Recently, various nanomaterials are used in order to develop nanotechnology‐based rapid diagnostic tests, such as metallic nanoparticles, quantum dots (QDs), silica nanospheres, magnetic nanoparticles, carbon nanotubes (CNTs), silicon nanowires (SiNWs), nanopores, graphene, nanostructured surfaces, and metal films. This novel nanodiagnostic approach will further develop point‐of‐care (POC) diagnostics and monitoring technologies. Nanobiosensors and microarrays of biosensors can create biochip systems and microfluidic platforms that are the most used nanofabrications for rapid diagnostic tests. These nanoplatforms are constructed for the rapid detection of various diseases or pathogen‐specific biomolecules/markers, such as DNA, proteins, whole cells (e.g., circulating tumor cells), and others. The fabrication of small‐scale portable devices with the incorporation of nanostructures will offer many advantages in the early detection of various diseases and health‐threatening infections by pathogens and in the treatment selection and treatment monitoring. The use of nanostructures in in vitro diagnostics gives the opportunity to augment the sensitivity and specificity required in clinical practice, lowers the cost and test time of the assays, and enables portable microfluidic platforms suitable for resource‐constrained settings. In this chapter, all the state‐of‐the‐art advantages in this field are discussed, starting with the nanostructures used for the fabrication of nanobiosensors, nanobiosensors arrays, and nanofluidic platforms and the nanodiagnostic use of rapid tests in the detection of pathogens, in cancer management, and glucose monitoring for the management of diabetes disease.
- point‐of‐care devices
- low‐cost and rapid diagnosis
Nanostructures are used in order to create specific nanodevices for the manipulation of biological systems at the molecular level, and this is what currently defines
Rapid diagnostic test, potentially in the doctor's office or bedside tests, for the initial diagnosis and treatment selection and treatment monitoring to the doctor/hospital or even at home.
The early detection of several diseases in comparison with the efficiency of current techniques. The early detection is very important as it offers the opportunity for earlier diagnosis and thus more therapeutic opportunities.
This chapter summarizes the nanostructures used in nanodiagnostic tests and their applications for the development of rapid diagnostic tests for point‐of‐care disease management and public health.
2. Nanostructures used in nanodiagnostics
The use of nanomaterials in the design of
2.1. Metallic NPs
Metals, especially gold and silver, have the advantageous ability to interact with external fields such as light, radiofrequency, and X‐rays. Under a specific wavelength, metals exhibit surface plasmon resonance (SPR), the oscillation of free electrons in a particle's surface; thus, they can successfully be combined with conventional methods such as colorimetry or absorption spectroscopy. A typical example of SPR biosensing consists of the liquid sample part and an immobilized ligand (e.g., an antibody) on an SPR‐active gold‐coated glass slide. This system can create a thin flow cell in which the sample will be able to flow in the aqueous solution, and when light (visible or near infrared) is projected through the glass slide and onto the gold surface at angles and wavelengths near the SPR condition, the optical reflectivity of the gold changes in a specific way when an actual interaction occurs between the sample and the ligand of the solid phase. The most frequent medical use of these NPs is the rapid tests, for example, pregnancy test kits, where gold nanoparticles are used as a color marker . Moreover, metallic NPs are suitable for surface‐enhanced Raman spectroscopy (SERS), since they produce Raman signal. So, when molecules are in close proximity to a metal surface, they exhibit a dramatic augmentation in the electromagnetic field, yielding high Raman intensity. Thus, SERS surface biosensors are usually performed on Ag, Au, or Cu surfaces. SERS is an excellent assay for the sensitive and specific detection of low‐concentration molecules, for example, the detection of biomarkers for bacillus spores or the measurement of glucose after the appropriate chemical modifications of the SERS surfaces . Another example is the molecular sentinels, which are comprised of metal NPs decorated with a Raman label‐conjugated stem‐loop DNA. Thus, when the DNA molecule is in close proximity to the metal surface, the Raman intensity is maintained high. In contrast, in the bound state, there is a disruption of the stem‐loop and the Raman label is no longer in close proximity to the metal. This approach was used to detect the
2.2. Quantum dots (QDs)
In the field of
2.3. Silica nanospheres
Just like QDs, inorganic dye‐loaded silica particles are characterized by good photostability, sharp emission peaks, and long‐lasting fluorescence lifetimes. They are appropriate for dispersion aqueous solutions, due to their hydrophilic surface. They are usually used to conjugate optical labels in order to increase the detection signal, such as organic or inorganic dye molecules (lanthanide‐based and ruthenium‐based) .
