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A novel stimuli-responsive hydrogel for K +-induced controlled-release
Abstract
A novel family of stimuli-responsive smart hydrogel is developed in this study for K+-induced self-regulated controlled-release, which is featured with isothermally K+-induced pulse-release mode at a certain temperature due to the isothermally K+-induced shrinking behavior of the hydrogel by recognizing the increase of K+ concentration in the environment. The proposed poly(N-isopropylacrylamide-co-benzo-15-crown-5-acrylamide) hydrogel is composed of crown ether 15-crown-5 as ion-signal sensing receptor and poly(N-isopropylacrylamide) as actuator. The selective formation of stable 2:1 “host-guest” complexation between the crown ether 15-crown-5 and potassium ion drives the polymeric network of the hydrogel to shrink; as a result, the hydrogel exhibits especial and selective response to potassium ions. A K+-recognition pulse-release performance of loaded drug from the fabricated hydrogel is achieved by using the K+-induced isothermal shrinkage property of the hydrogel. The proposed hydrogel provides a new mode of K+-recognition volume change for stimuli-responsive smart actuators, which is highly attractive for targeting drug delivery systems, biomedical devices, and sensors and so on.
... When 15-crown-5 groups are incorporated with PNIPAM chains, the LCST value of this copolymer in pure water (34°C) is close to that of PNIPAM [35,36]. However, when K + ions are added into the copolymer aqueous solution, the hydrogen bonding between the oxygen atoms of the crown ether groups and the hydrogen atoms of the water molecules is disrupted because the 15-crown-5 receptors from the adjacent P(NIPAM-co-AAB 15 C 5 ) capture K + to form 2:1 "sandwich" complexes [35,[37][38][39]. In other words, the presence of K + in the environmental solution enhances the hydrophobicity of P(NIPAM-co-AAB 15 C 5 ) and consequently makes its LCST decrease [35,36,39]. ...
... However, when K + ions are added into the copolymer aqueous solution, the hydrogen bonding between the oxygen atoms of the crown ether groups and the hydrogen atoms of the water molecules is disrupted because the 15-crown-5 receptors from the adjacent P(NIPAM-co-AAB 15 C 5 ) capture K + to form 2:1 "sandwich" complexes [35,[37][38][39]. In other words, the presence of K + in the environmental solution enhances the hydrophobicity of P(NIPAM-co-AAB 15 C 5 ) and consequently makes its LCST decrease [35,36,39]. When the environmental temperature is chosen between the two LCST values, the polymer chains will isothermally shrink and aggregate in response to the presence of K + [35][36][37][38]. ...
Thin-film composite (TFC) nanofiltration (NF) membranes were fabricated via the interfacial polymerization of piperazine (PIP) and 1,3,5-benzenetricarbonyl trichloride (TMC) on polysulfone (PSf) support membranes blended with K+-responsive poly(N-isopropylacryamide-co-acryloylamidobenzo-15-crown-5) (P(NIPAM-co-AAB15C5)). Membranes were characterized by ATR-FTIR, XPS, AFM, SEM, contact angle, and filtration tests. The results showed that: (1) under K+-free conditions, the blended P(NIPAM-co-AAB15C5)/PSf supports had porous and hydrophilic surfaces, thereby producing NF membranes with smooth surfaces and low MgSO4 rejections; (2) with K+ in the PIP solution, the surface roughness and water permeability of the resultant NF membrane were increased due to the K+-induced transition of low-content P(NIPAM-co-AAB15C5) from hydrophilic to hydrophobic; (3) after a curing treatment at 95 °C, the improved NF membrane achieved an even higher pure water permeability of 10.97 L·m-2·h-1·bar-1 under 200 psi. Overall, this study provides a novel method to improve the performance of NF membranes and helps understand the influence of supports on TFC membranes.
... Since the extent of alginate gel swelling was tuned by the volume of wound exudates, the release rate of nano-silver was effectively self-regulated during the wound healing process, achieving a closed-loop drug delivery strategy. Chu and coworkers also developed a K + -sensitive hydrogel consisting of crown ether 15-crown-5 as the ion-sensor and poly(Nisopropylacrylamide) as the actuator for self-regulated controlled release (Mi et al., 2010). In this system, K + bound to the crown ether 15-crown-5 based on a 2:1 "host-guest" complexation formulation to drive the shrinkage of the hydrogel, giving a pulse-release mode that was regulated by changing environmental K + concentration. ...
... Targeting drug delivery (Mi et al., 2010) ...
Controlled drug delivery systems are able to improve efficacy and safety of therapeutics by optimizing the duration and kinetics of release. Among them, closed-loop delivery strategies, also known as self-regulated administration, have proven to be a practical tool for homeostatic regulation, by tuning drug release as a function of biosignals relevant to physiological and pathological processes. A typical example is glucose-responsive insulin delivery system, which can mimic the pancreatic beta cells to release insulin with a proper dose at a proper time point by responding to plasma glucose levels. Similar self-regulated systems are also important in the treatment of other diseases including thrombosis and bacterial infection. In this review, we survey the recent advances in bioresponsive closed-loop drug delivery systems, including glucose-responsive, enzyme-activated, and other biosignal-mediated delivery systems. We also discuss the future opportunities and challenges in this field.
... Thus, ion-sensitive drug delivery systems have been developed by using ions to trigger drug release [315]. Some ion-sensitive materials could be applied to construct this type of nanocarriers [316][317][318][319][320][321], such as, crown ethers, gellan gum, alginates, MOF, carboxymethyl chitosan, carboxymethyl cellulose, poly(styrenedivinyl benzene) sulfonic acid and methacrylate, etc. For instance, the Ca 2+ -responsive Pickering emulsions were prepared by poly(4styrenesulfonic acid-co-maleic acid) sodium salt (PSSMA) nanoaggregates [322]. ...
... Poly(N-isopropylacrylamide) (PNI-PAM) is a thermo-sensitive polymer. The crown ether moiety of BCAm can form complexes with K + , which alters its hydrophilicity and induces the phase transition of poly-(NIPAM-co-BCAm). Owing to their K + -responsiveness, hydrogels, 29,30 membranes, 31−34 colloidal particles, and microspheres 35,36 have been widely investigated. Using poly-(NIPAM-co-BCAm) as the arms of star polymers, novel ionresponsive star polymers are expected to be developed. ...
Stimuli-responsive star polymers are promising functional materials whose aggregation, adhesion, and interaction with cells can be altered by applying suitable stimuli. Among several stimuli assessed, the potassium ion (K+), which is known to be captured by crown ethers, is of considerable interest because of the role it plays in the body. In this study, a K+-responsive star copolymer was developed using a polyglycerol (PG) core and grafted copolymer arms consisting of a thermo-responsive poly(N-isopropylacrylamide) unit, a metal ion-recognizing benzo-18-crown-6-acrylamide unit, and a photoluminescent fluorescein O-methacrylate unit. Via optimization of grafting density and copolymerization ratio of grafted arms, along with the use of hydrophilic hyperbranched core, microsized aggregates with a diameter of 5.5 μm were successfully formed in the absence of K+ ions without inducing severe sedimentation (the lower critical solution temperature (LCST) was 35.6 °C). In the presence of K+ ions, these aggregates dispersed due to the shift in LCST (47.2 °C at 160 mM K+), which further induced the activation of fluorescence that was quenched in the aggregated state. Furthermore, macrophage targeting based on the micron-sized aggregation state and subsequent fluorescence activation of the developed star copolymers in response to an increase in intracellular K+ concentration were performed as a potential K+ probe or K+-responsive drug delivery vehicle.
... Within the range of temperatures, the hydrogel could undergo isothermally volume shrinkage upon the recognition of K + , which served as a trigger to release preloaded drugs. 528 In summary, noncovalent interactions have been a powerful tool for designing stimuli-responsive hydrogels, because of extensive choices of building blocks, facile tunability, easy controllability, benign biocompatibility, and so on. ...
Noncovalent interactions, which usually feature tunable strength, reversibility, and environmental adaptability, have been recognized as driving forces in a variety of biological and chemical processes, contributing to the recognition between molecules, the formation of molecule clusters, and the establishment of complex structures of macromolecules. The marriage of noncovalent interactions and conventional covalent polymers offers the systems novel mechanical, physicochemical, and biological properties, which are highly dependent on the binding mechanisms of the noncovalent interactions that can be illuminated via quantification. This review systematically discusses the nanomechanical characterization of typical noncovalent interactions in polymeric systems, mainly through direct force measurements at microscopic, nanoscopic, and molecular levels, which provide quantitative information (e.g., ranges, strengths, and dynamics) on the binding behaviors. The fundamental understandings of intermolecular and interfacial interactions are then correlated to the macroscopic performances of a series of noncovalently bonded polymers, whose functions (e.g., stimuli-responsiveness, self-healing capacity, universal adhesiveness) can be customized through the manipulation of the noncovalent interactions, providing insights into the rational design of advanced materials with applications in biomedical, energy, environmental, and other engineering fields.
... Since the extent of alginate gel swelling was tuned by the volume of wound exudates, the release rate of nanosilver was effectively self-regulated during the wound healing process, achieving a closed-loop drug delivery strategy. Mi and coworkers also developed a K+sensitive hydrogel consisting of crown ether 15crown-5 as the ion-sensor and poly(Nisopropylacrylamide) as the actuator for self-regulated controlled release [25]. In this system, K+ bound to the crown ether 15-crown-5 based on a 2:1 "host-guest" complexation formulation to drive the shrinkage of the hydrogel, giving a pulse-release mode that was regulated by changing environmental K+ concentration. ...
During the past several decades, many sensing mechanisms have emerged, which provide new control strategies for designing closed-loop drug delivery systems. For such systems, numerous bioresponsive materials are utilized to construct functional modules for the desired devices. The typical closed-loop drug delivery systems recently reported in this review. The stimuli-responsive polymers serve to provide a snapshot of the utility and complexity of polymers that can sense, process, and respond to stimuli in modulating the release of a drug. Stimuli-responsive drug delivery vehicles come in the form of polymersomes, liposomes, micelles and dendrimers. Therapeutics is designed to be controlled released from drug carriers through the structural transformations such as shrinking, swelling, and dissociation or unique responsive cleavage route.
... Smart hydrogels have attracted increasing attention since they can exhibit dramatic change of volume or other properties in responding to external stimuli, such as temperature [1][2][3], pH [4][5][6][7][8], humidity [9][10][11][12], special ions or molecules [13][14][15][16], ionic strength or electric field [17,18]. They are often involved in liquid environments, i.e., salt solutions, organic solvents, or both of them when applied in the field of cell culture, drug delivery, plant cultivation, soft actuator, etc. ...
In this paper, the reentrant solvation of dual nanocomposite hydrogel poly-N-isopropylacryl-amide/Laponite/SiO2 (PNIPAM/Laponite/SiO2) upon shrinkage/reswelling process has been investigated. Depending on the unique hierarchical microstructure of inorganic hybrid crosslinking of Laponite and SiO2 as well as the preferential interaction of polar solvents with PNIPAM chains, the hydrogel exhibited rapid coil-to-globule-to-coil transition in water-polar solvent mixtures. The solvation behavior could be controlled through varying types of organic solvents. Shrinkage in water-polar solvent mixtures occurred as a conse-quence of strong interaction between polar solvents and PNIPAM chains, whereas reswelling resulted from the direct interaction of the solvent molecules with the intermolecular water in the hydrogel. The attractive competing effects on forming hydrogel-water and hydrogel-polar solvent hydrogen bonds were considered to be indispensable to the solvation. The rapid response rate was attributed to the synergistic effect of the unique heterogeneous microstructure with inorganic hybrid crosslinking and preferential interaction of polar solvents with polymer chains. The mechanism proposed in this paper provides a new reference on design of smart soft matter systems. Moreover, several solvation effects described in this paper can be incorporated in theory of cononsolvent-induced conformational transitions in the nanocomposite hydrogels with inorganic hybrid crosslinking.
... N-isopropylacrylamide (NIPAM, purchased from Rhawn) is purified by recrystallization with a hexane/acetone mixture (v/ v, 50/50). Benzo-15-crown-5-acrylamide (B15C5Am) is synthesized from 4′-nitro-benzo-15-crown-5 (NB15C5, TCI) according to previously reported procedures (Mi et al., 2008;Mi et al., 2010). N, N-dimethylacrylamide (DMAm, Sigma-Aldrich) is passed through a previously washed prepacked column of inhibitor removers (Aldrich). ...
