Surface Plasmon Resonance Clinical Biosensors for Medical

Perspective pubs.acs.org/acssensors

Surface Plasmon Resonance Clinical Biosensors for Medical Diagnostics Jean-Francois Masson*,†,‡ †

Département de chimie, Université de Montréal, C.P. 6128 Succ. Centre-Ville, Montreal, Quebec H3C 3J7, Canada Centre for self-assembled chemical structures (CSACS), McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada

‡

ABSTRACT: The design and application of sensors for monitoring biomolecules in clinical samples is a common goal of the sensing research community. Surface plasmon resonance (SPR) and other plasmonic techniques such as localized surface plasmon resonance (LSPR) and imaging SPR are reaching a maturity level sufficient for their application in monitoring biomolecules in clinical samples. In recent years, the first examples for monitoring antibodies, proteins, enzymes, drugs, small molecules, peptides, and nucleic acids in biofluids collected from patients afflicted with a series of medical conditions (Alzheimer’s, hepatitis, diabetes, leukemia, and cancers such as prostate and breast cancers, among others) demonstrate the progress of SPR sensing in clinical chemistry. This Perspective reviews the current status of the field, showcasing a series of early successes in the application of SPR for clinical analysis and detailing a series of considerations regarding sensing schemes, exposing issues with analysis in biofluids, and comparing SPR with ELISA, while providing an outlook of the challenges currently associated with plasmonic materials, instrumentation, microfluidics, bioreceptor selection, selection of a clinical market, and validation of a clinical assay for applying SPR sensors to clinical samples. Research opportunities are proposed to further advance the field and transition SPR biosensors from research proof-of-concept stage to actual clinical applications. KEYWORDS: surface plasmon resonance (SPR) biosensors, clinical chemistry, disease monitoring, clinical samples, serum, urine, biofluids

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CONTEXT OF SPR SENSING IN BIOANALYSIS Modern medicine relies heavily on biomolecular information for diagnosis and monitoring the progression of diseases. In addition, it is often customary to analyze dosage or response of a patient to a therapy to ensure the safety and efficacy of drugs and other treatments.1 This information is typically obtained from the analysis of biofluids with standard clinical chemistry techniques such as enzyme-linked immunosorbent assays (ELISA), chromatography, and mass spectrometry. These workhorses of clinical laboratories are broadly applicable to different classes of biomolecules and were designed to be highly effective for processing relatively large numbers of samples. However, these advantages come with a significant financial cost, limiting the availability of these technologies to large centers and often at the expense of lower speed of analysis. These limitations are most important in the case of medical conditions requiring rapid medical action for which current assay times are prohibitive, for conditions requiring frequent measurements of an analyte, such as continuously monitoring biomolecules for clinical applications,2 and for measurements in remote or resource-limited regions of the world.3,4 This pressing need for new analytical solutions to rapidly monitor biomolecules, drugs, and metabolites in clinical samples is best © 2016 American Chemical Society

exemplified by the large body of literature reporting new aspects of biosensing and point-of-care diagnostics. Biosensors are ideally positioned to provide a solution to clinical chemistry5 and to the field of portable point-of-care devices.6−8 Among the different biosensing techniques, surface plasmon resonance (SPR) sensors are applicable to different classes of analytes of clinical interest.9 Hence, SPR sensing has now been applied for the detection of cancer markers, antibodies, drugs, and hormones, among other biomolecular markers.10 The theory of SPR has been detailed extensively in a series of recent reviews,10−12 such that it will not be a topic of discussion in this perspective. SPR sensing can now be carried out using various transducer configurations, such as the classical Kretschmann configuration of the prism coupling, which includes SPR imaging (SPRi),13 as well as nanoparticle-based localized surface plasmon resonance (LSPR),12 long-range SPR,14 fiber-optic configuration,15 and phase sensing16 among others. All of these sensing platforms rely on the same general underlying principle and can be adapted for clinical analysis. In Received: November 28, 2016 Accepted: December 23, 2016 Published: December 23, 2016 16

DOI: 10.1021/acssensors.6b00763 ACS Sens. 2017, 2, 16−30

Perspective

ACS Sensors Table 1. Sensors Applied for the Clinical Analysis of Antibodies in Human Samples medical condition Antiphospholipid syndrome (APS) Antiphospholipid syndrome (APS) Blood grouping Blood grouping Cancer Cancer treatment Chagas disease Congenital Hemophilia A Dengue Dengue Diabetes Diabetes Diabetes Epstein−Barr virus Gene therapy Hepatitis A Hepatitis B Hepatitis C treatment Inflammatory bowel disease treatment Leukemia Leukemia Lyme borreliosis infection Neonatal alloimmune thrombocytopenia Neuropathy Omalizumab (Xolair) therapy Peanut allergies Pure red cell aplasia Rheumatoid arthritis Rheumatoid arthritis Syphilis Systemic lupus erythematosus Systemic lupus erythematosus Typhoid

