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Summary: The advent of high‐throughput combinatorial synthesis techniques in drug discovery has stimulated efforts to apply these techniques to the discovery of biomaterials. To be of practical utility, combinatorial approaches to biomaterials design require (i) the availability of parallel synthesis techniques to generate libraries of polymers, (ii) efficient assays for the rapid characterization of biorelevant material properties, and (iii) computational methods to efficiently model different biological responses in the presence of polymers. Here we report the integration of these methodologies and illustrate the potential of this approach to accelerate the development of new biomaterials. The parallel synthesis of a library of 112 biodegradable polyarylates has been reported previously. This library was used to develop efficient screening techniques to determine biorelevant polymer properties (fibrinogen adsorption, gene expression in macrophages, growth of fetal rat lung fibroblasts (RLFs)). A Surrogate (semiempirical) Model was developed (i) to determine molecular‐scale polymer properties that correlate to various biological responses, and (ii) to predict fibrinogen adsorption and RLF growth on polymeric surfaces. For 38 out of 45 polymers, the model predicted the amount of fibrinogen adsorbed correctly within the error of the experimental measurements. The growth of rat lung fibroblasts was correctly predicted by the model for 41 out of 48 polymers. The correlation factor between the model's predicted values and the experimentally determined data was 0.54 ± 0.09 and 0.69 ± 0.12 for fibrinogen adsorption and RLF growth, respectively. The results presented here demonstrate the utility of combinatorial and computational approaches for the rational design of polymers for biomedical applications.Design of the library of polyarylates, which are copolymers of a diacid and a diphenol. Chemical diversity was created by variations in the structure of the diacid (marked as “Y”) and the pendent chain (marked as “R”).magnified imageDesign of the library of polyarylates, which are copolymers of a diacid and a diphenol. Chemical diversity was created by variations in the structure of the diacid (marked as “Y”) and the pendent chain (marked as “R”).

We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.