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W25: ICS Institute - School of Modern Technology:

Adaptation of Technology to Functional Urology: New Era Workshop Chair: Emre HURI, Turkey

04 September 2019 14:30 - 17:30

Start End Topic Speakers

14:30 14:35 Introduction Emre HURI

14:35 14:50 A new generation wireless implantable tibial nerve stimulator

for refractory OAB

Alex Digesu

14:50 15:05 Stem cell therapy in functional urology Sherif Mourad

15:05 15:20 The role of artificial urinary sphincter in male and female

incontinence and new designs

Frank Van der Aa

15:20 15:35 Mesh implant technologies: why they fail ? Vik Khullar

15:35 15:50 3D medical printing and augmented reality clinical applications

in future of functional urology

Emre HURI

15:50 16:05 Discussion Emre HURI

Alex Digesu

Sherif Mourad

Frank Van der Aa

Vik Khullar

16:05 16:20 Break None

16:20 17:30 Hands-On Training Programme : Patient- specific CT-

Reconstructed 3D Printed Pelvic Model (TOT and TVT Training )

/Augmented Reality Cystoscopy and Laparoscopic Exercise

Emre HURI

Alex Digesu

Sherif Mourad

Frank Van der Aa

Vik Khullar

Aims of Workshop

The School of Modern Technology will work to deliver gold standard educational resources and project proposals in Modern

Technology to ICS members through eLearning and work placements at international centres of excellence. The aims of the

hands-on training course are: - talking on novel technological improvements related to functional urology - increasing awareness

of 3D medical printing and simulation modalities - exercise on 3D printed model and augmented reality model as a novel training

tools in new era.

Learning Objectives

learning novel technologies and application to functional urology

Target Audience

Urology, Urogynaecology, Basic Science

Advanced/Basic

Intermediate

Suggested Learning before Workshop Attendance

www.medtrain3dmodsim.eu

https://www.ics.org/institute/technology

A new generation wireless implantable tibial nerve stimulator for refractory OAB

Alex Digesu

The 3-years results of a prospective, multicenter, international clinical trial to assess the efficacy and safety of a novel wireless

implantable tibial nerve stimulator for the treatment of patients with refractory overactive bladder (OAB) will be presented

The aims of study were to determine the long term safety and performance of a novel implantable tibial neurostimulation

device (the BlueWind Medical RENOVA iStimTM System) for the treatment of OAB.

In this study a wireless peripheral neurostimulator device (BlueWind Medical Ltd.) was implanted on the posterior tibial nerve

approximately 5 cm above the medial malleolus and 2 cm posterior to the tibia in patients with refractory OAB. Local

anaesthesia was used unless general anaesthesia was clinically indicated. The implant that electrically stimulates the tibial nerve

is wirelessly powered by an external control unit (ECU). The ECU controls the therapeutic parameters and is worn by the patient

during a specified treatment period whilst at home. A Physician Programmer is also used to remotely set individual stimulation

parameters for each patient to optimize therapeutic outcome.

Refractory OAB patients with symptoms of urinary frequency greater than 8 times/24 hours and/or urinary urgency leaks of at

least 2 leaks/24 hours (both male and female) were enrolled, while those with clinically predominant stress urinary incontinence

or those suffering from any neurological disease or disorder were excluded The efficacy and safety of BlueWind Medical

RENOVA iStimTM system were assessed using a 3 day frequency volume chart, quality of life questionnaire (OAB-q) as well as

clinical examination for up to 36-months post activation. The McNemar's test for paired proportions was applied to compare to

the clinical improvement (i.e. ≥50% improvement in either number of urge-related incontinence episodes or number of urgent

voids) at 6-months with that of longer follow-up periods.

A total of 36 patients were recruited for the original pilot study and were followed for 6 months post activation of the device. All

36 patients were implanted successfully with mean procedure duration of 34.8 minutes. These results have been previously

reported.

Twenty-three OAB RENOVA iStim system implanted subjects were re-enrolled for the extended, 3-year follow-up study. Up to

date, 11 patients have reached 30-months follow-up. No SAEs were reported during the extended follow-up. In the per-protocol

analysis, 9 of the 11 patients (82%) have shown more than 50% improvement in either number of urge-related incontinence

episodes or number of urgent voids as compared to baseline. In the intent-to-treat analysis, 18 out of the 23 patients have

shown above 50% improvement (78%).

Therefore BlueWind Medical RENOVA iStim system demonstrates long term safety and efficacy. When comparing the results of

the long term follow-up to the 6-months follow-up, responders’ rates were similar at 6- and 30-months follow-up periods (74%

and 78%, respectively).

The BlueWind Medical RENOVA iStim System for the treatment of OAB demonstrates safety as well as sustainable successful

efficacy long-term results. A larger multicentre, international study is planned to confirm these promising preliminary data.

Stem cell therapy in functional urology

Sherif Mourad

The role of artificial urinary sphincter in male and female incontinence and new designs

Frank Van der Aa

Artificial urinary sfincter remains to date the best solution for severe incontinence both in males and females.

