Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1998-02-23
2001-07-03
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C324S309000, C424S009300
Reexamination Certificate
active
06256527
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for determining the oxygen concentration of a sample, for example a human or animal body, more particularly to the use of electron spin resonance enhanced magnetic resonance imaging (OMRI) of a sample to determine its oxygen concentration, and especially to the use of OMRI for the generation of images indicative of dissolved oxygen concentration in a sample.
BACKGROUND OF THE INVENTION
Oxygen plays a key role in the metabolic processes of biological systems and many conditions may be linked to abnormal levels of oxygen in the body. To provide a better understanding of this metabolic role and to aid clinical diagnosis, there is clearly a need to improve the means by which the level of oxygen in bodily tissues may be measured.
Conventional methods for determining oxygen concentrations are unsatisfactory. One such technique involves inserting a Clark electrode directly into a blood vessel to determine the local oxygen concentration. Clearly such a technique is of limited scope being invasive and usable only locally.
Non-invasive techniques have been slow to develop and generally are not suited to the study of tissues lying deep beneath the surface of a sample.
The most well-developed and accurate method for use ex vivo is that of “spin-label oximetry” in which changes in the esr linewidth of a free radical caused by the presence of oxygen are monitored. Such techniques generally use solid phase immobilized paramagnetic species as the spin-label and thus are not suited for in vivo measurements.
Electron spin resonance enhanced MRI, referred to herein as OMRI(Overhauser MRI) but also referred to in earlier publications as ESREMRI or PEDRI, is a well-established form of MRI in which enhancement of the magnetic resonance signals from which the images are generated is achieved by virtue of the dynamic nuclear polarization (the Overhauser effect) that occurs on VHF stimulation of an esr transition in a paramagnetic material, generally a persistent free radical, in the subject under study. Magnetic resonance signal enhancement may be by a factor of a hundred or more thus allowing OMRI images to be generated rapidly and with relatively low primary magnetic fields.
OMRI techniques have been described by several authors, notably Leunbach, Lurie, Ettinger, Grücker, Ehnholm and Sepponen, for example in EP-A-296833, EP-A-361551, WO-A-90/13047, J. Mag. Reson. 76:366-370(1988), EP-A-302742, SMRM 9:619(1990), SMRM 6:24(1987), SMRM 7:1094(1988), SMRM 8:329(1989), U.S. Pat. No. 4,719,425, SMRM 8:816(1989), Mag. Reson. Med. 14:140-147(1990), SMRM 9:617(1990), SMRM 9:612(1990), SMRM 9:121(1990), GB-A-2227095, DE-A-4042212 and GB-A-2220269.
In the basic OMRI technique, the imaging sequence involves initially irradiating a subject placed in a uniform magnetic field (the primary field B
o
) with radiation, usually VHF radiation, of a frequency selected to excite a narrow linewidth esr transition in a paramagnetic enhancement agent which is in or has been administered to the subject. Dynamic nuclear polarization results in an increase in the population difference between the excited and ground nuclear spin states of the imaging nuclei, i.e. those nuclei, generally protons, which are responsible for the magnetic resonance signals. Since MR signal intensity is proportional to this population difference, the subsequent stages of each imaging sequence, performed essentially as in conventional MRI techniques, result in larger amplitude MR signals being detected.
In any OMRI experiment under ambient conditions, paramagnetic oxygen will have a finite effect on the spin system present. Generally speaking, this may be dismissed as a secondary effect when compared to the primary interaction of the radical electron spin and the nuclear spin system. Nonetheless, it has been proposed that this effect may be used to determine oxygen concentration within a sample. However such research has concentrated particularly on the use of nitroxide spin labels; radicals which suffer the inherent disadvantage of having broad linewidth esr resonances and therefore low sensitivity to the effects of oxygen. Thus, to date, the effect of oxygen has been recognised only in a qualitative sense and any attempt to attach a quantitative significance to the oxygen effect has failed.
For example, Grücker et al (MRM, 34:219-225(1995)) reported a method for calculating oxygen concentration by measuring the Overhauser effect in a nitroxide radical and relating the non-linear effect of oxygen on the Overhauser Factor to its concentration. This involved taking two images, one on-resonance and one off-resonance, and using a first order approximation to arrive at the oxygen concentration. However, Grücker observed that the correlation between actual and calculated oxygen concentration was poor and therefore that the method was inherently inaccurate. This was attributed to the large number of parameters involved in the calculation.
Ehnholm (U.S. Pat. No. 5,289,125) has proposed an OMRI technique in which signals from a paramagnetic material are detected under at least two different sets of operating parameters whereby to generate images of various physical, chemical or biological parameters. While oxygen tension was one of several such parameters, Ehnholm did not demonstrate the use of the technique to quantitate dissolved oxygen.
SUMMARY OF THE INVENTION
The present invention relates to a non-invasive method for determining the oxygen concentration of a sample. It involves manipulation of the Overhauser effect in which polarisation is dynamically transferred to protons when an electron spin resonance transition of an administered persistent free radical is saturated. More specifically, the method is based on observing and manipulating the varying enhancement of a proton signal due to the changed saturation characteristics of a free radical in the presence of oxygen.
Thus viewed from one aspect the present invention provides a method of determining oxygen concentration in a sample, for example a human or non-human, preferably mammalian, subject, said method comprising the following steps: introducing into said sample an effective amount of a physiologically tolerable free radical (generally a persistent radical) having an esr transition with a linewidth (measured in water at 37° C.) of less than 400 mG, preferably less than 150 mG; irradiating said sample with radiation (generally referred to herein as VHF radiation) of an amplitude (i.e. power) and frequency selected to stimulate an electron spin resonance transition of said radical; detecting electron spin resonance enhanced magnetic resonance signals from said sample under at least first, second and third conditions, whereby under said first and second conditions said radiation is of a first frequency, under said third conditions said radiation is of a second frequency different from said first frequency, under said first, second and third conditions said radiation is of a first, second and third amplitude, said first and second amplitudes at least being different from each other; and manipulating said detected signals whereby to determine oxygen concentration in said sample.
REFERENCES:
patent: 4984573 (1991-01-01), Leubach
patent: 5289125 (1994-02-01), Ehnholm
patent: 5494030 (1996-02-01), Swartz et al.
patent: 5765562 (1998-06-01), Leunbach et al.
Ardenkjaer-Larsen Jan Henrik
Leunbach Ib
Bacon & Thomas
Lateef Marvin M.
Mantis Mercader Eleni
Nycomed Imaging AS
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