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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 149-160

A clinical review of nanotechnology in maxillofacial practice


Department of OMFS, Government Dental College, Alappuzha, Kerala, India

Date of Submission10-May-2020
Date of Decision03-Feb-2021
Date of Acceptance14-May-2021
Date of Web Publication22-Jun-2021

Correspondence Address:
Naveen Nandagopal
Department of OMFS, Government Dental College, Alappuzha, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jorr.jorr_16_20

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  Abstract 


Nanotechnology is an emerging boon to change the health care in a fundamental way. Currently nanomedicine is in the transition stage from the world of fiction to a revolutionizing world of healthcare. Nanotechnology is the manipulation of matter at the molecular and atomic levels. The wide range of its clinical applications makes it to offer a promising future in the field of medicine as well as dentistry. Nanorobotics will expand enormously the effectiveness, comfort, and speed of treatments and significantly reducing their risk, cost and invasiveness. Although this rapidly advancing field of medicine offers a promising future, it may also pose a risk for misuse and abuse. Further extensive researches should be needed to pave a way for these breath-taking devices to revolutionize the future of healthcare.

Keywords: Nanodentistry, nanomedicine, nanorobots, nanotechnology


How to cite this article:
Nandagopal N, Usha M, Sreejith S, Rajan S. A clinical review of nanotechnology in maxillofacial practice. J Oral Res Rev 2021;13:149-60

How to cite this URL:
Nandagopal N, Usha M, Sreejith S, Rajan S. A clinical review of nanotechnology in maxillofacial practice. J Oral Res Rev [serial online] 2021 [cited 2021 Dec 4];13:149-60. Available from: https://www.jorr.org/text.asp?2021/13/2/149/319004




  Introduction Top


Nanotechnology is one of the emerging science in the present world. Nanotechnology is popularly known as the science of manipulating matter, measured in the billionths of meters or manometer, roughly the size of two or three atoms or scientifically described as the technology to develop materials and structures of the size range from 1 to 10 nm.[1] Emerging interest in the medical applications of nanotechnology has paved a way to a new medical era of nanomedicine. Nowadays most of the researches in the field of medicine will be based on the diagnosis and treatment at the molecular level, using molecular tools and molecular knowledge of the human body, what is now known as “nanomedicine.” One of the aspects of nanomedicine gaining widespread interest is the development of miniature machines called nanorobots. Most broadly, nanomedicine is the process of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using the molecular tools and molecular knowledge of the human body.[2]

Nanorobotics is the technology of creating machines or robots at or close to the microscopic scale of nanometers. Nanorobots (or nanobots) are typical devices ranging in size from 0.1 to 10 μm and constructed of nanoscale or molecular components which allows precision interactions with nanoscale objects, or can manipulate with nanoscale resolution. “Nano” is derived from the Greek word which stands for “dwarf.” Nanomaterials are those materials with components <100 nm in at least one dimension, including clusters of atoms, grains <100 nm in size, fibers that are <100 nm diameter, films <100 nm in thickness, nanoholes, and composites that are a combination of these.

Nanorobots or molecular nanotechnology (MNT) are so tiny that they can easily traverse the human body which will allow doctors to perform the surgery directly on individual human cells with great precision, effectiveness, and reduced invasiveness and risk. Recent researches with nanotechnology in modern dentistry have led a new era of nanodentistry, which involves the application of nanotechnology to local anesthesia, diagnosis and treatment of oral cancer dentition, creation of artificial bone and teeth, renaturalization, the permanent cure of hypersensitivity, complete orthodontic realignment in a single visit, covalently bonded diamondized enamel, and continuous oral health maintenance using mechanical dentifrobots.

Nanomachines are largely in the research-and-development phase. The purpose of this article is to review nanotechnology, nanomedicine, and nanodentistry in the present and future scenario and its clinical applications in the field of oral and maxillofacial surgery.


  Historical Perspective Top


There are a lot of controversies regarding the history of nanotechnology. Some researchers believe that it is a scientific evolutionary form that did not develop until the late 1980s, but the evidence of nanotechnology dates back to 1959. Others believe that humans have used nanotechnological methods unintentionally for thousands of years, perhaps even longer. Despite that, nanotechnology is still fresh, providing a new era for scientific research in medicine. One of the first mentions in nanotechnology was in 1867 regarding the use of that name. At that time, James Clerk Maxwell proposed a tiny entity called Maxwell's Demon that was able to handle individual molecules. In 1914, Richard Zsigmondy made the first observations on size measurements of nanoparticles (NPs).

The term nanotechnology was coined by Prof. Kerie E. Drexler, a researcher and writer of nanotechnology. In 1959, Nobel Prize-winning American theoretical physicist Richard Feynman explored the implications of matter manipulation in a famous lecture called “Plenty of Room at the Bottom.”[3] Later, the Feynman's visions became a serious area of inquiry, when Eric Drexler, published a technical paper suggesting that it might be possible to construct, from biological parts, nanodevices that could inspect the cells of a living human being and carry on repairs within them. A decade later, by Drexler's seminal technical book laying the foundations for molecular machine systems and molecular manufacturing and subsequently by Freita's technical books on medical nanorobotics.[4],[5] Applications began in the 1980s by the invention of the scanning tunneling microscope and the discovery of carbon nanotubes and fullerenes.


