Accepted Manuscript Materials and methods of signal enhancement for spectroscopic whole blood analysis: Novel research overview Jafar Soleymani, David Perez-Guaita, Mohammad Hasanzadeh, Nasrin Shadjou, Abolghasem Jouyban PII:
S0165-9936(16)30109-1
DOI:
10.1016/j.trac.2016.10.006
Reference:
TRAC 14840
To appear in:
Trends in Analytical Chemistry
Received Date: 18 April 2016 Revised Date:
17 October 2016
Accepted Date: 18 October 2016
Please cite this article as: J. Soleymani, D. Perez-Guaita, M. Hasanzadeh, N. Shadjou, A. Jouyban, Materials and methods of signal enhancement for spectroscopic whole blood analysis: Novel research overview, Trends in Analytical Chemistry (2016), doi: 10.1016/j.trac.2016.10.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Materials and methods of signal enhancement for spectroscopic whole blood analysis: Novel research overview Jafar Soleymani
a,b,*
, David Perez-Guaita c, Mohammad Hasanzadeh
, Nasrin Shadjou
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Abolghasem Jouyban a,g
a,d
a
e,f
,
Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. c Department of Analytical Chemistry, University of Valencia, Burjassot, Spain. d Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. e Department of Nanochemistry, Nano Technology Center, Urmia University, Urmia, Iran. f Department of Chemistry, Faculty of Chemistry, Urmia University, Urmia, Iran. g Kimia Idea Pardaz Azarbayjan (KIPA) Science Based Company, Tabriz University of Medical Sciences, Tabriz 51664, Iran.
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b
*Corresponding author. E-mail:
[email protected],
[email protected]. Tel: +989148660544, Fax: +984133363231. 1
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ABSTRACT The early diagnosis of diseases is crucial for reducing morbidity and mortality and also for improving the quality of treatment process. Among various biological samples used to follow up
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the concentrations of disease markers, whole blood sensing can efficiently decrease analysis time by means of introducing methods with no pretreatment. In addition, the direct detection of markers in whole blood facilitates testing procedure and minimize the possibility of the loss of
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analytes in the process. Therefore, the assay of unprocessed whole blood is becoming increasingly important in clinical diagnostics and biomedical research. Incorporation of new
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advanced materials plays a major role in the spectroscopic sensing methods and improving the detection sensitivity of the optical probes. This review, comprehensively summarize the latest articles and patents from 2000 to 2015 on the application of new advanced materials for the detection of disease markers and environmental analytes in whole blood using intensity based
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optical methods. This review shows how new advanced materials have made significant contributions in the developments of intensity based optical sensing methods. More importantly, different aspects of the intensity based optical sensors such as type of advanced materials,
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detection techniques, analytes and the corresponding sensitivities have been discussed in details.
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Keywords: Nanomaterials, Unprocessed whole blood, Sensing, Point-of-care, Spectroscopy, Optical.
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Prostate-specific antigen PSA Quantum dots QDs Reflectometric interference spectroscopy RIfS Refractive index RI Refractive index unit RIU Reverse transcription quantitative polymerase chain reaction RT-qPCR Self-assembled monolayer SAM Single-walled carbon nanotubes SWCNTs Sodiumtetrakis-[3,5-bis (trifluoromethylphenyl)]borat NaTFPB Surface plasmon fluorescence spectroscopy SPFS Severe acute respiratory syndrome SARS Surface plasmon resonance SPR Surface Enhanced Raman SER Surface plasmon-coupled directional luminescence SPCL Surface-enhanced Raman spectroscopy SERS Thiocholine TCh Upconverting nanoparticles UCNPs World health organization WHO 8-hydroxypyrene-1,3,6trisulfonic acid HPTS
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Acetylcholine ACh Acetylcholinesterase AChE Acetylthiocholine ATCh Acquired immune deficiency syndrome AIDS Acridine orange AO AIDS clinical trials group ACTG Alcohol oxidase AOX Amplex ultrared AUR Anodic aluminum oxide AAO Atomic absorption AA Atomic emission AE Au nano shells GNS Bovine serum albumin BSA Butyrylcholinesterase BChE Cancer antigen 15.3 CA 15.3 Charge-coupled device CCD Chromoionophore-9(diethylamino)-5octadecanoylimino-5Hbenzo(a)phenoxazine ETH 5294 Circulating tumor cells CTCs Department of health and human services DHHS Department of health and human services DHS Dithiobissuccinimidyl protioate DSP Environmental protection agency EPA N-ethyl-N’-(3dimethylaminopropyl) carbodiimide EDC Extraordinary optical transmission EOT Fluorescein isothiocyanate FITC Fluorescence in situ hybridization FISH
Förster resonance energy transfer FRET Glucose recognition polypeptide GRP Glucose binding protein GBP Glucose oxidase GOx Hemoglobin Hb Horseradish peroxidase HRP Human chorionic gonadotropin hCG Human immunodeficiency virus HIV Hydrogen cyanide HCN Infrared IR Interferometric Reflectance Imaging Sensor IRIS Limit of detection LOD Localized surface plasmon resonance LSPR Matrix metalloproteinase-2 MMP-2 Metal-enhanced fluorescence MEF Microfluidic purification chip MPC N-(2-(1-maleimidyl) ethyl)7-(diethylamino) coumarin-3carboxamide MDCC Nanoparticles NPs Near-infrared fluorescence NIRF Near-infrared NIR N-hydroxysuccinimide NHS Partial least squares regression PLS Point-of-care POC Poly (vinylchloride) PVC Polyacrylamide PAA Porous silica PS Potassiumionophore III, 2dodecyl-2-methyl-1,3propanediylbis (N-(5′nitro(benzo-15-crown-5)-4′-yl) carbamate) BME-44
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Abbreviations:
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Table of contents 1. Introduction ......................................................................................................................................... 5
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1.1. Importance of early diagnosis........................................................................................................ 5 1.2. Why whole blood sensing?............................................................................................................ 6 1.3. Optical methods in early diagnosis ................................................................................................ 7 1.4. The role of new materials in the intensity based optical sensing methods ....................................... 8
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2. Intensity based spectroscopic sensing methods..................................................................................... 9 2.1. Quantum dots (QDs) ..................................................................................................................... 9 2.2. Upconverting nanoparticles (UCNPs).......................................................................................... 12
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2.3. Carbon nanotubes (CNTs) ........................................................................................................... 16 2.4. Au based materials ...................................................................................................................... 17 2.4.1. Au nanoparticles (AuNPs) .................................................................................................... 17 2.4.2. Au nanoshells (GNSs) and Au nanorods ............................................................................... 21 2.5. Silver nanoparticles (AgNPs) ...................................................................................................... 24 2.6. Polymers..................................................................................................................................... 25 2.7. Magnetic nanoparticles (MNPs) .................................................................................................. 27
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2.8. Si based materials ....................................................................................................................... 30 2.9. Other papers of interest ............................................................................................................... 31 3. Conclusions and perspectives............................................................................................................. 39 Acknowledgments ................................................................................................................................. 41
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References............................................................................................................................................. 41
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1. Introduction 1.1. Importance of early diagnosis
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Early detection of diseases implies several advantages: (i) it greatly increases the chance of successful treatment, (ii) an early detection and diagnosis has critical impact on the physical, emotional and financial conditions of the patient, (iii) identifying patients with early stage of a
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disease allows clinicians to begin treatment sooner, when interventions are generally more effective and less expensive and (iv) in infectious diseases, early detection and treatment can also
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prevent the transfer of infection to others. Patients in the early stages of the disease will be better able to report symptoms and understand their own disease process. Unfortunately, clinicians do not routinely assess the cognitive health of their patients often, resulting in delayed diagnosis and post diagnostic care. The early detection of diseases has two major components: screening tests
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and medical tests, which are to find health problems before appearing the symptoms and to find a disease early in its course, respectively [1, 2]. Most of screening tests rely on follow up of some analytes called biomarkers in the biological fluids. Biomarkers play impotants roles in diagnosis
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and/or follow up of various diseases. Concerning the systemic diseases, levels of biomarkers in the blood, serum or plasma are frequently investigated for early detection of serious diseases.
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According to National Institute of Health working group, a biomarker is defined as: “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathologenic processes or pharmacologic responses to a therapeutic intervention” [3]. An ideal biomarker possesses some detailed characteristics including; specificity to a given pathological condition, validity of its determination method according to analytical validation criteria, stability in storage condition, ease of sample collection, its levels should not be affected
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by diet, sex, age, exercise, stress etc, and prediction capability in diagnosis and/or follow up processes [4-6]. Although traditional biomarkers are extensively used to screen the patients for a number of diseases such as glucose level of blood for diabetes, most of biomarkers failed to
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fullfil with all of the mentioned characteristics. Regarding the items related to analytical techniques for biomarker quantification and due to their very low concentrations, providing new materials are promising [7] and a number of papers deals with future details. Frangogiannis [8]
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summerized the hopes and challenges of identifying, verification, validation and impementation of new biomarkers. Soper et al. reviewed the point of care biosensors for diagnosis of cancer in
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which the used metrials to construct the sensors are novel materials [9]. Immunoaffinity capillary electophoresis is another promising analytical method to follow up of biomarkers and recent advances were summerized by Guzman and Phillips [10]. Features of immunoaffinity capillary electophoresis were compared with those of other methods used for determination of biomarkers,
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i.e. high performance liquid chromatography, western blotting, ELISA and multiplex assays [10].
1.2. Why whole blood sensing?
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The early detection of diseases requires the development of analytical methods used for detection of biomarkers related to the diseases under study. Whole blood or unprocessed whole
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blood matrix contains information related to biological conditions of the human body and contains diseases’ biomarkers. Designing of multichannel devices to assay of multiple symptoms of a disease or different diseases in a single drop of whole blood samples are the main purpose of sensor designing projects. Whole blood sensing based methods are able to quantify the analyte without any pretreatment of the blood resulting in deceased assay time. In this regard, development of the new methods with capability of detecting in whole blood matrices are crucial in detection-treatment process. Point-of-care (POC) methods including lab-on-a-chip and lab-on-
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a-desk provide a handheld and portable device to fast detection of biomarkers of various diseases without any additional requirements. POC testing methods are medical testing at or near the site of the patient care. The basic aim of POC testing methods is to provide rapid response and
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facilitate evidence-based medical diagnostics [11-14]. These devices can be easily used in various patient centric places including home, private clinics, roads, rural areas, and also in clinical or commercial diagnostic laboratories. The POC based methods can give information
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about various medical-emergency parameters including physiological and bimolecular markers
1.3. Optical methods in early diagnosis
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and assist in the early detection and diagnostic of diseases [15-18].
