JPH0676342B2 - NMR diagnostic skin marker - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention identifies the body surface of a patient when measuring the lesion position of the patient who needs radiation treatment to the internal lesion or the surgical treatment to the internal lesion. In NMR (Nuclear Magnetic Resonance) tomography for determining the positional relationship with a lesion based on points, the skin marker that can be visualized together with the lesion is provided on a local area of the body surface of the patient.

<Conventional Technology and Problems> Prior to adding invasion for the purpose of examination / treatment of a patient having a body lesion, the body surface specific local area of the patient is used as a base point,
Accurate recognition of the three-dimensional location of the lesion is essential for minimizing the damage to normal tissue in the vicinity of the lesion and increasing the effectiveness of surgical procedures.

As a method for observing the inside of a living body, X-ray-CT (Compute
α Tomography), Positron emission tomography (PET, PE-C
T) and ultrasonic diagnosis (US) have been tried, but the former two are concerned about the exposure of normal tissue by X-rays and radioisotopes, respectively, and in the US, there is a lot of noise and the resolution is not always sufficient. In addition, PE-CT is inferior in resolution because X-ray-CT and US are disturbed by skeleton and air.
NMR-CT (Nuclear Magnetic Resonance Tomography) has been attempted as a diagnostic method for overcoming these difficulties. In this case, although many internal organs and various lesions are clearly depicted without invading the living body, their position, especially the positional relationship with the body surface specific region is not explicitly shown.

In irradiation treatment or various surgical treatments and surgical procedures, it is intended to destroy or ablate lesion tissue in a living body through a specific site on the body surface (skin). Therefore, the positional relationship between the specific site on the skin and the lesion Must be known correctly in advance.

If a lesion such as a hematoma or tumor is accidentally present on the skin surface, both the skin lesion and the lesion inside the body can be clearly displayed on the NMR tomographic image, but such a coincidence is completely reliable. Can not.

In order to visualize the specific position on the body surface along with the internal lesion on the NMR tomographic image, a different kind of NMR signal from normal skin tissue is clearly emitted to the local skin (body surface, normal skin) on the cross section that crosses the internal lesion. It is convenient to apply some substance, but it is not easy to find a substance (skin marker) that can always meet this requirement under the operating conditions (within range) of NMR diagnosis. For this purpose, water (pure water) is considered first. Compared to the skin (water content: 51-69%), water has a much stronger proton signal, the longitudinal (T ₁ ) and transverse (T ₂ ) magnetic relaxation times are both long, and it is harmless to the skin. However, it lacks shape retention on the skin surface. By applying a water-filled bag on the skin surface, this difficulty can be avoided. However, in the process of initially applying a marker of arbitrary shape and size on the body surface and repeating the operation of drawing as a tomographic image with the lesion, the edges of the marker are sequentially cut to bring it closer to the shape (dimension) of the lesion, and finally In addition, it is desirable to embody a lesion image (shape / dimension) on the skin surface, and since the water bag cannot be cut, this demand cannot be satisfied. It is a highly water-containing product that is close to pure water, yet emits an NMR signal similar to water.
Materials that can be cut according to the shape and size of the lesion include jelly, jam, agar, carrageenan, carboxymethyl cellulose, polyvinyl alcohol / boric acid complex, tofu,
Gels such as alginic acid, agarose, curdlan, acrylonitrile-starch graft, xanthan gum, locust bean gum, tragacanth gum, furceleran, methylcellulose, fucoidan, tamarind gum, karaya gum, and gum tea gum are all considered, but these are all mechanical. It is poor in mechanical strength, often lacks in shape retention, and is not suitable for adhesion and fixation to specific areas on the skin surface.

Congo red complex of polyvinyl alcohol has a high water content and is an elastic body like soft rubber, but it is harmful to living tissues (S.Niedermeier; Graefes Archiv fur Ophthalmol., 161,547 (1960), C.
L. Schepens et al., Arch.Ophthalmol., 64,868 (1960), WC Everett; Klin.Monatsbl. Augenheilkd., 141,764 (1962), Hide Sakagami, Clinical Ophthalmology, 1
8, (1) 7 (1964)), which is not preferable. Polyacrylamide gel is also harmful to living organisms and has the drawback of being mechanically fragile.

Konjac retains its shape despite containing about 98% water and gives a NMR signal similar to water and can be cut, but it is immersed and stored in a strong alkaline solution (pH 11 to 12) tank containing a preservative. Unless it is easily deformed, flows, and undergoes severe syneresis / contraction / deformation, it is difficult to store and is not suitable for any occasion, quick, and convenient use in clinical settings.

