Originally published March 1996
ROBSON F. STOREY AND JEFFREY S. WIGGINS
Several semicrystalline polyesters exhibiting blood compatibility are widely used as resorbable material for implantable devices and surgical articles (see Figure 1).13 These polyesters biodegrade hydrolytically, and the resulting biologically active or nontoxic carboxylic acids are processed through normal metabolic pathways. Cross-linked analogs of semicrystalline polyesters can be used as matrix resins in bioabsorbable composites that possess physical properties uniquely suited to rigid fixation applications such as bone plates. (Figures not yet available on-line.)
For example, replacing high-modulus metal bone plates with a material whose modulus more closely resembles that of bone could promote healing of fractures.4 Current rigid fixation devices shield the fracture site and surrounding bone area; loads are transferred through the plate, often leading to stress-protection osteopenia. The shielded bone resorbs, becomes porous, and remains susceptible to refracture after surgical removal of the metal bone plate. Instead of acting as a shield, a plate made from absorbable polymers would gradually transfer loads into the fracture area as it degrades, enhancing bone regeneration. In addition, hydroxyapatite or other minerals and nutrients can be incorporated into the composite and, once released, can often stimulate bone growth. Of course, totally resorbable composites eliminate the need for surgical removal.
The degradation behavior of cross-linked, amorphous, absorbable matrices is also advantageous for rigid fixation applications. Semicrystalline polymers display heterogeneous degradation due to distinct amorphous and crystalline regions.5 The differing rates of degradation yield a product that decreases in physical strength at a faster rate than it decreases in mass. Heterogeneous degradation produces a composite matrix that will prematurely lose its physical strength, whereas degradation of wholly amorphous, cross-linked polyesters should show a more linear decrease in physical strength with loss of mass, thus retaining properties over time.
Monomers that typically yield semicrystalline polymers can be used to produce cross-linkable, amorphous prepolymers through careful selection of comonomer composition and control over molecular weight. Totally absorbable composites may be fabricated by using biodegradable fibers for directional reinforcement in a degradable matrix. The matrix resin used in the present work, poly(D,L-lactide-co-glycolic acid) fumarate, was chosen for its design flexibility and the manner in which it facilitates composite fabrication via free-radical curing techniques. Polyglycolic acid surgical mesh, a knitted fabric with high tensile strength, provided the directional reinforcement for the composite. The physical properties exhibited by this combination of materials justify continued research into the development of totally absorbable composites for surgical applications.
Matrix Resin Synthesis. Unsaturated poly(D,L-lactide-co-glycolic acid) fumarate oligomer was synthesized as reported previously.6 To a 500-ml, three-necked reaction flask equipped with a mechanical stirrer and West condenser were added 44.05 g (0.50 mole) 2-butene-1,4-diol as initiator; 144.02 g (1.0 mole) racemic D,L-lactide; 76.05 g (1.0 mole) glycolic acid; and 1.02 g stannous octoate. Under nitrogen purge, the reaction temperature was slowly raised to 120°C and held for 24 hours, at which time a 2-torr vacuum was applied, maintained for 8 hours, and slowly increased to 0.1 torr over an additional 8 hours. The hydroxy-terminated oligomer that resulted was reacted under nitrogen purge with 116.12 g (1.0 mole) fumaric acid at 160°C for 40 hours, and at 180°C for an additional 10 hours. At this time the reaction was continued for 48 hours at 165°C, as the vacuum was slowly increased from 10 to 4 torr. The resulting oligomer was dissolved in chloroform, vacuum filtered, precipitated into cold methanol, stored under methanol at -5°C for 16 hours, collected by filtration, and vacuum dried for 72 hours at 60°C.
Curing Techniques. Oligomer (175 g) was dissolved in 35 g tetrahydrofuran (THF) to make a stock resin that was prepromoted with 1.05 g cobalt naphthenate and stored under dry nitrogen until use. For the curing studies, 2- butanone peroxide was used in varying concentrations as a free-radical initiator. This curing system was chosen because of its known efficiency; its biological activity has not yet been addressed.
