (2D) nanoparticles consist of nanofilms, nanoplates, and nanosheets. These 2-dimensional nanostructures could be synthesized via thermal decomposition and co-precipitation strategies with the precise control of annealing temperatures and conditions, furthermore, they are convenient candidates for several biomedical implementations. On the other hand, the anisotropic three-dimensional (3D) nanoparticles consist of nanospheres, nano-cubes, and nanoflowers. 3-Dimentional nanostructures could be synthesized via thermal decomposition and co-precipitation strategies, etc., with the accurate handling and control of annealing temperatures and conditions, over and above, they are convenient nanocrystals for several biomedical implementations [17]. These diverse morphological nanostructures of nano-ferrites are indicated in Figure 1 [17].

Figure 1.

TEM images of different shapes of MnFe₂O₄ nanoparticles (a) nanospheres, (b) nano-cubes, (c) nanorods, (d) nanowires, (e) nanorods, (f) triangular, (g) polyhedron, and (h) nano-octahedron [17].

2. Biomedical applications of nano-ferrites

Biomedical implementations of nano-ferrites extensively dependent on the toxicity and biocompatibility of these nanocrystals. There are some considerable parameters that influence the toxicity and bio-compatibility of these ferrite nanoparticles such as morphological shape and size of nanoparticles including their coatings as well as their magnetic response. The main outstanding merits of nano-ferrite crystals in order to be utilized in various biomedical implementations in in vivo and in vitro are biodegradability, low toxicity, supreme magneto-responsive attribute, and long blood retention time. Obviously, nano-ferrites possess versatile expanding biomedical implementations including, cell signaling, hyperthermia, magnetic resonance imaging (MRI), nanorobots, drug delivery, anti-cancer function, anti-fungi, anti-bacteria, biosensors, etc. [11, 12, 13, 14, 15, 16, 17]. Figure 2 illuminates ferrite nanoparticles and various polymer stabilization methods over them [17, 18, 19].

Figure 2.

Ferrite nanoparticles and various polymer stabilization methods over them [17].

2.1 Toxicity impact

Toxicity impact in cell culture/blood components is a significant parameter that must be examined before any use of nano-ferrites in an in-vivo investigation. There exist several sorts of cytotoxicity examination such as Alamar Blue, MTT, and Trypan Blue assay, which lack standard procedure, hence several examination tests should be done. MTT colorimetric assay (3-[4,5-dimethylthiazol- 2-yl]-2,5 diphenyl tetrazolium bromide) is the most cost-effective and classical assay for cytotoxicity investigation. For the Alamar Blue assay, viable cells are found after whole number of cells are brood with non-fluorescent resazurin dye. Exclusion test (Trypan blue dye assay) is used to determine dead cells. Reactive oxygen species (ROS) assay is utilized to examine the cytotoxicity of nano-ferrites. It is intended to determine ROS generation as an indicator of cellular oxidative stress. Nano-ferrites such as Mn ferrite nanoparticles are efficient nanocrystals for magnetic hyperthermia and their toxicity level was examined for various cancer cell lines like human melanoma cell line (MW35), mouse melanoma cell line (B16F10), human lung adenocarcinoma (A549) cell line, HeLa cell line, etc. As nano-ferrite concentration increases, cancer cell viability decreases [17, 18, 20]. Toxicity effect of CoFe₂O₄ nanoparticles (CF-NPs) and Mg_0.05Co_0.95Fe₂O₄ nanoparticles (MCF-NPs) on human breast cancer cells (MCF-7) via MTT assay indicated that, with the increase of ferrite nanocrystals concentration, the cytotoxicity was influenced and is dose-dependent, and the viability of the MCF-7 cells decreased as indicated in Figure 3 [20].

Figure 3.

Cytotoxicity (cancer cell death) of CoFe₂O₄ nanoparticles (CF-NPs) and Mg_0.05Co_0.95Fe₂O₄ nanoparticles (MCF-NPs) against human breast cancer cells MCF-7 [20].