Curcumin (CUR) is a natural bioactive compound that has attracted attention as a “golden molecule” due to its therapeutic properties against several types of tumors. Nonetheless, the antitumor application of CUR is hampered due to its extremely low aqueous solubility and chemical instability. Herein, a novel type of CUR-loaded polymeric micelles with intracellular K⁺-responsive controlled-release properties is designed and developed. The polymeric micelles are self-assembled by poly (N-isopropylacrylamide-co-acryloylamidobenzo-15-crown-5-co-N, N-dimethylacrylamide)-b-DSPE (PNDB-b-DSPE) block copolymers, and CUR. CUR is successfully loaded into the micelles with a CUR loading content of 6.26 wt%. The proposed CUR-PNDB-DSPE polymeric micelles exhibit a significant CUR release in simulated intracellular fluid due to the formation of 2 : 1 ‘‘sandwich’’ host–guest complexes of 15-crown-5 and K⁺, which lead to the hydrophilic outer shell of micelles to collapse and the drug to rapidly migrate out of the micelles. In vitro, the B16F10 cell experiment indicates that CUR-PNDB-DSPE micelles exhibit a high cellular uptake and excellent intracellular drug release in response to the intracellular K⁺ concentration. Moreover, CUR-PNDB-DSPE micelles show high cytotoxicity to B16F10 cells compared to free CUR and CUR-PEG-DSPE micelles. The polymeric micelles with intracellular K⁺-responsive controlled release properties proposed in this study provide a new strategy for designing novel targeted drug delivery systems for CUR delivery for cancer treatment.
... In general, to deliver drugs in locally heated tissue, the load of such materials should remain stable in normal tissues at 37 C, but sensitive to and responsive to slight temperature changes (such as changing from hydrophilic to hydrophobic) [20]. Temperature-sensitive materials are the key component of thermo-responsive nano-carriers, which mainly include poly (N-isopropyl acrylamide) (PNIPAM) [80,81], poly (Ninylisobutyramide) (PAMAM) [82], poly (2-oxazoline) (POxs) [83], poly [2-(2-methoxyethoxy) ethylmethacrylate] [PMEOMA] [84], etc. As far as we know, the affected area of arthritis is characterized by a higher temperature than that of normal tissue even without external thermal stimulus [85]. ...
Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.
... With the degradation of the hydrogel and the decomposition of the complex sCT-OCA, the calcitonin was sustained release slowly from the insitu gel system [107]. The temperature sensitive materials are mainly including poly (N isopropylacrylamide) (PNIPAM) [108,109], poly (Ninyisobutyramide) (PAMAM) [110], poly(2-oxazoline) (POxs) [111], and poly [2-(2-methoxyethoxy) ethyl methacrylate] [PMEOMA], etc. Besides, another strategy for achieving thermal-sensitivity is to incorporate thermal-unstable materials inside nanocarriers. For instance, the NH4HCO3 incorporated liposome could generate CO2 after giving local hyperemia (42°C) to make liposome swollen and collapse [112], leading to drug release for efficient intracellular drug delivery. ...
This review describes some commercially accessible stimuli-responsive polymers of synthetic and natural origin, and their applications in drug delivery with the help of nanocarriers and treating cancer like dosages. The polymers of natural origin such as gelatin, albumin, cellulose, and chitosan are found to exhibit both pH-responsive and thermo-responsive properties and these features of the biopolymers impart sensitivity to act differently under different pH and temperatures conditions. Stimuli-responsive biomaterials that include logic gates maintain excellent potential for detecting and responding to pathological markers as phase of medical treatments that they are not perfecting. Some virtually essential thermo-responsive polymers such as poly (N-isopropyl acrylamide) (pNIPAAM)and Pluronic F127 (PF127) of synthetic origin has been mentioned in the review. In recent years, a lot of progress has been impelled in stimuli-responsive nanocarriers, that might response to the pathological and intrinsic physicochemical factors in diseased regions to extend the specificity Currently, various nanocarriers are designed with physicochemical changes in responding to external stimuli, like ultrasound, thermal, light, and magnetic field, as well as internal stimuli, including hydro gen ion concentration. This review has summarized the general strategies of developing stimuli-responsive nanocarriers and recent advances, presented their applications in drug delivery, treatment and tumor diagnosis with help of stimuli-responsive polymers. Owing to precise stimuli response, stimuli-responsive drug delivery systems will management drug release, thus on improve the curative effects, reduce the harm of organs and normal tissues and reduce the side effects of traditional anti-cancer medicine.
... 2 Of particular interest is the 15-crown-5 cavity, which is able to form a complex stoichiometry of 1:1 with either Li + or Na + but 2:1 with K + . 3−5 This 2:1 sandwich-type structure is widely adopted for the development of drug release systems, 6 smart membranes, 7 and highly selective sensors 8−11 through the detection of K + -induced changes in electrochemical impedance, absorbance, or fluorescence. However, the detection of K + -induced changes in the junction conductance of crown ethers has not been fully addressed at the molecular level. ...
The formation of a 2:1 sandwich-type complex of 15-crown-5 with K+ has been previously used for the development of smart materials and devices through detecting K+-induced changes in absorbance, electrochemical impedance, and fluorescence. However, K+-induced changes in the junction conductance of crown ethers have not been fully addressed at the molecular level. An understanding of such properties would not only advance our fundamental knowledge of electronic transport in crown ethers, but also lead to practical sensing applications. Here, we synthesized a rigid and structurally well-defined oligo(phenyleneethynylene) (OPE) molecular wire functionalized with a 15-crown-5 ether moiety (1) as a binding framework, to measure conductance in the presence of various metal cations using the STM-BJ technique. The conductance of 1 with either Li+, Na+ or Rb+ experienced a slight increase over that of 1 alone, and followed an ascending linear trend with the increasing effective ionic charge (ze/r), Conversely, the conductance of 1 with K+ exhibited a significant four-fold increase over that of 1. Quantum transport calculations subsequently confirmed that the K+-induced increase in conductance was due to the formation of a 2:1 K+ sandwich-type complex junction, with a ‘4-anchor’ binding mode found to be the favored configuration. These findings provide a solid foundation for the design of practical molecular electronic components that can be incorporated into novel sensing devices.
... Hydrogels have extensive industrial applications, therefore, research on the development of new class of hydrogels and the modification of already existing are significantly increasing. Hydrogels have intermediate properties of solid and liquid materials and most of their applications are related to their ability to respond with a little change in different external stimuli such as temperature, pH, salt, electrical and magnetic fields [1][2][3][4][5]. Some characteristic properties of hydrogels such as ability to swell in water without changing shape, inert nature towards most of the chemicals, higher loading capacity and non-toxicity make them a suitable material to use extensively in a large number of industrial applications such as slow and restricted release of various drugs and agrochemicals [6][7][8], soft tissue engineering [9], making of contact lenses [10], wound dressing [11] and water purification [12][13][14]. ...
This work reports the synthesis of lipase enzyme catalyzed biodegradable hydrogel interpenetrating polymer network (hydrogel-IPN) of natural gum polysaccharide i.e. gum tragacanth (GT) with acrylamide (AAm) and methacrylic acid (MAA) and their potential application in the delivery of agrochemicals. Biodegradation experiments were performed using composting and soil burial methods of biodegradation. Complete degradation of synthesized hydrogel-IPN occurred within 77 days using composting method, while using soil burial method 81.26% degradation occurred after 77 days. Furthermore, effect hydrogel-IPN degradation on the fertility of soil was also studied through macro-analysis of soil. Water retention capacity of clay soil and sandy loam soil was improved after mixing swelled sample of hydrogel-IPN with these soil samples. The potential of hydrogel-IPN was also tested for sustained and slow release of two agrochemicals i.e. urea and calcium nitrate. Kinetics of agrochemicals release revealed that the release rate of both the fertilizers was initially higher which kept on decreasing with time. Diffusion mechanism of agrochemicals followed Case-II diffusion type behavior. Therefore, synthesized hydrogel-IPN is important from agriculture view point and can be used for sustained and controlled release of agrochemicals.
... The space between the sheets, where the water molecules and P-OH groups are, allows for ion-exchange activity, whereby some or all of the H + as well as water molecules can be displaced by metal cations, such as K + , Na + , and Cs + [20]. The abnormal increase of K + concentration at pathological sites could be taken as a stimulus for selfregulated targeted drug delivery [21]. ...
... Shrinking behaviours of the hydrogel. The test of volume shrinking behaviours of CS LiOH-urea system were carried out by measuring the diameter change of hydrogel discs 35 . The mould was unloaded after enough thermal gelation time, and then the gel was rinsed for 5 min in 100 ml deionized water before every measurement. ...
Alkaline-urea aqueous solvent system provides a novel and important approach for the utilization of polysaccharide. As one of the most important polysaccharide, chitosan can be well dissolved in this solvent system, and the resultant hydrogel material possesses unique and excellent properties. Thus the sound understanding of the gelation process is fundamentally important. However, current study of the gelation process is still limited due to the absence of direct observation and the lack of attention on the entire process. Here we show the entire gelation process of chitosan LiOH-urea aqueous system by aggregation-induced emission fluorescent imaging. Accompanied by other pseudo in situ investigations, we propose the mechanism of gelation process, focusing on the formation of junction points including hydrogen bonds and crystalline.
After entering the human body, drugs for treating diseases, which are prone to delivery and release in an uncontrolled manner, are affected by various factors. Based on this, many researchers utilize various microenvironmental changes encountered during drug delivery to trigger drug release and have proposed stimuli-responsive drug delivery systems. In recent years, metal-organic frameworks (MOFs) have become promising stimuli-responsive agents to release the loaded therapeutic agents at the target site to achieve more precise drug delivery due to their high drug loading, excellent biocompatibility, and high stimuli-responsiveness. The MOF-based stimuli-responsive systems can respond to various stimuli under pathological conditions at the site of the lesion, releasing the loaded therapeutic agent in a controlled manner, and improving the accuracy and safety of drug delivery. Due to the changes in different physical and chemical factors in the pathological process of diseases, the construction of stimuli-responsive systems based on MOFs has become a new direction in drug delivery and controlled release. Based on the background of the rapidly increasing attention to MOFs applied in drug delivery, we aim to review various MOF-based stimuli-responsive drug delivery systems and their response mechanisms to various stimuli. In addition, the current challenges and future perspectives of MOF-based stimuli-responsive drug delivery systems are also discussed in this review.
Membranes have been extensively studied and applied in various fields owing to their high energy efficiency and small environmental impact. Further conferring membranes with stimuli responsiveness can allow them to dynamically tune their pore structure and/or surface properties for efficient separation performance. This review summarizes and discusses important developments and achievements in stimuli-responsive membranes. The most commonly utilized stimuli, including light, pH, temperature, ions, and electric and magnetic fields, are discussed in detail. Special attention is given to stimuli-responsive control of membrane pore structure (pore size and porosity/connectivity) and surface properties (wettability, surface topology, and surface charge), from the perspective of determining the appropriate membrane properties and microstructures. This review also focuses on strategies to prepare stimuli-responsive membranes, including blending, casting, polymerization, self-assembly, and electrospinning. Smart applications for separations are also reviewed as well as a discussion of remaining challenges and future prospects in this exciting field. This review offers critical insights for the membrane and broader materials science communities regarding the on-demand and dynamic control of membrane structures and properties. We hope that this review will inspire the design of novel stimuli-responsive membranes to promote sustainable development and make progress toward commercialization.
Temporal-spatial precision has attracted increasing attention for the clinical intervention of neurological disorders (NDs) to mitigate adverse effects of traditional treatments and achieve point-of-care medicine. Inspiring steps forward in this field have been witnessed in recent years, giving the credit to multi-discipline efforts from neurobiology, bioengineering, chemical materials, artificial intelligence, and so on, exhibiting valuable clinical translation potential. In this review, the latest progress in advanced temporally-spatially precise clinical intervention is highlighted, including localized parenchyma drug delivery, precise neuromodulation, as well as biological signal detection to trigger closed-loop control. Their clinical potential in both central and peripheral nervous systems is illustrated meticulously related to typical diseases. The challenges relative to biosafety and scaled production as well as their future perspectives are also discussed in detail. Notably, these intelligent temporally-spatially precision intervention systems could lead the frontier in the near future, demonstrating significant clinical value to support billions of patients plagued with NDs.
