Abstract:
A diode pumped solid state laser/OPO system widely tunable in mid infrared spectrum for infrared matrix assisted laser desorption/ionization (MALDI) mass spectroscopy is disclosed. Up to a few tens of milli-Joule, short pulse, tunable near infrared laser pulse is generated from an all solid state laser at a high pulse repetition rate up to one kHz. The tunable near-infrared laser pumps a Quasi-Phase Matching (QPM) OPO system to further shift the wavelength to the mid-IR range and to broaden the tuning range to as much as 3 μm to effectively generate a widely tunable spectral output. The wide range tuning of the infrared output is accomplished by a narrow range tuning of the pump laser. The pump laser output is generated by a diode pumped tunable solid state laser module using either a Yb:YAG crystal or any other efficient tunable laser crystals. The wavelength range (2-5 μm) covered by the solid state laser system is optimum for MALDI applications. This wavelength range is especially beneficial for large mass DNA analysis. A light detection and ranging system is also disclosed.

Description:
This invention was made with Government support under the contracts F29601-98-C-0105 and MDA 972-98-C-0012 awarded by the Air Force Research Laboratory Department of The Air Force and Defense Advanced Research Projects Agency (DARPA), respectively. The government has certain rights in the invention. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a tunable solid state laser system designed for matrix-assisted laser desorption/ionization (MALDI) applications, for example, large bio-molecules and DNA analysis. 
     2. Discussion of the Background 
     Mass spectrometric (MS) analysis of large biologically important molecules has made significant advances over the past several years. Increasingly, mild desorption methods have made possible the analysis of progressively larger macromolecules with minimal fragmentation, allowing the analysis of complex biological mixtures. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was first introduced by Karas, M.; Hillenkamp, F. Anal. Chem. 1988, 60, 2299, the entire content of which is hereby incorporated by reference. 
     MALDI-MS is now increasingly applied to the study of peptides, proteins and other bio-molecules for amino acid sequencing, structural analysis, modifications and non-covalent interactions. In comparison to the rapid development of MALDI for peptide and protein analysis, MALDI work on nucleic acids has been somewhat slower. This is due, in part, to the polyelectrolytic nature of nucleic acids, which combines well with most matrices and requires a relatively large deposition of energy to affect desorption of the macro molecules with an attendant risk of increased fragmentation. Recently, considerable attention has been directed to overcome these difficulties because of the great benefits which reliable, routine mass spectrometric techniques would offer in the field of molecular biology, and especially in the areas of gene analysis, identity testing, forensics, diagnosis of genetic disorders, and DNA sequencing. 
     Although MALDI-MS holds great potential for the analysis of DNA fragments with increased throughput and minimum sample degradation, it is presently limited mainly by the low ionization efficiency and fragmentation problems. MALDI-MS is further limited by the restricted selection of matrices that are accessible with fixed wavelength lasers. 
     Many of these limitations are a consequence of the current reliance on ultra violet (UV) lasers such as Nitrogen (337 nm), or frequency tripled, or quadrupled Nd:YAG (355 nm or 266 nm) lasers for MALDI. Although hundreds of potential matrix materials exist, only a limited number of useful matrices (approximately 30) are suitable for use with the conventional fixed wavelength lasers. The most successful matrix materials for nucleic acids in the UV range are picolinic acid and its derivatives, whereas succinic acid works well in the near IR region as demonstrated by Nordhoff et al, Nucl. Acids Res. 1994, 22, 2460, the entire content of which is hereby incorporated by reference. On the other hand, infrared IR laser sources can overcome the difficulties of molecular fragmentation, and also permit the use of a wide variety of laser desorption matrices, as shown by Cramer et al, J. Am. Soc. Mass Spectrom. 1996, 7, 1187, the entire content of which is hereby incorporated by reference. In studies, the IR MALDI resolution was found to be higher, and the sample molecules were stable during IR radiation, while the stability of the same sample molecules degraded under UV radiation. See Siegel et al, Anal. Chem. 1997, 69, 2716-2726, the entire content of which is hereby incorporated by reference. 
     CO 2  (10.6 μm) lasers have been used effectively since 1983 for laser desorption studies. Both fixed wavelength lasers such as Er:YAG (2.94 μm) and CO 2  and tunable sources such as free electron lasers (typically 2.2 to 7.0 μm) and very recently tunable (2 to 3.5 μm) Optical Parametric Oscillators (OPO) including Cr:LiSAF pumped KTA OPO have been utilized in a limited number of IR MALDI experiments. However, the high cost along with the complexity and size of these IR lasers, especially the free-electron lasers, have historically limited the use of IR lasers to only a few selected research groups. Furthermore, the commonly used OPO pumped by a Nd:YAG laser, which can generate IR output in the 2.7-3.2 μm wavelength range, is cumbersome, expensive and requires expertise to operate and are thus mainly suitable for research facilities. 
     An examination of the literature reveals that the IR MALDI technique is not nearly as mature as the UV MALDI, and a great deal of work remains to be done before its full potential is realized. For example, the mass resolution obtained using a conventional IR-MALDI system is less than satisfying. Also, the influence of sample preparation and laser wavelength on the resulting mass spectra is significant. 
     Most time-of-flight (TOF) mass spectrometers are large, expensive instruments requiring considerable expenditure of time and personnel for their routine operation. This expense and expenditure has motivated the development of miniaturized, low cost TOF mass spectrometers that could have sufficient sensitivity and resolution to be utilized for all the comparative sequencing applications mentioned earlier. Taking advantage of the high time-resolution of current digitizers and using reflectrons to improve mass resolution, a miniature endcap TOF MS was recently demonstrated as being capable of providing structural information for biological molecules. See Cornish et al, in Proceedings of the 45 th  ASMS Conference on Mass Spectrometry and Allied Topics, 1997, the entire content of which is hereby incorporated by reference. 
     SUMMARY OF THE INVENTION 
     Although, in general, detection of oligomers with approximately 30 nucleotide bases (primers plus extensions) is required for most of the hybridization schemes that are being considered now, one object of the present invention is to permit facile, high sensitivity detection and resolution of oligomers up to 100-mer. The latter is indeed difficult utilizing current UV laser-based MALDI instruments, but utilization of the IR laser at optimal wavelengths as provided by the present invention is expected to greatly improve the signal to noise ratio in that range. 
     Thus, a widely tunable, compact, solid state IR (infrared) laser source covering a wide range of wavelengths from 2 to 5 μm is critically needed for MALDI applications in order to expand the capabilities of MALDI MS to the range of IR wavelengths, where a large number of potential matrices exist. 
