FIELD OF THE INVENTION The present invention relates to the field of medical ultrasound scanning. More specifically, the invention relates to elastomeric ultrasound scanning. Especially, the invention provides a reference material element shaped to fit on a scanning head of an ultrasound probe and a method for elastomeric ultrasound scanning of the human uterine cervix and.

BACKGROUND OF THE INVENTION

Elastomeric ultrasound measurements of the uterine cervix can be performed with a vaginal ultrasound probe. The ultrasound equipment can provide a certain degree of quantification of the compliance of the uterine cervix, which allows important medical diagnoses, e.g. with respect to assess the state of the uterine cervix of pregnant women to identify if the cervix is so soft that the pregnant woman is about entering birth state. Present elastomeric ultrasound equipment allows read out of elastic properties of the biological tissue under test using a color scale, which allows a comparison of the elastic properties of different parts of the scanning area. E.g. it is possible to determine the relative stiffness of different areas of the uterine cervix. However, it is not possible to precisely quantify the elastic properties of the uterine cervix so as to allow a development of an overall elastomeric measure of the uterine cervix between women. Such overall measure would enable establishment of an elastic property value below which a pregnant woman is assumed to be about to enter the birth state, or other similar important clinical measures, based on a simple elastomeric scanning.

SUMMARY OF THE INVENTION

Following the above description, it may be seen as an object of the present invention to provide a solution to the problem of precisely quantifying the elastic properties of biological tissue, e.g. the uterine cervix. In a first aspect, the invention provides a reference material element with a known elastic property, wherein the element is shaped to allow attachment on an ultrasonic probe in order to cover at least ultrasound transmitting parts of a scanning head of the ultrasonic probe, so as to allow elastomeric measurement on the reference material element during elastomeric scanning on biological tissue with the ultrasonic probe, wherein the reference material element is made of an elastic material comprising a mixture of silicone and oil.

Such reference material element is suitable for precisely determining the elastic property of the biological tissue, e.g. the human uterine cervix, since it can be used during known elastomeric ultrasound scannings. It allows the possibililty to determine, in one simultaneously obtained ultrasonic scanning image, the elastomeric properties of the biological tissue and the elastomeric properties of the reference material. Hereby it is possible to determine a measure of the elastic property of the biological tissue, or a selected area thereof, by determining the measured elastomeric property of the biological tissue and the measured elastomeric property of the reference material element. Since the elasticity of the reference material element is known, it is possible to precisely calculate the elastic property of the biological tissue, namely based on the measure ratio between the elastomeric properties measured for the biological tissue and the reference material element. Alternatively, the final data value may simply be a ratio between the two mentioned elatomeric values, in case a standard hardness of the reference material element is accepted.

With such precise elastic property of the biological tissue, e.g. the uterine cervix of a pregnant woman, it is possible to collect data to allow an objective

assessment of the state of the cervix based on an elastomeric ultrasound scanning. This provides an easy way of determining if the pregnant woman is about to enter the birth state, which is important in a number of clinical applications. E.g. for giving medicaments to women with a soft cervix indicating that they are are about to enter a premature birth, or for giving medicaments to women who still have a hard cervix during the birth state.

It is to be understood that the reference material element is also suitable for precisely determining elastic properties of other types of biological tissue. The reference material element and its use is easy to implement in existing ultrasonic elastomeric equipment, since the reference material element can be shaped to fit e.g. as a cap, on an existing ultrasonic probe such that it is fixed to the probe during normal use, e.g. within a condom which is normally used for hygienic purposes in case of a vaginal probe. The mentioned calculation of a ratio between two areas, e.g. user selectable areas, of a scanning image can easily be implemented in software without changing the existing user interface.

By "known elastic property" of the reference material element is simply

understood that this property could be measured for the actual composition of the material used, since this property is required for precise calculation of the biological tissue under test. It is preferred that the reference material element has an elasticity which is rather close to the expected property of the biological tissue under test, in order to provide the highest precision for calculation of the ratio between the elastomeric reading of the area with representing the reference material and the area representing the biological tissue under test.

