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WO1990007575A1 - Substances microporeuses stabilisees et substances a base d'hydrogel - Google Patents

Substances microporeuses stabilisees et substances a base d'hydrogel Download PDF

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Publication number
WO1990007575A1
WO1990007575A1 PCT/US1989/005864 US8905864W WO9007575A1 WO 1990007575 A1 WO1990007575 A1 WO 1990007575A1 US 8905864 W US8905864 W US 8905864W WO 9007575 A1 WO9007575 A1 WO 9007575A1
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WO
WIPO (PCT)
Prior art keywords
water
phase
cubic
surfactant
macropores
Prior art date
Application number
PCT/US1989/005864
Other languages
English (en)
Inventor
David M. Anderson
Original Assignee
Anderson David M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anderson David M filed Critical Anderson David M
Publication of WO1990007575A1 publication Critical patent/WO1990007575A1/fr

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    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
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    • A—HUMAN NECESSITIES
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    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
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    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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Definitions

  • the present invention is in the field of microporous membrane materials, especially polymeric
  • membranes and particularly the use of such materials in connection with biologically active agents, in critical filtrations, and in applications involving microstructure such as critical phase transition measurements,
  • the invention pertains to hydrogel applications, particularly soft contact lenses, but also other medical/ biological applications where high strength at high water content, biocoinpatibility, and/or macroporosity are necessary or desirable.
  • MF filtration - - microfiltration
  • UF ultrafiltration
  • RO hyperfiltration or reverse osmosis
  • the ultimate membrane would have identical, highly interconnected pores comprising a porespace with perfect three-dimensional periodic order. This ideal has been approached in the development of polymeric microporous membranes but never achieved.
  • the simplest type of sieve is a net filter, where each layer in the filter is a woven mesh. The geometry of the pore space in a given layer is thus a close approximation to a finite portion of a
  • glass capillary bundle filters are made from close-packed arrays of parallel glass capillaries.
  • Capillary arrays can also be formed from hollow fibres of organic polymers, although these are not yet available commercially.
  • cylindrical-pore filters is the lack of porespace branchings and reconnections, which leaves only one pathway for a fluid particle entering a given pore; thus clogging becomes a serious problem, as does sensitivity to handling.
  • cylindrical pores can provide a narrow distribution of pore sizes without necessarily lying on a doubly-periodic lattice; for example, nucleation-track filters have randomly placed parallel cylindrical pores. But this randomness means that the number of pores per unit cross-sectional area must be kept small to maintain monodispersity, so that these filters have the additional drawback of low porosity and thus low filtration rates. Nevertheless, nucleation-track filters are considered the best membrane filters available for sieving below 60 microns, despite these obvious
  • U. S. Patent no. 4,280,909 describes a microporous membrane which is, strictly speaking, triply-periodic, but the topology of the porespace is exactly the same as in the capillary array membranes, namely the flow channels are strictly linear and there are no porespace branchings or reconnections.
  • the periodicity in the third dimension refers only to the vertical stacking of tapered pores of equal height, so that the cylindrical pores of the capillary array membrane have become instead tubular pores with a periodically varying diameter.
  • This membrane does not satisfy one of the most important desired features, namely the intricate yet controlled porespace.
  • the membrane that is most commonly used in particle filtration has high porosity but a random
  • zeolites provide fairly well-controlled, triply-periodic pore
  • porosities of zeolites are nearly always less than 50% Furthermore, most zeolites selectively absorb polar molecules because most are themselves highly polar, having high local electrostatic fields and field gradients [Barrer 1978]. Perhaps most importantly, the macroscopic size of zeolite crystals has very serious practical limitations making such materials unsuitable for forming reasonably large membrane-like structures with the necessary degree of continuity.
  • the invention involves a polymeric, microporous membrane material characterized by a continuous,
  • the pore size ranges from two nanometers to sixty microns, preferably in the range of two nanometers to one micron and particularly preferably on the order of ten nanometers.
  • the material of the invention is characterized by high porosity: greater than fifty percent and, for certain applications, greater than ninety percent. The invention involves controlled variation of the pore
  • the invention involves several related methods for forming microporous membrane materials, including
  • phase-segregated systems especially systems which are substantially ternary or binary.
  • the invention is particularly directed to materials developed from an equilibrium cubic phase of a binary or ternary system
  • hydrophobic/hydrophylic/surfactant in which any of the oil, aqueous, or surfactant phases is polymerized after equilibriation.
  • a further aspect of the invention is particularly directed to applications of these novel materials in:
  • FIG. 2 shows an electron micrograph of membrane material according to the invention. Dark regions correspond to PMMA, and light regions to void. Regions of particularly good order are outlined. (Magn. 1,000,000).
  • FIG. 3 is the optical diffraction pattern of the negative used to make FIG. 2.
  • the eight-spot pattern indicated with circles provides further demonstration of cubic symmetry.
  • FIG. 4 A,B, and C are computer-generated pictures of a theoretical model structure, from Anderson, 1986, the applicant's doctoral thesis.
  • the surface has constant mean curvature, and divides space into two interpenetrating labyrinths, one threaded by graph A and the other by graph B.
  • FIG. 5 A and B show digitized electron micrograph of:
  • the model used was determined by the constant-mean-curvature surface of the 'D' family (Pn3m symmetry) which matches the volume fractions of the sample.
  • a computer was used to send projection rays through the theoretical model, and the grey level at each pixel
  • FIG. 6 combines the views of FIGS. 5 A and B for clearer comparison.
  • FIG. 7 sets out thre equations used in the
  • Figures 8 and 9 illustrate some results from evaluation of size and dispersity of pore sizes in certain cubic phases by thermo porous thermoporimet ry. Clarification of some technical terms.
  • Membrane This word has two quite distinct meanings, but notably these can easily be distinguished from the context.
  • One meaning relates to a microporous material, generally fabricated to be of very small thickness, but much larger in the other two dimensions. The other meaning is much more microscopic, and originates from biological contexts.
  • This second meaning is that of a lipid bilayer (into which are incorporated enzymes), which serves to separate different regions of the cell, or to enclose the cell itself, or more generally it refers to the generic bilayer independently of any biological function it may serve (such as used by theoreticians who study surfactant bilayers and their properties).
  • Minimal surface constant mean curvature surface, spontaneous mean curvature.
  • a surface which has zero mean curvature at every point is called a minimal surface, by definition.
  • a surface which has the same value of mean curvature at every point on the surface is called a surface of constant mean curvature (or an 'H-surface' for short).
  • H-surfaces are important for two reasons: first of all, they minimize surface area under a volume fraction constraint; second, and more importantly here, the balance of steric, van der Waals, and electrostatic forces between surfactant molecules (and other molecules which may penetrate into the surfactant film) determines a "preferred” or “spontaneous" mean curvature of the film, which in most interpretations is registered at the polar/apolar interface at or just inside of the surface describing the location of the surfactant head groups; since the composition of the surfactant film is rather homogeneous in most cases, a surface of constant mean curvature is a very good representation of the interface.
  • the lamellar phase is not bicontinuous, because there are no sample-spanning paths in a direction perpendicular to the lamellae.
  • Some authors use a much stronger definition, namely that it is possible, for either component, to connect any two points lying in the same component (say, water) with a path through only that component.
  • the bicontinuous cubic phases satisfy both definitions, so that this difference in definitions does not pose any difficulty.
  • a ternary surfactant/oil/water bicontinuous phase e.g., a cubic phase, microemulsion, or L3 phase
  • the surfactant is also continuous by necessity, and thus the structure is actually tricontinuous; however, this latter term has not been adopted by the community.
  • Triply-periodic Possessing periodicity in three directions, which are linearly independent; that is, none is simply a linear combination of the other two (thus, the third vector points outside of the plane determined by the first two).
  • An infinitely wide checkerboard would be doubly-periodic; a lattice of gold atoms is triply-periodic (in the present context we do not require infinite extent.)
  • Birefringent Having different refractive indices in different directions. This property is, with transparent materials, very easy to test for, because birefringent materials placed between polarizing lenses oriented at right angles allow light to pass through, and usually give rise to beautiful colors and textures through such crossed polars.
  • the lamellar and hexagonal phases are generally
  • the (unstrained) cubic phases are non-birefringent by virtue of the equivalence of the principle directions.
  • Vesicle Liposome. If a surfactant bilayer closes up to form a closed, often roughly-spherical, sack enclosing an aqueous interior and also having an aqueous exterior, then this is called a unilamellar vesicle (ULV). A nesting or such vesicles is called a multilamellar vesicle (MLV). By convention, when such structures are made from lipids they are called liposomes. Most liposomes have diameters measured in microns. Most are also rather dilute in
  • a surface which has a property, that any closed loop on the surface can be reduced to a point by continuously shrinking the loop without ever leaving the surface is called simply-connected.
  • More complicated surfaces are not simply-connected, the simplest multiply-connected surface being a circular annulus; the annulus is in fact doubly-connected, because a single cut in the surface (such as a radial cut) can reduce the surface to a simply-connected one.
  • the surface which describes the midplane of the bilayer in a surfactant/water bicontinuous cubic phase is very highly-connected, and in fact the unbounded, triply-periodic idealization of this surface is infinitely-connected.
  • a bicontinuous morphology is distinguished by interpenetrating, labyrinthine networks of ordinarily immiscible substances [Scriven 1976], in which macroscopic phase separation is prevented by one of at least two
  • triply-periodic bicontinuous morphology (TPBM hereafter) is further distinguished by long-range
  • TPBMs were proposed in the late 1960's and 1970's as possible microstructures in binary surfactant/water 'cubic phases' [Luzzati et al. 1968; Lindblom et al. 1979], and in ternary surfactant/water/oil cubic phases [Scriven 1976] (cubic phases are also known as 'viscous isotropic phase' liquid crystals). This has been fairly well established certain binary cubic phases [Longely and McIntosh 1983;
  • TPBM's have also been demonstrated in phases of cubic symmetry occuring in block copolymers [Alward et al. 1986; Hasegawa et al. 1986]. Described herein is the first polymeric microporous membrane with a highly-branched, triply-periodic network of submicron pores, which has been produced by radical chain polymerization of the oleic component (e.g. methyl methacrylate) of a ternary
  • components are present but do not affect the development of the desired phase-segregation.
