Preparations for time-limited marking of biopsy sites

FIELD OF THE INVENTION

The present invention belongs in general to the field of medicine and surgery, and more particularly to a material that can be used to mark the location from which a tissue sample has been removed, so that treatments can be carried out. posterior (for example, surgical removal, radiotherapy, drug therapy, etc.) precisely in that location.

BACKGROUND OF THE INVENTION

A. Use of tissue biopsies in modern medicine and surgery

In modern medical practice, small tissue samples, known as biopsy, tumors, lesions, organs, muscles and other body tissues, are often removed. Such tissue sample extraction can be carried out by open surgery techniques (i.e., removal of a small tissue sample through a small surgical incision using a local anesthetic), or through the use of a specialized biopsy instrument, such as a biopsy needle. After the extraction of tissue samples, they are typically subjected to diagnostic tests or examinations such as: a) macroscopic and microscopic examination to determine cytology and / or histology, b) biochemical analysis to determine the presence or absence of chemical substances that indicate certain disease states, c) microbiological culture to determine the presence of bacteria or other microbes, and / od) other diagnostic procedures. The information obtained from these tests and / or diagnostic tests can then be used to make or confirm a diagnosis and / or to formulate treatment plans for the patient.

B. Special considerations in relation to breast cancer biopsy

About one in nine women in America will develop breast cancer at some point in their life. Currently, breast cancer is the most common cancer in women, and is the second leading cause of cancer death in women. Periodic physical examination of the breasts is important for the early detection of potentially cancerous lesions. Additionally, specialized X-ray studies, known as mammograms, are a proven tool for the diagnosis of breast cancer in women over 40 years of age. Mammography is also considered by many medical professionals as beneficial for diagnosis in younger women. On mammography, the breast is compressed between two plates while specialized X-ray images are taken.

If an abnormal mass is found in the breast by physical examination or mammography, ultrasound can be used to determine if the mass is a solid tumor or a cyst filled with fluid. Cystic lesions are usually benign and the diagnosis of a cystic lesion is often confirmed by aspiration with a needle of fluid from inside the cyst. (It should be noted, however, that needle aspiration of cystic lesions is different from "needle biopsy" of solid masses, as discussed hereafter). However, solid masses are usually subjected to some type of tissue biopsy to determine if the mass is cancerous.

If a solid mass or lesion is large enough to be palpable (that is, detected by scanning with the fingertips), a tissue sample may be removed from the mass by a variety of techniques, including, but not limited to, biopsy. by open surgery or a technique known as Fine Needle Aspiration Biopsy (BAAF). In the open surgery biopsy an incision is made and a quantity of tissue is removed from the mass for a subsequent histopathological examination. In the BAAF procedure, a small sample of mass cells is aspirated through a needle and the aspirated cells are then subjected to cytological examination.

If a solid breast mass is small and not palpable (for example, of the type typically found by mammography), a relatively new biopsy procedure known as "stereotactic needle biopsy" may be used. In performing a stereotactic needle biopsy of a breast, the patient lies on a special biopsy table with her breast compressed between the plates of a mammography device and two digital X-ray images are taken slightly separated from two points of view different. A computer calculates the exact position of the lesion in X and Y coordinates as well as the depth of the lesion inside the breast. After this, a stereotactic mechanical device is programmed with the coordinate and depth information calculated by the computer, and said device is used to advance the biopsy needle precisely towards the small lesion. Depending on the type of biopsy needle (s) used, this stereotactic technique can be used to obtain cytological samples (obtained through BAAF) and / or histological samples (obtained by central needle biopsy). Normally at least five separate biopsy samples are obtained from locations around the small lesion as well as one from the center of the lesion.

1) potential delay time between the biopsy and the beginning of surgery or other treatment

For some types of biopsy (other than breast lesions), "frozen sections" of the biopsy samples may be prepared by a pathologist and such frozen sections can be used to arrive at a reasonably accurate diagnosis within minutes of the removal of the biopsy sample Such frozen sections are prepared by rapidly freezing the tissue, cutting the tissue into sections of thickness greater than 10 micrometers and mounting the sections on glass slides for an immediate microscopic examination by a pathologist. Frozen sections of this type are not typically used for biopsies of breast lesions because the usual frozen section is too thick for visualization and definitive diagnosis of cell types found in breast tumors. In contrast, breast biopsy samples are normally prepared for a histopathological examination by a more traditional non-freezing technique in which the tissue sample is immersed in a chemical fixative solution (e.g., formalin, glutaraldehyde, etc.) during a sufficient period of time to produce a cross-linking of the connective tissue proteins present in the tissue, The fixed tissue is cut into thin sections approximately 8 micrometers thick, the tissue sections are placed on slides and selective histological stains of cells are applied to stain the tissue before microscopic examination. This technique of tissue preparation without freezing typically requires at least 24-48 hours to complete and, as a consequence, the diagnosis of the breast lesion pathologist may not be available until 24 to 72 hours after the sample of Biopsy has been removed from the breast. Thus, for these reasons, the histopathological examination and diagnosis of breast lesions may be much longer than the examination and histopathological diagnosis of other types of lesions. After this, if a breast lesion has been diagnosed as cancerous, the patient may require some time (for example, several days to more than a week) to consider each of the surgical options available to her, seek second opinions and Make a decision about treatment. The surgical options available for cancerous lesions of the breast include various degrees of mastectomy or lumpectomy. Moreover, in some cases, depending on the histology (type of cancer), grade (how aggressive it looks under the microscope), stage (how large the cancer is and how far it has spread), and additional prognosis or predictive information, the doctors may recommend that some radiation therapy be performed

or chemotherapy before proceeding with surgical lumpectomy.

