WO1990007545A2 - Matieres microporeuses et matieres d'hydrogel stabilisees - Google Patents
Matieres microporeuses et matieres d'hydrogel stabilisees Download PDFInfo
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- WO1990007545A2 WO1990007545A2 PCT/US1990/000050 US9000050W WO9007545A2 WO 1990007545 A2 WO1990007545 A2 WO 1990007545A2 US 9000050 W US9000050 W US 9000050W WO 9007545 A2 WO9007545 A2 WO 9007545A2
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/64—Animal cells
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/18—Pore-control agents or pore formers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/026—Sponge structure
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/02—Details relating to pores or porosity of the membranes
- B01D2325/0283—Pore size
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/10—Catalysts being present on the surface of the membrane or in the pores
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2205/00—Foams characterised by their properties
- C08J2205/02—Foams characterised by their properties the finished foam itself being a gel or a gel being temporarily formed when processing the foamable composition
- C08J2205/022—Hydrogel, i.e. a gel containing an aqueous composition
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2533/00—Supports or coatings for cell culture, characterised by material
- C12N2533/30—Synthetic polymers
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M50/00—Constructional details or processes of manufacture of the non-active parts of electrochemical cells other than fuel cells, e.g. hybrid cells
- H01M50/40—Separators; Membranes; Diaphragms; Spacing elements inside cells
- H01M50/409—Separators, membranes or diaphragms characterised by the material
- H01M50/411—Organic material
- H01M50/414—Synthetic resins, e.g. thermoplastics or thermosetting resins
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01M—PROCESSES OR MEANS, e.g. BATTERIES, FOR THE DIRECT CONVERSION OF CHEMICAL ENERGY INTO ELECTRICAL ENERGY
- H01M50/00—Constructional details or processes of manufacture of the non-active parts of electrochemical cells other than fuel cells, e.g. hybrid cells
- H01M50/40—Separators; Membranes; Diaphragms; Spacing elements inside cells
- H01M50/489—Separators, membranes, diaphragms or spacing elements inside the cells, characterised by their physical properties, e.g. swelling degree, hydrophilicity or shut down properties
- H01M50/491—Porosity
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
Definitions
- FIGURES Pages ( 1 /17 )-( 17 /17 )
- 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 microstrucure such as critical phase transition measurements,
- the invention pertains to hydrogel applications, particularly soft contact lenses, but also other
- 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.
- sintered-particle filters have retention ratings at or above 0.7 microns.
- 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.
- hydrophobic/hydrophilic/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:
- critical filtrations including chiral separations, affinity-based separations, dialysis, protein sieving, and active transport; processes such as measure of critical phase transitions; and in microelectronics, molecular electronics, and
- 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
- FIG. 5 A and B show digitized electron micrograph of:
- the model used was determined by the
- FIG. 6 combines the views of FIGS. 5 A and B for clearer comparison.
- FIG. 7 sets out thre equations used in the
- FIG.s 8 and 9 illustrate some results from evaluation of sizes and dispersity of pore sizes in certain cubic phases by thermoporimetry.
- Figure El Phase diagram of the binary C 12 E 5 - water system, adapted from reference 4.
- LAM or D
- lamellar phase Ll
- L2 normal fluid isotropic solution
- inverted fluid isotropic solution L3
- the phase that is the subject of this paper Vl (or V), bicontinuous normal cubic phase; V2, bicontinuous inverted cubic phase
- Hi or H
- normal hexagonal phase H2
- inverted hexagonal phase W
- S or XTLS
- solid crystalline surfactant solid crystalline surfactant.
- Figure E2 A portion of the phase diagram at 25° for Aerosol OT - NaCl - water, adapted from reference 6.
- the NaCl scale has been enlarged for clarity.
- the L3 phase region extends over a wide range of water/AOT ratios at nearly constant salinity, then joins up with the V2 phase in a two-phase region. This 2 phase is believed to have the Ia3d or 'gyroid' structure.
