Composite Hydrogels for Sustained Release of Therapeutic Agents

The goal of this research is to develop a composite hydrogel system for sustained release of therapeutic agents. The hydrogel composites were prepared by embedding drug‐loaded, biodegradable poly (DL‐lactide‐co‐glycolide) (PLGA) microparticles in semicrystalline hydrogels of polyvinyl alcohol (PVA). The gels were physically cross‐linked by the formation of the crystallites. The presence of the crystallites and the composite nature of the structure were confirmed by using differential scanning calorimetry and ATR‐FTIR spectroscopy. The distribution of microparticles in the hydrogel matrix was evaluated by using confocal laser scanning microscopy with coumarin‐6 as a fluorescence marker. The numbers of particles in the hydrogel matrix increased along the scanning depth, indicating uneven distribution. The release behavior of a model therapeutic agent, hydrocortisone, was evaluated, and the hydrogel composite system provided for better control of release than the microparticles and hydrogels alone. The addition of outer layers of PVA to the original single‐layer composite further reduced the initial burst effect from the microparticles and allowed for a linear release profile for greater than 1 month.     

Xylan hemicellulose improves chitosan hydrogel for bone tissue regeneration

The hemicellulose xylan, which has immunomodulatory effects, has been combined with chitosan to form a composite hydrogel to improve the healing of bone fractures. This thermally responsive and injectable hydrogel, which is liquid at room temperature and gels at physiological temperature, improves the response of animal host tissue compared with similar pure chitosan hydrogels in tissue engineering models. The composite hydrogel was placed in a subcutaneous model where the composite hydrogel is replaced by host tissue within 1 week, much earlier than chitosan hydrogels. A tibia fracture model in mice showed that the composite encourages major remodeling of the fracture callus in less than 4 weeks. A non‐union fracture model in rat femurs was used to demonstrate that the composite hydrogel allows bone regeneration and healing of defects that with no treatment are unhealed after 6 weeks. These results suggest that the xylan/chitosan composite hydrogel is a suitable bone graft substitute able to aid in the repair of large bone defects. Copyright © 2016 John Wiley & Sons, Ltd.     

Multipurpose smart hydrogel systems

This paper represents the review of the last investigations in the field of smart polymeric hydrogels and our contribution to this matter. New hydrogel systems and nanocomposites based on acrylic monomers (acrylamide, acrylonitrile, acrylic acid, N-isopropylacrylamide etc.) with incorporated nanosized colloidal silver, hydroxyapatite and carbon nanotubes with a new set of properties have been obtained and examined. These systems can sharply change their characteristics when minor external physical (electric and magnetic fields, temperature etc.) or chemical (pH, ionic strength) stimuli are applied. Such stimulus-responsive polymeric systems are very promising from the standpoint of different medical applications, especially for the development of intelligent drug delivery systems. On the base of designed hydrogel iontophoretic transdermal therapeutic systems, endoprosthesis for the replacement of bone tissue and hydrogel burns coatings with immobilized mesenchymal cells were obtained and tested.     

A Novel Methacryloyl Chitosan Hydrogel Microneedles Patch with Sustainable Drug Release Property for Effective Treatment of Psoriasis

Psoriasis is a chronic and recurrent skin disease that often requires long-term treatment, and topical transdermal drug delivery can reduce systemic side effects. However, it is still a challenge in efficient transdermal drug delivery for psoriasis treatment due to low penetration efficiency of most drugs and the abnormal skin conditions of psoriasis patients. Here, a safe and effective methacryloyl chitosan hydrogel microneedles (CSMA hMNs) patch is developed and served as a sustained drug release platform for the treatment of psoriasis. By systematically optimizing the CSMA preparation, CSMA hMNs with excellent morphological characteristics and strong mechanical properties (0.7 N needle⁻¹) are prepared with a concentration of only 3% (w/v) CSMA. As a proof-of-concept, methotrexate (MTX) and nicotinamide (NIC) are loaded into CSMA hMNs patch, which can produce a sustained drug release of 80% within 24 h in vitro. In vivo experiments demonstrated that the CSMA hMNs patch can effectively inhibit the skin thickening and spleen enlargement of psoriatic mice and has a good biosafety profile at sufficient therapeutic doses. This study provides a new idea for the preparation of hMN systems using modified CS or other biocompatible materials and offers an effective therapeutic option for psoriasis treatment.     

