Search

Microwave assisted synthesis of graft copolymer of polymeric blend of Fenugreek seed mucilage (FSM)-Polyvinyl alcohol (PVA) with acrylamide (AM) was done by free radical polymerization using ammonium per sulfate (APS) as initiator. Varying amount of AM and APS was used to optimize the best grade based on highest percentage grafting efficiency and investigated with intrinsic viscosity measurement, Fourier Transformation infrared spectroscopy (FTIR), 13 C NMR spectra, X-ray diffraction, elemental analysis, Thermogravimetric analysis, Scanning electron microscopy. The results of intrinsic viscosity indicate that the optimized sample GF4 has longer chain length than in comparison to the native mucilage and thus exhibits more swelling tendencies and thus can be used as very good controlled release matrix system. The thermal analysis and X-ray indicates that GF4 is more stable and possess more amorphous properties than the native FSM. The NMR and FT-IR studies reveal that in GF4 there is prominent presence of amide and the hydroxyl groups indicating that grafting mechanism has efficiently taken place. Histological studies & SEM image for optimized grade implanted on animals revealed sufficient tissue growth and exhibited biodegradability proving the material to be biocompatible and suitable to be used as tissue engineered scaffolds. The controlled release behavior of the optimized polymeric system GF4 was evidenced by 95% release of loaded drug Enalapril maleate for 16 h. Graphical abstract.

In this study, we developed ticagrelor-dispersed nanosuspension (TCG-NSP) to enhance the dissolution and oral bioavailability of ticagrelor (TCG) through a statistical design approach. TCG, a reversible P2Y 12 receptor antagonist, is classified as a biopharmaceutics classification system (BCS) class IV drug with low solubility and permeability, resulting in low oral bioavailability. Nanosuspension (NSP) is an efficient pharmaceutical technique for overcoming the disadvantages. First, we optimized TCG-NSP consisting of D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinyl alcohol (PVA), which exhibited homogeneously dispersed TCG particle (233 nm) and low precipitation (3%). Characterization studies demonstrated that TCG-NSP provided amorphous TCG particles and supersaturation effect, resulting in higher dissolution than a commercial product. In addition, everted gut sac and pharmacokinetic studies confirmed that TCG-NSP improved the gastrointestinal permeation of TCG by 2.8-fold compared to commercial product, thereby enhancing the oral bioavailability (2.2-fold). These results suggested that TCG-NSP could be successfully used as an efficient pharmaceutical formulation to achieve the enhanced dissolution and oral bioavailability of TCG., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Penetration of antibiotics into and through the cornea is a major limiting factor in the treatment of ocular infections. Several strategies are in vogue to overcome this limitation such as use of fortified drops, gels, and subconjunctival injections. Here, we present the fabrication of rapidly dissolving polymeric microneedle array to effectively deliver besifloxacin through the cornea. Microneedles were prepared using polyvinyl alcohol and polyvinyl pyrrolidone by the micromolding technique. The model fluoroquinolone antibiotic, besifloxacin, was loaded in 36 microneedles arranged in a 6 × 6 array format within a 1 cm 2 area. The average height and base width of microneedles was 961 ± 27 and 366 ± 16 μm, respectively. Each microneedle array contained 103.4 ± 8.5 μg of besifloxacin. Cryosectioning and confocal microscopy of excised human cornea revealed that microneedles penetrated to a depth of up to 200 μm. Microneedles were found to completely dissolve in the cornea within 5 min. Application of microneedles for 5 min significantly (p < 0.05) improved the besifloxacin deposition and permeation through the cornea compared with free besifloxacin solution. Similarly, besifloxacin-loaded microneedles showed greater antibacterial activity in Staphylococcus aureus-infected cornea in comparison to free besifloxacin solution. Taken together, rapidly dissolving microneedles can be developed to effectively deliver besifloxacin to treat bacterial infections in the cornea and eye.

