35 research outputs found

    Bioinspired Heparin Nanosponge Prepared by Photo-crosslinking for Controlled Release of Growth Factors

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    Indexación: Scopus.Growth factors have great therapeutic potential for various disease therapy and tissue engineering applications. However, their clinical efficacy is hampered by low bioavailability, rapid degradation in vivo and non-specific biodistribution. Nanoparticle based delivery systems are being evaluated to overcome these limitations. Herein, we have developed a thermosensitive heparin nanosponge (Hep-NS) by a one step photopolymerization reaction between diacrylated pluronic and thiolated heparin molecules. The amount of heparin in Hep-NS was precisely controlled by varying the heparin amount in the reaction feed. Hep-NS with varying amounts of heparin showed similar size and shape properties, though surface charge decreased with an increase in the amount of heparin conjugation. The anticoagulant activity of the Hep-NS decreased by 65% compared to free heparin, however the Hep-NS retained their growth factor binding ability. Four different growth factors, bFGF, VEGF, BMP-2, and HGF were successfully encapsulated into Hep-NS. In vitro studies showed sustained release of all the growth factors for almost 60 days and the rate of release was directly dependent on the amount of heparin in Hep-NS. The released growth factors retained their bioactivity as assessed by a cell proliferation assay. This heparin nanosponge is therefore a promising nanocarrier for the loading and controlled release of growth factors.https://www.nature.com/articles/s41598-017-14040-5.pd

    Visible-Light-Initiated Thiol−Acrylate Photopolymerization of Heparin-Based Hydrogels

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    An in situ heparin-based forming hydrogel that cures under visible-light is formulated using eosin Y as a photoinitiator with triethanolamine as an electron donor to initiate reaction of thiolated-heparin with acrylate-ended poly(ethylene glycol). Formulations and irradiation conditions are presented for control of heparin content (1.6 to 3.3% w/v), modulus (100–10 000 Pa), and gelation time (30–600 s). Encapsulation of 3T3 fibroblasts in the hydrogel gave over 96% viability for all conditions examined. In vitro characterization of epidermal growth factor released from the hydrogel confirmed that the growth factor remains bioactive. The ability to deliver growth factors, fast gelation kinetics under visible light, and independent control of physical and biochemical properties makes this system a promising candidate for use in regenerative medicine. In particular, irradiation conditions that achieve gelation in 150s are compatible with the stringent light exposure limits of the retina, which affords a wide safety margin for use with other tissues

    In situ Forming Hydrogels Using Self-Assembly of Fluoroalkyl-Ended Poly(ethylene Glycol)s

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    Telechelic polymers with hydrophilic midblocks (poly(ethylene glycol), PEG) and hydrophobic end groups (fluoroalkyl, Rf) are synthesized and explored as candidates for in situ forming hydrogels for biomedical applications. Relevant physical properties, including phase behavior, rheology and erosion kinetics, are characterized to guide rational design of polymers for specific applications, including controlled release of therapeutic proteins and deposition of biocompatible surface layers. Disruption of the aggregation of the end groups using biocompatible complexing agents or solvents produces a low viscosity liquid that is injectable; self-assembly of the gel once inside the body can be achieved gently by diffusion of the complexing agent or solvent out into the surrounding tissue. By modulating molecular structure, the mechanical and erosion properties of these hydrogels can be systematically varied over a wide range for desired applications. With increasing fluoroalkyl length relative to PEG length, the phase behavior of these fluoroalkyl-ended PEGs (Rf-PEGs) polymers in aqueous solution changes from singlephase behavior (continuous transition in properties from solution-like to gel-like with increasing concentration), to sol-gel coexistence, to an insoluble precipitate (Chapter 2). For sol-gel coexisting polymers, the equilibrium gel concentration and the modulus of the gel phase are governed by the length of the PEG midblock, whereas the relaxation time is determined by the hydrophobe length. The erosion characteristics of these hydrogels correlate with their phase behavior: the gels of sol-gel coexisting species exhibit surface erosion in an open system with slow dissolution rate controlled by the end-group length, whereas gels showing single-phase behavior exhibit bulk erosion that is relatively fast. Aqueous solutions of Rf-PEGs exhibit ordering transitions, with increasing concentration (Chapter 3). The hydrophobic cores of the micelle-like aggregates order into a body-centered-cubic (BCC) structure. The aggregated state of the hydrophobic core is determined by the length of the hydrophobic end group, and is insensitive to the concentration of the polymer solution or the temperature. A shorter PEG length for a given end group produces a much enhanced ordering compared to a longer one. This micelle packing effect is manifested in changes in the viscoelastic properties: the single-relaxation behavior evolves to the appearance of a new low frequency elastic plateau in the dynamic moduli, and a linear response changes to a yielding behavior in creep. The gel phase of sol-gel coexisting polymers can be transformed into an injectable state by the addition of a bio-tolerable organic solvent, such as N-methyl pyrrolidone (NMP), and this solution can be restored to a hydrogel state quickly after injection by removal of the organic solvent by diffusion. Release of Human growth hormone (hGH) using this injectable formulation (Chapter 4) reveals that hGH remains stable inside the hydrogel formed, and more than 2 weeks of prolonged release of hGH pretreated with zinc is obtained using the injectable formulation without irreversible aggregation. For the Rf-PEGs examined here, the release rate of hGH is determined by the rate of diffusion through the hydrogel. The telechelic Rf-PEGs that exhibit sol-gel equilibrium or precipitated gel phase behavior provide a facile route to hydrophilic modification of poly(tetrafluoroethylene) (PTFE) surfaces that are frequently encountered in biomedical devices (Chapter 5). Dip coating of PTFE into 1 wt % Rf-PEGs in ethanol, followed by immersing into water, converts the surface of PTFE from hydrophobic to hydrophilic. The lifetime of this modification is correlated to the phase behavior of the bulk gel state, and stable in the various ranges of shear rates. An Rf-PEG that is insoluble in water gave a stable modification over a period of weeks in the absence of shear, and persisted for days when subjected to the highest shear stresses encountered in arteries (3-4Pa). Telechelic Rf-PEGs are effective, while monofunctional PEGs with a single fluoroalkyl group are not. The swelling and drying behaviors of thin films of RfPEGs (~0.1 [mu]m) show abnormalities relative to glassy and semi-crystalline films (Chapter 6). In a humidity ramp test starting from a dry state, thin films of Rf-PEGs show a distinctive hysteresis behavior; as humidity increases, little swelling occurs until ~ 85% humidity, then the film swells rapidly; as the humidity decreases, a rapid deswelling occurs near ~75% humidity. In a humidity step test, following a step-up the mass increase shows an overshoot, followed by a gradual approach to the equilibrium value, whereas the film tracks the equilibrium state very rapidly and monotonically following a step down from high to low humidity.</p