Viscoelasticity,mechanical properties,and in vivo biocompatibility of injectable polyvinyl alcohol/bioactive glass composite hydrogels as potential bone tissue scaffolds

Abstract

An injectable composite hydrogel composed of polyvinyl alcohol (PVA) and bioactive glass (BG) particles were synthesized by a physical crosslinking approach. The morphology, mechanical properties, and viscoelasticity of the PVA/BG composite hydrogel were characterized. Scanning electronic microscopy (SEM) showed uniform and homogeneous distribution of BG particles throughout the composite hydrogel. The incorporation of 2.5?wt% of BG particles in the composite hydrogel formulations, enhanced the static compressive strength and static elastic modulus by 325% and 150%, respectively. The storage molds (G′) was greater than the loss modules (G′′) at all the frequency range studied, which revealed a self-standing elastic composite hydrogel with a smooth injectability. The PVA/BG composite hydrogel was also implanted subcutaneously in the dorsal region of adult male rats. After 4?weeks of implantation, no inflammatory cells were seen within and around the implant, which indicated that the composite hydrogel was biocompatible. The properties of the synthesized injectable PVA/BG composite hydrogel demonstrate its capability toward bone regeneration.     

Injectable Graphene Oxide/Graphene Composite Supramolecular Hydrogel for Delivery of Anti-Cancer Drugs

Injectable hydrogels have attracted a lot of attention in drug delivery, however, their capacity to deliver water-insoluble or hydrophobic anti-cancer drugs is limited. Here, we developed injectable graphene oxide/graphene composite supramolecular hydrogels to deliver anti-cancer drugs. Pluronic F-127 was used to stabilize graphene oxide (GO) and reduced graphene oxide (RGO) in solution, which was mixed with α-cyclodextrin (α-CD) solution to form hydrogels. Native hydrogel was used as control. GO or RGO slightly shortened gelation time. The storage and loss moduli of the hydrogels were tracked by dynamic force measurement. The storage modulus of GO or RGO composite hydrogels was larger than that of the native hydrogel. Hydrogels were unstable in solution and eroded gradually. GO or RGO in Pluronic F-127 solution could potentially improve the solubility of the water-insoluble anti-cancer drug camptothecin (CPT), especially with large drug-loaded CPT amount. Drug release behaviors from solutions and hydrogels were characterized. The nanocomponents (GO or RGO) were able to bind more drug molecules either for CPT or for doxorubicin hydrochloride (DXR) in solution. Therefore, GO or RGO composite hydrogel could potentially enable better controlled and gentler drug release (for both CPT and DXR) than native hydrogel.     

Membrane-controlled transdermal therapeutic system containing clonazepam and anticonvulsant activity after its application

A trial transdermal dosage form designed to sustain a suitable plasma concentration of clonazepam (CZP) was produced using a porous membrane (Hipore 2100 or 4050) and applied to rabbits and rats for pharmacokinetic and pharmacodynamic evaluations. The release rate constants for the drug through the porous membranes were significantly smaller than that without any membrane. The transdermal system (Hipore 4050 system, ointment 0.25 g, 2.25 cm2) provided a well sustained plasma concentration of CZP and the therapeutic plasma concentration range was maintained for about 26 h. When the Hipore 4050 system with an increased amount of ointment and enlarged absorption area (0.5 g, 4.0 cm2) was applied, the therapeutic range was sustained for about 40 h, and slightly higher plasma levels over the whole application period and much higher bioavailability (37%) were obtained compared with those after the 2.25 cm2-Hipore 4050 system. The transdermal system exerted an excellent anticonvulsant activity in rats, with the best (3+ or 4+) protective score. The plasma concentrations of CZP when the activity was estimated were in the therapeutic range. Thus, the transdermal system has the potential to be an efficient drug delivery system.     