2) Brand of biopsy sites to facilitate subsequent location and treatment of the lesion

In order to direct the surgeon oncologist or radiologist in the surgical treatment

<dl>&lt;dt /&gt;<dd>or radiologically to the precise location of the breast lesion several days or weeks after the biopsy procedure has been performed, it is desirable that a marker of the biopsy site be placed on or on the patient's body to serve as a signal for the subsequent location of the lesion. Several types of biopsy site markers of the prior art are known. For example, the prior art has included visually discernible markers that are applied externally to the patient's skin, as described in US Patent Nos. 2,192,270 (Carswell, Jr.) and 5,147,307 (Gluck). Additionally, the prior art has included radiographically visible markers that can be introduced at the biopsy site, such as marker wires that are inserted through the biopsy needle after the tissue sample has been removed and can then remain sticking out of the patient's body, and tissue radiographic markers (eg clips or staples) that are attached to the skin adjacent to the site from which the biopsy sample has been removed, as described in International Patent Publication No. WO 98/06346 (Biopsys Medical, Inc.). However, due to the consistency of the breast tissue and the fact that these biopsy site markers are typically introduced while the breast is still compressed between the mammographic plates, those prior art biopsy markers may end. attached to bandages or adjacent connective tissues that do not remain at the specific biopsy location after the breast is decompressed and removed from the mammogram. In addition, at least part of the prior art biopsy site markers may remain present at the implantation site for an indefinite period of time if they are not surgically removed. Thus, if it is estimated that surgery is not indicated at that time (or if the patient chooses not to have surgery), radiographic markers from the prior art biopsy site may</dd></dl>

remain intact indefinitely and may obscure or interfere with mammograms

<dl>&lt;dt /&gt;<dd>or studies by follow-up or later images. Although International Patent Publication No. WO 98/06346 mentions that the clip-like tissue markers disclosed in that document may be "biodegradable," said publication does not provide information on what materials could be used to make said "biodegradable tissue marker." ", Or the preferred period of time in which the tissue marker must remain present (ie, not degraded and visible) at the biopsy site. </dd></dl>

Thus, a need remains in the art to develop biopsy site markers that a) can be applied inside the cavity created by the extraction of the biopsy sample (and not in the tissue that is located outside that cavity). of biopsy), b) do not migrate from the biopsy cavity even when the breast tissue is moved, manipulated or decompressed, c) remain detectable at the biopsy site (for example, inside the biopsy cavity at the site where the biopsy cavity once existed) until at least a first predetermined moment in time (for example, two weeks after the biopsy) to facilitate the subsequent location of the biopsy site by a surgeon or radiologist and d) be sufficiently removed from the biopsy site or otherwise do not interfere with the imaging diagnosis of the biopsy site and of adjacent tissues at a second predetermined moment in time (for example, 6 months after the biopsy) in order not to darken or interfere with mammograms

<dl>&lt;dt /&gt;<dd>or diagnostic imaging processes. </dd></dl>

SUMMARY OF THE INVENTION

The present invention relates to the use of a material that can be removed from a site inside the body of a breast patient from which a tissue sample has been removed and which is characterized by:

<dl><dt>(i) </dt><dd>remain present on the site in an amount sufficient to allow detection and location of the site for at least 2 weeks after its introduction, and </dd></dl>

<dl><dt>(ii) </dt><dd>be sufficiently removed from the site so as not to interfere with the diagnostic imaging visualization of the adjacent tissue of the site 5 to 8 months after its introduction, </dd></dl>

as a detectable marker to mark said site inside the body of the breast patient.

Thus, the invention provides a method for marking biopsy sites, in which a detectable marker (i.e., a substance or article that is detectable by diagnostic imaging and / or palpation and / or visualization) is introduced inside. of the cavity created by the extraction of a biopsy sample (for example, the "biopsy cavity") in such a way that (i) the marker remains present and detectable at the biopsy site at an early stage in time (for example, 2 weeks after introduction), and (ii) the marker is sufficiently removed from the biopsy site, or otherwise it is not detectable by diagnostic imaging in order not to interfere with the diagnostic imaging of the biopsy site and adjacent tissues at a second time (typically, 5-8 months and preferably in about 6 months after its introduction).

