Annals of Biomedical Engineering

, Volume 44, Issue 9, pp 2591–2610 | Cite as

Multiscale Modeling in the Clinic: Drug Design and Development

  • Colleen E. Clancy
  • Gary An
  • William R. Cannon
  • Yaling Liu
  • Elebeoba E. May
  • Peter Ortoleva
  • Aleksander S. Popel
  • James P. Sluka
  • Jing Su
  • Paolo Vicini
  • Xiaobo Zhou
  • David M. Eckmann
Multi-Scale Modeling in the Clinic


A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models.


Pharmacology Mathematical Multiscale modeling Simulation Drug delivery 



Agent-based model




Bone marrow stromal cell


Between-subject variability




Computer-aided design




C-X-C chemokine receptor type 4


Dissipative particle dynamics


Extracellular matrix


Enhanced permeability and retention


Human papillomavirus


Interstitial fluid pressure


Monte Carlo


Markov chain Monte Carlo


Molecular dynamics


Multiscale factorization


Myeloma initiating cell


Multiple myeloma








Physiologically-based pharmacokinetic


Cancer progenitor cell


Protein Data Bank


Quantum mechanics/molecular mechanics


Residual unknown variability


Systems chemical biology


Stromal cell-derived factor 1


Terminal multiple myeloma cell


Weighted histogram analysis method



This work was supported in part by NIH grants R01CA138264 (ASP), U01HL126273 (CEC), U01EB016027 (DME), R01EB006818 (DME), R01-GM-115839 and P30-DK-42086 (GA), R01GM077138 (JPS) and R15EB015105 (YL) as well as EPA grant R835001 (JPS). WRC was funded under the Laboratory Directed Research Program at the Pacific Northwest National Laboratory. PNNL is operated by Battelle for the U.S. Department of Energy under Contract DE-AC06-76RLO.


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Copyright information

© Biomedical Engineering Society 2016

Authors and Affiliations

  • Colleen E. Clancy
    • 1
  • Gary An
    • 2
  • William R. Cannon
    • 3
  • Yaling Liu
    • 4
  • Elebeoba E. May
    • 5
  • Peter Ortoleva
    • 6
  • Aleksander S. Popel
    • 7
  • James P. Sluka
    • 8
  • Jing Su
    • 9
  • Paolo Vicini
    • 10
  • Xiaobo Zhou
    • 9
  • David M. Eckmann
    • 11
  1. 1.Department of PharmacologyUniversity of CaliforniaDavisUSA
  2. 2.Department of SurgeryUniversity of ChicagoChicagoUSA
  3. 3.Computational Biology GroupPacific Northwest National LaboratoryRichlandUSA
  4. 4.Department of Mechanical Engineering and Mechanics, Bioengineering ProgramLehigh UniversityBethlehemUSA
  5. 5.Department of Biomedical EngineeringUniversity of HoustonHoustonUSA
  6. 6.Department of ChemistryIndiana UniversityBloomingtonUSA
  7. 7.Department of Biomedical EngineeringJohns Hopkins UniversityBaltimoreUSA
  8. 8.Biocomplexity InstituteIndiana UniversityBloomingtonUSA
  9. 9.Department of RadiologyWake Forest UniversityWinston-SalemUSA
  10. 10.Clinical Pharmacology and DMPKMedImmuneCambridgeUK
  11. 11.Department of Anesthesiology and Critical CareUniversity of PennsylvaniaPhiladelphiaUSA

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