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Innovative regenerative treatment for the tympanic membrane perforation

Medical Research Institute Kitano Hospital. Innovative regenerative treatment for the tympanic membrane perforation. Shin-ichi Kanemaru, M.D., Ph.D. 1) Hiroo Umeda, M.D. 2) , Yoshiharu Kitani, M.D. 2) , Satoshi Ohno, M.D. 2) ,

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Innovative regenerative treatment for the tympanic membrane perforation

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  1. Medical Research Institute Kitano Hospital Innovative regenerative treatment forthe tympanic membrane perforation 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, Japan 2) Department of Otolaryngology–Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan 3)Department of Bioartificial Organs, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan New York University, May 52011, New York, USA

  2. Background Hearing loss, Decline of speech articulation Tinnitus, aural fullness and etc. Easy and recurrent infection Disadvantages of TM perforation? Restrictions of daily life activities

  3. Cancellation effect

  4. Collision of sounds in the cochlea Rapid attenuationof energy

  5. Greatest disadvantage of TM perforation Large TMP often causes over 50dBHL conversation：40-60dB 50dBHL Hearing Aid Hearing aid amplifies the "cancellation effect"

  6. What are the present treatments of TM perforation？ Operation Necessity of skin incision and harvest of auto-tissue Necessity of hospitalization Failure and sequelae of operation Mental/physical burden and costs

  7. Tissue engineering Approach for Regeneration of TM Cells in situ tissue engineering Regulatory factors Scaffold Gelatin sponge B-FGF Good regenerative conditions Seal by fibrin glue Regeneration of TM

  8. Method and Procedures b-FGF Gelatin sponge TM perforation Fibrin Glue Disruption of the perforation edge After 3 weeks

  9. Patients who are susceptible to this treatment Dry TM and tympanic cavity without active inflammation during the previous 3 years Proper 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

  10. 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 after operation/ventilation tube 24 2 insertion

  11. Case 1. 65y.o. male OMC for 30years Subtotal perforation Disruption of the perforation edge Gelatin Sponge with b-FGF

  12. After 3 weeks Hearing Level Before: 61dB After: 33dB After 4 months After 4 months

  13. dB 0 10 20 30 40 50 60 70 80 90 100 3 months after Conversation range Before treatment 0.125 0.250 0.5 1 2 4 8 kHz

  14. Case 2. 39-y.o. female Total perforation after TM tube insertion Hearing Level Before: 50dB After: 10dB After 3 months After 1 month

  15. dB 0 10 20 30 40 50 60 70 80 90 100 3 months after Before treatment 0.125 0.250 0.5 1 2 4 8 kHz

  16. Overall Results of b-FGF group Classification by GradeIGradeIIGradeIII perforation size(n=37) (n=64) (n=47) Number of times 1-31-41-4 for treatment（Ave.） (1.31)(1.31)(1.95) Closure rates94.6％　　 　　　 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 Grade I：PS<1/3, GradeII:PS 1/3～2/3, GradeIII：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

  17. Comparison between the two groups * ** *** % *<0.001, **< 0.001, ***<0.001: Mann Whitney U test

  18. Speech articulation % 100 90 80 70 60 After treatment Before treatment 0 40 50 60 70 80 90 100 dB

  19. Why can we easily achieve to TM regeneration? Gelatin sponge ＋ bFGF

  20. Factors for making possible to regenerate TM Tissue stem cells/Progenitorcells Gelatin sponge as a scaffold b-FGF as a growth factor Creating optimal regenerative conditions

  21. Cells Disruption of the perforation edge

  22. Cells Auditory Epithelial Migration

  23. 43 year old male , OMC for 28year Process of the TM regeneration 1 2 3 Before after 9days after 1m

  24. Cells Disruption of the perforation edge There are tissue stem cells/progenitorcells that are origin of regenerative TM around the perforation edge.

  25. 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

  26. Growth factor：　b-FGF B-FGF Strong inducer for blood capillaries improvement in the local regenerative conditions Fibroblast growth factor Suitable for regeneration of the intermediate layer of TM

  27. Histology of TM Epithelial layer Intermediate Fibrous layer EAM side

  28. Spontaneous regenerated part of TM

  29. Regenerated TM by this treatment Before 2 ms after

  30. Differences in growing speed Spontaneous regeneration I II III Regenerated TM by this treatment I II III Gelatin sponge with b-FGF I: epithelial layer, II: intermediate fibrous layer, III: mucosal layer

  31. Creating optimal regenerative conditions Fibrin glue Seal by fibrin glue Protection of dry and infection Ideal cell culture condition

  32. Remarkable advantages 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

  33. 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.

  34. Our dream coming true! Medical Research Institute Kitano Hospital, Osaka, Japan

  35. Hybrid Tympanoplasty

  36. Background Tympanoplasty TM regeneration Hearing improvement adaptation safety sequelae cost-effective

  37. What is the Hybrid Tympanoplasty? After mastoidectomy and posterior tympanotomy, cleaning of the tympanic cavity through mastoid cavity To perform regeneration of the TM though external auditory meatus No need to exfoliate soft tissue of EAM and TM No need to harvest of temporal fascia for reconstruction of TM

  38. I II III Procedures of Hybrid Tympanoplasty Mastoidectomy Posterior tympanotpmy IV Regeneration of MACs Regeneration of TM

  39. Merits of the Hybrid Tympanoplasty It is possible to fully regenerate normal TM morphology and to improve hearing up to maximum level. Minimum sequelae are associated with this procedure because of no Wide renge of applications. There are low risks of damage to chorda tympani nerve. Restrictions are not placed on the patient’s daily life. Day or short stay surgery.

  40. Adaptation of Hybrid Tympanoplasty Chronic otitis media Intact case of ossicular chains No adaptation for cholesteatoma, adhesive otitis media No adaptation for post operative cases

  41. 4 weeks after Hybrid Tympanoplasty Hearing level: 42.5dB/15.0dB (before/after)

  42. Histology of TM

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