Development of infection resistant polyurethane biomaterials using textile dyeing technology.

Infection is a major complication when using biomaterials such as polyurethane in the clinical setting. The purpose of this study was to develop a novel infection resistant polyurethane biomaterial using textile dyeing technology. This procedure results in incorporation of the antibiotic into the polymer, resulting in a slow, sustained release of antibiotic from the material over time, without the use of exogenous binder agents. Polycarbonate based urethanes were synthesized that contained either a non-ionic (bdPU) or anionic (cPU) chain extender within the polymer backbone and cast into films. The fluoroquinolone antibiotic ciprofloxacin (Cipro) was applied to bdPU and cPU using textile dyeing technology, with Cipro uptake determined by absorbance reduction of the "dyebath." These dyed bdPU/cPU samples were then evaluated for prolonged Cipro release and antimicrobial activity by means of spectrophotometric and zone of inhibition assays, respectively. Cipro release and antimicrobial activity by dyed cPU segments that were aggressively washed persisted over 9 days, compared with dyed bdPU and dipped cPU control segments that lasted < 24 hours. Dyed cPU segments, which remained in a static wash solution, maintained antimicrobial activity for 11 days (length of study), whereas controls again lost antimicrobial activity within 24 hours. Thus, application of Cipro to the cPU polymer by means of dyeing technology results in a slow sustained release of antibiotic with persistent bacteriocidal properties over extended periods of time.

End-stage renal disease (ESRD) and vascular access grafting: a critical review.

End-Stage Renal Disease (ESRD) is a major disease state, costing the U.S. $9.5 billion in 1992, and increasing 10% yearly. The growth in the number of ESRD patients can be attributed principally to demographic trends: the aging of the general population and the improved treatment and increased survival rate of patients with diabetes, hypertension, and other illnesses that lead to ESRD. Moreover, improved dialysis technology has enabled older patients and those who previously could not tolerate dialysis due to other illnesses to benefit from this treatment. Three modalities exist for the treatment of ESRD: hemodialysis, peritoneal dialysis, and kidney transplant. This article reviews the medical treatments and the synthetic polymers used in the manufacture of vascular access grafts. We report on the development of a new, polyurethane-based microporous vascular graft, which displays self-sealing and improved compliance characteristics for use in vascular access grafting.

Synthesis of a novel small diameter polyurethane vascular graft with reactive binding sites.

Development of a small diameter (4 mm inner diameter [ID]) prosthetic vascular graft with functional groups accessible for covalent binding of recombinant hirudin (a potent anticoagulant) should create a more hemocompatible surface. The purpose of this study was to develop a technique for generating carboxylic acid groups on the surface of precast 4 mm ID poly-(carbonate urea)-urethane vascular grafts and to evaluate the accessibility of these groups. A polycarbonate based urethane with the chain extender 2,2-bis(hydroxymethyl)propionic acid was synthesized. A precast 4 mm ID poly(carbonate urea)-urethane vascular graft (Chronoflex [CF]; CardioTech International, Woburn, MA) was then placed into a 4% carboxylated polyurethane (cPU) solution (in 1% dimethyl acetamide) and incubated for 30 minutes (cPU graft). To determine the accessibility of the carboxylic acid groups, a standard textile technique using methylene blue dye was used. Macroscopic cross-sections, which were cut and evaluated for dye penetration, showed greatest concentration of carboxylic acid groups at the luminal and capsule surfaces, with minimal penetration into the mid-portion of the graft. Analysis of dye baths for absorbance reduction resulted in the cPU grafts having 3.7-fold and 5.4-fold more accessible carboxylic acid groups compared with untreated and dimethyl acetamide dipped CF grafts. Thus, a novel small diameter vascular graft has been developed that contains reactive carboxylic acid groups accessible for protein binding.

Bioengineering of a novel small diameter polyurethane vascular graft with covalently bound recombinant hirudin.

Development of a small diameter prosthetic vascular graft with surface based antithrombin properties should aid in maintaining early graft patency in small vessel reconstruction. The purpose of this study was to bind covalently a basecoat protein (canine serum albumin [CSAJ) and a potent antithrombin agent (recombinant hirudin [rHir]) to 4 mm inner diameter poly(carbonate urea) urethane grafts with reactive carboxylic acid groups (cPU). 125I-CSA was covalently bound to 1 cm length segments of cPU grafts using the carbodimide cross-linker, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). To bind 125I-rHir covalently, CSA was modified with the heterobifunctional cross-linker sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulfo-SMCC) before linkage to the cPU surface with EDC (cPU-CSA-SMCC). 125I-rHir was modified with Traut's reagent and reacted with the cPU-CSA-SMCC surface, covalently linking 125I-rHir to surface bound CSA. 125I-CSA binding to the cPU graft surface (34,235 ng/segment) was ninefold, sevenfold, and 10-fold greater than controls with nonspecifically bound 125I-CSA. Covalent linkage of 125I-rHir to the cPU-CSA-SMCC surface (9,974 ng/segment) was 172, 192, and 142-fold greater than controls with nonspecifically bound 125I-rHir. Surface antithrombin properties were characterized using a chromogenic assay to measure residual thrombin activity. Evaluation of surface antithrombin activity showed significantly greater 131I-thrombin inhibition and binding by the cPU surface with covalently bound 125I-rHir, as compared with controls. Release of 125I-rHir from the cPU surface was minimal as compared with controls. Therefore, rHir can be covalently linked to a novel small diameter polyurethane vascular graft surface while maintaining its potent antithrombin properties.

