title: Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE2RD) for diagnostics.
abstract: Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes.
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304;
authors.forename: Fatih
authors.initials: F
authors.lastname: Inci
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Chiara
authors.initials: C
authors.lastname: Filippini
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304; jeanne.thompson@stanford.edu utkan@stanford.edu.
authors.forename: Murat
authors.initials: M
authors.lastname: Baday
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304;
authors.forename: Mehmet Ozgun
authors.initials: MO
authors.lastname: Ozen
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304;
authors.forename: Semih
authors.initials: S
authors.lastname: Calamak
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94304; Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304;
authors.forename: Naside Gozde
authors.initials: NG
authors.lastname: Durmus
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, 310003, China; Institute for Translational Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, China;
authors.forename: ShuQi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Emily
authors.initials: E
authors.lastname: Hanhauser
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Hobbs
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Franceline
authors.initials: F
authors.lastname: Juillard
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Ping Ping
authors.initials: PP
authors.lastname: Kuang
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vetter
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Margot
authors.initials: M
authors.lastname: Carocci
authors.affiliation: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Hidemi S
authors.initials: HS
authors.lastname: Yamamoto
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takagi
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304;
authors.forename: Umit Hakan
authors.initials: UH
authors.lastname: Yildiz
authors.affiliation: Molecular Imaging Program at Stanford, Center for Cancer Nanotechnology Excellence, Stanford University, Palo Alto, CA 94305; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304;
authors.forename: Demir
authors.initials: D
authors.lastname: Akin
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304;
authors.forename: Duane R
authors.initials: DR
authors.lastname: Wesemann
authors.affiliation: Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Singapore 138648;
authors.forename: Amit
authors.initials: A
authors.lastname: Singhal
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Max L
authors.initials: ML
authors.lastname: Nibert
authors.affiliation: Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Daryl T-Y
authors.initials: DT
authors.lastname: Lau
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Henrich
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaye
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Steven C
authors.initials: SC
authors.lastname: Schachter
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304;
authors.forename: Lars M
authors.initials: LM
authors.lastname: Steinmetz
authors.affiliation: Molecular Imaging Program at Stanford, Center for Cancer Nanotechnology Excellence, Stanford University, Palo Alto, CA 94305; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94304; Department of Bioengineering, Stanford University, Stanford, CA 94305; Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305; Bio-X Program, Stanford University, Stanford, CA, 94305;
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Gambhir
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94304; Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304; jeanne.thompson@stanford.edu utkan@stanford.edu.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Davis
authors.affiliation: Demirci Bio-Acoustic-Microelectromechanical Systems in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Radiology Department, Stanford University School of Medicine, Palo Alto, CA 94304; Department of Electrical Engineering (By courtesy), Stanford University, Stanford, CA 94305 jeanne.thompson@stanford.edu utkan@stanford.edu.
authors.forename: Utkan
authors.initials: U
authors.lastname: Demirci
mesh_terms: D015374:Biosensing Techniques / Q000295:instrumentation*; D045744:Cell Line, Tumor; D060085:Coinfection / Q000175:diagnosis; D019937:Diagnostic Techniques and Procedures / Q000295:instrumentation*; D004560:Electricity; D004777:Environment; D004797:Enzyme-Linked Immunosorbent Assay; D004867:Equipment Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057230:Limit of Detection; D044085:Microfluidics; D049329:Nanostructures / Q000737:chemistry*; D009994:Osmolar Concentration; D015203:Reproducibility of Results; D013696:Temperature
keywords: biodetection; label-free; multiple biotargets; nanoparticle; point-of-need