- FIG. E3 A slice, at constant surfactant concentration (16.6%), of the C 12 E 5 - tetradecane - water ternary phase diagram as a function of temperature (adapted from reference 13).
- Wm refers to a water-rich microemulsion Om to an oil-rich microemulsion.
- the L3 phase has two branches, one at low oil and high temperature, and one at high oil and low temperature. Both of these branches, and the Wm and Om regions, join up in an apparently continuous fashion to a region of roughly equal volume uptake in the microemulsion, around 45°C; in this range the microemulsion is probably bicontinuous
- Figure E4 One mathematical idealizaiton of the surfactant bilayer, in cross-section. Given a base surface Sb, one can move a constant distance L away from each point in a direction given by the surface normal at that point, or in the opposite direction, and this defines two displaced 'parallel' surfaces. One can imagine the polar/apolar dividing surfaces of the surfactant bilayer as being
- the distance L to the displaced suface varies in such a way that the two displced surfaces are of constant mean curvature. In the cases treated here these two
- 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
- 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).
- curvature are called the principle curvatures. One-half the sum of these curvatures is called the mean curvature, and the product of these curvatures is the Gaussian
- 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 of 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 two 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 for certain binary cubic phases [Longely and Mclntosh 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.
- 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
- FIG. 1 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. In 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
- 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.
- the membrane type described herein can be fabricated in many ways. As mentioned above, bicontinuous microstructured phases (of 'cubic symmetry) occur also as equilibrium morphologies in block copolymers, and chemical erosion of one component can result in a similar membrane type. It has been shown [Alward et al. 1986] that the lattice size scales as the 2/3 power of the molecular weight of the copolymer, if the ratio of the two components is fixed. Since anionic polymerization reactions can produce star-block copolymers with extremely narrow molecular weight distributions, fabrication with copolymers provides a means of producing a membrane of prescribed pore size. The surfactant DDDAB was chosen for the
- 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
- nonionic 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 likely 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 final monomer since the triple-periodicity 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.
- Class 1 processes.
- 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.
- 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).
- cosurfactant, amphiphile, block copolymer or alcohol were traditionally used for the compound or mixture (recall that 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.
- 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.
- a variation of the process would allow a much larger variety of polymers since they could be synthesized beforehand under any desired conditions. The applicant has done work
- 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.
- bicontinuous cubic phases have also been formed with a variety of ionic surfactants.
- the first proposed bicontinuous cubic phase was in a binary soap system, potassium laurate/water [Luzzati and Spegt 1967].
- Other examples of binary bicontinuous cubic phases formed with anionic surfactants are: sodium laurate, and relatives with other chain lengths [Luzzati et al. 1968]; potassium octanoate, and with other chain lengths; and sodium
- 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.
- 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.
- epoxides used as the hydrophilic blocks ares ethylene oxide, glycidol, butadiene dioxide, all of which have a oxygen to carbon atom ratio at least 0.4.
- 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 and syndiotactic PMMA can be prepared with Ziegler-Natta catalysts, and these have been used in dialysis membranes [Sakai et al. 1980]. 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.
- 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 multib-lock 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.
- the 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.
- 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.
- 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 hydrogen ions, while Mylar (polyethylene terephthalate) requires ions at least as heavy as oxygen. A diblock copolymer selectively tracked in one component could then be immersed in acid or base to etch away pores. Olefin metathesis is another reaction that is used today to degrade polymers. Again what is required is the presence of double bonds in the polymer backbone, so that as in the discussion of ozonolysis the PS/PI block copolymers would be
- 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. Homopolymers 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
- perfluorinated ionomers perfluorinated ionomers
- 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; such reactions are the subjects of investigations in present-day polymer research and promise to open up new possibilities for the grafting of ionogenic polymers in a post membrane formation process.
- graft copolymers might be used as the basis for type 2) processes, for recent evidence [Hasegawa 1986] indicates that graft copolymers can form bicontinuous cubic phases.
