WO2008103970A2

WO2008103970A2 - Low-noise wideband preamplifier for fourier transform mass spectrometry

Info

Publication number: WO2008103970A2
Application number: PCT/US2008/054815
Authority: WO
Inventors: Peter B. O'connor; Raman Mathur
Original assignee: Trustees Of Boston University
Priority date: 2007-02-23
Filing date: 2008-02-23
Publication date: 2008-08-28
Also published as: WO2008103970A3

Abstract

An ion cyclotron resonance (ICR) mass spectrometer includes an ICR cell having detection plates generating a detection current signal, detection circuitry generating a digital signal from the detection current signal, and a processor calculating a mass spectrum from the digital signal, wherein the detection circuitry includes a preamplifier having a differential pair of input junction field effect transistors (JFETs) receiving the detection current signal from the ICR cell, a pair of second JFETs in cascode configuration with the input JFETs, and an analog to digital converter generating the digital signal from a differential voltage signal generated by the second JFETs.

Description

LOW-NOISE WIDEBAND PREAMPLIFIER FOR FOURIER TRANSFORM MASS SPECTROMETRY

BACKGROUND

Mass spectrometry has played a key role in the analysis of biological proteins and other compounds of significance. In addition to providing structural information, a mass spectrometer can also be used to study interactions between proteins. However, these studies pose considerable challenges owing to the complexity of the cellular protease. Thus, in time several types of mass spectrometers have evolved to provide a range of solutions to researchers. Some of the popular types are time-of-flight mass spectrometer (TOFMS), ion trap mass spectrometer (ITMS), quadrupole mass spectrometer, and Fourier transform ion cyclotron resonance mass spectrometer (FTICRMS). Among these, FTICRMS has recently emerged as an instrument of choice for the biological studies due to its high mass accuracy, superior mass resolution and wide dynamic range.

Another significant performance parameter of FTICRMS is its limit of detection. Limit of detection is determined by the minimum number of unit charged ions that can be detected reliably in the mass analyzer of FTICRMS, also known as the Ion Cyclotron Resonance (ICR) cell. By reducing the limit of detection, the sensitivity of the instrument in increased. This allows detection of low abundant compounds which often have biological significance. The best which can be done is to be able to detect a single ion with unit charge, commonly referred as unit charge detection sensitivity. Other important implication of improving sensitivity of a FTICRMS are increase in dynamic range and mass accuracy.

In the ICR cell of a FTICRMS, the ions of a sample to be analyzed are excited into coherent cyclotron orbit by the application of a resonant R.F. voltage to excitation electrodes. Coherent rotating packets of ions induce an image charge on detection electrodes of the ICR cell. The induced image current is amplified using a transimpedance detection amplifier. This detection amplifier is typically divided into two stages: (i) a first "preamplifier" stage, which is mounted close to the detection plates of the ICR cell to minimize capacitance, and (ii) a second stage, which is usually placed outside the vacuum. The output of the detection amplifier is sent to a digitizer that converts the analog signal into a digital format. Fast Fourier transform of the digital data yields the frequency domain spectrum of the ion signal. Finally, the frequency spectrum is converted into a mass spectrum using a calibration equation. The detection plates, amplifier and analog-to-digital converter (ADC) constitute the detection circuitry of the FTICRMS.

An equivalent electrical model for the detection scheme in ICR experiments has been presented. In this approach, the resonantly excited coherent ion packet is modeled as a rotating electric monopole. Expressions have been computed for the induced image current and voltage on the plates of a cubic ICR cell using this rotating monopole model. In the derivation it is assumed that the parallel detection plates are infinitely long. This assumption is not typically valid when the dimensions of the cell plates are comparable to the spacing between them. A comprehensive analytical solution for the induced differential charge in an ICR cell with arbitrary geometry has also been derived. Using Green's function, the magnitudes of the Fourier coefficients of the signal induced by an ensemble of ions in a circular orbit have been computed. It has also been known to achieve improved sensitivity in the detection amplifier by use of a junction field-effect transistor (JFET) differential input stage.

