Abstract-This paper reviews our first miniature nuclear magnetic resonance (NMR) system originally reported in [1], [2], which, weighing only 2 kg, is 60 times lighter, 40 times smaller, yet 60 times more spin mass sensitive than a 120-kg state-ofthe-art commercial benchtop NMR system. The miniaturization was made possible by combining the physics of NMR with a high-performance CMOS radio-frequency integrated circuit. The system is aimed at sensing biomolecules such as cancer marker proteins, and represents a circuit designer&apos;s approach to pursue low-cost diagnostics in a portable platform. Our most recent development of even smaller NMR systems [3] will not be reviewed here, as it has yet to be exposed in full through a journal publication first

Donhee Ham

Hakho Lee

Nan Sun

Ralph Weissleder

Yong Liu

CiteSeerX

Silicon RF NMR Biomolecular Sensor — Review
(Invited Paper)
Nan Sun1, Yong Liu1, Hakho Lee2, Ralph Weissleder2, and Donhee Ham1
1Harvard University, Cambridge, MA 02138
2Harvard Medical School, Boston, MA 02114
Abstract—This paper reviews our first miniature nuclear
magnetic resonance (NMR) system originally reported in [1], [2],
which, weighing only 2 kg, is 60 times lighter, 40 times smaller,
yet 60 times more spin mass sensitive than a 120-kg state-of-
the-art commercial benchtop NMR system. The miniaturization
was made possible by combining the physics of NMR with
a high-performance CMOS radio-frequency integrated circuit.
The system is aimed at sensing biomolecules such as cancer
marker proteins, and represents a circuit designer’s approach
to pursue low-cost diagnostics in a portable platform. Our most
recent development of even smaller NMR systems [3] will not
be reviewed here, as it has yet to be exposed in full through a
journal publication first.
I. INTRODUCTION
In recent years we have developed three miniature nuclear
magnetic resonance (NMR) systems in decreasing size [1]–[3],
which are orders-of-magnitude smaller than the state-of-the-
art commercial benchtop NMR system [4]. The works were
made possible by combining the physics of NMR with CMOS
radio frequency (RF) integrated circuits (ICs). The small NMR
systems can be used for biomolecular sensing aimed at low-
cost disease screening.
The purpose of this invited paper is not to report on a new
work, but to review our first miniature NMR system shown
in Fig. 1 [1], [2], the largest among the three systems yet the
first step towards the miniaturization, and its application in
biomolecular sensing. We will leave out our latest development
of the other two systems that are even smaller [3], as these
works still need to be exposed in full through a journal
publication first. This paper, as a review, will extensively
borrow materials from our earlier publication in [1] that
reported on the first miniature NMR system.
When disease develops, biomolecules characteristic to the
disease, such as disease marker proteins, emerge in blood or
urine. The ability to sense these biomolecules would facilitate
disease detection. In pursuit of such benefits for human health-
care, researchers from many areas of science and engineering
are developing a variety of biosensors. Our CMOS RF NMR
biosensor may be viewed as a circuit designer’s way to pursue
low-cost diagnostics in a portable platform.
The underpinning physical phenomenon of our biomolec-
ular sensing method is nuclear magnetic resonance (NMR).
NMR is an energy exchange between RF magnetic fields
and atomic nuclei, such as hydrogen protons, which act like
tiny bar magnets due to their spins. The presence of target
biological objects in an aqueous sample alters the dynamics
of hydrogen protons, which can be detected by performing an
NMR experiment. This NMR-based biosensing method was
developed in 2002 [5] and had been performed using a state-
of-the-art commercial benchtop NMR system [4], which is
bulky and heavy (120 kg).
Fig. 1. Our first miniature CMOS RF NMR biosensor. Reprinted from [1],
[2]
Our first miniature NMR system [Fig. 1] occupies only 2.5
liters and weighs only 2 kg. As compared to the state-of-the-
art commercial benchtop NMR system, it is 60 times lighter,
40 times smaller, yet 60 times more mass sensitive. To achieve
this drastic miniaturization, we took an approach opposite
the convention. The usual way to construct an NMR system,
consisting of a magnet, a sample coil, and a transceiver, is to
use a large magnet to produce a strong NMR signal (larger-
sized magnet yields stronger NMR signal, even with the same
magnetic field), hence relaxing the sensitivity requirement
on the transceiver design, but leading to the bulky NMR
instrumentation. In contrast, to shrink the system size, we
opted to use a small magnet the size of a hamburger [Fig.
1]; and to detect the NMR signal substantially weakened by
the small magnet, we designed a high-performance CMOS
RF transceiver and a separately micro-fabricated coil. As a
biosensor, the mini NMR system detected down to 20 fmol, 1.4
978-1-4244-5271-2/10/$26.00 ©2010 IEEE 121
ng avidin (protein) in a 5-μL sample volume. This detection
threshold can be even further improved, for it is currently
not limited by our transceiver sensitivity, but by the specific
bioassay used [6], [7].
II. CMOS RF TRANSCEIVER IC DESIGN
A. Transceiver Architecture
The architecture of our CMOS RF transceiver is shown in
Fig. 2. The transceiver excites an NMR sample placed on
the planar microcoil [Fig. 1], then subsequently receives a
response NMR signal from the sample/coil system. The coil is
modeled as an inductor, L = 500 nH, in series with parasitic
resistance, R = 4.2Ω [Fig. 2, right].
