Spin valve sensors for ultrasensitive detection of superparamagnetic nanoparticles for biological applications

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Abstract

We present giant magnetoresistance (GMR) spin valve sensors designed for detection of superparamagnetic nanoparticles as potential biomolecular labels in magnetic biodetection technology. We discuss the sensor design and experimentally demonstrate that as few as ∼23 monodisperse 16-nm superparamagnetic Fe3O4 nanoparticles can be detected by submicron spin valve sensors at room temperature without resorting to lock-in detection. A patterned self-assembly method of nanoparticles, based on a polymer-mediated process and fine lithography, is developed for the detection. It is found that sensor signal increases linearly with the number of nanoparticles.

Introduction

For the past several years, giant magnetoresistance (GMR)-based magnetic biodetection technology, which involves labeling biomolecules with magnetic micro- or nanometer-sized particles and detecting the magnetic fringing fields of the particle labels by GMR sensors after capture by target-probe biomolecular recognition, has received increasing research and development efforts [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. This is because the GMR biosensors are promising for sensitive, large-scale, inexpensive, and portable biomolecular identification. They are also compatible with standard silicon IC technology, and suitable for integration into a lab-on-chip system. Compared to the superconducting quantum interference device (SQUID)-based ultrasensitive magnetic biodetection [15], [16], the GMR technology has advantages of room-temperature operation, less complex instruments, and hence more portable and flexible implementation. Moreover, given the nature of the solid-state thin film sensors and the IC compatible fabrication, the GMR biosensors can be integrated into a very high density, individually addressable array similar to the magnetic random access memory (MRAM), and hence such a GMR sensor array will be well suited for multi-analyte biodetection [2], [3].

Up to date, most magnetic particle labels in the literature are micron or submicron sized, usually composed of a polymer matrix with imbedded magnetic nanoparticles or a polymer core coated with magnetic nanoparticles [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. However, in order to achieve ultrahigh biodetection sensitivity, e.g., single molecule detection, the dimension of magnetic particle labels should be comparable to that of biomolecules. In the case of detecting DNA fragments, it is ideal to have the particle labels at 20 nm or smaller in diameter [17]. Such small nanoparticles would not block bimolecular interactions, such as hybridization between complementary gene fragments. Moreover, one nanoparticle label may be conjugated with one or at most a few DNA fragments, which will help establish a quantitative relationship with a sufficient accuracy between the number of captured particle labels and the actual biorecognition events. In contrast, it is quite difficult to do so with microbeads because of their large size mismatch with biomolecules. The monodispersity of crystalline magnetic nanoparticles in both size and magnetic moment [18], [19] also benefits the signal quantification, in contrast to the large variations of the microbeads in magnetic moment [1], [10].

Given all these desirable properties, magnetic nanoparticles with a diameter of 20 nm or smaller become desirable biomolecular labels for ultrasensitive, highly quantitative magnetic biodetection technology. On the other hand, such tiny magnetic nanoparticles are a great challenge to the detectors, because their magnetic moments are very low due to their limited physical volume, relatively large surface area, and significant thermal disturbance to magnetic moments, i.e., superparamagnetism. In this paper, we present a GMR spin valve sensor designed and fabricated for detecting monodisperse superparamagnetic nanoparticles as potential biomolecular labels. The sensor design will be discussed first, and then we will present experimental results demonstrating the quantitative detection of a few tens to hundreds of magnetic nanoparticles (16-nm Fe3O4) by spin valve sensors at room temperature.

Section snippets

Spin valve sensor

The physical volume of magnetic nanoparticles limits their magnetic moments and hence their magnetic fringing fields. Therefore, the nanoparticle sensor is required to possess high field sensitivity. For that reason, a GMR spin valve has been chosen as the sense element for magnetic nanoparticle detection because of its high sensitivity to low magnetic fields [20]. The spin valve with a synthetic antiferromagnet pinned layer is the preferred structure for its large dynamic range of field, good

Sensor fabrication

The spin valve sensors with synthetic pinned layers and a magnetoresistance (MR) ratio of 11.3% were fabricated at submicron scale by e-beam lithography with a width of about 0.2 μm. Reducing sensor width from micron to submicron size will increase the effective field of the magnetic nanoparticles in the sensor and therefore enhance the sensor's detection sensitivity [7], [11], [12], [13]. The sensor fabrication started with the spin valve thin film deposition on a 4-in. silicon wafer with the

Conclusions

Prototype GMR spin valve sensors have been designed and fabricated at a submicron scale for detection of magnetic nanoparticles intended as biomolecular labels in a magnetic biodetection technology. We demonstrate experimentally the detection of 16-nm superparamagnetic Fe3O4 nanoparticles in various quantities from hundreds down to a few tens by spin valve sensors at room temperature. A linear relationship between sensor signal and nanoparticle quantity has been found. These experiments provide

Acknowledgements

The work was supported by the US Defense Advanced Research Projects Agency (DARPA) through US Navy grant no. N000140210807. The authors acknowledge fruitful discussions with Dr. D.B. Robinson, Dr. J.T. Kemp, Dr. H. Persson, Dr. C.D. Webb, and Prof. R.W. Davis at Stanford University, and support from other BioMagneticICs project members at Stanford and IBM. Assistance from Dr. Chang-Man Park is also gratefully acknowledged.

