CA2190599A1 - Instrument for the diagnosis of cervical changes - Google Patents
Instrument for the diagnosis of cervical changesInfo
- Publication number
- CA2190599A1 CA2190599A1 CA002190599A CA2190599A CA2190599A1 CA 2190599 A1 CA2190599 A1 CA 2190599A1 CA 002190599 A CA002190599 A CA 002190599A CA 2190599 A CA2190599 A CA 2190599A CA 2190599 A1 CA2190599 A1 CA 2190599A1
- Authority
- CA
- Canada
- Prior art keywords
- cervical
- fluorescence
- cervix
- effacement
- light
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0082—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
- A61B5/0084—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for introduction into the body, e.g. by catheters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
- A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
- A61B5/4318—Evaluation of the lower reproductive system
- A61B5/4331—Evaluation of the lower reproductive system of the cervix
Abstract
The present invention relates to a method and instrumentation for detecting the changes in cervical connective tissues associated with cervical dilation or effacement. 7 his method uses an optical system to determine changes by laser or other light (12) induced native fluorescence spectroscopies (LIF) of cervix. The method is non-invasive and instant. It operates by shining excitation light (17) of a selected wavelength on cervical tissue and measuring fluorescent emissions. The measurement is completed in seconds. This method is an excellent fit with the clinical needs for determining the status of cervical dilation.
Description
2 1 ~059q DES~ ~ l vL~
'KI~V(JIINI~ OF T~R lNV~'`'L~
This invention relates to a non-invasive method for detecting changes in cervical connective tissue using light-induced native fluorescence spectroscopy. More exactly, this invention relates to a procedure useful for det~rrn;ninrJ changes in cervical tissues by recording connective tissue intrinsic fluorescence signals from the cervix of females using light-induced native fluorescence spectroscopy. The extent and progress of such changes relate to maternal readiness for fetal delivery and may be used to diagnose slow progress of labor or other complications .
The cervix is composed almost entirely of connective tissue comprising collagen and macromolecular components which make up the extracellular matrix of this tissue.
Many biochemical studies show that there are changes in cervical connective tissue during cervical ripening and dilation during labor. Collagen degradation resulting from increased collagenase activity may be a major element in cervical changes associated with labor.
Therefore, an instrument or procedure for instantly and non-invasively measuring these changes would be of great benefit to objectively evaluate the state of the cervix during labor.
Fluorescence spectroscopy is a widely utilized research tool in the biosciences (U~f~nfr~-~n~, 1962), primarily because of the amount of information that it can reveal in terms of molecular physical states (Cantor and Sr~; 1, 1980). Fluorescent spectra offer important details on the structure and dynamics of macromolecules , _ _ _ .... , . .. . _ W 9513 929 .~ J~5..
o 1 2 1 qO599 and their location at micro3copic levels (Lakowicz, 1986) .
Native fluorescence from intrinslc fluorophors in 5 tissues and cells provides a basis for diagnostic techniques relating to certain diseases (Glassman, 1993 ~ .
The intrinsic fluorophors, fllnrti~nntn~ as part of the unique but complicated biological system, change along with the status of cells and tissues. When 10 appropriately applied, tissue fluorescence can provide the medical and veterinary medical fields with a m;n;r~lly invagive yet highly accurate diagnostic technique. Thi8 fluorescence technique has been found to be useful for distinguishing some of the physiological 15 states of abnormal tissues as compared to the co~rr-Rpnnr~inS normal tissues (Alfano and Yao, 1981;
Alfano et al., 1984; Alfano et al., 1984; Alfano et al., 1987; Alfano et al., 1991). For example, studies have observed differences in the laser or other light-induced 20 native fluorescence spectra between normal tissues and neoplastic tumors in several types of the organs (Tang et al. 7989; Glassman et al. 1991; Cothren et al. 1990;
Richards-Kortum et al., 1991; Derk~lh~AI-m, et al. 1989; Ma et al., 1990; t~lAr et al., 1984). Similar studies 25 have also been done to determine diseased states such as mali~nAnr; f'R and~dysplasia with human reproductive organs such as cervix, ovary, and uterus (~ =E-~-n et al., 1991;
~llA~r~-n et al., 1994), however this technique has not been applied before to the diagnosis of cervical ripening 3 0 during pregnancy .
Presently there is no objective manner to evaluate cervical changes associated with rl;lAt;nn and effacement of the cervix during pregnancy. During pregnancy the 35 cervix is normally firm and closed. At the end of pregnancy the cervix becomes softer and dilates as the uterine contractions increase during labor. ~owever, . ...
Wo 95/31929 . ~
there are many timee when the cervix fails to dilate with advancing labor or when the cervix dilates ~ll tl1rely, prior to labor. The attending physician currently monitors progress of the cervix by visual inspection or 5 by manual examination . However, these subj ective tests are often inadequate and vary from physician to physician. An instrument or procedure to more accurately measure cervical changes associated with labor would be invaluable to the diagnosis of cervical problems such as lO premature dilation or prolonged labor and fetal distress due to delayed cervical dilation.
The present invention provides, for the first time, the ability to accurately and quantitatively determine 15 the status of cervical dilation during pregnancy, and particularly during the last stages of pregnancy and during labor. Differences in the intrinsic fluorescence spectra from the irradiated cervix are observed and compared at various time points during pregnancy and 20 during labor, giving the physician, veterinarian or research scientist instant knowledge of the status of the cervix and cervical opening of an animal or human subject. This knowledge is important for determination of proper tr~ . The present invention offers a 25 great; uv~ over manual palpation and subjective estimation of cervical status as currently practiced.
Use of the method described herein will enable safer and more accurate diagnoses concerning the preparation or lack thereof of a prenatal human or animal patient for 30 delivery and recovery.
~Y ûF l~IE l~VJ~ .LL~
The present invention relates to a method and 35 instL, ~;on for detecting the physiological and biochemical changes in cervical connective tissues associated with various stages of pregnancy, labor, W0 95/31929 r~
delivery and recovery. This method uses an optical syatem comprising laser or other light induced native fluorescence spectroscopies (LIF) from the cervix for monitoring these changes. The method is non-invasive and instant. It operates by shining excitation light of a selected wavelength on the cervix and measuring fluorescent emissions. The mea~u,~ - ~ is completed in seconds and a decrease in f luorescence or other relative changes in the f luorescence spectral prof iles indicates ~ t-;nn progress. This method fulfills an immediate clinical need for det~rm;n;n~ the status of cervical ta~; on during labor.
In more detail, the present invention involves a method for measuring relative cervical ~ l-; nn to follow the state of labor and anatomical readiness for fetal delivery. In addition, the method can be used to monitor l'ff~ , the obliteration of the cervix in labor when it is 80 changed that only the thin external 08 remains.
This method comprises irradiating cervical tissue with excitation light in an amount and at a wavelength sufficient to excite ;ntr;n~;c fluorophors in cervical connective tissue to f luoresce . The measurement of the fluorescent emissions from the irradiated cervical tissue is 18-; 1; 7C~ to monitor changes in the state of cervical ~l;l;lt-;nn, with a decrease in fluorescence indicating an increase in cervical ~ t l nn, The excitation light is preferably ultraviolet, more preferably from 300 to 380 nm, and even more preferably between 315 and 350 nm. By ultraviolet is meant light of wavelengths ju8t shorter than visible light. ~owever, it is understood that any excitation wavelength that induces intrinsic f luorescence in the cervical tissue without causing harm to said tissues is acceptable in the practice of the invention.
Fluorescent F.m; R~; nns~ measured are from 340 to 700 nm, more preferably from 340 to 500 nm, and may vary according to the excitation wavelength.
WO 95131929 2 ~ 9 0 5 9 9 ~ u~ ~
An instrument for measuring cervical tissue fluorescence from the surface is described. Such an instrument comprises an excitation means capable of producing light in the wavelength range from 300 to 380 5 nm. Such means includes a lamp or laser, as well as appropriate gratings, prism, lenses and/or filters. Any light source with grating, prism with selection slit and/or optical f ilters and lens that will produce a narrow band or even a monochromatic excitation light spectrum between about 300 nm to about 380 nm is suitable for the present invention. A preferred ' ~;r comprises a Xenon lamp and a narrow band 340 nm filter associated with a lens, however other light sources and means that produce the preferred excitation light would 15 also be acceptable. Other exemplary light sources might include, but are not limited to mercury lamps, selected monochromatic laser lights, for example, argon-ion lasers, pulsed nitrogen lasers, pulsed Ti: sapphire lasers and the like. It is also understood that any other light 20 source yielding adequate amountg of the n~r~8slry wavelengths of light, either directly or after appropriate filtering, or through grating or prism or other optical systems, to excite connective tissue compositions to fluoresce may be used.