Suppose an NMR experiment on hydrogen protons in an
aqueous sample. The sample is placed on top of the microcoil,
which altogether is subjected to a DC magnetic field B0 ∼ 0.5
T from the hamburger-sized magnet [Fig. 1]. Subsequently, the
transmitter [Fig. 2, upper half] sends in an RF signal to the
coil, which produces an RF magnetic field inside the sample.
Hydrogen protons in the sample are nucleic magnets, and
when subjected to B0, they have a characteristic frequency:
ωL/2π = 42.6 · B0 = 21.3 MHz. If the RF magnetic field’s
frequency is ωL, it resonantly excites the proton magnets.
After a while, the RF transmission is ceased, and the receiver
is turned on [Fig. 2, lower half]. From this point, the excited
proton magnets electromagnetically interact with the coil,
inducing an AC voltage signal across the coil. This NMR
signal, appearing at node 2© after the matching network, is
a weak signal (available power: 0.5 fW) centered at ωL with a
narrow bandwidth of 1 kHz. It is detected by the heterodyne
receiver.
We set the intermediate frequency (IF) of the heterodyne
receiver, δ at node 3©, to be 3 kHz. This is high enough
to mitigate the mixer 1/f noise, yet low enough to facilitate
the rejection of the out-of-band noise by placing a band-pass-
filter at the mixer output. For frequency down-conversion, two
mixers driven by quadrature oscillator signals are used. The
two outputs from the mixers are digitized by an off-chip ADC
and subsequently processed by an off-chip signal processing
unit to perform image rejection. This image rejection is to
avoid the extra 3 dB degradation in the noise figure (NF) due
to the frequency down conversion.
We use one clock source [Fig. 2, left] to produce both the
excitation signal in the transmitter and the local oscillator (LO)
signal in the receiver, instead of using two separate clocks. The
frequency of our single clock is set at a value 3 kHz larger
than ωL/2π so as to produce the IF of 3 kHz. Therefore the
excitation signal at node 1© is not at ωL, but it can still excite
protons, because the signal transmission time is finite, thus,
the excitation signal has a non-zero bandwidth that is large
enough to include ωL in it. The advantage of this one-clock
scheme is its simplicity: we only need to tune the frequency
of one clock instead of tuning two clocks separately while
keeping their frequency difference to be 3 kHz.
The digital pulse generator is to produce various NMR
pulse sequences (e.g., the CPMG pulse sequence [8]), which
is crucial in practical NMR experimentations.
B. Receiver Design
Fig. 3 shows the detailed schematics of the heterodyne
receiver, which is comprised of a low noise amplifier (LNA), a
variable gain amplifier (VGA), and a double-balanced Gilbert
mixer. When PA is driving the coil, a large excitation signal
appears at the LNA input. In order to protect the receiver
from entering saturation under this situation, we use switches
S1 ∼ S6 to short the load of the LNA and the VGA, and
disconnect the LNA, the VGA, and the mixer.
The LNA is a fully-differential common-source amplifier
with common-mode feedback. To detect the weak NMR signal
(peak-to-peak: ∼100 nV), it is critical to design a highly
sensitive LNA with as low a noise figure (NF) as possible.
To minimize the NF, not only the LNA’s input referred noise
should be minimized, but also an optimum noise matching
should be provided between the LNA and the NMR coil.
First, to minimize the input referred noise of the LNA, we
take the following measures: i) PMOS devices are chosen as
input devices to minimize 1/f noise and substrate coupling
from digital circuits; ii) a large tail current (4 mA) and wide
input transistors (900 μm) are used to boost gm and hence
lower the channel thermal noise; iii) the load transistors are
biased with a large overdrive voltage to reduce their noise
contribution; iv) cascode transistors are added to attenuate
coupling between the local oscillator and the LNA. From
SPICE simulation, the input referred noise of the LNA at ωL
of 21.3 MHz is 1.3 nV/
√
Hz and its voltage gain is 41 dB.
Second, for the optimum LNA-coil noise matching, we
place a capacitor Cm in parallel with the coil [Fig. 3, right],
where Cm resonates with the coil inductance L at ωL. This
resonance network passively amplifies both the signal and the
noise from the coil with voltage gain of Q = 16, where Q is
the coil quality. As Cm has negligible loss as compared to the
coil, this passive amplification introduces inappreciable extra
noise. It enhances both the signal and noise from the coil
beyond the LNA’s input referred noise, and thus, signal-to-
noise-ratio (SNR) is minimally degraded by the LNA, leading
to minimum NF.
The VGA is to handle various signal levels and ensure re-
ceiver linearity. It is a fully-differential amplifier with tunable
loads shown within the two dashed boxed [Fig. 3]. As the
control voltage VC increases from 0 to Vdd, the active loads
undergo transitions from cut-off to pinch-off to triode, leading
to decreasing output impedances and gain. By setting up
different transitions points in the three branches and combining
them in parallel, the overall load impedance is tuned more
smoothly over a wider range of VC as compared to the case
of any single branch is used alone. The gain tuning range of
this VGA is from 0.8 to 22.
The double-balanced Gilbert mixer with active loads exhibit
a gain of 26 dB. Cascode transistors are added to mitigate the
undesired feed-through from the local oscillator to the LNA’s
input path.
122
Digital pulse
generator
LNAMixer VGA
PABuffer Planar microcoil
 L+