2.4. Magnetic NPs
Last but not least is the use of
2.5. Carbon nanotubes or nanopores (CNTs–CNPs)
There are a variety of challenges associated with the flow of liquids through carbon
2.6. Silicon nanowires (SiNWs)
2.7. Graphene, metal films and nanostructured surfaces
Graphene, metal films, and nanostructured surfaces are all in the class of 2D nanostructures which are structures with one dimension of ∼100 nm in size. Their incorporation in nanodiagnostic is their use as racks in order to conjugate and immobilize ligands for targeted binding when the sample comes across them. They usually are sheets of a certain nanomaterial, which have special properties different from that of the corresponding bulk material. For example, metal films exhibit the same advantages with metal NPs, for example, the SPR effect, and thus, they are used in the construction of label‐free SPR biosensors. As for nanostructured surfaces, they are in reality electrodes with their surface linked with nanotubes or nanoparticles. Finally, graphene will offer great sensitivity in rapid diagnostic tests, since it is an incredibly stable one‐layer 2D surface of carbon atoms with unique optical and conductive properties .
3. Nanotechnology‐on‐a‐chip or nanofluidics
A nanobiochip is comprised of integrated biomolecules or biologically active artificial structures which are usually smaller than that of cell's. The chip contains microarrays, which are minitest sites, on a solid surface, and this allows for multiple tests to be carried out simultaneously. Therefore, identification of a specific molecular signature, which will be unique to the diagnosis, can be done through thousands of biochemical reactions being performed on the nanobiochip [9, 10].
The identification and quantification of a variety of molecules will be permitted through the combination of nanotechnologies, such as nanofluids and nanobiosensors, with biochips, and this will lead to the generation of future
4. Applications of nanotechnology in
in vitro nanodiagnostics
Up to now, nanostructures are successfully incorporated to
4.1. Nanosensors for glucose monitoring
The management of diabetes disease, besides the great progress in the maintenance of insulin, is still intriguing. In the current clinical practice, diabetes patients need to tolerate tandem blood samples in order to monitor blood glucose and therefore minimize the possibility of hyper‐ or hypoglycemia, together with the aftermaths. Thus, it is still now an essential task to design a management approach for the monitoring of blood glucose that is non‐invasive, fast, and sensitive. The use of nanotechnology for the fabrication of a rapid and portable diagnostic test offers the aforementioned advantages. However, it is difficult task to design the ideal test, since the ideal biosensor has to be small, low‐cost, with simple function, accurate in the measurement and of course portable. Furthermore, this future test will have to minimize the blood volume needed for the test and the possible contaminations and to assure the accuracy of the measurement. Even further, an implantable microfluidics biosensor could provide a more accurate management of
Recently, a type of miniaturized sensors called optodes has attracted the scientists’ attention. Nano‐optodes consist of a chemical that responds to an analyte, a polymer to immobilize the chemical transducer and instrumentation (optical fiber, light source, detector, and other electronics) . They can be integrated with several optical measurement schemes such as reflection, absorption, evanescent wave, luminescence (fluorescence and phosphorescences) that is the most popular methodology, chemiluminescence and surface plasmon resonance. Balaconis et al.  used nanofiber fluorescent nano‐optodes in order to measure the dynamic changes of glucose concentrations based on the competitive binding between a hydrophobic boronic acid recognition molecule, a chromophore and glucose. The concentration change of glucose in the membrane was monitored by measuring the change of the optical signal. Nano‐optodes are proven to be functional both
