Wearable HATH-1 Auditory Therapy: Total Hearing Effect? Michael DeSalvio, John Chi, Michael Nguyen, Kevin Ip, Khine Win

WHAT: THE? John Chi – Electrical Engineer: System architecture, Software design John Chi – Electrical Engineer: System architecture, Software design Michael J. DeSalvio - Molecular Biologist: Interface design, Biocompatibility Michael J. DeSalvio - Molecular Biologist: Interface design, Biocompatibility Kevin Ip - Molecular Biologist, Regulatory Contact Kevin Ip - Molecular Biologist, Regulatory Contact Mike Nguyen – Molecular Biologist and Lab Specialist: Drug delivery design, GLP contact Mike Nguyen – Molecular Biologist and Lab Specialist: Drug delivery design, GLP contact Khine Win – Material Science and Engineering: Fluid transport design, process fabrication Khine Win – Material Science and Engineering: Fluid transport design, process fabrication We are not researchers, we are designers! We are not researchers, we are designers!

Problem Most hearing loss is caused by damaged cochlear hair cells, which do not regenerate Most hearing loss is caused by damaged cochlear hair cells, which do not regenerate Hearing loss now affects 1 in 5 American teenagers (JAMA, ) Hearing loss now affects 1 in 5 American teenagers (JAMA, ) 15% of adults between 20-69, 26 million adults, suffer from noise- induced hearing loss (NIHL, National Institute on Deafness and Other Communication Disorders) 15% of adults between 20-69, 26 million adults, suffer from noise- induced hearing loss (NIHL, National Institute on Deafness and Other Communication Disorders) 25-40% of 60+ in US is hearing impaired - worsening (Yueh et al, 2003) 25-40% of 60+ in US is hearing impaired - worsening (Yueh et al, 2003)

Current Solutions Cochlear Implant Cochlear Implant Hearing Aids Hearing Aids Underlying cause not addressed (hair cell destruction) Underlying cause not addressed (hair cell destruction)

Cochlear Implant FDA approved in 1984 FDA approved in 1984 Approximately $40,000 for procedure Approximately $40,000 for procedure As of 2009, 188,000 worldwide received implants. (Davis, J 2009 Peoria Journal) As of 2009, 188,000 worldwide received implants. (Davis, J 2009 Peoria Journal) Cochlear Implants rely on electrical connections to auditory nerve, destroying existing structures in the ear Cochlear Implants rely on electrical connections to auditory nerve, destroying existing structures in the ear Infection, physical damage to unit, wear and tear (permanent) Infection, physical damage to unit, wear and tear (permanent) Developed by Cochlear Limited Australia, Advanced Bionics, Cochlear Corporation, Med-El, etc. Developed by Cochlear Limited Australia, Advanced Bionics, Cochlear Corporation, Med-El, etc.

Hearing Aid Removable prosthetic Removable prosthetic Many different shapes and sizes Many different shapes and sizes $150 to $5,000 $150 to $5,000 Many different manufacturers and designs Many different manufacturers and designs No surgery No surgery Can be bulky and cumbersome Can be bulky and cumbersome Need constant adjustment (feedback, loud noises) Need constant adjustment (feedback, loud noises)

HATH-1 Therapy Math1 allows transdifferentiation of cochlear cells into functioning auditory hair cells Math1 allows transdifferentiation of cochlear cells into functioning auditory hair cells These transgenic cells shown to be stable and growing after 10 weeks with significant restoration of auditory function (2003, Izumikawa) These transgenic cells shown to be stable and growing after 10 weeks with significant restoration of auditory function (2003, Izumikawa) Need multiple injection sites Need multiple injection sites Need to distribute throughout cochlea using micropump to optimize hair cell regeneration densit Need to distribute throughout cochlea using micropump to optimize hair cell regeneration densit

HATH-1 Effectiveness

Routes of Entry Two routes of entry into ear Two routes of entry into ear Systemic Route: drug circulates through blood stream Systemic Route: drug circulates through blood stream Local Application to inner ear (targeted drug delivery) Local Application to inner ear (targeted drug delivery)

Device Microfluidic circulating pump delivers drug safely to delicate cochlear region Microfluidic circulating pump delivers drug safely to delicate cochlear region Intracochlear drug delivery device to deliver chemotherapy Intracochlear drug delivery device to deliver chemotherapy Built-in Piezoelectric ABR testing Built-in Piezoelectric ABR testing Extracochlear stimulation maintains auditory regions in brain Extracochlear stimulation maintains auditory regions in brain FDA Class 2 Device and Class 2 Software FDA Class 2 Device and Class 2 Software