Researchers all around the world are working tirelessly to develop successful targeted
nanotheranostics for cancer diagnosis and treatment [1e3]. In recent years, nanomedicine researchers have facilitated the production of “smart” nanocarriers or nanotheranostics, which comprise nanovehicles that simultaneously transport medications and
act as imaging agents in a single system [4,5]. This technology improves the monitoring of drug biodistribution. It also offers flexibility in analyzing target site accumulation of nanomedicines, allows the quantification and visualization of triggered drug
release from nanomedicines [6]. The tailored nanomedicines-based chemotherapeutic
interventions available today have been effective in enhancing the patient compliances. The uses of nanomaterials have generated interest in their potential, such as
the incorporation of radionuclides with conventionally used nanomaterials to impart
new traits for the purpose of cancer diagnosis and treatment [7,8]. Researchers have
made the uses of nanoparticles to emit ionizing radiation in therapeutic settings for
the purposes of diagnostics as well as theranostics [9,10]. The success of
nanoparticle-mediated radionuclide therapy is linked to their ability to provide the targeted administration of ionizing radiation for a set amount of time for curative or palliative treatments as well as in a theragnostic approach. The composition of
nanomedicines may differ from one another. Various nanomedicines can be classified
as biodegradable polymers (i.e., chitosan, dextran, phospholipids, polylactic acid,
polylactic-co-glycolide, etc.), carbon-based (i.e., graphene, nanotubes etc.), metallic
(i.e., metal oxides, sulfides, etc.), and semiconductors (i.e., quantum dots [QDs])
[11,12]. Because of unique physicochemical features, theranostics are being investigated not only as drug-delivery nanocarriers but also as synthetic scaffolding for imaging probes used in cancer diagnosis [1,3]. The applications and biopharmaceutical
performances of these nano-based systems are highly influenced by features like chemical compositions (such as metallic, polymeric, lipid-based and carbon-based)
(Fig. 13.1), surface characteristics (such as charge and hydrophobicity), physical characteristics (such as size, shape, and stiffness), and surface functionalizations.
Taking inspiration from the extremely flexible motion abilities in natural organisms, soft actuators have emerged in the past few decades. Particularly, smart film actuators (SFAs) demonstrate unique superiority in easy fabrication, tailorable geometric configurations, and programmable 3D deformations. Thus, they are promising in many biomedical applications, such as soft robotics, tissue engineering, delivery system, and organ-on-a-chip. In this review, the latest achievements of SFAs applied in biomedical fields are summarized. The authors start by introducing the fabrication techniques of SFAs, then shift to the topology design of SFAs, followed by their material selections and distinct actuating mechanisms. After that, their biomedical applications are categorized in practical aspects. The challenges and prospects of this field are finally discussed. The authors believe that this review can boost the development of soft robotics, biomimetics, and human healthcare.
Recent progress in the field of material science and drug delivery systems has enabled the research community to develop nanocarriers capable of the site- and time-specific cargo release. This development has garnered much attention worldwide for the development of stimuli-responsive delivery systems. The nanocarriers employed for stimuli-sensitive systems need to be biocompatible and sensitive to external (light, ultrasound, and magnetic field) or internal (pH, redox, and enzyme) stimuli for cargo release. The sensitivity to the stimuli could be achieved by modifying the nanocarriers with stimuli-responsive moieties. However, the tremendous potential for developing a disease-specific treatment strategy with significantly reduced side-effects due to controlled release has yet to be realized completely. As a result, the development of stimuli-sensitive nanocarrier is an immensely active field of research. This introductory chapter provides an overview of stimuli-responsive nanocarriers and various strategies for their development.
Ionic species are important to dominate phase separation behaviors of poly(N-isopropylacrylamide) (PNIPAm) in aqueous solutions. Herein, photoresponsive azobenzene-based salts with various ions are prepared and their photoresponsive ion effects on clouding temperatures (TcpS) of PNIPAm in aqueous solutions are explored. It is found that, despite of various structures of anions and cations, trans-TcpS under vis light irradiation are always higher than cis-TcpS under UV irradiation. Particularly, Hofmeister effect of anions on TcpS is roughly observed. For example, azobenzene with kosmotropic CO3²⁻ gives the lowest cis-Tcp while in use of typical chaotropic anions, such as ClO4⁻, azobenzene isomerization less affects values of Tcps. In another hand, azobenzene-based metallic salts containing lithium, sodium, and potassium cations also demonstrate photoresponsive Hofmeister effect. Trans-metallic azobenzene demonstrates a chaotropic effect on Tcps while UV induces kosmotropic behaviors on TcpS. Additionally, ionic conduction of the solution along with photoresponsive phase separations is also investigated and PNIPAm aggregations induce a sharp reduction of ion conduction during UV light illumination.
We introduce a new facile synthetic methodology for the preparation of alkyl pyridinium-containing acrylamide monomers. Inclusion complexes of these new monomers with CB[8] facilitate supramolecular crosslinking in a series of hydrogels formed through in situ polymerisation. The resulting hydrogels not only show greatly enhanced mechanical properties over a purely acrylamide-based gel, but also by selecting fluorescent pyridine moieties, the materials are endowed with the fluorescence properties desirable for several sensing applications.
The immune system is the key target for vaccines and immunotherapeutic approaches aimed at blunting infectious diseases, cancer, autoimmunity, and implant rejection. However, systemwide immunomodulation is undesirable due to the severe side effects that typically accompany such strategies. In order to circumvent these undesired, harmful effects, scientists have turned to tailorable biomaterials that can achieve localized, potent release of immune‐modulating agents. Specifically, “stimuli‐responsive” biomaterials hold a strong promise for delivery of immunotherapeutic agents to the disease site or disease‐relevant tissues with high spatial and temporal accuracy. This review provides an overview of stimuli‐responsive biomaterials used for targeted immunomodulation. Stimuli‐responsive or “environmentally responsive” materials are customized to specifically react to changes in pH, temperature, enzymes, redox environment, photo‐stimulation, molecule‐binding, magnetic fields, ultrasound‐stimulation, and electric fields. Moreover, the latest generation of this class of materials incorporates elements that allow for response to multiple stimuli. These developments, and other stimuli‐responsive materials that are on the horizon, are discussed in the context of controlling immune responses. “Stimuli‐responsive” biomaterials hold strong promise for delivery of immunotherapeutic agents to disease‐relevant sites with high spatial and temporal accuracy. This review provides an overview of stimuli‐responsive biomaterials that can modulate the immune system in response to environmental changes in pH, temperature, enzymes, redox environment, photo‐stimulation, molecule‐binding, magnetic fields, ultrasound‐stimulation, electric fields, and multiple stimuli.
Micro-scale intelligent actuators capable of sensitive and accurate manipulation under external stimuli hold great promise in various fields including precision sensors and biomedical devices. Current microactuators, however, are often limited to multiple-step fabrication process and multi-materials. Here, a pH-triggered soft microactuator (<100 μm) with simple structure, one-step fabrication process and single material is proposed, which is composed of deformable hydrogel microstructures fabricated by an asymmetric femtosecond Bessel beam. To further explore the swelling-shrinking mechanism, the hydrogel porosity difference between expansion and contraction states is investigated. In addition, by introducing the dynamic holographic processing and splicing processing method, more complex responsive microstructures (S-shaped, C-shaped and tortile chiral structures) are rapidly fabricated, which exhibit tremendous expected deformation characteristics. Finally, as a proof of concept, a pH-responsive microgripper is fabricated for in situ capturing polystyrene (PS) particles and neural stem cells rapidly. This flexible, designable and one-step approach manufacturing of intelligent actuator provides a versatile platform for microobjects manipulation and drug delivery.
Over the last few decades, hydrogels have attracted the considerable interest of researchers for crafting potential controlled drug delivery systems. It may be attributed to their high water imbibing capacity, soft and rubbery nature, which enables them to exhibit physical properties resembling that of the body tissues. Recently, the environment-sensitive hydrogels have received the special attention of the researchers because of the alteration in their properties in response to a stimulus. The special focus on the environment-sensitive hydrogels has facilitated breakthrough advances in drug delivery (e.g., decrease in dose frequency, increase in the duration of release with reduced side effects, ease of preparation and administration) for the better treatment of various pathological conditions. This paper provides comprehensive information regarding the types of stimuli (i.e., physical, chemical and biological) which can be used to stimulate drug release from the hydrogels and recent advances in the development of stimulus-sensitive hydrogels for drug delivery applications. Finally, the current challenges and the future scope of research in the field of environment-sensitive hydrogels have also been highlighted.
The design, fabrication and controlled release properties of environmental stimuli-responsive microcapsule membranes are introduced here. These smart microcapsule membranes can modulate their permeability, mass transport, targeting/sensing, or surface features responding to diverse environmental stimuli, such as temperature, pH, magnetic field, specific molecules/ions and so on. Especially for drug delivery systems, the smart microcapsules can load a variety of drugs or chemicals and release them at a suitable time and rate, and in a desired place where ambient conditions such as pH or temperature differ from those in other places. Two types of controlled release modes are presented here, i.e., controllable burst release and controllable on–off release.
Stimuli-responsive hydrogels have been considered to have various applications in numerous fields. In the present work, a double-network (DN) hydrogel has been synthesized. The copolymer of 2-acrylamide-2-methylpropane sulfonic acid (AMPS) and acrylamide (AM) [P (AMPS-co-AM)] are prepared as the 1st network and polyacryly acide (PAAc) as the 2nd network. This DN hydrogel is sensitive to glucose by introducing the glucose-sensitive group phenylboronic acid (PBA) to the network. The tribological properties of this glucose-sensitive DN hydrogel have been investigated using a universal mechanical tester (UMT-5). The tribological results show that the friction coefficient varied with the glucose solution. The friction coefficient increased to a maximum of 0.06, and finally decreased to 0.025 with the increase in the glucose concentration. An adjustable friction coefficient of the hydrogel, between 0.025 and 0.056, was achieved along with the change of lubricant. According to the tribological experimental results and the analysis of the DN structure, it can be deduced that a hydrated layer exists in the interface of the hydrogel. The hydrated layer consisting of water molecules are bounded with the hydrophilic group of the hydrogel network by hydrogen bonds. The change in the number of water molecules leads to the difference in the water content of the hydrogel, which further resulted in the various tribological properties. In addition, the hydrogel's mesh size also has an impact on the change in friction coefficient. In general, the adjustable friction of the hydrogel in a glucose environment is achieved.
Host-guest interactions for sensor applications have been widely applied to various platforms ranging from hard to soft nanoparticles or bulk materials. Their combination with stimuli-responsive polymers such as thermosensitive polymeric...
In this chapter, the authors' group developed core-shell microparticles with an oil core and a shell consisting of various stimuli-responsive hydrogels for controllable encapsulation and triggered release. The chapter introduces the microfluidic fabrication of core-shell microcapsules with a shell consisting of thermoresponsive, alcohol-responsive, ion-responsive, and pH-responsive hydrogels and their performances for encapsulation and triggered release. Typically, microcapsules with core-shell structures can be produced using the inner droplet of double emulsions as the inner core compartment and the outer drop as the outer shell. The core-shell microcapsules for alcohol-responsive burst release are composed of a PNIPAM shell and an oil core. The resultant core-shell microcapsules, with a shell consisting of thermo-responsive, alcohol-responsive, ion-responsive, and pH-responsive hydrogels, allow controllable encapsulation of oil-soluble components and nanoparticles for controlled release under triggers including temperature, alcohol, K+, and pH.
For decades, plasmonic nanostructures have been used as important optical sensing platforms, however, the necessity of sensitive optical instruments for detection greatly limits their practical application. Herein, a multi-responsive naked eye plasmonic indicator has been prepared through introduction of a responsive polymer brush (PNIPAm) into the cavity of a Ag nanovolcano array (Ag NVA). According to the phase change of the PNIPAm brush under different external conditions, the as-prepared Ag NVA shows responsive monochromatic colors, which allow the Ag NVA to serve as a plasmonic indicator detected by the naked eye. Importantly, the as-prepared Ag NVA also possesses a rapid response rate as well as excellent repeatability, and is compatible with conventional micro-fabrication methods. All of these excellent features make the as-prepared Ag NVA an attractive candidate for future optical indicating and intelligent color display applications.
Alternative compounds to capture metal ions are triazenes 1-oxide since they are basic compounds O(N) with negative charge in the deprotonated form. The proximity of both coordination sites (O and N) enables these compounds to have good chelating ability and a tendency to stabilize in the formation of rings with soft and hard transition metal ions. The structure analysis by single crystal X-ray diffraction of compounds (1) and (2) demonstrate the formation of 3D supramolecular arrangements through ion-ion, ion-dipolo and dipolo-dipolo interactions. In one of them, there are [(H2O)(2)(CH3CH3SO)K-2](2+) as linkers of polymerization and, in another complex, there are [(H2O)(CH3CH3SO)Ni(H2O)(6)](2+) as a linker of polymerization. These linkers act in the polymerization of the novel mononuclear complex [bis(1-methyl (p-arboxylatephenyl) triazenide 1-oxide) Ni-II] (3). The crystallography analysis of (1) and (2) showed distorted quadratic geometry for Ni (II), thus, there are two axial positions available in Ni (II) to be used in catalysis studies and as sensor or biosensor. In addition, this study shows the support of this novel mononuclear complex of Ni (II) (3) on protonated chitosan chains.(4). The compounds (3) and (4) were characterized by spectroscopic analysis, infrared (IR) and energy dispersive X-ray detector (EDS), and by differential scanning calorimetry analysis (DSC). The specificity of ligand 1-methyl (p-carboxyphenyl) triazene 1-oxide to capture potassium and nickel ions will be tested at different pH values, as well as the capacity of the triazenide 1-oxide of Ni (II) complex, supported on chitosan polymer, or not, to act as a catalyst for organic reactions and biomimetic organic reactions.
