Geometry for a linear time-of-light mass spectrometer with very high resolution

A linear time-of-flight mass spectrometer which operates using ionization of analyte substances adsorbed on a sample support plate and an improvement in mass resolution through delayed acceleration of the ions in front of the sample support plate. The geometric design of the mass spectrometer consists of focusing the flight time of the ions in second or higher order by maintaining geometric requirements for the lengths of acceleration paths in the ion source relative to the field-free flight path length. In computer simulations, resolutions of flight time greater than one million have been obtained even for very high ion masses provided there is a correlation in space and velocity distribution when switching on the acceleration.

FIELD OF INVENTION 
The invention relates to a linear time-of-flight mass spectrometer which 
operates using ionisation of analyte substances adsorbed on a sample 
support plate and an improvement in mass resolution through delayed 
acceleration of the ions in front of the sample support plate. It 
especially relates to the geometric design of the mass spectrometer for 
very high mass resolution in the spectrum. 
PRIOR ART 
Second order focusing relative to varying initial velocities has not been 
explicitly known for a linear mass spectrometer with delayed acceleration. 
However, in the publication "Space-Velocity Correlation Focusing" by S. M. 
Colby and J. P. Reilly, Anal. Chem. 1996, 68, 1419-1428, deviation curves 
in flight times for varying initial velocities are represented which 
suggest a second order focusing, without the authors describing it as 
such. These curves were calculated by simulation programs, although their 
basis has not been represented in such detail that they can be verified 
without further explanations by the authors. The general basis for the 
simulations is a strict correlation of space and velocity distribution of 
the ions when switching on the acceleration such as has been customary for 
the MALDI process of ionization. 
Since this article concerns an unusual, very short mass spectrometer with 
two other post-accelerating paths after the field-free flight path, it 
cannot not be excluded that the combination of four accelerating paths in 
total, one of which with delayed ion acceleration, causes this type of 
focusing. The voltages were not temporally altered after switching on the 
acceleration, with the exception of an experiment in switching on the 
acceleration with finite rise time, which however, as stated by the 
authors, causes no substantial change in focusing results. Statements 
regarding the reasons for good focusing or a systematic analysis of the 
geometric or electrical parameter ranges for good focusing are not 
included in the article. 
For stationary, unswitched acceleration in two consecutive accelerating 
regions with subsequent field-free flight path, the occurrence of second 
order focusing only occurs under spatial distribution of the resulting 
ions is known. This second order focusing only occurs under geometrically 
restricted circumstances. In a recent patent application of the same 
inventors (BFA 45/96), second order focusing is described using an 
accelerating field which varies temporally after switching on, which can 
be applied to practically all known geometric designs of time-of-flight 
mass spectrometers. 
Among the methods for ionization of macromolecular substances on sample 
supports, matrix assisted desorption by laser light flashes (MALDI=matrix 
assisted laser desorption and ionization) has found the widest acceptance. 
After leaving the surface, the ions generally have a substantial average 
velocity, which is to a large extent the same for ions of all masses, and 
a large spread around the average velocity. The average velocity leads to 
a non-linear relationship between the flight time and the root of the 
mass, i.e. the mass scale. The spread leads to a low mass resolution when 
measuring the signals of the individual ion masses; however a method has 
been known for some time for improving mass resolution. For normal linear 
time-of-flight mass spectrometers (including all those commercially 
available), a first order focusing thereby results. 
However, similar conditions also apply for other methods of ionization of 
substances which are applied to a surface. Examples of this are secondary 
ion mass spectrometry (SIMS), normal laser desorption (LD) or so-called 
plasma desorption (PD), which is obtained by high-energy fission products 
on thin films. 
For ionization by matrix-assisted laser desorption (MALDI), the large 
sample molecules are stored on a sample support in or on a layer of 
low-molecular matrix substance. A light pulse of a few nanoseconds 
duration from a laser, which is focused onto the sample surface, vaporizes 
a small amount of the matrix substance in a quasi-explosive process, 
whereby the sample molecules are also transferred into the initially tiny 
vapor cloud. 
The vapor cloud expanding into the vacuum not only accelerates the 
molecules and ions of the matrix substance through its adiabatic 
expansion, but also the molecules and ions of the sample substance through 
viscous entrainment, which thereby receive higher kinetic energies than 
would correspond to the thermal equilibrium. Even without an accelerating 
field, the ions attain average velocities of about 500 to 700 meters per 
second, dependent upon the energy density of the laser beam; the 
velocities are to a large extent independent of the mass of the ions, 
however they have a large spread of velocities which range from about 200 
up to 1,200 meters per second. 
