Cell-based therapies, where naturally or artificially engineered cells secreting therapeutic
proteins are grafted onto the body to act as biological drug factories, are an attractive
approach for long-term treatment of chronic diseases such as hemophilia, diabetes and liver
disorders. However, ‘off the shelf’ therapeutic cells are immunogenic to the host and must be
protected from the host immune system. Cell-encapsulation has emerged as an attractive
strategy to transplant these cells without chronic immunosuppression. Here, cells are placed
in an immune-isolating device which physically separates the cells from the components of the
immune system while providing access to oxygen and nutrients. Retrievable macroscale cell-
encapsulation devices (macrodevice), are attractive in this context as they provide a safer
path to clinical translation. Unfortunately, a standalone macrodevice that remains functional in
humans over long-periods (>6 months) is yet to be realized due to two core challenges: 1) a
foreign-body reaction to the implanted device causing inflammation and fibrosis, and 2)
inadequate supply of oxygen and nutrients to the encapsulated cells. Here, we propose to
build on several promising recent advances in biomaterials design, microfabrication,
bioelectronics and cell engineering from our team to develop an advanced “smart”
macrodevice platform with integrated electronic components which overcomes the major
limitations of current device designs. First, we will develop an engineered cell line which is
amenable to long term encapsulation and suitable for clinical translation. Landing pads within
these cells will ensure stable transgene expression, allowing for broad control of therapeutic
protein secretion (Aim 1). Separately, we will develop a bioelectronic macrodevice as a
platform for long- term transplant of these cells in vivo. Our device will incorporate novel
membranes with uniform/controlled pore-sizes and enhanced oxygen transport properties. In
parallel, we will develop new surface coating techniques to minimize fibrosis and ensure long-
term graft survival. We will integrate proton exchange membranes and optoelectronic
components to allow a) in-situ oxygen generation, and b) optical gene activation to allow for
triggerable control of protein production by the encapsulated cells (Aim 2). Finally, we will test
the device in B6 mice using a model protein (SEAP) to test for long term survival of cells and
external control of protein delivery. We will develop the device as a platform to delivery of
Factor VIII for the treatment of Hemophilia A (Aim 3) as a model disease. If successful, the
platform will represent a qualitative technological advancement in the field of cell therapy.