SUMMARY

Disclosed is Fourier transform ICR mass spectrometer (FTICRMS) including a detailed discussion of design parameters involved for the ICR detection circuit. A low noise, wide bandwidth differential transimpedance amplifier is described along with performance data from use in a FTICRMS. More specifically, the ICR mass spectrometer includes an ICR cell having detection plates generating a detection current signal, detection circuitry generating a digital signal from the detection current signal, and a processor calculating a mass spectrum from the digital signal. The detection circuitry includes a preamplifier having a differential pair of input junction field effect transistors (JFETs) receiving the detection current signal from the ICR cell, a pair of second JFETs in cascode configuration with the input JFETs, and an analog to digital converter generating the digital signal from a differential voltage signal generated by the second JFETs. The use of JFETs as input transistors along with the second JFETs in cascode configuration provides for desired low-noise amplification of the detection current signal, improving the detection sensitivity of the FTICRMS. BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the invention will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

Figure l is a block diagram of a Fourier transform ion cyclotron resonance (ICR) mass spectrometer according to an embodiment of the present invention;

Figure 2 is a diagram of a model of detection in an ICR mass spectrometer; Figure 3 is a plot of detection voltage versus frequency;

Figure 4 is a schematic diagram of a preamplifier;

Figure 5 is a schematic diagram of a main amplifier;

Figure 6 is a plot of voltage gain versus frequency;

Figure 7 is a plot of voltage noise versus frequency; and Figure 8 (including Figures 8 A and 8B) is a pair of mass spectra obtained using the disclosed preamplifier versus a prior art commercial amplifier.

DETAILED DESCRIPTION

Figure 1 is a block diagram of a FTICRMS. An RF generator 10 generates an RF excitation voltage signal and provides it to excitation electrodes of an ICR cell 12. In the cell 12, the ions of a sample to be analyzed are excited into coherent cyclotron orbit, and the coherent rotating packets of ions induce an image charge on detection electrodes of the ICR cell 12, which are connected to the differential input of a transimpedance detection amplifier 14. The detection amplifier includes a preamplifier 16, normally mounted close to the detection plates of the ICR cell 12 to minimize capacitance, and a main amplifier 18 which is usually placed outside the vacuum. The output of the detection amplifier 14 is sent to an analog-to-digital converter (ADC) 20 that converts the analog signal into a digital format. A processor 22 computes a Fast Fourier transform of the digital data to yield the frequency domain spectrum of the ion signal, and converts this spectrum into a mass spectrum using a calibration equation. The mass spectrum is typically provided to a display or to other input/output devices, including a storage device. The detection plates of the ICR cell 12, the amplifier 14 and the ADC 20 constitute the detection circuitry of the FTICRMS. Figure 2 presents a model of the ICR detection circuitry. Image current Is is induced on the plates of a cubic ICR cell due to cyclotron motion of the ions as given by Eq. 1 below. The theory is based on the work of Shockley who calculated the induced current in electrodes in proximity of a moving charge.

where N is the number of ions with mass to charge ratio m=q rotating in an orbit with cyclotron radius r in a magnetic field of strength B, and d is the distance between the plates of the ICR cell.

Now, the cyclotron frequency, ω_c, is given by Eq. 2.

ω_{c ≡} ^- (2) m

Thus, using Eq. 2 in Eq. 1 : τ ( Nqr λ

^IΛrms)={τsr ^<3)

In reference to the model of Figure 2, the voltage Vs induced on the plates (i.e. at the input of the preamplifier) is given by: V₃ = IARbWXc) (4) where X_c is the reactance due to the total capacitance C at the input of the preamplifier, and Rb is the value of the input bias resistor. The reactance X_c is given by:

^Xc = ^ ω_cC (5)

Hence,

If the bias resistor R_b is selected such that R_b »X_C, then (R_b\ \X_C) ~ Xc. Therefore,

Thus, the r.m.s. induced signal voltage in the ICR cell is given by:

As has been noted, the intriguing aspect of Eq. 8 is the absence of the frequency term ω_c. This independence of induced voltage on frequency (m/z ratio) ensures a flat response of the detection circuit (over a working range in m/z) which makes the quantification of the ion signal simpler (provided that the amplifier has a flat response in the bandwidth of interest). Figure 3 shows a plot of induced voltage with respect to cyclotron frequency for various values of bias resistor, illustrating the above-discussed frequency independence. From Eq. 8, the induced signal voltage V_s is inversely proportional to the total capacitance C at the input of the preamplifier, which includes the detection plate capacitance, stray capacitance of the wires connecting the preamplifier to the detection plates, and the intrinsic capacitance of the FETs used in the circuit of the preamplifier. It is best to minimize this capacitance.