A. Types of Markers

1) Marker embodiments visible in diagnostic imaging

In embodiments of the invention in which the marker is detectable by diagnostic imaging, it will typically be visible in the diagnostic imaging by a suitable diagnostic imaging apparatus or means. For example, the marker may be radiographically visible (for example, more radiopaque

or more radiolucent than the surrounding tissue so as to be visible by diagnostic imaging with X-rays, CT scanners, mammography, fluoroscopy, or other roentgenological means. In other visible embodiments in diagnostic imaging, the marker may be visible in diagnostic imaging by other means such as magnetic resonance imaging (MRI), ultrasound, Doppler or other diagnostic imaging techniques currently known or developed from From now.

2) Palpable marker realizations

In embodiments of the invention in which the marker is detectable by palpation, the marker will comprise a space that occupies substance or object (s) that, when introduced inside the cavity created by the biopsy sample extraction, will form a palpable mass that can be located by thorough palpation of the breast and / or by local palpation by a surgeon during dissection of the surrounding tissue of the breast. The space occupied by markers that are palpable include balloon (s), granules, microspheres of bulking fluid materials, such as collagen.

3) Visually discernible marker realizations

In embodiments of the invention in which the label is visually detectable, the label will comprise a substance or object (s) that is of a color different from the color of the breast tissue and blood, such that, when introduced Inside the cavity created by the extraction of the biopsy sample, the marker will be visually detectable by a surgeon during dissection of the surrounding breast tissue.

4) Power station marker realizations

In some embodiments of the invention, the marker can emit energy that is detectable by a suitable detection apparatus. For example, the label may comprise a radioactive substance that is detectable by means of a gamma ray detector, a scintillation counter or other apparatus for detecting radiation. Similarly, the marker may comprise a signal emission apparatus (for example, transmitter or transponder) that emits a signal (for example, radio frequency, ultrasound, etc.) continuously or occasionally when interrogated by ultrasound or another type of questioning energy, which can be detected by an apparatus used to detect that particular type of signal.

5) Marker embodiments detectable by more than one detection means

In some embodiments of the invention, the detectable marker can be detectable by a combination of any two or more of the visual diagnostic imaging, visual, palpation and / or emission / detection techniques summarized above. For example, a marker visible in diagnostic imaging of the present invention may additionally comprise a palpable component such as the one described above (for example, an article or material occupying a space) in order to make the marker both visible in diagnosis by images as palpable after implantation at the biopsy site. Alternatively, a marker visible in diagnostic imaging of the present invention may additionally be provided with a visible component such as that described above (for example, a colored substance or article) in order to make the marker both visible in diagnosis by images as visually discernible after implantation at the biopsy site. Similarly, by way of illustration, a marker visible in diagnostic imaging of the present invention may additionally comprise a palpable component such as the one described above (for example, an article or material occupying a space) and a visible component such as the one described above (for example, a substance or colored article) in order to make the marker visible in diagnostic imaging, palpable and visible during surgery.

B. Consistency and properties of the marker

1) Substantially insoluble marker substances

According to the invention, the detectable label can comprise a substance (for example, a gas, lipid, oil, powder, suspension or slurry) that can be applied within the cavity formed by the extraction of a biopsy sample (i.e., the "biopsy cavity"), and which has solubility and / or biodistributive properties that allow it to remain present and detectable (for example, visible on diagnostic imaging, palpable, emitting energy and / or visible) at the biopsy site until at least the first predetermined moment in time (for example, at least 2 weeks after the introduction), but which will allow the substance to be substantially removed (for example, dissolved, distributed or metabolized locally) from the biopsy site at a second predetermined moment in time (for example, 6 weeks after introduction).

2) Soluble marker substances combined with element (s) that delay their elimination

On the other hand, according to the invention, the detectable marker may comprise a) a detectable substance (for example, visible in diagnostic imaging, palpable, energy emitting and / or visible) which, if applied only inside the cavity formed by the extraction of the biopsy sample would be removed from said biopsy cavity so as not to be more detectable at the first predetermined moment in time (for example, two (2) weeks after its introduction) in combination with b) an eliminating limitation element (for example, a polymeric matrix limiting diffusion, a liposomal membrane or capsule, a biodegradable matrix or encapsulant, etc.) which will limit the dissolution, biodistribution and / or local metabolism of the detectable substance to remain present and detectable at the biopsy site for at least 2 weeks after its introduction, but which will allow the detectable substance to be substantially removed (e.g., dissolved, distributed or metabolized locally) from the biopsy site at the second predetermined time in time (e.g., 5-8 months and preferably in about 6 months later of its introduction).

