Accepted Manuscript Title: Supramolecular Hydrogels as Drug Delivery Systems Author: Mohammad reza Saboktakin Roya Mahdavi Tabatabaei PII: DOI: Reference:

S0141-8130(15)00075-6 http://dx.doi.org/doi:10.1016/j.ijbiomac.2015.02.006 BIOMAC 4879

To appear in:

International Journal of Biological Macromolecules

Received date: Revised date: Accepted date:

16-1-2015 27-1-2015 7-2-2015

Please cite this article as: M. Saboktakin, R.M. Tabatabaei, Supramolecular Hydrogels as Drug Delivery Systems, International Journal of Biological Macromolecules (2015), http://dx.doi.org/10.1016/j.ijbiomac.2015.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Supramolecular Hydrogels as Drug Delivery Systems

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Mohammad reza Saboktakin*, Roya Mahdavi Tabatabaei

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Nanostructured Materials Synthesis Lab., NanoBMat Company, GmbH, Hamburg, Germany

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Abstract

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Drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative

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way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We

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report here on the development of supramolecular hydrogels for this application. Chain-

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extended hydrogelators containing hydrogen bonding units in the main chain, and

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bifunctional hydrogelators end-functionalized with hydrogen bonding moieties, were made.

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The influence of these hydrogels on the renal cortex when implanted under the kidney

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capsule was studied. The overall tissue response to these hydrogels was found to be mild, and

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minimal damage to the cortex was observed, using the infiltration of macrophages, formation

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of myofibroblasts, and the deposition of collagen III as relevant read-out parameters.

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Differences in tissue response to these hydrogels could be related to the different physico-

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chemical properties of the three hydrogels.

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Keywords : Drug delivery, Supramolecular hydrogels, physical properties.

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* Corresponding author : Mohammad Reza Saboktakin, Nanostructured Materials Synthesis Lab., NanoBMat

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Company, GmbH, Hamburg, Germany

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Tel/Fax: +040-2263470 E-mail : [email protected]*

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Introduction

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Although a low molecular mass gelator was discovered in the early nineteenth century, the

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supramolecular nature of these materials was poorly understood and they were largely

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neglected until the late 20th century. In the recent past, molecules of a great structural

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diversity, for instance from the simplest alkanes to the complex phthalocyanines, have been

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discovered to be gelators. Incidentally, the discovery of such molecules has been largely

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serendipitous (typically from a failed crystallization attempt!). However, with the knowledge

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gained on the aggregation of gelator molecules during the past decade, attempts are being

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made to ‘design’ gelators through the incorporation of structural features (for instance, H-

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bonding motifs such as amides, ureas and saccharides) that are known to promote one-

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dimensional aggregation.

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Gels of a low molecular mass compound are usually prepared by heating the gelator in an

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appropriate solvent and cooling the resulting isotropic supersaturated solution to room

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temperature. When the hot solution is cooled, the molecules start to condense and three

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situations are possible (Fig. 1): (1) a highly ordered aggregation giving rise to crystals i.e.,

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crystallization (2) a random aggregation resulting in an amorphous precipitate or (3) an

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aggregation process intermediate between these two, yielding a gel.

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Fig. 1- Classification of gels.

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The process of gelation involves self-association of the gelator molecules to form long,

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polymer-like fibrous aggregates, which get entangled during the aggregation process forming

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a matrix that traps the solvent mainly by surface tension. This process prevents the flow of

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solvent under gravity and the mass appears like a solid. The matrix structure is heterogeneous

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and superstructures ranging in size from nanometers to micrometers can be found as a result

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of the hierarchal aggregation process.

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At the microscopic level, the structures and morphologies of supramolecular gels have been

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investigated by conventional imaging techniques such as SEM, TEM, and AFM, while

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thermal and mechanical studies are used to understand the interactions between these

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structures. However, at the nanoscale, X-ray diffraction, small angle neutron scattering and

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X-ray scattering (SANS, SAXS) are required to elucidate the structures of supramolecular

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gels. In spite of all these investigations, several aspects of the process by which gelators

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aggregate to form gels are poorly understood and the process of gel formation remains an

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area of intense interest. However, despite the lack of a detailed understanding of the mode of

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aggregation of gelators, or the structures of the aggregates, a wide variety of futuristic

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applications have been envisioned for these materials. Several reviews and articles have

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described the diversity of the molecular structures of gelators and have attempted to shed

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light on the structure and properties of their supramolecular aggregates. This review will

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describe the drug delivery applications of the supramolecular gels in order to develop a

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variety of functional gels which may have possible applications[1,2].

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Fig. 2- SEM of an aqueous of a cationic bile acid derivative.

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1. Biomedical applications of Supramolecular hydrogels.

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Hydrogels of natural and synthetic polymers are being widely explored as media for tissue

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engineering, owing to their structural similarity to the macromolecular components in the

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body[3].

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As many supramolecular hydrogels are derived from naturally occurring molecules, they are

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likely to be biocompatible and may therefore be explored for similar applications. Also, gels

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are promising media for applications involving controlled release of molecules, specifically

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for drug delivery. Site-specific controlled release of drugs is an important issue in current

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therapeutics and programmed delivery of a pharmaceutically active agent may be achieved by

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the use of stimuli sensitive gels as drug delivery agents. A few efforts have been made to

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investigate supramolecular gels for their drug delivering potential, which are discussed in the 3 Page 3 of 37

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following. Multicomponent organogels of sorbitan monostearate containing niosomes

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(vesicle in water) has been investigated for their in vivo drug delivery capability[4]. Model antigens bovine serum albumin (BSA) and haemagglutinin (HA) used for depot and

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immunogenicity studies, respectively, were entrapped in the vesicle prior to gel formation. A

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short-lived depot effect was observed following the administration of the BSA containing gel

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into rats. The antigen cleared from the injection site over a period of days. Gels containing

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HA showed immunoadjuvant properties and enhanced the primary and secondary humoral

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immune responses to the antigen, HA. The release of model drugs, 8-aminoquinoline (AQ)

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and 2-hydroxyquinoline (HQ) from the hydrogel of N,N9-dibenzoyl-L-cystine has been

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studied in vitro[5].