  • components may be present in such small relative quantities that the system is equivalent to a binary or ternary system for the purposes of this invention.
  • one component may consist of sub-components which present nearly identical phase
  • the definition includes a ternary
  • hydrophobe/water/surfactant system whose water portion is a 50-50 mix of water and deuterated water and/or whose
  • hydrophobic component is a mix of sub-components which segregate substantially together under the fabrication conditions to be applied.
  • DDDAB didodecyldimethylammonium bromide
  • MMA methyl methacrylate
  • AIBN azobisisobutyro-nitrile
  • the capillary was then placed in a photochemical reactor having four UV lights, emitting radiation at 350 nm.
  • the sample was exposed for 36 hours, to bring about radical chain polymerization of the MMA via the decomposition of AIBN into initiating radicals. By the end of this time the sample was opaque white in appearance.
  • the sample was first examined by Small Angle X-ray Scattering.
  • a Kratky small-angle camera equipped with a position-sensitive detector was used, with tube power set at 1000 watts, and data collected for five hours.
  • the result is shown in FIG. 1, and it is clear that distinct Bragg peaks are recorded. This verifies that the sample has long-ranged periodic ordering.
  • FIG. 1 are indicated the theoretical peak positions for a body-centered cubic space group, Im3m, and it is seen that the theoretical peaks are represented by the data.
  • FIG. 3 is an optical
  • FIG. 4 shows a theoretical model of a TPBM of Im3m symmetry that was discovered by the present applicant [Anderson 1986; see also Nitsche 1985].
  • FIG. 4a is a color computer graphic of the surface
  • 4c is a line drawing of the same surface.
  • FIG. 4b is a (111) projection of the model structure. As described in the present
  • MMA in the 40.6 cubic mm of sample investigated should have been 9.7% of that sample, which corresponds to 0.004 gm, as observed. Note that since MMA increases in density by 20% on polymerization, the volume fraction of PMMA in the capillary is only 8%. Yet the PMMA is continuous as evidenced by its integrity; a single connected piece has remained intact floating in methanol for many weeks.
  • the surfactant DDDAB was chosen for the fabrication of this first example because it has been shown to form bicontinuous phases with many oil-like compounds: hexane through tetradecane [Blum et al. 1985]; alkenes
  • Zadsadsinski [1985 J has synthesized a polymerizable phospholipid, and produced lamellar phase liquid crystals which retained the same periodic spacing after polymerization, as checked by
  • a similar end product can be obtained by chemical alteration of a cubic phase formed from block copolymers, as mentioned above.
  • One aspect of the present invention relates to the final product irrespective of the particular process used to derive it.
  • the polymerization of the oleic component of a binary or ternary hexagonal phase, or chemical alteration of a block copolymer cylindrical phase, to yield a membrane with a doubly-periodic arrangement of cylindrical pores, would also be an useful modification of the present invention, as would the polymerization of a microemulsion containing a
  • polymerizable component for the definition of a
  • the monomer could be chosen to form a
  • surfactants can be made which have as few as 20 carbons (see [Kilpatrick 1983] for a discussion of the minimum carbon number for these amphiphilic alcohols to be true
  • a hybrid process will be dicussed in which a membrane formed by a type 1) process (or less like a type 2) process) is infiltrated with a polymerizable material that is then polymerized, after which the original material is eroded away.
  • the initial membrane would be of low porosity, say 10%, so that a 90% porosity membrane would finally result, and there would be a great deal of freedom in choosing the f inal monomer since the triple-periodici ty would already be imposed by the initial membrane.
  • a further variation of this process would be to infiltrate with a polymer that is above its melting temperature, and then allowing the polymer to solidify; the polymer that formed the original matrix would then be dissolved away by a method such as those discussed in this section.
  • a surfactant or mixture of surfactants is needed, which may or may not be polymerizable, and except in the case of a binary polymerizable surfactant/water mixture, another nonaqueous, usually oil-like or at least hydrophobic component which must be polymerizable if the surfactant is not. Since the working definition of a surfactant is an amphiphile which is liquid crystal, any amphiphilic compound or mixture of compounds that can form a triply-periodic fluid phase together with water and/or another nonaqueous component would have to be considered a surfactant, whether or not that title or some other title such as cosurfactant,
  • amphiphile, block copolymer or alcohol were traditionally used for the compound or mixture (recall that cubic phases are considered 'liquid crystals' by convention).
  • cubic phases are considered 'liquid crystals' by convention.
  • recent work in Sweden [Guering and Lindman 1983] has shown that bicontinuous microemulsions can be formed with alcohols that are normally used as cosurfactants.
  • work in that same group [Lindman 1986] has shown that bicontinuous phases can be formed without water, using water substitutes; because the same is probably then true of bicontinuous cubic phases, and because it should be possible to form bicontinuous cubic phases without any water-like component such as with a binary surfactant/oil mixture, water should not be considered essential to the process although it will nearly always be involved (it is
  • process type 1 Another possible variation of process type 1) would be to form a bicontinuous triply-periodic phase with a surfactant, water, and a polymer above its melting point. Once the phase has been annealed it would be brought down below its melting temperature and the solidified polymer would then exhibit triply-periodic porosity.
  • surfactant/water mixtures can change phase behavior by relieving stretching energy costs [Kirk and Gruner 1985], so that bicontinuous cubic phases should be expected to arise on the addition of a third component, as in the case of DDDAB/water.
  • surfactant/water cubic phases have shown the ability to solubilize various hydrophobic or amphiphilic components.
  • the cubic phase in the 1-monoolein/water binary system has been shown to solubilize diglycerides [Larsson 1967], protein, and cholesterol up to a molar ratio of 1:3 with monoolein.
  • a bicontinuous cubic phase in the dioleoylphosphatidyl glycerol/water system can actually solubilize the anesthetic dibucaine [Rilfors et al. 1986].
  • DDDAB and water can solubilize up to 11% dodecane in a bicontinuous cubic phase, and also styrene and methyl methacrylate as shown herein, as well as other alkanes
  • bicontinuous cubic phases with zwitterionic, cationic, and anionic surfactants bicontinuous cubic phases with zwitterionic, cationic, and anionic surfactants.
  • surfactant/water edge - - that is, they cannot be obtained by addition of a third (usually oleic) component to a binary cubic phase.
  • a third component usually oleic
  • no cubic phase occurs in the DDDAB/water binary system, even though the addition of only a few percent oil can yield a bicontinuous cubic phase.
  • Block copolymer polyol surfactants were first manufactured under the trade name PLURONIC by BASF Wyandotte Corporation in 1950. Among the epoxides used as the
  • hydrophobic blocks are [US Pat. 3,101,374]: propylene oxide, butadiene monoxide, 1,2-butylene oxide, styrene oxide, epichlorohydrin, cyclohexene oxide, tetrahydrofuran, and glycidyl alkyl ethers; these epoxides satisfy the condition that the oxygen to carbon ratio is not greater than 0.4. And among the epoxides used as the hydrophilic blocks are:
  • the molecular weight of these surfactants can be as low as 767 ('PE 71') or can be in the thousands.
  • the ethoxylated alcohol C12E8 is of low molecular weight but is a true surfactant [Kilpatrick 1983].
  • Plasma is another means by which polymerizations could be carried out in cubic phases, and it is known that hydrophobic monomers such as 4-picoline and 4-ethylpyridine can become hydrophilic polymers on plasma polymerization.
  • Photoinitiation by, for example, ultraviolet light is a very inexpensive means to polymerize a monomer, and also versatile, so that if volatile components were needed the mixtures could be protected from evaporation losses by materials transparent to UV light - - such as quartz if thick walls were necessary (which is unlikely since
  • photoinitiation is usually done at atmospheric pressure) or ordinary glass if thicknesses are not large and the UV wavelength is kept at or above 350nm.
  • UV wavelength is kept at or above 350nm.
  • the post-polymerization step for recycling using a solvent for the surfactant which is a not a good solvent for the polymer as was done with methanol in the main example. Since the UV light need only penetrate micron-thick layers and since the photoinitiator can be chosen to be much more sensitive to UV light than the surfactant, and since the reaction can be done at room temperature and pressure, the polymerization reaction should have little effect on the surfactant.
  • condensation polymerization by photoinitiation; initiation could be by thermal decomposition, redox, radiations such as neutrons, alpha particles or electrons, plasma as mentioned above, or even electrolysis [Pistoia and Bagnerelli 1979]. It is even feasible for a condensation polymerization to be performed, if the condensate is something like water or a short-chained alcohol that would be incorporated into the water phase or the surfactant-rich interface. From the standpoint of the stability of the finished membrane, it should be remembered that addition polymers generally have greater thermal and chemical stability than condensation polymers.
  • Isotactic polystyrene has high thermal and hydrolytic stability as well as stiffness.
  • Other relatives of PMMA provide potential materials for process 1) membranes, some offering particular advantages for certain membrane applications.
  • methacrylic acid is a relative of MMA that is the basis of some weak-acid cation exchange membranes, as is acrylic acid. Often copolymers with divinyl benzene are used.
  • UF membranes Another member of the acrylic family, polyacrylonitrile, is commonly used in UF membranes (usually as a copolymer with a few mole percent of another monomer such as styrene or vinyl chloride), and these are resistant to both hydrolysis and oxidation.
  • Polyvinyl chloride (PVC) and its copolymers are free-radical initiation polymers which are also important membrane materials.
  • PVC exhibits high stiffness and good solvent resistance, and is
  • Chlorinated PVC is denser and exhibits greater thermal stability. Copolymerization with propylene yields a polymer that is resistant to most acids, alkalis, alcohols, and aliphatic hydrocarbons.
