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-9925310-B2
Publication Date
2018-03-27
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 relates to biocompatible, bioabsorbable deacetylated and reacetylated chitosan compositions. The compositions comprise a reacetylated chitosan having a molecular weight of about 90 kDa to about 170 kDa and a degree of N-deacetylation between about 15% and 40%.
The disclosure addresses compositional control of reacetylated chitosan behavior through defined structural and chemical parameters, including initial aqueous solubility at or below about pH 6.5 and an acid content that can be adjusted within a stated range. Changing acid content is associated with cytotoxicity, adhesion, and cellular infiltration, while the compositions exhibit rapid bioabsorption typically within about 90 days.
In addition to the compositions, the document discloses an invention-developed modified acute systemic toxicity assay using lysozyme-primed or partially biodegraded chitosan and correlation of toxicity with IL-1β elevation. The disclosure reports IL-1β and atopic dermatitis-like lesions associated with higher DDA chitosans and mitigation for lower DDA chitosans, and it connects these findings to bioabsorption and cellular infiltration behavior.
The disclosure also describes cross-linked variants of the reacetylated chitosan compositions, including crosslinking with gelatin and collagen, and reporting hemostatic efficacy in a swine context for low-acid gelatin/chitosan foamed or compressed compositions. Physical or device forms are described, including sponges, scaffolds, and coatings, consistent with the stated goal of providing biocompatible, bioabsorbable reacetylated chitosan materials for biomedical use.
Claims Coverage
The partial content provides three independent claims: a composition, a method, and a composition. Across these independent claims, the core inventive features are the defined reacetylated chitosan composition parameters, the use of carbonic acid to resolubilize reacetylated chitosan from a specified DDA range, and an optional crosslinking structure with gelatin and collagen together with stated compositional constraints.
Reacetylated chitosan with defined molecular weight and DDA
A biocompatible, bioabsorbable deacetylated and reacetylated chitosan composition comprising a reacetylated chitosan having a molecular weight of about 90 kDa to about 170 kDa and a degree of N-deacetylation of between about 15% and 40%.
Carbonic-acid resolubilization of reacetylated chitosan
A method of making a biocompatible, bioabsorbable chitosan composition comprising obtaining deacetylated chitosan; producing reacetylated chitosan from the deacetylated chitosan having a degree of N-deacetylation of between 15% and 30%; and resolubilizing the reacetylated chitosan to aqueous solution using carbonic acid.
Cross-linked reacetylated chitosan with DDA range
A biocompatible, bioabsorbable deacetylated and reacetylated chitosan composition comprising a reacetylated chitosan having a degree of N-deacetylation of between 15% and 30% and cross-linked with at least one of gelatin and collagen.
Overall claim coverage centers on reacetylated chitosan compositions defined by molecular weight and degree of N-deacetylation, a method requiring carbonic acid resolubilization of reacetylated chitosan made from a defined DDA range, and a cross-linked composition option using gelatin and/or collagen. Dependent claim refinements further specify quantitative acid content and initial aqueous solubility at or below pH 6.5.
Stated Advantages
The compositions are biocompatible.
The compositions are bioabsorbable, with rapid bioabsorption typically within about 90 days.
The disclosure reports cytotoxicity and IL-1β-related toxicity mitigation for lower DDA chitosans compared to higher DDA chitosans in the modified acute systemic toxicity assay.
The disclosure reports hemostatic efficacy in a swine context for low-acid gelatin/chitosan foamed or compressed compositions.
Documented Applications
Biomedical use of biocompatible, bioabsorbable derivatized reacetylated chitosan compositions, including formulation into physical or device forms such as sponges, scaffolds, and coatings.
Hemostatic use, supported by hemostatic efficacy in a swine context for low-acid gelatin/chitosan foamed or compressed compositions.
Dermal and systemic toxicity evaluation using a modified acute systemic toxicity assay with lysozyme-primed or partially biodegraded chitosan, with IL-1β elevation and atopic dermatitis-like lesions reported.
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