Liang, H, Russell, SJ orcid.org/0000-0003-0339-9611, Wood, DJ orcid.org/0000-0001-8269-9123 et al. (1 more author) (2018) A hydroxamic acid–methacrylated collagen conjugate for the modulation of inflammation-related MMP upregulation. Journal of Materials Chemistry B, 6 (22). pp. 3703-3715. ISSN 2050-750X
Abstract
Medical devices with matrix metalloproteinase (MMP)-modulating functionality are highly desirable to restore tissue homeostasis in critical inflammation states, such as chronic wounds, rotator cuff tears and cancer. The introduction of MMP-modulating functionality in such devices is typically achieved via loading of either rapidly diffusing chelating factors, e.g. EDTA, or MMP-cleavable substrates, raising issues in terms of non-controllable pharmacokinetics and enzymatic degradability, respectively. Aiming to accomplish inherent, long-term, device-induced MMP regulation, this study investigated the synthesis of a hydroxamic acid (HA)–methacrylated collagen conjugate as the building block of a soluble factor-free MMP-modulating hydrogel network with controlled enzymatic degradability. This was realised via a two-step synthetic route: (i) type I collagen was functionalised with photonetwork-inducing methacrylic anhydride (MA) adducts in the presence of triethylamine (TEA); (ii) this methacrylated product was activated with a water-soluble carbodiimide prior to reaction with hydroxylamine, resulting in MMP-chelating HA functions. Nearly-quantitative methacrylation of collagen amines was observed via 2,4,6-trinitrobenzenesulfonic acid (TNBS) assay; this was key to avoiding intramolecular crosslinking side reactions during the carbodiimide-mediated activation of collagen carboxyl groups. The molar content of HA adducts was indirectly quantified via the conversion of remaining carboxyl functions into ethylenediamine (EDA), so that 12–16 mol% HA was revealed in the conjugate by both TNBS and Ninhydrin assays. Resulting UV-cured, HA-bearing collagen hydrogels proved to induce up to ∼13 and ∼32 RFU% activity reduction of MMP-9 and MMP-3, respectively, following 4-day incubation in vitro, whilst displaying an averaged mass loss in the range of 8–21 wt%. Dichroic and electrophoretic patterns of native type I collagen could still be observed following the introduction of HA adducts, suggesting preserved triple helix architecture and chemical sequence in respective HA–methacrylated collagen conjugate. No hydrogel-induced toxic response was observed following the 4-day culture of G292 cells, whilst a lower compression modulus and gel content were measured in HA-bearing compared to methacrylated hydrogels, likely related to HA radical scavenging activity. The novel synthetic strategies described in this work provide a new insight into the systematic chemical manipulation of collagen materials aiming at the design of biomimetic, inflammation-responsive medical devices.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) The Royal Society of Chemistry 2018. This Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licence; https://creativecommons.org/licenses/by/3.0/ |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Arts, Humanities and Cultures (Leeds) > School of Design (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Dentistry (Leeds) > Oral Biology (Leeds) |
Funding Information: | Funder Grant number EPSRC (Engineering and Physical Sciences Research Council) EP/K029592/1 EPSRC (Engineering and Physical Sciences Research Council) EP/R511717/1 The Clothworkers Foundation ANDREW BLESSLEY |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Apr 2018 13:49 |
Last Modified: | 25 Jun 2023 21:19 |
Status: | Published |
Publisher: | Royal Society of Chemistry |
Identification Number: | 10.1039/C7TB03035E |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:130063 |