  • polyethylenes as in Celgard membranes
  • copolymers such as with vinyl acetate or acrylic acid, or with propylene as in polyallomers
  • fluorinated polymers such as
  • polytetrafluoroethylene polyvinylidine fluoride
  • cellulose and its derivatives including cellulose nitrate, cellulose acetate and triacetate (in a binary surfactant/polymer cubic phase, since cellulose is extremely hydrophilic);
  • polyamides which fall into three subclasses, fully aliphatic, aromatic, and fully aromatic, all three of which have examples that are used as membrane materials.
  • Membranes made from polypiperazines exhibit long lifetimes and chlorine resistance; other special polymers, such as polyparaphenylene sulfide which is melt-processable and can readily be made conducting [Baughman et al. 1983].
  • Such processes are now more feasible in light of new research [Charvolin 1985] on naturally-occuring surfactants with very good thermal stability.
  • the polymers could be solidified inside the pore space of a triply-periodic (low porosity) membrane made of dissolvable material, avoiding the
  • a triply-periodic phase is prepared which incorporates a multiblock or graft copolymer, using a solvent or temperature elevation, or both, to enhance mobility, and one or more of the blocks form(s) the membrane matrix after elimination of one or more component(s) to form the pore space.
  • polymerization reaction(s) can be carried out before the formation of the triply-periodic phase.
  • the study of the morphologies of phase-segregated block copolymers is quite young and has not received a great deal of attention.
  • annealing temperature will of course depend on the polymers used, but the general procedure will be similar. What was not carried out, however, was the leaching out of one phase to create voidspace. Methods and materials will now be discussed for such a process.
  • ozonolysis can provide a means to leach block A.
  • the decomposition of the ozonides can be accomplished in a number of possible ways: 1) they can be oxidized, for example using a reduced platinum oxide catalyst; 2) they can be decomposed by steam distillation, using an alcohol solvent, in which case no reduction step is necessary; 3) a modification of 2) is to carry out the ozonolysis in an alcohol such as methanol; 4) reducing agents such as zinc dust in acetic acid can be used. If the block A is chosen to be radiation
  • block A with radiation and leave a relatively intact polymer matrix.
  • Many polymers suffer degradation on intense radiation, and in fact some are used in the
  • PMMA is radiation sensitive, for example, and PMMA/polyisoprene or polybutadiene copolymers should be capable of forming bicontinuous cubic phases, in analogy with polystyrene.
  • nucleation-track membranes As in nucleation-track membranes, a combination of ionizing radiation and chemical etching could be used that would be selective to one block. It is known that for every polymer (in fact every substance) there is a lower limit of heavy ion mass below which tracks are not produced. For example, tracks are produced in cellulose nitrate by
  • Thermal decomposition by choosing one block with a lower ceiling temperature, is another possible means, which could circumvent the need for reactive chemicals.
  • poly-a-methyl styrene undergoes an unzipping reaction above 50 degrees C.
  • Biodegradable polymers are another possibility, currently of interest because of their application in controlled drug-release. Hom ⁇ polymers and copolymers of lactic acid and glycolic acid are examples that have been examined for use in the body, but many other biodegradable polymers have been investigated for applications to the dispensing of herbicides and insecticides.
  • Ionomeric membrane polymers that could be copolymerized with a leachable polymer include random copolymers with etylenically unsaturated monomers containing ionogenic groups. The first such example was a copolymer of acrylic acid with ethylene incorporating inorganic ions
  • copolymers with desired block properties will increase.
  • the model used for the double-diamond morphology is one of the
  • the surface in the finite element solution is represented by triangular patches (much as in a geodesic dome), and because the normal direction is fixed over a given triangle in space, this integral can be done
  • a fundamental patch of the surface was represented by 800 such triangular patches; a unit cell of surfaces can be broken down into 24 identical fundamental patches. The from factor calculated in this way is mathematically exact for the structure so represented.
  • the applicant's thesis contains demonstrations of the accuracy of the finite element representation of these constant-mean-curvature surfaces.
  • triply-periodic membrane with either an ionomer (above its melt temperature), or a monomer that can be polymerized, and modified if necessary, to form an ionogenic polymer; and d) formation of a triply- periodic morphology with a block or graft copolymer one component of which is
  • ionomeric polymers in membranology are the styrene-type and
  • perfluorinated ionomers perfluorinated ionomers, and the primary focus of this part will be on these, although other classes of ionomers may be found to be compatible with the types of processes described herein. Reactions for grafting ionogenic polymers or oligomers to neutral polymers will be briefly discussed;
  • Styrene polymers, and copolymers with, for example divinyl benzene and/or ethyl vinyl benzene are excellent starting materials for the formation of ionomers, becaus e of the reactivity of the aromatic rings for chloromethylation , nitration, and particularly sulfonation.
  • Such polymers can be converted to strong acids by sulfonation with sulfuric or chlorosulfonic acid, and this can be followed by conversion to the sodium form by addition of a slight excess of alkali.
  • Weak-acid cation exchange polymers can be made by with acrylic or methacrylic acids, as mentioned above. These reactions can be performed after the formation of the membrane with the neutral polymer.
  • Strong-base anionic-exchange polymers can also be produced from styrene-based polymers or copolymers in a post membrane-formation step. Chloromethylation by methyl
  • chloromethyl ether followed by amination with a tertiary amine, yields strong-base polymers even in pure polystyrene.
  • Redox membranes which are oxidation and reduction agents lacking actual charged groups, can be produced by addition polymerization of styrene, divinyl benzene, and esterified hydroquinone.
  • Perfluorinated ionomers are presently the most important cation-exchange membrane polymers, primarily because of their strength and chemical stablility. As an example of the possibilities of production of these types of ionomers, consider starting with a copolymer of
  • 6-dioxa-4-methyl-7-octene-sulfonyl fluoride 6-dioxa-4-methyl-7-octene-sulfonyl fluoride.
  • the sulfonate groups can be converted to the sulfonic acid form by nitric acid, after which oxidation in n-butyl alcohol followed by hydrolysis with sodium hydroxide yields a polymer suitable for use as an electrolysis membrane. Reaction with vaporous phosphorous pentachloride followed by treatment with
  • substituted amine This in turn can be converted to an amine oxide, by reaction with hydrogen peroxide, or to a cationic quaternary surfactant by reaction with an alkylating agent.
  • Polyurethane can be obtained by reacting with diisocyanate.
  • Anionic. surfactants can be produced by addition of
  • cationic surfactants can also be produced from block copolymeric surfactants by reaction with ethylene or propylenimine, or by methylation.
  • Electroactive polymer films have been produced by electropolymerization of aromatic heterocyclic compounds [Diaz et al. 1983].
  • Highly conducting membrane polymers have been produced by iodine-doping
  • Free radicals can be produced for grafting sites by peroxides or redox catalysts, or by exposure to electrons, gamma rays or UV radiation.
  • membranes have been associated with filtration processes for purification or concentration of fluids, or recovery of particles as in the recovery of colloidal paint particles from spent electrolytic paint particle suspensions, and the very important application of recovering of lactose-free protein from whey.
  • RO also known as hyperfiltration
  • Desalinated water obtained from RO of seawater could be an important solution to the fresh water shortages that are projected over the next few decades.
  • the literature on desalination by RO is extensive. From the point of view of the present invention, the two characteristics that distinguish the RO membrane from UF and MF membranes - - namely smaller pore size (less than 10 Angstrom) and lower porosity - - would result from the polymerization of the surfactant of a binary surfactant/ water bicontinuous cubic phase.
  • the very concept of bicontinuity first arose in experiments on binary surfactant/water cubic phases, and there are now many such binary cubic phases believed to be bicontinuous, most of which occur near 50% volume fraction water and with channel diameter less than 4nm.
  • RO membranes of intermediate porosity roughly 70%, would result from chemical erosion of one component of a block copolymer cubic phase of low molecular weight.
  • Reverse osmosis is finding new applications every year.
  • RO and UF are being investigated [Drioli et al. 1981] for the treatment of must and wines without the addition of sulfur dioxide, which is routinely added to remove certain enzymes that would otherwise cause an oxidized taste.
  • the concentration of tomato juice by RO has been applied on a semicommercial scale, and results in enhanced taste and color over conventional processes [Ishii et al. 1981].
  • a recent study [Farnand et al. 1981] has shown that RO can also be used to separate inorganic salts from nonagueous solvents such as methanol; the latter solvent is of
  • HTLV-III human immunodeficiency virus III
  • HIV human immunodeficiency virus
  • Angstroms now believed to be responsible for the disease AIDS as well as other neurological disorders and perhaps even the cancers.
  • the potential importance of a membrane of the type disclosed herein is demonstrated by the fact that some hemophiliacs developed AIDS after receiving infusions of a plasma preparation called Factor VIII, which had been passed through a filter that was fine enough to remove bacteria but not virus particles [Gallo 1987].
  • solute permeates through a membrane from a more concentrated to a less concentrated solution; thus it differs from UF in that in the latter the solute flux is coupled to the solvent flux.
  • the dialysis of blood to remove urea and creatinine from uremia patients, known as hemodialysis, is believed to be presently the largest single application of membranes to separations. Dialysis is also used in the pharmaceutical industry to remove salts, in the rayon industry, and in the metallurgical industry to remove spent acids.
  • dialysis membranes are generally very finely porous - - with molecular weight cutoffs of around 1,000 - - the present invention could be applied in these areas; in the case of hemodialysis, where human suffering is involved, advantages offered by a more precisely controlled membrane could well justify a higher cost, if the present invention were more expensive than the extruded cellulose hydrogels that are presently used.
  • first-order release constant concentration over time in the body
  • first-order release a concentration that fluctuates in response to physiological conditions
  • biodegradable polymers such as lactic acid and glycolic acid homopolymers and copolymers.
  • first-order systems for the release of insulin in the treatment of diabetes a glucose-sensitive membrane is being investigated [Kost 1987] in which the enzyme glucose oxidase is immobilized in a poly-N,N dimethylamino-methyl
  • methacrylate/poly-HEMA copolymer So far the membrane has shown the ability to release ethylene glycol in response to glucose concentration, but porosity of greater than 50% is required to release insulin.