4.2. Detection of bacteria and viruses
Nowadays, pathogen detection is performed using very sensitive techniques such as ELISA, PCR, and sequencing techniques. However, the aforementioned techniques are considered very expensive; they require excessive sample preparation and have long validation times with no early response; and they need expertise personnel to perform the test. Therefore, the advantageous optical, magnetic, electrical, and catalytic characteristics of nanomaterials can offer faster, more sensitive, specific, and cheaper diagnostic assays that no experts will be needed for their use, in order to detect microbial pathogenesis. Pathogens express on their membranes various molecules such as glyco‐, lipoproteins, glycopeptides, carbohydrates, and lipids. Thus, nanotechnology usually uses antibodies as targeting ligands for the development of various immunoassays. For example, gold and silver NPs have been broadly used for conjugation with affinity ligands, finding attractive applications as chemical sensors or even further for the generation of nanoscale arrays of pathogen‐targeting ligands. Moreover, NPs can also be conjugated with specific oligonucleotides sequences that bind pathogen nucleic acid sequences to generate colorimetric changes. Other nanoparticles including fluorescent QDs and CNTs have been used in various applications including DNA detection and the development of immunoassays for the detection of bacteria and viruses. Besides NPs based‐assays, miniaturized microfluidic system or lab‐on‐a‐chip (LOC) is a futuristic and attractive field of research for accurate and point of care management of microbial infections.
Very recently, Wu et al.  fabricated a Microbead Quantum‐dots Detection System (MQDS) in order to identify and measure target DNAs of pathogenic microorganisms and substitute PCR amplifications. All reporter probes and internal control probes were conjugated with quantum dots that fluoresce at different emission wavelengths using the click reaction, in order to monitor the binding process by flow cytometry . Zhang et al.  created an innovative microfluidic microbead array with QDs tags for HBV genotyping. This method detected
Besides DNA, antimicrobial peptides (AMPs) are promising affinity agents for the development of biosensors due to the possibility of recognizing a various pathogenic biomarkers (bacteria, fungi, toxins, viruses), in order to design biosensors that exhibit more specificity and sensitivity regarding the detection limits. In the bound state, the biosensor can be evaluated via electrochemical impedance and fluorescence spectroscopies. Mannoor et al.  fabricated an array electrobiosensor functionalized with the AMP magainin I on the surface of AuNPs, in order to detect pathogenic bacteria. When the specific reaction occurs between magainin I and the sample, dielectric alterations of the surface's properties are detected, a change that allows the selective detection of pathogenic Gram‐negative bacteria
As already mentioned, 2D nanostructures can offer great sensitivity in rapid diagnostic tests. Mevold et al.  used graphene–PDDA nanosheets absorbed with AuNPs. PDDA is a homopolymer for the dispersibility of graphene, since it charges positively the graphene and protects the solution from the aggregation of graphene. The positive charge of AuNPs/graphene–PDDA nanosheets serves to easily capture the negative charge of
4.3. Nanotechnology in cancer diagnosis
The incorporation of nanotechnology in cancer diagnosis is essential, since early detection of the disease can improve the chances of treatment. In addition, the reduction of the needed time for the nanotest will lead in more precise decision‐making in every day clinical practice and treatment costs.