<Purpose of the Invention> The present invention is a different type of NMR characteristics (moisture content,
T ₁ , T ₂ ) is stably retained, and the shape retention is good,
Provided is a skin marker for NMR diagnosis, which can be cut into an arbitrary shape and is harmless to a living body.

<Means for Solving Problems> According to the present invention, the saponification degree is 98 mol% or more, and the average polymerization degree is 1.
An aqueous solution containing 000 or more polyvinyl alcohol and having a polyvinyl alcohol concentration of more than 8 wt% and 20 wt% or less is poured into a molding mold, which is then cooled, frozen and molded at a temperature of -10 ° C or less. Then, this is thawed, and the high water content gel obtained by setting the cumulative freezing number of this freezing / thawing operation to 1 to 8 or the cooled / frozen body is thawed without thawing it. A weight loss rate of frozen body) A NMR diagnostic skin marker composed of a highly hydrous gel obtained by performing vacuum / partial dehydration at 3 wt% or more and 60 wt% or less.

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

In the present invention, the skin marker is produced by using a high water content gel according to the specific treatment method described below.

The polyvinyl alcohol used in the present invention has a saponification degree of 98 mol% or more, preferably 98.5 mol% or more. The degree of polymerization of polyvinyl alcohol needs to be 1,000 or more.

In the present invention, first, an aqueous solution containing the above-mentioned polyvinyl alcohol is prepared. The concentration of polyvinyl alcohol is more than 8 wt% and 20 wt% or less, preferably 9 to 15 wt%.

In the present invention, the polyvinyl alcohol aqueous solution is poured into a mold suitable for desired molding such as a disc, an elliptical plate, and a strip plate, and after cooling and freezing, it is thawed to obtain a high water content that can be used in the present invention. A gel can be obtained. Also,
In particular, when a skin marker having a high mechanical strength is desired, a high water content gel (rubber which can be used in the present invention can be provided by repeating the above-mentioned freeze / thaw series of operations to set the cumulative freezing number to 2-8. ) Can be obtained. While increasing the cumulative freezing number, the hardness of the resulting high water content rubber is also improved, but after the cumulative freezing number 8 the effect almost disappears (Masabu Nanbu, Polymer Processing, 32,523 (1983)). Two
~ 8 is economical.

In the present invention, after the above-mentioned cooling / freezing, instead of repeating the thawing / refreezing operation thereto, without thawing the frozen body,
Vacuum and partial dehydration may be applied. In this case, the dehydration rate (weight reduction rate of the cooled / frozen gel) increases and
The mechanical strength of the gel is also improved, but it is not necessary to significantly increase the dehydration rate to obtain a strong gel, and the dehydration rate is 3 wt%.
Or more, preferably 8 wt% or more and 60 wt% or less, preferably 3
It is preferable to keep the content at 5 wt% or less from the viewpoints of the shape retention of the gel and the processability.

The vacuum / partial dehydration referred to here is a slight dehydration under reduced pressure, and the degree of reduced pressure is not particularly limited. For example, 1 mmHg
Hereafter, it can be carried out at preferably 0.1 mmHg or less, and further 0.08 mmHg or less. As the molding template, as described above, there is no particular limitation in addition to obtaining a desired shape such as a band, a disk, an elliptical plate, but depending on the actual situation of NMR diagnosis, the thickness (uniformity or Thickness distribution), size, shape, etc. can be selected.

In the present invention, a single component of polyvinyl alcohol is used as a gel material (gelling component). However, the coexistence of a component that does not inhibit gelation of polyvinyl alcohol does not affect the present invention, and the coexistence amount thereof can be, for example, 1/2 amount or less of that of polyvinyl alcohol.

Examples of the components that do not inhibit gelation of polyvinyl alcohol include alcohols such as isopropyl alcohol, glycerin, propylene glycol and ethyl alcohol, proteins such as casein, gelatin and albumin, lipids such as lecithin, monostearin and tristearin. , Sugars or polysaccharides such as glucose, agar, carrageenan, organic compounds such as butyl p-hydroxybenzoate, phthalocyanine blue, flavanthrone, nickel salts, copper salts, manganese salts, iron salts, graphite, activated carbon, silica-alumina, Zeolites, inorganic compounds such as calcium silicate, inorganic salts, organic acid salts, etc. are listed.
As it is, or as an aqueous solution or a suspension, it is added to an aqueous polyvinyl alcohol solution in advance, and then stirred to uniformly disperse, after which the above-mentioned freezing and the subsequent treatment can be performed.