The ions are accelerated in the ion source with electrical fields at 
energies of around 5 to 30 keV, are shot into the flight path of the mass 
spectrometer and detected with high time resolution at the end of the 
flight path. From their flight time, their mass-to-charge ratio can be 
determined. To arrive at good measuring conditions and good mass 
resolutions, the flight path must be as long as possible; time-of-flight 
mass spectrometer with flight paths up to six meters in length are 
available commercially. Since-this type of ionization practically supplies 
only singly charged ions, the term "mass determination" will be used 
throughout the following discussion, not the more correct term 
"determination of the mass-to-charge ratio". 
Flight times are converted into mass via a calibration curve which can be 
stored in table form as a sequence of value pairs, flight times and 
masses, in the memory of the data processing system, or also in the form 
of parameter values for a mathematical function of the mass relative to 
the time of flight. Due to the average initial velocity of the ions, the 
relationship between mass and square of the flight time is nonlinear, and 
the determination of mass from the flight time is therefore not trivial. 
All influences on the average initial velocity, such as laser energy, 
laser focusing or MALDI preparation, also change the relationship between 
flight time and mass. 
For mass determination, the flight time .tau. must be determined exactly to 
within fractions of a nanosecond. Since the mass signal is available as a 
line profile of ion current versus flight time, the centroid of this line 
profile is normally used for exact determination of the flight time. The 
line profile is scanned according to current technology using a transient 
recorder with 1 or 2 gigahertz. Transient recorders with 4 and 10 
gigahertz scanning rates are being developed. 
Generally, the measurements from several measuring cycles are cumulated 
before the centroid is created. 
During formation of the vapor cloud, a small part of the molecules, and 
these are both matrix and sample molecules, are ionized. But during 
explosive expansion of the vapor cloud, continuous ionization of the large 
molecules takes place through further ion-molecule reactions at the cost 
of the smaller matrix ions. The large spread of velocities and the 
time-smeared formation process of the ions limit the mass resolution both 
of linear as well as energy-focusing, reflecting time-of-flight mass 
spectrometers, if no special measures are taken. 
A method for improvement of mass resolution under these conditions has been 
known for some time. This method is based upon the fact that for all 
desorption methods there is a correlation between the space and velocity 
distribution if the ions were allowed to spread out in a field-free space. 
The ions of the cloud are therefore first allowed to fly a brief time .tau. 
in a drift region without any electrical acceleration. The faster ions 
thereby distance themselves further from the sample support electrode than 
the slow ions, and the distribution of the ion velocities results in a 
spatial distribution. Only then is the acceleration of the ions switched 
on. The acceleration takes place in a temporally constant, homogeneous 
accelerating field, i.e. with a spatially and linearly declining 
accelerating potential. The faster ions are then further away from the 
sample support electrode, and therefore at a somewhat reduced accelerating 
potential, which gives them a somewhat lower final velocity for the drift 
region of the time-of-flight spectrometer than the initially slower ions. 
With correct selection of the time lag .tau. and potential drop (i.e. the 
strength of the acceleration field), the initially slower, but after 
acceleration faster ions catch up again with the initially faster, but 
after acceleration slower ions exactly at the detector. In this way, ions 
are dispersed at the location of the detector relative to the mass, but if 
of equal mass, are focused again relative to the flight time. In this way, 
a relatively high mass resolution is achieved even in a linear 
time-of-flight mass spectrometer. There is an analogous method for 
time-of-flight spectrometers with reflectors. 
Delayed ion acceleration must not mean to switch the entire accelerating 
voltage U. It is not only that switching of such high voltages in 
extremely short times of a few nanoseconds is still almost unattainable 
today and associated with high costs but introduction of an intermediate 
diaphragm also leads to better focusings. 
Switching of a partial accelerating voltage U.sub.1, is sufficient by 
installing an intermediate electrode in the acceleration path. Then only 
the space between the sample support electrode and the intermediate 
electrode, which are a relatively small distance d.sub.1 from one another, 
need be field-free at first and then switched over after a delay into an 
acceleration field with a strength of U.sub.1 / d.sub.1. The distance 
d.sub.1 of the sample support to the intermediate electrode should be as 
small as possible in order to switch the lowest possible voltages U.sub.1. 