The design of the most frequently used device hasn’t changed over the last 30 years. Due to the vast experience clinicians have

with this device, we know several points were improvement for our patients could be achieved, for example better continence

rates, lower revision rates and easier device handling.

Currently, new devices with different design features are becoming available. We will discuss the differences in design and the

possible advantages of these new devices. Are these novel designs an answer to clinicians and patients expectations? Another

promising and imminent evolution is the incorporation of electronics into the device.

Besides new designs of the devices themselves, minimal invasive implantation techniques are also of interest. Pre-connected

devices decrease operation times and flaws in preparation of the filling solution or in connections. Certainly in females, robot

assisted implantation of AUS seems to deliver lower morbidity and even superior results.

As with all implants, high quality studies are sparse. When novel devices are introduced on the market, clinicians are confronted

with the dilemma to use the old device with its known values and defaults or to use the novel device that claims to have similar

or superior results.

Finally, the area of AUS is changing and innovations are coming on the market. These are exciting times for urologists using

these devices and for patients seeking help with severe incontinence.

3D medical printing and augmented reality clinical applications in future of functional urology

Emre Huri

Simulation has become widely accepted as a supplementary method of training. Within urology, the greatest number of

procedure-specific models and subsequent validation studies has been carried out in the field of endourology. Of the available

modalities, VR simulators are most commonly used for endourology and robotic surgery training, the former also employing

many high-fidelity bench models. Smaller dry-lab and ex vivo animal models have been used for laparoscopic and robotic

training, whereas live animals and human cadavers are widely used for full procedural training. Newer concepts such as

augmented-reality (AR) models and patient-specific simulators have also been introduced. Recently, the effectiveness of the

various type of simulations was indicated by many authors in the subdivisions of urological surgery training including urolithiasis

and stone treatment procedure , prostate surgery, transurethral surgery, ureteroscopy , percutaneous renal access(PCA) and

pediatric urological surgery . Additive manufacturing, or 3D printing (3DP) as it is commonly known, is a process used to create

3D objects from computer-aided designs (CAD). Using sophisticated software, the CAD-image files are graphically sliced into

successive two-dimensional layers representing the entire 3D object. These CAD images are then processed by 3D printers to be

assembled from an array of assorted materials. It was invented by Charles Hull in 1986. The advent of 3DP technology has

enabled the creation of a tangible and complex 3D object that goes beyond a simple 3D-shaded visualization on a flat monitor.

Since the early 2000s, 3DP machines have been used only in hard tissue applications. The potential applications of 3DP in clinical

medicine are numerous. It can allow physicians to create patient- specific models of pathology with such precise anatomic detail

that it facilitates pre-procedural planning prior to treatments. 3DP can also serve as an important teaching tool and training

adjunct in medical education not only for medical students and residents, but also in the counseling of patients and their

families with regards to disease management and procedural description. Finally, 3DP can allow for the creation of bio-printed

cells for the testing and development of novel medications or targeted agents to better replicate its potential use and efficacy in

actual patients. The most important surgical procedures in functional urology can be mimicked by 3D models and bio-cad

applications to obtain good surgical results and surgical education

Mesh implant technologies: why they fail?

Vik Khullar

The development of prosthetic materials for the treatment of pelvic organ prolapse is based on previously published

reoperation rates for POP of being as high as 30%. The main rationale for mesh use was the potential improvement of

anatomical restoration of pelvic floor structures and hypothetical reduction of the presumably high recurrence after standard

vaginal surgery. The material must be biologically compatible, chemically and physically inert, non-carcinogenic and

mechanically strong while remaining flexible, non-allergenic, non-modifiable by body tissue and non-inflammatory. However,

none of the currently available materials fulfills these requirements. This is one reason why the use of mesh is associated with a

non-negligible risk of complications such as vaginal exposure and extrusion, potential consecutive infections, granulomas,

dyspareunia, vesico-vaginal fistulas and chronic pain.

Many of these complications required further surgical intervention. In 2011, after the FDA issued a warning concerning

transvaginal mesh kits, many of these kits were voluntarily withdrawn from the market under economic and juridical pressure

and the use of synthetic material in POP surgery has dramatically decreased. Among the few studies which have analyzed the

risk factors for mesh exposure or retraction, one publication clearly identified tobacco use as a risk factor. Other potential risk

factors are diabetes mellitus, obesity, age, associated total hysterectomy, and surgical experience. However, little is known

about the exact role and the reaction of the host during and after mesh surgery. The inflammatory response as well as the

microbiological vaginal environment may be a determinant factor in the outcome after mesh implantation.

There will be a discussion about mesh, the problems and how complications could be reduced.

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ICS Institute - School of Modern Technology: Adaptation of Technology to Functional

Urology: New Era

AIMS:- talking on novel technological improvements related to

functional urology - increasing awareness of 3D medical printing and simulation

modalities - exercise on 3D printed model and augmented reality model

as a novel training tools in new era.Nikolaus Veit-RubinWorkshop Speaker

Affiliations to disclose†:

Funding for speaker to attend:

Self-funded

Institution (non-industry) funded

Sponsored by:

All Speakers

X

† All financial ties (over the last year) that you may have with any business organisation with respect to the subjects mentioned during your presentation

Please complete the in-app evaluation in the workshop before leaving.

