Abstract:
An intracorporeal marker, for marking a site within living tissue of a host, includes an outer body portion of biodegradable material. An inner body portion is located in the outer body portion. The inner body portion includes biological material that becomes calcified in the living tissue of the host over time. An agent interacts with the biological material to promote calcification of the biological material of the inner body portion in the living tissue of the host.

Description:
PRIORITY DATA AND INCORPORATION BY REFERENCE 
     This application is a continuation of U.S. patent application Ser. No. 12/519,656 filed Jun. 17, 2009, which is a U.S. national phase of International Application No. PCT/US2007/087768, filed Dec. 17, 2007, which claims priority to U.S. Provisional Patent Application No. 60/870,502, filed Dec. 18, 2006, which are incorporated by reference in their entirety. 
    
    
     TECHNICAL FIELD 
     The invention relates generally to a biopsy tissue markers. More specifically, the invention further relates to a biocompatible tissue site marker that is visible under various modes of imaging. 
     BACKGROUND 
     Advances in modern medical imaging technologies such as X-ray, ultrasound, or magnetic resonance imaging make it possible to identify and to biopsy tumors while they are still small. When dealing with a small tumor, especially after a portion of the tumor has been removed for biopsy, it is sometimes difficult to relocate the tumor at a later time for treatment. This is particularly true in the case of tumors in the breast, where the ability to visualize a small growth may depend upon the manner in which the breast is positioned or compressed during the procedure. In addition, prior to surgically removing a tumor, it is often advantageous to try to shrink the tumor by chemotherapy or irradiation. This is especially true in the case of breast cancer, where conservation of breast tissue is a concern. Shrinkage of the tumor can sometimes make it difficult for the surgeon to locate the tumor. 
     A solution to this problem is to place a marker within the target tissues at the time of biopsy which can be visualized under a variety of imaging modalities to facilitate finding the tumor at a later time. When a suspicious mass is detected, a sample is taken by biopsy, often, but not necessarily, using a specialized instrument such as a biopsy needle. The needle is inserted in the breast while the position of the needle is monitored using fluoroscopy, ultrasonic imaging, X-rays, MRI or other suitable imaging modalities. 
     In a new procedure, called stereotactic needle biopsy, the breast is compressed between the plates of a mammography apparatus and two separate X-rays are taken from different points of reference. The exact position of the mass or lesion is calculated within the breast. The coordinates of the lesion are then programmed into a mechanical stereotactic apparatus which guides the biopsy needle to the lesion. 
     Irrespective of the biopsy technique, the surgical site may need to be examined or accessed for surgical treatment of a cancerous lesion. Treatment requires the surgeon or radiologist locate the lesion precisely and this may need to be done repeatedly over a period of time. Since treatment may alter the host tissue, the function of a marker even more important. 
     U.S. Pat. No. 6,725,083 for “Tissue site markers for in vivo imaging” describes biopsy site markers and methods that permit conventional imaging techniques to be used, such as ultrasonic imaging. The biopsy site markers have high ultrasound reflectivity due to high contrast of acoustic impedance resulting from gas-filled internal pores. The markers may have a non-uniform surface. The patent discloses the use of materials such as metal, ceramic materials, metal oxides, polymer, and composites and mixtures thereof. 
     U.S. Pat. No. 6,350,244 for “Bioabsorable markers for use in biopsy procedure” discloses a breast tissue marker that allows the marker to be left in place avoiding the need for surgical removal. One type of marker takes the form of hollow spheres made of polylactite acid filled with iodine or other radiopaque material to make them visible under X-rays and/or ultrasound. The radiopaque materials are also bioabsorbable. Another type of marker disclosed is a solid marker of pre-mixed radiopaque material and a bioabsorbable material. The solid markers may also include dyes and radioactive materials. 
     U.S. Pat. No. 6,347,241 for “Ultrasonic and x-ray detectable biopsy site marker and apparatus for applying it” shows a biopsy site marker of small bodies or pellets of gelatin which enclose substantially a radioopaque object. The pellets are deposited at the biopsy site by an applicator device inserted in the biopsy site. Several gelatin pellets are deposited through the tube. The radio opaque core in the gelatin bodies are of a non-biological material and structure which are readily identified during X-ray observations. 
