Temperature-responsive Materials Research Articles

Thermo-sensitive gellan maleate/N-isopropylacrylamide hydrogels: initial “in vitro” and “in vivo” evaluation as ocular inserts

Hydrogels are among the most used polymer–drug systems, polysaccharide-based materials presenting many advantages to be used for controlled release applications. Gellan maleate/NIPAm hydrogels are hydrophilic swelling matrixes that were originally developed for biomedical applications as controlled release dosage forms. The purpose of this study is to explore the ability of gellan maleate/NIPAm thermoreversible hydrogels for ophthalmic applications as ocular inserts. Studied hydrogels were synthesized by free radical grafting/polymerization of unsaturated esters (gellan maleate) with N-isopropylacrylamide (NIPAm) and N,N′-methylenebisacrylamide as cross-linker. They are evaluated for swelling degree, in vitro inclusion and release of drugs (adrenaline and chloramphenicol) and in vivo biocompatibility. The hydrogel is shown to be a temperature-responsive material with a LCST close to 36 °C. The swelling properties and the release of biologically active compounds occur when polymer conformation changes determining phase transition at LCST. Gellan-based hydrogels present reproducible responses to alternation between ambient temperature and human body one. The stability and biocompatibility were evaluated in vitro and in vivo. Tissue response to implantation of hydrogel was determined by histological analysis (haematoxylin–eosin–methylene blue and periodic acid–Schiff). A thin fibrous capsule was observed around the implanted hydrogels. No necrosis, calcification and acute inflammatory reaction were noted. Successful preliminary results were obtained for ophthalmic applications.

Synthesis and characterization of novel trimellitic anhydride isothiocyanate-cross linked chitosan hydrogels modified with multi-walled carbon nanotubes for enhancement of antimicrobial activity.

Novel trimellitic anhydride isothiocyanate was successfully synthesized and utilized in various concentrations to obtain four novel cross linked chitosan hydrogels H1-H4. Three multi-walled carbon nanotube (MWCNT) biocomposites based on H1 were also prepared. Their structures were proven by elemental analysis, FTIR, XRD, SEM and TEM. They were found to be pH- and temperature-responsive materials. Their swell abilities appreciably depend on their cross linking moiety contents and MWCNTs concentration. They are more potent against Bacillis subtilis, Streptococcus pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Geotrichum candidum, Candida albicans, Aspergillus fumigatus, and Syncephalastrum racemosum than chitosan as judged by their greater inhibition zone diameters and their lower minimum inhibitory concentration (MIC) values. Their antimicrobial activities increased with increasing their cross linking moiety contents. They showed a better potency against Gram-positive than Gram-negative bacteria. The hydrogel H4 and H1/MWCNT composites have comparable or even higher activities than the reference bactericides or fungicides against some of tested microbes. Thus, combination between chitosan and the functionalized groups of the incorporated cross linker as well as MWCNTs in one system has efficiently improved the chitosan features. It is a good way for attaining adequate systems as antimicrobial agents that can be taken as promising candidates in biomedical fields.

Study of poly (N-isopropyl acrylamide) electrospinning magnetic fiber as a cell attach/detach substrate

In this study, we used electrospinning technology to develop a novel composite material with temperature and magnetic responsive characteristics which physical and chemical parameters were verified. Poly(N-isopropylacrylamide), PNIPAAm polymer was chosen as the main material for the spinning process, to prepare the temperature-responsive material with a hydrophobic/hydrophilic fiber structure. The fibers prepared by the electrospinning method resulted in high pores and high volume-surface area that can serve as substrates for cell tissue engineering applications. The material was then integrated with magnetic nanoparticles which led to composite materials of magnetic temperature-responsive spinning fibers and can further be used as a substrate material in the biomedical engineering field. Field-scanning emission electron microscopy (FSEM) and transmission electron microscopy (TEM) were used to characterize the spinning fibers diameter and surface morphology. The superconducting quantum interference device (SQUID) and thermogravimetric analyzer (TGA) were used to analyze the amount of magnetic nanoparticles confined in the magnetic temperature-responsive spinning fiber. The proportion of magnetic particles in magnetic temperature-responsive spinning fiber from SQUID and TGA analysis was 3.44% and 4.07%, respectively. This study successfully established the preparation of temperature-responsive spinning fiber with extracellular matrix structure through an electrospinning technique. In the future, this composite material with the advantage of switchable hydrophilic/hydrophobic temperature-responsive and magnetic induction properties can further be used in the field of biomedical engineering applications, such as drug-carrier, drug release, skin wound healing, and magnetic high-frequency heat treatment.

