Self-assembled dextrin nanogel as protein carrier: controlled release and biological activity of IL-10

Interleukin-10 (IL-10) is an anti-inflammatory cytokine, which active form is a non-covalent homodimer. Given the potential of IL-10 for application in various medical conditions, it is essential to develop systems for its effective delivery. In previous work, it has been shown that a dextrin nanogel effectively incorporated and stabilized rIL-10, enabling its release over time. In this work, the delivery system based on dextrin nanogels was further analyzed. The biocompatibility of the nanogel was comprehensively analyzed, through cytotoxicity (lactate dehydrogenase (LDH) release, MTS, Live, and Dead) and genotoxicity (comet) assays. The release profile of rIL-10 and its biological activity were evaluated in vivo, using C57BL/6 mice. Although able to maintain a stable concentration of IL-10 for at least 4 h in mice serum, the amount of protein released was rather low. Despite this, the amount of rIL-10 released from the complex was biologically active inhibiting TNF-α production, in vivo, by LPS-challenged mice. In spite of the significant stabilization achieved using the nanogel, rIL-10 still denatures rather quickly. An additional effort is thus necessary to develop an effective delivery system for this cytokine, able to release active protein over longer periods of time. Nevertheless, the good biocompatibility, the protein stabilization effect and the ability to perform as a carrier with controlled release suggest that self-assembled dextrin nanogels may be useful protein delivery systems.     

Controlling degradation of low-molecular-weight natural polymer "dextrin" using gamma irradiation

Dextrin, which is widely used throughout many industries for their functional properties, was selected for studying the influences of gamma irradiation on its viscosity, physicochemical properties and dextrin granule structure. The formation of radicals during irradiation process of dextrin in air condition was investigated by electron spin resonance (ESR) showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals. Two major radicals or groups of radicals are observed. The radicals show g-values varying among g=2.0102+/-0.0002 and g=2.0126+/-0.0006. Irradiation was observed to induce increases in the intensity of single. The material left behind after irradiation treatment was characterized using thermal analysis, TGA and DSC. A structural analysis was made using SEM and X-ray diffraction to investigate whether the partial hydrolysis had any influence on the granular structure and the crystallinity of the dextrin. The results show that dextrin undergoes oxidative degradation under the influence of gamma radiation.     

In situ cross-linkable novel alginate-dextran methacrylate IPN hydrogels for biomedical applications: mechanical characterization and drug delivery properties

In situ polymerizable hydrogels are extensively investigated to implement new biomedical and pharmaceutical approaches. In the present paper a novel polysaccharidic matrix based on calcium alginate (Ca(II)-Alg) hydrogel and dextran methacrylate derivative (Dex-MA), showing potential applicability in the field of pharmaceutics is described. The semi-interpenetrating polymer system (semi-IPN) obtained by a dispersion of Dex-MA chains into a Ca(II) hydrogel leads to a hydrogel with rheological properties quite different from those of Ca(II)-Alg, allowing to inject the semi-IPN easily through an hypodermic needle. The UV curing of the semi-IPN, by cross-linking of the methacrylate moieties, leads to an IPN strong hydrogel that can be used for a modulated delivery of bioactive molecules. In the present paper, rheological and mechanical behaviors of the semi-IPN and of the IPN are discussed. The release of model molecules, including a protein, are also presented to show the suitability of the novel system as a drug delivery system.     

壳聚糖基温敏水凝胶的研究进展

壳聚糖是一种由甲壳素脱乙酰化得到的氨基多糖,具有生物相容性、低细胞毒性和可生物降解性等特点。壳聚糖/β-甘油磷酸钠溶液温敏水凝胶在组织工程、药物缓释等领域多有报道,其成胶性能取决于凝胶的组分和浓度。针对单纯壳聚糖水凝胶强度较低、降解较快、药物突释等缺陷,通常对壳聚糖进行改性或引入新材料共混,获得更符合实际需要的壳聚糖基温敏水凝胶。对近年来壳聚糖基水凝胶的研究进展进行综述,包括改性壳聚糖、共混体系等,概述了其在组织工程(软骨、血管、神经修复)、药物缓释(癌症药物缓释、糖尿病治疗)领域中研究和应用的新进展,以期为后续温敏水凝胶的进一步研究提供参考。     

