Hydrogels for cell therapy
Inventors
Soula, Gérard • GEISSLER, Alexandre • LAURENT, Nicolas • Plancq, Baptiste
Assignees
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Publication Number
US-12421327-B2
Publication Date
2025-09-23
Expiration Date
Abstract
A crosslinked dextran polymer, bearing carboxylate groups, wherein at least two saccharidic units of dextran belonging to two different polymer chains are covalently linked by at least one at least divalent radical, this at least divalent radical being a linear, branched or cyclic alkyl radical including at least 15 carbon atoms and optionally heteroatoms such as oxygen, nitrogen or sulfur.
Core Innovation
The invention provides a cross-linked dextran polymer bearing carboxylate groups. At least two saccharidic units of dextran belonging to two different polymer chains are covalently linked by at least one at least divalent radical L(-)i, and the radical L(-)i is covalently bound to the dextran polymer backbone with i-(R1)mG1-radical.
L(-)i is defined as a linear or branched polyether bearing at its ends and heteroatoms, with i between 2 and 8, while m is an integer equal to 0 or 1. R1 is a linear or branched alkyl divalent radical comprising from 1 to 6 carbon atoms, and G1 is a linear or branched or cyclic alkyl divalent radical comprising from 1 to 6 carbon atoms and may comprise heteroatoms.
The invention also concerns dextran-based functional polysaccharides, including dextran maleimide derivatives and dextran carboxymethyl derivatives, characterized by degrees of substitution for carboxymethyl groups and maleimide or vinylsulfone reactive groups. Cross-linked hydrogels are prepared from these dextran functional polysaccharides crosslinked with thiol-functional PEG-SH using Mal–SH chemistry or VS–SH chemistry, and the hydrogel embodiments are characterized by gelation, rheological behavior, swelling, water content, stability in physiological media, and optical transparency.
The disclosure evaluates mechanical properties and performance in encapsulation settings, including encapsulation of macromolecular dextran probes. Biological characterization includes cytotoxicity testing by ISO 10993-5 extract test, islet viability and insulin secretion maintenance in vitro, long-term in vitro viability and function, and in vivo survival and function with immuno-isolation and glucose regulation efficacy. Local tissue tolerance is assessed using ISO 10993-6 scoring in rabbits and rats.
Claims Coverage
The combined claim coverage includes two independent claims. One is directed to a cross-linked dextran polymer bearing carboxylate groups, and one is directed to a hydrogel comprising that cross-linked dextran polymer; both center on covalent inter-chain linking of dextran saccharidic units using a defined divalent radical L(-)i with structural constraints on L(-)i, R1, G1, i, and m.
Cross-linked dextran polymer linked by divalent radical L(-)i
A cross-linked dextran polymer bearing carboxylate groups, where at least two saccharidic units of dextran belonging to two different polymer chains are covalently linked by at least one at least divalent radical L(-)i, wherein L(-)i is covalently bound to the dextran polymer backbone with i-(R1)mG1-radical, and L(-)i is a linear or branched polyether bearing at its ends and heteroatoms, with i in the range 2 to 8 and m equal to 0 or 1.
Defined backbone substituents
R1 is a linear or branched alkyl divalent radical comprising from 1 to 6 carbon atoms, and G1 is a linear or branched or cyclic alkyl divalent radical comprising from 1 to 6 carbon atoms and may comprise heteroatoms.
Hydrogel comprising covalently linked dextran polymer
A hydrogel comprising a cross-linked dextran polymer bearing carboxylate groups, where at least two saccharidic units of dextran belonging to two different polymer chains are covalently linked by at least one at least divalent radical L(-)i, with L(-)i covalently bound to the dextran polymer backbone with i-(R1)mG1-radical.
Overall, the claim coverage centers on covalent inter-chain crosslinking of dextran saccharidic units via a divalent radical L(-)i bound to the dextran backbone through an i-(R1)mG1-radical, together with the corresponding hydrogel embodiment and the stated structural limitations.
Stated Advantages
permselectivity/immune isolation through hydrogel mesh
favorable mechanics/mesh characteristics
low degradability of the hydrogel framework
No cytotoxicity in the ISO 10993-5 extract test.
Islet viability and insulin secretion maintenance in vitro.
Long-term in vitro viability and function.
In vivo survival and function with immuno-isolation and glucose regulation efficacy.
Local tissue tolerance assessed by ISO 10993-6 scoring in rabbits and rats.
Documented Applications
cell therapy/implantable delivery using the dextran-based crosslinked hydrogel, including pseudoislets and insulin-secreting cells
therapeutic use for diabetes and pancreatic endocrine dysfunction
an insulin secretion response assessment comparing naked vs encapsulated islets
Encapsulation performance for macromolecular dextran probes (FITC) and dextran probes in hydrogels is evaluated.
Encapsulation of pancreatic islets, including pseudoislets and primary islets, with reported in vitro viability/function and in vivo survival/function under immuno-isolation and glucose regulation efficacy.
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