WO2008027420A2 - Implantable devices for producing insulin - Google Patents
Implantable devices for producing insulin Download PDFInfo
- Publication number
- WO2008027420A2 WO2008027420A2 PCT/US2007/018975 US2007018975W WO2008027420A2 WO 2008027420 A2 WO2008027420 A2 WO 2008027420A2 US 2007018975 W US2007018975 W US 2007018975W WO 2008027420 A2 WO2008027420 A2 WO 2008027420A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- networks
- amphiphilic
- peg
- membrane
- insulin
- Prior art date
Links
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
- A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/022—Artificial gland structures using bioreactors
Definitions
- the present invention generally relates to implantable devices for producing insulin in diabetic animals.
- Some embodiments include amphiphilic biomembranes for use in biological applications (e.g., as an alternative and/or supplemental insulin source).
- Some embodiments also include live insulin-producing cells contained within one or more amphiphilic membranes so as to prevent or diminish an immuno- response and/or rejection by the host.
- a well known disease that can be remedied by implanting biological material and/or a pharmacological agent is Type I diabetes mellitus, wherein the production of insulin by pancreatic Langerhans islet cells is substantially deficient, impaired, or nonexistent. +
- Type I or insulin dependent diabetes mellitus is a major, expensive public health problem causing renal and vascular disease, heart disease, blindness, nerve damage, major disability, and premature death.
- One treatment approach is the transplantation of insulin producing pancreatic islet cells (9,000 to 12,000 islets/kg), which can return blood sugar levels to normal and free patients from the need to take exogenous insulin. If blood sugars, insulin, and C-peptide levels can be normalized at an early stage of the disease, the complications of diabetes can be avoided.
- Major barriers to the clinical application of islet cell transplantation have been the problems of graft rejection, the scarcity of human organs, and the expense of their procurement.
- the medications used to prevent rejection are costly, increase the risk of infection, and can, themselves, induce hyperglycemia, hyperlipidemia, hypertension, and renal dysfunction, although progress is being made towards less toxic drug regimens.
- Injection of islet cells is appealing because it is less invasive than whole organ pancreatic grafts and entails a lower morbidity rate.
- Transplanted human islets (allografts) have been shown to survive in the liver after administration of immunosuppressive drugs, but reliable long term function has been difficult to achieve. Injection into the liver is usually accompanied by heparinization to avoid thrombosis, which can increase the risk of ocular complications.
- human islets are a scarce and expensive cell type. Therefore, many researchers have suggested using animal cells (xenografts), particularly porcine islets. Pigs are plentiful, although porcine islets are relatively difficult to isolate and are fragile.
- pore diameters of 30 nm can exclude the immigration of immunoglobulins, complement, and cytokines (e.g., tumor necrosis factor) providing immunoisolation. Unless immune tolerance can be established, such membranes should also prevent the out-migration of xeno- antigens into the host where they can activate the indirect pathway resulting in T helper cell activation. Immune graft rejection by direct cytotoxicity appears to be a major cause for loss of transplanted cells since donor cell viability is better in immune-compromised (CD4+- T cell depleted) mice. In addition, CD4+ cells secrete interferon-fgamma] that attracts and activates macrophages and NK cells.
- cytokines e.g., tumor necrosis factor
- Macrophages recruit T-cell help and initiate rejection.
- B-cell humoral mediated immunity also plays a role in xenograft rejection. There is, however, ample evidence that the immune response is not the sole source of xenograft failure.
- HEMA hydroxyethyl methacrylate-methyl methacrylate
- the present invention generally relates to implantable devices for producing insulin in diabetic animals.
- Some embodiments include amphiphilic biomembranes for use in biological applications (e.g., as an alternative and/or supplemental insulin source).
- Some embodiments also include live insulin-producing cells contained within one or more amphiphilic membranes so as to prevent or diminish an immuno- response and/or rejection by the host.
- the present relates to an implantable device for providing insulin comprising: at least one spacing member having a suitable thickness, a first face, and a second face, wherein the first face and second face are substantially parallel to one another, a first immunoisolatory membrane affixed to the first face of the at least one spacing member, and a second immunoisolatory membrane affixed to the second face of the at least one spacing member, wherein the combination of the at least one spacing member, the first immunoisolatory membrane and the second immunoisolatory membrane yield an internal volume bounded by the spacing member, the first immunoisolatory membrane and the second immunoisolatory membrane where such internal volume is capable of receiving insulin producing cells suspended in an amphiphilic network.
- Figure 1 is a drawing illustrating the conformational changes that the amphiphilic networks undergo in THF, hydrocarbon and water;
- FIG. 2 is a drawing showing a generalized chemical structure of one membrane material of the present invention, and the starting materials thereof;
- Figure 3 is a graph showing a general experimental design for proving the efficacy of the present invention.
- Figure 4 is a drawing of one artificial pancreas embodiment of the present invention with 4(a) detailing a top view, 4(b) detailing a cutaway top view, 4(c) detailing a cutaway side view and 4(d) detailing a side view ;
- Figure 5 illustrates a strategy for the synthesis of bi-continuous amphiphilic networks/co-networks in accordance with one embodiment of the present invention
- Figure 6 is a 1 H NMR spectrum of St-PEG-St
- Figure 7 is a MALDI-TOF spectrum of St-PEG-St
- Figure 8 is a 1 H NMR spectrum of a chain extender/crosslinker according to one embodiment of the present invention
- Figure 9a is a GPC-RI trace of the polymer charge materials and the MBC-42 (see Table 1 below);
- Figure 9b is a GPC-UV and Rl signal trace of MBC-42
- Figure 10 is a 1 H NMR spectrum of a multiblock copolymer according to one embodiment of the present invention (MBC-42 from Table 1 below);
- Figure 11 is an illustration of an idealized structure of an amphiphilic co- network formed in accordance with one embodiment of the present invention in which the tetra-functional crosslinks are emphasized, the arrows indicate the newly formed oxygen bridges; the ⁇ indicate continuing polymer segments; and the dashed lines indicate continuing crosslinks;
- Figure 12 is an illustration of the swelling behavior of PEG/PDMS amphiphilic co-networks in water and n-heptane.
- S H2O and Sc 7 are swelling ratios relative to the dry mass of the co-networks
- SH 2 O.PEG and SC 7 are swelling ratios of the swollen PEG and PDMS phases relative to the dry masses of PEG and PDMS;
- Figure 13 is a series of plots that permit the calculation of the oxygen permeability of various amphiphilic co-networks made in accordance with one embodiment of the present invention
- Figure 14 is a graph of the oxygen permeabilities and water contents as a function of the PDMS volume fraction in water-swollen amphiphilic co-networks made in accordance with one embodiment of the present invention
- Figure 15 is a graph of the stress-strain curves of various water-swollen amphiphilic co-networks made in accordance with one embodiment of the present invention.
- Figure 16 is a plot of the DSC traces of PEG/PDMS amphiphilic co-networks, where the up arrow indicates the glass transition temperature of PDMS and the down arrows indicate melting peaks of the PDMS and PEG phases.
- the present invention is generally directed to devices and materials capable of correcting, remediating, and/or mitigating diabetes in mammals. More particularly, some embodiments include implantable devices that contain insulin-producing cells. Furthermore, some embodiments include compositions and/or components that isolate the cells contained therein from immu ⁇ oresponses of the host. Some such compositions and/or components include semipermeable membranes that are capable of passing insulin, gases, waste products, and the like while preventing the passage of immune system components.
- Some aspects of the present invention include: (1 ) the synthesis of three immunoisolatory membranes having varying proportions of PEGWPDMS; (2) that are capable of protecting xenografts (porcine PECs) from the immune system of the host without immunosuppressive drugs; and (3) that are biocompatible and exhibit mechanical properties amenable to implantation in vivo.
- Some embodiments of the present invention are capable of correcting or mitigating diabetes in mammals such as dogs or humans. In one embodiment, correction or mitigation is achieved through implantation of a bio-artificial pancreas (BAP) 100.
- BAP bio-artificial pancreas
- such a BAP 100 comprises an immunoisolatory device utilizing polymeric membrane 104 adapted for xeno-immunoisolation thereby enabling the encapsulation therein of insulin producing porcine endocrine cells (PEC).
- PEC porcine endocrine cells
- the BAP 100 device can take on any of a variety of forms provided the device is capable of containing and maintaining viable islet cells while providing insulin to a host.
- Many embodiments include a spacing member 102, which defines the distance between two membranes 104.
- some embodiments include a ring or washer-shaped spacing member 102 to which immunoisolatory membranes 104 can be affixed.
- the ring can be substituted for any appropriate shape, as long as it provides a spacing 108 between the affixed membranes 104 sufficient to provide a thickness of up to about four islet cell diameters, i.e. about 600 microns (as measured from the outer surface of one membrane to that of the other membrane).
- the BAP 100 includes one or more fill ports 106, and/or vent for filling the BAP 100 device.
- the device can include a fill port 106 that is adapted to receive a syringe needle for filling the device with islet cell culture.
- Such a device can also include one or more vent ports that operate in consort with the fill port, wherein displaced gases are allowed to escape through the vent as islet cells are added to the device.
- the BAP 100 device is implanted in a diabetic host. Any of a variety of implant locations can be appropriate provided the location has sufficient blood flow and is capable of providing a sufficient means for exchanging nutrients and waste products thereby maintaining the living islet cells, and for distributing secreted insulin throughout the host's body. Some implant locations that provide such sufficient means include subcutaneous and intraperitoneal loci.
