3D nanocomposite alginate hydrogel loaded with pitavastatin nanovesicles as a functional wound dressing with controlled drug release; preparation, in-vitro and in-vivo evaluation

Carboxymethyl cellulose-based nanocomposite hydrogel was produced through in-situ free-radical copolymerization for use in drug delivery study. The pure hydrogel and their nanocomposite structure were systematically identified by XRD, FTIR, SEM, TEM, TGA-DTA techniques. The swelling and deswelling properties, which are affected by several factors such as pH (due to the carboxylate groups) and time were studied. The swelling rate improved with the SiO2 nanoparticles. Also, the swelling ratio in NaCl, CaCl2 and AlCl3 salt solutions were investigated and it was found that swelling capacity was 41 and 37 g/g for pure and nanocomposite hydrogel in NaCl solution, respectively. Diclofenac sodium was utilized as a model of drug and the drug release after loaded in the nanocomposite hydrogels was studied. The results revealed essential performances on the subject of physiological-simulated pH media. The maximum cumulative drug releases attained were 90.13% and 79.26% at pH values of 7.4 for nanocomposite and pure hydrogel, respectively. The applicability of drug release kinetic models such as Ritger–Peppas, zero and first-order kinetic models was proved. According to the information obtained from Ritger–Peppas model, the drug release mechanism follows non-Fickian diffusion and indicates an anomalous transport.

Hyaluronic acid (HA) is made up of repeating disaccharide units (β-1,4-d-glucuronic acid and β-1,3-N-acetyl-d-glucosamine) and is a major constituent of the extracellular matrix. HA and its derivatives which possess excellent biocompatibility and physiochemical properties have been studied in drug delivery and tissue engineering applications. Tyramine-based HA hydrogel with good compatibility to cell and tissue has been reported recently. However, inferior mechanical property may limit the biomedical application of the HA hydrogel. In this study, HA/graphene oxide (GO) nanocomposite (NC) hydrogel was prepared through a horseradish peroxidase catalyzed in situ cross-linking process. As compared with pure HA hydrogels, incorporation of GO to the HA matrix could significantly enhance the mechanical properties (storage moduli 1800 Pa) of the hydrogel and prolong the release of rhodamine B (RB) as the model drug from the hydrogel (33 h) as well. In addition, due to the multiple interactions between GO and RB, the NC hydrogels showed excellent pH-responsive release behavior. The release of RB from the NC hydrogel was prolonged at low pH (pH 4.0) in the presence of GO, which could be attributed to the enhanced interactions between GO and HA as well as with RB. In situ three-dimensional encapsulation of mouse embryonic fibroblasts (BALB 3T3 cells) in the NC hydrogels and cytotoxicity results indicated the cytocompatibility of both the enzymatic cross-linking process and HA/GO NC hydrogels (cell viability 90.6 ± 4.25%). The enzymatically catalyzed fabrication of NC hydrogels proved to be an easy and mild approach, and had great potential in the construction of both tissue engineering scaffolds and stimuli-responsive drug release matrices.

Nanocomposite hydrogel biomaterials represent an exciting Frontier in biomedicine, offering solutions to longstanding challenges. These hydrogels are derived from various biopolymers, including fibrin, silk fibroin, collagen, keratin, gelatin, chitosan, hyaluronic acid, alginate, carrageenan, and cellulose. While these biopolymers possess inherent biocompatibility and renewability, they often suffer from poor mechanical properties and rapid degradation. Researchers have integrated biopolymers such as cellulose, starch, and chitosan into hydrogel matrices to overcome these limitations, resulting in nanocomposite hydrogels. These innovative materials exhibit enhanced mechanical strength, improved biocompatibility, and the ability to finely tune drug release profiles. The marriage of nanotechnology and hydrogel chemistry empowers precise control over these materials' physical and chemical properties, making them ideal for tissue engineering, drug delivery, wound healing, and biosensing applications. Recent advancements in the design, fabrication, and characterization of biopolymer-based nanocomposite hydrogels have showcased their potential to transform biomedicine. Researchers are employing strategic approaches for integrating biopolymer nanoparticles, exploring how nanoparticle properties impact hydrogel performance, and utilizing various characterization techniques to evaluate structure and functionality. Moreover, the diverse biomedical applications of these nanocomposite hydrogels hold promise for improving patient outcomes and addressing unmet clinical needs.

