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.