- the present invention utilizes a membrane 104 adapted to immunoisolate foreign cells from the immune system.
- such immunoisolating membranes are biocompatible, biostable, non-fouling, implantable/explantable, rubbery (mechanically robust), highly O 2 permeable, sterilizable, soft and/or smooth.
- the membranes disclosed herein meet these demanding criteria and can be synthetically tailored to the features desirable for a BAP.
- Some semipermeable membranes of the present invention include amphiphilic membranes having pore size-controlled bi-continuous hydrophilic and hydrophobic domains and hydrophilic pore/channel (i.e. conduit) dimensions of about 3.0 to 4.0 nm. Some such membranes may enable survival of porcine endocrine cells (PECs) in mammals for up to three weeks or more without immunosuppression.
- Three immunoisolatory amphiphilic membranes can be synthesized from co- continuous covalently-linked hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polydimethylsiloxane (PDMS) segments, crosslinked by tris(dimethylsilyloxy)-phenylsilane (Compound Y) units.
- Some embodiments include amphiphilic water-swollen membranes having size-controlled hydrophilic pore/channel (conduit) dimensions in the about 3.0 to 4.0 nm range.
- Some embodiments include immunoisolatory devices comprising the foregoing membranes, and can include bio-artificial pancreas devices. Such devices benefit from properties of membranes in accordance with the present invention including biocompatible; biostable; non-fouling; implantable/explantable; mechanically robust; highly O 2 permeable; sterilizable; soft and smooth. At the same time the membranes of the present invention are semi-permeable with size- controlled conduit dimensions.
- the membranes can be prepared with varying compositions of PEG/Y/PDMS (in weight percents) (40/7/53, 35/7/58, or 30/7/63) having pore sizes of about 3.0 to 4.0 nm.
- PEG/Y/PDMS in weight percents
- the present invention is not limited to above combinations of PEG, Compound Y, and PDMS. Rather, any suitable combination of the above-mentioned compounds can be used, depending upon design criteria, to produce a membrane. BAPs are then constructed from each of the above membranes.
- Some embodiments are capable of protecting xenografts (e.g. porcine PECs) from the immunoproteins of the host (e.g. dog) thereby eliminating the need for immunosuppressive drugs.
- xenografts e.g. porcine PECs
- the host e.g. dog
- the membranes are biocompatible and exhibit mechanical properties that are amenable to implantation in vivo. This is accomplished by examining the tissues around the BAPs for signs of external inflammation, neo-vascularization, and fibrosis by light and electron microscopy.
- Macroencapsulation entails the protection of large numbers of cells and allows cells to be implanted and removed easily.
- macroencapsuiating membranes are biocompatible and have desirable mechanical properties that resist breakage.
- Amphiphilic networks i.e., networks that contain approximately equivalent quantities of randomly crosslinked co-continuous hydrophilic and hydrophobic chain elements), which swell in water, generally have desirable mechanical properties and well-defined conduits. These networks undergo conformational rearrangements rapidly in response to a contacting medium ("smart" medium-responsive microstructures).
- Figure 1 illustrates the structural rearrangements that occur rapidly and reversibly upon change of the surrounding medium from tetrahydrofuran (THF) to water (H 2 O), to hydrocarbon (HC).
- amphiphilic networks in accordance with the present invention are bio- and hemocompatible, and non-fouling in vivo they can be exploited for biological applications including, but not limited to, bio-artificial pancreases. Suitable embodiments of amphiphilic networks are disclosed in copending PCT application PCT/US2005/027163 and are also described below.
- Amphiphilic membranes in accordance with the present invention exhibit properties that are desirable for immunoisolatory membranes. For example, some properties include (1) biocompatibility with the host (e.g. human) and guest (e.g.
- porcine islets (2) hemocompatibility; (3) bio-stability for longer than six months; (4) rapid oxygen and water transport through the membrane; (5) smooth, slippery, non- clogging, non-fouling and non-thrombogenic surfaces; (6) controlled semi- permeability: Size-controlled conduit dimensions having narrow pore-size distributions (molecular weight cutoff ranges) that allow the passage of aqueous solutions of nutrients and biologically active molecules (insulin) and the exit of metabolic wastes, but exclude immunoproteins, antibodies, and white blood cells; (7) physiologically satisfactory bidirectional fluxes of glucose, insulin, nutrients, and metabolites; (8) thin membrane walls (few micrometers) to minimize diffusion paths; (9) flexible/rubbery membranes of good mechanical properties (e.g., strength, modulus, elongation, fatigue) for the implantation and explantation of large numbers (approximately 8 x 10 5 ) of islets; (10) enabling all the above properties to be maintained for long periods of time (e.g., six
- the membranes of the present invention are comprised of fully synthetic polymers with nano-architectures expressly engineered for xeno-immunoisolation.
- the membranes of the present invention are amphiphilic co- networks of co-continuous covalently-linked hydrophilic segments (e.g., poly(ethylene glycol) (PEG), certain acrylates, etc) and hydrophobic segments (e.g., polydimethylsiloxane (PDMS)).
- PEG poly(ethylene glycol)
- PDMS polydimethylsiloxane
- properties of the membranes of the present invention can be fine-tuned.
- conduit size and the size distribution thereof can be controlled using hydrophilic and hydrophobic segments of well-defined length (i.e. molecular weight) and length distribution (i.e. molecular weight distribution).
- mechanical properties can be controlled by manipulating synthesis parameters.
- biocompatible surfaces can be obtained by using certain biocompatible pre-polymer species.
- the membranes of the present invention have superior O 2 permeability. In this embodiment, special efforts were made to demonstrate the superiority of O2 permeability of membranes in accordance with the present invention.
- the O2 transparency of membranes in accordance with one embodiment of the present invention is so high that the conventional Fatt method to measure O 2 permeability is inadequate, and the membranes of the present invention necessitated building special equipment and developing a new methodology to quantitatively determine the O 2 permeabilities of the membranes of the present invention.
- the O2 permeability of a typical hydrogel is 10 to 20 barrer units, while that of the present invention is in the range of about 200 to 400 barrer units.
- some membranes of the present invention have extremely high oxygen permeability. Specific oxygen permeabilities are controlled through composition and process conditions.
- the present invention entails the preparation of implantable/explantable devices for xenotransplantation of living pancreatic porcine islets into diabetic dogs, and thus will enable the elimination and/or substantial reduction of their diabetic condition.
- the membranes of the present invention are adapted to protect the guest tissue (healthy porcine islets) from the immune system of the diabetic host and still allow molecular communication between the islets and dog thus enabling correction of hyperglycemia without the need for immunosuppression.
- the host animals are followed for three weeks and then the devices are removed and the blood sugar measured. The blood sugar rises following explantation, thereby demonstrating that the implanted islets are responsible for correcting the hosts' hyperglycemia.
- the relatively small size and high O2 permeability of the membranes of the present invention permit a BAP made therefrom to be implanted intraperitoneally (IP) or subcutaneously (SQ).
- Some alternative embodiments include the synthesis of amphophilic networks containing about equal amounts of hydrophilic polyacrylates, randomly crosslinked with hydrophobic polyisobutylene (PIB) segments.
- PIB polyisobutylene
- the microstructure and properties of these materials have been found to have surface and mechanical properties appropriate for medical applications.
- the tensile strength equal to about 0.5 to about 3.0 MPa
- the elongation is equal to about 50 to 600%.
- the present invention includes amphiphilic networks prepared by free radical solution copolymerization of hydrophilic monomers [N, N- dimethyl acrylamide (DMMAAm), 2-hydroxyethy) methacrylate (HEMA), N-(dimethyl- amino)ethyl methacrylate (DMAEMA) and sulfoethylmethacrylate (SEMA)] with a hydrophobic crosslinker, methacrylate-telechelic polyisobutylenes. Further development of amphiphilic membranes has shown that they are biocompatible and non-thrombogenic.
- hydrophilic monomers N, N- dimethyl acrylamide (DMMAAm), 2-hydroxyethy) methacrylate (HEMA), N-(dimethyl- amino)ethyl methacrylate (DMAEMA) and sulfoethylmethacrylate (SEMA)
- Networks containing approximately 50/50% DMAEMA/PIB exhibit excellent biocompatibility and stability in rats, integrate well with tissue, resist bacterial contamination, and provoke little or no fibrosis or adhesion.
- DMAEMA/PIB 5,000 g/mole
- the number of cells and total protein on amphiphilic networks are similar to negative controls (polyethylene, silicone rubber, glass) indicating no toxic response.
- Cell adhesion and anti-adhesion experiments with human monocytes have shown inhibition of monocyte adhesion for various amphiphilic networks and glass (negative control) relative to polystyrene (positive control).
- Amphiphilic networks made with DMAAm or HEMA with 50% PIB have also been shown to adsorb less fibrinogen, Hageman factor, and albumin from human plasma than glass, silicone rubber or polyethylene. Together with blood counts, these data suggest that amphiphilic networks in accordance with various embodiments of the present are well accepted in vivo.
