Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials

In recent years, intelligent hydrogels which can change their swelling behavior and other properties in response to environmental stimuli such as temperature, pH, solvent composition and electric fields, have attracted great interest. The hydrogels based on polysaccharides incorporated with thermo-responsive polymers have shown unique properties such as biocompatibility, biodegradability, and biological functions in addition to the stimuli-responsive characters. These "smart" hydrogels exhibit single or multiple stimuli-responsive characters which could be used in biomedical applications, including controlled drug delivery, bioengineering or tissue engineering. This review focuses on the recent developments and future trends dealing with stimuli-responsive hydrogels based on grafting/blending of polysaccharides such as chitosan, alginate, cellulose, dextran and their derivatives with thermo-sensitive polymers. This review also screens the current applications of these hydrogels in the fields of drug delivery, tissue engineering and wound healing.     

(Bio)polymeric Hydrogels as Therapeutic Agents

Hydrogels derived from both natural and synthetic polymers have gained significant scientific attention in recent years for their potential use as biomedical materials to treat human diseases. While a great deal of research efforts have been directed towards investigating polymeric hydrogels as matrices for drug delivery systems, examples of such hydrogels exhibiting intrinsic therapeutic properties are relatively less common. Characteristics of synthetic and natural polymers such as high molecular weight, diverse molecular architecture, chemical compositions, and modulated molecular weight distribution are unique to polymers. These characteristics of polymers can be utilized to discover a new generation of drugs and medical devices. For example, polymeric hydrogels can be restricted to the gastrointestinal tract, where they can selectively recognize, bind, and remove the targeted disease-causing substances from the body without causing any systemic toxicity that are associated with traditional small molecule drugs. Similarly hydrogels can be implanted at specific locations (such as knee and abdomen) to impart localized therapeutic benefits. The present article provides an overview of certain recent developments in the design and synthesis of functional hydrogels that have led to several polymer derived drugs and biomedical devices. Some of these examples include FDA-approved marketed products.     

Natural or Natural-Synthetic Hybrid Polymer-Based Fluorescent Polymeric Materials for Bio-imaging-Related Applications

Fluorescent polymeric materials such as hydrogels and particles have been attracting attention in many biomedical applications including bio-imaging, optical sensing, tissue engineering, due to their good biocompatibility, biodegradability, and advanced optical property. This review article aims at summarizing recent progress in fluorescent hydrogels and particles based on natural polymers or natural-synthetic hybrid polymers as the building blocks with a concentration on their bio-imaging-related applications. The challenges and future perspectives for the development of natural or natural-synthetic hybrid polymer-based fluorescent hydrogels and particles are also presented.     

Nanocomposite hydrogels based on carbon dots and polymers

Nanocomposite hydrogels based on carbon dots(CDs) and polymers have emerged as new materials with integrated properties of individual components,leading to their important applications in the field of soft nanomaterials.This perspective highlights recent advances in the development of nanocomposite hydrogels from CDs and polymers.We review the preparation methods of nanocomposite hydrogels based on CDs and polymers,and emerging applications of these nanocomposite hydrogels such as environmental remediation,energy storage,sensing,drug delivery and bioimaging.We conclude with the discussion of new research directions in the development of new type of nanocomposite hydrogels based on CDs and polymers.     

Injectable and biodegradable hydrogels: gelation, biodegradation and biomedical applications

Injectable hydrogels with biodegradability have in situ formability which in vitro/in vivo allows an effective and homogeneous encapsulation of drugs/cells, and convenient in vivo surgical operation in a minimally invasive way, causing smaller scar size and less pain for patients. Therefore, they have found a variety of biomedical applications, such as drug delivery, cell encapsulation, and tissue engineering. This critical review systematically summarizes the recent progresses on biodegradable and injectable hydrogels fabricated from natural polymers (chitosan, hyaluronic acid, alginates, gelatin, heparin, chondroitin sulfate, etc.) and biodegradable synthetic polymers (polypeptides, polyesters, polyphosphazenes, etc.). The review includes the novel naturally based hydrogels with high potential for biomedical applications developed in the past five years which integrate the excellent biocompatibility of natural polymers/synthetic polypeptides with structural controllability via chemical modification. The gelation and biodegradation which are two key factors to affect the cell fate or drug delivery are highlighted. A brief outlook on the future of injectable and biodegradable hydrogels is also presented (326 references).     