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The rate of drug release depended on the gelator–drug interaction – the release of HQ being

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faster than that of AQ, which binds more strongly to the gel strands via an additional

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electrostatic H-bonding. The initial release rate of AQ (but not with HQ) from the gel was

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proportional to the rate of gel degradation, as observed with biodegradable polymer gels. The

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release process was found to be independent of the gelator concentration (in a narrow range)

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or the aqueous medium. These encouraging results point at the promise held by molecular

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gels for controlled drug delivery. The well-known antibiotic vancomycin functionalized with

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pyrene was found to be a hydrogelator[6]. Interestingly, the gelator molecules assembled in

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the form of helical ribbons in the aqueous gel exhibited improved antibiotic activity. Such

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gels can potentially be used for wound dressing.

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2. The uses of supramolecular hydrogels as intrarenal drug delivery systems

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The supramolecular building blocks based on ureido-pyrimidinone (UPy) units are excellent

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elastomeric biomaterials[7]. Also, bioactive supramolecular materials could be made by

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simple mixing of UPy-modified prepolymers and UPy-functionalized peptides. In the past,

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the tissue response to these UPy-modified biomaterials have been studied subcutaneously.

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Here, this supramolecular and modular principle to design hydrogels by introduction of UPy-

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moieties on poly(ethylene glycol) (PEG) prepolymers[8-11].

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Recently have been published an extensive study on the properties of different telechelic

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UPymodified PEGs.18 Here, we show the difference between two types of PEG

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hydrogelators, containing UPy-moieties in the main chain, or at the chain ends (i.e. telechelic

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UPy- PEGs)[12-18]. After discussing the synthesis, formulation procedure and rheological

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behaviour of these hydrogels have reported on their intrarenal behaviour and tissue response,

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and propose possible therapeutic applications in relation to their physical properties[19-24]. 4 Page 4 of 37

Praveen Kumar Vemula and et al. have been reported a novel approach for the controlled

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delivery of an antiinflammatory, chemopreventive drug by an enzyme-triggered drug release

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mechanism via the degradation of encapsulated hydrogels. The hydro- and organogelators are

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synthesized in high yields from renewable resources by using regioselective enzyme

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catalysis, and a known chemopreventive and antiinflammatory drug, i.e., curcumin, is used

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for the model study. The release of the drug occurred at physiological temperature, and

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control of the drug release rate is achieved by manipulating the enzyme concentration and/or

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temperature. The byproducts formed after the gel degradation were characterized and clearly

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demonstrated the site specificity of degradation of the gelator by enzyme catalysis. The

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present approach could have applications in developing cost-effective controlled drug

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delivery vehicles from renewable resources, with a potential impact on pharmaceutical

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research and molecular design and delivery strategies[25].

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3. Novel injectable systems based on supramolecular hydrogels A novel injectable system is a simple and biocompatible in situ gel-forming system

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composed of hyaluronic acid–tyramine (HA-Tyr) conjugates using a peroxidase-catalyzed

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oxidation reaction. Hydrogels are formed in vivo by injecting two solutions through syringes:

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a solution of horseradish peroxidase (HRP) as a model catalyst, which induces the oxidative

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coupling of the phenol moiety; and HA-Tyr solution containing H2O2 as an oxidant of HRP.

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The hydrogel that is formed does not need to be surgically removed after treatment, as it can

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be safely degraded in the body. HA, a major constituent of the extracellular matrix (ECM), is

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a glycosaminoglycan made up of repeating disaccharide units (ß-1,4-Dglucuronic acid and ß-

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1,3-N-acetyl-D-glucosamine). We cast HA as the backbone polymer in the hydrogel because

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of its excellent biocompatibility and biodegradability[26]. Thus, this novel gel-forming

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system allows the formation of hydrogels without any inflammation and redundant reactions,

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with bioactive agents loaded in the hydrogels. Drugs are released from the hydrogel because

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of hydrogel degradation. Prolonged and sustained drug release can be achieved by controlling

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the hydrogel degradation. This is programmed through the design of the cross-link

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density[27].

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4. Bioactive systems based on Chitosan supramolecular hydrogels

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Advanced bioactive systems with defined macroscopic properties and spatio-temporal

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sequestration of extracellular biomacromolecules are highly desirable for next generation

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therapeutics. Here, chitosan hydrogels were prepared with neutral or negatively-charged

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crosslinkers in order to promote selective electrostatic complexation with charged drugs.

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Chitosan (CT) was functionalised with varied dicarboxylic acids, such as tartaric acid (TA), 5 Page 5 of 37

poly(ethylene glycol) bis(carboxymethyl) ether (PEG), 1.4-Phenylenediacetic acid (4Ph) and

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5-Sulfoisophthalic acid monosodium salt (PhS), whereby PhS was hypothesised to act as a

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simple mimetic of heparin. ATR FT-IR showed the presence of C=O amide I, N-H amide II

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and C=O ester bands, providing evidence of covalent network formation. The crosslinker

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content was reversely quantified by 1H-NMR on partially-degraded network oligomers, so

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that 18 mol.-% PhS was exemplarily determined. Swellability (SR: 299±65–1054±121 wt.-

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%), compressability (E: 2.1±0.9–9.2±2.3 kPa), material morphology, and drug-loading

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capability were successfully adjusted based on the selected network architecture. Here,

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hydrogel incubation with model drugs of varied electrostatic charge, i.e. allura red (AR, --),

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methyl orange (MO, -) or methylene blue (MB, +), resulted in direct hydrogel-dye

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electrostatic complexation. Importantly, the cationic compound, MB, showed different

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incorporation behaviours, depending on the electrostatic character of the selected crosslinker.

