Paper-Based Surface-Enhanced Raman Spectroscopy for Diagnosing

We show that we can measure trace amounts of human amniotic fluids of patients with subclinical intra-amniotic infection (IAI) and preterm delivery (P...
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Paper-Based Surface Enhanced Raman Spectroscopy for Diagnosing Prenatal Diseases in Women Wansun Kim, Soo Hyun Lee, Jin Hwi Kim, Yong Jin Ahn, Yeon-Hee Kim, Jae Su Yu, and Samjin Choi ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b02917 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018

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Paper-Based Surface Enhanced Raman Spectroscopy for Diagnosing Prenatal Diseases in Women

Wansun Kima,1, Soo Hyun Leeb,1, Jin Hwi Kimc,1, Yong Jin Ahna, Yeon-Hee Kimc*, Jae Su Yub*, Samjin Choia*

a. Department of Biomedical Engineering, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea b. Department of Electronic Engineering, Kyung Hee University, Gyeonggi-do 17104, Republic of Korea c. Department of Obstetrics & Gynecology, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggi-do 11765, Republic of Korea

*Address for correspondence: Yeon-Hee Kim, M.D. & Ph.D., Jae Su Yu, Ph.D., Samjin Choi, Ph.D. Department of Biomedical Engineering, College of Medicine, Kyung Hee University 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, South Korea Tel: +82 2 961 0290; fax: +82 2 961 5515 E-mail addresses: [email protected] (Y.H. Kim), [email protected] (J.S. Yu), [email protected] (S. Choi)

1

These authors contributed equally to this work.

Abstract We report the development of a surface-enhanced Raman spectroscopy (SERS) sensor chip by decorating gold nanoparticles (AuNPs) on ZnO nanorod (ZnO NR) arrays vertically grown on cellulose paper (C). We show that these chips can enhance the Raman signal by 1.25×107 with an excellent reproducibility of 92% clinical sensitivity and specificity. Our technology has potential to be used for the early detection of prenatal diseases and can be adapted for point-of-care applications.

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*Keywords: SERS, cellulose paper, ZnO NR array, AuNPs, amniotic fluid

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Raman spectroscopy is an optical technique based on inelastic scattering. Most biological molecules can generate unique Raman signals, allowing the biochemical composition of tissues to be determined. However, since the Raman scattering is weak, many researchers can amplify these signals by using metal substrates, leading to a surfaceenhanced Raman spectroscopy (SERS) effect.1,2 The basic concept of SERS is that the signals of the analyte are amplified through localized surface plasmon resonance (LSPR) phenomena generated by light3,4 when it interacts with plasmonic nanoparticles, such as silver and gold.5,6 The SERS enhancement factor (EF) is typically in the range of 104– 107, although substrates that can achieve EF >1010 have been developed.7 Although many studies have been undertaken to increase EFs further (e.g., >1012), the average EF in most studies is less than 106.8 This is caused by the poor reproducibility of substrates, misunderstandings of the LSPR effect, and misquoted SERS EF calculations. In order to overcome these problems, researchers have been focused on fabricating nano-patterned structures for SERS applications.9–11 However, these SERS substrates are not cost-effective for mass-production for point-of-care (POC) testing because they rely on expensive and complicated processing equipment. To overcome this, we aim to develop a zinc oxide (ZnO) nanorod (NR) on a cellulose paper substrate coated with plasmonic materials.12–16 Preterm delivery (PTD) is the second largest direct cause of death in children under five years of age and it is a major cause of perinatal mortality.24 Infection has long been suspected as the underlying cause of idiopathic PTD and microbial intra-uterine infections are a confirmed leading cause of PTD. In particular, bacterial invasion of the amniotic cavity is the major cause of neonatal mortality worldwide.25,26 Intra-amniotic infection (IAI) is an infection that causes inflammation in any components of the amniotic fluid, placenta, fetus, chorion, amnion, or decidua.27 IAI is present in 94% and a specificity of >92% for classifying each amniotic fluid through the SVM algorithm (>93% accuracy) with a linear kernel using the training data (n=60). This ML-optimized rule decisionmaking could be used to identify the amniotic fluid types of newly collected specimens. However, bioinformatics based on ML classification with larger sample sizes and more amniotic fluids with prenatal diseases is still required. In general, uterine cervices are primarily investigated to find pathological or physiological changes in cervical collagen tissues and amniotic fluid samples are investigated for only fetal malformation. This study aims to analyze the differential expression of the Raman spectrum based on the presence or absence of subclinical IAI and to verify the possibility of predicting subsequent PTD. Therefore, the highly discriminatory power of the well-defined AuNPs/ZnONRs/C SERS sensor on a cellulose paper substrate, supported by a multivariate statistics-derived MLtrained bioclassification method, is desirable for identifying and predicting amniotic fluid-mediated diseases during pregnancy.