Prototype (Animal model)

Advantages Does not destroy vestibular structure Does not destroy vestibular structure Temporary prosthetic surgical solution Temporary prosthetic surgical solution Permanent hearing restoration Permanent hearing restoration No need for post-treatment prosthetic No need for post-treatment prosthetic Monitored treatment developmet Monitored treatment developmet Maintenance is almost identical to existing cochlear implant Maintenance is almost identical to existing cochlear implant

Disadvantages Suppress vestibular (balance) system function—with sometimes only minor effects on hearing. Suppress vestibular (balance) system function—with sometimes only minor effects on hearing. Risk of developing meningitis Risk of developing meningitis General risk of infection General risk of infection Cost: $45,000- $150,000 total cost Cost: $45,000- $150,000 total cost

Where and When Business location local to Southern California Business location local to Southern California Group competencies allow most development to take place in-house Group competencies allow most development to take place in-house Approximately 3 years to market with drug delivery device Approximately 3 years to market with drug delivery device Milestone 1 – Develop prototype Milestone 1 – Develop prototype Milestone 2 – 510K Registration with FDA Milestone 2 – 510K Registration with FDA Milestone 3 – Commence clinical trials Milestone 3 – Commence clinical trials Milestone 4 – Complete clinical trials Milestone 4 – Complete clinical trials

How does it work? Delivering Hath 1 transcription factor and other drugs Delivering Hath 1 transcription factor and other drugs Microfluidic pump system with inlet and outlet tubule for delivery Microfluidic pump system with inlet and outlet tubule for delivery Use of intracochlear imaging system to monitor distribution of delivered substances Use of intracochlear imaging system to monitor distribution of delivered substances Use of Extracochlear stimulation during recovery period Use of Extracochlear stimulation during recovery period 10 week treatment course 10 week treatment course Khine Figure: Prototype (Human Model)

How is it Different? Does not remove vestibular hair cells Does not remove vestibular hair cellshttp:// Can monitor hair cell growth through non-invasive ABR testing Can monitor hair cell growth through non-invasive ABR testing Higher distribution of delivered substances compared to delivery through RWM Higher distribution of delivered substances compared to delivery through RWM Extracochlear stimulation does not destroy cochlea as opposed to intracochlear device Extracochlear stimulation does not destroy cochlea as opposed to intracochlear device

Cochlear Anatomy Contains two & three quarter turns (Basal, Middle & Apex) Contains two & three quarter turns (Basal, Middle & Apex) 3 fluid filled spaces located in parallel 3 fluid filled spaces located in parallel  scala vestibuli, tympani & cochlea duct Fluid contains ionic compositions of Na+, K+, Ca2+ & Cl- (Endolymph & Perilymph) Fluid contains ionic compositions of Na+, K+, Ca2+ & Cl- (Endolymph & Perilymph)

Surgery Surgery Surgery Opening in the basal turn is made Opening in the basal turn is made Carbide micro drills modified fitted with insertion stops Carbide micro drills modified fitted with insertion stops Medical grade adhesive & dental cement are used Medical grade adhesive & dental cement are used Almost identical to already used implant surgery Almost identical to already used implant surgery

System Overview

Extracochlear Stimulator Can re-stimulate portions of the brain responsible for hearing even after prolonged “atrophy.” Documented patient Baron Jack Ashley, UK House of Lords Can re-stimulate portions of the brain responsible for hearing even after prolonged “atrophy.” Documented patient Baron Jack Ashley, UK House of Lords Can improve hearing after complete deafness Can improve hearing after complete deafness Reliable and efficient, long life cycle Reliable and efficient, long life cycle Restore hearing without damaging structures in ear canal Restore hearing without damaging structures in ear canal Michael N

Fluid Transport System (overview) Microfluidic pump Inlet tubule + precision thermal flow sensor Reservoir (contains Artificial perilymph solution) outlet tubule + precision thermal flow sensor Ear Microcontroller

Fluid Transport (Materials) Polyetheretherketone (PEEK) tube Polyetheretherketone (PEEK) tube Biocompatible Biocompatible Excellent mechanical and thermal resistance Excellent mechanical and thermal resistance Good for application require vacuum environment Good for application require vacuum environment ISO standard & fully USP Class VI, FDA, NSF and European Pharmacopoeia criteria ISO standard & fully USP Class VI, FDA, NSF and European Pharmacopoeia criteria

