The aim of this study was to investigate the effect of phagocytosed poly(L-lactic acid) particles on the morphology and viability of phagocytes, mainly macrophages. Therefore, predegraded poly(L-lactic acid) (P-PLLA) and nontreated PLLA (N-PLLA) particles, both having diameters not exceeding 38 microns, were injected intraperitoneally in mice. P-PLLA particles were obtained by 25 kGy gamma-irradiation of N-PLLA particles. N-PLLA and P-PLLA particles were injected using an 0.3% ethanol/0.9% saline solution intraperitoneally to the mice. We also studied the release of the absorbed ethanol as a possible model for the release of low molecular weight, potentially toxic products. As control, nondegradable polytetrafluoroethylene (PTFE) particles and the carrier solution were used. After 1, 2, 3, 4, 5, and 7 days, the cells of the abdominal cavity were harvested to study the effect of phagocytosis of polymer particles on phagocytic cell morphology and viability. Studies with transmission electron microscopy indicated that, upon injection of particles in the peritoneal cavity, macrophages demonstrated signs of cell damage, cell death, and cell lysis due to phagocytosis of a large amount of P-PLLA particles. The morphology of the cells that had phagocytosed the N-PLLA and PTFE particles did not differ substantially from those of control animals in which only the solution was injected. Also, in the controls, hardly any cell death and no debris was observed. When the PLLA particles were injected as a suspension in a 0.3% ethanol/0.9% saline solution, no difference was observed between N-PLLA and P-PLLA. After phagocytosis, both cause cell damage, sometimes leading to cell death.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of solid-liquid demixing, liquid-liquid demixing and vitrification on the morphology of polylactide membranes has been investigated. To study the effects of crystallization of polylactides on the membrane formation and morphology, polylactides of varying stereoregularity were used. The polymers applied were poly-L-lactide (PLLA) and copolymers with different molar ratios of L-lactide and I>lactide [poly-L95/D5-1actide (PLA95), poly-L80/D20-1actide (PLA80) and poly-L50/D50-1actide (PDLLA) ]. Solutions of polylactides in chloroform cast on a glass plate were immersed in methanol. From solutions containing the slowly crystallizing PLA80 or uncrystallizable PDLLA porous membranes were obtained if the phase separated system was removed from the nonsolvent bath within a few hours after immersion. After longer equilibration times in methanol the structure collapsed. The swelling in the nonsolvent methanol was too high to allow stabilization of the liquidliquid demixed structure by vitrification. Stable membranes were easily obtained with more rapidly crystallizing polymers like PLLA. Casting solutions with low PLLA concentrations gave membranes with a cellular morphology due to liquid-liquid demixing by nucleation and growth of a polymer poor phase. Crystallization only played a role in the fixation of the liquidliquid demixed structure. At increasing PLLA concentrations the demixing sequence gradually reversed to crystallization followed by liquid-liquid demixing. In these cases membranes with porous spherulites or spherulites surrounded with a cellular layer were obtained.

The influence of porosity on the degradation rate of poly(L-lactic acid) (PLLA) films was investigated in vitro and in vivo. Non-porous, porous and "combi'" (porous with a non-porous layer) PLLA films were used. Changes in Mw, Mn, polydispersity (Mw/Mn) ratio, melting temperature (Tm), heat of fusion, tensile strength, E-modulus, mass and the remaining surface area of cross-sections of the PLLA films were measured. In general, during the degradation process, the porous film has the highest Mw, Mn, Mw/Mn ratio and Tm, while the nonporous film has the lowest. In contrast, the highest heat of fusion values were observed for the non-porous film, indicating the presence of relatively smaller molecules forming crystalline domains more easily. The tensile strength and E-modulus of the non-porous film decrease faster than those of the porous and the combi film. None of the three types of films showed massive mass loss in vitro nor a significant decrease in remaining polymer surface area in light microscopical sections in vitro and in vivo. Heavy surface erosion of the non-porous layer of the combi film was observed after 180 days, turning the combi film into a porous film. This is also indicated by the changes in tensile strength, Mw, Mw/Mn, Tm and heat of fusion as a function of time. It is concluded that non-porous PLLA degrades faster than porous PLLA. Thus, in our model, porosity is an important determinant of the degradation rate of PLLA films.

SYNOPSIS The influence of liquid-liquid demixing, solid-liquid demixing, and vitrification on the membrane morphologies obtained from several polylactide-solvent-nonsolvent systems has been investigated. The polymers investigated were the semicrystalline poly-L-lactide (PLLA) and the amorphous poly-DL-lactide (PDLLA). The solvent-nonsolvent systems used were dioxane-water, N-methyl pyrrolidone-water and dioxane-methanol. For each of these systems it was attempted to relate the membrane morphology to the ternary phase diagram at 25OC. It was demonstrated that for the amorphous poly-DL-lactide the intersection of a glass transition and a liquid-liquid miscibility gap in the phase diagram was a prerequisite for the formation of stable membrane structures. For the semicrystalline PLLA a wide variety of morphologies could be obtained ranging from cellular to spherulitical structures. For membrane-forming combinations that show delayed demixing, trends expected on the basis of phase diagrams were in reasonable agreement with the observed membrane morphologies. Only for the rapidly precipitating system PLLA-N-methyl pyrrolidone-water were structures due to liquid-liquid demixing obtained when structures due to solid-liquid demixing were expected. Probably, rapid precipitation conditions promote solid-liquid demixing over liquid-liquid demixing, because the activation energy necessary for liquidliquid demixing is lower than that for crystallization.

In this study, the influence of surface morphology and wettability of both degradable and nondegradable polymer films on the inflammatory response after subcutaneous implantation in the rat was investigated. Degradable nonporous, porous, and "combi" (porous with a nonporous layer on one side) poly(L-lactic acid) (PLLA) films and nondegradable polytetrafluoroethylene (PTFE) and (porous) expanded PTFE (e-PTFE) were used. Contact angles measurements indicate that PLLA is more hydrophillic than PTFE. Assessment of the inflammatory response was performed after various periods of implantation (up till 180 days), with both conventional light microscopy and immunohistochemistry using monoclonal antibodies (mAbs). The inflammatory response observed initially can largely be considered as part of the wound healing reaction, and up till day 40 the inflammatory response against PLLA was minimally more intense than against PTFE (porous as well as nonporous). From day 40 on, the PLLA films provoke a more intense inflammatory response as compared to the PTFE films. Both porous PLLA and the porous side of the "combi" PLLA film provoke a more intense inflammatory response than nonporous PLLA and the nonporous side of the "combi" PLLA film, respectively. In general, PTFE and e-PTFE films provoke an inflammatory response which is minimally more intense than the one provoked by the sham operation. Almost no ingrowth of tissue was observed in the porous e-PTFE films. In contrast, there was abundant tissue ingrowth in and an inflammatory response against porous PLLA. It can be concluded that biodegradable PLLA films provoke a more intense inflammatory response than nondegradable PTFE films. Also, porosity enhances the inflammatory response. However, porosity enhances the inflammatory response only when the wettability of a biomaterial permits cellular ingrowth.