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Impact of Hydrogel Cross-Linking Chemistry on the in Vitro and in VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.ORCID iD: 0000-0003-2896-2765
Maisonneuve-Rosemont Hospital Research Centre & Department of Ophthalmology, University of Montreal.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6947-9601
Department of Surgical Sciences, Section of Orthopedics, Uppsala University Hospital.
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2019 (English)In: ACS Applied Bio Materials, ISSN 2576-6422Article in journal, Editorial material (Refereed) Published
Abstract [en]

Designing strategies to deliver functional proteins at physiologically relevant concentrations using chemically cross-linked biocompatible hydrogels is a major field of research. However, the impact of cross-linking chemistry on the encapsulated protein bioactivity is rarely studied. Here we examine the two well-known cross-linking reactions namely; hydrazone cross-linking chemistry and thiol-Michael addition reaction to form hyaluronic acid (HA) hydrogels. As a therapeutic protein, we employed recombinant human bone morphogenetic protein-2 (rhBMP-2) for this study. Incubation of rhBMP-2 with HA functionalized with a thiol diminished phosphorylation of Smad 1/5/8, a signal transducer for osteogenic differntiation, whereas an aldehyde functionalized HA had no effect. This indicates that thiol functionalized polymers indeed has an impact on protein function. To validate this result in an in vivo setting we performed BMP-2 induced bone formation in a rat ectopic model. These experiments revealed that the hydrazone-cross-linked HA-hydrogel induced significantly higher bone formation (18.90 ± 4.25 mm3) as compared to the HA-thiol-Michael hydrogels (1.25 ± 0.52 mm3) after 8 weeks as determined by micro-computed tomography. The histological examination of the neo-bone indicated that hydrazone-hydrogels promoted a better quality of bone formation with improved mineralization and collagen formation as compared to the thiol-Michael hydrogels. We believe such a direct comparison of two cross-linking chemistries will provide new insight for developing biomaterials for protein delivery for in vivo applications.

Place, publisher, year, edition, pages
2019.
Keywords [en]
bone tissue engineering; cross-linking chemistry; drug delivery; hyaluronic acid; regenerative medicine
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-382321DOI: 10.1021/acsabm.9b00060OAI: oai:DiVA.org:uu-382321DiVA, id: diva2:1306576
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-04-24

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Publisher's full texthttps://pubs.acs.org/doi/abs/10.1021/acsabm.9b00060

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Paidikondala, MaruthibabuHilborn, JönsVarghese, Oommen P.

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