~ ight from the source is transmitted through an optical f iber system so that the cervical tissue may be irradiated. Fluorescent light from the irradiated tissue is collected via a second optical fiber, or optical fiber 30 bundle, that transmits fluorescent light through the appropriate lenses and f ilters, or grating or prism system, to a means for measurement and/or spectral analysis. The means for mea~u~ t includes various optical sensing systems well known to those of skill in 35 the art, such as optical multichannel analysis, charge-coupled devices or photomultiplier tubes, for example.
Spectral analysi8 is ;Ir ~ h ~d by comparing the wo 95/3l929 ~ J~
measured fluorescence intensities, fluorescence spectral profile changes, and/or the changes in the ratios of the fluorescence intensities at different wavelengths.
The instrument of the present invention may further comprise a small optical catheter suitable for use in a human patient . Such a catheter comprises a means f or holding optical fiber bundles such that the tips of said bundles may be placed near the cervix, by for example, insertion of the catheter into the vagina. The catheter may further comprise an endoscope to aid the practitioner in locating the catheter near the cervix.
BRIEF DES~:K~ lCJN OF THE D~ rr FIG. 1. Fluorescence spectrum of collagen when excitation wavelength is 351 nm.
FIG. 2. A schematic of instrumentation for measuring the cervix fluorescence spectra.
FIG. 3. An exemplary excitation light spectrum.
FIG. 4. Average spectrum and the 95~ confidence interval from the middle ~band of cervix of the rats on 19 days of pregnancy .
FIG. 5. Average spectrum and the 9596 confidence interval f rom the middle band of cervix of the rats on 22 days of pregnancy but non-delivery.
FIG. 6 . Average- spectrum and the 95~ confidence interval from the middle :band of cervix of the rats on 22 days of pregnancy and in delivery.
Wo 95/31929 A ~,l/~,.,5,~
FIG. 7 . Average spectrum and the 95~ rrnf; r~PnrP interval from the middle band of cervix of the rats on normal 17 days of pregnancy.
.
5 FIG. 8 . Average spectrum and the 95~ c~nf; ~Pnre interval rom the middle band of cervix of the rats on 17 days of pregnancy with RU 38.486 treatment.
FIG . 9 . Total f luorescence counts between wavelength range 370 nm to 500 nm versus different stages of gestation. Error bars indicate the Mean~SEM.
FIG. 10. Fluorescence spectrum of elastin when excitation wavelength is 351 nm.
FIG . 11. Fluorescence spectrum of f ree ~ADH .
FIG. 12. Schematic diagram of the catheter for use in human patients in a side view and top view.
FIG. 13. Schematic diagram of the r~thPtP~ in place in the vagina of a subject.
DETZ~Tr-P!n IJl~ ' Kl~,lYJ!~ OF ~T~ S'K~ KK~ill P!MR-')17TMl;~
The present invention concerns an instrument and procedure for measuring cervical changes to objectively evaluate the state of the cervix bef ore during or even after labor. Such objective evaluation has not been 30 possible before the present invention.
It is extremely important for obstetricians to evaluate cervical changes associated with ~ t; t~n during pregnancy, especially by a non-invasive and rapid method.
3s The close monitoring of the cervical change is important for determin~t~rn of proper trP;~ ' ~. Optical methods using fluorescence spectroscopy and optical fiber WO 95/31929 1 ~ . 'C - .
technology may be used to evaluate connective tissues changes in the reproductive system. The method is based on changes in fluorescence spectra of the cervix due to cervical tissue alterations during dilation in labor.
The cervix contains connective tissue comprising collagen and macromolecular, ~ ~n~ that make up the extracellular tissue matrix (Fosang et al) and there are h; t~rhl~m; cal changes in cervical connective tissue during 10 cervical ripeni~g and ~ tirn during labor (Fosang et al.; Granstrom et al., 1989). Collagen degradation from increased collagenase activity associated with labor, may be a major element in cervical changes (Osmers et al., l990; Kokenyesi and Woessner, 1991). Collagen presents a 15 characteristic f luorescence spectrum as shown in FIG .
(Glassman, 1993). The fluorophors in the collagen are ;tl~nt;f;rd as pyridinoline, a 3-hydroxypyridinium ring derived from three residues of hydroxylysine.
Pyridinoline plays a role in crosglinking the crl 1 ;~n 20 fibers (Eyre et al., 1984).
r~nn~ctive tissue changes of the reproductive system in pregnancy and during labor may be monitored by measuring native f luorescence spectra . The native 25 fluorescence spectra from the cervix of pregnant rats demonstrate such monitoring. The fluorescence spectra f rom the cervix of pregnant rats in the process o~ labor were measured . Dif f erences were f ound between fluorescence spectra from pregnant rats and from pregnant 3 0 rats in labor . Cervical dilation is accompanied by a decrease in f luorescence around certain wavelengths .
Therefore, cervical dilation may be monitored by a comparison of intrinsic fluorescence from the cervical tissue over the course of time, with a decrease in 35 fluorescence indicating cervical ~ t;rn.
Wo 95/31929 1 ~ -"~
21 ~05~9 A preferred method of quantifying these differences is by comparing the fluorescence peak intensity at about 390 nm either by its absolute fluorescence intensity and/or by its relative fluorescence intensities compared to the intensities at other wavelengths or from other - objects. The6e differences may be observed when exciting tissue with a light ~ource (laser or lamp). Detection and mea:juL, ~ of fluorescence is preferably accomplished with filter~, a monochromator, an OMA or CCD
10 camera, or photomultiplier tubes and a computer system with display and print or platter. Thi~ method preferably uses optical fibers to deliver the excitation light and to collect fluorescence signals.
15 The excitation light source can be in the wavelength range of 315 nm to 380 nm, produced by a lamp with selective filters or selective means with grating or prism, or lasers which have output wavelength in thi~
range. A preferred lamp i5 a Xenon lamp. Fluorescence 20 intensity is preferably measured from 320 nm to 700 nm, which can be varied according to the excitation light.
The fluorescence wavelength is always greater than the excitation wavelength.
25 The following examples are included to demonstrate useful ~omho~ ~ of the present invention but are not ; n~n~d to limit the scope of this invention unless otherwise specified in the claims.
3 0 ~MPI~E
Optical Spectroacopy Methods The equipment 10 used in the fluorescence spectral mea~LILt ~ of rat cervix is schematically shown in FIG.
35 2. The excitation light source 12 i; a xe~on lamp (Type No. L2274, with power supply (150W-GS) Model C2499-01, HAM~MATSU P~OTONICS). ~ight passes through an ACS lens WO 95/31929 P~ r E ~ .
14 (Newport Corporation) placed in front of the light house with a ground glass window to collect the light.
The excitation wavelength is selected with a narrow band optical filter 16 with center wavelength at 340 nm (Model ~o. 53390, orial Corp., P.O. sox 872, Stratford, CT
06497-9988). The selected light 17 is focused through a fused silica lens 18 (ESCO Product~, Inc. f=2.5cm) at one end 19 of an optical fiber 24 (Model Number ~ICG-M0550T-10, Ensign-Bickford optics Company, 150 Fisher Drive, Avon, Connecticut 06001) held in an optical fiber holder 22 for delivery of .oY~ it~t;on light. The ground glass window and the 340 nm narrow band filter æhaped the excitation light spectrum as a narrow peak centered at 348 nm with band width of 5 nm (as shown in FIG. 3). The excitation light 17 delivered through the f iber 24 to the fiber tips 25 and irradiates the measured site 26. The light power at this point is about 12 I~W. The fluorescence emission light is collected by the tips 27 of a ~econd optical fiber 28 (Ensign-Bickford Optics Company, 150 Fisher Drive, Avon, ~Annlo~t;rllt 06001). The other end 30 of collPrt;n~ fiber 28 is located at the focus point of a BK7 glass lens 32. The collected signals are transmitted through a long path color yla~s filter 34 (0-51, ESCO products Inc. ) with cut off wavelength at 360 nm (196 transition at this wavelength), focused by an achromatic lens (PAC 052, Newport, Co) 36, off a mirror 38 into a yrating monochromator 40 (1200G/mm, Instruments SA, Inc., 173 Essex Avenue, Metuchen, New Jersey 08840). The spectra are then recorded by an optical multichannel analyzer 42 (OMA) (Model 1460, EG & E Princeton Applied Research, 6 DeAngelo Drive, Bedford, M~RR~h,lR~tts 01730) . The time required for taking a complete spectrum is less than 10 ~econds. This time may be greatly reduced by the use of a more sensitive rPcnrtl;n~ system such as CCD camera 44.
A charge-coupled device (CCD) camera would also make it possible to monitor the signal changes on a real time Wo 95/31929 2 1 9 0 5 q 9 r~
basis. The spectra measuring time can be decreased if the excitation light power increases. However, for in vivo applications, it is better to use low light power and more sensitive rlPtP~-t;nn devices.