     Accordingly, one object of this invention is to provide an innovative, variable IR wavelength, miniaturized laser system to be used with a mass spectrometer, for example, a miniaturized endcap reflectron time-of-flight mass spectrometer (wich corresponds to a special mass spectrometer design known to those skilled in the art). The present invention provides higher sensitivity, higher resolution and higher mass accuracy measurements in MALDI applications. In addition, the laser system of the present invention furnishes the ability to select new amenable matrices and ultimately can provide analytical capabilities on a compact, user friendly, and inexpensive instrument that can be utilized in a variety of analytical, medical, environmental, and forensic settings. The laser system can also be applied to other MALDI configurations that include, general time of flight MS and ion trap MS. 
     Another object of the present invention is to provide a tunable infrared laser system that provides an infrared laser wavelength at 2-5 μm range with a pulse energy up to a few mJ, thus providing a desorption and ionization source for the MALDI mass spectrometers. 
     Another object of the present invention is to provide an infrared laser system including a tunable diode pumped solid state (DPSS) laser and associated quasi-phase matched optical parametric oscillator (QPM OPO) or other nonlinear crystal, whereby a wide tuning is accomplished by tuning the pump laser frequencies without resetting the OPO crystal parameters. 
     Another object of the invention is to provide a tunable DPSS laser system based on Yb:YAG crystal which is effectively pumped by a semiconductor diode laser array(s) through an end-pumping or a side-pumping geometry to provide high quality beam laser pulses for pumping the OPO to generate stable IR laser pulses. 
     Another object of the invention is to provide a technique to convert the pump laser wavelength to an infrared wavelength by using a quasi-phase-matching nonlinear optical material such as PPLN, PPRTA, or other infrared laser material. 
     Another object of the invention is to provide a small, diode-pumped widely tunable, high repetition rate, laser source which is critically needed for a robust low cost IR-MALDI-MS instrument. 
     It is yet another object of the invention to provide interface optics designed for, and a method of, delivering the infrared laser pulse to the bio-sample inside the MS with an optimum efficiency and focusing for the maximum energy density at an optimum (controllable) size for best ionization efficiency and sensitivity of the MALDI/MS. 
     Another object of the present invention is to provide a novel Light Detection And Ranging (LIDAR) system including a novel infrared laser system. 
     These and other objects are achieved according to the present invention by providing a laser system and methods which integrate a DPSS tunable laser and OPO in a compact system, thereby generating an intermediate energy tunable near infrared laser pulse using a Yb:YAG laser crystal, tuning the output wavelength using a birefringent tuner BRT in a laser cavity, pumping the OPO with the output of this laser cavity to convert from a wavelength in the near infrared to a wavelength in the infrared region, and amplifying the tuning range by the OPO cavity from 2-5 μm without angular rotation or temperature tuning of the OPO crystal. Output from the laser system can be focused onto samples for MALDI-MS analysis. 
     The entire laser system is integrated into a compact package, has low power consumption through an efficient diode pumping design, and provides stable laser output due to the reduced thermal loading of the laser system. This configuration consequently provides a long lifetime for the laser operation and robust performance that does not require intense maintenance and highly skilled operators. 
     The output of the above described laser/OPO system provides medium pulse energy, up to a few mJ, for example, 1-10 mJ, with relatively short pulses (up to 40 nsec) at a relatively high pulse repetition frequency PRF, for example, 2-100 Hz, or up to 1 kHz, if required. The compact design and low thermal dissipation from the efficient diode pumping design combined with the robust optomechanical design provides a high level of laser energy output stability (less than 3% fluctuation), which is a desirable feature for MALDI applications to assure high sensitivity and resolution. The output laser beam produces a well defined Gaussian profile which enables tight focusing at the sample location in the MS. The threshold for MALDI ionization is thus significantly reduced and sample consumption is minimized for economic sample analysis and improving the sensitivity. Combining the flexibility of focusing of the Gaussian laser beam with the wavelength tunability in the infrared region, this system provides a unique feature for MALDI analysis of large mass biomolecules including DNA and RNA, which has not been previously possible. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     A more complete appreciation of the present invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein: 
     FIG. 1 is a schematic illustration of a tuned IR laser/OPO system employing a tunable diode-pumped Yb:YAG laser and a QPM OPO, wherein widely mid-IR output is achieved. 
     FIG. 2 is a schematic illustration of a diode-pumped Yb:YAG laser employing birefringent tuner for wavelength tuning. 
     FIG. 3 is a plot of experimental performance of a laser according to the present invention, i.e., a Yb:YAG laser end-pumped by a 940 nm diode bar stack in long pulse mode. Experimental results (symbols) are compared with predicted performance (dashed, solid and dotted lines) for T=10%, 5% and 2%. 
     FIG. 4 illustrates a Q-switched output performance of the diode-pumped Yb:YAG laser of the present invention as a function of incident pump energy, with an output coupler T=10%, and an incident energy threshold=97 mJ. 
     FIG. 5 is a schematic illustration of a diode-pumped Yb:YAG laser of the present invention, with total internal reflection resonator and side-pump geometry. 
     FIG. 6 is a more detailed embodiment based upon the embodiment of FIG. 5 in the AA section. The overlap between pump absorption and laser mode region is shown in the shadow area. 
     FIG. 7 is a schematic illustration of a QPM OPO cavity according to the present invention. 
     FIG. 8 is a schematic illustration of a laser beam delivery layout of a MALDI-MS system according to another embodiment of the present invention. 
     FIG. 9 is a schematic illustration of an optical fiber laser beam delivery layout of a MALDI-MS system according to another embodiment of the present invention. 
     FIG. 10 is a schematic illustration of an optical scanning configuration for a MALDI-MS system according to another embodiment of the present invention. 
     FIG. 11 is a schematic illustration of an optical scanning configuration for a MALDI-MS system according to another embodiment of the present invention. 
     FIG. 12 is a schematic illustration of a light detection and ranging (LIDAR) system employing a tunable mid-IR source as transmitter according to another embodiment of the present invention. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Referring now to the drawings, wherein like reference numerals designate identical or corresponding parts throughout the several views, and more particularly to FIG. 1 showing a schematic of a compact laser system that can be tuned rapidly over a wide mid-infrared wavelength range covering 2 to 5 μm. The laser system includes a diode pumped solid state (DPSS) tunable Yb:YAG laser  1 , a mode matching lens  2  configured to mode match the pumping beam from the laser  1 , and a simple, fixed, quasi-phase matched optical parametric oscillator (QPM OPO)  3  pumped by laser  1 . A QPM OPO  3  is a nonlinear frequency conversion device which converts input pump photons into two photons of lesser energy through the parametric generation process in a nonlinear crystal  6 . The input pump wave with a frequency ω P  generates two waves, i.e., a signal wave  9  and an idler wave  10  with frequencies ω S  and ω I , respectively, subject to the energy conservation condition, ω P =ω I +ω S . The QPM-OPO includes two mirrors  7  and  8  forming a cavity. The output waves of OPO  3  can be separated using beam splitters  4  and  5 . The tuning properties of the material are dependent upon the further condition of phase or momentum-matching, k P =k S +k I , where the momentum is k=nω/c, with n is the refractive index, ω is a frequency, and c is the speed of light. Tuning is thus dependent upon the refractive indices at the three wavelengths. Subject to these criteria, the most practical pump sources for the generation of tunable 2.5 to 5.5 μm radiation are lasers operating in the 700 nm to 1.1 μm region. 