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In light of this tuneable drug-loading capability, these CT hydrogels would be highly

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attractive as drug reservoirs towards e.g. the fabrication of tissue models in vitro[28].

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5. Supramolecular hydrogels based on Cyclodextrin

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Supramolecular materials with non-covalent bonds have attracted much attention due to their

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exclusive properties differentiating them from materials formed solely by covalent bonds.

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Especially interesting are rotor molecules of topological complexes that shuttle along a

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polymer chain. The shuttling of these molecules should greatly improve the tension strength.

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Our research employs cyclodextrin (CD) as a host molecule, because CD effectively forms

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polyrotaxanes with polymers. Herein we report the formation of supramolecular hydrogels

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with an α-CD dimer (α,α-CD dimer) as a topological linker molecule, and a viologen polymer

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(VP) as the polymer chain. The supramolecular hydrogel of α,α-CD dimer/VP forms a self-

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standing gel, which does not relax (G' > G'') in the frequency range 0.01–10 rad·s−1. On the

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other hand, the supramolecular hydrogel decomposes upon addition of bispyridyl

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decamethylene (PyC10Py) as a competitive guest. Moreover, the β-CD dimer (β,β-CD dimer)

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with VP does not form a supramolecular hydrogel, indicating that complexation between the

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C10 unit of VP and the α-CD unit of the α,α-CD dimer plays an important role in the

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formation of supramolecular hydrogels[29].

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6. Supramolecular hydrogels based on nonsteroidal anti-inflammatory drugs. The supramolecular hydrogelators made of nonsteroidal anti-inflammatory drugs (NSAID)

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and small peptides. The covalent linkage of Phe–Phe and NSAIDs results in conjugates that

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self-assemble in water to form molecular nanofibers as the matrices of hydrogels. When the

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NSAID is naproxen (1), the resultant hydrogelator 1a forms a hydrogel at a critical

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concentration (cgc) of 0.2 wt % at pH 7.0. Hydrogelator 1a, also acting as a general motif,

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enables enzymatic hydrogelation in which the precursor turns into a hydrogelator upon

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hydrolysis catalyzed by a phosphatase at physiological conditions. The conjugates of Phe–

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Phe with other NSAIDs, such as (R)-flurbiprofen (2), racemic flurbiprofen (3), and racemic

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ibuprofen (4), are able to form molecular hydrogels, except in the case of aspirin (5)(Fig 3).

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After the conjugation with the small peptides, NSAIDs exhibit improved selectivity to their

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targets. In addition, the peptides made of D-amino acids help preserve the activities of

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NSAIDs. Besides demonstrating that common NSAIDs are excellent candidates to promote

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aromatic–aromatic interaction in water to form hydrogels, this work contributes to the

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development of functional molecules that have dual or multiple roles and ultimately may lead

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to new molecular hydrogels of therapeutic agents for topical use[30].

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Fig. 3- The supramolecular hydrogelators made of nonsteroidal anti-inflammatory drugs (NSAID)

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7. Site-specific gel-delivery system of coenzyme Q10

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Zaki have been developed a site-specific gel-delivery system of coenzyme Q10 (CoQ10) for

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periodontal therapy. Poloxamer 407 (P407) was employed to confer a thermoreversible

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gelling character while carbopol 947P (CBP) and sodium alginate (Alg) were also included

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for their mucoadhesive power giving rise to Gel-A and Gel-B respectively. The gels were

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evaluated in adult patients with chronic periodontitis and the clinical parameters viz. plaque

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index (PI), gingival index (GI) and probing depth (PD) were recorded over a sufficient period

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of treatment (1-21 days). Results revealed that the two formulas had gelation temperature

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(Tsol-gel) in the physiological range whereas they differed in their mucoadhesive force being

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significantly higher for Gel-A. Both gels displayed a shear thinning property suitable for

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intrapocket periodontal injection; nevertheless, Gel-A had higher thixotropic behaviour. The 7 Page 7 of 37

release profile and kinetics of CoQ10 from the gels indicated zero-order release from Gel- A

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but Higuchi-type diffusion from Gel-B(Fig. 4). Clinical evaluation was performed in ten

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patients with chronic periodontitis who received a clinical (plaque index, gingival index,

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probing depth) examination at the baseline and at 1, 7, 14 and 21 days. The results of the

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clinical study showed that, the group treated with Gel-A demonstrated significantly higher

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reduction in all clinical recordings compared to the groups treated with Gel-B or CoQ10

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suspension. In conclusion, the significant improvement in clinical parameters indicated the

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potential of site-specific delivery of CoQ10 in an in situgel formulation with high

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mucoadhesive power and optimized rheological properties[31].

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8. Novel bioelectrocatalytic hydrogel based on protein building blocks

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A novel bioelectrocatalytic hydrogel constructed from bifunctional protein building blocks.

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Mixtures of electronconducting and catalytic building blocks will self-assemble into a

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bioelectrocatalytic supramolecular hydrogel. The physical properties and bulk function of the

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hydrogel can be independently tuned, because those properties depend on the identity and

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amount of each building block. The building blocks are based on a previously designed

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triblock polypeptide, here termed HSH, composed of two-helical leucine zipper domains (H

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domain) separated by a randomly coiled domain (S domain). The helical domains assemble

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into tetramic coiled coils, thus forming an ordered supramolecular hydrogel. Catalytic

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functionality is derived from an oxidoreductase to which H domains, identical to those of the

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triblock polypeptide (HSH), have been genetically fused. Electron conduction functionality is

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achieved through modification of the HSH building block with a redox moiety[32](Fig. 5).

