Immobilization of living cells or other biomaterials in alginate gels is a well-known technology used in an increasing number of biomedical and industrial applications. Cells immobilized in alginate gels maintain good viability during long-term culture due to the mild environment of the gel network. In tissue engineering applications immobilized cells or tissue can be used as bioartificial organs as the alginate gel may function as a protective barrier towards physical stress and to avoid immunological reactions with the host. Such bioreactor systems, of which the entrapped cells are selected or manipulated to excrete therapeutic products, are currently being developed for the treatment of a variety of diseases like cancer and diabetes. For most uses, and in particular those involving immobilization of living cells, microcapsules are used. Smaller beads/capsules have the advantage of a higher surface to volume ratio allowing good transport of essential nutrients and are also less fragile. Diffusion limitations within larger beads may limit cellular metabolism as the lack of essential substances like oxygen supply to the interior of the beads may lead to cell death as a result of consumption from the surrounding cells. Therefore a good control of bead size and shape is crucial and should be carefully controlled. A suitable methodology for production of small beads under controlled conditions is therefore also necessary. The bead generators shown here are recommended alternatives for research use in the production of small spherical alginate beads containing biological materials and having a narrow size distribution.

Commonly used principle for immobilization of cells in alginate beads for transplantation purposes. The beads may also be coated with other biopolymers and alginate for improved properties.

Small alginate beads with a narrow size distribution, ranging in size down to about 150 µm, can easily be manufactured by using the electrostatic bead generator. The basic principle of the instrument is the use of an electrostatic potential to pull the droplets from a nozzle tip. An electrostatic voltage of a few kV is set between the needle feeding the alginate solution and the gelling bath. The droplet size is also largely determined by selecting an appropriate nozzle size.

Small size alginate beads with a relatively narrow size distribution, ranging in size down to about 600 µm can be manufactured by the use of the coaxial bead generator. The basic principle of the instrument is the use of a coaxial air stream to pull droplets from a needle tip into a gelling bath. Bead size is controlled by adjusting the solution and gas- flow rates.

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In contrast to most other polysaccharide gels, alginate gels can develop and set at constant temperature. This unique property is particularly useful in applications involving fragile materials like cells or tissue with low tolerance for higher temperatures. An alginate gel will develop instantaneously in the prescence of divalent cations like Ca2+, Ba2+ or Sr2+ and acid gels may also develop at low pH. Gelling occurs when the divalent cations take part in the interchain ionic binding between guluronic acids blocks (G-blocks) in the polymer chain giving rise to a three dimensional network. Such binding zones between the G-blocks are often referred to as “egg-boxes” and consequently alginates with a high content of G-blocks induce stronger gels. Gels made of M-rich alginate are softer and more fragile and may also have a lower porosity. This is due to the lower binding strength between the polymer chains and to the higher flexibilities of the molecules. The gelling process is highly dependent upon diffusion of gelling ions into the polymer network and there are essentially two main methods for the preparation of alginate gels: the dialysis/diffusion method and the internal gelling method. In the dialysis/diffusion method (diffusion setting) gelling ions are allowed to diffuse into the alginate solution. This method is most commonly used in biotechnology for immobilization of living cells in alginate gel. An alginate solution can, however, also be solidifed by internal gelation method/internal setting, i.e. in situ gelling. Here a calcium salt with limited solubility or complexed Ca2+-ions are mixed with an alginate solution into which the calcium ions are released, usually by the generation of acidic pH with a slowly acting acid such as D-glucono-δ-lactone (GDL). This method is chosen if the purpose is to create a homogenous, non-syneretic alginate macrogel to fill the space of a given container. The main difference between internal and diffusion setting is the gelling kinetics. Consequently, the gel network will also be different. premium investment llc

PRONOVA™ UP is a series of highly purified and well-characterized sodium alginates developed for use in biomedical and pharmaceutical applications. Production is in compliance with cGMP ISO and ICH guidelines. A Drug Master File covering these products has been submitted to the US FDA.

Diffusion gelling is characterized by rapid diffusion of gelling ions (e.g. Ca2+) into the polymer network. This high-speed setting is indeed utilized for immobilization purposes where each droplet and alginate solution makes one single gel bead that entraps the active agent/biological material. An important feature of the diffusion gelling is that the final gel may exhibit an inhomogeneous alginate distribution, as the alginate concentration gradually decreases towards the center of gel. The homogeneity of a diffusion gel can partly be controlled. A high degree of inhomogeneity is obtained by using a low concentration of gelling ions in the absence of non-gelling ions. A more homogeneous gel is obtained when gelling occurs in the presence of high concentrations of both gelling and non-gelling ions.

Internal gelling is based on the addition of an inactive form of the cross-linking ion (Ca2+) into an alginate solution. Controlled release is usually maintained by change of pH or through the limited solubility of the calcium salt source.

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Applications utilizing the entrapment of living cells or other biomaterials in small biopolymer beads have found several uses. This includes implantation of alginate beads containing living cells which have been manipulated to excrete therapeutic substances for the treatment of human diseases. This principle may be used in the treatment of a variety of diseases including Diabetes, Parkinsons and Cancer among others. For the manufacturing of functional beads a suitable bead generator is needed and for many applications the use of an electrostatic bead generator have been found to be the best choice. The instrument is designed for low scale production of small beads in a highly controllable manner. The use of a coaxial air flow bead generator may, however, also be a good alternative.

Coaxial gas flow bead generator

An easy way for production of small alginate beads in a controllable manner is the use of a coaxial-air-flow bead generator. The basic principle of the instrument is the use of a coaxial air stream which pulls droplets from a needle tip into the gelling bath. The instrument is suitable for production of spherical beads ranging in size down to around 600 µm.

Electrostatic Bead Generator

will often be the best alternative, in particular for applications involving small sample entrapment of living cells. The instrument is designed for production of beads ranging in size down to about 150 µm. The instrument utilizes an adjustable electrostatic voltage of a few kV between the nozzle and gelling bath in order to reduce the droplet size. Different nozzles are available for the choice of desired bead size NovaMatrix offers a range of different grades of ultrapure alginates with low endotoxin levels suitable for use in cell encapsulation application. In contrast to most other polysaccharide gels, alginate gels can develop and set at constant temperature. This unique property is particularly useful in applications involving fragile materials like cells or tissue with low tolerance for higher temperatures. An alginate gel will develop instantaneously in the presence of divalent cations like Ca2+, Ba2+ or Sr2+ and acid gels may also develop at low pH. Gelling occurs when the divalent cations take part in the interchain ionic binding between guluronic acids blocks (G-blocks) in the polymer chain giving rise to a three dimensional network. Such binding zones between the G-blocks are often referred to as egg-boxes, and consequently alginates with a high content of G-blocks induce stronger gels. Gels made of M-rich alginate are softer and more fragile, and may also have a lower porosity. This is due to the lower binding strength between the polymer chains and to the higher flexibilities of the molecules. Choice of alginate can have an impact on bead properties. Some of parameters that have been seen influencing the bead formation and size are G/M ratio, viscosity, concentration and flow rate. PRONOVA ultrapure and sterile alginate product range should give you the possibility to cover different options in cell encapsulations. Visit our store to view different grades available References: [1] Controlling the size of alginate gel beads by use of a high electrostatic potential. Klokk TI, Melvik JE. J Microencapsul. 2002 Jul-Aug;19(4):415-24. [2] J Microencapsul. 2006 Sep;23(6):613-21. Effect of alginate composition and gelling cation on microbead swelling. Darrabie MD1, Kendall WF, Opara EC.

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