In the present invention, a desired gel (skin marker) having a water content of 80 to 92% can be obtained. The gel water content is
It depends on the initial formulation composition of the polyvinyl alcohol aqueous solution (or suspension). When the polyvinyl alcohol aqueous solution (or suspension) is frozen and then partially dehydrated,
The gel water content is calculated by considering the dehydration amount. Regarding the gel obtained by simply freezing and thawing (or repeating it) without omitting the partial dehydration operation, the initial polyvinyl alcohol aqueous solution (or suspension) is gelled as it is, so the gel water content is easily It is calculated.

In the present invention, by adjusting the composition of the initial aqueous solution of polyvinyl alcohol, the water content is less than 80%, for example,
It is possible to obtain a gel of 30 to 79%, but considering the use as a skin marker, the water content of living skin (51 to 69%)
A water content higher than 5% (56 to 74% or more), preferably 80% or more, is convenient for obtaining a clear image.

In the present invention, by producing a molding mold in advance as desired, a marker having an appropriate shape can be obtained, and after obtaining a gel having an arbitrary shape, it is cut with scissors or a sharp blade to obtain a desired shape. Can be In this case, a suitable shape, that is, a desired shape, can conform to a lesion (or a presumed lesion), and a membrane (or plate) that can cover a wide range of skin surfaces depending on the lesion size.
, A blank part (hollowed part) that conforms to the lesion shape is provided,
There is no problem in utilizing the skin surface corresponding to this blank portion as a skin marker site.

<Effects of the Invention> The skin marker of the present invention contains 80% to 92% by weight of water, which is clearly different from that of living skin (water 51 to 69%).
As a signal, it is depicted together with the lesion on the tomographic image.

Thus, the skin marker of the present invention has a shape-retaining property even at 37 ° C. even though it contains a large amount of water, and is molded into a desired shape. Can be used in close contact with any local area on the surface. As a fixing method, simply apply a bandage (or bandage) on the marker on the skin surface, and as the diagnosis of the lesion shape progresses, insert scissors around the skin marker and make the shape and size of the lesion as desired. Can be cut together.

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) of an arbitrary shape is covered and packaged with a polyethylene film, a polypropylene film, a nylon film, or the like. Can be used as it is, or can be further cut into desired dimensions. In any case, the skin marker of the present invention is extremely easy to store, and in a sealed container, it does not change to a high water content state for more than half a year, and retains NMR characteristics that are clearly different from those of living skin.

<Examples> Examples of the present invention will be described below. The percentages are based on weight.

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

A 18.6% aqueous solution of polyvinyl alcohol having an average degree of polymerization of 1,000 and a degree of saponification of 98 mol%, 314 g, was poured into a disc molding mold having a thickness of 1 cm and a diameter of 20 cm, and the frozen body obtained by cooling it to −30 ° C. After removing 22 g of water under a reduced pressure of 0.1 mmHg,
After returning to room temperature, a disk-shaped gel having a water content of 80% was obtained and stored in a sealed container. This water content depends on human skeletal muscle (water content 79-80
%), Small intestine (80%), stomach (78-81%), uterus (80%)
%), Lung (80-85%), heart (76-80%), thymus (76-82%), bladder (82%), kidney (76-82%)
%), Spleen (77%), pancreas (75%), brain white matter (82)
Although it is close to ~ 84%), it is clearly higher than that of living skin (51 ~ 69%).

Next, this disc was taken out from the sealed container and opened by using a cork borer to obtain about 60 small discs having a diameter of 1 cm, which were again sealed and stored.

After sterilizing one of these with chlorhexidine, it was implanted subcutaneously in the dorsal region of the rabbit for 6 months. No foreign body reaction such as inflammation or cell infiltration was observed in the living tissue, nor was excessive proliferation of connective tissue observed ( Nambu Masao, Polymer processing, 32,523 (19
83)), similarly, a mongrel adult dog was intubated under general anesthesia, and under controlled respiration, the left fourth intercostal space was thoracotomy, and a 1 cm incision was made in the pericardium, and a thin film cut from the marker to this defect ( Thickness 1m
m) was continuously sutured with Tefdeck thread. One year later, the anatomy results showed that there was no abnormality around the highly water-containing material of the present invention,
Similarly, when sewn onto the chest wall of the thoracotomy site of an adult dog, no foreign body reaction was observed after 7 months.