Step 1, open app and select programme by day

Step 2, locate workshop

Step 3, scroll to find evaluation button

Step 4, complete survey –

• Handout for all workshops is available via the ICS app, USB stick and website.

• Please silence all mobile phones

• PDF versions of the slides (where approved) will be made available after the meeting via the ICS website so please keep taking photos and video to a minimum.

• During question time please stand up and giveyour name and country you are from.

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Self-funded


Sponsored by:

Alex Digesu

ICS Board of Trustee

ICS Educational Committee

ICS Urodynamics Committee

ICS Sczientific Committee

ICS Institute Steering Committee

Associate Editor Neurourology and Urodynamics Journal

IUGA Academy Chair

International Urogynecology Consultation Chair

Associate Editor NeInternational Urogynecology Journal

Investigator for Bluewind Trial

International Continence Society


Peripheral Neuromodulation:

It is not a new treatment!

▪ Scribonius Largus - in the first century AD

▪ Shocks from the torpedo fish, an electric ray, for headache

and gout.

EFFICACY

PTNS

• 60-80% of patients respond1-3

• Provides clinically significant

reductions in:

– Daytime voiding frequency 1

– Nigh-ttime voiding frequency 4-6

– Leakage episodes5, 7-8

1. Govier FE et al. Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J Urol 165: 1193 - 8, 2001.

2. Stoller M. Afferent nerve stimulation for pelvic floor dysfunction. Eur Urol 35(suppl 2): 16, 1999.

3. Visit www.uroplasty.com to view clinical abstracts highlighting patient response.

4. Vandoninck V et al. Posterior tibial nerve stimulation in the treatment of urge incontinence. Neurourol Urodyn 22: 17 - 23, 2003.

5. Ruiz BC et al. Peripheral afferent nerve stimulation for treatment of lower urinary tract irritative symptoms. Eur Urol 45: 65 - 9, 2004.

6. Klingler HC et al. Use of peripheral neuromodulation of the S3 region for treatment of detrusor overactivity: a urodynamic-based study. Urol 56: 766 - 71, 2000.

7. van Balken MR et al. Posterior tibial nerve stimulation as neuromodulative treatment of lower urinary tract dysfunction.

J Urol 166: 914 - 8, 2001.

8. Vandoninck V et al. Percutaneous tibial nerve stimulation in the treatment of overactive bladder: urodynamic data. Neurourol Urodyn 22: 227 - 32, 2003.

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▪ 11 patients successfully treated with PTNS

▪ Bladder diaries and Short Form-36 and IQoL

- after PTNS (T1)

- after a 6-week pause (T2)

- after retreatment (T3)

Maintenance is necessary for patients

with OAB who are successfully

treated with PTNS

WHAT NEXT ?

Proprietary & Confidential 10

Implantable wireless device?

Passive ImplantWearable

External Control

Unit

Physician

Programmer

11BlueWind RENOVA iStim™ system

• BlueWind RENOVA iStim™ system - A peripheral implantable neurostimulation device for the treatment of OAB

• The miniature implant is Battery-less, Wirelessly powered by an external control unit worn by patients at home for 30min daily

• The device electrically stimulates the Tibial nerve, modulating the neuronal signals to the bladder, urinary sphincter and pelvic floor

• A Physician Programmer is also used to remotely set individual stimulation parameters for each patient to optimize therapeutic outcome


RENOVATM

• New generation implantable tibial nerve stimulator device

• Minimally invasive and wireless

• Radiofrequency technology

• Electrode – 2.5 cm platinum iridium with silicone wings

• The implant does not contain a battery

• Powered by an external wearable unit/pacemaker (wirelessly)

• Frequency 0 – 20 Hz

• Intensity 0 – 9 mA

• External neuromodulator – 300 complete rechargeble cycles

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WHY THE POSTERIOR TIBIAL

NERVE?


ANATOMY OF

POSTERIOR TIBIAL

NERVE

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IMPLANTATION

PROCEDURE

Mean “skin to skin duration: 34 min

MARKING THE INCISION SITE SKIN INCISION

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INCISION OF THE FASCIA IDENTIFICATION OF N-V

BUNDLE

ELECTRODE OVER THE N-V

BUNDLE

TESTING SENSORY & MOTOR

RESPONSE

SECURING THE

ELECTRODECLOSING THE SKIN

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OPTIMIST Study design

36 implanted patients at 4 centers in The

Netherland and UK

Patients &

Clinical sites

Patients with OAB with or without urge

incontinence

Patient

Population Incidence of SAE (system and/or procedure

related)

Primary Endpoint

• Six-month clinical improvement

o Number of voids/day

o Volume voided/void

o Degree of urgency prior to void

o Number of leaks per day

In the presence of urge incontinence:

o Leakage episodes/day

o Severity of leaking episodes

o Absorbent pads used due to leaking/day

• Quality of Life Questionnaire – OAB-q

Secondary

Endpoints


Results - Demographics

Dry: 5 (14%)


Results - Safety

Single SAE (1/36; 2.8%):

– 41 year old

– Inflamed implantation site, pain and swelling.

