ArticleLiterature Review

In situ-forming hydrogels - Review of temperature-sensitive systems

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Abstract

In the past few years, an increasing number of in situ-forming systems have been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. There are several possible mechanisms that lead to in situ gel formation: solvent exchange, UV-irradiation, ionic cross-linkage, pH change, and temperature modulation. The thermosensitive approach can be advantageous for particular applications as it does not require organic solvents, co-polymerization agents, or an externally applied trigger for gelation. In the last 2 decades, several thermosensitive formulations have been proposed. This manuscript focuses on aqueous polymeric solutions that form implants in situ in response to temperature change, generally from ambient to body temperature. It mainly reviews the characterization and use of polysaccharides, N-isopropylacrylamide copolymers, poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (poloxamer) and its copolymers, poly(ethylene oxide)/(D,L-lactic acid-co-glycolic acid) copolymers, and thermosensitive liposome-based systems.

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... Polymer size was found to increase with the increase in AAc concentration, as well as a shift in VPTT to a higher temperature due to the hydrophilic nature of AAc [39]. [40]. It is an attractive biomaterial for the synthesis of thermosensitive drug delivery systems, as it was approved by the FDA for human use. ...
... Although PNIPAAm-based copolymers have garnered great interest in research, there are other thermosensitive particles derived from other types of polymers. For example, Pluronic F127 (Poloxamer 407) is an amphiphilic ABA-type triblock copolymer composed of poly(ethylene oxide) 98 -poly(propylene oxide) 67 -poly(ethylene oxide) 98 blocks (PEO 98 -PPO 67 -PEO 98 ) [40]. It is an attractive biomaterial for the synthesis of thermosensitive drug delivery systems, as it was approved by the FDA for human use. ...
... It is an attractive biomaterial for the synthesis of thermosensitive drug delivery systems, as it was approved by the FDA for human use. In addition to their reversible gelation capabilities, non-toxicity, biodegradability, and biocompatibility, Pluronic F127-based systems exhibit prolonged drug residence times [40,41]. Table 1 presents some studies that proposed Pluronic F-127-based systems for different drug delivery applications. ...
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Temperature excursions within a biological milieu can be effectively used to induce drug release from thermosensitive drug-encapsulating nanoparticles. Oncological hyperthermia is of particular interest, as it is proven to synergistically act to arrest tumor growth when combined with optimally-designed smart drug delivery systems (DDSs). Thermoresponsive DDSs aid in making the drugs more bioavailable, enhance the therapeutic index and pharmacokinetic trends, and provide the spatial placement and temporal delivery of the drug into localized anatomical sites. This paper reviews the fundamentals of thermosensitive polymers, with a particular focus on thermoresponsive liposomal-based drug delivery systems.
... From a thermodynamic viewpoint, the balance between the hydrophobic and hydrophilic groups on the polymer chain and the free energy of mixing (∆G ∆H T∆S result in marked alteration of the aqueous solubility of the polymer and cause sol-to-gel phase transition [1,6]. Since the enthalpy (ΔH) is smaller than the entropy (ΔS), an increase in temperature (T) results in negative free energy of association (−ΔG), which increases the preference of polymer-polymer and water-water interactions to polymerwater interactions and causes the dehydration of solvated polymers [1,161]. In the case of amphiphilic polymers, an increase in polymer concentration above CMC results in the packaging of micelles in an ordered manner, forming a hydrophobic core and hydro- ...
... From a thermodynamic viewpoint, the balance between the hydrophobic and hydrophilic groups on the polymer chain and the free energy of mixing (∆G = ∆H − T∆S) result in marked alteration of the aqueous solubility of the polymer and cause sol-to-gel phase transition [1,6]. Since the enthalpy (∆H) is smaller than the entropy (∆S), an increase in temperature (T) results in negative free energy of association (−∆G), which increases the preference of polymer-polymer and water-water interactions to polymer-water interactions and causes the dehydration of solvated polymers [1,161]. In the case of amphiphilic polymers, an increase in polymer concentration above CMC results in the packaging of micelles in an ordered manner, forming a hydrophobic core and hydrophilic shell, and ultimately forms a gel [1,161,162]. ...
... Since the enthalpy (∆H) is smaller than the entropy (∆S), an increase in temperature (T) results in negative free energy of association (−∆G), which increases the preference of polymer-polymer and water-water interactions to polymer-water interactions and causes the dehydration of solvated polymers [1,161]. In the case of amphiphilic polymers, an increase in polymer concentration above CMC results in the packaging of micelles in an ordered manner, forming a hydrophobic core and hydrophilic shell, and ultimately forms a gel [1,161,162]. Various mechanisms of stimuli-responsive gelation are shown in Table 4. ...
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Approaches for effective and sustained drug delivery to the female reproductive tract (FRT) for treating a range of gynaecological conditions remain limited. The development of versatile delivery platforms, such as soluble gels (sol–gels) coupled with applicators/devices, holds considerable therapeutic potential for gynaecological conditions. Sol–gel systems, which undergo solution-to-gel transition, triggered by physiological conditions such as changes in temperature, pH, or ion composition, offer advantages of both solution- and gel-based drug formulations. Furthermore, they have potential to be used as a suitable drug delivery vehicle for other novel drug formulations, including micro- and nano-particulate systems, enabling the delivery of drug molecules of diverse physicochemical character. We provide an anatomical and physiological perspective of the significant challenges and opportunities in attaining optimal drug delivery to the upper and lower FRT. Discussion then focuses on attributes of sol–gels that can vastly improve the treatment of gynaecological conditions. The review concludes by showcasing recent advances in vaginal formulation design, and proposes novel formulation strategies enabling the infusion of a wide range of therapeutics into sol–gels, paving the way for patient-friendly treatment regimens for acute and chronic FRT-related conditions such as bacterial/viral infection control (e.g., STDs), contraception, hormone replacement therapy (HRT), infertility, and cancer.
... To prevent crystallization of longer PEG in system 2, we use the so-called brush-on-brush strategy, which yields comb-like polymers with brush-like side chains (43). In both systems, we deliberately keep the volume fraction of linear block ( L ) below 0.3 to ensure formation of spherical domains (44,45). ...
... Like other temperature-responsive copolymers (44,46,47), the PNIPAM-bbPEG-PNIPAM triblocks promptly self-assemble upon reaching their lower critical solution temperature (LCST) (Fig. 3A and fig. S7) to produce two types of polymer networks: hydrogels at body temperature and elastomers after water evaporation ( Fig. 3B and movie S1). ...
... The mechanical resilience is corroborated by uniaxial compression test, where an LBL hydrogel (15 wt %) withstands up to fourfold compression (Fig. 5B). This behavior is on par with covalently crosslinked hydrogels and represents a substantial improvement of physically crosslinked injectable hydrogels that are typically very brittle (4,5,8,9,44). Furthermore, the 10 to 30 wt % LBL hydrogels do not exhibit any sign of syneresis, which is attributed to a relatively high equilibrium swelling ratio ranging from 12 to 24 (table S7). ...
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Injectable hydrogels are desired in many biomedical applications due to their minimally invasive deployment to the body and their ability to introduce drugs. However, current injectables suffer from mechanical mismatch with tissue, fragility, water expulsion, and high viscosity. To address these issues, we design brush-like macromolecules that concurrently provide softness, firmness, strength, fluidity, and swellability. The synthesized linear-bottlebrush-linear (LBL) copolymers facilitate improved injectability as the compact conformation of bottlebrush blocks results in low solution viscosity, while the thermoresponsive linear blocks permit prompt gelation at 37°C. The resulting hydrogels mimic the deformation response of supersoft tissues such as adipose and brain while withstanding deformations of 700% and precluding water expulsion upon gelation. Given their low cytotoxicity and mild inflammation in vivo, the developed materials will have vital implications for reconstructive surgery, tissue engineering, and drug delivery applications.
... The association free-energy varies with enthalpy, entropy, and temperature (∆G = ∆H-T∆S) because the positive enthalpy term ∆H is smaller than the entropy term ∆S. An increase in temperature results in an increase in T∆S; a negative ∆G value favors polymer chain association [33,34]. Some molecular interactions, such as hydrogen bonds and hydrophobic effects, help with phase separation. ...
... The association free-energy varies with enthalpy, entropy, and temperature (∆G = ∆H − T∆S) because the positive enthalpy term ∆H is smaller than the entropy term ∆S. An increase in temperature results in an increase in T∆S; a negative ∆G value favors polymer chain association [33,34]. Some molecular interactions, such as hydrogen bonds and hydrophobic effects, help with phase separation. ...
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Article
Thermosensitive hydrogels, having unique sol–gel transition properties, have recently received special research attention. These hydrogels exhibit a phase transition near body temperature. This feature is the key to their applications in human medicine. In addition, hydrogels can quickly gel at the application site with simple temperature stimulation and without additional organic solvents, cross-linking agents, or external equipment, and the loaded drugs can be retained locally to improve the local drug concentration and avoid unexpected toxicity or side effects caused by systemic administration. All of these features have led to thermosensitive hydrogels being some of the most promising and practical drug delivery systems. In this paper, we review thermosensitive hydrogel materials with biomedical application potential, including natural and synthetic materials. We describe their structural characteristics and gelation mechanism and briefly summarize the mechanism of drug release from thermosensitive hydrogels. Our focus in this review was to summarize the application of thermosensitive hydrogels in disease treatment, including the postoperative recurrence of tumors, the delivery of vaccines, the prevention of postoperative adhesions, the treatment of nervous system diseases via nasal brain targeting, wound healing, and osteoarthritis treatment.
... They have biomedical applications (e.g., implant, drug delivery, and scaffold) because they can form hydrogels with good biocompatibility. [11][12][13][14] These polymers appear only in recent decades but many of them show promising and advanced functions. Unlike many biological polymers that have their secondary, tertiary, and higher-order structures well characterized by their revealed related functions, most of the synthetic polymers are only defined by their primary chemical structure of the building block, making their structure-function relations far less understood. ...
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Article
Polyvinyl alcohol (PVA) is a water-soluble synthetic polymer that can be used to make hydrogels for biomedical applications as well as biodegradable bags and films; however, compared to other plastics currently used for containers, it lacks mechanical strength, thermal stability, and can easily absorb water from humid environments. Although mechanical improvement has been observed by blending PVA with collagen in a hybrid hydrogel, there is a lack of fundamental understanding of the molecular mechanism, and it is not clear whether the improvement is limited to a hydrated state. Here, using classical molecular dynamics simulations based on fully atomistic models, we develop the equilibrated molecular structure of PVA with collagen and characterize its mechanics. We show that by interacting with a collagen molecule, PVA is equilibrated to a more ordered structure with each residue interacting with the near neighbors by forming more hydrogen bonds locally, making the structure stiffer than pure PVA. The structure shows higher thermal stability before melting, as well as higher rigidity in water. Our results provide the mechanism of the mechanical advantages of hybrid PVA-collagen polymer. The study demonstrates that the structure and mechanics of a synthetic polymer can be tuned by a tiny amount of a natural polymer at the molecular interface. Moreover, it may shed light on identifying a way to improve the mechanics of biodegradable polymer materials without adding much cost, which is crucial for environmental safety. Impact statement Blending natural and synthetic polymers (e.g., polyvinyl alcohol [PVA] and collagen in a hybrid hydrogel) has shown advantages in polymer mechanics, but there is a lack of fundamental understanding. Using molecular dynamics (MD) simulations based on fully atomistic models, we develop the equilibrated structure of the PVA with collagen and characterize its mechanics. We show that by interacting with a collagen molecule, PVA is equilibrated to a more ordered structure with each residue interacting with the near neighbors by forming more H-bonds locally and the structure is stiffer than pure PVA. Moreover, the structure shows a higher thermal stability before the melting point of PVA, as well as higher rigidity in water. Our results demonstrate that the structure and mechanics of a synthetic polymer can be tuned by a tiny amount of a natural polymer at the molecular interface. It provides the mechanism of the mechanical advantages as experimentally observed. This study paves the way for the multiscale modeling and mechanical design of the hybrid polymer material. It sheds light on identifying a way to improve the mechanics of biodegradable materials without adding much cost for both material functionality and environmental safety. Graphical abstract
... The major advantage of thermosensitive polymeric systems is the avoidance of toxic organic solvents, the ability to deliver both hydrophilic and lipophilic drugs, reduced systemic side effects, site specific drug delivery, and sustained release properties. In spite of these advantages several drawbacks associated with these systems include high-burst drug release, low mechanical strength of the gel leading to potential dose-dumping, lack of biocompatibility of the polymeric system and gradual lowering of pH of the system due to acidic degradation 37,38 . Table 4 lists various applications of thermosensitive polymers for drug delivery systems. ...