- Styrene polymers and copolymers with, for example divinyl benzene and/or ethyl vinyl benzene, are excellent starting materials for the formation of ionomers, because 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. Amination of the same chloromethylation product with primary or secondary amines yields weak-base anion-exchange
- 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
- 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 triethylamine and immersion in a solution of water, dimethyl sulfoxide and potassium hydroxide, or by treatment with aqueous ammonia, also yield ionomeric polymers suitable for electrolysis. Polyol surfactants can be subjected to reactions that induce an ionic character.
- the terminal hydroxyl groups can be converted to various functional groups [Lundsted and Schmolka 1981], such as to a halide and subsequently to a tertiary amine by reaction with a
- 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.
- 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. As discussed earlier, 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 nonaqueous 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.
- membranes Another medical application for membranes is in controlled drug-delivery systems.
- the simplest description of these is that a drug is imbibed into the pores of a membrane, and released slowly so as to approximate a constant concentration over time in the body (zero-order release), or a concentration that fluctuates in response to physiological conditions (first-order release).
- 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
- Membrane metering devices are potentially of great utility in the release of other 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, and 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 prediction from the constant-mean-curvature-interface model.
- 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.
- Electrodialysis is the most important
- Electrodialysis for ion-exchange of Na+ to Ca+, K+, or Mg+ is being
- 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
- connectivities which cover a range including that from 3 to 8 pore throats emanating from each cell.
- 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
- Proteins in particular enzymes, can be any substance that can be any substance.
- 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, immunoadsorption
- 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 25-200
- Angstroms which is an order of magnitude smaller than the smallest pore dimensions of the microporous material described in the patent 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
- monoolein cubic phase in water is stable from less than 20C° to over 90C°.
- Inherent in the present invention is a direct
- glucose oxidase can be used to detect concentrations of glucose in serum, and glucose oxidase can be entrapped in the monoolein/water cubic phase (C. Tilcock and D. Fisher, Biochim. Biophys. Acta, 1982, vol. 685, pp. 340-346).
- Cubic phases can be used in controlled-release drug delivery.
- 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 incorporating proteins and enzymes, as described elsewhere, as biosensors.
- pancreatic islets can be encapsulated and protected from the body's immune system while insulin and glucose could pass freely into the islets.
- insulin and glucose could pass freely into the islets.
- 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 living cell; 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 functioning 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 of 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 by 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.
- the present invention would be very valuable even if its sole novel feature were a surfactant-lined porewall. Also in such applications the extremely high specific surface area of the present invention, as well as the precisely
- micellar phases For applications in which the present technology calls for the solubilization of catalysts or coenzymes in micellar phases, it is likely that the same catalysts could also be solubilized in cubic phases, in stable or metastable states.
- 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 and 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, orders of magnitude lower than that of the cubic phases. Therefore, it is not surprising that a recent attempt to polymerize a bicontinuous microemulsion failed to preserve the bicontinuity due to a fundamental change in structure during the polymerization (Candau, Zekhnini, and Durandi 1988). This appears to be inevitable since polymerization generally takes hours, whereas the time scale for
- 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 transmembrane 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).
- TiO 2 (Reichman and Bjork 1981). Hydrogen and oxygen can be formed photochemically on a TiO 2 -RuO 2 catalyst using 310 nm light (Kawai and Sakato 1980).
- 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 of 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 of monoolein/water/lysozyme, extending to over 30 per cent lysozyme. The same lipid with water can also form
- dioleoylphosphotidylethanolamine N-methylated DOPE
- phosphotidyl choline PC
- egg lysophosphotidyl choline egg LPC
- MGluDG monoglucosyldiglyceride
- DGDG diglucosyldiglyceride
- egg lecithin glycerol
- Beside polymerizable surfactants another means to immobilize enzymes within the present invention is to incorporate them into a hydrophobic or hydrophilic
- 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.
- 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-embolization which can lead to pulmonary leuko-embolization.