Up to now, several nanomaterials, such as AuNPs, semiconductor II–VI QDs, silicon nanowires (SNWs), carbon CNTs, and graphene, have been used in order to detect various cancer markers (proteins/peptides or DNA/RNA) in a sensitive and specific manner, especially when used for the construction of high‐performance nanobiosensors. For instance, FET‐SNWs have been used for the detection of several prostate cancer biomarkers, such as prostate‐specific antigen (PSA) at the level of fg/ml of PSA for monitoring prostate cancer and predicting the risk of early biochemical relapse and the prostate biomarker 8‐hydroxydeoxyguanosine (8‐OHdG) by using a SNWs functionalized with antibodies against 8‐OHdG . PSA, prostate‐specific membrane antigen, platelet factor‐4, and interleukin‐6 prostate cancer biomarkers have also been detected by electrochemical NTs [27, 28].
Furthermore, using a nanowire technology (nCounter Analysis System), ribonucleic acid (RNA) expression levels of cancer‐testis antigens (CTAs) have been measured, as biomarkers for aggressive prostate cancer. This nanowire technology offers the possibility of a sensor chip, is able to simultaneously detect more than one of cancer marker, and measures a panel of biomarkers related to a specific cancer type and/or individual, thus contributing to the personalization of cancer diagnosis . Lee et al.  developed a nanowire substrate‐enabled laser‐scanning imaging combined with flow cytometry for the isolation and quantitation of circulating tumor cells from a human lung carcinoma sample mixture of tumor cells and leukocytes.
Interestingly, CNTs and SNWs have been utilized for detection of various volatile organic compounds (VOCs) in breath samples of lung and gastric cancer patients, respectively . Thus, Tran et al.  constructed a portable read‐out NWs on‐a‐chip device, by the addition of a complementary metal‐oxide semiconductor (CMOS) on FET‐SiNWs, creating a nanoplatform that could detect ALCAM in serum at a detection limit of 15.5 pg/ml, in <30 min. Besides cancer biomarker detection, FET‐SiNWs and zinc oxide nanowires (ZnONWs) have been used to detect ssDNA and mi‐RNAs related to the initiation and progression of various cancer types .
Just like other nanobiosensors, nanocantilevers were demonstrated to be able to detect PSA at low levels (0.2 ng/ml–60 μg/ml) for the detection of prostate cancer. Huber et al.  used microcantilever arrays to detect BRAFV600E mutation nanomechanically without amplification, from total RNA samples isolated from malignant melanoma cells. Wang et al.  fabricated a new cantilever array‐based biosensor based on MEMS for the detection of alpha‐fetoprotein (AFP), a liver cancer biomarker, with high accuracy, while Liu et al.  detected the same biomarker for hepatocellular carcinoma at the level of ng/ml, using a resonant microcantilever electromagnetic resonance‐exciting and piezoresistive read‐out elements on‐chip integrated, in order to measure frequency‐shift versus specific‐adsorbed mass.
So far, nanostructures such as QDs, AuNPs, and superparamagnetic NPs have been the most successfully incorporated in
5. Discussion and future perspectives
Up to now, the incorporation of nanostructures in medicine is offering the development of diagnostic tools of high sensitivity, advantageous contrast agents compared to traditional dyes already in use, novel personalized treatment approaches, and drug delivery vehicles. Taking into consideration small‐sized sample volumes, fast reaction times, specificity and sensitivity of nanosystems, in the near future they will be able to bring mobile testing devices into every day clinical practice. Regarding
NPs are the most versatile material for developing diagnostics, since they can be conjugated with various agents and serve as tags or labels. Thus far, there are several efforts in the way in order to develop nanoparticle‐based systems for disease detection. Nanosphere, Inc. has launched the Verigene system which uses AuNPs. Verigene system is a molecular diagnostic system for rapid diagnostic evaluation that enables rapid treatment decisions regarding targeted therapy for various infections in bloodstream, respiratory tract, and gastrointestinal tract. The technology can also be applied in the future for other life‐threatening diseases such as cardiovascular, autoimmune diseases, and cancer. T2 Biosystems developed T2MR, a diagnostic detection method that uses miniaturized magnetic resonance technology in order to measure how water molecules react under magnetic fields. The T2MR technology platform offers a fast, simple, and sensitive alternative to existing diagnostic methodologies and uses magnetic nanoparticles to identify proteins, nucleic acids, and other materials. T2MR technology enables low limit of detection, as low as 1 cell/mL, compared to the 100–1000 cell/mL required by PCR‐based
Currently, QD technology is the most broadly employed nanotechnology for diagnostic developments, especially for cancer management. The only concern about QDs is the
Regarding circulating cancer cell detection, researches have recently published the NanoFlare genetic‐based technology that enables the detection of living circulating tumor cells in bloodstream. A NanoFlare is designed to enter cells and to hybridize with cancer‐specific oligonucleotide sequences. NanoFlare has a great advantage, such as all nanoparticles due to their size: the fact that they can enter inside the cell gives the opportunity of the use of various biomolecules that are present inside the cell and not only markers anchored on the cell's surface. So when NanoFlare attaches to the cancer‐specific target into the cell, a reporter “flare” is released that produces a detectable fluorescent signal.