  Manufacturing Approaches Top


There are mainly two approaches for manufacturing nanorobots: Organic and inorganic, which was suggested by Adriano Cavalcanti, a researcher at the Centre for Automation of Nanobiotech, Brazil.[6]

Organic nanorobots

These are also known as bionanorobots which are primarily adenosine triphosphate and DNA-based molecular machines or modified microorganisms to attain biomolecular computation, sensing, and actuation for nanorobots.

Inorganic nanorobots

The development of inorganic nanorobots is based on building customized miniature nano electronic devices. While comparing with bionanorobots, considerably higher complexity of integrated nanoscale components could be achieved in this field that is suitable for nanorobotic dentistry. Due to their exceptional diamondoid molecular structure of saturated hydrocarbons, they are chemically and thermally stable, can self-assemble and light in weight, making them suitable for nanorobot construction. Spherical-shaped aromatic carbon compounds called fullerenes is another type of material holding promise for customizing miniature nanodevices.


  Perspectives of Approaching Nanodentistry Top


  • Bottom-up Approach - building up particles by combining atomic elements[4],[7]


    • Local Nanoanesthesia, Hypersensitivity cure, Tooth Repositioning, Nanorobotic dentifrice (Dentifrobots), Nanodiagnostics (Photosensitizers and carriers), Therapeutic aid in oral diseases, Nanotherapeutics/Drug delivery, Gene Therapy, Diagnosis and treatment of oral cancer


  • Top-down Approach - Using equipment to create mechanical nanoscale objects[8]


    • Nanocomposites, Nanosolution (Nanoadhesives), Nano Light-curing glass ionomer restorative, Impression materials, Nano-composite denture teeth, Nanoencapsulation, Dentifrices, Laser Plasma Application for periodontia, Bone replacement materials, Prosthetic Implants, Radiopacity, Orthodontic wires, Nanoneedles, Nano sterilizing solution:


  • Regenerative nanotechnology - Bio-Mimicry[9],[10]


    • Dentition renaturalization, Dentition replacement therapy (Major tooth repair).


Nanomaterials

These are those materials with components <100 nm in at least one dimension. These may include atoms clusters, grains, fibers, films, nanoholes, and composites from these combinations. Nanomaterials in one dimension are termed as sheets, in two dimensions as nanowires and nanotubes, and as quantum dots in three dimensions. Their properties vary majorly from other materials due to two reasons:

  • The increase in surface area
  • Quantum effects.


Types of nanotechnologies in nanomedicine

Usually nanomedicine based on three potent molecular technologies:

  • Nanoscale materials and devices to be applied in advanced diagnostics and biosensors, targeted drug delivery, and smart drugs
  • Molecular medicine through genomics, proteomics, artificial biobotics (microbial robots)
  • Molecular machines and medical nanorobots which helps in immediate microbial diagnosis and treatment, and enhancement of physiological functions.


Nanorobots

Nanorobots are made of components with size ranges from 1 to 100 nm and diameter of about 0.5–3 μ. Carbon will be the primary component in the form of diamondoid or fullerenes form.[6],[10] Nanorobots would respond to definite programs enabling clinicians to execute accurate procedures with great accuracy, effectiveness, and speed at the cellular and molecular level. Nanorobots may also find use in the field of gerontology, with diverse applications in pharmaceutics, diagnostics, dental therapy, in the reversal of atherosclerotic damage, enhancing lung function, aiding natural immunity, repairing brain injury, modifying cellular DNA sequences, and repairing cellular damage. For example, when an MNT atomic force microscope configured to perform nanomanipulation, it can be considered as a nanorobotic instrument. Macroscale robots or microrobots, which can move with nanoscale precision can also be considered nanorobots.[11]

Nanosensors

Nanosensors have been used in the military to identify airborne harmful materials, weapons of chemical warfare and drugs, and other substances in expired air.

Implantable nanomaterials

These materials can be applied in various fields:

  • Tissue healing and substitution
  • Implant materials
  • Osseous repair
  • Sensory aids
  • Cochlear and retinal implants
  • Tissue regeneration scaffolds
  • Bioresorbable materials
  • Diagnostic and therapeutic devices
  • Smart materials.


Nanophase materials[10],[12]

Nanophase materials are promising materials for various bio-applications like repair of bone defects, as implant materials, etc. It improves both mechanical as well as biological properties.

Nanophase hydroxy apatite

Nanophase hydroxyapatite (HA) has increased osteoblastic adhesion and growth compared to traditional HA. In addition, nanophase alumina and titania also show similar features. HA NPs used to treat bone defects are:

  • Ostim HA
  • Vitosso HA + TCP (tricalcium phosphate)
  • NanOSSTM HA.


Nanophase carbon

Extra ordinary mechanical properties and nanoscale dimensions enables carbon nanofibers to use as a maxillofacial implant material.


  Mechanism of Application Top


Nanorobot will primarily be constructed of carbon atoms in a diamondoid structure because of its inert properties and strength, which provides super-smooth external surface allowing its motility unimpeded and lessen the likelihood of triggering the body's immune system. Glucose or natural body sugars and oxygen might be a source for propulsion and the nanorobot will have other biochemical or molecular parts depending on its task. They might use specific motility mechanisms to travel through human tissues with navigational precision. They will acquire energy and sense and manipulate their surroundings and controlled by an onboard nanocomputer that executes pre-programmed instructions in response to local nanorobots via acoustic signals or other means.