- RDS respiratory distress syndrome
- dialysis-induced amyloidosis in which deposits of amyloid (the primary constituent of which is ⁇ 2- 2-microglobulin) are present in the joints, synovium, capsula, subchondral bone and vertebral disks, for example; in fact 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.
- amyloid the primary constituent of which is ⁇ 2- 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.
- 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 monovalent 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 HCO 3 -.
- 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 5 ⁇ 10 -13 m2/sec.
- the protein F 0 F 1 -ATPase from Rhodospirillum rubrum has been polymerized into synthetic vesicles, and interestingly its activity actually increased upon polymerization (Wagner, Dose, Koch, and Ringsdorf 1981). Of course, this is not to say that all proteins retain their functionality upon fixation of the bilayer.
- ions and small molecules are transferred across bilayers through transport proteins which open and close in response to specific ligand-binding, (ligand-gated channels) and others in response to changes in membrane potential (voltage-gated channels). These offer additional mechanisms by which the molecular transport could be regulated in the context of the present invention.
- 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.
- 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.
- HLB hydrophile-lipophile 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 structure should become more disordered, while still maintaining the basic topological characteristics of the ordered cubic phases.
- 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
- 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 molecules), 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
- bicontinuous structure is a simple consequence of spontaneous mean curvature toward water in a bilayer structure and it is demonstrated that the locations of L3 phases in surfactant/water phase diagrams strongly indicate spontaneous curvature toward water.
- 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 structure could easily rearrange significantly during the polymerization process; recall that, as noted above, a recent attempt to polymerize a bicontinuous microemulsion resulted in a loss of bicontinuity (Candau, Zekhnini and Durandi 1988).
- labyrinths chemical, electrical, or geometrical - in order to effect a separation between reactants, reaction products, catalysts, or filtrates.
- the precise mechanism is not known by which this asymmetry is created in living cells.
- the very nature of the bioprocesses, such as photosynthesis, which rely on this asymmetry prove that chemical asymmetry is indeed created, and in the case of the thylakoid membrane and the prolamellar body there electron microscopy data which demonstrate geometrical asymmetry.
- measurements made from micrographs of prolamellar bodies - which are known to have cubic symmetry - indicate that the surface areas of the two head group surfaces differ by approximately 30% (Israelachvili and Wolfe 1980).
- the cubic phase is of the Ia3d type discussed in the previous paragraph, and the cylinders of the hexagonal phase grow along the directions given by the 'tunnels' of the cubic phase. If such a system is polymerized, this creates accesses to the two labyrinths of the cubic phase through two distinct systems of hexagonal phase cylinders distinguished by their orientations. This would be in close analogy with the microstructure in the endoplasmic reticulum, in which the smooth ER is a finely porous network, observed in some electron micrographs to possess cubic symmetry (Alberts, Bray, Lewis, Raff, Roberts, and Watson 1983), that connects to the rough ER of much coarser structure and simpler topology. Examples of
- 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.
- 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. For example, polymerizable conjugated diacetylene surfactants become intensely colored upon polymerization
- cytochrome c is a colored protein which acts as an electron carrier in the electron-transport chain of the cell.
- 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 different compositions, and we can sieve particles 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 Angstroms.
- 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 incorporated into a cubic phase, smeared onto the tip of a pH meter probe, and fixed by polymerization. The probe is then dipped into a glucose solution and the pH measured as a function of time. A drop in the pH would indicate the oxidation of glucose by the immobilized enzyme.
- an enzyme such as glucose oxidase can be incorporated into a cubic phase, smeared onto the tip of a pH meter probe, and fixed by polymerization. The probe is then dipped into a glucose solution and the pH measured as a function of time. A drop in the pH would indicate the oxidation of glucose by the immobilized enzyme.
- 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.
- Photocatalysis We can perform the photocatalytic experiments described by Willner et al. but in polymerized bicontinuous cubic phases, in which the surfactant is the polymerized species.