3) Markers that remain present at the biopsy site without interfering with subsequent diagnostic imaging studies

Even in accordance with the invention, the detectable label may comprise a substance or article that is detectable by a detection method other than the diagnostic imaging method that is intended to be used for diagnostic imaging of the biopsy site and adjacent tissues, thus allowing the marker to reside at the biopsy site beyond the second moment in time (i.e. that time period in which diagnostic imaging studies should be performed) or even indefinitely, without interfering with such diagnostic imaging studies. For example, the marker can be detectable by palpation, visualization and / or ultrasound, but not visible with X-rays, thus allowing follow-up studies with X-rays without marker interference while remaining localizable by palpation, visualization, detection specialized and / or ultrasound, in case a surgeon, radiologist or other physician may require to subsequently locate the biopsy site.

4) Markers that adhere to the wall (s) of the biopsy cavity

Still in accordance with the invention, the detectable label of the present invention may comprise, or may be combined with, an adhesive that will cause the detectable label to adhere to the tissue immediately adjacent to the empty space created by the biopsy sample extraction.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a perspective view of a human breast that has a lesion from which a biopsy sample has been removed, and which shows an syringe and an introduction cannula operatively positioned for the introduction of a detectable marker of the present invention inside the cavity created by the extraction of the biopsy sample.

Figure 1a is an enlarged perspective view of a portion of the breast of Figure 1 after the detectable marker has been introduced and after the syringe and the introduction cannula have been removed.

Figure 2a-2g are schematic step-by-step views of a preferred method of using a detectable marker of the present invention to mark the site of a lesion that has been biopsied while the breast is compressed in a mammography apparatus.

Figure 3a is a schematic view of a first embodiment of a detectable marker of the present invention after its introduction into the biopsy site.

Figure 3b is a schematic view of a second embodiment of a detectable marker of the present invention after its introduction into the biopsy site.

Figure 3c is a schematic view of a third embodiment of a detectable marker of the present invention after its introduction into the biopsy site.

Figure 4 is a longitudinal sectional view of an injector device that can be used to introduce a solid marker substance (eg, powdered, particulate or granular) of the present invention into a biopsy site.

Figures 5a-5c are views of a preferred method of cutting and extracting tissue that is within a predetermined area located on all sides or only on one side of the boundaries of a previously created biopsy cavity.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following detailed description and the accompanying drawings to which it refers are provided for the purpose of exemplifying and illustrating examples and representative embodiments of the invention.

Figure 1 shows a human breast B that contains a lesion L such as a mass suspected of being cancerous. An outer cannula 12 has been inserted percutaneously into the lesion L and a biopsy needle (not shown) has been passed through the outer cannula 12 and used to extract a biopsy sample from the center of the lesion, forming it mode a BC biopsy cavity inside the lesion L. After removal of the biopsy needle (not shown), a cannula 15 of insertion of the marker has been passed through the outer cannula, such that its distal end 12d is located inside the biopsy cavity BC . A device 14 for applying a fluid detectable label 10 of the present invention is coupled to the proximal end 12p of the introduction cannula 12 and is used to inject an amount of the detectable label 10 into the biopsy cavity BC, as sample.

A. Properties and functional requirements of the detectable marker

1) Visible embodiments in diagnostic imaging and detectable by preferred instruments

The detectable markers 10 of the present invention may be visible in an image created by the particular type of image diagnostic device (s) available during the procedure. In many cases, a type of roentgenographic imaging will be used (for example, mammography, X-rays, fluoroscopy, CT, etc.) and, thus, the visible marker in diagnostic imaging will comprise a material that is more or less radiolucent or more or less radiopaque than the tissue surrounding the biopsy cavity (for example, air, other gas, lipid, oil, a metal salt, barium powder, etc.) such that the marker 10 can be visible by said X-ray devices In other cases, ultrasound imaging can be used and the visible detector in imaging diagnosis will comprise a material or substance that has different ultrasound reflective properties (and a possible different radiographic density) than the body tissue surrounding the biopsy cavity BC (for example, air, carbon dioxide, other gases, saline, other liquids, etc.). In other cases a magnetic imaging diagnostic technique such as magnetic resonance imaging (MRI) and the visible marker in diagnostic imaging 10 may comprise a ferromagnetic material or a material (for example iron powder) having a different magnetic density than the body tissue that surrounds the BC biopsy cavity.

Similarly, the marker 10 may be a substance or article that emits energy (eg, radiation) that is detectable by an instrument (for example, a gamma ray detector)

2) Preferred palpable embodiments

Palpable embodiments of the invention preferably comprise a substance (for example, a collagen material such as that described in US Patent No. 4066083) or an article (for example, balloon (s), count (s), etc.) which has a sufficient mass to be palpated and located by tactile means while it is arranged inside the biopsy site.

3) Preferred visible embodiments

Preferred visible embodiments of the invention may comprise a colored substance such as an ink or a dye (for example, methylene blue, methylrosaniline chloride, indigo, inks used in tattoos, etc.) or coloring particles (eg, Chinese ink , indigo, carbon particles or the carbon preparations described in Carbon Localization of Impalpable Mammographic Abnormalities, of Langlois, SLP and Carter, ML, Australas Radiol. 35: 237-241 (1991) and / or Stereotaxis Technique for Preoperative Marking of Non - Palpable Breast Lesion, of Svane, GA, Acta Radiol. 24 (2): 145-151 (1983).