In preferred embodiments, the elastic property of the reference material element is similar or substantially similar to a normal human uterine cervix. Such mechanical property of the reference material element has been found to provide a good possibility of providing a precise detection of the elastic property of the uterine cervix with ultrasonic scanning. At the same time, such elasticity of the reference material allows easy mounting on the scanning probe.

The mix of silicone and oil has been tested to provide a suitable reference material, since it is possible to provide with an elastic property to match e.g. human uterine cervix with a reasonable material thickness, and still provide an adequately low attenuation of ultrasound signals so as to not disturb the scanning image. Still further, the material of such mixture is mechanically stable.

In preferred embodiments, the elastic material may comprise at least 30% of oil, such as at least 40% of oil, such as at least 50% of oil, or such as at least 55% of oil. In one embodiment, the elastic material consists of a mixture of silicone and oil, where a fraction of silicone is between 30% and 60%. Especially, the elastic material may consist of a mixture of silicone and oil, where a fraction of silicone is between 35% and 55%. The above-mentioned fractions or ratios between silicone and oil are weight ratios. It is to be understood that a small fraction of other materials may be added, but in preferred embodiments, the reference material element is made of a material which has at least a weight fraction of more than 90% of silicone and oil, such as at least 95% of silicone and oil, such as at least 99% of silicone and oil, such as at least 99.5% of silicone and oil.

The elastic material element preferably has a thickness of at least 2 mm in an area covering the scanning head. Preferably the elastic material element has a thickness of 2-8 mm or 3-6 mm in an area covering the scanning head.

The reference material element may be shaped to cover 5-20% of a longitudinal extension of an associated ultrasonic probe. Especially, the reference material element may be shaped as a cap for covering the scanning head of the probe only. Alternatively, the reference material element may be shaped to cover an entire longitudinal extension of the ultrasonic probe or at least 80% of an entire longitudinal extension of the ultrasonic probe. The elastic material element may be arranged within a cover material serving to protect biological tissue from getting into contact with the ultrasonic probe during scanning. The elastic material element may be molded or in other ways formed intergrally with the cover material, or the elastic material element may be glued or in other ways fixed to the cover material which may be made of another material than the reference material element. The cover material may be thin compared to the reference material element.

For embodiments with a cover material or for embodiments where the reference material element extends in the entire longitudinal extension of the ultrasonic probe, the reference material element can be formed as a disposable element which is attached to the probe before scanning and thrown away after scanning, so as to keep the biological tissue out of contact with the ultrasonic probe itself. In this way the reference material element forms part of a disposable serving a hygienic purpose, such as a condom or the like, which is normally used for elastomeric ultrasonic scannings using a vaginal probe. In a second aspect, the invention provides an ultrasonic scanning system comprising

- an ultrasonic probe comprising a scanning head with at least one ultrasonic transducer arranged to transmit ultrasound, and

- a reference material element according to the first aspect.

In one embodiment, the ultrasonic probe is a vaginal probe. The system may comprise a scanning unit functionally connected to the ultrasonic probe, so as to allow elastomeric scanning of biological tissue. Especially, the scanning unit may be arranged to determine a value representing an elastic property of the biological tissue based on an elastomeric property of one area of a scanning image representing the biological tissue and on an elastomeric property another area of the scanning image representing the reference material element.

In preferred embodiments, the system is a medical scanning system arranged for biological tissue. In a third aspect, the invention provides a method for measuring elasticity of biological tissue, such as a human uterine cervix, the method comprising

- ultrasound scanning of the biological tissue with an ultrasonic probe on which a reference material element with known elastic properties has been placed to cover a scanning head of the ultrasonic probe,

- generating an ultrasonic scanning image representing elastic properties of different scanning areas, and

- comparing an elasticity property for an area of the ultrasonic scanning image representing the biological tissue with an elasticity property for an area

representing the reference material element.

