Biocompatible hydrogel capsules and process for preparing same
Inventors
Barney, Lauren Emily • Heidebrecht, Richard • Johnston, Erika Ellen • Miller, Robert James
Assignees
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Publication Number
US-12162994-B2
Publication Date
2024-12-10
Expiration Date
Abstract
Described herein are compositions and methods for preparing hydrogel capsules using a cross-linking solution comprising a process additive. The process additive improves the quality of the resulting hydrogel capsules, such as increasing the number of defect-free capsules.
Core Innovation
The invention relates to preparing a hydrogel capsule composition from an alginate polymer solution. The alginate polymer solution comprises an afibrotic hydrogel-forming alginate polymer and an unmodified hydrogel-forming alginate polymer, and the process contacts a plurality of droplets of the alginate polymer solution with an aqueous cross-linking solution for a period of time sufficient to produce hydrogel capsules. The alginate polymer solution further comprises a cell suspension comprising a plurality of cells to form hydrogel capsules containing the cells.
The aqueous cross-linking solution comprises a cross-linking agent comprising a divalent cation, a buffer, an osmolarity-adjusting agent and a surfactant. The surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) PEO-PPO-PEO triblock copolymer, and specific cross-linking solutions use BaCl2, HEPES buffer, mannitol, and poloxamer 188.
The afibrotic hydrogel-forming alginate polymer is defined as an afibrotic compound on an alginate backbone, including salts, based on a compound defined by Formula (I) and related sub-formulas. The disclosure additionally specifies that the process produces hydrogel capsules characterized by capsule defects, including that at least 95% of the capsules are spherical, and supports defect-free spherical capsules with smooth surfaces.
Claims Coverage
The independent claims cover droplet contacting of an alginate polymer solution containing both an afibrotic hydrogel-forming alginate polymer and an unmodified hydrogel-forming alginate polymer with an aqueous cross-linking solution to form hydrogel capsules. The claims further require a cross-linking solution with divalent cations, buffer, osmolarity adjustment, and a PEO-PPO-PEO triblock copolymer surfactant, and include a cell suspension in the alginate polymer solution. One independent claim further narrows the cross-linking solution to BaCl2, HEPES buffer, mannitol, and poloxamer 188.
Droplet-based hydrogel capsule formation from mixed afibrotic and unmodified alginate polymers
A process for preparing a hydrogel capsule composition from an alginate polymer solution, wherein the alginate polymer solution comprises an afibrotic hydrogel-forming alginate polymer and an unmodified hydrogel-forming alginate polymer, and wherein the process comprises contacting a plurality of droplets of the alginate polymer solution with an aqueous cross-linking solution for a period of time sufficient to produce hydrogel capsules.
Aqueous cross-linking solution with divalent cation, buffer, osmolarity-adjusting agent, and surfactant
The process wherein the cross-linking solution comprises a cross-linking agent comprising a divalent cation, a buffer, an osmolarity-adjusting agent and a surfactant, wherein the surfactant is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) PEO-PPO-PEO triblock copolymer.
Cell suspension incorporated into the alginate polymer droplets
The process wherein the alginate polymer solution further comprises a cell suspension comprising a plurality of cells.
Afibrotic hydrogel-forming alginate polymer defined by Formula (I) compounds or salts
The process wherein the afibrotic hydrogel-forming alginate polymer includes (or is a salt of) a compound defined by Formula (I) comprising substituents A, L1, M, L2, P, L3, and Z with specified meanings for each variable.
Specific cross-linking solution composition using BaCl2, HEPES buffer, mannitol, and poloxamer 188
A process for preparing a hydrogel capsule composition from an alginate polymer solution, wherein the cross-linking solution comprises BaCl2, HEPES buffer, mannitol, and poloxamer 188, and wherein the alginate polymer solution comprises an afibrotic hydrogel-forming alginate polymer and an unmodified hydrogel-forming alginate polymer and the process comprises contacting a plurality of droplets of the alginate polymer solution with the aqueous cross-linking solution for a period of time sufficient to produce hydrogel capsules.
The independent claims require capsule formation by contacting multiple droplets of an alginate polymer solution containing both afibrotic and unmodified hydrogel-forming alginate polymers with an aqueous cross-linking solution. They further require the cross-linking solution to include divalent-cation cross-linking, buffer, osmolarity-adjustment, and a PEO-PPO-PEO triblock copolymer surfactant, with one independent claim expressly limiting the cross-linking solution to BaCl2, HEPES buffer, mannitol, and poloxamer 188, while including a cell suspension in the alginate polymer solution.
Stated Advantages
Improved capsule quality and loading.
Tween 20 improves spherical microcapsule quality dose-dependently.
Tween 20 does not increase fibrosis in mice.
Tween 20 increases cell loading and prevents non-capsule debris.
Poloxamer 188 uniquely yields smooth capsules.
Poloxamer 188 enables higher cell loading (up to about 10-fold) with preserved anti-fibrotic properties ex vivo/in vivo.
Increases the number of defect-free spherical capsules, including smooth surfaces.
Supports robust manufacture across broad alginate viscosities.
Unexpectedly increases cell loading capacity.
Documented Applications
Therapeutic agents produced by encapsulated cells across classes including sugars/glycans, sugar alcohols, lipids (including liposome-forming lipids), small-molecule natural products and engineered statin production, and antigens (viral, bacterial, fungal, plant, environmental, tumor; nucleic-acid/peptide/protein/sugar/lipid antigens).
Use of afibrotic alginate hydrogel capsule formulations where preserved anti-fibrotic properties are maintained ex vivo/in vivo.
Afibrotic hydrogel-forming polymer use, where the polymer includes an attachment group that links an afibrotic compound defined by Formulas (I)-(IV) to the polymer; alginate is described as an example hydrogel-forming polymer.
Encapsulation of engineered cells, including ARPE-19.
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