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Article
Novel drug delivery system utilizing smart polymer to get significant and attracting changes in the targeting of drugs, increasing the bioavailability of drugs, enhancement patient compliance and gene therapy. The scientific community tries to mimic nature in the way that living organisms adopt their behavior as a function of environmental conditions to improve survival. In this sense, smart polymers offer materials that respond to numerous stimuli (temperature, pH, electric and magnetic fields, light intensity, biological molecules, etc.), and scientists must devise the best way to apply them in all research areas. Smart polymers are representing promising means for targeted drug delivery, enhanced drug delivery, gene therapy, actuator stimuli and protein folders. Smart polymers are very promising applicants in drug delivery, tissue engineering, cell culture, gene carriers, textile engineering, oil recovery, radioactive wastage and protein purification. The study is focused on the entire features of smart polymers and their most recent and relevant applications. Keywords: Smart polymer, Novel drug delivery system, Stimuli, Gene therapy
... As a waterinsoluble drug, ASA shows relatively high toxicity and side effects, which restricts its practical applications. Recently, in vivo temperature-sensitive chitosan gel has progressively become a good drug delivery system for decreasing the toxicity and side effects of drugs (Eve and Leroux, 2004). In detail, chitosan and glycerol phosphate are used to prepare thermosensitive hydrogels loaded with adriamycin (an effective drug for treating malignant tumors), which achieve better therapeutic effects by decreasing toxicity and side effects. ...
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Article
Alzheimer’s disease (AD) is a neurodegenerative disorder accompanied by the loss and apoptosis of neurons. Neurons abnormally enter the cell cycle, which results in neuronal apoptosis during the course of AD development and progression. However, the mechanisms underlying cell cycle re-entry have been poorly studied. Using neuroblastoma (N) 2a SW and APP/PS1 transgenic (Tg) mice as in vitro and in vivo AD models, we found that the expression of cyclin-dependent kinase (CDK)1/2/4 and cyclin A2/B1/D3/E1 was increased while the protein expression of p18 and p21 was decreased, which led to enhanced cell cycle re-entry in a β-amyloid protein (Aβ)-dependent mechanism. By preparing and treating with the temperature-sensitive chitosan-encapsulated drug delivery system (CS), the abnormal expression of CDK1/2/4, cyclin A2/B1/D3/E1 and p18/21 was partially restored by acetylsalicylic acid (ASA), which decreased the apoptosis of neurons in APP/PS1 Tg mice. Moreover, CDK4 and p21 mediated the effects of ASA on activating transcription factor (TF) EB via peroxisome proliferator-activated receptor (PPAR) α, thus leading to the uptake of Aβ by astrocytes in a low-density lipoprotein receptor (Ldlr)-dependent mechanism. Moreover, the mechanisms of Aβ-degrading mechanisms are activated, including the production of microtubule-associated protein light chain (LC) 3II and Lamp2 protein by ASA in a PPARα-activated TFEB-dependent manner. All these actions contribute to decreasing the production and deposition of Aβ, thus leading to improved cognitive decline in APP/PS1 Tg mice.
... Upon their administration, the temperature of these polymer solutions increases above their T CP , thereby in situ forming insoluble hydrogels, which remain at the site of administration. [7,9] The resulting soft 19 magnetic resonance imaging ( 19 F MRI). [12,39,40] However, 19 F MRI is only sensitive to polymers with a high fluorine content. Nevertheless, in vivo fluorescence (IVF) and photoacoustic (PAI) imaging have recently emerged as sensitive, non-invasive imaging techniques for assessing the biodistribution and quantities of fluorescently labeled compounds over time. ...
Article
Aqueous solutions of some polymers exhibit a lower critical solution temperature (LCST); that is, they form phase separated aggregates when heated above a threshold temperature. Such polymers have many promising (bio)medical applications, including in situ thermogelling with controlled drug‐release, cell/ tissue cultures, polymer‐supported radiotherapy (brachytherapy), immunotherapy, wound dressing and healing, and cell tracking, among others. Yet, despite extensive research of medicinal applications of thermoresponsive polymers, their biodistribution and fate after administration remain largely unknown. Thus, we studied the pharmacokinetics of four different thermoresponsive polyacrylamides after intramuscular administration in mice. In vivo, these thermoresponsive polymers formed depots of various densities, which subsequently dissolved with two‐phase kinetics (depot maturation, slow redissolution). Their half‐lives ranged from 2 weeks to 5 months, depending on their structure and thermal properties as vitrified depots led to longer half‐lives. Additionally, the density of intramuscular depots increased with the decrease in the TCP of the polymer solution. Moreover, we detected secondary polymer depots in the kidneys and liver. The evolution of these secondary depots also followed a two‐phase kinetics (depot maturation and slow dissolution), with half‐lives ranging from 8 to 38 days (kidneys) and from 15 to 22 days (liver). Overall, our findings may be used to tailor the properties of thermoresponsive polymers to meet the demands of their medicinal applications, and our method may become a benchmark for future studies of polymer biodistribution. This article is protected by copyright. All rights reserved
... They are capable of hosting both hydrophobic and hydrophilic drug molecules [13]. In-situ hydrogels have shown promising potential in drug delivery [14][15][16]. The polymeric gels undergo sol-gel transition at physiological body temperature. ...
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Recent study designed to fabricate and analyse interpenetrating polymer network (IPN) nanogels using combination of hydrophilic polymers beta-cyclodextrin (β-CD) and chitosan (CS) for enhancing the solubility of rosuvastatin (RST). Grafting was effectively conducted by freeradical polymerization method. Spongy nano matrices were evaluated by percentage drug entrapment, zeta sizer, solubility studies, sol-gel analysis, FTIR, powder X-ray diffraction, TGA, DSC, XRD, SEM, swelling studies, and in vitro studies. Acute oral toxicity evaluation were carried out to analyse the safety of oral administration of prepared β-CD/CS-co- poly(AMPS) IPN nanogels. Porous and spongy network were confirmed by SEM images. Complex development and thermal constancy of components were analyzed by FTIR, TGA, and DSC spectra. XRD analysis discovered decrease in Rosuvastatin crystallinity in spongy matrices. Particle size of optimized preparation was calculated in the range of 182 ± 3.48nm. The significant modification with reference product approved that drug solubility and release parameters were evidently improved by the fabricated nanogels. Toxicity evaluation validated that prepared nanogels were non-toxic and well-suited to biological system. In vivo experiments on developed nanogels in hyperlipidemic induced animals were examined to observe the antihyperlipidic efficicency. Efficient method of fabrication, excellent physicochemical properties, improved dissolution, high solubilization, and nontoxic nanogels might be a capable methodology for the oral administration of poorly water-soluble drugs.
... Negative thermosensitive hydrogels transform from sol to gel above the LCST, suggesting that they could be exploited to make hydrogels with delayed release, longer skin retention time, and minor systemic side effects [20]. Some previous extensive review articles also summarize the various theories and mechanisms of thermogelation [21][22][23]. Smart materials have demonstrated numerous promising applications in an aqueous medium. The nature of thermoresponsive hydrogels is similar to living tissue and hence could be utilized as an efficient carrier or delivery system in the biomedical field. ...
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Article
A prominent research topic in contemporary advanced functional materials science is the production of smart materials based on polymers that may independently adjust their physical and/or chemical characteristics when subjected to external stimuli. Smart hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) demonstrate distinct thermoresponsive features close to a lower critical solution temperature (LCST) that enhance their capability in various biomedical applications such as drug delivery, tissue engineering, and wound dressings. Nevertheless, they have intrinsic shortcomings such as poor mechanical properties, limited loading capacity of actives, and poor biodegradability. Formulation of PNIPAM with diverse functional constituents to develop hydrogel composites is an efficient scheme to overcome these defects, which can significantly help for practicable application. This review reports on the latest developments in functional PNIPAM-based smart hydrogels for various biomedical applications. The first section describes the properties of PNIPAM-based hydrogels, followed by potential applications in diverse fields. Ultimately, this review summarizes the challenges and opportunities in this emerging area of research and development concerning this fascinating polymer-based system deep-rooted in chemistry and material science.
... Vaginal in-situ gelling requires biocompatible polymers that are structurally altered under conditions such as pH, temperature, and ionic strength with minor adjustments. During instal-lation into the vaginal cavity, in-situ formation gels are liquids and then undergo rapid gelation in response to body temperature [12,13]. The present invention aims to develop a thermoreversible gel containing nanoparticulate MTDZ and to test its efficiency against the infection of T. vaginalis. ...
Article
Objective: Trichomoniasis is a common sexually-transmitted disease that is associated with increased perinatal morbidity and human immunodeficiency virus (HIV) transmission. This study aimed to develop a Metronidazole-loaded nanoparticulate thermoreversible gel for gynecological infection of Trichomonas vaginalis (T. vaginalis). Methods: The optimized nanoparticulate formulation was used in thermoreversible gel and characterized for physico-chemical properties, antiparasitic activity, and in vivo efficacy in the BALB/c mouse model. Result: A nearly threefold rise in antiparasitic activity of the optimized formulation was observed as compared to that of regular gel. Formulation F5 successfully cured the trichomoniasis within 3 days, while regular gel and pure Metronidazole (MTDZ) failed to cure this infection (P<0.05). Conclusion: The present investigation confirms the ability of thermoreversible gel containing nanoparticulate metronidazole againstthe infection by T. vaginalis. The developed gel could be an alternative to the existing drug delivery system for the treatment of trichomoniasis.
... At low temperature, F127 can self-assemble to form micelles above the critical micelle concentration (CMC) in the aqueous solution due to its amphiphilic structure [35]. With increasing temperature, the micelles were closely packed to form large micellar cross linked network, and lead to gel formation [36]. However, the gel structure of F127 could not maintained for long time at the physiological condition due to low mechanical strength which caused rapid erosion. ...
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The objective of this study was to develop and characterize a novel combined systems of amphotericin B-loaded silk fibroin nanoparticles (AmB-FNPs) and in situ hydrogel for ocular administration. Three different formulations of AmB-FNPs were successfully prepared, by desolvation method, using polyethylenimine (PEI) or polyethylene glycol (PEG) as a coating polymer. All AmB-FNPs exhibited mean size of ~ 200 nm with narrow size distribution. The uncoated AmB-FNP and AmB-FNP-PEG were spherical in shape with zeta potential of ~ − 23 mV, whereas AmB-FNP-PEI exhibited cubic shape with zeta potential ~ + 36 mV. AmB was entrapped in FNPs in a partial aggregated form of AmB, which could reduce eye irritation compared to the marketed AmB deoxycholate. Then, AmB-FNPs were incorporated into two optimal thermosensitive in situ hydrogels; pluronic F127 (F127), and F127 and hyaluronic acid (F127/HA). All AmB-FNPs-in situ hydrogels exhibited homogeneous solutions with translucent light–yellow color, pH ~ 7, and osmolality of ~ 320–370 mOsmo/kg. At the ocular temperature, 35 °C, they manifested a pseudoplastic flow behavior and showed a rapid sol–gel transition within 30 s. In addition, the in vitro drug release studies showed an initial AmB burst release within 5 min. Finally, sterility test confirmed no microbial growth of all formulations. Overall results indicated that AmB-FNPs-in situ hydrogels showed satisfactory physicochemical properties as an ophthalmic formulations, which would reduce toxicity of AmB, increase precorneal residence time and improve patient compliance due to less frequent administration.