The steps of comparing the elasticity property for the areas with the biological tissue under test and the reference material element can be performed in software which can easily be implemented and processed by existing scanning equipment. Based on the known reference material value, it is possible to calculate an elasticity value which can be presented on a display to the operator. It is understood that the same advantages as described for the first aspect apply as well for the second and third aspects, and the same principal embodiments from the first aspect apply as well for the second and third aspects. These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

BRIEF DESCRIPTION OF THE FIGURES Embodiments of the invention will be described in more detail in the following with regard to the accompanying figures. The figures show one way of implementing the present invention and is not to be construed as being limiting to other possible embodiments falling within the scope of the attached claim set. Fig. 1 shows a photo of an existing ultrasonic vaginal probe for elastomeric measurement of e.g. the uterine cervix.

Fig. 2 shows a cap shaped embodiment of the reference material element for covering the scanning head of an ultrasonic vaginal probe.

Fig. 3 shows a photo of an ultrasonic vaginal probe with the reference material element of Fig. 2 attached to its end, thus covering the scanning head of the probe. Fig. 4 shows a scanning image based on an ultrasonic scanning made with a vaginal probe on a pregnant woman. The grey color shades indicate the elastic properties of the different areas of the tissue and of the reference material element. DETAILED DESCRIPTION OF AN EMBODIMENT

Fig. 1 shows an existing medical vaginal ultrasound scanning probe with a scanning head (grey color) at its end. In the opposite end of the scanning head, there is a handle (not shown). The scanning head has ultrasound transducers arranged to transmit ultrasonic signal to allow scanning of e.g. the uterus or the uterine cervix or the fetus of pregnant women. Especially, the probe can be used for elastography, i.e. elastomeric measurements of the tissue under test by means of ultrasonic signals. Fig. 2 shows an example of a reference material element according to the invention, namely in the form of a 3-5 mm thick cap of a silicone and oil mixture. The cap is shown to the left from the outside, and to the right from the inside. The cap is sized and shaped to fit to cover the scanning head of the vaginal probe of Fig. 1. However, it is to be understood, that the reference material element could in general be shaped to fit other probes. Especially, it may be shaped to fit a larger portion of the probe than the scanning head. In case of a vaginal probe, it may be contained inside a thin cover material, such as a condom or the like, to provide a hygienic protection. However, the reference material itself may be shaped to cover the major longitudinal extension of the probe to provide such protection itself without the need for further protection material. Thus, the reference material element may be a disposal element, or it may be re-used, if used inside a cover material.

Fig. 3 shows a photo of the vaginal probe of Fig. 1 with the reference material cap of Fig. 2 mounted thereon. As it is seen, the reference material covers the scanning head.

Fig. 4 shows a normal ultrasonic elastomeric scanning image obtained on a pregnant woman with the vaginal probe of Fig. 3, i.e. including the reference material cap. The grey shades (originally colors) indicate the elasticity of the biological tissue in the different areas of the scanning image. The elastic property of the reference material is found on the lower part of the image which is seen to provide a rather uniform shade, and thus this property can be used to compare with the elasticity property of other areas of the scanning image, thus

corresponding to different parts of the biological tissue under test.

On the image of Fig. 4 an area corresponding to the uterine cervix A_CV is indicated. In a practical implementation, an average reading of the color in this area A_CV could be compared with the color of an area corresponding to the reference material element, e.g. A_RM. Based on known elastic properties of the reference material element, it is possible to precisely calculate a measure of the elasticity of the area A_CV under test, and thus in this example it is possible to precisely quantify the elastic property of the uterine cervix. Especially, the existing scanning eqipment may be modified with respect to its software so as to allow a read-out on the display of the calculated elasticity value of the area under test A_CV. The operator may be able to enter an elasticity value representing the reference material element used, and the operator may with the cursor on the display be able to enter the area A_CV under test.

