JPS61249935A - Skin marker for nmr diagnosis - Google Patents

Abstract

PURPOSE:To obtain the titled harmless skin marker capable of keeping the NMR characteristics stably and having high shape-retainability, by pouring a specific PVA solution in a forming mold, carrying out the cumulative freezing or partially dehydrating the frozen solution in vacuum, and using the obtained highly hydrated gel as the marker. CONSTITUTION:A PVA having a saponification degree of >=98mol% and an average polymerization degree of >=1,000 is dissolved in water to obtain an aqueous solution having a concentration of 8-20wt%, preferably 9-15wt%, and the solution is poured into a forming mold. The solution in the mold is poured into a forming mold. The solution in the mold is frozen at <=-10 deg.C, thawed, and the freezing and thawing operations are repeated 1-8 times to obtain a highly hydrated gel. As an alternative method, the frozen solution is partially dehydrated in vacuum to a dehydration ratio of 3-60wt% without thawing to obtain the gel. The gel gives a harmless skin marker for NMR diagnosis having a water-content of 80-92%, stably keeping NMR characteristics (water-content, T1 and T2) different from those of the skin of a living body, having excellent shape-retainability and cuttable to arbitrary shape.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention provides a method for identifying the patient's body surface when measuring the location of a patient's lesion in the body requiring radiotherapy or surgical treatment for the lesion in the body. When performing NMR (nuclear magnetic resonance) tomographic imaging to determine the positional relationship with a lesion based on a point, a skin marker is provided that can be applied to a local part of the patient's body surface and visualized together with the lesion.

<Conventional techniques and problems> Prior to performing an invasion for the purpose of testing or treating a patient with a lesion in the body,
Accurately recognizing the three-dimensional position of a lesion is essential for minimizing damage to normal tissue near the lesion and increasing the effectiveness of surgical procedures.

X-ray CT (Com
puterized tomography (puterized tomography), positron emission tomography (PET, PE-CT), and ultrasound diagnosis (US), but the former two have concerns about the exposure of normal tissues to X-rays and radioactive isotopes, respectively. Furthermore, in US, there is a lot of noise and sufficient resolution cannot always be obtained, and in addition, X-ray CT.

In US, PE-CT is inferior in resolution due to interference from skeletons, air, etc. As a diagnostic method to overcome these difficulties,
NMR-CT (nuclear magnetic resonance tomography) has been attempted. In this case, it certainly does not invade the living body,
Although many of the internal organs and various lesions are clearly depicted, their positions, especially their positional relationships with specific areas on the body surface, are not clearly depicted.

In radiation therapy, various surgical treatments, and surgical procedures, the intention is to destroy or remove focal tissue in the body through a specific site on the body surface (skin), so the positional relationship between this specific skin site and the lesion is important. must be known correctly in advance.

If a lesion such as a hematoma or a tumor happens to exist on the skin surface, both the skin lesion and the lesion inside the body can be clearly depicted on an NMR tomographic image, but such a coincidence is completely unreliable. Can not.

In order to depict specific positions on the body surface together with internal lesions in NMR tomographic images, it is necessary to use a different type of NMR from normal skin tissue locally on the skin (body surface, normal skin) on the cross-sectional plane that crosses the internal lesions.
Give a clear signal. Although it is convenient to apply some kind of substance, it is not easy to find a substance (skin marker) that can always meet this requirement under the operating conditions (within the range) of NMR diagnosis. For this purpose, water (pure water) is considered first.