  • Some other drugs which are being investigated for membrane release are nitroglycerine, progesterone, and epinephrine, to name only a few examples. The importance of high porosity and therefore high
  • effectors such as fragrances, insecticides, and herbicides.
  • Polymer UF membranes provide supports for liquid membranes, in which the liquid is immobilized in the
  • porespace of the solid microporous membrane by capillarity The immobilized liquid membrane offers the advantages over solid membranes of higher diffusivities, higher
  • Concentrated CsHCO 3 aqueous solutions can be use to recover carbon dioxide from gaseous mixtures [Ward 1972].
  • Liquid membranes are also used to recover carbon dioxide from the products of carbon dioxide-based tertiary oil recovery methods, and to remove ammonia from wastewater.
  • Immobilized liquid membranes have been proposed for the removal of toxic materials such as dichromate ions from electroplating rinsewaters [Smith et al. 1981].
  • UF membranes also provide possible supports for so-called dynamically-formed
  • Pervaporation is a membrane-based separations process capable of separating complex azeotropic mixtures. It also circumvents the problem in RO of high osmotic pressures that oppose flux in attempts to concentrate a solute to high purity. Pervaporation has been shown to be capable of separating linear hydrocarbons from olefins, from branched hydrocarbons [Binning et al. 1961]. Thus interest in membranes with precisely controlled porespaces has arisen in the petroleum industry. Diffusion of the components through the membrane is the rate-limiting step, and thus high porosity and uniform pores are important in pervaporation as well as in the recent modification of the process known as membrane-aided distillation.
  • Electrophoresis is a separations process for macromolecules such as proteins which is based on an imposed electric field, where a porous membrane must be used to frustrate remixing via thermal convection. Finely porous membranes such as agarose or polyacrylamide gels with pore sizes on the order of 1,000 Angstroms result in enhanced separation over that of cellulose acetate membranes with pores on the order of 1 micron, due to a combination of both the electrophoretic effect and sieving. Electrophoresis is an important tool today in biological and bioengineering research, and it is anticipated that it will be realized in large scale separations processes, and in three dimensions, in the near future. Certainly in cases where sieving is a significant contribution to the separation, a membrane with triply-periodic submicron pores may be of importance. The applicant has demonstrated [Anderson 1986] that the
  • progressions of structures that occur in phases of cubic symmetry should also include structures that consist of interconnected sphere-like domains, which would be the perfect geometry for an electrophoresis membrane.
  • the electron micrograph of FIG. 2, and the model structures in FIG. 4 indeed indicate an interconnected-sphere structure.
  • the model that is to date the best model for the cubic phase occuring in the star-block copolymers of Thomas et al.
  • FIG. 5 shows the comparison between a (digitized) electron micrograph of a star-block copolymer cubic phase and the theoretical
  • a reference electrode is separated from the test solution by a selective membrane; the species to be detected diffuses through the membrane and reacts so as to produce an ion that is measured by an ion-selective electrode.
  • membranes including both neutral and ionomeric membranes, and enzymes immobilized in microporous membranes.
  • Selective membrane electrodes are used to detect carbon dioxide in blood and fermentation vats, ammonia in soil and water, sulfur dioxide in stack gases, foods, and wines, sulfur in fuels, nitrite in foods, and hydrogen cyanide in plating baths and waste streams, for some examples.
  • Ionomeric membranes Ionomeric membranes .
  • ion-exchange membranes and resins - - in particular in applications where precise porespace characteristics are required, such as when ion-exchange or electromembrane processes are enhanced by or combined with sieving.
  • neutral membranes the field of ion-exchange membranes and resins is large and ever-expanding, so that only a brief overview of the applications with respect to the present invention can be given here.
  • Electrodialysis is the most important
  • Electrodialysis for ion-exchange of Na+ to Ca+, K+, or Mg+ is being
  • polystyrene-based membranes for example [Kedem and Bar-On 1986].
  • Ion-exchange membranes are used in batteries in part because their electrical conductances are higher than in the silver halides of conventional solid-electrolyte cells. They are also used in fuel cells such as the Bacon cell, in which hydrogen and oxygen are combined to form water with the release of heat and electricity.
  • the Bacon cell can be operated at relatively low temperatures, opening up the possibiliity of using an ion-exchange membrane as as solid-state electrolyte.
  • the ideal electrolyte would be permeable to only one ionic species, and if this were to be accomplished or aided by membrane sieving, very uniform pores would be required.
  • the present invention could prove to be the best possible electrolyte in such a cell.
  • Both neutral and ionomeric membranes of the type described herein could be used in a variety of other reactions, for example by doping the membrane with a catalyst or by controlling the reaction rate precisely by diffusion limitation.
  • the large specific surface, 3500 sq. m./gm, and highly-controlled diffusion paths and reaction sites could allow for a greater degree of control than has been possible with prior art membranes.
  • substantially cylindrical to spherical, and cell diameter to pore diameter ratios which cover a range including that from 1 to 5, and
  • the porespace comprises an isotropic
  • the microporous polymer creates exactly two distinct, interwoven but disconnected porespace labyrinths, separated by a continuous polymeric dividing wall, thus opening up the possibility of performing
  • microporous material exhibits in all cases a precisely controlled, reproducible and preselected morphology, because it is fabricated by the polymerization of a periodic liquid crystalline phase which is a thermodynamic equilibrium state, in contrast to other membrane fabrication
  • the present invention presents a stabilized form of such phases.
  • the components can be chosen so that the material is biocompatible, allowing use in controlled- release drug-delivery and other medical and biological applications that call for nontoxicity. Furthermore, in dialysis, immunoadsorpt ion
  • polymerization of cubic phases can immobilize enzymes (such as protein A) and effect the
  • microporous materials in which the effectiveness is critically dependent on the monodipersity of the pores is the sieving of proteins.
  • ultrafiltration membrane have high selectivity for proteins on the basis of size, the pore dimensions must first of all be on the order of
  • the microporous material disclosed which is formed through a nonequilibrium process, is subject to variability and nonuniformity, and thus
  • the microstructure is determined at thermodynamic equilibrium, thus allowing uniformly microporous materials without size or shape limitations to be produced.
  • the cubic phase consisting of 65% dodecyldimethylamine oxide in water is stable over a temperature range of more than 80°C, so that addition of monomer into the water (e.g., acrylamide) or the
  • DDAB/methyl methacrylate/water cubic phase disclosed in the original application is stable at least to 55C°, and furthermore at least 25 % monomeric acrylamide can be
  • glucose oxidase can be used to detect concentrations of glucose in serum, and glucose oxidase can be entrapped in the monoolein/water cubic phase
  • Polymerized drug-bearing cubic phases provide for controlled-release applications with high stability.
  • the combination of the biocompatibility and entrapping properties of many cubic phases with the increased stability upon polymerization leads to new delivery systems, and even first-order drug release - - release in response to physiological conditions - - by
  • biosensors incorporating proteins and enzymes, as described elsewhere, as biosensors.
  • first-order release material One can polymerize an outer coating on a particle which would contain glucose oxidase immobilized in a cubic phase. When glucose levels in the blood got high, then this would cause a drop in pH due to the action of glucose oxidase on glucose. Methods are then known for using a pH change to cause release of insulin.
  • pancreatic islets can be
  • the present invention represents a synergistic combination of many previously unattainable qualities in microporous polymeric materials for use in catalysis, including precisely controlled pore size and shape, fixed coordination number, and a biocompatible and highly
  • lipid bilayer represents the environment that is closest to the natural environment of the protein-rich lipid bilayer of the li ving cel l ; this lipid bilayer is the site of a myriad of biochemical reactions and transport processes, and it is well-established that the optimal environment for the ⁇ unct ioning of proteins and enzymes in technological
  • isotropic microporous materials have been of one of two types; A) the porespace (except for isolated, inaccessible pores) is connected into one labyrinthine subspace, as in the material described by Castro; or B) two distinct labyrinths are present which are very different in porewall
  • the present applicant has synthesized a polymerizable analogue of DDAB, so that both of these classes or materials are attainable in the present
  • cubic phases offer the unique opportunity to create a new, third type of
  • microporous polymeric material displaying exactly two aqueous labyrinths, as present in many biological systems (there in unpolymerized form, of course) such as the
  • thylakoid membranes the endoplasmic reticulum, and possibly also in the digestion of fats (Patton 1981). Indeed, some of the potential applications of such a material are suggested oy biological processes in plant and animal cells: catalytic reactions, particularly those involving proteins, creation of membrane potentials as in photosynthesis), and
  • some or all of the surfactant is polymerized and is thus present along the porewalls, making it very straightforward to take advantage of the known catlytic properties of surfactant aggregates. Clearly this is not the case with other surfactant aggregates.
  • microporous materials such as those described in the patent of Castro et al., nor with the other prior materials.
  • Micelles are extremely dynamic structures, and in fact the average residence time of a molecule in a micelle is on the order of 0.1 microseconds.
  • the bicontinuous nature of the cubic phases of the present invention offers access to both hyrophobic and hydrophilic regions, in contrast with closed micellar aggregates in which the surfactant layer must be crossed in order to access the component in the interior of the micelle.
  • the mean curvature of the microscopic interface is much smaller in magnitude in the cubic phase, and it is know that the rates and efficiencies of catalysis in surfactant microstructures is dependent on this curvature.
  • the lamellar phase zero mean curvature interface
  • oxidation of benzaldehyde in the alkyl betaine/benzaldehyde/water system is reduced most in lamellar phases over micellar.
  • Water-in-oil microemulsions have been demonstrated to have the ability to provide a reaction medium for coupled redox reactions which mimic the photosensitized
  • EDTA the primary acceptor benzylnicotinamide, being amphiphilic, located itself at the surfactant-laden
  • ternary polymerizable surfactant/oil/water cubic phases of the present invention could offer important advantages over the inverse micellar solution utilized in the experiments of Willner et al .