In the following, a non-limiting description of the invention and embodiments thereof, taken from a paper by the inventors.

Elastography has been introduced as a method to evaluate the stiffness (compressibility) of the uterine cervix as a supplement to cervical length assessment when evaluating woman at risk of preterm delivery and planning which method to use for induction of labor. The method is based on tissue compression by the transducer during ordinary B-mode scanning followed by computerized analysis of changes in the speckle distance. The difference in strain within a region of interest (ROI) is often illustrated by a color map, where low stiffness (soft tissue) is indicated in red, middle stiffness in green and high stiffness (hard tissue) in blue. The equipment can further calculate the strain ratio between two ROIs. The stiffness of tissues can be expressed as Young's modulus (N/mm ² ), which is the ratio of the uniaxial stress (force) divided by the uniaxial strain (deformation).

Concerning the uterine cervix, elastography is restricted by the absence of natural reference material in that anatomical area, opposite from the breast where adipose tissue is used as a reliable reference material. For this reason it has not been possible to make a quantitative comparison of the stiffness of the uterine cervix among women.

When assessing the strain by elastography, the distance between the ROI and the transducer must be taken into account as the tissue closest to the transducer receives more compression than the tissue further away, thus leading to the erroneous conclusion that the tissue at some distance from the transducer is harder. This magnitude depends on the algorithm used by the ultrasound software, and it will differ among brands. It is therefore preferably described for the specific equipment used. Regarding the quantitative elastography of the posterior cervical lip, the soft cervical channel interposed between the transducer and ROI might constitute a more complex situation (not evaluated).

The aim of this study was to develop a reference material allowing for quantitative elastography of the uterine cervix with the calculation of an approximation of the Young's modulus (N/mm ² ). Further, we wanted to test the elastography equipment on phantoms from a clinical perspective regarding the distance dependence and the influence of a heterogeneous material.

The phantoms and the reference caps were made of silicone and oil and produced by Danish Phantom Design (httgi /w w^^ The three phantoms were cylinder shaped, with the length six cm and diameter six cm. Two were made of homogeneous material but with different Young's moduli (0.22 and 0.07 N/mm ² ); whereas the third phantom (Young's modulus 0.22 N/mm ² ) had a five mm soft layer (Young's modulus 0.07 N/mm ² ) introduced five mm below the surface (Figure 1). The third phantom was designed to imitate tissue having areas with different degrees of stiffness similar to the uterine cervix with its less stiff cervical channel. The soft layer of the phantom was placed perpendicular to the scanning direction, similar to the direction of the cervical channel. The scanning was conducted using a 2D transvaginal transducer (IC5-9-D) connected to a Voluson E8 Expert scanner with the BT13 software.

A quality bar indicated whether two consecutive image frames contained the same anatomical structures and whether the strain values were within a plausible range defined by the manufacturer. From cineloops of three to five seconds each, three frames approved by the quality bar were randomly selected for analysis. For each frame three to four ROIs were placed in separate areas. The average strain in each circle was then determined by the H48681GB software, which also calculated the strain ratio between the ROIs. All the equipment and software described in the last two paragraphs was manufactured by GE,

Healthcare Austria GmbH & Co OG, Tiefenbach 15, 4871 Zipf/Austria.

Ten cineloops of three seconds each were obtained from each phantom with the transducer placed perpendicular to the surface. To evaluate whether the results were influenced by the distance from the transducer, four ROIs (five mm each) were placed 0-5 mm (reference circle), 5-10 mm, 10-15 mm, and 15-20 mm from the transducer. The reference ROI was given the Young's modulus of the phantom (0.07 and 0.22 N/mm ² ), whereas the approximated Young's moduli of the other ROIs were calculated by multiplying the strain ratio by the Young's modulus of the phantom.

Further, to evaluate whether the results were influenced by the position of the ROIs, the ROI in the middle of the compression and decompression direction (reference ROI) was compared with ROIs placed 50° to each side. The

measurements were performed 0-5 mm and 5-10 mm, respectively, from the probe.

