DSIMS characterization of a drug-containing polymer-coated cardiovascular stent.

Dynamic Secondary Ion Mass Spectrometry (DSIMS) was used to study the release behavior of cytochalasin D, an actin polymerase inhibitor effective in the reduction of smooth muscle cell (SMC) proliferation, from a polymer-coated cardiovascular stent. High-performance liquid chromatography (HPLC) was used to determine the percentage of drug released as a function of time and showed the typical behavior of a drug-releasing system that is comprised of a core drug-polymer dispersion surrounded by a drug-free polymeric membrane: an initial burst of the drug followed by a gradual elution over time. DSIMS profiles, as a function of release time, indicated that depletion of the drug initially occurred only in the outer layers of the coating. As release progressed the DSIMS profile showed a gradual decrease of cytochalasin D with increasing depth. This study shows that DSIMS is a powerful tool for the determination of drug distributions in, and the release behavior from, thin polymer layers.

(Electron) microscopic observations on tissue integration of collagen-immobilized polyurethane.

The foreign body reactions to collagen-immobilized polyurethane (PU-CI) films during subcutaneous implantation in rats were characterized. The underlying concept is that collagen-immobilization will improve the tissue integration. Since the method of collagen-immobilization involves the covalent coupling of collagen to an acrylic acid (AA) based surface graft, both non-modified PU and PU-AA were used as controls. Bare PU has a flat surface, whereas both PU-AA and PU-CI displayed a slightly roughened surface. Implantation showed that PU-CI induced early after implantation a far more intense foreign body reaction than PU and PU-AA. This reaction consisted of increased presence of fibrin, granulocytes and macrophages. Roughening of the surface as with PU-AA induced only a small increase in fibrin formation and cellular migration. At day 5 the reaction to PU-CI had slowed down; giant cell formation now slowly started but was decreased compared to PU and PU-AA. At day 10 capsules around each type of material looked similar, but in contrast to PU. PU-CI films could no longer be dissected from their capsules. Only at week 3 this also occurred with PU, at which time point again similar capsules with the three materials were observed. At week 6, of the three materials PU-CI showed the thinnest capsule with most immediate adherence of connective tissue. These results show that collagen-immobilization of PU increased the early tissue reaction and therefore the tissue integration. The thin capsule observed at 6 weeks may be beneficial in e.g. infectious circumstances, when easy access for immune reactions is needed. This, and the long-term performance of PU-CI will be a matter of future investigations.

Tissue reactions to bacteria-challenged implantable leads with enhanced infection resistance.

Tissue reactions to implantable pacemaker leads were investigated in an early infection model in rabbits. Both standard leads and surface-modified leads were used. The surface modification technique was applied to achieve controlled release of the antibiotic gentamicin. The insulating polyurethane tubing material of the leads was provided with an acrylic acid/acrylamide copolymer surface graft and then loaded with gentamicin. Implantation periods varied from day 4, to week 3 1/2, to week 10. We investigated tissue reactions in the absence of an infectious challenge and also the efficacy of surface-modified leads in preventing infection after challenge with Staphylococcus aureus was evaluated. It was demonstrated that the applied surface modification did not induce adverse effects although during early postimplantation an increase in infiltration of granulocytes and macrophages and wound fluid and fibrin deposition were observed. After bacterial challenge, standard leads were heavily infected at each explantation period, denoted by abscesses, cellular debris, and bacterial colonies. In contrast, little or no infection was observed, either macroscopically or by bacterial cultures, with the surface-modified leads. Microscopy showed little evidence of the bacterial challenge, and that primarily at day 4. It was concluded that the applied surface modification demonstrated enhanced infection resistance and thus represents a sound approach to the battle against infectious complications with biomaterials.

Tissue reactions to bacteria-inoculated rat lead samples. I. Effect of local gentamicin release through vicinal sponge or solution-dipping.

The effect of local gentamicin release through a vicinal collagen sponge or through preoperative solution-dipping of rat lead samples was investigated in an early-infection model. The efficacy of these methods and their effect on tissue response were determined. It was demonstrated that both methods of local gentamicin release suppress lead-related infectious complications as compared to the control lead, which showed a high presence of inflamed/infected tissues and bacterial growth at each explantation time point. The first day the vicinal collagen sponge was more effective in suppressing the infection than was the solution-dipped lead, probably because there is a faster and higher dose release of gentamicin from the sponge. However, continued implantation time revealed that gentamicin release from the solution-dipped lead was more effective than the sponge. This supports our hypothesis that the presence of lumina are decisive for bacterial growth and persistence of implant-related infections.

Tissue reactions to bacteria-inoculated rat lead samples. II. Effect of local gentamicin release through surface-modified polyurethane tubing.

A surface modification technique was developed to achieve controlled release of gentamicin from implanted polyurethane (PU) rat lead samples. PU tubing first was provided with an acrylic acid/acrylamide copolymer surface graft and then loaded with gentamicin. This surface modification technique resulted in release of gentamicin base (GB) and was applied either to the inner luminal surface only (PU-GB-1x) or to both the inner and outer surfaces (PU-GB-2x). First we investigated whether the early tissue response was harmfully compromised when surface-modified rat lead samples were implanted without any infectious challenge. Additionally, the efficacy of this type of local gentamicin therapy was investigated by establishing its effect on tissue response and its ability to prevent lead-related infections after inoculation with Staphylococcus aureus. It was demonstrated that the applied surface modification(s) did not induce adverse effects although an increase in the infiltration of granulocytes and macrophages and an increase in the formation of wound fluid and fibrin were observed. This effect was stronger with PU-GB-2x than with PU-GB-1x. With bacterial inoculation the applied surface modification successfully suppressed the infectious challenge, PU-GB-2x more effectively than PU-GB-1x. PU-GB-2x also was more effective when compared to the gentamicin-delivery methods discussed in the first part of this two-part study, i.e., release through a vicinal gentamicin-containing collagen sponge and preoperative gentamicin solution-dipping of rat lead samples.

A first screening for hemocompatibility of a universal support for selective and specific hemoperfusion.

A modified filmadsorber is presented, intended to be used for selective and specific hemoperfusion. It consists of a spirally wound cellulose nitrate film, onto which--after chemical activation with sodium periodate--albumin is bound, stabilized, sterilized and activated with glutaraldehyde. Various bioactive ligands containing amino groups can be coupled to this support. A subsequent treatment with dimethylamino borane stabilizes the bonds between cellulose nitrate, albumin, glutaraldehyde and ligand. Columns in which a second layer of albumin is bound to the support as a model for a bioactive ligand were first screened for hemocompatibility using rabbits. Leukocyte, thrombocyte and hematocrit behaviour during hemoperfusion showed that hemocompatibility of the support was good.