Study on Stimuli-responsiveness of Biomedical Intelligent Polymer Materials

Research on Stimuli Response of Biomedical Intelligent Polymer Materials ZHANG Zhibin1,2 TANG Changwei2, QIU Kai2, CHEN Yuanwei2, XIONG Yanfang2 2 WanChanxiu2, â–³Revision school1 (Department of Bioengineering, Southwest Jiaotong University, Chengdu 610031) 2(Polymer Science of Sichuan University And School of Engineering, Chengdu 610065, China) A significant change has occurred in the form of a solid, a solution, or an adsorption on a carrier surface, including an aqueous solution of a water-soluble polymer, a crosslinked water-soluble polymer (ie, a hydrogel), and immobilization on Carrier surface polymer. This article reviews the research and application of smart polymer materials in biology and medicine.

1 Introduction 2 Intelligent water-soluble polymer stimuli-responsive intelligence Polymer is a type of polymer that undergoes corresponding mutations in its own physical and chemical properties under the stimulus of external factors, also known as "smart polymerisation". "or" stimulus-responsive polymer "

Or "environmentally sensitive polymers". The smart polymer may be an aqueous solution of a hydrophilic polymer, or may be a polymer and a cross-linked water-soluble polymer (ie, a hydrogel) immobilized on a carrier surface. Environmental stimuli include temperature, pH, and solution composition ions. Intensity, light intensity, electric field, stress, and identification magnetic field, etc. When these stimulus signals change, the smart polymer's own properties such as phase, shape, optics, mechanics, electric field surface energy, reaction rate, permeation rate and identification performance, etc. Changes will occur Water-soluble environmentally sensitive polymers can be precipitated from aqueous solutions under special environmental conditions. Polymer systems with this property can be used as switches for temperature or pH indicators. Chen et al. combined biomolecules with polymers, selectively separated from the solution due to slight changes in conditions, and used this method to separate and purify the products obtained by enzyme catalysis in biological processes. The enzymes are also easily separated by phase. By recycling Hoffman et al., Hoffman et al. used a biomolecule with a recognition function or a ligand for a certain receptor, such as a cell receptor peptide or an antibody, to bind to an intelligent polymer for precipitation-induced affinity separation. With this method, IgG (immunoglobulin) can be recovered from the solution, and CD44 cells can also be isolated from lysozyme. When the aqueous solution smart polymer is mixed with lysosomes or cell suspension, the polymer can receive an external stimulus. The phase separation occurs and can interact with lysosomes or cell membranes, and cells or lysosomal membrane components are linked to a thermosensitive polymer to form a complex, when the complex interacting with the cell membrane phase separates. The formation of a gel, cells can be cultured on the surface of the polymer reversibly 3 surface smart polymer stimulus-responsive intelligent polymer is immobilized on the surface of a solid polymer carrier by chemical grafting or physical adsorption. Minor changes in the external environment (such as solution temperature, pH, or some ionic strength, etc.) will significantly alter the thickness, wetting, or surface charge of the surface layer. Because the surface coating is very thin, this response speed is faster than the hydrogel. Precipitating the smart polymer into the pore surface of the porous surface can create a permanent "switch" to control the pore opening or closing state of the protein. Or when cells interact with smart polymer surfaces that are in the on or off state, they selectively adsorb to the more hydrophobic surface. On the one hand, they adsorb proteins or cells on the surface, which can reduce the loss caused by changes in temperature. The degree of activity on the other hand is that the cell culture is reversibly carried out on a chemically grafted polymer surface having a low critical solution temperature, and that simply changing the external environment to convert the polymer surface into a hydrophilic one, the protein or cell will Automatically free without the addition of trypsin. If a ligand for a cellular receptor, peptide-RGD, is attached to a thermosensitive polymer-forming complex (its LCST is close to room temperature), the polymer is immobilized on The specific carrier surface has the property of adsorption and desorption to thermally reversible cell culture when stimulated by changes in the ambient temperature. The monoclonal antibody was attached to a polymer having LCST properties and applied to a membrane-type immunoassay. When the analyzed solution flows through the micropore surface, the thermosensitive polymer part in the polymer-antibody complex can be selectively adsorbed on the surface of a certain kind of cellulose acetate film capable of preventing protein adsorption at room temperature due to the heat-sensitive polymer. The LCST is near room temperature and its composition is designed to selectively interact with cellulose acetate.