There is a lower limit of about two millimeters for this distance, which 
is hardly realizable however for practical designs of ion sources. In 
practice, this distance d.sub., is about three millimeters. 
An ion source for delayed initiation of acceleration therefore generally 
has at least one intermediate diaphragm between the sample support and the 
base electrode, which is at the potential of the field-free flight path. 
The ion source is therefore operated with at least two accelerating 
voltages, of which the first is applied between the sample support and the 
first intermediate electrode and the last between the last intermediate 
electrode and the base electrode. Normally, only one intermediate 
electrode is used, in which case there are then two accelerating voltages. 
The method of delayed ion acceleration does however also have its 
disadvantages. It provides the optimum mass resolution only in a narrow 
range of the mass scale. In the other parts of the total spectrum, the 
resolution is still considerably improved but not up to its optimum limit 
value. This range of optimum resolution may be adjusted to any desired 
position on the mass range by changing the time lag .tau. or by changing 
the partial accelerating voltage U.sub.1, so that this disadvantage does 
not have too great an influence. 
This does not apply to another, extremely decisive disadvantage for exact 
mass determination in the higher mass range: optimum mass resolution 
quickly decreases the higher the mass. For reasons of first order initial 
ion velocity focusing, the mass resolution is dependent on the velocity 
spread of the ions in front of the sample support. For a velocity 
distribution between 0 and 1,200 meters per second, mass resolution during 
first order focusing is limited theoretically to maximum values of about 
R.sub.m =40,000,000 amu/m, according to a rule of thumb derived from 
computer simulations. This rule is essentially independent from the length 
of the flight path, i.e. of the size of the mass spectrometer. 
Here, departing from the standard definition, mass resolution is understood 
to be the flight time of ions divided by the complete line width at the 
foot of the line (measured in the same time units), and not by the usual 
width at half height. For ions of the mass m=1,000 amu, a resolution of 
about R.sub.m =40,000 is thereby obtained which however drops for ions of 
the mass m=8,000 amu to R.sub.m =5,000. This means that two ions of the 
masses m.sub.1 =8,000 amu and m.sub.2 =8,001 amu can no longer be 
separated from one another. Therefore, for higher masses, the known 
isotope patterns of organic ions certainly cannot be resolved. In 
practice, these values even appear somewhat worse. 
The poor mass resolution for ions of a higher mass also leads to a poorer 
signal-to-noise ratio, and therefore to poorer sensitivity and to poorer 
detection capability. 
OBJECTIVE OF THE INVENTION 
It is the objective of the invention to considerably improve the achievable 
mass resolution of simply designed, linear time-of-flight mass 
spectrometers, especially in the higher mass range. 
BRIEF DESCRIPTION OF THE INVENTION 
The invention is based on the discovery that--even using delayed 
acceleration of ions--second order focusing is essentially only then 
possible if the sum of the lengths of the accelerating paths in the ion 
source is essentially larger than one eighth of the field-free flight path 
d.sub.3. The achievable resolution increases with the length of the 
acceleration paths; however, if the sum of the accelerating path lengths 
becomes greater than half the field-free flight path d.sub.3, there will 
no longer be any second order focusing. In addition, the first 
acceleration path should amount to 1/3 of the total acceleration path 
length in maximum. No time-of-flight spectrometer known today satisfies 
these requirements. Optimum focusing will be achieved if the sum of 
acceleration lengths is in the range between d.sub.3 /4 and d.sub.3 /2 and 
the first acceleration path is less than 1/10 of the total acceleration 
path length.. 
It is, therefore, the basic claim of the invention to construct a 
time-of-flight mass spectrometer in such a way that these requirements are 
satisfied. 
If two acceleration regions of lengths d.sub.1 and d.sub.2 are used, the 
analysis has shown that the resolution is better if the first accelerating 
path length d.sub.1 is rather small relative to the second accelerating 
path length d.sub.2. Then there even exists an optimum with third order 
focusing which is, however, mass dependent. 
It is therefore a further claim of the invention to design the mass 
spectrometer in such a way that the first accelerating path d.sub.1 is 
smaller than one tenth of accelerating path d.sub.2. The optimum is 
somewhere in the range of d.sub.2 /60&lt;d.sub.1 &lt;d.sub.2 /20. 