As reported in Table 1, various spectroscopic methods have been used for direct analysis of whole blood. These methods show both advantages and disadvantages. Luminesce based
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methods are extremely sensitive to very low concentrations of analyte even single-molecule detection. In addition, fluorescence approaches are relatively simple and allow the characterization of analyte with a non-invasive manner where near infrared (NIR) light passes
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through several centimetres of tissue without any invasive effect. The fluorescent based measurements can be made in two modes fluorescence intensity and fluorescence decay times.
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Beside applications in detection of various analytes, fluorescence based methods can be applied to observe the structure and distribution of biomolecules. However, autofluorescence interference of the matrices is the main obstacle of the fluorescence based methods. Infrared (IR) spectroscopy analysis is capable to introduce more automatable and
informative devices. Recently, near-infrared fluorescence (NIRF) imaging techniques have brought high attentions in non-invasive assessments with high sensitivity and specificity. The use
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of emission on low frequency region (650-900 nm) is of great importance because it provides a non-invasive detection. Due to less tissue auto fluorescence, light absorption and penetration of NIR across tissues, the NIR is extremely used in biomedical recognitions. Ultraviolet -visible
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spectrophotometry methods are very simple, portable, and cost effectiveness. For example, in colorimetry methods the sensing event can be observed by the naked eye. However their poor sensitivity and selectivity are the main disadvantages of absorption based methods.
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Refractive index (RI)-based methods such Surface Plasmon Fluorescence Spectroscopy (SPFS), surface plasmon resonance (SPR) and Localized surface plasmon resonance (LSPR) are
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capable to assay biomolecules down to the femtomolar range. SPFS method collects the fluorescence spectroscopy and SPR techniques advantages together to reach a more selective method [19, 20].
1.4. The role of new materials in the intensity based optical sensing methods
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Currently, there is an enormous demand for new advanced materials to design devices that can be used to accurate diagnosis of human health markers by various assays such as immunoassay methods. Among different materials, advanced nanomaterials not only decease
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time of assay but also increase the sensitivity of assay being related to their high surface-tovolume ratio. From the discussed papers, it is clear that advancements in the used materials in
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bio-sensing are tightly related to modify the analysis methods which is discussed in the following paragraphs.
Generally, fluorophores of the fluorescence based methods often suffer from small Stokes
shifts, poor photo–stability, fast photo–bleaching, aggregation and high binding rates to plasma proteins. To solve these limitations, various types of nanomaterials including quantum dots, upconversion nanomaterials and nanoclusters as fluorophores come to work enabling more
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stable, sensitive and accurate detections [21-29]. In addition to fluorescence based methods, SPR provides a label-free and high sensitive optical method to assay the analytes based on the RI changes on the surface of the sensor. SPR based works, could be used as a flow cell system for
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on-line determinations. In addition, modifications of the surface of the biosensors using the new advanced materials allow creating different types of SPR sensors. The recent achievements of SPR method as well as other methods are owed to develop nanomaterials for improving the
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sensitivity of the SPR based methods [30]. Also, commence of new materials such as metallic nanoparticles make the localized surface plasmon resonance (LSPR) based methods participate
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as powerful strategy for chemical and biological sensing aims which highly dependent on the composition, size or shape of the nanoparticles [31, 32].
This review aims to explore progresses on various features of materials for sensing and biosensing in whole blood medium where the microfluidics based papers were reviewed by Li et
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al. [33]. Also, Hasanzadeh et al. [34] reviewed the electrochemical sensing in whole blood. Moreover, as another aim of this review is to provide insight into the intensity based spectroscopic methods in recent 15 years which are applied to whole blood sensing discussing
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their advantages and disadvantages. More importantly, detailed discussions on different aspects of the applied bio-sensors (e.g., formation, detection techniques, labels and sensitivity) are
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provided. Consequently, several outstanding properties of the bio-sensors, research opportunities and the development potential and prospects are discussed. 2. Intensity based spectroscopic sensing methods 2.1. Quantum dots (QDs) QDs are currently used as promising materials for sensitive implementation on biosensing. QDs have very special spectral advantages including high emission quantum yields,
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broad absorption peaks, narrow and symmetric emission peaks and favor stabilities. In addition, it is possible to change the surface of functional groups of the QDs, which enables the modification of the surface for a given aim of interest [35].
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Khan et al. [36] used a non-contact bioassay of CdSe/ZnS core/shell QDs films for detection of glucose. The methodology is based on the reaction between enzyme funcutionalized-QDs and glucose to produce a non-fluorescent product, nicotinamide adenine
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dinucleotide, at 575 nm. The quenched photoluminescence of the QDs indicates indirectly the glucose concentration in the whole blood samples. The limit of detection (LOD) of the biosensor
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is 3.5 µM, which is competitive with existing contact-based bioassays. Furthermore, by using this label-free method, it is possible to develop systems which are optimized to determine glucose in its entire clinically relevant range (1-25 mM). As Khan et al. declared, in contrast to the contact approaches, their proposed methodology provides a high stability of QDs, waste-free,
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reusable, photostable, cost-effective, portable. In addition, the method could be implemented with low-cost detectors such as mobile phone cameras for POC applications. Most biological recognition events are often kinetically very slow and requiring long
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incubation times (often longer than 10 min). Aslan et al. [37] used local heating by means of microwaves to resolve this problem. With this process, the bioassay was kinetically completed
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within 1 min. In brief, by non-continuous exposing of silver nanoparticles (NPs) with microwave radiation (≈3 GHz), local heating is induced around the silver nanostructures. Furthermore accelerating of assay kinetics is also occurred without denaturation of the protein structure. A 50nm thick gold disk with a black body was used as the substrate to enable the completion of the analysis. Streptavidin conjugated QDs and surface-bound biotinylated-bovine serum albumin (BSA) were used to determine streptavidin with concentration range of 10–1250 nM within 1
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min being 30-fold faster kinetics as compared to the assay undertaken at room temperature. Collaboration of QDs and streptavidin is resulted in high selectivity and sensitivity in whole blood samples.
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In 2014, a group in china [38] were reported a QD based strip to determine blood-borne diseases. To achieve this aim various QDs were tested which are reported in the Table 2. The reported multi-purpose strip, was prepared according the following steps: A) coupling of QD and
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antibody/antigen using N-ethyl-N’-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and NHS (N-hydroxythiosuccinimide) to synthesis the sensing ligand, B) preparation of the test
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strip assembly. As reported, two shapes of strip i.e. pad and membrane are produced for easy use of the strip. Also, in another work [39], they applied the same strategy for assay of multiple indices of teratism disease.
Strano et al. [40] introduced a biosensing method with collaborating of hydrogel and a
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photoluminescent nanostructure where the single-walled carbon nanotubes (SWCNTs) as a photoluminescent agent is embedded to the hydrogel (poly(vinyl alcohol)) network. The claimed method possess wide variety of uses including the detection of glucose, beta-estradiol, small
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proteins (e.g., insulin), and antigens (e.g., prostate specific antigen (PSA)), also it is able to detect the changes in temperature and pH. For each uses, it is important that the surface of the
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hydrogel sensitized to a given analyte of interest. For example, biosensing of the glucose was done by attaching of the glucose binding protein (GBP) to the surface of the nanocomposite. By binding of glucose to the GBP, the change in conformational structure of GBP resulted in quenching of SWNT fluorescence, where the quenched fluorescence was linear with the concentration of glucose. Bruchez et al. [41] developed a fluorescent tagging method to detect a specific complementary of DNA or RNA sequence. The reported method is based on the various
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QDs (Table 2) which is sensitized with oligonucleotide to determine the target molecules. In the reported patent, the fluorescence in situ hybridization (FISH) approach is applied where by bounding of the target molecule to the probe, the fluorescence signal is emitted as a result of
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hybridization which is detected and amplified with a fluorescence microscope. Other QDs based reported patents in whole blood matrices are summarized in Table 2.
As mentioned, QDs has various superior properties while the toxicity of QDs to living
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cells limit their uses in biorecognition applications. QDs toxicity depend on various physicochemical properties and environmental conditions. Leaching and biodegradation of some
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QDs as a result of mechanical instability release heavy metals to the environments [42]. 2.2. Upconverting nanoparticles (UCNPs)
Whilst the many types of optical based bio-sensing methods show great potential for monitoring biomedical species at clinically relevant levels, most of these methods encountered
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with the problem of serum or whole blood auto-fluorescence. In order to solve the mentioned problem, the upconversion material comes to the work. UCNPs, are capable to convert the lowenergy excited light in NIR region to high-energy emitting light at the visible and NIR region.
