Cited by 30Bone fractures and treatmentsBone Tissue Engineering MaterialsMedicinal Plant Pharmacodynamics Research

Treatment of Bone Defects and Nonunion via Novel Delivery Mechanisms, Growth Factors, and Stem Cells: A Review

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Ehlen, Quinn T., Costello, Joseph P., Mirsky, Nicholas A., Slavin, Blaire V., Parra, Marcelo, Ptashnik, Albert, Nayak, Vasudev Vivekanand, Coelho, Paulo G. +1 more·2024·ACS Biomaterials Science & Engineering

Abstract

Bone nonunion following a fracture represents a significant global healthcare challenge, with an overall incidence ranging between 2 and 10% of all fractures. The management of nonunion is not only financially prohibitive but often necessitates invasive surgical interventions. This comprehensive manuscript aims to provide an extensive review of the published literature involving growth factors, stem cells, and novel delivery mechanisms for the treatment of fracture nonunion. Key growth factors involved in bone healing have been extensively studied, including bone morphogenic protein (BMP), vascular endothelial growth factor (VEGF), and platelet-derived growth factor. This review includes both preclinical and clinical studies that evaluated the role of growth factors in acute and chronic nonunion. Overall, these studies revealed promising bridging and fracture union rates but also elucidated complications such as heterotopic ossification and inferior mechanical properties associated with chronic nonunion. Stem cells, particularly mesenchymal stem cells (MSCs), are an extensively studied topic in the treatment of nonunion. A literature search identified articles that demonstrated improved healing responses, osteogenic capacity, and vascularization of fractures due to the presence of MSCs. Furthermore, this review addresses novel mechanisms and materials being researched to deliver these growth factors and stem cells to nonunion sites, including natural/synthetic polymers and bioceramics. The specific mechanisms explored in this review include BMP-induced osteoblast differentiation, VEGF-mediated angiogenesis, and the role of MSCs in multilineage differentiation and paracrine signaling. While these therapeutic modalities exhibit substantial preclinical promise in treating fracture nonunion, there remains a need for further research, particularly in chronic nonunion and large animal models. This paper seeks to identify such translational hurdles which must be addressed in order to progress the aforementioned treatments from the lab to the clinical setting.

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Crossref · 10.1021/acsbiomaterials.4c01279

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  • MSCs release wound-healing factors including VEGF, PDGF, HGF, TGF-β1, IL-8, and MCP-1 that through paracrine signaling induce cell survival, migration, ECM deposition, and tissue regeneration.

    “Additionally, MSCs release various wound-healing factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), transforming growth factor-beta 1 (TGF-β1), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1). Through paracrine signaling, these factors induce cell survival, migration, and extracellular matrix (EC”

    From From signaling pathways to clinical trials: mesenchymal stem cells as multimodal regenerative architects in liver cirrhosis therapy (2025) · cites this paper as [19]

    The Stem Cells > Acute Administration section reports improved bone healing with MSC-seeded scaffolds, and the Growth Factors section discusses VEGF, PDGF, and TGF-β in bone repair. The passages do not say that MSCs release the listed factors—including HGF, IL-8, and MCP-1—or that those factors act through paracrine signaling to produce the specified effects. Page numbers were not available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured
  • MSCs release growth factors and cytokines including HGF, VEGF, EGF, and MMPs, which participate in tissue regeneration.

    “MSCs release several growth factors and cytokines, including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and matrix metalloproteinases (MMPs), which participate in tissue regeneration.”

    From From signaling pathways to clinical trials: mesenchymal stem cells as multimodal regenerative architects in liver cirrhosis therapy (2025) · cites this paper as [19]

    The Growth Factors section says VEGF contributes to bone remodeling and regeneration, and Stem Cells > Acute Administration describes faster bone healing with MSC-seeded scaffolds (page numbers unavailable). Neither passage says MSCs release VEGF, HGF, EGF, or MMPs; the claimed secretion of those substances is unsupported by our copy. (LLM, conf=0.82)

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Research works printed but not linked: 10

  1. Thomas J. D.; Kehoe J. L. Bone Nonunion. 2023. https://www.ncbi.nlm.nih.gov/books/NBK554385/#:~:text=Nonunion%20of%20bone%20is%20the,of%20healing%20for%20three%20monthshttps://www.ncbi.nlm.nih.gov/books/NBK554385/#:~:text=Nonunion%20of%20bone%20is%20the,of%20healing%20for%20three%20months (accessed 2023 September 26).
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  3. Stone W. L.; Leavitt L.; Varacallo M. Physiology, Growth Factor. 2023. https://www.ncbi.nlm.nih.gov/books/NBK442024/ (accessed 2023 September 26). 28723053
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  8. Friedlaender G. E.; Perry C. R.; Cole J. D.; Cook S. D.; Cierny G.; Muschler G. F.; Zych G. A.; Calhoun J. H.; LaForte A. J.; Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J. Bone Joint Surg Am. 2001, 83-A (Pt 2), S151– 158. 10.2106/00004623-200100002-00010. PMC1425155 11314793 · DOI
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Authors
Ehlen, Q. T., Costello, J. P., Mirsky, N. A., Slavin, B. V., Parra, M., Ptashnik, A., Nayak, V. V., Coelho, P. G., & Witek, L.
Affiliations
  • University of Miami (US)
  • Universidad de La Frontera (CL)
  • New York University (US)
Corresponding author
Witek, Lukasz
Venue
ACS Biomaterials Science & Engineering
Published
2024-11-11
Volume
10
Issue
12
Pages
7314-7336
ISSN
2373-9878 (ISSN-L)
OpenAlex
W4404230350
Cited by
29
References
196
Citations by year
2026: 16 · 2025: 13
FWCI
1.91
Type
journal article
Language
en
Open access
Locations
  • ACS Biomaterials Science & Engineering (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Omeka S (Universidad de La Frontera) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Epidemiology › Bone fractures and treatments
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Medicinal Plant Pharmacodynamics Research
Keywords
nonunion, bone defects, bone morphogenic proteins, vascular endothelial growth factor, platelet-derived growth factor, mesenchymal stem cells, growth factor delivery, bioceramics, polymers, angiogenesis, heterotopic ossification, bone regeneration, paracrine signaling, osteogenic differentiation
MeSH terms
Animals, Fractures, Ununited, Humans, Osteogenesis, Drug Delivery Systems, Fracture Healing, Intercellular Signaling Peptides and Proteins, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells

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