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PubMed2004

Sustained delivery of vascular endothelial growth factor with alginate beads.

Therapeutic angiogenesis is the growth of blood vessels from a pre-existing vasculature for clinical applications such as treating myocardial and limb ischemia. Vascular endothelial growth factor (VEGF) is a potent signal transduction molecule that acts specifically on vascular endothelial cells. Encapsulation of VEGF in a polymer matrix not only protects protein against enzymatic degradation in the body, but also allows proteins to be released at a controllable rate into a localized area. In this study, VEGF was encapsulated in calcium alginate beads by the extrusion/external gelation method, and was subsequently released in PBS and in serum media. The objective was to optimize VEGF encapsulation yield and obtain VEGF release at a constant rate from alginate matrices in vitro. The incorporation of low concentrations of VEGF and NaCl can increase encapsulation yield to 97%. The rate of VEGF release from alginate beads was higher in serum than in PBS, which was due to the capacity of the serum in reducing the electrostatic interaction between alginate and VEGF. The presence of CaCl(2) in the release supernatant can shield the alginate interaction with VEGF, and a constant release rate of 6 ng/ml/day may be sustained for 14 days. These results suggest that the alginate-VEGF delivery system may be useful in the development of vascular tissue engineering and wound healing applications.

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PubMed2004

Cross-linked alginate-gelatine beads: a new matrix for controlled release of pindolol.

This work is focused on the development of a new particulate drug delivery system using a sodium alginate matrix containing pindolol as a model drug molecule for intestinal drug prolonged release. Calcium alginate beads are known to be unable to control the release of most insoluble drugs. Pindolol-loaded alginate-gelatine beads have been developed using a solvent-free technique that involves a cross-linking reaction. Modifications in matrix structure and physicochemical behaviour caused by the cross-linking reaction were assessed during particle formation and drug release. Several parameters, such as matrix gelling rate, encapsulation efficiency, drug release profile and matrix erosion rate, were investigated. Physicochemical characterisation indicates the formation of a new alginate-gelatine matrix and shows that pindolol does not interfere with the matrix formation process. Matrix swelling of calcium alginate beads induced by phosphate buffer ends up in erosion and destruction. However, for cross-linked beads swelling does not lead to complete erosion, which may be the main cause of pindolol retention within the matrix. The modifications introduced in the initial calcium alginate formulation by means of an appropriate method such as the use of a cross-linking agent successfully changed the matrix performance, allowing the controlled release of pindolol.

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PubMed2006

Polyionic hydrocolloids for the intestinal delivery of protein drugs: alginate and chitosan--a review.

The protein pharmaceutical market is rapidly growing, since it is gaining support from the recombinant DNA technology. To deliver these drugs via the oral route, the most preferred route, is the toughest challenge. In the design of oral delivery of peptide or protein drugs, pH sensitive hydrogels like alginate and chitosan have attracted increasing attention, since most of the synthetic polymers are immunogenic and the incorporation of proteins in to these polymers require harsh environment which may denature and inactivate the desired protein. Alginate is a water-soluble linear polysaccharide composed of alternating blocks of 1-4 linked alpha-L-guluronic and beta-D-mannuronic acid residues where as chitosan is a co polymer of D-glucosamine and N-acetyl glucosamine. The incorporation of protein into these two matrices can be done under relatively mild environment and hence the chances of protein denaturation are minimal. The limitations of these polymers, like drug leaching during preparation can be overcome by different techniques which increase their encapsulation efficiency. Alginate, being an anionic polymer with carboxyl end groups, is a good mucoadhesive agent. The pore size of alginate gel microbeads has been shown to be between 5 and 200 nm and coated beads and microspheres are found to be better oral delivery vehicles. Cross-linked alginate has more capacity to retain the entrapped drugs and mixing of alginate with other polymers such as neutral gums, pectin, chitosan, and eudragit have been found to solve the problem of drug leaching. Chitosan has only limited ability for controlling the release of encapsulated compound due to its hydrophilic nature and easy solubility in acidic medium. By simple covalent modifications of the polymer, its physicochemical properties can be changed and can be made suitable for the peroral drug delivery purpose. Ionic interactions between positively charged amino groups in chitosan and the negatively charged mucus gel layer make it mucoadhesive. The favourable properties like biocompatibility, biodegradability, pH sensitiveness, mucoadhesiveness, etc. has enabled these polymers to become the choice of the pharmacologists as oral delivery matrices for proteins.

