SE506333C2 - Implantable prostheses with improved bio-compatibility - Google Patents

Abstract

Surgically implantable prostheses comprises an outer flexible envelope which encloses a hydrogel (I) having both hydrophobic and hydrophilic regions. The hydrophobic regions are polymerised N-vinylic hydrophobic monomers (II) and/or hydrolysed polyacrylonitriles (III). The hydrophobic regions of (I) are pref. held together with hydrophobic, ionic, dipolar, or H-bonding forces or mixts. The outer envelope may be prepd. of non-porous material (filled with a blend of (I) particles dispersed in a liq. carrier); or porous or semipermeable material (porosity to allow fluid interchange without large mol. or cellular infiltration; constructed of woven, knitted, felted veloured or foamed fabric, or materials which have been stretched or expanded; opt. to allow controlled amt. of tissue ingrowth and capsule formation), when the (I) filling comprising particles of size greater than the porosity of the outer envelope.

Description

50.6 333 10 15 20 25 30 35 The use of silicone elastomer bags filled with saline solution and double cavity implants, the outer chamber containing saline solution, reduces the inflammatory response. However, the rupture of the silicone elastomer bag, especially along the seams, is more common in implants filled with saline solution. This is because the bag rubs against itself, the material often bends as the patient moves, the low viscosity of the filling material and the reduced lubricity of the saline solution compared to a silicone gel. When an implant filled with saline solution ruptures, this causes the tissue cavity to shrink as the saline solution is absorbed by the surrounding tissue.

U.S. Patent No. 4,157,085 to Austad discloses hydrophilic polymers, such as poly-N-vinylpyrrolidone, carboxymethylcellulose or polyethylene glycol, encapsulated within a membrane permeable to extracellular body fluids under osmotic pressure. The preferred material is a very thin silicone membrane with the ability to let liquids through and which can be stretched as the liquid concentration of the entrapped material increases. This device is intended to be used to stretch a tissue as the polymer inside the casing absorbs liquid. When the tissue expansion is completed, the device is removed and replaced with a suitable prosthesis.

This is necessary because the polymers inside the housing are water-soluble, non-crosslinked and could easily spread in the body if they were to leak out of the device when its membrane cracked or tore.

Polmanteer discusses in U.S. Patent No. 4,383,382 the use of hydrophilic gels which are copolymers of hydrolyzable olefin silanes and water-soluble vinyl constituents. These gels swell in the presence of water using siloxane [šSi-O-Siš] as a covalent crosslinking moiety to form a loose, crosslinked network. However, this results in a gel which in dissociation can dissociate in water according to the equilibrium reaction N = Si-OH and thereby become soluble. Such gels would be slowly absorbed by the tissue in case the casing tore or tore.

U.S. Patent No. 4,517,326 to Cordts discloses the use of a polyurethane gel which includes an aqueous dispersion for use as an implantable prosthesis. The water content of the gel can only be varied from 25% to 65%, which limits the softness of the device. In addition, such a device would involve a macroporosity in the form of dispersed water droplets and would be susceptible to calcification and tissue ingrowth.

Bone and cartilage can be used to fill a soft tissue defect, but unless the submerged surface is due to a defect in the underlying bone structure, the lack of flexibility of the enlarged surface will be unsatisfactory. The surgical technique of inserting bone, cartilage or skin often involves extensive erosion of soft tissues and the formation of significant, often additional scars at the recipient site.

There is also a tendency for such grafts to be subjected to resorption, which is often not exactly foreseeable.

In addition, the fine-tuning of many small surfaces is often extremely difficult with such grafts. Donor sites to obtain autogenous bone and cartilage grafts are rather limited, and a noticeable scar is often formed at the donor site.

Problems with the donor site do not occur when material in the form of an allogeneic transplant is used. However, allogeneic skin grafting is unsuitable because it is always rejected. Rejection may be a minor problem with allogeneic bone and cartilage grafts, but the results are unpredictable.

