Method for producing gas-phase metal anions

Monatomic metal anions are generated in the gas phase by collision-induced dissociation of the anions [26] of a dicarboxylic acid salt of the metal. This method is applicable to a number of metals, including sodium, potassium, cesium, and silver. The metal anions produced in this way can subsequently be stored in an ion trap [88] or transmitted as a focused beam [52]. The metal anions of this invention undergo collisional cooling and have low kinetic energy, which distinguishes them from ions produced by other high energy processes (with kinetic energy in excess of 1 keV). Metal anions so produced can be used to pattern nanoscale features on surfaces [56], used as electron transfer agents or reducing agents in ion-molecule reactions, or used for surface [122] modification of biomaterials [124].

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not applicable.

FIELD OF THE DISCLOSURE

The present disclosure pertains to the field of generating gas-phase ions and, more specifically, to a method for generating gas-phase metal anions that have low kinetic energies and are suitable for use in mass spectrometry, chemical synthesis, imaging and patterning of nanoscale surface features.

BACKGROUND OF THE INVENTION

Prior to the present disclosure, methods were known for generating metal anion beams with high kinetic energies (e.g., kinetic energies in a range of 1-1000 keV). However, for numerous processes, it would be desirable to have access to low-energy gas-phase metal anions generated under mild conditions. As used herein, “mild” refers to conditions that do not impart a large excess of kinetic energy to the anion beyond the energy needed to produce it. In the field of mass spectrometry, processes operating under such conditions may also be referred to as “soft”, as opposed to “hard”, ionization processes. A practical reason for preferring mild (or “soft”) processes is that the ions formed from such processes often exhibit a different gas-phase chemistry than those produced under more energetic (or “hard”) processes. A method for efficiently generating low-kinetic-energy metal anion beams using bench-top laboratory equipment has potential applications for the production of nanoscale materials, for the production of reagent ions to induce chemical transformations in gas phase-microreactors, for surface analysis, for imaging science, for medical research, and for uses in other areas of science and engineering. For example, metal ion beams are essential for applications in the field of accelerator mass spectrometry for the analysis of rare isotopes and trace elements. Gas-phase anions with low electron affinities (e.g., alkali metal anions, or “alkalides”) also have important applications as electron transfer agents in an emerging technique for protein structure elucidation called electron transfer dissociation (ETD). The production of alkali metal anions is also a required first step for some nuclear physics research experiments.

BRIEF SUMMARY OF THE DISCLOSURE

The present disclosure addresses a process for producing monatomic gas-phase metal anions having low kinetic energies. In one aspect, the invention comprises a process for producing monatomic gas-phase metal anions from organic salts of the metal. In an embodiment of this process, the organic salt is a metal dicarboxylate salt. In an embodiment of this process, a conventional electrospray ionization (“ESI”) source is used to generate a nebulized spray of charged droplets containing dicarboxylate anions and metal cations from a solution of a metal dicarboxylate salt in a solvent or a mixture of solvents. Singly-charged metal dicarboxylate anions generated by the ESI source are selected in an electromagnetic separation step, and dissociated in a collision cell to form anions of the metal. The metal anions are isolated from among other reaction products in a second electromagnetic separation step, and collimated into a beam of metallic anions.

In a second aspect of the invention, a method of patterning nanoscale structures onto a substrate includes the step of impacting a beam of gas-phase metal anions onto a surface of the substrate, and moving the substrate so that the gas-phase metal anions are deposited on the surface in a pre-determined pattern.

In a third aspect of the invention, a method of elucidating the structure of a large molecule includes a step of impacting a beam of gas-phase metal ions into a sample of the large molecules, and analyzing the resulting charged fragments and radical fragments of the of the large molecule by means of a mass spectrometer. In an embodiment of this third aspect, the large molecule is a protein.