The features rendering orodispersible films (ODFs) patient-centric formulations are widely discussed in the scientific literature. However there is a lack of research studies exploring ODF characteristics with a potential impact on end-user acceptability. The aim of this study was to identify the key ODF characteristics affecting end-user acceptability by developing in vitro test methods for the prediction of ODFs acceptability and correlate these formulation characteristics with the data obtained from a human panel study. Four drug-free single-polymer films were prepared by solvent casting. Solutions of poly(vinyl) alcohol (PVOH) 39 KDa (P1), PVOH 197 KDa (P2), carboxymethylcellulose (CMC) 395 KDa (C1), and CMC 725 KDa (C2) were prepared. Texture analysis and Dynamic Mechanical Analysis (DMA) were used to assess film tack. Petri dish and drop methods were used to assess disintegration time. A human panel of 24 healthy young adults was employed to identify end-user acceptability criteria of the four study film samples. Texture analysis data of ODF tack were not found to be in agreement with the in vivo perceived stickiness in the mouth. However, measurement of the area under the adhesive force curve obtained by DMA correlated with in vivo perceived stickiness data for all samples. The disintegration times obtained by drop method were more comparable to human panel data than the petri dish method. Hence DMA and drop methods proved to be promising methodologies for the prediction of the end-user acceptability. The type and molecular weight of the film-forming polymer had a strong influence on stickiness perception, whereas only polymeric molecular weight influenced perceived disintegration time. The human panel study showed that Participant Reported Outcomes (PROs) for the perceived stickiness in the mouth and disintegration time of test films received significantly different scores between samples, and thus were identified as the key attributes with the potential to affect the end-user acceptability. ODF stickiness and disintegration time should therefore be evaluated at an early stage of the drug product design., (Copyright © 2018 Elsevier B.V. All rights reserved.)

pH-Degradable PVA nanogels, which are prepared by photo-crosslinking thermo-preinduced PVA nanoaggregates in water without any surfactants or toxic organic solvents, are used for intracellular PTX release and anticancer treatment. These nanogels fast degraded at mildly acidic conditions with a pH-triggered PTX release, and the degradation products are only native PVA and poly(hydroxyethyl acrylate) (PHEA) as well as acetaldehyde without any toxic byproducts. The nanogel sizes could be tailored by different temperatures during the crosslinking process. The results of confocal microscopy and flow cytometry revealed that smaller nanogels exhibited enhanced internalization with MCF-7 cells than the ones treated with larger nanogels, by which the smaller PTX-loaded nanogels induced a more significant cytotoxicity against MCF-7 cells. GRAPHIC ABSTRACT: pH-Degradable PVA nanogels can be prepared by photo-crosslinking of thermo-preinduced nanoaggregates with tailored nanogel sizes given their pH-triggered PTX release and fast acid-degradation into native PVA and cell-compatible poly(hydroxyethyl acrylate) (PHEA) as well as acetaldehyde., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Targeted delivery of carmustine (BCNU), an efficient brain tumor therapeutic, has been challenged with bioavailability issues due to the Blood Brain Barrier (BBB). The currently effective delivery approach is by implants at the site of the tumor, but this is highly invasive. The intranasal route, which is non-invasive and bypasses the BBB, may be alternative route for delivering BCNU to the brain. In this work, polyvinyl alcohol/polyethyleneimine/fIuorecein isothiocyanate complex (Polyplex) coated iron-oxide nanoparticles (Magnetite) were synthesized employing co-precipitation, epoxidation and EDC/NHS coupling reactions. The Polyplex coated magnetite (Nano-co-Plex) was loaded with BCNU for potential magnetically targeted delivery to the brain following intranasal administration. The Nano-co-Plex was characterized employing Thermogravimetric analysis (TGA), Superconducting Quantum Interference Device (SQUID) magnetometry, Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), X-ray Diffractometry (XRD), Transmission Electron Microscopy (TEM) and Zetasize analysis. Results revealed superparamagnetic hexagonally shaped "core-shell" nanoparticles with cell labeling attributes, of size ranging between 30-50 nm, and a zeta potential value of + 32 ± 2 mV. The Nano-co-Plex synthesized was found to possess high degree of crystallinity with 32% Polyplex coating. The loading and release studies indicated a time-dependent loading with maximum loading capacity of 176.82 μg BCNU/mg of the carrier and maximum release of 75.8% of the loaded BCNU. Cytotoxicity of the BCNU-loaded Nano-co-Plex displayed superiority over the conventional BCNU towards human glioblastoma (HG) cells. Cell studies revealed enhanced uptake and internalization of BCNU-loaded Nano-co-plex in HG cells in the presence of an external magnetic field. These Nano-co-Plexes may be ideal as an intranasal magnetic drug targeting device for BCNU delivery., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The aim of this study was to develop and to investigate a film of compound Calculus Bovis Sativus (CBS) and ornidazole film. A uniform mucoadhesive film was herein successfully obtained by a film-forming solusion containing insoluable drug. This film, as a valid adjunct for the treatment of oral mucosal ulcer, consisted of two main drugs (CBS, ornidazole) and three polymers (hydroxypropyl methyl cellulose, chitosan, poly(vinyl alcohol) (PVA)). The film was prepared with the film-forming suspension, using casting-solvent evaporation technique. The drug content, release behavior, swelling index and mucoadhesive properties of the film were detected. Then the effects of the prepared film on a glacial acetic acid-induced oral mucosal ulceration model of rabbits were evaluated. Moreover, the in vivo release of bilirubin and ornidazole in saliva were also detected in the oral mucosae of healthy volunteers. The films showed favorable in vitro drug release behaviors and swelling properties. Mucosal wounds in the animals were significantly relieved. With the films well tolerated, the salivary concentrations of ornidazole were maintained above the minimum inhibitory concentration against CBS for about 2 h. The compound CBS and ornidazole film functioned better than the film only containing CBS and ornidazole did. Therefore, it is a potentially efficient drug delivery system for the treatment of oral ulcers.