Evaluation of Physical and Mechanical Properties of Porous Poly (Ethylene Glycol)-co-(L-Lactic Acid) Hydrogels during Degradation

Porous hydrogels of poly(ethylene glycol) (PEG) have been shown to facilitate vascularized tissue formation. However, PEG hydrogels exhibit limited degradation under physiological conditions which hinders their ultimate applicability for tissue engineering therapies. Introduction of poly(_L-lactic acid) (PLLA) chains into the PEG backbone results in copolymers that exhibit degradation via hydrolysis that can be controlled, in part, by the copolymer conditions. In this study, porous, PEG-PLLA hydrogels were generated by solvent casting/particulate leaching and photopolymerization. The influence of polymer conditions on hydrogel architecture, degradation and mechanical properties was investigated. Autofluorescence exhibited by the hydrogels allowed for three-dimensional, non-destructive monitoring of hydrogel structure under fully swelled conditions. The initial pore size depended on particulate size but not polymer concentration, while degradation time was dependent on polymer concentration. Compressive modulus was a function of polymer concentration and decreased as the hydrogels degraded. Interestingly, pore size did not vary during degradation contrary to what has been observed in other polymer systems. These results provide a technique for generating porous, degradable PEG-PLLA hydrogels and insight into how the degradation, structure, and mechanical properties depend on synthesis conditions.     

Drug loading into and drug release from pH- and temperature-responsive cylindrical hydrogels

Hydrogels that undergo deformation upon appropriate changes in pH or temperature have considerable promise as drug delivery vehicles. Drug uptake in swelling and nonswelling cylindrical hydrogels and drug release from these into a target fluid are investigated here. A mathematical model for hydrogel-solution composite, a composite of a distributed parameter system (cylindrical hydrogel) and a lumped parameter system (surrounding solution), is developed. The polymer network displacement in a swelling/deswelling hydrogel is described by a stress diffusion coupling model. The analytical solution for network displacement is used to predict solvent intake by swelling hydrogels, solvent efflux from deswelling hydrogels, and changes in pressure, porosity, and effective drug diffusivity. These in turn influence drug uptake during and after hydrogel swelling and drug release from hydrogel during and after deswelling. Numerical results illustrate benefits of hydrogel swelling for drug loading and merits of different modes of drug release. Drug uptake and drug release by temperature-responsive hydrogels are compared with those by hydrogels not subject to deformation.     

One-step synthesis of interpenetrating network hydrogels: Environment sensitivities and drug delivery properties

A novel interpenetrating network hydrogel for drug controlled release, composed of modified poly(aspartic acid) (KPAsp) and carboxymethyl chitosan (CMCTS), was prepared in aqueous system. The surface morphology and composition of hydrogels were characterized by SEM and FTIR. The swelling properties of KPAsp, KPAsp/CMCTS semi-IPN and KPAsp/CMCTS IPN hydrogels were investigated and the swelling dynamics of the hydrogels was analyzed based on the Fickian equation. The pH, temperature and salt sensitivities of hydrogels were further studied, and the prepared hydrogels showed extremely sensitive properties to pH, temperature, the ionic salts kinds and concentration. The results of controlled drug release behaviors of the hydrogels revealed that the introduction of IPN observably improved the drug release properties of hydrogels, the release rate of drug from hydrogels can be controlled by the structure of the hydrogels and pH value of the external environment, a relative large amount of drug released was preferred under simulated intestinal fluid. These results illustrated high potential of the KPAsp/CMCTS IPN hydrogels for application as drug carriers.     