     U.S. Pat. No. 6,161,034 for “Methods and chemical preparations for time-limited marking of biopsy sites” describes markers that remain present to permit detection and location of the biopsy site. The markers are later absorbed by the host. The patent discloses gelatin, collagen, balloons and detectability provided by AgCl; Agl; BaCO 3 ; BaSO 4 ; K; CaCO 3 ; ZnO; Al 2 O 3 ; and combinations of these. 
     US Patent Publication No. 2006/0079805 for “Site marker visible under multiple modalities” describes site markers that include balls or particles which are bonded together to form a marker body. The balls or particles are made from biocompatible materials such as titanium, stainless steel or platinum. The balls or particles are described as being bonded together by sintering or by adhesive such as epoxy. An alternative embodiment has at least one continuous strand of wire of biocompatible material such as titanium, stainless steel, platinum, or other suitable material, compressed to form a mass that resembles a ball of yarn. Another alternative is a resonating capsule, or a rod with drilled holes. 
     US Patent Publication No. 2006/0036165 for “Tissue site markers for in vivo imaging” shows ultrasound-detectable markers whose shapes are distinct in an image from biological shapes. Various shapes are disclosed including cylinders, coils, and other more complex shapes. 
     US Patent Publication No. 2005/0234336 for “Apparatus and method for marking tissue” describes permanent biopsy markers that support visualization under multiple modalities such as MRI, X-ray and ultrasound. The marker has a body made of a resilient, preferably non-absorbable polymer material that is radiopaque and echogenic. The material expands in situ. The materials for the marker include polyacrylates, ethylene-vinyl acetates (and other acyl-substituted cellulose acetates), polyurethanes, polystyrenes, polyvinyl oxides, polyvinyl fluorides, poly(vinyl imidazoles), chlorosulphonated polyolefins, polyethylene oxides, polyvinyl alcohols (PVA), polytetrafluoroethylenes and nylons, with the preferred material being polyvinyl alcohol (PVA) and alkylated or acylated derivatives thereof. 
     U.S. Pat. No. 5,676,146 shows an implant used to repair skeletal defects and irregularities. The implant is of radiolucent material and with a resorbable radiopaque marker, such as nondemineralized or partially demineralized bone particles. A radiopaque component, which is resorbable in its entirety, is included. Examples of materials include demineralized bone sheet, particles, etc., collagen and collagen derivatives, plastic such as polyethylene cetabular cups. 
     Collagen has been proposed as a material for implants and various methods of preparation and types of materials are known. Examples are disclosed in U.S. Pat. Nos. 5,800,541; 5,162,430; 5,328,955; and 5,475,052 
     It is believed that most known tissue markers have a disadvantage in that they are not visible under all available imaging modalities. The features of a marker that make it stand out under X-rays do not necessarily make them stand out under MRI or ultrasound imaging. One prior art mechanism for addressing the need for multiple-imaging-mode markers is to employ a combination of metal structure and biodegradable foam to provide ultrasonic imaging visibility, MRI visibility and x-ray visibility. In this case, the metal structure provides x-ray visibility and biodegradable foam provides visibility in ultrasonic imaging. 
     There is a need for site markers made from biocompatible materials that are visible under various modes of imaging to reduce the number of procedures that patients must undergo in detection and treatment of cancer or any disease requiring the user of tissue markers. It will be a valuable contribution to the art for a marker with a simple design and superior biocompatibility can be provided. 
     SUMMARY OF THE INVENTION 
     A biopsy marker, preferably a breast biopsy marker, has radio-opaque properties that are derived in situ, preferably based on a natural a biological response, such as calcification or accumulation or tissue-concentration of a chemical agent that acts as an imaging contrast. In an embodiment, a biodegradable foam such as collagen foam or gelatin foam is embedded with a biological tissue that is susceptible to the calcification. The biopsy marker is implanted to mark the biopsy site. The foam material provides ultrasonic visibility to access the implantation site. The biological tissue undergoes calcification in 30 days to 5 years depending on the chemistry of biological tissue used. The calcification generated in the biological tissue provides visibility in magnetic resonance imaging (MRI) and X-ray imaging. As a result, the marker may be located using radiation-based imaging or ultrasonic imaging. 