In the example below, the excitation light fiber 52 tip 55 and the emission light fiber 53 tip 55 were placed at 15 degree angles. The tips were kept the same distance of 1 mm away from the measuring site of the tissue. A catheter design is also disclosed (FIG. 12) that is suitable for applications in human patients.
~X ~MPLE 2 Measurir~g Native Fluore~ce.-ce ~pectra fro~ Rat Cervix ill vivo Method~
Rats were anesthetized with IP inj ection of Ketamine HCI/Xylazine (15 mg/2mg). Dissection was performed to 20 open abdomens of the rats in order to allow optical fiber tips to reach the cervix. The mea ,uL~ were performed in vivo on various lo~t;f~nc of the middle band of the cervix.
A total of 37 rata at various stages of gestation and the labor process were used in this example. Rats were separated into 9 groups as shown in Table 1 (which indicates the number of rats and total points of mea~uL - ). The groups were first divided according to the days of pregnancy: 15 days (dl5), 17 days (dl7), 19 days ~dl9), 20 days (d20) and 21 days (d21). At term, on day 22 of pregnancy, there were three groups: non-delivery (d22nd), pup engaged, i.e. in the birth canal (d22eng) and at delivery with 2-3 pups delivered 35 (d22del).
Wo 95/31929 ~ 12 -There is a second group (dl7RU) of rats at 17 days of pregnancy. These rats were treated with IP injection of vehicle (castor oil & benzoyl benzoate) plus RU 38.486 (10 mg per rat) at 16 days of pregnancy, and measured approximately 24 hours later. RU 38.486 is a progesterone receptor antagonist that is used as an abortifacient and contraceptive. RU 486 is the popular name for mifepristone and RU 38.486 is the popular name for miegyne, 11~-[4-(N,N-dimethylamino)phenyl]-17c~!-(prop-1-ynyl)-~4~9-estradiene-17,l~-ol-3-o~e.
Administration of RU 38.486 induces cervical softening and preterm delivery. This effect of the drug would al90 result in cervical changes similar to those seen in normal labor and delivery. Therefore, RU 38.486 is a positive control or the methods disclosed herein.
The physiological change in the cervix can be clearly observed after dissection, even though the pups were not clearly engaged. In contrast, one control rat was IP injected at day 16 with only the vehicle (castor oil & benzoyl b~-n70at-~) and the meabUl t was performed 24 hours later on day 17. This rat showed the spectra similar to the untreated rats on day 17, and was thereore grouped with dl7.
Table 1: Li_t of the Groupa of Rat~ and MeaD~ e ta Sta3~s D15 D17 D19 D20 D21 D22nd D22 D22 D17 eng ~el RU
No. of 4 3 4 4 6 4 4 3 4 Rats 30 Total # of lO 8 10 11 l9 12 13 ll 15 Measure-ments Wo 95/31929 P~ ,0' 2lqas~s There were clear changes in the f luorescence intensities but small fluorescence profile changes in the tested groups. The average spectra and its 95~
confidence margin from the cervix on gestational day 19, 5 day 22 non-delivery and day 22 delivery are shown in FIG.
'KI~V(JIINI~ OF T~R lNV~'`'L~
This invention relates to a non-invasive method for detecting changes in cervical connective tissue using light-induced native fluorescence spectroscopy. More exactly, this invention relates to a procedure useful for det~rrn;ninrJ changes in cervical tissues by recording connective tissue intrinsic fluorescence signals from the cervix of females using light-induced native fluorescence spectroscopy. The extent and progress of such changes relate to maternal readiness for fetal delivery and may be used to diagnose slow progress of labor or other complications .
The cervix is composed almost entirely of connective tissue comprising collagen and macromolecular components which make up the extracellular matrix of this tissue.
Many biochemical studies show that there are changes in cervical connective tissue during cervical ripening and dilation during labor. Collagen degradation resulting from increased collagenase activity may be a major element in cervical changes associated with labor.
Therefore, an instrument or procedure for instantly and non-invasively measuring these changes would be of great benefit to objectively evaluate the state of the cervix during labor.
Fluorescence spectroscopy is a widely utilized research tool in the biosciences (U~f~nfr~-~n~, 1962), primarily because of the amount of information that it can reveal in terms of molecular physical states (Cantor and Sr~; 1, 1980). Fluorescent spectra offer important details on the structure and dynamics of macromolecules , _ _ _ .... , . .. . _ W 9513 929 .~ J~5..
o 1 2 1 qO599 and their location at micro3copic levels (Lakowicz, 1986) .
Native fluorescence from intrinslc fluorophors in 5 tissues and cells provides a basis for diagnostic techniques relating to certain diseases (Glassman, 1993 ~ .
The intrinsic fluorophors, fllnrti~nntn~ as part of the unique but complicated biological system, change along with the status of cells and tissues. When 10 appropriately applied, tissue fluorescence can provide the medical and veterinary medical fields with a m;n;r~lly invagive yet highly accurate diagnostic technique. Thi8 fluorescence technique has been found to be useful for distinguishing some of the physiological 15 states of abnormal tissues as compared to the co~rr-Rpnnr~inS normal tissues (Alfano and Yao, 1981;
Alfano et al., 1984; Alfano et al., 1984; Alfano et al., 1987; Alfano et al., 1991). For example, studies have observed differences in the laser or other light-induced 20 native fluorescence spectra between normal tissues and neoplastic tumors in several types of the organs (Tang et al. 7989; Glassman et al. 1991; Cothren et al. 1990;
Richards-Kortum et al., 1991; Derk~lh~AI-m, et al. 1989; Ma et al., 1990; t~lAr et al., 1984). Similar studies 25 have also been done to determine diseased states such as mali~nAnr; f'R and~dysplasia with human reproductive organs such as cervix, ovary, and uterus (~ =E-~-n et al., 1991;
~llA~r~-n et al., 1994), however this technique has not been applied before to the diagnosis of cervical ripening 3 0 during pregnancy .
Presently there is no objective manner to evaluate cervical changes associated with rl;lAt;nn and effacement of the cervix during pregnancy. During pregnancy the 35 cervix is normally firm and closed. At the end of pregnancy the cervix becomes softer and dilates as the uterine contractions increase during labor. ~owever, . ...
Wo 95/31929 . ~
there are many timee when the cervix fails to dilate with advancing labor or when the cervix dilates ~ll tl1rely, prior to labor. The attending physician currently monitors progress of the cervix by visual inspection or 5 by manual examination . However, these subj ective tests are often inadequate and vary from physician to physician. An instrument or procedure to more accurately measure cervical changes associated with labor would be invaluable to the diagnosis of cervical problems such as lO premature dilation or prolonged labor and fetal distress due to delayed cervical dilation.
The present invention provides, for the first time, the ability to accurately and quantitatively determine 15 the status of cervical dilation during pregnancy, and particularly during the last stages of pregnancy and during labor. Differences in the intrinsic fluorescence spectra from the irradiated cervix are observed and compared at various time points during pregnancy and 20 during labor, giving the physician, veterinarian or research scientist instant knowledge of the status of the cervix and cervical opening of an animal or human subject. This knowledge is important for determination of proper tr~ . The present invention offers a 25 great; uv~ over manual palpation and subjective estimation of cervical status as currently practiced.
Use of the method described herein will enable safer and more accurate diagnoses concerning the preparation or lack thereof of a prenatal human or animal patient for 30 delivery and recovery.
~Y ûF l~IE l~VJ~ .LL~
The present invention relates to a method and 35 instL, ~;on for detecting the physiological and biochemical changes in cervical connective tissues associated with various stages of pregnancy, labor, W0 95/31929 r~
delivery and recovery. This method uses an optical syatem comprising laser or other light induced native fluorescence spectroscopies (LIF) from the cervix for monitoring these changes. The method is non-invasive and instant. It operates by shining excitation light of a selected wavelength on the cervix and measuring fluorescent emissions. The mea~u,~ - ~ is completed in seconds and a decrease in f luorescence or other relative changes in the f luorescence spectral prof iles indicates ~ t-;nn progress. This method fulfills an immediate clinical need for det~rm;n;n~ the status of cervical ta~; on during labor.
In more detail, the present invention involves a method for measuring relative cervical ~ l-; nn to follow the state of labor and anatomical readiness for fetal delivery. In addition, the method can be used to monitor l'ff~ , the obliteration of the cervix in labor when it is 80 changed that only the thin external 08 remains.