Molecular-recognition-responsive characteristics of a novel poly(N-isopropylacrylamide-co-benzo-12-crown-4-acrylamide) (PNB12C4) hydrogel have been investigated. In the prepared PNB12C4 hydrogel, benzo-12-crown-4 (B12C4) groups act as guest molecules and γ-cyclodextrin (γ-CD)-receptors, and poly(N-isopropylacrylamide) (PNIPAM) networks act as phase-transition actuators. The formation of stable γ-CD/B12C4 complexes enhances the hydrophilicity of the PNB12C4 hydrogel networks, and induces positive shift of the volume phase transition temperature (VPTT) of PNB12C4 hydrogel. Moreover, the PNB12C4 hydrogel also shows thermoresponsive adsorption property selectively towards γ-CD. The γ-CD-recognition sensitivity of PNB12C4 hydrogel can be dramatically improved by increasing γ-CD concentration in solution or B12C4 content in PNB12C4 copolymer networks. The results in this study provide valuable information for developing crown ether-based smart materials in various applications.
Poly(N-isopropylacrylamide-co-N-isopropylmethacrylamide) (poly(NIPAAm-co-NIPMAAm)) is synthesized as an attractive thermo-responsive copolymer by an original procedure. Due to the similar structure of the two co-monomers, the poly(NIPAAm-co-NIPMAAm) copolymer displays a very sharp phase transition, under physiological conditions (phosphate buffer solution at pH = 7.4). The copolymer, showing the 51/49 co-monomer NIPAAm/NIPMAAm molar ratio, displays a lower critical solution temperature (LCST) close to that of the human body temperature (36.8 °C). The poly(NIPAAm-co-NIPMAAm) microgels obtained at the 51:49 co-monomer ratio displays a volume phase transition temperature (VPTT) slightly smaller than LCST. The deswelling rate of the microgels is very high (k = 0.019 s−1), the shrinkage occurring almost instantaneously, whereas the swelling rate is slightly lower (k = 0.0077 s−1). The microgels are loaded with the model drug dexamethasone and the drug release is investigated at different temperatures, below and above the VPTT. Under thermal cycling operation between 32 and 38 °C, the pulsatile release of dexamethasone is observed.
Inclusion complexation between cyclodextrins (CDs) and various guests has been extensively investigated in supramolecular chemistry. Besides CDs, there are several important macrocyclic host families, such as crown ethers and cucurbiturils. Until now, the contribution of these other families to macromolecular self-assembly has been small compared to CDs. This chapter will focus on CDs as hosts for interaction with guest monomers to form hydrogels. CD interactions with other monomers were made possible depending on proper molecular recognition. Macroscopic molecular recognition can be categorized by three types of interactions: main chain (polyrotaxane), side chain, and sequential complexes. Utilizing CD as host molecule, polymers such as polyethers, cationic polymers, polyamines, polyesters, π-conjugated polymers, polyolefins, polyamides, polyurethanes, and inorganic polymers could interact to form inclusion complexes. This chapter will attempt to discuss these studies. Depending on the functional groups attached to the polymeric component, supramolecular formation can be altered based on the stimuli response. Introducing polymer side chains or groups that respond selectively towards external stimuli could affect the hydrogel formation. This chapter also discusses the stimuli response of such systems.
A novel and facile assembly strategy has been successfully developed to construct smart nanocomposite (NC) hydrogels with inhomogeneous structures using nanoclay-crosslinked stimuli-responsive hydrogel subunits as building blocks via rearranged hydrogen bonding between polymers and clay nanosheets. The assembled thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAM-co-AM)) hydrogels with various inhomogeneous structures exhibit excellent mechanical properties due to plenty of new hydrogen bonding interactions created at the interface for locking the NC hydrogel subunits, which are strong enough to tolerate external forces such as high levels of elongations and multi-cycles of swelling/deswellling operations. The proposed approach is featured with flexibility and designability to build assembled hydrogels with diverse architectures for achieving various responsive deformations, which are highly promising for stimuli-responsive manipulation such as actuation, encapsulation and cargo transportation. Our assembly strategy creates new opportunities for further developing mechanically strong hydrogel systems with complex architectures that composed of diverse internal structures, multi-stimuli-responsive properties, and controllable shape deformation behaviors in the soft robots and actuators fields.
Alternative compounds to capture metal ions are triazenes 1-oxide since they are basic compounds O(N) with negative charge in the deprotonated form. The proximity of both coordination sites (O and N) enables these compounds to have good chelating ability and a tendency to stabilize in the formation of rings with soft and hard transition metal ions. The structure analysis by single crystal X-ray diffraction of compounds (1) and (2) demonstrate the formation of 3D supramolecular arrangements through ion-ion, ion-dipolo and dipolo-dipolo interactions. In one of them, there are [(H2O)2(CH3CH3SO)K2]²⁺ as linkers of polymerization and, in another complex, there are [(H2O)(CH3CH3SO)Ni(H2O)6]²⁺ as a linker of polymerization. These linkers act in the polymerization of the novel mononuclear complex [bis(1-methyl (p-carboxylatephenyl) triazenide 1-oxide) NiII] (3). The crystallography analysis of (1) and (2) showed distorted quadratic geometry for Ni (II), thus, there are two axial positions available in Ni (II) to be used in catalysis studies and as sensor or biosensor. In addition, this study shows the support of this novel mononuclear complex of Ni (II) (3) on protonated chitosan chains (4). The compounds (3) and (4) were characterized by spectroscopic analysis, infrared (IR) and energy dispersive X-ray detector (EDS), and by differential scanning calorimetry analysis (DSC). The specificity of ligand 1-methyl (p-carboxyphenyl) triazene 1-oxide to capture potassium and nickel ions will be tested at different pH values, as well as the capacity of the triazenide 1-oxide of Ni (II) complex, supported on chitosan polymer, or not, to act as a catalyst for organic reactions and biomimetic organic reactions.
A novel type of composite hollow microfibers with K+-responsive controlled-release characteristics based on host-guest system is prepared by embedding K+-responsive poly(N-isopropylacrylamide-co-acryloylamidobenzo-15-crown-5) (P(NIPAM-co-AAB15C5)) microspheres in the wall of poly(lactic-co-glycolic acid) (PLGA) microfibers as “micro-valves” via a controllable microfluidic approach. By adjusting the volume change of microspheres in response to environmental K+ concentration, the release rate of encapsulated drug molecules from the composite hollow microfibers can be flexibly regulated owing to the change in interspace size between microfiber wall and microspheres. When the environmental K+ concentration is increased, due to the formation of stable 2:1 “sandwich-type” host-guest complexes of 15-crown-5 units and K+ ions, P(NIPAM-co-AAB15C5) microspheres change from a swollen state to a shrunk state. Thus, the interspace size becomes larger, resulting in a rapid increase in the release rate of encapsulated drugs. When the ambient K+ concentration is decreased, the interspace size becomes smaller due to isothermally swelling of microspheres caused by the decreased amount of host-guest complexes, resulting in a decrease in the release rate. The K+-responsive drug release behaviors are reversible. This kind of K+-responsive hollow microfibers with K+-concentration-dependent controlled-release property provides a new mode for designing more rational drug delivery systems, which is highly attractive for biomedical applications.
In this chapter, the design, fabrication, and performance of the ion-recognizable smart hydrogels with crown ether as ion-recognition receptor and thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) as actuator are introduced. Smart responsive hydrogels capable of recognizing heavy metal ions or potassium ion are fabricated with different crown ethers for different purposes. Smart hydrogels with 18-crown-6 as ion-recognition receptor could respond to Pb2+ and Ba2+ due to the formation of 1:1 (ligand to ion) “host-guest” complex; smart hydrogels with 15-crown-5 as ion-recognition receptor could respond to K+ due to the formation of 2:1 (ligand to ion) sandwich “host-guest” complex.
In this chapter, the design, fabrication, and performance of the ion-recognizable functional microcapsules with crown ether as ion-recognition receptor and poly(N-isopropylacrylamide) (PNIPAM) as actuator are introduced. The microcapsules with different capsule structures and/or different crown ether receptors are developed for different purposes. For the porous microcapsule with ion-recognizable smart gates using 18-crown-6 as the ion receptor, the functional gates in the pores can close by recognizing Ba2+. For the microcapsule with ion-recognizable cross-linked hydrogel membrane using 15-crown-5 as the ion receptor, the microcapsule shrinks isothermally by recognizing K+. For the microcapsule with ion-recognizable cross-linked hydrogel membrane using 18-crown-6 as the ion receptor, the microcapsule swells isothermally by recognizing Ba2+ or Pb2+. These ion-recognizable microcapsules provide new modes for smart controlled-release systems, which are highly attractive for drug delivery systems, chemical carriers, sensors, and so on.
Present work reports the under pressure preparation of reduced gum rosin and acrylamide-based GrA-cl-poly(AAm) green flocculant. Characterization of the synthesized product was carried out by different techniques such as Fourier transform infrared spectroscopy, X-ray diffraction method and scanning electron microscopy. In addition, several variables such as time, physiological pH, solvent, pressure, monomer, cross-linking agent and initiator were examined to obtain maximum flocculation efficiency and explore the salt resistant swelling of the system. The maximum percentage swelling (P
s) at pH 7.0 and pressure 8.0 psi was found to be 578 %. Thermal behavior of the flocculant was investigated and the synthesized sample showed higher thermal stability than the gum rosin. The effect of ionic strength and charges of various cations (Na+, Ba+2, Fe+3, Sn+4) on salt resistant swelling of GrA-cl-poly(AAm) flocculant, in different salt solutions such as sodium chloride, barium chloride, ferric chloride and stannic chloride (NaCl, BaCl2, FeCl3 and SnCl4), was also studied. The synthesized sample was found to show ionic charge and salt concentration related behavior. Further, the removal of colloidal particles from wastewater through flocculation showed that GrA-cl-poly(AAm) exhibited significant flocculation efficiency (95.18 %) at a dose rate of 55 mg at 30 °C and pH 5.0. Flocculant capacity in saline medium was found to be maximum (99 %) at 1 % concentration. Further, increase in saline concentration resulted in decreased flocculant capacity. The kinetics of the aggregation of particles, deflocculation and reflocculation was analyzed through the Smoluchowski classical model based on first-order and second-order kinetics.
Acrylamide monomer was directly grafted onto chitosan using ammonium persulfate as an initiator and methylenebisacrylamide as a crosslinking agent under an inert atmosphere. Infrared spectroscopy and thermogravimetric analysis were carried out to confirm the chemical structure of the hydrogel. Moreover, morphology of the samples was examined by scanning electron microscopy. The rheology behavior of the synthesized hydrogels was preliminarily investigated with oscillating and rotational rheometer.
In this research, to follow synthesis of a graft copolymer based on alginate via graft copolymerization hydrophilic monomers onto alginate backbones, kinetic polymerization and it, s relationship with effective parameters were investigated. According to the empirical rates of the polymerization and the graft copolymerization of AAm and AMPS onto alginate backbone, the overall activation energy of the graft copolymerization reaction was estimated to be 33.40 kJ/mol.
A novel positively K+-responsive membrane with functional gates driven by host-guest molecular recognition is prepared by grafting poly(N-isopropylacrylamide-co-acryloylamidobenzo-15-crown-5) (poly(NIPAM-co-AAB15C5)) copolymer chains in the pores of porous nylon-6 membranes with a two-step method combining plasma-induced pore-filling grafting polymerization and chemical modification. Due to the cooperative interaction of host-guest complexation and phase transition of the poly(NIPAM-co-AAB15C5), the grafted gates in the membrane pores could spontaneously switch from “closed” state to “open” state by recognizing K+ ions in the environment and vice versa; while other ions (e.g., Na+, Ca2+ or Mg2+) can not trigger such an ion-responsive switching function. The positively K+-responsive gating action of the membrane is rapid, reversible, and reproducible. The proposed K+-responsive gating membrane provide a new mode of behavior for ion-recognizable “smart” or “intelligent” membrane actuators, which is highly attractive for controlled release, chemical/biomedical separations, tissue engineering, sensors, etc.