For certain ratios of the lengths d.sub.1, d.sub.2 and d.sub.3, third order 
focusing points result for one mass. The resulting high time-of-flight 
resolution (and therefore also high mass resolution) can be adjusted to 
any mass of the mass range by slight variations in those geometrical 
ratios. Here it arises that, below this mass for which a third order 
focusing was geometrically adjusted, also the second order focus points, 
adjustable purely through electrical changes, display unusually high 
resolutions. 
It is therefore a further claim of the invention to select the geometric 
ratios in such a way that a third order focusing is achieved for the upper 
limit of the mass range of interest.

DETAILED DESCRIPTION OF THE INVENTION 
Systematic analysis of the focusing conditions produced by delayed ion 
acceleration has shown that second or even third order focusing can exist 
when certain geometric requirements are fulfilled. These geometric 
requirements are highly unusual for modem time-of-flight mass 
spectrometers. The requirements are very difficult to derive by analytical 
mathematics, therefore it is simpler to examine them using computer 
simulation programs. 
A very simple time-flight mass spectrometer with two homogenous 
accelerating regions in the ion source and a subsequent field-free flight 
path was analyzed. In principle, almost all commercial mass spectrometers 
have this simple configuration even if they are not designed within the 
geometric parameter range required for higher order focusing. Additional 
post-accelerations after the field-free flight path did not show any 
effect upon resolution and focusing. 
We will use the following definition to characterize the order of a focus. 
It is first order when the deviations of flight times of ions of different 
initial velocities, applied over the initial velocity, produce a parabola, 
the summit of which represents the average velocity. It is second order if 
this curve is a third order curve, the turning point of which represents 
the average velocity. It is third order if the deviation form a parabola 
of fourth order. This definition results from the definition of focus 
orders as zero points of the corresponding derivatives. 
It was first determined in the analyses that second order focusing is 
essentially only then possible if the sum of the two accelerating paths 
d.sub.1 +d.sub.2 is larger than one eighth of the field-free flight path 
d.sub.3. In addition, d.sub.1 should be smaller than d.sub.2 /2. No 
time-of-flight spectrometer known today satisfies this requirement. 
Under unfavorable conditions for the ratio d.sub.1 /d.sub.2, there are some 
slight exceptions from the rule presented here. One of these exceptions is 
the focusing condition in the above quoted article. The resolution in 
these exceptions is not very favorable. 
If the accelerating path length is greater than half the field-free flight 
path d.sub.3, there will no longer be any second order focusing. Optimum 
focusing is achieved only in the range d.sub.3 /4.ltoreq.(d.sub.1 
+d.sub.2).ltoreq.d.sub.3 /2. 
It is the basic claim of the invention to construct a time-of-flight mass 
spectrometer in such a way that these requirements are satisfied. 
This means however that the accelerating path will be very long in general. 
Its field must therefore (as is already normally done for reflectors) be 
supported by homogenization diaphragms. The homogenization diaphragms are 
supplied with voltages via a voltage divider in such a way that a constant 
field is obtained in the interior. 
The analyses have also shown that the resolutions provided by the focusings 
are better if the first accelerating path d.sub.1 is small in relationship 
to the second accelerating path d.sub.2. There even exists--with 
relatively small lengths d.sub.1 for the accelerating path--an optimum 
with third order focusing which is, however, mass dependent. 
It is therefore a further claim of the invention to construct the mass 
spectrometer in such a way that the first accelerating path d.sub.1 is 
somewhere in the range of d.sub.2 /60 &lt;d.sub.1 &lt;d.sub.2 /20. 
For certain ratios of the lengths d.sub.1, d.sub.2 and d.sub.3, third order 
focusing points result for one mass. These sharpest mass signals of very 
high time-of-flight resolution (and therefore also high mass resolution) 
can be adjusted to any mass of the mass range by slight variations in 
those geometrical ratios. Here it arises that below this mass for which a 
third order focusing was geometrically adjusted, also the second order 
focus points, adjustable purely through electrical changes, display 
unusually high resolutions. 
It is therefore a further claim of the invention to select the geometric 
ratios in such a way that a third order focusing is achieved for the upper 
limit of the mass range of interest If, for example, the mass range of 
interest extends to 32,000 amu, one can then push the third order focus 
point onto the mass 32,000 amu with the ratio d.sub.1 :d.sub.2 :d.sub.3 
=9:200:550 (first example), and there one obtains--at about 30 kilovolts 
total accelerating voltage--a theoretical flight time resolution of about 
R.sub.t =900,000. This ratio is however not the only one which will give 
an optimal resolution at a mass of 32,000 amu. With the ratio d.sub.1 
:d.sub.2 :d.sub.3 =5:244:550 (second example) one can even reach a 
time-of-flight resolution of a million at the mass 32,000 amu. The 
resolutions are completely independent from the absolute size of the 
spectrometer in this theoretical case of a strictly valid correlation 
between spatial distribution and velocity distribution; only the geometric 
ratios are important. 
