Table 2.

Selection of existing computational models addressing metabolism with potential relevance for surgical planning, sorted according to spatial scale (cell to organism).

Scale	Modeling Approaches
Cell	Metabolization of drugs • Toxicity and timescale analysis, acetaminophen detoxification—ODE (Reddyhoff et al., 2015; Sluka et al., 2016)
	Glucose metabolism • Glucose homeostasis and hormonal regulation—ODE (König and Holzhütter, 2012; König et al., 2012)
	Lipid metabolism—ODE • Steatosis development (Schleicher et al., 2014) • Insulin resistance & high intake diets (Ashworth W. et al., 2016) • Beta-oxidation (van Eunen et al., 2013)
	Genome scale metabolism—FBA • Flux predictions under various conditions (Gille et al., 2010; Jerby et al., 2010; Agren et al., 2014; Naik et al., 2014) • Gain and loss of enzymes (Pagliarini et al., 2016) • Integration of transcriptomics & metabolic data (Hyötyläinen et al., 2016) • Alterations of pathways in NAFLD (Mardinoglu et al., 2014)
Lobule	Perfusion • Resolved hepatic microvascular system—PDE (Rani et al., 2006) • Anisotropic permeability—multiphase-PDE (Ricken et al., 2010, 2013) • Role of vascular septa—PDE (Debbaut et al., 2014) • Multilevel approach CFD—PDE (Peeters et al., 2015) • CFD boundary conditions—PDE (Aramburu et al., 2016)
	Perfusion + glucose metabolism • Glycogen patterns & zonation—multiphase-PDE + ODE (Ricken et al., 2015) • Zonated glucose metabolism—ODE (Chalhoub et al., 2007; Ashworth W. B. et al., 2016)
	Perfusion + lipid metabolism • Zonated lipid metabolism—ODE (Schleicher et al., 2014) • Zonated damage & steatosis—ODE (Ashworth W. et al., 2016)
	Perfusion + drug clearance • Sinusoidal unit/representative sinusoid—PDE+ODE (Schwen et al., 2015)
	Perfusion + ammonia detoxification • CCl4 damage—AB+ODE (Schliess et al., 2014; Ghallab et al., 2016)
Organ	Perfusion + Metabolization • Well-stirred compartments for acetaminophen detoxification (Reddyhoff et al., 2015)—ODE • Spatially resolved porous medium (Schwen et al., 2014)—PDE+ODE
Organism	Pharmacokinetics • Physiologically based whole-body PK, coupling GEMs to PK/PD—FBA+ODE (Bordbar et al., 2011; Krauss et al., 2012; Naik et al., 2014) • Lumped compartment PK models, e.g. acetaminophen liver model in PK/PD—ODE (Geenen et al., 2013) • With inter-individual differences (Krauss et al., 2013)—parameter adaption
Multi-Scale Integration	• Cellular metabolic network model integrated in whole-body PBPK model (Krauss et al., 2012)—FBA+ODE • Representative sinusoid: contains cells, contributes to organ, embedded in organism—PDE+ODE (Schwen et al., 2015) • Glucose regulation (sinusoidal models & PK/PD)—ODE (Ashworth W. B. et al., 2016) • Acetaminophen detoxification on multiple scales—ODE (Sluka et al., 2016)

AB, Agent-based; CFD, computational fluid dynamics; FBA, flux-balance analysis; NAFLD, non-alcoholic fatty liver disease; ODE, ordinary differential equations; PDE, partial differential equations; PK/PD, pharmacokinetic/pharmacodynamic modeling.