The cytotoxic properties against human breast (MCF-7) cancer cells by MTT assay and their reactive oxygen species (ROS) are obviously showing an increased trend with the increase of concentration. It was obvious thatthe viability cells were dose-dependent. Cytotoxicity results occurred by decreasing cell viability with increasing nano-ferrites concentrations by the exposure to different kinds of Ferrite nanoparticles as indicated in Figure 3. The explanation for this is related to the entrance of NPs towards cancer cells, geometry, size, and distinctive properties of NPs were responsible for the cell death. Cell membranes exhibit small pore-like passages that facilitate to entry of ferrite nanoparticles into cells and damage to the upper layer of the cell membrane. The nanostructures can be easily entered into the cytoplasm of the cell and react with cell’s organelles diminishing the growth of cancer cells. Further, morphological changes in cancer cells in the presence of Ferrite nanoparticles are occurring. Additionally, to know the cytotoxicity of cancer cells and the role of nano-ferrites in the mechanism, the reactive oxygen species (ROS) for 24 hours is also measured, as indicated in Figure 4. It was considered that the production ROS by interaction of nano-ferrites play the key role in mechanism of cytotoxicity because they can directly disturb the many components of cells such as DNA structure, proteins and lipids which in turn prime cause of cell death. Consequently, dose-dependent features and upsurge rate of ROS generation support the cytotoxicity results and cancer cell death as well [20].

Figure 4.

The reactive oxygen species (ROS) generation by nano-ferrites for CoFe₂O₄ nanoparticles (CF-NPs) and Mg_0.05Co_0.95Fe₂O₄ nanoparticles (MCF-NPs) against in human breast cancer cells MCF-7 [20].

2.2 Drug delivery and release

Biocompatible nano-ferrites are distinguishable imputing to their drug delivery and release, tumor treatment capability, and safe liberation from bio-systems. Utilization of these nanocrystals reduces the required drug amount and avoids side effects, where nano-ferrite particles serve as a core covered with a shell of biocompatible organic moieties such as Chitosan, dextran, polyethylene-glycol, etc. Furthermore, a gold shell is utilized to protect nano-ferrites core from oxidation. Anticancer drug is embedded inside nanocomposites or bonded to the outer surface of nanocomposites via a linker. Nano-ferrite cores assist in guiding anticancer drugs via the use of external magnetic fields, whilst shells serve as surface modifiers or stabilizers at which they surge targeting potential. Drug release mechanisms are widely utilized, e.g., light, redox stimuli, enzyme, PH, thermal, etc. [20].

2.2.1 Drug delivery

Drug delivery agents like ferrite nanocrystals guided with external magnetic fields are the main focus for scientists from all over the world imputing to their efficient strategy, simple mechanism, simple synthesis procedure, cost-effectiveness, and targeting their accurate function in biological systems. These smart nanoparticles can be directed toward a specific cell or tissue maximizing their effect. Furthermore, nano-ferrites can deliver drugs like Dox and Cisplatin by encapsulating them inside a polymer matrix to the tumor tissue. They can also carry drugs circulate without leakage and move more flexibly to targeted tumors with aid of external magnetic field, thus assisting in giving an efficient therapeutic cure to the cancer. Once it is delivered to tumor tissue, the drug will be released and provide its therapeutic effects. Hybrids composed of nano-ferrites, anticancer drugs, semiconductors, and biocompatible coating agents (such as chitosan nano-ferrites hybrid with folate-conjugated tetrapeptide nanocomposite) are special agents for efficient cancer therapy [9, 20, 21, 22].

2.2.2 Drug release

The marvelously efficient drug release mechanisms, e.g., light, redox stimuli, enzyme, PH, thermal, etc., are extensively used. Another efficient procedure that also impacts drug release is using magnetic nano-ferrites with the aid of external magnetic fields. Magnetic guidance of drug release is obviously a marvelous route or strategy for controlled drug release. Then, nano-ferrites are extremely important agents acting in drug delivery and on the other hand, greatly impact drug release. Moreover, they are utilized in remote-controlled drug release. An example, for DOX loaded into nano-ferrite-chitosan as they are delivered to the target (tumor tissue) and influenced by alternative magnetic field, by heat generated by ferrite nanocrystals as well as the mechanical deformation occurring, DOX is easily released. As magnetic field amplitude surges the rate of DOX release increases up to an optimum rate of release. Furthermore, hyperthermia is a precise efficient strategy for drug delivery and release [20, 21, 22].

