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Innovative regenerative treatment Innovative regenerative treatment
forfor the tympanic membrane the tympanic membrane perforation perforation
New York University, May 5New York University, May 5 2011, New York, USA2011, New York, USA
Shin-ichi Kanemaru, M.D., Ph.D.1) Hiroo Umeda, M.D. 2), Yoshiharu Kitani, M.D. 2), Satoshi Ohno,
M.D. 2), Tsuyoshi Kojima, M.D. 2), Tatsuo Nakamura, M.D., Ph.D. 3), Shigeru Hirano, M.D., Ph.D.2), Juichi Ito, M.D., Ph.D. 2)
1) Department of Otolaryngology–Head and Neck Surgery, Medical Research Institute, Kitano Hospital, Osaka, Japan2) Department of Otolaryngology–Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan3)Department of Bioartificial Organs, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
Medical Research InstituteKitano Hospital
Disadvantages of TM perforation?Disadvantages of TM perforation?
Background
Hearing loss, Decline of Hearing loss, Decline of speech speech articulationarticulation
Easy and recurrent infection Easy and recurrent infection
Tinnitus, aural fullness and etc. Tinnitus, aural fullness and etc.
Restrictions of daily life activities Restrictions of daily life activities
Cancellation effectCancellation effect
Collision of sounds in the cochlea
Collision of sounds in the cochlea
Rapid attenuation of energy
Greatest disadvantage of TM
perforation
Greatest disadvantage of TM
perforation
Large TMP often causes over 50dBHLLarge TMP often causes over 50dBHL
Hearing aid amplifies the "cancellation effect" Hearing aid amplifies the "cancellation effect"
conversation : 40-60dB50dBHL Hearing Aid
What are the present treatments of TM perforation ??
What are the present treatments of TM perforation ??
Necessity of skin incision and harvest of auto-tissue
Necessity of hospitalization
Failure and sequelae of operation
Mental/physical burden and costs
OperationOperation
Cells
Scaffold Regulatory factors
in situ tissue engineering
Tissue engineering Approach for Regeneration
of TM
Gelatin sponge B-FGF
Good regenerative conditions
Seal by fibrin glue
Regeneration of TM
Method and Procedures
Gelatin spongeGelatin spongeb-FGFb-FGF
TM perforationTM perforationTM perforationTM perforationFibrin GlueFibrin Glue
After 3 weeks After 3 weeks Disruption of the perforation edgeDisruption of the perforation edge
Patients who are susceptible Patients who are susceptible to this treatmentto this treatment
Dry TM and tympanic cavity without active inflammation during the previous 3 yearsProper aeration and no regions of soft tissue density in the mastoid and tympanic cavities based on Temporal bone CTs Intact ossicular chains
No cholesteatoma and no invasion of epithelia into tympanic cavity
Patients Patients
Patients/ears: n=140/158 (M/F:59/81), Age: 10-91
Causes of b-FGF group Control group TM perforation n=148 n=10
Otitis media 90 5
Postoperatively 14 2
Old trauma 20 1
Residual perforation afteroperation/ventilation tube 24 2insertion
Subtotal perforationSubtotal perforationDisruption of the perforation edgeDisruption of the perforation edgeGelatin Sponge with b-FGFGelatin Sponge with b-FGF
Case 1. Case 1. 65y.o. male OMC for 65y.o. male OMC for 30years30years
After 3 weeksAfter 3 weeks After 4 months After 4
months After 4 monthsAfter 4 months
Hearing LevelBefore: 61dB After: 33dB
0.125 0.250 0.5 1 2 4 8 kHz
3 months after
Before treatment
dB0
10
20
30
40
50
60
70
80
90
100
Conversation range
Case 2. 39-y.o. female
After 1 month
Total perforation after TM tube insertion
After 3 months
Hearing Level Before: 50dB After: 10dB
3 months after
Before treatment
dB0
10
20
30
40
50
60
70
80
90
1000.125 0.250 0.5 1 2 4 8 kHz
Overall Results of b-FGF group
Grade I : PS<1/3, Grade II:PS 1/3 ~ 2/3, Grade III : PS>2/3 NA: Average hearing level of 0.5, 1 and 2 kHz
LA: Average hearing level of 0.125, 0.25 and 0.5 kHz *TO: Temporary otorrhea **RTM: Retraction of tympanic membrane
***Chole: Cholesteatoma
Classification by Grade I Grade II Grade III perforation size (n=37) (n=64) (n=47) Number of times 1-3 1-4 1-4 for treatment ( Ave. ) (1.31) (1.31) (1.95) Closure rates 94.6 % 85.9 % 83.0% (35/37) (55/64) (39/47) Improvement NA:14.1dB 20.6dB 24.5dB of the ave. HL LA :28.7dB 31.1dB 35.3dB
Adverse *TO: n=3 n=10 n=12 events ** RTM: n=2 n=5 n=5 ***Chole: n=0 n=2 n=2
%* ** ***
*<0.001, **< 0.001, ***<0.001: Mann Whitney U test
Comparison between the two groups
0 40 50 60 70 80 90 100 dB
% 100 90
80
70
60
Speech articulation Speech articulation
Before treatment
After treatment
Why can we easily achieve to TM regeneration?
