Translational Systems Biology: Introduction of an Engineering Approach to the Pathophysiology of the Burn Patient

Abstract

The pathophysiology of the burn patient manifests the full spectrum of the complexity of the inflammatory response. In the acute phase, inflammation may have negative effects via capillary leak, the propagation of inhalation injury, and development of multiple organ failure. Attempts to mediate these processes remain a central subject of burn care research. Conversely, inflammation is a necessary prologue and component in the later stage processes of wound healing. Despite the volume of information concerning the cellular and molecular processes involved in inflammation, there exists a significant gap between the knowledge of mechanistic pathophysiology and the development of effective clinical therapeutic regimens. Translational systems biology (TSB) is the application of dynamic mathematical modeling and certain engineering principles to biological systems to integrate mechanism with phenomenon and, importantly, to revise clinical practice. This study will review the existing applications of TSB in the areas of inflammation and wound healing, relate them to specific areas of interest to the burn community, and present an integrated framework that links TSB with traditional burn research. BURNS, BIOCOMPLEXITY, AND THE NEED FOR A TRANSLATIONAL METHODOLOGYThe burn community held its State of the Science meeting (Sponsored by the American Burn Association, the National Institutes of Health/National Institute of General Medical Sciences, the Shriners Hospitals for Children, the National Institute on Disability and Rehabilitation Research, the Department of Veterans Affairs and the U.S. Army Medical Materiel Command) from October 26-29, 2006, in order to determine the areas and foci of the community's research emphasis for the decade to come. These areas were defined primarily by their clinical manifestations or situations, such as resuscitation issues, inhalation injury, multiple organ failure, and wound healing. However, discussions invariably included references to the investigation of means by which known or suspected cellular and molecular pathophysiologic mechanisms could be translated into effective clinical treatments. These discussions included both the process of discovery for new

Using a mathematical model to analyze the role of probiotics and inflammation in necrotizing enterocolitis

“…In this way, we hope to improve clinical translation, as part of our larger Translational Systems Biology framework [29,[36][37][38][39]. In particular, we have included mathematical terms in our model that represent important effects that have been implicated in the development of NEC and some of the mechanisms through which probiotics are thought to act to effect its progression [1,14].…”

Computational Modeling of Inflammation and Wound Healing

“…By providing a means of synthesizing disparate aspects of biomedical knowledge, mechanistic computational modeling provides a plethora of opportunities to continue exploring, make new insights, and ultimately help patients. 2,[13][14][15]29,48,49 At the level of the population, an ABM of DFU was used to give insights into how current therapies work (or do not) in given patients, and also to suggest novel therapies. 38 At the other end of the spectrum, an ABM of acute phonotrauma was not only able to recapitulate inflammatory mediator dynamics observed in the laryngeal secretions of human subjects, but also able to accurately predict those levels and time points beyond model calibration range.…”

“…[14][15][16] Equation-based models have been used to explore all phases of wound healing, from inflammation, 17,18 to wound closure, 19,20 to tissue remodeling. 21 This modeling framework, while extremely useful from a basic, mechanistic point of view, cannot be readily used to create tissue-realistic simulations that involve stochastic biological effects.…”

“…[24][25][26][27] We propose that ABMs are also well suited to a translational role to bridge basic science knowledge and the rational development of clinically applicable strategies. 14,23,28,29 We have developed a series of ABMs with this specific goal in mind. Figure 1 is a schematic diagram that shows the general ABM rules used by our group for models of inflammation and wound healing.…”

BioCAE: A New Strategy of Complex Biological Systems for Biofabrication of Tissues and Organs

“…The biological systems are made up of many spatial and temporal scales. These diverse levels coupling intra and interscale interactions make a biological system extremely complex, requiring advanced mathematical and computational models for the integration of the different scales [15,16]. There is a range of multi-scale modelling methods that could potentially be employed in systems biology [17][18][19][20][21][22] and consequently in the biofabrication of tissues and organs.…”