Wound Healing in Healthy Volunteers

NCT03433820 | Completed

• 1 other identifier: CHDR1736
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

The skin plays a critical role in protection where it acts as a barrier from damage and pathogens between the external and internal environments. Wounds compromise its protective role by disrupting the function and the normal structure of the skin and the underlying soft tissue. As a response to injury wound healing occurs in order to rapidly restore the defect. This process involves activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets and consists of multiple phases including hemostasis, inflammation, migration and cellular proliferation, and maturation and remodeling. A simplified schematic of the course of wound healing is depicted in Figure 2. Hemostasis occurs immediately after dermal injury. The inflammation phase is characterized by cellular recruitment and increased vascular permeability. The epithelization phase is achieved by proliferation of basal cells and migration of epithelial cells. The last phase is known as the maturation and remodeling phase where collagen cross-linking and remodeling, wound contraction, and repigmentation takes place. Due to the broad involvement of various cell types, extracellular matrix and many reactive molecules each phase in wound healing produces characteristic changes within the tissue. A deficiency in any part of the process can lead to delayed wound healing, abnormal scar formation or chronic wounds. To study wound healing in healthy volunteers a challenge model with skin punch biopsies has been described in literature previously. However, the characterization of this model was not performed comprehensively since advanced analysis of biopsies were omitted. Furthermore, analyses performed in previous studies only partially described wound healing processes either by insufficient time points for characterization or scarce simultaneous evaluations of multiple wound healing modalities. The overall aim of this study is to develop a standardized model to temporarily and locally induce a skin trauma to investigate wound healing and monitor wound closure. This clinical model will enable future application as proof-of-pharmacology and proof-of concept studies as well as drug profiling in early drug development programs. More specifically, the objective of the trial is to explore and characterize the induction of well-defined skin trauma and natural wound healing process over the course of the different phases using a battery of dermatological assessments after skin punch biopsies in healthy volunteers. Furthermore, safety and tolerability will be assessed. Characterization and monitoring of wound healing effects following skin punch biopsies will be performed by means of biophysical, biochemical, imaging, clinical parameters and subject reported outcomes.

Conditions

Wound Healing

Outcome Measures

Primary Outcomes (14)

• Biopsy biomarkers

  Histology with hematoxylin and eosin (HE) staining

  3 months after end of study

• Local skin biomarkers

  Local skin biomarkers for wound healing related biomarkers (e.g. VEGF-A, TNFα, IL-8, TLSP, MMP-3, IL-4) by transdermal analysis patch (TAP)

  3 months after end of study

• Clinical imaging

  2D photography

  3 months after end of study

• Clinical evaluation

  Erythema grading scale. Wounds are scored on the basis of redness of the wound (from better to worse: absence, mild, moderate, or severe).

  3 months after end of study

• Skin microbiome

  Skin microbiome (healthy and biopsy lesions). Collection of skin culture samples is a non-invasive procedure where a sterile polyester flock tip per site is passed along the surface of the 3 different areas. The target areas are i) regions surrounding one of the biopsy lesions on the lower back, ii) a control site of healthy, unaffected skin in proximity of a biopsy lesion and iii) a control area on the lower back with a minimum distance of 10cm from a biopsy site. The skin swab will be placed in a 2 ml lysis tube containing DNA/RNA shield to stabilize and preserve the DNA. The DNA extraction will be performed using adapted DNA extraction method based on the Zymo Research fecal DNA extraction methodology. After DNA extraction, the variable regions 3 and 4 of the 16S rRNA gene are amplified giving an amplicon of around 450 base pairs. This amplicon is analyzed by capillary systems using standard protocols.

