Insulin release dynamics from poly(diethylaminoethyl methacrylate) hydrogel systems

Novel glucose‐sensitive systems for the release of insulin from poly(diethylaminoethyl methacrylate) (PDEAEM) microparticles and nanoparticles decorated with glucose oxidase and catalase enzymes have been developed. The effect of polymer composition and loading conditions on the insulin loading efficiency and release was studied. The optimal conditions for loading insulin into PDEAEM microparticles were found to be at a loading pH of 5.6, particle to insulin mass ratio of 7:1, a concentration of 1.0 mg/mL insulin, and a collapsing pH of approximately 9.5. Microparticles exhibited a responsive (pH) or intelligent (glucose) release of insulin from a stimulus. Microparticles that had a nominal crosslinking ratio of 10% released a third of the insulin payload after a single stimulus, compared to nearly 70% for microparticles with a 3% crosslinking ratio. PDEAEM microparticles of 150 μm diameter showed promise as components of a system of automated, intelligent delivery method for insulin to type I diabetics. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3578–3585, 2013     

Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.     

Dual responsive block copolymer coated hollow mesoporous silica nanoparticles for glucose-mediated transcutaneous drug delivery

A self-regulated anti-diabetic drug release device mimicking pancreatic cells is highly desirable for the therapy of diabetes. Herein, a glucose-mediated dual-responsive drug delivery system, which combines pH- and H₂O₂-responsive block copolymer grafted hollow mesoporous silica nanoparticles (HMSNs) with microneedle (MN) array patch, has been developed to achieve self-regulated administration. The poly[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate]-b-poly[2-(dimethylamino)ethyl methacrylate] (PPBEM-b-PDM) polymer serves as gate keeper to prevent drug release from the cavity of HMSNs at normoglycemic level. In contrast, the drug release rate is significantly enhanced upon H₂O₂ and pH stimuli due to the chemical change of H₂O₂ sensitive PPBEM block and acid responsive PDM block. Therefore, incorporation of anti-diabetic drug and glucose oxidase (GOx, which can oxidize glucose to gluconic acid and in-situ produce H₂O₂) into stimulus polymer coated HMSNs results in a glucose-mediated MN device after depositing the drug-loaded nanoparticles into MN array patch. Both in vitro and in vivo results show this MN device presents a glucose mediated self-regulated drug release characteristic, which possesses a rapid drug release at hyperglycemic level but retarded drug release at normoglycemic level. The result indicates that the fabricated smart drug delivery system is a good candidate for the therapy of diabetes.     

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associated to modulation of endoplasmic reticulum stress markers IRE1α and XBP1. These pathways are Sig-1R specific since they were not produced in Sig-1R knockout mice. These findings suggest that Sig-1R is a promising target for the treatment of MN cell death after neural injuries.     

Glucose‐sensitive and blood‐compatible nanogels for insulin controlled release

For insulin delivery, many reported glucose‐sensitive materials are designed to response to the glucose in the blood. However, few particular studies on their blood compatibility have been reported. In this article, for controlled insulin release in diabetes therapy, a glucose‐sensitive nanogel was prepared through thermally initiated precipitation polymerization using the aminophenylboronic acid‐containing monomer to copolymerize with methacrylic acid. The obtained nanogels showed the uniform and spheroidal morphology as observed by SEM, and their sizes in aqueous solution are dependent on the concentration of glucose. Through in vitro and in vivo insulin release tests, it was found that nanogels showed the glucose‐dependent insulin release and prolonged effect of lowing blood glucose level. The blood compatibility of nanogels has also been explored through various assays including the hemolysis, activated partial thromboplastin time, prothrombin time as well as the thromboelastography. All results indicated that the obtained glucose‐sensitive nanogels showed good blood safety. Moreover, their low cytotoxicity suggested a potential application in diabetes therapy. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43504.     

