1. Field of the Invention
The present invention relates to articles formed primary of polymers selected from acrylic polymers, methacrylic polymers, copolymers and mixtures of these, with modified surface characteristics to create biomimetic products. More specifically, the invention involves the method of making such articles and the products resulting from that method.
2. Information Disclosure Statement
Hydrophobic plastics, such as silicone rubber, polymethylmethacrylate, polyethylene or polyvinylchloride are often used in medical devices (e.g., as catheters, stents or implants) and are exposed to contact with tissues or body fluids.
One of the problems with the use of these materials in device applications is their interaction with proteins. Proteins from body fluids are rapidly and irreversibly adsorbed onto the hydrophobic surfaces. The strongly bound proteins can denature and initiate an autoimmune reaction. Moreover, the deposited protein layer conditions the surface for subsequent cell attachment, including bacterial adhesion. The proteins, cells and microorganisms form a "biofilm" on the hydrophobic surface that is a source of potential problems, such as a bacterial colonization and the consequent risk of material-centered infections and seeded infections that are dangerous and difficult to treat. See Anthony G. Gristina: "Biomaterial-Centered Infection: Microbial Adhesion Versus Tissue Integration", Science, (1987) Volume 237, pages 1588 through 1595. In addition, such surfaces are recognized by the immune system as foreign, causing foreign body reactions during which leukocytes, such as macrophages, attempt to surround and eliminate the invader.
Hydrogels were considered an answer to this problem since they do not adsorb proteins as strongly as hydrophobic plastics or metals. However, this turned out to be only partly true. Although largely hydrophilic, most hydrogels do contain some hydrophobic domains which bind protein in much the same way as hydrophobic plastics. Thus, hydrogels differ from other plastics quantitatively rather than qualitatively (i.e., less protein is adsorbed on the hydrogel surface, but at least part of the adsorbed protein is bound by the same strong hydrophobic interactions that are responsible for the complications in hydrophobic plastics).
Moreover, most hydrogel surfaces are recognized by the immune system as foreign bodies, causing long-term irritation and sterile inflammation. It has been found by Smetana and others that the presence of anionic carboxylate groups on the surface of an implanted hydrogel will reduce or prevent protein adsorption, see Karel Smetana, Jr., Jiri Vacik, M. Houska, Dana Souckova, Jaromir Lukas "Macrophage Recognition of Polymers; Effect of Carboxylate Groups", Journal of Materials Science: Materials in Medicine 4 (1993), pages 526 through 529, prevent attachment and spreading of many cells and prevent recognition of the hydrogel by macrophages as a "foreign body", see Karel Smetana, Jr., Jiri Vacik, Dana Souckova, Zuzana Krcova, Jiri Sulc "The Influence of Hydrogel Functional Groups on Cell Behavior", Journal of Biomedical Materials Research, Volume 24, (1990) pages 463 through 470. Furthermore, the presence of carboxylate groups delays or prevents calcification of implants, see K. Smetana, Jr., M. Stol and M. Novak: Artificial Mineralization In Vitro--A Model Of Tissue Mineralization, Folia Biologica (Praha), Volume 39, 1993. In Smetana's opinion, the carboxylates are functioning in this manner by masking with their electric charge and their high hydration, various functional groups (hydroxyl, amine, amide or various hydrophobic groups) that could otherwise be loci of interaction with proteins or cell surfaces. In Smetana's view, the surface of a carboxylated hydrogel mimics the charge and high hydration of the surface layer (glycocalyx) of certain cells (such as fetal tissue cells or cells of certain pathogenic bacteria) that are rich in sialic acid and known to be unrecognized by immune system, see Karel Smetana, Jr.: "Cell Biology of Hydrogels", Biomaterials (1993), Volume 14; No. 14, pages 1046 through 1050. This biomimetic behavior is valuable for various implants because it can diminish foreign body reaction, improve healing and reduce the risk of post-surgical complications. Consequently, hydrogels with high carboxyl content were synthesized and used for devices like mammary and intraocular lens implants, see Karel Smetana, Jr., Jiri Vacik, Dana Souckova, Sarka Pitrova: "The Influence of Chemical Functional Groups on Implant Biocompatibility", Clinical Materials (1993), pages 47 through 49).
High carboxyl content can be achieved in various ways. The most usual method is a crosslinking copolymerization of acrylic or methacrylic acid with less polar monomers such as 2-hydroxyethylmethacrylate (HEMA) or methylmethacrylate. However, the benefit of carboxylate groups is rather limited in this case. A disadvantage of the homogeneous increase of carboxylate content is the increase of overall water content and consequent decrease of some essential hydrogel properties (such as tensile strength, tear strength and refractive index). Therefore, the carboxylate concentration has to be kept low and its benefit is thereby limited. If a more hydrophobic comonomer (such as benzylmethacrylate) is used to compensate for the extreme hydrophilicity of the acrylic or methacrylic acid (so that a higher carboxylate concentration can be achieved), then there is a danger of causing a phase separation resulting in the formation of hydrophobic domains and/or micropores--both very detrimental to biocompatibility.
