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The choice of crosslinking chemistry for hydrogel development influences BMP-2 stability and bioactivity in vivo
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
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(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Abstract [en]

Site-specific administration of bone morphogenetic protein-2 (BMP-2) at the site of a bone fracture via scaffolds can minimise systemic side-effects and exhibit sustained biological effects. While this method requires sufficient scaffolds to preserve the BMP-2 structure and tuned release patterns, the incorporation of thiol-acrylate chemistry has shown great success in scaffold synthesis. However, thiolates attack the sulphur atoms of disulphide bonds, displacing the other sulphur atom and forming a new disulphide bond, hence at physiological conditions, thiol-modified scaffold components could potentially attack inter-chain disulphide bonds of BMP-2 by thiol-exchange reactions. This therefore led us to compare hyaluronic acid (HA) hydrogels synthesised via thiol-acrylate (HA-S) and hydrazone crosslinking chemistry (HA-H) formed BMP-2 carriers. The study revealed the integrity of BMP-2 dimer structures can be disrupted and reveals the osteogenic capacity of BMP-2 by HA derivatives (HA-SH). BMP-2 bioactivity released from HA-S hydrogels are decreased when compared to HA-H hydrogels. This was further confirmed via the rat ectopic bone model, showing that bone volume was significantly higher when induced by HA-H hydrogels with BMP-2 than compared to HA-S hydrogel with BMP-2. This study gives new insights into scaffolds synthesis, showing that biomolecule bioactivity needs to be considered when choosing a chemistry for scaffolds synthesis. 

Keyword [en]
Hyaluronic acid, in vivo, bone morphogenetic protein, thiol-acrylate chemistry.
National Category
Medical Materials
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-307686OAI: oai:DiVA.org:uu-307686DiVA: diva2:1049878
Available from: 2016-11-25 Created: 2016-11-20 Last updated: 2016-11-27
In thesis
1. New insights into principles of scaffolds design for bone application
Open this publication in new window or tab >>New insights into principles of scaffolds design for bone application
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents deeper insights into bone applicable biomaterials’ design. Poor affinity of BMP-2 towards scaffolds required supra-physiological dose administration. Though molecules containing sulfate could sustain BMP-2 release, side effects occurred due to BMP-2 supra-dose, or these sulfate-containing biomolecules.

Improved affinity between BMP-2 and scaffolds was first witnessed by using an acidic carrier (paper I). Hyaluronic acid (HA) hydrazone derived hydrogels having a pH of 4.5-loaded BMP-2 showed sustained release of bioactive BMP-2 in vitro and enhanced bone formation in vivo, while pH 7 HA hydrogels showed Fickian behavior and less bone formation in vivo. Computational evaluation revealed stronger electrostatic interactions between BMP-2, and HA were predominant at pH 4.5, whereas, weaker Van der Waals interactions played a key role at pH 7.

During the pre-bone formation phase, endogenous cell responses to pH 4.5 and 7 with or without BMP-2 were investigated. HA hydrogels exhibited extraordinary biocompatibility and recruitment of neutrophils, monocytes, macrophages and stromal cells regardless of hydrogels’ pH and BMP-2 presence.  The different inflammatory responses to HA hydrogels were observed (Appendix).

Thiol derivatives can cleave the disulfide bond of BMP-2 to generate inactive monomeric BMP-2. In paper II, thiol-acrylate chemistry-based HA hydrogels (HA-SH) were compared to hydrazone-based HA hydrogels as BMP-2 carriers. Thiol modified HA disrupted BMP-2 integrity and bioactivity. HA-SH hydrogels with BMP-2 exhibited less bioactive BMP-2 release in vitro and induced less bone formation in vivo.

Accumulated evidence has shown great osteogenic potential of lithium ions (Li). In paper III, we coordinated Li onto HA-PVA hydrazone hydrogels (Li-gel); Li-gel enhanced 3D cultured hMSCs osteogenic differentiation and induced higher bone formation in CAM defect model.

Instead of BMP-2 protein, delivery of BMP-2-coding-plasmid can produce BMP-2 over a long term at a closer physiological level. Yet, efficient gene delivery reagents are needed. In paper IV, two novel gene delivery nanoplexes were developed by post coating DNA-nanoplexes with chondroitin sulfate (CS). To ensure the stability, aldehyde-modified CS (CS-CHO) reacted with free amines of pDNA/PEI complexes. We provided first evidence that CS-CHO coated nanoplexes controlled the release from endosomes, which is essential for higher transfection efficiency.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1459
Keyword
Chondroitin sulfate, hyaluronic acid, pH, cross-linking chemistry, bone morphogenetic protein, lithium, mesenchymal stem cell, in vivo.
National Category
Medical Materials
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-308318 (URN)978-91-554-9767-5 (ISBN)
Public defence
2017-01-17, Room 80121, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2016-12-20 Created: 2016-11-24 Last updated: 2016-12-20

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