Intrauterine HIFU: A New Treatment for Uterine Fibroids

Marie-Caroline Faisant

, Benzion Amoyav

, Quentin Perrier

, Laura Eling

and Jayashree Rangaraja

Grenoble-Alpes University Hospital, University Gynaecology and Obstetrics Department, F-38000 Grenoble, France

The Institute for Drug Research, The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

Grenoble-Alpes University Hospital, University Pharmacy Department, F-38000 Grenoble, France

Rayonnement Synchrotron et Recherche Médicale, Université Grenoble Alpes, F-38000 Grenoble, France

Friedrich-Alexander University of Erlangen-Nuernberg, Erlangen, Germany

Keywords: Uterine Fibroid, HIFU (High Intensity Focused Ultrasound).

Abstract: Uterine fibroids are the most common benign tumours among women of child- bearing age with a prevalence

varying from 5.4% to 77%. The most common symptoms of uterine fibroids include: heavy menstrual

bleeding, pelvic pressure or pain and infertility. Symptoms can be influenced by the location, size and number

of fibroids. Fibroids are most often identified during a routine pelvic examination by a physician. Treatments

may include temporary medical treatments, surgery or uterine artery embolization. As all of the methods

above have considerable disadvantages, we propose a medical device using High Intensity Focused

Ultrasound (HIFU) in a minimally procedure in which an ultrasound probe is inserted into the uterus to

precisely ablate the fibroid and shrink it. Our new medical device proposal is aimed at improving clinical

efficacy and patient satisfaction.

1 INTRODUCTION

We are a team of biomedical engineers, pharmacists

and physicians including a gynaecologist who have

met during the Clinmed 2018 Summer School

organised by the EIT Health committee and the CIC-

IT network (Clinical Investigation Centre -

Technologic Innovation).

The Clinmed 2018 Summer School was an

immersive experience with the opportunity to meet

other students from various fields, assist to lectures

and workshops. It aimed at understanding the unmet

needs in healthcare industry and finally proposing a

feasible technological innovation from initial concept

till final development. Several teams were created

and associated to a specific CIC-IT centre. Our team

was located in Grenoble and supervised by Pr

Alexandre Moreau-Gaudry. Our goal was to create an

innovative medical device, in a two-week period,

during the summer school.

We address a current problem in gynaecology,

called uterine fibroids, which is widely known and

concerns a majority of women around the world. The

idea arose after interactions with healthcare

professionals and surgeons at the University Hospital

of Grenoble. The presentation of modern robots for

knee surgery kindled our interest on computer

assisted medical procedures and out of our expertise

we discovered the lack of efficient and less invasive

treatment of uterine fibroids in women. To overcome

important limits concerning sterilization and

maintenance of medical devices, the sterilization and

biomedical engineering department at the hospital

increased our awareness of today’s needs in health

care industry. Since health care-associated infections

are a non-negligible risk, we propose an innovation

that will reduce surgical site infection and take full

advantage of advanced computer technology to guide

the physician to target the fibroid and to ablate it.

Uterine fibroid is the most common benign

tumour among women. They occur in almost 70 % of

Caucasian women and in more than 80 % of African

American women by age 40 and a third of them are

symptomatic (Baird et al, 2003) (Khan and al, 2014)

(Stewart et al, 2017). Symptoms are heavy and long

menstrual bleeding, acute and chronic pelvic pain,

infertility, anaemia, urinary and digestive symptoms

(constipation). Symptoms depend on the localization

of the uterine fibroid as classified by the international

FIGO system.

Faisant, M., Amoyav, B., Perrier, Q., Eling, L. and Rangaraja, J.

Intrauterine HIFU: A New Treatment for Uterine Fibroids.

DOI: 10.5220/0007695205950602

In Proceedings of the 12th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2019), pages 595-602

ISBN: 978-989-758-353-7

595

2 TREATMENT OPTIONS

2.1 Current Treatment Options

2.1.1 Medical Treatment

Medical treatments for fibroids are only symptomatic

or temporary treatments. NSAIDS (non-steroidal

anti-inflammatory drugs) are used to treat acute

pelvic pain and tranexamic acid to treat heavy

bleedings. Hormonal treatments (GnRH) can be used

on a 3 to 6 months period or to prepare surgery.

Acetate ulispristal which induces apoptosis in

fibroid cells and therefore reduce significantly the

fibroid size. This treatment is indicated before

surgery or for women in whom surgery is not suitable.

However, this treatment has been reviewed recently

because of reported cases of liver injury and hepatic

failure.