  3 months after end of study

• Biopsy biomarkers

  Immunohistochemistry with wound healing related biomarkers (e.g. CD31, collagen I, collagen III, aSMA, fibronectin)

  3 months after end of study

• Biopsy biomarkers

  RNA-seq or qRT-PCR for wound healing related biomarkers (e.g. VEGFα, TGFβ1, TGFβ2, TGFβ3, PDGF, CTGF, TNF, IL-1B, IL-4, GM-CSF, IL-6, IL-10, MMP1, MMP3, OSM, LOX)

  3 months after end of study

• Clinical imaging

  3D photography

  3 months after end of study

• Clinical imaging

  Thermography

  3 months after end of study

• Clinical imaging

  Laser speckle contrast imaging (LSCI)

  3 months after end of study

• Clinical imaging

  Trans epidermal water loss (TEWL)

  3 months after end of study

• Clinical imaging

  Colorimetry

  3 months after end of study

• Clinical evaluation

  Red-Yellow-Black (RYB) wound assessment scale. Wounds are scored based on the color of the wound bed (from healthy to least healthy: red, yellow, or black). The least healthy color is chosen in multi-color wounds. Furthermore, a humidity subscale (dry, humid, or wet) is added to further classify the health status of the wounds.

  3 months after end of study

• Clinical evaluation

  POSAS. The observer scale of the POSAS consists of six items (vascularity, pigmentation, thickness, relief, pliability and surface area). All items are scored on a scale ranging from 1 ('like normal skin') to 10 ('worst scar imaginable'). The sum of the six items results in a total score of the POSAS observer scale. Categories boxes are added for each item: * Vascularity category: pale, pink, red, purple, mix * Pigmentation category: hypo, hyper, mix * Thickness category: thicker, thinner * Relief category: more, less, mix * Surface area category: expansion, contraction, mix Furthermore, an overall opinion is scored on a scale ranging from 1 to 10. All parameters are preferably compared to normal skin on a comparable anatomic location.

  3 months after end of study

Secondary Outcomes (5)

• Adverse events (AEs)

  3 months after end of study

• Local tolerance

  3 months after end of study

• Local tolerance

  3 months after end of study

• Local tolerance

  3 months after end of study

• Local tolerance

  3 months after end of study

Study Arms (1)

randomized repeated biopsy

EXPERIMENTAL

The study will entail 1 cohort with a randomized repeated biopsy collection time. Three skin punch biopsies (3 mm) of the lower back will be taken from each volunteer on day 0. One biopsy sample taken on day 0 will serve as a baseline measurement for the repeated samples regarding the histology, immunohistochemistry, and RNA sequencing (RNA-seq) or real-time reverse transcription polymerase chain reaction (qRT-PCR) assessments. Repeated biopsies of the same location as on day 0 will be taken on day 7, 14 or 21 (biopsy lesion and day randomized), and day 28, 42 or 56 (biopsy lesion and day randomized) for all subjects. The observation biopsy (biopsy lesion randomized) will serve as primary biopsy and followed for all measurements.

Other: Observation of wound healing

Interventions

Observation of wound healing OTHER

Observation of wound healing after skin biopsy

randomized repeated biopsy

Eligibility Criteria

• Age: 18 Years - 30 Years
• Gender Eligibility Details: 18 to 30 years of age (inclusive)
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy subjects, 18 to 30 years of age (inclusive). The health status is verified by absence of evidence of any clinical significant active or uncontrolled chronic disease following a detailed medical history, a complete physical examination including vital signs, blood sampling of hematology, chemistry, and virology, urinalysis, urine drug and cotinine testing, and alcohol breath testing. In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects.
• Body mass index (BMI) between 18 and 30 kg/m2, inclusive
• Fitzpatrick Skin type I-II (Caucasian type).
• Eligible lower back to perform biopsies (no excessive hair growth, no local skin disorder)
• Willing to give written informed consent and willing and able to comply with the study protocol.