This method comprises irradiating cervical tissue with excitation light in an amount and at a wavelength sufficient to excite ;ntr;n~;c fluorophors in cervical connective tissue to f luoresce . The measurement of the fluorescent emissions from the irradiated cervical tissue is 18-; 1; 7C~ to monitor changes in the state of cervical ~l;l;lt-;nn, with a decrease in fluorescence indicating an increase in cervical ~ t l nn, The excitation light is preferably ultraviolet, more preferably from 300 to 380 nm, and even more preferably between 315 and 350 nm. By ultraviolet is meant light of wavelengths ju8t shorter than visible light. ~owever, it is understood that any excitation wavelength that induces intrinsic f luorescence in the cervical tissue without causing harm to said tissues is acceptable in the practice of the invention.
Fluorescent F.m; R~; nns~ measured are from 340 to 700 nm, more preferably from 340 to 500 nm, and may vary according to the excitation wavelength.
WO 95131929 2 ~ 9 0 5 9 9 ~ u~ ~
An instrument for measuring cervical tissue fluorescence from the surface is described. Such an instrument comprises an excitation means capable of producing light in the wavelength range from 300 to 380 5 nm. Such means includes a lamp or laser, as well as appropriate gratings, prism, lenses and/or filters. Any light source with grating, prism with selection slit and/or optical f ilters and lens that will produce a narrow band or even a monochromatic excitation light spectrum between about 300 nm to about 380 nm is suitable for the present invention. A preferred ' ~;r comprises a Xenon lamp and a narrow band 340 nm filter associated with a lens, however other light sources and means that produce the preferred excitation light would 15 also be acceptable. Other exemplary light sources might include, but are not limited to mercury lamps, selected monochromatic laser lights, for example, argon-ion lasers, pulsed nitrogen lasers, pulsed Ti: sapphire lasers and the like. It is also understood that any other light 20 source yielding adequate amountg of the n~r~8slry wavelengths of light, either directly or after appropriate filtering, or through grating or prism or other optical systems, to excite connective tissue compositions to fluoresce may be used.
~ ight from the source is transmitted through an optical f iber system so that the cervical tissue may be irradiated. Fluorescent light from the irradiated tissue is collected via a second optical fiber, or optical fiber 30 bundle, that transmits fluorescent light through the appropriate lenses and f ilters, or grating or prism system, to a means for measurement and/or spectral analysis. The means for mea~u~ t includes various optical sensing systems well known to those of skill in 35 the art, such as optical multichannel analysis, charge-coupled devices or photomultiplier tubes, for example.
Spectral analysi8 is ;Ir ~ h ~d by comparing the wo 95/3l929 ~ J~
measured fluorescence intensities, fluorescence spectral profile changes, and/or the changes in the ratios of the fluorescence intensities at different wavelengths.
The instrument of the present invention may further comprise a small optical catheter suitable for use in a human patient . Such a catheter comprises a means f or holding optical fiber bundles such that the tips of said bundles may be placed near the cervix, by for example, insertion of the catheter into the vagina. The catheter may further comprise an endoscope to aid the practitioner in locating the catheter near the cervix.
BRIEF DES~:K~ lCJN OF THE D~ rr FIG. 1. Fluorescence spectrum of collagen when excitation wavelength is 351 nm.
FIG. 2. A schematic of instrumentation for measuring the cervix fluorescence spectra.
FIG. 3. An exemplary excitation light spectrum.
FIG. 4. Average spectrum and the 95~ confidence interval from the middle ~band of cervix of the rats on 19 days of pregnancy .
FIG. 5. Average spectrum and the 9596 confidence interval f rom the middle band of cervix of the rats on 22 days of pregnancy but non-delivery.
FIG. 6 . Average- spectrum and the 95~ confidence interval from the middle :band of cervix of the rats on 22 days of pregnancy and in delivery.
Wo 95/31929 A ~,l/~,.,5,~
FIG. 7 . Average spectrum and the 95~ rrnf; r~PnrP interval from the middle band of cervix of the rats on normal 17 days of pregnancy.
.
5 FIG. 8 . Average spectrum and the 95~ c~nf; ~Pnre interval rom the middle band of cervix of the rats on 17 days of pregnancy with RU 38.486 treatment.
FIG . 9 . Total f luorescence counts between wavelength range 370 nm to 500 nm versus different stages of gestation. Error bars indicate the Mean~SEM.
FIG. 10. Fluorescence spectrum of elastin when excitation wavelength is 351 nm.
FIG . 11. Fluorescence spectrum of f ree ~ADH .
FIG. 12. Schematic diagram of the catheter for use in human patients in a side view and top view.
FIG. 13. Schematic diagram of the r~thPtP~ in place in the vagina of a subject.
DETZ~Tr-P!n IJl~ ' Kl~,lYJ!~ OF ~T~ S'K~ KK~ill P!MR-')17TMl;~
The present invention concerns an instrument and procedure for measuring cervical changes to objectively evaluate the state of the cervix bef ore during or even after labor. Such objective evaluation has not been 30 possible before the present invention.
It is extremely important for obstetricians to evaluate cervical changes associated with ~ t; t~n during pregnancy, especially by a non-invasive and rapid method.
3s The close monitoring of the cervical change is important for determin~t~rn of proper trP;~ ' ~. Optical methods using fluorescence spectroscopy and optical fiber WO 95/31929 1 ~ . 'C - .
technology may be used to evaluate connective tissues changes in the reproductive system. The method is based on changes in fluorescence spectra of the cervix due to cervical tissue alterations during dilation in labor.
The cervix contains connective tissue comprising collagen and macromolecular, ~ ~n~ that make up the extracellular tissue matrix (Fosang et al) and there are h; t~rhl~m; cal changes in cervical connective tissue during 10 cervical ripeni~g and ~ tirn during labor (Fosang et al.; Granstrom et al., 1989). Collagen degradation from increased collagenase activity associated with labor, may be a major element in cervical changes (Osmers et al., l990; Kokenyesi and Woessner, 1991). Collagen presents a 15 characteristic f luorescence spectrum as shown in FIG .
(Glassman, 1993). The fluorophors in the collagen are ;tl~nt;f;rd as pyridinoline, a 3-hydroxypyridinium ring derived from three residues of hydroxylysine.
Pyridinoline plays a role in crosglinking the crl 1 ;~n 20 fibers (Eyre et al., 1984).
r~nn~ctive tissue changes of the reproductive system in pregnancy and during labor may be monitored by measuring native f luorescence spectra . The native 25 fluorescence spectra from the cervix of pregnant rats demonstrate such monitoring. The fluorescence spectra f rom the cervix of pregnant rats in the process o~ labor were measured . Dif f erences were f ound between fluorescence spectra from pregnant rats and from pregnant 3 0 rats in labor . Cervical dilation is accompanied by a decrease in f luorescence around certain wavelengths .
Therefore, cervical dilation may be monitored by a comparison of intrinsic fluorescence from the cervical tissue over the course of time, with a decrease in 35 fluorescence indicating cervical ~ t;rn.
Wo 95/31929 1 ~ -"~
21 ~05~9 A preferred method of quantifying these differences is by comparing the fluorescence peak intensity at about 390 nm either by its absolute fluorescence intensity and/or by its relative fluorescence intensities compared to the intensities at other wavelengths or from other - objects. The6e differences may be observed when exciting tissue with a light ~ource (laser or lamp). Detection and mea:juL, ~ of fluorescence is preferably accomplished with filter~, a monochromator, an OMA or CCD
10 camera, or photomultiplier tubes and a computer system with display and print or platter. Thi~ method preferably uses optical fibers to deliver the excitation light and to collect fluorescence signals.
15 The excitation light source can be in the wavelength range of 315 nm to 380 nm, produced by a lamp with selective filters or selective means with grating or prism, or lasers which have output wavelength in thi~
range. A preferred lamp i5 a Xenon lamp. Fluorescence 20 intensity is preferably measured from 320 nm to 700 nm, which can be varied according to the excitation light.
The fluorescence wavelength is always greater than the excitation wavelength.
25 The following examples are included to demonstrate useful ~omho~ ~ of the present invention but are not ; n~n~d to limit the scope of this invention unless otherwise specified in the claims.
3 0 ~MPI~E
Optical Spectroacopy Methods The equipment 10 used in the fluorescence spectral mea~LILt ~ of rat cervix is schematically shown in FIG.
35 2. The excitation light source 12 i; a xe~on lamp (Type No. L2274, with power supply (150W-GS) Model C2499-01, HAM~MATSU P~OTONICS). ~ight passes through an ACS lens WO 95/31929 P~ r E ~ .
14 (Newport Corporation) placed in front of the light house with a ground glass window to collect the light.