– Sequelae: Event resolved following easy removal of the device

Easy and quick procedure with no complications and good healing

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UI: improvement > 50% – 51.7%

dry rate @ 6 months – 27.6%

7.120.7

27.6

42.924.1

24.1

14.313.8

6.9

0

10

20

30

40

50

60

70

80

90

100

Month 1 (n=28) Month 3 (n=29) Month 6 (n=29)Pe

rce

nt

of

UI i

mp

rove

me

nt

30-50%

50-99%

100%


Results: Improvement of urgency – 66.7%

34.5

53.366.7

13.8

23.3

23.3

0

10

20

30

40

50

60

70

80

90

100

Month 1 (n=29) Month 3 (n=30) Month 6 (n=30)

Pe

rce

nt

of

urg

en

cy s

ub

ject

s %

30-50%

50%≤


Results: Clinical Performance in UF Symptoms

12

9.59 9.4

7.5

6.1

4.1 3.8

161.7

180.7 183.6 179.3

0

20

40

60

80

100

120

140

160

180

200

0

2

4

6

8

10

12

14

Baseline Month 1 Month 3 Month 6

Vo

lum

e m

l

Pe

r d

ay

Void/day

Urgency degree

Volume/void

**

*

**

*

*

**


Discussion & Conclusion

• The RENOVA™ novel peripheral nerve stimulator is feasible & safe

– 66.7% of patients showed >50% improvement of OAB at 6 months

– 27.6% of UI subjects were dry at 6 months

– There is a trend toward improvement of the responders over time

– OAB-q results demonstrated significant improvements

• Advantages:

– 2.5 cm new generation implantable PTNS

– Battery-less

– Wireless

Simple and safe implantation procedure achieving objective and

subjective improvement for patients suffering from OAB

RENOVA iStim® System for the Treatment of OAB

Long Term – 3 Years Follow-Up Study

Digesu GA, Elneil S, Heesakkers JPFA, Van Kerrebroeck P

Patients Status

34Completed the pilot study

6 months FU

20 With at least one FU in

Extended study45

Pilot

(n=34, wet=29)

Extended

(n=20, wet=16)

Wet 29/34 16/20

BL voids 12 12

BL leaks 6.6 6.5

Age 54.1 56.1

Gender (F) 88% 80%

Success 74% 75%

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Durable Long-Term Effect of OAB Symptoms Relief

• Clinical Success: proportion of patients with ≥50% reduction in urgent voids (UF) or leaks (UI) or normalization of voids (<8 voids/day)

• Intent to treat (ITT) cohort – Patients with at least one FU data point in the study;

n=20

*LOCF– Last Observation Carried Forward, Mean follow-up duration of 34

months

71% 71% 75%

0%

20%

40%

60%

80%

100%

6m (n=34) 24m (n=17) 36m (n=16)

% r

esp

on

der

s

OAB Symptoms ReliefPer Protocol

70% 75%

0%

20%

40%

60%

80%

100%

6m *LOCF

% r

esp

on

der

sOAB Symptoms ReliefIntent To Treat (n=20)

• 16 out of 20 patients were wet OAB

• Clinical success: ≥50% reduction in leaks

52% 54% 58%

0%

20%

40%

60%

80%

6m (n=29) 24m (n=13) 36m (n=12)

% r

esp

on

der

s

UI ReliefPer Protocol

50% 50%

0%

20%

40%

60%

80%

6m LOCF

% r

esp

on

der

s

UI ReliefIntent To Treat (n=16)

Durable Long-Term Effect of Urinary Incontinence (UI) Relief

• Clinical success analyzed separately for:

o ≥50% reduction in leaks

o ≥ 50% reduction in large leaks*

Durable Long-Term Effect of Urinary Incontinence (UI) Relief

52%

85%

54%

86%

58%75%

0%

20%

40%

60%

80%

100%

Leaks Largeleaks

Leaks Largeleaks

Leaks Largeleaks

6m (n=29) 24m (n=13) 36m (n=12)

% r

esp

on

der

s

UI Relief Per Protocol

50%

80%

50%

80%

0%

20%

40%

60%

80%

100%

Leaks Large leaks Leaks Large leaks

6m LOCF

% r

esp

on

der

s

UI ReliefIntent To Treat (n=16)

* Large volume leaks characterize urge incontinence as opposed to the small volume leaks which characterize stress

incontinence episodes

Durable Long-Term Effect of Quality Of Life

Improvement

• Based on the validated OAB quality of life

questionnaire

• MID (minimal important difference) of 10 points

improvement in their QoL score is considered as

clinically meaningful improvement and acceptable

success thresholds

75%65% 73% 70%

0%

20%

40%

60%

80%

100%

6m (n=20) 24m (n=17) 36m (n=15) LFU (n=20)

% r

esp

on

der

s

HRQL (OABq) responders (>10 MID)

29.2 32.2

0

10

20

30

40

50

6m (n=20) LOCF (n=20)

HR

QL

sco

re im

pro

vem

ent

Health Related Quality of Life Improvement (OABq - HRQL)

MID

improvement in QoL scores - 3 folds higher than the accepted

meaningful important difference of 10.

