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Cited by 108Tendon Structure and TreatmentElectrospun Nanofibers in Biomedical ApplicationsCellular Mechanics and Interactions

Substrate fiber alignment mediates tendon cell response to inflammatory signaling

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Schoenenberger, Angelina D., Foolen, Jasper, Moor, Pascal, Silvan, Unai, Snedeker, Jess G.·2018·Acta Biomaterialia
DOI 10.1016/j.actbio.2018.03.004
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Abstract

Healthy tendon tissue features a highly aligned extracellular matrix that becomes disorganized with disease. Recent evidence suggests that inflammation coexists with early degenerative changes in tendon, and that crosstalk between immune-cells and tendon fibroblasts (TFs) can contribute to poor tissue healing. We hypothesized that a disorganized tissue architecture may predispose tendon cells to degenerative extracellular matrix remodeling pathways, particularly within a pro-inflammatory niche. This hypothesis was tested by analyzing human TFs cultured on electrospun polycaprolactone (PCL) mats with either highly aligned or randomly oriented fiber structures. We confirmed that fibroblast morphology, phenotype, and markers of matrix turnover could be significantly affected by matrix topography. More strikingly, the TF response to paracrine signals from polarized macrophages or by stimulation with pro-inflammatory cytokines featured significant downregulation of signaling related to extracellular synthesis, with significant concomitant upregulation of gene and protein expression of matrix degrading enzymes. Critically, this tendency towards degenerative re-regulation was exacerbated on randomly oriented PCL substrates. These novel findings indicate that highly aligned tendon cell scaffolds not only promote tendon matrix synthesis, but also play a previously unappreciated role in mitigating adverse resident fibroblast response within an inflammatory milieu. STATEMENT OF SIGNIFICANCE: Use of biomaterial scaffolds for tendon repair often results in tissue formation characteristic of scar tissue, rather than the highly aligned type-1 collagen matrix of healthy tendons. We hypothesized that non-optimal biomaterial surfaces may play a role in these outcomes, specifically randomly oriented biomaterial surfaces that unintentionally mimic structure of pathological tendon. We observed that disorganized scaffold surfaces do adversely affect early cell attachment and gene expression. We further identified that disorganized fiber surfaces can prime tendon cells toward pro-inflammatory signaling. These findings represent provocative evidence unstructured fiber surfaces may underlie inflammatory responses that drive aberrant collagen matrix turnover. This work could be highly relevant for the design of cell instructive biomaterial therapies that yield positive clinical outcomes.

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  • Several studies demonstrated that fiber diameter and organization within the scaffold structure influence macrophage polarization and the degree of the inflammatory response.

    “For example, several studies demonstrated that fiber diameter and organization within the scaffold structure influence macrophage polarization and the degree of the inflammatory response [211,212,213].”

    From Resorbable Biomaterials Used for 3D Scaffolds in Tissue Engineering: A Review (2023) · cites this paper as [213]

    The Discussion and Results (§3.2; page unavailable) report that scaffold fiber alignment affects tendon fibroblasts’ responses to inflammatory signaling. They do not show that fiber diameter or organization changes macrophage polarization: the Methods (§2.2; page unavailable) describe chemically polarizing macrophages before co-culture. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Results suggested that aligned fibers with bigger diameter sizes were more favorable for M2 polarization.

    “Results suggested that aligned fibers with bigger diameter sizes were more favorable for M2 polarization.”

    From Resorbable Biomaterials Used for 3D Scaffolds in Tissue Engineering: A Review (2023) · cites this paper as [213]

    Section 2.2 (Macrophage differentiation; page unavailable) says M2 macrophages were produced by IL-4 stimulation. Section 3.2 (page unavailable) places those macrophages in a separate Transwell chamber while tendon fibroblasts grew on aligned or random fibers. The passages found do not test whether fiber alignment or larger fiber diameter favors M2 polarization; searches for fiber diameter and M2 polarization found no such result. (LLM, conf=0.77)

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Cited by

Sorted by citations

Authors
Schoenenberger, A. D., Foolen, J., Moor, P., Silvan, U., & Snedeker, J. G.
Affiliations
University of Zurich (CH)
Corresponding author
Snedeker, Jess G.
ORCID
Venue
Acta Biomaterialia
Publisher
Elsevier BV
Published
2018-04
Volume
71
Pages
306-317
ISSN
1742-7061 (ISSN-L)
DOI
10.1016/j.actbio.2018.03.004
OpenAlex
W2792360188
Cited by
108
References
2
Citations by year
2026: 7 · 2025: 22 · 2024: 11 · 2023: 14 · 2022: 15 · 2021: 12 · 2020: 17 · 2019: 9 · 2018: 1
FWCI
10.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Biomaterialia (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • TU/e Research Portal (publishedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • TU/e Research Portal (submittedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • TU/e Research Portal (submittedVersion, cc-by-nc-nd)
  • ETH Zürich Research Collection
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Tendon Structure and Treatment
  • Physical Sciences › Materials Science › Biomaterials › Electrospun Nanofibers in Biomedical Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
tendon fibroblasts, extracellular matrix remodeling, tendon degeneration, inflammation, macrophage polarization, inflammatory cytokines, polycaprolactone scaffolds, electrospun nanofibers, collagen synthesis, matrix degradation, tendon repair
MeSH terms
THP-1 Cells, Adult, Cell Communication, Extracellular Matrix, Fibroblasts, Humans, Macrophages, Male, Polyesters, Tendons, Up-Regulation, Cytokines

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