Fluid Transport (Materials) Polyetheretherketone (PEEK) tube Polyetheretherketone (PEEK) tube Biocompatible Biocompatible Excellent mechanical and thermal resistance Excellent mechanical and thermal resistance Good for application require vacuum environment Good for application require vacuum environment ISO standard & fully USP Class VI, FDA, NSF and European Pharmacopoeia criteria ISO standard & fully USP Class VI, FDA, NSF and European Pharmacopoeia criteria

Fluid Transport Precision thermal sensor Precision thermal sensor Utilizing temperature shift caused by fluid flow Utilizing temperature shift caused by fluid flow Relationship between temp and volume of fluid flow Relationship between temp and volume of fluid flow Microfluidic pump Microfluidic pump Nano Liter application Nano Liter application Zero net transfer Zero net transfer Continuous inflow and outflow (not reciprocating Continuous inflow and outflow (not reciprocating

QFD – Power Subsystem

QFD - Battery

Input Tubing Materials Tubing Materials Microprocessors Microprocessors Casing Materials Casing Materials Drug Drug Sensors Sensors Circuitry Circuitry Pumps Pumps Software and updates Software and updates

Change Over Time Wearing of pumps Wearing of pumps Degradation of tubing Degradation of tubing Degradation of drug Degradation of drug Circuitry corrosion Circuitry corrosion Loosening of delivery template Loosening of delivery template Degradation/loosening of seals Degradation/loosening of seals Degradation of battery Degradation of battery Wear on moving parts Wear on moving parts Degradation of synthetic endolymph Degradation of synthetic endolymph Bodily immune response Bodily immune response

Noise External heat/cold External heat/cold Water/humidity Water/humidity Leaking Leaking User opens device User opens device Device falls off Device falls off Blunt force trauma Blunt force trauma Bubbles in fluid line Bubbles in fluid line Flow regulation failure Flow regulation failure Electromagnetic interference Electromagnetic interference Intracochlear tissue Intracochlear tissue Internal heating Internal heating Battery failure, leaking Battery failure, leaking Charging mechanism seizes Charging mechanism seizes Particulates in fluid line Particulates in fluid line Software bugs Software bugs Overheating Overheating Accumulation of biofilm Accumulation of biofilm

Control Factors Water tight seals Water tight seals Flow rate sensors Flow rate sensors Heat sensors Heat sensors Pressure sensors Pressure sensors Electromagnetic shielding Electromagnetic shielding Ultrasonic agitator for fluid lines, bubble trap Ultrasonic agitator for fluid lines, bubble trap Redundant systems (firmware, tubing, pumps) Redundant systems (firmware, tubing, pumps) Sealed battery compartment Sealed battery compartment Accessible internal components for servicing Accessible internal components for servicing Use biologically inert materials Use biologically inert materials Consistent software reviews Consistent software reviews Reversible flow – self backflushing Reversible flow – self backflushing Simulation environments Simulation environments

Error States Cooked/frozen drug Cooked/frozen drug Short circuit Short circuit Clogged pump mechanism Clogged pump mechanism Premature emptying of drug reservoir Premature emptying of drug reservoir Seizure of motor Seizure of motor Cracked casing Cracked casing Water infiltrates system Water infiltrates system Infection Infection Memory/firmware failure Memory/firmware failure Device fails to charge Device fails to charge

Ideal Function Correct dosage Correct dosage Distribution of drug Distribution of drug Motors powered correctly Motors powered correctly Body accepts implant Body accepts implant No leakage No leakage ABR measurement of intracochlear cell restoration ABR measurement of intracochlear cell restoration Healthy cochlea, restored hearing Healthy cochlea, restored hearing

Summary Site specific target allows for precise calculation of dosage Site specific target allows for precise calculation of dosage Targeted drug delivery which mitigates drug exposure to other tissues (HATH-1 effects in body) Targeted drug delivery which mitigates drug exposure to other tissues (HATH-1 effects in body) Can be used for middle ear cancers and tumors Can be used for middle ear cancers and tumors Can be used in conjunction with surgery to deliver antibiotics Can be used in conjunction with surgery to deliver antibiotics No additional equipment or maintenance once treatment is complete No additional equipment or maintenance once treatment is complete

Questions?