     Many types of implantable tissues can be used to prepare a biopsy marker described in this invention. The implantable tissues used include but not limited to: bovine pericardium tissue, porcine dermal tissue, bovine or porcine arterial tissue, porcine aortic wall tissue and the like. A tissue that is rich in elastin such as porcine aortic wall tissue is even more preferred. It is believed that elastin rich tissue is highly susceptible to calcification. Biomaterials that are derived from elastin protein may also be used. The biological tissue is preferred to be crosslinked or stabilized using glutaraldehyde. The tissue crosslinked using 0.2 to 2% glutaraldehyde is even more preferred. In addition, biological ingredients that promote calcification may also be added in the tissue. These additives include bioactive and non-bioactive substances like bone growth factor, phospholipids, polyethylene glycol and the like. 
     In another embodiment, an elastic protein-based biomaterial is processed to cause the material to have a 60 to 90% porosity. The material is further processed to cause crosslinking using glutaraldehyde, 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) or other suitable crosslinker. The elastin foam is then implanted as a biopsy marker where it undergoes rapid calcification. The calcification is then detected using standard X-ray or MRI imaging techniques. 
     According to an embodiment, an intracorporeal marker marks a site within living tissue of a host. The marker has a body having a first portion of porous biodegradable material having gas-filled voids and at least one second portion including biological material that tends to become calcified in a human host over time. Preferably, the biological material includes a material with elastin as a substantial component. More preferably, the biological tissue includes porcine aortic wall tissue. Even more preferably, the biological tissue includes a material with elastin that has been cross-linked. In any of these embodiments, an agent may be incorporated in the biological material that promotes bone growth. The calcification may be enhanced by use of a bone growth factor, phospholipids, or polyethylene glycol. 
     In another embodiment, the first portion defines a cylindrical shape and the second portion is encased within it. The biological material may be entirely encased with the body. Preferably, the body (first portion) has gas-filled pores. In an embodiment the first portion includes collagen and/or gelatin. 
     According to an embodiment, an intracorporeal marker marks a site within living tissue of a host. The marker has a body having a first portion of porous biodegradable material having gas-filled voids and at least one second portion including biological material that tends to become imageable in a human host over time due to a physiological mechanism of the host. Preferably, the biological material includes a material with elastin as a substantial component. More preferably, the biological tissue includes porcine aortic wall tissue. Even more preferably, the biological tissue includes a material with elastin that has been cross-linked. In any of these embodiments, an agent may be incorporated in the biological material that promotes bone growth. The calcification may be enhanced by use of a bone growth factor, phospholipids, or polyethylene glycol. 
     In another embodiment, the first portion defines a cylindrical shape and the second portion is encased within it. The biological material may be entirely encased with the body. Preferably, the body (first portion) has gas-filled pores. In an embodiment the first portion includes collagen and/or gelatin. In another embodiment, the biological material is capable of interacting with an antibody carrying a chemical substance that can be detected by an imaging modality. 
     According to another embodiment, a method of in vivo identification of a position in soft tissue, includes: inserting a marker having a first portion that can be imaged with ultrasound and a second portion that promotes calcification; imaging under ultrasound at a first time and imaging under radiation at a second time following the first. The second time preferably follows the first by an interval during which calcification of the second portion occurs. The method may include waiting for the second portion to calcify. The method may include the step of making the marker which may further include using an agent in the marker that promotes bone growth. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate exemplary embodiments of the invention, and, together with the general description given above and the detailed description given below, serve to explain the features of the invention. 
         FIG. 1  is a cross-sectional view of a tissue marker of biodegradable foam with biological tissue inside. 
         FIG. 2  shows the tissue marker of  FIG. 1  from the side. 
         FIG. 3  ghost oblique view of the tissue marker of  FIGS. 1 and 2 . 
         FIG. 4  shows a method of making the tissue marker of  FIGS. 1-3  and subsequently using the marker. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     A biopsy marker, preferably a breast biopsy marker, has radio-opaque properties that are derived in situ, preferably based on a natural a biological response, such as calcification or accumulation or tissue-concentration of a chemical agent that acts as an imaging contrast. In an embodiment, a biodegradable foam such as collagen foam or gelatin foam is embedded with a biological tissue that is susceptible to the calcification. The biopsy marker is implanted to mark the biopsy site. The foam material provides ultrasonic visibility to access the implantation site. The biological tissue undergoes calcification in 30 days to 5 years depending on the chemistry of biological tissue used. The calcification generated in the biological tissue provides visibility in magnetic resonance imaging (MRI) and X-ray imaging. As a result, the marker may be located using radiation-based imaging or ultrasonic imaging. 