Water is skin F:! Compared to Ti (water content 51-69%), it has a much stronger proton signal, longer longitudinal (Ti) and transverse (T2) magnetic relaxation times, and has the advantage of being harmless to the skin. This difficulty can be avoided by applying a water-filled bag, which lacks shape retention on the skin surface, to the skin surface. However, in the process of initially pasting markers of arbitrary shapes and dimensions on the body surface and depicting them together with the lesion as a tomographic image, the edges of the markers were successively cut to approximate the shape (dimensions) of the lesion, and the final image was Generally, it is desirable to embody the image of the lesion (shape and size) on the skin surface, and the ice bag described above cannot meet this requirement because it cannot be cut. NMR close to water
Materials that emit a signal and can be cut according to the shape and size of the lesion include jelly, jam, agar, carrageenan,
Carboxymethyl cellulose, polyvinyl alcohol,
Gels such as boric acid complexes, tofu, alginic acid, agarose, curdlan, acrylonitrile-starch grafts, xanthan gum, locust bean gum, tragacanth gum, furcellulan, methylcellulose, fucoidan, tamarind gum, karaya gum, and ghatti gum are also considered. However, these all have poor mechanical strength and often lack shape retention, making them unsuitable for close contact and fixation to specific areas of the skin surface.

The polyvinyl alcohol Fungo Red complex has high water content and is a soft rubber-like elastic body.

Harmful to living tissues (S, Niadermeie
r ; Graefes Archlv fur
Ophthalmol, 161, 547 (1960)
.

C, L, 5chepens, etc., Arch, Ophtha
lmol, , 64, 868 (1960), Td, CE
verett; K11n, Monatgbl.

Augenheilkd, 14U, 764 (1
962), Hide Itakami, Clinical Ophthalmology 1, Biliary Medicine, (1) 7 (196
4)) Polyacrylamide gel, which is undesirable, is also harmful to living organisms and has the disadvantage of being mechanically brittle.

Konnyaku retains its shape even though it contains approximately 98% water, gives an NMR signal similar to water, and can be cut, but it cannot be cut in a strong alkaline solution (pH 11-12) containing preservatives.
) Unless stored immersed in a tank, it will easily lose its shape, flow,
Because it causes severe syneresis, contraction, and deformation, it is difficult to store and is not suitable for occasional, quick, and simple use in clinical settings.

<Object of the Invention> The present invention provides NMR characteristics (water content,
To provide a skin marker for NMR diagnosis that stably holds Tx, Tz), has good shape retention, can be cut into any shape, and is harmless to living organisms.

<Means for Solving the Problems> According to the present invention, a polyvinyl alcohol having a saponification degree of 98 mol% or more and an average polymerization degree of 1,000 or more, and
The concentration of the polyvinyl alcohol exceeds 8% + 1%, 2
After injecting an aqueous solution of 0 wt% or less into a mold, it is cooled to a temperature of -10°C or less, solidified, and molded. Next, it is thawed, and the cumulative number of times of this freezing/thawing operation is 1 to 1. 8
without melting the high water content gel obtained by or the above-mentioned cooled and solidified product, subjecting it to vacuum/partial dehydration to a dehydration rate (weight loss rate of assimilate) of 3 wt% or more and 60 wt% or less. An NMR diagnostic skin marker consisting of a high water content gel obtained by the above method is obtained.

Hereinafter, the present invention will be explained in more detail.

In the present invention, a skin marker is manufactured using a high water content gel according to the specific treatment described in the first section.

The polyvinyl alcohol used in the present invention requires a degree of saponification of 98 mol% or more, preferably 98.5 mol% or more. In addition, the degree of polymerization of polyvinyl alcohol is l, 0
Requires 00 or more.

In the present invention, first, an aqueous solution containing the aforementioned polyvinyl alcohol is prepared. The concentration of polyvinyl alcohol is more than 8 wt% and less than 20 wt%, preferably 9 to 1
It is set to 5wt%.

In the present invention, the polyvinyl alcohol aqueous solution is injected into a mold suitable for desired molding of a disk, elliptical plate, band-shaped plate, etc., and after cooling and freezing, it is thawed. You can get gel. Also,
In particular, when a skin marker with high mechanical strength is desired, the high water content gel (rubber ) can be obtained. As the cumulative number of times of freezing increases, the hardness of the obtained high water content rubber also improves, but after 8 cumulative times of freezing, this effect almost disappears (Nanbu 8, Kobunshi Kako, 32, 523 (1983)). , 2 to 8 above are economical.

