Peering inside a portable, $200 cancer detector, part 1

Jim MacArthur, Electronic Instrument Design Laboratory, Harvard University -June 09, 2011

Peering inside a portable, $200 cancer detector imageAs part of a project to design the electronics for a portable, low-cost cancer detector, I had to understand NMR (nuclear magnetic resonance), a measurement technique that excites and measures the spin precessions of atomic nuclei. I also relied on the expertise of Hakho Lee, PhD, and David Issadore, PhD, two researchers at Massachusetts General Hospital’s Center for Systems Biology. Lee had been using magnetic-relaxation switching to explore ways to reduce the size and bulk of an NMR machine to the point at which it could be carried into the field to perform medical diagnostics.

Lee had refined an NMR-based technique for detecting tuberculosis-specific proteins, using a fist-sized permanent magnet and a rack full of electronics. My task was to squeeze that rack into a book-sized unit. The electronics box needed to create a string of RF pulses of precisely controlled frequency in the range of 20 to 30 MHz, and the phase between the first and subsequent pulses also had to change by a precisely controlled amount. This discussion requires some background on NMR techniques.

NMR 101

“NMR” refers to any of several measurement techniques that excite and measure the spin precessions of atomic nuclei. Think of a proton as a sphere with its charge uniformly distributed throughout. The proton’s spin can be understood as making it rotate at a fixed rate. This rotation makes every bit of charge move in a circle. Then, analogous to current in a solenoid, these moving charges create a magnetic field, or “moment,” that aligns on the spin axis. As with a macroscopic magnet, this magnetic moment tends to align with an externally applied magnetic field.

Just as perturbing a gyroscope makes it precess around the axis of the external gravitational field, perturbing a proton with a burst of RF (radio-frequency) energy at a certain frequency in the presence of a magnetic field makes its moment precess at the same frequency. This resonant frequency, the Larmor frequency, is a function of the magnetic-field strength in the proton’s neighborhood. Irish physicist and mathematician Joseph Larmor in 1896 proposed the Larmor frequency, which stipulates that a magnetic moment in a magnetic field tends to align with that field. As the proton’s magnetic moment gradually realigns with the external magnetic field, the proton emits RF energy, again at its Larmor frequency.

Not only protons but also many atomic nuclei—those possessing an odd number of protons or neutrons—have spin, with different Larmor frequencies. Hydrogen’s frequency, for example, is 42.58 MHz/tesla. One tesla equals 10,000 gauss; one gauss is approximately equal to the earth’s magnetic-field strength. Nitrogen’s frequency is 3.09 MHz/tesla. Conversely, the common isotopes of oxygen and carbon have no net spin; therefore, NMR cannot detect them.

In NMR spectroscopy, each element has a unique frequency, and nearby atoms slightly shift a given atom’s Larmor frequency, making it possible to infer the molecular structure of a sample (Reference 1). NMR spectroscopy’s success depends on correctly interpreting tiny changes in Larmor frequencies, which themselves are functions of the surrounding magnetic field. As such, the technique requires care in creating a uniform and stable magnetic field.

In addition to determining a proton’s Larmor frequency, the RF signal also provides the two time constants of the decay in spin precession. After a proton is perturbed, it relaxes to bulk thermal equilibrium with a time constant of T1. Interaction with neighboring spins causes a shorter time constant, T2. These interactions detune the individual precessions, causing destructive interference and shortening the decay time.

T2 describes the immediate magnetic environment of each nucleus and, thus, its molecular composition; T2 also provides information about the inhomogeneity of the bulk magnetic field. The greater the inhomogeneity, the more the individual Larmor frequencies will interfere and the faster the RF signal will decay. In all but the most carefully controlled magnetic fields, the bulk field’s inhomogeneity effects completely overwhelm the more interesting information about a proton’s immediate neighborhood. You can solve this problem using spin echo, an elegant technique, which works as follows.

Start by sending an RF pulse with enough energy to bring the precession angle of the magnetic moments down to 90° with respect to the bulk magnetic field. At first, the precessions are all in phase with each other, with emitted RF at a maximum. Nearly immediately, however, the Larmor frequencies cause the precessions to dephase. After a few milliseconds, the dephasing reaches its maximum, and the net radiated RF is consequently low.

Next, send another RF pulse that is twice as long as the original. Because the first pulse rotates each magnetic moment by 90°, the second pulse rotates it 180° more. To picture what happens next, imagine holding a closed paper fan before your face and then slowly opening it to represent the dephasing process. The righthand part of the fan represents the faster moments, and the lefthand part represents the slower moments. Now, flip the fan around. The faster moments are now on the left; they begin catching up with the slower moments, closing up the fan and restoring the RF signal.

Peering inside a portable, $200 cancer detector figure 1

You can repeat this process until the precessions completely decay (Figure 1). By plotting the decay of the peaks of the echoes, you can get an accurate assessment of T2.