Novel poly(N-isopropylacrylamide)-clay (PNIPAM-clay) nanocomposite (NC) hydrogels with both excellent responsive bending and elastic properties are developed as temperature-controlled manipulators. The PNIPAM-clay NC structure provides the hydrogel with excellent mechanical property, and the thermoresponsive bending property of the PNIPAM-clay NC hydrogel is achieved by designing an asymmetrical distribution of nanoclays across the hydrogel thickness. The hydrogel is simply fabricated by a two-step photo polymerization. The thermoresponsive bending property of the PNIPAM-clay NC hydrogel is resulted from the unequal forces generated by the thermoinduced asynchronous shrinkage of hydrogel layers with different clay contents. The thermoresponsive bending direction and degree of the PNIPAM-clay NC hydrogel can be adjusted by controlling the thickness ratio of the hydrogel layers with different clay contents. The prepared PNIPAM-clay NC hydrogels exhibit rapid, reversible, and repeatable thermoresponsive bending/unbending characteristics upon heating and cooling. The proposed PNIPAM-clay NC hydrogels with excellent responsive bending property are demonstrated as temperature-controlled manipulators for various applications including encapsulation, capture, and transportation of targeted objects. They are highly attractive material candidates for stimuli-responsive “smart” soft robots in myriad fields such as manipulators, grippers, and cantilever sensors.
In this research, we synthesize of a graft copolymer based on alginate via simultaneously graft copolymerization acrylamide (AAm) and 2-acrylamido-2- methylpropanesulfonic acid (AMPS) onto alginate backbones. The polymerization reaction was carried out in an aqueous medium and in the presence of ammonium persulfate (APS) as an initiator. Infrared spectroscopy and TGA thermal analysis were carried out to confirm the chemical structure of the copolymer. A proposed mechanism for hydrogel formation was suggested.
In-depth investigations of the specific ion-responsive characteristics based on 2:1 "sandwich" structures and effects of crown ether cavity sizes on the metal-ion/crown-ether complexation are systematacially performed with a series of PNIPAM-based responsive copolymers containing similar contents of crown ether units with different cavity dimensions (12-crown-4 (12C4), 15-crown-5 (15C5), 18-crown-6 (18C6)). The lower critical solution temperature (LCST) values of copolymers in deionized water shift to lower temperatures gradually when the crown ether contents increase or the ring sizes decrease from 18C6 to 12C4. With increasing the concentrations of alkali metal ions (Na+, K+, Cs+) or the contents of pendent crown ether groups, the copolymers with different crown ether cavity sizes exhibit higher selectivity and sensitivity to corresponding cations. Importantly, the ion-sensitivities of the copolymers in responsive to corresponding alkali metal ions increase dramatically with an increase in the crown ether cavity size. Interestingly, a linear relationship between the crown ether cavity size and the diameter of corresponding cation for formation of stable 2:1 "sandwich" complexes is found for the first time, from which the size of metal ions or other guests that able to form 2:1 "sandwich" complexes with crown ethers can be deduced. The results in this work are valuable and useful for further developments and practical applications of various crown ether-based smart materials.
Hydrogels have applications in surgery and drug delivery, but are never considered alongside polymers and composites as materials for mechanical design. This is because synthetic hydrogels are in general very weak. In contrast, many biological gel composites, such as cartilage, are quite strong, and function as tough, shock-absorbing structural solids. The recent development of strong hydrogels suggests that it may be possible to design new families of strong gels that would allow the design of soft biomimetic machines, which have not previously been possible.
Chemical sensors respond to the presence of a specific analyte in a variety of ways. One of the most convenient is a change in optical properties, and in particular a visually perceptible colour change. Here we report the preparation of a material that changes colour in response to a chemical signal by means of a change in diffraction (rather than absorption) properties. Our material is a crystalline colloidal array of polymer spheres (roughly 100 nm diameter) polymerized within a hydrogel that swells and shrinks reversibly in the presence of certain analytes (here metal ions and glucose). The crystalline colloidal array diffracts light at (visible) wavelengths determined by the lattice spacing, which gives rise to an intense colour. The hydrogel contains either a molecular-recognition group that binds the analyte selectively (crown ethers for metal ions), or a molecular-recognition agent that reacts with the analyte selectively. These recognition events cause the gel to swell owing to an increased osmotic pressure, which increases the mean separation between the colloidal spheres and so shifts the Bragg peak of the diffracted light to longer wavelengths. We anticipate that this strategy can be used to prepare 'intelligent' materials responsive to a wide range of analytes, including viruses.
Hydrogels have been developed to respond to a wide variety of stimuli, but their use in macroscopic systems has been hindered by slow response times (diffusion being the rate-limiting factor governing the swelling process). However, there are many natural examples of chemically driven actuation that rely on short diffusion paths to produce a rapid response. It is therefore expected that scaling down hydrogel objects to the micrometre scale should greatly improve response times. At these scales, stimuli-responsive hydrogels could enhance the capabilities of microfluidic systems by allowing self-regulated flow control. Here we report the fabrication of active hydrogel components inside microchannels via direct photopatterning of a liquid phase. Our approach greatly simplifies system construction and assembly as the functional components are fabricated in situ, and the stimuli-responsive hydrogel components perform both sensing and actuation functions. We demonstrate significantly improved response times (less than 10 seconds) in hydrogel valves capable of autonomous control of local flow.
In skeletal muscle, excitation may cause loss of K+, increased extracellular K+ ([K+]o), intracellular Na+ ([Na+]i), and depolarization. Since these events interfere with excitability, the processes of excitation can be self-limiting. During work, therefore, the impending loss of excitability has to be counterbalanced by prompt restoration of Na+-K+ gradients. Since this is the major function of the Na+-K+ pumps, it is crucial that their activity and capacity are adequate. This is achieved in two ways: 1) by acute activation of the Na+-K+ pumps and 2) by long-term regulation of Na+-K+ pump content or capacity. 1) Depending on frequency of stimulation, excitation may activate up to all of the Na+-K+ pumps available within 10 s, causing up to 22-fold increase in Na+ efflux. Activation of the Na+-K+ pumps by hormones is slower and less pronounced. When muscles are inhibited by high [K+]o or low [Na+]o, acute hormone- or excitation-induced activation of the Na+-K+ pumps can restore excitability and contractile force in 10-20 min. Conversely, inhibition of the Na+-K+ pumps by ouabain leads to progressive loss of contractility and endurance. 2) Na+-K+ pump content is upregulated by training, thyroid hormones, insulin, glucocorticoids, and K+ overload. Downregulation is seen during immobilization, K+ deficiency, hypoxia, heart failure, hypothyroidism, starvation, diabetes, alcoholism, myotonic dystrophy, and McArdle disease. Reduced Na+-K+ pump content leads to loss of contractility and endurance, possibly contributing to the fatigue associated with several of these conditions. Increasing excitation-induced Na+ influx by augmenting the open-time or the content of Na+ channels reduces contractile endurance. Excitability and contractility depend on the ratio between passive Na+-K+ leaks and Na+-K+ pump activity, the passive leaks often playing a dominant role. The Na+-K+ pump is a central target for regulation of Na+-K+ distribution and excitability, essential for second-to-second ongoing maintenance of excitability during work.
Certain proteins undergo a substantial conformational change in response to a given stimulus. This conformational change can manifest in different manners and result in an actuation, that is, catalytic or signalling event, movement, interaction with other proteins, and so on. In all cases, the sensing-actuation process of proteins is initiated by a recognition event that translates into a mechanical action. Thus, proteins are ideal components for designing new nanomaterials that are intelligent and can perform desired mechanical actions in response to target stimuli. A number of approaches have been undertaken to mimic nature's sensing-actuating process. We now report a new hybrid material that integrates genetically engineered proteins within hydrogels capable of producing a stimulus-responsive action mechanism. The mechanical effect is a result of an induced conformational change and binding affinities of the protein in response to a stimulus. The stimuli-responsive hydrogel exhibits three specific swelling stages in response to various ligands offering additional fine-tuned control over a conventional two-stage swelling hydrogel. The newly prepared material was used in the sensing, and subsequent gating and transport of biomolecules across a polymer network, demonstrating its potential application in microfluidics and miniaturized drug-delivery systems.
The pore size and permeability control of a glucose-responsive gating membrane with plasma-grafted poly(acrylic acid) (PAAC) gates and covalently bound glucose oxidase (GOD) enzymes were investigated systematically. The PAAC-grafted porous polyvinylidene fluoride (PVDF) membranes with a wide range of grafting yields were prepared using a plasma-graft pore-filling polymerization method, and the immobilization of GOD was carried out by a carbodiimide method. The linear grafted PAAC chains in the membrane pores acted as the pH-responsive gates or actuators. The immobilized GOD acted as the glucose sensor and catalyzer; it was sensitive to glucose and catalyzed the glucose conversion to gluconic acid. The experimental results showed that the glucose responsivity of the solute diffusional permeability through the proposed membranes was heavily dependent on the PAAC grafting yield, because the pH-responsive change of pore size governed the glucose-responsive diffusional permeability. It is very important to design a proper grafting yield for obtaining an ideal gating response. For the proposed gating membrane with a PAAC grafting yield of 1.55%, the insulin permeation coefficient after the glucose addition (0.2 mol/l) was about 9.37 times that in the absence of glucose, presenting an exciting result on glucose-sensitive self-regulated insulin permeation.
Ultraviolet (UV)-light-induced volume changes of a poly(acrylic acid) (PAA) gel containing Cu2+ and TiO2 nanoparticles were analyzed. The PAA gel incorporating TiO2 nanoparticles was prepared by radical polymerization, and the resulting PAA TiO2 gel was immersed in aqueous AgNO3. The gel was shrunk due to osmotic pressure and/or complex formation between Ag+ and two carboxyl groups, and shrunken gel was observed to be more rigid than the swollen one. The delayed response of the hydrogel to the blacking out indicated that the swelling process is controlled by the structure change of the gel including water uptake. Localized shrinking was impossible because the shrinking was driven by chemical oxidation of Cu particles by dissolved oxygen in a solution. It was observed that swollen gel keeps its size and shape in dark, and localized irradiation with UV and visible light causes localized swelling and shrinking.
Dual temperature- and pH-sensitive comb-type grafted cationic hydrogels are successfully synthesized by grafting polymeric chains with freely mobile ends, which are composed of both N-isopropylacrylamide (NIPAM) segments and N,N-dimethylamino ethyl methacrylate (DMAEMA) segments, onto the backbone of crosslinked poly(NIPAM-co-DMAEMA) networks. Equilibrium and dynamic swelling/deswelling properties of the prepared hydrogels responding to pH and/or temperature are investigated. The prepared hydrogels demonstrate a lower critical solution temperature (LCST) at about 34°C and a pKa value at about pH 7.3. At lower pH and lower temperature, both the swelling degree and the swelling rate of the comb-type grafted hydrogel are larger than those of the normal-type crosslinked hydrogel. The comb-type grafted poly(NIPAM-co-DMAEMA) hydrogel exhibits a more rapid deswelling rate than that of the normal-type hydrogel in response to a pH jump from 2.0 to 11.0 at a fixed temperature. The volume changes of the poly(NIPAM-co-DMAEMA) hydrogels are acute in a series of fixed buffer solutions with an abrupt increase of environmental temperature from 18°C to a temperature higher than the LCST. The comb-type grafted poly(NIPAM-co-DMAEMA) hydrogels show quite fast shrinking behaviors in response to simultaneous dual temperature and pH stimuli. Drug-release in vitro from the prepared poly(NIPAM-co-DMAEMA) hydrogels is carried out when the environmental temperature and pH are changed synchronously. The results show that the model drug Vitamin B12 is released much more rapidly from the comb-type grafted hydrogel than that from the normal-type hydrogel. The proposed dual temperature/pH-sensitive comb-type grafted cationic poly(NIPAM-co-DMAEMA) hydrogel in this study may find various potential applications, e.g., for fabricating rapid-response smart sensors, actuators, and chemical/drug carriers and so on.
Benzo[18]crown-6 was incorporated into pendent groups of poly(N-isopropylacrylamide) to obtain chemical-responsive polymer systems. The aqueous solution of the polymer containing 11.6 mol% pendent benzo[18]crown-6 groups underwent a phase transition from the phase-separated to the homogeneous state at 32°C by the addition of K+ and Na+. The threshold ion concentration to induce the phase transition depended on the kind of metal ion. A very small amount of K+ was sufficient to induce the transition, while 6.0 × 10−2 M Na+ was required. At 37°C only K+ could induce the phase transition.
