Biocompatible and bioabsorbable derivatized chitosan compositions
Inventors
McGrath, Barbara • McCarthy, Simon • KUHN, Sam • Wold, Alysha • Stolten, Michael • Bennett, Amanda
Assignees
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Publication Number
US-11229724-B2
Publication Date
2022-01-25
Expiration Date
Abstract
The invention relates to biocompatible, bioabsorbable derivatized non-crosslinked chitosan compositions optionally crosslinked to gelatin/collagen by 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) for biomedical use and methods of making and testing such compositions, including a modified acute systemic toxicity test. The compositions comprise derivatized chitosan reacetylated to a degree of N-deacetylation (DDA) of between about 15% and 40%. The compositions are typically bioabsorbed in about 90 days or less and can be made to bioabsorb at differing rates of speed. The compositions are initially soluble in aqueous solution below pH 6.5. The compositions have an acid content that can be adjusted between about 0% (w/w) and about 8% (w/w) to customize the composition for uses that require and/or tolerate differing levels of cytotoxicity, adhesion, composition cohesion, and cell infiltration into the composition.
Core Innovation
The invention provides a biocompatible, bioabsorbable reduced amine functionality chitosan composition defined by a degree of N-deacetylation of between about 15% and 40% and an acid content between about 2% (w/w) and 8% (w/w). The composition is cross-linked to at least one of gelatin and collagen, and the described composition includes derivatized, non-crosslinked chitosan compositions and cross-linked variants that use EDC-crosslinked gelatin/collagen while maintaining the claimed reduced-amine character.
The invention addresses residual acid and N-deacetylation level as controllable parameters. It specifies residual acid content and relates it to effects on cytotoxicity, adhesion, and infiltration, with residual acid content above about 5% impairing matrix structure and cellular infiltration and low-acid compositions of about 3% improving adherence in simulated arterial wound sealing.
The invention further characterizes biological compatibility through cytokine response and biodegradation-related outcomes. Implant outcomes are reported not to elevate IL-1β cytokine and not to produce toxic biodegradation species, together with bioabsorption-related toxicity and dermal lesion observations, hemostatic efficacy in swine models using DDA-selected compositions and specified acid levels, and bioabsorbability within about 90 days in the described context.
Claims Coverage
The partial content identifies two independent claims: one directed to a composition and one directed to a method of making the composition. Across these independent claims, the document centers on three main inventive parameter groups: reduced-amine chitosan defined by degree of N-deacetylation, residual acid content, and cross-linking to gelatin/collagen, and a manufacturing sequence using reacetylation, reduction of free amine functionality, resolubilization, volatilization of residual bound acid, and retaining the targeted acid content.
Reduced-amine chitosan with N-deacetylation and residual acid ranges
A biocompatible, bioabsorbable reduced amine functionality chitosan composition having a degree of N-deacetylation of between about 15% and 40%, and an acid content between about 2% (w/w) and 8% (w/w).
Gelatin/collagen cross-linking of the reduced-amine chitosan composition
The composition is cross-linked to at least one of gelatin and collagen.
Reacetylation, reduction of free amine functionality, and resolubilization with residual acid control
A method of making a biocompatible, bioabsorbable chitosan composition comprising reacetylation of chitosan with a degree of N-deacetylation at least about 80% to at least about 65%, reducing chitosan free amine functionality of the reacetylated chitosan to obtain a degree of N-deacetylation of between about 15% and 40%, resolubilizing the reacetylated chitosan into an acidified aqueous solution, volatilizing residual acid bound to the reacetylated chitosan, and allowing an acid content between about 2% (w/w) and 8% (w/w) to remain.
Overall, the claim set ties biocompatible, bioabsorbable reduced-amine chitosan to specific ranges of degree of N-deacetylation and residual acid content, while requiring cross-linking to gelatin and/or collagen in the composition claim. The method claim operationalizes these same target parameters via reacetylation, reduction to the specified N-deacetylation range, resolubilization in an acidified aqueous solution, volatilization of residual bound acid, and leaving the residual acid within the claimed 2% to 8% (w/w) window.
Stated Advantages
Reported implants do not elevate IL-1β cytokine.
Reported implants do not produce toxic biodegradation species.
Residual acid above about 5% impairs matrix structure and cellular infiltration, while low-acid compositions of about 3% improve adherence in simulated arterial wound sealing, indicating tunable adhesion and infiltration behavior via residual acid content.
Compositions are reported to be bioabsorbable within about 90 days in the described context.
The document reports hemostatic efficacy in swine models with DDA-selected compositions and specified acid levels.
Documented Applications
Simulated arterial wound sealing, where low-acid compositions are reported to improve adherence.
In vivo implantation and biodegradation evaluation in the context of dermal lesions and bioabsorption-related toxicity and IL-1β response.
Hemostatic efficacy evaluation in swine models using DDA-selected compositions and specified acid levels, including foamed and freeze-dried/compressed foam or sponge formats.
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