In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair

David Gothard; Michael Rotherham; Emma L. Smith; Janos M. Kanczler; James Henstock; Julia A. Wells; Carol A. Roberts; Omar Qutachi; Heather Peto; Hassan Rashidi; Luis Rojo; Lisa J. White; Molly M. Stevens; Alicia J. El Haj; Felicity R.A.J. Rose; Richard O.C. Oreffo

Mechanobiology in Medicine (Dec 2024)

In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair

David Gothard,
Michael Rotherham,
Emma L. Smith,
Janos M. Kanczler,
James Henstock,
Julia A. Wells,
Carol A. Roberts,
Omar Qutachi,
Heather Peto,
Hassan Rashidi,
Luis Rojo,
Lisa J. White,
Molly M. Stevens,
Alicia J. El Haj,
Felicity R.A.J. Rose,
Richard O.C. Oreffo

Affiliations

David Gothard: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
Michael Rotherham: Institute for Science and Technology in Medicine, Keele University, Guy Hilton Research Centre, Stoke-on-Trent, ST4 7BQ, UK; Healthcare Technologies Institute, School of Chemical Engineering, Institute of Translational Medicine, University of Birmingham, Birmingham, B15 2TH, UK; Corresponding author. Healthcare Technologies Institute, School of Chemical Engineering, Institute of Translational Medicine, University of Birmingham, Birmingham, B15 2TH, UK.
Emma L. Smith: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
Janos M. Kanczler: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
James Henstock: Institute for Science and Technology in Medicine, Keele University, Guy Hilton Research Centre, Stoke-on-Trent, ST4 7BQ, UK; Department of Applied Sciences, Pandon Building, Northumbria University, Newcastle-upon-Tyne, NE2 1XE, UK
Julia A. Wells: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
Carol A. Roberts: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
Omar Qutachi: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, University of Nottingham, Centre for Biomolecular Sciences, University Park, Nottingham, NG7 2RD, UK; Leicester Institute for Pharmaceutical Innovation (LIPI), Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, United Kingdom
Heather Peto: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, University of Nottingham, Centre for Biomolecular Sciences, University Park, Nottingham, NG7 2RD, UK
Hassan Rashidi: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling, University of Nottingham, Centre for Biomolecular Sciences, University Park, Nottingham, NG7 2RD, UK; Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH, UK
Luis Rojo: Department of Materials, Imperial College London, Royal School of Mines, London, SW7 2AZ, UK; Department of Bioengineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK; Instituto de Ciencia y Tecnología de Polímeros (ICTP), CSIC, Calle Juan de la Cierva, 3, 28006 Madrid, Spain; Consorcio Centro de Investigación Biomédica en Red, CIBER-BBN, Instituto de Salud Carlos III, Calle Monforte de Lemos 3–5, 1128029 Pabellón, Madrid, Spain
Lisa J. White: Nottingham Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK
Molly M. Stevens: Department of Materials, Imperial College London, Royal School of Mines, London, SW7 2AZ, UK; Department of Bioengineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK; Institute for Biomedical Engineering Imperial College London, South Kensington Campus, London, SW7 2AZ, UK; Department of Physiology, Anatomy, & Genetics, Department of Engineering Science, and Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK
Alicia J. El Haj: Institute for Science and Technology in Medicine, Keele University, Guy Hilton Research Centre, Stoke-on-Trent, ST4 7BQ, UK; Healthcare Technologies Institute, School of Chemical Engineering, Institute of Translational Medicine, University of Birmingham, Birmingham, B15 2TH, UK
Felicity R.A.J. Rose: Nottingham Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK
Richard O.C. Oreffo: Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK; Corresponding author.

Journal volume & issue: Vol. 2, no. 4
p. 100096

Abstract

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Bone tissue engineering requires a combination of materials, cells, growth factors and mechanical cues to recapitulate bone formation. In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction. Hybrid hydrogels consisting of alginate and decellularized, demineralised bone extracellular matrix (ALG/ECM) were seeded with Stro-1+ human bone marrow stromal cells (HBMSCs). Dual combinations of growth factors within staged-release polylactic-co-glycolic acid (PLGA) microparticles were added to hydrogels to mimic, in part, the signalling events in bone regeneration: VEGF, TGF-β3, PTHrP (fast release), or BMP-2, vitamin D3 (slow release). Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles (MNP) targeted to TREK1 ion channels. Hybrid hydrogels were implanted subcutaneously within mice for 28 days, and evaluated for bone formation using micro-CT and histology. Control hydrogels lacking HBMSCs, growth factors, or MNP became mineralised, and neither growth factors, HBMSCs, nor mechanotransduction increased bone formation. However, structural differences in the newly-formed bone were influenced by growth factors. Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD3 increased bone formation. However, fast-release of TGF-β3 and VEGF resulted in thin trabeculae. Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD3. Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure. This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.

Published in Mechanobiology in Medicine

ISSN: 2949-9070 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General): Medical technology
Website: https://www.sciencedirect.com/journal/mechanobiology-in-medicine

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