Event Abstract Back to Event Synthesis of a novel clay-based nanocomposite hydrogel with attractive mechanical properties and its potential application in 3D-Printing Xinyun Zhai1, 2*, William Lu1* and Wenguang Liu2* 1 The University of Hong Kong, Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, Hong Kong, SAR China 2 Tianjin University, School of Materials Science and Engineering, China Introduction: In our study a novel nanocomposite hydrogel (NC gel) was successfully prepared by in situ free-radical photo-polymerization of the acrylic acid derivatives – 4-Acryloylmorpholine in the presence of exfoliated clay platelets in aqueous systems with different clay contents. Although N-isopropylacrylamide (NIPAM) and N, N-dimethylacrylamide (DAMAA) have already been used as monomers in the clay-based hydrogel, this was the first time to add this kind of acrylic acid derivative into clay system and hydrogel could form without using an organic cross-linker[1],[2]. The obtained hydrogel not only exhibits dramatic improvements in mechanical properties but also has drug loading and release behaviors. Materials and Methods: 4-Acryloylmorpholine (monomer) and 2-Hydroxy-2-methylpropiophenone (1173, initiator) were purchased from Sigma-Aldrich. Synthetic hectorite clay of sol-forming grade LAPONITE XLS (Rockwood Ltd., 92.32 wt % of Mg5.34Li0.66Si8O20(OH)4Na0.66 and 7.68 wt % of Na4P2O7) was used directly. The 4-Acryloylmorpholine/clay nanocomposite hydrogels were synthesized by in situ free-radical photo-polymerization of 4-Acryloylmorpholine in the presence of exfoliated clay. Firstly, clay was dispersed in water under ultrasonication for 1 h. Secondly, 4-Acryloylmorpholine and 1173 were added to the clay suspension. After the solution was mixed well, it was transferred into plastic tubes with about 2 mm inner diameter. Photo-polymerization was carried out for 50 min in a crosslink oven (XL-1000 UV Crosslinker, Spectronics Corporation, NY, USA). The clay content was varied from 1 to 10 wt % with respect to the 4-Acryloylmorpholine weight and the solid content of the nanocomposite hydrogel was varied from 20% to 30%. Tensile tests, compression tests, FTIR, XRD, SEM, TEM, XRD and Raman spectrum were used in our experiment. Results and Discussion: Mechanical tests show that the obtained 4-Acryloylmorpholine clay-based hydrogel has the best tensile strength (about 400 kPa) and excellent stretch ability (higher than 5000%) when clay content and solid content are 5% and 20% respectively. The compression strength of the hydrogel is higher than 8 MPa and can recover to its original shape when compression ratio is less than 80% which will be very attractive for tissue engineering. It is very different from the original physically cross-linked nanocomposite hydrogels that the resulting hydrogel can still stretch up to 2000% in the swollen state. Unlike conventional physically cross-linked hydrogels, this kind of clay-based hydrogel is insoluble in PBS or hot water even the temperature is 80~90 ℃ due to the high hydrogen bonds exist between 4-Acryloylmorpholine polymer and clay which has been confirmed by Raman spectroscopy. Both the XRD and TEM results demonstrate the uniform dispersion of clay in the nanocomposite hydrogel and the formation of the clay-based hydrogel. Furthermore, by using 4-Acryloylmorpholine as the monomer, the hydrogel has drug loading and release behaviors, as the weight ratio of 4-Acryloylmorpholine increases, higher drug release can be observed. Conclusion: Nanocomposite hydrogels composed of 4-Acryloylmorpholine and Laponite XLG clay showed attractive fracture strain up to 5000% and good compression strength (higher than 8 MPa). This kind of hydrogel was synthesized by in situ photo-polymerization of 4-Acryloylmorpholine with the presence of exfoliated Laponite XLG clay. The strong hydrogen bonds between 4-Acryloylmorpholine polymer and clay are suggested to account for the good mechanical properties of the hydrogel. More interestingly, the obtained hydrogel has good biocompatibility and high viscosity before photo-polymerization, which means this kind of hydrogel is a very suitable bioink candidate of the layer-by-layer bioprinting method for the fabrication of stratified tissues[3].