  Structural and Functional Framework Top


The design is a major consideration for a systematic and proper functioning of nanorobots. The designing and its internal structure is based on two key factors:

  • Navigatory path of a nanorobot especially in a liquid environment
  • Attachment to the tumor cells.


The basic structure[13] of a nanorobot includes:

  • A microcomputer which forms the brain
  • Carbon nanotube which forms the body.
  • Ultrasonic sensors/chemical sensors
  • Tentacles
  • Flagella and its motors
  • Folate materials.


Nanorobots should have a smooth trajectory path in the blood environment without causing any damage to other cells. A microcomputer consisting of a miniature processor forms the “brain” of nanorobot.[13] Carbon nanotube forms its body due to its intrinsic property to absorb near-infrared light waves, which help to pass harmlessly through human cells.

Ultrasonic sensors on the body of the nanorobot avoid collisions with each other and other cells in the blood vessels. Chemical sensors in the nanorobot monitor E-cadherin gradients so that nanorobots programmed for such a task can make a detailed screening of the patient whole body and can retrieve the information regarding the patient conditions in mobile phones, in which electromagnetic waves are used to command and detect the current status of nanorobots inside the patient.

The tentacles should have high responsive rate to capture the cancerous cell once it is detected. Folate materials on the body of the nanorobot act as the folate-receptor cells which attracts the device to the cancerous cells and helps to have a better visualization of the treatment process. The flagella, powered by a set of motors which helps for the movement and pathway of nanorobots in the bloodstream, depending on the change of concentration of nutrients in the surroundings. The flagella motors allow the nanorobot to move at speed as much as 25 μm/s with directional reversals occurring approximately 1/s. The assembled nanorobot has the size of approximately 0.5–0.8 μ, taking into consideration the size of the smallest blood vessels. Depending on the case, different gradients on temperature, the concentration of chemicals in the bloodstream, and electromagnetic signature are the relevant parameters for diagnostic purposes.

Complementary metal-oxide semiconductor is the most safest and effective method to maintain energy in nanorobots as long as it is in operation so that it can be used for active telemetry and power supply as well as for digital bit encoded data transfer from inside a human body. It is available as a chip providing 1.7 mA at 3.3 V power, allowing the operation no significant losses during transmission.

Radiofrequency (RF)-based telemetry is an advancing technology which uses inductive coupling and RF identification (RFID) demonstrated good results in patient monitoring and power transmission. It saves the energy received while the nanorobot is in inactive modes and becomes active when signal patterns require it to do so.[14] RFID is recently used in electroencephalograms for data collection and transmission.

Acoustic, light, RF, and chemical signals can be used for data communication and transmission depending on the applications.[15] Chemical signaling is more useful for nearby communication among nanorobots for teamwork coordination. Integrated sensors is the better option for data transfer in implanted devices. Single-chip RFID CMOS-based sensors with sub-micron SoC design could be used for longer distance communication among nanorobots via acoustic sensors.[16] The low power consumption makes CMOS-based sensors more advantageous. The nanorobot computation is performed through embedded nanosensor and the significant measured data can be then transferred automatically to the mobile phone.

Smart nano robots

The nanorobot prototype

A DNA computing software, Cadnano is used to design a folded, 3-D hexagonal DNA nanorobot which carries molecular “cargo” within its structure with the help of two DNA-aptamer “locks”– called staples until the destination cells are reached. These molecular locks will respond to specific key combinations of proteins on the cell surface to deliver the cargo when the intended cell's receptors have the right combination. This principle by Douglas can be used to target human cancers and T-cells.[17]

A nano “smart box”

It is a method of delivering drugs to cancer cells potentially reducing the side effects. It was described by Douglas to recognize and deliver drugs to certain kinds of cancer cells. The box has two different locks on the lid, so that it will open only when both keys of specific proteins on the surface of cancer cells are encountered.[2]

[TAG:2]Approaches of Nanorobots[2][/TAG:2]

  1. Biochip: Practical nanorobots can be structured as biochips like nanoelectronics devices, allowing teleoperation and medical instrumentation. Biochips is an integration of nanoelectronics, photolithography, and new biomaterials which directs the required manufacturing technology toward nanorobots for medical applications, such as surgical instrumentation, diagnosis, and drug delivery
  2. Nubots (Nucleic acid robots): They are synthetic robotics devices at the nanoscale which includes the several DNA walkers reported by Ned Seeman's group at NYU, Niles Pierce's group at Caltech, John Reif's group at Duke University, Chengde Mao's group at Purdue, and Andrew Turberfield's group at the University of Oxford
  3. Positional nanoassembly: It is a part of Nanofactory Collaboration founded by Robert Freitas and Ralph Merkle in 2000. It aims to develop diamondoid medical nanorobots with the help of positionally-controlled diamond mechanosynthesis and diamondoid nanofactory[18]
  4. Bacteria based: This is a kind of biological integrated device using biological microorganisms like Escherichia coli bacteria, a flagellum for its propulsion and electromagnetic fields to control its motion[19]
  5. Open Technology: This approach aims to accelerate nanorobotics development and benefit the society and human heritage in future generations, which based on ethical practices for peaceful purposes.[20]



  Applications Top


Nanodiagnostics

Nanodiagnostic devices can be used for early disease identification at the cellular and molecular levels by collecting human fluids or tissue samples and analyzing multiple times at the subcellular level. Nanomedicine could increase the efficiency and reliability of in vitro diagnostics. From an in vivo perspective, nanodevices might be inserted into the body to identify the early presence of a disease or to identify and quantify toxic molecules, tumor cells, and so forth, which was well explained by Lampson, 1995 and Freitas, 2000.