Nanosensors and blood sensors capable of detecting multiple pathogens or chemical compounds are one such example. Point‐of‐care diagnostics are possible with nanosensors and also an attractive technology towards point‐of‐care diagnosis that will be easy for the patient to use at home and will enable the integration of diagnostics with therapeutics and the development of personalized treatment approaches. Blood sensors, especially cantilevers arrays, are characterized by important advantages since the technology of nanomechanical detection requires no labels and/or external probes, and optical excitation and is rapid, highly specific, sensitive, and portable. The above give the opportunity to detect pathogens or molecules in blood samples and are a great example of future point‐of‐care diagnostic tools. Furthermore, the upper goal regarding the construction of diagnostic biochips will be the miniaturization of the biosensor chips to range of “nano”‐dimensions. Thus, the use of nanotechnology in rapid diagnostic tests will lead to devices with nanodimensions, sensitive, easy to use, and non‐expensive in order to allow direct signal observation, manipulation, analysis, and result validation of a single biological molecule from a single cell. This offers new opportunities and provides powerful tools in the fields of genomics, proteomics, molecular diagnostics, and high‐throughput screening.
Majdalawieh A, Kanan MC, El‐Kadri O, Kanan SM. Recent advances in gold and silver nanoparticles: synthesis and applications. J Nanosci Nanotechnol. 2014 Jul;14(7):4757–80. Review.
Kong K, Kendall C, Stone N, Notingher I. Raman spectroscopy for medical diagnostics—from in‐vitro biofluid assays to in‐vivo cancer detection. Adv Drug Deliv Rev. 2015 Jul 15;89:121–34.
Wabuyele MB, Vo‐Dinh T. Detection of human immunodeficiency virus type 1 DNA sequence using plasmonics nanoprobes. Anal Chem. 2005 Dec 1;77(23):7810–5.
Wabuyele MB, Yan F, Vo‐Dinh T. Plasmonics nanoprobes: detection of single‐nucleotide polymorphisms in the breast cancer BRCA1 gene. Anal Bioanal Chem. 2010 Sep;398(2):729–36.
Mukherjee A, Shim Y, Myong Song J. Quantum dot as probe for disease diagnosis and monitoring. Biotechnol J. 2016 Jan;11(1):31–42.
Shamirian A, Ghai A, Snee PT. QD‐based FRET probes at a glance. Sensors (Basel). 2015 Jun 4;15(6):13028–51.
Choi S, Tripathi A, Singh D. Smart nanomaterials for biomedics. J Biomed Nanotechnol. 2014 Oct;10(10):3162–88. Review.
Singh D, McMillan JM, Kabanov AV, Sokolsky‐Papkov M, Gendelman HE. Bench‐to‐bedside translation of magnetic nanoparticles. Nanomedicine (Lond). 2014 Apr;9(4):501–16.
Su W, Gao X, Jiang L, Qin J. Microfluidic platform towards point‐of‐care diagnostics in infectious diseases. J Chromatogr A. 2015 Jan 16;1377:13–26.