However, if the ICR cell geometry is made smaller to reduce the capacitance, it leads to increased ion density in the ICR cell. This causes space charge effects such as ion coalescence which is detrimental to the mass accuracy and resolving power of the FTICRMS. Moreover, the number of ions which can be efficiently trapped/excited/detected in the ICR cell is smaller for a smaller cell. This causes a reduction in the amplitude of the induced ICR signal.

Similarly, mounting the preamplifier in close proximity of the detection plates to minimize the lead wire capacitance is not always feasible. The ICR cell detection plates are placed in the homogenous high field region of a super conducting magnet. Most of the commercial low-noise FETs don't operate well in such high magnetic fields due to the Hall effect. A possible solution is to design the printed circuit board of the preamplifier such that the channel of the FETs are aligned with the magnetic field. However, this strategy doesn't work for most of the commercial FETs with non- linear channels.

Finally, the intrinsic capacitance of the FETs can be minimized with its respective trade-off which is discussed below. Referring to the electrical model of the ICR detection circuit in Figure 2, the total mean square equivalent noise input voltage is calculated as:

where ni is the total equivalent noise voltage at the input node of the preamplifier, i^ is equivalent Johnson current noise spectral density due to R_b (equal to^4kTAf/R_b ), and Zs is the source impedance due to total capacitance at the input of the preamplifier, equal to 1 =jωC. C includes both cell capacitance C_c and stray capacitance C₅. A typical value of capacitance to ground of the plates of the open cylindrical cell with a 3 inch outside diameter is 20 pF. If the input capacitance of the preamplifier and the connecting wires is 2 pF, the total capacitance C at the input of the preamplifier is 22 pF.

The maximum value of impedance due to this capacitance will occur at the lowest cyclotron frequency of interest, e.g., 10 kHz:

Zs = 530 kΩ (10)

Now, if the bias resistor in the ICR detection circuit is selected such that R_b » Z_s, then

Z R_h

Z +&

From Eq. 9,

^en

4kTAf 9

+ et R, ωjC ωjC

Thus to minimize the noise contribution of the bias resistor, the value of Rb is selected such that:

Rb » Z_s

The maximum value of the bias resistor which can be used in determined by the tolerable DC potential on the detection plates. The leakage current builds up a charge on the input capacitance of the preamplifier which shifts the DC quiescent point of the FETs, eventually driving the inputs to the rails. Also, this build up DC potential on the detection plates can effect the motion of the resonantly excited ions packets in the ICR cell.

As mentioned above and shown in Figure 3, the ICR signal can be modeled as a current source in parallel with a capacitance. The dominant source of noise in such high impedance sensors is the current noise of the input transistors. Thus it is desirable to use Junction Field Effect Transistors (JFETs) at the input stage which have lower current noise compared to bipolar junction transistors (BJTs). Moreover, the low leakage current of the JFETs (on the order of 1 pA) allows a high input bias resistor which helps attenuating the noise further as discussed above. Selection of a particular type of JFET depends primarily on its input gate to source capacitance. The ICR signal arises by integrating the image current over the total input capacitance consisting of cell plates, connecting wires and JFET input capacitance. Hence reducing this capacitance increases the ICR signal which is evident from Eq. 8. Again as the geometry of the ICR cell plates is fixed, it is in interest to minimize the connecting wire capacitance and the JFET input capacitance for maximizing the ICR signal. However, noise in a JFET decreases as the device is made bigger, or, in other words, the smaller the device, the lower the input capacitance and noisier the JFET will be.

Along these lines, it has been shown that an optimal ICR signal to noise ratio is obtained when the input JFET is just large enough so that the sum of its capacitance and the wiring capacitance is equal to the capacitance of the detection plate. If the JFET is small and the net input capacitance is less than the cell capacitance, the JFET can be made bigger to reduce the noise without causing significant reduction in signal, thus improving the overall signal to noise ratio. Similarly, if the JFET contributes to this capacitance such that the net capacitance is greater than the cell capacitance, the JFET can be made smaller and the increase in the signal will be higher compared to that of the noise. Therefore, in the ICR preamplifier design a JFET with a capacitance slightly smaller than the capacitance of the cell plates is selected.