In a fourth aspect of the invention, a method of modifying a surface of a material includes steps of passing a beam of gas-phase metal anions through an aperture to diverge the beam, and impacting the diverged beam onto the surface of the material, thereby uniformly depositing the metal onto the surface. In an embodiment of this fourth aspect, the metal is silver and the material is a biomaterial for implantation in a human body.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, a process for generating gas-phase metal anions, which is referred to herein after as the “dicarboxylate process”, can efficiently generate metal anion beams with low kinetic energy using bench-top laboratory equipment. The procedure provides a new mild route for generating gas-phase metal anions, such as Na−, K−, Cs−, and Ag−, by collision-induced dissociation (CID) of the singly-charged anions of their dicarboxylic acid salts [A+M]−. Metals suitable for producing gas-phase metal anions according to a method of the present invention include those that form monovalent cations in aqueous solution with the selected dicarboxylic acid. Such metals include sodium, potassium, cesium, silver, copper, cobalt, gold, thallium, gallium, and indium.

In an embodiment of the present invention, the dicarboxylate salt is a salt of oxalic acid (i.e., a metal oxalate salt.) In other embodiments of the invention, metal anions are produced from the singly-charged anions of other dicarboxylic acid salts, including, but not exclusively limited to, metal salts of maleic acid, fumaric acid, succinic acid, malonic acid, malic acids, tartaric acids, glutamic acids and aspartic acids.

In an embodiment of a process according to the present invention, a metal dicarboxylate salt is dissolved in a polar solvent or a mixture including a polar solvent. Suitable polar solvents include, but are not limited to, water, acetonitrile, and methanol. A mixture of solvents that may be used advantageously comprises one part water blended with one part acetonitrile or methanol. In various embodiments of the process, the concentrations of metal cation and dicarboxylic acid dianion dissolved in the solution are in a range of 0.1-1.0 mM. A pH modifier may be added to this solution to adjust the solution pH to optimize production of the desired precursor anions.

FIG. 1is a schematic diagram of an assembly10comprising an electrospray ionization (ESI) device12hyphenated to a triple quadrupole mass spectrometer14. The assembly10may be used to produce a collimated beam of monatomic metal anions with low kinetic energies from electrosprayed metal dicarboxylate salt solutions by a process in accordance with an embodiment of the present invention. The process may be described in two stages, with the operation of the ESI device12being the first stage and the operation of the mass spectrometer14being the second stage.

The first stage of the process is carried out using an ESI device, such as the ESI device12ofFIG. 1. The ESI device12includes a metal capillary16at least partially surrounded by a tube18. In a process of preparing metal anions according to an embodiment of the present invention, a solution20of a metal dicarboxylate salt is pumped through the metal capillary16at a flow rate sufficient to provide an optimized, stable, high yield of precursor [A+M]−anions. For example, the flow rate of the solution20may be fixed in the range of 1-10 μL min−1. A high negative voltage within the range of about 1 kV to about 5 kV is applied to the capillary16to promote formation of negatively-charged spray droplets22. The voltage may be applied using a voltage source (not shown) electrically connected to the metal capillary16. A nebulizer gas24may be passed through the tube18in a direction concurrent with the flow of the solution20to assist in the nebulization and evaporation of the solvent from the spray droplets22. In an embodiment of the present invention, the nebulizer gas24may be warmed (e.g., to a temperature of about 85° C.) to promote rapid evaporation of the solvent and desolvation of the precursor ions and other reaction products in the spray droplets22. In another embodiment, the environment of the spray droplets22may be maintained at an elevated temperature. In other embodiments, the droplets22may evaporate under ambient conditions at a pressure of approximately 1 atm (i.e., about 105Pa).

The solvent evaporation from the charged droplets22proceeds until all of the water and organic solvent is removed, following processes which are well known, such as those described in the following articles: (1) G. D. Wang, R. B. Cole.Analytica Chimica Acta,406(1) (2000) 53-65; (2) P. Kebarle.Journal of Mass Spectrometry,35(7) (2000) 804-817; (3) P. Kebarle, M. Peschke.Analytica Chimica Acta,406(1) (2000) 11-35; and (4) M. Labowsky, J. B. Fenn, J. F. de la Mora.Analytica Chim. Acta,406(1) (2000) 105-118, each of which is incorporated by reference herein in its entirety. After the water and organic solvent has been removed, desolvated negative and positive ions, ion pairs, and salt clusters remain as a vapor phase26.