In the present invention, instead of repeating the thawing and refreezing operations after the above-mentioned cooling and freezing, without thawing the frozen body,
Vacuum/partial dehydration may be applied; in this case, the dehydration rate (weight loss rate of the cooled/assimilated gel) increases and the mechanical strength of the gel also improves. However, keeping the dehydration rate at 3 wt% or more, preferably 8 wt% or more and 60 wt% or less, preferably 35 wt% or less improves the shape retention of the gel.
Preferable from the viewpoint of processability.

The vacuum/partial dehydration referred to here means slight dehydration under reduced pressure, and the degree of reduced pressure is not particularly limited, but for example, 1■Hg
or less, preferably 0.1 mHg or less, more preferably 0.0
It can be done with less than 8-8g. As described above, the mold for molding is a belt-shaped mold or a disc-shaped mold.

There are no particular restrictions other than that a desired shape such as an elliptical plate can be obtained, but the thickness (uniformity or thickness distribution) dimension, shape, etc. can be selected as appropriate depending on the actual situation of NMR diagnosis.

In the present invention, a single polyvinyl alcohol component is used as a gel material (gelling component).

However, the coexistence of a component that does not inhibit the gelation of polyvinyl alcohol is acceptable to the present invention, and the amount thereof can be, for example, 172 or less of the polyvinyl alcohol.

The above-mentioned components that do not inhibit the gelation of polyvinyl alcohol include alcohols such as isopropyl alcohol, glycerin, propylene glycol, and ethyl alcohol, proteins such as casein, gelatin, and albumin, and lipids such as lecithin, monostearin, and tristearin. , sugars or polysaccharides such as glutenose, agar, carrageenan, butyl p-hydroxybenzoate, phthalocyanine, organic compounds such as flavanthrone, nickel salts, copper salts, manganese salts, iron salts, graphite, activated carbon, silica/alumina, Examples include inorganic compounds such as zeolite and calcium silicate, inorganic salts, and organic acid salts.
It can be added as is or as an aqueous solution or suspension to an aqueous polyvinyl alcohol solution, stirred and dispersed uniformly, and then subjected to the above-mentioned freezing and subsequent treatments.

In the present invention, a desired gel (skin marker) with a water content in the range of 80 to 92% can be obtained. The gel water content depends on the formulation composition of the initial polyvinyl alcohol aqueous solution (or suspension).

When a polyvinyl alcohol aqueous solution (or suspension) is partially dehydrated after freezing, the gel water content is calculated by considering the amount of dehydration. For gels obtained by simply freezing and thawing (or their repetition) without partial dehydration, the gel water content can be easily reduced because the initial polyvinyl alcohol aqueous solution (or suspension) has already gelled. Calculated.

In the present invention, by adjusting the composition of the initial polyvinyl alcohol aqueous solution, it is possible to obtain a gel with a water content of less than 80%, for example, 30 to 79%. Moisture content (51
In order to obtain a clear image, it is advantageous to set the water content to 5% or more (56 to 74% or more), preferably 80% or more.

In the present invention, a marker of an appropriate shape can be obtained by preparing a mold as desired in advance, and after obtaining a gel of an arbitrary shape, it is cut into a desired shape by cutting it with scissors or a sharp blade. It can be done. In this case, the appropriate shape, that is, the desired shape, is the lesion (
In addition to the membrane (or plate) that can cover a wide range of skin surface depending on the size of the lesion,
There is no problem in providing a blank area (hollowed area) that corresponds to the shape of the lesion and using the skin surface corresponding to this blank area as a part of the skin marker.

<Effects of the Invention> The skin marker of the present invention contains water ranging from 80 to 92% lt%, and can be visualized together with lesions on tomographic images as an NMR signal of a clearly different type from that of living skin (51 to 69% water). be done.