Objectives: The aim of this study was to assess a novel semisolid material as a potential topical drug delivery system for acute laceration. The objectives were to correlate physical characterization data using rheologic studies and to compare with clinical assessment of performance in an emergency department (ED)., Methods: Polyvinyl alcohol (PVA) hydrogels, cross-linked using tetrahydroxyborate (THB), were characterized using texture profile analysis. Formulation samples were applied to acute lacerations presented to the ED and factors, such as in vivo residency time and cohesive removal, were assessed., Results: Viscosity was shown to be related to mechanical characteristics, whereas adhesiveness depended on the THB concentration. Residence in, and clean removal from, lacerations was evaluated on 29 patients. Formulation F3 (10.0% PVA, 2.5% w/w THB) displayed the most appropriate characteristics for clinical use by scoring highest in qualitative assessments. Other formulations exhibited difficulties in application and removal due to excessive adhesiveness. The release of a model local anesthetic drug was proportional to the concentration of drug incorporated, but was not substantially affected by small changes in the formulation constituents., Conclusions: Using a combination of pharmaceutical evaluation and clinical assessment, it was shown that cross-linked PVA semisolids are a suitable formulation for drug administration to acute lacerations, with potential for induction of anesthesia prior to wound repair., (© 2011 by the Society for Academic Emergency Medicine.)

We have recently described an innovative drug delivery system, a water-based and vapor permeable film intended for dermal and/or transdermal delivery. The aim of this work was to modulate the delivery of the model drug lidocaine hydrochloride from the transdermal film across rabbit ear skin. The effect of drug loading, of film-forming polymer type and content, of adhesive and plasticizer on lidocaine transport across the skin was evaluated. Additional objective was to evaluate the effect of occlusion on the kinetics of lidocaine transport, by applying an occlusive backing on the surface of the transdermal film. From the data obtained it can be concluded that the transdermal film acts as a matrix controlling drug delivery. The film-forming polymer molecular weight had a negligible effect on drug penetration, while its content was more effective. The choice of the adhesive seems to be the most important variable governing drug transport. In particular, the presence of lauric acid combined with a basic drug, such as lidocaine, can produce a relevant improvement in permeation, because of the formation of an ion pair. Concerning the kinetics, drug depletion is responsible for the declining permeation rates observed in the late times of permeation.

