Patent Application
20080082177
As used herein, the term “microporous coating” is defined to be a coating in which the pores sizes range between 5 microns and 150 microns. A “macroporus structure” is defined to be a structure in which the pore size is greater than 200 microns. In one embodiment, the device of the present invention can have a macroporous structure containing individual components that are coated with a microporous coating. The macroporus structure can be constructed from a variety of conventional, biocompatible materials including biodegradable, non-biodegradable, and natural polymeric materials. The optional individual components of the macroporous structure are preferably fibers or a bundle of fibers. The macroporous structure may have a variety of constructs including a flat sheet, a rolled sheet, a hollow structure, a solid structure, and a 3-dimensional structure, is preferably in the form of a knitted or woven mesh. If desired, radio opacity may be added to the construct by rendering at least a portion of the macroporous component radioopaque. This can be achieved by weaving in a radioopaque fibrous component to mark different regions of the macroporous structure.
The individual components of the macroporous structure of the tissue implant of the present invention can be comprised of any biodegradable or non-biodegradable biocompatible material, including textiles with woven, knitted, warped knitted (i.e., lace-like), non-woven, and braided structures. In an exemplary embodiment the macroporous structure has a mesh-like structure. In any of the above structures, the mechanical properties of the structure can be altered by changing the density or texture of the material, or by embedding particles in the material. Fibers used to make the individual components of a macroporous mesh-like structure can be monofilaments, yarns, threads, braids, or bundles of fibers. These fibers can be made of any biocompatible material including biodegradable or non-biodegradable materials.
Non-biodegradable materials include cotton, linen, silk, polyamides, polyesters, fluoropolymers, polyolefins and combinations thereof.
Biodegradable polymers readily break down into small segments when exposed to moist body tissue. The segments then either are absorbed by the body, or passed by the body. More particularly, the biodegraded segments do not elicit permanent chronic foreign body reaction, because they are absorbed by the body or passed from the body, such that no permanent trace or residual of the segment is retained by the body. Biodegradable materials include polymers such as polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polydioxanone (PDO), trimethylene carbonate (TMC), polyvinyl alcohol (PVA), copolymers or blends thereof. In one embodiment, the fibers are formed of a polylactic acid and polyglycolic acid copolymer at a 95:5 mole ratio.
In another embodiment, the fibers that form the individual components of a macroporous structure having a mesh-like construct can be made of a biocompatible, biodegradable glass. Bioglass, a silicate containing calcium phosphate glass, or calcium phosphate glass with varying amounts of ionic substitutions for calcium added to control resorption time are examples of materials that could be spun into glass fibers and used for the individual components of the macroporous structure. Suitable ions that may be substituted for calcium include iron, magnesium, sodium, potassium, and combinations thereof.
The individual components of the macroporous structure are coated with a microporous coating. The microporous coating is preferably in the form of a biodegradable foam. The microporous coating of the tissue implant device may be formed and/or applied in a variety of conventional processes including lyophilization, supercritical solvent foaming, gas injection extrusion, gas injection molding or casting with an extractable material, such as salts, sugar or similar suitable materials, preferably by lyophilization.
The microporous coating may also be applied by other conventional processes such as dipping, injecting, pouring, or otherwise placing, the appropriate polymer solution into a mold set-up comprised of a mold and the macroporous structure. Care must be taken to coat the macroporous structure to prevent the microporous coating from filling the pores of the macroporous structure.
The mold set-up is cooled in an appropriate bath or on a refrigerated shelf and then lyophilized. In the course of forming the foam coating, it is believed to be important to control the rate of freezing of the polymer-solvent system. The type of pore morphology that is developed during the freezing step is a function of factors such as the solution thermodynamics, freezing rate, temperature to which it is cooled, concentration of the solution, and whether homogeneous or heterogenous nucleation occurs. One of ordinary skill in the art can readily optimize the parameters without undue experimentation.
The steps involved in the preparation of these foams include choosing the right solvents for the polymers to be lyophilized and preparing a homogeneous solution. Next, the polymer solution is subjected to a freezing and vacuum drying cycle. The freezing step phase separates the polymer solution and vacuum drying step removes the solvent by sublimation and/or drying, leaving a microporous polymer structure.
