RESUMO
The purpose of this work was to develop a family of cross-linked poly(xylitol adipate salicylate)s with a wide range of tunable release properties for delivering pharmacologically active salicylic acid. The synthesis parameters and release conditions were varied to modulate polyester properties and to understand the mechanism of release. Varying release rates were obtained upon longer curing (35% in the noncured polymer to 10% in the cured polymer in 7 days). Differential salicylic acid loading led to the synthesis of polymers with variable cross-linking and the release could be tuned (100% release for the lowest loading to 30% in the highest loading). Controlled release was monitored by changing various factors, and the release profiles were dependent on the stoichiometric composition, pH, curing time, and presence of enzyme. The polymer released a combination of salicylic acid and disalicylic acid, and the released products were found to be nontoxic. Minimal hemolysis and platelet activation indicated good blood compatibility. These polymers qualify as "bioactive" and "resorbable" and can, therefore, find applications as immunomodulatory resorbable biomaterials with tunable release properties.
Assuntos
Materiais Biocompatíveis/química , Reagentes de Ligações Cruzadas/química , Preparações de Ação Retardada/química , Ceratolíticos/farmacologia , Poliésteres/química , Polímeros/química , Ácido Salicílico/farmacologia , Animais , Varredura Diferencial de Calorimetria , Sobrevivência Celular/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Camundongos , Células NIH 3T3 , Adesividade Plaquetária/efeitos dos fármacos , Coelhos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The objective of this work was to develop a versatile strategy for preparing biodegradable polymers with tunable properties for biomedical applications. A family of xylitol-based cross-linked polyesters was synthesized by melt condensation. The effect of systematic variation of chain length of the diacid, stoichiometric ratio, and postpolymerization curing time on the physicochemical properties was characterized. The degradation rate decreased as the chain length of the diacid increased. The polyesters synthesized by this approach possess a diverse spectrum of degradation (ranging from â¼4 to 100% degradation in 7 days), mechanical strength (from 0.5 to â¼15 MPa) and controlled release properties. The degradation was a first-order process and the rate constant of degradation decreased linearly as the hydrophobicity of the polyester increased. In controlled release studies, the order of diffusion increased with chain length and curing time. The polymers were found to be cytocompatible and are thus suitable for possible use as biodegradable polymers. This work demonstrates that this particular combinatorial approach to polymer synthesis can be used to prepare biomaterials with independently tunable properties.
Assuntos
Plásticos Biodegradáveis/química , Técnicas de Química Combinatória/métodos , Ácidos Dicarboxílicos/química , Poliésteres/química , Xilitol/química , Plásticos Biodegradáveis/metabolismo , Ácidos Dicarboxílicos/metabolismo , Células HeLa , Humanos , Poliésteres/metabolismo , Xilitol/metabolismoRESUMO
The goal of this work was to design a device for rapid screening of crosslinked thermoset polymers. This gradient curing platform is capable of yielding a library of polyesters with systematically varying mechanical and physicochemical properties and the resultant cellular response. A library of poly(xylitolsebacate) polyesters was prepared in this device by differential curing to yield a gradient polymer. The resultant polymer exhibits a gradient in the storage modulus (1 to 5â¯MPa), wettability (70°â¯<â¯water contact angleâ¯<â¯110°), degree of crosslinking, degradation rate (3-25% in 7â¯days), drug release and biological response (ability to support stem cell proliferation and differentiation) from one end of the polymer to the other. Primary human mesenchymal stem cells were cultured to assess the cellular response in vitro. Maximal stem cell proliferation and osteogenesis was observed on the highly crosslinked polyester segments that provide high stiffness, are hydrophobic and are slow degrading as compared to the lower cured counterparts. Under in vivo conditions, this material showed differential response across the gradient without displaying significant concerns for inflammation or infection. This gradient curing device is capable of ascertaining suitable curing conditions to obtain appropriate polymers for application specific requirements. This gradient platform was further used to identify optimal processing parameters to prepare three-dimensional tissue scaffolds such as electrospun fiber mats and porous foams. Thus, this versatile combinatorial platform is well suited for rapid screening of thermoset polymers for biomedical applications.
Assuntos
Tecnologia Biomédica/métodos , Técnicas de Química Combinatória , Polímeros/química , Temperatura , Adulto , Animais , Diferenciação Celular , Módulo de Elasticidade , Humanos , Implantes Experimentais , Masculino , Teste de Materiais , Células-Tronco Mesenquimais/citologia , Osteogênese , Poliésteres/química , Porosidade , Ratos Sprague-Dawley , Engenharia Tecidual , Alicerces Teciduais/químicaRESUMO
This work reports the synthesis of a novel, aspirin-loaded, linear poly (anhydride ester) and provides mechanistic insights into the release of aspirin from this polymer for anti-inflammatory activity. As compared to conventional drug delivery systems that rely on diffusion based release, incorporation of bioactives in the polymer backbone is challenging and high loading is difficult to achieve. In the present study, we exploit the pentafunctional sugar alcohol (xylitol) to provide sites for drug (aspirin) attachment at its non-terminal OH groups. The terminal OH groups are polymerized with a diacid anhydride. The hydrolysis of the anhydride and ester bonds under physiological conditions release aspirin from the matrix. The resulting poly(anhydride ester) has high drug loading (53%) and displays controlled release kinetics of aspirin. The polymer releases 8.5 % and 20%, of the loaded drug in one and four weeks, respectively and has a release rate constant of 0.0035h-0.61. The release rate is suitable for its use as an anti-inflammatory agent without being cytotoxic. The polymer exhibits good cytocompatibility and anti-inflammatory properties and may find applications as injectable or as an implantable bioactive material. The physical insights into the release mechanism can provide development of other drug loaded polymers.
