Stem cell mechanobiology and tissue engineering

Research in this subgroup focuses on developing and optimizing strategies related to the culture and conditioning of pluripotent and mesenchymal stem cells for applications in regenerative medicine, including disease modelling, therapeutic drug testing, and engineering tissue for the replacement of damaged tissues of the cardiovascular system. Projects involve the utilization of novel biomaterials and measurement techniques, the development of bioreactors, and screening conditions for optimal stem cell culture.

Three most recent publications

  • Callaghan Neal, Hadipour-Lakmehsari Sina, Lee Shin-Haw, Gramolini Anthony O., Simmons Craig A., Modeling cardiac complexity: Advancements in myocardial models and analytical techniques for physiological investigation and therapeutic development in vitro. APL Bioengineering. 2019 | AIP

  • Zhang Xiaoqing, Battiston Kyle, Simmons Craig A, Santerre J Paul. Differential regulation of extracellular matrix components by using different vitamin C derivatives in mono-and co-culture systems. ACS Biomaterials Science & Engineering. 2017 | ACS

  • Zhang Xiaoqing, Battiston Kyle G, Labow Rosalind S, Simmons Craig A,Santerre J Paul. Generating favorable growth factor and protease release profiles to enable extracellular matrix accumulation within an in vitro tissue engineering environment. Acta Biomaterialia. 2017;54:81-84 | PubMed

Microfabrication and microfluidics to control cell environment

Microenvironmental cues in the form of various biochemical and mechanical stimuli have significant impact on the phenotype and function of cells, however, current cell culture systems are a poor mimic of the complex  environments within which cells reside in vivo. Our work in microfluidics aims to address this problem. By integrating microfabrication with cell mechanics and advanced biology, we are developing platforms which enable us to better simulate in vivo environments involving mechanobiological stimuli.

Our current work focuses on microfluidic platforms for vascular cell culture, and includes models of brain microvasculature, vascularized liver constructs, co-culture setups for enhanced microvascular assembly, and integration of on-chip vascular biomolecule quantitation. Our microfabricated arrays of miniaturized mechanobioreactors permit perturbation of small populations of cells in a combinatorial, highly parallel fashion which minimizes reagent requirements and, when coupled with advanced biological tools, permits rapid, high content, real-time monitoring of biological effects.

Three most recent publications

  • Wong Jeremy, Simmons Craig A. Microfluidic assay for the on-chip electrochemical measurement of cell monolayer permeability. Lab on a chip. 2019 | RSC 

  • Fitzsimmons Ross EB, Aquilino Mark S., Quigley Jasmine, Chebotarev Oleg, Tarlan Farhang, Simmons Craig A. Generating vascular channels within hydrogel constructs using an economical open-source 3D bioprinter and thermoreversible gels. Bioprinting: 2018; 9:7-18 | ScienceDirect

  • Wong F. Jeremy, Young Edmond W.K, Simmons, Craig A. Computational analysis of integrated biosensing and shear flow in a microfluidic vascular model. AIP Advances. 2017; 7: 115116 | AIP

 Heart valve mechanobiology and disease

Cardiovascular diseases are the underlying cause of one third of all deaths in Canada. Sclerosis (thickening and calcification) of the aortic valve is one of the most common cardiovascular diseases and is associated with significant morbidity. While traditionally believed to be a degenerative ‘wear and tear’ disease, recent evidence suggests the etiology of valvular calcification is far more complex, involving active cell-mediated processes, such as inflammation, lipid modification, and actual bone tissue formation within the valve matrix. However, until the cellular and molecular regulators of these processes are identified, the only treatment available for valve sclerosis is surgical replacement.

Notably, the regions of the valve most susceptible to calcification are exposed to distinct hemodynamic and biomechanical stimuli, suggesting a previously unrecognized mechanobiological basis for the disease. Using state-of-the-art microgenomics approaches, we are profiling spatial variations in gene expression by endothelial and interstitial cells from disease-prone versus disease-protected regions of the valve. This approach has generated novel insights and several hypotheses regarding the molecular regulators of valvular calcification. We are investigating many of these hypotheses using in vitro co-culture systems that allow us to mechanically stimulate valves cells and probe their phenotypic expression. In support of the cell culture studies, we are developing multiscale finite element approaches to relate tissue-level deformations to cellular-level deformations, thereby allowing better characterization of the mechanical stimuli experienced by valve interstitial cells.

By integrating functional genomics studies in vivo, mechanistic experiments in vitro, and computational biomechanics, we aim to determine cause-effect relationships between mechanobiological stimuli, the molecular regulators of valvular calcification, and the progression of the disease. In doing so, we hope to better understand the cellular and molecular basis for valvular calcification, with the goal of identifying therapeutic targets for its prevention and treatment.

Three most recent publications

  • Liu Haijiao, MacQueen Luke A., Usprech Jenna F., Maleki Hoda, Sider Krista L., Doyle  Matthew G., Sun Yu, Simmons Craig A.  Microdevice arrays with strain sensors for 3D mechanical stimulation and monitoring of engineered tissues. Biomaterials. 2018;172:30-40 |ScienceDirect

  • Zhong, Aileen, Mirzaei, Zahra, Simmons, Craig A. The Roles of Matrix Stiffness and ß-Catenin Signaling in Endothelial-to- Mesenchymal Transition of Aortic Valve Endothelial Cells. Cardiovascular Engineering and Technology. 2018;9:158-167|Springer

  • Blaser MC, Wei K, Adams RLE, Zhou YQ, Caruso LL, Mirzaei Z, Lam AY, Tam RKK, Zhang H, Heximer SP, Henkelman RM, Simmons CA. Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice. Circulation Research. 2018; 2(122): 405-416 | PubMed