Chemically cross-linked chitosan hydrogel loaded with gelatin for chondrocyte encapsulation

Composite hydrogels can be used as a scaffolding material for chondrogenesis, which requires a biomimetic environment to maintain chondrocyte morphology and phenotype. In this study, gelatin molecules were loaded into a hydrogel polymerized from a chitosan derivative (CML) to form a semi-interpenetrating polymer network. While the porous structure of the hydrogels in the dry state was not dependent on the gelatin content, the collapse extent and pore size decreased as the gelatin content increased. The gelatin loading also reduced the swelling ratio of the CML hydrogel and enhanced the hydrogel strength at 20°C due to gelation of the gelatin. The release behavior of the gelatin from the CML hydrogel could be controlled by many factors, such as the amount of gelatin, temperature, and solution pH. The weight loss of the composite hydrogel was expedited after gelatin loading and showed a positive relationship with the gelatin content. The results of in vitro cell culture in the hydrogels revealed that gelatin loading improved cell viability and promoted proliferation and glycosaminoglycans secretion of chondrocytes. This new scaffold production technology for chondrocyte encapsulation provides a further step towards CML applications in tissue engineering and other biomedical areas.     

Novel vaginal drug delivery system: deformable propylene glycol liposomes-in-hydrogel

Deformable propylene glycol-containing liposomes (DPGLs) incorporating metronidazole or clotrimazole were prepared and evaluated as an efficient drug delivery system to improve the treatment of vaginal microbial infections. The liposome formulations were optimized based on sufficient trapping efficiencies for both drugs and membrane elasticity as a prerequisite for successful permeability and therapy. An appropriate viscosity for vaginal administration was achieved by incorporating the liposomes into Carbopol hydrogel. DPGLs were able to penetrate through the hydrogel network more rapidly than conventional liposomes. In vitro studies of drug release from the liposomal hydrogel under conditions simulating human treatment confirmed sustained and diffusion-based drug release. Characterization of the rheological and textural properties of the DPGL-containing liposomal hydrogels demonstrated that the incorporation of DPGLs alone had no significant influence on mechanical properties of hydrogels compared to controls. These results support the great potential of DPGL-in-hydrogel as an efficient delivery system for the controlled and sustained release of antimicrobial drugs in the vagina.     

Synthesis and characterization of modified starch hydrogels for photodynamic treatment of cancer

The objective of the present study was to develop carboxymethyl starch (CMS) and dextran sulfate (DS) hydrogels that are able to efficiently encapsulate 5-,10-,15-,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP), a porphyrin-based PS agent. The study showed that the lifetime of the triplet state for porphyrin PS is significantly increase when encapsulate into hydrogel. In addition to the possible enhancement of (1)O(2) generation, other advantages to incorporating porphyrin-based PS agents into hydrogel include the ability to solubilize these generally hydrophobic agents, the small and uniform size of hydrogels, and potential for passive targeting of solid tumors via the enhanced permeation and retention effect decreasing systemic photosensitization. This novel type of carboxymethyl starch (CMS) hydrogel using dextran sulfate (DS) as a polyanionic polymer was developed to achieve complex coacervation for the incorporation and controlled release of an anti-angiogenesis hexapeptide, this was the first report describing the use of DS to formulate CMS based hydrogels.     