Results from in vitro experiments were used to select the Young's moduli for three five mm thick reference caps. The caps had the Young's moduli of 0.40 N/mm ² (hard), 0.32 N/mm ² (medium), and 0.22 N/mm ² (soft). Six mid-pregnant women with gestational ages between 19 ⁺⁰ weeks and 23 ⁺⁵ weeks, who all delivered at term and five term pregnant women were included. Exclusion criteria were previous conization and prior preterm delivery. The transvaginal scans were all performed manually by one investigator and a sagittal view of the uterine cervix with the cervical canal perpendicular to the axis of the compression and decompression direction was provided. Each woman had a cineloop of five seconds obtained with each of the three reference caps. At the elastography image, the ROI was placed within the reference cap, whereas a second ROI was placed in the anterior cervical lip, in the stiffest area possible in the middle third between the external and the internal os as well as the middle third between the cervical canal and the cervical surface. Using the same method a ROI was placed in the posterior cervical lip. All ROIs were placed within 20° from the center-line of the image. The approximate Young's modulus of the cervical lip was calculated by multiplying the strain ratio, between the reference ROI and the other ROI, with the Young's modulus of the cap. This part of the study was approved by the Scientific Ethics Committee of Aarhus County (no. 20100149) and The Danish Data Surveillance Authority (2007-58-0010). Written and verbal informed consent was obtained from all participants.

Approximate Young's moduli were expressed as means with a minimum to maximum range as medians are less applicable because of the low number of participants. Non-parametric tests were used. For comparison within groups, the Friedman test was used. The groups were compared with the use of the Wilcoxon rank-sum test for non-matched data. A p-value < 0.05 was considered significant in two-tailed tests. The STATA statistical software package, version IC10 (StataCorp. College Station, TX, USA), was used for all analyses. The recordings from the two homogeneous phantoms showed that the approximate Young's modulus was identical to the Young's modulus of the phantom at a distance of 5-10 mm from the transducer (equivalent to a distance of 0-5 mm from the reference cap). At a distance of 10-15 mm, this figure increased by 23% (range: 18-30%) for the hard phantom and 0% for the soft phantom. Equivalent figures at 15-20 mm were 52% (range 44-64%) and 28% (range 7-43%). For the heterogeneous phantom, which included a softer layer imitating the cervical canal, the increase was 76% (range: 66-84%). For the ROIs at an angle 50° to the compression and decompression direction 5-10 mm from the transducer, the approximate Young's modulus increased by 24% (range: 19- 31%) for the hard phantom and 32% (range: 13-48%) for the soft phantom compared with the ROI in the center-line of the image.

Satisfactory elastography scans were obtained from all the mid-pregnant and term-pregnant women. The quality of the B-mode images, however, was reduced by the reference cap. The strain value within each cap was 0.06 % (range: 0.01-0.21 %) for the soft cap, 0.06 % (range: 0.01-0.19 %) for the medium hard cap and 0.04 % (range: 0.01-0.11 %) for the hard cap. Average approximate Young's modulus of the anterior cervical lip measured with the soft reference cap was significantly different between the mid-pregnant and term- pregnant women. The results obtained from the medium hard and hard reference caps showed the same tendency. In term pregnant women, the approximate

Young ^' s modulus of the posterior cervical lip was more than two times that of the anterior cervical lip. This difference was less pronounced in the mid-pregnant women. The described study shows that it is possible to determine an approximate Young's modulus of the anterior cervical lip by the use of

elastography in combination with a synthetic reference material.

Despite the limitations of the study, the fact that the three reference caps with different Young's moduli gave similar results ensures that the method is not much affected by the choice of reference material. When comparing approximate Young ^' s moduli from the anterior lips of different women, one must take into account that the distance between the ROI and the reference cap should be kept as constant as possible. If it differs by more than one and a half cm, an error of more than 23% might be introduced.

