Abstract:
A detector suitable for mass spectroscopy uses a thin membrane that converts the kinetic energy of impinging molecules into corresponding photons, the latter detected with a suitable photosensor. The arrival of molecules at the membrane is detected by detection of the corresponding photons.

Description:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     This invention was made with government support under FA9550-08-1-0337 awarded by the USAF/AFOSR. The government has certain rights in the invention. 
    
    
     CROSS REFERENCE TO RELATED APPLICATION 
     BACKGROUND OF THE INVENTION 
     The present invention relates to mass spectrometers and the like and in particular to a detector suited for, but not limited to, the detection of large ionized molecules in a mass spectrometer. 
     Mass spectrometers are analytic instruments that may provide for the precise measurement of the mass of molecules. Generally, the molecules to be measured are given an electrical charge and then accelerated by an electrical field. The velocity of their acceleration will be generally proportional to the mass-to-charge ratio (m/z) and so for a given and known charge the mass may be precisely determined by a charge, velocity, or energy measurement. 
     One method of determining velocity is the use of a “sector” type analyzer, which bends the trajectories of the charged particles using a magnetic field. When the particles exit the magnetic field, the angle of their trajectories (and spatial separation at a measurement point) will be in proportion to m/z and may be measured by a series of spatially separated collectors. 
     An alternative detection system uses a “time of flight” analyzer in which relative velocities of different molecular species are deduced based on the time it takes them to reach a detector. Common detectors used for time of flight analysis include so-called “Faraday cups” which are conductive metal cups, which catch charged particles and are attached to sensitive electrical amplifiers and “dynode” or microchannel detectors, which provide an amplification of received charge through electron multiplier techniques. 
     Mass spectrometry is increasingly applied to extremely large molecules, for example, proteins, that may be ionized by various techniques such as matrix assisted laser desorption/ionization (MALDI) in which the fragile proteins are protected with a matrix material that is struck by a laser beam. The matrix absorbs the energy of the beam and is removed from the protein while transferring a charge to the protein. 
     The large mass of proteins and similar bio-molecules decreases the sensitivity of a time of flight spectrometer because the velocity of the proteins is lower and thus the difference between velocities of large masses is less. In addition, common microchannel detectors experience a decrease in secondary electron yield with increasing ion mass. 
     U.S. Pat. Nos. 8,274,059; 8,507,845; and 8,686,375, all assigned to the same assignee as the present invention and hereby incorporated by reference, teach detector systems for large ions that provide detector membranes that convert the kinetic energy of the impinging ions, at a front surface of the membrane, into electrons ejected from the rear surface of the membrane by field emission and/or secondary electron emission. The ejected electrons may be then detected by a microchannel plate. By combining the membrane in front of the microchannel plate, improved sensitivity to large molecules may be obtained. 
     SUMMARY OF THE INVENTION 
     The present invention provides a detector that incorporates a thin membrane converting the kinetic energy of molecules impinging on its front surface into photons emitted through a rear and/or front surface. The photons are detected and converted to an electrical signal. 
     By using photons as a detection intermediary, it is believed that greater sensitivity to the detection of large molecules may be realized, in part, through greater signal-to-noise ratio of the detected signal. Photon intermediaries may further permit improved spatial discrimination with respect to the point of impingement of the molecule on the membrane, information that can be valuable for sector-type mass spectroscopy applications. 
     In one embodiment, the invention provides a detector that may detect impinging molecules. The detector includes a membrane positioned to receive impinging molecules at a front face and provides a structure converting the kinetic energy of the impinging molecules to light photons emitted from a rear or front face of the membrane. An electronic photosensor is positioned to detect photons from the membrane to provide an electric signal corresponding to receipt of impinging molecules. 
     It is thus a feature of at least one embodiment of the invention to provide light-mediated detection of the kinetic impact of large molecules, a detection mechanism that may be more sensitive to the impact of large molecules and/or which may provide better spatial sensitivity. 
