Non-invasive imaging of Peripheral Vascular Disease with MultiSpectral Optoacoustic Tomography (PVD-MSOT), a Pilot Study.

This proposal describes an exploratory study, in which the feasibility and
clinical performance of a new imaging method, Multispectral Optoacoustic
Tomography (MSOT), is investigated in the context of Peripheral Vascular
Disease (PVD). PVD is a highly prevalent disease in the lower extremities
caused by an insufficient blood supply to the peripheral tissue, resulting in
significant morbidity, including limb amputation, and mortality [1]. The
prevalence in the general population is estimated at 19.1%, with a prevalence
of 8.1% in the age group 55-59 years to 55.8% in 85+ age group [2].
PVD severity is clinically divided into stages according to the Fontaine
Classification [3]. These stages are asymptomatic (Fontaine I), intermittent
claudication (pain) after walking (II), pain at rest (III) and ulceration/
necrosis (IV). This classification is used in the guidelines for diagnostics
and treatment of PVD at the UMCG [4].

The current practice in diagnosing PVD is medical history, combined with
physical examination, the Ankle Brachial Index (ABI), and supplemented with a
Duplex Ultrasound (DUS) to evaluate the severity and localization of arterial
obstructions. Digital Subtraction Angiography can be used for planning vascular
interventions. These current diagnostic modalities evaluate blood flow and
extent of stenosis in the major vessels, but this provides only indirect and
limited information about the blood supply to peripheral tissue and thus
severity of condition. The underlying cause of morbidity is a lack of
oxygenated blood delivered to peripheral tissue, which is not directly assessed
in current clinical practice. MSOT imaging could address this problem by
noninvasively imaging both large arteries and the microvasculature of the
foot. MSOT has the ability to provide physiological information about the
underlying peripheral tissue viability; i.e. hemoglobin concentration and
oxygenation. This approach could therefore provide previously unavailable
clinically relevant information about the extent of ischemia and most severely
affected regions at a macro- and microvascular level. This information could
ultimately enable earlier diagnosis, improved planning of interventions, and
more accurate treatment monitoring in patients with PVD.

To provide more reliable objective quantitative outcome measures in vascular
related diseases, such as PVD, there is a need for improved visualization and
characterization (i.e. quantification) of perfusion and oxygenation status
prior and after initiation of therapeutic measures.
Non-invasive MSOT imaging has several advantages over current methods for
quantitative measurements of perfusion and oxygenation: it does not use
ionizing radiation, it provides real-time molecular information on presence and
heterogeneity of a target with high-resolution real-time images, it is
relatively inexpensive, and it can be used as part of non-invasive procedures
in various disease states. We believe that this approach can provide insight
into the dynamic changes of revascularization or compromised
perfusion/oxygenation in PVD, thereby guiding treatment to improve outcome.
This study will investigate the feasibility and clinical performance of MSOT
imaging in patients with PVD in Fontaine stages II, III, and IV.
A total of 24 patients (8 per stage) will be imaged.

This study aims to investigate the feasibility and clinical performance of MSOT
imaging of the feet in PVD patients. Our main objective is to investigate and
obtain new information about the state of arteries in PVD patients using MSOT.
Our second objective is to investigate the use of MSOT compared to duplex
ultrasound and standard diagnostic work-up (including Fontaine classification)
in providing more information on microvascular perfusion and oxygenation in the
extremities in relation to severity of the PVD.

Patients diagnosed with PVD will be imaged using MSOT in this non-randomized,
non-blinded, prospective, single center feasibility study. The patients will be
imaged on both feet at particular landmarks, which include large arteries
(arteria tibialis posterior and dorsalis pedis) and microvasculature (on each
of the toes). The images will be compared to duplex ultrasound images of the
large arteries, which are acquired as part of the standard of care, as well as
other available diagnostic information, including the Fontaine classification.

Explanation of the safety of optoacoustic imaging for the non-expert
In a previous study using the same imaging system (LOW-MSOT, ABR43587, UMCG,
November 2013) on 10 healthy volunteers, no side effects or adverse events were
observed.

The only potential for side effects is from the laser beam applied to the
patient. The following facts provide assurance that the laser beam will not
cause side effects:
1. The applied light is nonionizing radiation. Only light in the red/near
infrared wavelength range will be applied. This means that the light cannot
cause the side effects that ionizing radiation can, e.g. DNA damage.

2. The use of lasers is governed by well-known standards (e.g. EN 60825-1
in Europe). These standards specify Maximum Permissible Exposure (MPE) limits
for the eyes and the skin, because eye damage and skin burns are considered to
be the potential biological risks. The study will comply to these standards.
Persons in the room will wear compliant laser safety glasses. The energy levels
will be kept below the MPE for skin. Compliance was tested before the previous
study (LOW-MSOT) by the person responsible for safety, along with technology
experts, at the UMCG. Regular checks with external reference measurement
systems as well as a continuous built-in monitoring of the laser energy density
will be performed to ensure compliance.

In addition to the theoretical safety and standards compliance, we summarize
the findings on the safety of optoacoustic imaging, as reported in the
scientific literature. To the best of our knowledge, there have been the
following clinical trials using optoacoustic imaging, using different devices,
but the same physical principle:
1. A study investigating imaging of breast cancer was published in 2007 by a
group at the University of Twente, the Netherlands [8]. The study was approved
by the METC of the Medisch Spectrum Twente. 13 patients participated in the
study.
2. A second study investigating imaging of breast cancer was published by the
same group in 2012 [9]. 17 patients participated in that study (although only
12 complete measurements were obtained).
3. A study of breast cancer imaging by a group in Texas was published in 2009
[10]. 27 patients participated.
4. An optoacoustic system for imaging arthritic finger joints was studied on 6
healthy participants by a group at the University of Michigan Medical School
[11].
5. A study of osteoarthritis by a group at the University of Florida,
Gainesville was published in 2011 [12].

No adverse events were reported in any of these studies.

Because the technology is considered to be safe, and it is being investigated
in many physics/ engineering laboratories globally, there have also been
publications describing studies on humans that are not clinical trials (i.e. no
involvement of patients or medical doctors), of which the following examples
involve similar devices to the proposed study:
1. Using the same device as in the proposed study, healthy volunteers were
imaged at the Technical University Munich (TUM) as described in a publication
in 2013 [5].
2. Using a different device, the same group in Munich imaged the neck and arm
in healthy volunteers [13].
3. A healthy volunteer was imaged on the arm by a group in Texas [14].

No side effects or adverse events have been reported in optoacoustic imaging
studies.