The long-term objective of this research is to develop materials to enable the regeneration of bony tissues for reconstructive dental and craniofacial applications. The overall hypothesis guiding our work is that the fate of stem cells within an engineered tissue can be regulated by the presentation of appropriate signals in the microenvironment of the cells. The specific hypothesis to be tested in this application is that the viscoelasticity, particularly the rate of stress relaxation and creep, of biomaterials to which cels adhere controls their response to the material stiffness, and will control stem cell differentiatio. This will be studied with the following aims: (1) alginate hydrogels will be fabricated that displa a range of stress relaxation and creep times ranging from seconds-hours, and used to characterize the relation between initial moduli, stress relaxation/creep rate and MSC fate, (2) the impact of stress relaxation on established mechanotransduction pathway will be analyzed, and (3) the role of stress relaxation in the rate and extent of bone formation will be tested in vio from MSCs transplanted in hydrogels of varying initial mechanical properties and rates of stress relaxation. Successful completion of these aims will have significant impact in our understanding of how adhesion substrate mechanical properties regulate stem cell fate, and may lead to improved therapies for regenerating bone defects in the future. The impact of the viscoelastic properties of materials on stem cell fate has been largely ignored to date, and these studies are anticipated to motivate the development of new biomaterials that exploit this relation to drive bone regeneration. The principles and materials that arise from these studies will likely be broadly applicable in a number of biological settings, and many applications of biomaterials in the future.
Craniofacial bone tissue is often required in reconstructive surgery following trauma, resection due to cancer, or correction of genetic defects. This project addresses how the mechanical properties of biomaterials impacts stem cells capable of promoting bone formation. Success in these studies could lead in the future to new clinical strategies to promote craniofacial bone in patients.
|Alonso-Nocelo, Marta; Raimondo, Theresa M; Vining, Kyle H et al. (2018) Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells. Biofabrication 10:035004|
|Li, Jianyu; Weber, Eckhard; Guth-Gundel, Sabine et al. (2018) Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs. Adv Healthc Mater 7:e1701393|
|Vidovic-Zdrilic, I; Vining, K H; Vijaykumar, A et al. (2018) FGF2 Enhances Odontoblast Differentiation by ?SMA+ Progenitors In Vivo. J Dent Res 97:1170-1177|
|Darnell, Max; Gu, Luo; Mooney, David (2018) RNA-seq reveals diverse effects of substrate stiffness on mesenchymal stem cells. Biomaterials 181:182-188|
|Darnell, Max; O'Neil, Alison; Mao, Angelo et al. (2018) Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells. Proc Natl Acad Sci U S A 115:E8368-E8377|
|Li, J; Celiz, A D; Yang, J et al. (2017) Tough adhesives for diverse wet surfaces. Science 357:378-381|
|Vining, Kyle H; Mooney, David J (2017) Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol 18:728-742|
|Lee, Hong-Pyo; Gu, Luo; Mooney, David J et al. (2017) Mechanical confinement regulates cartilage matrix formation by chondrocytes. Nat Mater 16:1243-1251|
|Darnell, Max; Young, Simon; Gu, Luo et al. (2017) Substrate Stress-Relaxation Regulates Scaffold Remodeling and Bone Formation In Vivo. Adv Healthc Mater 6:|
|Chaudhuri, Ovijit; Gu, Luo; Klumpers, Darinka et al. (2016) Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater 15:326-34|
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