... In this application, methylcellulose reaches its critical temperature after the use of an external stimulus (a heated curling wand), which initiates its sol-gel transformation [2]. This same sol-gel transformation is triggered by human body temperature in medical utilization [2][3][4][5]. The methylcellulose hydrogels are loaded with delivery components such as drugs or cells, which in the in-situ system go through the sol-gel transition once they are injected into the human body [5], another example of its smart abilities. ...
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Article
Methylcellulose and chitosan served as promising ingredients for a thermoresponsive hair styling gel after successful application in the medical industry. Both ingredients uphold the clean beauty standard without infringing on performance. By combining these two ingredients, a hair gel can be created that promises an extended hold of style once a heated external stimulus, such as a curling wand, is applied to the hair. Chitosan serves as the cationic biopolymer to adhere the gel to the hair, whereas the methylcellulose acts as the smart biopolymer to lock the desired hairstyle in place. Various ranges of chitosan and methylcellulose concentrations were explored for formulation optimization with rheology and curl drop testing. The rheology testing included a flow sweep test to understand the shear-thinning behavior of the sample as well as the effect of concentration on viscosity. Another rheology test completed was a temperature ramp test from room temperature (25 °C) to 60 °C to study the effect of heat on the various concentrations within the samples. A curl drop test was performed as well, over a 48-h period in which the different samples were applied to wet hair tresses, dried, curled, and hung vertically to see how the style held up over a long period of time with the influence of gravity.
... Exosomes are mixed with both polymers and crosslinkers simultaneously, and injected in situ with a dual-chamber syringe. After irradiation, ion exchanges, or environmental changes, polymerization can be achieved, inducing gelation [101]. In situ gelation can realize precise conformation to irregular cavities, and result in excellent integration and retention rates in the injection sites [102,103]. ...
Article
Hydrogels, which are hydrophilic polymer networks, have attracted great attention, and significant advances in their biological and biomedical applications, such as for drug delivery, tissue engineering, and models for medical studies, have been made. Due to their similarity in physiological structure, hydrogels are highly compatible with extracellular matrices and biological tissues and can be used as both carriers and matrices to encapsulate cellular secretions. As small extracellular vesicles secreted by nearly all mammalian cells to mediate cell-cell interactions, exosomes play very important roles in therapeutic approaches and disease diagnosis. To maintain their biological activity and achieve controlled release, a strategy that embeds exosomes in hydrogels as a composite system has been focused on in recent studies. Therefore, this review aims to provide a thorough overview of the use of composite hydrogels for embedding exosomes in medical applications, including the resources for making hydrogels and the properties of hydrogels, and strategies for their combination with exosomes.
... However, the application of automated liquid handling translates poorly when MCTSs are embedded in commercial thermogelling hydrogels. The use of thermogelling materials requires a highly controlled working environments and rapid processing due to their temperature-sensitive gelation conditions (51). Additionally, the batch-to-batch variability observed with some hydrogels considerably impacts the assay quality and reproducibility, crucial to ensure consistency when conducting MTS/HTS (52). ...
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Multicellular tumor spheroids are largely exploited in cancer research since they are more predictive than bi-dimensional cell cultures. Nanomedicine would benefit from the integration of this three-dimensional in vitro model in screening protocols. In this brief work, we discuss some of the issues that cancer nanomedicine will need to consider in the switch from bi-dimensional to three-dimensional multicellular tumor spheroid models.
... Anterior segment [2]. International Journal of Health Care and Biological Sciences [9] drug can be improved be the prolonging their residence time in the CLU-DE-SAC (deadend barrier/one side opened) and by increased their corneal permeability. ...
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Ocular drug delivery is the most challenging and interesting field in the pharmaceutical industry and pharmaceutical scientist. Blindness and vision impairment are the most problematic global health problem. In ophthalmic in-situ gels, various polymers are used. Generally, hydrogels are used. These polymers will increase the viscosity of the solution. In the physiology of the eye, this organ is impermeable to foreign particles. Novel drug delivery systems focus to overcome the biological barrier which can obstruct efficient ocular drug delivery. The conventional ophthalmic formulation shows a short pre-corneal residence time and poor bioavailability. Many attempts have been made towards the development of stable sustained-release in-situ gels. In this review, we specify a brief note about in-situ gels, various approaches for in-situ gelling systems, different types of polymers used in in-situ gels, their mechanisms of gel formation, and evaluation of polymeric in-situ gel.
... In general, this strategy requires the use of a dual-cavity syringe, which has the ability to inject the hydrogel with exosomes directly into the defect site (Ghosh et al., 2005;Riau et al., 2019). There are a variety of mechanisms that can be used for in-situ gelation, such as ultraviolet radiation, ion exchange, pH changes, and temperature changes (Ruel-Gariépy and Leroux, 2004). This strategy is very significant in filling the critical size defects of complex shapes, allowing the combined biomolecules to have good viability. ...
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Article
In-situ bone tissue regeneration, which harnesses cell external microenvironment and their regenerative potential to induce cell functions and bone reconstruction through some special properties of biomaterials, has been deeply developed. In which, hydrogel was widely applied due to its 3D network structure with high water absorption and mimicking native extracellular matrix (ECM). Additionally, exosomes can participate in a variety of physiological processes such as cell differentiation, angiogenesis and tissue repair. Therefore, a novel cell-free tissue engineering (TE) using exosome-laden hydrogels has been explored and developed for bone regeneration in recent years. However, related reviews in this field are limited. Therefore, we elaborated on the shortcomings of traditional bone tissue engineering, the challenges of exosome delivery and emphasized the advantages of exosome-laden hydrogels for in-situ bone tissue regeneration. The encapsulation strategies of hydrogel and exosomes are listed, and the research progress and prospects of bioactive hydrogel composite system for continuous delivery of exosomes for in-situ bone repair are also discussed in this review.
... Several types of hydrogels based on natural polymers have been investigated in the field of thermoresponsivity 38 ; in particular, poly(N-isopropylacrylamide) (PNIPAAm) has attracted high interest in recent years. Indeed, PNIPAAm is nonbiodegradable and has a sharp phase transition, with a VPTT close to the human body temperature (at~32°C in pure water) 39 . ...
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One of the most fascinating areas in the field of smart biopolymers is biomolecule sensing. Accordingly, multifunctional biomimetic, biocompatible, and stimuli-responsive materials based on hydrogels have attracted much interest. Within this framework, the design of nanostructured materials that do not require any external energy source is beneficial for developing a platform for sensing glucose in body fluids. In this article, we report the realization and application of an innovative platform consisting of two outer layers of a nanocomposite plasmonic hydrogel plus one inner layer of electrospun mat fabricated by electrospinning, where the outer layers exploit photoinitiated free radical polymerization, obtaining a compact and stable device. Inspired by the exceptional features of chameleon skin, plasmonic silver nanocubes are embedded into a poly(N-isopropylacrylamide)-based hydrogel network to obtain enhanced thermoresponsive and antibacterial properties. The introduction of an electrospun mat creates a compatible environment for the homogeneous hydrogel coating while imparting excellent mechanical and structural properties to the final system. Chemical, morphological, and optical characterizations were performed to investigate the structure of the layers and the multifunctional platform. The synergetic effect of the nanostructured system’s photothermal responsivity and antibacterial properties was evaluated. The sensing features associated with the optical properties of silver nanocubes revealed that the proposed multifunctional system is a promising candidate for glucose-sensing applications.
... Due to the aforementioned limitations of IV DEX, in situ forming gel was proposed in the current study for sublingual administration of DEX to induce sedation and analgesia while controlling over the fluctuations in heart rate and blood pressure. In situ gels are solutions that form gels upon exposure to physicochemical changes in the medium (e.g., change in pH or temperature) [6]. Gels degrade slowly while allowing the release of the entrapped drugs over an extended period of time. ...
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Article
Intravenous dexmedetomidine (DEX) is currently approved by the FDA for the sedation of intubated patients in intensive care units to reduce anxiety and to augment postoperative analgesia. Bradycardia and hypotension are limitations associated with the intravenous administration of DEX. In this study, DEX sublingual in situ gels were developed and assessed for their pH, gelling capacity, viscosity, mucoadhesion and in vitro drug release. The optimized gelling system demonstrated enhanced mucoadhesion, superior gelling capacity, reasonable pH and optimal rheological profile. In vivo, compared to the oral solution, the optimal sublingual gel resulted in a significant higher rate and extent of bioavailability. Although the in situ gel had comparable plasma levels to those observed following intravenous administration, significant amelioration of the systemic adverse reactions were attained. As demonstrated by the hot plate method, a sustained duration of analgesia in rats was observed after sublingual administration of DEX gel compared to the intravenously administered DEX solution. Furthermore, no changes in systolic blood pressure and heart rate were recorded in rats and rabbits, respectively, after sublingual administration of DEX. Sublingual administration of DEX in situ gel provides a promising approach for analgesia and sedation, while circumventing the reported adverse reactions associated with intravenous administration of DEX.
... Furthermore, PEG copolymers have a special usage in the formulation of hydrogels for chemical cross-linked and temperature-responsive applications. A temperature-responsive system is an injection method for drug delivery systems [118]. The conjugation of different drugs/molecules (such as insulin, lipids, daunmorubicine and camptothecin) with PEG was also studied previously [119]. ...
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One of the basic challenges in polymeric membrane fabrication is the control of pore size and the porosity of the membranes. In this review paper, the role of polymeric additives is overviewed in membrane fabrication processes, such as the formation of pores in membranes, increasing permeability, hydrophilicity and even the creation of a desirable property such as antifouling and antibacterial properties. The polymeric additives could dissolve in water during the phase inversion process (a pore forming agent) or remain in the membrane matrix (hydrophilic and antifouling agent) or could have both roles. The additives could also act as proton exchanger and gas transport facilitating agents. This review concentrates on the introduction of new polymeric additives. In the blended membranes, the miscibility of chosen polymeric additives at the molecular levels make it a challenge to use the modification method. Molecular interactions between polymers such as hydrogen bonding and charge transfer play the main roles of the quality of blending. Different methods of polymer/co-polymer addition to the polymeric matrix of membranes are investigated to identify the best polymeric additives in various types of polymeric membranes including: pervaporation, contactor membrane, distillation membrane, etc. Moreover, the mixability of the additive polymer with the matrix polymer solution and the effectiveness of some functional additives are described in this review.
... Poly (N-isopropylacylamide) (PNIPAAm) is a thermoresponsive polymer that exhibits an LCST of 32 • C. At this temperature, the PNIPAAm shows hydrophilic characteristics, whereas, above this temperature, it became hydrophobic. Thus, the carrier, through its thermosensitivity, is destabilized at the cancer temperature (hyperthermia) through polymeric erosion or disruption followed by the release of drug after passive targeting at the tumor site [274,275]. Liu et al., 2005 [252], prepared thermosensitive micelles of P(PNIPAAAm-co-DMAAm)b-PLGA (Poly (N-isopropylacrylamide-co-N, N-dimethylacrylamide)-b-poly(D,L-Lactideco-glycolide)) loaded with doxorubicin. Thermosensitive block co-polymers were successfully synthesized and then doxorubicin was incorporated into micelles. ...
Article
Liposomes have gained attention as a well-accepted nanocarrier for several chemotherapeutic drugs and are considered a drug delivery system of choice for a wide range of products. These amphipathic spherical vesicles primarily consist of one or more phospholipid bilayers, showing promise for drug delivery of both hydrophilic and hydrophobic components in addition to unique properties such as biocompatibility, biodegradability, low toxicity, and non-immunogenicity. Recent advances in liposomes are mainly centered on chemical and structural modification with the multifunctional approach to target the cancer cells activating the offensive mechanisms within the proximity of the tumors. Stimuli-responsive liposomes are a precisive approach to deliver and release chemotherapeutic drugs in the tumor site in a controlled fashion, thus reducing damage to normal tissues and preventing the side effects of the conventional chemotherapy regimen. The unique characteristics in the tumor microenvironment facilitate applying an endogenous stimulus (pH, redox potential, or enzymatic activity) to trigger the release of the drug, or external stimulus (heat or light) could be applied to tailor the drug release from liposomes. This review focuses on newer developments in stimuli-sensitive liposomal drug delivery systems designed to apply either exogenous (temperature, light, and magnetic field) or endogenous (pH changes, enzymatic triggers, or redox potential) approaches.