Influence of hydration and crosslinking in transdermal delivery of nicotine from chitosan-based gels by thermal analysis

Chitosan is a biopolymer that forms hydrogels after swell in acid medium. The environment of the three-dimensional network of the chitosan-based hydrogels can be modified by its degree of swelling and crosslinking. In this way, nicotine was incorporated in the hydrogel formulations, with or without crosslinking with glutaraldehyde (0.01%), in different swollen states. Transdermal delivery of nicotine by chitosan-based hydrogels was studied in order to achieve the prolonged administration of the drug. Thermal analysis indicated a preliminary stability of these formulations, and the mechanism of drug release from hydrogels was dependent of the swelling degree and crosslinking. These formulations were able to control the transdermal flux of nicotine for up to 48 h following zero-order kinetics. The hydrogels with higher amounts of water or the partially dried crosslinked hydrogels reduced the partition of nicotine into the skin, leading to a minor transdermal flux of the drug (<3.4 µg cm⁻² h⁻¹). On the other hand, the partially dried non-crosslinked hydrogels lead to a major transdermal flux of the drug (20.19 µg cm⁻² h⁻¹) due to modifications of the environment into the hydrogel. In this way, these transdermal formulations were promising vehicles for prolonged administration of nicotine.

     

肝素钠/聚乙烯醇复合水凝胶的制备与性能

通过循环冷冻-解冻法,制成了肝素钠/聚乙烯醇(HS/PVA)复合水凝胶材料。 探讨了不同质量分数肝素钠对复合水凝胶材料的可见光透过率、含水率、亲水性、力学性能以及肝素钠释放量的影响。 结果表明,复合水凝胶的可见光透过率为92%以上,溶胀平衡的含水率为72%~78%,亲水性较纯PVA水凝胶有所提升,拉伸强度和断裂伸长率都稍有下降。 细胞粘附实验结果表明,适量的肝素钠的释放可以达到减少细胞粘附的效果。 这种HS/PVA复合水凝胶材料有望用作人工角膜中心区材料。     

In vitro drug release from silicone rubber–polyacrylamide composite

Composite materials containing drugs were prepared from silicone rubber and hydrogel. Cross linked polyacrylamide (PAAm) hydrogel particles were incorporated into a silicone rubber to enhance the hydrophilicity and drug release capacity of silicone rubber as a matrix. Progesterone and Thymol Blue were used as a hydrophobic and hydrophilic drug model, respectively. Different amounts of polyacrylamide (PAAm) were mixed with the drugs and uncured silicone rubber at room temperature. The composite matrices were formed using a compression molding press and cured by thermal and γ-irradiation curing methods. In vitro drug release behavior of composites and their physical and mechanical properties were investigated. The results indicated that the hydrophilic character of silicone rubber was more pronounced with increasing the amount of PAAm. Also, a significant effect on the drug release profiles was observed. The γ-irradiation curing method improved mechanical properties of composites and affected the drug release profiles. It was found that the amounts of released progesterone from γ-irradiated samples increased in comparison with the thermally cross linked composite since released Thymol Blue was reduced.     

Electroaddressing agarose using Fmoc-phenylalanine as a temporary scaffold

Electroaddressing, the use of imposed electrical stimuli to guide assembly, is attractive because electrical stimuli can be conveniently applied with high spatial and temporal resolution. Several electroaddressing mechanisms have been reported in which electrode-induced pH gradients trigger stimuli-responsive materials to undergo localized sol-gel transitions to form hydrogel matrices. A common feature of existing hydrogel electrodeposition mechanisms is that the deposited matrix retains residual charged, acidic, or basic (macro)molecules. Here, we report that pH-responsive fluorenyl-9-methoxycarbonyl-phenylalanine (Fmoc-Phe) can be used to codeposit the neutral and thermally responsive polysaccharide agarose. Upon cooling, an agarose network is generated and Fmoc-Phe can be removed. The Fmoc-Phe-mediated codeposition of agarose is simple, rapid, spatially selective, and allows for the electroaddressing of a bioactive matrix.     

Bio-electrosprayed living composite matrix implanted into mouse models

We show that composite de novo structures can be generated using bio-electrosprays. Mouse lung fibroblasts are bio-electrosprayed directly with a biopolymer to form cell-bearing matrices, which are viable even when implanted subcutaneously into murine hosts. Generated cell-bearing matrices are assessed in-vitro and found to undergo all expected cellular behaviour. Subsequent in-vivo studies demonstrate the implanted living matrices integrating as expected with the surrounding microenvironment. The in-vitro and in-vivo studies elucidate and validate the ability for either bio-electrosprays or cell electrospinning to form a desired living architecture for undergoing investigation for repairing, replacing and rejuvenating damaged and/or ageing tissues.     