     Many types of implantable tissues can be used to prepare a biopsy marker described in this invention. The implantable tissues used include but not limited to: bovine pericardium tissue, porcine dermal tissue, bovine or porcine arterial tissue, porcine aortic wall tissue and the like. A tissue that is rich in elastin such as porcine aortic wall tissue is even more preferred. It is believed that elastin rich tissue is highly susceptible to calcification. Biomaterials that are derived from elastin protein may also be used. The biological tissue is preferred to be crosslinked or stabilized using glutaraldehyde. The tissue crosslinked using 0.2 to 2% glutaraldehyde is even more preferred. In addition, biological ingredients that promote calcification may also be added in the tissue. These additives include bioactive and non-bioactive substances like bone growth factor, phospholipids, polyethylene glycol and the like. 
     In another embodiment, an elastic protein-based biomaterial is processed to cause the material to have a 60 to 90% porosity. The material is further processed to cause crosslinking using glutaraldehyde, 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) or other suitable crosslinker. The elastin foam is then implanted as a biopsy marker where it undergoes rapid calcification. The calcification is then detected using standard X-ray or MRI imaging techniques. 
     The shape of the marker can depend on the clinical application. In general cylindrical, spherical, disk like shapes are preferred. Irregular shapes may also be used. 
     Referring now to  FIGS. 1-3 , a tissue marker  100  has an external layer of biodegradable foam  110  with a core of biological tissue  150 . The biodegradable foam has biocompatible gas within its voids. The biocompatible gas provides a low density structure within the marker body which provides high contrast when viewed using ultrasonic imaging equipment. This makes the marker visible under ultrasonic imaging modalities. The biological tissue  150  within is a material chosen for its tendency to calcify when placed in a human host. When the marker is placed within the body of a host, the biodegradable foam is broken down while the biological material  150  calcifies and eventually becomes visible under radiation imaging modalities. 
     The period during which ultrasound can be used may last between weeks and many months, for example six months. In many therapeutic situations, this is more than sufficient time. The time during which the calcified remainder can be imaged may last for many years or it may be permanent. The calcification may take a year or two to occur. Again, in many therapeutic situations, the radiation-imaging provided in the later stages is all that is required. Therefore the loss of the ability to image under ultrasound is inconsequential. 
     The benefits of the above device should be apparent. The calcified biological tissue is highly compatible with the host. Some of the bulk of the marker which may be desirable for ultrasound imaging can be lost which may be desirable as well. In a preferred embodiment, which is by no means limiting of the invention, the marker may be generally cylindrical with a diameter of about 4 mm and a length of about 6 mm. The core of biological tissue may be about 1 mm in diameter and about 3 mm long. 
     One example of a method for making and using the marker is illustrated in  FIG. 4 . In step S 1 , a collagen solution is poured into a mold to partly fill the mold. Just enough solution to create a spacer for the biological tissue is all that is required. Then, in step S 2 , the collagen solution frozen in the mold. The biological material is inserted in the mold and collagen solution is poured into the space around it in step S 4 . Then the whole mold is frozen and the frozen collagen solution lyophilized in step S 5  to remove the ice while leaving the collagen matrix behind. 
     To use the marker, in step S 6 , the marker is implanted in a host. This step may be done as part of a biopsy procedure, for example. Then, in step S 7 , the marker is imaged. Step S 7  may occur repeatedly over a range of time, perhaps a year, after implantation. In step S 8 , perhaps over a year after implantation, the marker is imaged using radiation imaging modalities. Steps S 7  and S 8  may overlap and are not necessarily chronologically-sequential in all instances. Other steps are not necessarily sequential either. For example, steps S 3  and S 4  could be done simultaneously—the flow chart presents merely one example of the manufacturing and use processes. 
     Instead of using collagen foam to form voids, it is possible to form voids in a biodegradable material using other means. For example, voids could be molded in or machined into a piece of material Implantation of a biological material can be done in a similar way, but forming a hole in a pre-made body of biodegradable material, inserting the biological material into the hole and subsequently sealing the hole. 