  • Microemulsions are in general very sensitive to changes in temperature and
  • inverted micelles have a very short lifetime and are often poorly-defined in contrast to textbook figures which show highly-organized spherical entities.
  • the aim is to establish a continuous flow of reactants and products, and avoid saturation of concentration gradients, clearly the bicontinuous nature of the present invention is
  • Bicontinuous microemulsions also have continuous oleic ano aqueous labyrinths and low interfacial curvatures, but as in micellar solutions the structure is undergoing constant thermal rearrangement on microsecond timescales. Furthermore, the viscosity of a microemulsion is very low, oruers of magnitude lower than that of the cubic phases.
  • the lipid in the thylakoid membrane is in the form of a bilayer, separating two aqueous compartments, with the stroma side of the bilayer acting as a cathode and the intrathylakoid side acting as an anode.
  • Tien (1981) states that the chlorophyll dispersed in the lipid bilayer acts as a semiconductor, in that the absorption of light excites an electron to the conduction band and leaves a hole in the valence band.
  • compartments is important in natural photosynthesis: first, as well as providing an appropriate environment for the pigments, the bilayer acts as a barrier to prevent
  • each electron/hole pair can be generated by two photons, thus providing an upgrading of the photon energy.
  • a membrane potential of about 160mV is created across the bilayer, as well as a pH gradient of about-1pH unit, and the energy of the flow of protons created by this electrochemical proton gradient is used by the transmemorane protein complex ATP synthetase to
  • Photo-Kolbe reactions using semiconductors could be applied to the treatment of waste streams, giving methane and other alkanes as fuels (Tegner 1982).
  • Immobilized enzymes offer many advantages over enzymes in solution, including
  • An enzyme immobilized in a polymerized cubic phase of the present invention is in a precisely controlled environment, chemically, geometrically, and electrostatically.
  • the chemical environment or the enzyme has a crucial effect on the enzyme's activity and stability, and a polymerized bilayer is very close to the natural environment in which the enzyme functions in vivo.
  • the precise geometrical environment provided by the present invention can be utilized to bias the registry between the enzyme and the substrate toward the optimal orientation and proximity, in addition to providing additional control of the chemical environment through selection on the basis of size.
  • biocompatible surfactants can incorporate a wide variety of proteins and enzymes. As mentioned above, there is a large cubic phase region in the phase diagram at room temperature or monoolein/water/lysozyme, extending to over 30 per cent lysozyme. The same lipid with water can also form equilibrium cubic phases incorporating glucose oxidase, a-lactalbumin, soybean trypsin inhibitor, myoglobin, pepsin, bovine serum albumin, conalbumin, and diglycerides.
  • dioleoylphosphotidylethanolamine N-methylated DOPE
  • phosphdtidyl choline PC
  • egg lysophosphotidyl choline egg LPC
  • MGluDG monoglucosyldiglyceride
  • DGDG diglucosyldiglyceride
  • egg lecithin glycerol
  • Beside polymerizable surfactants another mean to immobilize enzymes within the present invention is to
  • collagen is a powerful platelet antagonist
  • chemotherapeutic agents such as Cisplatin (Quinn, Frair, Saff, Kavanagh, Roberts, Kavanagh, and Clark 1988).
  • the present invention could have important research and clinical applications in immunoabsorption processes, which have been tried in cases of systemic lupus erythematosus, rheumatoid arthritis,
  • Angstroms diameter which is an order of magnitude too large to allow IgG to be separated from the blood components having molecular weights lower than that of IgG.
  • Immunoadsorption processes are examples of extracorporeal circuit processes, which also include
  • hemodialysis membrane plasmapheresis, cardiopulmonary bypass, filtration leukopheresis, and hemoperfusion.
  • a significant complication with these treatments is the activation of complement, causing side effects that are well-known in the field of clinical hemodialysis; fever, sweating, respiratory distress, chest pain, nausea,
  • the complement C5a can lead to pulmonary leuko-embolizat ion which can
  • RTS respiratory distress syndrome
  • dialysis-induced amyloidosis in which deposits or amyloid (the primary constituent of which is ß2-2-microglobulin) are present in the joints, synovium, capsula, subchondral bone and vertebral disks, for example; in ract the amyloidosis may be systemic (Bardin, Zingroff, Kuntz, and Drueke 1986), for small vascular deposits have been demonstrated in rectal mucosa of dialysis patients, as well as in the heart, liver and lungs.
  • deposits or amyloid the primary constituent of which is ß2-2-microglobulin
  • the dialysis membrane - in particular the selectivity, thickness and adsorption characteristics - are critical in determining the extent of these complications.
  • the pore uniformity and biocompatibility of the present invention could reduce or circumvent these complications.
  • the present invention opens up the possibility of developing a hemodialysis or hemofiltration technique which would utilize the monodispersity and
  • creatinine which have molecular weights of 60.1 and 131.1 respectively, and thus should be able to pass through a microporous membrane with pores small enough to reject typical proteins.
  • application of the present membrane could very well eliminate complications associated with transfer of larger molecules such as complements,
  • membrane considerably lower than the 75 micrograms/ml measured using a polyacrylonitrile membrane. It is well-established that membrane-induced leukopenia is complement mediated. As discussed above the level of biocompatibility that can be achieved in the present invention is very high, and furthermore since it has been demonstrated that membrane thickness should be kept to a minimum in order to minimize complement activation (Van der Steen 1986), the high degree of uniformity of the present invention could be important in allowing reductions in thickness without reductions in efficiency or selectivity.
  • microencapsulation of cells such as pancreatic islets followed by implantation in the body is an attractive alternative to organ transplants, which is now the fastest growing area in diabetes research.
  • the islets are protected from the body's immune system by encapsulation using a semipermeable membrane which allows the free diffusion of insulin and glucose into and out of the islets, but isolates the islets from the antibodies and lymphocytes of the host. Considering that the molecular weight of insulin is 11,466, while that of a typical IgG-fraction antibody is about
  • the best encapsulating material can be formed by the polymerization of a cubic phase formed by a
  • polymerizable analogue of a biological lipid such as those mentioned above, which would in many cases have natural pore diameters close to 50 Angstroms.
  • Microencapsulation has also been suggested for use in other disorders requiring cell transplants, such as diseases of the liver, pituitary, and parathyroid.
  • linear polypeptide antibiotic Gramicidin A allows small raonovalent cations to cross a lipid bilayer, by forming channels (Chappell and Crofts 1965).
  • channels Chappell and Crofts 1965.
  • band III proteins which appear to play a fundamental role in the exchange of oxygen for carbon dioxide.
  • band III protein creates a transbilayer channel of just the right charge and size to pass Cl- and HCO3-.
  • many proteins have fairly high lateral diffusion rates; measurements of the lateral diffusion coefficient in the bilayer of rhodopsin, for example, indicate values of roughly 5x10 - 13 m 2 /sec.
  • the protein F 0 F 1 -ATPase from Rhodospirilium rubrum has been polymerized into synthetic vesicles, and interestingly its activity actually increased upon polymerization (Wagner,
  • the protein-free phopholipid bilayer is highly permeable to water but impermeable to ions (the permeability coefficient of Na across a lipid bilayer is on the order of 10 -12 cm/sec, for example). This could have implications as far as applications of the present invention in the desalination of water, for example.
  • microporous materials in such applications.
  • transition temperatures are affected by porous materials. For example, there is an effect known as capillary
  • condensation in which the effect of pores is to cause thin films of condensate to develop on the pore walls.
  • Luzzati and coworkers have recently developed a new technique of x-ray analysis which yields good-resolution electron density maps. The present
  • hydrophile-lipophi le balance or HLB hydrophile-lipophi le balance
  • metastable state - is to use very dilute surfactant
  • Lecithin is a component of certain cell bilayers (eggs and soybeans are common sources), and since the lattice parameters observed in prolamellar bodies and ER membranes are on the order of 0.1 micron or more, it is not surprising that these large lattice parameters can be created in vitro as well.
  • the ordered cubic phases For example, at approximately 40 percent surfactant and 70°C, the above-mentioned bicontinuous cubic phase appears, and is joined by a small two-phase region to an L3 phase region which extends to lower water contents.
  • this L3 phase region extends to a few percent surfactant, and at these low concentrations length scales on the order of
  • our proposed microstructure for the L3 phase is locally a bilayer, which is highly-connected and topologically complicated as in the bicontinuous cubic phases but unlike the cubic phase is undergoing constant thermal disruption and thus does not posses long-range order.
  • a base surface S which is the mid-surface of the bilayer (the location of the ends of the hydrocarbon tails of the surfactant molecule ), and the polar/apolar interface then consists of two parallel surfaces displaced a constant distance L on either side of S, where the length L is the bilayer half-thickness.
  • this dimensionless number is within 8 percent of 2.2.
  • the theory also has the power to predict the location of cubic and L3 phase regions in phase diagrams based on molecular parameters of the surfactant.
  • equation (47) of a paper by Cantor R. Cantor,
  • the degree of water penetration into the head group region of the surfactant bilayer can be estimated from a knowledge of the Flory-Huggins interaction parameter between the polar moiety and water.
  • this interaction parameter is known from experiments by
  • L3 phases are bicontinuous, then they provide another means to produce microporous materials in the manner of the present
  • a polymerized L3 phase would possess many of the favorable and novel features of a polymerized cubic phase with the exception of triple-periodicity.
  • a primary technical complication in the actual production of such a material would be the fact that as in microemulsions, the structure is thermally roiled and undergoing continual rearrangement on microsecond timescales, so that the
  • the target biomolecule to be separated from solution attaches to a ligand with specificity toward the target molecule.
  • the ligand+target is then separated from the other proteins in the solution by ultrafiltration, and the target and ligand are then dissociated and
  • ultrafi ltration is used again to separate these.
  • the use of this technique is limited by the fact that a ligand must be chosen which is much larger than the target molecule: the rule of thumb presently is that the ligand should be at least 10 times larger than the target, due to the polydispersity of present ultrafiltration membranes.
