Eustachian Tube Stent

Pilot study of a resorbable poly-l-lactide Eustachian Tube stent;

feasibility and tolerability in two animal models

JA Litner M.D., CJ Linstrom M.D.,

P Presti, MD, CA Silverman Ph.D.,

S McCormick M.D.,

GP Yu M.D., J Arigo M.D.

Middle Ear Disease

Susceptibility is clearly multifactorial

Hypoventilation is regarded as the root cause

ET dysfunction is the principal culprit

Background:The Eustachian tube:

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Theories of Causality

Eustachian tubes are mechanically obstructedTubal stenosis noted in nearly half of chronic ears1

No significant post-mortem alteration in tube caliber2

Eustachian tubes are functionally obstructedTubal hypercompliance, The Floppy Tube3

Alteration in tubal surface tension dynamics4-8

1Tos M. Journal of Laryngology and Otology 1980;94:25-302Sade et al. American Journal of Otology 1986;7(6)3Bluestone CD. Head and Neck Surgery- Otolaryngology. Ch. 111; 19934Miura M et al. Acta Otolaryngologica. 1996;116:840-445Fornadley JA et al. Otolaryngology- Head and Neck Surgery. 1994;110:110-46Nemechek AJ et al. Otolaryngology- Head and Neck Surgery. 1997;117:475-97Passali D et al. Respiration. 1987;51 supp.1:52-98Sujana S et al. Laryngoscope. 2004:114 ; 472-485

Significance

Most Common Reason For Sick visits to PMD’s for Children <3

5 Billion spent annually1

One Million children undergo myringotomy annually 1

Morbidity associated with MT

Frequent returns to the OR

Over prescription of Abx and rising resistance

No Modality that specifically addresses the underlying pathophysiology: Eustachian Tube Dysfunction

1Gates GA. Otolaryngology Head Neck Surg. 1996;114:525-530

Bluestone CD. Head and Neck Surgery- Otolaryngology. Ch. 111; 1993

Historical Interventions

ET insufflation prior to 19501

Elaborate surgical shunts, ET irradiation in 1960’s2-4

Armstrong tube invented in 19545

―Permanent‖ vent tubes

Silverstein tube6

Jahn Hydroxylvent tube7

1Shapiro SL. Eye Ear Nose and Throat Monthly. 1969;48:72-72Drettner B et al. Archives of Otolaryngology. 1969;90:122-8 3Goode RL et al. Laryngoscope. 1975;85:100-124House WF et al. Laryngoscope. 1969;79:1765-82 5Armstrong BW. Archives of Otolaryngology. 1954;59:653-46Silverstein H. Archives of Otolaryngology. 1970;91:313-87Jahn AF. Otolaryngology- Head and Neck Surgery. 1991;105(5):758-60

Problems with Current Approach

MedicalIncreased antibiotic resistance

SurgicalExtrusion

Scarring/Perforation

Infection

Cholesteatoma

Disruption of graft healing

Failure to alter natural course

About 25% of procedures are repeat

ET Stenting

Wright Jr., 1976 –Silastic Eustachian Tube Prosthesis (SETP)

Series of 138 patients with average 26 month follow-up

80% had an aerated ME behind intact TM after 6 months

Poor results after 6 months

No serious complications

Wright Jr. JW et al. Laryngoscope. 1977;87:207-14

Wright Jr. JW et al. ORL. 1978;86:834-7

Hypothesis

Functional restoration most physiologically sensible approach

ET Stenting should augment function and restore ventilation

Success achievable through advances in biomaterials science & capacity to elute drugs

Successful applications to other hollow viscera1-6

1Korpela A et al. Chest. 1999;115:490-952Tamai H et al. Circulation. 2000;102:399-4043Lumiaho J et al. Journal of Urology. 2000;164:1360-34Middleton JC et al. Medical Plastics and Biomaterials. 1998;March5van Berkel A et al. Gastrointestinal Endoscopy. 2000;51:19-226Sung JJY. Journal of Industrial Microbiology. 1995;15:152-5

Stent Design Issues

Stent Deployment

Stent Retrieval

Indwelling Effects

Perforation

Migration

Occlusion

Extrusion

Ascending infection

Reflux

Autophony/Patulous

symptoms

Longevity

Specific Aims

Aim 1– Explore technical ease

Aim 2– Establish safety profile

Aim 3– Determine tissue response

Aim 4– Assess extent of stent resorption

Stent Prototype

Manufactured by

PPD Méditech

Waterville, QC

Stent Location

Methodology- Study 1

Adult Chinchilla ear model

NYMC Dept. Comp. Med. facility—IACUC approved

Sample size of 5 animals

Baseline tympanograms & otomicroscopy

Stent implanted randomly via transbullar approach

Remaining ear matched control

Methodology

All animals treated with peri-operative systemic antibiotics

Serial testing at 4,6,8,10,14,18,22,26 weeks

Digital otomicro photos taken at each interval

One animal sacrificed at 10, 18, & 26 weeks

Temporal bones sectioned and evaluated blindly by head and neck pathologist

Statistical comparison of between-group differences in ME pressures over time

Results

2 animals died intra-operatively due to respiratory arrest

Follow-up available for 3 animals up to time of sacrifice

One animal developed transient post-operative otorrhea in implanted ear via existing myringotomy incision; resolved with ototopical antibiotics