I
Mixer
Q

Power
matching
+
Noise
matching
Hilbert
Transformer
DSP
1
2
3
L
 L+ L
L
 L+
2
N
On-chip
clock option
Local
oscillator
R = 4.2 
L = 500 nH
MUX
CMOS IC
Audio amp;
BPF; ADC
Audio amp;
BPF; ADC
Off-chip
clock option
Fig. 2. NMR RF transceiver IC Architecture. Reprinted from [1].
Vb2
Vout CMFB
S2
S3
Vdd
S5
S6
VC
LO
LO
CMFB
S4
ENABLE
Vb2LO
Vdd Vdd
LNAVGAMixer
ENABLE
VC
S1
Vb1 Vb1 Vb1ENABLE
ENABLE
Tunable load Tunable load
NMR
Coil
Cm
R
L
Resonance
matching
(passive
amplification)
Vin
Fig. 3. The receiver chain. Reprinted from [1].
III. EXPERIMENTS
The NMR transceiver chip [Fig. 1] was implemented in
0.18-μm CMOS technology. As we deal with weak NMR
signals, the most important aspect of our design is the receiver
NF, which we obtained by directly measuring the receiver
input referred noise. After feeding an RF signal to the receiver
input (node 2©, Fig. 2), we measured the output at node 3©
using a spectrum analyzer. From this, we extracted the gain
and the output noise of the receiver. By dividing the output
noise by the gain while factoring out the image noise, which is
taken care of by the image rejection architecture [Fig. 2], we
obtained the input referred noise of 1.8 nV/
√
Hz. It is larger
than the SPICE-simulated value of 1.3 nV/
√
Hz, for noise from
the power supply and substrate are not taken into account in
the simulation. From the measured input referred noise and
measured impedance of the coil, we obtain the noise figure of
the receiver. Thanks to the resonance noise matching [Fig. 3,
right], the overall NF is only 0.7 dB.
We assembled the entire NMR system of Fig. 1 by putting
together the RF IC with auxiliary electronics on the printed
circuit board, along with the hamburger-sized commercially-
available magnet and the planar microcoil fabricated using
standard photolithography. A 5-μL aqueous sample is held on
the microcoil inside a microfluidic container mounted on top.
Fig. 4, top shows the measured down-converted NMR signal
in a water proton NMR experiment. The ringings, result of a
specific transmitted pulse sequence (the CPMG pulse sequence
[8]), are the NMR signal. It decays with a characteristic time,
123
T2, which reflects the sample’s internal dynamics and is a key
quantity in our NMR-based biomolecular sensing [5], as will
be seen shortly. From the exponentially decaying envelope of
the signal, shown as the dotted line, T2 = 523 ms is extracted.
The repeated large spikes are the coupling of the transmitted
excitation signal, but they do not compromise the observation
of the conspicuous NMR signal, as they occur at different time
instances.
The physics of NMR prescribes that T2 decreases if mag-
netic nanoparticles [Fe] are suspended in the water. Figure
4, bottom, shows that when 0.17 mM magnetic nanoparticles
(30 nm) are added into the water, the measured T2 decreases
to 60 ms. We also tested our system for various magnetic
nanoparticle concentrations. Experiment results show that the
T2 decreases proportionally as the nanoparticle concentration
increases, which conforms to the NMR theory, affirming our
system’s functionality.
Voltage Signal
at the Mixer Output [V]
Time [ms]
140
0
-6
T = 523 ms2
6
12
0 20 40 60 80 100 120
0
-6
6
1400 20 40 60 80 100 120
Voltage Signal
at the Mixer Output [V]
T = 60 ms2
Time [ms]