Intracellular imaging may use innately fluorescent proteins or quantum dots which enable various biochemical reactions to act as a photosensitizer and carrier. They attach the antibody to the target cell and on stimulation by UV light, result in the formation of reactive oxygen species which destroy the target cells.[21] Diagnosis using nanotechnology will overcome some drawbacks of biochip technology.

Local anesthesia[5],[22]

In nanoanesthetics, a colloidal suspension containing millions of active analgesic micron-size dental robots will be instilled on the patient's gingiva, from where the ambulating nanorobots reach the pulp via the gingival sulcus, lamina propria and dentinal tubules, guided by chemical gradient, temperature differentials. Once instilled in the pulp, the analgesic dental robots were commanded to shut down all the sensitivity in the particular tooth that requires the treatment. After oral procedures are completed, the nanorobots were commanded to restore all sensation, to relinquish control of nerve traffic and to egress from the tooth by similar pathways used for ingress. All these procedures were under the control of the surgeon with the help of onboard nanocomputer.

[TAG:2]Nanoneedles and Nanotweezers[23],[24][/TAG:2]

Nanoneedles were manufactured from nanosized stainless steel crystals (Sandvik Bioline RK 91 needles, Sweden). Nano tweezers are also under the way of development, which may enable cell surgery feasible in near future. Femtolaser is a recently developed nano-scissors-like technology for axotomy of neurons by vaporizing tissue locally leaving the adjacent tissue unharmed, after which the axons can be functionally regenerated.

Diagnosis and treatment of oral cancer[22],[25]

Nanorobotics promotes early diagnosis of cancer and successful treatment for patients by the development of efficient diagnostic aids and targeted drug delivery to decrease the side effects from chemotherapy. The nanoelectromechanical system, oral fluid nanosensor test, and optical nanobiosensor can be used for diagnosing oral cancer. Nanoshells are recently evolved tools in cancer therapeutics. These are miniscule beads with outer metallic layer, which selectively destroys cancer cells and leaves the normal cells intact. As proteomic and genomic markers like exosomes in saliva get elevated in malignancies, saliva can be used as an inexpensive and noninvasively obtained diagnostic medium for molecular disease identification. This marker has been studied by using atomic force microscopy, which employs NPs. Brachytherapy using NP-coated, radioactive sources which can be placed close to or within the tumor to destroy it is still under trial.

Nanorobots with embedded chemical biosensors can be used for the detection of tumor cells in the early stages of development inside the patient's body by sensing the gradient changes on E-cadherin signals. The nanorobots are positioned near the vessel wall to improve the sensing and responsive capabilities. Nanorobots can be programmed to attach tumor sites via acoustic signals regarding its accurate position. A predefined number of other nanorobots get attracted later for incisive chemotherapeutic action with precise drug delivery above the tumor. A network of special stationary nanorobots can be strategically positioned throughout the body and programmed to keep track of all devices in the body, which helps the surgeon to monitor a patient's progress and to change the instructions of the nanorobots in vivo to progress to another stage of healing. Once the task is completed, the nanorobots could be flushed from the body.

The nanorobots could distinguish the malignant and normal cells with the help of chemotactic sensors keyed to specific antigens on the target cells. These sensors can also detect different levels of E-cadherin and beta-catenin in primary and metastatic phases. Thereby medical nanorobots provide a non-depressed therapy for cancer patients by destroying the cancerous cells only.

Nanotechnology can also be used to monitor the surgical resection of tumourous/cancerous cells thereby improves the therapeutic effectiveness of radiation-based and other existing treatment methods and increases the survival rate causing lesser risk to the cancer patients. CALAA-01 NPs which can suppress oral cancer tumor growth using an RRM2-siRNA[26] and a novel multifunctional self-assembling NP construct of tyrosine kinase, have been targeted as an effective therapy for head and neck squamous cell carcinoma.[27]

Nanorobots in cancer detection and treatment[13],[28],[29]

There is a wide range of nanomaterials used in cancer diagnosis which includes near-infrared (NIR)-absorbing carbon (graphing and carbon nanotubes), metal (Au, Ag, Pt, Pd), quantum dots (CdTe, CdSe) based nanostructures, magnetic (iron oxides) and upconversion composite NPs (NaGdF4:Yb: Er). Nanotechnology offers matchless promises in cancer diagnosis and staging especially molecular diagnosis because panels of biomarker on complete cancer cells and tissue specimens can be quantified using NP probes.[30] Smart NP containing target-specific contrast agents, multimodality imaging probes, or multifunctional reagents for concurrent imaging and therapy were recently designed to overcome the major drawback of prolonged circulation time of NPs with sizes between 10 and 100 nm.