- M C , H I /.e., the molecular weight of the hydrophilic chain segment between crosslink sites
- MWCO molecular weight cut off
- amphiphilic membranes containing approximately 50/50 PDMAAm/PIB with M C ,HI approximately 4500 g/mole have semi- permeability and diffusion rates suitable for immunoisolation of pancreatic islets. These membranes allow the counter-current diffusion of glucose and insulin (M n equal to 180 and 5700 g/mole, respectively) but prevent the diffusion of albumin (M n approximately 66,000 g/mole). The diffusion rates of glucose and insulin are deemed appropriate for islet isolation. Pig islets placed in such semi-permeable amphiphilic polymer tubules are viable for at least 4 months and produce insulin upon glucose challenge.
- a diabetic rat fitted with a BAP containing pig islets has a reversal of diabetes without immunosuppression.
- the amphiphilic membranes of the present invention contain well-defined (in terms of molecular weight and molecular weight distribution) polyethylene glycol (PEG) and polydimethylsiloxane (PDMS) strands co-cross!inked by hydrosilation with one or more unique oxyphilic multifunctional siloxane crosslinking agents.
- PEG polyethylene glycol
- PDMS polydimethylsiloxane
- Membranes formed from such combinations can allow rapid glucose and insulin transport but impedes or precludes the diffusion of IgG.
- These diffusion embodiments are carried out with water-swollen amphiphilic membranes by the use of fluorescent-labeled insulin and IgG.
- select membranes are first incubated with IgG for several days and subsequently used to determine glucose and insulin diffusion. The rates of glucose and insulin transport through such membranes remain unchanged, demonstrating
- the rate and extent of O ⁇ diffusion through membranes formed in accordance with the present invention are so high that they could even be considered for extended-wear soft contact lens applications.
- one important parameter for this application is the highest O2 permeability.
- the membranes of the present invention are optically clear in the dry and water-swollen state.
- Some membrane embodiments for BAPs contain PEG and PDMS segments crosslinked by tris(dimethylsilyloxy)-phenylsilane ⁇ Compound Y) units.
- the membranes of the present invention also entail a simple, reproducible, inexpensive synthesis procedure for precision-tunable immunoisoiatory membranes.
- the membranes of the present invention are prepared as follows. First styryl-telechelic PEG (St-PEG-St) is prepared and is end-functionalized by hydrosilation with stoichiometric quantities of Compound Y. The product, PEG having SiH end groups, is further hydrosilated by vinyl-telechelic PDMS (V-PDMS-V) in the same reactor. The product of the second hydrosilation is a diblock polymer of PEG and PDMS segments separated by Compound Y units. This diblock can be easily purified (i.e., separated from the starting materials by precipitation) because it does not form micelles. Diblock purification by simple precipitation represents a significant process improvement.
- the Compound Y units are crosslinked by the addition of acid and an amphophilic co-network in accordance with the present invention is obtained.
- This network is ideal because the molecular weights and molecular weight distributions of all of its strands are the same as those of the pre-polymers, and the network is tetra-functional because exactly four chains emanate from each crosslink junction.
- Figure 2 illustrates the starting materials and the structure of one possible network in accordance with the present invention.
- Figure 2 emphasizes the enchainment of the hydrophobic PDMS and Compound Y domains.
- the molecular weights (lengths) and their distributions of the segments can be determined by controlling the nature of the starting materials. Further, by precisely defining the molecular weights, the overall composition of the membrane can be controlled, which in turn allows specific tailoring of conduit dimensions, water uptake, O 2 permeability, and mechanical properties.
- immunoprotective tri-component amphophilic membranes having narrow polydispersities (M n and M w /M n ) PEG and PDMS strands co- crosslinked by hydrosilation with unique oxyphilic multifunctional siloxane crosslinking agents are synthesized.
- the following general procedure can be followed to prepare membranes within the scope of the present invention.
- Styryl-telechelic PEG having a M n equal to 4,600g/mol, and vinyl- telechelic PDMS having a M n equal to 6,000g/mol are synthesized and their homogeneity and structures established by GPC and NMR spectroscopy, respectively. The quantitative end-functionalization of these pre-polymers are demonstrated.
- the extender/crosslinker tris(dimethylsilyloxy)phenylsilane (Compound Y) is synthesized and characterized by NMR spectroscopy. Three membranes are prepared with different compositions: PEG/Y/PDMS weight percents of 40/7/53, 35/7/58, and 30/7/63.
- the BAP 100 is a hollow disc prepared from two approximately 50 micron thick amphiphilic membranes 104, the rims of which are glued with a silicon glue to a 0.60 mm thick stainless steel or titanium ring having a 3.1 cm aperture.
- Figure 4 shows a sketch of the envisioned BAP 100.
- the metal ring 102 provides reinforcement/dimensional stability, x-ray contrast and acts as the spacer 108 between the two membranes 104.
- Figure 4 details a circular embodiment, any number of configurations are possible.
- the present invention can be configured as an oval, egg-shaped, rectangle, square, triangle, pentagon, hexagon, or any other related structure.
- Islet tissue can be cultured overnight in PRMI-1640 medium containing 10% fetal calf serum, 100 IU/mL of penicillin, and 100 ⁇ g/mL of streptomycin.
- the BAP 100 device is sterilized by autoclaving at 120 0 C for 15 minutes and allowed to cool in a tissue culture hood.
- the islets/cells are loaded into a syringe and injected between the two membranes 104 through a 0.4 mm wide port 106 drilled in the metal ring 102. Injection occurs under sterile conditions.
- the port 106 is plugged with a silicone plug, which in turn is sealed with cyanoacrylate.
- the volume of the device as defined by the aperture of the ring (3.1 cm) and ring thickness (0.60 mm), is 0.46 ml_.
- This volume is appropriate for accommodating the approximately 132,000 islets (0.23 ml_ volume) plus 0.23 mL of the suspending medium (alginate).
- the ready-to-be-used filled BAP 100 contains approximately 4.0 layers of islets.
- the maximum path for O 2 diffusion is approximately 2 islet diameters (about 300 microns).
- Glucose tolerance is performed by administering glucose 500 mg/kg body weight intravenously over 2 to 3 minutes. Blood glucose and insulin levels are drawn at -5, 0, 5, 10, 15, 20, 30, 45, and 60 minutes. The amount of blood required for these tests totals approximately 20 mL. Diabetes is induced by intravenous injection of alloxan (50 mg/kg) (Sigma Chemical Co. St.
- the drugs are freshly prepared aseptically as solutions, containing 100 mg/mL in trisodium citrate buffer, pH 4.5 and sterilized by filtration through 0.22 ⁇ m filters.
- in vivo function of a BAP embodiment is assessed in a dog model by means of fasting blood sugars, IV glucose tolerance tests, insulin, and C- peptide levels before, after placement, and after removal of the BAP.
- Blood glucose levels are monitored every six hours for 24 hours. Thereafter, animals are fed regular dog chow every 12 hours and receive twice daily human insulin 70/30 0.5 to 1.5 U/kg SQ (or more if glucose levels exceed 250 mg/dl) after each feeding to prevent ketosis and death. Dogs with fasting blood sugars ⁇ 250 mg two weeks after chemotherapy are not utilized. Porcine C-Peptide and insulin are measured using radio-immunoassays (Linco Research, St. Charles, MO). The tissues around the grafts and the contents of the BAP are examined for signs of rejection (inflammatory infiltrates), neo-vascularization, cell necrosis, fibrosis, and islet cell de-granulation. No rejection occurs.
- BAP macroencapsulation devices Two to four weeks after receiving STZ/ALX, the diabetes is treated with macroencapsulated porcine cells (12,000 islets per kg).
- Three different polymers are used to make BAP macroencapsulation devices. Each polymer is tested in 5 animals.
- No immunosuppression is used.
- Accucheck glucometers are used to monitor glucose levels daily prior to morning feeds for the first 5 days after chemotherapy and for the first five days after implantation. No exogenous insulin is administered beyond five days after implantation.
- FIG. 3 An example of a research design is summarized in Figure 3.
- all dogs undergo pre-operative and weekly postoperative serum C-peptide, IV glucose tolerance tests (IVGTT), insulin levels, as well as fasting blood sugars by glucometer every Monday, Wednesday, and Friday, to determine islet cell function in vivo.
- a complete blood count (CBC) is obtained weekly to assess inflammation.
- Liver function tests i.e. alkaline phosphatase, alanine aminotransferase (ALT), and aspartate amhotransferase (AST)
- renal function tests blood urea nitrogen (BUN and creatinine (Cr)
- BAPs blood urea nitrogen
- the BAPs are removed at 3 weeks, the dogs recover for 24 to 48 hrs, and the IVGTT and insulin levels are repeated prior to euthanizing the animals with intravenous BEuthansia-D (1 mU5 kg).
- IP intraperitoneally
- SQ subcutaneously
- a BAP is implanted in each of five STZ diabetic dogs and then in vivo pancreatic function (PF) tests are performed, which include IV glucose tolerance tests (IVGTT), serum insulin, and serum C-peptide. These tests are performed prior to implantation and weekly thereafter. The BAPs are removed at three weeks, and the animals are allowed to recover for one to three days. Pancreatic function (PF) is then retested to confirm that insulin and C-peptide secretion are coming from the BAP and not the native pancreas.
- PF pancreatic function
- the BAPs are recovered from the host and the contents thereof are tested for viable, functioning, islet cells. This can be done by immunostaining for insulin and glucagon, and preparing slides for light microscopy to assess islet morphology and granulation. Additionally, electron microscopy can be used to assess islet cell fine structure. A test for the absence of IgG within the BAP can also be conducted to show that immunochemicals from the host did not penetrate the BAP.