... Based on their structure, PCL-PEG copolymers, designated as AB di-block, ABA or BAB tri-block, and star-shaped block structures. For the synthesis of PCL-PEG di-block copolymer, the most recommended method is ring-opening copolymerization from monomethoxy-PEG (MPEG) and ε-CL in the presence of a catalyst organic solvents, residual unreacted monomers, catalysts, crosslinkers, etc., are not used for the formulation [68,69]. The chemical composition of the copolymers and the manner of treatment of the hydrous copolymers can bring about a significant change in the sol-gel transition behavior. ...
Article
A number of stimuli-responsive-based hydrogels has been widely explored in biomedical applications in the last few decades because of their excellent biodegradability and biocompatibility. The development of synthetic chemistry and materials science leads to the emergence of in situ stimuli-responsive hydrogels. In this regard, several synthetic and natural polymers have been synthesized and utilized to prepare temperature-sensitive in situ forming hydrogels. This could be best used via injections as temperature stimulus could trigger in situ hydrogels gelation and swelling behaviors. There are many smart polymers available for the formulation of the in situ based thermoresponsive injectable hydrogel. Among these, poly (ε-caprolactone) (PCL) polymer has been recognized and approved by the FDA for numerous biomedical applications. More specifically, the PCL is coupled with polyethylene glycol (PEG) to obtain amphiphilic thermosensitive “smart” copolymers (PCL-PEG), to form rapid and reversible physical gelation behavior. However, the chemical structure of the copolymer is a critical aspect in determining water solubility, thermo-gelation behavior, drug release rate, degradation rate, and the possibility to deliver a diverse range of drugs. In this review, we have highlighted the typical PCL-PEG-based thermosensitive injectable hydrogels progress in the last decade for tissue engineering and localized drug delivery applications to treat various diseases. Additionally, the impact of molecular weight of PCL-PEG upon gelling behavior has also been critically highlighted for optimum hydrogels properties for potential pharmaceutical and biomedical applications.
... Kontrollü salım sistemlerinde polimerler etkin bir şekilde kullanılmaktadır. Polimerik malzemeler ile ilaç etken maddeleri birleştirilerek (Liechty ve diğ., 2010), enkapsülasyon, misel oluşturma(Duncan, 2003;Ruel-Gariépy & Leroux, 2004), hidrojeller(Peppas ve diğ., 2000) ile kombine etme veya polipleksler(Vinogradov ve diğ., 2005) ile polimer ilaç konjugatları oluşturularak çeşitli şekillerde uygulamalar yapılmıştır.2.5.1 MIPnp'ler ile kontrollü ilaç salımıMoleküler baskılanmış polimer nanopartiküller (MIPnp), ilaç (antibiyotik) molekülleri ile etkileşim için oldukça fazla bölgeye sahip olmasından dolayı çokça bellek oluşturma yeteneğine sahiptir. MIPnp'ler hedef molekülleri uzun süre tutabilme kapasitesinden dolayı ilacın salımını yavaşlatır, vücuttaki yarılanma süresini arttırabilir ve ilacın zararlı yan etkilerini olabildiğince düşük tutar. ...
Thesis
Moleküler baskılanmış polimerler (MIP), kalıp moleküle özgü seçici tanıma bölgeleri olan özel tasarım malzemelerdir. MIP’ler, hazırlanması kolay, ucuz ve dayanıklı, akıllı polimerlerdir. İlaç taşıyıcı olarak MIP’lerin kullanımı, ilaç etken maddesinin (kalıp molekül) fonksiyonel monomerlere olan afinitesi ve buna bağlı olarak ilacın kalış süresini arttırması, MIP’lerin yüksek ilaç yükleme kapasitesine sahip olması, ilaç etken maddesinin hedef bölgeye ulaştırılması, ilacın yavaş ve sürekli salımı gibi özelliklere sahip olması, bu malzemelerin kullanılmasında önemli avantajlar sunmaktadır. Sunulan bu tez çalışmasında, ilk olarak siprofloksasin baskılanmış polimer nanopartiküller (MIPnp) sentezlenmiş ve elektro-eğirme tekniği kullanılarak üretilen nanofiberlere immobilize edilmiştir. MIPnp’lerin sentezi yenilenebilir kaynaklardan üretilen monomerler ile termal başlatıcı varlığında, çökeltme (presipitasyon) polimerizasyonu yöntemiyle gerçekleştirilmiştir. Elektro-eğirme tekniği ile hazırlanan MIPnp yüklenmiş nanolifler, Polivinil alkol (PVA) ile üretilmiş ve fonksiyonel özellikte olan yara örtüsü membranlar bu şekilde geliştirilmiştir. Üretilen polimer nanopartikül yüklenmiş yara örtüsü membranların karakterizasyon çalışmaları şu şekildedir: MIPnp’lerin boyut analizi Dinamik Işık Saçılım Spektrometresi (DLS) ile, boyut ve şekli geçirimli elektron mikroskobu (TEM) ile incelenmiştir. MIPnp’lerin bağlanma ve salım testlerinde süpernatant içerisindeki siprofloksasin (CIPRO) konsantrasyonu 200-500 nm spektral tarama aralığında 278 nm’de UV-vis spektrofotometre ile ölçülmüştür. Termal kararlılığı belirlemek amacıyla MIPnp’lerin Termogravimetrik (TGA) ve Diferansiyel Taramalı Kalorimetre (DSC) analizleri yapılmıştır. MIPnp’lerin, MIPnp yüklenmiş nanoliflerin morfolojik yapıları taramalı elektron mikroskobu (SEM) ile, kimyasal bağ yapıları ise Fourier Dönüşümlü Kızılötesi Spektroskopisi (FTIR) ile incelenmiştir. Sonuç olarak, sunulan bu tez çalışmasında yenilenebilir kaynaklardan elde edilmiş olan fonksiyonel monomerler ile siprofloksasin baskılanmış özgün polimer nanopartiküller üretilmiş olup, elektro-eğirme yöntemi ile üretilen yara örtüsü membranına başarılı bir şekilde immobolize edilmişlerdir. DEVELOPMENT OF ANTIBIOTIC IMPRINTED POLYMER NANOPARTICLE LOADED WOUND DRESSING Molecularly imprinted polymers (MIPs) are special designed materials that have selective particular recognition sites for the template molecule. MIPs are cheap, durable, easy to prepare, and smart polymers. The utilizations of MIPs as drug carriers provide greatest advantages, including the affinity of the drug active substance (template molecule) to functional monomers and consequently increase the duration of the drug; the high drug loading capacity of the MIPs; the delivery of the drug active substance to the target site; the slow and continuous release of the drug. In this study, firstly, ciprofloxacin imprinted polymer nanoparticles (MIPnp) were synthesized and immobilized to nanofibers manufactured using electro-spinning technique. The synthesis of MIPnps was carried out by precipitation polymerization method in the presence of a thermal initiator with monomers produced from renewable resources. MIPnp loaded nanofibers prepared by electro-spinning technique were produced with Polyvinyl alcohol (PVA) and functional properties acquired wound dressing membranes were developed in this way. The characterization studies of the produced polymer nanoparticle-loaded wound dressing membranes are as follows: Size distribution analysis of MIPnps was investigated by Dynamic Light Scattering Spectrometer (DLS), its size, morphology and shape were examined by transmission electron microscopy (TEM). For binding and release tests of MIPnps, the concentration of ciprofloxacin (CIPRO) in the supernatant was measured with a UV-vis spectrophotometer at 278 nm in the 200-500 nm spectral scanning range. Thermogravimetric (TGA) and Differential Scanning Calorimetry (DSC) analyzes of MIPnp were performed to determine the thermal stability. The morphological structures of MIPnp and MIPnp-loaded nanofibers were investigated by scanning electron microscopy (SEM), and chemical bond structures were examined by Fourier Transform Infrared Spectroscopy (FTIR). In conclusion, in this presented thesis, novel ciprofloxacin imprinted polymer nanoparticles were created with functional monomers obtained from renewable resources, and they were successfully immobilized to the wound dressing membrane produced by the electrospinning method.
Chapter
Adaptation is the key feature that permits the living system to respond to the external environment and get accustomed to the changing conditions. In a similar way, scientists have tried to develop polymers that could mold themselves according to the external/surrounding changes (stimulus) and form a more compatible system. This leads to the emergence of “smart polymers” that undergo physical or chemical changes in response to small environmental changes (temperature, light, pH, etc.), which proves the versatility as well as the sensitivity of the smart polymers. It could be stated that smart polymers lead to the development of much tunable, programmable, and accurate systems. Smart polymers were extensively used in the field of biomedicine which includes tissue engineering, the cell culture system, drug delivery system, sensors or actuators, and biomedical devices. This chapter provides a wide overview of smart polymers and the most interesting applications developed so far.
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With the continued advancement in the design and engineering of hydrogels for biomedical applications, there is a growing interest in imparting stimuli-responsiveness to the hydrogels in order to control their physicomechanical properties in a more programmable manner. In this study, an in situ forming hydrogel is developed by cross-linking alginate with an elastin-like polypeptide (ELP). Lysine-rich ELP synthesized by recombinant DNA technology is reacted with alginate presenting an aldehyde via Schiff base formation, resulting in facile hydrogel formation under physiological conditions. The physicomechanical properties of alginate-ELP hydrogels can be controlled in a wide range by the concentrations of alginate and ELP. Owing to the thermoresponsive properties of the ELP, the alginate-ELP hydrogels undergo swelling/deswelling near the physiological temperature. Taking advantage of these highly attractive properties of alginate-ELP, drug release kinetics were measured to evaluate their potential as a thermoresponsive drug delivery system. Furthermore, an ex vivo model was used to demonstrate the minimally invasive tissue injectability.
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Development and characterizing of AS1411aptamer conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study to increase the drug safety and efficacy in the treatment of solid tumors. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA). The liposomal structure was examined by Fourier Transform Infra-red Spectroscopy and field emission scanning electron microscopy. In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. An atomic absorption spectrometer was used to quantify the encapsulation efficiency and in vitro drug release. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in Murine melanoma (B16) and Mouse Embryonic Fibroblast cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5 % and 58.7 ± 4.2 %, respectively. The enhanced cellular uptake of aptamer-conjugated liposomes was displayed by Fluorescence imaging. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice in the CHAL group survived to the end of treatment and showed body weight gain. However, the distinct antitumor effect was observed in the AP-CHAL-treated group, and the tumor protrusion completely disappeared in 50 % of the mice. The inhibition rate of tumor growth of CHAL and AP-CHAL was 92.73 % and 97.67 %, respectively. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in mice tissues. AP-CHAL can be used as an effective drug delivery system with high potential in treating solid tumors.
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Stimuli-responsive hydrogels with programmable shapes produced by defined patterns of particles are of great interest for the fabrication of small-scale soft actuators and robots. Patterning the particles in the hydrogels during fabrication generally requires external magnetic or electric fields, thus limiting the material choice for the particles. Acoustically driven particle manipulation, however, solely depends on the acoustic impedance difference between the particles and the surrounding fluid, making it a more versatile method to spatially control particles. Here, an approach is reported by combining direct acoustic force to align photothermal particles and photolithography to spatially immobilize these alignments within a temperature-responsive poly(N-isopropylacrylamide) hydrogel to trigger shape deformation under temperature change and light exposure. The spatial distribution of particles can be tuned by the power and frequency of the acoustic waves. Specifically, changing the spacing between the particle patterns and position alters the bending curvature and direction of this composite hydrogel sheet, respectively. Moreover, the orientation (i.e., relative angle) of the particle alignments with respect to the long axis of laser-cut hydrogel strips governs the bending behaviors and the subsequent shape deformation by external stimuli. This acousto-photolithography provides a means of spatiotemporal programming of the internal heterogeneity of composite polymeric systems.