Fig. 4. Measured, down-converted echo signals: (top) pure water; (bottom)
water with magnetic nanoparticles (0.17 mM). Reprinted from [1], [2].
We used our system to detect various biomolecules. Figure 5
shows one example, the detection of avidin protein. Magnetic
nanoparticles coated with biotins are put into a 5-μL aqueous
sample. In the absence of avidin [Fig. 5, top], the particles stay
mono-dispersed, yielding T2 = 73 ms. When avidin exists in
the sample, the magnetic particles self-assembled into clusters
around the avidin proteins [5], reducing T2 to 31 ms [Fig. 5,
bottom]. The reduction of T2 indicates the presence of avidin.
The minimum detectable quantity of avidin was 20 fmol and
1.4 ng in the 5-μL sample volume. In comparison to the state-
of-the-art commercial benchtop NMR system [4], our system
is 60 times more sensitive in terms of the absolute detectable
quantity.
0 20 40 60 80 100
Time [ms]
0
-6
6
12
0 20 40 60 80 100
Time [ms]
0
-6
6
Biotin
Avidin
(protein)
T = 73 ms2
T = 31 ms2
Magnetic
nanoparticle
Voltage Signal
at the Mixer Output [V]
Voltage Signal
at the Mixer Output [V]
Fig. 5. Experimental avidin detection. Reprinted from [1], [2].
IV. CONCLUSION
In this paper, we reviewed our first miniature NMR system
that was originally reported in [1], [2]. The miniaturization was
enabled by combining the physics of NMR with CMOS RF
integrated circuits. The NMR system, which can be used for
sensing biological molecules in the low-cost portable platform,
is an addition to the arsenal of biomolecular sensors being
developed for diagnostics purposes.
REFERENCES
[1] N. Sun, Y. Liu, H. Lee, R. Weissleder, and D. Ham, “CMOS RF
biosensor utilizing nuclear magnetic resonance,” IEEE Journal of Solid-
State Circuits, vol. 44, no. 5, pp. 1629-1643, May 2009.
[2] Y. Liu, N. Sun, H. Lee, R. Weissleder, and D. Ham, “CMOS mini nuclear
magnetic resonance system and its application for biomolecular sensing,”
IEEE Int. Solid-State Circ. Conf. Dig. Tech. Papers, pp. 140-141, Feb
2008.
[3] N. Sun, T. Yoon, H. Lee, W. Andress, V. Demas, P. Prado, R. Weissleder,
and D. Ham, “Palm NMR and one-chip NMR,” IEEE Int. Solid-State
Circ. Conf. Dig. Tech. Papers, pp. 488-489, Feb. 2010.
[4] Bruker Optics, “The minispec TD-NMR Analyzers,” [online]:
http://www.brukeroptics.com/minispec.html
[5] J. M. Perez, L. Josephson, T. O’Loughlin, D. Hoegeman, and R.
Weissleder, “Magnetic relaxation switches capable of sensing molecular
interactions,” Nature Biotechnology, vol. 20, pp. 816-820, Aug. 2002.
[6] H. Lee, E. Sun, D. Ham, & R. Weissleder, “Chip-NMR biosensor for
detection & molecular analysis of cells,” Nature Medicine, vol. 14, no.
8, pp. 869-874, August 2008.
[7] I. Koh, R. Hong, R. Weissleder, L. Josephson, “Sensitive NMR sensors
detect antibodies to infuenza,” Angew. Chem. Int. Ed. Engl., vol. 47, no.
22, pp. 4119-4121, 2008.
[8] D. Canet, Nuclear Magnetic Resonance: Concepts and Methods, John
Wiley & Sons, 1996.
[9] N. Sun, T.-J. Yoon, H. Lee, W. Andress, V. Demas, P. Prado, R.
Weissleder, and D. Ham, “Palm NMR and one-chip NMR,” IEEE Int.
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Silicon RF NMR Biomolecular Sensor -Review (Invited Paper)

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Silicon RF NMR Biomolecular Sensor -Review (Invited Paper)

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