Covalent linkage of recombinant hirudin to a novel ionic poly(carbonate) urethane polymer with protein binding sites: determination of surface antithrombin activity.

Surface thrombus formation on implantable biomaterials such as polyurethane is a major concern when utilizing these materials in the clinical setting. Thrombin, which is responsible for thrombus formation and smooth muscle cell activation, has been the target of numerous surface modification strategies in an effort to prevent this phenomenon from occurring. The purpose of this study was to covalently immobilize the potent, specific antithrombin agent recombinant hirudin (rHir) onto a novel polyurethane polymer synthesized with carboxylic acid groups which served as protein attachment sites. The in vitro efficacy of thrombin inhibition by this novel biomaterial surface was then evaluated. Bovine serum albumin (BSA), which was selected as the basecoat protein, was reacted with sulfo-SMCC in a 1:50 molar ratio. This BSA-SMCC complex was then covalently linked to the carboxylated polyurethane (cPU) surface via the crosslinker EDU (cPU-BSA-SMCC). This cPU-BSA-SMCC surface was then reacted with Traut's-modified 125I-rHir, a procedure which created free sulfhydryl groups on rHir (cPU-BSA-SMCC-S-125I-rHir). Using these crosslinking procedures, the cPU-BSA-SMCC-S-125I-rHir segments bound 188 +/- 40 ng/cm2 (n = 60) whereas the controls with non-specifically bound 125I-rHir (Mitrathane + EDC + BSA + 125I-rHir-SH and cPU-BSA + 125I-rHir-SH) bound 13 +/- 8 ng/cm2 and 4 +/- 8 ng/cm2, respectively. Evaluation of these cPU-BSA-SMCC-S-125I-rHir segments for 131I-thrombin inhibition using a chromogenic assay for thrombin showed that a maximum of 2.64 NIHU thrombin was inhibited in contrast to the controls which inhibited bound 0.76 and 0.70 NIHU. Controls with nonspecifically bound 125I-rHir also had 0.31 and 0.76 NIHU 131I-thrombin adherent to their respective surfaces whereas the maximum 131I-thrombin binding to the cPU-BSA-SMCC-S-rHir segments was 1.51 NIHU. Exposure to 131I-thrombin did not result in any release of covalently bound 125I-rHir from the cPU-BSA-SMCC-S-125I-rHir segments. Thus, these results demonstrate that rHir can be covalently bound to this novel polyurethane surface and still maintain potent antithrombin activity.

In vitro and in vivo biodurability of a compliant microporous vascular graft.

Polyurethanes have unique mechanical and biologic properties that make them ideal for many implantable devices. However, certain polyurethanes are affected by some in vivo degradation mechanisms. For example, poly(ester)urethanes are subject to hydrolytic degradation and are no longer used in long-term implanted devices. Poly(ether)urethanes while hydrolytically stable, are subject to oxidative degradation in several forms, including environmental stress cracking and metal ion oxidation. We have developed a second-generation poly(carbonate)urethane with superior biostability. This material has been fabricated by our patented method into small diameter microporous vascular grafts. We evidenced the biodurability of our vascular graft by in vitro qualification tests which compared the poly(carbonate)urethane with a traditional poly(ether)urethane. This poly(carbonate)urethane graft has also proven to be biodurable in in vivo experimental implants up to twenty months duration with no evidence of hydrolysis or environmental stress cracking (ESC).

Chemical and physical characterization of a novel poly(carbonate urea) urethane surface with protein crosslinker sites.