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Therefore, those particles significantly minimize background interference, photobleaching and photodamage of biomolecules [29, 43, 44]. Furthermore, the UCNPs show large antistokes shift
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which causes easy separation of the discrete emission peaks from the excitation source [45]. Nevertheless, applications of UCNPs in optical-chemical sensing or biosensing in biofluids are much less reported [46-50]. The advantages of using UCNPs in bioconjugation and bioimaging have already been well reviewed by Mader et al. [51]. Xie et al. [52] applied NaYF4:Er,Yb upconverting nanorods assisted optode for analysis of potassium ions in whole blood of sheep. The proposed sensor is constructed by dissolving the
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chromoionophore ETH 5294, cation-exchanger NaTFPB, K+ selective ionophore BME-44, upconverting nanorods together with polyvinyl chloride (PVC) and the plasticizer bis(2ethylhexyl) sebacate to get a sensing membrane with 7 µm thickness. The response of the optode
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is based on changes in the upconverting luminescence intensity induced from the absorption change of the chromoionophore. The response range of this sensor is linear from 10−4 M to 10−2 M with an LOD of 10-4 M, which covers the biological level of K+. The obtained results by this
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report were comparable with the results obtained by inductively coupled plasma mass spectroscopy and ion selective electrodes methods, thus evidencing the capability of the method
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for further application in clinical diagnosis. Both excitation and emission wavelengths of the upconversion-assisted optode is located on the NIR window to prevent absorption and autofluorescence of the biological sample. As reported the major disadvantage of bulk optodes is their cross-sensitivity to pH which is caused by using of chromoionophore. By applying this
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effect, Xie et al. [50] presented optodes incorporating upconverting nanorods and chromoionophore of ETH 5418 in PVC films for pH and metal ion sensing in whole blood samples. Polymeric film was utilized to host nanorods and sensing components to provide
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repeatable and reversible measurements. Due to the strong spectral interference of the blood sample in the ultraviolet and visible wavelengths, the routine pH measurements are currently
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based on electrochemical sensors. By using UCNPs pH of the blood samples were determined at 656 nm with excitation wavelength of 980 nm. The NaYF4:Er,Yb upconverting nanorods and chromoionophore ETH 5418 were used as sensor components which can sense pH and metal ions (Na+, K+, Ca2+ and Cu2+) with excellent sensitivity, selectivity and reproducibility. The reduced fluorescence of the probe is linear from 10-5 to 10-2 M and up to 10-4 M, for Na+ and
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Ca2+, respectively. In pH sensing application, a linear range from pH 6 to 11 is observed where the luminescence intensity of the sensor is increased along with pH values. Recently, Yuan et al. [53] presented a fluorescence based method which applied
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lanthanide-doped UCNPs to determine glucose and H2O2 in whole blood samples. Authors evidenced that the fluorescence of NaYF4:Yb,Tm@NaYF4 UCNPs can effectively be quenched by MnO2-mediated nanosheets on the UCNPs. The quenched fluorescence can be reversed by
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adding H2O2, where the recovery of fluorescence may be attributed to the H2O2-mediated reduction of MnO2 to Mn2+. The H2O2 is produced on the enzymatic conversion of glucose by
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glucose oxidase (GOx). The developed probe is suitable for diabetes mellitus research and diagnosis. The LOD and dynamic range of the proposed method are 3.7 µM and 0-400 µM, respectively. It is observed that the constituents of the human blood samples including various saccharides, metal ions, proteins and amino acids have minor interfering effect on the efficiency
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of the nanosystem. The proposed methods have several favor outstanding features including LOD, selectivity and cost-effectiveness. The nanosystem can be easily applied to the detection of various H2O2-involved analytes.
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Matrix metalloproteinase-2 (MMP-2) is a very important biomarker of almost every type of human cancer, diabetes and hypertension in blood. Hence, the quantification of MMP-2 is of interest
in
biomedical
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great
diagnosis.
Briefly,
by
using
a
polypeptide
chain
(GHHYYGPLGVRGC) containing both the MMP-2 specific substrate domain (PLGVR) and a π-rich motif (HHYY) and UCNPs as the energy donor − acceptor pair, a Förster resonance energy transfer (FRET) based biosensor was prepared by Wang et al. [54]. The FRET process is initiated by the π−π interaction between the peptide anchored on the UCNPs and CNPs which thus quenched the fluorescence of the donor. The quenched fluorescence was recovered by
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addition of the concentration of MMP-2 within the range of 10−500 pg/mL. Due to the NIR excitation nature of used UCNPs, the FRET nanosensor was successfully applied to the direct determination of MMP-2 in whole blood and plasma samples without founding any significant
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interference from their matrices. The NIR excitation window reduces the background interference in complex matrices and makes the sensor directly applicable in biological samples. Figure 1 depicts a MMP-2 UCNPs based biosensor in whole blood medium. The advantages of
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this sensor lie in its ability to detect concentration as low as 10 pg/mL requiring less than 1 µL of whole blood sample, which capacitate the methods for using in the POC diagnostics.
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Figure 1 here
In 2015, Kerimo et al. [55] reported a biosensor which is claimed to be able to bioassay analytes in a body fluid e.g., blood, serum, plasma, synovial fluid, cerebrospinal fluid, and urine. The reported bioassay system has various parts including a waveguide with resonance grating
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structure and an enhancement region. After covering of the enhancement region surface with UCNPs, the first antibody attached to the surface of UCNPs; and then a second antibody coupled to the UPCNs which is sensitized to the target analyte. As claimed, this invention could be used
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as an immunoassay kit for fast detecting of proteins, pathogens, and electrolytes in body fluids where it is not limited to analysis of these samples.
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From the discussed examples, it is found that although the application of UCNPs in the
sensing of biological molecules and ions but the fabrication of UCNPs is very complicated and it requires to use strict reaction condition, long reaction time and high reaction temperature. Moreover, the leaching of UCNPs can be released the toxic heavy metals into the environment.
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2.3. Carbon nanotubes (CNTs) The novel properties of CNTs have generated keen interests among research groups to develop CNT-based sensing methods. CNTs display high electrical conductivity, chemical
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stability and mechanical strength. Recent advances in carbon nanotechnology have led to the discovery of fluorescent SWCNTs ranging from 900 to 1600 nm. This region is particularly transparent to biological tissue, which is an important benefit in the whole blood-based bio-
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sensing. Due to the surface activation possibility of the SWCNT, Barone et al. [56] utilized SWCNTs as sensing elements sensitized to determine glucose in whole blood samples. The main
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limitation of this technology is its limited lifetime (due to consumption of reagent). CNTs with superior optical properties have functional groups to modify the surface for making them selective for a given analyte. Although CNTs have demonstrated their great potential for sensing, but it is obvious that applications of CNTs in whole blood medium are less
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reported, may be related to the difficulties in sensing in whole blood medium. For example, Barone et al. [57] functionalized the surface of carbon nanotubes with GOx-suspended SWCNT and then with K3Fe(CN)6 to sensitize the constructed NIR base probe for determination of
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glucose in whole blood medium with an LOD of 34.7 µM. Briefly, GOx enzyme converts glucose to the gluconolactone with the hydrogen peroxide co-product. Afterwards, the produced
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H2O2 reacted with the Fe(CN)63– functional groups on the exposed nanotube surface to recover the quenched fluorescence.
In a published patent work, Strano et al. [58] applied a sensing probe to detect glucose
using a polymer with applying SWCNTs. Sensing is as result of the interaction between glucose and GOx enzyme which is selectively attached with glucose. As a result of interaction between glucose and enzyme, the fluorescence intensity of the carbon nanotube change according the
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concentration of glucose. This biosensing probe showed a detection limit of 34.4 µM, with response time of less than 80 s. The main points of the other available patents are summarized in Table 2.
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2.4. Au based materials 2.4.1. Au nanoparticles (AuNPs)
Among metal nanoparticles, AuNPs have been widely used in bio-sensing in biological
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media. This tendency to AuNPs is related to their fascinatingly physical properties including optical, electro-chemical, catalytic and electromagnetic properties, stability and biological
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compatibility. In addition, morphology and size dispersion of AuNPs are controllable and easy to improve surface properties. In AuNPs assisted bioassay, the plasmon resonance frequency changes because of coupling of the electric fields between particles [59]. The maximum level of lead in adult’s whole blood established by the World Health
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Organization (WHO) is 300 ppb. Li and coworkers [60] employed an oligonucleotide (T30695) modified gold nanoparticle for sensing of lead ions in blood by using fluorimetric method. In presence of H2O2, the Au-Pb complex is formed. The oligonucleotide–Pb2+ complex catalyzes
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H2O2-mediated oxidation of non-florescence Amplex UltraRed (AUR) to a highly fluorescent oxidized AUR product (Figure 2). In 584 nm excitation, the increased fluorescence signal is
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linear over the Pb2+ concentration range of 0.1–100 nM with an LOD of 0.05 nM. The 40T30695–AuNPs/AUR probe is able to in situ and on-time analysis of Pb2+ in whole blood and environmental samples.
Figure 2 here Noble metals, especially gold and silver are the most frequently used materials for plasmonic applications. The most extensively employed optical biosensors are those based on
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SPR changes in thin gold films with advantages of showing a fast response to environmental changes, ease of fabrication and capacity for real-time monitoring. Despite silver emits sharper
being favored its preferential application for biosensing [61].
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and more intense LSPR peaks than gold, the gold nanostructures have higher chemical stability
Infectious diseases such as human immunodeficiency virus (HIV) have a tremendous global healthcare impact. Early-stage diagnosis and monitoring of these diseases prevents a
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humanitarian crisis and the whole blood sensing based methods provide fast detection opportunities. Inci et al. [62] achieved a fast, accurate, fluorescence free and sensitive POC
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platform based on unique nanoplasmonic properties of nanoparticles. In their work, immobilized antibodies are used to selective capture of the different HIV subtypes by grabbing on the antibody anchored on the AuNPs coated surface (Figure 3). To anchor HIV on the biosensor surface the following steps were employed. Firstly surfaces were modified by poly-L-lysine to create
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amine groups. Then, layer-by-layer modifications were carried out on the amine-activated surface by AuNPs, 11-mercaptoundecanoic acid, EDC, and N-hydroxysulfosuccinimide (NHS) coupling, NeutrAvidin, and biotinylated anti-gp120 polyclonal antibody. As Inci et al. revealed
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the system performance showed favor repeatability for multiple HIV subtypes in whole blood media with accuracy comparable to gold standard (i.e., RT-qPCR method). The LOD of the
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reported method covers the range of values recommended in the current WHO, Department of Health and Human Services (DHHS) and AIDS Clinical Trials Group (ACTG) [63-65]. The method is versatile, by adapting the surface of the nanoparticles with other antibodies; the presented platform can be broadly applied to detect other pathogens. In order to increase the specificity of method toward HIV, BSA was utilized as a blocking agent. Considering the
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advantages, this method can be regarded a promising POC diagnostic methods which can be used on side of patients, private clinics, airports etc. Figure 3 here
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Malaria is a disease caused by some parasites from the genus plasmodium. Half of the population of the planet is at the risk of malaria and it is estimated that this disease can cause up to 1.200.000 fatalities per annum [66]. Accurate and early detection are essential for reducing
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mortality and transmission. The detection of the plasmodium in red blood cells using PCR and microscopy of Giemsa stained thick films are currently used as main gold standards on the
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hospital laboratories [67, 68]. However, these approaches require trained personnel and laboratory equipment to prepare blood samples resulting in very time-consuming and very complicated procedures. Recently Cho and coworkers [69] detected plasmodium in whole blood samples with applying diffraction-assisted extraordinary optical transmission (EOT) method. In
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this procedure, the (dithiobis succinimidyl protioate) DSP-Au nanoparticles were applied as a substrate to anchor a protein and subsequently the antibody. DSP has NHS ester ends which reacts with the primary amines (-NH2) of protein A to form stable amide bonds. After binding
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protein A to the DSP-treated gold film, antibodies were immobilized on protein A to bind target molecule (Figure 4). According to this report, the proposed plasmon biosensor shows favor
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refractive index sensitivity of 378 nm/refractive index (RIU) in the visible region (710 nm), and provides a cost effective and selective diagnostic POC tool for malaria diagnostics. Taking the advantages of the demonstrated biosensor including its compact feature, high sensitivity and selectivity to target molecules of plasmodium, this biosensor offers great potential for rapid and low-cost POC diagnostic devices. Figure 4 here
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Interferometric Reflectance Imaging Sensor (IRIS) is a tunable laser which illuminates different wavelengths on the surface and collects reflections from the surface by a chargecoupled device (CCD) camera. Some features including detection of proteins at attomolar
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concentration, instrumental simplicity, portable and robustness make IRIS as an ideal tool for clinical and diagnostic applications. Monroe et al. [70] investigated an IRIS based biosensor to perform discrete detection of β-lactoglobulin using AuNPs functionalized secondary antibodies
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in whole blood samples, which the results were validated with fluorescence based methods. The IRIS analysis was performed on the simple planar modified surface of Si-SiO2 substrate using
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CCD camera (Figure 5). The calculated LOD of the method for β-lactoglobulin in serum and whole blood samples was 60 aM and 500 aM, respectively. The long assay time disadvantage of IRIS method may be potentially reduced with the incorporation of microfluidics. Figure 5 here
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Schneider et al. [71] have developed a Hartman interferometer based optical chip to determine human chorionic gonadotropin (hCG) in whole blood samples. This immunosensor is based on the binding of antigen to specific antibodies on the biosensor to make a change in the
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RI of the surface layer. In order to signal amplification, the colloidal gold nanoparticles conjugated to a second anti-hCG monoclonal antibody to enhance the assay sensitivity. The
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response of constructed biosensor was linear over the hCG concentration range of 0.5–5 ng/mL with an LOD of 0.5 ng/mL.