- amphiphil ⁇ c networks and/or co-networks can be used to form the amphiphilic membranes of the present invention.
- Some exemplary amphiphilic networks and/or co-networks are discussed below.
- the present invention is not limited to the following examples. Rather, any suitable amphiphilic network and/or co-network can be used in conjunction with the present invention so long as such networks and/or co-networks can provide a "support means" for living insulin producing cells.
- suitable amphiphilic networks and/or co-networks can be found in co-pending PCT Patent Application No.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are based upon amphiphilic copolymer networks or co-networks that are both hydrophobic and hydrophilic, where the copolymer networks and/or co-networks comprise polyalkylene glycol segments and disubstituted polysiloxane segments.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are synthesized using functional multiblock co-polymers according to the formula (AY) x (BY) y , where A represents an alkylene glycol polymer having n repeating alkylene glycol units, B represents a disubstituted siloxane polymer having m repeating siloxane units, and Y represents a molecule (e.g., a silane) that functions both as a chain extender and a crosslinker.
- A represents an alkylene glycol polymer having n repeating alkylene glycol units
- B represents a disubstituted siloxane polymer having m repeating siloxane units
- Y represents a molecule (e.g., a silane) that functions both as a chain extender and a crosslinker.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention comprise at least one hydrophilic segment and at least one hydrophobic segment.
- the hydrophilic segments include at least one polyalkylene glycol (e.g., polyethylene glycol (PEG)) and the hydrophobic segments include at least one disubstituted polysiloxane (e.g., polydimethylsiloxane (PDMS)).
- PEG polyethylene glycol
- PDMS polydimethylsiloxane
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are ideal (i.e., the lengths of each hydrophilic segments and the hydrophobic segments are identical). In another embodiment, the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention do not have to be ideal. That is, if so desired, the hydrophilic segments and the hydrophobic segments can have different lengths.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are based upon amphiphilic networks that contain therein a molecule Y that acts as both a chain extender and a crosslinker.
- Y is at least a tri-functional molecule.
- Y is a tetra-functional molecule.
- the bottom of the Y molecule binds to another Y molecule bottom during a crosslinking reaction to yield amphiphilic co-networks in accordance with the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device.
- two Y molecules combine to yield a tetra-functional crosslinking/chain extending molecule.
- Y is a tri-functional silane.
- Y can be a silane according to the Formula (I) shown below:
- Y is shown minus the polymer chains to which it binds. As will be explained below, Y binds to two polymer chains thereby acting as a chain extending agent. During the crosslinking reaction, two Y molecules link to form the aforementioned crosslinks and yield the following tetra-functional sub-molecule
- Polymer Chain denote bonds that are formed with a suitable hydrophilic polymer (denoted by A in the above-mentioned generic formula) or a suitable hydrophobic polymer (denoted by B in the above-mentioned generic formula).
- the chain extension bonds are formed via a one. to one reaction between a terminal end of a polymer chain with each of the hydrogens in the silane according to Formula (I).
- the two chain extending Y molecules are then crosslinked via each Y molecule's ethoxy group to yield the above tetra-fu ⁇ ctional chain extender/crosslinker.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention can utilize other molecules that can function both as a chain extender and a crosslinker. All that is required for a compound to be used as molecule Y is that the compound fulfills at least the above two functions. First, the compound that is chosen to function as molecule Y must be able to extend the incompatible hydrophilic and hydrophobic polymers used to form the functional multiblock copolymers of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention according to the formula (AY) x (BY) y .
- the compound that is chosen to function as molecule Y must be able to subsequently crosslink the polymer blocks of the multiblock copolymers according to the formula (AY) x (BY) y thereby yielding an amphiphilic network/co-network.
- one problem associated with the synthesis of amphiphilic co- networks is how to overcome the thermodynamic incompatibility of the hydrophilic and hydrophobic constituents, and to unite two incompatible pre-polymers and/or polymers into a bi-continuous/bipercolating construct.
- crosslinking of such systems is carried out in homogeneous solution in a common good solvent at low pre-polymer and/or polymer concentrations, followed by the addition of a suitable crosslinker ⁇ i.e., by dissolving the two pre-polymers which are generally incompatible in their dry states). While this method yields uniform co-networks, the removal of the common solvent is accompanied by massive shrinkage, which renders the method technically impractical.
- the dimensional stability of such co-networks is poor, the surface properties are hard to control, and the co-networks (or products formed therefrom) are fragile and difficult to manipulate.
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device overcome one or more of the above mentioned drawbacks.
- the synthesis schemes of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device utilize one or more functional multiblock copolymers according to the formula (AY) x (BY) y , where A represents an alkylene glycol polymer having n repeating alkylene glycol units, B represents a disubstituted siloxane polymer having m repeating siloxane units, and Y represents a silane that functions both as a chain extender and a crosslinker.
- the one or more functional multiblock copolymers according to the formula (AY) ⁇ (BY) y are random multiblock copolymers.
- the one or more units of the functional multiblock copolymers according to the formula (AY) x (BY) y are then crosslinked via two or more of the Y units by intermolecular condensation.
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device initially involve preparing one or more random functional multiblock copolymers according to the formula (AY) x (BY) y , where A represents an alkylene glycol polymer having n repeating alkylene glycol units, B represents a disubstituted siloxane polymer having m repeating siloxane units, and Y represents a silane that functions both as a chain extender and a crosslinker.
- A represents an alkylene glycol polymer having n repeating alkylene glycol units
- B represents a disubstituted siloxane polymer having m repeating siloxane units
- Y represents a silane that functions both as a chain extender and a crosslinker.
- the one or more random functional multiblock copolymers according to the formula (AY) x (BY) y are prepared extending telechelic, for example, PEG and PDMS pre-polymers with a suitable chain extender/crosslinker Y. Subsequently, the one or more random functional multiblock copolymers are crosslinked via an acid catalyzed condensation reaction of the Y units.
- the amphiphilic networks and/or co- networks used in conjunction with the insulin producing device encompass other crosslinking strategies so long as the crosslinker functions as both a chain extending agent and a crosslinking agent.
- amphiphilic copolymer networks or co-networks of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device contain at least one hydrophobic polymer and at least one hydrophilic constituent that have been bounded together by a suitable chain extending molecule.
- the chain extending molecule also functions as a crosslinking molecule during the formation of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device's amphiphilic networks/co-networks.
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device utilize a combination of at least one polyalkylene glycol polymer with at least one disubstituted siloxane polymer.
- the at least one polyalkylene glycol polymer functions as the hydrophilic polymer, while the at least one disubstituted siloxane polymer functions as the hydrophobic polymer.
- the polymers are used to form the functional multiblock copolymers according to the formula (AY) x (BY)y.
- Each polymer used to form the functional multiblock co-polymers according to the formula (AY) x (BY) y independently contain from about 5 to about 5,000 repeating polymer units, or from about 10 to about 2,500 repeating polymer units, or from about 25 to about 1,000 repeating polymer units, or even from about 40 to about 500 repeating polymer units.
- individual range limits may be combined.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are not limited to polymers having the above-mentioned number of repeating units. Instead, the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention can utilize any suitable combination of hydrophilic and hydrophobic polymers having any number of repeating units so long as the polymers used can form functional multiblock co-polymers according to the formula (AY) x (BY) y .
- amphiphilic networks/co-networks of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention is the intended use for the amphiphilic network/co-network.
- amphiphilic network/co-network As would be apparent to one of ordinary skill in the art, depending upon the desired use for the amphiphilic networks/co-networks used in conjunction with the insulin producing devices of the present invention, one may have to take into consideration a wide variety of physical, chemical and/or mechanical properties of the polymers used to form such networks.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing device utilize a combination of at least one polyethylene glycol polymer with at least one polydimethylsiloxane polymer.
- exemplary polyethylene glycol styryl-ditelechelic polyethylene glycol (St-PEG-St)
- polydimethylsiloxane polymers V- PDMS-V are shown below in Formulas (II) and (IM), respectively.
- n is equal to an integer in the range of about 5 to about 5,000, or from about 10 to about 2,500, or from about 25 to about 1 ,000, or even from about 40 to about 500, and
- m is equal to an integer in the range of about 5 to about 5,000, or from about 10 to about 2,500, or from about 25 to about 1,000, or even from about 40 to about
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing device are not limited to just the polyethylene glycol and polydimethylsiloxane polymers of Formulas (II) and (III). Rather, in this embodiment any suitable combination of polyethylene glycol and polydimethylsiloxane polymers can be used.
- the polydimethylsiloxane polymer of Formula (III) can, for example, be purchased from Gelest, Tulleytown, PA. Alternatively, if so desired, the polymer of Formula (III) could be synthesized thereby permitting one to control the number of repeating units present in the polymer of Formula (III). With regard to the polymer of Formula (II), this polymer can be synthesized by the reaction scheme shown below: HO+CH r CH;c4— H
- hydroxyl ditelechelic polyethylene glycol HO-PEG-OH having a M n equal to 4600 grams/mole — available from Aldrich
- 0.032 grams (0.0001 moles) of tetrabutylammonium bromide Aldrich
- HO-PEG-OH hydroxyl ditelechelic polyethylene glycol
- Aldrich tetrabutylammonium bromide
- 7.8 grams (0.195 moles) of powdered NaOH (Fisher) is added to the above solution.