     The membrane may be structured to provide room temperature light emission from at least a 5 kDa molecule impinging on the membrane with the kinetic energy of 25 keV. 
     It is thus a feature of at least one embodiment of the invention to provide a structure that may allow the detection of single large molecule impacts. 
     The membrane dimensions may be constrained to prevent kinetic energy of the impinging ionized molecules from being dissipated as heat without stimulation of electrons between quantum states. 
     It is thus a feature of at least one embodiment of the invention to promote photon emission over thermal energy dissipation by control of the membrane structure size. 
     The membrane may provide at least one quantum-well defining quantum states through which electrons may be promoted by the kinetic energy of the impinging molecule and in which electrons may decay to provide radiative relaxation emitting the photons. 
     It is thus a feature of at least one embodiment of the invention to promote photon emission stimulated by phonons through the use of a quantum-well structure. 
     The membrane may include a semiconducting material. 
     It is thus a feature of at least one embodiment of the invention to employ a material that can be fabricated using well-established integrated circuit techniques to produce thin membranes and/or heterostructures. 
     The membrane may provide an assembly of different materials producing at least one quantum-well, the quantum-well defining quantum states through which electrons may be promoted by the kinetic energy of the impinging molecule and through which electrons may decay to provide radiative relaxation emitting the photons. 
     It is thus a feature of at least one embodiment of the invention to provide a simple method of fabricating quantum-wells using different materials, for example, semiconductor materials of different bandgap levels. 
     The membrane may provide two quantum-wells proximate to each other to permitting tunneling therebetween. 
     It is thus a feature of at least one embodiment of the invention to provide a dual coupled quantum-well structure that may permit improved sensitivity. 
     The detector may employ electrical conductors adjacent respectively to the front and rear surface of the membrane to allow the imposition of an electrical field therebetween. 
     It is thus a feature of at least one embodiment of the invention to provide an energy offset between quantum states of the two adjacent quantum-wells to provide a method of supplying electron-hole pairs to the quantum-wells from an external energy source such as may promote sensitivity. 
     The photosensor may provide for multiple channels selectively receiving photons from different portions of the rear face to identify a location of photon emission caused by an impinging molecule over an area of the membrane. 
     It is thus a feature of at least one embodiment of the invention to provide a spatially discriminating detector that can determine a location on the membrane where the molecule strikes. 
     The photosensor may provide at least one electron multiplier. 
     It is thus a feature of at least one embodiment of the invention to employ an extremely sensitive light detector to enhance sensitivity of the device. 
     The impinging molecules may be ionized. 
     It is thus a feature of at least one embodiment of the invention to provide a detector suitable for use with ionized molecules in mass spectroscopy. 
     The detector may include an electronic computer executing a stored program and communicating with the detector to record the quantity of molecules striking the front face. 
     It is thus a feature of at least one embodiment of the invention to permit sensitive experiments in which molecule arrivals must be quantified. The invention contemplates that individual molecule strikes may be detected. 
     The detector may further include an assembly for receiving and ionizing molecules for analysis and at least a first and second electrode for accelerating ionized molecules received from the assembly along a path directed to the membrane. The electronic computer may execute the stored program to output a spectrograph. 
     It is thus a feature of at least one embodiment of the invention to provide an improved mass spectrograph suitable for measuring small quantities of large molecules. 