Olkhov et al. [72] presented the capabilities of AuNPs array to assay allergen-specific
antibodies in whole blood and sera where the nanoarray functionalized with four different allergens i.e. catdander (Feld1), dustmite (Derp1), peanutallergen (Arah1) and dog dander (Canf1). The sensing areas are formed by AuNPs deposited on the substrate surface where the
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scattered light intensity changes along with addition of analyte. This biosensor is able to detect the specific response of allergen antibodies in whole blood samples. Due to localized surface plasmon array format, this probe can be applied to the simultaneous multi analyte detection in
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unprocessed blood samples. The sensitivity of the nanoarray was extremely enhanced using a secondary anti-IgG detection antibodies where the LOD of 2 nM is obtained. 2.4.2. Au nanoshells (GNSs) and Au nanorods
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Nanoshells are a member of core-shell materials with dielectric core of silica and thin metallic shell. These materials have plasmon resonance response that intensifies optical
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absorption and scattering. GNSs offer high biocompatibility and facile bioconjugation to antibodies. Their NIR optical properties make them as an ideal vehicle for whole blood immunoassay. For example, Hirsch et al. [73] applied GNSs for immunosensing of immunoglobulins in NIR region where the plasmon resonance frequency of the nanoparticle is as
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function of the relative dimensions of the core and shell layers. Upon addition of the immunoglobulins to the GNSs and subsequent reaction between the anchored antibodies on the surface of the nanoshells and the immunoglobulins, the absorbance of the probe is decreased at
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720 nm. The deceased absorbance is linear in the ranging from 0.8 to 88 ng/mL with LOD of 100 pg/mL. The method is able to detect immunoglobulin in saline, serum and whole blood within
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about 10-30 min.
Also, Wang and coworkers [74] reported a real-time detection method using the LSPR of
GNS self-assembled monolayer (SAM). As Figure 6 shows, the sensor is consisted of a silica core covered with GNSs where LSPR properties can be changed by changing the relative dimensions of the core and the shell layers and can be adjusted to the NIR region of 700 -1300 nm. After modification of GNSs-SAMs with cystamine and biotin-NHS, the constructed probe
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was applied to determine the streptavidin–biotin in unprocessed whole blood samples without any sample preparations. The recorded absorbance of streptavidin–biotin at 730 nm showed a
Figure 6 here
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linear range of 3-50 µg/mL and LOD of 3 µg/mL.
Through excellent properties, gold nanomaterials have been significantly developed and have become more important in biochemistry and biotechnology. By the modification of the
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surface of the AuNPs, many different types of label free LSPR sensors can be created. Chen et al. [75] evaluated the functionalized Au nanorods immobilized on glass for LSPR based
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biosensing of streptavidin. This method is highly dependent upon the local environment of the nanoparticle (i.e. changes in RI). The probe is served as a useful sensor to selective detection of the streptavidin with an LOD of 25 ng/mL. Results showed that the spectral λmax shifts is linear to the concentrations of streptavidin in the range of 0.025–20.0 µg/mL. As Chen et al.
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mentioned, the sensor operates in the NIR spectral region and is potentially useful for detecting low concentration of analytes in whole blood media within minutes without any sample preparation.
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From the above examples, it is found that both GNSs and Au nanorods based optical sensors show great sensing performance through the absorbance at NIR spectra but their
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preparation are rather complex and troublesome, which could potentially limit their wide uses in biomedical applications.
Natan et al. [76] developed a surface-enhanced Raman spectroscopy (SERS) based
method for detection of the concentration of bioagents (target nucleic acid or protein), certain viruses or bacteria in a tissue or blood sample. In this work, SERS signal of the activated surface of an AuNPs is decreased by interaction between target molecules and surface anchored
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oligonucleotide molecules. The resulting interaction causes to eliminate the Raman signal of the probe. As an advantage of the present work provides a simple and cheap assay which can be carried out using non-specialized equipment. In another SERS-based work, Thomas et al. [77]
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developed a sensing probe by applying the SERS-active AuNPs, wherein the SERS-active reporter ligand is covalently bound to the outer layer of the AuNPs. By applying this functionalized AuNPs, various analytes were detected including glucose, lactate, PSA and etc.
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The basic strategy of the present work, is the selective binding of the anchored molecule with the target analytes. The use of a functionalized SERS-active nanoparticle provides more selective
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interactions with analytes where often target molecules have not any Raman signal. Walker et al. [78] proposed the encapsulation of SERS AuNPs in phospholipids macrovesicles. The reported method comprises the following steps: i) mixing AuNPs with a solution containing a suspension of phospohlipids and the organic dye molecule of interest, ii)
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phospholipid encapsulation using sonication and iii) separation of the encapsulated gold nanoparticles from unbound phospholipids and excess of dye molecules. Particles can then be conjugated to specific antibodies targeting cell surface antigens. One of the main advantages of
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the encapsulated Au nanoparticles is that they allow the SERS analysis of in-vivo samples. In the patent inventors provide examples for the detection chronic lymphocyte leukemia cells.
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The use of Au based NPs is not limited to SERS analysis. Weissleder et al. [79] disclosed
a method for detecting target constituents in a sample by bounding them to metal nanoparticles and analyzing changes in the diffraction patterns. The system includes a radiation source, a sample holder, and a detector of diffraction patterns and can also include a microfluidic device, and can be integrated in a smartphone, being this device ideally suitable for the POC analysis.
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Inventors provide examples of the analysis of A431 cancer cells using the proposed method, obtaining results in good agreement with the reference method. 2.5. Silver nanoparticles (AgNPs)
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Due to favor spectral properties of AgNPs, i.e. high extinction coefficients and scattering light, there are growing interests in utilizing AgNPs as optical detecting agent in bio-sensors industries.
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Acetylcholine (ACh) is a neurotransmitter which regulates muscle tones, learning, sleep, etc. The ACh can be found in both the peripheral and central nervous systems. Increased level of
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ACh causes a decrease in heart rate and increase the production of saliva, while decreased level is associated with motor dysfunction as well as Parkinson's and Alzheimer's diseases. Acetylcholinesterase (AChE) catalyzes the conversion of ACh to choline. Sensitive and accurate determination of total AChE (AChE and butyrylcholinesterase, BChE) activities in whole blood
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is an important procedure in medical sciences, especially in POC diagnostics. Recently Ma et al. [80] published a new article for in situ detection of total AChE in whole blood samples based on metal-enhanced fluorescence (MEF) effects of the Ag@SiO2 core–shell nanoparticles. In brief,
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upon catalytic effect of AChE, acetylthiocholine (ATCh) is converted to thiocholine (TCh) to produce a positively charged complex. Due to negative-charged property of Ag@SiO2NPs, the
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positive-charged TChs is electrostatically bound to the surface of Ag@SiO2NPs (Figure 7). Subsequently, the negatively charged fluorescent dye molecule of 8-hydroxypyrene-1,3,6trisulfonic acid (HPTS) can be attached to the surface of Ag@SiO2NPs through electrostatic interaction. The MEF-induced enhanced fluorescence is used to determine AChE activity. The introduced in situ MEF nanosensor can determine the AChE activity in dynamic range of 0
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U/mL to 0.005 U/mL with LOD of 0.05 mU/mL in the sub-micro liter human whole blood samples. Figure 7 here nanostructures
are
becoming
more
attractive
over
monometallic
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Core–shell
nanostructures due to their improved optical, electronic and catalytic properties. The properties of the core-shell materials are adjustable by changing of either core or shell materials and
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constituting materials [81].
Chung-Pei et al. [82] reported a colorimetric detection method to detect proteins and
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genes in whole blood samples without any manipulation. This group utilized semiconductor based printed electronics onto a flexible plastic with using inorganic materials such as AgNPs and organic materials such as polyaniline. By attaching the surface antibodies of probe with target molecules, biosensing of various analytes including HIV, herpes virus, nucleic acid or
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proteins of bacterial proteins for syphilis, chlamydia, gonorhea; lipoproteins or the nucleic acids thereof; glycoproteins or the nucleic acids thereof etc. were carried out. Recently, Lednev et al. [83] presented a patent, focused on the diagnosis of Alzheimer’s disease
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using SERS based methods in whole blood, plasma, or cerebral spinal fluid. In the reported method, SERS of human blood with using advanced statistical analysis was used to introduce a
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simple blood test for Alzheimer's disease detection. Table 2, listed some more reported patents using silver nanoparticles in whole blood.