Samples were cured by adding approximately 2 g of prepromoted resin to an aluminum dish; 2-butanone peroxide was subsequently added in varying amounts from 1 to 10 wt% relative to polymer, and cured for 48 hours at 60°C. All cured samples were then stored in a desiccator until evaluation by differential scanning calorimetry (DSC).
Composite Fabrication. Polyglycolic acid surgical mesh was cut into 1.5 x 3-in. samples and saturated with initiated polyester prepolymer. In some cases, the mesh--prior to saturation with resin--was immersed for 2 hours in a mixture of 3 g of bis(dimethylamino)-methylvinylsilane diluted in 100 g of absolute ethanol, and then dried overnight at room temperature. Laminated plates consisting of four layers of mesh were fabricated using standard vacuum bagging techniques. These plates were cured for 5 hours at room temperature, removed from the vacuum bag, and cured for an additional 40 hours at 60°C. The reinforcement-to-matrix weight ratio for all composites was approximately 40:60, reflecting minimum air voids.
Characterization. Tensile strengths for the composite samples were measured on an Instron Model-1130 universal test machine using a 500-kg load cell at 40% range, with chart and crosshead speeds of 5 cm/min. Fourier transform infrared spectroscopy (FTIR) was performed on a Perkin Elmer Model 1600 spectrophotometer. The molecular weight of the matrix prepolymer was obtained using a Waters Associates gel permeation chromatograph (GPC) equipped with a Rheodyne injector, a Model 6000A solvent-delivery module, four Ultrastyragel columns with nominal pore sizes of 100, 500, 103, and 104 Å connected in series, and a 410 differential refractometer.
THF--freshly distilled from calcium hydride--served as the mobile phase and was delivered at a flow rate of 1.0 ml/min. Adalab Chromatochart software with GPC enhancement was employed to determine molecular weight as compared with polystyrene standards (Polysciences Corp.). Scanning electron microscopy (SEM) was performed with an Electro Scan Model E-20 and DSC was carried out using a Mettler Model 30 calorimeter with a heating rate of 10°C/min. The glass-transition temperature (Tg) was taken as the midpoint of a straight line drawn between the inflection points of the peak's onset and end point.
Chain extension reactions by esterification of the hydroxy-terminated oligomers with the Kreb's cycle intermediate fumaric acid (see Figure 2) have proven effective for incorporating unsaturated moieties into the backbone of a bioabsorbable polyester, and for providing control over the polymer's final molecular weight. The presence of hydroxyl end groups after the initial synthetic step has been confirmed by FTIR. Based on initial reaction conditions, the original hydroxy-terminated oligomer has a theoretical molecular weight of 546 g/mole--below the range of the polymer standards used in our GPC calibration yet within the range of molecular sizes separable by our particular combination of gel columns. In fact, based on the sharp individual peaks in Figure 3a, the product is most likely a series of dimers, trimers, tetramers, etc. Reaction of this hydroxy-terminated oligomer with excess fumaric acid gave an acid-terminated polymer with a final molecular weight of approximately 9200 g/mole (see Figure 3b).
Free-radical curing of unsaturated polymer with 2- butanone peroxide yielded matrices for which the glass-transition temperatures increased with increasing peroxide concentrations (see Table I). The breadth of the polymer's glass transition from onset to end point also increased with increasing peroxide concentration.
Curing was monitored using FTIR by observing a decrease in the absorbance due to the olefinic groups. Although the unsaturations in the resin are all 1,2-disubstituted, and thus low kinetic chain lengths are expected, sufficient network properties may still be obtained with high conversion. The nearly complete reaction of double bonds was confirmed by observing the essentially quantitative disappearance, after complete curing, of the C=C peak in the FTIR spectrum of the matrix polymer. Cross-linking was further confirmed by insolubility of the matrix in THF after curing.
Completely absorbable composites were fabricated by reinforcing the resin with polyglycolic acid surgical mesh. The authors have demonstrated that increasing interfacial adhesion between fiber and matrix is necessary for maximizing the properties of the bioabsorbable composite.