- 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 surfactant self-diffusion has been found to be 8 ⁇ 10 -10 m 2 /sec (Nilsson, Wennerstrom, and Lindman 1983), whereas in the discrete cubic phase the surfactant self-diffusion 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]:
- T 64.67/(R-0.57) for freezing.
- DSC differential scanning calorimeter
- thermoporometry over other porosimetry methods, such as BET porosimetry, are 1) it is a simple, straightforward measurement made with standard equipment, and 2) the sample does not need to be dried, and thus supercritical drying need not be performed. Thus, 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
- 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.
- cross-linked polyacrylamide gel is used to entrap the enzyme.
- the polymer concentration and the extent of cross-linking must be such that the msh 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 competing 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 independently of the concentration of polymer and
- cross-linker in the aqueous phase is cross-linker in the aqueous phase.
- unpolymerized components, DDAB and decane, and the diameter of these pores can be varied between 60 and 100 Angstroms by varying the total concentration of the water + acrylamide + cross linker between 35 and 65%.
- cross-linker can be varied so as to adjust the final
- the present material can be used in the immobilization of enzymes, or biocatalysts in general, besides entraping the biocatalysts in the polymerized component.
- this material is potentially of use in all of the presently-used methods for immobilization. Besides 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
- enzymes can be covalently bonded to the porewall surface of the polymerized cubic phase, htereby inheriting the precision, biocompatibility, and versatility of the invention together with the usual advantages associated with covalently bonded enzymes.
- covalently bonded enzyme exhibits enhanced chemial or physical characteristics over the soluable enzyme, due to the alteration in its actual chemical structure. Furthermor 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 creat a reaction medium in which the pore size would be selected so as to allow access to the enzyme only for selected
- 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 adsorbd through the skin, for example, or to make the enzyme more accessible to the substrate through simple diffusion.
- dispersions of cubic phase there are many possible methods which could be used to produce dispersions of cubic phase
- glycerol monooloeate (monoolein) has been shown to form polyhedral microcrystallites of bicontinuous cubic phase (M. Lindstrom, H. Ljusberg-Wahren, K. Larsson and B. Borgstrom 1981). Furthermore, a small amount of sodium cholate can be used to obtain a dispersion which is quite stable. Conjugated bile salts can also be used to disperse particles. It should also be mentioned that 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
- Sunflower oil monoglycerides are available for a remarkably inexpensive price: approximately 25 SEK per kilogram.
- the sonication breaks up the cubic phase into particles which are each actually a micro crystallite, because it is at the microcrystallite boundaries that the continuity of the polystyrene is probably most disturbed, a these low concentrations of styrene in the cubic phase.
- 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 simpl 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 monoglycerol 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 inti 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
- Another technique is to use a solvent, such as ethanol, in which the surfactant or lipid is soluable, and mix together a dilute surfactant solution of water in the solvent and then evaporate off 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
- the cells or enzymes could themselves act as the nucleation sites for the formation of cubic phase
- 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.
- 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
- 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 possibilities in biocatalysis using this approach, both by increasing the effectiveness and reliability of existing processes, and by making
- diameters of an enzyme and its substrate is usually much less than 10, and often only two or three.
- the requirements on the containing membrane are thus in many cases that the pores be substantially monodisperse.
- water-insoluable polymers have inherently low effectiveness because of the steric repulsion between the polymer and the substrate.
- the acton of the enzyme is to breakdown a higher-MW 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.
- the enzyme solution can be removed and reused. Furthermore, several biocatalysts can be simultaneously immobilized, while minimizing the problems associated with other immoblization 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.
- 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 (Lindh et al. 1982) are able to reach the electrode where they produce spurious results.
- This example serves to demonstrate 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
- polymerizable phospholipids with latent aldehydes in the polar groups can be photopolymerized and subsequently bonded with
- alpha-chymotrypsin S. Regen, M. Singh, and N.K.P. Samuel 1984.
