In the United States, annually 6.5 million chronic wounds cost over $50 billion dollars. According to the current standard of wound care, wound closure is assessed visually. The current proposal contends that visual inspection of wounds is insufficient to certify closure - a critical endpoint that drives treatment decisions and reimbursement. Considering that almost two-third of all chronic wounds are estimated to be biofilm infected, and our observation that biofilm-infected wounds may be visually closed but functionally (barrier function) open, the significance of our hypothesis is substantial. The proposed work may change the wound care paradigm by requiring that measurement of skin barrier function (as expressed by trans-epidermal water loss or TEWL) be the new endpoint to define wound closure. The primary function of skin as an organ is to serve as a barrier between the body and its environment. This barrier is maintained by (i) cutaneous lipids of which about 50% are ceramides (Cer) and (ii) intercellular seal of tight junctions (TJ). This proposal rests on our novel observation that biofilm infection of wound may result in a state where the wound appears closed (visually, standard of care) but is actually not because barrier function has been compromised. The proposed work rests on our finding that biofilm infection disrupts skin Cer homeostasis causing loss of barrier function. In support of the above-mentioned hypothesis we observe, (i) lower Cer levels in biofilm infected wound-edge skin; (ii) that host skin ceramide synthase is silenced by biofilm-inducible microRNAs (miRs) and (iii) that in biofilm form bacteria overexpress (500-fold) ceramidase enzyme may hydrolyze skin ceramide. The following two aims are proposed:
Aim 1. Examine how bacterial biofilm products and biofilm-induced host skin microRNAs disrupt ceramide homeostasis and barrier function of the healing skin. 1.1 Biofilm-inducible microRNAs (miRs) 146a and 106b silence ceramide synthase 3 (CerS3) in host skin. 1.2 Bacterial ceramidase (bCDase) is overexpressed in biofilm infection and degrades structural host skin ceramides.
Aim 2. In patients with biofilm infected wounds test whether current standard of care deciding on wound closure is inadequate. 2.1. A history of wound biofilm infection results in elevated TEWL at wound sites that appear closed; 2.2. Defectively closed wounds featuring high TEWL show higher recurrence rate than functionally closed wounds with low TEWL; 2.3. Topical application of a FDA approved ceramide emulsion restores barrier function of defectively closed wounds.

Public Health Relevance

The current standard of care that informs the clinical decision making process in wound care is for a physician to visually assess the wound for closure. This proposal challenges that decision making process based on our evidence that wounds infected by bacteria in biofilm configuration may close, as appreciated visually, but functionally remains open because the repaired skin lacks barrier function. Furthermore, the proposed work asks whether such defective repair of wounds lends itself to a higher rate of recurrence or post-closure complication in patients. Finally, this work seeks to repurpose a FDA approved topical emulsion with the goal to take such defectively repaired skin in patients to fully functional closure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR015676-06
Application #
9638593
Study Section
Special Emphasis Panel (ZNR1)
Program Officer
Tully, Lois
Project Start
2015-05-06
Project End
2020-02-29
Budget Start
2019-04-02
Budget End
2020-02-29
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Surgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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