Branched polyesters consisting of poly (vinyl alcohol) (PVA) grafted with chains of poly (lactic-co-glycolic acid) (PLGA) represent a new class of biodegradable polymers showing significant potential for the development of a variety of drug delivery vehicles. The amphiphilic character and the resulting increase in hydrophilicity of this class of polymers provide advantages when packaging sensitive drug molecules, such as proteins, peptides or DNA. Furthermore, the PVA backbone can be modified, for example, with sulfobutyl moieties or amine structures, to create polymers with negative or positive charges. The ability to modify not only the backbone but also the length of the PLGA side chains results in an extremely flexible polymer system, which can be adapted to meet the needs of almost any drug substance. Further, the rate of biodegradation may also be manipulated through polymer modification to achieve half-lives ranging from several hours to several weeks. This review provides an overview of the three major groups of branched polyesters based upon poly (vinyl alcohol)-grafted poly (lactic-co-glycolic acid) (PVA-g-PLGA), namely, the neutrally charged PVA-g-PLGA, the negatively charged sulfobutyl-modified PVA-g-PLGA and the positively charged amine-modified PVA-g-PLGA, as well as their use in various drug delivery systems.

Polymeric micelles based on polyvinyl alcohol substituted with oleic acid were used as vehicles for progesterone and folic acid. The ability of this amphiphilic polymer to entrap lipophilic drugs and to generate stable micelles in aqueous neutral medium makes it a good candidate for drug delivery. The release of the loaded drugs in acidic environments represents another important property of these systems. Size of micelles, their stability, and their drug-loading capacity were evaluated, as well as the in vitro controlled-release profiles at pH 7.4 and 5.5.

Sequential interpenetrating network (IPN) of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) were prepared and crosslinked with glutaraldehyde (GA) to form pH-sensitive microspheres by the water-in-oil (w/o) emulsification method. Microspheres were used to deliver a model anti-inflammatory drug, diclofenac sodium (DS), to the intestine. The formed IPN was analyzed by Fourier transform infrared spectroscopy (FTIR). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses were done on the drug-loaded microspheres to confirm the polymorphism of DS. Results indicated a molecular level dispersion of DS in the IPN. Microspheres formed were spherical with the smooth surfaces as evidenced by scanning electron microscopy (SEM). Particle size and size distribution was studied using laser light diffraction particle size analyzer. Particle size analysis was also done by optical microscope for the selected microspheres; the change in diameter of the microspheres when soaked in different media at different time intervals was measured by optical microscope. Microspheres showed a pulsatile swelling behavior when the pH of the swelling media was changed. The swelling data were fitted to an empirical equation to understand the phenomenon of water transport as well as to calculate the diffusion coefficient (D). Values of D in acidic media were lower than those found in basic media. The values of D decrease with increasing crosslinking of the matrix. In-vitro release studies have been performed in 1.2 and 7.4 pH media to simulate gastric and intestinal conditions. The results indicated a dependence on the pH of the release media, extent of crosslinking and the amount of drug loading.

Two antibiotics, tylosin tartrate and oxytetracycline hydrochloride, were entrapped in poly(vinyl alcohol) (PVA) hydrogels (MW 31,000-50,000) by a cryogen procedure obtaining a controlled release system suitable for veterinary application. It was found that at a low drug matrix loading (10 mg/ml), the in vitro release rate of both antibiotics could be reduced by a previous freeze drying of the gel, while no reduction in drug rate took place in heavily loaded matrices (300 mg/ml). When PVA hydrogels containing tylosin were administered to rats per os the drug could not be detected in the blood, but it was found in organs,: liver, kidneys, and muscles, for up to 120 h. On the other hand, when the same amount of drug was administered orally as powder, no appreciable organ accumulation was detected, while the drug was found in faeces and urine. These data show that PVA hydrogels can be a suitable slow release system for tylosin administration. Oxytetracycline could also be quantitatively entrapped and released from PVA hydrogels, but once administered per os to rats, it was not detected in blood or organs.