If one fixes these geometric ratios in a mass spectrometric apparatus, high 
resolutions can be achieved for all masses beneath this limit mass through 
pure electrical adjustments by second order focusing. The electrical 
settings refer here to the time lag .tau. and the first accelerating 
voltage U.sub.1. 
If the mass range of interest only extends to 16,000 amu, one can adjust 
the third order focus point to this mass with only slightly changed ratios 
d.sub.1 :d.sub.2 :d.sub.3 =8:200:550 (for the first example) or d.sub.1 
:d.sub.2 :d.sub.3 =4.45:244:550 (for the second example) and obtain 
electrically adjustable time resolutions above four million in the entire 
mass range of interest. 
The short first accelerating path d.sub.1 , according to the ratios 
provided by the second example, is very favorable: 
First, the field does not need to be homogenized using additional 
diaphragms. This primarily benefits the switching of the accelerating 
voltage, which needs a low electrical capacity for a rapid switching 
procedure. 
Second, the accelerating voltage to be switched is reduced in this way. 
This is proportional to the path d.sub.1. 
Third, the time lag .tau. however also becomes proportionally reduced. This 
causes the axial and especially the lateral expansion of the vapor and ion 
cloud to be smaller and the spatial focusing of the laterally escaping 
ions is more successful. 
It is therefore very important to make the first accelerating path as short 
as at all possible. However, there is also a lower limit for the 
accelerating path d.sub.1. If it is too small (such as with d.sub.1 
:d.sub.2 :d.sub.3 =4.3:250:550), the expanding ion cloud collides against 
the intermediate diaphragm within the optimum set time lag for heavy ion 
masses. This case can therefore practically not be used. It is therefore a 
further claim of this invention to construct a mass spectrometer with the 
optimum ratios d.sub.1 :d.sub.2 :d.sub.3 =5 (.+-.20%) :244 (.+-.10%):550. 
Two adjustment parameters suffice for the electrical adjustment of the 
optimum second or third focus points via the mass range. It has proven 
favorable to only change the time lag .tau. and the first accelerating 
voltage U.sub.1. In this case the accelerating voltage U.sub.1 need only 
to be changed by about 0.3%. If this accelerating voltage U.sub.1 is kept 
at the optimal value for a mass of 32,000 amu, and only the time lag .tau. 
is changed, no second order focusings will then occur over the entire mass 
range anymore, but there will still be resolutions which exceed those at a 
mass of 32,000 amu. Therefore an operation is possible in which only one 
single adjustment parameter is required for the shifting of the point of 
optimum focus (optimum resolution). 
This manner of operation has the additional advantage that not only the 
once calibrated mass relationship remains undisturbed by the adjustment, 
but also that the flight time in this particular case is in practice 
strictly proportional to the root from the mass. Deviations from the 
proportionality are below one millionth of the flight time. In this way, 
calibrations of the relationship of mass to flight time become 
extraordinarily simple. It is therefore a further claim of this invention 
to shift the range of optimum focus only via the time lag and keep the 
accelerating voltages (with the exception of switching on) constant. 
The great length of the accelerating paths for the ions also has 
disadvantages however. Since the ions obtain considerable lateral 
velocities in the explosively expanding vapor cloud, the ion beam diverges 
within the accelerating path. It is therefore a further claim of this 
invention to integrate an ion-optical lens for the ions in the second 
accelerating paths. This lens focuses the ion beam onto the detector, or 
makes the ion beam parallel This lens is already necessary if the 
intermediate diaphragm is designed as a grid; for a gridless design, 
further defocusing occurs at the entrance to the second acceleration path, 
so a lens is especially necessary here. Since another other defocusing 
occurs at the entrance to the field-free flight path, a second lens is 
favorable here. This may be designed as an Einzel lens. 