- 19.9 grams (0.13 moles) of vinylbenzyt chloride (Aldrich) are added during vigorous stirring of the solution and the temperature is raised to 6O 0 C.
- this polymer can be readily obtained from inexpensive commercially available starting materials, i.e., HO-PEG-OH and vinylbenzyl chloride.
- Figure 6 shows the NMR spectrum of St-PEG-St together with assignments.
- the amphrphilic networks and/or co-networks used in conjunction with the insulin producing device utilize a molecule Y that acts as a chain extender that enables/facilitates the bonding of one polymer chain to another polymer chain.
- the chain extender Y of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device enable/facilitate the bonding of at least one hydrophilic polymer chain to at least one hydrophobic polymer chain thereby yielding functional multiblock copolymers according to the formula (AY) x (BY) y .
- Molecule Y also mediates the condensation/crosslinking of the multiblocks thereby yielding the desired amphiphilic networks/co-networks.
- the crosslinking function served by molecule Y can be accomplished by crosslinking to any one or more of another Y molecule in another functional multiblock copolymer chain, or to any suitable portion of the polymer chains contained in another functional multiblock copolymer chain.
- the crosslinking function accomplished by Y is the result of a crosslinking bond formed between two Y molecules, each Y molecule being located in a separate functional multiblock copolymer chains
- molecule Y can be any molecule that is at least a tri-functional molecule.
- Y is a tetra- functional molecule.
- Y is a tri-functional silane.
- Y can be a silane according to the Formula (I) shown below:
- the compound according to Formula (I) - bis(dimethylsilyloxy) ethoxydimethylsilyloxy phenylsilane - (Ph)Si(OSi(CH3) 2 H) 2 (OSi(CH3) 2 OEt) - is effective for the synthesis of an target amphiphilic network because (Ph)Si(OSi(CH 3 ) 2 H) 2 (OSi(CH 3 )2 ⁇ Et) contains two Si-H groups to extend vinyl- tefeche ⁇ c polymers by cohydrosilation, and a Si-OEt group to condense two Y units to form a crosslink.
- the central silicon Si atom in (Ph)Si(OSi(CH 3 ) 2 H)2(OSi(CH 3 ) 2 ⁇ Et) is connected to three oxygens and can be more vulnerable to hydrolysis than the polymers used in the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device. Accordingly, to increase the hydrolytic stability of this Si atom a phenyl substituted compound can be used.
- the compound according to Formula (I) can be synthesized by reacting tris(dimethylsilyloxy) phenylsilane with ethanol (EtOH) at a molar ratio of silane to alcohol of 1 :0.333 in the presence of the Karstedt's catalyst.
- EtOH ethanol
- This reaction yields the target molecule (Formula (I)), plus di- and tri-OEt substituted by-products.
- the boiling points of these products are significantly different (approximately 10 to 15°C/OEt group), and the by-products can be easily separated by a spinning band column.
- the acetate substituent increases the boiling point differences between the mono-, di- and tri- substituted acetic acid reaction products to approximately 30 to 40°C/AcO group, and the target monoacetate can be obtained by simple vacuum distillation.
- the subsequent substitution of the AcO by EtO is a process known to those of ordinary skill in the art and a discussion herein is omitted for the sake of brevity. It should be noted however, that acetylation tends to yield small quantities of unidentified side products. Accordingly, in some circumstances it may be desirable to the EtOH synthesis route described above to yield the desired molecule Y for multiblock syntheses.
- amphiphilic networks or co-networks used in conjunction with the insulin producing device are synthesized using functional multiblock co-polymers according to the formula (AY)*(BY)y, where A represents an alkylene glycol polymer having n repeating alkylene glycol units, B represents a disubstiiuted siloxane polymer having m repeating siloxane units, and Y represents a molecule (e.g., a silane) that functions both as a chain extender and as a crosslinker.
- A represents an alkylene glycol polymer having n repeating alkylene glycol units
- B represents a disubstiiuted siloxane polymer having m repeating siloxane units
- Y represents a molecule (e.g., a silane) that functions both as a chain extender and as a crosslinker.
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device utilize the dual purpose chain extender/crosslinker Y to accomplish this task.
- the first step is the coupling of two incompatible telechelic pre-polymers and/or polymers to create a functional multiblock copolymer by the use of a dual-purpose chain extender/crosslinker Y in a solvent that adequately dissolves the hydrophilic and hydrophobic polymers that are to comprise the basis of the amphiphilic co-network.
- the functional multiblock co-polymers of the amphiphilic networks and/or co- networks used in conjunction with the insulin producing device can be synthesized from any suitable combination of at least one hydrophilic polymer and at least one hydrophobic polymer.
- the synthesis reaction that yields the desired functional multiblock copolymers of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device also utilize a suitable chain extending/crosslinking molecule Y, as is discussed above in detail.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing device is not limited thereto, one such suitable set of reactants is St-PEG-ST (see Formula (II)), V-PDMS-V (see Formula (III)), and (Ph)Si(OSi(CH 3 ) 2 H) 2 (OSi(CH 3 ) 2 ⁇ Et) (see Formula (I)).
- St-PEG-St is molecule A
- V-PDMS-V is molecule B in the generic formula (AY) x (BY) x .
- these three reactants yield a functional multiblock copolymer having the following formula:
- n and m are independently equal to an integer in the range of about 5 to about 5,000, or from about 10 to about 2,500, or from about 25 to about 1,000, or even from about 40 to about 500, and x and y are independently equal to an integer in the 5 to about 50,000, or from about 50 to about 25,000, or from about 100 to about 10,000, or from about 250 to about 5,000, or even from about 500 to about 1 ,000.
- a random multiblock with controlled molecular weights can be obtained as a result of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device.
- the molecular weight of the multiblock copolymer can be controlled by the relative concentrations of the reaction partners (i.e., the chain extender Y in relation to the amount of polymers A and B).
- Y is a dual-purpose chain extender/crosslinker. In one embodiment, Y is tri-functional, two functions of which are designed to extend the telechelic pre-polymers and/or polymers to a random functional multiblock copolymer, while the third function (crosslinking) is inert during extension.
- the second step is to crosslink the functional multiblock copolymer via Y, thereby yielding an amphiphilic co-network.
- Another significant advantage of the use of functional multiblock copolymers according to the generic formula (AY) x (BY) y over end-functional di- or tri-blocks is in crosslinking.
- Crosslinking of (AY) x (BY) y copolymers is efficient and rapid because it involves much less structural reorganization than end-linking of telechelic AB or ABA blocks.
- multiblocks self-aggregate into co-continuous morphologies over a broad composition range
- di- or tri-blocks produce mostly lamellar or cylindrical morphologies which may not give co-continuous architectures upon crosslinking.
- multiblocks do not contain gel, and, unlike branched amphiphilic blocks, are easily processible.
- Co-networks formed by the crosslinking of well-defined multiblocks are, in most cases, ideal ⁇ i.e., the lengths of each hydrophilic and hydrophobic chain elements, respectively, are identical).
- co-networks contain tetra- functional crosslinkers as is shown in the generic formula below that represents a portion of a co-network and in Figure 5.
- Polymer Chain denote bonds that are formed with a suitable hydrophilic polymer (denoted by A in the above-mentioned generic formula) or a suitable hydrophobic polymer (denoted by B in the above-mentioned generic formula).
- the chain extension bonds are formed via a one to one reaction between a terminal end of a polymer chain with each of the hydrogens in the silane according to Formula (I).
- the two chain extending Y molecules are then crosslinked via each Y molecule's ethoxy group to yield the above tetra-functional chain extender/crosslinker.
- the fact that exactly four chains emanate from each crosslink site is desirable for narrow hydrophilic pore size distribution.
- hydrophilic and hydrophobic polymers e.g., St-PEG-St and V-PDMS-V
- a suitable chain extender/crosslinker Y e.g., (Ph)Si(OSi(CH 3 ) 2 H) 2 (OSi(CH 3 )2 ⁇ Et)
- AY generic formula
- BY BY
- the above multiblock copolymer contains an ether linkage between the PEG and styryl moieties. This bond is inert during hydrosilation and subsequent crosslinking and it has the same or better overall chemical stability as PEG. Chain end modification did not affect the narrow molecular weight distribution of the starting HO-PEG-OH used to form the St-PEG-St. The molecular weight distribution of the PEG segment should be narrow to obtain membra nes/co-networks with well-defined hydrophilic channel dimensions.
- the multiblock copolymer, -(PEG-Y) x -(PDMS-Y) y -, shown in the above reaction immediately above is synthesized as follows, where Y is converted to structure (Ia) shown below in order to link the polymers and yield the desired multiblock copolymer.
- Polymer Chain denote the fact that at least one hydrophilic polymer chain and/or at least one hydrophobic polymer chain are bonded to structure (Ia).
- the reaction product is permitted to cool for an hour, and then the toluene solvent is evaporated and the product is dried under vacuum.
- the copolymer product is extracted by 2x500mL hexane, dried in vacuum, extracted by 3x800 ml_ methanol, and dried in vacuum. The yield is 12.2 grams.
- the multiblock copolymer is a slightly yellow rubbery material.
- Toluene is used as the solvent in which the reaction is carried out because it is inert with respect the polymer charges used to produce the desired multiblock copolymer.