4) Preferred combination embodiments

The markers 10 of this invention can combine the attributes of any of the visible embodiments in diagnostic imaging, palpable and / or visible to make possible the detection of the marker 10 by multiple means, such as a) visualization in diagnostic imaging and palpation, b) visualization in diagnostic imaging and visualization, c) visualization in diagnostic imaging, palpation and visualization, od) visualization and palpation.

4a) Example of radiographically visible / palpable marker material formed by metal ions in combination with a collagenous or gelatinous matrix.

US Patent No. 4,847,049 (Yamamoto) describes a chelation or impregnation technique with ions in which an ion can be impregnated or chelated to collagen in order to impart antimicrobial properties to the collagen preparation. Thus, using this technique, ions visible in diagnostic imaging, such as radiographically visible metal ions, can be attached to a bulky collagenous material to form a marker 10 that can be a) visible in diagnostic imaging by radiographic means and b ) located by palpation of the tissue surrounding the biopsy site. For example, a renatured collagen compound with silver ions can be prepared by the following process:

Step 1 - Renaturation of collagen (or gelatin)

Collagen can be renatured in an insoluble form from the processing of denatured collagen that has been obtained from a natural source such as bovine skin (leather), bovine tendon and swine skin. Alternatively, insoluble collagen preprocessed in the form of a commercially available hemostatic material such as CollastatTM and AviteneTM nonwoven fabrics can be purchased. Collagen renaturation methods are known in the literature, including, for example, the methods described in US Pat. Nos. 4,294,241 and 3,823,212.

A particularly preferred form of renatured collagen for use in accordance with the present invention is one that has been renatured and its cross linking has been achieved covalently. This collagen can be prepared using readily available polyfunctional cross-linking agents or fixatives, such as dialdehydes, dicarboxylic acids, diamines and the like. Typically, the tropocollagen is dissolved in a buffer solution with a pH of 3.0 to 5.0 to provide a solution containing approximately 1 to 2% by weight of collagen. Then, 1% of a cross-linking agent of dialdehyde such as glutaraldehyde or formaldehyde is added. The mixture is then frozen and stored for approximately 24 hours. After thawing and washing to remove the cross-linking agent that has not reacted, the renatured cross-linked collagen is then ready to come into contact with a solution containing silver ions.

Step 2 - Union of metal ions to renatured collagen

The source of silver ions may be a water soluble silver salt, preferably silver nitrate. Although the concentration of silver ions in the solution is not particularly critical, it will normally be convenient to use solution in the concentration range of about 10 to 103 millimolar.

The renatured collagen is preferably contacted with a solution containing silver ions in the pH range of about 4 to 9. The pH of the solution containing silver ions can be controlled by the addition of an appropriate titrant, such as nitric acid, or potassium hydroxide, as required, to maintain the pH at less than about 9.0 to prevent degradation of silver. It is not considered that there is any lower limit for pH; however, normally a pH of about 4.0 will be convenient. A particularly preferred pH range is 7.0 to 7.5. The binding capacity of silver by collagen is particularly effective within this preferred pH range, although the measurement of silver binding by collagen is further controllable by the concentration of the solution containing the silver ions and / or for the time of exposure of the collagen to the solution containing the silver ions. Simultaneously or after exposure of the collagen to the solution containing the silver ions, the collagen is also exposed to ultraviolet radiation of sufficient energy and duration to strengthen the binding of the silver ions to the collagen without substantial formation of metallic silver formed as result of the oxidation of the various functional groups in the collagen by the silver ion. Although the exact limits of the ranges of conditions that will be sufficient to strengthen the binding of silver ions without substantial formation of metallic silver are not precisely determinable, it will generally be sufficient to maintain the pH of the environment of collagen - silver at less than 8 , 0 while the collagen is exposed to ultraviolet radiation in the wavelength range of approximately 210 to 310 nm for approximately 5 to 10 min. The exposure time to UV rays to complete the reaction is inversely proportional to the intensity of the light, which is preferably in the range of 100 to 1,000 microwatts / cm. A slight coloration of the collagen due to exposure to ultraviolet radiation is acceptable, that is, a change from white to a color between light brown and yellow, which indicates a mild oxidation reaction that occurs in the collagen; however, the radiation should not reach such a point that dark or black brown areas occur in the collagen due to over oxidation and / or a substantial formation of metallic silver. Normally, the exposure will be carried out at room temperature, that is, in the range of about 20 ° C to 25 ° C; however, it is not considered that there is any reason why exposure cannot occur at higher or lower temperatures, provided that the temperature is not high enough to cause degradation of collagen and / or silver ion. It is not considered that there is any lower limit for the temperature at which exposure can take place, provided that it is above the freezing point of the solution containing the ions.

Ultraviolet radiation can be provided by any conventional ultraviolet radiation source of appropriate wavelength, such as germicidal lamps and mercury / xenon lamps.