A major complication which occurs with implantable polyurethane biomaterials is bioincompatibility between blood and the biomaterial surface. Development of a novel biodurable polyurethane surface to which biological agents, such as growth factors or anticoagulants could be covalently bound, would be beneficial. The purpose of this study was to synthesize a novel poly(carbonate urea) urethane polymer with carboxylic acid groups which would serve as "anchor" sites for protein attachment. Physical characteristics such as tensile strength, initial modulus, ultimate elongation, tear strength, water/alcohol uptake and water vapor permeation were then evaluated and compared to other biomedical-grade polyurethanes. Covalent linkage of the blood protein albumin to this novel surface was then examined. A biodurable polycarbonate-based polyurethane containing carboxylic acid groups (cPU) was synthesized using a two step procedure incorporating the chain extender 2,2-bis(hydroxymethyl)-propionic acid (DHMPA). Tensile strength of this cPU film was 2.7 and 2.6 fold greater than both a polycarbonate-based polyurethane synthesized with a 1,4-butanediol chain extender (bdPU) and Mitrathane (Mit) controls, respectively. The cPU polymer also possessed 7.8 and 31 fold greater structural rigidity upon evaluation of initial modulus as compared to the bdPU and Mit, respectively. Ultimate elongation for the bdPU films was slightly higher than the cPU and Mit films, which had comparable elongation properties. The force required to tear the bdPU film was 1.9 and 32 fold greater than the cPU and Mit films, respectively. Alcohol solution uptake by all of the polyurethane segments increased with increasing alcohol concentrations, with the cPU having the greatest uptake. Water uptake was minimal for all the polyurethanes examined and was not affected by altering pH. Water vapor permeation was lowest for the cPU films as compared to both bdPU and Mit. Swelling the cPU in 50% ethanol prior to evaluation slightly increased water vapor permeation through the films. Covalent linkage of the radiolabelled blood protein albumin (125I-BSA) to the cPU segments incubated with the heterobifunctional crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) was greatest in the higher percent of ethanol as compared to controls. These results serve as foundation for developing a novel poly(carbonate urea) urethane with physical characteristics comparable to other medical-grade polyurethanes while having protein binding capabilities.

Resistance to biodegradative stress cracking in microporous vascular access grafts.

Degradative cracking, more commonly known as "environmental stress cracking" (ESC) has been observed in many implanted polyetherurethane elastomers. This phenomenon has been attributed to biochemical and cellular interactions at the surface of the implanted material causing polymer chain cleavage. This may result in surface fissuring followed by the deep cracking associated with considerable biodegradation of the polymer, resulting in loss of mechanical strength and the formation of aneurysms in an in vivo situation. These cracking effects are believed to be due to mechanical stress combined with the oxidising actions of macrophages and giant cells, as surface cracking has been observed to occur directly under adherent macrophages on a polyetherurethane implant. These cells form part of the body's immune response which uses enzymes and reactive oxygen species (O2, O2-, and HO. and H2O2) to degrade foreign material. We describe a modification of an in vitro test method developed by Zaho et al. [1] using glass wool and a Hydrogen Peroxide/Cobalt (II) Chloride (H2O2/CoCl2) mixture to replicate the oxidising effects of macrophages in vivo. The modifications were made to establish a routine testing system for resistance to biodegradation which could be used to screen a range of polymers designed for use in microporous vascular grafts. The grafts are pre-stressed by a method devised by Stokes et al. [2] where each graft is stretched to a predetermined elongation over a mandrel and the strain is fixed by tying PTFE tape around each end of the mandrel.

Modern wound dressings: a systematic approach to wound healing.

The advent of modern wound care management constitutes one of the most innovative applications of medical device technology. The foundation for wound care recent advances has been built upon the developments achieved in polymer technology over the last three decades. New and unique materials have been engineered to provide properties with significant technical and clinical benefits. These new wound care products were made possible by the convergence of three interrelated disciplines: (1) more complete understanding of the underlying principles of dermal wound healing processes, (2) new elastomeric polymers capable of being fabricated into protective dressings, and (3) advances in breathable adhesive technology. The following discussion provides a critical review of the current status of technology and the worldwide opportunities for improved wound management products. Particular attention is focused on the clinical applications of the newer, breathable dressing products, which approximate a temporary synthetic artificial skin.

Biostable polyurethane elastomers.

The generic term polyurethane represents the most versatile family of synthetic polymers. The unsurpassed physical and chemical properties of polyurethanes, coupled with their biocompatibility, have led to their use in a wide range of biomedical applications. Although polyurethanes have been shown to be stable in vitro for many years, they can undergo rapid microcracking when implanted. These microcracks not only weaken the polymer but also serve as nucleation sites for thrombus formation and lead to catastrophic failure. In this article, the authors report on the development and testing of a new ether-free polyurethane that does not exhibit surface microcracking under accelerated in vivo condition.

In vivo testing of a biostable polyurethane.

At present all the commercially available "medical grade" urethane elastomers exhibit a phenomenon known as environmental stress cracking (ESC). This phenomenon is characterized by surface microcracking when the elastomer is elongated while in vivo. The degree of strain that is required to initiate microcracking varies from composition to composition. It has been found that harder compounds generally tend to have a higher strain threshold than corresponding softer ones. We theorized that this degradation occurs when certain enzymes (present only in vivo) attack and break down the ether linkages that link the polymer molecules together. Those elastomers that contain more ether linkages (such as the softer compositions) appear to microcrack more easily than elastomers with fewer ether linkages (such as the harder ones). The molecular composition of ChronoFlex urethane has been chosen so that the finished elastomer will be free of ether linkages; thus, it is expected to be immune from environmental stress cracking.