Trial Information

Clinical Validation Study of a 'Hand-held' Point-of-Care Fluorescence Digital Imaging Device for Real-time Detection and Diagnosis of Wound Infections and Longitudinal Monitoring of Wound Healing Status

Introduction and Rationale:

Wound care is a major clinical challenge and presents an enormous burden to health care
worldwide. As wounds (chronic and acute) heal, a number of key biological changes occur at
the wound site at the tissue and cellular level. Among these are inflammation, reformation
of the epidermal barrier, and remodeling of the connective tissue in the dermis. However, a
common major complication arising during the wound healing process, which can range from
days to months, is bacterial infection. This can result in a serious impediment to the
healing process and lead to significant complications, especially in chronic non-healing
wounds. Currently, the standard wound care includes monitoring for possible infection by
direct visual inspection under white light and by taking samples for analysis in the
laboratory which takes approximately two days to provide a result. However, qualitative
visual assessment only provides a gross view of the wound site (i.e., presence of purulent
material and crusting) but does not provide the critically important information about
underlying changes that are occurring at the tissue and cellular level (i.e., infection,
matrix remodeling, inflammation, and necrosis).

All chronic wounds contain bacteria. But whether the wound is in bacterial balance
(contamination with organisms on the surface or colonization with organisms in the tissue
arranged in micro colonies without causing damage) or bacterial imbalance (critical
colonization and infection) is of primary importance to healing. It is important to note
that there is a continuum of bacterial presence pro¬gressing from bacterial balance to
bacterial damage in a chronic wound. The diagnosis of infection is typically made clinically
based on signs and symptoms in and around the local wound bed, the deeper structures, and
the surrounding skin. The presence and severity of bacterial infection is typically
diagnosed based on the clinical appearance of the wound under white light (i.e., pain,
purulent exudate, crusting, swelling, erythema, heat). A major problem is that bacterial
contamination within and around a wound cannot be determined directly by visualization of
the bacteria themselves under white light, but is based on clinical signs and symptoms
caused by bacterial contamination and/or infection within the wound (i.e., pain, purulent
exudate, crusting, swelling, erythema, heat).

The remodeling and healing of connective tissues in wounds involves simultaneous synthesis
and degradation of collagen fibrils. These bacteria include common species typically found
at wound sites (i.e., Staphylococcus and Pseudomonas species). Bacterial swabs are
collected at the time of wound examination and have the advantage of providing
identification of specific bacterial/microbial species and quantification of bacterial
burden. However, often, multiple swabs are collected randomly from the wound site and these
are not targeted, and some swabbing techniques may spread the microorganisms around with the
wound during the collection process, thus affecting patient healing time and morbidity. This
may be a problem especially with large chronic (non-healing) wounds where the detection
yield for bacterial presence is suboptimal, despite the collection of multiple swabs.
Furthermore, bacteriological culture results often take about 2-4 days to come back from the
laboratory, thus significantly delaying diagnosis and treatment. Thus, bacterial swabs do
not provide real-time detection of infectious status of wounds. In addition, although wound
swabbing appears to be straightforward, it can lead to inappropriate treatment, patient
morbidity and increased hospital stays if not performed correctly. An image-based method
that allows real-time monitoring of wound healing, particularly early dermal connective
tissue remodeling, and the presence of bacterial contamination and/or infection over time
could have a significant clinical impact.

Autofluorescence imaging has been used in gastroenterology to image both collagen and
bacterial fluorescence in clinical studies. We wish to expand the use of tissue
autofluorescence imaging technology to wound care and management in order to provide obtain
biologically relevant information of the wound site at the tissue and biomolecular levels in
real-time during the healing process. When used to assess wounds, tissue autofluorescence
may aid in determining the degree of wound healing and the presence of bacterial infection.
In preliminary preclinical testing, we have discovered that when wounds are illuminated a
specific wavelength combination of excitation light, endogenous tissue components emit a
characteristic fluorescent signal, while bacteria emit a unique fluorescence signal.

We have recently developed an innovative optical molecular imaging platform based on
high-resolution fluorescence and white-light technologies in a hand-held, real-time,
high-resolution, non-invasive (e.g. non-contact) format. This invention offers real-time
detection of important biological and molecular information of a wound for the first time,
and could have significant impact on improving conventional wound care and management.
Based on extensive preclinical testing, the proposed technology has the capability of
collecting autofluorescence images of wounds and detecting the presence and relative changes
in connective tissue content and biodistribution involved in wound healing. It can also
detect the earliest indication of bacterial/microorganism contamination within the wound
(that are occult to standard white light visually-based assessment), thus providing a
measure of infection status. This could significantly impact clinical wound care and
management by i) reducing the complications associated with missed detection of bacteria
infection, ii) facilitating image-guided swabbing/biopsy and iii) monitor wound healing over
time. Furthermore, the compact and portable design of the imaging device platform makes it
ideal for the clinical wound care environment as well as for point-of-care use for
home-health care visits.

Study Objectives and Specific Aims

The primary objective of this clinical study is to evaluate the use and effectiveness of our
'handheld' fluorescence digital imaging device platform for real-time non-invasive clinical
monitoring of chronic wounds for healing and bacterial contamination/infectious status over
time. This will enable us to determine if the device can detect and longitudinally track
intrinsic changes that may occur during the wound healing process including, but not limited
to, collagen re-modeling and bacterial infection of the wound site.

As a secondary objective, we wish to obtain valuable end-user data on the clinical utility
of the device within the wound clinic environment. This information will be used to optimize
subsequent versions of the device during product development.

Most importantly, we hope to conclusively verify the added value that this imaging device
brings to traditional wound care practice, and to what extent it will change the gold
standard.

Specific Aims:

1. To determine if the fluorescence imaging device can detect changes in connective tissue
over time that can be correlated with wound healing or re-modeling, compared with
changes in wound size over time.

2. To determine the effectiveness of the fluorescence imaging device in detecting the
presence (or contamination) of bacteria in and around a wound (including infection),
compared with standard best practice methods (e.g. white light visualization and
clinical signs and symptoms, with swabbing and bacteriology as the 'gold standard').

3. To identify the relationships between autofluorescence imaging of tissues and bacteria
in wounds (including the wound margin) and the following: i) clinical signs of
infection, ii) microbial load (i.e., number of organisms per gram of wound tissue), and
iii) diversity of microbial species in the wound (i.e., number of different species
isolated per wound), and Gram signing.