The Design And Investigation Of Ureido-Pyrimidinone Based Quadruple Hydrogen Bonding Superamolecular Hydrogels

It is well known that the gelation mechanism of hydrogel based on supramolecular interaction is that the cross-linking is driven by the reversible physical interactions which could resume to their initial state after suffering from external stimuli.Therefore,the supramolecular interactions are widely applied as the crosslinking approach in the preparation of injectable hydrogel which is one of the most promising candidate as the bioactive material carrier for the application of minimally invasive surgery.The purpose of this work is to design and prepare a series of supramolecular multiple functional hydrogel with different polymer main chains based on the quadruple hydrogen bonding derived from UPy-UPy dimers via simple methods,and the potential application in biomedical field when serving as carries has also been characterization via the ex-situ drug release test.In addition,the synergetic effects of quadruple hydrogen bonding and other none-covalent bonds have also been investigated in this work and applied to prepare novel dual physical crosslinking hydrogels with fascinating properties,which is of great significance and can guide the design and development of other dual physical crosslinking supramolecular hydrogels.The main content of this research is detailed as following:1.First,we successfully synthesized the acrylate UPy functional monomer by coupling reaction between N-Methylol acrylamide and 2（6-isocyanatohexylaminocarbonylamino）-6-methyl-4[1H]pyrimidinone.The UPy monomer was then copolymerized with acrylamide in dimethyl sulfoxide（DMSO）via radical polymerization using AIBN as initiator.The obtained PAM-UPy supramolecular polymer could dissolve in deionized water with certain concentration under elevated temperature,and the hydrogel instantly form through the self-assembly of UPy moieties in the polymer chain after cooling to room temperature.We characterized the prepared hydrogel using rheological test and optical self-healing measurements and the result showed a good self-healing behavior and an excellent shear-thinning property of the prepared PAM-UPy hydrogel,which suggest a promising application potential of the hydrogel as carrier in biomedical field.2.Using supramolecular interactions based on quadruple hydrogen bonding and its synergistic effect with other none-covalent physical interactions to build up the three dimensional networks of polymer hydrogel has become one of hot research fields during the past years.We synthesized a new UPy functional monomer with better solubility via the coupling reaction between hydroxyethyl acrylate and 2（6-isocyanatohexylaminocarbonylamino）-6-methyl-4[1H]pyrimidinone,and then the monomer was copolymerized with tert-butyl acrylate in dioxane followed by hydrolysis using trifluoroacetic acid in dichloromethane.The supramolecular polymer termed PAA-UPy was finally obtained after dialysis against deionized water followed by freeze drying.The supramolecular hydrogel was obtained by dissolving the polymer gelator into ultra pure water under certain conditions.The rheological test and the optical self-healing measurement indicate an excellent shear thinning and rapid self-healing property of the prepared hydrogel.Furthermore,we also crosslinked the PAA-UPy hydrogel in situ using CaCO₃ and obtained a novel PAA-UPy-CaCO3 hydrogel which also showed intriguing self-healing property,suggesting a promising application in biomedical field.3.When the hydrogels are applied as carriers caring drug,protein,biomedical dose to repair the damaged tissues,we offer demand the hydrogel matrix degrade into harmless small molecules automatically after finish the carrier mission,and then it will cause little or no harm to human body.Therefore,design and preparation of injectable hydrogels with fascinating biodegradable possibility is quite significant.In this work,we used the natural polymer-gelatin as the main chain and modified the gelatin with UPy moieties to prepare the biodegradable gelatin-UPy supramolecular polymer.In addition,the abundant carboxyl groups in the gelatin chains was also used to build the coordination crosslink network using Fe³⁺,and generating the novel dual physical crosslinking supramolecular hydrogel.The excellent in situ gelatin ability,self-healing behavior,and intriguing biodegradable possibility make the supramolecular hydrogel one of the most promising candidates as carriers for biomedical application.4.Just like the most of other hydrogen bonds,the quadruple hydrogen bonding of UPy which can form UPy-UPy dimers via self-reorganization and self-assembly could also be affected by the water molecule,this is quite different from that of none-proton solvent.It is well known that the water molecules own hydrogen bonds donor and acceptor at the same time,and these donors and acceptors will compete with the hydrogen bonding sites in UPy moieties,and thus decrease the UPy quadruple hydrogen bonding dramatically.However,it is difficult and not reality to introduce too many UPy moieties in a hydrophilic polymer chain given the intrinsic hydrophobic property of UPy itself.Therefore,in this work,we designed a novel UPy quadruple hydrogen bonding based hydrogel with local hydrophobic micro-environment protection,which enhanced the strength of quadruple hydrogen bonds and thus forming a robust supramolecular hydrogel.We first introduced the RAFT reagent at the both ends of PEG（Mw=20KDa）and then using it as macromolecule RAFT reagent to copolymerize UPy monomers and MMA.The obtained triblock supramolecular polymer was then dissolved into deionized water under some conditions to prepare the hydrogel.The rheological test and the optical self-healing measurement were conducted and the results indicate an excellent shear thinning,injectable behavior rapid self-healing property of the prepared hydrogel,which indicate a good application potential in biomedical field.5.Designing local hydrophobic micro-environment for UPy moieties to protect it from direct contacting with water molecules is a vital and significant strategy to enhance the strength of quadruple hydrogen bonding.This kind of synergetic effect between hydrophobic interaction and quadruple hydrogen bonding will guide the design of supramolecular hydrogels based on multiple none-covalent interactions.In the previous work,we showed how a hydrophobic PMMA micro-environment protect the UPy from contacting with water and enhanced the quadruple hydrogen bonding interaction.However,the local micro-environment derived from the PMMA cannot change under external stimuli.In this work,we designed a supramolecular method for fabricating dynamic hydrogel with many desirable properties.Water-soluble tri-block copolymer containing a central PEG part and two terminal poly（N-isopropylacrylamide）（PNIPAm）blocks and randomly incorporated ureido pyrimidinone（UPy）moieties,was prepared via RAFT polymerization.Fast gelation triggers upon raising temperature above the lower critical solution temperature of the hydrogel,where PNIPAm block become hydrophobic and self-assemble into micelles,which subsequently provide hydrophobic micro-environments boosting UPy dimerization to‘lock’polymer chains and thus forming strong physical crosslinking points.The obtained hydrogels reveal remarkable self-healing ability after mechanical damage.Furthermore,the thermos-reversible and injectable properties allow it to withstand repeated deformation and 3D construction of complex objects.Bone mesenchymal stem cells（BMSCs）mixed with the supramolecular hydrogel and injected through needles remain high viability.