4 Smart polymer hydrogel stimulation - Responsive water-soluble polymers crosslink or copolymerize with hydrophobic monomers to form hydrogels. The stimuli-responsive polymer gel is a gel whose structural physical properties and chemical properties can change with the external environment. When the gel is subjected to environmental stimuli, it will respond accordingly, that is, when the solution is composed of pH, ionic strength, When the stimulus signal such as temperature or light electric field changes, or when it is stimulated by a specific chemical substance, the gel will mutate and show the phase transition behavior. This response reflects the volume phase of the gel polymer gel 4.1. Conversion of Polymer Gels Polymers composed of a network structure (cross-linked structure) of a polymer and a solvent and a network structure can not be dissolved by a solvent, but can absorb a large amount of solvent and swell. The volume phase transition of a gel refers to the phenomenon that the volume of the gel in a solution changes discontinuously with the change of external environmental factors (solvent composition, ionic strength, pH temperature, light, electric field, and magnetic field). From swelling to contraction phase, or from contraction to swelling phase. The transition is continuous, but under certain conditions it can produce discontinuous transitions (ie, mutations) that vary in volume from tens to thousands of times, giving it some sort of intelligent behavior. Polymer gels can change with environmental stimuli. The internal causes of phase transitions are several interaction forces existing in the system, namely Van der Waals forces, hydrogen-bond hydrophobic interaction forces, and electrostatic forces. Due to the mutual combination and competition of these forces, the gel swells or contracts, resulting in a volumetric phase transition.

4.2 Responsiveness of polymer gels 4.2.1 pH-responsive gels pH-responsive gels are high-molecular gels whose volume changes with the ionic strength of the ambient pH. These gels have an ionic dissociation group in the macromolecular network. The network structure and charge density vary with the pH of the medium and have an effect on the osmotic pressure of the gel. At the same time, because of the presence of ionic groups in the network, changes in ionic strength also cause volume changes.

Horbett and Ratner reported an insulin controlled release system. Glucose oxidase and insulin were first embedded in the basic compounds N,N'dimethylethanolamine methacrylate and 2-hydroxyethyl methacrylate (HEMA). ) Copolymerized in a gel film. Glucose diffuses into the gel and reacts with glucose oxidase to produce gluconic acid. The acid protonates the basic functional group in the gel and becomes positively charged. The gel swells due to electrostatic repulsion and increases the permeability of the membrane. Therefore, insulin Can be diffused out. In the absence of glucose, the hydrogel is not swollen and impermeable. If a carboxyl group is present in the hydrogel, it shrinks due to the formation of hydrogen bonds in -COOH in the acidic state, and the pH-responsive gel expands due to the repulsion between -COO- in the basicity, and generally forms a molecular network through cross-linking. . There are weak acid and (or) weak base groups in the gel. These groups are ionized in solutions of different pH values ​​and different ionic strengths. The gels are thus charged and dissociate the hydrogen bonds in the network, leading to gelation. Discontinuous volume change.

4.2.2 Temperature Sensitive Gels Thermosensitive polymer gels can deform (swell and shrink) in response to temperature changes because the conformation of such gel macromolecular chains can change in response to temperature stimuli. Gels in water at low temperatures Swelling (hydrogen bond, hydration) macromolecular chains are stretched due to hydration. When they reach a certain temperature, the hydrogen bonds are broken, and the gel undergoes rapid dehydration due to the mutual attraction of hydrophobic groups, and the large temperature-sensitive condensate The glue is divided into a high temperature shrinkage type and a low temperature shrinkage type. Polyisopropyl acrylamide (PIPAAm) is a low temperature, high temperature shrinkable gel. Polymeric network (IPN) hydrogels formed from polyacrylic acid (PAAc) and poly(N,N-dimethyl acrylamide) (PDMAAm) are low temperature shrinkage and high temperature swelling types. The PAAc in IPN is a hydrogen bond donor and forms complexes through intermolecular and intramolecular hydrogen bonding. This complex is very stable in aqueous solutions below 60C, but the complex swells above 60C when the complexes dissociate. The introduction of a certain kind of monomer for copolymerization can adjust the LCST of the polymer gel.