Drug-Loaded Biocompatible Nanocarriers Embedded in Poloxamer 407 Hydrogels as Therapeutic Formulations.

Hydrogels are three-dimensional networks of hydrophilic polymers able to absorb and retain a considerable amount of water or biological fluid while maintaining their structure. Among these, thermo-sensitive hydrogels, characterized by a temperature-dependent sol–gel transition, have been massively used as drug delivery systems for the controlled release of various bioactives. Poloxamer 407 (P407) is an ABA-type triblock copolymer with a center block of hydrophobic polypropylene oxide (PPO) between two hydrophilic polyethyleneoxide (PEO) lateral chains. Due to its unique thermo-reversible gelation properties, P407 has been widely investigated as a temperature-responsive material. The gelation phenomenon of P407 aqueous solutions is reversible and characterized by a sol–gel transition temperature. The nanoencapsulation of drugs within biocompatible delivery systems dispersed in P407 hydrogels is a strategy used to increase the local residence time of various bioactives at the injection site. In this mini-review, the state of the art of the most important mixed systems made up of colloidal carriers localized within a P407 hydrogel will be provided in order to illustrate the possibility of obtaining a controlled release of the entrapped drugs and an increase in their therapeutic efficacy as a function of the biomaterial used.

Synthesis of Thermally Switchable Chromatographic Materials with Immobilized Ti4+ for Enrichment of Phosphopeptides by Reversible Addition Fragmentation Chain Transfer Polymerization

Reversible phosphorylation of proteins is one of the most crucial types of post-translational modifications (PTMs). And it shows significant work in diversified biological processes. However, the separation technology of phosphorylated peptides is still an analytical challenge in phosphoproteomics, because phosphopeptides are alway in low stoichiometry. Thus, enrichment of phosphopeptides before detection is indispensable. In this study, a novel temperature regulated separation protocol was developed. Silica@p (NIPAAm-co-IPPA)-Ti4+, a new Ti(IV)-IMAC (Immobilized Metal Affinity chromatography) materials was synthesized by reversible addition fragmentation chain transfer polymerization (RAFT). By the unique thermally responsive properties of poly(N-isopropylacrylamide) (PNIPAAm), the captured phosphorylated peptides could be released by changing temperature only without applying any other eluant which could damage the phosphopeptides. We employed isopropanol phosphonic acid (IPPA) as an IMAC ligand for the immobilization of Ti(IV) which could increase the specific adsorption of phosphopeptides. The enrichment and release properties were examined by treatment with pyridoxal 5’-phosphate (PLP) and casein phosphopeptides (CPP). Two phosphorylated compounds above have temperature-stimulated binding to Ti4+. Finally, silica@p (NIPAAm-co-IPPA)-Ti4+ was successfully employed in pretreatment of phosphopeptides in a tryptic digest of a-casein and human serum albumin (HSA). The results indicated a great potential of this new temperature-responsive material in phosphoproteomics study.

Thermally Induced Bending of ReS2 Nanowalls.

Among the variety of stimuli-responsive materials, temperature-responsive materials (TRMs) can adapt to the surrounding environment in the presence of a thermal stimulus, and they have attracted considerable attention in sensors, actuators, and surface engineering. However, polymers, as the most representative TRMs, are far from ideal with respect to long-term reliability and durability. Here, for the first time, an inorganic material, ReS2 , is analyzed, which possesses an unexpected temperature-responsive behavior that is triggered by stable and reversible thermally induced bending (TIB). Due to thermal fluctuations in the ReS2 layers, intrinsic ripples tend to aggravate rapidly with rising temperature. Then, the weak interlayer interaction of ReS2 is further weakened, thus resulting in interlayer sliding. Due to a decrease in bending rigidity with increasing temperature, out-of-plane bending spontaneously occurs in the ReS2 layers. Interestingly, this TIB of ReS2 can recover to its initial configuration when the temperature drops, which is further confirmed by the reversible wetting measurement. Above all, the TIB behavior of ReS2 exhibits great potential in smart applications, such as smart windows and microfluidic devices, and fills the significant gaps of inorganic TRMs.

Thermoresponsive graphene oxide - starch micro/nanohydrogel composite as biocompatible drug delivery system.

