Scaling and Systems Biology for Integrating Multiple Organs-on-a-Chip.

Scaling and systems biology for integrating multiple organs-on-a-chip.

Lab Chip. 2013 Jul 5;
Wikswo JP, Curtis EL, Eagleton ZE, Evans BC, Kole A, Hofmeister LH, Matloff WJ

Coupled systems of in vitro microfabricated organs-on-a-chip containing small populations of human cells are being developed to address the formidable pharmacological and physiological gaps between monolayer cell cultures, animal models, and humans that severely limit the speed and efficiency of drug development. These gaps present challenges not only in tissue and microfluidic engineering, but also in systems biology: how does one model, test, and learn about the communication and control of biological systems with individual organs-on-chips that are one-thousandth or one-millionth of the size of adult organs, or even smaller, i.e., organs for a milliHuman (mHu) or microHuman (?Hu)? Allometric scaling that describes inter-species variation of organ size and properties provides some guidance, but given the desire to utilize these systems to extend and validate human pharmacokinetic and pharmacodynamic (PK/PD) models in support of drug discovery and development, it is more appropriate to scale each organ functionally to ensure that it makes the suitable physiological contribution to the coupled system. The desire to recapitulate the complex organ-organ interactions that result from factors in the blood and lymph places a severe constraint on the total circulating fluid (?5 mL for a mHu and ?5 ?L for a ?Hu) and hence on the pumps, valves, and analytical instruments required to maintain and study these systems. Scaling arguments also provide guidance on the design of a universal cell-culture medium, typically without red blood cells. This review presents several examples of scaling arguments and discusses steps that should ensure the success of this endeavour. HubMed – drug


Prevention System Mediation of Communities That Care Effects on Youth Outcomes.

Prev Sci. 2013 Jul 5;
Brown EC, Hawkins JD, Rhew IC, Shapiro VB, Abbott RD, Oesterle S, Arthur MW, Briney JS, Catalano RF

This study examined whether the significant intervention effects of the Communities That Care (CTC) prevention system on youth problem behaviors observed in a panel of eighth-grade students (Hawkins et al. Archives of Pediatrics and Adolescent Medicine 163:789-798 2009) were mediated by community-level prevention system constructs posited in the CTC theory of change. Potential prevention system constructs included the community’s degree of (a) adoption of a science-based approach to prevention, (b) collaboration on prevention activities, (c) support for prevention, and (d) norms against adolescent drug use as reported by key community leaders in 24 communities. Higher levels of community adoption of a science-based approach to prevention and support for prevention in 2004 predicted significantly lower levels of youth problem behaviors in 2007, and higher levels of community norms against adolescent drug use predicted lower levels of youth drug use in 2007. Effects of the CTC intervention on youth problem behaviors by the end of eighth grade were mediated fully by community adoption of a science-based approach to prevention. No other significant mediated effects were found. Results support CTC’s theory of change that encourages communities to adopt a science-based approach to prevention as a primary mechanism for improving youth outcomes. HubMed – drug