4.2.3 Photosensitive gels Photosensitive gels are photoisomerization of light-sensitive groups in the gel network when irradiated with gels that undergo volumetric phase transitions due to light irradiation (light stimulation). Or photodissociation, which leads to swelling of the gel due to changes in radical conformations and dipole moments. The study of the relationship between the swelling volume of polyisopropyl acrylamide containing a colorless triphenylmethane cyano group and the temperature shows that the gel undergoes a continuous volume change at 3C without UV irradiation. Photodissociation occurred after cyanolysis; when the temperature rose to 326C, the volume mutated, rose to 35C and then cooled, discontinuous swelling occurred at 31. 5C, the volume plus 10 times. If the gel is subjected to alternating UV irradiation and de-irradiation at 32C, the gel undergoes discontinuous swelling-shrinkage, acting like a switch. Reflects the composite effect of photosensitizing groups and thermosensitive groups 4.2.4 Magnetic field-responsiveness Superabsorbent gels with magnetic particles embedded in magnetic gels are called magnetic field-responsive gels. This gel can be used as a light switch, an image display board, and the like. The ferromagnetic “seed” material is embedded in the gel. When the gel is placed in a magnetic field, the ferromagnetic material is heated to increase the local temperature of the gel, causing the gel to expand or contract; the magnetic field is removed, and the gel is cooled , restore it to its original size. Embedding ferromagnetic methods are: one is to put fine nickel needle crystals into a pre-formed gel; one is to coat polyvinylpyrrolidone on micron-size nickel sheets, and then polymerize with the monomer solution and then polymerize. The two methods of gelation can be used in implantable drug delivery systems, where a watch-sized device consisting of a power supply and a coil generates a magnetic field that causes the gel to contract and release a dose of drug. This type of method can also produce artificial muscle type actuators. 4.2.5 Electrically Stimulus-Responsive Gels This is a kind of switch and rate that can control the drug release by controlling the release of drugs through electrochemical methods. The drugs can be buried in the form of physical adsorption. In the polymer carrier, it can also be chemically grafted in the polymer, and the corresponding changes in the polymer under electrical stimulation (chemical bond cleavage, ion state transition to neutral state, gel shrinkage, ion exchange, etc.) such as drugs Y-aminobutyric acid and glutamic acid bind to the amide bond of polystyrene. After the current is applied, the chemical bond between the polymer and the drug is broken, and the drug behavior is released due to the stimulation of the specific substance. For example, the drug releases condensate. The gel system feeds back on the changes in chemical substances caused by the lesions, controlling the opening and blocking of drug release through the swelling and contraction of the gel. An insulin release system responsive to blood glucose concentration, for example, is a glucose-sensitive sensing moiety that is reversible by the reversible bonding of a polyvalent hydroxyl group with a boronic acid group, which is a phenylboronic acid-containing ethyl pyrrolidone copolymer. Among them, boric acid is bonded with the cis-diol of polyvinyl alcohol (PVA) to form a closely-structured polymer complex. When glucose molecules infiltrate, the valence bond between phenylboronic acid and PVA is replaced by glucose, and the above-mentioned intermolecular bonds are dissociated, and the degree of swelling is large. This macromolecular complex can be used as a carrier for an insulin controlled release system. The equilibrium and dissociation of the polymer complex in the system varies with the glucose concentration, that is, it can sense the glucose concentration information and thus perform the drug release function. Conclusion The smart polymer produces a sharp response to external stimuli when the polymer Many properties will change. When the water-soluble polymer is precipitated, it will selectively precipitate from the solution and appear turbid; if the polymer is grafted or adsorbed on the surface of the solid support, it will reversibly change the adsorption polymer. The amount of water adsorbed changes the wettability of the surface; when the hydrogel is stimulated to shrink, the water in the micropores of the hydrogel is discharged to become opaque, the mechanical strength is strong, and the volume shrinks. One of the most widely used hydrogels is smart polymer materials. Its development is based on PFlory's gel swelling theory, which uses intermolecular force field, ion force field and photochemistry to make the gel volume and swelling response to the system selection. From the point of view, most foreign countries use synthetic polymers, such as pH, temperature, electric field, light and glucose, such as homopolymer grafts or block copolymer interpenetrating polymer networks (IPN) polymeric microspheres (PMS). Concentration response system. The future biomaterials will be divided into: synthetic materials or modified natural materials used in medicine and biology; bionic natural materials or artificial materials; see bionic intelligent biological materials in response to specific stimuli. Polymer materials are expected to play an increasingly important role in advanced controlled release systems, biomimetic materials, bone biomaterials, diagnostic systems, molecular structural protein analogs, and tissue engineering.