Introduction: Stimuli-responsive hydrogels, which indicate a significant response to the environmental change (e.g., pH, temperature, light, …), have potential applications for tissue engineering, drug delivery systems, cell therapy, artificial muscles, biosensors, etc. Among the temperature-responsive materials, poly (N-isopropylacrylamide) (PNIPAAm) based hydrogels have been widely developed and their properties can be easily tailored by manipulating the properties of the hydrogel and the composite material. Graphene oxide (GO), as a multifunctional and biocompatible nanosheet, can efficiently improve the mechanical strength and response rate of PNIPAAm-based hydrogels. Here, hydrogel composites (HCs) of PNIPAAm with GO was developed using the modified starch as a biodegradable cross-linker. Methods: Micro/nanohydrogel composites were synthesized by free radical polymerization of NIPAAm in the suspension of different feed ratio of GO using maleate-modified starch (St-MA) as cross-linker and Tetrakis (hydroxymethyl) phosphonium chloride (THPC) as a strong oxygen scavenger. The HCs were characterized by FT-IR, DSC, TGA, SEM, and DLS. Also, the phase transition, swelling/deswelling behavior, hemocompatibility and biocompatibility of the synthesized HCs were investigated. Results: The thermal stability, phase transition temperature and internal network crosslinking of HCs increases with increasing of the GO feed ratio. Also, the swelling/deswelling, hemolysis, and MTT assays studies confirmed that the HCs are a fast response, hemocompatible and biocompatible materials. Conclusion: The employed facile approach for the synthesis of HCs yields an intelligent material with great potential for biomedical applications.

Xanthate-Functional Temperature-Responsive Polymers: Effect on Lower Critical Solution Temperature Behavior and Affinity toward Sulfide Surfaces.

Xanthate-functional polymers represent an exciting opportunity to provide temperature-responsive materials with the ability to selectively attach to specific metals, while also modifying the lower critical solution temperature (LCST) behavior. To investigate this, random copolymers of poly(N-isopropylacrylamide) (PNIPAM) with xanthate incorporations ranging from 2 to 32% were prepared via free radical polymerization. Functionalization with 2% xanthate increased the LCST by 5 °C relative to the same polymer without xanthate. With increasing xanthate composition, the transition temperature increased and the transition range broadened until a critical composition of the hydrophilic xanthate groups (≥18%) where the transition disappeared completely. The adsorption of the polymers at room temperature onto chalcopyrite (CuFeS2) surfaces increased with xanthate composition, while adsorption onto quartz (SiO2) was negligible. These findings demonstrate the affinity of these functional smart polymers toward copper iron sulfide relative to quartz surfaces, presumably due to the interactions between xanthate and specific metal centers.

Injectable Reverse Thermal Gel Biopolymers may Act as an Extracellular Matrix and Cell Vehicle for Cardiac Tissue Engineering

Background: Recent investigations demonstrated that tissue engineering represents a promising strategy to repair diseased hearts. We hypothesized that temperature-responsive materials could be developed as extracellular matrix scaffolds and cell delivery vehicles could be used in cardiac tissue engineering.Methods and results: We developed injectable reverse thermal gel (RTG) biopolymers that are designed to transition from low viscous liquid to a solid gel by exposure to body temperature. This allows deployment through a small gauge needle to the target area with minimal surgical intervention. For this study we tested different RTG biopolymers with and without chemical incorporation of laminin. In vitro 3D culture experiments were performed with adult rat ventricular myocytes (ARVM) by mixing 3x103 cells with 50 μl of liquid-phase polymeric solution (25°C) and permitting transition to a gel at 37°C. These cultured cells were incubated 8 days in the gel matrix. As controls, ARVMs were plated on 2D traditional laminin coated dishes. Compared to control groups, we found that the 3D matrix improved ARVM viability: after 3 days of culture, ARVM viability increased by 27% and 17% in the RTG-laminin and in the RTG, respectively. At the 8th day of culture, 63% of the ARVMs in the RTG-laminin group were rod shaped and viable, while in RTG and control groups, most of the ARVMs were round shaped and non-viable.Conclusion: These preliminary proof-of-concept results demonstrate excellent cell viability in the RTG-laminin biopolymer for up to 8 days and show feasibility of a novel cell delivery system that permits reversible liquid-to-gel transition from room to body temperature. This holds tremendous potential for cardiac tissue engineering.