Preparation of high molecular weight poly(N‐vinylcarbazole) in high yield by low‐temperature precipitation polymerization of N‐vinylcarbazole

To produce high molecular weight poly(N‐vinylcarbazole) (PVCZ) with high conversion, N‐vinylcarbazole (VCZ) was heterogeneously polymerized in methanol at 30, 40 and 50 °C using a low temperature initiator, 2,2′‐azobis(2,4‐dimethylvaleronitrile) (ADMVN), and the effects of polymerization temperature and concentration of initiator and solvent on the polymerization behaviour and molecular parameters of PVCZ investigated. Globally, experimental results correspond to predicted ones. Low polymerization temperature using ADMVN and a heterogeneous system using methanol proved to be successful in obtaining poly(N‐vinylcarbazole) (PVCZ) of high molecular weight and high conversion with small temperature rise during polymerization, although free radical polymerization by azoinitiator was used. The polymerization rate of VCZ in methanol at 30 °C is proportional to the 0.88th power of ADMVN concentration. The molecular weight is higher and the molecular weight distribution is narrower with PVCZ polymerized at lower temperatures. For PVCZ produced in methanol at 30 °C using an ADMVN concentration of 0.0001 mol/mol of VCZ, a weight average molecular weight of 1 750 000 g mol⁻¹ is obtained, with a polydispersity index of 1.82 © 2000 Society of Chemical Industry     

Preparation of glucose‐sensitive and fluorescence micelles via a combination of photoinitiated polymerization and chemoenzymatic transesterification for the controlled release of insulin

Glucose‐sensitive and fluorescence copolymer micelles were designed and prepared via a combination of photoinitiated polymerization and enzymatic transesterification. The water‐soluble photoinitiator and emulsifier 2‐oxooctanoic acid self‐polymerized dimer molecules under UV irradiation were characterized by mass spectrometry. The fluorescence dye (9‐anthracene alcohol) and biocompatible hydrophilic chains [poly(ethylene glycol)] were introduced to the polymer chains during the photopolymerization and enzymatic transesterification processes. The as‐prepared copolymers were confirmed by ¹H‐NMR spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and dynamic light scattering. The resulting copolymers exhibited excellent glucose sensitivity and stability against protein. The optical fluorescence properties of the copolymer micelles were investigated with fluorescence spectrophotometry, fluorescence microscopy, and confocal laser scanning microscopy. Because of the amphiphilic feature, the micelles could be self‐assembled and used to load insulin. The controlled release of insulin was evaluated and was triggered by glucose in vitro. This study provided a new strategy for fabricating functional carriers as self‐regulated insulin‐release systems. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43026.     

Hemolglobin encapsulation in chitosan/calcium alginate beads

A mild chitosan/calcium alginate encapsulation process, as applied to encapsulation of hemoglobin, was investigated. The first procedure consisted of adding dropwise a hemoglobin-containing sodium alginate mixture in a chitosan solution, then hardening the interior of capsules thus formed, in the presence of CaCl₂. In the second method, the droplets were directly pulled off in a chitosan–CaCl₂ mixture. Both procedures led to beads containing a high concentration in entrapped hemoglobin as more than 90% of the initial concentration (150 g/L) were retained inside the beads provided that the chitosan concentration was great enough. The molecular weight of chitosan (M?_u 245,000 or 390,000) and the pH of its solution (2, 4, or 5.4) had only a slight effect, the best retention being obtained with beads prepared at pH 5.4. The hemoglobin release during the bead storage in water was found to depend on the conditions of their formation and especially on the chitosan molecular weight. The best retention during storage in water was obtained with beads prepared with the high M?_u chitosan solution at pH 2. Considering the total loss in hemoglobin during the bead formation and after 1 month of storage in water, the best results were obtained by preparing the beads in an 8 g/L solution of a 390,000 chitosan at pH 4 (less than 7% of loss with regard to the 150 mg/L initial concentration). © 1994 John Wiley & Sons, Inc.     

