This application relates to and claims priority from Provisional Application Ser. No. 61/192,896, filed on Sep. 23, 2008, which is incorporated herein in its entirety.
FIELD OF THE INVENTION
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The invention is generally directed to porous bioabsorbable implants, for cavities in soft tissue such as in breast tissue after biopsy or lumpectomy procedures. Implants embodying features of the invention are particularly suitable for supporting such cavities and are imageable to facilitate conformal three dimensional irradiation.
BACKGROUND OF THE INVENTION
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Biopsy and other tissue removal procedures in soft tissue can frequently lead to dimpling and other disfigurements unless a prostheses or implant is deployed within the cavity from which tissue has been removed. See for example U.S. Pat. No. 6,214,045, U.S. Pat. No. 6,638,308 and U.S. Pat. No. 6,881,226 (Corbitt et al.). Moreover, after tissue removing procedures involving cancer, such as lumpectomies, it is frequently desirable to irradiate the cavity lining to ensure effective treatment of any cancer cells that might remain.
While a number of implants have been proposed for filling body cavities after tissue removal procedures such as lumpectomies, few have met with significant commercial success.
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OF THE INVENTION
The invention is generally directed to an implant for a body cavity which comprises a porous body formed of a bioabsorbable material having an in vivo life of at least two weeks but not more than twenty weeks, preferably at least three weeks but not more than about ten weeks. The implant has a porosity or is capable of forming a porosity so as to form temporary scaffolding within a body cavity from which tissue has been removed to ensure tissue in-growth into the cavity before significant bio-absorption of the implant. The implant is provided with a radiopaque imaging agent to ensure that at least the exterior margins are imageable such as by CT scans in order to formulate dosing programs. Additionally, the implant is provided with an interior orientation marker such as at least two and preferably three radiopaque elements within the body of the implant to facilitate orientation of the cavity and an exterior radiation source such as a linear accelerator for conformal irradiation of the tissue lining the cavity which is more likely to contain residual cancer cells. Externally energized orientation markers such as RFID's are also suitable. See for example U.S. Pat. No. 7,535,363 which is incorporated herein by reference.
The bioabsorbable material of the implant is at least in part a bioabsorbable chitosan or alginate. The body may also include a bioabsorbable material selected from the group consisting of dextran, starch, polylactic acid, polyglycolic acid and co polymers thereof, and gelatin, preferably cross-linked gelatin. The radiopaque imaging agent may be selected from the group of barium sulfate, barium carbonate, Silver Chloride, Silver Iodide, Silver Nitrate, Calcium Carbonate, Zinc Oxide and radiopaque metallic powder or particulate. The radiopaque imaging agent is in particulate and preferably powdered form so as to facilitate imaging, particularly the exterior margins of the implant. The plurality of marker elements for orientation that are placed within the body of the implant may be selected from Gold, Titanium, Platinum, Iridium, Tantalum, Tungsten, Silver, Rhenium and non-magnetic stainless steel. These metallic markers are incorporated into the implant to present a line (defined by two marker elements) and preferably a plane (defined by three marker elements) which allows an exterior radiation source, such as a linear accelerator, and the cavity to be aligned for effective irradiation of tissue lining the cavity.
The implant is sized and shaped so as to fit within the body cavity and to conform tissue lining the cavity about the implant. Generally, the implant will be spherical or oval in shape, although other shapes may be employed. It is preferred that the implant expand somewhat after deployment within the cavity, e.g. the implant materials swell (by taking up water or hydrating) upon contact with aqueous based fluids such as body fluids and other fluids which may be at the cavity site to ensure that tissue lining the cavity conform to the exterior of the implant. The final shape of the conformed tissue lining need not be the same shape as the original implant but the conformed shape of the tissue lining is simplified which eases dosage determinations and simplifies the irradiation patterns. Body cavities resulting from lumpectomy procedures, such as in a female's breast, can range from about 0.5 to about 8 cm, and are typically about 3 to about 6 cm, in maximum dimensions, so the implant should be approximately the same size and preferably slightly larger to ensure tissue conformance.
The implant is porous and has sufficient compressive strength to support breast tissue. The porosity should be sufficient to facilitate tissue ingrowth when deployed within the intracorporeal cavity. Porosity can have a pore size ranging from about 10 to about 600 micrometers. The surface pores are typically about 20 to about 80 micrometers and the interior pores are about 50 to about 200 micrometers. Implant porosity is preferably formed in the implant prior to deployment within the body cavity in order to control the size and shape of the implant. Porosity can be formed by removing fluids or dissolving soluble materials from a solidified body after its formation or by incorporating a gas or a gas forming agent in a mixture which forms the implant prior to the implant setting into its shape. Preferably, Another example might be freezing an aqueous solution of the chitosan or alginate in a mold to form a body then freeze dry the frozen body (preferably outside the mold) to remove the frozen aqueous fluid.