Furthermore, approximate Young's moduli obtained at the lateral border of the eiastography image (i.e. 50° from the center-line of the image) are less

trustworthy. The recordings should therefore preferably be obtained relatively close to the center-line of the image. The heterogeneity within the anterior lip is also a challenge regarding evaluation of the mechanical stiffness of the entire cervix. We chose to determine the highest value that could be obtained from the middle third of the anterior lip, but other approaches should of course be tested. Furthermore, inter- and intra-observer variation experiments as well as normal values for different gestational ages should be obtained.

The perfect reference material would have no attenuation, the speed of sound would be about 1540 m/s, and the stiffness should not be too different from that of the uterine cervix. Agar can be considered as a possible material, since the speed of sound in agar is almost 1540 m/s and the attenuation is low. However, agar may be considered too breakable, even though a previous study has shown that agar was able to resist high pressure. Polyurethane and silicone are also possible materials, even though the attenuation (12-15 dB for a 7 mm reference cap) as well as the strain ratios of these materials may be considered to be higher than desirable. By reducing the thickness of the cap to five mm and by mixing silicone and oil, the attenuation was limited to four to six dB, and the stiffness of the cap became appropriate for term pregnant women. The stiffness of the soft reference cap was closest to the stiffness of the uterine cervix for the term-pregnant women; thus, this cap could be considered as a preferred choice. The speed of sound in this material is about 1050 m/s, so the cap appears larger on the screen than it actually is.

Concentration of collagen in the uterine cervix decreases by 75% through pregnancy and that this decrease is reflected by a softening of the uterine cervix. It is therefore remarkable that the decrease in the approximate Young's modulus determined in this study is of similar magnitude, suggesting a biological relevance of the figures obtained. There have been no studies published on the quantitative eiastography of the uterine cervix, i.e. with the use of a reference material.

However, the studies published on the eiastography of the pregnant uterine cervix agree that a reference material for quantitative comparison among women is needed. They also mention the need for standardization of the scanning procedure (compression force and compression and decompression direction) and post-scan analysis. The studies showed good reproducibility both for the scanning procedure and post-scan analyses. One of the studies differed according to the scanning procedure, which did not depend on manual compression but was generated by the woman's breathing or arterial pulsation. They found that the tissue around the internal os was softer for the women with successful induction of labor.

In conclusion, the study confirmed that elastography with a reference cap is a promising quantitative method that should be evaluated for supplementation to cervical length assessment when scanning women at risk of preterm birth and planning which method to use for induction of labor.

To sum up, the invention provides a reference material element shaped to allow attachment on an ultrasonic probe in order to cover at least ultrasound

transmitting parts of a scanning head of the ultrasonic probe. This allows elastomeric measurement on the reference material element during elastomeric scanning on biological tissue with the ultrasonic probe, thus allowing a precise calculation of the elastic property of the biological tissue under test. The reference material element is made of an elastic material comprising a mixture of silicone and oil, preferably a weight ratio of 35-60 of silicone with the remaining component of the reference material being oil. In special embodiments suited for elastic measurements of the uterine cervix, a weight ratio of silicone and oil in the range 40: 60 to 50: 50 is found to be suitable since it matches the elastic property of the uterine cervix. The reference material element can especially be shaped as a cap with a thickness of 3-5 mm for covering the scanning head of an ultrasonic vaginal probe.

Although the present invention has been described in connection with the specified embodiments, it should not be construed as being in any way limited to the presented examples. The scope of the present invention is set out by the accompanying claim set. In the context of the claims, the terms "comprising" or "comprises" do not exclude other possible elements or steps. Also, the mentioning of references such as "a" or "an" etc. should not be construed as excluding a plurality. The use of reference signs in the claims with respect to elements indicated in the figures shall also not be construed as limiting the scope of the invention. Furthermore, individual features mentioned in different claims, may possibly be advantageously combined, and the mentioning of these features in different claims does not exclude that a combination of features is not possible and advantageous.