2.6. Polymers Absorbance based bio-sensors have attracted considerable interest for many years because of their low cost, simplicity, portability, reproducibility and long term stabilities.
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Emerging of new materials are opening doors in the term of improved sensitivity and better selectivity in biological media. Colorimetry does not require any additional transducing element and the changes can even be observed by the naked eye. In the two following works, a network
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of polyacrylamide was attached the GOx and horseradish peroxidase (HRP) on the network. For example, Sanz et al. [84] developed a film-based biosensor by entrapping the HRP and GOx on a polyacrylamide (PAA) gel matrix. Glucose diffuses in the sensor film and reacts with GOx to
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produce H2O2 which in turn reacts with HRP. As a result of this process the absorbance is increased and reached to a plateau. The constructed biosensor works continuously with an
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acceptable linear response range (1.5 × 10−6 - 5.5 × 10−5 M). The proposed sensor has favor stability and in pH 6.0 can be utilized for at least 750 measurements using a sample volume of 300 µL. Despite the short dynamic range and low LOD, the method can be detected glucose continuously with very low required sample volumes.
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Considering the optical transducer qualities of the blood hemoglobin (Hb), Sanz et al. [85] proposed an indirect method to assay blood glucose. Based on, the blood glucose reacts with the GOx entrapped on the PAA film to produce H2O2 and subsequently the produced H2O2 reacts
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with the blood Hb (Figure 8). This reaction results in an absorbance changes in the linear range of 20 to 12000 mg/L glucose. As an advantage, the method is not dependent on the blood oxygen
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concentration. The main advantage of the last two reported works is that they provide a continuous system to assay in whole blood media. Figure 8 here
Alcohol is one of the most relevant markers in toxicology and also very vital in
emergency diagnostics. Steigert et al. [86] reported a lab-on-a-disk based sensor to detect alcohol in a single droplet of whole blood samples. Briefly, a disk is loaded with the reagents including
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alcohol oxidase (AOX), HRP, aminophenazone and hydroybenzonic acid. Afterwards, in the presence of O2, AOX catalyzes the oxidation of ethanol to H2O2. This reaction is followed by a HRP-catalyzed oxidation reaction to produce quinoneimine dye which correlates linearly with
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the concentration of H2O2 and subsequently with alcohol concentration (λ=530 nm). This method is fast and can be done in a microfluidic feature. In contrast with the previously reported methods, in this case the absorbance is measured in 0 degree to the source lights, which improves
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the absorption in one order of magnitude. As authors pointed out, the reported methods can be used as lab-on-disk POC methods.
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In 2013, Romey et al. [87] introduced a patent to estimate concentration of glucose in human blood samples. They reported a non-enzymatic chemosensor where fluorophore coupled to a glucose binding moiety. The emitted fluorescence is affected by binding glucose to the glucose binding moiety wherein the changed signal is related to the glucose concentration. The basic of
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this work is attachment of a fluorescent dye on a polymeric hydrogel network where interaction of glucose with anchored dye resulted to decrease in fluorescent intensity. Also Markel et al. [88] reported the same procedure for estimating of glucose in blood samples. They reported an optical
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fiber wherein the dye is immobilized by a hydrogel.
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2.7. Magnetic nanoparticles (MNPs) MNPs have been wieldy used in bio-sensing in biological media. MNPs with good
stability are of great interest in an effective separation of catalysts, biochemical products, and cells. The nontoxicity and biocompatibility of MNPs make them as promising materials for living cells studies.
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Recently, Dittmer et al. [89] presented an optomagnetic biosensor to assay troponin I and T (cTnI and cTnT) as biomarker of myocardial damage. As Figure 9 depicting the controlled synthesis of the optomagnetic was performed in three steps. First stage, highly antibody loaded
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magnetic nanoparticles run through to attach the troponin molecules. In the next step, the actuating magnets are applied to separate the particles bonded and non-bonded with the target molecules. Thereafter, by using a magnetic field oriented away from the detection surface the
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free and non-specifically bound particles are rapidly removed with a magnetic wash. The optomagnetic biosensor is able to determine the cTnI in the range of 0.03–6.5 ng/mL with an
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LOD of 0.03 ng/mL. The advantages of this approach include: (i) requirement of very small assay volumes, on the order of 1 µL (ii) the capability to use as disposal POC device in ambulance, hospital, and private clinics.
Figure 9 here
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Natan et al. [90] reported a magnetic bead-capture nanotag to determine target analytes including the detection of cells, viruses, bacteria, proteins, DNA, RNA, or small molecules and environmental samples. For example, in order to detection of DNA, oligonucleotide is used as
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binding agent with the target analytes. This approach can detect DNA target concentration as low as 0.28-4 pM. These sensing elements integrate an Au nanoparticle core, a SiO2 shell and an
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organic or inorganic Raman active molecule in the interface core-shell. Nanotags can be employed in homogenous and heterogeneous analysis and offer advantages as sensing elements. The most important one for direct blood analysis is that they can be excited in the NIR, which minimizes the fluorescence interference. They describe how plasma and whole blood does not produce any significant Raman scattering in the 700-1800 cm-1 region. For a heterogeneous test, a capture antibody, specific to the analyte under study, can be covalently attached to a surface of
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a container and sample is incubated in the container. After removal of the unbound analyte, the container is incubated with nanotags also conjugated with the specific antibody. If the analyte is present, the Raman spectrum recorded focusing in the surface will evidence the SERS bands of
measurement of DNA, virus and other biological structures.
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the nanotag attached to the analyte. Nanotags offer extremely low limits of detection for the
Nanotags can also be combined with magnetic particles conjugated with a specific
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antibody which captures and preconcentrates the analyte of interest using the so-called “magnetic pulldown”. The analyte can be detected or quantified using the signal emitted by the magnetic
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capture particle-analyte-SERS-nanotag complex. A method for magnetically capturing the analyte in a pellet was patented by Weideimader et al. [91].The patent also includes methods for creating pellets rotating the sample tube or the use of lysis reagent for increasing the assay performance. Huang and Bhana [92] patented a method which integrated of the magnetic particle
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and the SERS tag in the same nanostructure using Iron oxide-gold (IO-Au) core-shell NPs. Particles were created synthesizing silver-adsorbed iron oxide nanoparticles and then growing gold shell onto the silver-absorbed iron oxide nanoparticles. The optical-magnetic particles can
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be functionalized with a specific antibody and can be used for the analysis of biological structures and analytes such as circulating tumor cells, being the LODs reported on the patent in
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the range 1-2 cells/mL of blood. The aforementioned methods used organic molecules as a SERS reporters.
Also, Liu et al. [93] reported a method of diagnosing malaria infection in patients’ whole
blood by SERS method using core-shell MNPs of Ag where adsorption of sample hemozoin and β-hematin (as markers of malaria) onto the surface of Ag MNPs resulted in changes on the SERS signal of the probe. Authors reported a detection limit of 5 nM for determination of β-hematin.
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MNPs, especially Fe3O4, provide biocompatible materials to design the biodegradable bio-sensors. Magnetic properties along with particles size of MNPs aid superior sensing
etc.) on its surface to sensitize for an analyte of interest. 2.8. Si based materials
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properties. In addition, MNPs are capable to immobilize various labels (i.e. enzymes, antibodies,
Benefitting from the huge specific surface area, versatile surface functionalization, stable
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and highly ordered nanostructure and inherent filtering capabilities, materials with nanoscale pores, like zeolites and mesoporous materials have drawn much attention for biochemical
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sensing [94].
Sensing of target analytes in real-media implies the problem of coexisting species. These interferences cause high background signal, baseline drift and deviations in sensitivity due to cross-reactivity with interferences. Interestingly, Bonanno and DeLouise [31] solved the
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selectivity problem by using the porous silica (PS) materials to determine immunoglobulin G (IgG) in whole blood samples. PS possesses the inherent filtering capabilities which can be excluded the cells and proteins larger than the pores, resulting to increase the selectivity of the
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probe to the analyte. In short, the PS sensor was silanized and then streptavidin and biotinylated receptor antibody immobilized on the PS to detect IgG. Sensor reflectance response is linear over
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the concentration range of IgG from 1 to 10 mg/mL. Goldman [95] presented a multi-component test strip to analyze the blood components
i.e. glucose, glycosolated hemoglobin, cholesterol, cholesterol, triglycerides, hemoglobin, and clotting factors. For example, cholesterol sensing, the porous silica gel immersed in a fluid matrix to separate cholesterol from a surface interaction with the silica to determine concentration of cholesterol in whole blood samples.
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2.9. Other papers of interest Biomolecules with biodegradability and biocompatibility properties were used in medical applications, bio-sensing and drug delivery [96, 97]. These materials can be easily used in
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disposable POC devices and in vivo bioassays for various bio-sensing applications in medical diagnostics. Siegrist et al. [98] reported a glucose recognition polypeptide (GRP) based sensing system to detect glucose in whole blood samples. Sensing mechanism relays on GRP binding of
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glucose molecule and quenching of the fluorophore intensity. In order to sensitize the GRP conformation change to fluorescence, the GRPs were attached to a fluorophore of N-(2-(1-
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maleimidyl)ethyl)-7-(diethylamino)coumarin-3-carboxamide (MDCC) via thiol groups of the GBP. Afterwards, GRP-MDCC (as a continuous sensor) was immobilized in an acrylamide hydrogel matrix. When glucose added to the biosensor changes on the fluorescence intensity is proportional to glucose concentration, thus enabling glucose biosensing. The method provides a
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sensitive and precise monitoring of glucose in the biological range. As declared some improvements are required in both chemical and engineering design to be an accurate and reliable tool for sensing of glucose.