Objective: We developed a new type of platinum coil that has a polyvinyl alcohol (PVA) core to absorb and release various biologically active materials for the endovascular treatment of intracranial aneurysms. We evaluated its efficacy as an embolic material with basic fibroblast growth factor (bFGF) in an in vitro and in vivo study., Methods: A small PVA thread was inserted into the central space of the primary coil. This coil was named the PVA-core coil. Ten-millimeter segments of the PVA-core coil were used in this study. PVA-core coils were immersed in a bFGF solution for 1 hour. The PVA-core coil, which absorbed bFGF in the PVA-core, was named the FGF-core coil. Initially, the dose of bFGF released from the PVA core into saline was measured by performing an enzyme-linked immunosorbent assay. In the in vitro study, FGF-core coils, PVA-core coils, and unmodified coils were cultured with fibroblasts (NIH3T3), and then their surfaces were observed with electron microscopy. In the in vivo study, each coil was implanted into a rat common carotid artery. The rats were killed, and the arterial lumen was histologically examined at 14 and 28 days after coil implantation., Results: BFGF was released from the PVA core into saline within 24 hours by performing an enzyme-linked immunosorbent assay. Electron microscopic findings demonstrated remarkable cellular adhesion to the surfaces of the FGF-core coils, but no adhesion to the surfaces of the PVA-core coils and the unmodified coils was found. Histologically, remarkable cell proliferation in the vascular lumen was demonstrated in the common carotid arteries of the FGF-core coil implantation group at the 14th and 28th days. Cellular components proliferated around the implanted coil, and these components mainly stained blue with Masson trichrome. These changes did not occur in the PVA-core coil group and the unmodified coil group., Conclusion: We suggest that FGF-core coils may be effective in inducing fibrotic changes inside aneurysms. These coils may be used as an embolic material to cure cerebral aneurysms.

Purpose: The efficiency of encapsulation of water-soluble drugs in biodegradable polymer is often low and occasionally these microcapsules are associated with high burst effect. The primary objective of this study is to develop a novel microencapsulation technique with high efficiency of encapsulation and low burst effect., Method: Pentamidine was used as a model drug in this study. Pentamidine/polyvinyl alcohol (PVA) hydrogel was prepared by freeze-thaw technique. Pentamidine loaded hydrogel was later microencapsulated in poly(lactide-co-glycolide) (PLGA) using solvent evaporation technique. The microcapsules were evaluated for the efficiency of encapsulation, particle size. surface morphology, thermal characteristic, and drug release., Result: Scanning Electron Microscope (SEM) studies revealed that the microcapsules were porous. The microcapsules were uniform in size and shape with the median size of the microcapsules ranging between 27 and 94 microm. The samples containing 10% PLGA showed nearly three times increase in drug loading (18-53%) by increasing the hydrogel content from 0-6%. The overall drug release from the microencapsulated hydrogel, containing 3% and 6% PVA, respectively. was significantly lower than the control batches., Conclusion: The use of a crosslinked hydrogel such as PVA can significantly increase the drug loading of highly water-soluble drugs. In addition. incorporation of the PVA hydrogel significantly reduced the burst effect and overall dissolution of pentamidine.

Subfoveal choroidal neovascularization (CNV) causes significant visual loss, especially in patients with age-related macular degeneration (AMD). Several pharmaceutical treatments that use anti-angiogenic agents have been tried to inhibit the activity of CNV experimentally and clinically. In general, however, systemically administered drugs may reach not only targeted tissues but also other tissues, resulting in unwanted side effects. Also, to maintain therapeutic levels of the drugs in targeted tissues, frequent administration for an extended period of time is required. To solve these problems, drug delivery systems targeted to the CNV are being developed. Anatomic characteristics of CNV tissues resemble those of tumor vasculature, exhibiting enhanced permeability and retention effect. Drug targeting to CNV may be feasible in the same manner as it is to tumors. In this review, we describe two approaches of drug targeting to CNV: passive targeting and active targeting.