Peering inside a portable, $200 cancer detector figure 2This article provides only a cursory treatment of NMR, using classic analogies to describe an inherently quantum effect. However, my goal was to provide a taste of the engineering issues. Most of the Larmor frequencies of interest are in the decade between 10 and 100 MHz, which, from an engineering standpoint, is a good place to be because lots of earlier RF-design concepts are applicable. Although the design of the receiver chain isn’t trivial, for example, it’s a piece of cake compared with tuning in and identifying short-wave radio signals from thousands of miles away.

The SNR (signal-to-noise ratio) increases with the static magnetic field, so keep the field as high as possible. For large samples, this means using a massive magnet with supercooled coils. For small samples, on the other hand, you can create fields larger than 1 tesla with a handheld permanent magnet. The small magnet in the DMR-3, the official name for this instrument, creates a roughly 0.5-tesla field (Figure 2). Relaxation times are on the order of a few milliseconds to a few seconds. Demodulated signals range to tens of kilohertz; you must acquire data at 100 kHz, for example, for a second or so. This is not, in other words, a taxing data-acquisition problem.

Identifying the problem

While I was working on this project, Lee and Issadore were working on their goal of making the NMR portable. In pursuit of this goal, Lee used magnetic-relaxation switching, which binds magnetic nanoparticles to proteins by first binding the nanoparticles to protein-specific antibodies, which in turn bind to proteins. Peering inside a portable, $200 cancer detector figure 3Once these nanoparticles find the target proteins, they clump together, significantly decreasing the spin-relaxation time of nearby atoms. In other words, clumped nanoparticles translate to a shorter T2.

My design needed to demodulate the returned signal at the RF frequency and then digitize it at 100,000 samples/sec for several seconds. Several stacked runs’ results would be transmitted to a host computer for analysis. All pulse timing needed to be accurate to 1 μsec or better. The host computer controls all parameters over USB (Universal Serial Bus)- and asynchronous-interface ports. The box had to be rugged and portable, and the first deployment would be in Africa (references 2 and 3) in three months.

Peering inside a portable, $200 cancer detector figure 4Designing the system

The package for the system is a Lansing Instrument MicroPak enclosure. The top cover is replaced by a custom-milled piece of aluminum, doing double duty as a heat sink for the RF transmitter and a quiet enclosure for the RF-receiver chain. The instrument contains four PCBs (Figure 3). The controller, ADC, and DDS (direct-digital-synthesizer) boards live in the bottom section, and the new board containing the RF-receiver signal chain is up top (Figure 4). The controller board includes a Texas Instruments TMS320F28235 Delfino DSC (digital-signal controller), an ISSI (Integrated Silicon Solution Inc) IS61WV102416 asynchronous 1M-word×16-bit SRAM, and an FTDI (Future Technology Devices International) FT245 USB-interface chip.

The Delfino DSC performs speedy, 32-bit math and I/O operations, and it comes with an array of peripherals perfect for instrumentation, including high-resolution PWMs (pulse-width modulators) and time stampers, UARTs (universal asynchronous receivers/transmitters), CAN (controller-area-network) circuitry, and DMA (direct-memory-access) controllers. Most important, it features full silicon support for runtime debugging—not just for setting breakpoints but also for viewing, altering, and logging memory and register space when the processor is running at full speed.


Continue reading this article in "Peering inside a portable, $200 cancer detector, part 2."


Acknowledgment

The author would like to thank Hakho Lee and his talented team at the Massachusetts General Hospital Center for Systems Biology, especially physicist Dave Issadore and programmer Changwook Min. Thanks also to Keith Brown of Harvard SEAS for his NMR tutelage, and to Al Takeda for photographing the DMR-3 viscera.


References
  1. Reusch, William, “Nuclear Magnetic Resonance Spectroscopy,” Michigan State University.
  2. Haun, Jered B; Cesar M Castro; Rui Wang; Vanessa M Peterson; Brett S Marinelli; Hakho Lee; and Ralph Weissleder, “Micro-NMR for Rapid Molecular Analysis of Human Tumor Samples,” Science Translational Medicine, Volume 3, Issue 71, Feb 23, 2011, pg 71ra16.
  3. Issadore, David; Changwook Min; Monty Liong; Jaehoon Chung; Ralph Weissleder; and Hakho Lee, “Miniature magnetic resonance system for point-of-care diagnostics,” Lab on a Chip, May 5, 2011.

For More Information
    
Analog Devices
Apple Computer
Bergquist
FTDI
Harvard University
ISSI
Lansing InstrumentCorp
MassachusettsGeneral HospitalCenter for SystemsBiology
MathWorks
Mini-Circuits
National Instruments
Texas Instruments
Xilinx
  


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