2.3 Magnetic hyperthermia

Cancer treatment strategies involve radiotherapy, chemotherapy, hyperthermia (HPT), and surgery. Magnetic HPT is an elegant procedure of cancer therapy that is very destructive for cancer cells with the aid of an external AC magnetic field using magnetic nanocrystals like nano-ferrites. Nanocrystals ratio and their toxic effects are the major anxieties in magnetic HPT. HPT focuses on the accumulation of guided magnetic nanoparticles at tumor site, and generation of heat under influence of AC magnetic fields, which in turn selectively kill tumor cells. Core-shell nanostructures are more efficient for magnetic HPT than single-phase nano-ferrites, at which self-heating merits under AC magnetic fields have been early examined for HPT. Types of HPT are localized, regional, and whole-body HPT. HPT is heating specific tumors up to 46°C, at which the normal enzyme processes are destroyed and blood vessels inside the tumor have low thermic resistance. HPT is an essential therapy for cancers, where cancers accept much more heat imputing to their surging metabolism rate. Control of exposure spans and heating rate is the only way to make HPT more precise and efficient via utilizing magnetic nanoparticles with a certain specific absorption rate (SAR) at low concentrations. SAR is the rate of heat generated per unit mass, which is highly influenced by the magnetic nanoparticles size, distribution, shape, anisotropy constant, saturation magnetization, and morphology. Generated heat depends on nanoparticle size and type as well as the frequency and amplitude of the AC magnetic field [17, 20, 23]. The conducting strategies for thermotherapy are utilizing microwave, laser therapy, and ionizing radiation. Nanoparticles are commonly utilized for thermotherapy for elimination of cancer cells, such as gold nanotubes, nano-ferrites, etc. Gold nanotubes convert IR rays into thermal energy for the treatment of tumors. Cobalt nano-ferrite possesses higher anisotropy and can lose magnetic moment slowly, thus, tumor cells could absorb the resultant heat more robustly. However, graphene nanosheets conjugated Cobalt nano-ferrites have lower cytotoxicity. Furthermore, graphene platelets prevent aggregation of Cobalt nano-ferrites particles without reduction of their magnetic potency. Graphene/cobalt ferrite nanoparticles are utilized for magnetic HPT implementations. Biocompatibility of graphene oxide (GO)/cobalt ferrite nanoparticles on neural stem cells has been investigated indicating that these nanostructures are excellent candidates for HPT [24].

2.4 Magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI) is a delicate diagnostic strategy that can provide 3-dimensional anatomical images of the body. MRI of tumors is the first stage in cancer therapy for locating tumor position, its spread extent, and determining curing strategy. MRI is used for revealing the early stages of various tumors and tracking drug responses. The principle of nuclear magnetic resonance (NMR) is the fundamental basis for MRI, which produces extremely high-accuracy biological images. Magnetic nano-ferrite particles have been extensively utilized as MRI contrast agents. MRI signal promotion is imputed to super-exchange interactions inside nano-ferrites as well as dipole-dipole interaction between nano-ferrites and H₂O surrounding them, to limit longitudinal or transverse relaxation times. Superparamagnetic nano-ferrites have been extensively utilized for in vivo biomedical implementations, like drug delivery, hyperthermia, and MRI contrast agents. Cobalt nano-ferrites proved excellent efficiency in MRI imputing their rise in anisotropy constant, coercivity, mild saturation magnetization, extremely high chemical stability, and biocompatible merits (as illuminated in Figure 5) [9, 25].

Figure 5.

MRI images of liver and spleen (a) CA Fe₃O₄, (b) CA cobalt ferrites—20%wt, (c) CA cobalt ferrites—40%wt. (white arrow show anatomy of stomach of rabbit, green arrow shows liver of rabbit) [25].