     1. Compact Widely Tunable Infrared Laser/OPO Source 
     Conventionally, an OPO is pumped by a fixed wavelength source, such as a Nd:YAG laser operating at 1.06 μm. In such an OPO, birefringent phase-matching is utilized, and the output wavelengths are controlled by angle or temperature tuning of the refractive indices of the OPO. These tuning techniques have several limitations. Limitations of tuning by angle are: restricted angular acceptance, beam walk-off which limits the interaction length, and beam deviation which complicates alignment. Tuning by temperature is again limited to reasonable temperature ranges, and tuning is slow to allow for thermal stabilization. In addition, birefringent phase-matching constrains the interaction to involve only one wave polarized orthogonally to the other two and hence cannot operate with large diagonal components of nonlinear susceptibility. 
     Contrary to this conventional approach, wherein the wavelength of the pump laser is fixed, the present invention utilizes a quasi-phase matched material optical parametric oscillator (QPM-OPO) cavity interfaced with a tunable diode pumped solid state (DPSS) laser. The tunable DPSS laser  1  utilizes an electronically controlled birefringent controller  18  (See FIG.  2 ). The birefringent controller, or birefringent tuner,  18  is a fast tuning device. As an example of a birefringent controller  18 , a birefringent filter (quartz plate) is mounted on a mechanical rotator driven by a motor which is controlled by a controller (for example, a Motorized linear translation stage from National Aperture, Inc.). The built in encoder device recognizes the position of the stage and thus the precise rotation position of the quartz plate. The rotation of the quartz plate changes the optical axis inside the laser cavity and thus varies the birefringence within the laser cavity. The plate rotation can be controlled by control pad, or by computer control so as to effectively control or tune the laser. 
     The tunable laser pumps an optical parametric oscillator which produces a signal wave and an idler wave having wide ranges of wavelengths due to the variable frequency input from the tunable laser. The use of a broadly tunable pump laser to generate mid-infrared provides several distinct advantages to the overall system, some of which are: 
     1) very simple geometry for the OPO and the entire laser system; 
     2) rapid tuning of the OPO by pump wavelength tuning; 
     3) widest range of output wavelengths for accessing several of the absorption bands of the constituents of the matrix and samples including O—H bond at 2.94 μm, and C—H and N—H bonds at near 3.4 μm, and others. 
     Thus, pump wavelength tuning allows wide continuous spectral coverage and frequency agility without requiring adjustment of the OPO or realignment of the system, which is required with a fixed wavelength pump laser. Pump wavelength tuning allows high repetition rate and medium energy in tunable compact DPSS pumped OPO systems. 
     2. Materials for the QPM-OPO 
     To meet the need for a high repetition rate, mid-infrared source, several nonlinear materials have been examined which might potentially be used in an OPO. Factors to consider for selecting the materials are: 
     1) Transmission and phase-matching in the near to mid-infrared; 
     2) capability to tolerate tight pump beam focusing; 
     3) potential for low energy oscillation threshold; and 
     4) sufficient damage threshold. 
     Some commercially available crystals which meet these conditions to at least some extent are the following: 
     1) KTP or KTiOPO 4 , Potassium Titanyl Phosphate; 
     2) the Arsenate group of crystals KTA or KTiOAsO 4 , Potassium Titanyl Arsenate; RTA or RbTiOAsO 4 , Rubidium Titanyl Arsenate; CTA, or CsTiOAsO 4 , Cesium Titanyl Arsenate; and 
     3) periodically-poled crystals LiNbO 3  (Periodically Poled Lithium Niobate or PPLN), RTA (PPRTA) and KTP (PPKTP). 
     KTP suffers from the drawback of significant absorption beyond 4.5 μm wavelength. By contrast, arsenate isomorphs of KTP do not display this disadvantage and are transparent further into the infrared. Conventional nonlinear materials such as KTP and KTA rely upon their inherent birefringence to allow phase-matching at specific wavelengths which are defined by the material refractive indices. As a result, the phase-matching wavelengths are pre-defined by the material properties. 
     In contrast, periodically-poled materials may be fabricated to provide phase-matching at any given wavelength combination allowed by energy conservation. Furthermore periodically-poled materials allow the parametric interaction to occur using the largest nonlinear coefficient of the nonlinear material (d 33 =27 pm/V, for LiNbO 3 ) thereby resulting in very low oscillation thresholds (as low as 5 μJ). PPLN is just one of many materials which may use the quasi-phase-matching technique. Crystals including RTA (d 33 =16.7 pm/V) and KTP (d 33 =18.5 pm/V) have also been periodically poled and are available QPM materials. These materials correspond to different embodiments for the present invention. 
     Advantageously, the QPM-OPO materials (i.e., PPLN, PPRTA) of the present invention, have lower thresholds, higher conversion, and provide a much broader tuning when a tunable pump is utilized. The performance of the QPM-OPO materials is considerably superior to the bulk materials. Furthermore, PPLN and PPRTA are commercially available. When using PPLN, the non-linear crystal may be heated to about 100° C. to avoid photo refractive damage and provide wavelength tuning. 
     3 Diode Pumped Solid State (DPSS) Laser 
     A theoretical understanding of the energy threshold for IR MALDI has not been established clearly yet. However, power density for conducting IR-MALDI experiments are estimated to be on the order of ˜0.4 J/cm 2  (10 6  W/cm 2 ). By taking reasonable values for the transmission through the interface optics and the conversion efficiencies of the OPO, a pump laser output energy of 5 mJ is estimated. With a pump energy of 5 mJ, an energy of 0.4 mJ can be delivered to the sample with a PPLN OPO crystal (for which a 10% pump to mid-IR conversion efficiency is assumed). This level of energy is demonstrated to be more than adequate for MALDI since the energy density, when the beam is focused on a spot size of ˜100 μm, is 5 J/cm 2 . 
     Diode pumped solid-state lasers have advantages over flash-lamp pumped lasers. Some of these advantages are derived from the monochromaticity and spatial coherence of the diode source which result in high conversion efficiency, reduced heat load, and good mode match between the pump region and laser mode volume. The compactness, long life and maintenance-free operation of the diode pumping used in the present invention provides a valuable advantage over the prior art systems. 
     4. Diode Pumped Yb:YAG Laser 
     The inventors of the present invention have determined that Yb:YAG is well suited for the DPSS laser of the present invention. The ability of Yb to be doped into YAG, YLF, etc, the thermo-mechanical properties of the garnet host YAG, and the broad pump bands associated with it, are some of the considerations that make Yb:YAG a desirable choice. Table 1 lists the spectroscopic and thermo-mechanical properties of Yb:YAG. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Properties of some solid-state laser materials. 
               