pH响应型蔗渣木质素水凝胶的制备及其对蛋白质的控释性能

该研究以蔗渣木质素和甲基丙烯酸为原料合成了pH敏感型蔗渣木质素/聚甲基丙烯酸水凝胶,对其合成条件、pH敏感性、溶胀-退溶胀性能以及对牛血清蛋白的控释等性质进行研究,并采用红外光谱、扫描电镜等对凝胶进行表征。结果表明:(1)对凝胶溶胀比影响的因素由大到小依次为甲基丙烯酸用量、交联剂用量、催化剂用量、反应的温度、木质素用量。当甲基丙烯酸单体浓度为1.75 mol·L~(-1)、木质素浓度为25 g·L~(-1)、交联剂浓度为3.25×10~(-2)mol·L~(-1)、引发剂浓度为1.25×10~(-2)mol·L~(-1)、反应温度为65℃时,所得水凝胶在模拟肠液中的溶胀比最大(28.16 g·g~(-1))。与不加木质素的聚甲基丙烯酸水凝胶相比,蔗渣木质素/聚甲基丙烯酸水凝胶的溶胀比有所下降,但其敏感pH由4~5碱移至6~8。(2)蔗渣木质素/聚甲基丙烯酸水凝胶的溶胀—退溶胀可逆性受组成的影响较大,但相对于聚甲基丙烯酸水凝胶,蔗渣木质素/聚甲基丙烯酸水凝胶对pH值的敏感响应性更强、响应速率更快,同时能在更短时间内达到溶胀平衡。(3)加入木质素可以提高水凝胶对牛血清蛋白的负载量,所试验的蔗渣木质素/聚甲基丙烯酸水凝胶样品对牛血清蛋白的最大负载量可达577 mg·g~(-1)。(4)牛血清蛋白在12 h后基本可达释放平衡;在模拟胃液中,牛血清蛋白的释放率仅10%,而在模拟肠液中释放率达92%。pH响应型蔗渣木质素/聚甲基丙烯酸水凝胶可以作为口服型蛋白类药物的潜在载体。     

Characterization of photo-cross-linked oligo[poly(ethylene glycol) fumarate] hydrogels for cartilage tissue engineering

Photo-cross-linkable oligo[poly(ethylene glycol) fumarate] (OPF) hydrogels have been developed for use in tissue engineering applications. We demonstrated that compressive modulus of these hydrogels increased with increasing polymer concentration, and hydrogels with different mechanical properties were formed by altering the ratio of cross-linker/polymer in precursor solution. Conversely, swelling of hydrogels decreased with increasing polymer concentration and cross-linker/polymer ratio. These hydrogels are degradable and degradation rates vary with the change in cross-linking level. Chondrocyte attachment was quantified as a method for evaluating adhesion of cells to the hydrogels. These data revealed that cross-linking density affects cell behavior on the hydrogel surfaces. Cell attachment was greater on the samples with increased cross-linking density. Chondrocytes on these samples exhibited spread morphology with distinct actin stress fibers, whereas they maintained their rounded morphology on the samples with lower cross-linking density. Moreover, chondrocytes were photoencapsulated within various hydrogel networks. Our results revealed that cells encapsulated within 2-mm thick OPF hydrogel disks remained viable throughout the 3-week culture period, with no difference in viability across the thickness of hydrogels. Photoencapsulated chondrocytes expressed the mRNA of type II collagen and produced cartilaginous matrix within the hydrogel constructs after three weeks. These findings suggest that photo-cross-linkable OPF hydrogels may be useful for cartilage tissue engineering and cell delivery applications.     

Porphyrin-cross-linked hydrogel for fluorescence-guided monitoring and surgical resection

We demonstrate that porphyrins can be used as efficient cross-linkers to generate a new class of hydrogels with enabling optical properties. Tetracarboxylic acid porphyrins reacted with PEG diamines to form a condensation polyamide in a range of appropriate conditions, with respect to reaction time, diisopropylethylamine initiator concentration, porphyrin-to-PEG ratio, porphyrin concentration, and PEG size. The network structure of the hydrogel maintained a porphyrin spacing that prevented excessive fluorescence self-quenching despite high porphyrin density. The near-infrared properties readily enabled low background, noninvasive fluorescence monitoring of the implanted hydrogel in vivo, as well as its image-guided surgical removal in real time using a low-cost fluorescence camera prototype. Emission could be tuned by incorporating copper metalloporphyrins into the network. The approach of creating hydrogels using cross-linking porphyrin comonomers creates opportunities for new polymer designs with strong optical character.     

Hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds as a cell delivery vehicle: Characterization of PC12 cell response

The central nervous system (CNS) has a low intrinsic potential for regeneration following injury and disease, yet neural stem/progenitor cell (NPC) transplants show promise to provide a dynamic therapeutic in this complex tissue environment. Moreover, biomaterial scaffolds may improve the success of NPC‐based therapeutics by promoting cell viability and guiding cell response. We hypothesized that a hydrogel scaffold could provide a temporary neurogenic environment that supports cell survival during encapsulation, and degrades completely in a temporally controlled manner to allow progression of dynamic cellular processes such as neurite extension. We utilized PC12 cells as a model cell line with an inducible neuronal phenotype to define key properties of hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds that impact cell viability and differentiation following release from the degraded hydrogel. Adhesive peptide ligands (RGDS, IKVAV, or YIGSR), were required to maintain cell viability during encapsulation; as compared to YIGSR, the RGDS, and IKVAV ligands were associated with a higher percentage of PC12 cells that differentiated to the neuronal phenotype following release from the hydrogel. Moreover, among the hydrogel properties examined (e.g., ligand type, concentration), total polymer density within the hydrogel had the most prominent effect on cell viability, with densities above 15% w/v leading to decreased cell viability likely due to a higher shear modulus. Thus, by identifying key properties of degradable hydrogels that affect cell viability and differentiation following release from the hydrogel, we lay the foundation for application of this system towards future applications of the scaffold as a neural cell delivery vehicle. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1255–1264, 2013     

Synthesis and properties of thermo- and pH-sensitive poly(N-isopropylacrylamide)/polyaspartic acid IPN hydrogels

Various interpenetrating polymer network (IPN) hydrogels with sensitivity to temperature and pH were prepared by introducing the pH-sensitive polymer polyaspartic acid (PASP) hydrogel, into the poly(N-isopropylacrylamide) (PNIPAAm) hydrogel system for the purpose of improving its response rate to temperature. The morphologies and thermal behavior of the prepared IPN hydrogels were studied by both scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The IPN hydrogels showed a large and uneven porous network structure, without showing the common PNIPAAm hydrogel structure. The paper moreover studied their swelling properties, such as temperature dependence of equilibrium swelling ratio, shrinking kinetics, re-swelling kinetics and oscillatory swelling behavior in water. The swelling experiment results revealed that IPN hydrogels exhibited much faster shrinking and re-swelling in function of the composition ratio of the two network components. These fast responsive hydrogels foster potential applications in biomedical and biotechnology fields.     

Superabsorbent conducting hydrogel from poly(acrylamide-aniline) with thermo-sensitivity and release properties

Interpenetrating networks (IPN) poly(acrylamide-aniline) polymer was synthesized by a two-steps aqueous polymerization method, which aniline monomer was absorbed in the network of polyacrylamide and followed by a polymerization reaction between aniline monomers. The poly(acrylamide-aniline) hydrogel possessed a conductivity of 25.28 mS cm⁻¹. An interpenetrating network structure model with a three-dimensional network of polyacrylamide and a one-dimensional chain of polyaniline for poly(acrylamide-aniline) conducting hydrogel was proposed, and a conduction mechanism with charge carriers (protons) hopping along the polyaniline chain was suggested. The poly(acrylamide-aniline) hydrogels have predominant thermo-sensitivity. Poly(acrylamide-aniline) hydrogels possess loading and releasing properties, an anomalous release mechanism is found.     

Polysaccharide-poly(ethylene glycol) star copolymer as a scaffold for the production of bioactive hydrogels

The production of polysaccharide-derivatized surfaces, polymers, and biomaterials has been shown to be a useful strategy for mediating the biological properties of materials, owing to the importance of polysaccharides for the sequestration and protection of bioactive proteins in vivo. We have therefore sought to combine the benefits of polysaccharide derivatization of polymers with unique opportunities to use these polymers for the production of bioactive, noncovalently assembled hydrogels. Accordingly, we report the synthesis of a heparin-modified poly(ethylene glycol) (PEG) star copolymer that can be used in the assembly of bioactive hydrogel networks via multiple strategies and that is also competent for the delivery of bioactive growth factors. A heparin-decorated polymer, synthesized by the reaction of thiol end-terminated four-arm star PEG (M(n) = 10 000) with maleimide functionalized low molecular weight heparin (LMWH, M(r) = 3000), has been characterized via (1)H NMR spectroscopy and size-exclusion chromatography; results indicate attachment of the LMWH with at least 73% efficiency. Both covalently and noncovalently assembled hydrogels can be produced from the PEG-LMWH conjugate. Viscoelastic noncovalently assembled hydrogels have been formed on the basis of the interaction of the PEG-LMWH with a PEG polymer bearing multiple heparin-binding peptide motifs. The binding and release of therapeutically important proteins from the assembled hydrogels have also been demonstrated via immunochemical assays, which demonstrate the slow release of basic fibroblast growth factor (bFGF) as a function of matrix erosion. The combination of these results suggests the opportunities for producing polymer-polysaccharide conjugates that can assemble into novel hydrogel networks on the basis of peptide-saccharide interactions and for employing these materials in delivery applications.     