The embodiments described here for the mass spectrometer were all described 
with only one intermediate diaphragm. This embodiment is especially simple 
and already leads to sufficient resolutions. Even higher resolutions can 
be achieved with the introduction of further intermediate diaphragms at 
appropriate potentials. In particular, a mass spectrometer can be built in 
this way which generates precise second order focusings only by adjusting 
of the time lag .tau.. It is therefore a further claim of this invention 
to use more than just one intermediate electrode. 
Particularly Favorable Embodiments 
A design for a linear time-of-flight mass spectrometer with high resolution 
according to this invention is shown in principle in FIG. 1. Sample 
support 1 and intermediate electrode 2 have a relatively small distance 
d.sub.1 to one another; the switchable field needs no homogenization 
electrodes. The long distance d.sub.2 between intermediate electrode 2 and 
base electrode 3, on the other hand, requires homogenization of the field, 
implemented by the homogenization electrodes 11. These are supplied with 
voltage in the usual manner via the voltage divider with resistors 12. 
Without an early focusing of the ion beam, the long accelerating path would 
lead to considerable beam widening since the ions in the exploding 
substance cloud also obtain accelerations in the lateral direction. The 
initial velocities are vectors which are directed away from the origin of 
the cloud. It is therefore favorable to focus the ion beam, which is 
divergent in spite of axial acceleration, as early as possible. This 
focusing is generated through lens 13 which is integrated grated into the 
second accelerating path. The lens eliminates divergences which are 
generated by the feed through of the field of the second accelerating path 
into the field-free flight path. 
As designed above, the most favorable geometric embodiment is at a ratio of 
accelerating and flight paths of about d.sub.1 :d.sub.2 :d.sub.3 
=5:244:550. 
When using the above mentioned delayed ion acceleration, sample support 1 
and intermediate electrode 2 are first at potential U.sub.2. The sample 
support is switched up to the potential U.sub.1 +U.sub.2 after the time 
lag .tau. of several hundred to thousand nanoseconds after the ionizing 
laser flash. 
With the correct selection of time lag .tau. and the voltages U.sub.1, and 
U.sub.2, one achieves a high resolution at one mass in the spectrum by 
second order focusing, and for one mass, even third order focusing can be 
attained. Here, one of three adjustment parameters can be permanently 
selected, and for adjustment of the very high resolution, two adjustment 
parameters suffice. 
When operating with .tau. and U.sub.1, the accelerating voltage U.sub.1 
changes only minimally, so one therefore does better with variation of the 
time lag .tau. alone. Nevertheless this operation, which still does not 
bring about the practically unobtainable, very high resolutions, has 
enormous advantages since the function of mass versus flight time becomes 
very simple: the mass is practically proportional to the square of the 
flight time (for the ions of zero initial velocity, this condition is 
strictly fulfilled; for the ions of average initial velocity, there are 
minor deviations below a millionth of the mass). 
With this arrangement for a time-of-flight mass spectrometer, spectra of 
analysis substances can be scanned as usual. Scanning begins with 
ionization of the sample substances 8 on the sample support 1, as in the 
MALDI method of ionization described here. The ions are generated by a 
light flash of about 3 to 5 nanoseconds duration from laser 5. Usually, UV 
light with a wavelength of 337 nanometers is used from a moderately priced 
nitrogen laser. The light flash is focused through lens 6 as convergent 
light beam 7 onto the sample 8 on the surface of the sample support 1. The 
ions formed in the vapor cloud, which is generated by the laser focus, are 
accelerated after the time lag .tau., first in the electrical field of 
strength U.sub.1 /d.sub.1 between sample support 1 and intermediate 
electrode 2, and then in the electrical field of strength U.sub.2 /d.sub.2 
between intermediate electrode 2 and base electrode 3. The second 
accelerating field is only about half as strong as the first. The slightly 
defocused ion beam in the gridless electrode arrangement is focused at the 
beginning of the second accelerating path through lens 13 and at the 
beginning of the flight path in Einzel lens 4 onto detector 10. The flying 
ions form a temporally, strongly variable ion stream 9, which is measured 
at the end of the flight path by ion detector with high temporal 
resolution. 
Through the special MALDI process, mass signals can be generated at the 
detector which have a temporal width of far less than one nanosecond, even 
though the light flash of the laser has a temporal length of 3 to 5 
nanoseconds. (There is a "virtual", very sharply defined starting time for 
the adiabatic expansion). 
The time-variable, ion current provided by the ion beam is usually measured 
and digitalized at the detector with a scanning rate of 1 or 2 gigahertz. 