             
          
           
               
                 Laser Material 
                 Yb:YAG 
                 Cr:LiSAF 
                 Ti-Sapp 
                 Nd:YAG 
               
               
                   
               
             
          
           
               
                 Tuning Range, nm 
                 1020-1070 
                 760-1010 
                 660-1150 
                 1062 
               
               
                 Peak Abs wavelength 
                 941 (18), 
                 ˜630 
                 ˜500 
                 808 
               
               
                 nm and (band width) 
                 968 (4) 
                 broad 
                 broad 
                 (3) 
               
               
                 Peak Emission Cross 
                 2.3 
                 4.8 
                 30 
                 34 
               
               
                 Section, σ (10 −20  cm 2 ) 
                 (effective) 
               
               
                 Fluorescence Peak 
                 1030 
                 830 
                 790 
                 1062 
               
               
                 Wavelength (nm) 
               
               
                 Upper State Lifetime 
                 951 
                 67 
                 3.2 
                 230 
               
               
                 τ f , (μs) 
               
               
                 K ic , Fracture Tough- 
                 1.4 
                 0.4 
                 1.7 
                 1.4 
               
               
                 ness, MPa m ½   
               
               
                 κ, Thermal Conductiv- 
                 10 to 13 
                 3.09 ||c 
                 46 
                 13 
               
               
                 ity, W/m° C. 
                   