2.1.2 Surgical Treatment

Nowadays we can consider three main types of

surgeries: hysteroscopy, myomectomy and

hysterectomy (Chanelles et al, 2010).

Hysteroscopy is a quick and safe procedure,

however it is only applicable for fibroids which are

reachable from the cavity.

Myomectomy; the local removal of the fibroid is

not always possible since it depends on the

localization of the fibroid. It can weaken the uterus

muscle and may lead to a preventive caesarean

section in case of a future pregnancy.

A final option is the hysterectomy which is the

total removal of the uterus. Today, uterine fibroid is

the main indication for hysterectomy.

This surgery may be complicated by urinary and

digestive per-operative wounds. Furthermore, many

women refuse hysterectomy out of sensible personal

reasons.

2.1.3 Non Invasive Treatment

Other treatments which are less invasive than surgery

exist to treat fibroid. The uterine artery

embolization is performed by radiologists, however

the inflammation and necrosis induced by the

embolization lead to painful recovery. Furthermore, a

pregnancy is not possible after a uterine artery

embolization.

Radiofrequency ablation (RFA) is another option

to treat fibroids, it is quite new and not well evaluated

yet.

2.2 HIFU Technology

2.2.1 Definition

High Intensity Focused Ultrasound, known as HIFU,

is an innovative technology which could promote an

alternative in fibroid treatment (Donnez J, 2016)

(Marret et al, 2010).

Ultrasounds are vibrations delivered by an

external transducer with a very high frequency. The

produced waves deliver energy as they travel through

tissues.

However, by increasing the intensity of the waves

and focusing them, HIFU technology deposits large

amounts of energy into tissues, which leads to the

ablation of cells in a focal point

Two main mechanisms are involved: the thermal

effect and the acoustic cavitation. With regard to the

thermal effect, the absorption of ultrasounds energy

into the tissues in a few seconds (with each pulse)

causes a sharp increase in temperature higher than

70°C, which leads to cell damage. The cavitation

effect is induced by the interaction of HIFU and

micro-bubbles in the sonicated tissue, it enhances cell

membrane permeability and leads to tissue ablation.

Both of these mechanisms lead to the destruction of

the cells by a coagulative necrosis.

2.2.2 Medical Application

Since 2000, HIFU technology is well known in

various medical fields. Dermatologists use HIFU

technology to treat wrinkles, it is nowadays

considered as a safe and effective procedure to

improve skin elasticity (Ko et al, 2017). HIFU

technology is also used to treat localized prostate

cancer where a probe is introduced into the rectum

next to the prostate, so that the urologic surgeon can

target and ablate the cancer (Gelet and al, 2009).

HIFU technology has been tested on fibroids; it has

demonstrated high efficacy, however, there are

considerable limitations as shown below. The

procedure is as follows: the patient is laying on the

abdomen on a surgical table. The HIFU transducer is

situated underneath the table. The procedure is

supervised by an MRI machine which controls the

heat produced by the HIFU waves (Marret et al,

2010).

External HIFU technology efficacy is controlled

by two main factors: the acoustic intensities and the

focalization of the ultrasound waves. Power

converters are used to increase and obtain efficient

acoustic intensities (the main goal is to obtain a power

of 100W/cm²). Focalization of the ultrasounds is

possible thanks to the use of several transducers at the

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same time. The total energy released is around 7500

joules which is equivalent to a heat of 70°.

One of the main advantages of HIFU is the

theoretic preservation of fertility.

However, the HIFU technique used to date is

limited by its external use, due to the following

reasons: risk of bowel perforation of the digestive

tract, risk of skin lesion, costly associated MRI and

no reimbursement, contraindications such as

abdominal scars, localization of the fibroid (next to

the spine, intracavitary, sub-mucosal, retro-versed in

the posterior wall of the uterus) and obesity (Marret

et al, 2010) (Bohlmann et al, 2014) .

3 THE MEDICAL DEVICE

We propose an innovative medical device inserted

directly into the uterus through the vagina. The probe

combines imaging ultra sounds to target the fibroid

with HIFU to ablate and shrink it.

As illustrated, the medical device is divided into

three parts: the two functions probe, the stabilizing

arm, and the machine. The probe is the only part of

the device that needs to be sterile. Once the probe is

inserted into the uterine cavity, the surgeon can fix the

probe and leave the operative field. Then, he can

manage the fibroid ablation from the computer.

Figure 1: Schematic illustration of the device.