  • DOPE dioleoylphosphotidylethanolamine
  • reaction products In a reaction involving charged species, the reaction products, confined to the two separate labyrinths, could be routed in opposite directions through the use of an imposed electric or magnetic field.
  • a related possibility would be to take advantage of the opposite chiralities of the two labyrinths in the Ia3d cubic phase by imposing a rotational electric or magnetic field which would induce opposite net flows in the left- and right-handed screw networks.
  • the triple-periodicity of the present invention combined with the small length scale attainable - considerably less than 0.1 micron - brings up potential applications in metal and semiconductor microstructures, and indeed the frontiers of microfabrication are now moving into the range of molecular dimensions where this microporous device provides the only triply-periodic microenvironment avai lable , except for zeolites which are limited to 2 nanometers or less.
  • quantum effects become pronounced and in such a medium with extremely high surface-to-volume ratios properties are often dominated by the surface condition.
  • Roberts also discusses possible applications of magnetically ordered polymerized LB films as switches in superconducting junctions.
  • microstructures have been discussed as providing potential memory and switching devices because they involve a great deal of self-assembly, and also because electro-optical and photochromic effects are higher in organic than in inorganic materials.
  • polymerizable conjugated diacetylene surfactants become intensely colored upon polymerization (for example, by UV light), and electronic memories based on such photochromic effects have been speculated (Wilson
  • cytochrome c is a colored protein which acts as an electron carrier in the electron-transport chain of the cell.
  • semiconductors and metal electrodes for some examples.
  • the polymerized cubic phase of the present invention could be important in
  • Cross-linked cubic phases We have produced cross-linked polymerized cubic phases, which we intend to characterize by scanning electron microscopy, after drying by supercritical drying. SEM offers several advantages to TEM in this respect: first, since microtoming will not be necessary, there will be less disturbance to the sample during preparation for the microscopy; and second, this will give direct information concerning the structure of the material at the macroscopic surface, which is all-important in determining flow properties.
  • the particular cubic phase we have prepared for this experiment is a DDAB / styrene + cross-linker / water cubic phase, which has very good physical integrity and which should not undergo a
  • Two membranes can be prepared by the polymerization of two cubic phases at slightly dif ferent compositions , and we can sieve part ic les or macromolecules of a narrow and precise size fraction.
  • the DDAB / styrene + cross-linker / water cubic phase exhibits an increase in lattice parameter of approximately 3 Angstroms per percentile of water, so that the pore sizes in the two membranes can be chosen to be, say, 90 to 110
  • a solution containing microspheres of several sizes, say 100 and 125 Angstroms diameter, will be passed first through the 110 Angstroms membrane, and the filtrate then passed through the 90 Angstroms membrane, so that the 125 Angstroms spheres should be rejected by the first filter and the 100 Angstroms spheres by the second.
  • a mixture of a wide MW range of polymers or proteins can be passed through the two filters sequentially and the fraction rejected by the second filtration can be checked for
  • Single-crystal The C 12 E 6 cubic phase can be polymerized to obtain a monodomain (or "single crystal") specimen. This can be then characterized by single-crystal x-ray techniques; the orientation of the lattice would be known from the preparation. This would be an aqueous-phase polymerization, because the aqueous phase is a single labyrinth whereas the surfactant is divided into two, disjoint continuous networks. We have been able to
  • Enzyme incorporation Using a polymerizable surfactant, an enzyme such as glucose oxidase can be used.
  • Cytochrome-c incorporation We can incorporate cytochrome c into a cubic phase as in the experiments of Luzzati and coworkers, except with a polymerizable analogue of monoolein. After polymerization, racemic mixtures of different compounds would be passed through the membrane, and the filtrate tested for optical activity. It is not expected that every sized molecule can be separated by chirality in this manner, but for molecules with sizes slightly smaller than the pore size, the separation of enantiomers should be possible in many cases, with the separation increasing with the number of passes through the membrane.
  • the particular surfactant used can be a quaternary ammonium surfactant similar to DDAB but with two double bonds in each tail (so four polymerizable sites per molecule).
  • Ionic pore walls A cubic phase can be formed with styrene, water, and a polymerizable analogue of DDAB first of all because there are many different polymerizable quaternary ammonium surfactants in the literature, and second of all because DDAB is a very persistent cubic-phase former, as evidenced by the large cubic phase regions in many ternary DDAB/water/oil phase diagrams, then we can polymerize both the styrene AND the surfactant, so to create a microporous material with ionic pore walls.
  • Enzyme immobilized in a lipid-water cubic phase Proteins can be incorporated, in fairly high
  • Glycerol monooleate or -monoolein
  • lipid e.g., present in sunflower oil
  • monolinolein and the monolinolein-water phase diagram is know to be nearly identical with that of monoolein-water (36).
  • the #212 cubic phase structure has been found in the [monoolein/water/cytochrome-c] system, and the present authors have found the same structure at 6.7 wt% cytochrome, 14.8% water, and 78.5% monolinolein, where the monolinolein contains 0.4% AIBN. After equilibration, this cubic phase was placed in the UV photochemical reactor in a water-jacketed cell and bathed in nitrogen in the usual manner.
  • the successful polymerization of this cubic phas is also of potential importance in that, by keeping the ratio of ethylene oxide to hydrocarbon groups fixed and increasing the molecular weight of the surfactant, it is possible to produced polymerized bicontinuous cubic phases with a continuum of pore diameters up toward the micron range.
  • the surfactant self-diffusion has been found to be 8 x 10 - 10 m 2 /sec (Nilsson, Wennerstrom, and Lindman 1983), whereas in the discrete cubic phase the surfactant self-dirfusion rate in the high-MW case is actually higher than that in the low-MW discrete case, and only a factor of three lower than that in the known low-MW cubic phase; the factor of three is of course due to the slower diffusion associated with a higher-MW molecule (larger by about a factor of about six).
  • the high diffusion value for the water component then also demonstrates water continuity, which is not surprising because the sample is high in water content.
  • the X-ray results, indicating a bicontinuous structure are confirmed by this self-diffusion experiment.
  • Thermoporometry was used to characterize the pore size distribution of a polymerized cubic phase. This measurement is based on the principle that the melting (and freezing) temperature of water (or any fluid) is dependent on the curvature of the solid-liquid interface, which depends on the size of the pore in which the interface is located. For the melting of ice into water inside a cylindrical pore of radius R ( in nanometers), the melting temperature is decreased by an amount of T (in degrees Celsius) given by [Brun 1977]:
  • thermoporometry over other porosimetry methods, such as BET porosimetry, are 1) it is a simple, straightforward measurement made with
  • the sample does not need to be dried, and thus supercritical drying need not be performed.
  • the material is investigated under conditions which are most similar to those conditions encountered in normal use.
  • the cubic phase examined with thermoporometry was a monolinolein/water/cytochrome-c cubic phase prepared according to the method of Mariani, Luzzati, and Delacroix (1988; their preparation used monoolein instead).
  • the resulting sample was in the two-phase region at 23 °C, which is an equilibrium between two bicontinuous cubic phases, one with space group #212 and the other, at higher water
  • Our monolinolein sample contained AIBN as initiator, and was exposed to UV radiation for 48 hours. The polymerization of this lipid has been inconsistent. In some cases, complete polymerization results and the sample is quite solid, while in other cases, several days of exposure does not bring about complete
  • thermoporometry gives good evidence of monidisperse
  • This aqueous solution was mixed in a nitrogen atmosphere with 24.3 wt%f DDAB and 10.93 wt% decane, and the solution centrifuged for one hour to remove any remaining oxygen.
  • This water content 64.8%, was chosen based on SAXS study of the cubic phase as a function of water content in similar systems. Above about 63 vol% water, the lattice parameter is larger than 175 Angstroms with either decane or decanol, the aqueous regions should be large enough to contain the enzyme.
  • This example is a demonstration of a general application, namely in biosensors.
  • the substrates to be detected are of a higher molecular weight than glucose and the porespace created by the cubic phase microstructure can be tailored to the size of the substrate.
  • the pore size which is determined by the cubic phase microstructure, can be preselected independently of the mesh size of the cross-linked polymer network.
  • the polymer concentration and the extent of cross-linking must be such that the mesh size of the gel is a) small enough to entrap the enzyme with a minimum of leakage; but b) large enough to allow flow of the substrate and product(s) in and out of the gel; and c) optimal in terms of the mechanical properties of the gel. Often these are compering requirements and compromises must be made.
  • the access of the substrate to the enzyme is through the (periodic) pore system created by the cubic phase, and this can be adjusted independendy of the concentration of polymer and cross-linker in the aqueous phase.
  • the pores created by the cubic phase microstructure result from the removal of the unpolymerized components, DDAB and decane, and the diameter of these pores can be varied between 60 and 15 ⁇ A by varying the total concentration of water + acrylamide + cross-linker between 35 and 65%.
  • the relative concentrations of acrylamide, water, and cross-linker can be varied so as to adjust the final properties and entraping ability of the polymer gel.
  • the present material can be used in the immobilization of enzymes, or biocatalysts in general, besides entrapping the biocatalysts in the polymerized component.
  • this material is potentially of use in all of the presently-used methods for immobilization.
  • physical entrapment which has already been discussed and shown to be feasible, we now consider alternative methods of immobilization and the advantages that could be provided by the present material over and above the advantages traditionally associated with each method.
  • Covalent bonding and adsorption of enzymes When most people hear the term "Immobilized Enzyme", they think of enzymes which are covalently bonded to an insoluble support, which is usually polymeric.
  • enzymes can be covalently bonded to the porewall surface of the polymerized cubic phase, thereby inheriting the precision, biocompatibility, and versatility of the invention together with the usual advantages associated with covalently bonded enzymes.
  • advantages include permanence of the immobilization, so that the product is not contaminated with the enzyme and the enzyme is not lost due to changes in pH. temperature, etc., as in adsorbed enzymes.