     Also, instead of molding the foam, it is possible to form the marker by dipping the biological material body  150  into a collagen or other suitable solution and freezing it in repeated steps until a coating of suitable thickness is obtained before lyophilizing the resulting structure. 
     As discussed above, the biological tissue  150  may include bovine pericardium tissue, porcine dermal tissue, bovine or porcine arterial tissue, porcine aortic wall tissue and the like. As mentioned, a tissue that is rich in elastin such as porcine aortic wall tissue is even more preferred. It is believed that elastin rich tissue is highly susceptible to calcification. Biomaterials that derived from elastin protein may also be used. The biological tissue is preferred to be crosslinked or stabilized using glutaraldehyde. The tissue crosslinked using 0.2 to 2% glutaraldehyde is even more preferred. In addition, biological ingredients that promote calcification may also be added in the tissue. These additives include bioactive and non-bioactive substances like bone growth factor, phospholipids, polyethylene glycol and the like. 
     While the above marker example of a cylindrical body is a preferred configuration, other shapes and combinations can be used. For example, more than one body of biological tissue could be integrated in the porous biodegradable body. Also, the biological tissue need not be entirely encased within the body of the biodegradable portion. For example, an alternative method of manufacture may be to co-extrude under pressure such that the casing solution and the biological material are plastic but freeze quickly after exiting the extruder. The sublimation of the solute can then be done to the co-extruded billet before or after dividing it into pieces of appropriate length. 
     Markers having the above-described structures, or any similar structure, may be used according to the following method which may include steps 1 and 2, steps 1 through 3, or steps 1 through 4, according to different embodiments. 
     Step 1. Insert a marker at a location. The location can be marked at a time and location of biopsy or otherwise positioned in a tissue mass. 
     Step 2. Identify a location of the marker using a first imaging modality. The modality may be ultrasound-based imaging. This step may include passing a corresponding form of energy through a soft tissue mass of a living host. 
     Step 3. Wait a period of time for calcification to occur. 
     Step 4. Identify a location of the marker using a second imaging modality that is different from the first imaging modality in step 2. The second imaging modality may be X-ray-based imaging or MRI. This step may also include passing a corresponding form of energy through a soft tissue mass of a living host. 
     Note that in the above method, not all steps are essential or necessarily separate. For example, the waiting step may be inherent in step 2 or step 4. 
     This specification should not be interpreted as implying that any particular element, step or function is an essential element of any of the claims. The scope of the patented subject matter is defined only by the claims and their equivalents. 
     The calcification process is not the only kind of biological activity that could be exploited by a marker to cause the marker, or a portion thereof, to become imageable. A marker may incorporate any substance capable of concentrating an imageable substance. For example, the marker could incorporate a substance for which antibodies can be produced. In one exemplary approach, a marker may contain a biological tissue such as bovine pericardium tissue. A bovine tissue specific antibody could be made, labeled with a imaging tag and used. Such antibodies may be grown, radioactively labeled, and injected in the host. The marker would then cause the antibody to concentrate in and about the included substance. This in turn would cause the concentration of the radioactive label to be high in the vicinity of the marker. The process is due to the combined action the antibody and the host. The result may cause the marker to be imageable using a radiation detector. 
     Using isotopes with a conspicuously-high cross-section for externally applied radiation could also be used to make a marker imageable by the same type of process. That is, the marker may incorporate a substance for which an antibody can be grown. The antibody could be grown using the selected isotope. Due to the combined action the antibody and the host, the antibody concentrates at the marker site. Then, the externally applied radiation may be used to image the concentrated isotope. Antibodies could also serve as carriers of certain molecules or radicals that can be imaged using lower energy radiation due either to their absorption or stimulated-emission signatures. Other labeling methods such as fluorescent labeling useful in fluorescent imaging, paramagnetic labeling useful in MRI imaging and the like may also be used. 
     While the present invention has been disclosed with reference to certain embodiments, numerous modifications, alterations, and changes to the described embodiments are possible without departing from the sphere and scope of the present invention, as defined in the appended claims. Accordingly, it is intended that the present invention not be limited to the described embodiments, but that it has the full scope defined by the language of the following claims, and equivalents thereof.