Polyluminol/hydrogel composites as new electrochemiluminescent-active sensing layers

This paper reports on electrochemiluminescent sensors and biosensors based on polyluminol/hydrogel composite sensing layers using chemical or biological membranes as hydrogel matrices. In this work, luminol is electropolymerized under near-neutral conditions onto screen-printed electrode (SPE)-supported hydrogel films. The working electrode coated with a hydrogel film is soaked in a solution containing monomeric luminol units, allowing the monomeric luminol units to diffuse inside the porous matrix to the electrode surface where they are electropolymerized by cyclic voltammetry (CV). Sensors and enzymatic biosensors for H₂O₂ and choline detection, respectively, have been developed, using choline oxidase (ChOD) as a model enzyme. In this case, hydrogel is used both as the enzymatic immobilization matrix and as a template for the electrosynthesis of polyluminol. The enzyme was immobilized by entrapment in the gel matrix during its formation before electropolymerization of the monomer. Several parameters have been optimized in terms of polymerization conditions, enzyme loading, and average pore size. Using calcium alginate or tetramethoxysilane (TMOS)-based silica as porous matrix, H₂O₂ and choline detection are reported down to micromolar concentrations with three orders of magnitude wide dynamic ranges starting from 4?×?10^?7 M. Polyluminol/hydrogel composites appear as suitable electrochemiluminescence (ECL)-active sensing layers for the design of new reagentless and disposable easy-to-use optical sensors and biosensors, using conventional TMOS-based silica gel or the more original and easier to handle calcium alginate, reported here for the first time in such a configuration, as the biocompatible hydrogel matrix. Figure

Elaboration of electrochemiluminent polyluminol/hydrogel composite sensing layers     

New composite membranes based on crosslinked poly(acrylic acid) and porous polyethylene films

A process for the preparation of new composite membranes via free-radical copolymerization of acrylic acid with a macromolecular crosslinker (allyloxyethylcellulose) on the surface of porous polyethylene films was proposed. To reveal the effect of the porous matrix on the properties of the composites, homogeneous hydrogel membranes based on crosslinked poly(acrylic acid) were studied. The swelling ratio and transport characteristics of the membranes during separation of ethanol-water mixture by pervaporation were determined depending on the ethanol concentration. It was found that all membranes at low ethanol concentrations (0–30 vol %) exhibited high swelling ratios, which drastically decreased in the range 30–40 vol % as a result of gel collapse. The composite membranes had a higher selectivity for water over a broad range of ethanol concentrations than homogeneous membranes, but a lower flux. It was found that the strength and elasticity of porous matrices was retained in the composite membranes, which became mechanically more isotropic owing to the presence of the crosslinked component.     

Swelling Kinetics of Microgels Embedded in a Polyacrylamide Hydrogel Matrix

Composite hydrogels—macroscopic hydrogels with embedded microgel particles—are expected to respond to external stimuli quickly because microgels swell much faster than bulky gels. In this work, the kinetics of the pH‐induced swelling of a composite hydrogel are studied using turbidity measurements. The embedded microgel is a pH‐ and thermosensitive poly(N‐isopropylacrylamide‐co‐acrylic acid) microgel and the hydrogel matrix is polyacrylamide. A rapid pH‐induced swelling of the embedded microgel particles is observed, confirming that composite hydrogels respond faster than ordinary hydrogels. However, compared with the free microgels, the swelling of the embedded microgel is much slower. Diffusion of OH^? into the composite hydrogel film is identified as the main reason for the slow swelling of the embedded microgel particles, as the time of the pH‐induced swelling of this film is comparable to that of OH^? diffusion into the film. The composition of the hydrogel matrix does not significantly change the characteristic swelling time of the composite hydrogel film. However, the swelling pattern of the film changes with composition of the hydrogel matrix.     