The second stage of the process may be carried out in an electrostatic ion separation device, such as mass spectrometer14ofFIG. 1. In an embodiment of the invention, the mass spectrometer14is a bench-top mass spectrometer. The mass spectrometer14is equipped with aperture plate28and metal plate30which define a skimmer region32between them, which may be evacuated to a substantially constant pressure of about 102Pa by means known in the art. The plates28and30are provided with respective apertures34and36, through which the desolvated vapor phase26can be drawn. In an embodiment of the present invention, the mass spectrometer14includes, a first quadrupolar mass analyzer38, a collision cell40, and a second quadrupolar mass analyzer42. In other embodiments, other devices capable of electromagnetically separating ions may be used in place of the first and second quadrupolar mass analyzers38,42. In embodiments of the invention, the first mass analyzer38, the collision cell40and the second quadrupolar mass analyzer42may be evacuated to substantially constant pressures of about 10−4Pa, 10−3Pa and 10−4Pa, respectively, by methods well known in the art.

In an embodiment of the present invention, the vapor phase26is pulled through the aperture34in the plate28into the skimmer region32by action of a positive potential applied to metal plate30. A voltage difference of a few volts between the aperture plate28and metal plate30is typically enough to draw the negative anions into the skimmer region32. Negative anions in the vapor phase26include singly deprotonated dicarboxylic acid anions [HA]−, doubly deprotonated dicarboxylic acid anions [A]−2, singly charged metal dicarboxylic acid salt anions [A+M]−, and numerous dicarboxylic acid salt cluster anions. These anions exit the skimmer region32through the opening36in the metal plate30, and enter the first quadrupolar mass analyzer38. Positive ions (i.e., cations) in the vapor phase26are not attracted to the positively-charged plate30, and either are not drawn into the skimmer region32or are trapped therein.

As noted above, negative ions exiting the skimmer region through aperture36of plate30are drawn into the first quadrupolar mass analyzer38. The first quadrupolar mass analyzer38is operated to select only the [A+M]−anions (hereinafter, “the precursor anions”) from among the anions entering the first quadrupolar mass analyzer38, using separation techniques widely known in the art. Thus, the first mass analyzer38functions as a filter to transmit only the selected precursor anions as a collimated beam, discarding all other anions drawn into the mass analyzer38.

The precursor anions44selected by the first quadrupolar mass analyzer38pass into the collision cell40. A collision gas48is added to the collision cell40, providing means for dissociating the precursor ions44and maintaining the pressure in the collision cell40. A collision gas used in embodiments of the present invention is typically an inert gas, such as one of the noble gases (i.e., helium, neon, argon, krypton, or xenon). Nitrogen is also sufficiently inert to be used as a collision gas. It is preferable to choose an inert gas that has a high atomic or molecular mass (e.g., argon or xenon), because the high mass maximizes the fraction of collision energy converted into vibrational excitation of the colliding metal ion. In an embodiment of the process of the present invention, the collision gas is argon.

Voltages are applied to the opposite ends48,50of the collision cell40to draw the precursor anions through the collision cell40, with the voltage at end50being slightly positive relative to the voltage at end48. In accordance with known techniques of gas-phase chemistry, the physical length of the collision cell40may be selected to be greater than the mean free path of the precursor anions, which depends on the size of the precursor anions and the pressure of the collision gas46.

Without being bound by theory, it is believed that the precursor anions44undergo inelastic collisions with gas molecules in the collision cell40leading to an exchange of kinetic energy with internal rotational and vibrational energy within the anions44. It is further believed that a fraction of the precursor anions44thus achieve a vibrationally excited state exceeding a threshold dissociation energy (ΔE1), causing the precursor anions44to dissociate. The immediate products of the precursor dissociation include carbon dioxide and an intermediate metal complex anion, which is either weakly bound or metastable so that it further dissociates with a threshold energy (ΔE2), yielding a monatomic metal anion (M) as a product. This dissociation process; known as “collision-induced dissociation” (CID) is depicted in equations 1 and 2 of Dissociation Scheme 1, below, for the specific case of a singly-charged metal oxalate salt anion.

The metal anions and any undissociated precursor anions pass from the collision cell40into the second quadrupolar mass analyzer42. The second analyzer42selects only the metal anions and passes them through the mass analyzer42as a collimated anion beam52. The metal anions in the beam52have low kinetic energies, and can be transmitted or stored for various applications, as described in Examples 1-4, hereinbelow. A number of monoatomic metal anions may group together to form nanocluster metal anions, which would also be present in the collimated beam52.