Bis-(dimethylamino)-methylvinylsilane was evaluated as a coupling agent for reducing the interfacial surface-energy difference between fiber and matrix. Dimethylamino groups of the coupling agent are expected to form a strong dipole-dipole interaction with carbonyl groups of the polyglycolic acid mesh in the initial pretreatment of the fiber. The vinyl group of the silane will then cross-link--via free radicals--into the matrix resin, forming a covalent bond within the network. Improved wetting of the fiber surface with the matrix resin should yield an increased physical strength for the composite. An approximately 10% overall increase in the tensile strength--from 84 to 92 MPa--was observed following pretreatment of the surgical mesh fibers with the selected coupling agent (see Figure 4). SEM revealed a visible gap between the fiber and matrix and clear regions of fiber pullout in untreated samples. In the composites formed with silane-treated mesh, SEM indicated improved fiber wetting through more complete encapsulation of the fiber with matrix resin and less occurrence of fiber pullout.
DSC thermograms for the composite show a glass transition for the amorphous, cross-linked matrix at 55°C and a crystalline melt transition for the fiber at 225°C (see Figure 5). Thus, the composite is pliable at temperatures above 55°C but maintains rigidity at biological temperature. This means that the composite can be custom formed for use in specific surgical devices through the application of heat--a feature that could prove quite useful.
Degradation of the composite was studied in vitro by immersion in a buffered saline at 37°C. Figure 6 shows a plot of mean mass change versus time: the composites were observed to degrade rapidly, displaying an approximately 26% loss in mass in 43 days, by which time fragmentation of the samples had begun. The initial weight gain during the first 7 days is attributed to uptake of immersion fluid.
Poly(D,L-lactide-co-glycolic acid) fumarate, when cured by free-radical initiation, demonstrates properties suitable for use as a matrix resin in totally absorbable composites. The incorporation of polyglycolic acid surgical mesh provides directional strength for the material. A critical design consideration for resorbable composites is the use of a silane coupling agent to reduce the interfacial energy between the fiber and matrix. Thermal evaluation shows that the composite can be easily contoured at a temperature slightly above biological temperature. Because of their unique properties, completely absorbable composites warrant further investigation as candidates for biomaterials.
This paper is based on research supported in part by the National Science Foundation (grant #RII-8902064), the State of Mississippi, and the University of Southern Mississippi. The authors gratefully acknowledge Robert Pope of the University of Southern Mississippi for providing the SEM analysis and T. J. Nash of Davis and Geck for generously supplying polyglucolic acid surgical mesh.
1. Storey RF, Wiggins JS, Mauritz KA, et al., "Synthesis and Fabrication of Completely Absorbable Composites for Biomaterials," ACS Div Polym, Chem Polym Preprs, 30(2):492493, 1990.
2. Vacanti JP, Morse MA, Saltzman WM, et al., J Ped Surg, 23(1):39, 1988.
3. Gogolewski S, and Pennings AJ, "Biodegradable Materials of Polyactides, Porous Biomedical Materials Based on Mixtures of Polyactides and Polyurethanes," Makromol Chem, Rapid Commun, 3:839845, 1990.
4. Daniels AU, Chang MKO, Andriano KP, et al., J Appl Biomat, 1(1):5778, 1990.
5. Pitt CG, Hendren RW, Schindler A, et al., "The Enzymatic Surface Erosion of Aliphatic Polyesters," J Controlled Rel, 1:314, 1984.
6. Han YK, Edelman PG, and Huang SJ, "Synthesis and Characterization of Crosslinked Polymers for Biomedical Composites," J Macromol Sci-Chem, A25(57):847869, 1988.
Robson F. Storey, PhD, is professor of polymer science at the University of Southern Mississippi (Hattiesburg), where he has taught since 1983. His research interests include living polymerizations, block and star-branched polymers, ionomers, reactive oligomers, bioabsorbable polymers, and polymer coatings. Jeffrey S. Wiggins, PhD, is manager of new product development for thermoplastic polyurethanes at Bayer Corp. (Pittsburgh).