Examination of the foreign body response to biomaterials by nonlinear intravital microscopy
Open accessAbstract
Implanted biomaterials often fail because they elicit a foreign body response (FBR) and concomitant fibrotic encapsulation. To design clinically relevant interference approaches, it is crucial to first examine the FBR mechanisms. Here, we report the development and validation of infrared-excited nonlinear microscopy to resolve the three-dimensional (3D) organization and fate of 3D-electrospun scaffolds implanted deep into the skin of mice, and the following step-wise FBR process. We observed that immigrating myeloid cells (predominantly macrophages of the M1 type) engaged and became immobilized along the scaffold/tissue interface, before forming multinucleated giant cells. Both macrophages and giant cells locally produced vascular endothelial growth factor (VEGF), which initiated and maintained an immature neovessel network, followed by formation of a dense collagen capsule 2-4 weeks post-implantation. Elimination of the macrophage/giant-cell compartment by clodronate and/or neutralization of VEGF by VEGF Trap significantly diminished giant-cell accumulation, neovascularization and fibrosis. Our findings identify macrophages and giant cells as incendiaries of the fibrotic encapsulation of engrafted biomaterials via VEGF release and neovascularization, and therefore as targets for therapy.
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Local scavenging of VEGF around implants can inhibit extension of new blood vessels necessary to support fibrotic capsule and decrease fibrotic encapsulation.
“Local scavenging of VEGF around implants, a stimulator of endothelial growth released by anoxic tissue, can inhibit the extension of new blood vessels necessary to support the fibrotic capsule and decrease fibrotic encapsulation (Dondossola et al., 2017).”
From Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics (2021) · cites this paper as Dondossola et al., 2017
In “Therapeutic targeting of macrophages and neoangiogenesis” (page not provided), VEGF Trap prevented vessel formation and reduced collagen deposition around the implanted scaffold. The Methods describe administering VEGF Trap to scaffold-bearing mice, not locally scavenging it at the implant. The Discussion identifies implant-associated myeloid cells as a local VEGF source, but does not attribute its release to anoxic tissue. (LLM, conf=0.86)
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“Local scavenging of VEGF around implants, a stimulator of endothelial growth released by anoxic tissue, can inhibit the extension of new blood vessels necessary to support the fibrotic capsule and decrease fibrotic encapsulation (Dondossola et al., 2017).”
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- Authors
- Dondossola, E., Holzapfel, B. M., Alexander, S., Filippini, S., Hutmacher, D. W., & Friedl, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Queensland University of Technology (AU)
- Corresponding author
- Dondossola, Eleonora
- Friedl, Peter
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2016-12-19
- Volume
- 1
- Issue
- 1
- ISSN
- 2157-846X (ISSN-L)
- PMC
- PMC5624536
- OpenAlex
- W2562554519
- Cited by
- 215
- References
- 59
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 37 · 2023: 24 · 2022: 25 · 2021: 22 · 2020: 12 · 2019: 26 · 2018: 25 · 2017: 10
- FWCI
- 22.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Griffith Research Online (submittedVersion)
- Funders
- Prostate Cancer Foundation (CA016672)
- Cancer Prevention and Research Institute of Texas (P30CA016672, RP140482, CA016672)
- National Breast Cancer Foundation (IN‐15–047)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (P30 CA016672, 918.11.626)
- National Institutes of Health (CA- 016672)
- University of Texas MD Anderson Cancer Center ((CA016672), P30-CA-016672)
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- National Cancer Institute (CA 016672, P30CA016672)
- FP7 Ideas: European Research Council (617430)
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Materials Science › Biomaterials › Electrospun Nanofibers in Biomedical Applications
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Keywords
- foreign body reaction, biomaterial implantation, electrospun scaffolds, macrophages, M1 macrophages, multinucleated giant cells, vascular endothelial growth factor, neovascularization, fibrotic encapsulation, collagen capsule, clodronate, VEGF trap, intravital microscopy, 3D imaging
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