The first report on the atom transfer radical polymerization of an optically active acidic monomer based on L‐phenylalanine

For the first time, acidic monomer chiral N‐acryloyl‐L ‐phenylalanine was polymerized directly by atom transfer radical polymerization under mild conditions. Controlled polymerization was carried out in pure water, methanol/water mixture, or pure methanol using water‐soluble initiators, such as 2‐hydroxyethyl‐2′‐methyl‐2′‐bromopropionate and sodium‐4‐(bromomethyl)benzoate at room temperature. The corresponding optically active biocompatible amino acid‐based homopolymers were obtained in good yields with narrow molecular weight distributions. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Production of 2,3-butanediol from diverse saccharides via fermentation

The present study aimed to evaluate the potential use of whey to produce 2,3-BD via the fermentation of lactose and its monosaccharides, glucose and galactose, in a synthetic culture medium (medium 9, M9) using a modified strain of Escherichia coli K12 MG1655 (E. coli JFR12) at a 0.1 L/L (10 vol%) inoculum ratio, 37 °C, atmospheric pressure, an initial pH 7.4, and 100 rpm for 72 h varying the saccharide concentration from 12.5, 25, and 50 g/L. The 2,3-BD yield was ∼80 % of the theoretical yield using 25 g/L of glucose and lactose, corresponding to 0.38 g/g saccharides at a fermentation time of 48 h (glucose) and 72 h (lactose). However, the 2,3-BD yield was halved (0.19 g/g galactose), fermenting 25 g/L of galactose at 48 h. Taking into account these results, two important conclusions were determined: i) E. coli JFR12 could transform galactose into 2,3-BD although its yield was half of the yield observed with glucose at 48 h; and ii) E. coli JFR12 was as efficient as other natural 2,3-BD producers such as Klebsiella species fermenting lactose. However, the E. coli strain has the advantage of being an innocuous strain. To the best of our knowledge, there is no other study presenting the production of 2,3-BD from galactose and lactose with a genetically modified E. coli strain.     

Synthesis and applications of polyacrylamide gels catalyzed by silver nitrate

Polyacrylamide gels are widely used as matrices for biomolecular analysis and fractionation, and they are being developed as biomaterials for diverse medical and industrial applications. This study reports silver nitrate as a novel catalyst for the synthesis of polyacrylamide gels from acrylamide and N,N‐methylene bisacrylamide monomers. The conditions were defined for silver‐catalyzed, free‐radical‐induced polymerization, and a suitable buffer system was devised for the electrophoretic resolution of nucleic acids. A silver‐staining procedure was modified for these gels, and they were compared with N,N,N′,N′‐tetramethylethylenediamine‐catalyzed gels for sensitivity and gel background. Silver nitrate and ammonium persulfate at final concentrations of 100 and 625 μg/mL, respectively, polymerized the resolving gels within 20 min at room temperature. These gels exhibited antimicrobial properties. The gels with ≥10 μg/mL silver nitrate showed a zone of complete inhibition of Staphylococcus aureus growth on a Luria–Bertani agar plate. The silver‐catalyzed gels were also suitable as antigen‐ and drug‐delivery devices. Silver, acting as both a catalyst and a microbicidal agent, was better than N,N,N′,N′‐tetramethylethylenediamine for the synthesis of polyacrylamide gels as drug‐ and oxygen‐delivery devices for topical applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Lactic Acid Production by Lactobacillus paracasei 168 in Discontinuous Fermentation Using Lucerne Green Juice as Nutrient Substitute