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PubMed2005

Hepatocytes cultured in alginate microspheres: an optimized technique to study enzyme induction.

An important application of hepatocyte cultures is identification of drugs acting as inducers of biotransformation enzymes that alter metabolic clearance of other therapeutic agents. In the present study we optimized an in vitro system with hepatocytes cultured in alginate microspheres that allow studies of enzyme induction with excellent sensitivity. Induction factors obtained with standard inducers, such as 3-methylcholanthrene or phenobarbital, were higher compared to those with conventional hepatocyte co-cultures on collagen coated dishes. This is illustrated by activities of 7-ethoxyresorufin-O-deethylase (EROD) after incubation with 5 microM 3-methylcholanthrene (3-MC), a standard inducer for cytochrome P4501A1 and 1A2. Mean activities for solvent controls and 3-MC exposed cells were 2.99 and 449 pmol/min/mg protein (induction factor: 150) for hepatocytes cultured in microspheres compared to 2.72 and 80.6 pmol/min/mg (induction factor: 29.6) for hepatocytes on collagen coated dishes. To compare these in vitro data to the in vivo situation male Sprague Dawley rats, the same strain that was used also for the in vitro studies, were exposed to 3-MC in vivo using a protocol that guarantees maximal induction. Activities were 29.2 and 1656 pmol/min/mg in liver homogenate of solvent and 3-MC treated animals (induction factor: 56.7). Thus, the absolute activities of 3-MC exposed hepatocytes in microspheres are lower compared to the in vivo situation. However, the induction factor in vitro was even higher compared to the in vivo situation (150-fold versus 56.7-fold). A similar scenario was observed using phenobarbital (0.75 mM) for induction of CYP2B and 3A isoenzymes: induction factors for testosterone hydroxylation in position 16beta were 127.5- and 50.4-fold for hepatocytes in microspheres and conventionally cultured hepatocytes, respectively. The new in vitro system with hepatocytes embedded in solid alginate microspheres offers several technical advantages: (i) the solid alginate microspheres can be liquefied within 60s, allowing a fast and complete harvest of hepatocytes; (ii) alginate capsules are stable allowing transport and mechanical stress; (iii) high numbers of hepatocytes can be encapsulated in short periods; (iv) defined cell numbers between 600 hepatocytes, the approximate number of cells in one capsule, and 18 x 10(6) hepatocytes, the number of hepatocytes in 6 ml alginate, can be transferred to a culture dish or flask. Thus, encapsulated hepatocytes allow a flexible organization of experiments with respect to cell number. In conclusion, we optimized a technique for encapsulation of hepatocytes in alginate microspheres that allows identification of enzyme induction with an improved sensitivity compared to existing systems.

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PubMed2004

Sustained release of vascular endothelial growth factor from calcium-induced alginate hydrogels reinforced by heparin and chitosan.

A possible alternative for immunosuppression is a microencapsulation technique using hydrogels, which have been utilized for cell immobilization and drug delivery systems. Angiogenesis is crucial for delivery of the metabolic products to the host tissues as well as to supply oxygen and nutrients to cells. The local delivery of angiogenic growth factors, such as VEGF and basic FGF, has been recently studied to enhance angiogenesis on peripheral tissue of graft. In this study, we evaluated sustained VEGF release with a model using hydrogels coated with chitosan and heparin in vitro. We fabricated calcium alginate gels and chitosan-coated calcium alginate gels. Heparinized chitosan-coated calcium-induced alginate hydrogel beads were prepared by soaking chitosan-coated calcium alginate gels in heparin solution. We compared the stability and VEGF release manner between three kinds of hydrogels. To compare the stability, 5 mL of each hydrogel was incubated with 20 mL PBS under the rotational culture. Compression forces were measured using a rheometer. The amount of VEGF released from the gels was measured by ELISA. The heparin-coated chitosan alginate hydrogels showed the highest surface stability among the three hydrogels. VEGF from the heparinized gel was released in sustained manner up to 10 days in vitro. Chitosan-coated alginate gels released 90% of loaded VEGF within 5 days. These results suggest that local delivery of VEGF using a heparinized hydrogel may provide a long-term supply of angiogenic growth factor that might induce new vessel formation in vivo.