氧化石墨烯/聚合物复合水凝胶的研究进展

氧化石墨烯是一种具有单原子厚度的二维材料, 具有优异的力学性能和良好的水分散性, 其表面有大量的含氧官能团. 将氧化石墨烯引入水凝胶体系中可以提高水凝胶的机械性能, 丰富其刺激响应的类型. 目前, 氧化石墨烯水凝胶在高强度、 吸附、 自愈合及智能材料等很多领域均有出色的表现. 氧化石墨烯水凝胶的研究已有10年的历史. 本文总结了氧化石墨烯水凝胶的制备方法, 归纳了智能氧化石墨烯水凝胶在光热响应、 pH响应和自愈合3个方面的响应机理和研究进展, 并综合评述了其在高强度水凝胶、 生物医学、 智能材料和污水处理等方面的应用前景.     

Investigation of the swelling behavior of hydrogels derived from high-molecular-weight poly(2-ethyl-2-oxazoline)

Thermoresponsive hydrogels are of great importance as smart materials. They are usually composed of cross-linked polymers with a lower critical solution temperature (LCST). Although much is known about networks of poly(N-isopropylacrylamide), all other polymers are somewhat neglected. In this work, the temperature-dependent swelling behavior of differently cross-linked thermoresponsive poly(2-ethyl-2-oxazoline) (PEtOx) hydrogels were investigated with regard to varying parameters of the network composition. It was found that the degrees of swelling of the hydrogels converge for a certain polymer/solvent system at a distinct temperature independent of its degree of cross-linking. Furthermore, this temperature correlates with the LCST of the respective starting PEtOx. Its net chain molecular weight M_c only affects the maximum degree of swelling and thus, the swelling–deswelling rate of the hydrogel. The fundamental structure/property relations found in this study could be useful to predict the behavior of other thermoresponsive hydrogels.     

Responsive DNA‐Based Hydrogels and Their Applications

The term hydrogel describes a type of soft and wet material formed by cross‐linked hydrophilic polymers. The distinct feature of hydrogels is their ability to absorb a large amount of water and swell. The properties of a hydrogel are usually determined by the chemical properties of their constituent polymer(s). However, a group of hydrogels, called “smart hydrogels,” changes properties in response to environmental changes or external stimuli. Recently, DNA or DNA‐inspired responsive hydrogels have attracted considerable attention in construction of smart hydrogels because of the intrinsic advantages of DNA. As a biological polymer, DNA is hydrophilic, biocompatible, and highly programmable by Watson‐Crick base pairing. DNA can form a hydrogel by itself under certain conditions, and it can also be incorporated into synthetic polymers to form DNA‐hybrid hydrogels. Functional DNAs, such as aptamers and DNAzymes, provide additional molecular recognition capabilities and versatility. In this Review, DNA‐based hydrogels are discussed in terms of their stimulus response, as well as their applications.

     

仿生各向异性聚(N-异丙基丙烯酰胺)水凝胶智能响应驱动器的研究进展

各向异性水凝胶在外界的响应刺激下可以具有不同的反应机制与驱动过程. 本文综述了近期基于PNIPAM水凝胶智能响应驱动器的设计方法, 总结了多种各向异性结构对驱动性能的影响, 并对该领域所面临的挑战进行了讨论.     

Hydrogel design strategies for drug delivery

Hydrogels are water-swollen three-dimensional networks made of polymers, proteins, small molecules or colloids. They constitute a versatile platform for drug delivery because of their capacity to encapsulate and protect drugs and provide sustained and/or remotely programmable spatial and temporal release and have thus generated a substantial amount of research for the delivery of either small active compounds or biopharmaceuticals. This article discusses the features that make hydrogels attractive as matrices for delivery and reviews a range of designs, focussing on studies from recent years, in particular: ‘smart’ hydrogels (responding to temperature, light, magnetic fields, ultrasounds or combined stimuli); recent technologies: 3D printing and microneedles; and closes by discussing polymer-free drug delivery systems: peptides, small molecules and colloids.     

Stimuli‐Responsive Dipeptide–Protein Hydrogels through Schiff Base Coassembly

Different from the conventional irreversible covalent conjugations, a simple and efficient dynamic Schiff base covalent assembly is developed to construct the stable and smart dipeptide–protein hydrogels under mild conditions. Diphenylalanine–hemoglobin hydrogel is chosen to investigate the gelation formation process and mechanism. It is found that such assembled dipeptide–protein hydrogels are sensitive to pH variation, and simultaneously the proteins can be released without changing the native secondary structures from the gels. Furthermore, these adaptive hydrogels can encapsulate a series of small molecules, multicomponent proteins, and functional nanoparticles. These versatile hydrogels may find a great potential in bioapplications.     

