Preparing porous hydrogel products

Details Preparing porous hydrogel products Preparing porous hydrogel products

2002-04-18

2003-01-28

Foelak, Morton (Department: 1711)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Gas produced in situ by chemical reaction

C424S045000, C424S485000, C424S488000, C424S489000, C424S499000, C424S500000, C521S182000, C521S189000, C521S084100

Reexamination Certificate

active

06511650

ABSTRACT:

Alginate and other hydrogels are attractive materials for a variety of biomedical applications, including cell transplantation, and drug delivery. In many of these applications one desires to either seed cells into the material, or allow for cellular invasion following implantation into the body. However, alginate is typically used in the physical form of a hydrogel, with small pores (nm size scale) that do not allow for cell movement in or out of the material. This invention is directed to a new approach to form porous hydrogel materials by first creating gas pockets in the gel and then removing this gas. The removal of the gas creates a porous material, and the initial incorporation of sufficient gas allows one to create a material with an open, interconnected pore structure. Advantageous features of the resulting materials, in addition to their interconnected pore structure, may include that the pore structure is maintained over extended time periods and that the gels maintain a high mechanical integrity that allows seeding with cells and implantation without destruction or compression of the material.
The invention is in contrast to other processing approaches typically used to achieve a porous structure with these types of materials (e.g., lyophilization) in which the porous nature is lost as the material rehydrates and/or the material is significantly weakened by the process.
An approach to form and subsequently remove gas bubbles from alginate gels has been previously described (Gotoh et al.,
Cytotechnology
11, 35 (1993)). However, the methods described in this article did not lead to the formation of structures with a sufficient degree of porosity or a sufficiently open interconnected pore structure.
The method described herein is a considerable modification of the Gotoh et al. method and is conducted under conditions outside of the ranges described therein. An object of the invention is to provide biocompatible hydrogel materials, for example alginate materials, which have a significantly macroporous and open pore structure, e.g., such that the pores are sufficiently open and sized to allow cellular transport therein. This facilitates vascularization and structural integration with the surrounding tissue when used in tissue engineering applications. Thus, the macroporous hydrogel will preferably have pores of at least 1 &mgr;m, particularly from 10 to 1000 &mgr;m. While not limited thereto, the overall porosity is preferably from 30 to 90%, more preferably 35 to 75%. The total surface accessible interconnected porosity is preferably from 30-80%, more preferably 35-70%.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
Objects according to the invention can be achieved by a method for preparing a hydrogel material having macroporous open pore porosity, which comprises:
a) providing a solution of a hydrogel-forming material, a surfactant and, optionally, a gas-generating component which solution is capable of being mixed in the presence of a gas (either added or generated by the gas-generating component) to incorporate the gas in the solution and form a stable foam;
b) forming a stable foam by mixing the solution in the presence of a gas and/or, if the gas-generating component is present, by subjecting the solution to conditions or agents which result in generation of gas from the gas-generating component;
c) exposing the stable foam to conditions and/or agents which result in gelling of the hydrogel-forming material to form a hydrogel containing gas bubbles therein;
d) releasing the gas bubbles from the hydrogel, for example by subjecting it to a vacuum, to form a hydrogel material having macroporous open pore porosity.
Steps b) and c) may be performed simultaneously or in series.
Any hydrogel-forming material which can provide the desired effect of resulting in a foam which allows preparation of the open pore material can be used in the invention. Examples of materials which can form hydrogels include polylactic acid, polyglycolic acid, PLGA polymers, alginates and alginate derivatives, gelatin, collagen, agarose, natural and synthetic polysaccharides, polyamino acids such as polypeptides particularly poly(lysine), polyesters such as polyhydroxybutyrate and poly-&egr;-caprolactone, polyanhydrides; polyphosphazines, poly(vinyl alcohols), poly(alkylene oxides) particularly poly(ethylene oxides), poly(allylamines)(PAM), poly(acrylates), modified styrene polymers such as poly(4-aminomethylstyrene), pluronic polyols, polyoxamers, poly(uronic acids), poly(vinylpyrrolidone) and copolymers of the above, including graft copolymers.
A preferred material for the hydrogel is alginate or modified alginate material. Alginate molecules are comprised of (1-4)-linked &bgr;-D-mannuronic acid (M units) and (&agr;-L-guluronic acid (G units) monomers which vary in proportion and sequential distribution along the polymer chain. Alginate polysaccharides are polyelectrolyte systems which have a strong affinity for divalent cations (e.g. Ca
+2
, Mg
+2
, Ba
+2
) and form stable hydrogels when exposed to these molecules. See Martinsen A., et al.,
Biotech
. &
Bioeng.,
33 (1989) 79-89. Calcium cross-linked alginate hydrogels have been used in many biomedical applications, including materials for dental impressions (Hanks C. T.,et al.,
Restorative Dental Materials
; Craig, R. G., ed., Ninth Edition, Mosby (1993)), wound dressings (Matthew I. R. et al.,
Biomaterials,
16 (1995) 265-274), an injectable delivery medium for chondrocyte transplantation (Atala A., et al.,
J Urology,
152 (1994) 641-643), and an immobilization matrix for living cells (Smidsrod O., et al, TIBTECH 8 (1990) 71-78).
An alternative embodiment utilizes an alginate or other polysaccharide of a lower molecular weight, preferably of size which, after dissolution, is at the renal threshold for clearance by humans. Preferably, the alginate or polysaccharide is reduced to a molecular weight of 1000 to 80,000 daltons, more preferably 1000 to 60,000 daltons, particularly preferably 1000 to 50,000 daltons. It is also useful to use an alginate material of high guluronate content since the guluronate units, as opposed to the mannuronate units, provide sites for ionic crosslinking through divalent cations to gel the polymer.
Alginate can be &ggr;-irradiated in a controlled fashion to cause a random fission of the polymer chains and generation of appropriate low molecular weight alginate fragments [Hartman et al., Viscosities of cacia and sodium alginate after sterization by cobald-60. J. Pharm. Sci.; 1975, 64(5): 802-805; King K., Changes in the functional properties and molecular weight of sodium alginate following &ggr;-irradiation. Food Hydrocoll. 1994; 8(2): 83-96; Delincée H., Radiolytic effects in food. In: Proceedings of the international workshop on food irradiation. 1989, p 160-179]. In these earlier descriptions of the degradation of alginate utilizing &ggr;-irradiation, the conditions used were outside the range required to generate materials with molecular weights lower than 200 kD, or they were used on alginate solutions rather than the bulk material. Other methods for the controlled degradation of alginate are also available [Kimura et al., Effects of soluble alginate on cholesterol excretion and glucose tolerance in rats. J. Ethnopharn.; 1996, 54: 47-54; Purwanto et al., Degradation of low molecular weight fragments of pectin and alginates by gamma-irradiation. Acta Alimentaria; 1998, 27(1): 29-42], but &ggr;-irradiation is a reliable and simple technique for generating low molecular alginates. The reduction in molecular weight can also be effected by hydrolysis under acidic conditions or by oxidation, to provide the desired molecular weight. The hydrolysis may be conducted in accordance with a modified procedure of Haug et al. (Acta. Chem. Scand., 20, p. 183-190 (1966), and Acta. Chem. Scand., 21, p. 691-704 (1967)), which results in a sodium poly(guluronate) of lower mol

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