Miconazole nitrate, a fungicidal, is effective for the local treatment of vaginitis. The objective of this project was to develop a swelling-controlled release delivery system for miconazole. An aqueous solution of 15% w/w poly(vinyl alcohol) was mixed with a specific amount of miconazole powder. The resultant mixture was cross-linked by freeze-thawing. The effect of the number of freeze-thawing cycles was studied at four levels. The effect of the presence of PEG was studied by mixing different concentrations of two different PEG. The swelling at the end of 48 h was significantly higher (32%) for the batch that underwent four cycles. The swelling within the first 15 min for the batches containing PEG1000 was approximately 9%. However, the swelling for the batches containing PEG1450, at much lower concentration, within the same period was between 10 and 19%. The drug release profiles up to 108 h were independent of the number of freeze-thawing cycles. The cumulative percent miconazole released, in the absence of PEG, (two, four, six, eight cycles) at the end of 108 h was between 30 and 35%. The drug release was lower for the batches containing PEG1000, irrespective of the concentrations, compared with the batches containing PEG1450. A comparison of the value of diffusional exponent (n) indicates the predominance of a Fickian diffusion mechanism of release from the hydrogels.

A new oral erosion controlled drug delivery system on the basis of polyvinyl alcohols with a late burst in the release profile is developed. This late burst occurs after addition of sparingly soluble substances, either excipients like carboxylic acids and neutral cellulose or drugs like theophylline and theobromine. The onset time between 4 and 12 h and the extent of the burst between 20 and 60% are well reproducible and depend on the type of the used additive and the particle size of the basic polymer. For dissociating additives like glutamic acid, the pH within the swelling and eroding hydrocolloid tablet is decisive, differing from the pH of the dissolution medium and controlling the release process. Only polyvinyl alcohols with a ratio of viscosity number to degree of hydrolysis in the range from 2.3 to 3 exhibit acceleration of release in the final phase. As mechanism of the burst, enforced erosion of the gel layer, surrounding the tablet core, could be identified.

The incorporation of a model protein, bovine serum albumin (BSA), into poly(vinyl alcohol) (PVA) hydrogel films during the freezing and thawing process and its subsequent release behavior were investigated. The effect of the number of freezing and thawing cycles as well as the stability of BSA were examined. BSA release profiles were not significantly different from gels prepared after 3 or 5 cycles. However, the rate and overall amount of PVA dissolution were considerably higher for gels prepared after 3 cycles. These observations were then applied to the development of novel, freeze/thawed PVA laminates. Laminates containing gel layers prepared after 3 or 5 cycles were successfully prepared with good stability over a 6 month swelling period. These structures, containing distinct layers of very specific properties, could be used to achieve zero-order release behavior.