As shown in Figure 1, the ICR detection amplifier 14 is generally divided into two stages - the in-vacuum preamplifier 16 and the second stage or main amplifier 18 which is at atmospheric pressure. The preamplifier 16 is primarily to convert the high impedance of the ICR signal to a low impedance with corresponding current gain. The voltage amplification is done by the main amplifier 18 outside the vacuum which requires more power. This is done because extremely low pressures in the ICR cell 12 prevent efficient cooling of electronic devices, which can cause power de-rating or device failure. Thus most of the signal amplification is done in the second stage 18.

The ICR signal is inherently a differential signal, thus the current amplifier is a differential design. The differential configuration enables the extraction and amplification of the difference between two small signals while cancelling any common signal that both inputs share, such as interference due to 60 Hz AC etc. A cascode configuration is also used to reduce the Miller effect hence enhancing the bandwidth of the preamplifier. A close symmetry (matching) of the components in the two legs of the differential amplifier is required for a high common mode rejection ratio. It is desired to find JFETs with identical DC response curves.

The circuit diagram of the in-vacuum preamplifier 16 is shown in Figure 4. The cascode configuration is used to enhance the bandwidth. In a simple differential amplifier without a cascode, the capacitance at the gate of the input transistor becomes Cgs(l+A)Cdg, where A is the voltage gain from gate to drain. This apparent amplification of the Cdg is due to negative feedback from drain to gate of the input FET. This effect is known as the Miller effect and it is responsible in limiting the bandwidth of such amplifier configuration. In the cascode configuration the voltage gain from gate to drain is almost one at the input FET. Hence the apparent increase in Cdg is avoided. The amplification is achieved by the cascode devices Q3 and Q4 which have a common source connection. Here the voltage at the source (input) is in phase with the drain (output), this eliminating any negative feedback and the Miller effect.

The gates of the cascode devices Q3, Q4 are tied to the sources of the input devices Ql, Q2 to keep the input gate leakage current minimum. The drain to source voltage of Ql and Q2 now becomes the gate to source voltage of the Q3 and Q4. Thus the cascode devices are selected such that their gate to source turn off voltages are greater than the pinch off voltage of

Q3,Q4 in magnitude. This configuration limits the drain to source voltage of Ql, Q2 to a small value which keeps the leakage current negligible of the JFETs.

The emitter follower Q5, Q6 was used for impedance transformation. The low impedance signal on the relatively long lines running from the preamplifier 16 to the main amplifier 18 is less prone to interference pick up and noise coupling. Once the impedance level of the signal is low, a generic low noise operational amplifier (op amp) can be used for further amplification. Such a low noise instrumentation amplifier having standard op amps and used as the main amplifier 18 is shown in Figure 5.

Referring again to Figure 4, JFETs from Philips Semiconductor Inc., BF862, were used as the input transistors Q 1 , Q2 (Figure 4). Matched JFETs U431 from Vishay were used as the cascode devices Q3, Q4. The BF862 has an input capacitance of 10 pF and an input voltage noise of 0.8 nV/rtHz, a fair trade-off between noise and input capacitance. Low leakage JFETs and the above configuration allowed the use of high value input bias resistors, IG ohm, to elevate the signal to noise ratio. BF862's were biased a VDS=I.5 volts and IDS = 8mA giving a gm of approx. 50 mS. The 750 ohm RD provided a voltage gain of approx. 10 in the first stage. The emitter follower Q5, Q6 reduced the signal impedance to approx. 50 ohms, primarily due to the Ik balancing potentiometer and constant current sources Q6 - Q8 (Figure 5) which maintain the Vb_e of Q5 and Q6 the same. This ensures that the current gain (CMRR/differential gain) is identical for each signal line.

The voltage gain versus frequency characteristics of the amplifier 14 are shown in Figure 6. It is always recommended to remove any noise component outside the desired bandwidth using a filter. Thus a 1 lth order Butterworth filter from TTE Inc. was used before the digitizer to remove any unwanted noise outside the frequency range of 1OK Hz to IM Hz (10k Da to 100 Da). The equivalent input voltage noise was also measured using a spectrum analyzer and is shown in Figure 7.