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PubMed2003

Characterization of the alginates from algae harvested at the Egyptian Red Sea coast.

The alginates from five species of brown algae from the Egyptian Red Sea coast, namely: Cystoseira trinode, Cystoseira myrica, Sargassum dentifolium, Sargassum asperifolium, and Sargassum latifolium, were isolated and their compositions and structures studied by 1H NMR spectroscopy. All the alginates studied contain more guluronic acid (G) than mannuronic acid (M) and have a homopolymeric block-type structure (eta<1). The intrinsic viscosity of the alginate samples range from 8.6 to 15.2 and the gel strength ranges from 10.97 to 15.51. The constitutional G- and M-blocks of alginates from two different species (C. trinode and S. latifolium) were separated after partial acid hydrolysis. The 1H NMR spectral data of the blocks GG and MM obtained by chemical fractionation were compared with those of polymeric alginates. The monomeric uronic acids were separated by complete acid hydrolysis of S. asperifolium alginate and the G and M monomers were characterized by 1H, 13C NMR spectroscopy as well as by paper electrophoresis.

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PubMed2002

Characteristics of metal removal using carboxylated alginic acid.

Carboxylated alginic acid prepared through oxidation reaction with potassium permanganate had a high uptake capacity of 3.1 mmol/g dry mass at pH 4 and showed higher affinity to heavy metals compared to alkaline metals (Ca2+, Mg2+) in mixed metal system. The pHzpc value of the carboxylated alginic acid was 2.31, which was lower than pHzpc (2.83) of natural alginic acid. The increased number of carboxyl groups was confirmed by IR and 13C-NMR spectrum analysis, elemental analysis and carboxyl group number count. Lead adsorption by carboxylated alginic acid is an endothermic process since binding was increased as the temperature increased. When the temperature of wastewater is higher than room temperature, carboxylated alginic acid has an advantage over general adsorbents whose uptake capacity decreases as the temperature increases. Also, lead adsorbed on carboxylated alginic acid was desorbed effectively by about 80% by nitrilotriaceticacid.

Alginates↗

PubMed1997

Alginate based new materials.

Present and future applications of alginates are mainly linked to the most striking feature of the alginate molecule; i.e. a sol/gel transition in the presence of multivalent cations, e.g. Ca2+, almost independent on temperature. These very mild conditions, combined with the fact that alginates are highly characterised and understood both in the liquid and in the gel phase, makes this biopolymer unique compared to other gelling polysaccharides. Only pectins resemble alginate in the sol/gel transition behaviour, but this system can hardly be said to be as well characterised and understood as the alginates. The properties of alginate solutions and gels suggest biomedical and pharmaceutical uses. In this paper, the question of the specifications required by a polymer for applications in some biomedical areas will be discussed.

Alginates↗

PubMed2000

Alginates from wound dressings activate human macrophages to secrete tumour necrosis factor-alpha.