Purpose: The conjugation of drugs with water-soluble polymers such as poly(vinyl alcohol) (PVA) tends to prolong the half-life of drugs and facilitate the accumulation of drugs in tissues involving neovascularization. The purpose of this study was to evaluate the effect of TNP-470-PVA conjugate on the proliferation of endothelial cells in vitro and on experimental choroidal neovascularization (CNV) in vivo., Methods: TNP-470 was conjugated in PVA by a dimethylaminopyridine-catalyzed reaction. The effects of TNP-470-PVA and free TNP-470 on the proliferation of human umbilical vein endothelial cells (HUVECs) and bovine retinal pigment epithelial cells (BRPECs) were evaluated by the tetrazolium-based colorimetric assay (XTT assay). Experimental CNV was induced by subretinal injection of gelatin microspheres containing basic fibroblast growth factor, into rabbits. Thirty rabbits were intravenously treated either with TNP-470-PVA (n = 8), free TNP470 (n = 5), free PVA (n = 5), or saline (n = 12) daily for 3 days, 2 weeks after implantation of gelatin microspheres. Fluorescein angiography was performed to detect the area with CNV, and the evaluation was made by computerized measurement of digital images. These eyes were also examined histologically. To observe the accumulation of conjugate, 3 rabbits with CNV received rhodamine B isothiocyanate-binding PVA (RITC-PVA), and the lesion was studied 24 hours later by fluorescein microscopy., Results: The TNP-470-PVA inhibited the growth of HUVECs, similar to that of free TNP-470. The BRPECs were less sensitive to TNP-470-PVA than were the HUVECs. TNP-470-PVA significantly inhibited the progression of CNV in rabbits (P = 0.001). Histologic studies at 4 weeks after treatment demonstrated that the degree of vascular formation and the number of vascular endothelial cells in the subretinal membrane of the eyes treated with TNP-470-PVA were less than those of the control eyes. RITC-PVA remained in the area with CNV 24 hours after administration., Conclusions: These results suggest that TNP-470-PVA inhibited the proliferation of HUVECs more sensitively than that of BRPECs, and the targeted delivery of TNP-470-PVA may have potential as a treatment modality for CNV.

The aim of this study was to construct a novel drug delivery system suitable for controlled release of antibiotics. There is a need for devices that release antibiotics only during microbial infection, because prophylactic or prolonged use of antibiotics leads to serious problems, such as renal and liver toxicity and the emergence of drug-resistant bacteria (e.g., meticillin-resistant Staphylococcusaureus). We found previously that Staphylococcus aureus-infected wound fluid showed high thrombin-like activity; therefore, in this study we designed an antibiotic release system triggered by thrombin activity. We synthesized an insoluble polymer-drug conjugate in which gentamicin was bound to poly(vinyl alcohol) hydrogel through a newly developed thrombin-sensitive peptide linker. The conjugate released gentamicin when it was incubated with Staphylococcus aureus-infected wound fluid, with thrombin and leucine aminopeptidase, or with human plasma and Ca2+, whereas no biologically active gentamicin was released when the conjugate was incubated with noninfected wound fluid, with leucine aminopeptidase alone, with thrombin alone, or with plasma. Furthermore, the conjugate reduced the bacterial number in an animal model of Staphylococcus aureus infection. These results demonstrated that the conjugate has sufficient specificity and excellent potential as a stimulus-responsive, controlled drug release system.

Purpose: In spite of advances in technique and instrumentation, microvascular free tissue transfer remains associated with a persistent risk of flap failure. The use of systemic anticoagulants to overcome the formation of vasoocclusive thrombi at reactive anastomotic sites is associated with a high rate of flap hematoma and is ill advised in the operative setting. The purpose of this study was to investigate the use of a biodegradable, nontoxic polymer gel (polyvinyl alcohol, PVA) to effect a sustained localized release of perivascular heparin around thrombogenic venous anastomoses., Materials and Methods: A modified adventitial inclusion model was created in the femoral vein of 64 adult female Sprague-Dawley rats. Animals were divided into four experimental groups: 1) no treatment (controls), 2) periadventitial PVA gel contained in a vicryl chamber, 3) periadventitial PVA gel mixed with heparin, and 4) systemic heparin (intravenous pump). Patency rates in the femoral vein were checked at 10 minutes, 1 hour, 1 day, and 4 days after surgery. Systemic coagulation parameters and histology (scanning electron microscopy, SEM) were assessed in representative animals from all groups., Results: Patency rates for experimental groups showed a significant improvement in animals treated with PVA/heparin and systemic heparin over controls. Wound hematomas occurred in 7 of 16 animals in group 3, and in 4 of 16 animals in group 4. Activated partial thromboplastin times were elevated in group 4 only (> 150 seconds)., Conclusions: Continuous release of periadventitial heparin using a polymeric delivery system may represent an efficient means of attenuating the reactivity of microvenous anastomoses without affecting systemic coagulation parameters. In this model, however, its use was associated with a high rate of local wound hematoma.