- the charges should be dry to prevent the oxidation of -SiH groups to - SiOH groups (i.e., premature crosslinking), and/or the formation of too low molecular weight (Mw) products, and their slow condensation.
- the polymer charges can be dried with CaHb to reduce/eliminate the chance that premature crosslinking occurs.
- the first product that must arise is (Ph)SKOSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt)- PDMS-(Ph)Si(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt)- because one of the SiH functions in (Ph)Si(OSi(CH 3 )2H) 2 (OSi(CH 3 ) 2 OEt) is preferentially consumed by the vinyl termini of V-PDMS-V; negligible amounts of (Ph)Si(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt)-PEG-St may also form.
- the concentrations of V-PDMS-V and (Ph)Si(OSi(CH 3 ) 2 H) 2 (OSi(CH 3 ) 2 OEt) gradually diminish, while that of St-PEG-St remains essentially unchanged.
- the hydrosilation of St- PEG-St starts, however, at this point essentially all V-PDMS-V is consumed.
- the -SiH groups that remain to react with St-PEG- are mainly those attached to PDMS, i.e., -PDMS-Si(Ph)(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt).
- St-PEG-St is a chain extender of Si(Ph)(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt)-PDMS- Si(Ph)(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt) (or larger Si(Ph)(OSi(CH 3 ) 2 H)(OSi(CH 3 ) 2 OEt)- telechelic PDMS blocks). Due to this concentration drift, co-hydrosilation will be random and therefore random multiblock according to the formula (AY) x (BY) y will form.
- the M n range is about 30 to about 100 kg/mol (the degree of polymerization — DP n is in the range of about 6 to about 20). If the M n is less than about 30 kg/mol, significant amounts of di- or tri-blocks will form and crosslinking will be inefficient because these low M w species contain 1 to 4 SiOEt groups (depending on the type of chain ends) - not all of which may form crosslinks. If the M n is greater than about 100 kg/mol, multiblock copolymer processing will be cumbersome (high viscosity solutions and melts, residual stresses, etc will occur).
- the multiblocks with SiH termini should be stored under vacuum to avoid the oxidation of SiH to SiOH groups ⁇ i.e., premature crosslinking).
- Table 1 summarizes multiblock copolymers made in accordance with the amphophilic networks and/or co-networks used in conjunction with the insulin producing device and some of their characteristics.
- MBC multiblock copolymer
- Columns two and three show the relative amounts of polymers and Y in the charges used to form each multiblock copolymer, and r, respectively.
- Columns four and five give the results of multiblock copolymer extractions in terms of percent hexane and methanol soluble fractions.
- Column six shows the PEG content of the multiblock copolymers determined by 1 H NMR spectroscopy.
- columns seven and eight give molecular weight data obtained by GPC (with polystyrene calibration).
- M n 's number-average molecular weights
- M w 's weight-average molecular weights
- M w /M n molecular weight distributions
- Figure 9a shows the GPC-RI traces of the starting materials and the multiblock copolymer product MBC-42.
- the refractive index (Rl) trace of the multiblock shows mainly the PEG constituent, while the PDMS segments are almost invisible.
- the product exhibits a relatively broad molecular weight distribution, typical of polymers made by polycondensation.
- the multiblock copolymers of the Table 1 are insoluble and do not form micelles in hydrophilic or hydrophobic solvents, contamination from the polymer charges or from homopolymers can be readily removed by precipitation or extraction.
- the V-PDMS-V can be removed by hexane extractions (see column 4, Table 1) and the St-PEG-St (and/or homo-PEG blocks) can be removed by repeated extractions with methanol (column 5, Table 1).
- methanol column 5, Table 1
- the UV adsorption is due to the terminal phenyl groups in St-PEG-St and to the phenyl substituent in the chain extender/crosslinker Y.
- the Rl signal shows only the PEG component (dn/dCpoMs is less than 10% of dn/dcpE ⁇ ).
- the UV signal is proportional to the PEG plus the chain extender/crosslinker Y.
- M w molecular weight
- Figure 10 shows the 1 H NMR spectrum of a representative multiblock copolymer together with assignments.
- the spectra illustrate the absence of vinylsilyl and styryl end groups, which in turn indicates essentially quantitative extension.
- a slight excess of (Ph)Si(OSi(C Hs) 2 H) 2 (OSi(CH 3 J 2 OEt) is used in the examples of Table 1 (see Column 3), the SiH groups are invisible due to their very low concentration.
- the spectrum shows the expected resonances of the hydrosilated segments.
- the multiblock copolymers form optically transparent membranes. Optical clarity is evidence for the absence of macroscopic phase separation, and suggests that the dimensions of the incompatible PEG and PDMS domains are well below the wavelength of visible light.
- Amphophilic Co-Networks Amphophilic Co-Networks:
- the final step to obtain the co-networks of the amphiphilic networks and/or co- networks used in conjunction with the insulin producing devices of the present invention is to subject a suitable multiblock copolymer to crosslinking.
- crosslinking is accomplished via condensation of the pendant SiOEt groups and the formation of intermolecular - SiOSi- bridges.
- Figure 11 illustrates an idealized structure of an amphiphilic co- network formed in accordance with one embodiment of the amphiphilic networks and/or co-networks used in conjunction with an insulin producing device of the present invention.
- the domains labeled with reference numeral 200 are co-continuous hydrophilic domains
- the domains labeled with reference numeral 300 are co-continuous hydrophobic domains.
- Crosslinking of the multiblock copolymers of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are effected by condensation via addition of an acid miscible with the multiblock copolymer in a toluene solution.
- the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention utilize an alkylbenzene sulfonic acid. It should be noted that the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are not limited to solely the acid listed above. Those of ordinary skill in the art will recognize that other acids can be used to effect crosslinking of the multiblock copolymers formed in accordance with the with the insulin producing devices of the present invention.
- Alkylbenzene sulfonic acid performs satisfactorily at room temperature or, can be made to perform better at 60 0 C in the presence of moisture to enhance the rate of crosslinking. Since the solubility of sulfonic acids and their salts in the siloxane phase is low, a benzene sulfonic acid with a long (Cn- 13 ) alkyl substituent is utilized. This ensures good solubility in the PDMS phase. Crosslinking can be more efficient by the use of an acid partially neutralized with an amine. Accordingly, in one embodiment, a mixture of sulfonic acid/pyridinium sulfonate (50/50 mol/mol%) is used as a catalyst.
- the multiblock copolymers of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device are highly viscous liquids even above the melting point of PEG segments (approximately 50 0 C). Therefore, polymer membranes are prepared, as detailed below, by casting multiblock copolymers dissolved in toluene via the use of glass molds at 60 0 C. The solvent rapidly evaporates and crosslinking is complete within approximately 3 hours.
- Amphiphilic co-networks in accordance with the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are prepared by: (1) crosslinking well-defined (AY) x (BY) y multiblock copolymers (see APCN-16 and APCN-40 in Table 2 below), and (2) by crosslinking mixtures of different compositions of multiblock copolymers (see APCN-24 and APCN-32 in Table 2 below).
- the PEG content in the THF extract is generally a little higher than that of the charge. This results in a small decrease in the PEG content of the membrane. Alkyl sulfonate catalyst residues are also removed by extraction with THF. The final membranes are smooth and optically clear; optical clarity is construed as evidence for the absence of macroscopic phase separation of the PEG and PDMS segments.
- the synthesis of the amphiphilic co-networks detailed in Table 2 are accomplished as follows. Five one gram increments of each multiblock copolymer charge detailed in Table 2 are each dissolved in 10 ml_ of toluene. Given that there are four different multiblock copolymer combinations this yields a total of 20 samples.
- Each multiblock copolymer solution contains 0.0002 moles of SiOEt groups.
- 3.2 mg of alkylbenzene sulfonic acid (available from Alfa Aesar) and 0.3 mg pyridine are added to each of the 20 solutions.
- the solutions are then poured into individual glass molds. The molds each have a diameter of 6 cm. All of the molds are then heated in an oven at 60 0 C until the toluene evaporates (approximately 30 minutes). The remaining samples in each mold are then heated for 3 more hours at 60 0 C, removed from their respective molds, dried in vacuum and extracted with tetrahydrofuran until weight constancy.
- the co-networks produced by the above process are transparent rubbery sheets.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing device permit, among other things, the synthesis of nearly ideal tetra-functional amphiphilic co-networks consisting of PEG and PDMS segments.
- the synthesis can be achieved by using a dual-purpose chain extender/crosslinker - (Ph)Si(OSi(CH 3 ) 2 H) 2 (OSi(CH 3 ) 2 ⁇ Et) (see Formula (I)) - whose first function is to extend the incompatible PEG and PDMS polymers into functional multiblock copolymers according to the formula (AY) x (BY) y , and subsequently crosslink the multiblock copolymers by condensing the SiOEt functions into -Si-O-Si- bridges.