Demonstrating the production of gas-phase metal anions by a process such as that described above,FIGS. 2-8are graphs of mass spectra of product ions obtained by CID of singly-charged metal dicarboxylic acid salts. CID mass spectra were recorded using a Micromass™ (Beverly, Mass.) Quattro I triple quadrupolar mass spectrometer equipped with an ESI source. Samples were infused into the ESI source as acetonitrile/water (50:50) or as methanol/water (50:50) solutions at a rate of 5 μL/min. The ESI source temperature was held at 85° C. The argon gas pressure in the hexapolar collision cell was adjusted to attenuate precursor ion transmission by 50 percent. In-source fragmentation was used to optimize the production of the desired precursor anions. Typical ESI source (S) and collision (C) voltage settings that were used are summarized in Table 1. In practice, the ESI source (S) and collision (C) voltages can be varied over a wide range, and one having ordinary knowledge of mass spectrometric techniques, and given the present disclosure, would understand how to adjust these settings to maximize the abundance of the gaseous metal anions that are generated.

FIGS. 2-5show examples of product ion mass spectra obtained after CID of specific metal oxalate anion precursors, which had been selected in the first quadrupolar mass analyzer38, in which:

FIG. 2is a graph of a CID spectrum of m/z111derived from sodium oxalate, wherein the peak at m/z23represents the gas-phase Na−anion;

FIG. 3is a graph of a CID spectrum of m/z127derived from potassium oxalate, wherein the peak at m/z39represents the gas-phase K−anion;

FIG. 4is a graph of a CID spectrum of m/z221derived from cesium oxalate; wherein the peak at m/z133represents the gas-phase Cs−anion; and

FIG. 5is a graph of a CID spectrum of m/z195derived from silver oxalate, wherein the peak at m/z107represents the gas-phase Ag−anion.

FIGS. 6-8show examples of product ion mass spectra obtained after CID of specific potassium dicarboxylate anions, other than the oxalate dianion, which had been selected in the first quadrupolar mass analyzer38, in which:

FIG. 6is a graph of a CID spectrum of m/z155derived from potassium succinate, wherein the peak at m/z39represents the gas-phase K−anion;

FIG. 7is a graph of a CID spectrum of m/z153derived from potassium fumarate, wherein the peak at m/z39represents the gas-phase K−anion; and

FIG. 8is a graph of a CID spectrum of m/z153derived from potassium maleate, wherein the peak at m/z39represents the gas-phase K−anion.

EXAMPLES

The following Examples 1-4 are intended to describe representative applications of the above-disclosed procedure for generating gas-phase metal anions. They do not encompass the entire range of such applications or of the equipment that may be used to implement them.

Patterning of Nanomaterials

A beam of metal anions may be used for ion-beam patterning of nanomaterials onto solid substrates to create patterned nanoscale structures using a direct-writing methodology.FIG. 9is a schematic diagram of an ion-beam patterning assembly54according to an embodiment of the present invention, which may be used to transmit a metal anion beam52to the second surface56of a flat solid substrate58. The ion-beam patterning assembly54may be hyphenated to the second quadrupolar mass analyzer42ofFIG. 1to receive the ion beam52emitted from the second quadrupolar mass analyzer42.

In the present Example, the anion beam52emitted from the second quadrupolar mass analyzer42ofFIG. 1enters a series of at least two electrostatic lenses60,62. Each lens60,62consists of three respective concentric rings64,66,68,70,72,74aligned with the direction of the beam52. Voltages may be applied individually to the concentric rings64,66,68,70,72,74to collimate, guide and focus the metal anion beam52. Each electrostatic lens assembly62,64is also equipped with a respective four-fold segmented ring76,78to which voltages can be applied to steer the ion beam52for the purpose of correcting misalignments.