More applications include the use of near-infrared luminescent QD nanodevices capable of targeting specific cancer proteins[24] for sensitive cancer cell detection and super paramagnetic ironoxide NPs which carry contrasting components with varied aqueous solubilities that enable their retention in different tissues and makes for enhanced magnetic resonance imaging. Claw-shaped nano-punch biopsy devices also function for specimen collection from target sites. Highly sensitive and specific nanochips/biosensors for detection of oral cancer using salivary biomarkers (interleukin-8 [IL-8], IL-1 β, thioredoxin etc.) are also being explored.[10]

Recently NIR excitable upconversion NP based PDT agents have been developed to improve the conventional PDT by targeting epithelial growth factor receptor in advanced, solid oral head and neck cancers.[31] Using an in vivo rat model, Abbasi et al., showed that orally and intravenously administered doxorubicin-methotrexate-loaded NPs (DOX-MTX NPs) downregulated MMP-2 mRNA levels in 4-nitroquinoline-1-oxide induced oral squamous cell carcinoma.[32]

Various NPs used are cantilever, nanopores, nanotubes, and quantum dots.

Cantilever

The antibodies coated on the cantilever fingers selectively bind to the proteins secreted from cancer cells. The physical properties of the cantilever change in real-time and provide information regarding the presence and concentration of different molecular expressions.

Nanopore

Nanopores contain a tiny hole that allows DNA to pass through one stand at a time making DNA sequencing more efficient. It helps to detect errors in the gene that may contribute to cancer by the efficient reading of genetic codes.

Nanotubes

They are carbon rods about half the diameter of a DNA molecule to detect the altered genes and its exact location. These carbon nanotubes can be used as sensors for cancer drugs and other DNA damaging agents inside living cells.

Quantum dots

Quantum dots are tiny crystals that glow when they are stimulated by ultraviolet light. It has special coating to lock the deadly cancerous cells once it is encountered. The light particles would serve as a beacon to show doctors where the disease has spread. Lipid-coated targeted QDs were recently designed for multiplexed quantification of cancer-specific biomarkers on single cells.

Nanorobots for drug delivery

It includes dendrimer, nanoshells, liposomes, NPs, and micelles.

Dendrimers[28]

They are promising drug delivery vehicles to target the tumor with anti-cancer drugs. These are synthetic spherical and highly branched macromolecules with adjustable size and shapes. A dendrimer consists of a molecule to recognize cancer cell, a therapeutic agent to kill those cells and a molecule to recognize the signal for cell death.

Nanoshells[28]

It is a core of silica with a metallic outer layer to absorb near infra-red light, generating an intense heat that is lethal to cancer cells. They selectively damage the tumor site via enhanced permeation retention phenomenon.

Liposomes[ 33]

Liposomal drug delivery is possible by four mechanisms;

  1. Liposome formation in an aqueous solution saturated with soluble drug
  2. Using organic solvents and solvent exchange mechanisms
  3. Using lipophilic drugs
  4. pH gradient methods.


This approach offers advantages like their easy preparation, acceptable toxicity, and biodegradability profiles.

Polymeric nanoparticles[34]

They are drug delivery devices including nanospheres and nanocapsules with diameter ranging from 10 to 1000 nm, made of natural or artificial polymers which are generally biodegradable and in which therapeutic drugs can be adsorbed, dissolved, entrapped, encapsulated or covalently linked to the polymer backbone by means of a simple ester or amide bond that can be hydrolyzed in vivo through a change of pH. Even though polymers are more stable compared to the liposome, but are limited by poor pharmacokinetics due to its uptake by the reticulo-endothelial system.

Micelles[35]

Polymeric micelles are biodegradable spherical nanocarriers with a size range of 10–200 nm. They are considered ideal drug delivery vehicles because

  • Can deliver two or more therapeutic agents simultaneously in a regulated manner
  • Improved specificity and efficacy
  • Reducing their systemic toxicity.


Its hydrophobic core carries pharmaceuticals, especially lipophilic drugs, which are solubilized and physically entrapped in the inner region with high loading capacity. These encapsulated drugs are released through erosion of the biodegradable polymers and diffused through the polymer matrix. External conditions such as changes of pH and temperature can also induce drug release from micelles. Moreover, the surface modification of micelles with antibodies, peptides, or other small molecules can be used for its targeted delivery and uptake, thereby reducing their systemic toxicity and improving their specificity and efficacy.

Nanomaterials for brachytherapy like “BrachySil™” (Sivida, Boston and Perth, Australia) deliver 32P, are in the clinical trial.

Nano electromechanical system

It is an ultrasensitive mass detection technology that can be used for the diagnosis of oral cancer and diabetes mellitus and for the detection of bacteria, fungi, and viruses.[25] Here biochemical signals get converted to electrical signal and cantilever array sensor makes it ultrasensitive. There are ongoing attempts to build microelectromechanical system-based microrobots intended for in vivo use. For example, the “MR– Sub” project of the nanorobotics Laboratory of Ecole Polytechnique in Montreal will use a magnetic resonance imaging system for the propulsion of microrobots in the blood vessels. This project mainly aims to create nanorobots to carry out procedures in the blood vessels which are still inaccessible, so that it might be applied for targeted drug release, reopening of blocked arteries or taking biopsies. As a part of this project, Gorden's group at the University of Manitoba have proposed magnetically controlled “cytobots” and “karyobots” for performing wireless intracellular and intranuclear surgery, respectively.

