Microvascular Hydrodynamics

In general, the biological evolution of Earth can be divided into two major evolutionary periods. Until the oxidation of the atmosphere, the major metabolic pathways of life that facilitate all electron transfers evolved, which would become biogeochemical cycles. The second half of Earth's history is of biological adaptation, where organisms appropriated metabolic pathways that evolved early on, but rearranged them in new biological plans, which allowed them to be carried forward. My work endeavors to understand the mechanism exerted by gaseous regulators and develop therapies and strategies to treat and prevent diseases. My recent studies have highlighted gaseous ligands in novel, multi-component and targeted approaches, and their potential importance beyond drug delivery.

My research applies a multiscale approach, where the initial stage is set by molecular biochemical interactions that produce cellular effects, which together generate tissue changes. Their balance defines systemic regulation and new homeostatic set points. Fundamentally, I perceive my research as being gas-driven living cellular behavior reprogramming, in order to discover and analyze the underlying fundamental regulatory processes. The potential for translation to the clinic, from my research, is very significant, since most of the experimental studies are performed in whole mammalian organisms, including all the metabolic and regulatory mechanisms existing in physiological and pathophysiological conditions. By applying engineering tools and methods to analyze gas regulated biological processes, comprehensive and mechanistic analysis is accomplished.

The relevance and efficacy of the exogenous gas therapy is increased by the developments in nanoengineering gas delivery platforms, which include biocompatibility, efficacy, stability and cost. I intend to produce and physically characterize gas delivering platforms designed to enhance the release of bioactive forms of gaseous ligands to test and improve their in vivo functional efficacy. Several of these gas delivering platforms, specifically for O2 and NO, have been already developed and characterized in our laboratory, in order to elucidate the systemic, microcirculatory and cellular changes by exogenous supplementation of O2, NO, CO and H2S effects during physiological and pathological citation in vivo. Currently, we have implemented tools for the analysis of systemic parameters, vital organ function, and cardiac function, concurrently with microcirculatory information: (a) vascular tone, (b) perfusion, (c) tissue pH, (d) tissue oxygen, and (e) mitochondrial oxidative stress. The requested equipment in this application will provide the tools to study dynamic molecular mechanism in vivo and link them to the functional measurements already implemented. To identify the application of exogenous gaseous ligands therapies to prevent (a) oxidative metabolism, (b) vascular inflammation, (c) endothelial functional and viability changes, and (d) the results of these effects.

Experimental model: The major advantage of my experimental model, The hamster window chamber, is that it allows us to study systemic, microhemodynamic, and cellular parameters simultaneously for prolonged periods (> 7 days). Left: Implanted titanium frames on the dorsal skinfold for microvascular studies (12 mm window). Right: Intact tissue is studied in the absence of surgical trauma or anesthesia.

Our main focus is and will be integrated O2, NO, CO and H2S delivery and regulatory physiology. Our view is that these gases are critical factors in the evolution of life, and their influence persists in today's biological processes. These gases are unique because they can be easily administered and are easily disposed by diffusion. They constitute a niche of biological activity that can be readily deployed; however, with few exceptions, it has not been explored. Gases are endowed with important biological properties that are ideally suited for exploration and development in a bioengineering environment. They provide the ability to perform studies in precisely controlled experiments, a condition well suited for mathematics-based analysis.

We have made significant strides in establishing a research program in the area of gas regulation physiology under physiological conditions and disease. Our approach is to proceed in an integrative multiscale manner, building understanding from the entire organism to organs and tissues, and connect to molecular mechanism within the cellular environment, at all levels preserving the in vivo conditions. Although we have set in place functional markers for systemic, cardiac, vital organs and microvascular, this application will allow us to implement detailed cellular biology imaging to complete an entire multi-scale approach.

The significance of this research extends to virtually all areas of biology and medicine that relate to cellular and tissue respiration. The need to convert promising biologically-active molecules into effective therapeutic agents as rapidly as possible is driven by the importance of immediate treatment of life-threatening and debilitating diseases.