Modulation of Heparin-binding Epidermal Growth Factor Activity for Tympanic Membrane Healing

Inactive Publication Date: 2016-03-17
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]Another aspect of the present invention relates to the use of an agent with HB-EGF activity in the manufacture of a medicament for the treatment of a chronic perforation of

Problems solved by technology

In addition, large perforations may result from infection with necrotizing organisms.
Trauma to the ear is the other major cause of TM perforations.
Common causes of injury are blunt and penetrating insults, rapid barom

Method used

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  • Modulation of Heparin-binding Epidermal Growth Factor Activity for Tympanic Membrane Healing
  • Modulation of Heparin-binding Epidermal Growth Factor Activity for Tympanic Membrane Healing
  • Modulation of Heparin-binding Epidermal Growth Factor Activity for Tympanic Membrane Healing

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of HB-EGF

[0107]HB-EGF is critical to epidermal wound healing in a tympanic membrane model. The normalized signal intensity of HB-EGF like growth factor following perforation of the tympanic membrane in rats shows an 8.5 fold up regulation of HB-EGF like growth factor. Experimental inhibition of HB-EGF activity is shown herein to prevent a tympanic membrane perforation from healing.

[0108]EGFR Ligand Shedding can be Inhibited to Create a Chronic Tympanic Membrane Perforation Model.

[0109]Subtotal perforations were created in the pars tensa of TMs in 20 mice using a curved needle. OSU8.1 (10 mM), a selective HB-EGF inhibitor (see Tokumaru et al. (2000) J. Cell Biol.), was injected onto gel foam (placed through and onto the perforation) over seven days. Mice were sacrificed at time points (Day 2, 7,14,30,44,60 and 90) to observe the effects on keratinocyte migration. The contralateral ear was used as a control with saline placed onto gel foam. All of these were closed within 2...

example 2

Treatment of Chronic Tympanic Membrane Perforation

[0113]The efficacy of HB-EGF treatment for chronic TM perforations is demonstrated.

[0114]A Biocompatible Absorbable Injectable Polymer for Growth Factor Delivery in Ear Canal. To treat chronic TM perforation, it is desirable to have a liquid that can be dropped into the ear, which then hardens and slowly resorbs over the designated time frame while eluting out the medication. The degradation rate of the polymer and drug eluting rate are readily adjustable according to target of interest.

[0115]A biodegradable chitosan-based hydrogel for delivering growth factors was developed to provide a biocompatible, bioresorbable, injectable polymer that can carry a drug of choice and then can be instilled into the ear canal. The gel has two liquid components and can solidify within a few minutes after mixing the two components. This can be readily administered by a dual-bore syringe. Alternatively the solutions can be mixed with a cross-linking a...

example 3

[0128]A trans-tympanic method of delivery (FIGS. 5, 6 and 7). The vehicle for HB-EGF or HB-EGF delivery is placed against or through the tympanic membrane inserted either trans-canal or via the Eustachian tube. It can be removed after a period of time, or can be biodegradable. The vehicle may contain a design to restrain it within the tympanic membrane. This may be a collar, cuff, flange, groove or any change in width or height. It may have more than one of these to hold it in place. The vehicle may be perforated or have a lumen of any suitable dimension. There may be any number of flanges or any width and dimensions that are deemed sufficient or in excess of that required for the vehicle to be retained in the tympanic membrane.

[0129]Depicted in FIG. 5 is the ear canal 100; external ear 110; and tympanic membrane 120. A transmembrane drug delivery device 125 is also depicted, which has a width 130 and length 140.

[0130]Depicted in FIG. 6 is an alternative embodiment of a trans-tympan...

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Abstract

Compositions and methods are provided for the generation or treatment of chronic tympanic membrane perforation by modulation of HB-EGF activity.

Description

BACKGROUND OF THE INVENTION[0001]Perforation of the tympanic membrane TM most commonly arises as a result of either otitis media or trauma. Clinically, the most common manifestations of TM perforation are conductive hearing loss and chronic infection. The most common cause of TM perforation is infection. Perforations associated with uncomplicated acute otitis media are usually small; the vast majority heal spontaneously once the infection has abated. In addition, large perforations may result from infection with necrotizing organisms. Trauma to the ear is the other major cause of TM perforations. Common causes of injury are blunt and penetrating insults, rapid barometric pressure changes (barotrauma), and excessive acoustic pressure.[0002]Following injury, tissue is known to undergo several stages of healing. Although wound healing in the tympanic membrane involves initial hemostatic and inflammatory stages that are similar to conventional skin healing, the tympanic membrane prolife...

Claims

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Application Information

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IPC IPC(8): A61K38/18
CPCA61K38/1808A61K9/0046A61K9/06A61K47/36A61K9/7015A61L27/20A61L27/44A61L26/0023A61L26/0066A61L26/0076A61F11/00A61F2250/0068A61P27/16A61F11/202A61F2002/183A61K38/18
Inventor SANTA MARIA, PETER LUKEYANG, YUNZHI PETERKIM, SUNGWOODOMVILLE-LEWIS, CHLOE
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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