Safety:Surgical Intervention due to AE or Device

Replacement• One SAE post procedure –

suspected wound infection →explantation

• Other mild adverse events were mostly post-insertion and short lasting

• There were no long term surgical revisions neither due to AEs nor device failures

Long TermShort Term

30.9% due to an AE 33.5% due to IPG replacement

No New Revisions or failures

3% (1/36) due to wound complications

13%-33%

Noblett et al. 2017, Neurourology and UrodynamicsSiegel et al. 2018, J Urol

• First long-term study of implantable Tibial stimulation for the treatment of OAB

– 70% responders in OAB symptoms

– 50% and 80% responders in leaks and large leaks respectively

– 70% responders based on OABq

• The long-term ITT cohort accurately represents the original 6m ITT pilot cohort

• Very clean safety profile and no device technical failure over 3 years

• Advantages of the RENOVA iStim® system:– Miniature leadless, Battery-less, Wireless implant

– Simple and safe implantation procedure

– Home use

– Individually tailored treatment

– Significant short and long term improvement in OAB symptoms

Conclusion: Durable High Success Rates & Clean Safety Profile

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Is it the future for OAB?

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Stem Cell Therapy in Functional Urology

Sherif Mourad, MD PhD



Self-funded


Sponsored by:

Sherif Mourad

No COI

ICSx


Regenerative Medicine

• The goal of regenerative medicine is to replace or restore normal function of cells, tissues and organs that have been damaged by disease or injury.

• Regenerative medicine strategies usually fall into one of three categories:– cell-based therapy,

– the use of biomaterials (scaffolds) alone, or

– the use of scaffolds seeded with cells.

Aboushwareb and Anthony Atala, 2009

Stem Cells

• The stem cell has long been regarded as the ideal resource for cell-based therapeutic strategies.

• Stem cells are defined by three important properties:– The ability to self-renew.

– The ability to differentiate into a number of different cell types.

– The ability to easily form clonal populations.


Regenerative Medicine Strategies


Stem Cells in Urology

• Regenerative medicine and tissue engineering strategies are becoming a viable option for replacing diseased or damaged organs, particularly in the urinary tract.

• Adult stem cells would be an ideal source of autologous cells for production of new organs, but because they can be difficult to isolate and expand in vitro, their use has been limited.

Jensen UB et al. (2008)

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APPLICATIONS FOR STEM CELLTHERAPY IN UROLOGY

Lower Urinary Tract Reconstruction

• Stem cells could be used for seeding of artificial scaffolds, which could then be used for bladder replacement.

• These cells were successfully isolated from a small bladder biopsy sample, which yielded both urothelial and muscle progenitor cells, and were grown on a bladder-shaped scaffold.

Atalla et al, 2006

Lower Urinary Tract Reconstruction

• Patients with small neurogenic bladder were treated with augmentation cystoplasty with an autologous, bioengineered bladder.

• The engineered bladders demonstrated excellent tissue survival, and remodeling of the engineered bladder into normal bladder tissue was seen.

• To date, multiple clinical studies have shown successful urethral augmentation using an acellular bladder matrix graft.

El-Kassaby A et al. (2008)

APPLICATIONS FOR STEM CELLTHERAPY IN UROLOGY

Stem Cell Therapy for Urinary Incontinence

• Cell therapy for urinary incontinence resulting from sphincter insufficiency has been studied extensively, and clinical trials have been performed.

• Animal studies have shown temporary and long-term improvements to sphinctericfunction with treatment.

Cannon TW et al. (2003)

Sherif Badra1,2, Koudy Williams2, and Sherif Mourad1

1Department of Urology, Ain Shams University, Cairo, Egypt2Wake Forest Institute for Regenerative Medicine, WinstonSalem, North Carolina, USA

Cell Therapy in a Nonhuman Primate Model of Stress Urinary Incontinence

Introduction• Stress urinary incontinence (SUI) affects the quality of life

for millions of women worldwide.

• The different treatment strategies are still far from idealwith 30% of women undergoing a second anti-SUIsurgery.

• Autologous cell therapy has been proposed as a“permanent” cure of sphincter-related SUI, and is thesubject of ongoing clinical studies, but the role of injectedcells in regeneration of the sphincter complex remainsunclear.

Objective

• Female Nonhuman Primates (NHPs) sit at the nexus ofclinical translation because of their human-likereproductive physiology, lower urinary tract structure, andbi-pedal posture.

• Therefore, the objectives of the study were:

– To develop a NHP model of urinary incontinence.

– To explore the role of autologous muscle precursor celltherapy on regeneration of sphincter structure andfunction.