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Poloxamers possess unique gelling properties for use in drug delivery applications; however, their rheological and drug release properties are significantly affected by change in pH. In the current work, the effect of cellulose nanocrystals (CNCs) on rheological, liquid crystal properties of poloxamer 407 (PL) gel, and release of metronidazole drug at different pH values at 37 °C was studied. Addition of CNCs resulted in increasing the gelling temperature of PL prepared using water, pH 4.8 or 8 buffers. At 37 °C, CNCs resulted in improving strength of PL gel prepared in pH 4.8 and 8 buffers while their addition increased gel strength of PL prepared in water only at concentrations ≥ 3.75%. Addition of CNCs at concentration ≥ 1.25% to PL gel prepared using water and pH 4.8 buffer resulted in formation of new long-range birefringent marble texture of nematic and oily streaks chiral liquid crystalline phases, respectively, while in case of PL gel prepared in pH 8 buffer, discrete birefringent clusters with smectic lamellar phase was formed. Regarding release of metronidazole, CNCs resulted in more availability of metronidazole over the studied period (up to six days) when compared to neat PL gel, which shows availability of ~ 50 and 56%, respectively, while PL/CNC gel showed drug availability up to ~ 74 and 92% at the pH 4.8 and 8, respectively. Finally, presence of CNCs in the PL gel did not affect the antibacterial activity of metronidazole when tested against the Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria.
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Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration and uncontrolled biological responses at the treatment site. To address these challenges, we engineered a fully synthetic and ready‐to‐use injectable biomaterial that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into non‐toxic components with minimal impact on internal organs. Preclinical animal studies confirmed that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel was successfully administered to a socket site post tooth extraction and formed adhesive hydrogel that stabilized blood clot and supported soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings. This article is protected by copyright. All rights reserved
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Bacterial infections have become a great threat to public health in recent years. A primary lysozyme is a natural antimicrobial protein; however, its widespread application is limited by its instability. Here, we present a poly (N-isopropylacrylamide) hydrogel inverse opal particle (PHIOP) as a microcarrier of lysozyme to prolong and enhance the efficiency against bacteria. This PHIOP-based lysozyme (PHIOP-Lys) formulation is temperature-responsive and exhibits long-term sustained release of lysozyme for up to 16 days. It shows a potent antibacterial effect toward both Escherichia coli and Staphylococcus aureus, which is even higher than that of free lysozyme in solution at the same concentration. PHIOPs-Lys were demonstrated to effectively inhibit bacterial infections and enhance wound healing in a full-thickness skin wound rat model. This study provides a novel pathway for prolonging the enzymatic activity and antibacterial effects of lysozyme.
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Green chemistry has been a growing multidisciplinary field in recent years showing great promise in biomedical applications, especially for cancer therapy. Chitosan (CS) is an abundant biopolymer derived from chitin and is present in insects and fungi. This polysaccharide has favorable characteristics, including biocompatibility, biodegradability, and ease of modification by enzymes and chemicals. CS‐based nanoparticles (CS‐NPs) have shown potential in the treatment of cancer and other diseases, affording targeted delivery and overcoming drug resistance. The current review emphasizes on the application of CS‐NPs for the delivery of a chemotherapeutic agent, doxorubicin (DOX), in cancer therapy as they promote internalization of DOX in cancer cells and prevent the activity of P‐glycoprotein (P‐gp) to reverse drug resistance. These nanoarchitectures can provide co‐delivery of DOX with antitumor agents such as curcumin and cisplatin to induce synergistic cancer therapy. Furthermore, co‐loading of DOX with siRNA, shRNA, and miRNA can suppress tumor progression and provide chemosensitivity. Various nanostructures, including lipid‐, carbon‐, polymeric‐ and metal‐based nanoparticles, are modifiable with CS for DOX delivery, while functionalization of CS‐NPs with ligands such as hyaluronic acid promotes selectivity toward tumor cells and prevents DOX resistance. The CS‐NPs demonstrate high encapsulation efficiency and due to protonation of amine groups of CS, pH‐sensitive release of DOX can occur. Furthermore, redox‐ and light‐responsive CS‐NPs have been prepared for DOX delivery in cancer treatment. Leveraging these characteristics and in view of the biocompatibility of CS‐NPs, we expect to soon see significant progress towards clinical translation.
Chapter
Nanotechnology is considered as a potential field of technology having immense applications in the area of medicine, biology, and biotechnology. The fabrication of novel nanomaterials for drug delivery, therapeutic, diagnostic, targeting, and tissue‐engineering applications is anticipated to harvest tremendous health benefits in the near future. The advent of nanobiomedicine has led to the formation of promising multifunctional nanomaterials that are able to nullify the challenges associated with conventional nanomaterials used in the medicinal field. Multifunctional nanoparticles are considered functional nanomaterials having diverse properties obtained by conjugating or encapsulating therapeutic agents, antibodies, and contrast agents for a myriad of biomedical applications. The integration of diagnostic and therapeutic functions in a single nano‐hybrid is indeed a challenge and has achieved immense research interest due to the multifaceted applications offered by such materials. This chapter portrays the recent advances in the development of multifunctional nanomaterials and their applications in the medical field in a comprehensive way. This chapter also discusses the regulatory issues associated with the conjugated multifunctional hybrid‐nanomaterials focusing on the prospective development of these materials.
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Over the past ten years, in situ gelling drug delivery methods have attracted a lot of attention. Prior to injection, they are in a sol-state, and they can gel when exposed to a variety of endogenous stimuli, including temperature rise, pH changes, and the presence of ions. Such to accomplish the injection of a local or systemic medication, systems may be delivered by a variety of can also be employed effectively as carriers for nano- and microparticles that carry drugs. Natural or artificial or in conjunction with semi-artificial polymer exhibiting in situ gelling behaviour. For the development of such systems, coupling with mucoadhesive polymers is highly sought in order to prolong the duration spent at the site of action or absorption. Nasal drug administration is a superior option than oral and parental routes because of the high permeability of the nasal epithelium, rapid drug absorption, avoidance of hepatic first pass metabolism, improved bioavailability of the medication, and fewer adverse effects. adverse local and systemic effects, minimal dosage is required, Patient compliance has increased, direct distribution to the CNS and systemic circulation is available, and self-medication. The development of gastric ulcers can be prevented. Recent evidence indicates that many medications have greater oral bioavailability than nasal bioavailability. So, the focus of this review is on nasal drugs. Administration, various nasal architecture and physiology characteristics, the method of nasal absorption, and benefits, Evaluations of in situ gels' composition, use, and advantages and disadvantages. Keywords: Nasal formulation, sustained drug administration, mucoadhesive drug delivery system, and in-situ nasal gelation.
Article
As our research on the physiopathology of intervertebral disc degeneration (IVD degeneration, IVDD) has advanced and tissue engineering has rapidly evolved, cell-, biomolecule- and nucleic acid-based hydrogel grafting strategies have been widely investigated for their ability to overcome the harsh microenvironment of IVDD. However, such single delivery systems suffer from excessive external dimensions, difficult performance control, the need for surgical implantation, and difficulty in eliminating degradation products. Stimulus-responsive composite hydrogels have good biocompatibility and controllable mechanical properties and can undergo solution-gel phase transition under certain conditions. Their combination with ready-to-use particles to form a multiscale delivery system may be a breakthrough for regenerative IVD strategies. In this paper, we focus on summarizing the progress of research on the stimulus response mechanisms of regenerative IVD-related biomaterials and their design as macro-, micro- and nanoparticles. Finally, we discuss multi-scale delivery systems as bioinks for bio-3D printing technology for customizing personalized artificial IVDs, which promises to take IVD regenerative strategies to new heights.
Thesis
Les cellules dans l'organisme subissent des forces mécaniques, exercées par leur environnement, qui sont à l'origine de certains processus cellulaires. Ainsi, l'étude des relations étroites qui lient comportements cellulaires et contraintes mécaniques est aujourd'hui au cœur de la compréhension de nombreux phénomènes biologiques. Les travaux présentés dans ce manuscrit portent sur la conception et l'étude d'hydrogels photo-stimulables pouvant appliquer des contraintes sur des échantillons de tissus biologiques. Ces gels sont formés à partir de trois briques de construction, un polymère porteur d'un azobenzène tétrafluoré sensible à la lumière visible, un dérivé de ß-cyclodextrine et un polymère portant plusieurs fonctions mercapto. Ces briques sont liées par deux types de réseaux, un chimique et un physique. Le réseau chimique est formé par addition de Michael entre les thiols et les maléimides, portés par le polymère et le dérivé de cyclodextrine. Il permet au gel de posséder des propriétés mécaniques similaires à celles de l'environnement des cellules. Le réseau physique a pour rôle d'assurer le caractère photo-stimulable du matériau final par l'intermédiaire d'un complexe photo-sensible engageant l'azobenzène tétrafluoré et la ß-cyclodextrine. Le travail s'articule en trois parties. La première concerne le choix de l'azobenzène stimulable dans le visible et la caractérisation de ses propriétés et de sa complexation avec la ß-cyclodextrine, en fonction de son état d'isomérisation. La deuxième partie expose la synthèse des gels à partir des briques de construction et son optimisation, en faisant appel aux plans d'expériences. Les propriétés mécaniques de ces hydrogels et leur réponse à la lumière sont mesurées par microscopie à force atomique et par des essais de compression. La troisième partie décrit l'utilisation de ces gels en présence d'échantillons biologiques, mettant ainsi en lumière ses applications possibles en tant que support de culture cellulaire ou tissulaire. Ces travaux ont été réalisés dans le cadre du projet Gellight financé par l'Agence Nationale de la Recherche (ANR).
Article
Introduction: Peptides are widely recognized as therapeutic agents in the treatment of a wide range of diseases, such as cancer, diabetes etc. However, their use has been limited by their short half-life, due to significant metabolism by exo- and endo-peptidases as well as their inherent poor physical and chemical stability. Research with the aim of improving their half-life in the body, and thus improving patient compliance (by decreasing the frequency of injections) has gained significant attention. Areas covered: This review outlines the current landscape and industrial approaches to achieve extended peptide exposure and reduce dosing frequency. Emphasis is placed on identifying challenges in drug product manufacturing and desirable critical quality attributes that are essential for activity and safety, providing insights into chemistry and design aspects impacting peptide release, and summarizing important considerations for CMC developability assessments of sustained release peptide drugs. Expert opinion: Bring the patient and disease perspective early into development. Substantial advances have been made in the field of sustained delivery of peptides despite their complexity. The article will also highlight considerations for early-stage product design and development, providing an industrial perspective on risk mitigation in developing sustained release peptide drug products.
Chapter
Much recent progress has been achieved in delivering medications to our bodies. Drug delivery system development has grown exponentially. Some medications have a hurdle of low bioavailability; to counter this, hydrogels have been used as a tool to delimit low bioavailability and side effects. Nanoparticle (NP) and hydrogel composite (NPH) nanoformulations play a significant role in the site-specific or targeted and regulated supply of medicinal products. The field of nanotechnology comprises intracells and particles of 100 nm in size along with devices. Nanoformulations can cross the bloodebrain barrier, improving safety, effectiveness, and patient conformity. These formulations have the following properties: drug loading capability, drug stability, drug release rates, and targeting capacity. Hydrogels are made of cross-connected polymers that can swell out when in contact with water or aqueous media.
Chapter
This chapter describes briefly the processes of wound healing and the application of stem cell therapy for various wound healing. The current therapeutic outcomes suggest that a functional niche is needed to deliver stem cells toward improved cells engraftment, viability, and function. Hydrogels can be used as such delivery vehicles and thus, their components, means of fabrication, and their promising in wound healing are also discussed. In particular, injectable hydrogels formed by in situ cross‐linking transited from an aqueous mixture of gel precursors to a solid gel are in the focus. The injectable hydrogels are an attractive delivery niche for drugs and cells due to their tuneable mechanical and degradation properties that allow transplanting and localizing cells to a desired anatomic site. To design a device for an efficient healing outcome, key bioactive factors can be incorporated into the hydrogel scaffold. Advanced material science and techniques show great potential to create or mimic extracellular matrix niches, which will ultimately benefit the wound healing process.