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Fig. 5- Protein Constructs with partial sequences and the osmium redox sedes used un this study.

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9. Temperature‐sensitive poly(Nisopropylacrylamide) hydrogels

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Temperature‐sensitive poly(Nisopropylacrylamide) hydrogels as drug delivery systems, so

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changes in body temperature induced by pathogens could act like external stimuli to activate

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controlled release of the drugs incorporated in the hydrogel. In the distilled water combined

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release studies, we chose two model drugs: aminophylline and triamterene. The amount of

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drug released was measured by UV‐Vis spectroscopy following the evolution of the

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absorption peaks of aminophylline (271 nm) and triamterene (365 nm)(Fig. 6). The maximum

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release time was greater for triamterene than for aminophylline at 37 ºC, so these time‐release

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profiles enabled the active ingredients to work over different periods of time. By increasing

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molar mass or solubility of the drug, it observed that the diffusion coefficient decreased. On

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the contrary, increasing hydrophobicity of the drug leads to a diffusion coefficient increase.

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The evolution of pore size distribution of hydrogels during loading and releasing was

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measured by quasi‐elastic light scattering and by environmental electronic scanning

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microscope. When loading and releasing the drugs, the pore size of the hydrogel decreased

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and increased again without reaching the initial pore size of the hydrogel, respectively. It

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observed that the greater the concentration of drug loaded into the hydrogel, the greater the

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reduction in pore size[33].

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Fig. 6- Chemical structure of aminophyline (A) and triamterene (B).

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As reported before, hydrogels have emerged as promising biomaterials due to their unique

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characteristics. These polymeric networks, indeed, resemble living tissues closely in their

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physical properties because of their relatively elastomeric and soft nature and high water

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content, minimizing mechanical and frictional irritation. These materials show a minimal

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tendency to cell adhesion and to absorption of proteins from body fluids due to their very low

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interfacial tension. In addition, the swelling capacity allows to easily remove reagent residues

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[34, 35]. Unfortunately, the same water content which makes hydrogels such a special class

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of materials is also responsible for their biggest disadvantage, the poor mechanical properties.

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Hydrogels with improved mechanical properties could be obtained through the preparation of

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interpenetrating polymer networks (IPN) by chemical cross-linking. However, the presence

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of residual cross-linking agents could lead to toxic side effects [36].

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Burst or incomplete release of the therapeutic agent and the poor scalability of the

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manufacturing process represent other limitations in the use of hydrogel as drug delivery

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systems. In the aim to overcome these drawbacks, hydrogel composites materials have been

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developed [37].The synthesis of these materials involves the incorporation of nanoparticles

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into a hydrogel matrix enhancing mechanical strength, drug release profile, remote actuation

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capabilities, and biological interactions [38].

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10. Hydrogel nanocomposites

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The development of novel nanocomposite hydrogels was encouraged by the recent advances

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in the chemical, physical, and biological fields combined with rising needs in the biomedical

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and pharmaceutical sectors. Novel polymer chemistries and formulations as well as

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fabrication and processing techniques are supported by improved instrumentation that can

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measure and manipulate matter at the nanoscale level [39]. Hydrogel nanocomposites with

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different particulates, including clay, gold, silver, iron oxide, carbon nanotubes,

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hydroxyapatite, and tricalcium phosphate, have been synthesized and characterized to

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evaluate their potential application as biomaterials [40].

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11. Carbon nanotube hydrogels In 1994, the first polymer nanocomposites using carbon nanotubes as filler was reported [41].

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In earlier nanocomposites, nanoscale fillers such as carbon blacks, silica, clays, and carbon

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nanofibers (CNF) were employed in the aim to enhance the mechanical, electrical, and

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thermal properties of polymers [42]. In the last years, carbon nanotubes have received much

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attention as suitable materials to enhance the electrical and mechanical properties of polymers

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[43]. The technology implications of using CNTs-hydrogel are significant to many fields,

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from semiconductor device manufacturing to emerging areas of nanobiotechnology,

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nanofluidics, and chemistry, where the ability to mold structures with molecular dimensions

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might open up new pathways to molecular recognition, drug discovery, catalysis, and

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molecule specific chemobiosensing [44].

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Based on these considerations, the identification of the most effective synthetic strategy to

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prepare CNTs-hydrogel hybrid materials has been aroused by an increased and considerable

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interest. The adopted synthetic approaches can be classified into covalent and noncovalent

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functionalization of carbon nanostructures with polymeric materials. The structure of CNTs

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in the final composite represents the main difference between these two strategies. In the

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noncovalent approach, no modification of the CNT structure occurs; thus, the properties of

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the whole composite are determined by the intrinsic properties of the starting CNT materials;

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in the covalent approach, a significant modification of the CNT surface is performed and it is

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responsible of the composite final properties. The noncovalent functionalization approach is

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based on the molecular composition of CNTs. The sp2 bonded graphene structures at the

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sidewalls of CNTs, indeed, contain highly delocalized p electrons which can form

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functionalized CNTs with other p electron-rich compounds through

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organic functionalization method avoids modifying the intrinsic structures of CNTs and gives

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structurally intact CNTs with functionalities. Recently, the potential interaction between the

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interaction. This

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highly delocalized

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the polymer skeleton has generated much interest and provided the motivation for studying

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the optical and electronic properties of composites of CNTs and

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[45].

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The main strategies for the synthesis of CNTs-polymer composites by covalent

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functionalization consist of “grafting to” and “grafting from” approaches [46, 47].