In the present work, a nanocomposite hydrogel is designed consisting of gum acacia, poly(acrylamide) and carbon nitride by facile microwave approach. This nanocomposite hydrogel is sensitive to environmental stimuli which is essential for its application in environmental remediation and as a drug delivery system. The effects of carbon nitride percentage and microwave Watt variation on swelling capacity of gum acacia‐cl‐poly(acrylamide)@carbon nitride (Ga‐cl‐PAM@C3N4) nanocomposite hydrogel are analyzed. The structural characterizations are considered by numerous techniques such as FTIR (Fourier transform infra‐red spectroscopy), X‐ray diffraction, transmission electron microscopy, scanning electron microscopy, and elemental mapping. Batch experiment is performed for remediation of ciprofloxacin (CIP) drug from water. Various parameters such as effect of ciprofloxacin doses, Ga‐cl‐PAM@C3N4 nanocomposite hydrogel dosage, pH, time and temperature for adsorption of CIP on gum acacia‐cl‐poly(acrylamide)@carbon nitride nanocomposite hydrogel is examined. Maximum adsorption capacity of Ga‐cl‐PAM@C3N4 nanocomposite hydrogel observed is 169.49 mg g−1 at pH 6.4. The drug loading and drug release capacity of Ga‐cl‐PAM@C3N4 nanocomposite hydrogel is investigated for ciprofloxacin. Drug release is monitored in artificial ocular solution (pH 8), saline (pH 5.5), acetate buffer (pH 2.2), and distilled water. Maximum drug release is observed in artificial ocular solution.

Controlled drug release systems present a significant alternative to the conventional drug dosages providing drug release for prolonged time periods. Nanocomposite hydrogels offer an important potential for drug release with enhanced physicochemical properties. In this study, the preparation of carbon nanotube (CNT)-based Polyvinylalcohol-Polyvinylpyrolidone (PVA/PVP) nanocomposite hydrogels namely, CNT-25, CNT-50 and CNT-100 were succedded via the freeze/thawing method with the addition of different amounts of CNT. The nanocomposite hydrogels were characterized by swelling tests, FT-IR, DSC, SEM and BET measurements. It was determined that CNT-50 was the most suitable hydrogel for drug release studies having better morhological properties with homogenous distribution of CNT throughout the polymeric nanocomposite matrix. The release of 5-fluororacil (5-FU) as a model drug was investigated in-vitro. The release of 5-FU from CNT-based PVA/PVP nanocomposite hydrogels was exhibited controlled release for one week at pH 7.4. The amount of released of 5-FU was effectively increased with the addition of CNT into the hydrogel matrix. Korsmeyer-Peppas model was well fitted for determining the release mechanism of 5-FU from CNT-based PVA/PVP nanocomposite hydrogels corresponding the combination of diffusion of the drug and the dissolution of polymer chains.

Several hydrogels-based delivery systems are designed and studied in order to meet the requirements in biomedical fields. Herein, the possibility of carbon dots (CDs)-incorporated hydrogel nanocomposites was investigated for the drug release study. Highly fluorescent CDs synthesized from groundnuts using hydrothermal method were characterized with TEM, FTIR, UV–visible and fluorescence spectroscopy. pH-responsive biodegradable hydrogel nanocomposites were synthesized using agarose polymer and agarose–poly(vinyl alcohol) copolymer with the successful integration of CDs. CDs improved the swelling as well as the biodegradation properties of the prepared hydrogel nanocomposites. Structural changes of prepared hydrogel nanocomposites have been characterized using FTIR, SEM and TGA analysis. Hydrogel nanocomposites showed highly porous surface as shown by SEM analysis. In this study, norfloxacin (NFX) was used as a model drug to investigate the in vitro release behavior at two different pH (pH 1.2 and pH 7.4). NFX release from hydrogel nanocomposites followed zero-order kinetics, and Korsemeyer–Peppas model confirmed the release of NFX through erosion of hydrogel nanocomposites. Degradation of hydrogel nanocomposites films was checked using hen egg lysozyme enzyme which confirmed the biodegradable nature of prepared hydrogel nanocomposites films. MTT assay confirmed the nontoxic nature of hydrogel nanocomposites films when treated with blood cells (PBMC).

