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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.
02/10/2019
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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.
1 2
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19/09/2019
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Affiliations to disclose†:
Funding for speaker to attend:
Self-funded
Institution (non-industry) 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
† All financial ties (over the last year) that you may have with any business organisation with respect to the subjects mentioned during your presentation
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
Proprietary & Confidential 12
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
7 8
9 10
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Proprietary & Confidential 13
WHY THE POSTERIOR TIBIAL
NERVE?
Proprietary & Confidential 14
ANATOMY OF
POSTERIOR TIBIAL
NERVE
13 14
15 16
17 18
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4
Proprietary & Confidential 24
IMPLANTATION
PROCEDURE
Mean “skin to skin duration: 34 min
MARKING THE INCISION SITE SKIN INCISION
20 21
22 24
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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
27 28
29 30
31 32
19/09/2019
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Proprietary & Confidential 36
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
Proprietary & Confidential 37
Results - Demographics
Dry: 5 (14%)
Proprietary & Confidential 38
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
33 34
35 36
37 38
19/09/2019
7
Proprietary & Confidential 39
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%
Proprietary & Confidential 40
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%≤
Proprietary & Confidential 41
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
**
*
**
*
*
**
Proprietary & Confidential 42
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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Proprietary & Confidential 52
Is it the future for OAB?
52
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Stem Cell Therapy in Functional Urology
Sherif Mourad, MD PhD
Affiliations to disclose†:
Funding for speaker to attend:
Self-funded
Institution (non-industry) funded
Sponsored by:
Sherif Mourad
No COI
ICSx
† All financial ties (over the last year) that you may have with any business organisation with respect to the subjects mentioned during your presentation
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.
Aboushwareb and Anthony Atala, 2009
Regenerative Medicine Strategies
Aboushwareb and Anthony Atala, 2009
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
Affiliations to disclose†:
Funding for speaker to attend:
Self-funded
Institution (non-industry) funded
Sponsored by:
Frank Van der Aa
Proctor for Boston Scientific
Advisor for Boston Scientific, Promedon
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
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)
Lamraoui et al. IEEE/ASME transactions on
mechatronics 2010:5(6);916-24
Automated detection algorithm
• Three-axis accelerometer inside AAUS
• Rectus abdominis mechanomyogram
– Decubitus detection
– Walking, running, jumping,…
– Bending, lifting,
Lamraoui et al. IEEE/ASME transactions on
mechatronics 2010:5(6);916-24
Automated detection algorithm
Lamraoui et al. IEEE/ASME transactions on
mechatronics 2010:5(6);916-24
A Retro-Compatible device
Hached et al. IEEE/ASME transactions on
mechatronics 2014:19(4);1352-62
A Retro-Compatible device
Hached et al. IEEE/ASME transactions on
mechatronics 2014:19(4);1352-62
Control module Hydraulics
Hached et al. IEEE/ASME transactions on
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
Hached et al. IEEE/ASME transactions on mechatronics 2015:20(6);3040-52
• Fast pressure regulation
• Postoperative remote configuration and control
• Wireless power delivery system
• Safety features (system failure/urethralcatheterization)
A Retro-Compatible device
• 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
Hached et al. IEEE/ASME transactions on mechatronics 2014:19(4);1352-62
Hached et al. IEEE/ASME transactions on mechatronics 2015:20(6);3040-52
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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[email protected] ICS Institute-School of Modern Technology via
https://www.ics.org/institute/technology
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