3.1 The Probe

The probe will be made of stainless steel and will

include the imaging ultrasound device and the HIFU

transducer.

3.1.1 The Imaging Ultrasound

It consists of an ultrasound device which allows

precise real-time mapping and 3D reconstruction of

the organ including the fibroid. The treatment and

imaging process are interleaved to allow visual

tracking of the ablation.

This can be achieved by elastography and the

change of the speed of ultrasound waves due to

temperature change (Rueff & Raman, 2013)

(Tavakkoli & Sanghvi, 2011).

3.1.2 The Transducer

In the same probe a transducer is included which

allows HIFU ablation of the targeted tissue. The

ablation of the targeted tissue can be achieved due to

the thermic and the mechanic effect of HIFU (Donnez

J, 2016) (Rueff & Raman, 2013)

leading to a

coagulative tissue necrosis. The transducer is located

laterally and is approximately 6 cm long and 1 cm

wide. As explained above, we need several transducer

units to focalize the ultrasounds.

We will target the same goals as the external

HIFU technology: obtaining a power of 100W/cm²,

a total energy release of around 7500 joules which is

equivalent to a heat of 70°. This is a challenging

objective as we need to miniaturise the technology

currently used for HIFU technology. A first step

would be to try to adjust the frequency, the range and

the throb of the ultrasound waves. A second step

would be to work on various probe components to

find the one which maximises HIFU technology.

The transducer will be made of hard ceramic

piezoelectric material (e.g. titanium, nickel), that

characterized with low dielectric losses and

biocompatibility. This means that the probe can be

driven to higher frequencies and voltages, without

causing self-heating of the transducer (Vijaya, 2013).

For the time being, our device is limited to

laterally located fibroids, but we plan to create a

device which will reach any localization in the future.

Alternatively, we consider two different types of

HIFU transducer, one located laterally and one

located on top of the probe.

As illustrated below, we have planned to create a

probe with ceramic, within the probe, we need to

insert several transducers, the amplifier and the driver

pulse. The challenge is to obtain a 1 cm wide probe to

respect the uterine cervix.

Intrauterine HIFU: A New Treatment for Uterine Fibroids

597

Figure 2: Schematic illustration of the probe.

3.1.3 The Protective Cover

Due to the fact that the probe is inserted into a sterile

environment, it has to be covered with a sterile

disposable cover made of transparent and

biocompatible material which allows the transduction

of ultrasounds.

To allow the transduction of the ultrasounds, the

cover will be filled with and covered in conductive

gel.

To define the exact composition of the cover

material, the first lead is the plastic which is already

used for intra uterine cannulas (used in case of

aspiration curettage). Other sterile, latex-free covers

which are on the market are made of polyethylene but

are limited in our case due to the fragility and

therefore high risk of infection.

3.2 The Machine

3.2.1 The Screen

The screen allows the visualization of a 3D image of

the target and a colour code during the treatment in

accordance to the efficacy of the ablation (turning red

to green once the tissue is successfully ablated).

3.2.2 The Software

Contouring of the fibroid is done by the surgeon and

its precise localization in the uterus can be achieved

by the software. The energy and power level of the

HIFU pulses will be managed by the software.

3.2.3 The Arm

Since the treatment time may be long depending on

the fibroid size, the probe will be connected to a

stabilizing arm once it is set in place by the surgeon.

3.3 User Guide

A user guide will be provided with the device.

We recommend a gynaecologic positioning for

the patient for a better use of the probe.

A disinfection of the vagina and the use of an

operative field are necessary to reduce the risk of

infection.

A dilatation of the cervix to 11 mm is necessary

to insert the probe with its sterile cover.

Once the probe is in place, the surgeon uses the probe

to target the fibroid. The probe is then stabilized by

the arm and the HIFU ablation may start.

The patient should be fasting and we recommend

the placement of a urinary catheter to protect the

bladder.

Since the procedure is minimally invasive, the

patient is free to leave the same day without

hospitalization. It is expected that the recovery phase

will not take more than a few days, which is why sick

leave at work is kept at a minimum.

3.4 Advantages and Limitations

3.4.1 Advantages

With our device it is possible to avoid MRI control

during the HIFU ablation which therefore reduces the

cost of the operation.

It will be possible to treat fibroid in any

localization in the uterus since the probe is inserted in

close contact to the target. We will be able to treat

fibroids up to the size of 10 cm.