analyte

biofluid

techniquea

ref

Anticardiolipin

serum

SPR

152

2-Glycoprotein I−Reactive Autoantibodies

serum

SPR

153

LSPR SPR SPR SPR SPR SPR SPR SPR SPR SPR SPR SPR

127

anti-A IgG serum Anti-A/B IgM- and IgG-antibodies serum Carcinoembryonic antigen (CEA) autoantibodies serum Panitumumab antibodies serum Anti-Trypanosoma cruzi serum Antifactor VIII (FVIII) antibodies plasma Immunoglobulin M serum IgM monoclonal antibodies serum Insulin autoantibodies serum Proinsulin autoantibodies serum Insulin antibodies serum antibodies against viral capside antigen (anti-VCA), Epstein−Barr nuclear antigen (anti- serum EBNA), and early antigen (anti-EA) Antiadenoviral antibodies Serum and ascites fluid Hepatitis A virus antibodies serum Hepatitis B virus antibodies serum PEG-IFN-alpha2b serum Infliximab serum

SPR

164

SPR SPR SPR FO−SPR

165

Antiasparaginase immunoglobulins kappa and lambda Lyme borreliosis antibodies HPA-1a alloantibodies

serum serum serum serum

SPR LR−SPR SPR SPR

42,83

Anti-GM1 ganglioside antibodies IgE IgE Antierythropoiesis-stimulating agent Anticitrullinated protein antibodies Antiglucose 6-phosphate isomerase Treponema pallidum antibodies Protein S antibodies

serum serum serum serum serum synovial fluid serum plasma

SPR SPR SPRi SPR SPRi SPR LSPR SPR

169

Anti-double-stranded DNA monoclonal antibodies

serum

SPR

174

Salmonella typhi antibodies

serum

SPR

175

154 98 155 156,157 51 158 159,160 161 59 162 163

105 166 52

167 168 60

170 171 43 172 173 99 46

a

Abbreviations: SPR, Surface plasmon resonance; LR−SPR, Long-range SPR; SPR−FO, Fiber optic SPR; SPRi, Imaging SPR; LSPR, Localized surface plasmon resonance.

samples collected from patients afflicted with a specific disease, and comparing that with healthy controls, is the next step we must embrace in the SPR sensing community to accelerate the transition from proof-of-concept stage to actual applications in clinical chemistry. In this Perspective, early successes of SPR sensing with clinical samples will first be analyzed to provide a clear picture of the current status of the field. Reported SPR Sensors for Clinical Analysis. Nearly 100 research articles to date have reported the use of SPR sensing for the analysis of clinical samples (Tables 1−3). SPR sensing has been applied to a series of clinical tests for monitoring antibodies, proteins, enzymes, drugs, small molecules, peptides, nucleic acids, and viruses. Most of these early clinical studies enrolled around 10 patients (Figure 1 − left); however, studies with a greater number of patients would eventually be necessary to thoroughly validate the technology for clinical analysis. In most cases, the molecules detected were at concentrations of ng/mL, nanomolar, or higher (Figure 1 − center), while several

this Perspective, the differences between the numerous configurations of SPR sensing will not be underlined; instead the focus will be placed on the overarching properties and challenges of SPR devices in the context of clinical sensing.

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CURRENT STATE OF SPR SENSING FOR CLINICAL ANALYSIS There have been tremendous efforts deployed for the development of SPR sensing in clinical analysis. It is extremely encouraging to note that a significant fraction of the research articles report sensing of clinically important biomolecules at the desired levels for clinical analysis. For example, there have been a number of studies reporting the detection of proteins,17−25 antibodies,26 hormones,27,28 microRNA,29−35 and DNA.36 Despite these promising results, only about 1% of the papers published on SPR sensing report on the analysis of clinical samples from patients, which is usually the ultimate objective of researchers in the field. The analysis of clinical 17


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ACS Sensors Table 2. Sensors Applied for the Clinical Analysis of Proteins and Enzymes in Human Samples medical condition

analyte

biofluid

techniquea

Alzheimer’s disease Alzheimer’s disease Blood grouping Cancer Cardiopulmonary bypass surgery Diabetes Head and neck squamous cell carcinoma Heart disease Hematopoiesis, arthritis Hepatocellular Carcinoma Infectious gastroenteritis Inflammatory processes and neoplasms Lung cancer Osteoarthritis Ovarian cancer Preterm birth Preeclampsia Prostate cancer Prostate diseases Prostate diseases Putative kidney marker Regeneration and repair after injuries Tuberculosis Bladder cancer Botulism Breast cancer Head and neck squamous cell carcinoma Infection Leukemia Pancreatic cancer Rheumatoid arthritis or lung disease Rheumatoid arthritis or lung disease Several diseases

Tau protein Fibrinogen D-antigen on RBC Galectin-1 Cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) Insulin p53 C-reactive protein chemokine CXCL12 Lipocalin-2 Hepatocyte growth factor Ferritin Rac proteins TNF-alpha and MMP-3 human epididymis secretory protein 4 (HE4) Fibronectin Albumin Prostate specific antigen (PSA) IgG glycolysation Haptoglobin Transferrin Hepatocyte growth factor binding profile CFP-10 Podoplanin Botulinum neurotoxin endopeptidase COX-2 p38αMAP kinase Carbohydrate-binding proteins cathepsin G Activated cell leukocyte adhesion molecule cathepsin G cathepsin G Annexin A5

serum plasma RBC serum serum serum serum serum urine serum stool serum serum synovial fluid serum cervicovaginal secretions urine serum serum serum urine blood urine serum/urine serum serum serum serum WBC serum Endometrial tissue saliva serum

