Modulation of the Inflammatory Response and Bone Healing
Open accessAbstract
The optimal treatment for complex fractures and large bone defects is an important unsolved issue in orthopedics and related specialties. Approximately 5-10% of fractures fail to heal and develop non-unions. Bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Eventual healing is highly dependent on the initial inflammatory phase, which is affected by both the local and systemic responses to the injurious stimulus. Furthermore, immune cells and mesenchymal stromal cells (MSCs) participate in critical inter-cellular communication or crosstalk to modulate bone healing. Deficiencies in this inter-cellular exchange, inhibition of the natural processes of acute inflammation, and its resolution, or chronic inflammation due to a persistent adverse stimulus can lead to impaired fracture healing. Thus, an initial and optimal transient stage of acute inflammation is one of the key factors for successful, robust bone healing. Recent studies demonstrated the therapeutic potential of immunomodulation for bone healing by the preconditioning of MSCs to empower their immunosuppressive properties. Preconditioned MSCs (also known as "primed/ licensed/ activated" MSCs) are cultured first with pro-inflammatory cytokines (e.g., TNFα and IL17A) or exposed to hypoxic conditions to mimic the inflammatory environment prior to their intended application. Another approach of immunomodulation for bone healing is the resolution of inflammation with anti-inflammatory cytokines such as IL4, IL10, and IL13. In this review, we summarize the principles of inflammation and bone healing and provide an update on cellular interactions and immunomodulation for optimal bone healing.
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Excessive acute and chronic inflammation leads to a persistent inflammatory state and excessive production of pro-inflammatory cytokines, which results in increased bone resorption and suppression of bone formation.
“Excessive acute and chronic inflammation, caused by microbial infection, trauma, and autoimmune diseases, etc. lead to the persistent inflammatory state and excessive production of pro-inflammatory cytokines [47], which in turn, resulting in increased bone resorption and suppression of bone formation [47].”
From A tailored bioactive 3D porous poly(lactic-acid)-exosome scaffold with osteo-immunomodulatory and osteogenic differentiation properties (2022) · cites this paper as [47]
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- Authors
- Maruyama, M., Rhee, C., Utsunomiya, T., Zhang, N., Ueno, M., Yao, Z., & Goodman, S. B.
- Affiliations
- Stanford University (US)
- Corresponding author
- Goodman, Stuart B.
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2020-06-11
- Volume
- 11
- Pages
- 386-386
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC7325942
- OpenAlex
- W3034944990
- Cited by
- 541
- References
- 125
- Citations by year
- 2026: 99 · 2025: 128 · 2024: 107 · 2023: 102 · 2022: 65 · 2021: 36 · 2020: 4
- FWCI
- 7.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health (R01AR055650, R01AR063717, R01AR073145, RO1AR72613)
- Topics
- Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
- Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- bone regeneration, fracture healing, nonunion, acute inflammation, chronic inflammation, immunomodulation, mesenchymal stem cells, inflammatory cytokines, hypoxia, anti-inflammatory cytokines, inflammation resolution, bone defects
- MeSH terms
- Animals, Bone and Bones, Humans, Inflammation, Fracture Healing, Inflammation Mediators, Fractures, Bone, Mesenchymal Stem Cells
About these checks
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.
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