Implanting alloplastic materials, such as solid silicone elastomers, requires the receiving site to be hollowed out, resulting in a scar at the insertion site. These materials have a marked tendency to migrate, cause sera, become surrounded by hard fibrous tissue, and are sometimes infected or worn through overlying soft tissues.

Injecting alloplastic material, such as silicone fluids and silicone gels, reduces the surgical procedures and resulting scarring. However, it has been found that silicone fluids and silicone gels are not immobilized by the tissue and tend to migrate away from the intended recipient site and possibly accumulate in the lymph nodes.

Autoimmune disease, hard, fibrous encapsulation and deformation of the reconstruction or enlargement have been reported when these materials are used, both in direct injections and when included in a silicone pass typically used in breast implants.

Soluble collagen has been used as a subcutaneous implant to heal dermatological defects, such as scars, cuts and other defects in soft tissues. Collagen can be injected directly into the recipient site, minimizing scarring. Although this material seems to be readily accepted, the healing of the defects is temporary, as collagen and collagen-based materials can be broken down enzymatically by the body, ie by the action of collagenase, and patients need to repeat the treatment after 6 to 18 months. There have also been a number of negative tissue responses after the use of soluble collagen.

Various researchers in medicine have evaluated the implantation of hydrogel as a breast tissue substitute or a material for tissue substitutes. The hydrogel used has i (pHEMA). Depending on the water content, crosslinking agent, monomer content and primarily the poly (hydroxyethyl methacrylate) pore structure as well as other variables of these hydrogels or implant structures, a large number of tissue interactions have been reported. These interactions include encapsulation, small cell growth and growth of giant cells, vascularization, and calcification. In general, pHEMA hydrogels with high water contents exhibit poorer mechanical properties, vascularization, tendency to calcify, and are difficult to shape and are easily damaged during implantation due to their fragility. This tissue response is thought to be due to their macroporous structure at high water levels. pHEMA hydrogels with lower water content, which are homogeneous or which only have? microporosity, do not exhibit vascularization or calcification. However, they are generally stiffer and less malleable, making them unsuitable for expansion of soft tissues, and they have a greater tendency to induce fibrous capsule formation.

U.S. Patent No. 4,631,188 to Stoy et al. does not show water-soluble hydrogels, which are dissolved in a water-soluble solvent for soft tissue injection. When the solvent is absorbed by the body, it is partially replaced by the water, forming a semi-solid aquagel.

According to the state of the art, viscous materials implanted in the body are also shown, whereby the materials have been referred to as hydrogels. However, these materials are not true hydrogels, as they are polymers read in water, and thus they expand indefinitely upon addition of more solvents; or they form gels at certain temperatures and solutions at other temperatures, this conversion being reversible; or the water is not in equilibrium with the polymer, as in the case of true hydrogels.

For successful mastectomy reconstruction as well as other procedures involving implantation of a soft tissue prosthesis, there is a need for a prosthesis that is soft and malleable, that does not calcify or induce severe fibrous encapsulation, and that is resistant to leakage in the event that the casing breaks or tears. There is also a need for an implantable material which is soft and malleable, which does not calcify or induce unacceptable fiber encapsulation and which can be implanted or delivered to the site in question, either as a shaped mass or by injection through a small diameter needle.

Summary According to the present invention, these needs are met by an improved, implantable prosthesis for use in the human body, the prosthesis comprising a flexible housing which houses within itself a soft, malleable, biocompatible hydrogel filling comprising both hydrophobic and hydrophilic domains. The casing, which is formed from either a flexible porous or non-porous material, may consist of one or more cavities. The construction designs provide long-term stability even in the event of the casing being torn or broken.

The hydrogel according to the invention has a discrete dimension, ie it is not infinitely expandable, and when mixed with a physiological solution forms a non-reversible gel which has a certain water content, the gel not being enzymatically degraded by the body. The resulting hydrogel is homogeneous, biocompatible and relatively non-reactive with the body. The hydrogel can be crosslinked with polyvinylpyrrolidone, polymerized N-vinyl monomers, hydrolyzed polyacrylonitriles or combinations thereof.