Why can we easily achieve to TM regeneration?
Gelatin sponge+
bFGF
Gelatin sponge+
bFGF
Factors for making possible to regenerate TM
Tissue stem cells/Progenitor cells
Gelatin sponge as a scaffold
b-FGF as a growth factor
Creating optimal regenerative conditions
Cells
Disruption of the perforation edge
CellsAuditory Epithelial Migration
Process of the TM regeneration
43 year old male , OMC for 28year
Before after 9days after 1m
1 2 3
Cells
There are tissue stem cells/progenitor cells that are origin of regenerative TM around the perforation edge.
Disruption of the perforation edge
Scaffold Gelatin sponge
Gelatin sponge is made of a protein extracted from collagen and has an open space structure. A sustained release substrate for b-FGF
Strong inducer for blood capillaries
Strong inducer for blood capillaries
Fibroblast growth factorFibroblast growth factor
improvement in the local regenerative conditions
Suitable for regeneration of the intermediate layer of TM
Growth factor : b-FGF
B-FGF
Histology of TMEpithelial
layer
Intermediate Fibrous layer
EAM side
Spontaneous regenerated part of TM
Regenerated TM by this treatment
Before 2 ms after
Differences in growing speed
Spontaneous regeneration
Regenerated TM by this treatment
IIIIII
IIIIII
I: epithelial layer, II: intermediate fibrous layer, III: mucosal layer
Gelatin sponge with b-FGF
Seal by fibrin glueSeal by fibrin glue
Ideal cell culture
condition
Ideal cell culture
condition
Creating optimal regenerative conditions
Protection of dry and infection
Fibrin glue
No skin incision and no harvest of autologous tissues Wide application for various kinds/sizes of the TM perforation including total perforations
Only 10 minutes simple/easy treatments for outpatients
Ideal hearing up and tinnitus reduction immediately after the treatment No restrictions of the patient’s daily life No severe sequelae and no disadvantages
Cost-effective and alleviation of mental and physical burdens of the patients
No skin incision and no harvest of autologous tissues Wide application for various kinds/sizes of the TM perforation including total perforations
Only 10 minutes simple/easy treatments for outpatients
Ideal hearing up and tinnitus reduction immediately after the treatment No restrictions of the patient’s daily life No severe sequelae and no disadvantages
Cost-effective and alleviation of mental and physical burdens of the patients
Remarkable advantages
Summary
This study demonstrated that the combination of a gelatin sponge, b-FGF and fibrin glue was effective for regeneration of the TM perforation.
This is the innovative regenerative therapy: easy, simple, cost-effective and minimum-invasive treatment for outpatients.
Our dream coming true!
Medical Research Institute Kitano Hospital, Osaka, Japan
Hybrid Tympanoplasty
Tympanoplasty TM regeneration
safety sequelae
Hearing improvement
cost-effective
adaptation
Background
What is the Hybrid Tympanoplasty?
After mastoidectomy and posterior tympanotomy,cleaning of the tympanic cavity through mastoid cavity
No need to harvest of temporal fascia for No need to harvest of temporal fascia for reconstruction of TMreconstruction of TM
No need to exfoliate soft tissue of EAM and TM No need to exfoliate soft tissue of EAM and TM
To perform regeneration of the TM though external auditory meatus
I II
MastoidectomyPosterior tympanotpmy
III
Regeneration of MACs
IV
Regeneration of TM
Procedures of Hybrid Tympanoplasty
Merits of the Hybrid Tympanoplasty
Day or short stay surgery.
Minimum sequelae are associated with this procedure because of no
Restrictions are not placed on the patient’s daily life.
There are low risks of damage to chorda tympani nerve.
It is possible to fully regenerate normal TM morphology and to improve hearing up to maximum level.
Wide renge of applications.
Adaptation of Hybrid Tympanoplasty
Chronic otitis media
No adaptation for cholesteatoma, adhesive otitis media
No adaptation for post operative cases
Intact case of ossicular chains
4 weeks after Hybrid Tympanoplasty
Hearing level: 42.5dB/15.0dB (before/after)
Histology of TM