The excitation wavelength is selected with a narrow band optical filter 16 with center wavelength at 340 nm (Model ~o. 53390, orial Corp., P.O. sox 872, Stratford, CT
06497-9988). The selected light 17 is focused through a fused silica lens 18 (ESCO Product~, Inc. f=2.5cm) at one end 19 of an optical fiber 24 (Model Number ~ICG-M0550T-10, Ensign-Bickford optics Company, 150 Fisher Drive, Avon, Connecticut 06001) held in an optical fiber holder 22 for delivery of .oY~ it~t;on light. The ground glass window and the 340 nm narrow band filter æhaped the excitation light spectrum as a narrow peak centered at 348 nm with band width of 5 nm (as shown in FIG. 3). The excitation light 17 delivered through the f iber 24 to the fiber tips 25 and irradiates the measured site 26. The light power at this point is about 12 I~W. The fluorescence emission light is collected by the tips 27 of a ~econd optical fiber 28 (Ensign-Bickford Optics Company, 150 Fisher Drive, Avon, ~Annlo~t;rllt 06001). The other end 30 of collPrt;n~ fiber 28 is located at the focus point of a BK7 glass lens 32. The collected signals are transmitted through a long path color yla~s filter 34 (0-51, ESCO products Inc. ) with cut off wavelength at 360 nm (196 transition at this wavelength), focused by an achromatic lens (PAC 052, Newport, Co) 36, off a mirror 38 into a yrating monochromator 40 (1200G/mm, Instruments SA, Inc., 173 Essex Avenue, Metuchen, New Jersey 08840). The spectra are then recorded by an optical multichannel analyzer 42 (OMA) (Model 1460, EG & E Princeton Applied Research, 6 DeAngelo Drive, Bedford, M~RR~h,lR~tts 01730) . The time required for taking a complete spectrum is less than 10 ~econds. This time may be greatly reduced by the use of a more sensitive rPcnrtl;n~ system such as CCD camera 44.
A charge-coupled device (CCD) camera would also make it possible to monitor the signal changes on a real time Wo 95/31929 2 1 9 0 5 q 9 r~
basis. The spectra measuring time can be decreased if the excitation light power increases. However, for in vivo applications, it is better to use low light power and more sensitive rlPtP~-t;nn devices.
In the example below, the excitation light fiber 52 tip 55 and the emission light fiber 53 tip 55 were placed at 15 degree angles. The tips were kept the same distance of 1 mm away from the measuring site of the tissue. A catheter design is also disclosed (FIG. 12) that is suitable for applications in human patients.
~X ~MPLE 2 Measurir~g Native Fluore~ce.-ce ~pectra fro~ Rat Cervix ill vivo Method~
Rats were anesthetized with IP inj ection of Ketamine HCI/Xylazine (15 mg/2mg). Dissection was performed to 20 open abdomens of the rats in order to allow optical fiber tips to reach the cervix. The mea ,uL~ were performed in vivo on various lo~t;f~nc of the middle band of the cervix.
A total of 37 rata at various stages of gestation and the labor process were used in this example. Rats were separated into 9 groups as shown in Table 1 (which indicates the number of rats and total points of mea~uL - ). The groups were first divided according to the days of pregnancy: 15 days (dl5), 17 days (dl7), 19 days ~dl9), 20 days (d20) and 21 days (d21). At term, on day 22 of pregnancy, there were three groups: non-delivery (d22nd), pup engaged, i.e. in the birth canal (d22eng) and at delivery with 2-3 pups delivered 35 (d22del).
Wo 95/31929 ~ 12 -There is a second group (dl7RU) of rats at 17 days of pregnancy. These rats were treated with IP injection of vehicle (castor oil & benzoyl benzoate) plus RU 38.486 (10 mg per rat) at 16 days of pregnancy, and measured approximately 24 hours later. RU 38.486 is a progesterone receptor antagonist that is used as an abortifacient and contraceptive. RU 486 is the popular name for mifepristone and RU 38.486 is the popular name for miegyne, 11~-[4-(N,N-dimethylamino)phenyl]-17c~!-(prop-1-ynyl)-~4~9-estradiene-17,l~-ol-3-o~e.
Administration of RU 38.486 induces cervical softening and preterm delivery. This effect of the drug would al90 result in cervical changes similar to those seen in normal labor and delivery. Therefore, RU 38.486 is a positive control or the methods disclosed herein.
The physiological change in the cervix can be clearly observed after dissection, even though the pups were not clearly engaged. In contrast, one control rat was IP injected at day 16 with only the vehicle (castor oil & benzoyl b~-n70at-~) and the meabUl t was performed 24 hours later on day 17. This rat showed the spectra similar to the untreated rats on day 17, and was thereore grouped with dl7.
Table 1: Li_t of the Groupa of Rat~ and MeaD~ e ta Sta3~s D15 D17 D19 D20 D21 D22nd D22 D22 D17 eng ~el RU
No. of 4 3 4 4 6 4 4 3 4 Rats 30 Total # of lO 8 10 11 l9 12 13 ll 15 Measure-ments Wo 95/31929 P~ ,0' 2lqas~s There were clear changes in the f luorescence intensities but small fluorescence profile changes in the tested groups. The average spectra and its 95~
confidence margin from the cervix on gestational day 19, 5 day 22 non-delivery and day 22 delivery are shown in FIG.
4, FIG. 5 and FIG. 6, respectively. The results show a significant decrease in intensities from day l9 to day 22 non-delivery, and from day 22 non-delivery to day 22 delivery. The average spectra and its gs~ r~nfi~1~n~e 10 margin from the rats on day 17 and the rats on day 17 treated with RU 38.486 are shown in FIG. 7 and FIG. 8, re3pectively. The fluorescence intensity also shows significant decrease from normal ~L ::yl~lt day 17 rats to day 17 RU 38.486 treated rats.
Total counts of each mea~u" nt of fluorescence f rom the wavelength range 3 7 o nm to 5 0 0 nm have been calculated and analyzed for statistical significance.
The mean with SEM of each group at different stages of 20 gestation are shown in FIG. 9. The one-factor ANOVA
analysis was highly significant (F=10.4, p~ 001~. The a priori comparison results between individual groups are shown in Table 2. The total counts integrated within other narrower wavelength ranges, 395 nm to 415 nm for 25 example, have also been calculated. The statistical analysis showed similar results.
The results show the clear changes of the native cervical fluorescence during various stages of gestation 30 with high statistical sign; fic~n~e. The amount of fluorescence decreases when the pregnancy is close to term, and reaches its lowest point when pups are engaged and in delivery. RU 38.486 treatment on day 16 of gestation also caused the native fluorescence to 35 decrease. Although the decrease in fluorescence in the RU38.486 treated rats did not reach the levels of decrease in delivering rats, this is simply because the Wo 95131929 ~ n, r -- -2 t 90~99 treated rat6 were not monitored through delivery. ~ad the treated rats been monitored through delivery, it is understood that the f luorescence would have reached the lower levels observed in untreated delivering rats.
Table 2: A priori Comparisons Results between Group~
(LSD Nethod).
D15 D17 D19 D20 D21 D22nd D22 D22 D~7 ~n del RU
0 D15 ~ *~ .** ... .c D17 * .. .~. ... *
Dl9 '' * *** *** ***
D20 *** ~** *
D21 *** *.
15 D22nd D22eng D22del 20 * p-value < 0 . 05 ** p-value < 0 . 01 *** p-value < 0 . 001 These changes in the native cervical f luorescence may be the result of either or both biochemical and physiological changes of cervical tissues during gestation and labor. As stated above, the general structure of the fluorescence spectra from the cervix seems similar. The fluorescence of the cervix of rats may be mostly contributed by pyridinoline cross-links since the collagen concentration is very high in the rat cervix tissue (Leppert and Yu, 1991). There may be some Wo 95/31929 . ~
small amount of fluorescence contribution from elastin and NADX which overlap on the collagen gpectrum (rl~Rrm~n et al., 1991; r-lA~rm~n, 1993), Fluorescence spectra of elastin and NADH are shown in FIG. 10 and FIG. 11, 5 respectively. Generally speaking, collagen fluorescence has a relatively sharp fluorescence peak at 390 nm when the excitation wavelength is close to 350 nm. Free NADH
has a fluorescence band with a peak at ~60 nm, which ia blue shifted to 450 nm when the NADH is in the bound state. Elastin has a wide fluorescence spectrum band with peak at 420 nm when the excitation wavelength is close to 350 nm. In analysis of the fluorescence spectral structure of connective tissues, the peak or shoulder structure at the wavelength range of 380-390 nm are more likely the result of collagen fluorescence. The small fluorescence band at wavelength range 400 nm to 500 nm is more likely the result of elastin and NADH. The dip which sometimes occurs at wavelength 415 nm to 420 nm is caused by the reabsorption of blood (r~::lR , 1993;
Tang et al., 1989; Liu et al., 1990).
