Preparation And Properties Of Self-Healing Sustained-Release Collagen/NH₂-MIL-101（Fe） Composite Hydrogel

The development of suitable biomaterials as carriers of active substances is one of the hot research topics in the field of biomedicine.Collagen(Col),the important component of extracellular matrix,has excellent biological functions such as low immunogenic ity,biocompatibility,promotion of cell proliferation,and biodegradability.Pure collagen hydrogel has a three-dimensional mesh structure that can load bioactive molecules and allow for substance delivery.However,it has extreme difficulty in sustainably releasing small molecular bioactive substances due to the large network pores and rapid biodegradability in vivo;additionally,it cannot self-heal when damaged by the external environment,leading to a reduced service life.Therefore,the development of self-healing sustained-release collagen hydrogels is of practical value in the field of drug delivery.In this thesis,NH2-MIL-101(Fe),which has high porosity,prominent specific surface area and low toxicity,was introduced into collagen hydrogels by natural macromolecular cross-linker to improve the sustained-release performance of collagen hydrogels.Subsequently,the self-healing property was imparted to collagen/NH2-MIL-101(Fe)composite hydrogels by constructing dynamic borate ester bonds.The specific research works are as follows:(1)Firstly,NH2-MIL-101(Fe)was prepared by microwave hydrothermal method using FeCl3·6H2O and 2-aminoterephthalic acid(NH2-BDC)as raw materials.The morphology,crystal type and particle size of NH2-MIL-101(Fe)were used as indicators to optimize the preparation conditions,such as reaction temperature,metal ion concentration,and the ratio of central metal ion to organic ligand.When the reaction temperature was 110℃,Fe3+ concentration was 0.16 mol/L,and n(NH2-BDC):n(Fe3+)was 2:1,NH2-MIL-101(Fe)had a very regular octahedron with an average particle size of 353.7±74.2 nm and a specific surface area of 229.99 m2/g.Furthermore,it had good thermal stability and remained structurally stable before 300℃,which was suitable as an adsorption material.In addition,its dispersibility and static stability were enhanced due to the introduction of amino groups.The adsorption of small molecular drug ibuprofen(IBU)using NH2-MIL-101(Fe)in ethanol showed the highest adsorbing capacity of 1297 mg/g when CIBU and CMIL were 20 and 0.5 mg/mL,respectively.Subsequently,the kinetic model,isotherm model and thermodynamic model were used to fit the adsorption process and then analyze the adsorption mechanism.It was found that the adsorption was mainly chemisorption,which was a multi-molecular layer adsorption on a non-uniform surface.The adsorption reaction was spontaneous heat absorption reaction,and the main adsorption mechanism was electrostatic attraction between carboxyl groups of IBU and amino groups of NH2-MIL-101(Fe).(2)NH2-MIL-101(Fe)was introduced into the collagen solution by the cross-linker sodium oxidized carboxymethylcellulose(OCMC),and then the C-MIL composite hydrogels were constructed by collagen self-assembly.The results of FT-IR,XRD and stability characterization showed that the triple helix of collagen was preserved and NH2-MIL-101(Fe)was successfully bound to collagen without escape.With the increase of NH2-MIL-101(Fe)amounts,the performance of the C-MIL composite hydrogel firstly improved and then decreased.At NH2-MIL-101(Fe):Col(w/w)≤ 0.2:1,the properties of C-MIL composite hydrogel increased significantly due to the synergistic effect of thicker collagen fibrils and the strengthening and toughening of NH2-MIL-101(Fe).The storage modulus(G’)and thermal denaturation temperature reached 158.23 Pa and 69.6℃,respectively.Moreover,enzymatic degradation degree and swelling ratio were 58.74%±1.73%and 13509%±477%,respectively.When NH2-MIL-101(Fe):Col(w/w)was 0.4:1,the collagen fibrils became thinner,resulting in slightly reductions in mechanical properties and enzymatic resistance of C-0.4MIL,which were better than those of pure collagen hydrogel.At NH2-MIL-101(Fe):Col(w/w)≥0.8:1,NH2-MIL-101(Fe)gradually agglomerated and the properties of the composite hydrogels decreased significantly.The "step" sustained-release C-MIL composite hydrogel was achieved successfully due to the introduction of NH2-MIL-101(Fe)with small pore sizes and the cross-linking effect of OCMC.For C-0.2MIL,IBU showed explosive release with a release ratio of 37.4%in the first 1 h.Then the release rate decreased and the release ratio was 61.0%when the release time lasted until 48 h.After 48 h,the IBU release entered the“long-lasting release" stage and the final release ratio was 64.1%at 120 h;nevertheless,the cumulative release of IBU was only 1.96 mg.For C-0.4MIL,although the IBU release was slightly faster,the cumulative release was 4.18 mg.The release curves of C-0.2MIL and C-0.4MIL were well fitted by the first-order release model,indicating that the release rate of IBU was dependent on the drug loading dosage.(3)Self-healing sustained-release CM-P composite hydrogels were constructed by introducing borate ester bonds with the help of 1,4-phenylenediboronic acid(PDBA).The results of FT-IR,XRD and XPS confirmed the successful introduction of PDBA.The self-healing properties,thermal stability and enzymatic resistance of CM-P composite hydrogel were optimized by adjusting the pH value,OCMC and PDBA quantities.At pH=8,OCMC:Col(w/w)=2:1 and PDBA/Col(w/w)=1.2:1,the composite hydrogel CM-1.2P exhibited the best self-healing effect with a self-healing ratio of 99.7%,and the G’ value was still restored to its initial level after three cycles under 300%strain shear.In addition,PDBA imparted the composite hydrogels high thermal stability and enzymatic resistance,injectability,remodeling and good adhesion.The CM-P composite hydrogel was pH-responsive to the release of IBU.When the pH value was 5,IBU was released rapidly with a release ratio of～47.30%.Moreover,the release curve could be well fitted by the first-order release equation,indicating that the release rate of IBU depended on its drug loading dosage.Under normal physiological conditions(pH 7.4),the electrostatic attraction between ionized IBU and NH2-MIL-101(Fe)or collagen inhibited the diffusion of IBU,leading to the lower release rate.As a result,CM-P showed a better sustained-release performance with a release ratio of 14.58%in the first 6 h.Meanwhile,the release mechanism of IBU from CM-P composite hydrogels was Fickian diffusion.