-electrons correlated with the lattice of

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12. Novel supramolecular hydrogels based on cyclodextrin and copolymers

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-electrons of CNTs and the

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A materials design of a new supramolecular hydrogel self-assembled between a-cyclodextrin

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and a biodegradable poly(ethylene oxide)–poly[(R)-3-hydroxybutyrate]–poly(ethylene oxide)

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(PEO–PHB–PEO) triblock copolymer was demonstrated(Fig. 7). The cooperation effect of

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complexation of PEO segments with a-cyclodextrin and the hydrophobic interaction between

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PHB blocks resulted in the formation of the supramolecular hydrogel with a strong

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macromolecular network. The in vitro release kinetics studies of fluorescein isothiocyanate

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labeled dextran (dextran-FITC) model drug from the hydrogel showed that the hydrogel was

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suitable for relatively longterm sustained controlled release of macromolecular drugs, which

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many simple triblock copolymer hydrogel systems could not achieve. The hydrogel was

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found to be thixotropic and reversible, and can be applied as a promising injectable drug

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delivery system[48].

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Fig.7- Synthesis of PEO-PHB-PEO triblock copolymer.

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Supramolecular hydrogels based on cyclodextrin/polymer inclusion are an emerging

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injectable biomaterial for drug controlled-release and cell capsulation. Although the pH- and

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temperature sensitivity has been focused on contributing to intelligence, the system sensitive

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to physiological reduction condition caused by glutathione tri-peptide (GSH) has not been 12 Page 12 of 37

reported so far. In this work, novel reduction-sensitive supramolecular hydrogels were, for

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the first time, fabricated by the inclusion of [poly(ethylene glycol) monomethyl ether]-graft-

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[disulfide-linked poly(amido amine)] (mPEG-g-SS– PAA) with a-cyclodextrin (a-CD) in

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aqueous solution. The reduction-sensitivity was described to the disulfide linker in the SS–

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PAA main chain while various physical conjugations contributed to a reversible gel–sol

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transition under shearing as a key of injectable function. The drug release from such a

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supramolecular hydrogel showed a prominent sustained release profile, and the release rate

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could further be regulated depending upon the reduction condition. It is worth noting that

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incorporating a low loading-level of reducing agent did not inhibit the formation of hydrogel.

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As a result, it became possible to use the reduction-sensitivity to regulate the drug release

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profile in extracellular milieus and normal tissue. Combined with acceptable cytotoxicity, this

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kind of reduction-sensitive supramolecular hydrogel based on cyclodextrin/polymer inclusion

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showed a great potential as an injectable smart biomaterial for the application of drug

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controlled-release[49].

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13. Supramolecular hydrogels based on Ag(I)-glutathione (GSH) coordination

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polymers

A highly selective anion-responsive reversible gel–sol state transition in a supramolecular

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hydrogel of Ag(I)-glutathione (GSH) coordination polymers, which allows for facile and

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selective visual recognition of I- via naked eyes even in a strongly colored and/or fluorescent

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background(Fig. 8). Such a strategy overcomes the drawback of spectral interferences which

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are often encountered in conventional colorimetric and fluorimetric means. It was

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rationalized that I- functioned as a depolymerizing agent for the Ag(I)-GSH supramolecular

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hydrogels. A feasible quantitative assay for I- was established that afforded satisfactory

387

results for simulated wastewater samples. We believe that this strategy can in principle be

388

applicable to other species by following a smart gel–sol state transition in designed

389

supramolecular hydrogel[50].

391 392

te

Ac ce p

390

d

380

Fig. 8- Synthesis of poly(ethylene glycol) monomethyl ether- graft-[disulfide-linked poly(amido amine)].

393 394

Gelation is well known for aqueous biopolymer solutions (polysaccharides -carrageenan,

395

agarose - or proteins – gelatin) and occurs with decreasing temperatures. However, topical

396

formulations developed for pharmaceutical applications must be gels at the body temperature

397

(36°C) and fluids at room temperature (25°C). Synthetic triblock copolymers of ABA type 13 Page 13 of 37

(commercially available as Poloxamers and Pluronics) composed of A blocks of

399

Poly(ethylene oxide) (PEO) with n units and B blocks of Poly(propylene oxide) (PPO) with

400

m units, can be used in this case. They are synthesized in a large range of molecular weights

401

and PPO/PEO composition ratios. At low temperatures and/or concentrations the PEO-PPO-

402

PEO copolymers exist in solution as individual coils (unimers) and are fluids.

403

Thermodynamically stable micelles are formed with increasing copolymer concentrations

404

and/or temperatures. The micellization process is endothermic and driven by a decrease in the

405

polarity of ethylene oxide (EO) and propylene oxide (PO) segments as the temperature

406

increases and by the entropy gain when unimers aggregate into micelles (hydrophobic effect)

407

in water. In these solutions, gelation temperatures and gel structures can be efficiently

408

modulated by the molecular composition and architecture of the copolymers (linear or

409

branched) or by mixing triblock copolymers with different compositions[51].

410

A tailor-made polymer gels, Tetra-PEG gels. Tetra-PEG gels are prepared by cross-end-

411

coupling of two kinds of four-arm PEG prepolymer of the same size, tetraamine-terminated

412

PEG (TAPEG) and tetra-NHS-glutarate-terminated PEG (TNPEG).Here, NHS represents N-

413

hydroxysuccinimide. By mixing TAPEG and TNPEG aqueous solutions, Tetra-PEG gels can

414

be instantaneously formed, not only in the laboratory, but also in vivo. The molecular

415

weights, Mw, are so far 5k, 10k, 20k, and 40k. Typical polymer concentrations are 20 (Φ =

416

0.0177) to 160 mg/mL (Φ = 0.142). The degree of reaction reaches more than 90% according

417

to recent FTIR measurements. The coupling reaction is spontaneous, and its rate can be

418

controlled by pH and temperature. Tetra-PEG gels have extraordinarily low crosslinking

419

inhomogeneities, negligible defects and entanglements, as confirmed by small-angle neutron

420

scattering (SANS) and mechanical measurements. Tetra-PEG gels have controlled modulus,

421

extraordinarily high tenacity, and high deformability[52].

