No abstract

The objective of this study was to develop and evaluate a hydrogel vehicle for sustained release of growth factors for wound healing applications. Hydrogels were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI permeability was altered by changing the solids content of the gel and by adding hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase in model drug release was achieved by incorporating hydrophilic PVA fillers into the hydrogel. As filler molecular weight increased, TI flux increased. The mechanism for this is most likely an alteration in protein/gel interactions and transient variations in water content. The percent protein released was also altered by varying protein loading concentration. Release studies conducted using growth factor in vehicles with hydrophilic filler showed sustained release of platelet-derived growth factor (PDGF-beta,beta) for up to 3 days compared with less than 24 hours in the controls. In vitro bioactivity was demonstrated by doubling of normal human dermal fibroblast numbers when exposed to growth factor-loaded vehicle compared to control. The release vehicle developed in this study uses a rapid and simple fabrication method, and protein release can be tailored by modifying solid content, incorporating biocompatible hydrophilic fillers, and varying protein loading concentration.

Numerous studies conclude that the selective adsorption of plasma proteins on materials contacting blood or tissue affects all subsequent interactions related to the biocompatibility of artificial surfaces. However, there are only a few studies available, which clearly demonstrate that there is a correlation between surface chemistry and selective protein adsorption. Detailed knowledge of such correlations would facilitate the design of biocompatible materials. In this study, a rapid, fluorescence-based, screening technique using a 384-well format for polymer-protein interactions was developed. The screening assay was used to measure the adsorption of human fibrinogen on 46 test polymers (44 polyarylates selected from a combinatorial library of tyrosine-derived polyarylates, and two lactide-based polymers). In this library of polyarylates, structural changes are generated by variations in either the polymer backbone or the polymer pendent chain. Although no overall trend between polymer hydrophobicity and fibrinogen adsorption could be identified using the entire set of test polymers (R(2) = 0.43), fibrinogen adsorption was clearly correlated with variations in the pendent chain structure. Thus, when the test polymers were grouped by backbone composition, increased hydrophobicity of the pendent chain was significantly correlated with reduced fibrinogen adsorption. The following R(2) coefficients within the polymer backbone groups were determined: 0.87 (diglycolates); 0.98 (glutarates); 0.73 (adipates); 0.87 (suberates); 0.67 (3-methyl-adipates). Our results demonstrate that it is possible to screen for protein-material interactions in a cost-effective fashion using a miniaturized immunofluorescence technique. Further, we demonstrate that small changes in chemical composition can significantly influence the adsorption of human fibrinogen on polymer surfaces. The lactide-based polymers were among those polymers exhibiting the highest tendency to adsorb fibrinogen. This information may be useful when polymers have to be selected for specific biomaterial applications.

We are developing novel resorbable fiber-based scaffolds for reconstruction of the anterior cruciate ligament (ACL). For the first time, we report fabrication of fibers from poly(DTE carbonate) polymer. Poly(L-lactic acid) fibers were also fabricated for comparison purposes. The study was performed in three phases. In phase I, first-generation fibers were found to promote tissue ingrowth in a subcutaneous model. In phase II, second-generation fibers were fabricated from poly(DTE carbonate) and poly(L-lactic acid), with diameters of 79 and 72 microm, ultimate tensile strengths of 230 and 299 MPa, moduli of 3.1 and 4.9 GPa, and molecular weights of 65000 and 170000, respectively. These fibers were evaluated on the basis of molecular weight retention, strength retention, and cytocompatibility. After 30 weeks of incubation in phosphate-buffered saline, poly(DTE carbonate) and poly(L-lactic acid) fibers had 87 and 7% strength retention, respectively. Similar trends were observed for molecular weight loss. Fibroblasts attached and proliferated equally well on both scaffold types in vitro. Finally, in phase III, a prototype ACL reconstruction device was fabricated from poly(DTE carbonate) fibers with strength values comparable to those of the normal ACL (57 MPa). Collectively, these data suggest that poly(DTE carbonate) fibers are potentially useful for development of resorbable scaffolds for ACL reconstruction.

We compared mechanical properties, degradation rates, and cellular compatibilities of two synthetic polymer fibers potentially useful as ACL reconstruction scaffolds: poly(desaminotyrosyl-tyrosine dodecyl dodecanedioate)(12,10), p(DTD DD) and poly(L-lactic acid), PLLA. The yield stress of ethylene oxide (ETO) sterilized wet fibers was 150 ± 22 MPa and 87 ± 12 MPa for p(DTD DD) and PLLA, respectively, with moduli of 1.7 ± 0.1 MPa and 4.4 ± 0.43 MPa. Strength and molecular weight retention were determined after incubation under physiological conditions at varying times. After 64 weeks strength decreased to 20 and 37% of the initial sterile fiber values and MW decreased to 41% and 36% of the initial values for p(DTD DD) and PLLA, respectively. ETO sterilization had no significant effect on mechanical properties. Differences in mechanical behavior may be due to the semicrystalline nature of PLLA and the small degree of crystallinity induced by mesogenic ordering in p(DTD DD) suggested by DSC analysis. Fibroblast growth was similar on 50-fiber scaffolds of both polymers through 16 days in vitro. These data suggest that p(DTD DD) fibers, with higher strength, lower stiffness, favorable degradation rate and cellular compatibility, may be a superior alternative to PLLA fibers for development of ACL reconstruction scaffolds.