Technical NoteGeneration of porous microcellular 85/15 poly (dl-lactide-co-glycolide) foams for biomedical applications
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 Tg 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 Tg 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.
Section snippets
Material
The material used was 85/15 poly (dl-lactide-co-glycolide) acid or PLGA supplied by Birmingham Polymers Inc., Birmingham, AL 35211 (Lot # D96053). The material was received in the form of small white crystalline pellets with diameters ranging 3–5 mm, packaged under high purity nitrogen in polyethylene bags. Polyethylene bags were also heat-sealed and contained desiccant to absorb any moisture inside the bags. To prevent the hydrolysis of PLGA by moisture in the air, the pellets were stored in a
Sorption results
Fig. 2, Fig. 3 show the sorption results for CO2 into PLGA sheet at 25°C at 0.5, 3.0, and 5.0 MPa and at 35°C at 5 MPa, respectively. Because sorption times in a sheet are proportional to the thickness squared, and because the samples used for sorption experiments had different thicknesses, the sorption plots have been normalized for sample thickness. To normalize for thickness, the X-axis is plotted as the square root of the sorption time divided by the sample thickness. As expected, after a
Conclusion
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 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. Foams generated had relative densities ranging from 0.107 to 0.232. Foams showed evidence of
Acknowledgements
The authors gratefully acknowledge the financial support from NSF received via the UWEB Engineering Research Center to conduct this study. We thank John Kemnitzer and Betty Wong of Integra Life sciences of San Diego for providing the PLGA specimens and for many helpful discussions. Finally thanks are due to graduate student Ross Murray of Mechanical Engineering at University of Washington for his help in the laboratory.
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