Article
Epithelial surfaces protect exposed tissues in the body against intrusion of foreign, materials, including xenobiotics, pollen and microbiota. The relative permeability of the, various epithelia reflects their extent of exposure to the external environment and is in, the ranking: intestinal≈ nasal ≥ bronchial ≥ tracheal >vaginal ≥ rectal > blood-perilymph, barrier (otic), corneal > buccal > skin. Each epithelium also varies in their morphology, biochemistry, physiology, immunology and external fluid in line with their function. Each, epithelium is also used as drug delivery sites to treat local conditions and, in some, cases, for systemic delivery. The associated delivery systems have had to evolve to, enable the delivery of larger drugs and biologicals, such as peptides, proteins, antibodies and biologicals and now include a range of physical, chemical, electrical, light, sound and other enhancement technologies. In addition, the quality-by-design, approach to product regulation and the growth of generic products have also fostered, advancement in epithelial drug delivery systems.
Article
Acetylcholinesterase inhibitors are the most used drugs to manage Alzheimer's disease, although they show low bioavailability in the brain. In this sense, nasal administration has been considered as a promising route for the direct delivery these drugs to the brain (nose-to-brain delivery). In this work, in situ thermosensitive nasal gels with nanostructured lipid carriers (NLC) and nanoemulsion loaded with an acetylcholinesterase inhibitor (rivastigmine- RVG) were tested. In situ gels containing optimised rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion were first characterised (size, polydispersity index – PDI, zeta potential - ZP, encapsulation efficiency - EE, loading capacity – LC, pH, osmolarity, organoleptic and morphological analysis and accelerated stability). Afterwards, rheology and texture tests and in vitro studies were conducted to evaluate mucoadhesion, drug release, biocompatibility (with nasal and pulmonary cells, respectively RPMI-2650 and Calu-3) and drug deposition in a nasal cast model. The in situ gels of rivastigmine-loaded NLC and rivastigmine-loaded nanoemulsion had a respective particle/droplet size, PDI, ZP, EE, LC, pH and osmolarity of: 114.00±1.91 nm and 135.80±0.50 nm; 0.45±0.00 and 0.43±0.02; -3.58±1.62 mV and -4.06±1.03 mV; 95.13±0.34% and 89.86±0.19%; 9.30±0.03% and 8.70±0.01%; 7.00±0.01 and 7.01±0.00; 275±0.02 and 280±0.00 mOsm/kg. Organoleptic analysis showed homogeneous appearance, while morphological studies demonstrated that rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion had a spherical shape. Accelerated stability studies predicted good long-term stability. Rheological and texture analysis revealed that both in situ gels showed desirable characteristics for nasal administration. In addition, suitable nasal mucoadhesion and prolonged drug release were observed. Biocompatibility studies showed low and concentration-dependent cytotoxicity in RPMI 2650 and Calu-3 cells. Nasal deposition studies revealed that 4.0% of the drug was deposited in the olfactory region for both rivastigmine -loaded NLC and rivastigmine -loaded nanoemulsion alone, while in situ gels with these lipid-based nanosystems showed 8.0% of drug deposition. The results of this study highlight the potential of using thermosensitive in situ hydrogels containing lipid-based nanosystems to improve the nose-to-brain delivery of rivastigmine , providing a promising alternative therapeutic option to advance the management of Alzheimer's disease.
Article
The copolymer nanogels composed of two N-substituted acrylamides with different water solubility, N-isopropylacrylamide (NIPAM, water-soluble) and N-t-butylacrylamide (TBAM, water-insoluble), were prepared by free-radical polymerization in the presence of sodium dodecyl sulfate (SDS) as a dispersant and found to exhibit thermogelling ability at very low concentrations. To investigate the structure of the P(NIPAM-TBAM) nanogel and its formation mechanism in dispersion polymerization, we prepared the nanogels by changing the conditioning time, which is the time between the addition of SDS to the monomer solution and the start of polymerization, and compared the thermogelling properties of the resultant nanogels. As the conditioning time increased, (i) the hydrodynamic diameter of the nanogel decreased, (ii) the sol–gel and gel-syneresis transition temperatures of the nanogel dispersion decreased, and (iii) the storage moduli of the nanogel dispersion in a gel state increased. These results indicate that the P(NIPAM-TBAM) nanogel has a block-like structure composed of the TBAM-rich brushes and the NIPAM-rich core with three-dimensional polymer network, and that the TBAM ratio in the brushes increases with an increase in the conditioning time. It should be noted that the critical gelation concentration of the P(NIPAM-TBAM) nanogel dispersion was very low (∼1.3 wt%), compared with other thermogelling polymers reported in literatures. This low gelation concentration can be attributed to the gel structure of the nanogel core because the NIPAM-rich core can retain water inside even when the TBAM-rich brushes are dehydrated and crosslink with each other to induce gelation of the system.
Chapter
In recent times, biopolymer-based polymeric hydrogels have been widely investigated in pharmaceutical research. In respect to other hydrogels, in situ gelling systems offer accurate and reproducible dose administration. Various gel-forming mechanisms were employed in the development of in situ gelling system. This system also facilitates localization of drug in a particular region of the gastrointestinal tract (GIT). The in situ gel-forming ability of various marine biomaterials was explored by researchers. The abundant availability in nature, biocompatibility and biodegradability of marine polymers have contributed in its widespread application in pharmaceutical field. Three major marine biopolymers, alginate, chitosan and carrageenan, are extensively studied as gel-forming biomaterials for oral delivery of therapeutics. Oral in situ gelling system can exhibit both systemic and local action. This chapter represents a detailed discussion on investigated marine biopolymer-based in situ gels for oral drug targeting.KeywordsIn situ gelOral deliveryMarine biopolymersGastroretentive delivery
Article
Cutaneous wounds deteriorate the health of patients and liable for high economic loss. Previous studies showed promising wound healing potentials of bilirubin, however, this macromolecule constrained with poor water solubility and skin penetration. In this study, Pluronic F-127, a non-ionic copolymer surfactant, was used for the encapsulation of the wound healing agent the bilirubin. With this strategy, spherical shaped bilirubin nanoparticles of ∼100–150 nm with zeta potential ranging from −13.43 ± 0.56 to −17.53 ± 0.43 mV were obtained. Topical applications of bilirubin nanoparticle (0.3%) on cutaneous wounds of rats showed promising wound healing in comparison with other topical treatments. This topical nano-formulation also modulates the cytokine and growth factor responses in the treated group. On day 7 of healing, bilirubin nanoparticles treatment significantly reduced TNF-α and increased IL-10 levels with increased VEGF and TGF-β1 expressions. Simultaneously, prominent pro-healing activities could be observed histopathologically. These include increased blood vessels, reduced inflammatory cells, more myofibroblasts, increased deposition of collagen fibres, and early re-epithelialization. The changes were prominent in bilirubin nanoparticles (0.3%) treated group indicating better granulation tissue, quality of healing and wound maturity. In conclusion, the proposed new encapsulated bilirubin nanoparticles strategy significantly improved wound healing by modulation of cytokines and growth factors response in comparison with native bulk bilirubin. These observations support its potential as a novel biomaterial for wound healing in the future.
Article
The study aimed to fabricate naproxen sodium loaded in-situ gels of sodium alginate. Different in-situ gel forming solutions of naproxen sodium and sodium alginate were prepared and gel formation was studied in different physiological ions i.e., CaCl2 and Ca-gluconate. The prepared gel formulations were evaluated for different physical attributes such as gelation time, sol-gel fraction, ATR-FTIR spectroscopy and in silico molecular dynamics (MD) simulations. Drug release studies were carried out in a dialysis membrane using USP dissolution basket apparatus-I. In vivo anti-inflammatory studies were performed in Sprague-Dawley rats having carrageenan-induced hind paw inflammation. Higher polymer concentration in formulations resulted in decreased gelation time and an increased gel fraction. The ATR-FTIR and MD simulation revealed H-bonding between the alginate and naproxen sodium at 3500-3200 cm⁻¹ with a RMSD of ∼2.8 Å and binding free energy ΔGpred (GB) = -10.93 kcal/mol. In vitro drug release studies from F8CAG suggested a sustained release of naproxen sodium. In vivo studies revealed a continuous decrease in swelling degree (≈-5.28± 0.210 mm) in inflamed hind paw of Sprague-Dawley rats over 96 h. The in-situ gel forming injectable preparation (F8CAG) offers a sustained release of naproxen sodium in the articular cavity which promises the treatment of chronic inflammatory conditions such as arthritis.
Chapter
The rapid increase in world population and industrialization has triggered the demand and consumption of nonrenewable sources. For example, waste plastic demand increased significantly from 2 million tonnes per year in 1950 to 381 million tonnes per year in 2015. On the other hand, plastic waste disposal was negligible before 1980, resulting in 100% disposal. Incineration and recycling were started in 1980 and 1990, respectively. In 2015, the incineration and recycling percentage increased to 25 and 20, leaving 55% waste discarded. We aim to progress toward zero waste disposal and 100% recycling. The minimization of plastic wastes is only possible either by recycling in an environmentally friendly manner or using renewable sources. Recently, researchers are shifting from synthetic polymers to bio-degradable polymers such as cellulose or natural fiber-based composites. The low environmental impact, biodegradability, adequate specific strength, low density or lightweight, low cost, and ease of recycling make them highly attractive for sustainable technology development. These find applications in various fields, including the biocomposites, and have been extensively applied for food packaging, energy storage elements, biomedical sensing, sustainable energy harvesting systems, etc.
Article
Poloxamer 407 (P407) is widely used for targeted drug-delivery because it exhibits thermoresponsive gelation behavior near body temperature, stemming from a disorder-to-order transition. Hydrophobic small molecules can be encapsulated within P407; however, these additives often negatively impact the rheological properties and lower the gelation temperatures of the hydrogels, limiting their clinical utility. Here we investigate the impact of adding two BAB reverse poloxamers (RPs), 25R4 and 31R1, on the thermal transitions, rheological properties, and assembled structures of P407 both with and without incorporated small molecules. By employing a combination of differential scanning calorimetry (DSC), rheology, and small-angle x-ray scattering (SAXS), we determine distinct mechanisms for RP incorporation. While 25R4 addition promotes inter-micelle bridge formation, the highly hydrophobic 31R1 co-micellizes with P407. Small molecule addition lowers thermal transition temperatures and increases the micelle size, while RP addition mitigates the decreases in modulus traditionally associated with small molecule incorporation. This fundamental understanding yields new strategies for tuning the mechanical and structural properties of the hydrogels, enabling design of drug-loaded formulations with ideal thermal transitions for a range of clinical applications.
Article
The development of long-acting drug formulations requires efficient characterization technique as the designed 6-12 months release duration renders real-time in vitro and in vivo experiments cost and time prohibitive. Using a novel image-based release modeling method, release profiles were predicted from X-Ray Microscopy (XRM) of T0 samples. A validation study with the in vitro release test shows good prediction accuracy of the initial burst release. Through fast T0 image-based release prediction, the impact of formulation and process parameters on burst release rate was investigated. Recognizing the limitations of XRM, correlative imaging with Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) was introduced. A water stress test was designed to directly elucidate the formation of pores through polymer-drug-water interplay. Through an iterative correction method that considers poly(lactic-co-glycolic acid) (PLGA) polymer degradation, good agreement was achieved between release predictions using FIB-SEM images acquired from T0 samples and in vitro testing data. Furthermore, using image-based release simulations, a practical percolation threshold was identified that has profound influence on the implant performance. It is proposed as an important critical quality attribute for biodegradable long-acting delivery system, that needs to be investigated and quantified.
