The value of digital twins for prototyping controllers or interventions in a sandbox environment are well-established in engineering and physics. However, this is challenging for biophysics trying to seamlessly compose models of multiple spatial and temporal scale behavior into the digital twin. Two challenges stand out as constraining progress: (i) ensuring physical consistency of conservation laws across composite models and (ii) drawing useful and timely clinical and scientific information from conceptually and computationally complex models. Challenge (i) can be robustly addressed with bondgraphs. However, challenge (ii) is exacerbated using this approach. The complexity question can be looked at from multiple angles. First from the perspective of discretizations that reflect underlying biophysics (functional tissue units) and secondly by exploring maximum entropy as the principle guiding multicellular biophysics. Statistical mechanics, long applied to understanding emergent phenomena from atomic physics, coupled with the observation that cellular architecture in tissue is orchestrated by biophysical constraints on metabolism and communication, shows conceptual promise. This architecture along with cell specific properties can be used to define tissue specific network motifs associated with energetic contributions. Complexity can be addressed based on energy considerations and finding mean measures of dependent variables. A probability distribution of the tissue's network motif can be approximated with exponential random graph models. A prototype problem shows how these approaches could be implemented in practice and the type of information that could be extracted.
Keywords: functional tissue unit; multiscale modeling; physically consistent modeling; statistical mechanics; systems biology.
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