The results described demonstrate the usefulness of this new technique and in~L ~, ~. in the monitoring cervical changes during pregnancy and labor and in 25 ~F~tf~rm;ninr~ the phygiological or biochemical state of the cervix during the final stages of pregnancy. For a human subject, a small size fiber optical catheter is used.
Because the human cervix is also rich in collagen and because the cervix is accessible to the instrument 30 disclosed herein, human cervical ~ tit~n may be similarly measured by positioning the optical catheter through the vagina. The particular fluorescent intensities may differ from species to species, but the relative decrease in, e.~r., collagen fluorescence, that 35 is monitored over time will allow a more r~l~nt;t~tive or objective measurement of cervical changes incipient to _ _ _ . . . . ... . .. ..
Wo 95131929 21 ~59q birth and will be a valuable diagnostic and prognostic tool in the ield of obstetrics.
ExaMPLE 3 Design o~ Optical Catheter A preferred embodiment of the present invention is an optical r~thF~t~r suitable for use in a human patient as schematically shown in a side view and a top view in FIG. 12. The catheter 50 comprise~ a hollow tube 51 with an outer diameter of about 8 mm or less and forming an obtuse angle near the midpoint for correct positioning.
The optical fiber bundles for transmission of the excitation light 52 and the optical ~iber bundles for the collection of emission light 53 are disposed within the hollow tube and exit the tube through one end to be cr,nn~rt~ to the excitation light source and measuring means, respectively. At the other end of the tube is a receptacle 54 of about 4 mm in height and about 12 mm in diameter to receive the tips 55 of the two types of optical fiber bundles and to position the tips adjacent the measuring site on the cerYix. The catheter may also comprise an endoscope 56 with an endoscope head 57 projecting past the optical fiber tips to assist in locating the catheter near the cerYix.
FIG. 13 is an illustration of the optical catheter 50 in place in the vagina of a subject The endoscope 56 facilitates placing the catheter near the cervix 62, which separates the Yaginal wall 61 from the uterine wall 60 .
rr~nt;nllAll-l Monitoring of Human Patient In an example of a preferred embodiment of the methods and instruments o~ the present invention, a WO 95/31929 P~
2t 90599 pregnant patient visits her obstetrician for a routine perinatal exam at e.g., 26 weeks of pregnancy. The physician usee the methods and instruments disclosed herein to evaluate the state of the cervix. The 5 physician inserts the optical fiber probe (FI~. 12) into the vagina of the patient af ter dilating the vagina with the aid of a speculum to expose the cervix. Several regions of the cervix are probed and f luorescence spectra are obtained. These spectra are compared to known normal 10 and abnormal readings.
This procedure i8 repeated during weekly or bimonthly visits to the obstetrician. At term, about 38 to 40 weeks of gestation, the physician makes more 15 frequent analyses with the described methods. When the patient i9 admitted to the hospital in labor or where labor i8 ; ; n~n~, the instrument and methods are used at hourly intervals to evaluate the cervix and the progression of tl~lati~n If the patient begins to show signs of preterm dilation of the cervix, the physician may treat the patient with an agent (e.g. an antiprosta~l~n-l;n) to inhibit cervical dilation and then may follow the 25 progress of this treatment with the methods disclosed herein. If a patient fails to dilate at term with advancing uterine contractions, the physician may stimulate cervical ~ at;~n (e.g. with a prostaglandin) and follow the progress of the induced dilation with the 3 o methods of the invention .
It is also understood that certain problems may arise in recovery after delivery. In that case, the cervical monitoring may cr.nt;nl~ during the period of 35 postpartum recovery to assist in ~ gn~si q and treatment of any conditions that may arise.
3YANPLE: 5 Monitoring Patient~ at Term or Preterm Delivery In this example, a patient appears in labor and 5 delivery either at term or preterm in labor. A physician s~uickly evaluates the patient ' 8 cervix with the methods of the present invention to determ~ ine the extent of dilation and then ~ollows the patient cnnt; nllnusly until delivery as in Example 4.
Non-pregnant P~ltient A nUll~UL~:ylld~lt patient, age about 40 years for 15 example, may require a dilation and curettage (D&C) for abnormal uterine bleeding. The physician treats the patient with an agent such as a prostaglandin to dilate the cervix and then follows the progression of cervical rl;l~t;nn with the methods disclosed herein. At the 20 appropriate time, as indicated by the fluorescence spectra, the curettage of the uterine wall is completed.
~Y~MPLE 7 Nonitoring of Aninal Patient~
The present example demonstrates that the methods and in~tL ~q of the present invention will also be useful in the t:~eatment and monitoring of animals. A
veterinarian is called upon to monitor the delivery of a 30 valuable animal such as a horse, cow, dog or the like that is in labor, but is suffering from dystocia (i.e.
the inability for labor to progress). The practitioner f~Y~m; n~c the cervix of the animal with the methods and instruments of the present invention. The practitioner 35 may then either treat the animal appropriately with a labor accelerating agent such as oxytocin or WO 95131929 . ~~
~t ~3599 prostaglandin, or may abstain from treatment and follow the progression of the cervix with the disclosed methods.
The ~ollowing citations are incorporated by reference in pertinent part herein for the reasons cited in the above text.
Alfano, R. R. and Yao, 5.5. Journ. Dellt. Res. 60:120-122, 1981 .
Alfano, R. R., et al., IEEE ;r. of Quant. Elec. QE-20:1512-1516, 1984.
Alfano, R. R., et al., Laser induced fluorescence spectroscopy from native cancerous and normal tissues, IEEB J. of Quant. Electron. QE-20:1507, 1984.
Alfano, R. R., et al., IEEB ,J. Quantum Blectron. QE-23: 1806-181, 1987 .
Alfano, R. R., et al., BU11. N. Y. Acad. Med., second series, 67(2) :143, 1991.
Cantor, C.R., and Schimmel, P.R., Biophysical Chemistry, W.H. Freeman and Company, New York, 1980.
Cothren, R.D., et al., Ga~trointestinal Endoscopy, 36 (2 ~: 105, 1990 .
De~kPlh~llml L.I., et al., Laser~ in 5urgery and Medicine, 9: 205-214, 1989 .
Eyre , D . R ., et al , Quantitation of Hy~ sy~y~ idinium Crosslinks in Collagen by High-Performance LiSIuid Chromatography, Analytical Biochemistry, 137:380-388, 1984 .
WO 95131929 1 ~~
Eyre , D . R ., Pa z , M . A ., Ga l l op , P . M ., Cro 8 s - l inking in Collagen and Elastin, Ann. Rev. Biochenn 53:717-48, 1984.
Fosang, A.J. and Handley, C.J., Connective Tissue 5 Remodeling in the Ovine during Pregnancy and at Term, Connective Ti6sues Research, 17:277-285, 1988.
Fu j imoto , D ., Akiba , K ., Nakamura , N ., Bi ochern .
Biophysics Res. Commun. 76 :1124-29, 1977 .
Glassman, W. S., ~hesis, Graduate Center of city University of New York, 1993.
Glassman, W. S., et al., Excitation Spectroscopy from 15 Malignant and Non-malignant Gynecological Tissues, Lasers in the Life Sciences, 6(2), 1994.
t'.l;l-qr~n, W. S., et al, LaE~ers in the Life Sciences, 5(1-2) :49-58, 1991.
Granstrom, L., et al, Changes in the Connective Tissues of Corpus and Cervix IJteri during Ripening and Labour in term Pregnancy, British Journal of Obstetrics and Gynaecology, 96:1198-1202, 1989.
Granstrom, L., Ekman, G., Malmstrom, A., Insu~ficient , ~ '^11; nrj oi~ the uterine connective tissues in woman with protracted labor, British J Obstet Gynecol, 98:1212-1216, 1991.
Gun~a-Smith, Z. and Woessner, J.F., Content of the collagen and elastin cross-links pyridinoline and rP~nE; nP~ in the human uterus in various reproductive states, Am J Obstet Gynecol, 153:92-95, 1985.
Gunja-Smith, Z., Lin J., Woessner, J.F., Changes in Desmosine and Pyri~l;nnl ;nP Cross-links During Rapid WO 95131929 . ~
~ 21 90599 Synthesis and Degradation of Elastin and Collagen in the Rat Uterus, l~atrix, 9 :21-27, 1989 .
Kapadia, C.R., et al, Gastroenterology, 99:150, 1990.
Kokenyesi, R. and Woessner, J.F., Relat;r~n~hir between dilatation of the rat uterine cervix and a small dermatan sulfate proteoglycan, Biology of Reproduction, 42:87-97, 1990 .
Kokenyesi, R., and Frederick Woessner, J., Effects o~
Hormonal perturbations on the Small Dermatan Sulfate Proteoglycan and MechAnlr~l Properties of the Uterine Cervix of Late Pregnant Rats, Connective Tissue Re6earch, 26:199-205, 1991.