A novel temperature-dependent molecular-recognizable membrane, poly(N-isopropylacylamide-co-glycidyl methacrylate/cyclodextrin)-grafted-polyethylene terephthalate (P(NIPAM-co-GMA/CD)-g-PET) membrane, is prepared by the combination of plasma-induced pore-filling grafting polymerization and chemical reaction. Scanning electron microscope (SEM) images show that the surfaces and cross-sections of the prepared membranes are uniformly grafted by polymeric layer. Fourier transform infrared (FT-IR) results show that CDs are successfully induced onto the P(NIPAM-co-GMA) grafted chains through reaction with epoxy groups. When the environmental temperature increases from 25°C to 45°C, the contact angle of prepared P(NIPAM-co-GMA/CD)-g-PET membrane increases from 65° to 76.9°; whereas, that of substrate membrane decreases from 84.8° to 77.1°. During the dynamic adsorption experiments, the guest 8-anilino-1-naphthalenesulfonic acid ammonium salt (ANS) molecules are adsorbed onto the P(NIPAM-co-GMA/CD)-g-PET membrane at lower temperature (25°C) and desorbed from it at higher temperature (40°C) with good repeatability. This phenomenon of adsorption at low temperature and desorption at high temperature of the P(NIPAM-co-GMA/CD)-g-PET membrane is attributable to both the “swollen–shrunken” configuration change of P(NIPAM-co-GMA) grafted chains and the molecular recognition of CD toward ANS. The P(NIPAM-co-GMA/CD)-g-PET membrane show both good thermo-responsibility and temperature-dependent molecular-recognizable characteristics toward guest molecules, which is highly potential to be applied in temperature-controlled affinity separations.
The reactions of pyrimidine-phosphine ligand N-[(diphenylphosphino)methyl]-2-pyrimidinamine (L) with various metal salts of PtII, PdII and CuI provide three new halide metal complexes, Pt2Cl4(μ-L)2·2CH2Cl2 (1), Pd2Cl4(μ-L)2 (2), and [Cu2(μ-I)2L2]n (3). Single crystal X-ray diffraction studies show that complexes 1 and 2 display a similar bimetallic twelve-membered ring structure, while complex 3 consists of one-dimensional polymeric chains, which are further connected into a 2-D supramolecular framework through hydrogen bonds. In the binuclear complexes 1 and 2, the ligand L serves as a bridge with the N and P as coordination atoms, but in the polymeric complex 3, both bridging and chelating modes are adopted by the ligand. The spectroscopic properties of complexes 1-3 as well as L have been investigated, in which complex 3 exhibits intense photoluminescence originating from intraligand charge transfer (ILCT) π→π* and metal-to-ligand charge-transfer (MLCT) excited states both in acetonitrile solution and solid state, respectively.
A series of novel, thermo‐sensitive copolymers with different molar ratios of N ‐isopropylacrylamide (NIPAM) and hydrophobic cis ‐dibenzo‐18‐crown‐6‐diacrylamide ( cis ‐DBCAm) were prepared via free‐radical copolymerization. cis ‐DBCAm with polymerizable end groups was successfully synthesized by reacting the corresponding amino crown ether with acryloyl chloride. The copolymers were characterized by FT‐IR and elemental analysis, and the thermo‐sensitivities of the copolymers were evaluated by measuring their lower critical solution temperatures (LCSTs) in the absence or presence of various metal ions. The results indicated that incorporation of cis ‐DBCAm lowered LCSTs, and that the LCSTs of the copolymers decreased with the increase in cis ‐DBCAm content in the copolymers. When the cavities of the crown ether units captured either K ⁺ or Cs ⁺ ions, the LCST of the respective copolymer–metal ion complex was further decreased, whereas the capture of Na ⁺ or Li ⁺ ions did not have a significant influence on the LCSTs of the copolymers.
Incorporation of cis ‐DBCAm into PNIPAM resulted in a lower LCST. The LCST was decreased more when the cavities of the crown ether units captured K ⁺ ions.
magnified image Incorporation of cis ‐DBCAm into PNIPAM resulted in a lower LCST. The LCST was decreased more when the cavities of the crown ether units captured K ⁺ ions.
MANY polymeric hydrogels undergo abrupt changes in volume in response to external stimuli such as changes in solvent composition1, pH2, electric field3 and temperature4–6. For several of the potential applications of these materials, such as 'smart' actuators, a fast response is needed. The kinetics of swelling and de-swelling in these gels are typically governed by diffusion-limited transport of the polymeric components of the network in water, the rate of which is inversely proportional to the square of the smallest dimension of the gel7–9. Several strategies have been explored for increasing the response dynamics10–14, such as introducing porosity14. Here we show that we can induce rapid de-swelling of a polymer hydrogel by tailoring the gel architecture at the molecular level. We prepare a crosslinked hydrogel in which the polymer chains bear grafted side chains; the latter create hydrophobic regions, aiding the expulsion of water from the network during collapse. Whereas similar gels lacking the grafted side chains can take more than a month to undergo full de-swelling, our materials collapse in about 20 minutes.
We synthesized and characterized for the first time an ampholytic ion-recognition linear copolymer of [3-(methacryloylamino)propyl]trimethylammonium chloride (MAPTAC), acrylic acid (AA), and benzo[18]crown-6-acrylamide (BCAm). In this copolymer, the MAPTAC unit has a positive charge. The AA unit has a negative charge that depends on the pH. The crown receptor of the BCAm unit forms a complex with specific ions such as Ba2+ because of the high complex formation constant which behaved like a fixed positive charge. Thus, the copolymers behaved as an ion-recognition polyampholytes and shrank at a pH equal to the isoelectric point (IEP), which shifted to a higher pH when the BCAm complexed with a cation. At that time, the BCAm also became hydrophilic with water of hydration accompanied by the cation. As a result of the combination of these two effects, we found that the reverse behaviors of swelling and shrinking occurred at different pHs in response to the same ion signal.
A molecular recognition ion gating membrane opens and closes its pores using the volume phase transition of PE (polyethylene)-g-N-isopropylacrylamide (NIPAM)-co-benzo[18]crown-6-acrylamide (BCAm), which recognizes specific ions with its BCAm receptors and changes its volume by swelling and shrinking. In this study, we clarify the mechanism of the molecular recognition response of the PE-g-NIPAM-co-BCAm. The complex formation constant (log K) of the crown ether receptors contained in BCAm units was determined to be an order of magnitude lower than that of benzo[18]crown-6. Calculating from log K, we estimated the quantity of the complex of the crown ether receptor and the ion; the ratio of the BCAm units forming the complex to total monomer units that consists of NIPAM and BCAm (X) was below 5%. Although X was less than 5%, the complex affected the swelling and the shrinking of NIPAM units. Poly-NIPAM is well-known to change its volume at the lower critical solution temperature (LCST), being accompanied by the change of the enthalpy (ΔH). The differential scanning calorimetry (DSC) data of PE-g-NIPAM-co-BCAm showed that LCST increased and ΔH decreased with increasing X, regardless of ion species. ΔH is generated to compensate for the breakage of hydrogen bonds between the water molecules that surround the hydrophobic moieties of polymer chains; therefore, formation of the complexes of the crown ether receptors and the ions broke the hydrogen bonds and then shifted the LCST higher. In addition, the LCST determined by DSC predicts the temperature at which the membrane pores open. Therefore, this suggested mechanism contributes to both the molecular design of grafted stimuli-responsive copolymers and the design of the gating membrane function.
Formation constants, K, and single ion conductances, Ac, of complexes of Na+ and K+ with a series of 4′-substituted monobenzo-15-crown-5 and monobenzo18-crown-6 ligands were determined conductometrically in acetone at 25 °C. For the complexes of Na+ with benzo-15-crown-5 ligands a 25-fold difference in K is observed between the 4′-amino and 4′-nitro derivative. A good Hammett correlation is found by plotting log K vs. σp- + σm for nine 4′-derivatives, the ρ value being -0.45. The substituent effect in Na+/benzo-18-crown-6 complexes is much smaller, and almost negligible for electron with-drawing substituents. No Hammet correlation is found. It is argued that in this system the pronounced difference in the diameters of cation and crown cavity causes the distance between the cation and the aromatic oxygen atoms to change as a function of the nature of the substituent, which in turn can induce conformational changes in the polyether ring. Substituent effects are somewhat larger for K+/benzo-18-crown-6 complexes, but again no linear Hammett plot is obtained. In mixtures of K+ with monobenzo-15-crown-5, 1:1 and 2:1 crown-cation complexes can exist simultaneously, and, although no K values could be calculated, substituent effects on the complexation are quite pronounced.
Poly(N-isopropylacrylamide) (PNIPAM) hydrogels were fabricated with distinctly different internal microstructures. The internal microstructures of the PNIPAM hydrogels were characterized by SEM, and the effects of the internal microstructures of the PNIPAM hydrogels on their thermo-responsive volume phase-transition and controlled-release characteristics were experimentally investigated. The results showed that there were two kinds of microstructures of PNIPAM hydrogels, a homogeneous netlike microstructure and a heterogeneous microstructure with microgel clusters, and the thermo-responsive volume phase-transition behaviors and controlled-release characteristics of the PNIPAM hydrogels were found to be heavily dependent on their internal microstructures. The homogeneous internal microstructure caused a remarkably greater volume change, while the heterogeneous internal microstructure resulted in a more rapid responsiveness and a more ideal thermo-responsive controlled-release property. Consequently, for different applications, PNIPAM hydrogels should be designed and fabricated with different internal microstructures.
A novel thermo‐responsive smart copolymer that can selectively respond to specific ions, poly[( N ‐isopropylacrylamide)‐ co ‐(benzo‐15‐crown‐5‐acrylamide)], has been synthesized and characterized. The copolymer exhibits a negative shift of the lower critical solution temperature (LCST) for phase transition that is specifically responsive to certain alkali metal ions. The order of significance of the LCST shift that is induced by ions is K ⁺ > Cs ⁺ > Na ⁺ > Li ⁺ . The greater the number of crown ether units in the copolymer, or the larger the ion concentration, the higher the sensitivity and selectivity of the copolymer for cation recognition. Because of its novel ion‐responsive characteristics, the proposed smart copolymer is a promising new candidate material for sensors, actuators, switches, and so on.
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Unique molecular-recognition microcapsules for environmental stimuli-responsive controlled release have been developed. The microcapsules consist of a core-shell porous membrane. The pores contain linear-grafted poly(NIPAM-co-BCAm) chains, which act as the molecular-recognition gates.
In this study, we report on a novel composite membrane system for pH-responsive controlled release, which is composed of a porous membrane with linear grafted, positively pH-responsive polymeric gates acting as functional valves, and a crosslinked, negatively pH-responsive hydrogel inside the reservoir working as a functional pumping element. The proposed system features a large responsive release rate that goes effectively beyond the limit of concentration-driven diffusion due to the pumping effects of the negatively pH-responsive hydrogel inside the reservoir. The pH-responsive gating membranes were prepared by grafting poly(methacrylic acid) (PMAA) linear chains onto porous polyvinylidene fluoride (PVDF) membrane substrates using a plasma-graft pore-filling polymerization, and the crosslinked poly(N,N-dimethylaminoethyl methacrylate) (PDM) hydrogels were synthesized by free radical polymerization. The volume phase-transition characteristics of PMAA and PDM were opposite. The proposed system opens new doors for pH-responsive “smart” or “intelligent” controlled-release systems, which are highly attractive for drug-delivery systems, chemical carriers, sensors, and so on.
A novel thermoresponsive membrane for chiral resolution with high performance has been developed. The membrane exhibits chiral selectivity based on molecular recognition of beta-cyclodextrin (β-CD) and thermosensitivity based on the phase transition of poly(N-isopropylacrylamide) (PNIPAM). Linear PNIPAM chains were grafted onto porous nylon-6 membrane substrates by using a plasma-graft pore-filling polymerization method; the chains thus acted as microenvironmental adjustors for β-CD molecules. β-CD moieties were introduced into the linear PNIPAM chains by a chemical grafting polymerization method and acted as chiral selectors. The phase transition of grafted PNIPAM chains affects the microenvironment of β-CD molecules and, thus, the association between β-CD and guest molecules. The chiral selectivity of the prepared thermoresponsive membranes in chiral resolution operated at temperature below the lower critical solution temperature (LCST) of PNIPAM is higher than that of membranes with no thermosensitivity. Furthermore, the decomplexation ratio of enantiomer-loaded thermoresponsive membranes in decomplexation at temperatures above the LCST is much higher than that of membranes with no thermosensitivity. Thus, by simply changing the operation temperature, high, selective chiral resolution and efficient membrane regeneration are achieved. The proposed membrane provides a new and efficient way to solve the difficult decomplexation problem of chiral solid membranes, which is highly attractive for chiral resolution.
