Synthesis and characterization of polyphosphoester/polyethylene glycol composite hydrogels

Abstract

<p indent=0mm>The hydrogel, which has a three-dimensional (3D) cross-linked hydrophilic network structure, is widely used as biomedical scaffold for local drug delivery and tissue engineering. Especially, with the continuous development of 3D printing technology, hydrogel scaffolds are increasingly used in the field of regenerative medicine. Polyphosphoester is a class of biodegradable polymers with repeated phosphoester linkages in the backbone, and a series of polyphosphoester materials have been synthesized for biomedical applications. For instance, a variety of amphiphilic polyphosphoester-based copolymers have been synthesized by Wang’s group, and used as the nanocarriers of hydrophobic anticancer drugs as well as siRNA. In addition, Yan’s group has prepared hyper-branched polyphosphoester as the drug delivery systems of hydrophobic anticancer drugs and photodynamic agents. Recently, Wooley and co-workers have synthesize the amphiphilic co-polymer of poly(ethylene oxide) and polyphosphoester, and used to encapsulated paclitaxel (PTX) with high contents for cancer therapy. And, they also conjugated the PTX into the side chain of polyphosphoester with pH-labile linkages for efficient tumor treatments. As the tissue engineering scaffold, polyphosphoester-based scaffolds were first used for fabrication of nerve guide conduits. And then, Elisseeff and co-workers have found the great potentials of phosphate-containing hydrogel for bone tissue engineering. In addition, Leong et al. found that the photocrosslinkable polyphosphoester hydrogel exhibited good compatibility and potentially osteoinductive ability for goat bone marrow-derived mesenchymal stem cells. Therefore, polyphosphoester hydrogel could be a promising scaffold for bone tissue engineering. In this study, water-soluble macromers polyphosphate diacrylate (PEEP-DA) and polyethylene glycol diacrylate (PEG-DA) were first synthesized, and characterized by ¹H NMR. And then, the PEEP/PEG composite hydrogels at various polyphosphoester contents were controlled by varying the feed ratio of the macromers PEEP-DA and PEG-DA (1:29, 2:28, and 5:25), and the PEEP/PEG hydrogels were fabricated by exposing aqueous solutions of these macromers with photoinitiator to UV light irradiation. We systematically studied the structure, biodegradability, biocompatibility, and bone differentiation of the hydrogel scaffold. Compared with PEG hydrogel, these PEEP/PEG hydrogels exhibited better biodegradability due to the degradation properties of polyphosphoester. And, the PEEP/PEG composite hydrogels, which was prepared at PEEP-DA/PEG-DA mass ratio of 5:25, disappeared almost completely after post implantation into mice for 28 d. After encapsulating bone marrow mesenchymal stem cells (BMSCs) during the preparation process, the cell viabilities in the composite PEEP/PEG hydrogels were better than that in the control PEG hydrogel. In addition, the alkaline phosphatase activity, a key maker of early osteogenic differentiation, was evaluated after co-incubation for 7 or 14 d. It could be found that the alkaline phosphatase activity in the PEEP/PEG composite hydrogels, either for 7 or <sc>14 d,</sc> was significantly higher than that of the control PEG hydrogel. The differentiation process of BMSCs into bone is usually accompanied by the calcium deposition. The polyphosphoester has shown osteoinductivity according to previous reports. We found that the amount of calcium deposition was significantly higher in the PEEP/PEG composite hydrogels than that in the PEG hydrogel, especially after co-incubation for <sc>21 d,</sc> which is well consistent with the result of other groups. Collectively, this study reported a new PEEP/PEG composite hydrogels, which exhibited the potential as tissue engineering scaffolds.