     These particular objects and advantages may apply to only some embodiments falling within the claims and thus do not define the scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a simplified diagram of a matrix assisted laser desorption/ionization, time of flight (MALDI-TOF) mass spectrometer such as may be used with the detector of the present invention; 
         FIG. 2  is a simplified enlarged cross-section of the detector of  FIG. 1  having a membrane array positioned in front of a photodetector array, and further showing in an inset, a cross-sectional detail of one membrane array element; 
         FIG. 3  is a perspective, fragmentary view of the membrane array of  FIG. 2  with an expanded cross-sectional view of a membrane and its supporting array structure for one membrane element; 
         FIG. 4  is a perspective fragmentary view of the membrane element of  FIG. 3  showing attachment points for biasing voltage;  FIG. 5  is a simplified cross-sectional view of one embodiment of a membrane element providing for coupled quantum-wells, the cross-sectional view aligned with a quantum-well diagram showing the energy states of the quantum-wells; and 
         FIG. 6  is a fragmentary diagram of the system of claim  1  configured to detect light from both a front and rear surface of the membrane array 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     Referring now to  FIG. 1 , an example mass spectrometer  10  suitable for use with the present invention may include an ion generator  12 , for example, providing an introduction zone  14  into which matrix treated molecules  16  may be introduced and targeted by a laser  18  to provide a source of ions  20 . The ions  20  may be large molecules such as proteins, peptides, oligonucleotides and the like, that may be difficult to detect by conventional techniques. 
     The ions  20  may be accelerated along a travel axis  22  by means of various accelerating plates, for example, a repeller plate  24 , positioned on a rear side of the introduction zone  14  and an attractor plate  26  positioned on the front side of the introduction zone  14  (in the direction of desired ion travel) with the attractor plate  26  having a relatively lower electrical potential than the repeller plate  24  (for positive ions). An accelerator plate  28  behind the attractor plate  26  may further accelerate the ions  20  to a desired speed. The ions  20  may be focused by a set of steering plates  30  as understood in the art to enter a flight tube  32  providing a zone when the ions  20  of different velocities may further separate, improving the resolution of the system. The ions may then enter a detector  34 . 
     The detector may provide electrical signals to processing electronics  36  including, for example, amplifiers, filters and other signal processing elements understood to those of ordinary skill in the art. Output from the processing electronics  36  may be provided to an electronic computer  38  having a stored program  40  that may process the received electrical signals to provide a spectrograph output  42 , for example, on a display monitor  44  providing information about the mass of the ions  20 . Generally the electronic computer  38  will include a fast (bandwidth ˜500-MHz) data acquisition board which allows the electronic computer  38  to operate manner of a high speed oscilloscope. 
     Referring now to  FIG. 2 , the detector  34  of the present invention provides a membrane array  46  extending in a plane generally perpendicular to the axis  22 . The membrane array  46  includes multiple array elements  48  arranged in rows and columns, each of which may receive one or more impinging ions  20  accelerated against a front surface of the array element  48 . As will be discussed in greater detail below, the kinetic energy of the impinging ions  20  generates corresponding output photons  50   a  radiating from a rear surface of the array element  48  to be received by a photodetector  52 . As will be discussed below, additional output photons  50   b  may radiate from a front surface of the array element  48 . 
     In one embodiment, the photodetector  52  may be a multichannel light amplifier such as a photomultiplier array (such as when using avalanche photodiodes) able to detect and spatially locate photons  50  from one or more ions  20  over its area. In this way the detector  34  may distinguish in time and/or space closely adjacent impacts by impinging ions  20 . 
     Signals from the photodetector  52  are output from the detector  34  to the processing electronics  36  described above. 
     Referring still to  FIG. 2 , each array element  48  provides a thin membrane  54  supported only at its periphery and sized so that the kinetic, which is transferred into acoustic energy (phonons)  56  of the impinging ion  20  is constrained so that it is not dissipated (laterally) as heat before the stimulation of the membrane material necessary to produce the photon  50 . In one embodiment, the membrane  54  has a thickness  57  between five nanometers and 15 micrometers. In another embodiment the membrane  54  has a thickness between 20 nanometers and 50 nanometers. 
     The constraint dimensions of the membrane  54  ensure that light photons  50  are generated substantially only by radiative decay of electrons between quantized states and not by more conventional thermal emission. In this regard it is expected that the acoustic energy  56  will be transferred by high-energy ballistic phonons. As will be discussed below, the membrane  54  may be constructed of one or more semiconductor materials stacked together and providing interfaces perpendicular to the axis  22 . 