The aim of this study was the utilization of lucerne green juice (LGJ), obtained in 2005 and 2008, as nutrient substitute in lactic acid fermentation using Lactobacillus paracasei 168, in a discontinuous fermentation process with the addition of 55 g/L glucose and 15 g/L yeast extract. The LGJ after pressing fresh green mass contains a series of nitrogen‐containing compounds and inorganic salts that are essential for cell growth. The strain used, L. paracasei 168, achieved at 40.5 °C and pH 6.0 a maximum productivity of up to 2.56 g L^–1 h^–1 and a lactic concentration close to 45.97 g/L in trial A (LGJ 2008/glucose), 2.19 g L^–1 h^–1, 47.23 g/L in trial B (LGJ 2005/glucose), 2.93 g L^–1 h^–1, 42.27 g/L in trial C (LGJ 2008/glucose/yeast extract), and 2.68 g L^–1 h^–1, 47.33 g/L in trial D (LGJ 2005/glucose/yeast extract). Addition of yeast extract in trials C and D induced faster growth of L. paracasei 168. Lactate yields of about 87 % were obtained in all trials. The lactic acid formed was the optically pure L‐(+)‐isomer at up to 97 % in trial B. Pearson's analysis showed that the level of lactic acid in the control trial was positively and significantly correlated with trial A (r² = 0.9899), B (r² = 0.9582), C (r² = 0.9901), and D (r² = 0.9938), with p <0.0001.     

Preparation of novel amphiphilic copolymer microspheres and their drug‐release and glucose‐sensitive properties

A novel amphiphilic copolymer was prepared by the copolymerization of N‐acryloyl‐3‐aminophenylboronic acid with β‐cyclodextrin containing maleic anhydride. The copolymer was fully characterized with ¹³C‐NMR, ¹H‐NMR, IR, and scanning electron microscopy. The self‐assembling mechanism of the copolymer in H₂O–CH₃OH cosolvents was studied. Gliclazide as a model drug was loaded inside the copolymer microspheres, and the drug‐release behavior of the microspheres was studied. The results of in vitro oscillating release tests indicated that the microspheres responded to glucose rapidly in 30 min, and the microspheres exhibited self‐regulated on–off release behavior four to six times in 6 h between the solution with 3 g/L glucose and the medium without glucose; this met the clinical requirements of multidrug delivery. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Synthesis and characterization of a porous poly(hydroxyethylmethacrylate‐co‐ethylene glycol dimethacrylate)‐based hydrogel device for the implantable delivery of insulin

Poly(hydroxyethylmethacrylate‐co‐ethylene glycol dimethacrylate) [poly(HEMA‐co‐EGDMA)]‐based hydrogel devices were synthesized by a free‐radical polymerization reaction with 2‐hydroxyethylmethacrylate as the monomer, different concentrations of ethylene glycol dimethacrylate (EGDMA) as the crosslinking agent, and ammonium persulfate/N,N,N′,N′‐tetra‐methyl ethylenediamine as the free‐radical initiator. The porosity of the poly(HEMA‐co‐EGDMA) hydrogels was controlled with water as the porogen. The Fourier transform infrared spectrum of poly(HEMA‐co‐EGDMA) showed absorption bands associated with ? C?O stretching at 1714 cm^?1, C? O? C stretching vibrations at 1152 cm^?1, and a broad band at 3500–3800 cm^?1 corresponding to ? OH stretching. Atomic force microscopy studies showed that the hydrogel containing 67% water had pores in the range of 3500–9000 nm, whereas the hydrogel containing 7% water did not show measurable pores. The hydrogel synthesized with 1% EGDMA showed 50% thallium‐201 release within the first 30 min and about 80% release within 60 min. In vitro insulin‐release studies suggested that the hydrogel with 27% water showed sustained release up to 120 min, whereas the hydrogels with 47 and 67% water showed that nearly all of the insulin was released within 60 min. Hydrogel devices synthesized with 27% water and filled with insulin particles showed sustained release for up to 8 days, whereas the hydrogels synthesized with 47 and 67% water released insulin completely within 3 days of administration. Animal studies suggested that the hydrogel devices synthesized with 27% water and filled with insulin‐loaded particles (120 IU) were able to control blood glucose levels for up to 5 days after implantation. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Chitosan/calcium–alginate beads for oral delivery of insulin