Iron oxides like Fe₃O₄ and Fe₂O₄ have been widely used as contrast agents due to their chemical stability, no toxicity, and biodegradability. Co-ferrite are considered good candidates for developing T₂ contrast agents with higher relaxivity. Basically, Co-ferrite (CoFe₂O₄) nanoparticles perturbed the magnetic relaxation process of protons in the tissue and induced the shortening of the spin–spin relaxation time of the proton. The high saturation magnetization leads to the relaxivity enhancement of undergone tissue of the body. MRI study of Co-ferrites was performed at low field MRI unit (0.35 Tesla MAGNETOM) in order to get high contrast underwent organs such as the liver and spleen of rabbits. For this purpose, a solution 0.02 mg Fe/Kg of iron oxides and cobalt ferrites was prepared in saline water, and an intravenous dose of contrast agent was delivered through vein of ear. Four rabbits of equal weight were taken to compare the contrast enhancement on MRI images. Using IQ View software, it has been measured that the intensity of signal induced by contrast agents such as iron oxides (for liver, I = 1433 ± S.D. = 111.5, spleen, I = 1009 ± S.D. = 96.5), cobalt ferrites (for liver, I = 1513 ± S.D. = 102.2, spleen I = 1694 ± S.D. = 219.2) as shown in Figure 5a–c. It could be concluded that cobalt ferrites induced high signal intensity of T₂ contrast agents as compared to iron oxide nanoparticles. Metal-doped contrast agents may be used for clinical purposes to diagnose many diseases for clinical use of MR contrast agents [25].

2.5 Magnetic nanorobots

Magnetic nano-ferrites continue to surprise scientists in wide-spreading vistas of science, such as biomedicine, nano biosensors, magnetic nano-robots, etc. It could be collected as nanorobots of various styles, and magnetically guided to perform diagnosis and curing of illnesses. An example, a nanorobot has been created in a shape like a fan nanorobot covered by nano-liquid layer in order to precisely execute functions in the vitreous body of the eye and controlled in a delicate way. Also, a rectangular-shaped sheet magnetic robot has been fabricated from the hard magnetic NdFeB particles in silicon elastomer. Under the guidance of an external magnetic field over time, magnetic nanorobots could vary their appearance, climb, roll, walk, jump, crawl, and swim. Furthermore, they could grab objects, transport them to the target site, and eject cargos strapped onto magnetic nanorobot. DNA magnetic nanorobots based on a super-soft and super-elastic magnetic DNA hydrogel were able to exhibit shape-adaptive merits, and enhanced magnetically guided navigation velocity in limited and random spaces. Guided magnetic nanorobots are anticipated to provide elegant penetration in invasive medicine within the human body in the nearest future (as illustrated in Figure 6) [9].

Figure 6.

(A) Small-scale soft-bodied robot in medical applications, (B) schematic and optical images of a microscale ‘bird’ mimicking four flying modes, (C) schematic of magnetic DNA hydrogel synthesis, and (D) shape adaptation characteristics of DNA robots [9].

2.6 Biosensors

Magnetic nanoparticles like nano-ferrite crystals continue to surprise scientists and the scientific community as they are used in enormous numbers of research, application, and biotechnological implementation vistas such as contrast agents in MRI, drug delivery, biosensors, hyperthermia, magnetic nanorobots, cancer cells killers, etc. Biosensors are responsive to biological signals emitted from certain cells or tissues which could be converted into electrical signals. Core–shell nanoparticles possess large surface areas and ultra-tiny particle sizes, which in turn, increases interaction areas and biosensor sensitivity. Magnetic nanoparticles should own some vital merits in order to be utilized as biosensors, such as extremely high chemical stability, high corrosion resistivity, simple and easy synthesis, high magnetic susceptibility, extremely high stability in physiological ambiance, and excellent dispersibility. Nano-ferrite core–shell nanoparticles are excellent candidates for biosensor implementations, imputing their unique structural, optical, magnetic, and piezoelectric merits. Nano-ferrites magnetic core is surrounded by inert shell to protect them from oxidation and make them inert while maintaining their magnetic demeanor. Gold shell covering Cobalt ferrite core is utilized as deoxyribonucleic acid (DNA) biosensor. Thiol-modified peptide nucleic acid oligomers attached to Au/Cobalt ferrite core-shell nanoparticles can interact with DNA target molecules. This modified sample is a good platform for the immobilization of biomolecules which can be used to detect point mutations or single nucleotide polymorphisms in DNA. Enzyme-free Glucose biosensors have been the main focus recently for the detection of diabetics imputing to their high thermal stability, extreme chemical stability, and reproducibility. Enzyme-free Glucose biosensors with Zinc ferrite/polypyrrole core–shell nanoparticles nanocomposites interestingly possess promoted electrochemical effectiveness toward Glucose oxidation with excellent sensibility. Copper ferrite/Polypyrrole core–shell nanoparticles are advanced nanomaterials utilized as Glucose sensors. These biosensors showed extremely surging electrochemical activity toward Glucose electro-oxidation. Polyvinyl pyrrolidone (PVP) capped Cobalt ferrite/Cadmium Selenide core–shell nano-composites were affirmed as excellent electrochemical biosensors for the detection of Rifampicin antibiotic. These new excellent biosensors possess long time span stability, extremely high sensibility, and reproducibility, which makes them excellent future candidates as a novel platform for the fabrication of electrochemical biosensors and further sensor implementations [23].