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IR spectroscopy has attracted much attention on the study of biological systems. The IRbased analysis is automatable and high quality information of the sample can be obtained without
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need of any reagent. Most of the organic molecules show characteristic absorption bands in the mid and NIR ranges, and the ‘IR fingerprint’ of the metabolites contained in blood can be used for quantifying clinical parameters or in the diagnosis of pathological conditions. For example, Shen et al. [99] quantified glucose in whole blood using the second derivative FTIR transmission spectroscopy. For this purpose, the FTIR spectra of samples were acquired in the 950–1200 cm−1 range where the C-O stretching vibrations of the alcohol groups of the glucose are located. The
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glucose concentration was proportional to the normalized transmission of second derivative spectrum at 1082 cm−1. In most cases, IR bands are overlapped and multivariate statistics should be applied in
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order to extract information of the analytes. Partial least squares (PLS) regression is the most popular technique for the multi-analyte quantification in complex matrices. The combination of PLS and attenuated total reflectance is nowadays a promising tool for the POC determination of
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clinical parameters, which only requires the use of a small volume of untreated blood sample for providing a fast analysis of several parameters in whole blood, including albumin, cholesterol,
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glucose, total protein, urea and triglycerides [100] or Hb [101]. In the last work, red blood cell should be lysed in order to create an effective contact between the Hb and the crystal. Due to some features including rapidity, low-cost instrumentation, solvent and sample preparation free procedure, the proposed method serves green alternatives to the traditional ones used in medical
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institutes.
Based on the reported work by Ligler et al. [102], toxins can be detected in various matrices by applying a biosensing array system. Firstly, antibodies as recognition agents were
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immobilized on specific locations of the waveguide. In presence of analytes, the binding of fluorescent analyte or fluorescent immune-complex can be detected using a CCD camera. Using
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this method various toxins including staphylococcal enterotoxin B, ricin, cholera toxin, botulinum toxoids, trinitrotoluene and the mycotoxin fumonisin were analyzed in biological fluids (urine, plasma and whole blood), environmental and food samples with minimum sample pretreatment. The reported method can be automatized for simultaneous detection of multiple toxins at levels as low as 0.5 ng/mL.
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Bacterial or viral infections can be identified by quantifying and differentiating leukocytes. Currently, leukocytes sensing methods are required high-dilution level to prevent interference from erythrocytes where dilution is undesirable for micro hemacytometers. Zheng et
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al. [103] used fluorescent dye acridine orange (AO) to avoid undesirable dilution effects. AO binds strongly to the double-stranded DNA of leukocytes which provides indirect detection of leukocytes, emitting fluorescence in 525 nm. While fluorescent signal was emitted at 650 nm by
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binding to the single-stranded and RNA molecules. The green fluorescent signal at 525 nm is used for leukocyte count and red fluorescent signal at 650 nm is used for leukocyte
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differentiation. Results revealed that by using a photomultiplier tube detector, a throughput of up to about 1000 leukocytes per second is obtained.
Diabetes is a main worldwide problem. It has been estimated that 366 million of people suffered from this illness in 2012 [104]. It is well known that all kinds of diabetes are incurable
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and proper, real time and also non-invasive monitoring of glucose levels becomes the most important topic of the research groups. Most of the existing devices for glucose sensing are invasive and use blood of the patients. Due to change of dielectric properties blood of in
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presence of glucose, Choi et al. [21] constructed a non-invasive tool for assay of glucose in whole blood samples. The detection was realized by using microwaves whose penetrates to the
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body (about 1 cm) and subsequently the transmission is measured. The results are favorably comparable with commercial invasive blood glucose monitoring devices. SPFS combines fluorescence spectroscopy and SPR techniques. While SPR allows the
observation of reactions taking place on the metal surface via the change on the RI, one can detect the directional fluorescence emission coupled to surface plasmon. Aslan et al. [105] utilized SPFS to bio-recognition of biomaterials with applying the interactions of fluorescent (in
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NIR region) species with thin metal film of nickel. This method can be used to assay many biomolecules including DNA, proteins etc. SPR spectroscopy is a label free method to assay biomolecules down to the femtomolar
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range. Using this technique the RI of the environment is measured near a planar noble metal surface [106]. Sharma [107] reported a SPR based platform to determine Hb in blood samples. Due to dependence of the RI of human blood to the Hb concentration where the concentration of
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Hb is linear with RI at any wavelength. With applying a phase interrogation-based SPR biosensors, the sensitivity was improved in two orders of magnitude as compared with
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amplitude-interrogation method [108]. In this sensor silica and gold layer is used as substrate of the biosensor. As a special feature of the reported method, a biochemical layer of contaminationpreventing ensures the stability of probe.
Aslan et al. [109] presented a microwave-accelerated surface plasmon-coupled
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directional luminescence (MA-SPCL) method to detect DNA, RNA and streptavidin protein in whole blood samples. Hepatitis C specific DNA attached on the surface of gold disk to model DNA. Hybridization assay for MA-SPCL based detection of target DNA. Hybridization was
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done on the surface of gold disk in 1 min, while the identical assay took about 4 h at room temperature. The reported method offers a fast alternative approach to current DNA based
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detection technologies, especially when sensitivity is required. Up to 15% (about 8 million) of total human deaths are caused by various cancers where
metastatic disease as result of circulating tumor cells (CTCs) is the major reason of cancer death. Detection of the CTCs in the initial stages of malignancies is necessary to improve the treatment process [110-113]. Kumeria et al. [114] utilized reflectometric interference spectroscopy (RIfS) to determine CTCs in whole blood samples. The RIfS is an optical method in which the signal is
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produced upon interference between incident and reflected light beams caused by the upper and lower surfaces of a thin film or structure. This technique offers a non-invasive, label free detection, fast response time, high sensitivity and selectivity. The proposed work shows
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advantages of nano or sub microliter volumes sample requirement and able to be potentially integrated on a microfluidic system in a POC-able devices. In this approach biotinylated antiEpCAM antibody was attached on the Au-modified surface of nanoporous anodic aluminum
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oxide (AAO) whose binding provides a strong influence on the RIfS signal and causing a wavelength shift in the Fabry–Perot interference fringes. Regarding this method CTCs were
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detected in whole blood samples without any laborious enrichment process (Figure 10). This nanobiosensor is capable to detect cancer cells in the range of 1000–100,000 cells/mL, with an LOD of less than 1000 cells/mL where the response time is as short as 5 min and required sample volume is 50 µL.
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Figure 10 here
Measurements of critical care ions such as sodium and potassium in blood are very necessary in routine clinical blood analysis, and it would be valuable to have simple optical
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methods for rapid POC testing. D’Auria et al. [115] utilized the quenching effect of sodium ions on the intrinsic fluorescence of the pyruvate kinase enzyme to quantify sodium in whole blood
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samples where the quenched fluorescence is linear with the concentration of ions. The pyruvate kinase is stable and selective over other ions including potassium, magnesium and calcium in whole blood samples.
Various enzymes such as cholinesterase, GOx, HRP and urease are utilized for
determining metals [116-122]. Urease-based biosensors are of great interest due to its high sensitivity, selectivity, stability, low price and short response time. Tsai et al. [123] developed a
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urease-based sensor using sol–gel technique for the quantification of several metals. In short, the fluorescein isothiocyanate (FITC)-dextran (as fluorophore) was co-immobilized with urease on the strip. This fluorophore is sensitive to the changes in pH value. The fluorescence intensity (λ =
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520 nm) changed with the change of the pH, presumably due to the hydrolytic catalysis of urea by urease to produce NH4+, HCO3- and OH- where the activity of enzyme inhibited by heavy metals. This biosensor is especially sensitive to both Cu (II) and Cd (II) at an analytical range of
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10–230 µM with an LOD of 10 µM. At pH 7.1, the developed system is practical to determine heavy metals in whole blood real samples. In addition to Cu (II) and Cd (II), the FITC-dextran
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sensitized sensor was also applied to the determination of Zn (II), Ni (II), Pb (II), and Cr (III). The reported method have simple instrumentation and is a favor alternative for the old-fashioned spectroscopic methods such as AA, AE and inductively coupled plasma methods. Lactate can be used as a marker for the assessment of tissue perfusion and oxidative
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capacity. Also lactate concentrations higher than 4 mM have been found in association with myocardial infarction [124], cardiac arrest [125], circulatory failure [125, 126] and in emergency trauma situations [127, 128]. Therefore, determination of lactate concentrations in whole blood
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samples is of great prognostic significance. Interestingly, Lafrance et al. [129] presented a NIR spectroscopy based method to the quantitative determination of lactate by using second
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derivative spectra in the 2050-2400 nm spectral range. The obtained results is compared with the gold standard method of lactate which is confirmed the accuracy of the method. The results suggested that the reported NIR method may be provided a valuable tool to assess physiological status for both research and clinical needs. Hydrogen cyanide (HCN) and its common alkali metal salts (NaCN, KCN, etc.) are wellknown as their high toxicity; moreover they can be used as terrorist weapon [130]. On-time and
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fast quantification of blood cyanide is not only of great importance in clinical testing and forensic aims, but it is also adequate for emergency POC situations to detect and decide on antidote dosage. Ma et al. [131] developed an optical analyzer to POC based detection of CNs.
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Briefly, 0.2-1 mL of blood and H3PO4 added in a disposable microcentrifuge tube. A membrane containing borate-buffered (pH 9.0) hydroxoaquocobinamide (cobinamide) is located between a light source and a photo detector. Cobinamide is not only an antidote for cyanide; it undergoes a
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very significant spectral change as it binds to cyanide. The detection is based on the changes of the cobinamide being reacted HCN with the membrane. The main advantages of the reported
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method are its rapidity (5 min) and less sample volume (1 mL) requirements. By using this method, CNs are determined in rabbit blood samples with LOD of 0.5 µM. The measured transmission signal is linear over the concentration range up to 50 µM. The progesterone is a biomarker of pregnancy, endocrinopathy and virilism. The clinical
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relevant range of the progesterone concentration is 0.3–3 nM. Ehrentreich-Förster et al. [32] demonstrated a surface sensitive biosensor in conjunction with an integrated optical grating, being sensitized to the RI changes. In this sensor the progesterone is coupled as an activated
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substrate which contains progesterone/(o-carboxymethyloxime), N,N’-dicyclohexylcarbodiimide and NHS. The measurement was performed in an indirect competitive immunoassay format
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between antibody anchored on the surface of the sensor and progesterone. In the presence of progesterone, antibody binding to the surface is inhibited where the amount of inhibition corresponds to the concentration of free analyte. By applying the reported label free biosensor, the real-time detection of progesterone was done in a range between 0.005 and 10 ng/mL with LOD of 3 pM.