Xia D, Yan J, Hou S. Fabrication of nanofluidic biochips with nanochannels for applications in DNA analysis. Small. 2012 Sep 24;8(18):2787–801.
Xu Y, Jang K, Yamashita T, Tanaka Y, Mawatari K, Kitamori T. Microchip‐based cellular biochemical systems for practical applications and fundamental research: from microfluidics to nanofluidics. Anal Bioanal Chem. 2012 Jan;402(1):99–107.
Barone PW, Baik S, Heller DA, Strano MS. Near‐infrared optical sensors based on single‐walled carbon nanotubes. Nat Mater. 2005;4:86–92.
Huang X, Li S, Schultz JS, Wang Q, Lin Q. A MEMS affinity glucose sensor using a biocompatible glucose‐responsive polymer. Sens Actuators B Chem. 2009 Jul 16;140(2):603–609.
Lueke J, Moussa WA. MEMS‐based power generation techniques for implantable biosensing applications. Sensors (Basel). 2011;11(2):1433–60.
Balaconis MK, Billingsley K, Dubach MJ, Cash KJ, Clark HA. The design and development of fluorescent nano‐optodes for in vivo glucose monitoring. J Diabetes Sci Technol. 2011 Jan 1;5(1):68–75.
Balaconis MK, Luo Y, Clark HA. Glucose‐sensitive nanofiber scaffolds with an improved sensing design for physiological conditions. Analyst. 2015 Feb 7;140(3):716–23.
Wu TY, Su YY, Shu WH, et al. A novel sensitive pathogen detection system based on Microbead Quantum Dot System. Biosens Bioelectron. 2016 Apr 15;78:37–44.
Zhang H, Xu T, Li CW, Yang M. A microfluidic device with microbead array for sensitive virus detection and genotyping using quantum dots as fluorescence labels. Biosens Bioelectron. 2010 Jul 15;25(11):2402–7.
Fu X, Cheng Z, Yu J, Choo P, Chen L, Choo J. A SERS‐based lateral flow assay biosensor for highly sensitive detection of HIV‐1 DNA. Biosens Bioelectron. 2016 Apr 15;78:530–7.
Tsang MK, Ye W, Wang G, Li J, Yang M, Hao J. Ultrasensitive detection of Ebola virus oligonucleotide based on upconversion nanoprobe/nanoporous membrane system. ACS Nano. 2016 Jan 26;10(1):598–605.
Mannoor MS, Zhang S, Link AJ, McAlpine MC. Electrical detection of pathogenic bacteria via immobilized antimicrobial peptides. Proc Natl Acad Sci USA. 2010 Nov 9;107(45):19207–12.
Lillehoj PB, Kaplan CW, He J, Shi W, Ho CM. Rapid, electrical impedance detection of bacterial pathogens using immobilized antimicrobial peptides. J Lab Autom. 2014 Feb;19(1):42–9.
Cho IH, Irudayaraj J. In‐situ immuno‐gold nanoparticle network ELISA biosensors for pathogen detection. Int J Food Microbiol. 2013 Jun 3;164(1):70–5.
Mevold AH, Hsu WW, Hardiansyah A, et al. Fabrication of gold nanoparticles/graphene‐PDDA nanohybrids for bio‐detection by SERS nanotechnology. Nanoscale Res Lett. 2015 Dec;10(1):397.
Li S, Liu H, Deng Y, Lin L, He N. Development of a magnetic nanoparticles microarray for simultaneous and simple detection of foodborne pathogens. Biomed Nanotechnol. 2013 Jul;9(7):1254–60.
Gao A1, Lu N, Dai P, Fan C, Wang Y, Li T. Direct ultrasensitive electrical detection of prostate cancer biomarkers with CMOS‐compatible n‐ and p‐type silicon nanowire sensor arrays. Nanoscale. 2014 Nov 7;6(21):13036–42.
