Cited by 1,8493D Printing in Biomedical ResearchCellular Mechanics and InteractionsTissue Engineering and Regenerative Medicine

The DOI matches its Crossref record; 129 of the 131 references it cites were found in a registry or an index, and 2 are not checked yet; 44 of the 86 sources its claims cite were checked for support.

Modeling Physiological Events in 2D vs. 3D Cell Culture

Open access

Abstract

Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research.

Verified 2026-10-07 · 2 references not checked yet

Overview

Integrity signals

Registry

Crossref · 10.1152/physiol.00036.2016

Cites

129 of 131 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

44 of 86 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured

Show all 43 claims

  • It may state two separate claims as one. 16
  • Probably not a substantial claim. 14
25 of 25
  • The paper relies on this without support.

    Under some circumstances, 2D systems produce cell bioactivities that deviate appreciably from the in vivo response.

    “Although these approaches are well-accepted and have significantly advanced our understanding of cell behavior, growing evidence now shows that, under some circumstances, the 2D systems can result in cell bioactivities that deviate appreciably the in vivo response.”
  • The paper relies on this without support.

    2D cell culture approaches can still recapitulate in vivo behavior for many bioactivities.

    “additionally, 2D cell culture approaches can still recapitulate in vivo behavior for many bioactivities, while new advances in substrate”
  • The paper relies on this without support.

    A universal 3D platform does not currently exist.

    “the platform of choice is often dictated by the specific process of interest, and a universal 3D platform does not currently exist”
  • The paper relies on this without support.

    Most 2D methods do not provide control of cell shape.

    “However, most of these 2D methods do not provide control of cell shape, which determines biophysical cues affecting cell bioactivities in vivo.”
  • The paper relies on this without support.

    Hepatocytes do not survive well under traditional 2D culture methods.

    “Indeed, alternative methods to traditional 2D cell culture were developed for hepatocytes because they do not survive well under traditional 2D culture methods.”
  • The paper relies on this without support.

    A major problem in the field is the lack of a standard approach in three-dimensional cultures.

    “One major problem in the field is the lack of a standard approach in 3D cultures”
  • The paper relies on this without support.

    Two-dimensional cell culture practice is standard and roughly comparable.

    “whereas 2D cell culture practice is standard and roughly comparable.”
  • The paper relies on this without support.

    Three-dimensional studies are becoming increasingly necessary to replicate the behaviors of some in vivo conditions.

    “Classically, 2D studies have been favored, but 3D studies are becoming more necessary to replicate the behaviors of some in vivo conditions.”
  • The paper relies on this without support.

    Accurate measurements of the forces exerted on the extracellular matrix are necessary for understanding physiological processes such as cancer or immune cell migration.

    “Obtaining accurate measurements of forces exerted on the ECM are necessary to understand physiological processes such as cancer or immune cell migration.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Diagnostic-tool claim cites a scaffold study

    Minor

    Reference 95 is identified as a study of bone-scaffold porosity and stem cells, rather than microfluidic diagnostic tools.

  • Cancer-cell claim cites a paper on porous beads

    Minor

    The citation attached to the claim about cancer cells in 2D culture is listed as a paper on beads with controllable pore sizes.

  • PDMS claim cites a skin-grafting review

    Minor

    The cited reference 107 is identified as a paper on skin grafting and wound treatment, not PDMS behavior in cell-culture devices.

  • Gas-foaming citation identifies a bioreactor study

    Minor

    The reference given for scaffold fabrication by gas foaming is listed as a study of embryonic stem-cell cardiogenesis using a liquid-marble micro-bioreactor.

4 of 4

Citations

Cites

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Metadata

Authors
Duval, K., Grover, H., Han, L.-H., Mou, Y., Pegoraro, A. F., Fredberg, J., & Chen, Z.
Affiliations
  • Dartmouth College (US)
  • Drexel University (US)
  • University of Illinois Chicago (US)
  • Harvard University (US)
Corresponding author
Chen, Zi
Venue
Physiology
Published
2017-07
Volume
32
Issue
4
Pages
266-277
ISSN
  • 0886-1714 (ISSN-L)
  • 1548-9213
  • 1548-9221
OpenAlex
W2626725994
Cited by
1,849
References
129
Citations by year
2026: 184 · 2025: 240 · 2024: 251 · 2023: 252 · 2022: 241 · 2021: 268 · 2020: 234 · 2019: 127 · 2018: 46 · 2017: 4
FWCI
9.03
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Physiology (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Society in Science-Branco Weiss Fellowship
  • HHS | NIH | National Cancer Institute (NCI) (U01CA202123)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
2D cell culture, 3D cell culture, tissue engineering, regenerative medicine, mechanical microenvironment, metabolic waste, physiological modeling, biomechanics
MeSH terms
Animals, Cell Differentiation, Cell Movement, Extracellular Matrix, Humans, Cell Culture Techniques, Tissue Engineering, Biomedical Research, Cell Proliferation

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-10-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

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Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

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