Instead of being placed in a casing, the gel can be implanted as a shaped mass or it can be injected in a special shape to the desired location. Furthermore, the hydrogel can be implanted or injected, either completely hydrated, partially hydrated or in dehydrated form to replace or expand body fluid or body tissue, or to regenerate body tissue. Hydrogels, which give concrete expression of features according to the invention, can thus used to replace soft tissues, which have been surgically removed or consumed as a result of regenerating soft tissues, of age or use, damaged by external causes, to dilate body parts, such as for subcutaneous, dermatological use, breast augmentation and other common plastic surgery procedures, or to replace body fluids, such as synovial fluid or vitreous fluid in the eye.

Description Hydrogels having features of the invention are made by copolymerizing an N-vinylpyrrolidone with a multifunctional crosslinking agent or by copolymerizing a hydrophobic monomer with a hydrophilic monomer. A small amount of multifunctional monomer can also be used as a covalent crosslinking agent to provide a cured copolymer which is insoluble in both an aqueous environment and an organic environment. Even in the absence of a covalent crosslinking monomer, hydrogels in an aqueous environment will still be a gel due to the interactions of the hydrophobic domains. The interactions brought about by hydrophobic bonds, ionic bonds, dipole moments, hydrogen bonds or a combination of these forces result in a gel in which the polymer chains are "crosslinked" by the hydrophobic domains. In aqueous solutions, these hydrogels will swell and uniformly without any macroporosity or heterogeneity include water in the hydrophilic domains of the polymer. This homogeneity reduces or prevents calcification. The hydrophobic domains, which are evenly distributed throughout the gel matrix, hold the polymer chains together and do not allow them to dissolve and disperse in body fluids.

The water content of the hydrogel, which typically ranges from 40% to 99%, is controlled by the ratio of hydrophobic to hydrophilic domains. Hydrogels with water contents above 85% will generally resemble the texture of soft parts, have sufficient strength to allow handling and implantation, and have a homogeneous microporous structure so that vascularization and calcification are prevented. Suitable hydrophilic momomers that can be used to form the gel are biocompatible, water-soluble vinyl compounds. By the term "vinyl" is meant a compound or constituent which contains at least one unsaturated aliphatic linkage in the form of CH 2 = CRR '. Included in this class of hydrophilic monomers are N-vinylpyrrolidone, acrylates or methacrylates of the general formula cH2 = â-co2-R ', in which R is H or CH3, and R' are radicals obtained from mono- or dihydric alcohols, such as CH 2 -CH 2 -OH, CH 2 -CH (CH 3) -OH CH 2 -CH (OH) -CH 2 -OH, or monomers of the general formula or R cH 2 = α-co-NR "RIII in which R is H or CH 3, and R "and R" 'may be H, alkyl or alkane groups, such as CH 3 -, C 2 H 5 -, or monohydric alcohols, such as CH 2 -CH (OH) -CH 3.

Other vinyl constituents containing 2 or more vinyl groups can be used to modify the properties, such as gel swelling, solubility, flexibility and cohesiveness.

Suitable hydrophobic monomers which can react with the hydrophilic monomers are biocompatible, hydrophobic vinyl compounds. Included in the class of hydrophobic monomers are acrylates, methacrylates and RR'-N-CH2 = CH2. Examples include monomers of the following general formula R cH 2 = ε-coz-R 'in which R is H or CH 3, and R' is CH 3, CH 2 -CH 3 or higher alkyls, benzyl, phenyl or other suitable aromatic groups.

Other suitable hydrophobic monomers include non-water soluble derivatives of N-vinylpyrrolidone or aromatic derivatives of N-vinylpyrrolidone. The term aromatic derivatives of N-vinylpyrrolidone refers to N-vinylpyrrolidone having one or more aromatic rings attached thereto, such as N-vinoxycarbazole. These derivatives may also include pendant groups, such as oxygen, halogen or alkyls.

