Project Summary
Skin, being the first line of defense against foreign insults and pathogens, is the first organ to be affected by
radiation incidents. The threat of accidental exposures, wartime hazards, or terrorism-related incidents has been
intensified due to the increased use of radioactive materials in industry, medical facilities, and military
installations. Skin response to ionizing radiations has important implications for local and systemic treatment and
protection. Currently, there are very limited countermeasures for radiation-induced skin damage, and those that
are available have shown limited efficacy. A key factor hindering development of effective countermeasures is
the absence of a convenient and robust model possessing specific translatability to humans. It is therefore our
long-term objective to develop a portable tissue culture bioreactor capable of maintaining viability of full-thickness
human skin flaps via arterial perfusion. With this bioreactor, we will establish an in vitro human skin model for
studying the underlying mechanism of radiation-induced skin damage and will subsequently test the efficacies
of medical countermeasures. Our central hypothesis is that human skin supported by the perfusion bioreactor
will enable clinically relevant, long-term (~4 weeks) characterization of RI and the assessment of potential
therapies. RI is expected to induce DNA damage, inflammation, and apoptosis and treatment via topical
application of JP4-039 is expected to mitigate these effects in human skin perfusion model. In support of our
hypothesis, our preliminary work resulted in the successful fabrication of reproducible perfusion bioreactor. This
bioreactor is capable of controlling continuous fluid flow throughout vascularized skin tissue, accessed via arterial
cannulation. The system is equipped with real-time monitoring of venous and arterial pressures and can
dynamically adjust the fluid flow based on anatomically-relevant inputs. Additionally, real-time feedback systems
for maintenance of normothermic temperature have been installed, along with components responsible for
measuring gaseous CO2, gaseous O2, and perfusate pH. Using this perfusion bioreactor, we have shown
successful perfusion of human skin flap. We plan to test our central hypothesis by pursuing the following two
specific aims. Aim 1- Characterize radiation induced injury in an ex vivo full-thickness human skin perfusion
culture. Aim 2- Test the ability of antioxidant JP4-039 to mitigate radiation-induced skin damage. This novel
approach to use discarded human skin tissue for mechanistic studies and develop medical countermeasures
against radiation induced injuries holds a lot of promise. Our team has extensive experience in machine
development, plastic and reconstructive surgeries, the study of radiation induced damage, and the development
of medical countermeasures. We anticipate that the successful completion of this project will significantly
advance our understanding of the mechanisms involved in radiation-induced skin damage as well as validate
the use of our perfusion culture model as a platform of testing medical countermeasures.