     Referring now to  FIG. 3 , the membranes  54  of each array element  48  may be supported in the membrane array  46  by crossing supporting mullions  58  and muntins  60  providing a rectangular frame around each membrane  54 . The mullions  58  and muntins  60  are in turn supported within an outer peripheral frame  62  comprised of upper and lower rails  64  and left and right stiles  66 . The extremely thin membrane  54  may thus be adequately supported around its entire periphery by a thicker surrounding structure and may be fabricated by selectively etching from a larger structure. For example, photochemical etching of a substrate material to expose the membrane  54  and preserve the mullions  58 , muntins  60 , and outer frame  62 , may be performed. The fabrication process may be generally analogous to that described in U.S. Pat. No. 8,274,059 cited above and may make use of photolithographic manufacturing processes known in the art. 
     For example, the supporting structure of the mullions  58  and muntins  60  and outer peripheral frame  62  may be a silicon substrate of a silicon-on-insulator (SOI) wafer having a layer of silicon dioxide separating the silicon substrate structure from an upper silicon layer on which the membrane  54  is fabricated, for example, by physical or chemical vapor deposition or other similar techniques. 
     Referring now to  FIGS. 4 and 5 , in one embodiment, the membrane  54  may comprise multiple stacked internal layers  70  extending generally perpendicular to axis  22 . The multiple stacked internal layers  70  may be clad with a front conductive layer  72  receiving the ions  20  and a rear conductive layer  74  through which the photons  50  are emitted. The front conductive layer  72  and rear conductive layer  74 , for example, may be each a light-transmissive, five nanometer thick layer of Si or GaAs doped to a conductive state as is understood in the art and attached to respective metallization electrodes  78 . The metallization electrodes  78  may be displaced along opposed edges of the membrane  54  so as not to obstruct exiting light photons  50  at the rear face or impinging ions  20  at the front face. The electrodes  78  may be attached to an electrical DC voltage source  79  also connected in parallel to all other membranes  54  and imposing an electric field along axis  22  through the membrane  54  as will be described below. 
     In one embodiment, the multiple stacked internal layers  70  provide quantum heterostructures creating two adjacent quantum-wells  80  and  82  caused by the confinement of charge carriers in thin well layers  84  and  86  by dissimilar barrier layers  90 ,  92  and  94 . Specifically, a frontmost barrier layer  90  may fit against a front face of a first well layer  84 , and a barrier layer  92  may be positioned between well layers  84  and  86 , and barrier layer  94  may fit against a rear face of well layer  86 . 
     It will be appreciated that the structure of  FIG. 4  may also be used in a fashion inverted from what is shown when accompanied by a simple reversal of the polarity of the voltage from source  79 . In this case, the ions  20  will be received downward on the upper surface of the membrane as depicted. 
     In one embodiment the well layers  84  and  86  may be eight nanometer thick layers of group III/V semiconductors, for example, gallium arsenide (GaAs), while barrier layer  92  may be a five nanometer layer of aluminum gallium arsenide (AlGaAs), and barrier layers  90  and  94  may be each thirty nanometer thick layers of AlGaAs. The AlGaAs of barrier layers  90 ,  92  and  94  will have similar lattice constants to GaAs of well layers  84  and  86  but a substantially larger bandgap thereby constraining charge carriers against moving through the boundary by misalignment of the energy bands. 
     The barrier layer  90 ,  92  and  94  constrain the movement of charge carriers in the well layers  84  and  86  to a small dimension that generates in each of the well layers  84  and  86  a quantum-well enforcing a set of discrete energy levels or bands  100  and  102  within the quantum-well layers  84  and  86  with a sharp density of states characteristic of quantum-wells. 
