RESUMEN
Starting from L-tyrosine (Tyr) and its metabolites desaminotyrosine (Dat) and tyramine (Tym), four structurally related model dipeptides were prepared: Dat-Tym (neither N- or C-terminus present), Z-Tyr-Tym (N-terminus protected by benzyloxycarbonyl), Dat-Tyr-Hex (C-terminus protected by a hexyl ester group), and Z-Tyr-Tyr-Hex (both N- and C-termini present, protected by benzyloxycarbonyl and hexyl ester, respectively). The model dipeptides were used as monomers in the synthesis of polycarbonates. The polymerization reaction in the presence of either phosgene or triphosgene proceeded via the phenolic hydroxyl groups. Polymers with molecular weights of 105,000-400,000 da (by gel permeation chromatography, relative to polystyrene standards) were obtained. The physicomechanical properties (solubility, mechanical strength, glass transition and decomposition temperature, processibility) of the polymers were determined, and an attempt was made to correlate the polymer properties with the nature of the N- and C-terminus protecting groups. The presence of the urethane bond at the N-terminus protecting group was found to reduce solubility, ductility, and processibility, probably due to interchain hydrogen bonding. The presence of a C-terminus alkyl ester group increased solubility and processibility. Thus, the most promising candidate polymer for biomedical applications was obtained from Dat-Tyr-Hex, the monomer carrying a C-terminus protecting group only. Since very similar results had recently been obtained for a series of structurally related polyiminocarbonates, the structure property correlations seem to be generally valid.
Asunto(s)
Carbonatos/química , Polímeros , Tirosina/química , Estructura MolecularRESUMEN
The gradual shift from biostable prostheses to degradable, temporary implants represents one of the most significant trends in biomaterials research. In view of this trend, medical applications of degradable implant materials were reviewed with special emphasis on orthopedic polymeric implants. Among the polymeric implant materials derived from natural sources, collagen, various polysaccharides such as cellulose, and microbial polyesters have been intensively investigated. Among the synthetic, degradable polymers, aliphatic polyesters such as poly(glycolic acid), poly(lactic acid), poly(caprolactone) and polydioxanone, are most commonly investigated. Only recently, several new classes of polymers such as poly(ortho esters), polyanhydrides, and degradable polycarbonates have been introduced as potential implant materials. A particularly versatile group of new biomaterials with promising engineering properties are the "pseudo"-poly(amino acids), amino acid derived polymers in which conventional peptide bonds have been replaced by various chemical linkages.
Asunto(s)
Materiales Biocompatibles/uso terapéutico , Biotecnología/tendencias , Polímeros/uso terapéutico , Absorción , Biodegradación Ambiental , Humanos , Equipo Ortopédico , Prótesis e ImplantesRESUMEN
Compression-molded disks of two tyrosine-derived polymers [poly(desaminotyrosyl-tyrosine-hexyl ester carbonate) and poly(desaminotyrosyl-tyrosine hexyl ester iminocarbonate)], two polymers derived from Bisphenol A [poly(Bisphenol A iminocarbonate) and poly(Bisphenol A N-phenyliminocarbonate)], and two clinically used standard materials [poly(D,L-lactic acid) and high-density polyethylene] were implanted subcutaneously in the back of Sprague-Dawley rats. The tissue response elicited by these materials was evaluated histologically at 7, 30, and 120 days postimplantation, based on the total cell density (including fibroblasts, monocytes, giant cells, and macrophages) at the implantation site. The tissue response observed for the two tyrosine-derived polymers was mild, comparable to the two standard materials, medical-grade poly(L-lactic acid) and high density polyethylene. The two Bisphenol A-containing polymers elicited significantly more severe tissue responses. These results indicate that the use of derivatives of the natural amino acid L-tyrosine in the synthesis of degradable implant materials improved the tissue compatibility of these materials relative to chemically related polymers that contain Bisphenol A, an industrial diphenol. The tyrosine-derived polyiminocarbonate and polycarbonate are therefore promising candidates for a detailed evaluation of their biocompatibility, including long-term implantation studies in higher mammals.
Asunto(s)
Materiales Biocompatibles , Fenoles , Polímeros , Prótesis e Implantes , Animales , Biodegradación Ambiental , Estudios de Evaluación como Asunto , Reacción a Cuerpo Extraño , Fenoles/química , Polímeros/química , Ratas , Ratas Endogámicas , TirosinaRESUMEN
Structure-property relationships for the design of new polyiminocarbonates were established, based on the investigation of thermal stability and processibility, morphology, tensile strength, hydrolytic degradation and drug release profiles of 15 different polyiminocarbonates. The results indicated that some polyiminocarbonates were among the mechanically strongest, bioerodible polymers currently available. The iminocarbonate bond was highly unstable under physiological conditions, facilitating the design of rapidly degrading devices. The drug-release profiles of certain polyiminocarbonates exhibited lag periods, facilitating the design of pulsed-release or delayed-release devices. Possible limitations of the practical applicability of polyiminocarbonates as biomaterials were the low thermal stability of the iminocarbonate linkage and the complicated, two-phase degradation mechanism that led to the formation of slowly degrading residues of low molecular weight. To identify non-toxic diphenols as monomers for the synthesis of polyiminocarbonates, derivatives of tyrosine dipeptide were systematically explored. Using structure-property relationships as design guidelines, desaminotyrosyl-tyrosine hexyl ester was identified as a promising, tyrosine-derived diphenol. The corresponding poly(desaminotyrosyl-tyrosine hexyl ester iminocarbonate) formed amorphous, transparent films and was mouldable at about 70 degrees C. It had a tensile strength of 400 kg/cm2 and a tensile modulus of 16,300 kg/cm2. Under physiological conditions in vitro, a thin film made of high molecular weight poly(desaminotyrosyl-tyrosine hexyl ester iminocarbonate) degraded to low molecular weight oligomers within 5 d. The results indicated that polyiminocarbonates and in particular poly(desaminotyrosyl-tyrosine hexyl ester iminocarbonate) might be of interest in a variety of biomedical applications.