A material particularly suitable for injection is polyvinylpyrrolidone, which has been copolymerized by the addition of diethylene glycol dimethyl acrylate (DEGDMA). This provides a non-reversible, covalently cross-linked hydrogel with known water uptake and swelling properties.

Other hydrogel classes with both hydrophobic and hydrophilic domains, which are suitable for placement directly in contact with tissue, include polyurethanes containing a hydrophilic polyol domain and a hydrophobic alkyl or aryl diisocyanate. Similarly, hydrogels can be formed from hydrolyzed polyacrylonitriles containing carboxylic acid or amide groups forming the hydrophilic domains, as well as nitrile [NEC] groups, which interact strongly to form hydrophobic domains.

The casing comprising the hydrogel can be formed from any suitable material which is flexible and biocompatible. Non-porous materials, such as silicone or polyurethane with either a smooth surface or a textured surface, can be used. Porous materials made of fabricated polymers, which are woven, knitted, felted or roughened, or materials which are foamed, stretched or expanded, can also be used. The pore size of these materials should be smaller than the smallest particle size of the hydrogel used to fill the prosthesis to avoid loss of hydrogel from the casing. Permeable membranes, such as thin cellulosic plastic or silicone, can also be used.

EXAMPLE 1 V A single walled silicone elastomer bag is filled with hydrogel and then sealed to provide. a barrier to fluid and tissue exchange. The hydrogel inside the bag is a solid mass which preferably has a shape similar to the desired natural contour of the body. Such a hydrogel should preferably have a high water content, around 95% to 99%, to give the implant the desired softness. However, a hydrogel with a lower water content could be used if a stiffer implant was desired.

In the same way, the hydrogel inside the bag could consist of many pieces, which vary from large pieces to very small particles. The water content of the hydrogel should depend on the particle size and the desired softness of the implant. With large particle sizes, high water content hydrogels are preferably used, about 95% to 99%, similar to the solid mass described above. With smaller particle sizes, hydrogels with a lower water content, down to 40%, fluidity with the same effect were used. If hydrogels with higher water were used with smaller particles due to the tin content of the particles, a more "gelatinous" type of structure would be obtained.

EXAMPLE 2 A bag with a single wall made of porous material is filled with hydrogel and then sealed to prevent leakage of hydrogel. Suitable materials for the bag should be biocompatible, should not elicit a strong foreign body response and should have a pore size smaller than the particle size of the hydrogel. Preferred materials are textiles made from Teflon, Dacron or other biocompatible polymers, which may be woven, knitted, braided or shaped into felt or velor. Other preferred materials should include permeable membranes or expanded material, such as Teflon, which is made porous by stretching. Such a material is sold commercially under the name Goretex.

As in Example 1 discussed above, the hydrogel within the porous bag could be in several forms and water contents depending on the desired natural curvature and desired stiffness. In this example, cinnamon body fluids are transported through the porous bag so that the liquid content inside the bag will be in equilibrium with the surrounding tissue. However, the components of the hydrogel are retained inside the housing. Tissue growth is regulated, if so. desired, by the construction and pore size of the housing.

EXAMPLE 3 A dual cavity implant can be made from a bag inside a bag. The inner wall and the contents of the inner bag can be made of any material known in the art. This should include, for example, a silicone gel which is included in a bag of silicone elastomer. The inner cavity may also be designed in accordance with the present invention, as discussed in Examples 1 and 2 above. The outer cavity consists of hydrogel, which surrounds the inner wall, and is included inside the outer bag.

The hydrogel and the flexible outer bag can be designed as described in Examples 1 and 2 above.

EXAMPLE 4 V A multi-cavity implant can be designed in a manner similar to that described in Example 3. For a multi-cavity implant, all of the inner walls may be any material known in the art or encompassed by the present invention. The outer wall or walls are designed in accordance with the present invention as discussed in Examples 1 and 2.