The CMCh-PVA/Ag nanocomposite hydrogels have been introduced a new technique to deliver drugs, which is dependent on pH. They were prepared successfully in situ by forming of Ag nanoparticles within swollen CMCh-PVA hydrogels. The resulting hydrogels were examined by running various experimental procedures such as FT-IR, XRD, EDX, SEM, and TGA. XRD and EDX patterns verified the formation of Ag nanoparticles in the hydrogel networks; moreover, the formation of Ag nanoparticles with size range from 21 to 81 nm within the hydrogel matrix was confirmed by SEM micrographs. It was shown that increased Ag+ concentration led to increased number of Ag nanoparticles. The prepared nanocomposite hydrogels were studied in terms of the swelling behavior at the pH of 2.1 (simulated gastric fluid) and pH 7.4 (simulated intestinal fluid); the results show that the prepared nanocomposite hydrogels outperformed the pure CMCh-PVA hydrogels in terms of swelling capacity. The antibacterial activity of the nanocomposite hydrogels was examined, and mechanisms involved in their synthesis were reported; the results showed an excellent antibacterial behavior of the nanocomposite hydrogel. To study the efficiency of this new category of nanocomposite hydrogels to be used as an in vitro drug release test to controlled drug delivery system. Also, for CMCh-PVA hydrogels-containing Ag nanoparticles sustained and controlled drug releases were observed that increased with increase in Ag nanoparticles content which can lead to prolong the release of the drug. The objective of this study is to prepare a new, improved drug release using pH-sensitive polymers of carboxymethyl chitosan-PVA with the weight ratios of 3:1, 1:1, and 1:3 containing AgNPs. In this study, to synthesize the new CMCh-PVA/Ag nanocomposite hydrogels efficiently, the Ag+ ions were reduced in the CMCh-PVA hydrogel medium in situ. The effect of the concentration of the Ag nanoparticles in gel content measurement, the swelling/deswelling ratio and drug release behavior and antibacterial activity for the Gram-negative E. coli and Gram-positive S. aureus bacteria was considered.

Injectable and biodegradable double-network nanocomposite hydrogel with regulable sol-gel transition process and mechanical properties

Cartilage damage caused by injuries or degenerative diseases remains a major challenge in the field of regenerative medicine. In this study, we developed a composite hydrogel system for the delivery of melatonin and menstrual blood stem cells (MenSCs) to treat a rat model of cartilage defect. The composite delivery system was produced by incorporation of melatonin into the gelatin fibers and dispersing these fibers into calcium alginate hydrogels. Various characterization methods including cell viability assay, microstructure studies, degradation rate measurement, drug release, anti-inflammatory assay, and radical scavenging assay were used to characterize the hydrogel system. MenSCs were encapsulated within the nanocomposite hydrogel and implanted into a rat model of full-thickness cartilage defect. A 1.3 mm diameter drilled in the femoral trochlea and used for the in vivo study. Results showed that the healing potential of nanocomposite hydrogels containing melatonin and MenSCs was significantly higher than polymer-only hydrogels. Our study introduces a novel composite hydrogel system, combining melatonin and MenSCs, demonstrating enhanced cartilage repair efficacy, offering a promising avenue for regenerative medicine.Graphical

Nanocomposite of starch, gelatin and itaconic acid-based biodegradable hydrogel and ZnO/cellulose nanofiber: A pH-sensitive sustained drug delivery vehicle

Release of ciprofloxacin drugs by nano gold embedded cellulose grafted polyacrylamide hybrid nanocomposite hydrogels