Patterning of nanoscale structures typically requires rigorously clean conditions under ultra-high vacuum (UHV). Therefore, a mechanism is needed to guide the anion beam52into an UHV environment. The first lens60is separated from the adjacent lens62by an aperture plate80having a small opening82therethrough with a sufficiently-large diameter to allow the focused metal anion beam52to pass through. The aperture plate80also acts as a barrier to gas flow, allowing a difference in pressure to exist between the lenses60,62. The pressure difference may be maintained by two successive pumping stages (not shown), operating to maintain vacuum conditions in the respective lens60,62. The metal anion beam52can in this way be transmitted into a region with a different pressure than the pressure at which the metal anions in the beam52were formed. In an exemplary embodiment, the first lens60is held at a pressure that is about equal to that of the metal anion beam52(e.g., a pressure of about 10−4Pa). The second lens62and other elements to the right of the aperture plate80, as shown inFIG. 9, are maintained under an ultra-high vacuum (e.g., a pressure of 10−8Pa). One having skill in the art will understand thatFIG. 9is a simplified schematic, and will be aware of the additional elements that may be needed to maintain the desired pressure differences across the assembly.

The second lens assembly62focuses the metal anion beam52onto the planar surface56of a solid substrate58which is fixed to an adjustable substrate mount (not shown). The substrate mount is capable of moving at least in the X and Y directions with respect to the Z direction of the intersecting anion beam52. A shutter device84is also incorporated into the assembly54between the second lens assembly62and the substrate58. The shutter device84functions to selectively block or deflect the metal anion beam52so that it intermittently impinges on the surface56of the substrate58. A programmable control device (not shown) coordinates the movement of the substrate mount and the actuation of the shutter84so that metal from the metal anion beam52is deposited on the surface56of the substrate58in a pre-determined pattern.

FIG. 10is a schematic diagram of an ion trap/micro-reactor assembly86for delivering monatomic metal anions52to an ion trap88for temporary storage in a process according to an embodiment of the present invention. The assembly86can be hyphenated to the second quadrupolar mass analyzer42ofFIG. 1to receive the metal anion beam52.

The ion trap/micro-reactor assembly86includes an ion transfer device90mounted downstream from the second quadrupolar mass analyzer42ofFIG. 1. In some embodiments of the present invention, the ion transfer device90may be an octapolar or hexapolar device. The ion transfer device90guides the metal anions52into an ion trap88.FIG. 10schematically depicts a cylindrical quadrupolar ion trap88, but other ion trapping devices may be used, such as a Penning trap, an Orbitrap™ (Thermo Fisher Scientific, Inc., Waltham, Mass.), or a massively parallel array of micofabricated quadrupolar ion traps.

The quadrupolar ion trap88includes a ring electrode92(depicted schematically in cross-section) and two end-cap electrodes94and96(depicted schematically in cross-section). Metal anions from metal anion beam52enter the ion trap88through an opening98in the end-cap94. Anions within the trap88experience superimposed DC and RF potentials due to voltages applied to the ring electrode92and end-cap electrodes94,96. Anions are thus guided into closed stable trajectories within the interior100of the trap88. A neutral buffer gas (for example helium or argon) may also be admitted into the ion trap88at a partial pressure of approximately 0.1 Pa to dampen ion motions by collisional cooling. The anions can thus be stored in the ion trap88and used later as reagents for gas-phase ion-molecule reactions.

Metal anions in this example can be ejected from the ion trap88and transferred to an adjacent micro-reactor cell104by the application of a positive potential on the exit end-cap96. Anions will be attracted to the exit end cap96, and a portion of them will exit through an opening102in the end cap96. A gas-phase neutral analyte106flows into the micro-reactor cell104, where it reacts with the ejected metal anions108. Reaction products110, formed by the collision of metal anions108with the neutral analyte106, then exit the reactor104, where they may be received by appropriate analytical equipment, such as a mass spectrometer (not shown).

Electron Transfer Agents for Elucidating Protein Structure

A metal anion beam may be used to elucidate the structure of large molecules, such as proteins, through electron transfer dissociation (ETD). ETD is a process used in mass spectrometry to cause fragmentation of multiply-charged protonated cations, which often are polypeptides or proteins with structural units linked by amide bonds. ETD is an important process for protein structure elucidation, because the process cleaves many more bonds than conventional collision-activated dissociation processes. Almost all fragmentation of peptides initiated by ETD comes from one particular type of bond cleavage: the partial reduction of polypeptide cations [R+nH]n+to form radical cations of the form [R+nH](n−1)+•. Dissociation of these radical cations produces a complementary series of c and z•type ions (e.g., as shown inFIG. 11) as result of homolytic cleavage of C—Nαbonds. Types c and z•ions are dissociation products formed by breaking a nitrogen-alpha carbon bond in the backbone of a polypeptide chain. The dissociation of a peptide radical to generate c and z•type products adjacent to the radical site is depicted more explicitly inFIG. 11. The use of ETD processes for characterizing peptides and proteins are described in the following references: (5) Syka, J. E., et al., Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry,Proc. Natl. Acad. Sci. U.S.A.,101(26) (2004) 9528-33; and (6) Coon, J. J., et al., Anion dependence in the partitioning between proton and electron transfer in ion/ion interactions,Int. J. Mass Spectrom.236 (2004) 33-42, each of which is incorporated by reference herein in its entirety.