    Cellular infiltration in an injectable sulfated cellulose nanocrystal hydrogel and efficient angiogenesis by VEGF loading

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    Abstract Background Cellular infiltration and angiogenesis into implanted biomaterial scaffolds are crucial for successful host tissue integration and tissue regeneration. Cellulose nanocrystal (CNC) is a nano-sized cellulose derivative, which can form an injectable physical gel with salts. Sulfate groups of sulfated CNC (CNC-S) can act as a binding domain to various growth factors and cytokines with a heparin-binding domain for sustained release of them. Vascular endothelial growth factor (VEGF) can promote the proliferation of endothelial cells and angiogenesis. In this study, VEGF-loaded CNC-S hydrogel was evaluated as an injectable scaffold that can induce cellular infiltration and angiogenesis. Methods CNC-S was hydrolyzed to get desulfated CNC (CNC-DS), which was used as a negative control group against CNC-S. Both CNC-S and CNC-DS hydrogels were prepared and compared in terms of biocompatibility and VEGF release. The hydrogels with or without VEGF loading were subcutaneously injected into mice to evaluate the biocompatibility, cellular infiltration, and angiogenesis induction of the hydrogels. Results Both hydrogels possessed similar stability and shear-thinning behavior to be applicable as injectable hydrogels. However, CNC-S hydrogel showed sustained release (until 8 weeks) of VEGF whereas CNC-DS showed a very fast release of VEGF with a large burst. Subcutaneously injected CNC-S hydrogel showed much enhanced cellular infiltration as well as better biocompatibility with milder foreign body response than CNC-DS hydrogel. Furthermore, VEGF-loaded CNC-S hydrogel induced significant angiogenesis inside the hydrogel whereas VEGF-loaded CNC-DS did not. Conclusion CNC-S possesses good properties as a biomaterial including injectability, biocompatibility, and allowing cellular infiltration and sustained release of growth factors. VEGF-loaded CNC-S hydrogel exhibited efficient angiogenesis inside the hydrogel. The sulfate group of CNC-S was a key for good biocompatibility and the biological activities of VEGF-loaded CNC hydrogel

    Sustained release of human growth hormone from in situ forming hydrogels using self-assembly of fluoroalkyl-ended poly(ethylene glycol)

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    Poly(ethylene glycol)s modified with fluorocarbon end groups are capable of in situ transition from an injectable liquid to a viscoelastic hydrogel by hydrophobic interaction of the end groups; this class of materials is useful for a variety of biomedical applications, including sustained protein release. The hydrogel state can be transformed into an injectable state by the addition of a toxicologically acceptable organic solvent, such as N-methyl pyrrolidone; after injection, this solution quickly returns to a gel state by diffusion of the water-miscible organic solvent into the surrounding environment. In vitro characterization of sustained release of human growth hormone (hGH) using this injectable depot shows that hGH remains stable inside the hydrogel formed, and demonstrates more than 2 weeks of prolonged release of hGH complexed with Zn²⁺ ions without protein aggregation or initial burst

    Sustained release of human growth hormone from in situ forming hydrogels using self-assembly of fluoroalkyl-ended poly(ethylene glycol)

    No full text
    Poly(ethylene glycol)s modified with fluorocarbon end groups are capable of in situ transition from an injectable liquid to a viscoelastic hydrogel by hydrophobic interaction of the end groups; this class of materials is useful for a variety of biomedical applications, including sustained protein release. The hydrogel state can be transformed into an injectable state by the addition of a toxicologically acceptable organic solvent, such as N-methyl pyrrolidone; after injection, this solution quickly returns to a gel state by diffusion of the water-miscible organic solvent into the surrounding environment. In vitro characterization of sustained release of human growth hormone (hGH) using this injectable depot shows that hGH remains stable inside the hydrogel formed, and demonstrates more than 2 weeks of prolonged release of hGH complexed with Zn²⁺ ions without protein aggregation or initial burst
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