Carboxylate groups can also be introduced by hydrolysis of acrylic or methacrylic polymers. Hydrogels are preferred substrates for chemical modifications because of the mobility and accessibility of their functional groups. For bulk hydrolysis, the reagents need access to the interior of the substrate so that acid or base-catalyzed hydrolysis is usually carried out on acrylic or methacrylic hydrogels such as PolyHEMA, see Karel Smetana, Jr., Jiri Sulc, Zuzana Krcova, Sarka Pitrova: "Intraocular Biocompatibility of Hydroxyethyl Methacrylate and Methacrylic Acid Copolymer/Partially Hydrolyzed Poly(2-Hydroxyethyl Methacrylate)", Journal of Biomedical Materials Research (1987), Volume 21, pages 1247 through 1253, or aquagels such as polyacrylonitrile aquagel, see V. A. Stoy, G. P Stoy and J. Lovy: "Method for Preparing Polyacrylonitrile Copolymers by Heterogeneous Reaction of Polyacrylonitrile Aquagel", U.S. Pat. No. 4,943,618. This method provides better results than copolymerization in two respects--it yields stronger hydrogels for a given carboxyl content, and the material has a more distinct biomimetic behavior.
Notwithstanding the foregoing, the high carboxyl content in the hydrogel bulk limits its useful properties. For that reason, it has been proposed to treat only the surface of a hydrogel. In this way, one can create a surface with high carboxyl content while leaving the hydrogel bulk intact. The main problem is controlling the gradient of carboxyl composition and swelling in the hydrogel substrate. The gradient is controlled by the ratio between the rate of hydrolysis and the rate of diffusion of reagents and/or catalysts to the reaction site. Hydrogels suitable for long-term implants are usually highly permeable to water and low-molecular weight catalysts. At the same time, they have to be considerably stable against hydrolysis. Consequently, it is difficult to find conditions under which the reaction rate is much faster than diffusion, and surface hydrolysis often has to be carried out at extreme conditions that are difficult to control high concentrations of strong acids, see G. Stoy and V. A. Stay, "Guidewires With Lubricious Surface and Method of Their Production", U.S. Pat. No. 5,217,026, or bases, see Stanislav Sevcik, Jiri Vacik, Dana Chmelikova, Karel Smetana, Jr.: "Surface Alkaline Hydrolysis of 2-Hydroxyethyl and Methacrylate Gels" Journal of Materials Science: Materials in Medicine 6 (1995), pages 505 through 509, and high temperatures. Even at these conditions, water and catalyst have a tendency to penetrate deep into the hydrogel so that the gradient is shallow and hydrolysis proceeds in the hydrogel bulk as well as on the surface. Change of the bulk properties of the hydrogel is an undesirable complicating factor. In addition, the uncontrolled gradient of composition and swelling causes shape distortion and uneven, wrinkled surfaces. Control of the gradient by reaction kinetics is very difficult. For that reason, attempts were made to control the swelling gradient by running the reaction in a dehydrated state (for instance, in presence of high concentrations of salts that deswell the hydrogel due to the high osmotic pressure in the solution surrounding the hydrogel). However, consistent and controlled surface hydrolysis is difficult under these conditions.
One of the typical hydrogels selected for surface modification is covalently crosslinked poly(2-hydroxyethyl methacrylate) (PHEMA), used in products such as intraocular lenses (IOL). Previous attempts at surface modification of PHEMA IOLs centered around conventional base-catalyzed hydrolysis with NaOH and Na.sub.2 CO.sub.3. These attempts were not very successful because of the difficulties involved in containing the hydrolysis to the polymer surface. The shallow gradient of hydrolysis using this method resulted in the bulk material composing the lens being hydrolyzed as well as the surface. This increased the lens's swelling, and thus altered its optical properties. The difficulties of this method persisted even if used on pre-dried xerogels with short reaction times. The race between hydrolysis of the surface and diffusion into (and hydrolysis of) the bulk material proved unwinnable with the given catalysts.
In an attempt to contain the hydrolysis to the surface, the PHEMA IOLs were treated in a solution of H.sub.2 SO.sub.4 and NaHSO.sub.4, see Jiri Sulc, Zuzana Krcova: "Method for the Formation of Thin Hydrophilic Layers on the Surface of Objects Made From Non-Hydrophilic Methacrylate and Acrylate Polymers", U.S. Pat. No. 4,921,497. The idea being that the NaHSO.sub.4 would suppress the swelling of the lens, decreasing the acid's penetration into and hydrolysis of the bulk material. However, it was not deemed reliable enough for large-scale production. An alternative method used an acid-catalyzed reaction of polyacrylate and polymethacrylate derivatives with a hot (90-120.degree. C.) mixture of concentrated H.sub.2 SO.sub.4 and glycerol, see Otto Wichterle, U.S. Pat. No. 3,895,169. This reaction involves simultaneous hydrolysis, esterification and reesterification, sulphatation and crosslinking. The complicated reaction kinetics and the very harsh conditions made the process very sensitive and unforgiving, rendering it unsuitable for large-scale production of medical devices. In addition, sulfate groups do not have the same biomimetic effect as the more desirable carboxylate groups.
Hydrophobic plastics, such as polymethylmethacrylate (PMMA), can also in theory be hydrolyzed on the surface, forming a highly carboxylated hydrophilic surface layer. However, owing to autoaccelerating kinetics and increasing diffusion rate with reaction conversion, the surfaces of hydrophobic plastics, such as PMMA, are typically etched or pitted by the hydrolysis rather than covered by a continuous hydrogel layer.
Hydrophobic plastics are often hydrophilized by means of hydrogel coatings. The problems with adhesion of hydrogels to hydrophobic materials prevents the use of coatings with very high content of carboxylate groups. Most of the hydrogels used for coatings have a moderate hydrophilicity and no carboxylate groups. The main problem of coatings-of permanent application of this type is their durability. The hydrophilic moiety in these coatings, such as, polyethylene glycol or phosphoryl choline groups, can be removed by hydrolysis under certain conditions.