In a typical ETD process an appropriate reagent capable of capturing electrons (e.g., fluoranthene) is introduced into a chemical ionization (CI) source and converted into a radical anion (A−•) by a process of low energy electron capture. Typically, anion generation in a CI source requires that the precursor be sufficiently volatile to occupy the vapor phase. Formation of metal anions in a CI source at low temperature has been difficult to accomplish due to the low volatility of most metals. The generation of metal anions in a process such as that discussed with respect toFIG. 1circumvents the problems associated with the low volatility of metals, because the precursor is introduced as a solution-phase metal acid salt.

A typical ETD process involving an anion (A−) is described in equations (3) and (4) below:
[R+nH]n++A−•→[R+nH](n−1)+•+A  (3)
[R+nH](n−1)+•→dissociation products of typecandz•(4)

In an embodiment of the present invention, beams of gas-phase monatomic metal anions (M−) may be used to derive information about the primary structure of peptides by reacting M−with protonated peptide ions in an ETD-type process. In this process, metal anion beams produced as described with respect toFIG. 1would be directed onto a sample of a protein or other large molecule (e.g., using electrostatic lenses such as those discussed with respect toFIGS. 9 and 10), and the desorbed fragments of the sample would be guided (e.g., by a carrier gas) into an appropriate analytical device. In some embodiments, an assembly such as assembly86ofFIG. 10would be used to analyze a sample of a volatile large molecule in the gas phase. Analytical methods of the present invention which utilize beams of gas-phase metal anions are referred to herein as metal-anion assisted dissociation (MAAD) processes.

The MAAD process involving a metal anion (M−) is described in the equations (5) and (6), below:
[R+nH]n++M−→[R+nH](n−1)+•+M•(5)
[R+nH](n−1)+•→dissociation products of typecandz•(6)

In contrast to conventional ETD, MAAD produces additional diagnostic information about peptide structure via additional reactions between the peptide cation and a neutral metal radical, as described in equations (7) and (8), below:
[R+nH]n++M•→[R+nH](n−1)+•+M+(7)
[R+nH](n−1)+•+M•→[R+nH](n−2)++M+(8)

Several non-metallic neutral molecules or radicals have been used previously as precursors to generate ETD reagents. A comparison of the physical properties and ETD efficacy of these reagents is instructive in understanding the MAAD process. The electron affinities (EA) of several typical precursors for ETD are provided in Table 2, below, along with ratings of the resulting transfer agents' efficacy in producing ETD products from a protonated peptide cation. Data in Table 1 were taken from (7) Gunawardena, H. P., et al.,J. Am. Chem. Soc.127(36) (2005) 12627. It may be noted that the precursor molecules (or atoms) listed in Table 1 have electron affinities that vary in the range of about 5 to about 113 kcal/mol. The efficacy of electron transfer varies in a range of 0% to about 49%. Thus, Table 1 shows that there is a striking loss of efficacy for precursors with electron affinities greater than approximately 60 kcal/mol. Precursors having low electron affinities show a trend toward higher transfer efficacies.

Table 3, below, lists electron affinities of several exemplary metals that may be used as precursors for generating metal anions by the processes described herein as embodiments of the present invention. These metals have low electron affinities that fall within a range of about 10 to about 30 kcal/mol. Such values are consistent with the production of metal anions having high transfer efficacies.

Until the present disclosure, the art did not include metal anion beam sources that could be easily integrated into ETD experiments with existing benchtop equipment. However, based on the evaluation of the data of Table 2 discussed above, it can be reliably predicted that such metal anions can beneficially be used in ETD methods.