Drug delivery system that can cross the blood-brain barrier is the vision of the future with this technology. Parkinson's disease, Alzheimer's disease, brain tumors will be managed more efficiently. Periodontal diseases can also be managed via triclosan or tetracycline loaded NPs, releasing loaded drugs in increments to provide more time of contact at the diseased site.[36] Recent researches were on the way regarding the applications and effectiveness of various drug delivery systems like niosomes and fullerenes. Niosomes are chemically stable nonionic vesicles with improved penetration power through biological tissues, thereby offers a controlled and targeted drug delivery,[37] whereas Fullerenes are hollow carbon molecules in different shapes such as spheres, tubes, and ellipsoids. The buckminsterfullerene (C60) was the first and most stable fullerene discovered in the 1980s, resembling the geodesic domes designed by Buckminster Fuller, hence, named after him. Fullerenes can also be used as radical scavengers and as antioxidants.[38] Nano-sized liposome vesicles were available for non-invasive drug delivery in dental therapies. Carbon-based “buckyballs” and gold/magnetic NPs have been recently designed as drug delivery nanodevices.

Nanovectors for gene therapy

Gene therapy is a recently emerged therapeutic technique that is in an exploring stage to correct diseases like cancer, viral infections, arteriosclerosis at molecular level by repairing or replacing them. Medical nanorobots can readily treat genetic diseases by comparing the molecular structures of DNA and proteins in the cell to desired reference structures and by correcting the faulty genes by gene delivery systems like viral vectors, nonviral vectors, and the direct inoculation of genes into tissues (gene guns).[39]

Irregularities in DNA and proteins can be corrected and the proteins can be reattached to the DNA chain, which re-coils into its original form, to cures the diseases at the molecular level well beyond the reach of physicians. Stretching a supercoil of DNA between its lower pair of robot arms, the nanomachine gently pulls the unwound strand through an opening in its prow for analysis. At the same time, upper arms detach regulatory proteins from the chain to place it in an intake port. The molecular structures of DNA and proteins are compared to information stored in nanocomputer positioned outside the nucleus and connected to the cell-repair ship by a communications link.

Targeted cellular destruction

On UV stimulation, quantum dots can bind to antibody on the surface of the target cell to release reactive oxygen species, which mediates targeted cellular destruction and helps in cancer therapy.

In surgery

Nowadays, cellular nanosurgery is in an exploring stage. A surgical nanorobot act as a semiautonomous on-site surgeon inside the human body, which was introduced into the body through the vascular system or catheters into various vessels and other cavities in the human body. It was guided by a human surgeon to diagnose and correct the pathology by nanomanipulation. Recent researches give hope for NPs delivered enzymes (collagenase) with high probability for remodeling periodontal fibres in targeted oral surgery, without the need for scalpel invasion.

Wound care[40],[41],[42],[43],[44]

Wound care is one of the excellent and widely used applications of nanotechnology. The chronicity of wounds characterized by unresolved inflammation and nonmigratory epidermis is mainly due to impaired fibroblast function, extracellular matrix deposition, decreased angiogenesis, increased levels of proteases, and bacterial colonization. Nanotechnology target different phases of wound repair so that nanomaterials in wound healing must have intrinsic properties to create an ideal microenvironment for healing and serve as delivery vehicles for therapeutic agents.

Bioengineered human dermal substitutes, recombinant platelet-derived growth factor, and smart biomaterials like human skin equivalent and dermal substitutes are ideal to promote healthy healing process by its interaction with the wound environment like stimulation of chemotaxis of neutrophils, macrophages, proliferation of fibroblasts, and smooth muscle cells. Antimicrobial textile surfaces and wound care products are prepared by cotton and polyester fabrics treated with nanosized silver colloidal solutions (25–50 ppm) or by melt-spinning of polypropylene and silver NPs of 15 nm size. NPs and nanofibers for wound dressings have two layers of silver-coated, high-density polyethylene mesh along with electrospun nanofibrous membrane, polyurethane, or silk fibroin nanofibers.

The introduction of anti-microbial agents containing silver bactericidal properties has revolutionized burn wound care. Pure silver NPs markedly increase the rate of silver ion release. Nitric oxide-delivering NPs with broad-spectrum antibacterial property can be effectively used against both Gram-positive and Gram-negative bacteria (DeRosa et al.[45]), MRSA biofilm Miller et al.[46] and P. aeruginosa biofilms (Barraud et al.[47]). Future researches will be for nano scaffolds with added stem cell to stimulate wound healing. gene, rna interference (rnai), and small interfering rna (sirna) to stimulate the wound healing, thereby achieving cell-type specificity.

Cryostasis

Researchers are in search of medical technology based on nanotechnology to restore and reverse the damages. The studies on it were undergoing for decades to make an extraordinary medical technology a truth in near future by restoring health and reversing the frozen injury by the rapid introduction of cryoprotectants and other chemicals via the vascular system to cushion the tissues against further injury. All these medical prospects paved the way to a new branch of cryonics, in which dying patients could be frozen and stored at the temperature of liquid nitrogen for decades or even centuries until the necessary medical technology to restore health is developed.

Prevention and treatment of bone disorders[43],[48]

Nanotechnology promotes the bioavailability of nanosized calcium carbonate and calcium citrate to reduce the risk of osteoporotic disorders. Bone nanofillers, injectable nanomaterials along with polymethyl-methacrylate (PMMA) bone cement, calcium phosphate cement and calcium sulfate cement, and injectable hydrogels are the recent tools for bone healing and regeneration.

Nanosolutions as bonding agent[49],[50]

Nanosolutions constituted by dispersible NPs can be used as bonding agent, which gives a homogenous and perfectly mixed adhesive consistently. It provides higher dentine and enamel bond strength and stress absorption with durable marginal seal and longer shelf life. It also enables fluoride release.