Conclusions In summary, we demonstrated a SERS platform that could be used to help ensure normal delivery without prenatal diseases such as infection and preterm delivery. This SERS platform consisted of an AuNPs/ZnONRs/C chip and a rule-based decision supporting method with ML-trained datasets. In order to implement the low-cost and disposable POC device, porous cellulose paper was selected as a basal substrate. A vertically grown ZnO nanostructure with an increased surface area was fabricated on cellulose paper through a hydrothermal method (ZnONRs/C). To maximize the nanogap-induced LSPR phenomenon, SILAR-synthesized AuNPs were decorated on O2 plasma-treated ZnONRs/C substrates. Since ZnO materials could be easily dissolved under acidic conditions, a pH-neutralized gold reactive solution was first included in the SILAR cycles. The mechanism of Raman scattering for the AuNPs/ZnONRs/C chip fabricated by these multistage nanotechnologies, using only aqueous solutions, was estimated by a TEM-approximated finite element nanostructural model. The Raman performance of our AuNPs/ZnONRs/C chip, - 11 -

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which had solid and directional single crystallinity, was evaluated using a trace amount of a small Raman molecule; these chips achieved >107 AEF and >104 SEF with excellent reproducibility. To promote the practical applicability of our SERS platform, a multivariate statistics-derived ML-trained bioclassification method was added to the AuNPs/ZnONRs/C chip. Although trace amounts of real amniotic fluids of patients with IAI and PTD were used, our SERS platform could detect the presence of prenatal diseases and identify the types of prenatal diseases from amniotic fluids with high sensitivity and specificity. These experimental results indicate that our AuNPs/ZnONRs/C SERS sensor has potential for identifying and predicting any amniotic fluid-mediated diseases during pregnancy.

Experimental section Fabrication of the AuNPs/ZnONRs/C Chip The AuNPs/ZnONRs/C chip was fabricated by the following procedures (Scheme 2). A 2×2 cm2 piece of Whatman cellulose paper (GE Healthcare) was rinsed in ethanol and then dried with nitrogen gas. In order to form a uniform seed layer on the porous cellulose substrate, a ZnO seed solution was prepared by dissolving 30 mM of zinc acetate dehydrate (Zn(CH3COO)2·2H2O, Junsei Chemical Co., Ltd, Japan) in 30 mL of ethanol at 60 ºC. The cellulose substrate was coated with the seed solution drop by drop at 110 ºC and subsequently placed into a thermal oven at 150 ºC for 5 h. In order to vertically grow ZnO NRs, a growth solution was prepared by dissolving 25 mM zinc nitrate hexahydrate (Zn(NO3)2·6H2O, Sigma Aldrich) and 25 mM hexamethylenetetramine (HMTA; C6H12N4, Daejung Chemical & Metals, Korea) in 200 mL of deionized water at room temperature with continuous stirring for 2 h. The seed-coated cellulose substrate was immersed into the growth solution in an oven at 90 ºC. After 4 h, the ZnO NRs cellulose (ZnONRs/C) substrate was carefully removed from the solution and dried. AuNPs were directly synthesized and coated onto the ZnONRs/C substrate using a modified SILAR technique based on a previous study.40 The ZnONRs/C substrate was treated with O2 plasma for 30 s and then successively immersed for 30 s in a pH-adjusted reactive solution, gold (III) chloride trihydrate (HAuCl4·3H2O, Sigma Aldrich), and sodium borohydride (NaBH4, Sigma Aldrich); five to 10 SILAR cycles were used.

Scheme 2. Fabrication procedure of the AuNPs/ZnONRs/C chip. (A) Preparation of cellulose paper. (B) - 12 -

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Coating the ZnO seed layer on the as-prepared cellulose substrate. (C) Vertical growth of ZnO NRs by hydrothermal synthesis. (D) Formation of AuNPs on the O2 plasma-treated ZnONRs/C substrate by the SILAR method (with pH 7 adjustment).