422

14. Polyzwitterionic-containing hydrogel materials

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423

Polyzwitterionic-containing hydrogel materials been proposed for use in biomaterial

424

applications. Polyzwitterions contain anions and cations in the same monomeric unit, unlike

425

polyampholytes which contain them in different monomeric units. The use of cationic and

426

anionic monomers in stoichiometrically equivalent proportions produces charge-balanced

427

polyampholytes (PA) copolymers. Membranes prepared using either betaine-containing (BT)

428

polyzwitterionic copolymers or PA copolymers can share similar properties, but the range of

429

EWCs offered by membranes incorporating BT and PA monomers is greater than that for 14 Page 14 of 37

conventional neutral hydrogels and methacrylic acid-based systems. Here we compare

431

properties of BT-containing and PA-containing copolymer membranes, relevant to their

432

potential as biomedical materials[53]. The combination of hydrogels and calcium phosphate

433

particles is emerging as a well-established trend for bone substitutes. Besides acting as

434

binders for the inorganic phase, hydrogels within these hybrid materials can modulate cell

435

colonization physically and biologically. The influence of hydrogels on the healing process

436

can also be exploited through their capability to deliver drugs and cells for tissue engineering

437

approaches[54].

cr

15. Polyacrylamide hydrogels

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438

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430

Polyacrylamide based hydrogel was synthesized using sodium carboxymethylcellulose

440

(NaCMC). N,N'- Methylenebisacrylamide (MBA) as cross-linker, ammonium persulfate

441

(APS) and N,N,N',N'-tetra-methylethylenediamine (TEMED) as initiators. Magnesium oxide

442

(MgO) nanoparticles were added to the hydrogel network to investigate the antibacterial

443

activity of synthesized polymer. Hydrogels were characterized using Fourier Transform

444

Infrared Spectroscopy (FTIR), and Field Emission Scanning Electron Microscope (FESEM).

445

The physical and chemical characterizations of the prepared hydrogels give valuable

446

information on the morphological structure of polymer, swelling behavior, bonding formation

447

of gels and physical properties. The incorporation of NaCMC enhanced the hydrogel

448

properties physically and chemically in the aspects of swelling capacity, strength and

449

flexibility. This study also investigated the antibacterial activities of prepared hydrogels

450

against Escherichia coli which is a Gram negative food pathogenic bacteria. For this purpose,

451

agar diffusion test or agar plate test was carried out and inhibition area for each hydrogel was

452

determined. Polyacrylamide hydrogel with NaCMC showed a low inhibition zone towards E.

453

coli. However, interestingly, the addition of 0.03 gram of MgO nanoparticles into the

454

hydrogel network resulted in about triple inhibition strength relatively[55]. A biocompatible

455

method of glutathione (GSH) catalyzed disulfide bond reduction was used to form Fmoc-

456

short peptide based supramolecular hydrogels. The hydrogels could form in both buffer

457

solution and cell culture medium containing 10% of Fetal Bovine Serum (FBS) within

458

minutes. The hydrogel was characterized by rheology, transmission electron microscopy, and

459

fluorescence emission spectra. Their potential in three dimensional (3D) cell culture was

460

evaluated and the results indicated that the gel with a low concentration of the peptide (0.1

461

wt%) was suitable for 3D cell culture of 3T3 cells. This study provides an alternative

462

candidate of supramolecular hydrogel for 3D cell culture and cell delivery[56]. The diffusion

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15 Page 15 of 37

mechanism of a model anti-cancer drug in cross-linked poly(N-isopropylacrylamide/acrylic

464

acid) (P(NIPAAm/AA) copolymeric hydrogels was studied. The crosslinking ratiowas

465

constant but acrylic acid ratio ranged from 10:1 to 10:3. P(NIPAAm/AA) copolymeric

466

hydrogels were synthesized by redox-initiated free radical polymerization in water at room

467

temperature. The presence of poly(ethyleneglycol) in the hydrogel formulation resulted the

468

higher mechanical strength. Use of acrylic acid resulted in higher hydrogel swelling. Drug

469

size was also found to be a significant factor. 5-FU is used as amodel anti-cancer drug. The

470

effect of 5-FU solution on swelling characteristics P(NIPAAm/AA) copolymeric hydrogels

471

have also been studied. The percent swelling, equilibrium swelling, diffusion constant values

472

are evaluated for P(NIPAAm/AA) copolymeric hydrogels at 1.5% of 5-FU solution at room

473

temperature Based on the release kinetic of the 5-FU drug, the hydrogels displayed a non-

474

Fickian diffusion mechanism. According the diffusion kinetic data in hydrogels became clear

475

that diffusion kinetic data were best described by Peppas model. Permeation from

476

P(NIPAAm/AA) copolymeric hydrogels followed a Super Case II transport mechanism, most

477

likely driven by macro molecular chain relaxation and swelling of hydrophilic polymers[57].

cr

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an

M

478

ip t

463

16. Injectable and biodegradable supramolecular hydrogels Injectable and biodegradable supramolecular hydrogels were prepared by nucleobase

480

(adenine/thymine)-

481

cyclodextrin (a-CD). The supramolecular hydrogels were thoroughly characterized by

482

WXRD, rheometer, and SEM. The gelation time depended on the molecular weight of PEG

483

and the concentration of polymer precursors. The rheological studies showed enhanced

484

elastic modulus (G0) of hydrogels, because of the hydrogen-bonding between A and T acting

485

as additional network junctions. In vitro evaluation showed that the supramolecular hydrogels

486

have acceptable biocompatibility, and are suitable for sustained and controlled release of

