Matrix composed of a naturally-occurring protein backbone cross linked by a synthetic polymer and methods of generating and using same
Inventors
Seliktar, Dror • Almany, Liora
Assignees
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Publication Number
US-8007774-B2
Publication Date
2011-08-30
Expiration Date
Abstract
The present invention relates to biodegradable scaffolds composed of a naturally-occurring protein backbone cross-linked by a synthetic polymer. Specifically, the present invention provides PEGylated-fibrinogen scaffold and methods of generating and using same for treating disorders requiring tissue regeneration.
Core Innovation
The invention provides a biodegradable tissue-engineering scaffold formed as a PEG-fibrinogen hydrogel. The scaffold uses PEGylated, denatured naturally occurring proteins as a backbone, primarily fibrinogen, with optional collagen and denatured collagen protein fragments. The denatured protein retains activity of forming a scaffold and is covalently modified so that at least two PEG molecules are connected to free thiol groups on the denatured protein.
Each PEG molecule includes a functional group for cross-linking, enabling precursor molecules to be cross-linked to form a hydrogel matrix. The document describes cross-linking of PEGylated, denatured protein precursor molecules to create PEG-fibrinogen hydrogels. The scaffold is presented as biodegradable, with biodegradation attributed to protease activity such as trypsin and collagenase, and with the hydrogel properties associated with scaffold modulus of elasticity and PEG design parameters.
The disclosed scaffold concept is linked to biological outcomes by tuning degradation and bioactivity via PEG content and PEG chemistry. The document reports improved bioactivity versus PEG-only controls and protease-mediated biodegradability. It further describes in vivo critical-size rat tibia defect bone regeneration with intermediate degradation tuning, and ex vivo nerve regeneration, including DRG neurite outgrowth and the involvement of nerve growth factor (NGF), alongside control of degradation/bioactivity through PEG content.
Claims Coverage
The partial content provides three independent claims. Across these independent claims, the core coverage centers on PEGylated denatured fibrinogen or collagen precursor molecules with cross-linkable PEG functionality and the cross-linking of these precursors to generate a scaffold, together with retained tissue-regeneration activity after in vivo administration in selected embodiments.
Pegylated denatured fibrinogen or collagen precursor with cross-linkable PEG
A precursor molecule comprising a fibrinogen protein that is denatured and retains an activity of forming a scaffold, or a collagen protein that is denatured and retains an activity of forming a scaffold, and at least two PEG molecules covalently connected to free thiol groups of the denatured fibrinogen protein or the denatured collagen protein, where each of the at least two PEG molecules comprises a functional group for cross-linking.
Method of generating scaffold by preparing PEGylated denatured protein precursors and cross-linking
A method of generating a scaffold comprising generating a plurality of precursor molecules, wherein each precursor molecule comprises a fibrinogen protein that is denatured and retains an activity of forming a scaffold or a collagen protein that is denatured and retains an activity of forming a scaffold, and at least two PEG molecules covalently connected to free thiol groups of the denatured fibrinogen protein or the denatured collagen protein, each PEG molecule comprising a functional group for cross-linking; and subsequently cross-linking the plurality of precursor molecules to thereby generate the scaffold.
Pegylated denatured fibrinogen or collagen precursor retaining in vivo tissue-regeneration activity
A precursor molecule comprising a fibrinogen protein that is denatured and retains an activity of mediating tissue regeneration following in vivo administration, or a collagen protein that is denatured and retains an activity of mediating tissue regeneration following in vivo administration, and at least two PEG molecules covalently connected to free thiol groups of the denatured fibrinogen protein or the denatured collagen protein, each of the at least two PEG molecules comprising a functional group for cross-linking.
Collectively, the independent claim set covers PEGylated denatured fibrinogen/collagen precursors with cross-linkable PEG attached to free thiol groups, cross-linking of such precursor molecules to generate a scaffold, and embodiments where the denatured protein precursor retains mediating tissue regeneration activity following in vivo administration.
Stated Advantages
Improved bioactivity versus PEG-only controls.
Protease-mediated biodegradability.
In vivo critical-size rat tibia defect bone regeneration with intermediate degradation tuning.
Ex vivo nerve regeneration, including DRG neurite outgrowth with NGF effects.
Control of degradation/bioactivity via PEG content.
Documented Applications
In vivo bone regeneration in a critical-size rat tibia defect, with intermediate degradation tuning.
Ex vivo nerve regeneration assessed by DRG neurite outgrowth, with effects of NGF and degradation/bioactivity control via PEG content.
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