A variety of therapeutic or diagnostic agents may be incorporated into the implant including for example, hemostatic agents to form thrombus at the intracorporeal site, anesthetic agents to control pain, chemotherapeutic agents for treating residual neoplastic tissue or coloring agents to facilitate subsequent visual location of the site. Antibiotics, antifungal agents and antiviral agents may also be incorporated into the fibrous marker.
The implant can be formed by mixing about 0.5-4% (wt.) chitosan into an acidified (1-25% by weight acetic acid) aqueous solution along with about 0.5%-5% (wt.) powdered radiopaque imaging agent such as barium sulfate to facilitate the subsequent remote imaging of the implant. Up to 10% chitosan may be used, but the maximum solubility of chitosan is about 4.5% (wt.). The mixture can get quite viscous at the higher amounts of chitosan. The mixture is placed in a suitable mold which presents a desirable shape and the mixture is frozen at −1° to −196° C. for about 6-12 hours. The frozen body is removed from the mold and then placed in a lyophilizer (about 3 days) to remove water and to form a porous body. After freeze drying in the lyophilizer, the chitosan-containing body is neutralized using a base or buffer such as ammonium hydroxide (5-20% wt.), rinsed free of base or buffer with deionized water and then dried. The porous implant has the consistency of breast tissue.
In the case of an alginate, a soluble alginate such as sodium alginate is mixed into an aqueous solution along with a radiopaque agent as discussed above. The alginate-radiopaque agent mixture is poured into a suitable mold and then freeze dried or air dried to remove water to form the porous body. The porous body is removed from the mold and the soluble alginate is converted to a less soluble alginate by placing the porous body in a solution of calcium chloride which converts the sodium alginate to the less soluble calcium alginate. Gas bubbles may also be incorporated into the sodium alginate solution during mixing to provide porosity.
The plurality of radiopaque marker elements may be incorporated into the implant during its formation either as the solution solidifies in the mold or after the body has been formed. The plurality of marker elements should be placed inwardly from the exterior margin of the implant. Passageways may be formed in the porous body to desired locations for the radiopaque orientation elements.
The chitosan is preferably of high purity and high molecular weight. The degree of deacetylation is about 60 to 100% and preferably between 70 and 100%.
These and other advantages of the invention will become more apparent from the following detailed description of embodiments when taken in conjunction with the accompanying exemplary drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
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FIG. 1 is a flow chart that schematically illustrates a method for forming an implant embodying features of the present invention.
FIG. 2 is a schematic elevational view in section of a system for mixing components to make an implant embodying features of the invention.
FIG. 3 is a schematic elevational view in section illustrating pouring the mixture into a mold to form the implant.
FIG. 4 is a schematic elevation view in section illustrating placing the dried porous body into a solution of CaCl2 to convert the soluble alginate to a less soluble alginate.
FIG. 5 is a transverse cross-sectional view of an implant after treating in the solution of CaCl2.
FIG. 6 is a transverse of an implant embodying features of the invention having an orientation marker with three radiopaque elements.
FIG. 7 is a scanning electron micrograph (30×) of a sectional view of an implant embodying features of the invention taken near the surface of the implant.
FIG. 8 is a scanning electron micrograph (30×) of a sectional view of an implant embodying features of the invention taken in the interior of the implant.
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OF EMBODIMENTS OF THE INVENTION
FIG. 1 is a flow chart that schematically illustrates a method for forming an implant which embodies features of the invention. Specifically, in the first step 10 a bioabsorbable material (chitosan or a soluble alginate) is mixed with water along with a powdered or particulate radiopaque imaging agent such as barium sulfate. A pore forming agent such as a gas may also be incorporated into the mixture. In second step 11, the mixture, which has to a certain extent gelled, is poured into a mold. The mold has a forming surface which puts the mixture into a desired shape where it solidifies or hardens to the point where it is self-supporting in the formed shape. In the illustrated case, the shape is spherical. In the third step 12, the formed body is removed from the mold and in step 13 water is removed from the body, preferably by freeze drying or air drying, to form a porous body. In the fourth step 14a, if the porous body is formed of chitosan, the residual acid in the body is neutralized with a suitable base such as ammonium hydroxide, rinsed and dried. In the fourth step 14b, if the porous body is formed of alginate, the porous body is dipped into a solution of CaCl2, where at least part of the sodium alginate is converted to the less soluble calcium alginate, rinsed and dried. An orientation marker(s) may be inserted into the porous body by cannula or one or more passageways may be provided in the porous body so that the orientation marker(s) may be pushed to the desired location within body.