487

loaded antitumor drugs. Gel formation was also confirmed when the supramolecular

488

hydrogels were subcutaneously injected into rats. In addition, in vivo experiments employing

489

U14 cancer cell xeno graft bearing mice showed that the intra tumoral injection of a DOX-

490

loaded A-PEG-A/T-PEG-T/a-CD gel inhibited tumor growth more effectively than that of

491

free DOX, DOX-loaded PEG/a-CD gel, saline or gel alone. Hence, such a simple and

492

convenient anti-cancer drug delivery system of a A-PEG-A/T-PEG-T/a- CD supramolecular

493

hydrogel would be a promising candidate for many biomedical applications, especially in the

494

area of the chemotherapy of solid tumors[58].

poly(ethylene

oxide)s

(A-PEG-A/T-PEG-T)

and

a-

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16 Page 16 of 37

A steroidal gelator containing an imine bond was synthesized, and its gelation behavior as

496

well as a sensitivity of its gels towards acids was investigated. It was shown that the gels

497

were acid-responsive, and that the gelator molecules could be prepared either by a

498

conventional synthesis or directly in situ during the gel forming process. The gels prepared

499

by both methods were studied and it was found that they had very similar macro- and

500

microscopic properties. Furthermore, the possibility to use the gels as carriers for aromatic

501

drugs such as 5-chloro-8-hydroxyquinoline, pyrazinecarboxamide, and antipyrine was

502

investigated and the prepared two-component gels were studied with regard to their potential

503

applications in drug delivery, particularly in a pH-controlled drug release[59].

cr

us

505

17. Supramolecular hydrogels based on cyclodextrins and amphiphilic methoxy (polyethylene glycol)

an

504

ip t

495

Supramolecular hydrogels were instantaneously fabricated by mixing aqueous solutions of α-

507

cyclodextrins (α-CDs) and amphiphilic methoxy (polyethylene glycol) (MPEG)-ε-

508

caprolactone (CL) oligomer, which was synthesized via the ring-opening polymerization of

509

the CL monomer using low-molecular-weight MPEG (Mn of MPEG=2,000 g/mol) as an

510

initiator(Fig. 9). The supramolecular structure of the hydrogels was revealed by X-ray

511

diffraction (XRD) analyses. Rheological studies of the hydrogels revealed an elastic character

512

when the number of CL units in the oligomer was more than 2, and the obtained hydrogels

513

showed high storage modulus but relatively low shearing viscosity due to the low-molecular-

514

weight character of the oligomer, which was more preferable for use as an injectable delivery

515

system. The physical properties of the hydrogels could be modulated by controlling the chain

516

morphology and concentration of the oligomers, as well as the feed molar ratio of the

517

oligomer to α-CD. The components of the supramolecular hydrogels are biocompatible and

518

can readily be eliminated from the body. These features render the supramolecular hydrogels

519

suitable as drug delivery systems and tissue engineering scaffolds[60].

521 522

d

te

Ac ce p

520

M

506

Fig. 9- Formation of a supramolecular hydrogel of -CD and high- molecular-weight PEO.

523 524 525 526

18. Supramolecular hydrogels based on Tripeptide derivatives to conjugate with olsalazine

17 Page 17 of 37

Tripeptide derivatives to conjugate with olsalazine, a clinically used anti-inflammatory

528

prodrug, yield small molecules that self-assemble in water, which confer supramolecular

529

hydrogels that undergo sol-gel phase transition upon reduction, resulting in the controlled-

530

release of 5-aminosalicylic acid as the anti-inflammatory agent. This methodology will

531

ultimately lead to new biomaterials for site-specific drug delivery[61](Fig. 10).

ip t

527

532

Fig. 10- Illustration of drug release from olsalazine-containing supramolecular hydrogels upon.

cr

533 534

536

19. pH dependant supramolecular hydrogelators

us

535

Short peptides appropriately linked with an azobenzene conformational switch were found to

538

be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of

539

the short peptides linked with the conformational switch were studied in detail with respect to

540

dependence on amino acid residue, pH and salt effect. The presence of amino acids with

541

aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to

542

gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the

543

short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also

544

found to be important factors for the hydrogelation properties of the short peptides. A series

545

of short peptides with bioactive sequences were linked with the conformational switch and

546

their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels

547

were realized based on the E-/Z- transition of the conformational switch upon light

548

irradiation. Proper combination of amino acid residues in the short peptides resulted in smart

549

supramolecular hydrogels with responses to multiple stimuli[62].

550

Among various controlled-release drug delivery systems, in situ forming hydrogels are more

551

attractive than others due to their biodegradability and easy preparation.In this study, water

552

soluble and biodegradable triblock copolymer PCL– PEG–PCL was synthesized and used to

553

form supramolecular hydrogel by complexation with gamma cyclodextrin. Structural

554

properties of supramolecular hydrogel were investigated to achieve an injectable controlled-

555

release drug delivery system. Then, this system was studied to evaluate the in vitro release of

556

insulin.PCL–PEG–PCL copolymer was synthesized under microwave irradiation. Copolymer

557

was characterized by 1HNMR, DSC, SEM, XRPD, and swelling ratio measurement. At the

558

end of study, ANS was utilized to determine the stability of insulin configuration.

559

The synthesis of copolymer via microwave irradiation was very fast and efficient. The

560

formation of supramolecular assembly hydrogel was confirmed by the results of 1HNMR,

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18 Page 18 of 37

DSC, SEM, XRPD and swelling ratio measurement. The in vitro release rate of insulin was

562

measured by Bradford method. This system released approximately 95% of insulin during 37

563

days. Drug release profile was rise in the first twenty days and approximately 80% of insulin

564

released in this period. Then, drug release rate decreased and approximately 15% of insulin

565

released in the last 17 days. The result of insulin stability test indicated that the structural

566

stability of insulin has been preserved. The simple method of preparing and administering,

567

constant and slow drug release rate and Maintaining the structural stability of insulin, make

568

this supramolecular hydrogel as a suitable injectable sustain release system for peptide and

569

protein drugs[63].