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Experimental Design and Methods

38 adult female cynomologus monkeys. Age equivalent of 40 years-old women

Baseline urodynamic and nerve stimulation measurements

Divided into 3 groups:

control (n=4)

injured (n=18)

injured +cell treated(n=16)

Injured and Cell treated groups: Bilateral denervation of pudendal nerve branches to the urinary sphincter complex + muscle biopsy

6 weeks

Injection of 5 million lenti-GFP labeled cells in sphincter complex

Functional and structural changes at 3, 6, and 12 months

Pudendal Nerve Transection

Pre injury Post injury

Skeletal Muscle Progenitor Cells IsolationCynomolgus monkey Muscle biopsy Muscle minced

Passage 0 confluent Collagenase enzyme IMuscle progenitor cells migrating from myofibers

Cell Characterization and Labeling

Desmin -10xMyoD -10x MHC -10x

BF -10x GFP -10x GFP -40x

• Skeletal muscle biopsy was taken to isolate muscle precursor cells.• Cell characterization• Cells labeling: lenti-GFP (>90% labeling).• 5 million cells were injected in 4 locations around the sphincter.

Results: Resting Sphincter Pressure

Baseline 1 month 3 month 6 month 12 month

* * **

Results: Pudendal Nerve Stimulation

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Results: Cystourethrography

Radiography of the bladder neck showing • dilatation of the urethra in the sphincter region after injury• restoration of the outflow diameter cell injection

Results: Muscle Content by Immunohistochemistry

skeletal muscle red, smooth muscle green and nuclei blue

Control Injury Cell injection

Results: Labeled Cells Integrated within Skeletal Muscles of Sphincter

Conclusions

• We have developed a Nonhuman Primates (NHP)model of stable urinary sphincter dysfunction.

• Cell therapy promoted regeneration of urinarysphincter in a female nonhuman primate model.

• This study provides translational evidence thatcell therapy may be of use to treat this form ofurinary incontinence.

Conclusions• It is unclear which type of stem cell will

provide the best resource for cell-based therapy; in fact, the optimum cell type in a particular situation will depend on the clinical scenario.

• Tissue progenitor cells are excellent candidates for tissue engineering of organs, such as the bladder.

• Although tissue progenitor cells have restricted growth and differentiation potential, they have low potential to form tumors and mixed phenotype populations.

Thank You

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Frank Van der Aa

Functional and Reconstructive Urology

Neuro-urology

THE ROLE OF ARTIFICIAL URINARY SPHINCTER IN MALE AND FEMALE INCONTINENCE AND NEW DESIGNS



Self-funded


Sponsored by:

Frank Van der Aa

Proctor for Boston Scientific

Advisor for Boston Scientific, Promedon

X


CURRENT STATE

AUS anno 2019

• The best solution for males with moderate to severe SUI

• Most patients will cary 0 – 1 pad aftersphincter implant

• “not dry as a bone”

• Realistic expectations!

– Accept complication risks

– Accept dry rate (certainly on the long run)

Viers et al. J Urol 2016:196;838-43

AUS anno 2019

• First used in 1972, first report in 1974

• Deactivation button (1983)

• Narrow backed cuff (1987)

• Kink resistant tubing (colour coded) (1988)

• Quick (and Y) connectors

• Inhibizone coating (2001)

Scott et al. J Urol 1974:167;1125-9

But @ what price?

• High reoperation (26%, range 14,8 –44,8%) rate due to:

– Erosion/infection in 8,5% (3,3 – 27,8%)

– Mechanical failure in 6,2% (2,0 – 13,8%)

– Urethral athrophy in 7,9% (1,9 – 28,6%)

Van der Aa et al. Eur Urol 2013:63(4);681-9

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Female AUS

• More exceptional, underused?

• Robotic implant opens new perspectives?

– Less postoperative complications

– Shorter hospital stay

– Lower explantation rate

• Anterior approach versus posterior approach

Gondran-Tellier et al. BJU Int 2019: doi: 10.1111/bju.14884. [Epub ahead of print]

Peyronnet et al. Eur Urol 2019:75(1);169-75

Peyronnet et al. Int UroGyn J 2016:27(3);475-81

Current AUS: general weaknesses

• user friendliness (women, older people)

• low dry rate (relative)

• high revision rate due to mechanical (easy and completely solvable) but also due to tissue complications (sometimes irreversible) NOVEL DESIGNS ON THE MARKET

VICTO and VICTO plus

Knight et al. Eur Urol 2006:50;574-80

Weibl et al. Cent Eur J Urol 2018:71(2);248-9

Victo plus

• Stress Relief balloon (conditional occlusion)

• Pressure adjustment possible→ loweroperating pressure

Knight et al. Eur Urol 2006:50;574-80

* Data from Promedon

*

Victo (plus)

• Pre-moulded cuff

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Victo (plus)

• Adjustment of operating pressure

0

10

20

30

40

50

60

70

80

90

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PR

ESSU

RE

[cm

h20

]

Volume [ml]

Data on file (Promedon)

ZSI 375

• One piece preconnecteddevice

• No abdominal reservoir

Staerman et al. BJU Int 2012:111;E202-6

ZSI 375

• Pre-moulded cuff

• Pressure regulating tank with

– Hydraulic circuit

– Compensation pouch

Staerman et al. BJU Int 2012:111;E202-6

eAUS

eAUS

• Basic idea = simple replacement of manual pump by automated pump

• Opportunities:

– Integration of dynamic pressure components

– Data recording/analysis; feedback loops

– Smart design

Not a new idea…

Lamraoui et al. IEEE/ASME transactions on

mechatronics 2010:5(6);916-24

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Features

• No manual pump

• Conditional pressures

– Automated

– Patient controlled

• Safety features

– Catheter alert (high OCP detection)



