ABSTRACT
Spontaneous preterm birth (PTB) accounts for ~60% of all preterm births (15 million PTBs/year and 1 million
neonatal deaths around the globe). Balanced immune homeostasis by fetal and maternal compartments ensure
pregnancy maintenance and feto-placental growth. Premature disruption of immune homeostasis and
overwhelming host inflammatory response due to infectious or other non-infectious risk factors lead to majority
of PTBs. PTB rate has not declined in the past several decades, and current PTB prevention strategies do not
address fetal immune responses, a key mediator that triggers preterm labor. The proposing team has recently
used an innovative technology to engineer exosomes to be enriched with an inhibitor to NF-κB, termed as super
repressor IκBα [SR]. Pilot studies using a transgenic mouse model showed successful delay in PTB without any
side effects that was associated with reduction in inflammation at the feto-maternal interface tissues (F-M; fetal
membrane cells and maternal decidua). However, moving this to the next stage is challenging, as a very large
number of non-human primates, the animal model that most closely resemble the human F-M interface, will be
needed, which is cost prohibitive. An organ-on-chip (OOC) model that faithfully represents the structure,
functions, and responses of human F-M interface can overcome such challenges. The proposing team has
recently reported the first F-M interface OOC model, which was successfully utilized to show the interactive and
transitional properties of primary cells, resembling their biological functions in utero. In the UG3 phase, this model
will be expanded to include the full F-M interface, recreate a healthy and disease inflammatory state, and fully
validated for their cellular functions and responses predisposing to PTB. The UG3 aims are: Aim 1 To validate
the F-M interface OOC model; Aim 2 To establish disease F-M interface OOC models. The UH3 aims are:
Aim 3 To test extracellular vesicle (EV)-encoded experimental drug NF-kB repressor (SR) on normal and
disease F-M interface OOC models; Aim 4 Conduct pre-clinical trial using the OOC model to investigate
the impact of racial diversity and gender of fetus on the efficacy of the experimental drug. The success
of the proposed research will produce a personalized F-M interface OOC model that can mimic either healthy or
disease state of pregnancy, which can be used to test the effect of candidate therapeutic molecules to expedite
processes towards clinical trials and or eliminate/minimize certain steps from expensive clinical trials.