Lakowicz , J . R ., Principles of Fluorescence Spectroscopy, 3rd print, Plenum Press, 1986.
Leppert, P.C. and Yu, S.Y., Three-dimensional structures of uterine elastic f ibers: scanning electron microscopic studies, Connective Tissue Re6earch, 27:15-31, 1991.
Liu, C.H., et al., Lasers in Life Science, 3(3) :167, 1990.
Ma, P.Z., et al., Appl. La6ers, 4:235-238, 1984.
Osmers , R ., et al ., Collagenase Activity in the Cervix of 30 Non-pregnant and Pregnant Women, ArcA. Gynecol. Obstet., 248:75-80, 1990.
Richards-Kortum, R., et al ., PhotocAe n. & Photobiol ., 53 (6):777, 1991.
WO 95131929 r~
Tang, G.C., et al., Spectroscopic differences between human cancer and normal lung and breast tissues in L,asers in Surg. and Med,, 9:290-295, 1989.
5 Tang, G. C., et al ., Pulsed and CW laser fluorescence spectra from cancerous, normal, and chemically treated normal human breast and lung tissues, Appl. Opt.
28 (12):2337-2342, 1989.
10 Udenfriend, S., Fluorescence Assay in Biology and MP~;~-;nP, Vol. I, Academic Press: New York, 1962.
Total counts of each mea~u" nt of fluorescence f rom the wavelength range 3 7 o nm to 5 0 0 nm have been calculated and analyzed for statistical significance.
The mean with SEM of each group at different stages of 20 gestation are shown in FIG. 9. The one-factor ANOVA
analysis was highly significant (F=10.4, p~ 001~. The a priori comparison results between individual groups are shown in Table 2. The total counts integrated within other narrower wavelength ranges, 395 nm to 415 nm for 25 example, have also been calculated. The statistical analysis showed similar results.
The results show the clear changes of the native cervical fluorescence during various stages of gestation 30 with high statistical sign; fic~n~e. The amount of fluorescence decreases when the pregnancy is close to term, and reaches its lowest point when pups are engaged and in delivery. RU 38.486 treatment on day 16 of gestation also caused the native fluorescence to 35 decrease. Although the decrease in fluorescence in the RU38.486 treated rats did not reach the levels of decrease in delivering rats, this is simply because the Wo 95131929 ~ n, r -- -2 t 90~99 treated rat6 were not monitored through delivery. ~ad the treated rats been monitored through delivery, it is understood that the f luorescence would have reached the lower levels observed in untreated delivering rats.
Table 2: A priori Comparisons Results between Group~
(LSD Nethod).
D15 D17 D19 D20 D21 D22nd D22 D22 D~7 ~n del RU
0 D15 ~ *~ .** ... .c D17 * .. .~. ... *
Dl9 '' * *** *** ***
D20 *** ~** *
D21 *** *.
15 D22nd D22eng D22del 20 * p-value < 0 . 05 ** p-value < 0 . 01 *** p-value < 0 . 001 These changes in the native cervical f luorescence may be the result of either or both biochemical and physiological changes of cervical tissues during gestation and labor. As stated above, the general structure of the fluorescence spectra from the cervix seems similar. The fluorescence of the cervix of rats may be mostly contributed by pyridinoline cross-links since the collagen concentration is very high in the rat cervix tissue (Leppert and Yu, 1991). There may be some Wo 95/31929 . ~
small amount of fluorescence contribution from elastin and NADX which overlap on the collagen gpectrum (rl~Rrm~n et al., 1991; r-lA~rm~n, 1993), Fluorescence spectra of elastin and NADH are shown in FIG. 10 and FIG. 11, 5 respectively. Generally speaking, collagen fluorescence has a relatively sharp fluorescence peak at 390 nm when the excitation wavelength is close to 350 nm. Free NADH
has a fluorescence band with a peak at ~60 nm, which ia blue shifted to 450 nm when the NADH is in the bound state. Elastin has a wide fluorescence spectrum band with peak at 420 nm when the excitation wavelength is close to 350 nm. In analysis of the fluorescence spectral structure of connective tissues, the peak or shoulder structure at the wavelength range of 380-390 nm are more likely the result of collagen fluorescence. The small fluorescence band at wavelength range 400 nm to 500 nm is more likely the result of elastin and NADH. The dip which sometimes occurs at wavelength 415 nm to 420 nm is caused by the reabsorption of blood (r~::lR , 1993;
Tang et al., 1989; Liu et al., 1990).
The results described demonstrate the usefulness of this new technique and in~L ~, ~. in the monitoring cervical changes during pregnancy and labor and in 25 ~F~tf~rm;ninr~ the phygiological or biochemical state of the cervix during the final stages of pregnancy. For a human subject, a small size fiber optical catheter is used.
Because the human cervix is also rich in collagen and because the cervix is accessible to the instrument 30 disclosed herein, human cervical ~ tit~n may be similarly measured by positioning the optical catheter through the vagina. The particular fluorescent intensities may differ from species to species, but the relative decrease in, e.~r., collagen fluorescence, that 35 is monitored over time will allow a more r~l~nt;t~tive or objective measurement of cervical changes incipient to _ _ _ . . . . ... . .. ..
Wo 95131929 21 ~59q birth and will be a valuable diagnostic and prognostic tool in the ield of obstetrics.
ExaMPLE 3 Design o~ Optical Catheter A preferred embodiment of the present invention is an optical r~thF~t~r suitable for use in a human patient as schematically shown in a side view and a top view in FIG. 12. The catheter 50 comprise~ a hollow tube 51 with an outer diameter of about 8 mm or less and forming an obtuse angle near the midpoint for correct positioning.
The optical fiber bundles for transmission of the excitation light 52 and the optical ~iber bundles for the collection of emission light 53 are disposed within the hollow tube and exit the tube through one end to be cr,nn~rt~ to the excitation light source and measuring means, respectively. At the other end of the tube is a receptacle 54 of about 4 mm in height and about 12 mm in diameter to receive the tips 55 of the two types of optical fiber bundles and to position the tips adjacent the measuring site on the cerYix. The catheter may also comprise an endoscope 56 with an endoscope head 57 projecting past the optical fiber tips to assist in locating the catheter near the cerYix.
FIG. 13 is an illustration of the optical catheter 50 in place in the vagina of a subject The endoscope 56 facilitates placing the catheter near the cervix 62, which separates the Yaginal wall 61 from the uterine wall 60 .
rr~nt;nllAll-l Monitoring of Human Patient In an example of a preferred embodiment of the methods and instruments o~ the present invention, a WO 95/31929 P~
2t 90599 pregnant patient visits her obstetrician for a routine perinatal exam at e.g., 26 weeks of pregnancy. The physician usee the methods and instruments disclosed herein to evaluate the state of the cervix. The 5 physician inserts the optical fiber probe (FI~. 12) into the vagina of the patient af ter dilating the vagina with the aid of a speculum to expose the cervix. Several regions of the cervix are probed and f luorescence spectra are obtained. These spectra are compared to known normal 10 and abnormal readings.
This procedure i8 repeated during weekly or bimonthly visits to the obstetrician. At term, about 38 to 40 weeks of gestation, the physician makes more 15 frequent analyses with the described methods. When the patient i9 admitted to the hospital in labor or where labor i8 ; ; n~n~, the instrument and methods are used at hourly intervals to evaluate the cervix and the progression of tl~lati~n If the patient begins to show signs of preterm dilation of the cervix, the physician may treat the patient with an agent (e.g. an antiprosta~l~n-l;n) to inhibit cervical dilation and then may follow the 25 progress of this treatment with the methods disclosed herein. If a patient fails to dilate at term with advancing uterine contractions, the physician may stimulate cervical ~ at;~n (e.g. with a prostaglandin) and follow the progress of the induced dilation with the 3 o methods of the invention .
It is also understood that certain problems may arise in recovery after delivery. In that case, the cervical monitoring may cr.nt;nl~ during the period of 35 postpartum recovery to assist in ~ gn~si q and treatment of any conditions that may arise.
3YANPLE: 5 Monitoring Patient~ at Term or Preterm Delivery In this example, a patient appears in labor and 5 delivery either at term or preterm in labor. A physician s~uickly evaluates the patient ' 8 cervix with the methods of the present invention to determ~ ine the extent of dilation and then ~ollows the patient cnnt; nllnusly until delivery as in Example 4.
Non-pregnant P~ltient A nUll~UL~:ylld~lt patient, age about 40 years for 15 example, may require a dilation and curettage (D&C) for abnormal uterine bleeding. The physician treats the patient with an agent such as a prostaglandin to dilate the cervix and then follows the progression of cervical rl;l~t;nn with the methods disclosed herein. At the 20 appropriate time, as indicated by the fluorescence spectra, the curettage of the uterine wall is completed.