Automated detection algorithm

• Three-axis accelerometer inside AAUS

• Rectus abdominis mechanomyogram

– Decubitus detection

– Walking, running, jumping,…

– Bending, lifting,



Automated detection algorithm



A Retro-Compatible device

Hached et al. IEEE/ASME transactions on

mechatronics 2014:19(4);1352-62



mechatronics 2014:19(4);1352-62

Control module Hydraulics


mechatronics 2014:19(4);1352-62

A Retro-Compatible device: configurations

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Hached et al. IEEE/ASME transactions on mechatronics 2014:19(4);1352-62

A Retro-Compatible device: configurations


• Fast pressure regulation

• Postoperative remote configuration and control

• Wireless power delivery system

• Safety features (system failure/urethralcatheterization)


• Remote control for opening and closingAND for deactivation (nighttime “restingperiod”)

• Remote reconfiguration of cuff pressure

• Installation in patients who already have anAMS 800 without cuff/balloon change



Non-hydraulic devices

• Myopowers – ARTUS device

• Implanted in pigs and human cadavers

Ludwig et al. CJU 2015:22(6);8100-4

THE FUTURE

Shape memory alloys

• Crystal alloys (eg. Nickel-titanium)

• Temperature dependent shape changes

• Can be used for millions of cycles

• High power consumption, requiring high capacity batteries or sophisticated thermalisolation…

• Slow response rate…Muller et al. SWISS MED WKLY 2009:139(41-42;591-5

Valerio et al. BJU Int 2013:112;E337-343

Shape memory alloys

• Can be used for millions of cycles

• High voltage required

• Slow response rate

Muller et al. SWISS MED WKLY 2009:139(41-42;591-5

Valerio et al. BJU Int 2013:112;E337-343

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Electroactive polymer (EAP) actuators

• Two electrodes with isolating, deformablepolymer in between

• Very fast response rate

(milliseconds)

• Needs kilovolts!

Muller et al. SWISS MED WKLY 2009:139(41-42;591-5

wikipedia (image)

Conclusion

• Novel AUS designs are on the market

• They have promising features both forimproving dry rate and for decreasingrevision rates

• BUT they are currently understudied and did not yet proof equivalence

Conclusion

• eAUS designs are on the way…

• Although the concept in se is notrevolutionary, these devices might change the game

– Lower baseline pressure, variable pressure

– Smart design

– Safety features

Conclusion

• Novel materials such as electroactivepolymer actuators or shape memory alloysneed further basic development, but couldbecome interesting in the future

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3D Medical Printing and Augmented RealityClinical Applications in

Future of Functional Urology

Emre HURİ, MD-PhD, FEBUAssociate Professor of Urology

Hacettepe University, Faculty of Medicine, Urology DepartmentIEEE-EMBS 3D Based Medical Application WG Vice-Chair

MedTRain3DModsim EU Project DirectorICS School of Modern Technology, Director

3D APPLICATIONS(3D Printing-Simulation)

Healthcare Professionals

Engineering

3D Printing3D Simulation

- Virtual Reality (VR)

-Augmented Reality (AR)

3D Bio-CAD

(Computer Aid Design)

- Surgical Training

-Medical Education

-Surgical Planning

-Patient Education

3D MODELLING

FLOWCHART OF 3D MODELLINGFROM RADIOLOGIC IMAGES TO 3D MODELS

Segmentation-Modelling

AI Based 3D Organ Modelling

Visualization

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VIRTUAL 3D MODEL

PRINTED 3D MODEL

3D Modeling of Bone VS Kidney

Techniqually easier compared to soft tissue segmentation

• Medical images from hospitals consist of a two-dimensional (2D) dataset and provide human body information as a slice, but the human body has three-dimensional (3D) morphology

• If we should simulate this 3D morphology : to obtain more information about the body as well as contribute in the clinical environment to both treatment and surgical outcomes.

• Objective is to generate 3D medical data from 2D images.

• Although doctors expend a great deal of time and effort in this process, the resultant 3D data are different in each institute. This protocol, therefore, provides standard, easy, and accurate 3D data for clinical fields and even for industrial markets.

Functional UrologicClinical Use Case

«Pelvic-Perineal Region»

CT Reconstructive Image Rendering Surgical Planning Use Case

Vesicovaginal Fistula

Huri, Kim, Moon, ICS Congress, 2017

Materialise Software Mimics Programme

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ake

• 3D printing is currently a $700 million industry, with only $11 million (1.6%) invested in medical applications.

• In the next 10 years, however, 3Dprinting is expected to grow into an $8.9 billion industry, with $1.9 billion (21%) projected to be spent on medical applications.

More research sources and more clinical purposes in functional and reconstructive surgery

Additive Subtractive

3D Printing

• tissue and organ fabrication• creation of customized prosthetics, implants, and

anatomical models• production medical devices

•Real 3D printed educationalmaterials

•Processing to mimic thesurgical models

•Materials: silicone, metal, wax, plastic, recin, polyurethane, hydrogel, gelatin/agar mixture and high-acyl gum

DICOM: Digital Imaging and Communications in MedicineSTL: polygonal mesh

A digital file (DICOM) to createSTL (Standard Tesselation Language)

What is 3D Printing?