570

Meloxicam is a non-steroidal anti-inflammatory drug used in the treatment of rheumatoid

571

arthritis, osteoarthritis and other inflammatory diseases. However, its prolonged use is

572

associated to several side effects like gastrointestinal perforations, ulcerations and bleeding,

573

probably due its low aqueous solubility and wettability after oral administration. These side

574

effects can reduce patient compliance and discourage physician from prescribing this drug. In

575

this way, inclusion complexes between meloxicam and methyl-β-cyclodextrin were prepared

576

in aqueous solution by phase solubility studies and in solid state by freeze-drying method in

577

order to increase drug solubility. The physicochemical characterization of the prepared

578

complexes in solid state was performed by different techniques. Furthermore, hydrogels

579

containing poloxamers were prepared for topical administration of meloxicam. For this

580

purpose, solid inclusion complexes were incorporated in hydrogels with different poloxamers

581

composition. The rheological behaviour of these formulations was studied by different

582

methods and the drug release from optimised hydrogels was evaluated by Franz diffusion

583

cells, applying some mathematical models to analyse the drug release mechanism from

584

hydrogels. Results from phase solubility studies showed the formation of inclusion

585

complexes between meloxicam and methyl-beta-cyclodextrin in aqueous solution in a 1:1

586

stoichiometry and an increase in drug solubility. Different techniques employed indicated

587

complete formation of complexes in solid state prepared by the freeze-drying method.

588

Moreover, the performed set of rheological studies, easily adapted to similar systems,

589

demonstrated that hydrogels containing poloxamers and cyclodextrin may provide a suitable

590

supramolecular platform for meloxicam delivery as a novel strategy to increase drug

591

bioavailability[64].

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592 593 19 Page 19 of 37

594 595 596

Conclusions

598

Hydrogels (hydrophilic three‐dimensional cross‐linked polymer networks which contain a

599

large amount of water) are highly permeable to various drugs and the entrapped molecules

600

can be released through their web like structures. As compared to conventional

601

administration vehicles, drugs can prolong their duration time through the hydrogel drug

602

delivery system (DDS). Mechanical properties, as well as the swelling and shrinking

603

behaviour of the hydrogel, change in response to physical or chemical stimuli, such as

604

temperature, pH, ionic strength, solvent composition and electric fields. Hence, the hydrogels

605

behave as intelligent materials in drug delivery.

608 609 610 611 612

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607

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613 614 615 616 20 Page 20 of 37

617 618 619

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792

d

791

799 800 801 802 26 Page 26 of 37

803 804 805

1. Biomedical applications of Supramolecular hydrogels.

808

2. The uses of supramolecular hydrogels as intrarenal drug delivery systems

809

3. Novel injectable systems based on supramolecular hydrogels

810

4. Bioactive systems based on Chitosan supramolecular hydrogels

811

5. Supramolecular hydrogels based on Cyclodextrin

812

6. Supramolecular hydrogels based on nonsteroidal anti-inflammatory drugs.

813

7. Site-specific gel-delivery system of coenzyme Q10

814

8. Novel bioelectrocatalytic hydrogel based on protein building blocks

815

9. Temperature‐sensitive poly(Nisopropylacrylamide) hydrogels

816

10. Hydrogel nanocomposites

817

11. Carbon nanotube hydrogels

818

12. Novel supramolecular hydrogels based on cyclodextrin and copolymers

820 821 822 823 824 825 826 827

cr

us

an

M

d

te

Ac ce p

819

ip t

806 807

13. Supramolecular hydrogels based on Ag(I)-glutathione (GSH) coordination polymers 14. Polyzwitterionic-containing hydrogel materials 15. Polyacrylamide hydrogels

16. Injectable and biodegradable supramolecular hydrogels 17. Supramolecular hydrogels based on cyclodextrins and amphiphilic methoxy (polyethylene glycol) 18. Supramolecular hydrogels based on Tripeptide derivatives to conjugate with olsalazine 19. pH dependant supramolecular hydrogelators

828 27 Page 27 of 37

d

M

an

us

cr

ip t

Figure(s)

Ac ce p

te

Fig. 1- Classification of gels.

Page 28 of 37

ip t cr us an M d te

Ac ce p

Fig. 2- SEM of an aqueous of a cationic bile acid derivative.

Page 29 of 37

ip t cr us an M d

Ac ce p

te

Fig. 3- The supramolecular hydrogelators made of nonsteroidal anti-inflammatory drugs (NSAID)

Page 30 of 37

ip t cr us an M

Ac ce p

te

d

Fig. 4 Chemical Structure of CoQ10

Page 31 of 37

ip t cr us an M d te Ac ce p

Fig. 5 Protein Constructs with partial sequences and the osmium redox sedes used in this study.

Page 32 of 37

ip t cr us an M Ac ce p

te

d

Fig. 6 Chemical structure of aminophyline (A) and triamterene (B).

Page 33 of 37

ip t cr us an M d te Ac ce p

Fig.7- Synthesis of PEO-PHB-PEO triblock copolymer.

Page 34 of 37

ip t cr us an

Ac ce p

te

d

M

Fig. 8- Synthesis of poly(ethylene glycol) monomethyl ether- graft-[disulfide-linked poly(amido amine)].

Page 35 of 37

ip t cr us an M d te Ac ce p

Fig. 9- Formation of a supramolecular hydrogel of -CD and high- molecular-weight PEO.

Page 36 of 37

ip t cr us an M d

Ac ce p

te

Fig. 10- Illustration of drug release from olsalazine-containing supramolecular hydrogels upon.

Page 37 of 37