                 2.9 ⊥c 
               
               
                   
               
             
          
         
       
     
     For pumping Yb:YAG, the absorption line at 941 nm is about five times broader than the 808 nm absorption line in Nd:YAG. The broader bandwidth provides an increased efficiency in diode pumping. The line at 968 nm can also be utilized. CW and quasi-cw high power InGaAs laser diode bar arrays operating at 940 and 968 nm wavelengths are available commercially (CW powers 60 W/cm diode bars, from Opto Power, Inc). Furthermore, the commercial laser diode bar arrays are robust, with operational lifetimes of ˜10,000 hours, and have good efficiency. 
     By end-pumping a relatively long Yb:YAG rod (0.5% Yb) with 1700 W from a stack of diode arrays emitting at 940 nm, a cw output of 434 W can be obtained for an optical conversion efficiency greater than 27%. A shorted rod (0.4 mm thick) can be used with a higher concentration (20% Yb) to obtain 255 W for a pump power of 518 W. By Q-switching the same laser, 22.6 mJ pulses of 26 ns duration can be obtained at a 10 kHz repetition rate. High power, TEM 00 , single frequency output can also be obtained for output powers as high as 35 W for a 135 W pump. More than 100 W cw output can be obtained from a thin disc (0.4 mm thick) when pumped with 250 W power at 940 nm, resulting in a wall plug efficiency of over 15%. 
     FIG. 2 discloses the layout of the laser resonator and the compact end-pumping optical design of the present invention utilizing a Yb:YAG laser. An aspheric lens  14  collects and focuses the diode output on a dichroic coated face  15  (HR&gt;99%@1030 nm, HT&gt;80%@946 nm) of a 3×3×1 mm Yb:YAG crystal  16  (15% Yb). A second face of the crystal is antireflection coated (reflection&lt;0.2%@1030 nm). The crystal is placed in a thermo-electrically cooled crystal holder  17 . 
     A flat parallel laser cavity 21 is formed with the dichroic coated (HR&gt;99%@1030 nm, HT&gt;80%@946 nm) face of crystal  15  as one mirror and a flat output coupling mirror  20 . A birefringent controller, or birefringent tuner,  18  inside the cavity fast tunes the laser. As noted above, the birefringent controller  18  can include a quartz plate mounted on a mechanical rotator driven by a motorized stage which is controlled by a controller. The built in encoder device recognizes the rotation position of the motor and thus the precise position of the quartz plate. The rotation of the quartz plate changes the optical axis inside the laser cavity and thus varies the birefringence within the laser cavity. The plate rotation can be controlled by hand, or by computer control so as to effectively control or tune the laser. Output couplers with higher transmittances (T=2%, 5%, and 10% at 1060 nm) were tested. The performance of the Yb:YAG laser with the different output couplers is shown in FIG.  3 . For a pump energy of 311 mJ (corresponding to a diode current of 80 A and 1 ms pump duration) about 72 mJ output at 1030 nm was obtained in long pulse with T=2% mirror and the slope efficiency was about 27%. For the T=10% mirror, the output (66 mJ) and slope efficiency (25.5%) were both slightly lower. For the T=10% case, the performance is expected to improve when the pump power is increased. FIG. 3 also shows the results of a simulation from an analytical model which are in good agreement with the experimental results, hence confirming the validity of the model used. 
     For Q-switching the laser, a fused silica acousto-optic Q-switch  19  (manufactured by IntraAction Corp) controlled with a driver can be utilized. This plano-plano A-O modulator  19  is AR coated and the insertion loss is under 0.5%. Good Q-switching performance can be obtained with different output couplers (ranging from 2-11% transmittance). FIG. 4 shows the input-output performance of the Q-switched laser with the 10% transmitter mirror. The slope efficiency of the output as a function of incident energy is about 8%. In this particular example, the efficiency was relatively low because: 
     1) the coating was damaged (before damage the output energy was almost double); 
     2) only about 65% of the pump was absorbed; and 
     3) the output coupler was not optimal. The efficiency can be improved to 30% with proper coatings and optimization of the dopant level and output coupler. 
     As noted above, the laser cavity  21  can include birefringent tuner  18  that may include an electronically controlled motorized rotator configured to rotate a quartz plate thereby changing the optical axis and the birefringence within the laser cavity  21 . 
     5. Design of the Diode Pump Yb:YAG Laser 
     The pump energy required to obtain an OPO idler output of ˜10 mJ/pulse can be estimated with experimental data measured from the PPLN and PPRTA OPO crystals. For example, the energy threshold for the OPO to oscillate is approximately 0.68 mJ for a 20 mm long PPLN crystal or 1.1 mJ for a 15 mm long PPRTA crystal (beam waist=0.9 mm). A very low threshold of 300 μJ was measured in a PPLN crystal with 30 μm poling period (beam waist=0.4 mm, the beam waist being the minimum diameter of the laser beam at focused point). Including losses arising from the coupling optics such as for example, losses focusing lenses, mirrors, and isolators and losses from a non-uniform intensity distribution in the pump beam, etc., it is estimated that a pump energy per pulse of about 2 mJ or greater is required for reaching the energy threshold. Again, taking an average conversion efficiency 10-12% for tunable narrow line-width OPO, the pump laser energy required is estimated to be about 60-70 mJ/pulse. Table 2 shows the baseline specification for a diode pumped Yb:YAG laser. 
     
       
         
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Baseline Specifications for Tunable Laser Transmitter 
               
               
                 for chemical emission detection. 
               