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Stern et al. [132] introduced a nanobiosensor for PSA and cancer antigen 15.3 (CA 15.3) as biomarkers of prostate and breast cancer. This biosensor was functionalized either with antiPSA or anti-CA 15.3. Antibodies were immobilized to the sensor using NHS/EDC functional
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groups. The proposed label free biosensor acts in 4 steps. 1) Purification step: a whole blood sample flows through the chip containing anti-bodies bind specific biomarkers of PSA and CA 13.5, 2) the analyte capture step followed by purification step, 3) addition of washing buffer to
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the nanosensor chip containing the secondary antibodies on the nanowire surfaces to remove the non-bonded materials (Figure 11), 4) The cleavage step was done by using a photo degradable
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material of specific 19-mer DNA sequence to attach the antibodies on the avidin-functionalized chip. By irradiation of the UV lights the DNA based cross linker is broken and then the analyte is released from the chip to the buffer. The application of two specific antibody binding for purification and sensing operation improves significantly the selectivity over the other possible
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coexisting materials. This chip provides a versatile method to specific determination of CA 13.5 and PSA from a 10 µL sample of whole blood in less than 20 min. Figure 11 here
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Table 2 summaries the sensing parameters achieved for various optical methods in whole blood media. It can be concluded that about 30 percent of the reported papers are based on gold
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materials which depicts the main role in the whole blood sensing. Both chemically and technically reasons of the methods reported for detection of MMP-2 [54] and β-lactoglobulin [69] convinced us to introduce these methods as possessing the highest potential for practical diagnosis in a clinical application.
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3. Conclusions and perspectives General discussions are presented here regarding the application of new materials and methods for sensing, biosensing and also immunosensing in whole blood samples. The
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measurement of analytes in unprocessed whole blood samples is a major challenge in the field of medical instrumentation. Using whole blood as a primitive sample eliminates cell separation and serum dilution procedures providing the shortest time and minimum number of sample handling
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steps.
Absence of unique or common standardized strategies, techniques, and assays for whole
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blood sensing is an obstacle for POC detections arising from the very complicated matrix of the whole blood. Advanced materials allow us to carry out very sophisticated experiments on small structures. Meanwhile, progress in this area strongly depends on introduction of new materials and chemical and physical modification of the current materials. Generally, it is true to say that
of new materials.
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the progress of new portable diagnostic kits is directly based on the discovery and development
To date, vast range of new materials were utilized for providing whole blood
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applications. For example AuNPs based methods play a main role in whole blood biosensing accompanying with various spectroscopic methods. With engineering of AuNPs, their optical
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properties are improved to present different types of biomedical recognition, including the regulating of their PL or LSPR peaks to the transparent window for soft tissues in the NIR region. The reported sensors and biosensors are based on different optical transduction principles (absorbance, fluorescence, SPR, LSPR), so more research is needed on the development of new optical sensors and biosensors using other optical methods including SERS and Raman methods. The majority of the developed methods are based on fluorescence, but several new techniques
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such as SPR are powerful alternatives to compete with fluorescence based methods for whole blood sensing. Although the combination of nanomaterials and SPR methods provide benefits such as high selectivity and ultra-sensitivity, a simplification is needed for using as a POC tools.
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In comparison with other methods i.e. GC, electrochemical methods, optical methods possess superior abilities to simultaneous detection of multi-analyte samples with using diode array detectors resulting in reduced analysis time.
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Our survey also revealed that some very vital analytes including matrix CTC, glucose, plasmodium, MMP-2 and HIV can be detected in whole blood using spectroscopic methods
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which implies the ability of the spectroscopic methods in the whole blood medium. In general, although the existing literature shows that spectroscopic based sensors for effective detection of clinically relevant biomolecules in whole blood have excellent performance, there are still several challenging issues for the production and the
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commercialization of bioelectronics devices at an economically-viable price to reach the common user. But, there is a bright opportunity for further advances and developments of sensing devices based on spectroscopic methods, especially through further miniaturization and
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integration into lab-on-a-chip systems. The design of implantable sensors with the ability to monitor clinically relevant biomolecules in vivo and in real time is promising for the application
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of spectroscopic based sensors in whole blood, even though it is yet to be explored. Chemists therefore have a great deal to do to address the behavior of spectroscopic sensors for detection clinically relevant biomolecules in the future. On the other hand, many high-sensitivity spectroscopic techniques, despite their applicability for targeted clinically relevant biomolecules detection in whole blood, are hindered by the size and the complexity of the required excitation and detection apparatus. Spectroscopic sensors are currently hindered for quantitative analysis by
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the requirement of microscopes to image the sensor area adequately. It is worth noting that a handful of commercial clinically relevant biomolecules detection devices in whole blood contain suitably-miniaturized fluorescence and chemiluminescence detection apparatus.
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Finally, we anticipate that along with the progress of fluorescence-based in various features, other spectroscopic methods such as SERS-based and non-invasive methods will play some roles in future researches. In the future, there are two main challenges for the sensing
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community. First, use of the aforementioned materials in order to provide multifunction sensing devices for simultaneous detection of multiple targets with high sensitivity and selectivity,
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secondly materials should be adapted in order to provide compactable sensing techniques to provide POC devices. Multiple-use bio-sensors give the possibility to control more efficient and also these bio-sensors are generally cheaper than the single use ones especially in frequented
Acknowledgments
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control situations.
The authors would like to acknowledge the support of this work by Drug Applied Research
Iran.
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Figures and Tables captions:
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Figures Figure 1 Schematic representation of UCP−peptide−CNP FRET based sensor for detection of MMP-2. (UCPs: Upconverting phosphore, CNPs: Carbon nanoparticles, MMP-2: Matrix
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metalloproteinase-2).
Figure 2 Representation of fluorescence based method for determination of lead using H2O2 as
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oxidizing agent for conversion of non-fluorescent AUR to a fluorescent oxidized AUR product by (a) T30695, (b) Au NPs and (c) T30695–Au NP. (T30695: oligonucleotide). Figure 3 Schematic represenstation on HIV biosensor. (a) Anchored HIV on the antibody biosensing surface. (b) Mechanism of immobilization. mercaptoundecanoic
acid,
EDC
:
N-ethyl-N’
(PLL: poly-L-lysine, MUA: 11-
-(3-dimethylaminopropyl)
carbodiimide
polyclonal antibody).
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hydrochloride, NHS: N-hydroxysulfosuccinimide, NeutrAvidin, and biotinylated anti-gp120
treated substrate.
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Figure 4 Machnism of immobilization of antibodies with protein A on the surface of gold DSP-
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Figure 5 Biosensing mechanism of β-lactoglobulin with using anti-β-lactoglobulin modified AuNPs.
Figure 6 Fabrication steps of Au naoshell SAMs for streptavidin sensing. (APTES: 3aminopropyltrimethoxysilane). Figure 7 In situ MEF biosensor for determination of total AChE activity in unprocessed whole blood samples. (ATCh: acetylthiocholine, TCh: thiocholine, HPTS:8-hydroxypyrene-1,3,6-tri sulfonic
acid,
MEF:
metal-enhanced 51
fluorescence).
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Figure 8 Reaction mechanism of Hb biosensing. (G: glucose; GOx (glucose oxidase, oxidized form); L: glucolactone; HbIIO2: O2: linked ferrous blood hemoglobin; HbIII: ferrichemoglobine;
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HbIIIN3−: azide linked ferric hemoglobine; GOxH2: reduced form of GOx; DG, DH2O2 and DN3− are diffusion coefficients of glucose, H2O2 and azide, k; thermodynamic parameters). Figure 9 Detection steps of the magnetic sensing of troponin.
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Figure 10 Surface functionalization of gold modifided AAO substrate for RIfS based biosensing of CTCs cells. Step (a): formation of SAMs of carboxyl-containing thiol; Step (b): covalent
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attachment of streptavidin on activated SAMs after activation with coupling (NHS/EDC) agents; Step (c): immobilization of biotinylated Anti-EpCAM antibodies; Step (d): binding of CTC cell on anti-EpCAM antibodies. (MUA: mercaptoundecanoic acid)
Figure 11 Schematic biosensing steps of PSA and CA15.3 using avidin-functionalized MPC.
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(MPC: microfluidic purification chip).
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Tables Table 1 Reported articles included optical methods in whole blood media.
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Table 2 Reported patents included optical methods in whole blood media.
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Table 1 Analyte
Employed Material
LOD/LDR
Reflectance Reflectance Photoluminescence Luminescence
IgG Progesterone Glucose Potassium Sodium Calcium pH Glucose H2O2 MMP-2 Glucose Lead HIV Plasmodium β-lactoglobulin
PSi Antibody CdSe/ZnS QDs UCNPs
1 to 10 mg/mL 3 pM 3.5 µM 10−4 M 10-5 to 10-2 M up to 10-4 M 6 to 11 3.7 µM 0 ̶ 400 µM 10 pg/mL 34.7 µM 0.05 nM ̶ ̶ 500 aM
[31] [32] [36] [52]
AuNPs
0.5 ng/mL
[71]
AuNPs
2 nM
[72]
Au nanoshells Au nanoshells Au nanorods Ag@SiO2NPs
[73] [74] [75] [81]
Fluorescence
UCNPs UCNPs
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Fluorescence
Reference
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Method
[50] [53]
UCNPs CNTs AuNPs AuNPs AuNPs AuNPs
Absorbance
Glucose
PAA gel matrix
Absorbance
Glucose
PAA film
Absorbance Frustrated total internal reflection IR Fluorescence Fluorescence Transmission Luminescence SPR SPCL RIfS Fluorescence Fluorescence
Alcohol
AOX
100 pg/mL 3µg/mL 25 ng/mL 0.05mU/mL 1.5 × 10−6 - 5.5 × 10−5 M 20 and 12000 mg/L ̶
cTnI, cTnT
MNPs
0.03 ng/L
[89]
Glucose Glucose Leukocyte Glucose Streptavidin Hb DNA CTCs Sodium Copper &
̶ Hydrogel Fluorescent dye/AO Silver/Copper ring AgNPs QDs Silica/gold layer Gold disk Au/nanoporous AAO Pyruvate kinase enzyme Fluorophore
̶
[99] [102] [103] [21] [105] [107] [109] [114] [115] [123]
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Fluorescence Fluorescence Fluorescence Absorbance SPR IRIS RI based Hartman hCG interferometer Allergen-specific Light scattering antibodies Absorbance Immunoglobulins LSPR Streptavidin LSPR Streptavidin Fluorescence AChE
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̶ ̶ ̶ 10–1250 nM ̶ ̶ 1000 cells/mL ̶ 10–230 µM /10
[54] [56] [60] [62] [69] [59]
[84] [85] [86]
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IR Absorbance
µM (both) ̶ Cobinamide
̶ 0.5 µM
[129] [131]
Antibody
̶
[132]
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Fluorescence
Cadmium Lactate HCN PSA CA 15.3
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Method of sensing
Material or sensing elements
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Table 2 Type of analyte QDs
Fluorescence
Fluorescence
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Antibody/antigen interactions
-
Glucose, beta-estradiol, Antibody/antigen small proteins (e.g., insulin), interactions antigens (e.g., PSA) Multiplexed DNASpecific complementary of and RNA-based FISH DNA or RNA sequence Assay
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Fluorescence
Teratogenic disorders
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Fluorescence
Detection of blood-borne Antibody/antigen diseases such as hepatitis B, interactions hepatitis C, HIV and syphilis
PAMAM glycosylated dendrimer-quantum Glucose dot/gold particle
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Fluorescence
ZnS, CdS, HgS, ZnSe, CdSe, HgSe, CdTe, ZnTe, ZnO, PbSe, HgTe, CaAs, InP, InAs, InCaAs, CdS/ZnS, CdS/Ag2S, CdS/PbS, CdS/Cd(OH)2, CdS/HgS, CdS/HgS/CdS, ZnS/CdS and etc. ZnS, CdS, HgS, ZnSe, CdSe, HgSe, CdTe, ZnTe, ZnO, PbSe, HgTe, CaAs, InP, InAs, InCaAs, CdS / ZnS and etc. PbS, PbSe, CdS, CdSe, ZnS, and ZnSe And photoluminescent GBP/PVA-wrapped SWNT hydrogels ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, MgS, MgSe, MgTe, CaS, CaSe, CaTe, SrS, SrSe, SrTe and etc.
