Generation of porous microcellular 85/15 poly (dl-lactide-co-glycolide) foams for biomedical applications

Abstract

Porous 85/15 poly (dl-lactide-co-glycolide) or PLGA foams were produced by the pressure quench method using supercritical CO₂ as the blowing agent. The rate of CO₂ uptake and CO₂ equilibrium concentration in PLGA at different processing conditions were studied by performing sorption experiments. The effects of saturation pressure and temperature on average cell size and relative density of the resulting foams were also studied. The time required to approach equilibrium exhibited a minimum with increasing saturation pressure. The diffusion coefficient and equilibrium concentration of CO₂ in PLGA increased with an increasing pressure in an approximately linear relationship. Porous PLGA foams were generated with relative densities ranging from 0.107 to 0.232. Foams showed evidence of interconnected cells with porosities as high as 89%. The pore size ranged from 30 to 100 μm.

Introduction

Porous biodegradable polymer matrices are widely used in biomedical applications such as tissue engineering and guided tissue regeneration. Porous polymer matrices are used for both in vitro cell seeding and in vivo cell transplantation in tissue engineering studies [1], [2], [3], [4]. The matrix provides a temporary support for cell growth and is also used to deliver growth factors to the growing cells. As the cells grow within the polymeric scaffold, they secrete their own support matrix and the polymer, which is no longer needed, degrades over time. In guided tissue regeneration a polymer scaffold is placed directly into the body to encourage cellular growth in vivo [5], [6], [7], [8]. In this type of biomedical application, the porous biodegradable polymer functions as a size selective membrane and promotes cell growth at specific sites (e.g. bone regeneration) in the body by allowing nutrients and wastes to permeate while preventing the migration of undesirable cells and tissues to the healing site. Because the polymer's chemical composition and foam morphology (pore size, shape, and interconnectivity) can affect cellular growth, an ideal polymeric foam for tissue engineering and guided tissue regeneration should be highly porous to allow cell seeding and cell growth into the matrix. Overtime, the polymer matrix should also degrade into chemically benign components, which are not harmful to the growing cells.

Poly (lactic-co-glycolic) acid or PLGA is one of the most commonly used biodegradable polymers for fabricating porous foams for biomedical applications. PLGA is a desirable polymer because it biodegrades into lactic and glycolic acid, relatively harmless to the growing cells, and its use in other in vivo applications such as resorbable sutures has been approved by the Food and Drug Administration [9]. Also, the degradation rate of PLGA can be controlled by varying the ratio of its co-monomers, lactic acid and glycolic acid [10]. The techniques reported for generating porous PLGA foams include solvent casting–particulate leaching, fiber weaving, and phase separation [11], [12], [13], [14]. Although, PLGA foams with porosities as high as 95% and cell sizes ranging from 20 to 500 μm have been reported, a big drawback to these techniques is that they utilize organic solvents in the fabrication process. Residues of organic solvents left in the polymer after processing may be harmful to the transplanted cells in biomedical studies and can inactivate many biologically active factors (e.g. growth factors). Therefore, a pressure quench method using supercritical CO₂ as the blowing agent was employed to fabricate PLGA foams in our investigation.

The pressure quench method was used to produce polymer foams because it does not involve the use of organic solvents, required by other techniques of fabricating polymers into foams e.g. solvent casting/particulate leaching and phase separation techniques. Fig. 1 shows a simplified schematic of the pressure quench method. This method has two steps. A thermoplastic sample is placed in a pressure vessel and saturated with an inert gas, typically CO₂ in the supercritical region. CO₂ is used because it is chemically inert and highly soluble in most polymers. Upon a prolonged exposure to supercritical CO₂ at high pressure, the polymer absorbs enough gas to lower its glass transition temperature below the processing temperature of the pressure vessel, resulting in a polymer/gas solution. The second step is to rapidly drop the pressure to ambient pressure. This rapid quench in pressure decreases the CO₂ solubility in polymer and causes bubble nucleation due to super-saturation. As the bubbles grow the gas concentration in the polymer drops until the effective T_g of the polymer is above the temperature in the pressure vessel. The rapid depressurization of the vessel also causes the temperature in the vessel to drop, possibly limiting cell growth.

Several different research groups have produced open cell foams for biomedical applications using the pressure quench method [15], [16], [17]. The materials used were PLA, PGA, and PLGA. These polymers typically have glass transition temperatures in the range of 40–50°C, and therefore supercritical pressures are not required to depress the T_g enough to use the pressure quench foaming method. These polymers are quickly degraded by heat and water, so it is desirable to use a foaming method that requires neither.