               
                   
               
             
             
               
                 Q-switched Yb:YAG Laser for Pumping OPO 
               
             
          
           
               
                   
                 Pump Laser Diode Arrays 
                 InGaAs, 941 nm 
               
               
                   
                 Pump Diode Power 
                 4 × 150 W array stacks 
               
               
                   
                 Yb:YAG Laser crystal 
                 1.6 × 3 × 5 mm 
               
               
                   
                 Yb Dopant Concentration 
                 5-10 atomic % 
               
               
                   
                 Output Energy 
                 &lt;100 mJ 
               
               
                   
                 Repetition Rate 
                 1000 Hz 
               
               
                   
                 Pulse Duration 
                 30-40 ns 
               
               
                   
                 Output Wavelength 
                 1020 to 1065 nm 
               
               
                   
                 Output Line width 
                 &lt;.05 nm 
               
             
          
           
               
                 Pump Tuned Mid-IR PPRTA OPO 
               
             
          
           
               
                   
                 Idler Output Energy 
                 10 mJ 
               
               
                   
                 Signal wavelength Range 
                 1.45 to 1.95 μm 
               
               
                   
                 Idler wavelength Range 
                 2.3 to 5 μm 
               
               
                   
                   
               
             
          
         
       
     
     As seen from the laser requirement, an average output power of about 60-70 mJ in Q-switched output is needed. About 600 W of pump power is needed in this particular example. End-pumping with laser diodes is convenient and is a simple pump geometry. An upper limit to the scaling up of pump power input occurs when the thermal stresses are large enough to lead to the crystal fracture. Crystal fracture is caused by the temperature gradients set up in the crystal  15  by the absorbed energy and occurs when the temperature of the pumped region exceeds 70° C. This is especially important because Yb:YAG is a quasi-three level material, wherein any increase in the crystal temperature causes increased population in the terminal laser level with a resultant reduction in performance. Any increase in temperature will lead to a depletion of the  2 F 7/2  ground state population (see Table 3 below). In turn, this depletion causes a decrease in absorption of the crystal implying that a higher pump power is required for the same output. The higher pump requirement will lead to higher thermal loads inside the laser crystal. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Boltzman population of the  2 F 7/2  Ground State 
               
               
                 Stark Levels of Yb 3+  at various temperatures. 
               
             
          
           
               
                   2 F 7/2   Ground State 
                   
                   
                   
                   
               
               
                 Stark Levels 
                 300 K 
                 400 K 
                 500 K 
                 600 K 
               
               
                   
               
             
          
           
               
                 Energy Level 3 
                 0.020 
                 0.046 
                 0.070 
                 0.093 
               
               
                 Energy Level 2 
                 0.046 
                 0.084 
                 0.117 
                 0.14 
               
               
                 Energy Level 1 
                 0.058 
                 0.10 
                 0.133 
                 0.157 
               
               
                 Energy level 0 
                 0.876 
                 0.77 
                 0.68 
                 0.61 
               
               
                   
               
             
          
         
       
     