Redox‐Responsive Resilin‐Like Hydrogels for Tissue Engineering and Drug Delivery Applications

Resilin, a protein found in insect cuticles, is renowned for its outstanding elastomeric properties. The authors' laboratory previously developed a recombinant protein, which consisted of consensus resilin‐like repeats from Anopheles gambiae, and demonstrated its potential in cartilage and vascular engineering. To broaden the versatility of the resilin‐like protein, this study utilizes a cleavable crosslinker, which contains a disulfide bond, to develop smart resilin‐like hydrogels that are redox‐responsive. The hydrogels exhibit a porous structure and a stable storage modulus (G′) of ≈3 kPa. NIH/3T3 fibroblasts cultured on hydrogels for 24 h have a high viability (>95%). In addition, the redox‐responsive hydrogels show significant degradation in a reducing environment (10 mm glutathione (GSH)). The release profiles of fluorescently labeled dextrans encapsulated within the hydrogels are assessed in vitro. For dextran that is estimated to be larger than the mesh size of the gel, faster release is observed in the presence of reducing agents due to degradation of the hydrogel networks. These studies thus demonstrate the potential of using these smart hydrogels in a variety of applications ranging from scaffolds for tissue engineering to drug delivery systems that target the intracellular reductive environments of tumors.     

天然五环三萜有机功能分子

天然五环三萜在自然界中广泛存在,由六个异戊二烯单元组成,可以从动植物中分离获取。因具有手性刚性骨架、多反应位点、独特组装性能、良好生物相容性及药理活性,其在超分子化学、智能材料、界面化学、药物传输等领域有着不可忽视的潜力。本文基于课题组近年来在天然五环三萜有机功能分子方面的工作,概述了含甘草次酸和甘草酸骨架的功能小分子和高分子的设计、合成及其在水凝胶、有机凝胶、有机-无机复合凝胶、手性材料、温敏和自愈合材料、农用Pickering乳液、准聚轮烷等方面的应用。     

Fibrous crystalline hydrogels formed from polymers possessing a linear poly(ethyleneimine) backbone

Novel thermoreversible physical hydrogels formed from polymers with linear and star architectures possessing a linear poly(ethyleneimine) (PEI) backbone have been investigated. The hydrogelation occurred simply upon natural cooling of hot aqueous solutions of PEIs to room temperature. The X-ray diffraction and differential scanning calorimetry measurements for the resultant hydrogels unambiguously indicated that the hydrogelation originated from the formation of dihydrate crystalline structures of PEI. These crystalline hydrogels are structurally unique and hierarchical. Microscopic images revealed that the morphologies of the crystalline hydrogels depend on their molecular architectures. The linear PEI resulted in branched fibrous bundles organized by unit crystalline nanofibers with a width of ca. 5-7 nm. The six-armed star with benzene ring core produced fanlike fibrous bundles while the four-armed star with porphyrin core assembled into asterlike aggregates. The critical concentration of gelation (C(G)) was low (about 0.2 approximately 0.3%) and the thermoreversible gel-sol transition temperatures (T(G)) were controllable from approximately 43 to approximately 79 degrees C. The hydrogels formed in the presence of the various aqueous additives including organic solvents, hydrophilic polymers, physical cross-linker, chemical cross-linker, and base enabling modification and functionalization during synthesis. The mechanical properties of the hydrogels could be improved by chemical cross-linking of preformed hydrogels by glutaraldehyde. Physically and physical/chemical cross-linked hydrogels served as excellent template roles in biomimetic silicification, which produced silica-PEI hybrid powder or monolith constructed by nanofibers.     

Release of chlorambucil from poly(N-isopropylacrylamide) hydrogels with beta-cyclodextrin moieties

The present work is focused on investigating the behavior of controlled drug release poly(N-isopropylacrylamide) (PNIPA) hydrogels in the presence of beta-cyclodextrin (beta-CD). For this purpose, three types of NIPA hydrogels with beta-CD moieties were synthesized with different architectures according to our previous studies. An anti-cancer drug (chlorambucil, CLB), which can form an inclusion complex with beta-CD, was selected for loading and in vitro release studies. The drug was loaded into hydrogels via a swelling method. DSC was used to study the interactions between the CLB molecules and the polymers. The results indicate that the CLB-polymer interactions are at the molecular level. Loading CLB into these polymers can result in an evident decrease in the glass transition temperature (T(g)), and the variation of T(g) (DeltaT(g)) depends on the structures of the polymers and their beta-CD content. The controlled release experiments show that the presence of beta-CD can markedly enhance CLB release from shrunken PNIPA hydrogels and increase the ratio of CLB released in total drug loading content. Release profile of CLB from hydrogels 1a-c and 4 at pH 1.4 and 7.4, at 37 degrees C.     