- Another method for bilayer-bound enzymes involves the use of lipids or surfactants which contain a polymerizable group as part of a spacer that extnds 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 documents forms
- thol-bearing phophotidylcholine lipids can be polymerized and de-polymerized by a thiol-disulfide redox cycle; hence they have been referred to as "on-off"
- liposomes is the controlled release of antigens/haptens , because their lateral mobility and distribution are believed to play an important role in the immunilogical system (J.T. Lewis and H.M. McConnell 1978). It has been suggested that the lateral motion of haptens could be tuned through the use of vesicles composed of on-off lipids or surfactants. We suggest here that the same approach using bicontinuous cubic phases could be even more effective because of the
- phopholipids are expected to form bicontinuous cubic phases. These polymerizable/depolymerizable lipids are one example of polymerizable lipids which form polymers which are biodegradable.
- Another class of such compounds now being investigated consists of lipids or phospholipids with amino groups which polycondensate to form polypeptides. As early as 1948, Katchalsky and coworkers performed a successful polycondensation reaction of octadecyl esters of glycine and analine in Langmuir-Blodgett multilayers. Such studies are now being actively resumed in an attempt to produce
- biodegradable polymerized vesicles and as above we argue that similar chemistry, but carried out in the bicontinuous cubic phase instead of in vesicles, can be used to create biodegradable and/or controlled-release materials endowed with the inherent features of bicontinuous cubic phases.
- bilayer-bound catalysts The polymerization of counterions is similar in spirit to the use, in Nature, of polymeric frames that are attached to cell biomembranes and that lend the biomembrane an added degree of stability and
- a further step is the anchoring of the resulting polyelectrolyte to the (unpolymerized) lipid by covalent bonding oof the
- 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
- a hydrophilic substituent of a bicontinuous cubic phase is polymerized according to the methods disclosed in the copending
- 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
- hydrogel portions of the final material are hydrogel portions of the final material.
- a simpler way to understand this superstructure is to imagine taking an ordinary hydrogel, with say, 10 Angstroms average diameter micropores and "drilling" a network of pores of, say, 100
- the volume fraction phi of the hydrophilic substituent usually a hydrophilic monomer such as 2-hydroxyethyl methacrylate (HEMA) with added cross-linker and usually swollen with added water -- can be made considerably less than 50%. If phi is the volume fraction of monomer in the hydrophilic constituent then the volume fraction of water in the final macroporous hydrogel will be 1-phi g +phi g (1-phi m ); that is, the water content in the final material has two
- phig can be chosen between 11% and 70%, so that if phim 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 Gs 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
- the decrease in shear modulus would be expected to be on the order of only 30%, instead of a factor of fifty.
- the reason for the dramatic decrease in strength in the first case is of course due to the much lower concentration of cross-links in the simple gel, in addition to the higher water concentration.
- 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.
- the macropores provide for transport of higher-molecular weight tear components throughout the eye-lens system.
- the outermost layer of the lacrimal film is essential to a high quality refractive surface. This layer is also important in preventing tear evaporation and lowering surface tension.
- the lubricating and wetting roles of the POTF are necessary in blinking which in turn is necessary for cleaning the epithelial surface.
- the POTF plays an important role in protecting the epithelial surface from microbial attack and other toxins, and provides a compatible environment for the epithelium.
- the precise characteristics of the epithelial cells in turn, change the light
- the pre-lens tear film formed on contact lenses is noted for its decreased stability in comparison to the corresponding preocular tear film. This decreases as reflected in a quicker break up time, is due to the
- macropores of the present invention in reducing the effect of the lens on the composition and functioning of the tear film.
- Mucins are highly tensioactive (Holly and Hong 1982) and appear to be crucial in maintaining the wettability of the eye or the contact lens (Proust 1986); the mucins serve as a bridge between the hydrophobic epithelial surface of the cornea and the aqueous salt layer of the tear film. Thus without the mucin layer, the tear fluid would not wet the epithelium and would "bead up".
- Enzymes that are found in the normal POTF include lysozyme, peroxidase, amylase,
- the pore size in the present materials are in the correct range and monodispersity to allow for selection of the proteinaceous and macromolecular components which are to pass through the material.