- amphiphilic networks and/or co-networks used in conjunction with the insulin producing device relate to amphiphilic co-networks formed from multiblock copolymers of with the following structure -(PEG-(Ph)Si(OSi(CH 3 )2H)2(OSi(CH 3 )2 ⁇ Et)-PDMS-
- the equilibrium swelling characteristics of various amphiphilic co-networks made in accordance with the amphiphilic networks and/or co-networks used in conjunction with the insulin producing devices of the present invention are determined at room temperature. Suitable pre-weighed co-network samples (approximately 20 x 20 x 0.4 mm) are placed in distilled water, and periodically gently shaken. The extent of swelling is determined periodically by removing the membranes from the solvent, removing the water adsorbed to the surfaces by blotting with tissue paper, and weighing the membranes. Equilibrium swelling is recorded when the weight of the water-swollen membranes do not change for 24 hours in the solvent (water). The swelling of co-networks in water is obtained by the following formula:
- SH 2 O 100 (m sw .H 2 o - m d )/m d .
- m S w,H 2 o and ma are the masses of water-swollen and dry co-networks, respectively.
- m sw ,c 7 is the mass of n-heptane-swollen membrane.
- ⁇ TIPE G and ⁇ TI P D MS are the masses of the PEG and PDMS domains in the co- networks, respectively.
- Figure 12 shows the swelling behavior of various composition co-networks in water and n-heptane, S H2 o and Sc 7 , and the swelling of PEG domains in water and
- PDMS domains in n-heptane, SH 2 O,PEG and S C7 ,P DMS . as a function of PEG content (the PEG content corresponds to the number given in column 1 of Table 2).
- the swelling in water increases with increasing PEG content.
- the swelling decreases in n-heptane with increasing PEG content.
- the swelling in water can be smoothly back-extrapolated to approximately 13% PEG, suggesting that water starts to percolate at this PEG content.
- the fact that both water and n-heptane swell these co-networks indicates bi-continuous/bipercolating architecture of incompatible PEG and PDMS phases.
- amphiphilic co- networks investigated in Figure 12 are crosslinked not only by covalently bonded domains but also by physical van der Waals forces, akin to thermoplastic elastomer networks.
- the crystalline PEG is the hard domain and the n- heptane-swollen rubbery PDMS is the soft domain.
- the membranes are optically clear when placed in both water and n-heptane, and remain clear during swelling indicating a nano-structured morphology in which the dimensions of the incompatible PEG and PDMS domains is less than about 400 nm (i.e., much less than the wave length of visible light).
- Oxygen Permeability of Amphiphilic Co-Networks The oxygen permeability of the following co-networks from Table 2 - APCN-
- APCN-32, and APCN-40 - are determined by using the equipment and a methodology described below to measure the oxygen permeability of highly oxygen permeable membranes for various oxygen permeable-based applications.
- the oxygen permeability of water-swollen membranes (usually expressed by Dk in barrer units) is a critical parameter of many materials, including contact lenses. According to various analyses, the internationally accepted Fatt method for the determination of oxygen permeabilities of hydrogels, is, however, unsuitable to determine Dk's above 100 barrers (see International Standard ISO 9913-1 : 1996(E)). Accordingly, in order to determine precise Dk's values in the 100 to 800 barrer range the following method is utilized.
- the oxygen permeability of water-swollen membranes is obtained from the slopes of linear IfDk' versus / plots (where Dk' is the apparent permeability and / membrane thickness).
- Table 3 shows experimental data, and Figure 13 shows 1/Dk' vs. / plots for a series of membranes; for comparison, Figure 13 also shows a plot obtained with a PDMS membrane, whose permeability is determined to be 792 barrers, and a plot for a set of membranes used in extended-wear soft contact lenses (92 barrers, PureVision, Bausch & Lomb Co.). This data is used for comparison purposes to demonstrate the oxygen permeability of the networks and/or co-networks described above.
- the following data is one possible manner by which to gauge the oxygen permeability of a network for use in conjunction with the insulin producing devices of the present invention.
- Other methods and/or tests could be used and as such, the present invention is not limited to solely to oxygen permeability testing method described herein.
- the digits indicate the %PEG content in the amphiphilic co-networks.
- the apparent oxygen permeabilities are determined for membranes prepared in the 0.02 to 0.08 cm thickness range.
- the diffusional resistance of the boundary layer is set at 0.00009 cm/barrer (see the intercept on the y axis in Figure 9), a value characteristic of for the instrument used. This value does not vary much in the 100 to 800 barrer range, and therefore obtaining it by the indicated linear regression is acceptable.
- the apparent oxygen permeabilities of one example of these co-networks are 2 to 3 times higher than those of contemporary extended wear soft contact lens hydrogels. These values indicate that the oxygen permeabilities of co-networks formed in accordance with the amphiphilic networks and/or co-networks of the insulin producing device are far above those ever reported for hydrogels.
- Figure 14 shows the effect of PDMS content on the oxygen permeability of the three co-networks listed in Table 3.
- the solid line indicates the water content of the amphiphilic networks and/or co-networks used in conjunction with the insulin producing device's co-networks.
- the dashed line indicates the maximum permeability of an "ideal" PDMS/hydrogel co-network in which the PDMS phase is continuous over the entire composition range, is calculated by the following formulas:
- P-> is the permeability of PDMS
- P 2 is the permeability of the hydrogel (water- swollen PEG)
- V ⁇ is the volume fraction of the PDMS.
- the apparent oxygen permeabilities of the membranes formed from the co-networks listed in Table 3 are not much below the theoretical maximum permeabilities. According to the data, the co-networks used in conjunction with the insulin producing device are essentially bi- continuous even at relatively low PDMS contents.
- the tensile strength properties of water-swolfen membranes are determined by using an lnstron 5567 (20 N load cell) equipped with a mechanical extensometer at a crosshead speed of 5 mm/min. Microdumbells were die-cut according to ASTM 638-V (i.e., gauge length 7.62 mm, width 3.18 mm). Sample thickness is measured by a micrometer. Tensile strength properties of two or three specimens of each of the co-networks (co-networks APCN-16, APCN-24, APCN-32, and APCN-40) are determined and averaged.
- Figure 15 shows the stress/strain profiles of a series of water-swollen amphiphilic co-networks (co-networks APCN-16, APCN-24, APCN-32, and APCN- 40).
- Table 4 summarizes the mechanical properties of these water swollen co- networks.
- the tensile strengths and elongation percentage decrease with increasing PEG content, whereas the moduli show an increase with increasing PEG content.
- These trends are in line with overall co- network compositions, and reflect the effect of the swelling of the PEG phase on the mechanical properties.
- the tensile strength of even the APCN-40 i.e., the co-network with 40% PEG
- M c crosslink points
- crosslink density 0.6 MPa
- DSC scans are performed by a DuPont 2100 thermal analyzer under a nitrogen atmosphere with a heating rate of 10°C/min.
- the first order (melting) transition is the minimum of the DSC endotherm.
- Glass-transition temperatures (Tg's) are obtained after two heating/cooling cycles by the use of the midpoint method.
- Figure 16 shows the DSC scans of three amphiphilic co-networks of different PEG contents as listed therein.
- the traces indicate two first order (melting) transitions: one at -52 0 C associated with the crystalline PDMS phase and another at approximately 46 0 C due to the crystalline PEG phase.