In this paper, we report on a novel family of monodisperse thermo-sensitive core–shell hydrogel microspheres that is featured with high monodispersity and positively thermo-responsive volume phase transition characteristics with tunable swelling kinetics, i.e., the particle swelling is induced by an increase rather than a decrease in temperature. The microspheres were fabricated in a three-step process. In the first step, monodisperse poly(acrylamide-co-styrene) seeds were prepared by emulsifier-free emulsion polymerization. In the second step, poly(acrylamide) or poly[acrylamide-co-(butyl methacrylate)] shells were fabricated on the microsphere seeds by free radical polymerization. In the third step, the core–shell microspheres with poly- (acrylamide)/poly(acrylic acid) based interpenetrating polymer network (IPN) shells were finished by a method of sequential IPN synthesis. The proposed monodisperse core–shell microspheres provide a new mode of the phase transition behavior for thermo-sensitive “smart” or “intelligent” monodisperse micro-actuators that is highly attractive for targeting drug delivery systems, chemical separations, sensors, and so on.
A new type of glucose-responsive hydrogel with rapid response to blood glucose concentration change at physiological temperature has been successfully developed. The polymeric hydrogel contains phenylboronic acid (PBA) groups as glucose sensors and thermo-responsive poly (N-isopropylacrylamide) (PNIPAM) groups as actuators. The response rate of the hydrogel to environmental glucose concentration change was significantly enhanced by introducing grafted poly(N-isopropylacrylamide-co-3-acrylamidophenylboronic acid) [poly(NIPAM-co-AAPBA)] side chains onto crosslinked poly(NIPAM-co-AAPBA) networks for the first time. The synthesized comb-type grafted poly(NIPAM-co-AAPBA) hydrogels showed satisfactory equilibrium glucose-responsive properties, and exhibited much faster response rate to glucose concentration change than normal type crosslinked poly(NIPAM-co-AAPBA) hydrogels at physiological temperature. Such glucose-responsive hydrogels with rapid response rate are highly attractive in the fields of developing glucose-responsive sensors and self-regulated drug delivery systems. Copyright © 2008 John Wiley & Sons, Ltd.
An approach based on an enzyme-responsive chemically crosslinked hydrogel that undergoes a macroscopic transition such as hydrogel swelling, when triggered by a target protease, resulting in release of entrapped molecules was analyzed. Polyethylene glycol (PEG)-based crosslinked polymers were modified with peptides providing dual functions, thus creating a zwitterionic peptide that confers no overall charge when coupled to a hydrogel. The enzyme responsiveness of the PEGA particles was studied using three complementary methods that included analysis of accessibility of the hydrogel by two-photon microscopy, high-performance liquid chromatography (HPLC) analysis, and particle diameters obtained by optical microscopy. It was observed that the hydrogel responds by swelling specifically in response to target enzymes based on the enzyme cleavable linker employed in the PEGA-coupled peptide chain.
A novel type of dual stimuli-responsive microspheres that simultaneously exhibit ion-recognition property based on the supramolecular host–guest complexation of crown ether receptors (benzo-18-crown-6-acrylamide) (BCAm) with specific ions and thermo-sensitivity based on the phase transition of poly(N-isopropylacrylamide) (PNIPAM) is fabricated in this study. The prepared poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) (P(NIPAM-co-BCAm)) microspheres are characterized by FT-IR spectroscopy, UV–vis absorption spectroscopy, scanning electron microscopy (SEM), and dynamic light scattering (DLS). SEM images and DLS data show that the synthesized microspheres exhibit nearly perfect spherical shape and high monodispersity. Moreover, according to the DLS results, P(NIPAM-co-BCAm) microspheres exhibit satisfactory thermo-responsive behavior and ion-recognition property. In K+ solutions, due to the formation of crown ether/K+ complexes, the LCST of P(NIPAM-co-BCAm) microspheres shifts to a higher temperature and the colloidal stability is increased. The P(NIPAM-co-BCAm) microspheres undergo a volume change from shrunken state to swollen network isothermally at a certain temperature by the addition of metal ions. Due to dual thermo-responsive and ion-recognition behaviors, this kind of microspheres would serve as promising candidates for sensors, controlled drug delivery systems and possibly new biomaterials.Graphical abstract
A facile method to control the volume-phase transition kinetics of thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) microgels is presented. Monodisperse PNIPAM microgels with spherical voids are prepared using a microfluidic device. The swelling and shrinking responses of these microgels with spherical voids to changes in temperature are compared with those of voidless microgels of the same size and chemical composition prepared using the same microfluidic device. It is shown that the PNIPAM microgels with voids respond faster to changes in temperature as compared with their voidless counterparts. Also, the induced void structure does not have a detrimental effect on the equilibrium volume change of the microgels. Thus, the volume phase transition kinetics of the microgels can be finely tuned by controlling the number and size of the voids. The flexibility, control, and simplicity in fabrication rendered by this approach make these microgels appealing for applications that range from drug delivery systems and chemical separations to chemical/biosensing and actuators.
The adjustment or manipulation of response temperature of thermo-responsive membranes was systematically investigated by adding hydrophilic or hydrophobic monomers into N-isopropylacrylamide (NIPAM) monomer solution in the fabrication of thermo-responsive gates for the membranes. Plasma-induced grafting polymerization method was introduced to graft thermo-responsive polymers poly(N-isopropylacrylamide) (PNIPAM), poly(N-isopropyl-acrylamide-co-acrylamide) (PNA) and poly(N-isopropylacrylamide-co-butyl methacrylate) (PNB) as functional gates onto porous polyvinylidene fluoride (PVDF) or Nylon-6 (N6) membrane substrates. The SEM and XPS characterizations showed that PNIPAM, PNA and PNB were all successfully grafted onto the porous PVDF or N6 membrane substrates. The water flux experimental results showed that the response temperatures of grafted gating membranes were linearly increased with increasing the molar ratio of hydrophilic monomer acrylamide (AAM) in the NIPAM co-monomer solution, but linearly decreased with increasing the molar ratio of hydrophobic monomer butyl methacrylate (BMA) in the NIPAM co-monomer solution. The response temperature of PNA-g-PVDF membrane was raised to 40 °C when 7 mol% of AAM was added into the NIPAM co-monomer solution, and that of PNB-g-N6 membrane was reduced to 17.5 °C when 10 mol% of BMA was introduced into the NIPAM co-monomer solution. The relationship between the hydrophobicity and response temperature of grafted membranes was also investigated. The results in this study provided valuable guidance for the design and preparation of thermo-responsive gating membranes with desired response temperatures for different applications.
Novel dual temperature- and pH-sensitive comb-type grafted poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-co-AAc)) hydrogels were successfully prepared by grafting PNIPAM chains with freely mobile ends onto the backbone of a cross-linked P(NIPAM-co-AAc) network. The prepared comb-type grafted P(NIPAM-co-AAc) hydrogels exhibited a more rapid deswelling rate than normal-type P(NIPAM-co-AAc) hydrogels in ultrapure water in response to abrupt changes from 25 °C to 60 °C. The same was true in buffer solution with a pH jump from 7.4 to 2.0 at 25 °C. Unexpectedly, the comb-type grafted P(NIPAM-co-AAc) hydrogels showed abnormal shrinkage behaviors in a buffer solution when the temperature increased from 25 °C to 60 °C with a pH value fixed at 7.4 or 2.0. In a buffer solution of pH 7.4, when the environmental temperature jumped from 25 °C to 60 °C, the grafted comb-type hydrogels shrank slower than the normal-type hydrogels, while at pH 2.0, the gels shrank faster than the normal-type gels in the beginning, which was followed by a slower shrinking. Interestingly, the much quicker shrinkage of the comb-type grafted P(NIPAM-co-AAc) hydrogels was observed because of the cooperative thermo-/pH-responses when the simultaneous temperature and pH stimuli met from pH 7.4/25 °C to pH 2.0/60 °C. The results of this study provide valuable information regarding the development of dual stimuli-sensitive hydrogels with fast responsiveness.
A thermoresponsive cationic copolymer, poly( N-isopropylacrylamide- co- N-(3-(dimethylamino)propyl)methacrylamide)- b-polyethyleneimine (P(NIPAAm- co-NDAPM)- b-PEI), was designed and synthesized as a potential nonviral gene vector. The lower critical solution temperature (LCST) of P(NIPAAm- co-NDAPM)- b-PEI in water measured by UV-vis spectroscopy was 38 degrees C. P(NIPAAm- co-NDAPM)- b-PEI as the gene vector was evaluated in terms of cytotoxicity, buffer capability determined by acid-base titration, DNA binding capability characterized by agarose gel electrophoresis and particle size analysis, and in vitro gene transfection. P(NIPAAm- co-NDAPM)- b-PEI copolymer exhibited lower cytotoxicity in comparison with 25 kDa PEI. Gel retardation assay study indicated that the copolymer was able to bind DNA completely at N/P ratios higher than 30. At 27 degrees C, the mean particle sizes of P(NIPAAm- co-NDAPM)- b-PEI/DNA complexes decreased from 1200 to 570 nm corresponding to the increase in N/P ratios from 10 to 60. When the temperature changed to 37 degrees C, the mean particle sizes of complexes decreased from 850 to 450 nm correspondingly within the same N/P ratio range due to the collapse of thermoresponsive PNIPAAm segments. It was found that the transfection efficiency of P(NIPAAm- co-NDAPM)- b-PEI/DNA complexes was higher than or comparable to that of 25 kDa PEI/DNA complexes at their optimal N/P ratios. Importantly, the transfection efficiency of P(NIPAAm- co-NDAPM)- b-PEI/DNA complexes could be adjusted by altering the transfection and cell culture temperature.
The polymer gels called hydrogels may be induced to swell or shrink (taking up or expelling water between the crosslinked polymer chains) in response to a variety of environmental stimuli, such as changes in pH or temperature, or the presence of a specific chemical substrate. These gels are being explored for several technological applications, particularly as biomedical materials. When hydrogels swell or shrink, complex patterns may be generated on their surfaces. Here we report the synthesis and controlled modulation of engineered surface patterns on environmentally responsive hydrogels. We modify the character of a gel surface by selectively depositing another material using a mask. For example, we use sputter deposition to imprint the surface of an N-isopropylacrylamide (NIPA) gel with a square array of gold thin films. The periodicity of the array can be continuously varied as a function of temperature or electric field (which alter the gel's volume), and so such an array might serve as an optical grating for sensor applications. We also deposit small areas of an NIPA gel onthe surface of an acrylamide gel; the patterned area can be rendered invisible reversibly by switching the temperature above or below the lower critical solution temperature of the NIPA gel. We anticipate that these surface patterning techniques may find applications in display and sensor technology.
A novel thermo-induced self-bursting microcapsule with magnetic-targeting property is developed (see figure). The Fe3O4 nanoparticles-embedded PNIPAM shell enables magnetic-targeting and thermo-induced self-bursting of the microcapsules. Lipophilic chemicals dissolved in the oil core are completely released with the burst release of the encapsulated oil.
A novel polymeric lead(II) adsorbent is prepared by incorporating benzo-18-crown-6-acrylamide (BCAm) as metal ion receptor into the thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) hydrogel. Both stimuli-sensitive properties and the Pb(2+)-adsorption capabilities of the prepared P(NIPAM-co-BCAm) hydrogels are investigated. The prepared P(NIPAM-co-BCAm) hydrogels exhibit good ion-recognition and Pb(2+)-adsorption characteristics. When crown ether units capture Pb(2+) and form BCAm/Pb(2+) host-guest complexes, the lower critical solution temperature (LCST) of the hydrogel shifts to a higher temperature due to both the repulsion among charged BCAm/Pb(2+) groups and the osmotic pressure within the hydrogel. The adsorption results at different temperatures show that P(NIPAM-co-BCAm) hydrogels adsorb Pb(2+) ions at temperature lower than the LCST, but undergo desorption at temperature higher than the LCST due to the "stretch-to-shrink" configuration change of copolymer networks which is triggered by the change in environmental temperature. This kind of ion-recognition hydrogel is promising as a novel adsorption material for adsorption and separation of Pb(2+) ions. The adsorption and desorption of Pb(2+) could be rationally achieved by simply changing the environmental temperature.
Hydrogel nanoparticles have gained considerable attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials via combining the characteristics of a hydrogel system (e.g., hydrophilicity and extremely high water content) with a nanoparticle (e.g., very small size). Several polymeric hydrogel nanoparticulate systems have been prepared and characterized in recent years, based on both natural and synthetic polymers, each with its own advantages and drawbacks. Among the natural polymers, chitosan and alginate have been studied extensively for preparation of hydrogel nanoparticles and from synthetic group, hydrogel nanoparticles based on poly (vinyl alcohol), poly (ethylene oxide), poly (ethyleneimine), poly (vinyl pyrrolidone), and poly-N-isopropylacrylamide have been reported with different characteristics and features with respect to drug delivery. Regardless of the type of polymer used, the release mechanism of the loaded agent from hydrogel nanoparticles is complex, while resulting from three main vectors, i.e., drug diffusion, hydrogel matrix swelling, and chemical reactivity of the drug/matrix. Several crosslinking methods have been used in the way to form the hydrogel matix structures, which can be classified in two major groups of chemically- and physically-induced crosslinking.