Suitable solvents that may be used in the preparation of the foam coating include, but are not limited to, formic acid, ethyl formate, acetic acid, hexafluoroisopropanol (HFIP), cyclic ethers (e.g., tetrahydrofuran (THF), dimethylene fluoride (DMF), and polydioxanone (PDO), acetone, acetates of C2 to C5 alcohols (e.g., ethyl acetate and t-butylacetate), glyme (e.g., monoglyme, ethyl glyme, diglyme, ethyl diglyme, triglyme, butyl diglyme and tetraglyme), methylethyl ketone, dipropyleneglycol methyl ether, lactones (e.g., gamma-valerolactone, delta-valerolactone, beta-butyrolactone, γ-butyrolactone), 1,4-dioxane, 1,3-dioxolane, 1,3-dioxolane-2-one (ethylene carbonate), dimethlycarbonate, benzene, toluene, benzyl alcohol, p-xylene, naphthalene, tetrahydrofuran, N-methyl pyrrolidone, dimethylformamide, chloroform, 1,2-dichloromethane, morpholine, dimethylsulfoxide, hexafluoroacetone sesquihydrate (HFAS), anisole and mixtures thereof. Among these solvents, a preferred solvent is 1,4-dioxane. A homogeneous solution of the polymer in the solvent is prepared using standard techniques.
The applicable polymer concentration or amount of solvent that may be utilized will vary with each system. Generally, the amount of polymer in the solution can vary from about 0.5% to about 90% and, preferably, will vary from about 0.5% to about 30% by weight, depending on factors such as the solubility of the polymer in a given solvent and the final properties desired in the foam.
Various conventional biocompatible, biodegradable polymers can be used for the microporous coatings of the tissue reinforcement devices according to the present invention. Examples of suitable biocompatible, bioabsorbable polymers include polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes oxalates, polyamides, tyrosine derived polycarbonates, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly(anhydrides), polyphosphazenes, biomolecules (i.e., biopolymers such as collagen, elastin, bioabsorbable starches, etc.), collagen-glycosoaminoglycan (GAG), and blends thereof.
Currently, aliphatic polyesters are among the preferred absorbable polymers for use in making the microporous coatings according to the present invention. Aliphatic polyesters can be homopolymers, copolymers (random, block, segmented, tappered blocks, graft, triblock, etc.) having a linear, branched or star structure. Suitable monomers for making aliphatic homopolymers and copolymers may be selected from the group consisting of, but are not limited, to lactic acid, lactide (including L-, D-, meso and D,L mixtures), glycolic acid, glycolide, epsilon-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate (1,3-dioxan-2-one), and combinations thereof.
Biocompatible, elastomeric copolymers are also particularly useful in the practice of the present invention. Suitable elastomeric polymers include those with an inherent viscosity in the range of about 1.2 dL/g to 4 dL/g, more preferably about 1.2 dL/g to 2 dL/g and most preferably about 1.4 dL/g to 2 dL/g as determined at 25° C. in a 0.1 gram per deciliter (g/dL) solution of polymer in hexafluoroisopropanol (HFIP). Further, suitable elastomers exhibit a high percent elongation and a low modulus, while possessing good tensile strength and good recovery characteristics. In the preferred embodiments of this invention, the elastomer from which the microporous component is formed exhibits a percent elongation (e.g., greater than about 200 percent and preferably greater than about 500 percent). In addition to these elongation and modulus properties, suitable elastomers should also have a tensile strength greater than about 500 psi, preferably greater than about 1,000 psi, and a tear strength of greater than about 50 lbs/inch, preferably greater than about 80 lbs/inch.