Next, a length of 2c cut from the marker between the equatorial part and the serrated edge of the upper sclera of 10 rabbits weighing 2.5 kg and 20 eyes.
One m and 2 mm rods were sewn on each, and one year later, the eyes were enucleated. No abnormalities such as inflammation or rejection were observed in all cases. From these animal experiments, it was determined that the highly water-containing rubber (gel) of the present invention causes no problem even if it is brought into direct contact with living tissue.

Based on the assumption that the site to be irradiated is displayed on the skin of the anterior chest wall of the volunteer, one of the small disc gels (skin marker) is pasted on the skin, and the marker and the middle lobe of the lung (the lesion is assumed). As a result of taking an NMR tomographic image that crosses both sides, the skin surface itself is not visualized under the conditions of static magnetic field strength of 0.15 T, pulse interval of 525 ms, echo time of 48 ms, but both the skin marker and the middle lobe of the lung are clearly visible. Since it was visualized, the positional relationship between the skin marker application position and the middle lobe of the lung could be captured. In addition, while taking a tomographic image including this marker and the middle lobe from each direction, it was also possible to easily cut the peripheral edge of the marker with scissors according to the shape of the local lobe of the lung (assumed lesion).

The dynamic elastic modulus [10 ⁵ Nm ^-2 ] of the above high hydrous gel is 0.2 (equivalent to konjac), and stress relaxation in an air atmosphere (room temperature to 37 ° C)
Has been confirmed to have a shape-retaining property that is equivalent to that of silicone rubber. Further, its NMR characteristics were determined by an NMR spectrometer (0.47T). As a result, at 37 ° C, the water content was 80%, T ₁ = 0.55 seconds, and T ₂ = 0.12 seconds. 6
(3) The small disk (marker) that had been sealed and stored for a month was measured again by the NMR spectrometer, and the water content was 7
9%, T ₁ = 0.56 seconds, T ₂ = 0.11 seconds were obtained, which was almost unchanged during storage.

Example 2 The 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 poured into a 15 × 15 × 0.8 cm plate molding mold, and then frozen and thawed twice to obtain a high water content gel. The rate was 85%. The NMR characteristics are the same as those of Example 1.
T _{1 at} 37 ℃ as determined by a spectrometer
= 0.7 s, T ₂ = 200 ms, and live skin (moisture 51-69%, T ₁
= 0.5 s, T ₂ = 45 ms), the proton concentration and T ₂ value were higher, so that it was sufficiently predicted that the NMR signal intensity was high. In fact, a piece of 3 × 3 × 0.8 cm was cut out from the slab gel described above and applied to chest wall skin according to Example 1,
As a result of NMR diagnosis, under the same imaging conditions, the skin surface was not visualized, but the skin marker of the present invention and the middle lobe of the lung were both clearly visualized, and the relative relationship between the positions of both could be known. .

Example 3 A 15% aqueous solution of polyvinyl alcohol having an average degree of polymerization of 2,600 and a degree of saponification of 99 mol% was poured into a disk molding mold having a diameter of 30 cm and a height of 1.3 cm, frozen at -40 ° C, and then thawed. A highly hydrous gel was obtained. Its elastic modulus (10 ⁵ Nm ^-2 ) is 0.1
In 5, it was decided that the shape could be retained. The cut pieces of this disc were measured by the NMR spectrometer of Example 1 to have a water content of 85%, T ₁ = 0.7 s, T ₂ = 200 ms, and living skin (water content 51-69%, T ₁ = Compared with 0.5 s, T ₂ = 45 ms), T ₂ and water content (proton concentration) were higher, and as in Example 2, usefulness as a skin marker was shown.

When this marker was sealed and stored, after 180 days, the water content was measured at 84.5%, T ₁ = 0.7 s, T ₂ = 210 ms, and it was found that the NMR information was stable.

[Brief description 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] 1. A saponification degree of 98 mol% or more and an average degree of polymerization of 1,000.
An aqueous solution containing the above polyvinyl alcohol, and the concentration of the polyvinyl alcohol exceeding 8 wt% and adjusted to 20 wt% or less, was poured into a molding mold, and then cooled / frozen at a temperature of -10 ° C or less. After molding, thaw, and the high water content gel obtained by setting the cumulative freezing number of this freezing / thawing operation to 1 to 8 or the frozen body without thawing, the dehydration rate (weight reduction of frozen body) Rate) 3 wt% or more, 6
A skin marker for NMR diagnosis consisting of a highly water-containing gel obtained by performing a vacuum / partial dehydration of 0 wt% or less.