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Article
We report the development of a new gelation mechanism and a new family of polymers that self-assembles to form gels in a thermoreversible fashion. The polymers are block or star copolymers with a central hydrophilic poly(ethylene glycol) (PEG) segment (A) and temperature responsive poly(N-isopropylacrylamide) (PNIPAAm) terminal segments (B). Copolymers of various architectures, AB, A(B)2, A(B)4, and A(B)8, were synthesized to investigate the structures and properties relationship. At 5 °C, the viscosities of 20 wt % solutions were between 700 and 950 cP, and they could be easily injected through a 25 G needle. Upon warming to body temperature, A(B)2, A(B)4, and A(B)8 formed a strong associative network gel with aggregates of PNIPAAm segments acting as physical cross-links, whereas AB formed a weaker gel by micellar packing and entanglement. The values of elastic modulus, loss tangent, and yield strength were 1000−2500 Pa, 0.24−0.62, and 200−860 Pa, respectively. The gelation kinetic was fast; a typical gelation time for a solution of 5 mL in volume was less than a minute. No significant syneresis was observed after 2 months at 37 °C. DSC results indicated that the thermal behavior of material was completely reversible even after 30 heat-and-cool cycles. These materials are promising candidates for in-situ gelation applications such as injectable drug delivery, tissue engineering scaffolds, and anatomical barriers.
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Article
A new thermogelling chitosan-glycerophosphate system has been recently proposed for biomedical applications such as drug and cell delivery. The objectives of this work were to characterize the effect of steam sterilization on the in vitro and in vivo end performances of the gel and to develop a filtration-based method to assess its sterility. Autoclaving 2% (w/v) chitosan solutions for as short as 10 min resulted in a 30% decrease in molecular weight, 3–5-fold decrease in dynamic viscosity, and substantial loss of mechanical properties of the resulting gel. However, sterilization did not impair the ability of the system to form a gel at 37°C. The antimicrobial activity of chitosan against several microorganisms was evaluated after inoculation of chitosan solutions and removal of the cells by filtration. It was found that, although chitosan was bacteriostatic against the heat sterilization bioindicator Bacillus stearothermophilus, the bacteria could rapidly grow after separation from the chitosan solution by filtration. This indicated that B. stearothermophilus is an adequate strain to validate a heat sterilization method on chitosan preparations, and accordingly this strain was used to assess the sterility of chitosan solution following a 10 min autoclaving time. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 58: 127–135, 2001
Article
A novel graft copolymer composition is synthesized using grafting temperature-sensitive Pluronic side chains onto poly(acrylic acid) (PAAc) and chitosan backbones. The graft polymers are bioadhesive on mucosal surfaces and form low viscous solutions that gel when the temperature is raised above a critical temperature.
Article
For the characters of serious nonlinear and unknown or uncertain parameters, a backstepping control method based on neural networks is proposed to realize multi-object generator control. Neural networks are used to solve the contradiction between backstepping control and unmatching of systems. A special weight online tuning method is proposed in the system, and an off-line training phase was not required. According to the proof of stability, the method does not require the system parameters to be exactly known, and the system was robustness. The simulation result verified that the method is effective such as small overshoot, short tuning time and etc.
Article
Aqueous solutions of poly(N-isopropyl acrylamide) show a lower critical solution temperature. The thermodynamic properties of the system have been evaluated from the phase diagram and the heat absorbed during phase separation and the phenomenon is ascribed to be primarily due to an entropy effect. From viscosity, sedimentation, and light-scattering studies of solutions close to conditions of phase separation, it appears that aggregation due to formation of nonpolar and intermolecular hydrogen bonds is important. In addition, a weakening of the ordering effect of the water-amide hydrogen bonds as the temperature is raised contributes to the stability of the two-phase system.
Article
Arterial structure plays an important role in drug delivery from intraarterial depots. The internal elastic lamina forms a major diffusive resistance to the transport of macromolecular drugs from intimally-adherent hydrogel depots to the arterial media. The objectives of this study were to develop an approach by which to form a bilayer hydrogel depot with a higher permeability intimally-adherent layer, containing the drug, and a lower permeability luminal layer, and to evaluate ex vivo whether this luminal layer could enhance the delivery of a protein to the arterial media. Sequential interfacial photopolymerization of polyethyleneglycol diacrylate precursors (molecular weight 4000 for the luminal layer, 10,000 for the intimal layer) with eosin Y and triethanolamine as an initiation system was employed to form these bilayer hydrogels. Horseradish peroxidase was used as a model protein, and delivery to the arterial media was measured in rat carotid arteries ex vivo. The lower permeability luminal layer served to enhance delivery of the model protein into the arterial media for delivery periods at least up to 72 h. Thus, it was possible to compensate for the diffusional resistance of the internal elastic lamina on the one side of the hydrogel depot with a second diffusional resistance on the other side of the hydrogel.
Article
Physico-chemical properties of an injectable polymeric implant system were evaluated and utilized to predict and understand the in vivo release of a model drug. The injectable implant system is based on the principle that a water insoluble polymer, dissolved in a biocompatible solvent, will precipitate upon contact with water. The solubility parameter of poly(dl-lactide) and dl-lactide-co-glycolide copolymers were experimentally determined by evaluating the solubility of these polymers in hydrogen bonding solvents having solubility parameters ranging from 8.9 to 14.8 (cal/cm3)12. The appropriate Flory-Huggins interaction parameters were then calculated at 25 and 37°C. Analysis of ternary phase diagrams indicated that the quantity of water needed to initiate precipitation, as well as the precipitation threshold, increased with increasing temperature in agreement with theoretical calculations. Rats were subcutaneously administered formulations comprised of polymer concentrations above and below the precipitation threshold, i.e., 40% w/w polymer. Formulations with polymer concentrations below the precipitation threshold exhibited approximately twice the initial release compared to formulations having a polymer content above the precipitation threshold. A key factor affecting the initial release of a model drug from formulations was the polymer content of the formulation with respect to the precipitation threshold. The reported method of analysis may be utilized to screen polymers and biocompatible solvents for use in these injectable implant systems.
Article
Micellization of poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol), PEG-PLGA-PEG, triblock copolymers in water was studied by 13C-NMR (nuclear magnetic resonance), dye solubilization method, and light scattering. Critical micelle concentration was decreased by half by increasing temperature from 20 to 50°C. Enthalpy of micellization was calculated to be 10–20 KJ/mole. Apparent aggregation number, diameter of a micelle abruptly increased while second viral coefficient decreased at ≈30°C suggesting that micellar growth as well as an increase in polymer–polymer attraction occur at this temperature. These findings might suggest that the sol to gel transition at high concentration of aqueous solutions of this polymer is driven by conformational changes of micelles.
Article
The effects of steam sterilization and gamma-irradiation on chitosan and thermogelling chitosan-beta-glycerophosphate (GP) solutions containing polyol additives were investigated. The selected polyols were triethylene glycol, glycerol, sorbitol, glucose and poly(ethylene glycol) (PEG). They were incorporated to chitosan solutions prior to sterilization in a proportion ranging from 1 to 5% (w/v). The solutions were characterized with respect to their viscosity, thermogelling properties, compressive stress relaxation behavior and chitosan degradation. All polyols reduced the autoclaving-induced viscosity loss and had a positive impact on the solution thermogelling properties and compressive performance of the gels. Steam sterilization in the presence of glucose resulted in a substantial increase in the solution viscosity and gel strength. This was associated with a strong discoloration suggesting chemical alteration of the system. PEG was the most effective agent in preventing hydrolytic degradation of chitosan chains. Gamma-irradiation strongly decreased the chitosan solution viscosity regardless of the presence of additives, even when sterilization was carried out at -80degreesC. Moreover, the thermogelling properties were dramatically altered, and thus, gamma-irradiation would not be an appropriate method to sterilize chitosan solutions. In conclusion, polyols are potentially useful additive to maximise the viscoelastic and mechanical properties of chitosan-GP after steam sterilization.
Article
The thermogelling aqueous solution of poly(DL-lactic acid-co-glycolic acid) grafted with poly(ethylene glycol)s is developed, and the elegant instrumental methods to determine sol–gel transition temperature and the method to control gel duration are reported.
Article
A batch of poly(N-isopropylacrylamide-co-acrylic acid) synthesized in benzene shows distributions in molecular weight as well as polymer composition. The copolymer turns out to be a blend of polymers having various lower critical solution temperatures. An aqueous solution of the copolymer above a critical concentration experiences four distinct phases upon heating. One of the phases is a gel phase that shows reversibility in gel-sol transition without noticeable hysteresis or syneresis. Once the gel is formed, it does not dissolve or change in water content until the temperature reaches another transition point. This particular process is related to the molecular weight, the chain entanglement, the molecular transition at elevated temperatures from expanded coils to collapsed globules of a portion of the polymers, and the subsequent aggregation of the collapsed globules to make weak physical junctions. The junctions can be discriminated from the physical cross-linking involved in gelation processes known so far. The thermally induced molecular aggregation of the collapsed polymer chains may be responsible for the gel opacity, negligible gel induction time, lack of hysteresis, and non-elastic deformation.
Article
Nonionic polymers and surfactants in aqueous systems show in a large number of properties unusual or ‘anomalous’ temperature dependences which are briefly reviewed. It is also reported that these solutes in the presence of ionic amphiphilic cosolutes show anomalous effects such as a strong synergistic ionic surfactant-electrolyte effect in the phase behaviour and the formation of stiff gels at higher temperature. With the aim of understanding the effect of ethylene oxidecontaining and related systems in general, including homogeneous solutions, microheterogeneous self-assembled solutions and macroscopic interfaces, a general discussion of possible interactions is presented. Different observations suggest that in all these systems, the solute or interface becomes less hydrophilic at higher temperature, which is in agreement with recent quantumchemical calculations. The effects of conformational equilibria on phase diagrams is considered and in particular it is shown that complex phase equilibria of nonionic polymer-ionic surfactant systems can be rationalized by a simple model.
Article
Equilibrium swelling curves of N‐isopropylacrylamide (NIPA) gel and a series of its ionized counterparts were measured as a function of temperature. Nonionic NIPA gels underwent a sharp yet continuous volume change, whereas incorporation of a small amount of ionizable groups into the gel network drives the transition toward a discontinuous one. The critical ionic concentration and polymer network density at which the get undergoes a critical phase transition were determined. The results were analyzed using a mean field theory. Discrepancy between experimental data and theory is nontrivial, and may require the formulation of a more elaborate theory.
Article
Aqueous solutions of new biodegradable triblock copolymers, poly(ethylene glycol-b-(dl-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG−PLGA−PEG), have shown to have sol-to-gel (lower transition) and gel-to-sol (upper transition) transitions as temperature monotonically increases. The lower transition is important for drug delivery application because the solution flows freely at room temperature and becomes a gel at body temperature. In this paper, the mechanism of gelation was proposed, and the structure−property relationship of the sol−gel transition was investigated. The lower transition may be related to micellar growth and intra- and intermicelle phase mixing and packing, while the upper transition involves breakage of micellar structure. Critical gel concentration and critical gel temperature are controlled by polymer molecular parameters, such as block length and composition of PEG−PLGA−PEG triblock copolymers, and additives, such as salts.
