Mechanosensitive synthetic cell-regulatable hydrogels for tissue engineering

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Abstract There is great need for engineered functional tissues to address currently unmet medical need for replacement or restoration of damaged tissues and organs due to disease, injury and congenital defects. Biomaterial scaffolds can play a key role in engineering tissues because they not only provide mechanical support and deliver bioactive molecules and/or cells, but they also degrade to provide new space to support cell growth and extracellular matrix production. It is desirable for the scaffold to degrade in concert with the rate of new tissue formation. Scaffold degradation also dynamically affects its mechanical properties, which has been shown to regulate host and transplanted cell behaviors, such as spreading, proliferation, migration and differentiation. Although attempts have been made to predict and tailor the degradation rate of employed biodegradable scaffolds prior to implantation for specific tissue regeneration applications, it is currently difficult to control their degradation after implantation. To regulate scaffold degradation in a triggered fashion, exogenous or external stimuli, such as enzymes, pH, and light, have been employed. Few have considered forces as a trigger input. Biochemical molecules, such as enzymes secreted from hosted/transplanted cells, have already been reported in efforts to control the degradation rate of biomaterial scaffolds. However, there are still challenges regarding regulating the production amount of those molecules at a rate and level needed to match scaffold degradation profile with engineered tissue formation while providing a minimal loss in mechanical support. Therefore, dynamic regulation of the degradation of a tissue engineering scaffold via its response to its mechanical environment may allow for design of smart biomaterials that resorb as the newly formed tissue is able to support the required loads. A synthetic biology approach to create mechanosensitive synthetic cells (MSSCs) harboring mechanosensitive channels for mimicking the ability of cells to secrete biochemicals for dynamically degrading biomaterial scaffolds in response to environment mechanical signals is proposed. Synthetic cells are cell-sized lipid bilayer vesicles encapsulating cell-free expression system expressing proteins of interest. MSSCs loaded with different sized cargos will be created and their capability to release the payloads under compressive stress will be examined (Aim 1). The MSSCs will then be encapsulated in a hydrogel system for examining the capacity of external compressive stress-mediated payload release from MSSCs to regulate hydrogel degradation (Aim 2). Lastly, the capacity of external compressive stress-controlled hydrogel degradation in driving the function of hydrogel co-encapsulated cells will be examined (Aim 3). This work will create a new class of hydrogels with a distinct mechanism of mechanoresponsiveness that dynamically react to their physical environment and are anticipated to be valuable for engineering a wide range of tissues.