There is other strong evidence that metal anions are excellent electron transfer reagents. It is known in the art that gas-phase cesium atoms (in the absence of any ionization method) are capable of undergoing ETD reactions with protonated peptide cations. If transfer of an electron from a neutral metal atom is facile, then the transfer of an electron from the corresponding metal anion should be expected to be extremely efficient, because of the low binding energies of surplus electrons in metal anions.

Further, the use of metal anions in ETD would be more effective than the use of the anions (A−) of the molecules (or atoms) of Table 2. Some of the anions that are listed in Table 2 have a limited capability to undergo ion-ion reactions involving electron transfer, because they can also participate in an energetically more favorable process of proton transfer, in which the protonated cation transfers H+to the approaching anion to neutralize it. The competing proton transfer process is described in the equation below:
[R+nH]n++A−→[R+(n−1)H](n−1)++AH  (9)

In this competing, and undesirable process, the anion functions as a strong base with high proton affinity instead of functioning as a reducing agent. Some anions display a dual behavior in which both proton and electron transfer occurs. Gas-phase metal anions are not known to function as strong bases with a high proton affinity; therefore, the competing process of proton transfer is unlikely to reduce their efficacy in ETD reactions. A neutral hydride, such as CsH, that might be generated by a proton transfer to a Cs−ion would be expected to be only weakly bound in its ground state and susceptible to dissociation, forming Cs+and H−.

Persons having ordinary skill in the art of mass spectrometric techniques, given the present disclosure, will understand how the gas-phase metal anion beams of the present invention could be used in other analytical techniques. For example, such beams can be used as a primary ion source for secondary ion microscopy, which is a nanoscale imaging method used to characterize inorganic materials and biological tissue samples.

Metal Anions for Surface Treatment of Biomaterials

Methods for the surface treatment of biomaterials are important for improving the function and biocompatibility of medical devices such as orthopedic prostheses, catheters, and orthodontic appliances. Ion beam-based surface treatment processes provide a variety of beneficial surface property modifications without impacting the bulk properties of the devices. Ion beams with high kinetic energy interact with surfaces by a mechanism of ion implantation, which heats surfaces locally and transfers large amounts of energy, which can degrade the surfaces or impart other undesirable properties thereto. In contrast, embodiments of the present invention produce metal anion beams (such as metal anion beam52ofFIG. 1) having low kinetic energies, which can be used to modify delicate biomaterial surfaces without significant local heating.

In an embodiment of the present invention, metal anion beams having low kinetic energy are used to form infection-resistant coatings on implantable medical devices. For example, treatment of surfaces with silver has been demonstrated to be safe and effective in inhibiting microbial growth. Metal anion beams produced by processes according to embodiments of the present invention may be used to treat substrate surfaces of biomedical implants with silver or other metals.

FIG. 12is a schematic diagram of a metal anion deposition assembly112according to an embodiment of the present invention for delivering monatomic metal anions to an ultra-high vacuum deposition chamber. The assembly112can be hyphenated to the output anion beam52ofFIG. 1to guide the metal anions into a deposition chamber114under ultra-high vacuum.

In many respects, the metal anion deposition assembly112is similar to the ion-beam patterning assembly54ofFIG. 9, which is discussed in Example 1. Elements ofFIG. 12that have counterparts inFIG. 9are shown with the same reference numbers used for those elements inFIG. 9, incremented by 100. A more detailed description of such elements may be found in the discussion of Example 1, above.

In the metal anion deposition assembly112, voltages are applied to the concentric rings170,172,174and the four-fold segmented ring178of the lens162so as to focus the anion beam52so that it passes through an opening116in an aperture plate118into the deposition chamber114. The anion beam52diverges after passing through the aperture116forming a defocused anion beam120so that the anions will be deposited uniformly over a wide area on the surface122of biomedical device124. The biomedical device124will preferably be connected to a voltage source (not shown) that imparts a small positive potential to the biomedical device124, attracting the metal anions to its surface122. The medical device120might also be mounted on a rotating stage (not shown) that allows the three-dimensional object124to be more uniformly exposed to the defocused anion beam120.

It should be understood that the embodiments described herein are merely exemplary and that a person skilled in the art may make many variations and modifications thereto without departing from the spirit and scope of the present invention without departing from the spirit and scope of the invention as defined in the claims below.