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A bell-shaped dose–response of topical FGF-1 in accelerating dermal wound healing in aged female BALB/cByJ mice

Abstract

The objective of this study was to characterize the therapeutic dose–response characteristics for topical FGF-1 in the full-thickness dermal healing of aged female BALB/cByJ mice. The approach utilized a splinted excisional model of dermal healing, and a novel fine-sampled photographic methodology, to quantify key wound healing parameters for different doses of topical FGF-1. The histology of healed wounds, representative of each dose cohort, was also evaluated by section and staining. The results show that topical FGF-1 pharmacotherapy for accelerating dermal healing in aged BALB/cByJ female mice yields a narrow dose–response curve, with diminished therapeutic effect at high concentration (i.e., “bell-shaped” dose–response). The physiological response of FGF-1 in wound healing involves a combination of cell types (including vascular endothelial cells, epidermal keratinocytes and dermal fibroblasts). These individual cells types in culture can have different FGF-1 dose–response curves; however, only the response of fibroblasts is bell-shaped. The bell-shaped dose–response in dermal healing, therefore, principally reflects the effect upon fibroblasts. A narrow bell-shaped dose–response requires precise dosing of FGF-1 for therapeutic benefit. The results identify the practical dose range to elicit such a benefit.

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Data availability

Data is available upon request.

Abbreviations

ACUC:

Animal care and use committee

FGF-1:

Fibroblast growth factor-1

HS:

Heparin sulfate

HR:

Healing rate

ID:

Inside diameter

JAX:

The Jackson Laboratories

NIA:

National Institute of Aging

OD:

Outside diameter

PBS:

Phosphate buffered saline

R 0 :

Initial wound radius

SEM:

Standard error of the measurement

T c :

Time to wound closure

T i :

Inflammatory (wound stasis) phase

T p :

Active proliferative phase

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Acknowledgements

This work was supported by a research support agreement from Trefoil Therapeutics Inc., and a Grant from the FSU Institute for Successful Longevity, to M.B. A.J.B. was supported by an FSU College of Medicine Summer Fellowship. C.A.T. was supported by a McKnight Fellowship and the Department of Biomedical Sciences.

Funding

This work was supported by a research support agreement from Trefoil Therapeutics Inc. to MB and a Grant from the FSU Institute for Successful Longevity to MB. AJB was supported by an FSU College of Medicine Summer Fellowship. CAT was supported by a McKnight Fellowship and the Department of Biomedical Sciences.

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Authors and Affiliations

Authors

Contributions

BNH, AJB, LEM, HMC and BDP were responsible for all animal surgeries, dosing, photographic data collection, and tissue collection. BNH, LEM, HMC and CAT were responsible for analysis wound area measurements. TN was responsible for tissue section and staining and histological evaluation. MB was responsible for experimental design. MB and TN were responsible for manuscript preparation.

Corresponding author

Correspondence to Michael Blaber.

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Conflict of interest

M.B. acknowledges equity ownership in Trefoil Therapeutics, Inc.

Ethical approval

All procedures involving animals were approved by the Florida State University Animal Care and Use Committee (Protocol No. 1637) and the welfare of all animals was supervised by a staff veterinarian.

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Hagerott, B.N., Blumstein, A.J., McGarry, L.E. et al. A bell-shaped dose–response of topical FGF-1 in accelerating dermal wound healing in aged female BALB/cByJ mice. J Proteins Proteom 11, 183–191 (2020). https://doi.org/10.1007/s42485-020-00040-z

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  • DOI: https://doi.org/10.1007/s42485-020-00040-z

Keywords

  • Animal models
  • Splinted excision
  • Growth factors
  • Protein therapeutics