Alginates are used to manufacture a number of wound dressings. Clinical observations indicate that they may initiate or accelerate healing of chronic wounds after treatment of underlying pathology. Wound granulation tissue contains large numbers of macrophages and they are thought to regulate the healing process. As purified alginates have been demonstrated to activate macrophages this study was initiated to determine whether alginates present within wound dressings may interact with wound macrophages. Alginate fibres taken from four commercially available dressings were co-cultured with the human histiocytic lymphoma cell line U937 following its differentiation with PMA. Activation was assessed by measurement of TNFalpha production. Two of the dressings, Seasorb and Tegagen, had a minimal effect whilst Sorbsan at 1 mg/ml induced 302 + 19 pg/ml TNFalpha. This effect was inhibited by polymyxin B indicating that activation was due to endotoxin contamination. Kaltostat induced production of 839 + 36 pg/ml TNFalpha. This effect was induced both by polymyxin inhibitable endotoxin and a direct interaction with the alginate fibres. These data indicate that some alginate containing dressings have the potential to activate macrophages within the chronic wound bed and generate a pro-inflammatory signal which may initiate a resolving inflammation characteristic of healing wounds.

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PubMed2003

NMR properties of alginate microbeads.

Alginates are a family of unbranched polysaccharides with properties that vary widely depending on their composition. In the presence of multivalent cations (frequently Ca2+), alginates form a gel. Consequently, alginates have been used to encapsulate a variety of biological materials, including cells. In this study, we present NMR relaxation and diffusion data from alginate microbeads with similar size and properties to those used in the development of a bioartificial pancreas. Our data demonstrate that the transverse relaxation time (T2) of water within the gel depends on the guluronic acid content of the alginate, whereas the longitudinal relaxation time (T1) and the apparent diffusion coefficient of water do not. Our data further suggest that the diffusion of Ca2+ ions is hindered by the presence of a poly-L-lysine layer, a layer commonly added to provide mechanical support to the beads and immunoprotection to the encapsulated cells in the event of implantation. The impact of these data on our understanding of the role of alginate gels in the development of a bioartificial pancreas is discussed.

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PubMed1999

Alginate hydrogels as synthetic extracellular matrix materials.

Alginate hydrogels are used extensively in cell encapsulation, cell transplantation, and tissue engineering applications. Alginates possess many favorable properties required in biomaterials, but are unable to specifically interact with mammalian cells. We have therefore covalently modified alginate polysaccharides with RGD-containing cell adhesion ligands utilizing aqueous carbodiimide chemistry. The chemistry has been optimized and quantified with reaction efficiencies reaching 80% or greater. The concentration of peptide available for reaction was then varied to create hydrogels with a range of ligand densities. Mouse skeletal myoblasts were cultured on alginate hydrogel surfaces coupled with GRGDY peptides to illustrate achievement of cellular interaction with the otherwise non-adhesive hydrogel substrate. Myoblasts adhere to GRGDY-modified alginate surfaces, proliferate, fuse into multinucleated myofibrils, and express heavy-chain myosin which is a differentiation marker for skeletal muscle. Myoblast adhesion and spreading on these GRGDY-modified hydrogels was inhibited with soluble ligand added to the seeding medium, illustrating the specificity of adhesion to these materials. Alginate may prove to be an ideal material with which to confer specific cellular interactive properties, potentially allowing for the control of long-term gene expression of cells within these matrices.

Alginates↗

PubMed1999

Microcapsules of alginate-chitosan. II. A study of capsule stability and permeability.

The stability of alginate-chitosan capsules was shown to depend strongly on the amount of chitosan bound to the capsules. When the capsules were made by dropping a solution of sodium alginate into a chitosan solution (one-stage procedure), all the chitosan was located in a thin alginate-chitosan membrane on the surface. These capsules were much weaker than the capsules made by reacting calcium alginate beads in an aqueous solution of chitosan and calcium chloride (two-stage procedure). Capsules with high mechanical strength were obtained after shorter reaction times when the number-average molecular weight of the chitosan was reduced to around 15,000, when the capsules were made more homogeneous and when the capsule diameter was reduced to around 300 microm. When these capsules were treated with calcium sequestrant such as citrate under conditions where calcium alginate gels normally dissolve, they still had a gel core indicating the presence of chitosan throughout the capsule matrix. The permeability of the two-stage capsules was reduced when the chitosan molecular weight was increased and the degree of acetylation was increased, and when the capsules were made more inhomogeneous. The addition of another several layers of alginate and chitosan resulted in capsules virtually impermeable to IgG, suggesting an average capsule pore diameter less than 90 A.