- the second order transition (T g 's) of the PDMS phase is discernible in the range of -125°C to -100 0 C, however, the glass transition of the non-crystalline PEG could not be identified.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cell Biology (AREA)
- Transplantation (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Botany (AREA)
- Zoology (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200780040160.7A CN101528166B (en) | 2006-08-29 | 2007-08-29 | Implantable devices for producing insulin |
US12/439,057 US8361489B2 (en) | 2006-08-29 | 2007-08-29 | Implantable devices for producing insulin |
EP07837463.4A EP2056759B1 (en) | 2006-08-29 | 2007-08-29 | Implantable devices for producing insulin |
CA2662209A CA2662209C (en) | 2006-08-29 | 2007-08-29 | Implantable devices for producing insulin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US84082806P | 2006-08-29 | 2006-08-29 | |
US60/840,828 | 2006-08-29 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2008027420A2 true WO2008027420A2 (en) | 2008-03-06 |
WO2008027420A3 WO2008027420A3 (en) | 2009-01-08 |
WO2008027420A4 WO2008027420A4 (en) | 2009-03-05 |
Family
ID=39136557
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/018975 WO2008027420A2 (en) | 2006-08-29 | 2007-08-29 | Implantable devices for producing insulin |
Country Status (5)
Country | Link |
---|---|
US (1) | US8361489B2 (en) |
EP (1) | EP2056759B1 (en) |
CN (1) | CN101528166B (en) |
CA (1) | CA2662209C (en) |
WO (1) | WO2008027420A2 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2134295A1 (en) * | 2007-03-09 | 2009-12-23 | The University Of Akron | Bio-artificial pancreas and a procedure for preparation of same |
US9446168B2 (en) | 2010-06-07 | 2016-09-20 | Beta-O2 Technologies Ltd. | Multiple-layer immune barrier for donor cells |
US9540630B2 (en) | 2008-09-17 | 2017-01-10 | Beta O2 Technologies Ltd. | Optimization of alginate encapsulation of islets for transplantation |
JPWO2018088452A1 (en) * | 2016-11-11 | 2019-10-03 | 富士フイルム株式会社 | Immunoisolation membrane, implantation chamber, and implantation device |
EP3539574A4 (en) * | 2016-11-11 | 2019-11-13 | FUJIFILM Corporation | Immunoisolation membrane, transplantation chamber, and transplantation device |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9074098B2 (en) * | 2013-02-26 | 2015-07-07 | University Of Massachusetts | Telechelic based networks from novel macromonomers, compositions, preparation and uses thereof |
WO2014197699A1 (en) * | 2013-06-05 | 2014-12-11 | The University Of Akron | Generation of amphiphilic network with an ability to distinguish the transport of igg and insulin |
US9587063B2 (en) | 2013-06-05 | 2017-03-07 | The University Of Akron | Generation of amphiphilic network with an ability to distinguish the transport of IGG and insulin |
EP3569694A1 (en) | 2013-06-11 | 2019-11-20 | President and Fellows of Harvard College | Sc-beta cells and compositions and methods for generating the same |
JP6351384B2 (en) * | 2014-06-03 | 2018-07-04 | 株式会社メニコン | Contact lens and manufacturing method thereof |
JP6351385B2 (en) * | 2014-06-03 | 2018-07-04 | 株式会社メニコン | Contact lens manufacturing method |
CA3066055A1 (en) | 2017-06-14 | 2018-12-20 | Semma Therapeutics, Inc. | Devices and methods for delivering therapeutics |
WO2019004378A1 (en) * | 2017-06-29 | 2019-01-03 | 富士フイルム株式会社 | Transplant chamber and transplant device |
WO2019004381A1 (en) | 2017-06-29 | 2019-01-03 | 富士フイルム株式会社 | Transplant chamber, method for producing transplant chamber, transplant device and method for fusing porous membrane |
JP6790266B2 (en) | 2017-06-29 | 2020-11-25 | 富士フイルム株式会社 | Transplant chambers and devices |
US11951206B2 (en) | 2017-09-29 | 2024-04-09 | Vertex Pharmaceuticals Incorporated | Cell housing device |
CN112654331A (en) | 2018-08-22 | 2021-04-13 | 波士顿科学国际有限公司 | Cell encapsulation device comprising a porous tube |
CN109289090A (en) * | 2018-10-31 | 2019-02-01 | 陈津 | A kind of pancreatic islets transplantation microenvironment and its construction method |
KR20220070474A (en) | 2019-09-27 | 2022-05-31 | 이슬라 테크놀로지스, 인크. | bioprosthetic pancreas |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993021902A1 (en) | 1992-04-24 | 1993-11-11 | Somatix Therapy Corporation | Biocompatible, therapeutic, implantable device |
US5773286A (en) | 1987-11-17 | 1998-06-30 | Cytotherapeutics, Inc. | Inner supported biocompatible cell capsules |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5713888A (en) | 1990-10-31 | 1998-02-03 | Baxter International, Inc. | Tissue implant systems |
DK0585368T3 (en) * | 1991-04-25 | 1998-03-16 | Univ Brown Res Found | Implantable biocompatible immuno-insulating vehicle for delivery of selected therapeutic products |
US5425764A (en) * | 1992-07-30 | 1995-06-20 | The University Of Toledo | Bioartificial pancreas |
WO1995001203A2 (en) * | 1993-06-23 | 1995-01-12 | Cytotherapeutics, Inc. | Implantable membrane encapsulation apparatus |
US5855613A (en) | 1995-10-13 | 1999-01-05 | Islet Sheet Medical, Inc. | Retrievable bioartificial implants having dimensions allowing rapid diffusion of oxygen and rapid biological response to physiological change |
ATE297702T1 (en) * | 1995-10-26 | 2005-07-15 | Paul P Latta | INDUCTION OF IMMUNOLOGICAL TOLERANCE |
US6365171B1 (en) | 1999-11-04 | 2002-04-02 | The University Of Akron | Amphiphilic networks, implantable immunoisolatory devices and methods of preparation |
US6727322B2 (en) * | 2002-04-01 | 2004-04-27 | The University Of Akron | Amphiphilic networks, implantable immunoisolatory devices, and methods of preparation |
CA2575616C (en) * | 2004-07-30 | 2014-01-28 | University Of Akron | Amphiphilic co-networks, films made from amphiphilic co-networks and uses for such co-networks and films |
-
2007
- 2007-08-29 CA CA2662209A patent/CA2662209C/en not_active Expired - Fee Related
- 2007-08-29 EP EP07837463.4A patent/EP2056759B1/en not_active Not-in-force
- 2007-08-29 CN CN200780040160.7A patent/CN101528166B/en not_active Expired - Fee Related
- 2007-08-29 US US12/439,057 patent/US8361489B2/en active Active
- 2007-08-29 WO PCT/US2007/018975 patent/WO2008027420A2/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5773286A (en) | 1987-11-17 | 1998-06-30 | Cytotherapeutics, Inc. | Inner supported biocompatible cell capsules |
WO1993021902A1 (en) | 1992-04-24 | 1993-11-11 | Somatix Therapy Corporation | Biocompatible, therapeutic, implantable device |
Non-Patent Citations (1)
Title |
---|
See also references of EP2056759A4 |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2134295A1 (en) * | 2007-03-09 | 2009-12-23 | The University Of Akron | Bio-artificial pancreas and a procedure for preparation of same |
EP2134295A4 (en) * | 2007-03-09 | 2011-04-27 | Univ Akron | Bio-artificial pancreas and a procedure for preparation of same |
US9540630B2 (en) | 2008-09-17 | 2017-01-10 | Beta O2 Technologies Ltd. | Optimization of alginate encapsulation of islets for transplantation |
US9446168B2 (en) | 2010-06-07 | 2016-09-20 | Beta-O2 Technologies Ltd. | Multiple-layer immune barrier for donor cells |
JPWO2018088452A1 (en) * | 2016-11-11 | 2019-10-03 | 富士フイルム株式会社 | Immunoisolation membrane, implantation chamber, and implantation device |
EP3539575A4 (en) * | 2016-11-11 | 2019-11-13 | FUJIFILM Corporation | Immunoisolation membrane, transplantation chamber, and transplantation device |
EP3539574A4 (en) * | 2016-11-11 | 2019-11-13 | FUJIFILM Corporation | Immunoisolation membrane, transplantation chamber, and transplantation device |
US11045587B2 (en) | 2016-11-11 | 2021-06-29 | Fujifilm Corporation | Membrane for immunoisolation, chamber for transplantation, and device for transplantation |
US11051930B2 (en) | 2016-11-11 | 2021-07-06 | Fujifilm Corporation | Membrane for immunoisolation, chamber for transplantation, and device for transplantation |
Also Published As
Publication number | Publication date |
---|---|
CA2662209C (en) | 2015-02-17 |
CA2662209A1 (en) | 2008-03-06 |
EP2056759A2 (en) | 2009-05-13 |
CN101528166B (en) | 2014-05-07 |
WO2008027420A4 (en) | 2009-03-05 |
WO2008027420A3 (en) | 2009-01-08 |
EP2056759B1 (en) | 2015-01-14 |
CN101528166A (en) | 2009-09-09 |
US20100209468A1 (en) | 2010-08-19 |
EP2056759A4 (en) | 2011-11-30 |
US8361489B2 (en) | 2013-01-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8361489B2 (en) | Implantable devices for producing insulin | |
US8702810B2 (en) | Bio-artificial pancreas and a procedure for preparation of same | |
US7847025B2 (en) | Amphiphilic block copolymers and their use | |
AU2010286531B2 (en) | Methods and devices for cellular transplantation | |
US6858736B2 (en) | Hexa-arm polyethylene glycol and its derivatives and the methods of preparation thereof | |
Kurian et al. | Synthesis, permeability and biocompatibility of tricomponent membranes containing polyethylene glycol, polydimethylsiloxane and polypentamethylcyclopentasiloxane domains | |
CA2332333A1 (en) | Peg-poe, peg-poe-peg, and poe-peg-poe block copolymers | |
JP2020527382A (en) | N-oxide and ectoine monomers, polymers, their compositions and related methods | |
AU2005317689B2 (en) | Amphiphilic block copolymers and their use | |
Gadkari et al. | Preparation and biocompatibility of novel polar-nonpolar networks: I. Synthesis, characterization and histological-bacterial analysis of mixed polytetrahydrofuran-polyisobutylene networks | |
CN117567698A (en) | Photo-curing biocompatible material and drainage tube | |
Kennedy et al. | Two generations of synthetic membranes for biological/medical applications | |
Tegou et al. | CCL21 and beta-cell antigen releasing hydrogels as tolerance-inducing therapy in Type I diabetes | |
KR20110093211A (en) | Biocompatible and temperature-sensitive polyethyleneglycol/polyester block copolymer with high biodegradable property | |
JP2002500930A (en) | Compositions and methods for biocompatible implants | |
US6727322B2 (en) | Amphiphilic networks, implantable immunoisolatory devices, and methods of preparation | |
EP4306548A1 (en) | Hydrogels for cell therapy | |
EP4306549A1 (en) | Hydrogels for cell therapy | |
EP4306550A1 (en) | Hydrogels for cell therapy | |
AU2019203457B2 (en) | Methods and devices for cellular transplantation | |
CN111836847B (en) | Carbonate-linked surface-modified macromolecules | |
WO2005070998A1 (en) | Polymer for use in conduits and medical devices | |
Shamlou | Diffusional and biological characteristics of semipermeable amiphiphilic membranes | |
Daum | Novel Networks by the Polymerization of Cyclic Siloxanes | |
WO2023118599A1 (en) | Implantable device comprising a hydrogel |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200780040160.7 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07837463 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2662209 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 449/MUMNP/2009 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007837463 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: RU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12439057 Country of ref document: US |