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The development of bioabsorbable hydrogels on the basis of polyester grafted poly(vinyl alcohol)

The present work describes the synthesis and characterization of amorphous and covalently crosslinked polymer systems based on poly(vinyl alcohol) and polyesters. With regard to medical applications, for the synthesized materials only components are used that are already established as biomaterials. The hydrogels prepared are biocompatible and hydrolytically degradable. The chemical composition and the crosslinking density of the polymer networks can be controlled by variation of the monomer/initiator ratio and by the amount of polyester grafts relative to the amount of the poly(vinyl alcohol) backbone. The macroscopic properties, primarily the degradation rate, mass loss, water uptake, mechanical properties of the hydrogels can be tailored by variation of the polyester composition and the network structure. Covalently crossliked polymer networks were synthesized via a three step reaction. Short polyester chains were initially prepared by ring opening polymerization of lactide and glycolide. Hydroxyethyl methacrylate was used as an initiator which enables the simultaneous introduction of double bonds into the system. In the second step the hydroxy end groups of the polyesters were transferred into carboxylic groups by reaction with succinic anhydride. The third step was the grafting of the polyester chains onto the poly(vinyl alcohol) chain. Finally, crosslinking was accomplished through reaction of the double bonds using a free radical initiator. The chemical composition and structure of the networks was controlled by varying the stoichiometric ratio of components in the reaction mixture. The chemical composition of the networks was investigated by means of IR and NMR spectroscopy, whereas NMR was used to pursue each step of synthesis. It revealed agreement between the theoretical and experimental values concerning the length and composition of polyester grafts, which indicated a good control over the synthesis. Polyesters with 4, 8, 9, 16 and 18, repeating units were obtained. The ratio of lactide to glycolide in the polyester chains was varied between the molar ratios 100:0 ; 75:25 ; 50:50 and experimental values confirmed that. The theoretical degree of grafting on the backbone was 10%, 15% and 20%. Generally, the experimentally determined degree of grafting revealed lower values. The major deviation displayed the grafted copolymer Q (experimental degree of grafting DGexp of 11% compared to the theoretical DGthe of 20%), and the best match showed copolymer P (DGexp of 13% compared to the DGthe of 15%). The IR spectroscopy gave insight into the composition of the networks by means of the characteristic bands at 3300 cm-1 for OH, 1750 cm-1 for C=O, as well as in the fingerprint region.Thermogravimetry revealed the onset of a small mass loss in the temperature range between 265 oC and 285 oC. The major mass loss occurs in the temperature range between 301 oC and 318 oC. Networks with longer polyester chains showed the onset of the first small loss (T10%) at higher temperature when compared to networks with shorter grafts. The same networks display the major mass loss at lower temperature than the networks with shorter grafts. The glycolide amount showed only small influence on the thermal decomposition. DSC measurements showed only one characteristic transition temperature, the glass transition temperature Tg. All networks showed a glass transition temperature in the range between 51 oC and 71 oC. Networks with longer polyester chains showed a lower glass transition temperature. Moreover, networks with a glycolide content of 50 mol% display significantly lower glass transition temperature Tg relative to networks that contain pure polylactide grafts, especially networks with longer polyester grafts. The surface properties of hydrogel films were investigated using the captive-bubble method. Statistic contact angles were found to be between 28 degrees and 45 degrees, which demonstrates the possibility of obtaining materials of diverse hydrophilicity by varying the comonomers ratio. The mechanical properties of hydrogels clearly depend on the composition and structure. Mechanical testing showed Young’ s modulus E to have values between 0.01 and 103 MPa, however, the values of most of the hydrogels were below 4 MPa. Hydrogels with higher polyester content and higher crosslinking density have higher E moduli. Thus, variation of the length of polyester grafts and their number enables preparation of materials in a large range of mechanical properties. Biocompatibility was tested on hydrogel type P as an example with the assistance of primary human dermal fibroblasts (hF) cells. After four days of incubation the cells displayed good adhesion and viability, confirming the good biocompatibility of the material. Hydrolytical degradation experiments were carried out in an aqueous phosphate buffer solution at pH 7.4 and room temperature. The mass loss that accompanies the degradation of hydrogels was determined gravimetrically. The mass loss is influenced by the composition of the hydrogel. More hydrophilic hydrogels, as a result of shorter polyester grafts or a fewer number of grafts, show a faster mass loss. Glycolide in the polyester chains additionally contributes to a faster mass loss due to its more hydrophilic nature. Thus, the hydrogel with the longest polylactide grafts showed 10% of mass loss after 110 days of hydrolytical degradation while hydrogels with the shortest polyester chains, containing lactide and glycolide, showed 10% of mass loss within the first week of degradation. A hydrogel that was degraded both at room temperature and at 37 oC exhibits a continuous mass loss, but a faster one in the sample degraded