Alginates↗

PubMed1999

Effects of alginate composition on the metabolic, secretory, and growth characteristics of entrapped beta TC3 mouse insulinoma cells.

The effects of alginate composition on cell growth as well as the metabolic and secretory profile of transformed beta-cells entrapped in alginate/poly-L-lysine/alginate (APA) solid beads were investigated following entrapment of beta TC3 mouse insulinoma cells in alginate composed of either high mannuronic acid or high guluronic acid residues. Entrapped cultures were maintained in spinner flasks for 40-60 days. The pattern of cell growth and the overall rates of glucose consumption and insulin secretion were investigated. Cultures of beta TC3 cells entrapped in alginate composed predominantly of mannuronic acid units (77%) displayed a linear increase in the rates of glucose consumption and insulin secretion concomitant with an increase in cell population in the periphery of the beads. Conversely, cultures of beta TC3 cells entrapped in alginate composed predominantly of high guluronic acid units (69%) displayed a decrease in the rates of glucose consumption and insulin secretion during the first three weeks of culture, followed by a rapid recovery that surpassed the initial rates by day 40. This biphasic pattern was concomitant to a decrease in viable cells during the first three weeks as ascertained by histology, followed by an increase in cell proliferation. Cell growth in high guluronic acid alginate took place at random locations throughout the solid bead and not in the periphery, as was the case in high mannuronic acid alginate preparations. Possible reasons for these differences and the significance of these findings in the context of a bioartificial pancreas composed of APA entrapped transformed cells are discussed.

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PubMed2002

Cell and nucleus deformation in compressed chondrocyte-alginate constructs: temporal changes and calculation of cell modulus.

Mechanical loading is essential for the homeostasis of articular cartilage and may be necessary for achieving functional tissue engineered cartilage repair using isolated cells seeded in scaffolds such as alginate. Chondrocyte mechanotransduction is poorly understood, but may involve cell deformation and associated distortion of intracellular organelles. The present study used confocal microscopy to examine cell and nucleus morphology in isolated chondrocytes compressed in alginate constructs. Compression of 2% alginate resulted in cell deformation from a spherical to an oblate ellipsoid morphology with conservation of cell volume. Cell deformation was associated with deformation, to a lesser degree, of the nucleus. Despite constant cell deformation over a 25 min period of static compression, the nucleus deformation reduced significantly, particularly in the axis perpendicular to the applied compression. Constructs made of a lower alginate concentration exhibited a reduced compressive modulus with an altered cellular response to compression. In 1.2% alginate, compression resulted in cell deformation which was initially of a similar magnitude to that in 2% alginate but subsequently reduced over a 60 min period reflecting the viscoelastic behaviour of the gel. This phenomenon enabled the calculation of a stress-strain relationship for the cell with an estimated Young's modulus value of approx. 3 kPa.

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PubMed2001

Characterization of algG encoding C5-epimerase in the alginate biosynthetic gene cluster of Pseudomonas fluorescens.

The organization of the alginate gene cluster in Pseudomonas fluorescens was characterized. A bank of genomic DNA from P. fluorescens was mobilized to a strain of Pseudomonas aeruginosa with a transposon insertion (algJ::Tn501) in the alginate biosynthetic operon that rendered it non-mucoid. Phenotypic complementation in this heterologous host was observed, and a complementing clone containing 32 kb of P. fluorescens DNA was obtained. Southern hybridization studies showed that genes involved in alginate biosynthesis (e.g. algD, algG, and algA) were approximately in the same order and position as in P. aeruginosa. When the clone was mobilized to a P. aeruginosa algG mutant that produced alginate as polymannuronate due to its C5-epimerase defect, complementation was observed and the alginate from the recombinant strain contained L-guluronate as determined by proton nuclear magnetic resonance spectroscopy. A sequence analysis of the P. fluorescens DNA containing algG revealed sequences similar to P. aeruginosa algG that were also flanked by algE- and algX-like sequences. The predicted AlgG amino acid sequence of P. fluorescens was 67% identical (80% similar) to P. aeruginosa AlgG and 60% identical (76% similar) to Azotobacter vinelandii AlgG. As in P. aeruginosa, AlgG from P. fluorescens appeared to have a signal sequence that would localize it to the periplasm where AlgG presumably acts as a C5-epimerase at the polymer level. Non-polar algG knockout mutants of P. fluorescens were defective in alginate production, suggesting a potential role for this protein in polymer formation.