Peptides as New Smart Bionanomaterials: Molecular‐Recognition and Self‐Assembly Capabilities

Biomolecules express exquisite properties that are required for molecular recognition and self‐assembly on the nanoscale. These smart capabilities have developed through evolution and such biomolecules operate based on smart functions in natural systems. Recently, these remarkable smart capabilities have been utilized in not only biologically related fields, but also in materials science and engineering. A peptide‐screening technology that uses phage‐display systems has been developed based on this natural smart evolution for the generation of new functional peptide bionanomaterials. We focused on peptides that specifically bound to synthetic polymers. These polymer‐binding peptides were screened by using a phage‐display peptide library to recognize nanostructures that were derived from polymeric structural features and were utilized for possible applications as new bionanomaterials. We also focused on self‐assembling peptides with β‐sheet structures that formed nanoscale, fibrous structures for applications in new bottom‐up nanomaterials. Moreover, nanofiber‐binding peptides were also screened to introduce the desired functionalities into nanofibers without the need for additional molecular design. Our approach to construct new bionanomaterials that employ peptides will open up excellent opportunities for the next generation of materials science and technology.     

Radiation chemistry of smart polymers (A Review)

Radiation chemistry methods used to prepare smart polymers are surveyed. The properties of these polymeric materials are considered. The benefits of radiation-chemical procedures for manufacturing smart polymers are discussed. The areas of their practical use are outlined     

Synthesis and characterizations of various polyvinyl pyrrolidon/hydroxyl ethyl methacrylate nanocomposite hydrogels as drug delivery systems

Using polymer hydrogels and nanocomposites hydrogels still promising materials for many applications. Polyvinyl pyrrolidone (PVP) has been used with various polymers synthetic and natural for different applications. In this study PVP and hydroxyl ethyl methacrylate (HEMA) copolymer hydrogels were prepared by the aid of gamma radiation and the PVP/HEMA nanocomposite hydrogels were obtained by in situ adsorption and reduction method of iron salts and silver nitrates (AgNO₃) to form PVP/HEMA-Fe₃O₄ and PVP/HEMA-Ag nanocomposites. The prepared hydrogels and the formed nanoparticles were studied by various techniques; FTIR, TEM, SEM and also the gel content and swelling behavior were evaluated. The prepared hydrogels and nanocomposites hydrogels were examined as drug delivery systems for Ciprofloxacin HCl as model drug. The PVP/HEMA-Fe₃O₄ nanocomposite gave the suitable load and release behavior towards Ciprofloxacin HCl.     

Biodegradable thermo‐ and pH‐responsive hydrogels for oral drug delivery

In this article, novel smart hydrogels based on biodegradable pH sensitive poly(L ‐glutamic acid‐g‐2‐hydroxylethyl methacrylate) (PGH) chains and temperature‐sensitive hydroxypropylcellulose‐g‐acrylic acid (HPC‐g‐AA) segments were designed and synthesized. The influence of pH and temperature on the equilibrium swelling ratios of the hydrogels was discussed. The optical transmittance of the hydrogels was also changed as a function of temperature, which reflecting that the HPC‐g‐AA part of the hydrogels became hydrophobic at the temperature above the lower critical solution temperature (LCST). At the same time, the LCST of the hydrogels had a visible pH‐dependent behavior. Scanning electron microscopic analysis revealed the morphology of the hydrogels before and after enzymatic degradation. The biodegradation rate of the hydrogels was directly related to the PGH content and the pH value. The in vitro release of bovine serum albumin from the hydrogels were investigated. The release profiles indicated that both the HPC‐g‐AA and PGH contents played important roles in the drug release behaviors. These results show that the smart hydrogels seem to be of great promise in pH–temperature oral drug delivery systems. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Acidic polysaccharide mimics via ring-opening metathesis polymerization

An efficient and general synthetic strategy for the preparation of high-molecular-weight hydrophilic polymers bearing both carboxylic acid and hydroxyl pendant groups is described. Specifically, poly(5,6-dihydroxyoxanorbornane carboxylic acid) with molecular weight ranging from ～100?000 to 5?000?000 g/mol was prepared by ring-opening metathesis polymerization of methyl 5-oxanorbornene-2-carboxylate in the presence of Grubbs catalyst II and subsequently modified to tune the hydrophobic/hydrophilic properties by the introduction of either hydroxyl or carboxylic acid functionalities. These polymers mimic the natural acidic polysaccharide alginate and form hydrogels with polylysine. These polymers belong to a class of carbohydrate-like polymers, which are of interest for investigating the relationships between chemical structure and rheological properties as well as for providing new synthetic polysaccharide substitutes for applications in the biotechnology and pharmaceutical industries.