Step 3 (optional) - Adding a visible marker component to the collagen or gelatin matrix:

If it is desired that the marker be visually detectable, as well as by imaging or palpation, an amount of a visible substance having a color other than blood or tissue can be added. For example, carbon particles or an ink (eg, methylene blue, indigo) can be added to the collagen / silver ion preparation prepared above, to provide a collagen / colored silver ion marker 10 that is visible on diagnosis. by images (by radiographic means), palpable (by hand) and visible (under white light in the operating room).

The collagen-metal ion marker 10 described above (with or without a visible marker component) is introduced into the cavity created by the biopsy sample extraction. The introduced amount of this marker 10 may be sufficient to distend or stretch the biopsy cavity a bit, thereby creating a more palpable and obvious mass of marker material at the biopsy site.

A renatured gelatin or a cross-linked gelatin preparation such as GelfoamTM can be impregnated or combined with a metal ion to provide a metal-metal jelly-marker material. Gelatin can be prepared and bound to ions by the same method defined above for collagen.

4b) Example of radiographically visible or ultrasound / palpable marker material formed by a gas in combination with a collagenous or gelatinous matrix

Step 1 - Renaturation of collagen (or gelatin)

Collagen or gelatin are renatured by the same method described in Step 1 of the immediately preceding example and described in the literature, including, for example, the methods described in US Pat. Nos.

4,294,241 and 3,823,212.

Step 2 - Dispersion of air or other gas in the matrix of renatured collagen or gelatin

Next, air or other biologically inert gas (for example, carbon dioxide) is dispersed through the renaturated collagen matrix or gelatin by a suitable means such as mixing, mechanical combination, nucleation, bubbling, etc. This results in the formation of many small gas bubbles through the collagenous or gelatinous matrix and provides a marker substance 10 that can be introduced into the biopsy cavity through a cannula.

or tube and that is substantially more radiolucent than the tissue surrounding the biopsy cavity. In this sense, this marker 10 may be visible by means of X-rays or ultrasound but will not block or obscure the image of the tissue that is immediately adjacent to the biopsy cavity. Also, due to the volume of the collagen or gelatin matrix, this marker 10 is easily palpable and localizable by tactile means in the surrounding breast tissue or other tissues.

Step 3 (optional) - Adding a visible marker component:

If it is desired that the marker be visually detectable, as well as in diagnostic imaging and palpation, an amount of a visible substance having a color other than blood or tissue may be added. For example, carbon particles or an ink (eg, methylene blue, indigo) can be added to the collagen / gas or gelatin / gas preparation prepared above, to provide a colored collagen / gas or gelatin / gas marker 10 that It is visible in diagnostic imaging (by radiographic means), palpable (by hand) and visible (under white light in the operating room).

In routine use, the collagen / gas or gelatin / gas marker 10 described above (with or without a visible marker component) is introduced into the cavity created by the extraction of the biopsy sample. The introduced amount of this marker 10 may be sufficient to distend or stretch the biopsy cavity a bit, thereby creating a more palpable and obvious mass of marker material at the biopsy site.

5) Preferred residence time of the marker at the biopsy site

The detectable markers 10 of the present invention are formulated and / or constructed so as not to move or migrate from the biopsy site when flexed

or reconfigures the surrounding tissue (for example, as occurs when a breast is decompressed and removed from a mammography machine). Additionally, the detectable markers 10 are formulated and / or constructed to (i) remain present in the site in an amount sufficient to allow visualization by diagnostic imaging and site localization for at least two (2) weeks after introduction and (ii) be sufficiently removed from the site to allow imaging diagnosis of tissue adjacent to the site, without interference from said detectable marker, at six (6) months after its introduction.

Since the marker 10 is located at the biopsy site, and does not move or migrate from it, it serves as a signal that the surgeon can use to locate and treat or remove the remaining portion of the lesion without having to dissect and explore surrounding tissue when trying to locate the lesion. This aspect of the invention is particularly beneficial in cases (such as lumpectomy procedures of the breast) in which it is desired to surgically remove the L lesion with minimal disfigurement, scar or change in the surrounding tissue structure.

Because the marker 10 remains detectable at the biopsy site for at least two (2) weeks, the onset of medical or surgical treatment of the L lesion can take up to two (2) weeks after the removal of the Biopsy sample and marker 10 will still be present and useful to assist the surgeon or other physician who performs the treatment, to locate and direct the treatment to the remaining portion of the lesion. This minimum period of residence of two (2) weeks is especially beneficial in cases in which the immediate frozen sections cannot be analyzed by a pathologist, as in cases of suspected breast cancer in which a small piece of biopsy is biopsied. non-palpable lesion of the breast by stereotactic biopsy, and the biopsy sample is sent for routine histopathological evaluation (for example, fixation, staining and microscopic examination), which requires several days to complete.