- 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.
- lysozyme muramidase
- B-lysine B-lysine
- lactoferrin lactoferrin
- a-arysulphatase lactoferrin
- lacrimal immunoglobulins lacrimal immunoglobulins.
- 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. Other applications.
- 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
- 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 (cross-linked) polyacrylamide, 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. In particular, we have found that with 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.
- 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. Experimental; Clear
- CTAC single-tailed cationic surfactant cetyltrimethylammonium chloride
- CTAS sulfur as counterion
- CTAB bromide
- CTAF fluoride
- DoTAC DoTAC
- Balmbra et al. This is the same space group that is found for the cubic phases in many biological lipid/water systems (such as monoolein/water), but in the case of CTAC and related surfactants the cubic phase is normal rather than reversed -- that is, the two rod networks are filled with surfactant tails rather than water, and the water forms the continuous matrix which is bisected by the "gyroid" minimal surface. Thus the cubic phase is found between the normal hexagonal and the lamellar phases. This means that the appropriate component to polymerize is the aqueous
- the water component of the cubic phase at higher surfactant concentrations in the CTAC/water system was replaced by a 30 wt. % aqueous solution of acrylamide.
- the concentration of CTAC was 75.9% by weight.
- the crosslinking agent methylene-bis-acrylamide was added along with the water-soluble initiator 4
- 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. The former cubic phase is almost certainly bicontinuous since it lies between a hexagonal and a lamellar phase region. The latter cubic phase has not been fully characterized, although the water concentration and toluene content are very similar (50% and
- a bicontinuous cubic phase can be produced from sodium n-decanoate, or a related surfactant, and significant amounts of styrene, which behaves nearly identically to toluene.
- a surfactant can be used which is similar to SDS, or to sodium n-decanoate, but has a
- 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.
- the styrene in the DDAB/styrene/water cubic phase is indeed located preferentially near the head group region.
- SDS or sodium decanoate the styrene should be located almost entirely in a separate layer starting near the end of the surfactant tails. If these surfactant tails contained a methacrylate group at their ends, this would create nearly ideal conditions for a polymerization which would polymerize both the styrene and the surfactant.
- 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*11, with fee unit cell.
- nns 21*(n-1)+m
- n1 21*(nv-1)+nu
- n2 n1+1
- n3 n1+22
- hh1 h1(nf,k1,k2+1,k3+1)
- hh2 h2(nf,k1,k2+1,k3+1)
- hh3 h3(nf,k1,k2+1, k3+1)
- amp(k1,k2+1,k3+1) amp(k1, k2+1,k3+1)+
- amp(k1, k2+1,k3+1) amp(k1, k2+1,k3+1)+
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Abstract
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Cited By (45)
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EP0540549A1 (fr) * | 1990-07-18 | 1993-05-12 | The Australian National University | Formation de materiaux poreux |
WO1998025982A1 (fr) * | 1996-12-13 | 1998-06-18 | Novartis Ag | Polymeres de polyorganosiloxane poreux |
EP1331913A2 (fr) | 2000-06-29 | 2003-08-06 | The Procter & Gamble Company | Compositions cristallines liquides cubiques et procedes de production |
US7910124B2 (en) | 2004-02-06 | 2011-03-22 | Georgia Tech Research Corporation | Load bearing biocompatible device |
US8002830B2 (en) | 2004-02-06 | 2011-08-23 | Georgia Tech Research Corporation | Surface directed cellular attachment |
US8905963B2 (en) | 2010-08-05 | 2014-12-09 | Forsight Vision4, Inc. | Injector apparatus and method for drug delivery |
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Also Published As
Publication number | Publication date |
---|---|
WO1990007545A3 (fr) | 1990-11-01 |
AU5021390A (en) | 1990-08-01 |
AU4951690A (en) | 1990-08-01 |
WO1990007575A1 (fr) | 1990-07-12 |
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