As described above, the skin marker of the present invention retains its shape even at 37°C despite containing a large amount of water, can be molded into a desired shape, and can be used as a highly flexible rubber plate-like patch.
Can be used closely and fixed on any part of the body surface. For fixation, simply place an adhesive plaster (or bandage) over the marker on the skin, and as the diagnosis of the shape of the lesion progresses, insert scissors around the periphery of the skin marker to adjust the shape and size of the lesion as desired. Can be cut to match.

As the skin marker of the present invention, the high water content rubber (gel) itself can be used as it is, or the high water content rubber (gel) in any shape can be coated and packaged with polyethylene film, polypropylene film, nylon film, etc. It can be used as it is, or it can be further cut into desired dimensions. In any case, the skin marker of the present invention can be stored very easily, and in a sealed container, it remains in a highly hydrated state for more than half a year and maintains NMR characteristics that are clearly different from those of living skin.

<Examples> Examples of the present invention will be described below. Note that percentages are expressed on a weight basis.

Example 1 A skin marker 10 shown in FIG. 1 was manufactured.

314 g of an 18.6% aqueous solution of polyvinyl alcohol with an average degree of polymerization of 1,000 and a degree of saponification of 98 mol%.

The frozen body obtained by pouring into a disc mold with a thickness of 1 cm and a diameter of 20 cm and cooling it to -30°C was heated to 0.1 + nmH.
After removing 22 g of water under reduced pressure of H.

The temperature was returned to room temperature to obtain a disk-shaped gel with a water content of 80%, which was stored in a sealed container. This water content is human skeletal muscle (water 79~
80%), small intestine (80%), stomach (78-81%),
Uterus (80%), lungs (80-85%), heart (7%)
6-80%), thymus (76-82%), bladder (82%)
%), kidney (76-82%), pancreas (77%), pancreas (75%), brain white matter (82-84%),
This is clearly higher than that of living skin (51-69%).

Next, remove this disc from the sealed container and place it in a cork polar container.
Approximately 60 small disks with a diameter of 1a11 were obtained by punching holes using the same method, and these were again stored in a sealed container.

One of these sheets was sterilized with chlorhexidine and implanted subcutaneously on the back of a rabbit for 6 months, but no foreign body reactions such as inflammation or cell infiltration were observed in the living tissue, and no excessive proliferation of connective tissue was observed ( Nanbu 8th student, polymer processing, well, 523
(1983)), similarly, a mongrel adult was intubated under general anesthesia, and under controlled breathing, the thoracotomy was made between the left fourth intercostal space and the cardiac abdomen was opened 1al.
An incision was made, and a thin film (thickness: 1 mm) cut from the marker was continuously sutured to the defect using Tefdec thread. Autopsy results after one year showed no abnormalities around the high water content material of the present invention, and similarly, when it was sewn to the chest wall of an adult thoracotomy site, findings after seven months showed no foreign body reaction at all.

Next, one rod cut from the marker with a length of 2a++ and a diameter of 21m1 was sewn between the equator and the serration of the upper chasm of 10 domestic rabbits weighing 2.5kg and 20 eyes. The patient's eyeball was removed one year after the patient's arrival, but no abnormalities such as inflammation or rejection were found on the eye. Through these animal experiments, it was determined that the high water content rubber (gel) of the present invention poses no problem even when brought into direct contact with living tissue.

On the assumption that the area to be irradiated will be displayed on the skin of the anterior chest wall of the volunteer, one sheet of the small disc gel (skin marker) is pasted on the skin, and this marker and the middle lobe of the lung (assumed lesion) are displayed. As a result of taking an NMR tomographic image that crosses both parts), the static magnetic field strength is 0.15T, and the pulse interval is 525.
Although the skin surface itself was not depicted under the conditions of m5 and eco time of 48 m s, both the skin marker and the middle lobe of the lung were clearly depicted, making it possible to capture the positional relationship between the skin marker application position and the middle lobe of the lung. was completed. It was also possible to easily cut the periphery of the marker with scissors to match the shape of the localized area of the middle lobe of the lung (assumed lesion) while taking tomographic images including the marker and the middle lobe from all directions.