SPR FO−SPR SPR LSPR LSPR SPR LSPR SPR SPR SPR SPR SPR SPR LSPR LSPR SPRi LSPR SPRi SPR SPR SPR−EC SPR SPR SPRi SPR SPR SPR SPR SPRi SPR SPRi SPRi SPR

ref 176 49 177 120 100 178 126 179 82 148 101 106 180 102 128 181 129 103 182 183 184 185 186 187,188 50 189 190 45 191 29 61 191 192

a

Abbreviations: SPR, Surface plasmon resonance; SPR−FO, Fiber optic SPR; SPRi, Imaging SPR; LSPR, Localized surface plasmon resonance; SPR−EC: Surface plasmon resonance−electrochemistry.

Sensing Schemes. Most of the reported sensing schemes used direct detection of the analyte, while several others employed secondary signal amplification with antibodies or used indirect detection sensing schemes. Signal amplification can also be achieved with the use of SPR-active nanostructures of improved sensitivity, which can use nanoparticles,37−39 plasmonic nanostructures of greater refractive index sensitivity40 or nanostructures with field depth confined closer to the surface,41 leading to larger SPR shifts for a given detection event. The use of secondary detection with antibodies or with nanoparticles modified with antibodies is by far the most common signal amplification method implemented to date in a series of clinical analysis.42−53 Signal amplification is also an interesting method to avoid background effects by adding a secondary antibody detection step following the capture of the analyte in a biofluid. If appropriate washes are performed, the level of nonspecific response from the secondary antibody should be minimal. Quantification of the analyte is then possible in concentrated biofluids. However, this raises the issue of using a second costly antibody or nanoparticles for the detection, thus increasing the detection time and complexity of the assay due to a greater number of steps in the analysis procedure. The implementation of secondary detection is possible for clinical applications provided that skilled personnel

studies reported pg/mL or picomolar detection, and only a few detected concentrations below this level. These dynamic ranges are in agreement with usual SPR sensing where picomolar to nanomolar detection limits are common. Sensing has been performed in a broad range of biofluids including serum, urine, plasma, whole blood, stools, synovial fluid, cerebrospinal fluids, white blood cells (WBC) and red blood cells (RBC), saliva, endometrial tissue, cervicovaginal secretion, and ascites fluid (Tables 1−3). This breadth of biofluids analyzed via SPR sensing captures a majority of the potential clinical samples and demonstrates the broad applicability of this technique for sensing in complex matrices. In most cases, these samples were diluted in running buffer to reach a biofluid concentration of 10% or lower (Figure 1 − right) to minimize the impact of nonspecific adsorption on the SPR sensor. While this provides a solution for analytes found at higher concentrations, this could be prohibitive for lower concentration analytes or analytes with low affinity which could be diluted below their limit of detection in the process. Dilution of the sample could also increase the complexity of point-of-care sensors, where minimal sample handling is desirable; however, this issue is likely to be mitigated with microfluidic solutions. The results described here show great progress in the field of SPR sensing for clinical analysis. 18


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ACS Sensors Table 3. Sensors Applied for the Clinical Analysis of Other Classes of Molecules in Human Samples medical condition

analyte

biofluid

technique

ref

DNA Fetal sex identification Infection β-thalassemia Cancer treatment Cancer treatment Pancreatic cancer Alzheimer’s disease Alzheimer’s disease Celiac disease Inflammation Cancer Botulism Fertility monitoring Hormonal disorders/tumors/sport doping Putative oxidation damage marker HIV

Cell-free fetal DNA PCR products of Escherichia coli O157:H7 Genomic DNA Therapeutic Drugs Methotrexate Methotrexate microRNA miR-X (X = 21 and 10b) Peptides Amyloid-beta derived diffusible ligands Amyloid-beta Gluten peptide procalcitonin Phospholipid Nanovesicles Exosomes Small Molecules Botulinum neurotoxin B Estriol 16-glucuronide Human growth hormone 3-nitrotyrosine Virus HIV

maternal plasma stool blood

SPR SPR SPRi

193

serum serum

LSPR SPR

108

plasma

LSPR

171

cerebrospinal fluid cerebrospinal fluid urine serum

LSPR SPR SPR SPR

47

Ascites fluid

Nanohole arrays

48

serum urine serum urine

SPR SPR SPR SPR

197

whole blood

LSPR

107

194 44

109

53 195 196

198 104 199

Figure 1. (Left) The number of patients enrolled in most studies was below 10; however, some studies did enlist greater cohorts of patients. The number of patients should be increased in the future to provide strong clinical data for the application of SPR sensing to clinical chemistry. (Center) Distribution of the sensitivity of assays reported for clinical SPR sensing. Sensitivity will need to be improved for markers found at concentrations lower than picomolar. (Right) Most clinical data was acquired with biofluids diluted to 10% or less of its original concentration. Ideally, samples should be analyzed in undiluted (100%) biofluids.

