Download Imaging of the Chronic Wound and the Emerging Role of

Supplement to WOUNDS
Imaging of the Chronic
Wound and the Emerging
Role of Fluorescence
Microangiography
By William W. Li, MD and Jonathan Arnold, MD
T
echniques for imaging pathologi- development.4 Ischemic wounds seen in (ICG) — is a pragmatic and clinically
cal tissue are critical components severe peripheral arterial disease (PAD) useful approach.
of medicine and surgery practic- are unable to mount an adequate anes across many fields. While computed giogenic response.5 In pressure ulcers, Indocyanine Green Dye and
tomography (CT), magnetic resonance prolonged mechanical pressure prevents its Clinical Applications
imaging (MRI), ultrasound (US), and the completion of normal healing proIndocyanine Green (ICG) is a flustandard X-rays are occasionally used cesses, including angiogenesis, granu- orescent dye originally created by the
for anatomic assessment in patients with lation, and epithelialization. For these Eastman Kodak Company for use in
chronic wounds, there has been no spe- reasons, many advanced modalities have making a cyan-colored layer in color
cific modality for functional imaging in been developed and are in clinical use to photographic and movie film. Adapted
wound care until recently. Functional promote angiogenesis in the wound to for medical use in the 1950s as a bioimaging provides wound care practi- accelerate healing.
compatible dye detectable in blood, it
tioners information on parameters relatbecame FDA approved in 1956 for use
Advanced interventions that actively by cardiologists to measure cardiac outed to the ability for a wound to heal, and
helps to guide clinical decision-making stimulate wound angiogenesis include: put.6 As the dye is excreted exclusively
by directing treatment based on individ- • Recombinant growth factor
by the liver, it was used for hepatic an(becaplermin)
ual patient needs.
giography as well. Ophthalmologists
Angiogenesis, the growth of new • Platelet rich plasma (PRP)
began using ICG angiography to assess
blood vessels, is a critical process in • Living skin equivalents
the choroidal vasculature in the eye.6 An
1
(Apligraf, Dermagraft)
wound healing. New vessels contribute
ICG angiographic system called SPY
to forming granulation tissue and deliv- • Amnion/chorion membrane
was developed in 1999 to assess blood
(EpiFix, AmnioFix)
er oxygen, micronutrients, and paracrine
flow through vascular grafts and myosurvival factors to proliferating tissue after • Negative pressure wound therapy
cardial perfusion before, during, and after
injury. Notably, angiogenesis is compro- • Non-contact low frequency
cardiac bypass grafting.7 By 2007, SPY
ultrasound (MIST)
mised in virtually all wounds with detechnology was used in multiple medlayed healing. Defective angiogenesis is • Hyperbaric oxygen therapy (HBOT)
ical specialties ranging from plastic surobserved in diabetic foot ulcers (DFUs),
gery to gastrointestinal surgery.8 In 2013,
Despite a growing list of modalities, wound specialists began using ICG anvenous insufficiency ulceration, and in
wound care providers have been limit- giography to assess the microcirculation
ischemic and pressure ulcers.2
In people with diabetes, deficient ed to evaluating the wound and its re- of both acute and chronic wounds.
growth factors, impaired vascular en- sponse to treatment though superficial
Over its history, ICG has demondothelial cell response, and decreased visual assessment. The identification of strated excellent safety due to its short
vascular stem cell recruitment lead to biomarkers of wound angiogenesis is (3-5 minute) half-life, and its clearance
insufficient angiogenesis and wound therefore an important goal. While ge- by the liver.6 It is safe for patients with
healing.3 In contrast, venous leg ulcers nomic profiling of wound biopsies and compromised renal function. The only
(VLUs) exhibit morphologically ab- protein determination of wound fluid contraindication for ICG is in patients
normal microvessels that are stuck in are promising, imaging wound angio- with a history of sensitivity to iodides
genesis
— using
greenRoleand
the glomeruloid phase of microvascular
iodinated contrast
agents.9
Imaging of
the Chronic
Woundindocyanine
and the Emerging
of Fluorescence
Microangiography
1
This supplement was not subject to the peer-review process for WOUNDS
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Images courtesy of Stephen Guthrie, MD
Procedure and Generation
of Wound Data
Figure 1. Clinical case example 1: The initial clinical photo (left) shows a complex
wound on the medial aspect of the left ankle, posterior to the medial malleolus. This
patient had a previous motorcycle accident injury that required flap and graft repair.
The initial LUNA image (right) demonstrates a central area of relatively low signal
surrounded by hyperfluorescence. The darker low signal area suggests poor perfusion
while the brighter areas of high signal reflect inflammation-induced hyperpermeable
vessels around the wound.
Figure 2. Clinical case example 1: The follow-up clinical photo (left) after ten
hyperbaric treatments. The LUNA image (right) shows overall declining signal intensity.
Signal redistribution from the wound edge to the wound base suggests improved
microcirculation and better perfusion of soft tissues beneath the wound.
Figure 3. Clinical case example 1: The final clinical photo (left) shows near complete
epithelial tissue coverage of the wound. The final LUNA image (right) demonstrates
interval decline in fluorescent signal as surface wound healing nears completion.
