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.
Highlights
IntroductionDefect-matched implants for regenerative medicine has significantly developed over the last decade [1]
Additive manufacturing of custom, defect-matched implants for regenerative medicine has significantly developed over the last decade [1]
We previously showed that Glycosaminoglycan-binding Enhanced Transduction (GET)-RUNX2 can be used to direct human Mesenchymal Stromal Cells towards osteogenesis, removing the need to use pleiotropic compounds, or growth factors (GFs) which may trigger unwanted offtarget cellular responses
Summary
Defect-matched implants for regenerative medicine has significantly developed over the last decade [1]. For bone tissue engineering these approaches employ ceramic and polymeric materials to enable bone-like mechanically strong scaffolds to be generated, the manufacturing process may not be biocompatible (using high-temperatures, UV-light or organic solvents) [2]. As such only acellular implants are created and the incorporation of stem cells or therapeutic molecules can only occur post-fabrication. This prevents uniform seeding, patterning of cells or molecules to produce functionally complex tissues and long-term delivery is inhibited; bio-inductive strategies are often not effective or have less controlled activity [1]. Development of production processes which can be used intraoperatively; with cells and biomolecules directly included in the process is vital for their clinical use.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