Also, because the marker is substantially removed from the biopsy site within six (6) months after its introduction, it will not interfere or obscure subsequent diagnostic imaging of any remaining portion of the L lesion or surrounding tissue. This maximum residence time of six (6) months of the marker is especially beneficial in cases in which it is determined that the lesion is not cancerous at that time, but presents a risk of future tumorigenesis that justify the diagnosis by periodic imaging of the site of the lesion L and surrounding tissue.

5a) Embodiments in which the properties of the isolated detectable component of the marker result in the desired residence time

In some embodiments, the detectable label 10 may comprise a detectable material that has pharmacokinetic properties (eg, solubility, dissolution, potential for distribution from the biopsy site, potential for local metabolism or decomposition at the biopsy site) that cause it to remain present at the biopsy site in an amount sufficient to allow visualization by diagnostic imaging and localization of the site for at least 2 weeks after introduction, while removing sufficiently from the site to allow diagnostic imaging of the tissue adjacent to the site without interference of said detectable marker, 6 months after its introduction.

In many applications of the invention, the particular pharmacokinetic or biodistributive properties that determine the rate at which the marker 10 is removed from the biopsy site may include its solubility in the interstitial fluids that are present at the biopsy site. In this sense, it has been determined that when the marker 10 is formed by detectable material having a solubility coefficient of less than 1x10-3 grams per 100 cubic centimeters of water, a detectable material as such will have the desired detectable residence time in the biopsy site for at least two (2) weeks but not more than 5 to 7 months, and preferably not more than about 6 months. However, it will be appreciated that the detectable residence time of the marker 10 at the biopsy site will vary further with the amount of the marker material 10 that has been introduced into the biopsy cavity. In this sense, a large volume of a material having a relatively high solubility coefficient can be introduced into the biopsy cavity to ensure that, even if the material has a relatively high removal rate, it remains present at the biopsy site. a quantity visible in diagnostic imaging of the material until the first moment in time (for example, two (2) weeks). On the other hand, a relatively small volume of material having a low solubility coefficient can be introduced into the biopsy cavity and, due to its low elimination rate, will remain visible in imaging diagnosis at the biopsy site until the first moment of time (for example, two (2) weeks).

Specific examples of radiographically visible materials that, if introduced into the biopsy site alone will present the desired detectable residence time (for example, at least 2 weeks but not more than 6 months) include, but are not necessarily limited to: AgCl , AgI; BaCO3; BaSO4; K; CaCO3; ZnO; Al2O3, and the possible combinations thereof.

5b) Embodiments in which the properties of the detectable component of the marker will cause it to be removed from the biopsy site very quickly, but in which the detectable component is combined with a deletion delay element to provide the desired residence time

In other embodiments, the detectable label 10 may comprise a detectable material that, if introduced only at the biopsy site, will be substantially removed from the biopsy site in less than two (2) weeks from its introduction, thus failing in providing the minimum detectable residence time at the biopsy site of at least two (2) weeks. In embodiments as such, the detectable material will be combined (for example, mixed with, encapsulated by, suspended in, etc.) an elimination retarding element that will cause the detectable material to remain present at the biopsy site in sufficient quantity as to allow diagnostic visualization of the tissue adjacent to the site without interference of said detectable marker at 6 months after its introduction.

Examples of radiographically visible materials that would be removed from most biopsy sites in less than two (2) weeks include, but are not necessarily limited to: air, gas, lipids, oil, AgNO3, ammonia salts, sodium salts, potassium salts, etiodized oil (Ethiodol commercially available from Savage Laboratories, Mellville, NY) and certain radiographic contrast agents such as iohexol (Omnipaque, available in Nyegaard - Schering AG, available at Squibb / Bristol Myers).

Examples of elimination delay elements that can be combined with the detectable material to form a detectable label of the present invention include, but are not necessarily limited to: polylactic acid, polyglycolic acid, polycaprolactone, an encapsulating membrane surrounding the detectable material.

The following examples are currently preferred formulations for detectable markers 10 of this embodiment:

<dl><dt>Formulation 1 </dt>&lt;dd /&gt;</dl>

<dl><dt>Component </dt><dd>Quantity </dd></dl>

<dl><dt>AgNO3 </dt><dd>20 - 70 parts by weight </dd></dl>

<dl><dt>Polylactic acid </dt><dd>30 - 80 parts by weight </dd></dl>

Formulation 2 Component Quantity Ethiodol 10 - 50 parts by weight Polyglycolic acid 50 - 90 parts by weight

Formulation 3 Component Quantity Ethiodol 10 - 70 parts by weight Topical thrombin 30 - 90 parts by weight

Formulation 4 Component Quantity Polylactic acid 50 - 70 parts by weight Air 30 - 50 parts by weight

6) Shape and consistency of the detectable marker

Figures 3a-3c illustrate examples of the possible different shapes or consistencies of the detectable markers 10 of the present invention.

6a) Fluid markers

Figure 3a shows an example of a detectable marker 10a of a fluid consistency that is injectable through the volume of the injection cannula 15 into the BC biopsy cavity formed inside the lesion L. Typically, fluid markers 10a as such they will comprise a dry powder, a suspension or a solution. For example, a certain amount of dry AgCl powder with particle size of 10-1000 microns can be passed through the introduction cannula 15.