Two FTICRMSs were used to evaluate the low noise ICR amplifier. Both the instruments have open cylindrical ICR cell geometries. The preamplifier 16 was mounted close to the detection plates as described above. The outputs from the in-vacuum preamplifier 16 were connected to the main amplifier 18 via a con- flat BNC electrical feed through.

Several set of mass spectra were obtained to compare the signal to noise ratio of the detection amplifier 14 with a prior art commercial amplifier, which consists of a unity gain source follower as a preamplifier followed by a high gain instrumentation amplifier.

C60 was used as a standard for the studies on a home -built MALDI-FTMS. 1 uM solution of C60 in toluene was desorbed using a Nd-YAG laser from a stainless steel MALDI target plate. The ions were transferred to the ICR cell using a pair of hexapoles driven by high voltage RF oscillators. The ions were allowed to thermally stabilize for 50 mS and then resonantly excited into cyclotron orbits by the application of a broadband RF signal. The induced image current due to the rotation of the coherent ion packet on the detection plate was detected using the amplifier under test and digitized for data processing. The detected signal using the disclosed low noise differential preamplifier 16 demonstrated approximately 10 fold improvement in SNR compared to the commercial amplifier, as evident from Figure 8. Figure 8A shows the signal spectrum obtained using the commercial amplifier, and Figure 8B shows the signal spectrum obtained using the low-noise differential preamplifier 16.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. An ion cyclotron resonance mass spectrometer, comprising: an ion cyclotron resonance (ICR) cell having detection plates operative to generate a detection current signal; detection circuitry operative to generate a digital signal from the detection current signal; and a processor operative to calculate a mass spectrum from the digital signal; wherein the detection circuitry includes a preamplifier which includes: a differential pair of input junction field effect transistors (JFETs) receiving the detection current signal from the ICR cell; a pair of second JFETs in cascode configuration with the input JFETs, the second JFETs operative to generate respective differential voltage signals; and an analog to digital converter to which the differential voltage signal from the second JFETs are coupled, the analog to digital converter being operative to generate the digital signal from the differential voltage signal from the second JFETs.

2. An ion cyclotron resonance mass spectrometer according to claim 1, wherein each of the input JFETs has an input capacitance slightly smaller than a capacitance of a corresponding one of the detection plates to which the input JFET is connected.

3. An ion cyclotron resonance mass spectrometer according to claim 1, wherein: the preamplifier is located in an evacuated area adjacent to the ICR cell; and the detection circuitry further includes a main amplifier located in a non-evacuated area, the main amplifier having the differential voltage signal coupled thereto and generating a corresponding higher-amplitude signal provided to the analog-to-digital converter for conversion to the digital signal.

4. An ion cyclotron resonance mass spectrometer according to claim 3, wherein the preamplifier further includes a pair of emitter- follower transistors coupled to the second JFETs and operative to generate a low-impedance differential output signal provided to the main amplifier.

5. An ion cyclotron resonance mass spectrometer according to claim 1, wherein the input JFETs have gate to source turn off voltages being greater than pinch off voltages of the second JFETs to limit the source voltages of the input JFETs to a sufficiently small value to maintain negligible leakage current of the input JFETs.

6. A preamplifier for use in an ion cyclotron resonance (ICR) mass spectrometer, comprising: a differential pair of input junction field effect transistors (JFETs) operative to receive a detection current signal from a cell of the ICR mass spectrometer; and a pair of second JFETs in cascode configuration with the input JFETs, the second JFETs operative to generate respective differential voltage signals for coupling to an analog to digital converter of the ICR mass spectrometer.

7. A preamplifier according to claim 6, wherein each of the input JFETs has an input capacitance slightly smaller than a capacitance of a corresponding one of detection plates of a cell of the ICR mass spectrometer to which the input JFET is connected.

8. A preamplifier according to claim 6, wherein the preamplifier further includes a pair of emitter-follower transistors coupled to the second JFETs and operative to generate a low- impedance differential output signal.

9. A preamplifier according to claim 6, wherein the input JFETs have gate to source turn off voltages being greater than pinch off voltages of the second JFETs to limit the source voltages of the input JFETs to a sufficiently small value to maintain negligible leakage current of the input JFETs.