nonspecific adsorption of proteins to surfaces.55,56 The dextran surface chemistry was developed to minimize nonspecific adsorption in commercial SPR systems. While it does provide excellent performance in saline solutions or biofluids diluted more than 10 times, the reduction is not sufficient in undiluted serum for providing a stable baseline. As it would be desirable to analyze a biofluid directly without dilution, other concepts were also proposed to minimize the background response from serum. Membrane cloaking,57 pretreating the surface with blank serum,58 adding dextran to the sample,59 depleting the sample in background protein,51 and extraction of the analytes60,61 are all effective methods for reducing the impact of nonspecific adsorption. However, these methods have drawbacks in terms of sample handling or complexity. Surface chemistry might provide the best option for mitigating this issue, and different polymers and monolayers, including polyethylene glycol (PEG), were shown to reduce nonspecific adsorption by up to 99%.56,62−66 With this level of nonspecific adsorption, the

is performing the assay or that reactions are carried out in specifically designed microfluidics handling all detection steps. Therefore, improving the sensitivity and minimizing the issues of background response from biofluids has been a major field of research in SPR sensing to avoid the use of secondary detection schemes. Considerations about Biofluids and Surface Chemistry. As most markers are circulating in the bloodstream, serum is often the most appropriate biofluid for clinical sensing, and unsurprisingly, serum was used in the vast majority of reported cases. Serum is also one of the most complex sample matrices, with high levels of proteins which can impede the proper function of surface-based sensors such as those used in SPR. Proteins rapidly adsorb onto surfaces forming a layer on the sensor. This issue is ubiquitous to surfaces in contact with biofluids and is commonly known as surface fouling or the protein corona in the field of nanomaterials.54 Several surface chemistries have been developed to minimize the impact of 19


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Figure 2. Calibration curves for anti-L-asparaginase with asparaginase-modified SPR sensors. Calibrations were performed in PBS (black circles) and undiluted human serum (blue squares) with different types of asparaginase, Kidrolase (left) and Ntag26 (right). The SPR response in serum was corrected for nonspecific adsorption. The response in serum was lower with Kidrolase, while the response was slightly larger in serum with Ntag26. Adapted with permission from ACS Sensors 2016, 1 (11), 1358−1365. Copyright (2016) American Chemical Society.

of nonspecific adsorption is different in patients, which has been reported from the measurement of the SPR response of type-1 diabetic patient with healthy patients,75 from the measurement of the response difference between a series of healthy donors and pooled human serum,83 and from the difference in rates of adsorption of different serum samples.66 There is even a difference in adsorption profiles of serums from infants in comparison to adults.85 Therefore, calibration in pooled human biofluids can provide a good model to assess the general performances of the sensor at the development stage, but may fail in the applications with actual clinical samples.83 To solve this issue, secondary detection can be used, however, as stated before, this adds complexity to the sensing scheme, and thus comes at the expense of simplicity and “real-time” measurements. Others have proposed the use of a reference surface with a different antibody immobilized to the surface. However, this approach provides only partial compensation as each surface is slightly different with respect to nonspecific adsorption and results in a significant variability.86 It has been proposed to use a serum sample of the same individual, but depleted in the analyte or with the analyte rendered nonreactive to the SPR sensor (i.e., add an excess of the same antibody as on the capture surface to deplete the analyte in the sample) to provide an accurate compensation for background fluctuations of serum samples of an individual86 (Figure 3). In this method, the nonspecific adsorption and bulk contributions of the signal are identical in the reference and sensing channels. Thus, the specific signal is isolated from these measurements. While this method is highly promising, it could be limited in some cases where a reagent that can completely deplete the analyte is unavailable. Signal compensation of undiluted biofluids remains an issue to seriously consider. SPR Sensing vs ELISA. In order to be adopted, SPR sensing will need to replace existing technologies such as ELISA. Most SPR sensors adapted sensing schemes from ELISA assays, where antibodies or other biomolecular receptors were immobilized on the surface of the SPR chip. The analytes in SPR sensing have been detected using direct, indirect, or sandwich assays. Hence, SPR and ELISA were compared headto-head in several studies with independent SPR and ELISA

design of sensors working directly in crude biofluids with no or minimal sample preparation can now be envisioned. Hence, several SPR sensors were recently reported working in undiluted serum samples.19,57,58,62,63,67−80 Therefore, efforts should now be deployed to integrate these strategies of mitigation of nonspecific adsorption in clinical sample analysis. This would facilitate the consideration of the impact of biofluids on the sensor performance early on in the development process. Other factors are important to consider in the validation of sensors in crude biofluids. First, it is important to note that low fouling surface chemistries sometimes limit the adsorption of biomolecular receptors or show decreased performance with respect to nonspecific adsorption when a molecular receptor is bound to the surface. The biomolecular receptor can also become less effective in capturing the analyte when bound to the surface. These aspects can negatively impact the performance of the sensor in some cases. In addition, the analyte may bind to bulk proteins of the biofluids, mainly exemplified by the fraction bound to free prostate-specific antigen.81 This can lead to two possible scenarios. This association of the analyte with serum proteins can decrease the effective concentration of the analyte due to blocking of the binding site, which potentially impedes the capture of the analyte on the SPR chip lowering the sensitivity. This phenomenon has been suggested in the detection of CXCL12 in urine.82 CXCL12 can bind to glycosaminoglycans that can be found in urine of patients afflicted with some diseases, which can interfere with antibody recognition. This can influence the calibration of SPR sensors in biofluids, and one example is provided in Figure 2 (left) where the SPR signal decreased in serum compared to a saline solution. In another example, binding of proteins to the analyte does not affect binding to the molecular receptor. Hence, the increase of the molecular weight, thus the refractive index shift, of the molecular complex leads to a slightly larger response of the SPR sensor in serum (Figure 2 − right). Calibration in the biofluid is thus important to compensate for matrix effects. The use of pooled biofluids is increasingly being challenged due to the high variability of background response from individuals or between sources of pooled biofluids.84 The level 20