Exemplary bioabsorbable, biocompatible elastomers include but are not limited to elastomeric copolymers of epsilon-caprolactone and glycolide (including polyglycolic acid) with a mole ratio of epsilon-caprolactone to glycolide of from about 35:65 to about 65:35, more preferably from 35:65 to 45:55; elastomeric copolymers of epsilon-caprolactone and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio of epsilon-caprolactone to lactide is from about 30:70 or to about 95:5; elastomeric copolymers of p-dioxanone (1,4-dioxan-2-one) and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio of p-dioxanone to lactide is from about 40:60 to about 60:40; elastomeric copolymers of epsilon-caprolactone and p-dioxanone where the mole ratio of epsilon-caprolactone to p-dioxanone is from about from 30:70 to about 70:30; elastomeric copolymers of p-dioxanone and trimethylene carbonate where the mole ratio of p-dioxanone to trimethylene carbonate is from about 30:70 to about 70:30; elastomeric copolymers of trimethylene carbonate and glycolide (including polyglycolic acid) where the mole ratio of trimethylene carbonate to glycolide is from about 30:70 to about 70:30; elastomeric copolymers of trimethylene carbonate and lactide (including L-lactide, D-lactide, blends thereof, and lactic acid polymers and copolymers) where the mole ratio of trimethylene carbonate to lactide is from about 30:70 to about 70:30); and blends thereof.
One of ordinary skill in the art will appreciate that the selection of a suitable polymer or copolymer for forming the microporous coating depends on several factors. The more relevant factors in the selection of the appropriate polymer(s) that is used to form the coating include bioabsorption (or biodegradation) kinetics; in vivo mechanical performance; cell response to the material in terms of cell attachment, proliferation, migration and differentiation; and biocompatibility. Other relevant factors, which to some extent dictate the in vitro and in vivo behavior of the polymer, include the chemical composition, spatial distribution of the constituents, the molecular weight of the polymer, and the degree of crystallinity.
The thickness of the coating is typically in the range of about 10 to about 1,000 microns, preferably about 50 to about 500 microns. The microporous coating has pores sizes in the range of about 5 to about 150 microns, preferably about 10 to about 100 microns. This pore size is sufficient effective to encourage the attachment and proliferation of cells.
The size of the device must be sufficiently large to effectively cover at least a section of the defect and may vary in size based on the size of the defect. In a flat sheet embodiment, for example, the size of the device in one application may be about 24 centimeters by 24 centimeters and can be fashioned into various shapes (square, rectangle, trapezoid, etc.), based on the configuration of the defect, and the size will vary accordingly.
The location and coverage of the microporous coating on the macroporous structure will vary. In some embodiments, one or more sections of macroporous structure are coated with microporous structure. In order to accomplish this, portions or sections of the macroporous structure including optional individual components are dipped into the appropriate polymer solution, or the appropriate polymer solution is injected into, poured onto, or otherwise placed onto, portions of the macroporous structure and/or components.
In another embodiment, once the structure disclosed in the present invention is created, a secondary operation can be conducted to produce specific shapes or configurations to enhance the performance of the reinforcement. For example, in the case of a mesh-like construct, the material can be utilized as a flat sheet, cut to desired shapes, rolled into a tube structure producing a design with various diameters, wall thicknesses and lengths, etc.
If desired, a sufficiently effective amount of a bioactive agent may be incorporated within and/or applied to the tissue reinforcement device, and/or it can be applied to the viable tissue at the point of care. Preferably, the bioactive agent is incorporated within, or coated on, the device prior to the addition of viable tissue to the device. The bioactive agent(s) can be selected from among a variety of conventional effectors that, when present at the site of injury, promote healing and/or regeneration of the affected tissue. In addition to being compounds or agents that actually promote or expedite healing, the effectors may also include compounds or agents that prevent infection (e.g., antimicrobial agents and antibiotics), compounds or agents that reduce inflammation (e.g., anti-inflammatory agents), compounds that prevent or minimize adhesion formation, such as oxidized regenerated cellulose (e.g., INTERCEED® and Surgicel®, available from Ethicon, Inc.), hyaluronic acid, and compounds or agents that suppress the immune system (e.g., immunosuppressants).
One possible application of a tissue implant device of the present invention is as a matrix for use in herniation or pelvic floor repair surgical procedures. Herniation may include abdominal hernias, such as inguinal hernias, femoral hernias, umbilical hernias, and incisional hernias.