Test

Ear

Control

Ear

Baseline 4 weeks 12 weeks 26 weeks

Otomicroscopy

Tympanometry

Peak C

om

plian

ce (

daP

a) Test

Ear

Control

Ear

Data Points

Zero Point

-25

22 26-125

-100

-75

-50

0

25

50

75

100

Animal #2, Test ear

Time (weeks)

-50

-100

-75

-50

-25

0

25

50

75 Animal #3, Test ear

Base 4 6 8 10 14 18 22 26-100

-75

-50

-25

0

25

50

75

100

Animal #1, Control ear

Time (weeks)

Peak C

om

plian

ce

(daP

a)

Base 4 6 8 10 14 18 22 26-100

-75

-50

-25

0

25

50

75

100

Animal #1, Test ear

Time (weeks)

Peak C

om

plian

ce

(daP

a)

Base 4 6 8 10 14 18 22 26-125

-100

-75

-50

-25

0

25

50

75

100


Time (weeks)

Peak C

om

plian

ce

(daP

a)

Base 4 6 8 10 14 18

Base 4 6 8 10 14 18 22 26-100

-75

-25

0

25

50

75

100


Time (weeks)

Peak C

om

plian

ce

(daP

a)

Base 4 6 8 10 14 18 22 26

100

Time (weeks)

Peak C

om

plian

ce

(daP

a)

Peak C

om

plian

ce

(daP

a)

Pathology– Gross

Pathology– Micro

Control Ear

CLP

BO

TVP

N

Original Magnification x 60

Pathology– Micro

Test EarLP

C

B

O

TVP

N

Original Magnification x 60

Pathology– Micro

Test Ear

Control Ear

G

G

Pathology– Micro

Test Ear

TZ

C

Stent Resorption

Data Analysis

Number Mean Standard

deviation

Z value† P value

Animal #1

Left 5 6.0 8.2 0.00 >0.05

Right 5 8.0 26.1

Animal #2

Left 9 -11.7 48.5 2.49 0.013

Right 9 -40.6 58.4

Animal #3

Left 7 8.6 22.7 1.89 0.058

Right 7 -17.9 46.4

† Wilcoxon signed ranks test.

Peak Compliance(daPa)

Methodology- Study 2

Adult NZ White Rabbit ear model

NYMC Dept. Comp. Med. facility—IACUC approved

Sample size of 10 animals

Similar study protocol-serial otomicroscopy at 2 week intervals

All animals sacrificed at 6 months

ResultsTest

Animal

Week

1-2

Week

3-4

Week

5-6

Week

7-8

Week

9-10

Week

11-12

Week

13-14

Week

15-16

Week

17 –18

Week

19-20

Week

21 –22

Week

23-24

#1 Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal

#2 OM OM and Facial

Cellulitis

Resolved

OM

Normal Normal Normal Normal Normal Normal Normal Normal Normal

#3 Normal Normal Normal Normal OM OM Normal Normal Normal Normal Normal Normal


#5 Normal Normal OM Normal Normal Normal Normal Normal Normal Normal Normal Normal



#8 OM Resolved Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal



Findings on Otomicroscopy in Test Ears

Results

Specimen Implanted Ear Control Ear

1 No Inflammation No Inflammation


3 No Inflammation No Inflammation /

Cholesteatoma








Histologic Findings at 6 months

Results

Transient infections in 4 test ears

No chronic inflammatory response in all test ears after 6-month incubation

No remnants of stents noted at 6 months

Conclusions

Stents were easily implanted

Stents were well tolerated with development of transient otorrhea in few subjects

Stents engendered negligible inflammatory response

Differential resorption- Stents were minimally resorbed at 6 months in the Chinchilla model

Future Directions

Technology merits further testing for efficacy

Determine appropriate sterilization procedures

Clarify resorption spectrum

Explore use of surface agents or drug elution to improve biocompatilibity and reduce biofilm

Acknowledgments

Dr. Ellen Levee, DVM for supervision of animal care

New York Medical College DCM Staff

PPD Meditech, 50 Raymond, Waterville, QC

for manufacture and supply of stent prototypes

Documents

Eustachian Tube Stent