Figure 4 shows an example of an injector device 100 that can be used in place of the introduction cannula 15 to introduce a solid marker 10 (eg, powdered, particulate or granular) of the present invention into the interior of the site of biopsy. As shown, this device 100 comprises a non-conical tubular cylinder 110 having a substantially cylindrical inner wall 112 and a plunger 114 that can be advanced inside the cylinder 110. An amount of the solid marker material of this invention is loaded into the cylinder 110 of the device 100, the device 100 is inserted into the biopsy site and the plunger 114 is advanced to expel the marker material out of the distal end of the cylinder 110 and into the biopsy site

6b) Plurality of granules or pellets

Figure 3b shows an example of a detectable marker 10b comprising a plurality of granules or pellets approximately 10-1000 microns in diameter. Each granule or pellet can itself be formed by biodegradable detectable material or that can be otherwise removed from the biopsy site to present the desired detectable residence time, as described above, such as silver chloride or silver nitrate.

Alternatively, each granule or pellet may contain a detectable material therein and the outer surface of the granule or pellet may be a crust or encapsulant material that is biodegradable, such as polylactic acid, to provide the desired residence time detectable in the inside the biopsy site. Granules or pellets filled with air, carbon dioxide, or other suitable gas that are detectable either by ultrasound or by X-rays can be used as markers 10b of the present invention. However, even if such gas-filled markers 10b of the present invention are visible with X-rays, they will not obscure or block the diagnostic x-ray visualization of the tissue adjacent to the biopsy cavity and thus not they will need to biodegrade or be removed from the biopsy site at the second time (for example, 5-7 months).

6c) Inflatable balloon

Figure 3c shows an example of a detectable marker 10c comprising an inflatable balloon. Said inflatable balloon is passed through the introduction cannula and swollen inside the BC biopsy cavity formed within the lesion L. The material of the balloon itself can be detectable and biodegradable or capable of being otherwise removed from the Biopsy site to present the desired detectable residence time, as described above. An example of a material as such is a polyurethane that has undergone in situ hydrolysis. Alternatively, the balloon may contain a detectable material and the balloon itself may form a crust or encapsulant material (eg, polyurethane) that is biodegradable to provide the desired detectable residence time inside the biopsy site.

Balloons swollen with air, carbon dioxide or other suitable gas may be used as markers 10c of the present invention, which are detectable both by ultrasound and by X-rays. However, even if such markers 10c filled with gas of the present invention are visible with X-rays, these will not obscure or block the diagnostic visualization by X-ray images of the tissue adjacent to the biopsy cavity and, thus, will not need to biodegrade

or be removed from the biopsy site at the second time (for example, 5-7 months).

7) Optional adhesive to bond the marker to the tissue adjacent to the site

In any of the previously described embodiments of the invention, the marker 10 may have inherent adhesive properties, or the marker may further comprise an adhesive such as polyurethane, polyacrylic compound, polyhydroxymethacrylate, fibrin glue (eg, Tisseal ™), adhesive collagen or other biological or biocompatible adhesives that will cause the marker to adhere to the tissue adjacent to the BC biopsy cavity. An optional adhesive as such will further ensure that the marker 10 does not migrate or move from the biopsy site when the tissue surrounding the site moves, flexes, compresses or decompresses.

B. Method for surgical removal of tissue located within a specific distance and / or adjacent to a specific location on the contour of a biopsy site

Figures 5a-5c show a preferred method of using a visually discernible marker 10 of the present invention to guide the removal and removal of tissues located within a specific band, region or location adjacent to the boundaries of the biopsy cavity. As shown in Figure 5a, a visible marker 10 has been introduced inside the BC biopsy cavity to allow visualization of the BOU limits of the BC biopsy cavity by the surgeon. A visualization of the BOU limits of this BC biopsy cavity as such may allow the surgeon to selectively remove a tissue that is located within a general area Z1 of potentially cancerous tissue surrounding the entire biopsy cavity BC (Figure 5b) or within a specific zone Z2 located on only one side of the BC biopsy cavity (Figure 5c).

Specifically with reference to the image in Figure 5b, it can be

5 It is desirable to remove all tissue within a general zone Z1 that surrounds the entire BC biopsy cavity in cases where the pathology report indicates that the previously removed biopsy sample has unclear margins and is thus desirable. Remove all tissue within the Z1 area of ​​thickness X that surrounds the BC biopsy cavity around the contour.

10 Specifically with reference to the image of Figure 5c, it may be desirable to remove certain tissue within a specific zone Z2 located on one side of a projected axis through the BC biopsy cavity in cases where the pathology report indicates that the biopsy sample previously removed has clear margins on all but one side and, thus, it is desirable to remove only the tissue that

fifteen It is located within the specific zone Z2 of thickness X on one side of the BC biopsy cavity.