Synthesis and characterization of radiopaque iodine-containing degradable PVA hydrogels

Poly (vinyl alcohol) (PVA) hydrogels are highly attractive for biomedical applications, especially for controlled release of drugs and proteins. Recently, degradable PVA hydrogels have been described, having the advantage that the material disappears over time from the implantation site. Herein, we report the synthesis of radiopaque degradable PVA, which gives a further advantage that the position of the hydrogel can precisely be determined by X-ray fluoroscopy. Radiopacity has been introduced by replacing 0.5% of the pendent alcohol groups on the PVA with 4-iodobenzoylchloride. This level of substitution rendered the polymer adequately radiopaque. The subsequent modification of 0.8% of the pendent hydroxyl groups with an ester acrylate functional group allowed for cross-linking of the macromers. The radiopaque hydrogels degraded over a time span of 140 days. Rheology data suggested that the macromer solutions were appropriate for injection.     

Paclitaxel delivery to brain tumors from hydrogels: a computational study

Malignant gliomas are aggressive forms of primary brain tumors characterized by a poor prognosis. The most successful treatment so far is the local implantation of polymer carriers (Gliadel® wafers) for the sustained release of carmustine. To improve the effectiveness of local drug treatment, new polymer carriers and pharmacological agents are currently being investigated. Of particular interest is a set of novel thermo‐gelling polymers for the controlled release of hydrophobic drugs such as paclitaxel (e.g., OncoGel?). Herein, we use computational mass transport simulations to investigate the effectiveness of paclitaxel delivery from hydrogel‐forming polymer carriers. We found similar (within 1–2 mm) therapeutic penetration distances of paclitaxel when released from these hydrogels as compared with carmustine released from Gliadel® wafers. Effective therapeutic concentrations were maintained for >30 days for paclitaxel when released from the hydrogel as compared with 4 days for carmustine released from Gliadel® wafers. Convection in brain tissue prevented the formation of a uniform drug concentration gradient around the implant. In addition, the surface area to volume ratio of the gel is an important factor that should be considered to maintain a controlled release of paclitaxel within the degradation lifetime of the polymer matrix. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011     

One-step synthesis of biodegradable curcumin-derived hydrogels as potential soft tissue fillers after breast cancer surgery

A one-step synthesis of a curcumin-derived hydrogel (curcumin content of 25-75 mol %) is reported. Curcumin is incorporated into the hydrogel backbone and cross-linked through biodegradable carbonate linkages. Curcumin as a part of the polymer backbone is protected from oxidation and degradation, while hydrogel hydrolysis results in the release of active curcumin. Nontoxic poly(ethylene glycol) and desaminotyrosyl-tyrosine ethyl ester are used to tune the hydrophilic/hydrophobic hydrogel properties. In this way, hydrogels with a wide range of physical properties including water-uptake (100-550%) and compression moduli (7-100 kPa) were obtained. Curcumin release is swelling-controlled and could be extended to 80 days. In vitro, curcumin-derived hydrogels showed selective cytotoxicity against MDA-MB-231 (IC(50) 9 μM) breast cancer cells but no cytotoxicity to noncancerous quiescent human dermal fibroblasts even at high curcumin concentrations (160 μM). One possible application of these curcumin-derived hydrogels is as soft tissue filler after surgical removal of cancerous tissue.