2.7 Brain stimulation

Magnetic ferrite nanoparticles continue to be very exciting nanocrystals imputing their unique structural, spectral, optical, chemical, physical, thermal, and especially electrochemical features. Then, they are excellent candidates for versatile implementations such as using them in brain stimulation. These nanocrystalline structures could be utilized in brain stimulation, which is established on the magneto-thermal effect under the influence of the alternating magnetic fields (AMF), whilst this strategy is known as the magneto-thermos-genetics strategy (magneto-genetics). A small comparison between the traditional procedures that are based on the utilization of chemicals and electrodes, and, the second-generation procedures that are based on the utilization of opto-genetics, and ultrasound, on the other hand, magneto-genetics has superiority over the first strategies. Magnetogenetics possess the superiority of cell type specificity as well as their superior temporal and spatial resolution. All and above Magneto-genetics methodology does not require tethering animals to an energy source [9]. Thence, scientists have an enormous interest in utilizing such nanostructured Magneto-genetics to activate the heat-sensitive transient receptor potential vanilloid 1 (TRPV1, ˃ 316 K) to attain further brain stimulation. Superparamagnetic nanocrystals including Manganese nano-ferrites, Magnetite (Fe3O4), Ferritin, Cobalt nano-ferrite core @ Manganese nano-ferrite core–shell nanostructure, have been utilized in the activation of thermos-sensitive TRPV1 channel. Manganese nano-ferrites showed that by heated up they could activate the TRPV1 channel. Then, by side some results happened, like, intracellular calcium concentration increased, triggered action potentials in primary hippocampal neurons, and elicited retracting motions in partially anesthetized C. elegans worms. Ferri-magnetic Magnetite (Fe₃O₄) nanoparticles coated with anti-His antibody could target the TRPV1 channel with an extracellular His × 6 epitope tag, which could remotely activate TRPV1 and stimulate the synthesis and release of proinsulin for regulation of insulin production in mice [9]. Green fluorescent protein (GFP) tagged ferritin nanoparticles have also been synthesized and intracellularly associated with a camelid anti-GFP-TRPV1, which could initiate calcium-dependent insulin transgene expression and modulate neuronal activities to induce feeding. A mutated chloride-permeable TRPV1 was further developed, and the neuronal inhibition was achieved via the same heat stimulation that responded to blood glucose levels and decreased feeding. Ferri-magnetic Magnetite (Fe₃O₄) could remotely activate TRPV1 and recall excitation in the targeted ventral tegmental area in vivo. Cobalt nano-ferrites @ Manganese nano-ferrites core–shell was early synthesized, however, with their superior magneto–thermal performances, they were utilized to stimulate neurocircuit and modulate behavior in awake mice, as illuminated in Figure 7A. The heat lost by superparamagnetic nano-ferrite particles could trigger the release of tiny molecules (agonist or inhibitor) from the thermally sensitive lipid vesicles and be applied to the thermally sensitive lipid vesicles and be applied to chemo-genetic activation of engineered receptors, as illuminated in Figure 7B. The chemo-genetic modulation of targeted neural circuits using superparamagnetic nano-ferrite particles provides a vital and novel strategy for brain stimulation so as to investigate brain functions and neurological diseases [9].

Figure 7.

(A) Magnetic nano-ferrite particles (MNFPs) under alternating magnetic field (AMF) activate TPRV1 channels, (B) chemo-magnetic stimulation in vivo [9].