at 37 oC, particularly after 14 days. The sample degraded at 37 oC has 80% of residual mass after 14 days while the sample degraded at RT still has 80% residual mass after 35 days. All hydrogels exhibit an increase in swelling in the course of hydrolytical degradation although at different rate. Within the first eight weeks of degradation, the hydrogels display a weight related degree of swelling, S, in the range from less than 2% up to 30%. Hydrogels that were submitted to degradation for a longer period of time, showed a degree of swelling of up to 190%. The swelling behavior of the hydrogels depends strongly on composition and structure. Hydrogels with shorter polyester grafts show more rapid and more intensive swelling due to their more hydrophilic nature. Thus, samples with shorter polyester grafts initially display a several times higher degree of swelling and moreover the swelling increases at a higher rate. The influence of glycolide present in the polyester chains depends on the number of repeating units: it is more significant in hydrogels with shorter polyester grafts. The degree of substitution on the backbone has a strong influence on the swelling behavior. Therefore, hydrogels with a DGthe of 10% display an increase of swelling immediately which continues to increase at high rate, while hydrogels with a DGthe of 20% show a linear, small swelling at first which increases significantly after 60 days of degradation. The dependence of swelling on the degree of grafting is combined with the influence of the composition of the polyester chains. Thus glycolide present in the polyester grafts causes greater swelling than hydrogels with pure lactide grafts, this influence being intensified with time. The morphology change of hydrogels during hydrolytical degradation was examined by means of scanning electron microscopy. This method enables the surface and the cross section of the sample as a consequence of different mechanisms of degradation to be followed. It is difficult to follow separately each single influence: structure, composition and degree of grafting, while their influences combine. Thus, hydrogels with long polyester chains (e.g. F and I with DGthe of 20% or A and O with DGthe of 15%), ) show a conserved shape after eight weeks of degradation accompanied by a significant reduction of sample thickness in A and O. On the other hand, hydrogels with short polyester chains, during a degradation period of similar duration, exhibit a significant change in the sample shape, where the nature of the change depends on the degradation mechanism. Thus, some samples display a significant decrease of thickness characteristic of a surface erosion mechanisms (e.g. E, DGthe of 10%), ) while others display a highly deteriorated cross section due to a bulk degradation mechanism (e.g. D, DGthe of 15%) or large cracks were observed along the cross section (e.g. C, DGthe of 20%). Hydrogels with short polyester chains, containing both lactide and glycolide (N and Q), after only four weeks of degradation show highly deteriorated samples and both mechanisms of degradation: erosion and bulk. The decrease of the E modulus as a result of hydrolytical degradation is immanent to all hydrogels. Hydrogels with the shortest grafts (4 repeating units) exhibit an E modulus below 1 MPa after eight weeks of degradation. Some of these samples became so swollen and weak that it was not possible to measure their tensile strength after eight weeks of degradation (N and R). Hydrogels with medium length of polyester grafts (8 or 9 repeating units) have a modulus of 1.7-3 MPa while hydrogels with the longest polyester grafts have values between 15-175 MPa during the same course of degradation time. The contact angles of degraded hydrogels were measured. After eight weeks of degradation all hydrogels showed about the same value of 20 degrees. A difference was seen only when the time is considered within this value is reached. Therefore, hydrogels which were more hydrophobic initially due to higher polyester content need a longer period of time to become so hydrophilic as to have a contact angle around 20°. Hydrogels with the longest polyester grafts need up to eight weeks, while hydrogels with the shortest polyester grafts and resulting higher hydrophilicity show a contact angle of 20 degrees after only the first week of degradation. The investigation of the degradation process by means of IR spectroscopy was possible through the observation of characteristic IR bands. The intensity ratio of the bands OH/C-H and OH/C=O which increases indicates the decrease of the polyester content. The existence and relative intensity of characteristic bands in the fingerprint region give evidence for different compositions of the networks as well as for the change that occurs in networks during the degradation. Thermogravimetry was performed on several networks degraded for eight weeks or longer. After degradation, the networks with longer polyester chains show an earlier mass loss onset. All networks show an increase of the glass transition temperature with degradation time. The glass transition temperatures of samples which contain glycolide are lower than that of networks containing only lactide repeating units and stay lower during the whole period of degradation, but they exhibit a larger increase of Tg during degradation. Thus, network B after eight weeks of degradation shows an increase of 3 oC, while network P, during the same time shows an increase of 9 oC. All the analyses and tests performed confirm the possibility of tailoring the properties, predisposition and tendency of the materials to hydrolyze depending on their composition and structure.

polyester; poly(vinyl alcohol); biomaterials; hydrogels; graft copolymerization; degradation

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