The drug delivery approach was developed through effective preparation of nanocomposite hydrogels in situ while CuO nanoparticles were being formed within swollen CMCS/starch hydrogels. Nanocomposite hydrogel have obtained significant attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials by combining the characteristics of a hydrogel system with a nanoparticle. The obtained nanocomposite hydrogels were used as a potential candidate for controlled release of amoxicillin drug. Different experimental techniques, including XRD, EDX, and SEM were applied to study and compare the prepared hydrogels. XRD and EDX analyses confirmed the formation of nanoparticles in the hydrogel matrix, while SEM micrographs showed that CuO nanoparticles ranged from 13.89 to 47.78 nm within the same matrix, respectively. According to the results, increased number of nanoparticles resulted from increased ion concentration. At pH 1.2 and pH 7.4, the nanocomposite hydrogels were investigated in terms of the swelling behavior; in comparison with neat CMCS/starch hydrogel, they showed a pH-sensitive swelling ratio. Prolonged and more controlled drug releases were observed for CuO nanoparticle containing CMCS/starch hydrogel, which increased with the rise in CuO nanoparticle content. The objective of this study is to prepare a new, improved drug release using pH-sensitive polymers of carboxymethyl chitosan/starch with the weight ratios of 3:1, 1:1, and 1:3 containing copper oxide nanoparticles. Through in situ formation of nanoparticles in the CMCS/starch hydrogel matrix, the successful preparation of new CMCS/starch nanocomposite hydrogels was achieved. It was attempted to show how the concentration of the nanoparticles in the nanocomposite hydrogel influences the swelling behavior in buffer solutions and drug release behavior.

Nowadays polymer nanocomposites represent an important stake in scientific research and offer a combination of properties with respect to single components. The present work deals with nanocomposite hydrogels obtained from alginate, a biobased polymer, which is employed as a biocompatible matrix for the encapsulation of silver nanoparticles ( AgNPs ). Alginate nanocomposite hydrogels were obtained through crosslinking with calcium carbonate ( CaCO 3 ) and d ‐glucono‐δ‐lactone ( GDL ) at different AgNP concentrations. The effect of the encapsulation of AgNPs within alginate hydrogels on their porous structure and the AgNP dispersion was evaluated through field‐emission scanning electron microscopy. Oscillatory rheological measurements were carried out in order to determine the alginate/ AgNP ratio suitable for achieving a higher elastic modulus. Finally, nanocomposite alginate hydrogels were found to be effective against Escherichia coli and Pseudomonas aeruginosa bacteria, with inhibition zones ranging between 5 and 7 cm after 24 h of incubation at 37 °C. Therefore, the present work proposes a nanocomposite alginate hydrogel for application as bactericidal materials in the biotechnology and biomedical fields. © 2016 Society of Chemical Industry

Second near-infrared (NIR-II) responsive hydrogels have shown significant potential in biomedical applications due to their excellent remote actuation property and the high tissue penetrations of the NIR-II light. Nevertheless, hydrogels with a single NIR-II light response may not meet the diverse requirements and complex conditions of clinical applications. Here, a novel multi-responsive nanocomposite hydrogel with enhanced suitability for controlled drug release is developed. This nanocomposite hydrogel is constructed by combining alginate dialdehyde (ADA), polyethyleneimine (PEI), poly(N-isopropylacrylamide) (PNIPAM), and phenylboronic acid-modified polyethyleneimine (PBA-PEI) functionalized multi-walled carbon nanotubes (PP-CNT) through the formation of dynamic covalent bonds (i.e., imine bonds and boronate ester bonds), forming ADA/PEI/PNIPAM/PP-CNT (APN/PP-CNT) hydrogel. PNIPAM is incorporated into the hydrogel network to facilitate drug release triggered by its aggregation when subjected to the high temperatures produced by NIR-II light irradiation. The dynamic covalent bonds and CNT in the network provide the APN/PP-CNT nanocomposite hydrogels with responsiveness to multiple stimuli, including pH, hydrogen peroxide, temperature, and NIR-II light. The APN/PP-CNT nanocomposite hydrogel performs effective NIR-II light responsiveness in both in vitro and in vivo drug release, highlighting its potential as a promising drug delivery platform.