Transient recorders with a much higher temporal resolution will soon be 
available. Usually, the concurrent measured values from several scans are 
cumulated before the mass lines in the stored data are sought and 
transformed by means of peak recognition from the time scale into mass 
values via the mass calibration curve. 
The polarity of the high voltage used for the ion acceleration must be the 
same as the polarity of the ions being analyzed: positive ions are 
repelled and accelerated by a positively charged sample support, negative 
ions by a negatively charged sample support. 
Of course, the time-of-flight mass spectrometer can also be operated in 
such a way that the flight path is in a tube (not shown in FIG. 1), which 
is at accelerating potential U.sub.1 +U.sub.2 while the sample support 1 
is at ground potential. In this special case, the flight tube is at a 
positive potential if negatively charged ions are to be analyzed, and vice 
versa. This operation simplifies the design of the ion source, since the 
isolators for the holder of the exchangeable sample support port 1 are no 
longer necessary. In this case it is favorable to switch and vary the 
potential of the intermediate electrode. 
The focus range can be shifted as desired by control of two adjustment 
parameters, for example by the time lag .tau. and the initial accelerating 
voltage U.sub.1. It is possible to perform the shift in such a way that 
the calculated mass scale remains valid. To do this, the accelerating 
voltage U.sub.2 must also be very slightly changed in the appropriate 
manner. If this type of displacement of the focus range is permanently 
installed in the computer control of the mass spectrometer and no other 
control of the adjustment is permitted, this displacement of the focus 
range will not harm any mass determination, since the mass scale remains 
valid under these conditions. 
However, it is more favorable and simpler to use the above described method 
of focus adjustment just using the time lag, since the mass determination 
from the flight time then becomes especially simple. The linear connection 
between mass and flight time square leads to a one-point calibration if 
initiation point .tau. of the acceleration is sufficiently well known. 
However, since a finitely expanded voltage rise is present in practice, 
which slightly shifts the factual initiation of the acceleration compared 
to the initiation of the control system, a two-point calibration is used 
in practice. 
If the mass spectrometer is used for purposes during which the mass range 
of interest may shift extremely, one can make the distance d.sub.1 of the 
sample support-from the intermediate diaphragm variably adjustable, if 
possible even from outside the vacuum system. In this way, conformity to 
extreme conditions is possible. 
The invention is less well suited for mass spectrometers which are intended 
to measure fragment ions through MALDI-induced metastable decomposition 
(PSD=post source decay). The long accelerating path is unfavorable for 
this task. 
However the invention presented here is the best basis for a mass 
spectrometer which should allow routine molecular weight determinations on 
large numbers of samples. Its use is particularly suitable for production 
controls on polymers or genetically engineered pharmaceuticals, for 
genotyping, for DNA-mutation screening or for genetic fingerprints of 
different objectives. All these tasks share the fact that the expected 
molecular weights are known; the mass spectrometer can therefore be 
adjusted for every sample in such a way that the range of best focus and 
highest mass resolution is at the spectrum location of expected molecular 
weight. In this way not only the greatest mass resolution is provided in 
this range, but also an especially good ratio of signal to background 
noise through narrow mass signal profiles, and therefore an especially low 
detection limit The fast and simple calculation of the mass from the 
flight time is favorable for high sample throughput. Although high 
resolution may not be achieved in practical operation, the independence of 
the flight time achieved by this, and therefore the independence of the 
mass determination from the average velocity of the ions, is extremely 
valuable, which the ions could receive during alternating conditions for 
the MALDI process. Changes in laser energy or focusing conditions of 
lasers, variations in the preparation of the MALDI lasers with influences 
on the average velocity of the ions are no longer of any importance. 
The present tasks can be particularly well mastered if the molecule ions of 
interest are measured separately from neutral particles and fragment ions 
at the end of the field-free flight path, such as described in patent 
application BFA 46/96. 
In describing this invention, the MALDI method for ionization of substances 
on the sample support was assumed. However, similar conditions also apply 
for other methods of ionization of substances which are applied to a 
surface. Examples of this are secondary ion mass spectrometry (SIMS), 
normal laser desorption (LD) or so-called plasma desorption (PD), which is 
obtained by high-energy fission products on thin films. Although the focus 
has been on the MALDI method, the invention is not limited solely to this 
method, but relates to all methods by which ions are generated which have 
a spread of initial velocities, even if it is generally not as large as 
for the MALDI process.