Nano sterilizing solution (Eco Tru Disinfectant)

NPs have been used as sterilizing solutions in the form of nanosized emulsified oil droplets that bombard pathogens.[50] It was developed by Gandly Enterprises Inc Florida. This broad spectrum solution is hypoallergic, noncoroding, and ecofriendly. They does not stain fabrics, so that it requires no protective clothing. They are compatible with various impression materials.

Bone replacement materials

Bone is a natural nanostructure composed of organic compounds (mainly collagen) and reinforced with inorganic ones. Nanotechnology aims to simulate this natural structure for the development of nanobone. These are hydroxyapatite nanocrystalline particles with a loose microstructure and nanopores in between these crystals. The surfaces of the pores are modified with silica particles to adsorb protein. Hydroxyapatite NPs used to treat bone defects are

  • Ostim HA
  • VITOSSO HA + TCP
  • NanOSSTM HA.


These can be used in pathological lesions and injuries requiring bone graft, cleft patient and osseous defect.

Orthodontic treatment

Sliding a tooth along an arch wire involves a frictional type of force that resists this movement. The use of excessive orthodontic force might cause loss of anchorage and root resorption. There are various studies and researches underwent in search of methods to overcome these drawbacks of archwires. Katz in his study reported that friction can be reduced by coating the orthodontic wire with inorganic fullerene-like tungsten disulfide NPs (IF-WS2) due to their excellent dry lubrication properties.[51] Nanorobots may attain a significant role in near future of orthodontics by directly manipulating the periodontal tissues, allowing rapid and painless tooth straightening, rotation, and vertical repositioning within minutes to hours.

Hypersensitivity cure

Dentin hypersensitivity may be caused by changes in pressure transmitted hydrodynamically to the pulp, which increases the surface density and diameter of dentinal tubules. Dental nanorobots offer a quick and permanent cure by selectively and precisely occluding tubules using native biologic materials.

Nanoencapsulation

It is a controlled drug release system using nanomaterials like hollow spherical or core-shell structured nanotubes and nanocomposites. Have been widely explored for controlled drug release.

South West Research Institute developed specifically targeted release system in the form of nanocapsules for the delivery of vaccines, antibiotics, and various drugs with fewer adverse effects.[5] They also developed protecting outfit and mask, incorporating anti-pathogenic nano-emulsions and nano-particles, medical appendage dressings for immediate cure and bone targeting nanocarriers which integrate with natural bone easily. Piñón-Segundo et al. studied triclosan loaded NPs (500 nm) to obtain a novel drug delivery system for the treatment of periodontal diseases by reducing inflammation.[9] Arestin is a microsphered structure to deliver minocycline locally to a periodontal pocket. In 2003, Osaka University in Japan made possible the targeted delivery of genes and drugs to the human liver.

Tooth replacement

The studies and researches are on the way to generate whole new tooth with the principles of genetic engineering and tissue engineering and thereby manipulating cellular and mineral components at nanoscale. Chen et al. reported that NPs of calcium hydroxyapatite crystals which were oriented parallel to each other can simulate the natural biomineralization process and create dental enamel.[52]

Nanorobotic dentifrices (dentifrobots)[5],[10]

They are invisibly small purely mechanical devices, delivered by mouthwash or toothpaste, which can cover all subgingival surfaces, thereby metabolizing trapped organic matter into harmless and odorless vapors and destroy pathogenic bacteria in the plaque and elsewhere. They can safely deactivate themselves when swallowed.

Dentifrices

These are available as nanosized hydroxyapatite molecules and microbrite dentifrice. Nanosized HA molecules forms a protective shell on tooth surface to repair damaged areas. Microhydrin (1–5 nm) in microbrite dentifrice breaks down the organic food particles.[53]

Laser plasma application with nanoparticles

Application of nanosized titania particle emulsion on human skin followed by laser irradiation, leads to the disintegration of the particles via shock waves or microabrasion of hard tissues or stimulus to produce collagen. It can be applicable for periodontal therapy, melanin removal, soft-tissue incision without anesthesia and cavity preparation including enamel and dentin cutting.

Dental implants: Structure, chemistry, and biocompatibility

Surface contact area, surface topography, bone-bonding, and stability are the key factors for successful osseointegration so that recent researches are directed towards effects and subsequent optimization of microtopography and surface chemistry. Albrektsson et al., in 2008 and Goene et al., in 2007 demonstrated that the addition of nanoscale deposits of hydroxyapatite and calcium phosphate creates a more complex implant surface for successful osteoblast formation.[54],[55] Bone growth and osseointegration can be effectively attained with implants by using nanotechnology because they enhance the integration of nanocoatings resembling biological materials to the tissues. Antibiotics or growth factors can be incorporated as CaP nanocoating on Ti implants.

Nanophase silver incorporated as a power source into the implant design stimulates wound healing by eliminating the biofilm matrix formation around the implant. Drug-Eluting nanostructured coating materials can also be used to deliver antibiotics and other drugs on implant surfaces to prevent infection. Engineered nanomaterials (ENMs) such as nanocomposites and nanofillers may significantly controls the infection, directs and controls pulp stem cells for tooth regeneration and osseointegration enhancement, thereby decrease dental implants failure rates.

Impression materials

Nanotechnology can also be applied in impression materials to enhance its properties. For example, nanofillers have been added to polyvinylsiloxane material to have better flow, fewer voids, and enhanced detail precision.