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The complementarity of SPR and ELISA could lead to enhanced sensing schemes in the future. In one example, the use of dye-labeled antibodies is expected to enhance SPR detection due to the added mass of the detection step, while the fluorescence signal of the dye-labeled antibody of the ELISA assay could be increased from metal-enhanced fluorescence of the SPR chip. This is analogous to the concept of using the plasmon for enhancing fluorescence, which is highly attractive for a series of applications.110 However, this remains at the conceptual stage and should be developed in the future. Summary of Current State of SPR Sensing for Clinical Analysis. In summary, SPR sensing technologies have been used to detect a broad range of molecules indicative of medical conditions and the data collected with SPR sensors can be used to perform medical decisions100 (Figure 4 − right). The list of different medical conditions for which SPR sensors have been demonstrated is quite exhaustive and diverse; however, this list is far from complete and SPR sensors could be applied to a broader range of biomolecules. These early successes are encouraging and lay the foundation for the application of SPR sensing in clinical practices. Table 4 lists the considerations currently known that one should take in the process of developing SPR sensors for clinical chemistry. To further advance the field, the community needs to consider increasing the sensitivity to facilitate the detection of lower abundance molecules of high clinical interest, to integrate sample management to process whole blood, to create lab-on-a-chip technologies for storage of reagents and biomolecules, to investigate the use of different biological receptors to improve stability and reduce the need for cold chain storage, and a series of other considerations. The next section will reflect on these next steps that needs to be considered for improving the performance of SPR sensors and their implementation in clinical chemistry.

Figure 3. Scheme depicting the concept of signal compensation with the same biofluid sample depleted of the analyte. The sensing channel measures the specific and nonspecific contributions to the SPR response, while the reference channel accurately measures nonspecific signals. Reprinted with permission from Anal. Chem. 2013, 85 (12), 5637−5640. Copyright (2013) American Chemical Society.

measurements42,87−93 and recently using a single chip SPRELISA sensor.94 These studies showed that SPR and ELISA are typically sensitive in nearly the same dynamic range, with some studies showing better sensitivity for ELISA, while others for SPR sensing. The possibility of creating smaller devices with SPR is indeed interesting, but does not necessarily constitute a marquee advantage in comparison to ELISA, as smaller ELISAlike devices are increasingly being reported in the literature.95,96 The advantages of SPR in comparison to ELISA thus reside in the label-free, rapid, and direct detection of analytes. SPR sensing also requires fewer wash steps and thus is favored for the detection of molecules of lower affinity, which can otherwise be washed away in ELISA assays.97 Many clinical results obtained with SPR sensors were compared to ELISA assays, 43,98−105 chemiluminescence, 106 PCR, 107 or LCMS.108,109 Figure 4 (left panel) shows one example of a correlation study for a series of cytokines where the LSPR sensor was compared to ELISA.100 The slope of nearly 1 was indicative of the excellent agreement between techniques. In most cases reported to date, there was an excellent agreement of the data collected with SPR and other techniques. These correlation assays are important to demonstrate the performance of SPR sensors in comparison to the gold standards in clinical chemistry.

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FRONTIERS OF SPR SENSING OF CLINICAL SAMPLES Research efforts in the next few years should be directed toward solving the remaining issues for the implementation of SPR sensing in clinical practices. These issues include the improvement of sensor design for analysis in whole blood, evaluating other types of biological receptors for stable and sensitive sensing, solving the issues related to clinical variability of biofluids, improving sensitivity, identifying the best applications

Figure 4. (Left) Correlation of an LSPR multiplexed sensor for cytokines measured in serum samples with corresponding ELISA assays. The slope of 1.0071 indicates near-perfect correlation between the techniques. (Right) Cytokine levels in patients pre- and post-operation for cardiopulmonary bypass surgery. Cytokine levels were significantly higher on day 1 post-surgery and patients were released when the cytokine levels returned to the baseline. Reprinted with permission from ACS Nano 2015, 9 (4), 4173−4181. Copyright (2015) American Chemical Society. 21


Perspective

ACS Sensors Table 4. Considerations for the Development of Plasmonic Sensors for Clinical Sensing consideration Selection of biofluid

