Biomaterials with tunable biophysical properties hold great potential for tissue engineering. The adaptive immune system plays an important role in bone regeneration. Our goal is to investigate the regeneration potential of cell-laden alginate hydrogels depending on the immune status of the animal model. Specifically, the regeneration potential of rat mesenchymal stromal cell (MSC)-laden, void-forming alginate hydrogels, with a stiffness optimized for osteogenic differentiation, is studied in 5-mm critical-sized femoral defects, in both T cell-deficient athymic Rowett Nude (RNU) rats and immunocompetent Sprague Dawley rats. Bone volume fraction, bone mineral density, and tissue mineral density are higher for athymic RNU nude rats 6 weeks postsurgery. In addition, these animals show a significantly higher number of total cells and cells with non-lymphocyte morphology at the defect site, while the number of cells with lymphocyte-like morphology is lower. Hydrogel degradation is slower and the remaining alginate fragments are surrounded by a thicker fibrous capsule. Ossification islands originating from alginate residues suggest that encapsulated MSCs differentiate into the osteogenic lineage and initiate the mineralization process. However, this effect is insufficient to fully bridge the bone defect in both animal models. Alginate hydrogels can be used to deliver MSCs and thereby recruit endogenous cells through paracrine signaling, but additional osteogenic stimuli are needed to regenerate critical-sized segmental femoral defects. Impact statement T cell-deficient athymic RNU nude rats are commonly used to evaluate the regeneration potential of biomaterials in combination with cells of human origin. In this study, we show that the effect of mesenchymal stromal cell (MSC)-laden alginate hydrogels on bone regeneration differs depending of the immune status of the animal model. Furthermore, while alginate hydrogels are interesting materials to investigate the effect tunable biophysical properties on cell response and in vivo regeneration, their use in combination with rat MSCs is insufficient to fully bridge critical-sized segmental femoral defects. For this purpose, additional osteogenic stimuli such as growth factor delivery are necessary.
Keywords: alginate; animal model; bone regeneration; critical-sized bone defect; hydrogel; immune system.
In-situ tissue regeneration through SDF-1α driven cell recruitment and stiffness-mediated bone regeneration in a critical-sized segmental femoral defect.Acta Biomater. 2017 Sep 15;60:50-63. doi: 10.1016/j.actbio.2017.07.032. Epub 2017 Jul 21. Acta Biomater. 2017. PMID: 28739546
Regulation of the fate of dental-derived mesenchymal stem cells using engineered alginate-GelMA hydrogels.J Biomed Mater Res A. 2017 Nov;105(11):2957-2967. doi: 10.1002/jbm.a.36148. Epub 2017 Jul 14. J Biomed Mater Res A. 2017. PMID: 28639378 Free PMC article.
Oxidized alginate hydrogels for bone morphogenetic protein-2 delivery in long bone defects.Acta Biomater. 2014 Oct;10(10):4390-9. doi: 10.1016/j.actbio.2014.06.015. Epub 2014 Jun 17. Acta Biomater. 2014. PMID: 24954001 Free PMC article.
Hydrogel elasticity and microarchitecture regulate dental-derived mesenchymal stem cell-host immune system cross-talk.Acta Biomater. 2017 Sep 15;60:181-189. doi: 10.1016/j.actbio.2017.07.017. Epub 2017 Jul 12. Acta Biomater. 2017. PMID: 28711686 Free PMC article.
Alginate Formulations: Current Developments in the Race for Hydrogel-Based Cardiac Regeneration.Front Bioeng Biotechnol. 2020 May 8;8:414. doi: 10.3389/fbioe.2020.00414. eCollection 2020. Front Bioeng Biotechnol. 2020. PMID: 32457887 Free PMC article. Review.