The dynamic elastic modulus (10'Nm-'') of the above-mentioned high water content gel is 0
．． 2 (equivalent to konjac), the stress relaxation in an air atmosphere (room temperature to 37°C) was to the same extent as silicone rubber, and it was confirmed that it had shape retention.

In addition, its NMR characteristics were measured using an NMR spectrometer (
As a result, at 37°C, the water content was 80%, Ti = 0.55 seconds, and T2 = 0.12 seconds. The small disc (marker) that had been sealed and stored for 6 months was measured again using the NMR spectrometer, and the water content was 79%, T1 = 0.56 seconds, T2 = 0.11.
Example 2 A marker 20 shown in FIG. 2 was manufactured.

A 15% aqueous solution of polyvinyl alcohol with an average degree of polymerization of 2,000 and a degree of saponification of 99 mol% was heated in a 15×15×0.80
The water content of the high water content gel obtained by freezing and thawing twice after injecting into the plate molding mold No. m was 85%. Its NMR
The characteristics were determined using the NMR spectrometer of Example 1, and as a result, at 37°C, T = 0.7 s, T:
= 200 m s.

Living skin (moisture 51-69%, T = 0.5s, T
.

= 45 m s), the proton concentration and T2 value were high, so it was fully predicted that the NMR signal intensity would be high. In fact, from the above plate gel, 3 x 3 x 0.8 a
As a result of NMR diagnosis after cutting out a fragment of n and pasting it on the chest wall skin according to Example 1, the skin surface was not visualized under the same imaging conditions, but the skin marker of the present invention and the middle lobe of the lung were detected. Both were clearly depicted, allowing us to understand the relative relationship between their positions.

Example 3 A 15% aqueous solution of polyvinyl alcohol with an average degree of polymerization of 2,600 and a degree of saponification of 99 mol% was placed in a container with a diameter of 30 cm and a height of 1
．． The mixture was poured into a 3-arm disc mold, frozen at -40°C, and then thawed to obtain a high water content gel. The elastic modulus (10'Nm-'') was 0.15, and it was judged that the shape could be maintained.Example 1
As a result of measurement using an NMR spectrometer, the water content was 85%, T = 0.7 s, T2 = zoo m s.
, biological skin (moisture 51-69%, T, = 0.5s
, T, = 45 ms), the water content (proton concentration) was higher than that of T, and similarly to Example 2, its usefulness as a skin marker was demonstrated.

When this marker was stored in a sealed container, after 180 days, the moisture content was 84.5%, T = 0.7 s, Tt = 2
The time was measured to be 10 ms, indicating that the NMR information was stable.

[Brief explanation of drawings]

FIG. 1 is a perspective view showing an example of the skin marker for NMR diagnosis of the present invention, and FIG. 2 is a perspective view showing another example of the skin marker for NMR diagnosis of the present invention. In the figure, 10 and 20 are skin markers for NMR diagnosis.

Claims (1)

[Claims] After injecting into a mold an aqueous solution containing polyvinyl alcohol with a saponification degree of 98 mol% or more and an average polymerization degree of 1,000 or more, and in which the concentration of the polyvinyl alcohol is adjusted to be more than 8 wt% and 20 wt% or less, This at -10℃
After freezing, solidifying, and molding to the following temperature, thaw,
A high water content gel obtained by thawing the cumulative number of times of freezing in the thawing operation from 1 to 8, or without thawing the above-mentioned frozen body, with a dehydration rate (weight loss rate of the frozen body) of 3 wt% or more and 60 wt% or less A skin marker for NMR diagnosis consisting of a high water content gel obtained by subjecting it to vacuum/partial dehydration.