4D Printing Of Bionic Smart Responsive Hydrogels And Their Controlled Drug Release Properties

Traditional oral delivery forms are usually based on tablets and capsules,with the main problems being the fixed type and dosage of drugs,which cannot meet the needs of different individuals for on-demand drug release.With the increasing demand for disease-specific drug delivery systems and personalized drug delivery systems,the pharmaceutical researchers are urging the industry to develop new design and manufacturing methods for drug controlled release carriers.3D printing is a technology that uses digital model files as the basis for constructing objects by adding discrete materials layer by layer,with the advantage of "free manufacturing".It can provide the pharmaceutical industry with the advantages of rapid prototyping,multi-material integration,the fabrication of complex structures,and the use of multiple excipients to solubilize,target,or control the release of drugs to meet the challenges faced by the pharmaceutical industry.When using smart materials for 3D printing,the printed objects can change in shape,properties or function over time when stimulated by external environmental conditions,the process is known as 4D printing.As an emerging technology originating from 3D printing,4D printing can not only make 4D printed objects have complex and multiple three-dimensional structures,but also endow them with intelligence to respond to external environmental stimuli,instead of being purely static physical entities.Hydrogels are three-dimensional cross-linked networks of water-soluble polymers that provide an environment similar to natural tissues,and their unique physicochemical properties and biocompatibility are particularly suitable for loading peptides,proteins and other macromolecular active substances.Hydrogel drug carriers have excellent swallowing sensation,which can effectively reduce the pain of taking medication for patients,and are especially suitable for elderly and pediatric patients.However,the traditional manufacturing process can only manufacture hydrogel drugs with simple structures through the mold method,and is powerless for complex structures and drug shapes with special requirements.The rapid development of 3D printing technology is attracting many scholars and researchers to engage in the research of 3D printed hydrogel drug carriers.But the main problems of the current 3D printing of hydrogel drug carriers are: 1)the printed hydrogel drug carriers have poor shape fidelity;2)the loading modes of drugs are not flexible,and the types of drugs loaded are relatively single;3)the release modes of drugs are fixed,real-time intelligent controlled release cannot be achieved with in vivo environmental stimulation;4)the structures of the printed hydrogel drug carriers are simple,not fully utilized the advantages of 3D printing for "free manufacturing" in three-dimensional space.Therefore,it is necessary to further explore the potential of 3D printed hydrogel carriers in drug delivery.After billions of years of evolution,organisms in nature have optimized many special functions for survival and self-defense.The organisms can self-perceive and respond to external environmental stimuli provides an important bionic inspiration for the research of 4D printed smart hydrogel carriers and their controlled drug release.Inspired by the stomatal opening and closing function of plants,by combining 4D printing technology with smart responsive hydrogels,we have successfully prepared four types of bionic smart hydrogel delivery systems that can control drug release in a new and unique way.They can autonomously change the drug release behavior according to the temperature or pH of the environment,and the drug release profiles can also be regulated in many different ways.4D printing utilizes its unique advantage of "free manufacturing" to endow the hydrogel drug controlled release carrier with the intelligent ability to respond external environmental stimuli in four-dimensional space,which is more conducive to meeting the needs of different individuals for smart drug release.In contrast to the traditional passive drug release,the 4D printed bionic smart hydrogel delivery systems introduce an active controlled release method,which establish a new paradigm of drug smart controlled release carrier design and manufacturing.The main research contents and conclusions are as follows:(1)The core-shell hydrogel capsules for smart controlled drug release were successfully prepared by multi-material extrusion 4D printing method.After parameter optimization,the optimal concentration of carbomer(rheology modifier)in the Nisopropylacrylamide(NIPAM)inks for 4D printing was 1.0%(w/v),and the multimaterial extrusion-based 4D printing method can independent and precise control the material composition of each part of the printed capsule,as well as the type and dose of the loaded drug.The lower critical solution temperature(LCST)of the prepared poly(N-isopropylacrylamide)(PNIPAM)hydrogel was 34.96 ℃,and its excellent temperature sensitivity endows the core-shell smart hydrogel capsule with the ability of temperature-responsive release.In vitro drug release studies demonstrated that the4 D printed core-shell smart hydrogel capsule can autonomously change its drug release behavior according to the change of ambient temperature in human body,and its drug release behavior can also be regulated by adjusting the shell thickness of the smart hydrogel capsule.(2)The PNIPAM hydrogel was modified by polyethylene glycol(PEG),a fast temperature responsive smart hydrogel capsule was designed and fabricated by 4D printing method.The rheological properties analysis of the printing inks showed that the addition of PEG with different molecular weight had no significant effect on the performance of the NIPAM printing inks.The hydrogel capsules with hollow structure were fabricated by extrusion 4D printing have high fidelity,and the drugs can be freely loaded according to individual needs of different patients.The LCST of the prepared PNIPAM hydrogels with fast responsiveness were about 34.9 ℃,and the addition of PEG with different molecular weights can effectively improve the temperature stimulation response of the PNIPAM hydrogel.In vitro drug release studies showed that the 4D printed fast temperature responsive smart hydrogel capsules can autonomously change their drug release behavior according to the change of ambient temperature in human body,and the drug release behavior can also be regulated by adjusting the molecular weight of PEG.The smart hydrogel capsules are biocompatible and have great application potential in intelligent controlled release of macromolecular active substances.(3)A pH-sensitive sodium alginate(SA)/polyacrylamide(PAM)double-network hydrogel was developed,and multi-shape hydrogel tablets with different geometric parameters were designed and fabricated by 4D printing method.After parameter optimization,the optimal concentration of carbomer in the sodium alginate(SA)/acrylamide(AM)printing ink for 4D printing was 3.0%(w/v).The 4D printed SA/PAM double-network hydrogel tablets with different shapes exhibited high fidelity.The pH-responsive SA/PAM double-network hydrogel has excellent pH sensitivity.In vitro drug release studies showed that the specific surface area was the main geometric parameter that influenced the speed of drug release,and the 4D printed SA/PAM double-network hydrogel tablets can autonomously change their drug release behavior according to the pH change in the environment of human body,and also can regulate their drug release profiles by adjusting the specific surface area of the hydrogel tablets.In vitro biocompatibility studies showed that the developed SA/PAM double-network hydrogel has excellent biocompatibility.(4)The SA/PAM double-network hydrogel was modified by PEG,a fast pHresponsive SA/PAM double-network smart hydrogel tablet was designed and fabricated by 4D printing method.The rheological properties analysis of the printing inks showed that the addition of PEG with different molecular weight had no significant effect on the performance of the SA/AM printing inks.The fast pH-responsive SA/PAM doublenetwork hydrogel tablets fabricated by the extrusion 4D printing method have high fidelity and can be freely loaded with drugs according to the individual needs of different patients.The internal pore size of this fast pH-responsive SA/PAM dual network hydrogel can vary with ambient pH,and the addition of different molecular weights of PEG can effectively improve the pH stimulation response of SA/PAM double-network hydrogels.In vitro drug release studies showed that the 4D printed fast pH-responsive SA/PAM double-network hydrogel tablets can autonomously change their drug release behavior according to the pH change in the environment of human body,and the drug release behavior can be regulated by adjusting the molecular weight of PEG.The 4D printed smart hydrogel tablets have good biocompatibility,and are particularly suitable for loading drugs that are irritating to the stomach or other proteinbased drugs that are easily broken down or destroyed by gastric acid.