Analytical approach
Approach
CN 104198702 A [38] CN 104280546 A [39] US 2010027942 1 A1 [40]
-
US 2004016650 5 A1 [41]
Preparation implantable glucosesensing device
0 - about 600 mg/dL
US 2010022265 7 A1 [133]
Below 40 pM for microRNA and below 90 pM for ssDNA
WO 2015181101 A1 [134]
-
WO 2013101989
Fluorescence
Semiconductor quantum dots or quantum rods or a combination thereof in particular Oligonucleotide CdSe-ZnS core-shell
Fluorescence dye
Fluorescence/ FISH
Qdot™ products from Life Technologies, CTCs Inc
Automated characterization
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-
Reference
of
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CTCs
SWCNTs/GOx enzyme
Glucose
GOx enzyme
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Fluorescence
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Fluorescence
Upconverting nanoparticle Upconverting nanoparticle Proteins such as thrombin NaYF4:(Yb,Er,Tm), NaYbF4:(Yb,Er,Tm), Antibody/antigen and pathogens CaF2:(Yb,Er) and La2O3:(Yb,Er) CNTs
-
Light Emission
Fluorescence
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Luminescence
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US20150268 237A1 [55]
Detection US20070292 limit of 34.4 896A1 [58] µM 2.5 mM to 50 mM
US20130035 567A1[136]
-
US20100105 024A1 [137]
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Fluorescence
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Fluorescence
An organic polymer bound to the Carboxylated poly(vinyl alcohol)-wrapped Glucose photoluminescent SWNTs (cPVA/SWNTs) nanostructure and GBP Immobilization of DNA, RNA or a fragment of Oligonucleotide-functionalized antibodies or a DNA or and RNA viruses nanoparticle capable of hybridizing with oligonucleotide on the such as HIV , Hepatitis B, surface of a the DNA and RNA Hepatitis C and SARS membrane Protein, nucleic acid (e.g. DNA, RNA, etc.), carbohydrate, and/or metal Selectively Carbon nanotube/silicon nanowire ions; and in environmental functionalization of applications to detect pH, the nanowires surface metal ions, or other analytes of interest Proteins, small molecules, Binding of analyte peptides, drugs or drug Carbon nanotube/silicon nanowirespecies to a candidates, hormones, Polymer immobilized protein vitamins, ligands, sugars, or an enzyme carbohydrates, nucleic acids Glycated protein e.g. Bindings between SWCNT or graphene nanoribbon glycated hemoglobin and antigen-antibody
A1 [135]
-
US7385267 B2 [138]
-
US20070264 623A1 [139]
-
WO2014080 519A1 [140]
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Photoluminescent
SWCNTs
Glucose AuNPs
anchored on the SWCNTs and graphene Binding of glucose to SWCNT backbone
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albumin
Provides the assay Bioagents e.g. target nucleic and method in a acid or protein multiplexed format Creation of new dyes Glucose, lactate, PSA and for enhancing the SERS Functionalized-AuNPs etc. performance of the SERS receptors Encapsulation of the Chronic lymphoid leukemia SERS (Au) core-shell NPs NPs in phospholipid cells microvesicles The presence of target cells bounded to Changes in labelled NPs provokes diffractions Au and other metals and metal oxides NPs CTCs changes in the patterns diffraction patterns of the sample Glucose, PSA, creatine kinase MB, cardiac troponin Covalently binding of I (cTnl), thyroidstimulating SERS/Luminescen SERS-active to an Functionalized-AuNPs hormone, influenza A ce outer surface of the antigen, influenza B antigen, nanoparticle respiratory syncytial virus antigen AgNPs Proteins and genes of various Semiconductor based printed electronics Antibody-antigen Colorimetric analytes such HIV and using AgNPs and other materials interaction lipoproteins etc.
WO2015191 389A2 [141]
-
US 2009029819 7 A1 [76]
-
US8962342 B2 [77]
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US 2013/027356 1 [78]
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US 2016/020216 3 [79]
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WO2008116 093 A2 [142]
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WO2015033 229 A2 [82]
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Nanowire Substrates
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SERS
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SERS-active colloidal silver nanoparticles
Bioluminescent
Silver nanoparticles Gold nanoparticles Magnetic nanoparticles
Microwaveaccelerated plasmonic
Gold or silver nanoparticles
Light scattering
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Silver nanoparticles
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SER
Gold or silver nanoparticles
Gold, silver or latex nanoparticle
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SERS
SERS of whole blood in presence of AgNPs An aptamer or a tagged protein that Pathogen and cell binds to the cells or pathogens Immobilization of capture nucleotide sequence probe Protein, a DNA sequence or complementary to a a RNA sequence and glucose known nucleotide sequence of the target pathogen Glucose, ascorbate, lactic Surface bound acid, urea, pesticides, reversibly-binding chemical warfare agents, receptor pollutants, and explosives Functionalization of the surface of Glucose, lactate, urea and nanoparticles with a ascorbate selective binding receptor Alzheimer's disease
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SERS
Proteins such as C-reactive Specific protein), myoglobin etc. receptor
target
and
-
US20150276 482 A1 [83]
-
US20040197 845 A1 [143]
-
US20120107 952 A1 [144]
-
US20100087 723 A1 [145]
Dynamic range (Glucose): 0-450 mg/dL
US20040180 379 A1[146]
-
WO2011034 678 A1 [147]
Polymers Non-enzymatic bindings Coupling of dye with glucose
Fluorescence
Hydrogel polymer/Dye
Glucose
Fluorescence
Hydrogel polymer/Dye
Glucose
Fluorescence
Porous biocompatible polymers
Nucleic acid, polypeptide Antibody/antigen and immunoglobulin (Cancer binding biomarkers)
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US20130287 631A1 [87] US20130267 802A1 [88] US8202697 B2 [148]
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Cancer cells
-
MNPs Cells, viruses, bacteria, Magnetic Bead DNA: 0.28Magnetic bead-capture probe hybridization proteins, DNA, RNA, or Hybridization 4 pM other small molecules Heterogenous and homogenous 100 pg/ml sandwich for Nanotag composed by an Au core and a Cells, viruses, bacteria, immunoassays with InterleukinSiO2 shell. Between the core and shell is proteins, DNA, RNA or SERS detection of the 4, 4 pM of encoded a reporter (Raman-active small molecules and etc. isolated analyte DNA and molecule) captured by an 4.1 pm of antibody conjugated HCV to the nanotag SERS measurement of a pellet contains a Combine Au nanotags and magnetic NPs Troponin I magnetic particleanalyte-nanotag complex SERS measurement of the complex-analyte 1-2 cells per (IO-Au) core-shell NPs CTCs (IO-Au) core-shell ml of blood NPs Detection limit (βAdsorption of the Malaria infection (hemozoin Fe3O4@AgNPs target analyte on the hematin): and β-hematin) surface of MNPs 5×10−9 M
SERS
SERS
Immunofluorescen ce
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SERS
Polymeric substrate
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Specifically binding of antibodies to target molecule
Magnetic ball
Surface modification of antibodies
CTCs
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US20120100 538A1 [149]
US20120164 624 A1 [90]
US 2012/016462 4 A1 [90]
US 2011/027506 1 A1 [91] US 2015/003781 8 [91]
US20120257 199A1 [93] CN1058070 57A [150]
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Si based materials
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Porous silica or silicate particles
Porous polymer-based particles
magnetic
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DNA
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Simultaneous isolation and quantitation of DNA
-
LOD: Tacrolimus 291 ng/µL and Rapamycin 20 ng/µL 0.15 to 10 ng of human DNA 350-950 ng of human DNA -
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UV
Porous MagneSil™ particles
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Preparation a multicomponent test strip Glucose lipids (cholesterol, for analyzing a LDL, HDL,triglycerides) and plurality of blood Glycosolated Hemoglobin components in a single blood sample Detection of an analyte in a sample of hemolyzed whole Tetracycline hydrochloride blood
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WO 2008148547 A1 [151]
US 2004008693 0 A1 [152] CA 2379503 A1 [153] WO 2001014590 A2 [153] EP 1204741 B1 [154]
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Highlights •
Whole blood sensing can efficiently decrease analysis time of markers by means of
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introducing methods with no pretreatment of samples. Incorporation of new advanced materials plays a major role in the spectroscopic sensing methods and detection sensitivity of optical probes.
AuNPs based methods play a main rule in whole blood biosensing accompanying
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with various spectroscopic methods.
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