Heparin-mimetic polyurethane hydrogels with anticoagulant, tunable mechanical property and controllable drug releasing behavior

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Abstract

In the present study, novel heparin-mimetic polyurethane hydrogels were prepared by introducing chemical crosslinked sulfated konjac glucomannan (SKGM). Scanning electron microscopy (SEM) results indicated that the introduction of SKGM and the increase of the molecular weight of diol segments could enlarge the pore sizes of the hydrogels. The swelling behavior corresponded with the SEM results, and the hydrogels could absorb more water after the modification. The modification also led to an improvement in the mechanical property. Meanwhile, the SKGM and the modified polyurethane hydrogels showed excellent hemocompatibility. The thromboplastin time of SKGM could reach up to 182.9 s. Gentamycin sulfate (GS) was used as a model drug to be loaded into the hydrogels, and the loading amount was increased ca. 50% after the introduction of SKGM, thus resulting in high bactericidal efficiency. The results indicated that the introduction of SKGM and the alternation in the diol’s molecular weight bestowed polyurethane hydrogels with promising properties of integrated blood-compatibility, mechanical properties and drug loading-releasing behavior. Therefore, the heparin-mimetic multifunctional polyurethane hydrogels have great potential to be used in biomedical applications.

Introduction

Polyurethanes (PUs) are materials composed of alternated hard and soft blocks, the microphase separation of which may enhance their thermal and mechanical properties [1]. The hard segment is mainly comprised of diisocyanates and chain extenders while the soft one is generally comprised of polyester, polyether, or polycarbonate diol [2]. The synthesis routine of PU materials is flexible and the properties of PU can be well-controlled under the adjustment of the structure of monomers and other reactants. Because of their versatile chemistry, millions of materials have been fabricated based on PUs [3]. In modern life, PUs have demonstrated their brilliance in biomedical devices [4], due to their mechanical properties and biocompatibility [5]. Recently, they were studied as materials for the immobilization of cells [6], vascular grafts [7] and etc [8]. When constructing polyurethanes, poly(ethylene glycol) (PEG) is the commonly used diol because it can increase hydrophilicity, reduce protein adsorption [9] and prevent the adhesion of endothelial cell (EC) [10]. Meanwhile, PEGs with different molecular weights can provide the synthesized PUs with viable properties.

Urethane polymers have been widely studied as foams [11], coatings [12], adhesives [13], elastomers [14], fibers [15] and etc. Among them, PU hydrogels are in vast applications in biomedical fields [16], [17]. Typically, they can be made into soft contact lens [18], soft tissues substitute [19] and wound dressing [20]. Compared to other hydrogels, the PU hydrogels have remarkable strength and elasticity [21], pore capacity [22] and biodegradability [23]. In addition, these properties can be substantially enhanced or even tunable after modification [24]. Meanwhile, the difference in the design of polyurethane segments can bring new properties like the responses to different stimuli [25], [26] and bacteria repulsion [27]. However, few researches have reported the modification of polyurethane hydrogels in their functions as blood-contacting materials.

Blood-contacting materials are one kind of biomedical materials widely used in clinical field, which require good hemocompatibility, including anticoagulant property [28]. Heparin, a commonly used injectable anticoagulant reagent in clinical practice, plays the anticoagulant role by interacting with the factors XIa, IXa, Xa and IIa (thrombin), especially Xa in the blood clotting cascade. These factors may bind to the heparin polymer at a site proximal to the pentasaccharde because of the strong electrostatic interactions [29]. Recently, the hydrogels based on heparin or modified heparin have been increasingly investigated. However, heparin is a relatively high-cost bio-macromolecule, which may restrict the scalable production of heparinized hydrogels. Konjac glucomannan (KGM) is a kind of polysaccharides extracted from natural plants [30], [31]. KGM and its derivatives are highly biocompatible [32]. They possess a similar glycan structure as heparin. Compared with heparin, whose main source is animal, the polysaccharide from plants will largely reduce the cost if it could be modified to mimic the structure of heparin. Researchers have taken efforts to introduce sulfate groups into KGM [33], [34], [35]. After sulfation, the anticoagulant property of KGM was improved and it could bring anti-HIV property to the molecules, and the effect was almost as high as that of the AIDS drug [33].

In this study, a heparin-mimetic compound was synthesized by introducing sodium sulfate (-OSO3Na) into KGM using sulfamic acid. The sulfated konjac glucommannan (SKGM) was introduced into polyurethane hydrogels with different diol segments. The anticoagulant property, swelling ability, mechanical performance and drug loading behavior were investigated. Gentamycin sulfate (GS), an antimicrobial drug, was chosen as the model drug for the drug loading and releasing experiments. The antibacterial activities of the drug-loaded polyurethane hydrogels were also determined.

Section snippets

Materials

N, N-dimethylformamide (DMF) (99.0 wt.%) and ethanol (99.0 wt.%) were derived from Chengdu Kelong Inc. (China). Sulfamic acid, heparin sodium salt (Hep), polyethylene glycol (MW = 1000 Da, PEG1000; MW = 2000 Da, PEG2000), diethylene glycol (DEG), 2,2′-dimethylol propionic acid (DMPA), 1,6-diisocyanatohexane (HDI), dibutyltin dilaurate (DBTDL), triethanolamine (TEA) and gentamycin sulfate (GS) were purchased from Aladdin reagent Co. Ltd. (China). Dialysis membranes (MW = 3500 Da) and KGM (MW  200,000 to

Elemental analysis

The results of elemental analysis are shown in Table 2. The existence of sulfur in the LSSK and HSSK indicated that the sodium sulfonic (−SO3Na) groups were successfully introduced into the polysaccharides. The DS in the table means the amount of sodium sulfonic (−SO3Na) groups per unit of pentasaccharde, and the HSSK had higher DS.

FT-IR

Fig. 1 shows the FT-IR spectra of the HSSK and LSSK. The peak at 1200–1260 cm−1 was corresponding to the asymmetric valence fluctuations of the Odouble bondSdouble bondO, and the peak at

Conclusions

Heparin-mimetic polyurethane hydrogels were successfully prepared by the introduction of SKGM. The SKGM showed prolonged APTT and TT, and thus played the vital role in preventing blood clots formation. The hemolysis analysis further suggested its potential to prepare blood-contacting materials. With the introduction of SKGM, the hydrophilicity of the hydrogels increased and consequently raised the swelling ratio and drug loading amounts. Meanwhile, the anticoagulant activity and mechanical

Acknowledgements

This work was financially sponsored by the National Natural Science Foundation of China (Nos. 51433007, 51503125, and 51673125), and State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University (LK1619). We thank our laboratory members for their generous help, especially for the favor from Dr. Chao He and Dr. Zhenqiang Shi in the bacterial tests.

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