You may not qualify if:

• History of pathological scar formation (keloid, hypertrophic scars)
• Any form of body modification of the lower back hindering biopsy collection of unaltered skin (e.g. tattoos, piercings, implants)
• Any disease associated with immune system impairment, including auto-immune diseases, HIV and transplantation patients.
• Requirement of immunosuppressive or immunomodulatory medication, including glucocorticoids, non-steroid anti-inflammatory drugs (NSAIDs), and chemotherapeutic drugs within 30 days prior to enrollment or planned to use during the course of the study.
• Have any current and/or recurrent pathologically, clinical significant relevant skin condition.
• Use of topical medication (prescription or over-the-counter (OTC)) within 30 days of the start of the study.in local treatment area.
• Pregnant, a positive pregnancy test, intending to become pregnant, or breastfeeding.
• Current smoker and/or regular user of other nicotine-containing products (e.g., patches).
• Average consumption of more than 14 units of alcohol per week
• Tanning due to sunbathing, excessive sun exposure or a tanning booth within 3 weeks of enrollment or planned to do so during the course of the study
• Participation in an investigational drug or device study within 3 months prior to screening or more than 4 times a year.
• Loss or donation of blood over 500 mL within three months prior to screening.
• Any (medical) condition that would, in the opinion of the investigator, potentially compromise the safety or compliance of the subject or may preclude the subjects' successful completion of the clinical trial.

Sponsors & Collaborators

• Centre for Human Drug Research, Netherlands: lead
• Maruho Co., Ltd.: collaborator

Study Sites (1)

Centre for Human Drug Research

Leiden, 2333 CL, Netherlands

Location

Related Publications (6)

• Dreifke MB, Jayasuriya AA, Jayasuriya AC. Current wound healing procedures and potential care. Mater Sci Eng C Mater Biol Appl. 2015 Mar;48:651-62. doi: 10.1016/j.msec.2014.12.068. Epub 2014 Dec 19.

  PMID: 25579968 BACKGROUND

• Greaves NS, Benatar B, Whiteside S, Alonso-Rasgado T, Baguneid M, Bayat A. Optical coherence tomography: a reliable alternative to invasive histological assessment of acute wound healing in human skin? Br J Dermatol. 2014 Apr;170(4):840-50. doi: 10.1111/bjd.12786.

  PMID: 24329481 BACKGROUND

• Greaves NS, Iqbal SA, Hodgkinson T, Morris J, Benatar B, Alonso-Rasgado T, Baguneid M, Bayat A. Skin substitute-assisted repair shows reduced dermal fibrosis in acute human wounds validated simultaneously by histology and optical coherence tomography. Wound Repair Regen. 2015 Jul-Aug;23(4):483-94. doi: 10.1111/wrr.12308. Epub 2015 Jul 31.

  PMID: 26053202 BACKGROUND

• Illigens BM, Gibbons CH. A human model of small fiber neuropathy to study wound healing. PLoS One. 2013;8(1):e54760. doi: 10.1371/journal.pone.0054760. Epub 2013 Jan 31.

  PMID: 23382960 BACKGROUND

• Ud-Din S, Greaves NS, Sebastian A, Baguneid M, Bayat A. Noninvasive device readouts validated by immunohistochemical analysis enable objective quantitative assessment of acute wound healing in human skin. Wound Repair Regen. 2015 Nov-Dec;23(6):901-14. doi: 10.1111/wrr.12344. Epub 2015 Nov 4.

  PMID: 26174693 BACKGROUND

• Ud-Din S, Perry D, Giddings P, Colthurst J, Zaman K, Cotton S, Whiteside S, Morris J, Bayat A. Electrical stimulation increases blood flow and haemoglobin levels in acute cutaneous wounds without affecting wound closure time: evidenced by non-invasive assessment of temporal biopsy wounds in human volunteers. Exp Dermatol. 2012 Oct;21(10):758-64. doi: 10.1111/exd.12005.

  PMID: 23078397 BACKGROUND

Related Links

• Basic principles of wound healing

MeSH Terms

Interventions

Wound Healing

Intervention Hierarchy (Ancestors)

Regeneration; Biological Phenomena

Study Officials

• Robert Rissmann, PhD

  CHDR

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Research Director

Model Details: A single-arm, observational study

Study Record Dates

• First Submitted: January 23, 2018
• First Posted: February 15, 2018
• Study Start: October 26, 2017
• Primary Completion: March 23, 2018
• Study Completion: March 23, 2018
• Last Updated: August 3, 2021

Record last verified: 2021-08

Locations

NL (1)