The term “pelvic floor” refers to the pelvic diaphragm, the sphincter mechanism of the lower urinary tract, the upper and lower vaginal supports, and the internal and external anal sphincters. It is a network of muscles, ligaments and other tissues that hold up the pelvic organs (vagina, rectum, uterus and bladder). When this system is torn or weakens, the organs may shift, bulge and push outward or against each other. A prolapse occurs when an organ drops from its natural position. As a result, women may suffer from urinary or fecal incontinence or obstruction, vaginal prolapse, vaginal pain, sexual dysfunction, and other problems. Women who vaginally delivered several children and those who experienced tears in the perineum and pelvic floor during childbirth, are at higher risk for pelvic floor disorders.
Additional factors contributing to pelvic floor relaxation include aging, menopause, connective tissue disorders, degenerative neurologic conditions, and prior pelvic surgery. Any of these factors alone or in combination may occur acutely or over time, and result in some of the most common and feared health problems faced by women.
In general, the method of treating a tissue injury using the tissue reinforcement device of the present invention comprises the steps of accessing the site of the damaged tissue, preparing the site for implant (i.e., device) placement, placing the tissue treatment device in a section of damaged tissue, securing the device to the site, and exiting the site of the damaged tissue. Access may be via incision or through laproscopy. The device may be secured by friction with the tissue. This can be accomplishes by sandwiching the device between layers of tissue. Alternatively, the device may be sutured in place.
For example, pelvic reconstructive surgery can be performed through the vagina or abdominally via traditional incision or through laproscopy. During the procedure, the surgeon will reposition the prolapsed organ and secure it to the surrounding tissues and ligaments. The tissue reinforcement device discussed herein is inserted into the region of the prolapse. It is initially held in place by friction or sutures. Body tissue then grows into the macropores of the device, creating the final support. The strength of this tissue is greatly enhanced by the presence of the device.
The various components in the device serve different functions. The macroporous structure encourages ingrowth into the device to be as rapid as possible, and provides for secure attachment to the area of application. The microporous coating or structure encourages the attachment and proliferation of cells. The structure can be optimized for cell infiltration by smooth muscle cells or fibroblasts, and for vascularization.
Examples of the types of specific procedures in which a device of this invention would be beneficial is the repair of the prolapse of the vagina by suspension from the sacral area. Sacrocolpopexy is attachment of the to the bone and sacrospinous fixation is attachment of the vagina to the sacrospinous ligament. This procedure is mostly done when the patient has previously or concomitantly had a hysterectomy. Alternately, the repair of a prolapse of the uterus into the vagina can be accomplished using a similar procedure again by suspension from the previously mentioned points in the sacral area. Since the uterus is still intact this procedure is a sacrohysteropexy.
The following examples are illustrative of the principles and practice of this invention. Numerous additional embodiments within the scope and spirit of the invention will become apparent to those of ordinary skill in the art.
A 10 weight percent solution of epsilon-caprolactone/glycolide copolymer in 1,4-dioxane was prepared as follows. 20.1 grams of 36/64 poly(epsilon-caprolactone-glycolic acid) copolymer (PCGA), obtained from American Polymer Incorporation (American Polymer Inc., Birmingham, Ala.), was added to 180 grams of 1,4-dioxane (Fisher Scientific, Raritan, N.J.) in a 250 milliliter Erlenmeyer screwed cap flask. The mixture was stirred for 4 hours in 60° C. water bath set on a temperature controlled heating plate. The polymer solution was filtered through an extra coarse thimble filter to remove any non-dissolved solids. This 10 weight percent solution was diluted to 5 weight percent by mixing 75.0 grams of 10 percent solution with 75.2 grams of 1,4-dioxane (Fisher Scientific, Raritan, N.J.).
A 3 weight percent solution was prepared by diluting 18.1 grams of 5 weight percent solution with 12.2 grams of 1,4-dioxane (Fisher Scientific, Raritan, N.J.).