Mohd Azmi MA, Tehrani Z, Lewis RP, et al. Highly sensitive covalently functionalised integrated silicon nanowire biosensor devices for detection of cancer risk biomarker. Biosens Bioelectron. 2014 Feb 15;52:216–24.
Chikkaveeraiah BV, Bhirde A, Malhotra R, Patel V, Gutkind JS, Rusling JF. Single‐wall carbon nanotube forest arrays for immunoelectrochemical measurement of four protein biomarkers for prostate cancer. Anal Chem. 2009 Nov 1;81(21):9129–34.
Takahashi S, Shiraishi T, Miles N, Trock BJ, Kulkarni P, Getzenberg RH. Nanowire analysis of cancer‐testis antigens as biomarkers of aggressive prostate cancer. Urology. 2015 Mar;85(3):704.e1–7.
Lee SK, Kim GS, Wu Y, et al. Nanowire substrate‐based laser scanning cytometry for quantitation of circulating tumor cells. Nano Lett. 2012 Jun 13;12(6):2697–704.
Shehada N, Brönstrup G, Funka K, Christiansen S, Leja M, Haick H. Ultrasensitive silicon nanowire for real‐world gas sensing: noninvasive diagnosis of cancer from breath volatolome. Nano Lett. 2015 Feb 11;15(2):1288–95.
Tran DP, Wolfrum B, Stockmann R, et al. Complementary metal oxide semiconductor compatible silicon nanowires‐on‐a‐chip: fabrication and preclinical validation for the detection of a cancer prognostic protein marker in serum. Anal Chem. 2015 Feb 3;87(3):1662–8.
Lu N, Gao A, Dai P, et al. CMOS‐compatible silicon nanowire field‐effect transistors for ultrasensitive and label‐free microRNAs sensing. Small. 2014 May 28;10(10):2022–8.
Huber F, Lang HP, Backmann N, Rimoldi D, Gerber C. Direct detection of a BRAF mutation in total RNA from melanoma cells using cantilever arrays. Nat Nanotechnol. 2013 Feb;8(2):125–9.
Wang J, Wang S, Wang X, Zhu Y, Yang J. Cantilever array sensor for multiple liver cancer biomarkers detection. Sensors. 2014;2014:343–346.
Liu Y, Li X, Zhang Z, Zuo G, Cheng Z, Yu H. Nanogram per milliliter‐level immunologic detection of alpha‐fetoprotein with integrated rotating‐resonance microcantilevers for early‐stage diagnosis of heptocellular carcinoma. Biomed Microdevices. 2009 Feb;11(1):183–91.
Jokerst JV, Raamanathan A, Christodoulides N, et al. Nano‐bio‐chips for high performance multiplexed protein detection: determinations of cancer biomarkers in serum and saliva using quantum dot bioconjugate labels. Biosens Bioelectron. 2009 Aug 15;24(12):3622–9.
Gazouli M, Lyberopoulou A, Pericleous P, et al. Development of a quantum‐dot‐labelled magnetic immunoassay method for circulating colorectal cancer cell detection. World J Gastroenterol. 2012 Aug 28;18(32):4419–26.
Wang Y, Zhang Y, Du Z, Wu M, Zhang G. Detection of micrometastases in lung cancer with magnetic nanoparticles and quantum dots. Int J Nanomed. 2012;7:2315–24.
Guo S, Chen YQ, Lu NN, Wang XY, Xie M, Sui WP. Ultrasonication‐assisted one‐step self‐assembly preparation of biocompatible fluorescent‐magnetic nanobeads for rare cancer cell detection. Nanotechnology. 2014 Dec 19;25(50):505603.
Kanwar SS, Dunlay CJ, Simeone DM, Nagrath S. Microfluidic device (ExoChip) for on‐chip isolation, quantification and characterization of circulating exosomes. Lab Chip. 2014 Jun 7;14(11):1891–900.