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Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair

Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair
Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair
Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting.

Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (~2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting.

The ability to create mechanically strong 'cancellous bone-like’ printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.
0168-3659
335-346
Awwad, Hosam
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Thiagarajan, Lalitha
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Kanczler, Janos
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Amer, Mahetab
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Bruce, Gordon
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Lanham, Stuart
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Rumney, Robin
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Oreffo, Richard
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Dixon, James
0ec5d360-2282-485c-962d-4c272a6b9a93
Awwad, Hosam
edd3083a-a643-475a-bd6d-c1be2eefa923
Thiagarajan, Lalitha
f6b38884-dfc6-447d-9746-5223ccd9f03d
Kanczler, Janos
eb8db9ff-a038-475f-9030-48eef2b0559c
Amer, Mahetab
4a0097c8-f1f3-4cc2-9ff2-4c2bbd1613b8
Bruce, Gordon
8010dc31-7239-4104-979c-5cb72553fa9e
Lanham, Stuart
28fdbbef-e3b6-4fdf-bd0f-4968eeb614d6
Rumney, Robin
fa3de9f8-b604-44e2-9e72-3e57980ce67f
Oreffo, Richard
ff9fff72-6855-4d0f-bfb2-311d0e8f3778
Dixon, James
0ec5d360-2282-485c-962d-4c272a6b9a93

Awwad, Hosam, Thiagarajan, Lalitha, Kanczler, Janos, Amer, Mahetab, Bruce, Gordon, Lanham, Stuart, Rumney, Robin, Oreffo, Richard and Dixon, James (2020) Genetically-programmed, mesenchymal stromal cell-laden & mechanically strong 3D bioprinted scaffolds for bone repair. Journal of Controlled Release, 325, 335-346. (doi:10.1016/j.jconrel.2020.06.035).

Record type: Article

Abstract

Additive manufacturing processes used to create regenerative bone tissue engineered implants are not biocompatible, thereby restricting direct use with stem cells and usually require cell seeding post-fabrication. Combined delivery of stem cells with the controlled release of osteogenic factors, within a mechanically-strong biomaterial combined during manufacturing would replace injectable defect fillers (cements) and allow personalized implants to be rapidly prototyped by 3D bioprinting.

Through the use of direct genetic programming via the sustained release of an exogenously delivered transcription factor RUNX2 (delivered as recombinant GET-RUNX2 protein) encapsulated in PLGA microparticles (MPs), we demonstrate that human mesenchymal stromal (stem) cells (hMSCs) can be directly fabricated into a thermo-sintered 3D bioprintable material and achieve effective osteogenic differentiation. Importantly we observed osteogenic programming of gene expression by released GET-RUNX2 (8.2-, 3.3- and 3.9-fold increases in OSX, RUNX2 and OPN expression, respectively) and calcification (von Kossa staining) in our scaffolds. The developed biodegradable PLGA/PEG paste formulation augments high-density bone development in a defect model (~2.4-fold increase in high density bone volume) and can be used to rapidly prototype clinically-sized hMSC-laden implants within minutes using mild, cytocompatible extrusion bioprinting.

The ability to create mechanically strong 'cancellous bone-like’ printable implants for tissue repair that contain stem cells and controlled-release of programming factors is innovative, and will facilitate the development of novel localized delivery approaches to direct cellular behaviour for many regenerative medicine applications including those for personalized bone repair.

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Awwad et al Accepted version - Accepted Manuscript
Restricted to Repository staff only until 3 July 2021.
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More information

Accepted/In Press date: 28 June 2020
e-pub ahead of print date: 3 July 2020
Published date: 10 September 2020

Identifiers

Local EPrints ID: 443113
URI: http://eprints.soton.ac.uk/id/eprint/443113
ISSN: 0168-3659
PURE UUID: 39f2ac00-48f8-49a2-9d9e-1f5bfeede31a
ORCID for Janos Kanczler: ORCID iD orcid.org/0000-0001-7249-0414
ORCID for Stuart Lanham: ORCID iD orcid.org/0000-0002-4516-264X
ORCID for Richard Oreffo: ORCID iD orcid.org/0000-0001-5995-6726

Catalogue record

Date deposited: 11 Aug 2020 16:31
Last modified: 07 Oct 2020 01:51

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