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PubMed2000

A new long acting ophthalmic formulation of carteolol containing alginic acid.

Alginic acid was evaluated as a potential vehicle in ophthalmic solutions for prolonging the therapeutic effect of carteolol. This anionic vehicle was expected to slow down drug elimination by the lacrimal flow, both by undergoing in-situ gel formation and by interacting with the mucus. In vitro studies indicated that carteolol is released slowly from alginic acid formulations, suggesting an ionic interaction. The adhesive behavior of alginic acid solution was better than that of another polymer, hydroxyethylcellulose (HEC). Intraocular pressure (IOP) measurements of rabbit eyes treated with a 1% carteolol formulation with or without alginic acid showed that this polymer significantly extended the duration of the pressure-reducing effect of carteolol to 8 h. The increased ocular bioavailability of 1% carteolol in the presence of alginic acid led to an equivalent concentration in the target tissue although administration was only once a day compared with twice a day for 1% carteolol alone. The overall results of this study indicate that the alginic-acid vehicle is an excellent drug carrier, well tolerated, and could be used for the development of a long-acting ophthalmic formulation of carteolol.

Adhesiveness↗

PubMed2000

Survival and stability of bifidobacteria loaded in alginate poly-l-lysine microparticles.

Bifidobacteria-loaded alginate microparticles were prepared by spraying a mixture of alginate and bifidobacteria culture using an air atomization method. Survival and stability of bifidobacteria loaded in microparticles were then evaluated. Survival of bifidobacteria from alginate poly-l-lysine microparticles was significantly increased when MRS broth or yeast extract was added in simulated intestinal fluid (pH 6.8). The number of bifidobacteria gradually increased for 8 h (10(8) cfu/g) and then reached about 10(9)-10(10) cfu/g when incubated over 12 h in intestinal fluid containing 0.5% yeast extract and 0.05% L-cysteine. The survival of bifidobacteria was highly dependent on the pH of the exposing media. When the bifidobacteria was immobilized with alginate or even poly-l-lysine treatment, the survival of bifidobacteria was highly enhanced in the low pH conditions (ca. > 10(8) vs. < 10(3) cfu/g). The stability of free flowing bifidobacteria-loaded alginate poly-l-lysine microparticles was significantly improved during storage at 4 degrees C in a refrigerator when compared to bifidobacteria cultures. The bifidobacteria-loaded alginate poly-l-lysine microparticles could be applied to various dairy products.

Alginates↗

PubMed2002

An in vitro mucosal model for prediction of the bioadhesion of alginate solutions to the oesophagus.

This paper discusses the development of an in vitro model utilised to assess the adhesion of alginate solutions to porcine oesophageal tissue. The methodology involved the construction of retention apparatus onto which sections of tissue were mounted. Fluorescently labelled alginate solutions of known rheological profile were dispensed onto the tissue at a concentration of 2% w/v. A washing solution was applied at a specified rate to mimic saliva flow and the eluted material collected. Fluorimetric analysis allowed dose retention to be assessed as a function of time. The effect of the nature of the washing solution and the choice of alginate were investigated. It was found that after 30 min up to 20% of the applied alginate dose remained associated with the tissue, regardless of the alginate selected from the range examined. The nature of the washing medium did not have a significant effect on retention, irrespective of the inherent mucin concentration. Overall this study indicated that the technique presented offers a viable means of studying bioadhesion of liquids and also demonstrates that alginate solutions may have an application as bioadhesive agents for localisation within the oesophagus.

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