A piece of 3 inch by 6 inch of polypropylene mesh sold under the tradename GYNEMESH* PS (Ethicon, Inc, Somerville, N.J.) was securely placed between two 2 inch by 5 inch aluminum frames. The aluminum frame containing mesh was dipped in 3 weight percent solution and the excess solution was shaken off prior to placement on a pre-cooled (−17° C.) shelf of a freeze-dryer (lypholyzation unit) (FTS Systems, Model TD3B2T5100, Stone Ridge, N.Y.). The following freeze-drying cycle was the used:
After completion of the lyophilization cycle, the tissue reinforcement device was removed from the aluminum frame, and stored in dry conditions.
Samples of the tissue reinforcement device made in Example 1 were mounted on a microscope stud and coated with a thin layer of gold using a EMS 550 sputter coater. SEM analysis was performed using the JEOL JSM-5900LV SEM. The surfaces and cross-sectional areas were examined for each sample.
Human fibroblasts were used for this experiment. Five samples of the tissue reinforcement device made in Example 1 were additionally coated with human fibroblast cells. As a control, five samples of polypropylene mesh were also coated with human fibroblast cells. The number of cells attached to the devices after overnight incubation were measured using a CyQuant kit from Molecular Probe Inc. A higher level of fluorescence indicates a higher level of cell attachment.
The tissue reinforcement device made in Example 1 had a fluorescence of 643.6+/−333.6, while the fluorescence of the polypropylene mesh control was 174.6+/−44.8. The mesh with individual fibers coated with polymer foam showed enhanced cell attachment.
A patient is prepared in a conventional manner for a sacrocolpopexy procedure. After accessing the site, the device is connected between the vagina and the sacrum, replacing the support to the vagina that would have been provided by the uterosacral ligaments. During the operation, the doctor stitches one end of the device to the top of the vagina and the other end to a bone near the spine (called the sacrum or sacral bone). Alternately it can be stitched to the sacrospinous ligament, which connects the sacrum to the ischial spine. This procedure can be done abdominally, either through keyhole surgery (laparoscopy) or a larger cut just above the bikini line, laporotomy. It can also be done transvaginally, which is through the vagina without making any incision in the external skin of the patient. This later procedure is accomplished by opening the back or apex of the vagina. In any one of these techniques the procedure is the same. The device is stitched or fastened to the outer surface of the vaginal apex on one side using sutures. The opposite end of the device is then pulled to approximate the vagina near the sacrum or sacrospinous ligament. This position represents the true anatomical position of the vagina. The end of the device is then fixed to the bone or ligament using a suture or a surgical fastener. A second device is then attached to the opposite side of the vagina at the apex as well, adjusted for the correct length and attached in the same way to the bone or ligament. In the trans-vaginal technique the apex is then stitched closed. For the laparoscopic technique and the open technique the abdominal incisions are then closed.
In the second mentioned procedure the uterus is re-suspended.
Treatments that suspend rather than remove the uterus are recommended for women who want to keep 11 their uterus or have children in the future. Procedures can be done either vaginally or abdominally. The procedure is called a sacrohysteropexy. This procedure uses the device to hold the uterus in place. The operation is done abdominally, either through a small (typically 15-cm) cut just above the pubic hairline or through keyhole surgery (laparoscopy), or trans-vaginally through the back of the vagina. The doctor attaches one end of the device to the cervix and top of the vagina using sutures and the other to a bone (sacrum or sacral bone) near the spine again using sutures or in some cases using surgical fasteners or anchors. Generally, a hard anchor is either screwed into the bone or wedged into a hole, which is drilled into the bone. Sutures attached to the anchor are then threaded through the device and adjusted to bring the device in contact with the bone and surrounding tissues. This portion of the procedure is repeated on the opposite side of the uterus. The device replaces the support to the uterus, which is normally provided by the uterosacral ligaments, the cardinal ligaments and the broad ligament.
The devices and the use of the devices of the present invention in surgical procedures have many advantages. The advantage of this type of device is that the small micropores can allow for the attachment of cells to the device. The macropores provide for growth of the cells into the device, and a secure attachment of the reinforcement material to the surrounding tissue. This can avoid encapsulation of the device. The thinness of the coating also allows the device to be more supple than other composite structures.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