A mild chitosan/calcium alginate microencapsulation process, as applied to encapsulation of biological macromolecules such as albumin and insulin, was investigated. The microcapsules were derived by adding dropwise a protein-containing sodium alginate mixture into a chitosan–CaCl₂ system. The beads containing a high concentration of entrapped bovine serum albumin (BSA) as more than 70% of the initial concentration were achieved via varying chitosan coat. It was observed that approximately 70% of the content is being released into Tris-HCl buffer, pH 7.4 within 24 h and no significant release of BSA was observed during treatment with 0.1M HCl pH 1.2 for 4 h. But the acid-treated beads had released almost all the entrapped protein into Tris-HCl pH 7.4 media within 24 h. Instead of BSA, the insulin preload was found to be very low in the chitosan/calcium alginate system; the release characteristics were similar to that of BSA. From scanning electron microscopic studies, it appears that the chitosan modifies the alginate microspheres and subsequently the protein loading. The results indicate the possibility of modifying the formulation in order to obtain the desired controlled release of bioactive peptides (insulin), for a convenient gastrointestinal tract delivery system. © 1996 John Wiley & Sons, Inc.     

Controlled co‐delivery of hydrophilic and hydrophobic drugs from thermosensitive and crystallizable copolymer nanoparticles

Functionalized amphiphilic block copolymers poly(N‐isopropyl acrylamide)‐b‐poly(stearyl methacrylate) (PNIPAM‐PSMA) are synthesized. Their self‐assembled core‐shell nanoparticles have the hydrophilic thermosensitive shell and hydrophobic crystallizable core. Nanoparticles exhibit volume phase transition at temperature of 38 °C and its poly(stearyl methacrylate) (PSMA) moiety could form nano size crystals to retain drugs, making them good carriers for drug co‐delivery system. Thermosensitivity and crystallinity of nanoparticles are characterized with dynamic light scattering (DLS), differential scanning calorimetry (DSC), small‐angle X‐ray scattering (SAXS), and atomic force microscopy (AFM). The interactions and relationship between chemical structures of copolymer nanoparticles and loading drugs are discussed. Different loading techniques and combined loading of hydrophobic/hydrophilic drugs are studied. Nanoparticles show a good and controllable drug loading capacity (DL) of hydrophilic/hydrophobic drugs. The drugs release kinetics is analyzed with Fick's law and Weibull model. A general method for analyzing drug release kinetics from nanoparticles is proposed. Weibull model is well fitted and the parameters with definite physical meaning are analyzed. PNIPAM‐PSMA nanoparticles show a quite different thermal response, temporal regulation, and sustained release effect of hydrophilic and hydrophobic drugs, suggesting a promising application in extended and controlled co‐delivery system of multi‐drug. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44132.     

Encapsulation of diclofenac sodium with acidic copolymer hydrogels based on PEG/poly(N‐isopropylacrylamide‐co‐2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid) semi‐interpenetrating network using in situ loading technique

A pH‐ and temperature‐responsive semi‐interpenetrating copolymer PEG6000/poly(NIPA‐co‐AMPS) (PEG/AMPS‐co‐NIPA SIPN), for short PEG SIPN, was made by ammonium persulfate‐initiated suspension copolymerization of N‐isopropylacrylamide, 2‐acrylamido‐2‐methylpropanesulphonic acid, and N,N′‐methylene‐bis‐acrylamide (MBAA; crosslinker) in the presence of PEG6000. The PEG SIPN copolymer matrices containing nanostructures made in the high‐temperature copolymerization resulted in channels for PEG and facile migration of drugs. In drug encapsulation or drug‐loading process, one can easily ignore or pay less attention to the interaction between a drug and its encapsulation materials; however, the ignored interactions may induce problems in drug properties or the release behavior in use. Sodium diclofenac (DFNa) precipitates as the carboxylic acid form in an acidic environment, and it is challenging to encapsulate sodium diclofenac in such an acidic matrix without precipitation of the sparingly soluble acid form of DFNa on the surface of the polymer substrate. To avoid bulky precipitation in drug loading, an in situ loading technique was developed for producing gel spheres with DFNa uniformly distributed in the polymer matrix. The technique is based on fast polymerization of spherical droplets of a pregel solution in which the drug is dissolved. Diffusion‐loading prodrugs were made in comparison with in situ loading prodrugs in thermal, release kinetics, and release behavior. Drug release profiles (in pH 7.4 phosphate buffer) show that the new drug loading technique gives controlled release during a period of about 7 days at 37°C. By contrast, gel spheres loaded with sodium diclofenac using the conventional diffusion technique produced almost total release of the drug within about 24 h. The thermal stability of sodium diclofenac, the PEG/AMPS‐co‐NIPA SIPN, and the prodrugs made with the SIPN and sodium diclofenac was studied. A near zero‐order release kinetics was found in the in vitro release of sodium diclofenac with in situ loading PEG SIPN prodrug. We have, for the first time, studied sodium diclofenac release behavior from the PEG SIPN hydrogel systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Process for production of arachidonic acid concentrate by a strain of mortierella alpina