Guanxiong Li was a PhD student from 1999 to 2004 at Stanford University while this work was conducted. He received his bachelor's degrees in materials science and engineering and in electronics and computer technology from Tsinghua University, Beijing, China, 1991, master's degree in microelectronics and solid-state electronics from Shanghai Institute of Metallurgy, Chinese Academy of Science, 1999, and PhD in materials science and engineering from Stanford University, 2005. Currently, he works

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    Guanxiong Li was a PhD student from 1999 to 2004 at Stanford University while this work was conducted. He received his bachelor's degrees in materials science and engineering and in electronics and computer technology from Tsinghua University, Beijing, China, 1991, master's degree in microelectronics and solid-state electronics from Shanghai Institute of Metallurgy, Chinese Academy of Science, 1999, and PhD in materials science and engineering from Stanford University, 2005. Currently, he works for Western Digital Corporation as a magnetic read head process engineer.

    Shouheng Sun is an associate professor in the Department of Chemistry of Brown University. He received his BSc from Sichuan University in 1984, MSc from Nanjing University in 1987, and PhD from Brown University in 1996 all in chemistry. Before joining Brown, he was a postdoctoral fellow and a research staff at IBM T.J. Watson Research Center from 1996 to 2004. His research interest is in chemical synthesis, self-assembly of monodisperse nanoparticles and their potential applications in biomagnetics, nanocomposites, information storage, and catalysis.

    Robert J. Wilson is a senior research engineer in the Department of Materials Science & Engineering at Stanford University. He received his AB and PhD degrees in physics from the University of California at Berkeley and an MS degree from the University of Chicago. Before joining Stanford, Wilson was with the IBM Almaden Research Center where he conducted research on surface and interface structure, nucleation and growth of thin films of atoms and molecules, and magnetic multilayer structures. His current research interests include nanomagnetics, nanofabrication techniques, and applications of nanotechnology in biology and medicine.

    Robert L. White is a professor emeritus of electrical engineering and of materials science and engineering at Stanford University. He received his BA, MA, and PhD degrees in physics from Columbia University. He was on the scientific staff of Hughes Research Laboratories and of the General Telephone and Electronics Laboratory before joining the faculty at Stanford. He was chairman of the Department of Electrical Engineering from 1981 to 1987, and held the William E. Ayer Endowed Chair in Electrical Engineering. From 1987 to 1990 he was director of the Exploratorium Science Museum in San Francisco. His research interests are in magnetic materials and the physics of magnetism, neuroelectronic prostheses, particularly the cochlear prosthesis for the profoundly deaf, and in the application of magnetic nanoparticles to genetic analysis. He has 160 refereed publications, has written one book, and edited two others. He was founder and director of the Institute for Electronics in Medicine at Stanford and of the Stanford Center for Research on Information Storage Materials. He is a fellow of the American Institute of Physics and of the Institute of Electrical and Electronic Engineers. He has held fellowships or visiting professorships at the University of Tokyo, Oxford University, the Swiss Federal Institute of Technology (ETH), the Toyota Technological Institute, and the National University of Singapore. He has been active in venture capital, and participated in seven start-up companies. He has been a consultant to the US Navy and to a number of companies, and is on a number of advisory and evaluation boards.

    Nader Pourmand currently serves as senior research scientist in the Department of Biochemistry, Stanford Genome Technology Center, at Stanford University and leads the Bio-electrical and Pathogen detection laboratory. His main interest is to discover and develop novel methods for genetic analysis. In 1999, he obtained his PhD in experimental medicine and rheumatology from the Karolinska Institute in Sweden; and then joined the Stanford Genome Technology Center and developed pyrosequencing as a method for viral typing and for multiplex analysis of DNA samples. He has also been involved in Genotyping by a Co-Spotted Single-Base Extension Assay. In 2001, he invented a new chip-based DNA sequencing technology, Charge-Perturbation Signature (CPS): a new technique for DNA sequencing by utilizing charge-detection of extension. In addition to CPS he developed Bioluminescence Regenerative Cycle (BRC) system for nucleic acid quantification. He also refined and applied Molecular Inversion Probe for pathogen genotyping. He recently invented a Branch-Migration assay for short tandem repeats detection in forensic DNA fingerprinting.

    Shan X. Wang currently serves as the director of the Center for Research on Information Storage Materials (CRISM), and is an associate professor in the Department of Materials Science & Engineering and jointly in the Department of Electrical Engineering at Stanford University. He is also with the Geballe Laboratory for Advanced Materials, and is affiliated with Stanford Bio-X Program. He received the BS degree in physics from the University of Science and Technology of China in 1986, the MS in physics from Iowa State University in 1988, and the PhD in electrical and computer engineering from the Carnegie Mellon University (CMU) at Pittsburgh in 1993. His current research interests lie in magnetic nanotechnologies in general and include bio-magnetic sensing, magnetic microarrays, novel magnetic nanoparticles, magnetoresistive materials and spin electronics, magnetic inductive heads and soft magnetic materials, as well as magnetic integrated inductors. He has published over 100 papers and holds 8 patents (issued and pending) on these subjects. He and Alex Taratorin also published a book titled “Magnetic Information Storage Technology” through Academic Press. Wang was among the inaugural group of Frederick Terman Faculty Fellows at Stanford University (1994–1997), and was an IEEE Magnetics Society Distinguished Lecturer (2001–2002).

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