FIG. 2 illustrates adding the bioabsorbable chitosan or sodium alginate and barium sulfate powder to a body of water 20 contained in a suitable container 21. The water 20 is mixed with the mixing element or propeller 22 attached to rotating shaft 23. Bubbles can be whipped into the mass or other pore forming agents can be introduced into the body of water 20. Additionally, water soluble materials can be added so that they may subsequently be dissolved away after the body has been dried. As shown in FIG. 3, the body of fluid or gel is then poured into a spherical mold 24 which has an upper half 25 and a lower half 26 that are interconnected by brackets 27 and 28. After the body has set, water is removed, e.g. by freeze drying, so as to form a porous spherical body 29. If the body contains chitosan, the body is treated with a base to neutralize the residual acid. If the body contains sodium alginate, then as shown in FIG. 4, the porous spherical body 29 is introduced into an aqueous CaCl2 solution 30 in container 31 where at least part of the sodium alginate is converted to calcium alginate that quickly precipitates. A transverse section of the final implant 32 is schematically illustrated in FIG. 5.
FIG. 6 is a transverse cross-section of an implant 33 which has three imageable radiopaque elements 34 (e.g. gold particles) situated within the interior of the implant and spaced inwardly from the outer surface. The three radiopaque elements (e.g. imageable gold particles) are shown at the apices of an equilateral triangle which can be used as a guide for the relative positioning between the patient's breast and a linear accelerator to provide effective irradiation of tissue surrounding the lumpectomy cavity in the patient's breast. Minimally, there should be two radiopaque elements to define a line and preferably three to define a plane. However, there may be more but they should be on the same plane. The radiopaque imaging agent (barium sulfate) in the implant enables the exterior margins of the implant to be imaged in a CT scan and this facilitates determining an appropriate irradiation dosage plan for the linear accelerator to ensure effective treatment of any residual cancer cells remaining in the cavity lining after the lumpectomy.
An acidic aqueous solution (12.5% acetic acid) was prepared containing 4% by weight chitosan and 2% by weight barium sulfate. The solution was placed in a spherical mold and was then frozen in the mold at −30° C. for 16 hours. The frozen body was removed from the mold and lyophilized for 3 days to remove water. The lyophilized body was neutralized in a 10% solution of ammonium hydroxide for one hour and then rinsed free of the ammonium hydroxide with deionized water. The body was vacuum dried for 16 hours. The body had the spongy consistency approximating breast tissue and had sufficient compressive strength to support breast tissue surrounding a lumpectomy cavity. It comprised 67% chitosan and 33% barium sulfate. An SEM micrograph (30×) of the surface porosity is shown in FIG. 6 and an SEM micrograph (30×) of the central porosity is shown in FIG. 7. The implant had the spongy consistency approximating breast tissue. The implant could be made harder by increasing the amount of chitosan.
A quantity of sodium alginate (0.5 to about 4% (wt.)) is dissolved in water to form a paste, viscous fluid or gel and air or other biocompatible gas is introduced into the mixture. The mixture is placed in a mold of a desired implant shape and then freeze dried or air dried in the desired shape. The formed implant structure of sodium alginate is introduced into a solution of calcium chloride (0.5 to about 4% (wt.)) where at least part of the sodium alginate is converted to calcium alginate which precipitates. The precipitated porous structure of the implant is introduced into a body cavity from which tissue has been removed. The implant remains at the site for sufficient period of time so as to act as scaffolding to facilitate tissue in-growth within the body cavity. Starch, such as corn starch in finely divided particulate form, can be incorporated into the sodium alginate-water mixture so that when the calcium alginate is formed, it precipitates about the starch particles to minimize shrinkage during the conversion of sodium alginate to calcium alginate. The starch degrades quickly within the body cavity in the presence of body fluid. The alginate on the surface of the implant degrades to open up the incorporated starch particles to degradation which provides an evolving porosity. The weight ratio of starch to alginate can range from about 15:1 to about 1:1.
This example is similar to Example II except 30 grams of salt (NaCl) granules are mixed with about 30 ml of 3% (wt.) sodium alginate aqueous solution. The solution placed in a spherical mold and then is frozen for 4 hours. The frozen implant was removed from the mold and placed in a 2% (wt.) calcium chloride solution, forming calcium alginate gel and dissolving at least some of the incorporated salt granules to form a porous structure. The implant had the spongy consistency approximating breast tissue. The implant could be made harder by increasing the amount of sodium alginate in solution, decreasing the amount of salt or decreasing the size of the salt granules.
While one or more particular forms of the invention have been illustrated and described herein in the context of an implant, particularly a breast implant for use after a lumpectomy, it will be apparent that the implant having features of the invention may find use in a variety of locations and in a variety of applications where tissue has been removed. Moreover, various modifications can be made without departing from the spirit and scope of the invention. Accordingly, it is not intended that the invention be limited to the specific embodiments illustrated. It is therefore intended that this invention to be defined by the scope of the appended claims as broadly as the prior art will permit, and in view of the specification, if need be. Moreover, those skilled in the art will recognize that features shown in one embodiment may be utilized in other embodiments.
Terms such as “element”, “member”, “device”, “section”, “portion”, “step”, “means” and words of similar import when used in the following claims shall not be construed as invoking the provisions of 35 U.S.C. §112(6) unless the following claims expressly use the term “means” followed by a particular function without specific structure or expressly use the term “step” followed by a particular function without specific action. All patents and patent applications referred to above are hereby incorporated by reference in their entirety.