~Y~MPLE 7 Nonitoring of Aninal Patient~
The present example demonstrates that the methods and in~tL ~q of the present invention will also be useful in the t:~eatment and monitoring of animals. A
veterinarian is called upon to monitor the delivery of a 30 valuable animal such as a horse, cow, dog or the like that is in labor, but is suffering from dystocia (i.e.
the inability for labor to progress). The practitioner f~Y~m; n~c the cervix of the animal with the methods and instruments of the present invention. The practitioner 35 may then either treat the animal appropriately with a labor accelerating agent such as oxytocin or WO 95131929 . ~~
~t ~3599 prostaglandin, or may abstain from treatment and follow the progression of the cervix with the disclosed methods.
The ~ollowing citations are incorporated by reference in pertinent part herein for the reasons cited in the above text.
Alfano, R. R. and Yao, 5.5. Journ. Dellt. Res. 60:120-122, 1981 .
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Alfano, R. R., et al., Laser induced fluorescence spectroscopy from native cancerous and normal tissues, IEEB J. of Quant. Electron. QE-20:1507, 1984.
Alfano, R. R., et al., IEEB ,J. Quantum Blectron. QE-23: 1806-181, 1987 .
Alfano, R. R., et al., BU11. N. Y. Acad. Med., second series, 67(2) :143, 1991.
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WO 95131929 1 ~~
Eyre , D . R ., Pa z , M . A ., Ga l l op , P . M ., Cro 8 s - l inking in Collagen and Elastin, Ann. Rev. Biochenn 53:717-48, 1984.
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Biophysics Res. Commun. 76 :1124-29, 1977 .
Glassman, W. S., ~hesis, Graduate Center of city University of New York, 1993.
Glassman, W. S., et al., Excitation Spectroscopy from 15 Malignant and Non-malignant Gynecological Tissues, Lasers in the Life Sciences, 6(2), 1994.
t'.l;l-qr~n, W. S., et al, LaE~ers in the Life Sciences, 5(1-2) :49-58, 1991.
Granstrom, L., et al, Changes in the Connective Tissues of Corpus and Cervix IJteri during Ripening and Labour in term Pregnancy, British Journal of Obstetrics and Gynaecology, 96:1198-1202, 1989.
Granstrom, L., Ekman, G., Malmstrom, A., Insu~ficient , ~ '^11; nrj oi~ the uterine connective tissues in woman with protracted labor, British J Obstet Gynecol, 98:1212-1216, 1991.
Gun~a-Smith, Z. and Woessner, J.F., Content of the collagen and elastin cross-links pyridinoline and rP~nE; nP~ in the human uterus in various reproductive states, Am J Obstet Gynecol, 153:92-95, 1985.
Gunja-Smith, Z., Lin J., Woessner, J.F., Changes in Desmosine and Pyri~l;nnl ;nP Cross-links During Rapid WO 95131929 . ~
~ 21 90599 Synthesis and Degradation of Elastin and Collagen in the Rat Uterus, l~atrix, 9 :21-27, 1989 .
Kapadia, C.R., et al, Gastroenterology, 99:150, 1990.
Kokenyesi, R. and Woessner, J.F., Relat;r~n~hir between dilatation of the rat uterine cervix and a small dermatan sulfate proteoglycan, Biology of Reproduction, 42:87-97, 1990 .
Kokenyesi, R., and Frederick Woessner, J., Effects o~
Hormonal perturbations on the Small Dermatan Sulfate Proteoglycan and MechAnlr~l Properties of the Uterine Cervix of Late Pregnant Rats, Connective Tissue Re6earch, 26:199-205, 1991.
Lakowicz , J . R ., Principles of Fluorescence Spectroscopy, 3rd print, Plenum Press, 1986.
Leppert, P.C. and Yu, S.Y., Three-dimensional structures of uterine elastic f ibers: scanning electron microscopic studies, Connective Tissue Re6earch, 27:15-31, 1991.
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Osmers , R ., et al ., Collagenase Activity in the Cervix of 30 Non-pregnant and Pregnant Women, ArcA. Gynecol. Obstet., 248:75-80, 1990.
Richards-Kortum, R., et al ., PhotocAe n. & Photobiol ., 53 (6):777, 1991.
WO 95131929 r~
Tang, G.C., et al., Spectroscopic differences between human cancer and normal lung and breast tissues in L,asers in Surg. and Med,, 9:290-295, 1989.
5 Tang, G. C., et al ., Pulsed and CW laser fluorescence spectra from cancerous, normal, and chemically treated normal human breast and lung tissues, Appl. Opt.
28 (12):2337-2342, 1989.
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Claims (15)
1. A method for determining occurrence of cervical dilation or effacement of a subject, the method comprising:
irradiating cervical connective tissues with excitation light in an amount and at a wavelength causing intrinsic fluorescence; and measuring fluorescent emissions from the cervical tissue;
wherein cervical dilation or effacement is correlated with changes in fluorescent emissions.
irradiating cervical connective tissues with excitation light in an amount and at a wavelength causing intrinsic fluorescence; and measuring fluorescent emissions from the cervical tissue;
wherein cervical dilation or effacement is correlated with changes in fluorescent emissions.
2. The method of claim 1 where the excitation light wavelength is ultraviolet.
3. The method of claim 1 where the excitation light wavelength is between about 300 nm and 380 nm.
4. The method of claim 1 where the fluorescent emissions are at a wavelength between about 320 nm and 700 nm.
5. The method of claim 1, wherein the cervical dilation or effacement is measured during pregnancy.
6. The method of claim 1, wherein the cervical dilation or effacement is measured during labor.
7. The method of claim 1, wherein the cervical dilation or effacement is measured in a non-pregnant subject.
8. The method of claim 1, wherein the cervical dilation or effacement is measured after delivery.
9. The method of claim 1, wherein a decrease in fluorescent emission over time or relative to a standard emission value is indicative of cervical dilation or effacement.
10. The method of claim 1 wherein a means for introducing excitation light and for collecting fluorescent emission is introduced through the vagina of a subject.
11. The method of claim 1 wherein the subject is a human.
12. An instrument for measuring cervical tissue fluorescence comprising:
a means for cervical surface excitation comprising a source of 300 to 380 nm light and optical fiber for guiding the light to a cervical surface;
a means for measuring cervical tissue fluorescence comprising an optical fiber collection means for transmitting cervical fluorescence to a means for measurement and spectral analysis of said fluorescence.
a means for cervical surface excitation comprising a source of 300 to 380 nm light and optical fiber for guiding the light to a cervical surface;
a means for measuring cervical tissue fluorescence comprising an optical fiber collection means for transmitting cervical fluorescence to a means for measurement and spectral analysis of said fluorescence.
13. The instrument of claim 12 further comprising a fiber optical catheter for use in a human patient.
14. A fiber optical catheter, comprising:
a hollow tube having two ends and forming an obtuse angle near the midpoint between said ends for correct positioning;
a plurality of optical fibers having tips for transmission of the excitation light and for the collection of emission light, disposed within said hollow tube and exiting the tube through one end; and a receptacle to receive said tips of said optical fiber bundles and to position said tips adjacent the measuring site on a cervix.
a hollow tube having two ends and forming an obtuse angle near the midpoint between said ends for correct positioning;
a plurality of optical fibers having tips for transmission of the excitation light and for the collection of emission light, disposed within said hollow tube and exiting the tube through one end; and a receptacle to receive said tips of said optical fiber bundles and to position said tips adjacent the measuring site on a cervix.
15. The fiber optical catheter of claim 14, further comprising and endoscope to assist in positioning of the catheter near the cervix of a subject.
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|---|---|---|---|
| US08/246,060 US5450857A (en) | 1994-05-19 | 1994-05-19 | Method for the diagnosis of cervical changes |
| US08/246,060 | 1994-05-19 |
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| CA2190599A1 true CA2190599A1 (en) | 1995-11-30 |
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| CA002190599A Abandoned CA2190599A1 (en) | 1994-05-19 | 1995-05-12 | Instrument for the diagnosis of cervical changes |
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| US (1) | US5450857A (en) |
| EP (1) | EP0759723A1 (en) |
| JP (1) | JPH10505244A (en) |
| AU (1) | AU696913B2 (en) |
| CA (1) | CA2190599A1 (en) |
| WO (1) | WO1995031929A1 (en) |
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| AU2550595A (en) | 1995-12-18 |
| EP0759723A1 (en) | 1997-03-05 |
| AU696913B2 (en) | 1998-09-24 |
| US5450857A (en) | 1995-09-19 |
| JPH10505244A (en) | 1998-05-26 |
| WO1995031929A1 (en) | 1995-11-30 |
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