LUNA Imaging of Wounds
LUNA is a fluorescence imaging system used in wound care for perfusion
assessment, consisting of a near-infrared
laser, high-definition camera, a central
processing unit, an operator touchscreen,
and a patient viewing screen. The system
can be moved easily to various exam
rooms. There is an articulating arm that
houses the camera head and light source.
The camera head is positioned over the
area being imaged and transmits the data
to the CPU, which is displayed on the
monitors in real-time following intravenous injection of ICG.10
Wound clinics use LUNA fluorescence
microangiography to obtain real-time vi-
sualization of tissue perfusion in patients
with diabetic ulcers, venous ulcers, ischemic ulcers, and other types of non-healing wounds. Its specific advantage is
providing visual as well as quantitative
assessment of wound and periwound
perfusion in a manner that is not possible with TcPO2 measurements or calculation of the ankle brachial index (ABI).
LUNA can directly assess the wound, aid
in precision-guided therapy, quantify the
impact of various wound healing techniques in driving the wound perfusion
back to tissue baseline over time, and assist physicians in determining when it is
appropriate to continue or switch treatments to optimize healing outcomes.11
ICG microangiography can be easily
performed in the outpatient wound clinic with the patient fully awake. Clinicians
place a peripheral intravenous catheter
and inject 2.5-3.0 mL of ICG intravenously followed by a saline flush injection. ICG enters the blood stream painlessly, is rapidly bound to plasma proteins,
and enters the microcirculation around
and within the wound bed.The resulting
fluorescence is captured by the HD video camera in real-time. Greater density of
microcirculation leads to increased fluorescence compared to the background.
Lesser density of microcirculation results
in a darker region within the image. The
wound microcirculation is analyzed by
the LUNA software and depicted on
viewing screens. The entire process takes
10 to 15 minutes per sequence.
Hyperfluorescence in Chronic
Wounds and its Resolution
with Proper Therapy
The observation of hyperfluorescence is often described with LUNA
images of chronic wounds. This phenomenon is typically asymmetrical and
seen around the wound periphery. Initially, hyperfluorescence was confusing
to clinicians who expected less fluorescence (hypofluorescence) in a poorly
healing wound due to deficient angiogenesis and granulation. However, this
phenomenon is easily explained by the
biology of activated microvasculature
in chronic wounds.
During normal wound healing, angiogenesis is stimulated by a variety of
growth factors delivered by platelets and
inflammatory cells. These factors activate
receptors on vascular endothelial cells
and stimulate new blood vessel growth.
One of them, vascular endothelial growth
factor (VEGF), is also a potent vascular
permeability factor.12 Accordingly, early
stages of wound healing angiogenesis exhibit leaky blood vessels with an increased
vessel density.As inflammation subsides in
normal wound healing, the permeability
decreases as inflammatory cells release less
VEGF and tissue oxygenation improves.
As the wound granulates and epithelial-
2 Imaging of the Chronic Wound and the Emerging Role of Fluorescence Microangiography
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Clinical Scenarios
Three common scenarios in which
wounds are imaged using the LUNA
system will be described with emphasis
given to the expected fluorescence image
findings. Clinical case examples of these
three common scenarios are illustrated in
figures 1-7.
Figure 7. Clinical case example 3: The follow-up clinic photo (left) shows a
dehisced amputation site. One week following percutaneous transluminal angioplasty
and stent placement within the right tibioperoneal trunk, LUNA image (right) shows
signal intensity increasing from 41% to 94% with reference to the left great toe.
Imaging of the Chronic Wound and the Emerging Role of Fluorescence Microangiography
novadaq_LUNA_September.indd 3
Images courtesy of Jonathan Arnold, MD, ABPM-UHM, CWS-P
izes, the neovasculature becomes pruned
to near basal levels, and eventually the activated blood vessels become quiescent.13
Chronic wounds are characterized by
persistent, sustained inflammation.14 The
activated vessels surrounding the wound
bed become stuck in the inflammatory,
hyperpermeable stage of healing. Wound
inflammation can be exacerbated by in- Figure 4. Clinical case example 2: The initial photo (left) of a dorsal left foot shotgun
fection, ischemia, repeated trauma, and a entry wound. The wound base extends to include deeper tissue layers and has disrupted
host of other etiologies associated with arterial and venous flow. Color contrast applied to the LUNA image (right) highlights areas
chronic wounds. Persistent inflammation of similar signal intensity. A reference marker has been applied to proximal non-wounded
leads to excessive and persistent expres- tissue and the central wound defect has been selected for further analysis. Comparing the
sion of VEGF and thus leakiness. In the reference marker to the selected region, LUNA shows a wound defect with 18% signal
chronic wound setting, ICG tends to col- intensity, confirming perfusion deficit.
lect in the activated blood vessels around
the wound perimeter and leak out due to
their inappropriate sustained permeability, resulting in hyperfluorescence.12
As proper wound care — sharp debridement, infection control, minimized proteases, maintenance of a moist
wound environment — is instituted, the
inflammatory stimuli are lowered. Initiation of an effective advanced wound Figure 5. Clinical case example 2: A follow-up photo of a shotgun wound (left)
therapy will actively promote cell pro- after one month of hyperbaric oxygen therapy. The central portion of the wound
liferation and migration that pushes the remains open with uncertain perfusion status due to magnitude of injury. The followwound from its dormant stage to con- up LUNA image (right) shows fluorescent signal increasing from 18% to 70%,
tinue through and complete the order- confirming effective angiogenesis.
ly sequence of healing.