Assuntos
Anidridos/química , Anti-Inflamatórios/administração & dosagem , Aspirina/administração & dosagem , Preparações de Ação Retardada , Ésteres/química , Portadores de Fármacos/química , PolímerosRESUMO
Unlike conventional polymeric drug delivery systems, where drugs are entrapped in polymers, this study focuses on the incorporation of the drug into the polymer backbone to achieve higher loading and sustained release. Crosslinked, biodegradable, xylitol based polyesters have been synthesized in this study. The bioactive drug moiety, p-aminosalicylic acid (PAS), was incorporated in xylitol based polyesters to impart its anti-mycobacterial activity. To understand the influence of the monomer chemistry on the incorporation of PAS and its subsequent release from the polymer, different diacids have been used. Controlled release profiles of the drug from these polyesters were studied under normal physiological conditions. The degradation of the polyesters varied from 48% to 76% and the release of PAS ranged from 54% to 65% of its initial loading in 7days. A new model was developed to explain the release kinetics of PAS from the polymer that accounted for the polymer degradation and drug concentration. The thermal, mechanical, drug release and cytocompatibility properties of the polymers indicate their suitability in biomedical applications. The released products from these polymers were observed to be pharmacologically active against Mycobacteria. The high drug loading and sustained release also ensured enhanced efficacy. These polymers form biocompatible, biodegradable polyesters where the sustained release of PAS may be tailored for potential treatment of mycobacterial infections. STATEMENT OF SIGNIFICANCE: In the present work, we report on novel polyesters with p-aminosalicylic acid (PAS) incorporated in the polymer backbone. The current work aims to achieve controlled release of PAS and ensures the delivered PAS is stable and pharmacologically active. The novelty of this work primarily involves the synthetic chemistry of polymerization and detailed analysis and efficacy of active PAS delivery. A new kinetic model has been developed to explain the PAS release profiles. These polymers are biodegradable, cytocompatible and anti-mycobacterial in nature.
Assuntos
Ácido Aminossalicílico , Antibacterianos , Plásticos Biodegradáveis , Infecções por Mycobacterium/tratamento farmacológico , Mycobacterium/crescimento & desenvolvimento , Poliésteres , Ácido Aminossalicílico/química , Ácido Aminossalicílico/farmacocinética , Ácido Aminossalicílico/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacocinética , Plásticos Biodegradáveis/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Camundongos , Infecções por Mycobacterium/metabolismo , Infecções por Mycobacterium/patologia , Células NIH 3T3 , Poliésteres/química , Poliésteres/farmacocinética , Poliésteres/farmacologiaRESUMO
Designing biomaterials for bone tissue regeneration that are also capable of eluting drugs is challenging. Poly(ester amide)s are known for their commendable mechanical properties, degradation, and cellular response. In this regard, development of new poly(ester amide)s becomes imperative to improve the quality of lives of people affected by bone disorders. In this framework, a family of novel soybean oil based biodegradable poly(ester amide)s was synthesized based on facile catalyst-free melt-condensation reaction. The structure of the polymers was confirmed by FTIR and (1)H -NMR, which indicated the formation of the ester and amide bonds along the polymer backbone. Thermal analysis revealed the amorphous nature of the polymers. Contact angle and swelling studies proved that the hydrophobic nature increased with increase in chain length of the diacids and decreased with increase in molar ratio of sebacic acid. Mechanical studies proved that Young's modulus decreased with decrease in chain lengths of the diacids and increase in molar ratio of sebacic acid. The in vitro hydrolytic degradation and dye release demonstrated that the degradation and release decreased with increase in chain lengths of the diacids and increased with increase in molar ratio of sebacic acid. The degradation followed first order kinetics and dye release followed Higuchi kinetics. In vitro cell studies showed no toxic effects of the polymers. Osteogenesis studies revealed that the polymers can be remarkably efficient because more than twice the amount of minerals were deposited on the polymer surfaces than on the tissue culture polystyrene surfaces. Thus, a family of novel poly(ester amide)s has been synthesized, characterized for controlled release and tissue engineering applications wherein the physical, degradation, and release kinetics can be tuned by varying the monomers and their molar ratios.