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The loading of biocompatible matrices with growth factors offers the opportunity to induce specific cell behavior. The attachment of heparan sulfate (HS) to these matrices may promote the binding, modulation, and sustained release of signaling molecules. In this study, basic fibroblast growth factor (bFGF) was bound to crosslinked collagenous matrices with and without covalently attached HS. The tissue response to these matrices was evaluated after subcutaneous implantation in rats. Attachment of HS to collagen matrices increased the bFGF binding capacity threefold and resulted in a more gradual and sustained release of the growth factor in vitro. bFGF primarily was located at the matrix margins. In vivo, the presence of HS without bFGF resulted in a transient vascularization, predominantly at the matrix periphery. Angiogenesis was further enhanced by combining HS with bFGF. In contrast to collagen-HS and collagen/bFGF matrices, collagen-HS/bFGF matrices remained highly vascularized throughout the matrix during the 10-week implantation period. In addition, these latter matrices revealed an intense and prolonged tissue response and considerably promoted the generation of new tissue. Foreign body reactions were only observed sporadically at this time interval. It is concluded that bFGF loading of collagen-HS matrices has additional value for those tissue-engineering applications that require enhanced angiogenesis and generation of new tissue.

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Passive-tension generation of diaphragm single fibers is reduced in patients with COPD. Our results suggest that alternative splicing of the titin gene, resulting in increased length of the elastic segment rich in proline, glutamate, valine, and lysine, is involved. Interestingly, these changes occur already in patients with mild to moderate COPD.

Several cationic amphiphilic compounds are known to induce phospholipidosis, a condition primarily characterized by excessive accumulation of phospholipids in different cell types, giving the affected cells a finely foamy appearance. Excessive storage of lamellar membranous intralysosomal inclusion bodies is the hallmark for phospholipidosis on the electron microscopic level. In case of alveolar phospholipidosis, foamy macrophages accumulate within the alveolar spaces of the lung. Based on such findings in a one-year toxicity study with gepirone in rats, we studied the molecular properties of this compound and compounds suspected of being phospholipidosis inducers by means of physicochemical calculations. Physicochemical molecular calculations of molecular weight, ClogP (partition coefficient octanol/water), logD at pH 7.4, and pKa were performed, for the cationic amphiphilic compounds chlorpromazine, amiodarone, imipramine, propranolol and fluoxetine, and for the structurally related compounds 1-phenylpiperazine (1-PHP), gepirone (and its major metabolites, 3-OH-gepirone and 1-pyrimidinylpiperazine [1-PP]), and buspirone. ClogP and calculated pKa cluster differently for the amphiphilic drugs compared to the chemical series of piperazines. In line with this analysis, lamellar inclusion bodies were found in an in vitro validation experiment in the human monoblastoid cell line U-937, incubated for 96 h at 10 microg/mL with cationic amphiphilic drugs (amiodarone, imipramine, or propranolol). No such lamellar inclusion bodies were seen for any of the compounds from the chemical series of piperazines including gepirone and its metabolites. The data presented support the use of simple physicochemical calculations of ClogP and pKa to discriminate rapidly between compounds suspected of being phospholipidosis inducers. Finally, the discriminative power of these physicochemical ClogP and pKa calculations to predict phospholipidosis-inducing potential was further validated by extension of the set of compounds.