New controlled drug-delivery systems are being explored to overcome the disadvantages of conventional dosage forms. For example, stimulated drug-delivery has been used to overcome the tolerance problems that occur with a constant delivery rate, to mimic the physiological pattern of hormonal concentration and to supply drugs on demand. Stimuli-sensitive polymers, which are potentially useful for pulsed drug delivery, experience changes in either their structure or their chemical properties in response to changes in environmental conditions. Environmental stimuli include temperature, pH, light (ultraviolet or visible), electric field or certain chemicals. Volume changes of stimuli-sensitive gel networks are particularly responsive to external stimuli, but swelling is slow to occur. As well as being useful in the controlled release of drugs, such systems also provide insight into intermolecular interactions. Here we report on a novel polymeric system, which rapidly changes from a solid state to solution in response to small electric currents, by disintegration of the solid polymer complex into two water-soluble polymers. We show that the modulated release of insulin, and by extension other macromolecules, can be achieved with this polymeric system.
Many polymer gels undergo reversible, discontinuous volume changes in response to changes in the balance between repulsive intermolecular forces that act to expand the polymer network and attractive forces that act to shrink it. Repulsive forces are usually electrostatic or hydrophobic in nature, whereas attraction is mediated by hydrogen bonding or van der Waals interactions. The competition between these counteracting forces, and hence the gel volume, can thus be controlled by subtle changes in parameters such as pH (ref. 4), temperature, solvent composition or gel composition. Here we describe a more direct influence on this balance of forces, by showing that the radiation force generated by a focused laser beam induces reversible shrinkage in polymer gels. Control experiments confirm that the laser-induced volume phase transitions are due to radiation forces, rather than local heating, modifying the weak interactions in the gels, in agreement with previous observations of light-induced chain association in polymer solutions. We find that, owing to shear-relaxation processes, gel shrinkage occurs up to several tens of micrometres away from the irradiation spot, raising the prospect that the combination of stimuli-responsive polymer gels and laser light might lead to new gel-based systems for applications such as actuating or sensing.
Environmentally sensitive hydrogels have enormous potential in various applications. Some environmental variables, such as low pH and elevated temperatures, are found in the body. For this reason, either pH-sensitive and/or temperature-sensitive hydrogels can be used for site-specific controlled drug delivery. Hydrogels that are responsive to specific molecules, such as glucose or antigens, can be used as biosensors as well as drug delivery systems. Light-sensitive, pressure-responsive and electro-sensitive hydrogels also have the potential to be used in drug delivery and bioseparation. While the concepts of these environment-sensitive hydrogels are sound, the practical applications require significant improvements in the hydrogel properties. The most significant weakness of all these external stimuli-sensitive hydrogels is that their response time is too slow. Thus, fast-acting hydrogels are necessary, and the easiest way of achieving that goal is to make thinner and smaller hydrogels. This usually makes the hydrogel systems too fragile and they do not have mechanical strength necessary in many applications. Environmentally sensitive hydrogels for drug delivery applications also require biocompatibility. Synthesis of new polymers and crosslinkers with more biocompatibility and better biodegradability would be essential for successful applications. Development of environmentally sensitive hydrogels with such properties is a formidable challenge. If the achievements of the past can be extrapolated into the future, however, it is highly likely that responsive hydrogels with a wide array of desirable properties can be made.
KChIP2, a gene encoding three auxiliary subunits of Kv4.2 and Kv4.3, is preferentially expressed in the adult heart, and its expression is downregulated in cardiac hypertrophy. Mice deficient for KChIP2 exhibit normal cardiac structure and function but display a prolonged elevation in the ST segment on the electrocardiogram. The KChIP2(-/-) mice are highly susceptible to the induction of cardiac arrhythmias. Single-cell analysis revealed a substrate for arrhythmogenesis, including a complete absence of transient outward potassium current, I(to), and a marked increase in action potential duration. These studies demonstrate that a defect in KChIP2 is sufficient to confer a marked genetic susceptibility to arrhythmias, establishing a novel genetic pathway for ventricular tachycardia via a loss of the transmural gradient of I(to).
Reported here is an efficient recognition of K+ by 15-crown-5 functionalized gold nanoparticles in aqueous matrix containing physiologically important cations, such as Li+, Cs+, NH4+, Mg2+, Ca2+, and excess amount of Na+. Upon exposure to K+, the colloidal solution changes from red to blue, in response to surface plasmon absorption of dispersed and aggregated nanoparticles. The concentration ranges of K+ detected in this study are 0.099-0.48 mM and 7.6 microM-0.14 mM, when concentrations of colloidal gold are 54.9 and 7.1 nM, respectively. Recognition of K+ and formation of the aggregates are proposed via a sandwich complex of 2:1 between 15-crown-5 moiety and K+. Also discussed is the possibility of a preorganized structure of 15-crown-5 at the water-organic interface for the efficient complexation with K+.
We have fabricated a molecular recognition ion gating membrane. This synthetic membrane spontaneously opens and closes its pores in response to specific solvated ions. In addition to this switching function, we found that this membrane could control its pore size in response to a known concentration of a specific ion. The membrane was prepared by plasma graft copolymerization, which filled the pores of porous polyethylene film with a copolymer of NIPAM (N-isopropylacrylamide) and BCAm (benzo[18]crown-6-acrylamide). NIPAM is well-known to have an LCST (lower critical solution temperature), at which its volume changes dramatically in water. The crown receptor of the BCAm traps a specific ion, and causes a shift in the LCST. Therefore, selectively responding to either K(+) or Ba(2+), the grafted copolymer swelled and shrank in the pores at a constant temperature between two LCSTs. The solution flux in the absence of Ba(2+) decreased by about 2 orders of magnitude over a solution flux containing Ba(2+). The pore size was estimated by the filtration of aqueous dextran solutions with various solute sizes. This revealed that the membrane changed its pore size between 5 and 27 nm in response to the Ba(2+) concentration changes. No such change was observed for Ca(2+) solutions. Furthermore, this pore size change occurred uniformly in all pores, as a clear cut-off value for a solute size that could pass through pores was always present. This membrane may be useful not only as a molecular recognition ion gate, but also as a device for spontaneously controlling the permeation flux and solute size.
Recently, there has been a great deal of research activity in the development of stimulus-responsive polymeric hydrogels. These hydrogels are responsive to external or internal stimuli and the response can be observed through abrupt changes in the physical nature of the network. This property can be favorable in many drug delivery applications. The external stimuli can be temperature, pH, ionic strength, ultrasonic sound, electric current, etc. A majority of the literature related to the development of stimulus-responsive drug delivery systems deals with temperature-sensitive poly(N-isopropyl acrylamide) (pNIPAAm) and its various derivatives. However, acrylic-based pH-sensitive systems with weakly acidic/basic functional groups have also been widely studied. Quite recently, glucose-sensitive hydrogels that are responsive to glucose concentration have been developed to monitor the release of insulin. The present article provides a brief introduction and recent developments in the area of stimulus-responsive hydrogels, particularly those that respond to temperature and pH, and their applications in drug delivery.
Two classes of polymers that are currently receiving widespread attention in biosensor development are hydrogels and conducting electroactive polymers. The present study reports on the integration of these two materials to produce electroactive hydrogel composites that physically entrap enzymes within their matrices for biosensor construction and chemically stimulated controlled release. Enhanced biosensing capabilities of these membranes have been demonstrated in the fabrication of glucose, cholesterol and galactose amperometric biosensors. All biosensors displayed extended linear response ranges (10(-5)-10(-2) M), rapid response times (<60 s), retained storage stabilities of up to 1 year, and excellent screening of the physiological interferents ascorbic acid, uric acid, and acetaminophen. When the cross-linked hydrogel components of these composite membranes were prepared with the amine containing dimethylaminoethyl methacrylate monomer the result was polymeric devices that swelled in response to pH changes (neutral to acidic). Entrapment of glucose oxidase within these materials made them glucose-responsive through the formation of gluconic acid. When insulin was co-loaded with glucose oxidase into these "bio-smart" devices, there was a twofold increase in insulin release rate when the devices were immersed in glucose solutions. This demonstrates the potential of such systems to function as a chemically-synthesized artificial pancreas.
With the advent of the genomic revolution and the sequencing of the human genome complete, the majority of pharmaceuticals under development are proteins. Consequently, new techniques to more effectively administer these new protein therapeutics need to be developed. One method that is gaining popularity in the research community involves the use of responsive hydrogel actuators for flow control in drug delivery devices. Responsive hydrogels are materials able to undergo a volume change in response to a stimulus from their local environment. The following paper overviews recent advances made using hydrogel actuators for flow control such as resistance based valves, hydrogel jacket valves, hybrid hydrogel membrane valve, electrically triggered valves, and biomimetic valves. Also reviewed are several hydrogel flow control systems such as a flow sorter and pH-regulation system. The chemistry of the hydrogel actuators can be tweaked to allow physiological variables to trigger the volume expansion of the hydrogel actuators as demonstrated by several glucose sensitive hydrogel valves reviewed below. Therefore, the door to physiological feedback controlling the infusion rate in a drug delivery device is opened and has the potential to revolutionize protein pharmaceutical drug delivery.
The pore size and permeability control of a glucose-responsive gating membrane with plasma-grafted poly(acrylic acid) (PAAC) gates and covalently bound glucose oxidase (GOD) enzymes were investigated systematically. The PAAC-grafted porous polyvinylidene fluoride (PVDF) membranes with a wide range of grafting yields were prepared using a plasma-graft pore-filling polymerization method, and the immobilization of GOD was carried out by a carbodiimide method. The linear grafted PAAC chains in the membrane pores acted as the pH-responsive gates or actuators. The immobilized GOD acted as the glucose sensor and catalyzer; it was sensitive to glucose and catalyzed the glucose conversion to gluconic acid. The experimental results showed that the glucose responsivity of the solute diffusional permeability through the proposed membranes was heavily dependent on the PAAC grafting yield, because the pH-responsive change of pore size governed the glucose-responsive diffusional permeability. It is very important to design a proper grafting yield for obtaining an ideal gating response. For the proposed gating membrane with a PAAC grafting yield of 1.55%, the insulin permeation coefficient after the glucose addition (0.2 mol/l) was about 9.37 times that in the absence of glucose, presenting an exciting result on glucose-sensitive self-regulated insulin permeation.
A molecular recognition gating ion membrane was prepared by graft copolymerization of N-isopropylacrylamide and benzo[18]crown-6-acrylamide onto the pore surface of porous polyethylene film. This membrane captured Ba2+ with its crown ether receptors and generated osmotic pressure in response to Ba2+ autonomously and reversibly. However, the membrane never generated osmotic pressure in response to Ca2+. In addition, the concentration gradient of both the ion and other solute such as dextran could be used as the driving force; using a dextran concentration gradient, we can control the critical concentration and the duration time of the osmosis response.
We developed a rapidly regenerable cell culture system in which the cell culture substrate detects cell death and selectively releases the dead cells. This culture material was achieved by combining a detector that responds to the signal from the dead cells and an actuator to release the dead cells. Benzo-18-crown-6-acrylamide (BCAm) with a pendant crown ether receptor was used as the sensor to recognize cellular signals and N-isopropylacrylamide (NIPAM) was used as the actuator. This copolymer of NIPAM and BCAm can respond to potassium ions and change its nature from hydrophobic to hydrophilic at the culture temperature of 37 degrees C. Living cells concentrate potassium ion internally; when cells die, potassium ions are released. The polymer surface recognizes the potassium ions released from the dead cells, the NIPAM hydrates, and the dead cells are selectively detached. This in vitro culture system is a novel one in which artificial culture materials work cooperatively with cellular metabolism by responding to this signal from the cells, thereby realizing in vitro tissue regeneration partly mimicking the mechanisms of in vivo homeostasis.
We have developed a novel cell culture material that regulates cell adhesion by changes in potassium ion concentration. The material is a polyethylene substrate grafted to a copolymer of the thermoresponsive polymer N-isopropylacrylamide (NIPAM) and benzo-18-crown- 6-acrylamide (BCAm), with a pendant crown ether as sensor. The crown ether recognizes potassium ion concentrations and NIPAM conformational changes lead to changes in the hydrophobicity/hydrophilicity balance of the entire polymer at constant cell culture temperatures. Although cells were successfully cultured on the ion recognition material in normal culture medium at 37 degrees C, the cells could be detached from the material surface by adding potassium ions alone, without proteolytic enzymes, because the surface to which the cells were attached altered its surface characteristics to a more hydrophilic state. Therefore, cell layers with intact cell-to-cell junctions and high activities were successfully recovered. Furthermore, by changing the target sensors, this material will be able to control cell adhesion through various cellular signals.