EXAMPLE 5 Several different compositions can be prepared, which are pimples, suitable for surgical implantation without an enclosing sac structure or which can be injected directly into the body as a replacement of tissue. For example, 80% N-vinylpyrrolidone, 10% N-vinylphthalamide and 1% DEGDMA were polymerized to provide a hydrogel containing 90% by weight water. This hydrogel had the consistency of soft tissue, was easily shaped into a desired, permanent shape and was easy to handle and insert into the body during surgery.

EXAMPLE 6 A hydrogel with 95% water content was prepared by copolymerizing 90% N-vinylpyrrolidone with 10% N-vinylphthalamide. After hydration, this material was easily injected into a site in the body tissue through a cannula as small as 30 gauge.

EXAMPLE 7 In another variant, a powder was prepared from the dehydrated hydrogel of Example 6. Before use, the powder was mixed with a physiological solution to form a suspension of hydrogel powder. This suspension was injected into a soft tissue at the site to be expanded. After the injection, the hydrogel powder absorbed body fluids and swelled, causing the tissue to expand at the enlargement site.

Due to the fact that the hydrogels according to the invention have a fixed water content when they are hydrated and thus a known degree of swelling when they are exposed to body fluids, structures can be formed in a dry state with dimensions which are smaller than in the hydrated state, and these structures with reduced size can be surgically implanted through a cannula of suitable size or through minimally invasive surgical devices, such as a laparoscope. As an example, the hydrogel from Example 5 was formed in the dry state into a geometry that would result in the desired shape or dimensions when fully hydrated.

In a second variant, the dry hydrogel from Example 1 was formed into a cylindrical shape 3 mm in diameter, and the cylinder was passed through the tube of an instrument to a body cavity, where after hydration it expanded to about 10 mm in diameter. Although the invention has been described with reference to certain preferred variants and their use, other variants and uses are possible without departing from the intended scope of the invention. the improved implantable devices of this invention, in addition to breast prostheses, are also made in various forms and shapes for the purpose of supplementing, enlarging or replacing tissue anywhere on or in the animal or human body for aesthetic, restorative medical purposes. In addition, the hydrogel may be prepared in various shapes or particle sizes and may be injected or implanted for the purpose of supplementing, expanding or replacing tissue or body fluids anywhere on or in an animal body or a human body for aesthetic or reconstructive purposes.

Claims (7)

506 333 N U 20 25 30 35 14 PATENT REQUIREMENTS A method of preparing a hydrogel for placement in contact with body tissue in a mammalian body for replacement or filling of breast tissue or body fluids, characterized in that a hydrophilic monomer and a hydrophobic N-vinyl monomer are copolymerized so that hydrophilic and hydrophobic domains achieved. A method according to claim 1, hydrophilic polyvinylpyrrolidone is copolymerized with a characteristic of hydrophobic N-vinyl monomer. A method according to claim 1 or 2, wherein the hydrogel is covalently crosslinked. k ä n n e t e c k n a t Hydrogel for placement in contact with body tissue in a mammalian body to replace or replenish breast tissue or body fluids, characterized in that the hydrogel consists of a polymer having hydrophilic domains of hydrophilic monomers and hydrophobic domains of polymerized N-vinyl. Hydrogel according to Claim 4, characterized in that it is a copolymer of hydrophilic polyvinylpyrrolidone and a hydrophobic N-vinyl monomer. Hydrogel according to Claim 4 or 5, characterized in that it is covalently crosslinked. Hydrogel according to Claim 4, characterized in that the hydrophilic monomer is a water-soluble compound of N-vinylpyrrolidone or a vinyl compound of the formula RR RI IIIII c fl fc-coz-R 'or c fl fc-co-NR' in which R is H or CH 3, R 'is cnz-c fl z-o fl, CH 2 -cfucnion or CH 3 -CH (OH) -CH 2 -OH, and R "and R"' are H, CH 3, C 2 H 5 or CH 2 -CH (OH) -CH 3 And the hydrophobic monomer is a water-insoluble compound of the formula R 1 I RN-cH = cH 2 in which R is H or CH 3, and R 'is CH 3, CH 2 -CH 3 or higher alkyls, benzyl, phenyl or other suitable aromatic groups.