Selection of biological assay format

Technological issues

implications Biofluid must be selected to accurately represent the condition of a patient. The level of a molecule must be directly correlated to the health status and should be at high concentration. Blood-based biofluids remain the most likely candidates for clinical diagnostics. Most markers are circulating in blood at higher concentrations. Whole blood would be optimal in terms of simplicity of sample preparation, but remains challenging for sensing due to the high complexity of the matrix. Few sensors working in whole blood have been reported. Serum and plasma remain the best option at this time. Complexity of sample is lower than blood. Sample dilution remains common, but examples of sensors working in undiluted patient samples have been reported. Urine and saliva pose fewer challenges for sensing (lesser complexity of the matrix) and sampling, but not all markers are found in these fluids or correlate to the circulating levels. Performing analysis on solubilized tissue sample could contribute to the diagnostics of diseases with low level of circulating markers Direct assays would be optimal. Fewer reagents involved, shorter assay time, and simplicity. Sensitivity needs to be improved for most molecules at concentrations of pM or below. Impact of variable background response from different patients remains to be fully solved. Indirect and competitive assays can offer greater sensitivity and selectivity. Involves a greater number of reagents and may require more complex fluidics solutions for implementation in final assay format, if handled by minimally trained persons. Signal amplification with nanomaterials can be desirable to enhance sensitivity for monitoring low concentration markers. Long-term stability and reproducibility of nanomaterials is currently suboptimal and must be improved. Surface chemistry should be low fouling. Signal compensation for variability of background response of biofluids should be optimized. Blocking reagents can be added to the SPR chip or in the sample or running buffer. Microfluidics should favor low volume, high interaction of samples with the SPR chip, while minimizing the possibility of clogging with biological samples. Selection of biological receptor and immobilization method to respectively achieve high sensitivity and high retention of biological affinity of the receptor. Storage and stability of biological receptors when immobilized on the SPR chip. Must the receptor be immobilized immediately before measurement? Need for cold chain storage? Reproducibility of calibration Comparison with established techniques such as ELISA

also not surprising that surface-bound LSPR sensors have been implemented in a larger number of clinical studies.47,100,102,107,125−129 Regardless of the LSPR configuration, the plasmon resonance should ideally be tuned to the biological window in the near-infrared region to avoid spectral interference for the detection of LSPR resonance in biofluids. To access the biological window, anisotropic, core−shell, or hollow nanoparticles are currently considered to achieve higher sensitivity and resonances in the near-infrared.130,131 Nanostructures are either prepared from colloidal syntheses132,133 or with nanofabrication techniques.134,135 Colloidal synthesis holds the advantage of simplicity and likely cost of fabrication, but colloidal-based sensors often suffer from reproducibility in synthesis and usually have a lower figure of merit (FOM: full width at half-maximum/sensitivity). Nanofabricated plasmonic structures can reach high FOM and thus their performance can exceed other SPR sensing platforms,136 but may be very costly and complex to fabricate. There is currently a large heterogeneity in nanostructures used for SPR sensing, and therefore focus should be placed on identifying the best anisotropic or branched colloidal nanostructures and optimize their synthesis to achieve highly reproducible fabrication, as well as identifying 2D nanofabricated surfaces that are relatively simple to fabricate and of high sensitivity. This constitutes the major challenge of plasmonic nanomaterials, as methods for classical SPR sensing should be translated with relatively few obstacles. SPR Instrumentation. SPR instruments that are affordable and sensitive will need to be designed and validated for broad acceptance of the technique in clinical chemistry. While the cost of the current instruments does not necessarily need to be significantly decreased for centralized clinical laboratories, cost

for SPR sensing in clinical chemistry, and translating the technology to clinical markets. Plasmonic Materials. The improvement of sensor design is by far the most active research field in contemporary SPR sensing, especially for LSPR sensors. This field is very broad and cannot be fully exposed in this perspective, such that only a brief discussion is provided here. Novel nanostructures for LSPR sensing are frequently reported for optimizing the sensitivity of sensors.111 LSPR is particularly interesting due to the possibility of performing colorimetric detection, which could ultimately lead to the naked eye sensing112,113 or smart phone114−117 based sensing. These possibilities are highly promising and the use of gold nanoparticles in microfluidicbased biosensing for point-of-care applications has been reviewed in detail elsewhere.118 LSPR biosensors can be designed for solution-phase or surface-bound sensors. Solution-based biosensors are interesting due to the simplicity of the measurement and of the assay. However, considerations must be given to the colloidal stability of nanoparticles in complex fluids due to the formation of a protein corona and ionic strength of the biofluids. The impact of complex fluids on LSPR sensors can be reduced with functionalization layers, biological scaffolds, and size selection,119 but remains an issue to consider. Dilution of the sample can also serve to minimize the impacts related to the biofluid, as shown for sensing clinical samples of patients.108,120 Solutionbased LSPR can also serve to reveal the response of an ELISA assay for clinical samples.99 Surface bound LSPR sensors, where the nanoparticles are immobilized on a solid substrate, alleviate the issues of the colloidal stability of nanoparticles in solution. This configuration is also simpler to multiplex on chip and to integrate with microfluidics. The field of integrated plasmonic devices is thus gaining a lot of attention recently.121−124 It is 22