     The electrical biasing provided by the voltage source  79  of  FIG. 4  elevates the energy bands  100   a  and  102   a  of well layer  84  with respect to the energy bands  100   b  and  102   b  of well layer  86 . By adjusting the electrical voltage, the two quantum-wells  80  and  82  may be tuned to provide a resonant electronic transition between quantum-well  80  and quantum-well  82 . 
     While the inventors do not wish to be bound by a particular theory, the resulting structure is believed to be capable of receiving the acoustic energy  56  from a striking ion  20 , passing through conductive layer  72  and barrier layer  90 , to cause an excitation of electrons  104  in the quantum-well  80  formed by well layer  84  from energy band  100   a  to energy band  102   a . Energy tunneling  106  of the electrons  104  through barrier layer  92  into well layer  86  may then occur, and then the electrons  104  may spontaneously decay from energy band  102   b  to energy band  100   b  causing a radiative emission of photons  50 , the latter passing through barrier layer  94  and conductive layer  74 . 
     The double quantum-well structure is believed to provide increased sensitivity but may alternatively be replaced with a single layer structure omitting barrier layer  92  and well layer  86 . Generally the amount of energy required to modify photon emissions should be much lower than that needed to generate field-emissions of the prior art. It is expected that the membrane may provide room temperature light emission from a 5 kDa to 5 MDa molecule impinging on the membrane with the kinetic energy of 25 keV. 
     Electrical voltage of voltage source  79  provides an independent source of charge carriers increasing the sensitivity of the system. An alternative approach may use optical carrier injection from a laser or the like. The electrical voltage may also be used to tune the detector sensitivity. 
     Referring now to  FIG. 6 , the membrane array  46 , upon receipt of ion  20  may emit light both from a rear surface (photon  50   a ) as has been discussed to be received by photodetector  52   a . In addition, the membrane array  46  may emit light from the front surface (photon  50   b ) which may be detected also or alternatively by a corresponding photodetector  52   b  positioned out of the line of travel of the ion  20 . In this case, signals from both the photodetectors  52   a  and  52   b  may be received by the computer  38  for independent or joint processing. 
     The present invention is not limited to a mass spectrometer of the MALDI-TOF design as described in simplified form above but may be used in any time-of-flight mass spectrometers including those that provide for reflection of the ions and other features well known in the art. Although the present detector is particularly desirable for large molecules such as proteins where high temporal resolution is required, it may find use in general-purpose spectroscopy as well. 
     Certain terminology is used herein for purposes of reference only, and thus is not intended to be limiting. For example, terms such as “upper”, “lower”, “above”, and “below” refer to directions in the drawings to which reference is made. Terms such as “front”, “back”, “rear”, “bottom” and “side”, describe the orientation of portions of the component within a consistent but arbitrary frame of reference, which is made clear by reference to the text and the associated drawings describing the component under discussion. Such terminology may include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first”, “second” and other such numerical terms referring to structures do not imply a sequence or order unless clearly indicated by the context. 
     When introducing elements or features of the present disclosure and the exemplary embodiments, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of such elements or features. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements or features other than those specifically noted. It is further to be understood that the method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It is also to be understood that additional or alternative steps may be employed. 
     References to “a microprocessor” and “a processor” or “the microprocessor” and “the processor,” can be understood to include one or more microprocessors that can communicate in a stand-alone and/or a distributed environment(s), and can thus be configured to communicate via wired or wireless communications with other processors, where such one or more processors can be configured to operate on one or more processor-controlled devices that can be similar or different devices. Furthermore, references to memory, unless otherwise specified, can include one or more processor-readable and accessible memory elements and/or components that can be internal to the processor-controlled device or external to the processor-controlled device, and can be accessed via a wired or wireless network. 
     It is specifically intended that the present invention not be limited to the embodiments and illustrations contained herein and the claims should be understood to include modified forms of those embodiments including portions of the embodiments and combinations of elements of different embodiments as come within the scope of the following claims. All of the publications described herein, including patents and non-patent publications, are hereby incorporated herein by reference in their entireties.