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Non-invasive monitoring of pharmacodynamics during the skin wound healing process using multimodal optical microscopy
  1. Jose Rico-Jimenez1,
  2. Jang Hyuk Lee1,
  3. Aneesh Alex2,
  4. Salma Musaad3,
  5. Eric Chaney1,
  6. Ronit Barkalifa1,
  7. Eric Olson2,
  8. David Adams2,
  9. Marina Marjanovic1,
  10. Zane Arp2,
  11. Stephen A Boppart1
  1. 1Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
  2. 2GlaxoSmithKline, Philadelphia, Pennsylvania, USA
  3. 3Interdisciplinary Health Sciences Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
  1. Correspondence to Dr Stephen A Boppart; boppart{at}illinois.edu

Abstract

Objective Impaired diabetic wound healing is one of the serious complications associated with diabetes. In patients with diabetes, this impairment is characterized by several physiological abnormalities such as metabolic changes, reduced collagen production, and diminished angiogenesis. We designed and developed a multimodal optical imaging system that can longitudinally monitor formation of new blood vessels, metabolic changes, and collagen deposition in a non-invasive, label-free manner.

Research design and methods The closure of a skin wound in (db/db) mice, which presents delayed wound healing pathologically similar to conditions in human type 2 diabetes mellitus, was non-invasively followed using the custom-built multimodal microscope. In this microscope, optical coherence tomography angiography was used for studying neovascularization, fluorescence lifetime imaging microscopy for nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) assessment, fluorescence intensity changes of NAD(P)H and flavin adenine dinucleotide (FAD) cofactors for evaluating metabolic changes, and second harmonic generation microscopy for analyzing collagen deposition and organization. The animals were separated into four groups: control, placebo, low concentration (LC), and high concentration (HC) treatment. Images of the wound and surrounding areas were acquired at different time points during a 28-day period.

Results Various physiological changes measured using the optical imaging modalities at different phases of wound healing were compared. A statistically significant improvement in the functional relationship between angiogenesis, metabolism, and structural integrity was observed in the HC group.

Conclusions This study demonstrated the capability of multimodal optical imaging to non-invasively monitor various physiological aspects of the wound healing process, and thus become a promising tool in the development of better diagnostic, treatment, and monitoring strategies for diabetic wound care.

  • pharmacodynamics
  • metabolic disturbances
  • microvascular changes
  • imaging systems
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • JR-J and JHL are joint first authors.

  • Contributors JRJ, JHL and AA built the optical system, acquired the images, processed the data, and wrote the manuscript. SM performed the data analysis. EC, RB and MM handled the animals and applied the treatment. EO, DA, ZA and SAB contributed to the study design and/or directed the study. SAB is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed and revised the manuscript prior to publication.

  • Funding This work was supported by GlaxoSmithKline.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request and through a collaborative agreement. All data relevant to the study are included in the article or uploaded as supplementary information. Imaging data generated during this study may be available upon request.

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