     The present invention overcomes these limitations by using following design considerations: 
     1) Limit the maximum temperature attained in the crystal due to absorption of the pump power to below 70° C. In the present invention, this is performed by using thermal-electric cooler  17  to active control and cool the laser crystal. 
     2) Obtain a good overlap between the pump region and the laser mode volume so as to utilize the entire pump power effectively. For example, 80% of the pump energy can be deposited into the laser mode volume. 
     3) Choose a laser rod geometry and dopant concentration based on the above two points, to limit the temperature rise and to obtain maximum overlap. For example, a 2 mm long rod having a 3 mm diameter and a Yb 15% dopant concentration. 
     4) Use a high fluence pump laser to limit the pumped volume in the crystal, which allows the use of smaller laser mode volume, permitting high conversion efficiency and reduced heating. For example, a fluence on the order of 2.5 kW/cm 2 . 
     The Yb:YAG crystal is pumped by a stack of diode array bars  12 . The pump source can include a commercially available, three bar stacks of 1 cm long InGaAs, 941 nm diode arrays, each capable of providing 100 W cw power at 941 nm (manufactured by Optopower Corp, Inc.). Although these diode arrays have a high power capability, such an extended source cannot be focused or a beam formed directly to provide a circular beam of sufficient quality to end pump Yb:YAG. The pump geometry and resonator can utilize the extended source to scale up the output power effectively. A side pumped geometry, as shown in FIGS. 5 and 6, and a simple total internal reflection laser resonator can be utilized for scaling up the energy. Specifically, an internal reflection refers to a cavity mode TIR at the point in the laser crystal where the diode pump is applied. Such a geometry is a simple way of scaling up the pump energy and to efficiently extract the stored energy without serious thermal roll off in previous lasers. 
     FIGS. 5 and 6 show another embodiment of the tunable high spectral purity laser according to the present invention wherein the laser crystal is side pumped. Good output performance and maximum efficiency occur by ensuring maximum overlap between the gain regions in the laser rods  44  and the laser mode volume  51 . The pump source includes a conductively cooled laser diode stack array  45 . A microlens  46  attached to each individual diode array to condition the output allowing the diode light to emerge with a far field 1/e divergence of ˜3° in a fast axis direction. The divergence in the slow axis direction is ˜10°. A fast (NA=0.4) aspheric lens  47  (f=12.0 mm) collects the pump light and focuses the entire diode output to an elliptic region of approximately 1.6 mm×5 mm on the side of the Yb:YAG slab  44  that is AR coated for 941 nm pump. Yb dopant concentration (˜5-10%) is chosen so as to achieve good pump absorption within 3 mm of the surface, such that a pump absorption region 5 mm (x direction)×1.6 mm (y)×3 mm (z) is obtained. A good overlap between the pump absorption region and the laser mode is obtained by arranging a near grazing angle (&lt;10°) incidence of the laser mode with the laser crystal. For this situation the overlap is computed to be nearly 80%. The pump power is distributed over a sufficiently large area so as to keep the peak temperature rise at the center of the pump region below 70° C. above which thermal roll-off becomes large. 
     The laser slab temperature can be controlled via a cooling mount  50 . The laser can further include a fast tuner  48 , an output coupler  49 , a laser mirror  41  and a Q-switch  42 . The fast tuner  48  can be a birefringent controller wherein a quartz plate is mounted on a mechanical rotator driven by a motor which is controlled by a controller (for example, a Motorized linear translation stage from National Aperture, Inc.). The built in encoder device recognizes the position of the motor and thus the precise position of the quartz plate. The rotation of the quartz plate changes the optical axis inside the laser cavity and thus varies the birefringence within the laser cavity. The plate rotation can be controlled by hand, or by computer control so as to effectively control or tune the laser. 
     In this system, the two laser crystal  44  faces are polished and optically contacted (diffusion bonded) with clear undoped YAG blocks  43 . This arrangement facilitates heat removal from the Yb:YAG and also removes the necessity of providing a coating directly on the surface where the pump energy is absorbed. One exposed face of the three stack composite crystal facing the pump laser is provided with an AR coating@941 nm, while the other face is provided with an AR coating @1030 nm. With a single 10 bar stack  45 , 600W of pump power is available for pumping the crystal. Assuming a 10% quantum deficit heating, the Yb:YAG heat load is ˜72 W. At this pump power, the cooling needs can be met with a small closed circuit fluid recirculator (−20° C.) which can transfer the heat from the laser crystal to an air-cooled heat spreader. A thermal model of the Yb:YAG crystal was used to determine the temperature distribution within the crystal, which yielded a maximum heat load of 70° C. at the center of the crystal. Water cooling with a closed system circulating chiller can be utilized for removing heat from the laser diode array stack  45 . 
     6. Design of the Compact Widely Tuned OPO 
     FIG. 7 discloses an embodiment of the OPO for the present invention. It is a singular resonant optical parametric oscillator with an OPO crystal  72  pumped by the DPSS laser output  74  to produce near-IR signal and mid-IR idler beams  75  in the wavelength region from 2 to 5 μm with pulse energy greater than or equal to 1 mJ/pulse. Advantageously, OPO crystal  72  does not have to be rotated, nor heated to tune the output optical beam. Thus, a non-heated, non-linear crystal can be used thereby increasing the simplicity, the reliability and the compactness of the system. 
     In the present invention, OPO crystal  72  can be a multiple grating periodically poled Lithium Niobate (PPLN), Potassium Titanyl Arsenate (PPRTA), or Potassium Titanyl Phosphate (PPKTP). The broad band wavelength tuning is achieved by linearly translating crystal gratings to the IR pump beam inside the OPO resonator. Due to the fact that different gratings correspond to different phase-matching, thus, different mid-IR output, broadly tuning in 2-5 μm is achieved. OPO crystal is attached on a motorized linear translation stage which is further controlled by an electronic controller. The crystal position can be identified and controlled by a built in encoder and an electronic servo loop (for example, a linear translation stage from National Aperture, Inc.). 
     A cavity is formed by two plane mirrors  71  and  73 , and the OPO crystal  72  is coated with an antireflection coating  76 . High energy capability, high conversion efficiency, extreme simplicity and robustness are emphasized in the design of the OPO of the present invention. 
     For PPLN OPO  72  pumped by a diode-pumped Cr:LiSAF, a threshold pump energy of ˜100 μJ was demonstrated for 250 ns long pulses. Significant increase of the conversion efficiency and reduction in OPO threshold is obtained by the improvements listed below: 
     1) Longer OPO crystal: Doubling the crystal length from 10 mm to 20 mm reduces threshold by a factor of four. 
     2) Antireflection (AR) coatings on the OPO crystal: Since refractive indices of KTA (n=1.8) and PPLN (n=2.2) are high, considerable Fresnel reflection losses occur in the uncoated crystal surfaces both for the pump and the intra cavity signal and idler waves. Reducing these losses will further reduce the threshold by a factor of 2. 
     3) Improved Mirror Coatings: Using higher quality coatings on cavity mirrors. For example, the reflectance can be 99.8% at the resonance frequency. Adopting pump reflection schemes reduces the threshold by a further factor of 4 and increase the output of the useful mid-IR. 
     4) Mode Matching: Better mode matching for the DPSS laser beam pump and the desired OPO mode to further minimize the threshold, for example, by selecting mode matching lenses. For a hemispherical resonator, the optimum pump focal spot diameter is ˜52 μm, which is much smaller than the estimated 200 μm focusing that is conventionally used. Therefore, a smaller focal spot size consistent with the maximum allowable fluence determined by optical damage can be utilized. 
     5) A pulse length of the DPSS laser longer than that of the flashlamp-pumped system, in the range of 200 to 300 ns, increases the threshold. The inventors of the present invention found a factor of 5 improvement, i.e., a decrease, in threshold (˜0.7 mJ) when a 5 ns pump was used instead of the 80 ns pump. 
     Several OPO cavity designs can be implemented in the present invention. Although the two plane mirror cavity configuration shown in FIG. 7 is convenient, other configurations such as a hemispherical, or a spherical resonator have advantages of moving the pump focus away from the vulnerable front surface. The radii of curvature for mirrors are chosen to obtain proper mode-matching with the pump beam. Also, non-linear crystal  72  may have a hemispheric shape. 
     Table 4 shows parameters for two examples of OPO&#39;s using KTA and PPLN crystals according to the present invention. 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Parameters of KTA, PPLN OPOs 
               
