NSF-SNSF: Morphogenesis by design: an integrated mechanobiology framework for the sculpting of architected biological tissues

Tissue morphogenesis, or the development of tissue shape, is driven by a combination of cellular forces, mechanical constraints, and changes in extracellular matrix (ECM) composition and architecture. This combination of parameters is difficult to study. It is still unknown how mechanical forces, including external forces applied to the tissue and forces within the tissue due to those external forces, influences the evolution of tissue shape.

The main hypothesis of the project is that cells can be directed to create a desired tissue shape, structure, and size by applying controlled dynamic mechanical signals. These mechanical signals can be applied and removed on-demand, and they can quickly spread long distances. The application of a force in the tissue can be controlled precisely using robotic micromanipulation tools.

The goal of this project is to use computational design tools to instruct robotic manipulation in a way that will uncover the mechanical laws and physical forces that drive connective tissue morphogenesis. The results will enable the use of mechanobiology to engineer tissues. Novel materials will be developed for undergraduate and graduate courses, and the next generation of engineers and scientists will be trained in microfabrication, cell biology, continuum mechanics, magnetics, materials science, and robotics.

This project aims to uncover fundamental mechanistic principles of connective tissue morphogenesis and introduce computational design tools that would instruct the use of robotic micromanipulation tools with the goal of harnessing mechanobiology to engineer architected tissues. Computational models based on continuum mechanics will be developed to predict force generation during the deformation and shaping of engineered microtissues.

These models will recapitulate the concurrent alignment, rearrangement and deposition of the ECM. Imaging and mechanical characterization techniques will spatiotemporally map tissue rheology and architecture, generating a dataset that will be used to validate the computational models. Combined experimental and computational work will aid in the discovery of the physical principles of mechanosensitive cell migration in morphing and structurally remodeling fibrous tissues.

The integrated model will predict the evolution of cell movement and ECM architecture along with the tissue morphology under dynamic mechanical loading. The integrative model that recapitulates both ECM remodeling and cell migration will guide tissue folding. Under robotic micromanipulation informed by the model, bilayer tissues will fold into 3D tissues with pre-defined shapes and internal architectures.

The work has scientific, societal, and educational impact. This work has the potential to uncover multi-cellular organization principles that drive developmental patterning, wound healing, and pathological responses such as fibrosis that involve cell migration and ECM remodeling in fibrous tissues. The framework will guide the engineering of a variety of complex biological tissues towards regenerative medicine, creation of living machines, and development of tissue culture systems for pharmaceutical screening.

This collaborative US-Swiss project is supported by the US National Science Foundation (NSF) and the Swiss National Science Foundation (SNSF), where NSF funds the US investigator and SNSF funds the partners in Switzerland.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.