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not be as strict for applications in clinical laboratories, where cost can be offset on a larger number of samples and the presence of qualified personnel to facilitate handling of sample preparation. It is nonetheless obvious that microfluidics is poised to play a significant role in SPR sensing for clinical applications. Bioreceptor Considerations. Biological receptors such as antibodies, enzymes, or proteins that are typically used in SPR sensing are fragile molecules that can denature under inappropriate storage or handling conditions. These molecules usually require a cold chain to ensure their biological activity and proper working on SPR sensors. This brings significant constraints on handling SPR sensors in the context of clinical chemistry. Sensors reported to date were quite surely (no data are available for this in papers) fabricated immediately before use. While this is adequate for the development of sensors, it is not ideal for future commercial applications. In all likelihood, storage conditions such as the ones implemented in the clinical diagnostic industry for other assays will need to be implemented in SPR sensing. To the best of my knowledge, this has not been demonstrated yet, but will be necessary to consider soon. While antibodies, enzymes, and proteins are workhorses in biosensing, the use of nucleic acids, including aptamers, is an increasingly popular bioreceptor alternative,141−146 which could provide more stable sensors and minimize the requirements for storage. Aptamers are short nucleic acids with a structural affinity to certain molecules. They hold the main advantage of greater stability, and in some cases, the sensitivity was shown to be superior to the antibody-based measurements. They have been applied to SPR sensing on numerous occasions7,9,10,147 and for clinical sensing of Lipocalin-2 in patients afflicted with hepatocellular carcinoma (HCC).148 Molecularly imprinted polymers (MIP) are also often considered for sensing applications, including the sensing of proteins in combination with SPR sensors.149 A recent article further advanced the field of MIP sensors for proteins by implementing a PEG protective coating on the MIP that significantly reduced nonspecific adsorption.150 The combination of MIPs for protein detection with antifouling polymers is highly promising. The commercial availability of MIPs and aptamers for a broad range of molecules is currently the main limiting factor for the application of these types of artificial receptors in SPR sensing for clinical chemistry. The use of artificial receptors such as MIP and aptamers should therefore be more common in the near future, once their development reaches a critical number of applications targeting molecules of clinical interest. Clinical Market Considerations. The best application for entering the clinical market with SPR sensors remains to be identified. While electrochemical sensors clearly had a frontrunner application in glucose monitoring, it seems that the SPR field is undergoing a greater struggle in finding an application where SPR clearly surpasses other techniques available and has a large market able to support development of the application. It is definitely encouraging that a high number of applications were already reported for SPR sensing of clinical samples (Tables 1−3) as it demonstrates the broad applicability of SPR to a series of important clinical issues. As the main advantage of SPR sensing in comparison to ELISA is speed, label-free and direct sensing and sensitivity for low affinity analytes that can be washed away in ELISA protocols, the applications for SPR sensors in clinical chemistry should target one of the following areas. The need of finding highly sensitive and complementary

would need to be tremendously lowered for point-of-care applications. This also applies to the cost of purchasing the sensors for detecting specific diseases. It is currently inconceivable that a single chip could be used to run different patient samples without running the risk of cross contamination. Therefore, the SPR sensors should be considered as single use, and thus, microfluidics should be disposable as well. There have been several small SPR systems that have been reported,11 which should fulfill the needs of centralized clinical laboratories. However, to further bring down the cost and facilitate large-scale deployment of point-of-care type SPR instruments, it seems that their integration into smart phones would be the best option at this time. However, one must keep in mind that technology evolves rapidly and smart phones might be obsolete in a not so distant future. A great cautionary example involves the use of data storage optical discs for chemical sensing applications. This media, and thus the infrastructure for reading these, is phasing out and should likely be obsolete in less than 10 years, making it difficult to sustain research that uses optical disc technology for sensing. This may apply to smart phones at some point and no one can foresee what technological development will replace them in the future. Regardless of this distant possibility, smart phones are currently ideal platforms for SPR sensing. Recent articles report on the integration of a fiber-optic SPR sensor117 or LSPR sensor114 into a smart phone and this field is set to expand in the near future. Although the integration of smart phones would require maintaining the performance of the SPR sensors to avoid the loss of sensitivity, the imaging capabilities of smart phone cameras also open the door to higher multiplexing of assays, and therefore, further advancement of the field in this direction seems logical. Microfluidics Considerations. Advanced microfluidics will need to be implemented for multiplexing, integrating sample preparation and reagents to provide a sensor that works directly in biofluids using a minimum volume corresponding to a finger prick. In an ideal case, direct detection of the analytes in whole blood would be achieved without sample preparation. This would significantly decrease the burden imposed on the microfluidics for interfacing the sample and sensor chip, if no sample preparation is needed. There have been a few reports lately exploring the idea of SPR sensing in whole blood using some type of filtering or dialysis systems imbedded into the SPR sensors137,138 or from the use of a synthetic tethered lipid membrane.139 However, research in this direction will need to be further refined to improve the performance of SPR sensing in whole blood, and hence, we should consider at this time that sample preparation will be needed on the short-term for extracting the serum or plasma from whole blood, and maybe even diluting the sample. This would be ideal to implement in the microfluidic cell to minimize sample handling. Another possibility involves the use of magnetic nanoparticles to extract the analyte from whole blood and injecting the purified sample to the SPR sensor. The use of a magnet could even enhance the SPR response by augmenting the contact of the analyte with the surface and providing enhancement from the large refractive index of the nanoparticle.140 A microfluidic platform that can separate magnetic nanoparticles from whole blood and then inject these nanoparticles onto the SPR chip may provide a solution for sensing in complex biofluids. In all cases, the microfluidic platform should ideally minimally increase the complexity and cost of the system to be adopted with point-ofcare applications. The costs and complexity constraints should 23