             
          
           
               
                   
                 Material 
                 KTA 
                 PPLN 
               
               
                   
                   
               
               
                   
                 Crystal cut 
                 x-cut 
                 z-cut 
               
               
                   
                 Pump Pulse duration (ns) 
                 100 
                 100 
               
               
                   
                 Pump beam waist (μm) 
                 100 
                 100 
               
               
                   
                 Signal beam waist (μm) 
                 120 
                 120 
               
               
                   
                 Mirror Reflectivity @ signal 
                 90% 
                 90% 
               
               
                   
                 Crystal length (mm) 
                 20 
                 20 
               
               
                   
                 OPO Cavity length (mm) 
                 35 
                 35 
               
               
                   
                 Nonlinear coefficient (pm/V) 
                 3.7 
                 18 
               
               
                   
                 Calculated threshold (μj) 
                 220 
                 22 
               
               
                   
                   
               
             
          
         
       
     
     7. IR Laser Interface Optics 
     FIGS. 8-11 show several optics interfaces according the present invention for the MALDI applications. A mid-IR laser/OPO device as disclosed above produces an IR beam that is focused to a focal point  85  ( 95 ,  104 ) on a sampler  84  ( 94 ,  105 ) where a biological sample is placed. The sampler  84  ( 94 ,  105 ) is placed in a MALDI mass spectrometer  86 . The mass spectrometer  86  can be a miniaturized endcap reflectron time-of-flight mass spectrometer (wich corresponds to a special mass spectrometer design known to those skilled in the art). 
     One important aspect of the MALDI process is the laser power density at the sample position. Effective enhancement of the power density is achieved by properly focusing the laser beam at the sample position by interface optics. In other words, an optical device that directs the infrared laser pulses to the sample can be configured to vary the power density of the infrared laser pulses at the sample location. Such optical device can include infrared lenses  81 ,  83 ,  103 , or  106  and steering mirrors  82  or  102  that direct the laser beam to the focal point  85  ( 95 ,  104 ). For example, in the embodiment shown in FIG. 8, a first lens system  81  (with positive or negative lenses) in front of the laser collimates the output laser beam and a second lens  83  (positive) focuses the beam onto the sampler  84 . By adjusting the separation distance, the focal spot at the sample position can be varied for the optimum power density. The interface optics assembly can be positioned on top of a window of the mass spectrometer, such as window  107  shown in FIG.  11 . The control of the relative distance between the lenses and the distance of the assembly relative to the sample position provides variability of the final focal spot size of the laser beam at the sample position. 
     An alternative design shown in FIG. 9 is equally applicable using a low numerical aperture (&lt;0.2) infrared optical fiber  92  and a single element focal lens  93  at the end of the fiber that will be located very close to the sample holder  94 . The nominal vignetting by this focal assembly in front of the sample is not a serious interference in the electric field configuration of the reflector due to the dielectric material property of the optical elements and the small volume of the assembly. The infrared fiber assembly interface optics provides a significant convenience in optical alignment and effective delivery of the laser power on to the sample with maximum stability. 
     Advantageously, the infrared beam can be scanned with a rapid optical scanning device configured to scan for large throughput MALDI operation without moving the sample holders. For example, as shown in FIG. 10, the infrared beam can be scanned with beam scanner  101 , reflected by a steering mirror  102 , and focused with a focusing lens  103  onto a focal point  104  located on a sampler  105 . Alternatively and as shown in FIG. 11, the infrared beam can be reflected by steering mirror  102 , scanned using a scanning and focusing lens  106 , and introduced into the mass spectrometer  86  through a clear window  107 . 
     An operator of the MALDI system according to the present invention can adjust the laser operation using a high resolution camera and a feedback control, the camera enabling the operator to verify the sharp focus and pointing of the output infrared laser pulses. 
     The inventors of the present invention have recently investigated IR MALDI and have shown that using of an endcap reflectron geometry, choosing a proper matrix, improving sample preparation and cooling of the sample will increase the sensitivity and achieve close to an order of magnitude improvement in mass resolution. 
     Even more exciting is the possibility offered by the present invention of utilizing natural matrices such as water ice and electrophoresis gels when a laser, widely tunable in the infrared, is utilized for IR MALDI 
     Advantageously, the tunable high spectral purity laser according to the present invention can be integrated into a Light Detection And Ranging (LIDAR) system, which provides laser-based remote sensing for measuring environment parameters. Examples of LIDAR system are disclosed in U.S. Pat. Nos. 5,914,776 and 5,889,490, the entire contents of which are hereby incorporated by reference. As shown in FIG. 12, the LIDAR system  200  according to the present invention includes a transmitter  210  having a tunable laser source  220 , a receiver  230  to collect the backscattered radiation, and a processor  240  connected to the receiver for analyzing a signal received. The processor  240  can be connected to the transmitter  210  and the receiver  230  for timing of emitted pulses. The LIDAR transmitter  210  of the present invention includes the tunable laser source  220  described above and shown in FIGS. 1-2 and  5 - 7 . The receiver  230  and the processor  240  are well known to those of ordinary skill in the art. 
     Numerous additional modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the present invention may be practiced otherwise than as specifically described therein.