Article
The hydrolytic properties of the novel biodegradable thermosensitive poly(organophosphazenes) with methoxypoly(ethylene glycol) (MPEG) and amino acid esters as side groups have been studied by means of gel permeation chromatography and 31P and 1H NMR spectroscopy and by identification of the hydrolysis products. The polymers substituted with α-amino acid esters were hydrolyzed faster than that with β-amino acid ester. The higher content of the amino acid ester in the polymer backbone caused enhanced hydrolysis. The rate of the polymer degradation decreased in the order of methyl > ethyl > benzyl esters. The polymer hydrolysis occurred more rapidly in both acidic and basic buffer solutions than in the neutral solution. The 31P NMR spectra of the polymers with high content of glycine ethyl ester showed that the polyphosphazene backbone underwent fragmentation mostly to small molecules after incubation in the buffer solution of pH 10 for 26 days. Phosphates and ammonia were formed as hydrolysis products in most cases. The hydrolytic behaviors of the present thermosensitive polyphosphazenes are consistent with the conventional acid-catalyzed degradation mechanism, and a detailed pathway to their hydrolytic degradation is proposed. The salt and pH effects on the thermosensitivity of the polymers were also examined by measuring their lower critical solution temperature (LCST) in aqueous solutions containing various inorganic and organic salts. When various inorganic salts were added to aqueous solutions of the polymers, their salting-in and salting-out effects were found to be mainly dependent on the anions of the salts. On the other hand, in the case of tetraalkylammonium halides which are organic salts, cations seem to play an important role:  the salting-in effect is stronger with increasing alkyl chain of the ammonium salt. The aqueous solutions of the polymers showed higher LCST in the acidic solution than in the neutral and basic buffer solutions.
Article
Novel thermosensitive poly(organophosphazenes) bearing methoxy-poly(ethylene glycol) (MPEG) and amino acid esters as substituents have been synthesized, and their lower critical solution temperature (LCST) was investigated. Differential scanning calorimetry (DSC) has shown that some of the polymers exhibit crystallinity, which is probably induced by the MPEG side chain of the polymers. Most of the polymers show their LCSTs in the range of 25.0−98.5 °C, depending on several factors such as mole ratio of the substituents, molecular weight of the MPEG, and kinds of amino acids and esters. The more hydrophilic composition of the polymers offers the higher LCST. The LCST of the polymers exhibits almost concentration-independent behavior in the range of 3−30 wt % of the polymers in aqueous solution.
Article
Rheological properties of thermoreversible hydrogels of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) have been studied. The relaxation exponent Δ = 0.69 is found from the frequency-independent loss tangent at the gel point. The distance from the gelation threshold (ε) is varied by changing the concentration or temperature. Dependencies of the zero-shear viscosity (ηo) and equilibrium modulus (Go) scale as ηo εs and Go εt. The transient exponents s = 1.26−1.28 and t = 2.64−2.65 are obtained in the vicinity of the gelation threshold. The scaling relation between all exponents is in excellent agreement with the Rouse model and is consistent with the percolation theory. Transient rheological properties exhibit complex scaling behavior above the gel point depending on ε. Scaling above the gel point correlates with the polymer structure.
Article
Differential scanning calorimetry (DSC) was performed on aqueous solutions of poly(N-isopropylacrylamide-co-butyl methacrylate-co-X), with X being hydrophilic, hydrophobic, cationic, or anionic comonomers, to elucidate the mechanism of temperature-induced phase separation and the effect of comonomer content, hydrophilicity, and charge on the lower critical solution temperature (LCST). The endothermic heat of phase separation, which is related to the breaking of hydrogen bonds between water molecules surrounding hydrophobic moieties on the polymer, was a linear, decreasing function of the LCST. This suggests that the hydrophobic interactions between polymer side groups, which are the major driving force for phase separation, are enhanced at elevated temperatures due to a decrease in the structuring of water around hydrophobic side groups. It is concluded that the changes in LCST caused by the incorporation of comonomers are due to changes in overall hydrophilicity of the polymer and are not due to a direct influence of comonomer hydrophilicity or charge on the structuring of water around hydrophobic groups.
Article
The phase behavior of poly(ethylene oxide)-POLY(Propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers dissolved in water has been studied using small-angle neutron scattering. The structural properties have been studied as a function of polymer concentration and temperature. At low temperature (T less-than-or-equal-to 15-degrees-C) and low polymer concentrations the unimers are fully dissolved GaUssian chains with radius R(g) = 17 angstrom. Close to ambient temperature, the hydrophobic nature of ppo causes aggregation of the polymers into spherical micelles with core sizes of the order of 40-50 angstrom, somewhat temperature dependent. The concentration of micelles increases roughly linearly with temperature, until either a saturation is reached, where all polymers are part of a micelle, or the volume density of micelles is so high that they lock into a crystalline structure of hard spheres. In the 60-70-degrees-C temperature range, the micellar structure changes from spherical form to prolate ellipsoid, leading to a decreasing intermicelle interaction. At high concentration, this causes melting of the cubic lattice and leads successively to the formation of a rodlike structure with hexagonal symmetry. Close to 95-degrees-C, large aggregates of polymers ordered in lamellae structure are formed, leading to an opaque suspension.
Article
Self-assembly in aqueous solutions of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) has been studied. The onsets of aggregation and the relative viscosity increase coincide. Below the gelation temperature both relative and zero-shear viscosities grow as the square root of total polymer concentration, defining polymer solutions as semidilute and unentangled. Significant differences between complex and steady-shear viscosities in the low-shear, low-frequency regions are observed, in contrast to the Cox−Merz rule. Gelation is characterized by the appearance of well-defined, slow relaxation modes above frequencies corresponding to the liquidlike flow. The gel elasticity can be related to the functionality of aggregates that increases with the polymer concentration.
Article
Binding isotherms of a cationic surfactant (N-tetradecylpyridinium bromide) to a nonionic polymer (ethyl(hydroxyethyl)cellulose) in water are presented. Surfactant binding was obtained by measurements of the surfactant ion activity in the presence and absence of polymer using a selective electrode. A strong cooperative binding to the polymer was detected at a surfactant concentration lower than the critical micelle concentration. Both an increase in salt concentration and a rise in temperature led to a more pronounced binding. The unusual temperature dependence is explained as an effect of conformational changes of the substituents and the backbone in ethyl(hydroxyethyl)cellulose. Thus, at elevated temperatures the polymer becomes more hydrophobic, which results in increased surfactant binding. As a consequence of this, the solubility of the polymer-surfactant complexes decreases when small amounts of salt are present. This was observed as a lowering of the cloud point of the system.
Article
The evolution of linear viscoelasticity during the thermoreversible gelation of the aqueous systems ethyl(hydroxyethyl)cellulose (EHEC)/cetyltriammonium bromide (CTAB), and EHEC/sodium dodecyl sulfate (SDS) was measured by oscillatory shear. The experiments were carried out at constant surfactant concentration but at different EHEC concentrations. The gel point, determined by the observation of a frequency independent loss tangent, was found to be shifted toward lower temperatures with increasing EHEC concentration for both systems. At the gel point, a power law frequency dependence of the dynamic storage modulus (G' similar to omega(n') and loss modulus (G'' similar to omega(n'')) was constantly observed with n' = n'' = n. The viscoelastic exponent n was observed to decrease slightly (0.43 to 0.38) with increasing EHEC concentration for the EHEC/CTAB system, while for the EHEC/SDS system a pronounced increase (0.24-0.41) was detected. The implications of these observations with respect to the structure of the critical gels are discussed qualitatively in the framework of the fractal model of Muthukumar. The critical gel strength parameter S was found, for both systems, to increase with EHEC concentration, but especially at low polymer concentration a significant difference in the value of S of the systems was revealed.
Article
Gelation in aqueous solutions of poly(acrylic acid) (PAA) grafted onto poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (Pluronic F127) has been studied. The gel point and onset of micellization are observed in Pluronic−PAA solutions at the same temperatures, confirming that the gelation occurs via formation of micelles that act as thermoreversible cross-links. The salt- and pH-dependent expansion or folding of the polyelectrolyte segments changes the gel elasticity. The increased polarity due to enhanced polymer ionization at higher pH or with salt addition causes the poly(propylene oxide) (PPO) segments to aggregate at lower temperatures. The weak dependence of the polymer concentration at the maximum reduced viscosity on the salt concentration is attributed to hydrophobic interactions among PPO segments.
Article
Pluronic poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) (PEO−PPO−PEO) block copolymers are copolymerized with poly(acrylic acid) (PAA) by a one-step free-radical polymerization of acrylic acid with the chain transfer to the Pluronic dissolved in the acrylic acid. Exponential increase of branching and cross-linking in the resulting Pluronic−PAA copolymers is observed at high degrees of conversion of acrylic acid. The solutions show reversible gelation within a narrow temperature range, with a gelled state resembling that of permanently cross-linked gels. Onset of thermogelation in Pluronic−PAA solution coincides with augmentation of light-scattering intensity of large scatterers and approaches the critical micellization temperature of the parent Pluronic. Effects of the overall PEO content and the length of the PPO segment in the parent Pluronic on the properties of copolymers are revealed.
Article
Poly(acrylic acid) (PAA) copolymers modified with block-copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) are inherently attractive for medicinal applications as their components are considered pharmaceutically safe. The laboratory-scale synthesis of poly(acrylic acid) bonded onto a PEO−PPO−PEO triblock (Pluronic) backbone via dispersion polymerization is reported. Initial optimization of the synthesis defines appropriate levels of initial loading of acrylic acid and Pluronic, with a mixture of 2,2‘-azobis(2,4-dimethylpentanenitrile) and lauroyl peroxide as an initiator system. The synthesis results in a copolymer with low residual monomer content and a very high degree of bonding between Pluronic and PAA. Diluted aqueous solutions of Pluronic-g-PAA exhibit rapid thermogelation. Rheological parameters of the copolymers urge on their ophthalmic applications.
Article
A thermally triggered liposome-based mineralization system is described that is metastable at ambient temperature but rapidly forms calcium phosphate mineral upon warming to physiologic temperature. Mixing of a calcium-loaded lipid vesicle suspension with aqueous inorganic phosphate resulted in a stable liposome suspension whose bulk ionic concentration was highly supersaturated with respect to hydroxyapatite and other calcium phosphate minerals. The mineralization activity of metastable liposome suspensions was found to be strongly dependent both on temperature and on the composition of the phospholipids that comprise the vesicle membrane. No detectable mineral formation occurred in the metastable liposome suspensions during storage for several weeks at room temperature. However, when the liposome suspensions were heated to near the lipid chain melting transition (Tm), Ca2+ was released from the lipid vesicles and reacted with extravesicular phosphate to form calcium phosphate mineral. Infrared spectroscopy and powder X-ray diffraction analysis of the reaction products indicated the formation of both apatite and brushite minerals, a finding that is consistent with the changing pH conditions of thermally triggered mineralization. Mixtures of miscible phospholipids (dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine) were used to tailor Tm to physiologic temperature. This strategy was employed for the preparation of metastable liposome suspensions that were stable for long periods of time at room temperature but that mineralized rapidly when heated to 37 °C. The potential medical and dental significance of thermally triggered liposomal mineralization is discussed.
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Thermosensitive poly(organophosphazenes) bearing R-amino-ω-methoxy-PEG (AMPEG) and hydrophobic L-isoleucine ethyl ester (IleOEt) as side groups have been synthesized, and their reversible sol-gel properties were investigated by means of 31 P NMR spectroscopy and viscometer. In an aqueous solution, the poly(organophosphazenes) exhibited four-phase transitions with temperature gradually increasing: a transparent sol, a transparent gel, a opaque gel, and a turbid sol. The gelation properties of the polymer were affected by several factors such as the composition of substituents, the chain length of AMPEG, and the concentration of the polymer solutions. The more hydrophilic composition of the polymers offers the higher gelation temperature. The gelation of the polymer is presumed to be attributed to the hydrophobic interaction between the side-chain fragments (-CH(CH 3)CH2CH3) of IleOEt which act as the physical junction in the polymer aqueous solution.
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As an approach to replacing islets of Langerhans in an implanted biohybrid artificial pancreas, thermally reversible polymers based on N-isopropylacrylamide were synthesized and then evaluated as an extracellular matrix for islets in an immunoprotecting membrane pouch. A high molecular weight poly(N-isopropylacrylamide-co-acrylic acid (2 mole % in feed)) demonstrated gelation at 37°C and became a solution below 30°C. This polymer exhibited minimum syneresis (water separation) upon gelation from a solution state when the temperature was raised from room temperature to 37°C, while poly(N-isopropylacrylamide) exhibited considerable syneresis under the same conditions. These properties influence the efficiency of islet entrapment. The copolymer was able to entrap rat islets almost 100%, but the homopolymer entrapped l