Various Mortierella alpina fungi were screened for their capacities to produce arachidonic acid. A strain of M. alpina was found to show the highest productivity. Arachidonic acid content of biomass and overall yield per litre of culture was highest in soya flour supplemented medium which produced dispersed mycelium. When the glucose concentration in the medium was varied from 30 to 100 g/L, biomass, lipid, arachidonic acid content of biomass and arachidonic acid yield increased with increasing glucose concentration. Several natural oils, when added to the growth medium, stimulated arachidonic acid production. After fermentation in a 20-L fermenter under optimal culture conditions, the arachidonic acid yield was 5.3 g/L, representing 34.2% w/w of total fatty acids and 13.7% w/w of biomass. An extract containing 72.5% w/w arachidonic acid was prepared from the recovered mycelium.     

Temperature and glucose dual-responsive carriers bearing poly(N-isopropylacrylamide) and phenylboronic acid for insulin-controlled release: A review

Insulin injection is a definitive therapy for diabetic patients, but mismatched dosage and untimely intervention lead to wide fluctuations in blood sugar levels. Therefore it is essential to combine exogenous insulin and intelligent carriers, which is promising to normalize glucose concentrations. The temperature and glucose dual-responsive materials bearing poly(N-isopropylacrylamide) (PNIPAAm) and phenylboronic acid (PBA) have been confirmed for insulin-controlled release in experimental stages. The recent progress on different types of smart PNIPAAm and PBA-containing carriers is summarized in this review. The new challenges and future direction regarding the studies on elaborate insulin-controlled-release systems are also proposed.     

Influence of a pore-forming agent on swelling,network parameters,and permeability of poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels: Application in transdermal delivery systems

We characterized hydrogels, prepared from aqueous blends of poly(methyl vinyl ether-co-maleic acid) (PMVE/MA) and poly(ethylene glycol) (PEG 10,000 Daltons) containing a pore-forming agent (sodium bicarbonate, NaHCO₃). Increase in NaHCO₃ content increased the equilibrium water content (EWC) and average molecular weight between crosslinks (M_c) of hydrogels. For example, the %EWC was 731, 860, 1109, and 7536% and the M_c was 8.26, 31.64, 30.04, and 3010.00 × 10⁵ g/mol for hydrogels prepared from aqueous blends containing 0, 1, 2, and 5% w/w of NaHCO₃, respectively. Increase in NaHCO₃ content also resulted in increased permeation of insulin. After 24 h, percentage permeation was 0.94, 3.68, and 25.71% across hydrogel membranes prepared from aqueous blends containing 0, 2, and 5% w/w of NaHCO₃, respectively. Hydrogels containing the pore-forming agent were fabricated into microneedles (MNs) for transdermal drug delivery applications by integrating the MNs with insulin-loaded patches. It was observed that the mean amount of insulin permeating across neonatal porcine skin in vitro was 20.62% and 52.48% from hydrogel MNs prepared from aqueous blends containing 0 and 5% w/w of NaHCO₃. We believe that these pore-forming hydrogels are likely to prove extremely useful for applications in transdermal drug delivery of biomolecules. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012