• A form of Additive Manufacturing– process of joining materials to make an object

from 3D model data; layer-by-layer process

• A manufacturing method in which objects are made by fusingor depositing materials—such as plastic, metal, ceramics, powders, liquids, or even living cells—in layers to produce a 3D object

Type of Additive Manufacturing“most commonly used 3D printer technologies in medical applications”

SLS (Selective Laser Sintering)

FDM (Fused Deposition Modeling)

Three Phases of Manufacturing Process using 3D Printer

31 research articles

•3D printing is thevehicle for productionof anatomical replicasfor two intents.

- study andvisualization (staticbiomodels)

- simulation of medical procedures(physical simulators).

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Benefits for Education3D Printing

• Decrease the cost (10 to 2600 US dolar) with using virtual based 3D printed and edited models compared the other models on trainingbasis

• Using technology and printed materials for better understanding 3D surgical anatomy

• Creating 3D printed medical models for dry lab training(laparoscopic/endoscopic/robotic surgeries)

• Once digital definitions (STL files) are secured, the specimen can be reproduced in any quantity, reusable material

• For biomodels, advantage of enlarging the specimen to increasevisibility for hard-to-see structures

• For simulation, is the ability tocomplete entire procedures in a no-risk environment

• 3D printed simulators affordstrainees the ability to repetitivelyperform and perhaps master thebasic maneuvers that are thecornerstone of the procedure.

Tai BL et al, J Neurosurg, 2015Waran V et al, J Neurosurg, 2014Balestrini C et al, Med Teacher, 2015Adams JW et al, Br J Oph, 2015

While various fields from the automotive industry to the aerospace industry have embraced this technology, healthcare has been slow to adopt this technology even though an excess of $155 billion is spent on medical devices yearly

Myth ? Real ?

Production Functional Organs

MODELS

VARIABLES KIDNEY URETER BLADDER PROSTATE + URETHRA PELVICB BONE SACRUM SILICON KIDNEY VESSEL

Image Process Variable

Pixel size 0.5 mm 0.5 mm 0.5 mm 0.5 mm 0.5 mm 0.5 mm N/A 0.5 mm

Slice thickness 1 mm 1 mm 1 mm 1 mm 1 mm 1 mm N/A 1 mm

Modeling Process Variables

Modeling Time ~ 8 hour ~ 3 hour ~ 4 hour ~ 3 hour ~ 5 hour ~ 4 hour ~ 12 hour ~ 3 hour

Anatomic suitability ± 1 mm ± 1 mm ± 1 mm ± 1 mm ± 1 mm ± 1 mm ± 1 mm ± 1 mm

Production and Post Process Variables

Production Technology SLA SLA SLA SLA FDM FDM Tersine Mühendislik SLA

Production resolution 0.025 0.025 0.1 0.1 0.2 0.2 0.1

Production Period ~ 16 hour ~ 8 hour ~ 10 hour ~ 9 hour ~ 32 hour ~ 18 hour ~ 36 hour ~ 10 hour

Post process Period ~ 3 hour ~ 2 hour ~ 1 hour ~ 2 hour ~ 2 hour ~ 2 hour ~ 5 hour ~ 2 hour

Material Type (soft/hard) Resin/Hard Resin/Hard Resin/Hard Resin/Hard PLA/Hard Resin/Hard silicon/soft Resin/Hard

Variables of 3D Printed Models

Huri,E. TJMS, 2019, Accepted Article

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Physician Role

• Decision for use

• Collaboration with engineers

• Anatomy knowledge

• Post-process of 3D printedmodels for usefullnes

• Standardization and validation

• Low-cost and re-usablemodels selections

• 3D Modelling (software-hardware)

- Segmentation

- Texture

- Volume rendering

• 3D Printing Technology

- Selection material

- Post-process

• Virtual model creation

• Cost-effectivety

Engineering Role

IEEE-EMBS Platform

Patient-specific 3D CT- Reconstructed Printed Physical Simulator

3D printed models are effective as muchas cadaveric models for surgical skill

training

M3DM UroExperimental

PHYSICAL 3D PRINTED URINARY SYSTEM(created from PATIENT SPECIFIC DATA)

Rectum

Prostate

Prostate nodüle(hard)

Basic 3D Printed Digital Rectal Examination Model(Benign/Malign Prostate)

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3D Printed Training Box VIRTUAL/AUGMENTED REALITY

• Type of simulation model, not 3D modelling

• CT scan is helpful for rendering

• Preoperative/Intraoperative Use Case

• Effective for:- patient education /

treatment- physician training /self

training- standardization of medical

data

AUGMENTED REALITY BASED CYSTOSCOPY(Leap Motion Technology)

Hu-Mo VR SimulatorCystoscopy Model

Hu-Mo VR SimulatorLaparoscopic Nephrectomy

New European Union Project Proposal for Hybrid Training in Pelvic SurgeryAnatomy- Based 3D Printed-VR/AR- Cadaveric- Live Surgery

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