Contrary to HIFU external use, the risks of skin

irritation and bowel perforation can be considerably

decreased. Furthermore, the treatment of obese

women and women who already underwent

abdominal surgery, leading to scar tissue, is not a

restriction.

Compared to external HIFU we are closer to our

target and can therefore increase ultrasound

frequency. This way the sound waves are absorbed

faster (low penetration depth due to absorption)

which could increase the speed of treatment.

The patient will undergo general or epidural

anaesthesia during the procedure.

As the uterus is in the pelvis, the impact of the

patient breathing movements should be non-

significant. The bladder is kept empty thanks to thE

urinary catheter. Finally, the stabilizing arm

maintains the probe in the good position.

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3.4.2 Limitations

There are still limitations which are common with all

the current surgical treatments such as infections

(endometriosis, vaginitis, urinary active infection)

and malignant cervix tumour.

Furthermore, patients with uterine malformation,

fibroids with a size over 10 cm and fibroids localized

too close to the digestive tract should not be treated

with our device.

Hyper sensibility to components of our device is

a contraindication.

4 DEVELOPMENT PLAN

4.1 Risk Analysis

Our device is classed as a IIb medical device.

Risk assessment is very important as it is

considered as an integral part of an occupational

health and safety management plan. We have created

a table which gives an overview of the risks for our

medical device according to the new guidelines (ISO

14971). We used a severity colour code (red is

extreme severity, yellow moderate severity and green

is low severity):

Table 1: Risk analysis.

Frequent

Likely

Occasional

Rare

Catastrophic

infertility

miscar-

riage

Electric

hazard,

Uterine

synechia

perforation

Death,

anaphyl

-actic

shock

Haemor

-rhage

Critical

Damage

to organs

Software

issues

surgical

site

infection

Failure

Significa

Pelvic

pain,

Hypersensi

-tivity to

component,

loss of

blood

Breach

sterile

cover,

scar

tissue

Minor

Nausea

and

vomiting

Fever

after

surgery

4.2 Essential Requirements

4.2.1 Biocompatibility

The probe must pass all the biocompatibility tests and

allow the focused ultrasound waves to pass through

the cover.

We will use a special designed piezoelectric

ceramic material that will address our requirements

regarding safety and efficacy.

4.2.2 Risk of Infection

To keep the infection level as low as possible; we

propose a one-time use sterile cover filled with sterile

conductive gel. After use, the probe and the robotic

arm must be disinfected.

4.2.3 Risk of Electrical Hazards

To reduce the risk of electrical hazards, we will use

insulated electric wires and backup power supply to

ensure continuity and stress free surgical procedures.

4.2.4 Safety and Usability

Every device will come with a safety and usability

manual to ensure that the involved person is well

trained to conduct the procedure (workshops to train

the physicians in technical and software knowledge

are envisioned).

4.2.5 Software Requirements

We will guaranty the maintenance of the software

regularly. It will be our responsibility to upgrade the

software with the latest cybersecurity precautions to

ensure information protection.

4.3 Usability Evaluation

4.3.1 Effectiveness

Our device offers an effective way of treating fibroids

in the uterus, it is less invasive than surgical

treatments and therefore there is less risk of infection.

4.3.2 Satisfaction

We will propose a detailed usability manual to help

physicians integrate easily with the new product.

As gynaecologist surgeons know how to use an

endovaginal (or transvaginal) ultrasound probe, we

assume the learning curve will be fast. However, it is

essential to train gynaecologist surgeons about HIFU

Intrauterine HIFU: A New Treatment for Uterine Fibroids

599

technology, this may be possible through workshop

sessions.

The procedure will be performed by the

gynaecologist surgeon, this is an innovative added

value: the surgeon can schedule directly the

procedure on the surgery program, there is no more

need for a radiologist ( as for external HIFU

technology.) As there is only one physician involved;

the procedure organization is faster, the risk of

medical error decreases and the patient trust

increases.

Intrauterine HIFU use may lead to cost savings in

terms of hospitalization (ambulatory hospitalization)

and sick leave period (we recommend a one week sick

leave whereas a three weeks sick leave is often

needed after hysterectomy, myomectomy or uterine

artery embolization).

Furthermore, it offers a psychological satisfaction

to the patient (not losing the uterus and chances of

retaining fertility, no scar). HIFU technology is more

efficient than medical treatment and less invasive

than surgical treatment. The procedure is under

general or epidural anaesthesia, this allows the

procedure to be safe and painless.

4.3.3 Efficiency

Using an internal delivery of the HIFU technology

may require less time than the external HIFU use.