Characterization of the AuNPs/ZnONRs/C Chip The structural properties of the AuNPs/ZnONRs/C chip were characterized using a field-emission scanning electron microscope (FE-SEM; Hitachi) with an accelerating voltage of 10 kV. The UV−vis absorption spectra of the AuNPs/ZnONRs/C chips fabricated with different conditions were characterized using a T60U UV−vis spectrophotometer (PG Instruments Ltd., Leicestershire, UK). The crystallinity of the AuNPs/ZnONRs/C chip was characterized via focused ion beam Quanta 3D FEG (FIB; FEI Company, Netherlands) milling with 0.1 nA at 30 kV and a scanning transmission electron microscope (STEM; JEM-2100F, JEOL, Japan) with energy-dispersive X-ray analysis (EDX) at an accelerating voltage of 200 kV. The crystalline phase of the AuNPs/ZnONRs/C chip was characterized using an ATX-G high-resolution X-ray diffractometer (HR-XRD; Rigaku, Japan) with Cu Kα X-rays in the 2θ range of 30 to 80° with a step size of 0.02°.

Raman Measurement All Raman spectra were measured using a SENTERRA confocal Raman spectroscope (Bruker Optics, USA) with a 785-nm diode laser with 10 mW of power and a 20× objective lens. Samples were processed within the fingerprint range of 417−1782 cm−1 with a spectral resolution of 5 cm−1 and twice the acquisition time of 10 s. Measurements were taken at 10 random points using a 2 µL drop of the Raman probe and amniotic fluids, which were dropped onto the AuNPs/ZnONRs/C chip and dried at room temperature. Crystal violet (CV; C25H30N3Cl, Sigma Aldrich) and L-phenylalanine (C9H11NO2, Sigma Aldrich) were used as the Raman probe molecule.

Collection of Clinical Specimens Amniotic fluids were sampled during cesarean sections or amniocentesis for assessment of IAI and fetal lung maturity in the near-term period from patients who were hospitalized for painless cervical dilation, threatened premature labor, or preterm premature rupture of the fetal membranes after less than 37 weeks of gestation. The control amniotic fluids were sampled from patients during elective cesarean sections without labor at the term period of gestation. Patients with concomitant obstetric complications of gestational diabetes, preeclampsia, or systemic infectious diseases (including hepatitis, syphilis human immunodeficiency virus (HIV), and diseases related to TORCH infections such as toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus-2) were excluded. The samples of amniotic fluids were classified randomly into three groups: (1) women without IAI and PTD, (2) women without IAI - 13 -

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who delivered a premature neonate, and (3) women with IAI. This prospective study was conducted at the Uijeongbu St. Mary’s Hospital of The Catholic University of Korea. The participants provided informed consent for all procedures and for inclusion in the present study. The protocol was approved by the institutional review board of the Catholic Medical Center of The Catholic University of Korea (UC16TISI0133).

Numerical Simulation The SERS effect of the AuNPs/ZnONRs/C chip was theoretically evaluated using the finite element method (FEM). The FEM computational model was designed based on TEM-estimated nanostructural information. The electric field distributions according to the presence and absence of plasmonic nanoparticles were computed, and the electric field values were represented as the maximum values of each computation. Three boundary conditions were used, including an active port boundary (for an incident wavelength boundary with the laser power) and a passive port boundary (for a bottom boundary that does not pass reflections). The Floquet boundary condition was also imparted on both sides to provide an electric field with a symmetrical parallel boundary in the analysis models. The maximum and minimum finite element sizes for electric field computation were set at 1 nm and 0.002 nm, respectively. The material properties for FEM computational models were selected from the literature.66 The refractive indices of air and cellulose paper at 785 nm are 1.0000 and 1.5570, respectively. The complex-valued permittivity of gold and ZnO are −15.0−0.9i and 3.53+0.000296i, respectively.16 FEM computation was performed by using the radiofrequency module of the COMSOL Multiphysics software.

Acknowledgements This research was supported by the National Research Foundation of Korea (2017R1A2B4002765 and 2017R1D1A1B03031412) and the Ministry of Health & Welfare, Republic of Korea (HI14C2241).

Supplementary information The Supporting Information is available. Fluorescence interference elimination, morphologies of AuNPs/ZnONRs/C chip with different synthesis conditions, cellulose material as a sensor base material, the reason for the use of ZnO NRs for SERS enhancement, optimization of SILAR conditions, elemental mapping, selectivity, estimations of the concentrations of real amniotic fluids by SERS intensities, clinical data, effect of confounding factors, and data analysis.

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