Nanocomposite[22],[24],[49]

Nanotechnology has revolutionarized restorative dentistry by providing nanofillers. These filler particles are very minute, higher proportions can be achieved, and result in indistinctive physical, mechanical, and optical properties. Nanocomposites are defined by filler-particle sizes of ≤100 nm. It can be nanohybrid or nanofilled resin-based composites. Nanofillers in nanocomposites improve finishing and polishing ability, shade matching, flexural strength, and hardness. Nanofillers can be of three different types namely nonagglomerated “discrete” silica NPs, barium glass, and prepolymerized filler. Filtek Supreme Universal Restorative pure nano is an example for nanocomposite in which nonagglomerated discrete NPs are homogeneously distributed in resin. They have superior strength, hardness, improved flexural strength, toughness, decreased polymerization shrinkage, excellent color density, high polish retention, and esthetics.

Nano-composite denture teeth

Nanocomposite denture teeth are made of PMMA and homogeneously distributed nanofillers.[5] They have the excellent polishing ability, stain resistant, wear resistance, surface hardness, and esthetics.

Nano light-curing glass ionomer restorative

It is a blending of fluoralumino silicate technology with nanotechnology in which nonagglomerated discrete NPs are homogeneously distributed in resin.[23] These products have better polish, wear resistance, and esthetics. These can be used for primary teeth restoration, transitional restoration, sandwich restoration, small class I restoration, class III and V restoration, and core build-up.

[TAG:2]Advantages of Nanotechnology[2][/TAG:2]

  • Better accuracy
  • Better efficiency and speed
  • Non-invasive technique
  • Computer-controlled operation with nobs to fine-tune the amount, frequency, time of release
  • Use of nanorobot drug delivery systems with increased bioavailability
  • Targeted therapy such as only malignant cells treated
  • Fewer mistakes on account of computer control and automation
  • Reach remote areas of human anatomy, which was not operatable at the surgeon's operating table
  • As drug molecules are carried by nanorobots and released where needed the advantages of the large interfacial area during mass transfer can be realized
  • Drug inactive in areas where therapy not needed minimizing undesired side effects.


[TAG:2]Disadvantages of Nanotechnology[10],[13],[56][/TAG:2]

Even though nanorobots may prove to be a boon to emerging medical technology, there are certain disadvantages/risks associated with it.

  • The initial design cost is very high
  • The design of the nanorobot is a very complicated one
  • Electrical systems can create stray fields which may activate bioelectric-based molecular recognition systems in biology
  • Electrical nanorobots are susceptible to electrical interference from external sources such as RF or electric fields, electromagnetic pulse, and stray fields from other in vivo electrical devices
  • Shielding these devices from electromagnetic fields may prove to be difficult leading to their malfunctioning
  • Hard to interface and customize
  • Nanorobots can cause a brutal risk in the field of terrorism.
  • The terrorism and anti-groups can make use of nanorobots as a new form of torturing the communities as nanotechnology also has the capability of destructing the human body at the molecular level
  • Privacy involved with Nanorobots.
  • As Nanorobots deals with the designing of compact and minute devices, there are chances for more eavesdropping than that already exists.
  • Require customization for specialized functions.


[TAG:2]Challenges Faced By Nanodentistry[25],[56][/TAG:2]

Engineering challenges

  • Precise positioning and assembly of molecular scale part
  • Manipulating and coordinating activities of large numbers of independent microscale robots simultaneously
  • Feasibility of mass production technique


Biological challenges

  • Synthesized with biocompatible materials to avoid foreign body reaction and rejection by host tissue
  • Should be non-replicating and capable of self-destruction once it achieved its function to avoid the risk of self replication
  • Developing biofriendly nanomaterial
  • Ensuring compatibility with all intricate of human body.


Social challenges

  • Public acceptance
  • Regulation and human safety
  • Ethics
  • Financing and tactical concerns.
  • Inadequate assimilation of clinical research.



  Future Top


Nanotechnology is an emerging boon to change health care in a fundamental way. Because the initial nanodevices will be basic, prototypical units, commercial applications will follow years later. Researches should aim to deal with the risks/challenges posed in the development of nanorobots. The Foresight Institute, a California-based research institute has offered the $250,000 Feynman Grand Prize to the first researcher or researchers who creates a nanoscale robotic arm capable of precise positional control and a nanocomputer. Christine Peterson, president of the Foresight Institute, estimates that the prize will be claimed between 10 and 30 years from now.[57] Further extensive researches should be needed to pave a way for these breath-taking devices to revolutionize the future of healthcare, including medicine and dentistry.


  Conclusion Top


Currently, nanomedicine is in the transition stage from the world of fiction to a revolutionizing world of healthcare. Amazing future is waiting with emerging technologies of nanomedicine. Nanomedicine offers a successful future in the field of medicine and dentistry by holding a wealth of promises from eradicating disease to reversing the aging process. They will provide surgical treatments with instant diagnostic feedback, improved efficacy, and reduced side effects. Nanorobotics will expand enormously the effectiveness, comfort and speed of treatments and significantly reducing their risk, cost and invasiveness. Although this rapidly advancing field of medicine offers a promising future, it may also pose a risk for misuse and abuse. Further researches, testing, and frank discussions with open sharing of ideas should be required to make this promising technology a reality.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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