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cover a broad range of assays in biofluids. In this Perspective, the focus was placed on SPR sensors that have actually been applied for the analysis of clinical samples from patients with a series of medical conditions. This is a great leap forward in the translation of SPR sensing technologies to clinical chemistry. Several considerations such as issues with biofluids, sensitivity, instrument integration, bioreceptors, and translation of the technology to clinical applications have been discussed and this will require further research to reach the next step in the process of applying SPR to clinical chemistry. The quest remains active to find the best applications of SPR for clinical chemistry. All examples shown in Tables 1−3 are definitely of interest and should be considered. However, we must identify applications that will greatly benefit from the implementation of SPR sensing in clinical analysis and for which SPR sensing is most suited. Considering these facts, it is not surprising that antibody and protein detection dominates the current applications of SPR sensing; however, the rise in the importance of genetic testing and microRNA detection in clinical practices could be an interesting niche for SPR applications in clinical chemistry. Therefore, efforts should continue to be deployed for the detection of nucleic acids with SPR sensing. The next few years should see novel integrated SPR systems either as standalone units or alongside existing technologies such as smart phones capable of detecting biomolecules with high sensitivity and ideally in undiluted biofluids. Research in surface chemistry, nanomaterials, chemical analysis, microfluidics, and systems engineering will need to be combined in order to achieve the objective of clinical sensing. Once this is accomplished, translation to market should shortly follow. Based on the early successes of SPR sensing in clinical chemistry exposed here, one can confidently claim that SPR is poised to significantly impact the field in the near future.

antibody pairs can sometimes prove challenging in ELISA, while SPR sensing only require a single highly sensitive antibody. In addition, binding small molecular receptors such as DNA, nucleic acids, or drugs and the use of MIP for sensing a broad range of molecules is not possible in ELISA, but effective in SPR sensing. Another significant impact for SPR sensing of molecules would be in cases where rapid action of clinicians would be required. This includes, among others, emergency care, surgical operations, and allergic reactions. SPR sensing can also be valuable for frequent monitoring of levels of molecules, such as monitoring protein levels related to diseases or molecules indicative of the response of patients to therapies, as well as monitoring therapeutic drugs, among others. These tests are often performed on a smaller number of samples or patients at any given time and location, situations in which ELISA may be too costly to run. Lastly, SPR sensing can be applied to remote or resource-limited locations in the point-ofcare format. Finally, the translation of academic research to the clinical market will require some considerations. Working with clinical samples involves planning and infrastructure, which includes the implementation of a procedure for working with actual clinical samples. This procedure necessitates, in addition to the usual sensor optimization steps, the need to secure the access to clinical samples through collaboration with clinicians, to obtain the approval of local ethics committee, training of scientific personnel in handling biological material, establishing a rigorous cleaning procedure of the instrument between runs to eliminate any possible biological safety issues or contamination, and the need to process samples in a biosafety laboratory (typically a biosafety level 2 lab is necessary). These steps are necessary to ensure confidentiality of patient information and the safety of the scientists working with the samples, as they are not necessarily tested for a broad range of transmissible diseases. These steps may be time-consuming, but ultimately bring us closer to the objective of translating technologies to the clinical laboratories as demonstrated below. Validation of New Clinical Assays. Several analytical parameters must be validated to homologate a new clinical assay.151 The measurement of the variability of a clinical test is important to assess with the measurement of the precision within a run and between runs, the day-to-day variation of the response, and the variation of the response across different locations and analysts. The calibration curve is critical in providing quantitative results, and thus its stability, linearity, and sensitivity are important to characterize. The analysis in biofluids can involve some matrix effects and the measurement of the percentage recovery across the dynamic range, the effect of biological interference, and the specificity of the analysis should be known. Greater numbers of patients will need to be enrolled and larger-scale correlation studies will need to be implemented for the accreditation of SPR sensors for clinical tests. Clinicians and clinical chemists should then be educated on the working principles and benefits of the technology to ensure its acceptance by the healthcare industry. Lastly, the technology will also need acceptance of governmental agencies and insurance companies for the reimbursement of clinical tests performed with SPR sensors.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +1-514-343-7342. ORCID

Jean-Francois Masson: 0000-0002-0101-0468 Notes

The author declares no competing financial interest.

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ACKNOWLEDGMENTS The author thanks financial support from the Canadian Institutes of Health Research (CIHR) and the Natural Science and Engineering Research Council (NSERC) of Canada.

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REFERENCES

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OUTLOOK SPR sensors have significantly increased in maturity in the past decade. Applications in SPR sensing were originally limited to saline solutions and simple biological assays, and now they 24


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Surface Plasmon Resonance Clinical Biosensors for Medical

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