  • a covalently bonded enzyme exhibits enhanced chemical or physical characteristics over the soluble enzyme, due to the alteration in its actual chemical structure.
  • Furthermore there is a high degree of development in this form of immobilization so that a wide variety of support polymers can be used and years of experience can be drawn on.
  • Covalent bonding or adsorption of a biocatalyst to the porewall surface of a polymerized cubic phase would create a reaction medium in which the pore size would be selected so as to allow access to the enzyme only for selected components. This would be of considerable importance in cases where the substrate was not isolated in a simple solution but rather present together with many other components, some of which could be detrimental to the desired reaction.
  • Clearly one important example would be blood, in which immunoglobulins, blood cells, and various macromolecules could be selectively excluded from enzyme contact by the monodisperse pores. In the more general case, it should be possible in many cases to use size exclusion to eliminate inhibitors (such as protein inhibitors) from the site of reaction while still allowing access of the substrate to the biocatalyst.
  • PAM polyacrylamide
  • Beads of PAM gel are commonly used to covalently bond enzymes, but with beads specific surface areas are on the order of at most tens of square meters per gram, whereas the present material offers hundreds or even thousands of square meters per gram.
  • initiators for the polymerization of acrylamide can be found in biological sources, such as riboflavin.
  • biocatalyst immobilized in a dispersion or suspension of particles such as when the preparation is to be injected into the body or absorbed through the skin, for example, or to make the enzyme more accessible to the substrate through simple diffusion.
  • dispersions of polymerized cubic phase particles including the following:
  • Photographs of these particles were published in the Winsor and Gray volume. At present we are at work to reproduce this experiment with AOT and hopefully, other surfactants and lipids, and eventually to polymerize such particles.
  • microcrystallites of hicontinuous cubic phase M T indström H Ljusberg Wahren, K. Larsson and B. Borgström 1981. Furthermore, a small amountof sodiumcholate canbe used to obtain a dispersion which is quite stable. Conjugated bile salts can also be usedto disperse the particles.
  • the cubic phase made from sunflower oil monoglycerides and water can incorporate hydrocarbons, at least up to 5:95 weight ratio of hexadecane to monoglycerides, and in principle then also polymerizable hydrophobes Sunflower oil monoglyceridesare a vailable for a remarkably inexpensive price: approximately 25 SEK per kilogram.
  • the DDAB / water / styrene cubic phase discussed at length in the original application and the Response to the first Office Action was prepared, using less than 7% styrene and no cross-linking agent. Under these conditions it is not surprising that after polymerization, the polymer could easily be broken up by mechanical disruption, and in fact after 30 minutes of sonication, a very fine dispersion of particles resulted. This sonication was performed after replacing the unpolymerized components with methanol, and sedimentation was then avoided by adding approximately 1.7 parts of 2-chloro-ethanol per 1 part of methanol, in order to match the gravimetric density of the fluid to that of the (microporous) polystyrene particles. The dispersion was white in transmitted light and slightly bluish, and some particles were just large enough to be visible to the naked eye, which together indicate particle sizes on the order of 1 to 10 microns.
  • the sonication breaks up the cubic phase into particles which are each actually a microcrystallite, because it is at the microcrystallite boundaries that the continuity of the polystyrene is probably most disturbed, at these low concentrations of styrene in the cubic phase.
  • the size of the particles in the final dispersion could be controlled by controlling a) the nucleation kinetics and thus the microcrystallite size; b) the concentration of monomer and, in particular, of cross-linking agent; and c) the extent of sonication.
  • the density matching is then a relatively simple step, and in cases where particle flocculation is a problem, standard techniques in emulsion science can be used to stabilize the dispersion against flocculation, such as the use of surfactants or adsorbing polymers.
  • Spray techniques can be used, in which for example tiny amounts of lipid or surfactant would be sprayed into a liquid, most likely water or aqueous solution, this method applying at least in cases where the lipid or surfactant forms a cubic phase which is in equilibrium with excess water.
  • the polymerizable lipid glycerol monolinoleate (“monolinolein", discussed in the Response to the first Office Action) forms a cubic phase which is in equilibrium with excess water over a wide temperature range, and therefore if a drop of monolinolein were introduced into an excess of water, it would spontaneously form a tiny clump of cubic phase, this being the equilibrium state.
  • Such clumps could be then polymerized to form the desired dispersion of solid, microporous particles.
  • Another technique is to use a solvent, such as ethanol, in which the surfactant or lipid is soluble, and mix together a dilute surfactant solution with a dilute solution of water in the solvent
  • the solvent should of course be more volatile than water. Due to the high dilution of the surfactant, which should be chosen to form a cubic phase in equilibrium with water, nucleation processes result in very small clumps of cubic phase, and these can be polymerized either before or after the evaporation of the volatile solvent. Preliminary experiments at Lunds Universitet have shown that dispersions of monoolein can be prepared in this way, although as yet polymerization has not been performed (e.g., by using monolinolein rather than monoolein) nor has it been demonstrated that the clumps are in fact cubic phase.
  • biocatalysts could be incorporated in the cubic phase particles.
  • the catalyst could be covalently bonded, or adsorbed, etc., to the porewalls of the cubic phase particles in the dispersed state.
  • the cells or enzymes could themselves act as nucleation sites for the formation of cubic phase microcrystallites. Note that in the latter case the demands on the surfactant-catalyst interactions are very nonspecific, for the simple reason that in general the creation of nucleation sites by
  • impurities does not require specific or permanent interactions at these nucleation sites. For example, water of very high purity can be undercooled many degrees below 0°C whereas any of a wide range of impurities will significantly reduce this undercooling.
  • controlled-release drug delivery is an exciting possibility opened up by the present invention, as the following example shows.
  • Particles could be prepared in which each particle had an outer coating consisting of a bicontinuous cubic phase laden with glucose oxidase. UV irradiation would proceed at least to the point where this outer coating was polymerized.
  • the oxidation of glucose by the immobilized enzyme would cause a lowering of the pH due to the production of hydrogen peroxide.
  • methods are known by which pH changes can be used to effect the release of, for example, insulin.
  • This latter example illustrates a feature of the present invention which is independent of the primary feature of monodisperse pores.
  • This feature is, namely, the fact that particles of a wide variety can be coated with bicontinuous cubic phase and polymerized to create an outer, microporous coating which can also contain biocatalysts.
  • the high viscosity of cubic phases together with the fact that many exist in equilibrium with excess water, make it possible to create the cubic phase coating under equilibrium conditions. If one were to try the same procedure with, for example, acrylamide, this would be impossible because the AM would be in solution and not on the surface of the particles.
  • Biocatalysts can be immobilized by placing a solution of the catalyst inside a cell which is used in the same way as a beaker but which is capable of continuous operation mode because of the use of a semipermeable membrane.
  • the membrane should allow reactants and products to pass freely but should contain the biocatalyst inside the cell.
  • the precision of the present microporous material could open up new possiblities in biocatalysis using this approach, both by increasing the effectiveness and reliability of existing processes, and by making feasible new combinations of catalyst and substrate which previously were not separable with existing membranes.
  • This method is one of the only methods which is effective with high-molecular weight or water-insoluble substrates.
  • Other methods such as enzymes bound to water-insoluble polymers, have inherently low effectiveness because of the steric repulsion between the polymer and the substrate.
  • the high monodispersity of the pores in the present materials can be used to control the molecular weight of the final product exitting from the reactor cell; with a smaller pore size, the substrate would be contained for a longer time in the cell and broken down into smaller fragments, until finally these were small enough to pass through the membrane.
  • porewall charge characteristics can be selected so as to retain the enzyme and allow passage of substrates and products.
  • many possible means for producing membranes with anionic, cationic, zwitterionic, polar, and nonpolar porewalls were discussed, and every year the number of successfully synthesized polymerizable surfactants increases, making more choices available for producing such membranes from polymerizable surfactants with desired electrostatic properties.
  • this method of immobilization there is no modification of the enzyme required, and in fact the enzyme is simply put into solution and placed inside the cell. After use, the enzyme solution can be removed and reused.
  • several biocatalysts can be simultaneously immobilized , while minimizing the problems associated with other immobilization methods when faced with several enzymes having different chemical and physical requirements.
  • glucose probe produced by Yellow Springs Instrument Company.
  • This probe consists of three layers placed in contact with a polarized platinum electrode; this electrode is sensitive to hydrogen peroxide.
  • the glucose oxidase on glutaraldehyde resin particles constitutes the middle layer which lies between a polycarbonate and a cellulose acetate membrane.
  • These membranes not only immobilize the enzyme, but they also minimize the amount of compounds reaching the probe electrode which would otherwise interfere with the measurement.
  • the pores of the polycarbonate membrane allow the passage of glucose and oxygen, but not cells or
  • cellulose acetate membrane allows hydrogen peroxide to reach the electrode but not glucose and acids such as uric or ascorbic acid.
  • glucose and acids such as uric or ascorbic acid.
  • other substances such as blood preservatives (Hall and Cook, 1982; Kay and Taylor 1983) and certain drugs (Lind et al. 1982) are able to reach the electrode where they produce spurious results.
  • This example serves to demostrate the potential importance of the present invention in biocatalysis applications due to its ability to exclude, on the basis of size, compounds which are not inert with respect to the catalysts or with associated probes.
  • bilayer-bound enzymes involves the use of lipids or surfactants which contain a polymerizable group as part of a spacer that extends out from the bilayer into the aqueous phase.
  • Laschewsky, Ringsdorf, Schmidt and Schneider (1987) have synthesized several such polymerizable lipids, including one form that is a phospholipid. Even if radical-generating initiators were used to initiate the polymerization of such lipids, they could be chosen so as to reside in the aqueous phase and thus the exposure of the enzyme to any radicals would be minimal or essentially nonexistent.
  • Two of the lipids synthesized by that group are, except for the polymerizable group, basically the same as the lipid glycerol monooleate (or monoolein), which as discussed at length in the earlier
  • thiol-bearing phosphotidylcholine lipids can be polymerized and depolymerized by a thiol-disulflde redox cycle: hence they have been referred to as 'on-off' surfactants.
