Research Of The Preparation And Application Of Multi-responsive Smart Hydrogels

Hydrogel is a soft material,and it is a ductile three-Dimensional cross-linked network structure.Besides,the hydrogel itself can absorb a lot of water,and can be molded into a variety of shapes,but maintain its overall nature the same.Hydrogels pose strong deformability.At the same time,hydrogels have similar structures with body tissues,therefore hydrogels have been widely used as biomaterials in various aspects.Such as in drug delivery,tissue engineering,and tissue repair.As well known that,in many biological microenvironments,dynamic changes in ECM(extracellular matrix)are often accompanied by many developmental and disease processes.Specific changes in the structure and composition of ECM will ultimately lead to changes in the biological properties of the matrix and thus have a profound effect on cellular behavior,including cell migration,cell arrangement,proliferation,and its morphological changes,progenitor cell differentiation.At the same time in the development of tissue,muscle fibrosis,tumor growth,and myocardial infarction,the strength of the matrix will change accordingly.Not only that,the hardness of different parts of the organism is not the same.To give a clinical relevant example,the elastic modulus of healthy breast tissue is about 100-200 Pa.While the breast tumor tissue is much harder,1-4 kPa.This is due to lesions during the remodeling of ECM around the breast and matrix protein hyperplasia,such as the continuous deposition of the collagen.And the hardness of the tumor will gradually increase with the time and the severity of the disease development.For example,in the process of muscle fibrosis in rats,any other histological evidences fail to detect the process of the tissue in mice,but the hardness of the tissue has already been harden than before.Hence,in order to adapt to the complexity of the biological system itself,we have higher requirements to precisely adjust the hydrogel’s mechanical properties and physical and chemical properties.It is important to prepare materials with adjustable hardness to mimic biological processes and detect diseases.However,early hydrogels can not adjust themselves to the dynamic environment in organisms,so in order to adapt to the changes,gradually,the responsive hydrogel began to receive widespread concerns.These stimuli include the pH,the redox,enzyme,temperature,magnetic field,electric field,ultrasonic field,lightand so on.In these stimuli-responsive hydrogels,the light response and acid response are relatively more favored and focused.The light stimulating effect,as a representative of the nature of the remote control,can adjust the mechanical properties of the hydrogel in the manipulation of the light,including the shape,the strength and the size,without touching the hydrogel itself.Besides,in the biological environment,the pH value of local changes is also very obvious.In response to acid stimulation,hydrogel materials often undergo physical or chemical changes,such as swelling,shrinking,decomposition,and gradual degradation.And in the intracellular environment,both endosomes and lysozymes are acidic.In the organic level,there are also significant pH gradients in the gastrointrestinal tract;In addition,cancer and inflammatory’ responses will also cause localized acidification.Acid stimulation response has been widely used as a signal for controlled release of drugs.Therefore,we mainly study the light and acid responsive hydrogel systems.The main results are as follows:Dual-light controlled hydrogels:photoresponsive hydrogels are able to control their sizes and mechanical properties in response to light stimuli.This kind of time and space controllable hydrogel material has very important application in many fields.However,a hydrogel could response to the UV and the NIR light at the same time is still challenging.While we just designed this kind of dual-light responsive supramolecular hydrogel.This hydrogel has light controlled host-guest recognition properties,temperature responsiveness,and near-infrared photothermal capabilities.And the hydrogel can quickly self-healing.Besides,under the control of ultraviolet and near-infrared light,it can change its hardness,softening or hardening.In addition to adjusting the hardness of the hydrogel,it can also manipulate the direction of bending the hydrogel by controlling the irradiation of UV light or NIR light.This intelligent hydrogel is expected to act as a biological material,through UV light or NIR light to regulate the controllable changes in cell microenvironments.Acid-stimulated responsive hydrogels:In biological systems,especially in the development of bacteria,most local environments are acidic.The aminoglycosides as a class wide-spectrum antimicrobial agents to inhibit the bacterial infection.However,there are still many clicical deficiencies.If the dosage is lower than the minimum inhibitory concentration of bacteria,the remaining viable bacteria will continue to form a bacterial biofilm,but high-dose administration will bring adverse side effects to the patients(e.g.nephrotoxicity and ototoxicity at high doses).In order to solve this sticky issue,we have designed an aminoglycoside hydrogel that responds to the regulation of on-demand delivery.The aminoglycoside drug itself is used as a cross-linker to crosslink the oxidized polysaccharide-dextran.And the modulus,degradation rate and release kinetics can be precisely modulated by tailoring the aminoglycoside dose during gel formation.Not only that,we found that aminoglycosides as a kind of wide-spectrum antibacterial drugs not only pose threat to the aerobic bacteria,but have no effect to anaerobic bacteria.In order to broaden antimicrobial spectrum of the antibacterial material,we introduced ornidazole--a special anaerobic bacterial drugs.We modified the ornidazole drugs to the amino-terminal dendrimers,together with the aminoglycoside drugs,to cross link with the oxidized dextran.In this way we have prepared a whole spectrum of antibacterial hydrogels.And this hydrogel shows fast gelation,self-healing and on-demand drug release behaviors,and whole-spectrum antibacterial activities against aerobic bacteria and anaerobic bacteria.In summary,the present dissertation provides a new method for the preparation of multi-functional hydrogels,which are responsive to stimuli.Compared with the traditional macromolecular hydrogels,the multi-functional hydrogels prepared by us can be precisely regulated to desired shape and size under the light stimulation,and can release and self-degrade the drug as needed.Besides,the method of preparing the hydrogel is simple and easy.Particularly,the acid-responsive hydrogel can be used for automatic identification of bacteria,on-demand administration,and can be self-degraded without any side effects,and has high clinical application value.