Formation of supported lipid bilayers on silica: relation to lipid phase transition temperature and liposome size

DPPC liposomes ranging from 90 nm to 160 nm in diameter were prepared and used for studies of the formation of supported lipid membranes on silica (SiO2) at temperatures below and above the gel to liquid-crystalline phase transition temperature (Tm = 41 °C), and by applying temperature gradients through Tm. The main method was the quartz crystal microbalance with dissipation (QCM-D) technique. It was found that liposomes smaller than 100 nm spontaneously rupture on the silica surface when deposited at a temperature above Tm and at a critical surface coverage, following a well-established pathway. In contrast, DPPC liposomes larger than 160 nm do not rupture on the surface when adsorbed at 22 °C or at 50 °C. However, when liposomes of this size are first adsorbed at 22 °C and at a high enough surface coverage, after which they are subject to a constant temperature gradient up to 50 °C, they rupture and fuse to a bilayer, a process that is initiated around Tm. The results are discussed and interpreted considering a combination of effects derived from liposome-surface and liposome-liposome interactions, different softness/stiffness and shape of liposomes below and above Tm, the dynamics and thermal activation of the bilayers occurring around Tm and (for liposomes containing 33% of NaCl) osmotic pressure. These findings are valuable both for preparation of supported lipid bilayer cell membrane mimics and for designing temperature-responsive material coatings.

Temperature-sensitive polymers for drug delivery

The ability to undergo rapid changes in response to subtle environmental cues make stimuli- responsive materials attractive candidates for minimally invasive, targeted and personalized drug delivery applications. This special report aims to highlight and provide a brief description of several of the significant natural and synthetic temperature-responsive materials that have clinical relevance for drug delivery applications. This report examines the advantages and disadvantages of natural versus synthetic materials and outlines various scaffold architectures that can be utilized with temperature-sensitive drug delivery materials. The authors provide a commentary on the current state of the field and provide their insight into future expectations for temperature-sensitive drug delivery, emphasizing the importance of the emergence of dual and multiresponsive systems capable of responding precisely to an expanding set of stimuli, thereby allowing the development of disease-specific drug delivery vehicles.

Dielectric Properties of Thermo-Reversible Hydrogels: The Case of a Dextran Copolymer Grafted with Poly(N-isopropylacrylamide)

We investigated the dielectric properties of aqueous solutions of a grafted copolymer, consisting of a polysaccharide, Dextran, grafted with a thermo-sensitive polymer, poly(N-isopropylacrylamide), [pNIPAAM], over broad temperature and frequency ranges. The graft copolymers, prepared by atom-transfer radical polymerization [ATRP], form temperature-responsive materials that represent a class of self-assembled structures in water of great interest because of their potential use as drug delivery formulations and in diverse biotechnological applications. In these systems, in the dilute regime and below the lower critical solution temperature, relaxation modes corresponding to two different length-scales have been observed and analyzed in terms of ion fluctuation dielectric models specifically developed to describe the dielectric relaxation in highly charged polyion aqueous solutions. Regardless of whether the ions were produced by the ionization of the polymer chain, as in polyelectrolyte solutions, or not, as in the present case, they represent a probe at a microscopic level that is expected to reveal the structural characteristics of the system at different scales. We have identified a characteristic length associated with the size of the polymer coil in the dilute regime and a length due to fixed cross-links, where ions are partially localized by the local profile of the Coulombic field. These lengths are in reasonable agreement with analogous lengths derived from structural information and from the hydrodynamic radius of the polymer coils, measured by means of a dynamic light-scattering technique.

Temperature-responsive cross-linked poly(ε-caprolactone) membrane that functions near body temperature

The objective of this study is to develop a sensitive temperature-responsive material that would function near body temperature. To achieve this purpose, we compounded 2-branched and 4-branched poly(ε-caprolactone) macromonomers to modulate the transition temperatures of the resulting cross-linked materials. The temperature-responsive properties were studied using differential scanning calorimetry and X-ray diffraction measurements. As a result, the mixing ratios of each macromonomer or the total macromonomer concentrations were very dominant in modulating the transition temperatures. The materials could successfully control the permeation of the model drug, prednisolone, near body temperature.

Responsive Polymer/Clay Aerogel Composites

AbstractClay aerogels are a relatively unexplored form of matter that are only now being investigated for use in the reinforcement of organic polymers. We have recently demonstrated an efficient process for producing these aerogels; we now report our preliminary work describing the preparation and properties of polymer/clay aerogel composites, including temperature-responsive materials.