2.8 Antibacterial applications

Nano-ferrite particles continue to be outstanding nanoparticles for versatile potential applications in numerous vistas including, biosensors, drug delivery, high-density information storage, magnetic refrigeration, etc. Among these, nano-spinels have been extensively investigated imputing their unique chemical and physical merits and their technological implementations in the biomedical vistas, antimicrobial, anti-fungi, photocatalysts, etc. Nanoscale substances like nano-ferrite possess almost similar sizes compared to biological molecules, so they can penetrate easily and interact with these biomolecules, and not possible for macromolecules. As these ultra-tiny nanoparticles were reduced to nano-scale extent they considerably changed their magnetic, optical, electrical, and chemical features, which also promoted these NPs to interact with biological systems in a unique strategy [26, 27, 28]. Aluminum Zinc nano-ferrite particles agglomeration influence has an important antibacterial activity, and fine dispersity of ultrafine nanoparticles, which is fundamental for efficient antibacterial activities. Antibacterial activity of Aluminum Zinc nano-ferrite particles obviously precisely occurs when prepared nanocrystals interact with cellular membrane resulting in production of Reactive Oxygen Species (ROS). The inhibition zone of E. coli and Pseudomonas aeruginosa against at Aluminum Zinc nano-ferrite particles and Nickel Zinc nano-ferrite particles is pictured and illuminated in Figure 8. Zinc nano-ferrite particles provided an antibacterial activity against Gram-negative with the maximum inhibition zone of 10 mm. For Aluminum Zinc nano-ferrite particles, they provided antibacterial activity against Pseudomonas aeruginosa with a maximum inhibition zone of 14 mm. Whilst, on the other hand, Nickel Zinc nano-ferrite particles provided antibacterial activity against E. coli with a supreme inhibition zone of 17 mm. Antibacterial activity of Aluminum Zinc nano-ferrite particles essentially occurs in an accurate mechanism when ultrafine nanocrystals interact with cell membranes resulting in the increased production of ROS. The affirming evidence proposes that when the biological cells are exposed to the ultra-tiny nano-ferrite particles, this can produce an imbalance in the cellular reduction–oxidation process of bacteria by changing reactive oxygen species that may interrupt the bacterial-antioxidant defense responses. The increased ROS level generates oxidative stress, which is believed to be the contributing factor in the antimicrobial activity of NPs [26, 27, 28].

Figure 8.

Antibacterial activity by agar well-cut diffusion method against E. coli of (a) zinc nano-ferrite at 400°C, (b) antibacterial effect against Pseudomonas aeruginosa of aluminum zinc nano-ferrite (0.05), (c) antibacterial effect against E. coli of aluminum zinc nano-ferrite (0.05), (d) antibacterial effect against E. coli of nickel zinc nano-ferrite (0.05) [26].

2.9 Anti-fungi applications

Superparamagnetic nano-ferrite particles have provided superior antibacterial features against various bacteria and fungi. Cobalt Ferrite nanoparticles are obviously utilized for biomedical implementations imputing their ability to combat various human infections. The ultra-fine size nature of these nano-ferrites as well as their high specific surface area makes them effective against harmful microorganisms [29]. The antifungal influence of Barium nano-ferrite particles has been precisely investigated as illuminated in Figure 9. The broth media of each condition was seeded in independent agar plates and the colony forming units (UFC) were assessed and referred over control (Figure 9).

Figure 9.

Growth of Candida albicans treated with different concentrations of barium ferrite nanoparticles over control [29].

2.10 Nano-ferrites for wound healing

Skin is the Extremely large body organ that spreads over the surface of the whole body. Skin including hair, nails, oil, and sweat glands form the human integumentary system. Skin main function is to defend the whole human body from external dangers such as; insects, parasites, bacteria, viruses, infections, wounds, sores, temperature, heat, humidity, chemicals, etc. Skin, the fundamental organ for humans, possesses esthetic nature as well as playing an active role in the immune system. Skin wounds essentially originate from accidents by sharp articles, metal fragments, sharp glass blades, or chronic ulcerations, thus it needs rapid therapeutic intervention or fast treatment and cure. Natural skin regeneration procedures may face several hurdles like bacterial infection, hence, hastening to heal is vital in skin regeneration healing. New synthesized nanostructured biomaterials must have several merits such as biocompatibility and biodegradability to avoid inflammation. Furthermore, they must have a special surface that assists cell adherence, splitting, and regeneration. Moreover, there should be a suitable porosity ratio that allows construction of blood vessels. Otherwise, diverse nanostructured biomaterials, such as bio-polymeric matrices (such as e-poly-caprolactone (PCL)/ampicillin fibrous nano-composition), have been proposed for enhancement of tissue integration [30, 31, 32, 33, 34, 35].