Moreover, with our device, there is no need for a

radiologist; the user of the device is the gynaecologic

surgeon.

Finally, the ambulatory hospitalization makes the

procedure easier and quicker.

4.4 Clinical Trial

We will conduct the necessary pre-clinical and

clinical tests (e.g. In vitro proof-of-concept test for

HIFU transducer) by accredited laboratories,

involving the required notified body with regard to

our medical device class.

4.4.1 Phase 1: In Vitro

We plan to study HIFU treatment efficacy on fibroma

cell culture. As for the safety test, we will study the

toxicity on myometrial and endometrial cell culture.

As we want our technique to be used for women

with infertility due to fibroid, we will be extremely

focused on the impacts of HIFU on the endometrial

tissue.

4.4.2 Phase 2a: In Vivo

We will test our device on animal models (healthy

sheep whose uterus have many similarities with

human uterus). We plan to obtain and study histologic

sampling post HIFU treatment to study the long term

effects on tissues ( study of the tissue after 3 days, 14

days, 2 months, 6 months, and finally after 1 year).

For each animal 4 treatment sites will be tested

(lateral, fundus, sub-mucosal, sub-serosal).

Other animal models are limited in our case, such

as horses (commonly concerned by fibroma, but too

expensive), ruminants(less expensive, but very rare

fibroma cases), rats (not comparable to humans due

to their size)

4.4.3 Phase 2b: Human Trials – Safety and

Efficacy

Our primary outcome will be the reduction of

symptoms according to the UFS-QOL scale and

patient satisfaction (opinion survey).

Our secondary outcome will be the reduction in

menstrual blood loss (using the PBAC score), the

decrease of the fibroid size (MRI 6 month after the

procedure).

Concerning the study population; the included

subjects will be women over 42 years old or women

older than 30 years with tubal ligation. Further

patients include those suffering from significant

fibroid symptoms for more than 3 months, uterine

fibroid FIGO classification type 1 to 7 or uterine

fibroid over 10 cm of size.

Subjects to be excluded are subjects with an

urgent need for surgery, pregnant women, less than

18 years old women, patient with a desire for

pregnancy, patients with severe endometriosis, pelvic

or uncontrolled systemic disease, history of lower

abdominal surgery and MRI contraindication.

So far, the exact number of patients is not known

but we estimate a total of 60 patients.

As for the trial follow-up we plan to evaluate the

success of the treatment with a MRI at 6 months to

measure the remaining fibroid tissue. We will control

the endometrial tissue by performing a hysteroscopy.

4.4.4 Phase 3: Human Trials – Comparison

We will study subjects with fibroma suitable for

external and internal HIFU (Fibroma type 4 to 6 with

an anterior localization), who are older than 18 years

old.

We will lead a prospective randomized study;

however, it won’t be possible to double-blind the

study.

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5 CONCLUSION

Intrauterine HIFU technology is the answer to a real

need for women.

Our device is promising, not only on a technical

point of view but also regarding the business and

marketing approach. Once this step is achieved, we

plan to improve our medical device by creating an

adjustable wide-angle probe and an automated

guidance arm to increase precision of HIFU treatment

of fibroids in every localization.

More indications will allow to expand our

technology, for instance endometrial hyperplasia or

patients with malign endometrium tumour who are

contraindicated to surgery.

ACKNOWLEDGEMENTS

This work received funding from EIT-Health campus

call (Project Grant Agreement n°18497).

We would like to thank the EIT Health committee and

its partners for organising the Clinmed 2018 Summer

School where we had the chance to meet and develop

our project. This was a rewarding experience.

This would not have been possible without the CIC-

IT from Grenoble and we would like to thank Pr

Alexandre Moreau-Gaudry, Isabelle Marque, Laura

Cotarla and the whole team.

We devote a special thanks to the University Hospital

of Grenoble for welcoming us in the different

departments we have visited. We warmly thank Dr

François Istasse from the gynaecology department

who answered our various questions about uterine

fibroids.

We would also like to thank Pr Frederic Patat and Pr

Jacques Felblinger who answered to our technical

questions about HIFU technology and helped to

feature our project.

Finally, we would like to thank Adria Maceira who

besides giving us marketing advices, supported us

and added to our project a special team spirit!

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APPENDIX

Competitors analysis :

GA = General anaesthesia

H = Hospitalization

SL = Sick leave

SSI = Surgical site infection

A = Anaemia

I = Infertility

FU = Final user, can be Gynecologist (G) or Radiologist (R) O = Occurrence

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