聚乙烯醇/聚乙烯吡咯烷酮/碘复合水凝胶的制备与性能

采用低温冷冻的方法, 通过改变聚乙烯醇(PVA)和聚乙烯吡咯烷酮碘络合物(PVP-I)的配比、 冷冻时间、 冷冻-解冻循环次数, 制备出一种可调控力学性能的PVA/PVP-I复合水凝胶. 研究了该复合水凝胶的机械 性能、 微观结构、 碘缓释性能和抑菌性质. 研究结果表明, PVA/PVP-I复合水凝胶可调控的力学性质可以满足伤口敷料对水凝胶力学性质的需求; 复合水凝胶的网络结构可以有效降低碘在紫外线下的分解速度, 实现对碘的稳定保护作用及控制释放, 从而发挥水凝胶持续抑菌性能, 为抑菌水凝胶的设计制备提供了新思路.     

An injectable mPEG-PDLLA microsphere/PDLLA-PEG-PDLLA hydrogel composite for soft tissue augmentation

Injectable filling material is a simple and efficient method for soft tissues reconstruction and is extremely popular in not only plastic surgery but also cosmetic industry. However, there is a lack of soft tissue fillers with perfect performance on the market currently. Here, we constructed a new microsphere/hydrogel composite and evaluated its potential as a candidate for soft tissue augmentation. mPEG-PDLLA microspheres were prepared by utilizing a SPG membrane emulsifier which endowed micros...     

Preparation of Biocompatible Graphene Oxide Composite Hydrogel to Deliver Ophthalmic Drugs

Considering that conventional hydrogels showed limited capabilities of controlling hydrophobic drug loading and releasing and graphene materials had interactions with hydrophobic drugs, we designed a graphene oxide (GO) composite hydrogel for drug delivery. But GO could not disperse well in monomer solution and agglomerated badly. Thus, water-soluble GO (GO-tripolymer) was first prepared under the stabilization of amphiphilic polymer, Pluronic F-127. The GO-tripolymer showed good solubility in PBS with the increase of polymer concentration. All GO-tripolymer solutions had the same UV absorption peaks as GO. Then, GO composite hydrogels (HNG hydrogels) were formed by the polymerization of hydroxyethyl methacrylate (HEMA), N-Vinyl pyrrolidone (NVP) and GO-tripolymer mixture. The introduction of GO-tripolymer had little effect on the gelation time and equilibrium swelling ratio of hydrogel. The freeze-drying hydrogel showed porous structure. The pore size decreased and the rough surface was detected with the increase of GO concentration. HNG hydrogel could load more puerarin and norfloxacin than conventional hydrogel (HN hydrogel). Moreover, HNG hydrogel could control puerarin and norfloxacin release more steadily than HN hydrogel. HNG exhibited low cytotoxicity.     

In-situ Synthesis and Characterization of Poly(vinyl alcohol)/Hydroxyapatite Composite Hydrogel by Freezing-thawing Method

Poly(vinyl alcohol)/hydroxyapatite(PVA/HA) composite hydrogel was successfully in-situ synthesized via three cycles of freezing-thawing. The composition and structure of products were investigated by X-ray diffraction( XRD), Fourier transformed infrared spectroscopy(FTIR) and scanning electron microscopy(SEM). The influence of different preparation methods and contents of material on the mechanical properties of PVA/HA composite hydrogel was discussed through tensile and compressive tests. The template of PVA could avoid the agglomeration of HA particles, which improves the mechanical properties of the composite hydrogel effectively. The tensile strength, modulus and compressive performances of the PVA/HA composite hydrogel prepared by the in-situ synthesis method were better than those of hydrogel obtained by the simple blend metliod. In addition, the effect of the content of PVA, HA, and the pH value on tlie properties of tlie PVA/HA composite hydrogel has been discussed in detail.     

丝素蛋白纤维/聚N-异丙基丙烯酰胺复合水凝胶的性能

以丝素蛋白纤维为填充材料,采用自由基聚合的方法制备复合聚N-异丙基丙烯酰胺(PNIPPAm)水凝胶,研究复合水凝胶的黏弹性能、溶胀性能和反复溶胀-收缩性能。结果表明:丝素蛋白纤维的加入改善了复合水凝胶的力学性能,其平衡溶胀率不仅与温度有关,而且与丝素蛋白纤维的含量有关。此外,处在表面的丝素蛋白纤维与水凝胶之间存在间隙,在反复溶胀-收缩过程中可以作为输水通道,有利于水分子进出,提高了PNIPPAm水凝胶对温度的响应速率并使其溶胀-收缩重复性更好。