Graphene oxide (GO) is a honeycomb crystalline structure formed of a single sheet or layer made up of a 2D array of Carbon atoms. GO is a new elegant and smart substance as it exhibits superior mechanical attributes and smart biocompatibility merits. It is obvious that GO possesses brilliant biological activity, and above this, the functional groups on GO surface, such as OH groups enhance hydrophilicity. There are several routes of synthesizing new intelligent nanocomposite structures in order to promote new smart structural, chemical, physical, thermal, and biological features. On the other hand, rare earth nanostructured crystals possess biological activity such as enhancing the therapeutic development in the new race of advancement of biomedical nanomaterials engineering. Thence, uniting nanostructured materials such as nano-ferrites, GO, rare earth nanostructures, etc., upon their unique functional demeanors could provide a delicate strategy in order to secure viable biomaterials in skin wound healing. Praseodymium oxide (Pr₆O₁₁), hematite (Fe₂O₃), graphene oxide (GO), and Polycaprolactone (PCL) based polymeric film nanocomposites (NCs) have been combined and synthesized to produce various polymeric nanocomposites for investigation of their biological activity and enhancement of skin wound healing. Pr₆O₁₁/Fe₂O₃/GO@PCL film NCs presented a promotion in skin wound healing at which it possesses a high capacity for healing, reaching around 80%, as it assists the division of normal cells promoting wound healing. Thence, these smart new nanocomposites could consolidate in production of new applicable marvelous nanostructures in wound healing applications [30, 31, 32, 33, 34, 35].

The contact/wettability angle is a pointer to bio-applicability owing to the fact that the lesser the contact angle the higher the biological potential. The studied compositions’ contact angle values according to Figure 10 are ≈ 43, 38, 46, 38, and 55° for PCL, Pr₆O₁₁@PCL, Fe₂O₃@PCL, Pr₆O₁₁/Fe₂O₃@PCL, and Pr₆O₁₁/Fe₂O₃/GO@PCL, respectively. The displayed data support the Pr₆O₁₁ effect on lessening contact angle, thus affecting nano-ferrites biological potential positively [30, 31, 32, 33, 34, 35].

Figure 10.

Contact angle of e-poly-caprolactone (PCL) based fibrous nano-composite; where (a) PCl, (b) Pr₆O₁₁@PCl, (c) Fe₂O₃@PCl, (d) Pr₆O₁₁/Fe₂O₃@PCl, and (e) Pr₆O₁₁/Fe₂O₃/GO@PCl [31].

3. Conclusion

Nano-ferrites are ultra-tiny crystalline structures and possess versatile expanding applications ranging from permanent magnets to internet, computer, and mobile technologies. Above this, they possess very important biomedical implementations including, drug delivery, anti-cancer function, anti-fungi, anti-bacteria, cell signaling, hyperthermia, brain stimulation, magnetic resonance imaging (MRI), nanorobots, biosensors, wound healing, etc. Nano-ferrites showed great success in anticancer function towards various types of cancer cells, such as breast cancer as well as drug delivery and drug release. Their success in magnetic hyperthermia extends to cancer treatment, where nano-ferrites have been used under the influence of external magnetic fields to eliminate cancer cells and tumors. Nano-ferrites are used as magnetic resonance imaging (MRI) contrast agents. Their obvious utilization in the magnetic nanorobots and biosensors industries adds a new success to their usage. Also, scientists have utilized Manganese nano-ferrites to activate the heat-sensitive transient receptor potential vanilloid 1 (TRPV1, ˃ 316 K) to attain further brain stimulation, so as to investigate the brain functions and neurological diseases. Moreover, nano-ferrites have excellent antibacterial and antifungal activity. Pr₆O₁₁/Fe₂O₃/GO@PCL film nanocomposites have been used in skin wound healing treatment.