Accordingly, with the initiation of
proper wound care, the hyperfluorescence seen by LUNA may transiently
increase as more angiogenic vessels are
stimulated to develop in the wound
bed. With progressive healing, the
wound area microcirculation becomes
less permeable and decreases in density
so the LUNA image will show progres- Figure 6. Clinical case example 3: The initial postoperative photo (left) of a
sively less fluorescence. Newly sprouted diabetic foot. LUNA imaging (right) confirms a suture line problem and identifies
angiogenic blood vessels are gradually decreased right second toe perfusion.
pruned back to more normal physiological levels.15 The resulting fluorescent signal decreases to more closely
approximate non-wounded tissue such
as the contralateral limb reference site.
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1. C
hronic wound. Following
injection of ICG, LUNA imaging
may demonstrate hyperfluorescence, compared to non-wounded
tissue, in an asymmetrical pattern
around the wound perimeter.
Within the wound perimeter,
there may be a hypofluorescence
in regions that lack perfusion and
require angiogenesis for healing.
Following the initiation of good
standard wound care, with or
without an advanced modality, the
healing wound may exhibit even
greater fluorescence, reflecting increasing angiogenesis. Subsequent
LUNA imaging should reveal
declining fluorescence as the tissue
heals and as the microcirculation
is pruned back to baseline levels
(Figures 1-3).
2. Acute wound. Fluorescent signal
behavior depends largely on the
mechanism, duration, and extent of
the injury. Soon after injury, ICG
penetration is limited by capillary
bed injury, causing affected areas to
appear hypofluorescent. These areas
of relatively low signal are associated
with compromised microcirculation and may be non-viable. With
appropriate treatment, the return of
microcirculation is seen by LUNA
as increased fluorescence, which will
then subside to basal levels as the
wound heals (Figures 4 and 5).
3. E
valuating vascular interventions. A low fluorescent signal
adjacent to the wound or injury suggests a proximal vascular
defect. LUNA imaging defines
areas of concern while establishing
a baseline, allowing for efficient
point-of-care monitoring before
and after intervention. Perfusion
improvements are verified by increasing signal intensity of specific
areas. Importantly, improved large
vessel hemodynamics noted on the
arteriogram may not translate into
improved microvascular status, thus
the value of visualizing functional
microcirculation at the wound
level (Figures 6 and 7).
Clinical Application of ICG
Fluorescence Microangiography
Chronic wounds
Obtain a baseline LUNA image of
the wound and surrounding area. For
reference purposes, image the contralateral limb or similar area. Perform
SPY-Q AutoView analysis of image
sequences. Monitor therapy via serial
monthly analysis. Effective therapy is
confirmed as AutoView metrics move
toward reference values.
for wound care by providing the first
visual biomarker to assess wound microvascularity at presentation, allowing
for the selection and precise application of advanced therapies and enabling longitudinal follow-up of this
biomarker until complete healing. Future wound interventions integrating
LUNA imaging during clinical trials
may discover a companion system for
optimizing wound management and
resource utilization.n
Acute wound, injury, or post-intervention
Obtain a LUNA image sequence of
the wound, injury, or poorly perfused
area. Repeat the LUNA sequence following intervention. Select the area of
interest using the SPY-Q region analysis tool. Increasing ingress and/or egress
values indicate improved status. Note
that vascular intervention effectiveness
may be visualized immediately and may
continue to improve over 1 to 2 weeks.
Dr. Li is the President and Founder of
the Angiogenesis Foundation in Cambridge,
Mass. He has disclosed that he is a consultant to Novadaq.
Summary
Wound bioimaging using ICG fluorescence microangiography is a new
technique that permits visualization
and qualitative and quantitative assessment of microcirculation surrounding
and within the wound bed. For chronic wounds, LUNA imaging is used to
assess the baseline status of the wound
microcirculation and monitor changes
reflecting therapeutic angiogenesis, improved perfusion, and return to normal
physiological vascularity. Hyperfluorescence is often observed asymmetrically in the wound perimeter, reflecting
an inadequate and abnormal angiogenic response where vessels are activated and stuck in a hyperpermeable
state. This form of hyperpermeability is associated with chronic inflammation and increased production of
VEGF. Successful treatment of chronic
wounds may lead to a transient increase in hyperfluorescence followed
by a reduction in fluorescence as the
microcirculation normalizes and returns to the physiological baseline.
Therefore, fluorescence microangiography represents a major advance
Dr. Arnold is the Medical Director of
the Great River Wound and Hyperbaric
Medicine Clinic at the Great River Medical
Center in West Burlington, Iowa. He has
disclosed that he is a consultant to Novadaq.
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This supplement was supported by NOVADAQ.
, LLC
an HMP Communications Holdings Company
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