  • One such possibility now being discussed in the literature on liposomes is the controlled-release of antigens/haptens. because their lateral mobility and distribution are believed to play an important role in the
  • polymerizable/depolymerizable lipids are one example of polymerizable lipids which form polymers that are biodegradable.
  • Another class of such compounds now being investigated consists of lipids or phospholipids with amino acid groups which polycondensateto form polypeptides. As early as 1948, Katchalsky and coworkers performed a successful
  • the optimal hydrophilic contact lens should have as high water content as possible, yet have good mechanical integrity and notch strength. High water content lessens the irritation of the eye, establishes a high degree of hydrophilicity which leads to better lubrication during blinking, and most importantly, it is known that the permeability of oxygen through the lens increases exponentially with water content.
  • the lens should have a large effective pore size so as to allow the passage of not only low-molecular weight tear film components, such as metabolites (glucose, urea, lactic acid, etc.) and ions, but also higher-MW components such as proteins and mucins, thus minimizing the effect of the lens on the distribution of these components in the preocular tear film (POTF) without the need for tear exchange under the lens.
  • low-molecular weight tear film components such as metabolites (glucose, urea, lactic acid, etc.) and ions, but also higher-MW components such as proteins and mucins, thus minimizing the effect of the lens on the distribution of these components in the preocular tear film (POTF) without the need for tear exchange under the lens.
  • POTF preocular tear film
  • prior art contact lenses these have represented conflicting requirements and compromises have had to be made.
  • good integrity requires a high degree of cross-linking and thus low water content and small effective porsize.
  • Lenses such
  • the diameter of these macropores can be preselected, by methods taught in the applications cited above, to be between 20 Angstroms and several hundred Angstroms or even higher, and in general will be much larger than the "micropores" within the
  • phi g can be chosen between 11% and 70%, so that if phi m is
  • the final water content can be chosen between 58 and 93%.
  • a fundamental advantage of this material is that the strength of the final material can be made much higher than a simple hydrogel at the same water content. This is because the shear modulus G s of a simple hydrogel is a very strong nonlinear function of the water content, whereas the same shear modulus of a macroporous material depends only linearly on the macroporosity. In a simple gel at
  • hydrophilic monomer which is polymerized in the same way as in the formation of a simple hydrogel.
  • chemistry of the final hydrogel is the same as in the simple hydrogel, after the removal of the unpolymerized surfactant (and possibly hydrophobic component), and the only
  • the macropores of the present invention represent a sensible and effective means of arriving at high water contents without sacrificing mechanical integrity.
  • macropores of the present invention in reducing the effect of the lens on the composition and functioning of the tear film.
  • the tensions at the surface of the lens should be low.
  • shear-thinning Kerura and Tiffany 1986. This is necessary to maintain the film when the eye is open, but to enhance lubrication, through shear-thinning, during blinking.
  • the macropores of the present invention could also be of importance in passing the bacteriacidal components of the tear film, which include lysozyme (muramidase),
  • B-lysine, lactoferrin, and a-arysulphatase, and lacrimal immunoglobulins For example, abnormally low concentrations of lysozyme in the tear film lead to keratoconjunctivitis sicca (KCS; Dougherty, McCulley, and Meyer 1986; Sen and Sarin 1986).
  • Other relatively high MW compounds that may reach the corneal epithelium through the tear film, and whose passage could be selectively controlled in the present invention by the presence of macropores of selected size, include nutritional components, such as Vitamin A, and topically-administered drugs (Ubels 1986). It has been shown that Vitamin A, a deficiency of which results in keratinizing, as well as retinoids can be therapeutic when administered topically to the eye. Thus the lenses of the present invention could be particularly beneficial in cases where corrective lenses are used in conjunction with such treatments.
  • Hydrogels are used in many other applications besides contact lenses, and the high strength at high water content, biocompatibility, and macroporosity of the present invention could make these materials of great potential importance in many of these, in particular in skin
  • the nonionic surfactant C 8 E 4 forms normal micelles in water to over 30% concentration at room temperature.
  • the applicant has determined that, although DDAB alone does not form normal micelles in water, it is capable of forming mixed micelles, apparently, with C 8 E 4 .
  • 5% DDAB was added to a 15% solution of C 8 E 4 in water, and the C 8 E 4 /water micellar solution remained a clear, isotropic, low viscosity
  • concentration of C 8 E 4 of 15% was reached in approximately two days.
  • the amount of water and C 8 E 4 used to remove the DDAB and decane in the specimen was large enough that the concentrations of DDAB and decane in the final solution were very small, considerably lower than 5%.
  • the specimen was then removed from this solution, except of course for the small volume of solution remaining in the macropores of the specimen, which was replaced with water by successive dilutions.
  • cytochrome-c was able to penetrate into the micropores as well as the macropores. This is quite possible because the MW of cyochrome is small enough that it could probably enter the micropores at the present concentrations.
  • cyochrome is small enough that it could probably enter the micropores at the present concentrations.
  • the final material was the consistency of rubber, and can be cut into thin slices each having good elastic properties. Because the volume fraction of the gel portion is 65%, and 15% of this gel is
  • the overall volume fraction of polymer is less than 10%, meaning that the water content is over 90%. This can be adjusted over a very large range.
  • styrene as the oil
  • the cubic phase region extends from about 70% water down to approximately 11% water, and the same range appears to hold with toluene as oil.
  • 15% acrylamide (plus cross-linker) is added to the water component, this range shrinks somewhat at the low water end but is still very large in extent; at 20% AM in the water the cubic phase is somewhat harder to locate, and at 30% harder still.
  • Polyacrylamide is one typical representative of a class of related hydrophilic polymers, and although the phase behavior will probably change slightly when another monomer such as HEMA is used instead, the cubic phase region will still be present in this DDA system. Furthermore, the following are examples of parameters which can be changed so as to counteract changes in the phase behaviour that might reduce the size of the cubic phase region: 1) the length of the hydrocarbon tails of the surfactant can be increased or decreased; 2) the counterion can be exchanged for chloride, fluoride, etc; 3) the temperature can be adjusted; 4) the oil can be changed (note that the effect of changing from decane to styrene is to extend the lower limit of the cubic phase region from about 30% down to 11%); 5) the head group area can be adjusted by substituting other moieties for the methyl groups, for example (this has been done in the case of DOPC and has induced a cubic phase; Sol Gruner and coworkers, 1988); 6) a co-surfactant, such as an alcohol, can be added.
  • CTAC single-tailed cationic surfactant cetyltrimethylammonium chloride
  • CTAS sulfur as counterion
  • CTAB bromide
  • CTAF fluoride
  • DoTAC DoTAC
  • test tube was broken open, and the air above the sample was replaced with nitrogen gas and the tube then sealed with a cork. This was then placed in a
  • cubic phases which are based on anionic surfactants: sodium dodecyl sulphate (SDS) and sodium n-dodecanoate. Based on earlier work by Tabony, we have formed a cubic phase with composition: 20% SDS, 0.8% butanol, 42% water, and 37.2% styrene. Then with the surfactant sodium n-decanoate, Kilpatrick and Bogard (1988) have shown that two cubic phases exist with this surfactant, one in the binary surfactant/water system above 67°C, and one in the ternary surfactant/water/toluene (or decane) system at about 20% toluene, at 60°C.
  • SDS sodium dodecyl sulphate
  • n-dodecanoate sodium n-dodecanoate
  • a surfactant can be used which is similar to SDS, or to sodium n-decanoate, but has a
  • the styrene would then be polymerized together with the surfactant. This is a preferred method for two reasons: 1) the electrostatic profile of the styrene molecule is such that it will not tend to penetrate into the head group region of the surfactant layer, so that the styrene/
  • methacrylate end group region should be a contiguous region rather than uninterrupted by the presence of hydrocarbon tails or surfactant polar groups, making for good
  • the porewalls of the resulting polymerized phase will be anionic, thus reducing or eliminating any tendency for absorption of tear
  • the aromatic ring of the styrene molecule can be roughly described as a "sandwich", with a middle layer of positive net charge surrounded by two layers of negative net charge.
  • This provides for a very favorable styrene/head group interaction in the case of a cationic surfactant, in which the styrene molecule is sandwiched between two cationic groups.
  • a cationic surfactant in which the styrene molecule is sandwiched between two cationic groups.
  • obstructions such as hydrocarbon tails in the component undergoing polymerization will create a favorable medium for polymerization which will lead to clear polymeric materials.
  • negatively charged porewalls are optimal in terms of reducing or eliminating absorption of proteinaceous material to the material.
  • c are 2*jj,2*kk,2*ll, with fee unit cell.
  • nns 21*(n-1)+m
  • n1 21*(nv-l)+nu
  • n2 n1+1
  • n3 n1+22

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Abstract

Un substitut hydrophile d'une phase cubique bicontinue en équilibre est polymérisé et des composants non polymérisés sont ensuite éliminés et remplacés par de l'eau, ce qui crée un hydrogel qui est fortement réticulé localement mais qui présente une haute teneur en eau, en raison de la présence d'un réseau périodique de macropores remplis d'eau superposés sur la matrice de l'hydrogel. Le diamètre de ces macropores peut être sélectionné préalablement entre 20 Angström et plusieurs centaines d'Angström, voire plus, et est en général plus élevé que le diamètre des micropores de l'hydrogel. L'hydrogel se caractérise par une haute teneur en eau, par une bonne compacité mécanique et par une excellente résistance à l'entaillage et une haute perméabilité à l'oxygène. La porométrie peut être choisie pour permettre le passage de molécules de grandeur préalablement sélectionnée. Un tel hydrogel est utile dans une lentille de contact et dans d'autres applications biologiques et médicales.
PCT/US1989/005864 1988-12-30 1989-12-29 Substances microporeuses stabilisees et substances a base d'hydrogel WO1990007575A1 (fr)

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