uels nih research plan compressed.docx

8/13/2019 UELS NIH Research Plan Compressed.docx

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SPECIFIC AIMS

This proposal finalizes the development and clinical validation of a low-cost, hand-held device(iBreastExam or iBE) for community healthcare workers(CHWs)to administer breast exams in settings withlimited medical infrastructure such as low-and middle-income countries (LMICs). Incidence and mortality forbreast cancer (BC) are now highest in LMICs.1Diagnosis typically occurs late, resulting in poor survival.2Thisin part, is due to the lack of screening programs. Screening mammographyis complex and expensive (cost pe

life-year-saved (LYS) for biennial mammography is >$3,468).

3

While clinical breast exam (CBE) is affordable(Int.$793 per LYS), training LMIC CHWsis challenging4and itseffectiveness is limited.5iBE standardizes theoperation of CBE andoptimizes performance without significant increase in cost. It can be used by existingCHWs as a quantitative adjunctto CBE with minimal training. iBE uses a novel piezoelectric sensor array torapidly and accurately measure tissue elasticity from the skin surface. Preliminary data shows that iBEdetectseven non-palpable, mammogram-visible lesions effectively. 6 The current commercial-grade prototypeincorporates several LMIC-ready attributes (battery powered, mobile-app, rapid results). Engineering andperformance evaluation will be completed in the U.S. (UH2), and the device validated in Brazil and India (UH3)

Aims Milestones/Criteria for Success Timeline

Aim 1 (UH2): Engineering for LMIC Readiness

(1)Make iBE durable for use in LMIC; (2)Reduce sensor fabrication cost and time; (3)

Validate specificity in models.

(1)Pass JESD22-B111 drop test; Sensor life of 200 hoursof operation (2,500 scans); Pass JISC0022 temperature and

moisture tests; (2)Reduce fabrication time (5 man-hoursavings/unit); (3)10% false-positives.

(1) Y1, 6M(2) Y1, 4M

(3) Y1, 4M

Aim 2 (UH2): Usability Validation for LMIC Operators

(1)Define and validate operator trainingprotocol; (2)Fabricate iBE v2.0 units for use inUH2 clinical study.

(1)Nursing students pass training program by scanning abreast model in 75% accuracy; (2)Manufacture 10 iBE v2.0 to design specifications.

(4) Y1, 3M(5) Y1, 3M

Aim 3 (UH2): Clinical Validation within Standard of Care Setting in USA

(1)Efficacy to detect T1c or larger cancers andother breast abnormalities; (2)Per-lesioncharacterization; (3)Inter-rater reliability; (4)Device specifications validation.

(1)iBE sensitivity, specificity and predictive value betterthan CBE and similar to mammography in 2,500 women; (2)is observational; (3)


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RESEARCH PLAN

1. BACKGROUND AND SIGNIFICANCE

1.1 Breast cancer (BC) is on the rise in LMICs and is characterized by late diagnosis and poor survival BC is the most common cancer in women worldwide, disproportionately affecting LMICs:

Today, 52.6% of new BC cases occur in LMICs, and this is expected to grow to 70% by year 2020.7Two-thirds of the estimated 15,000,000 healthy-life years lost annually to BC globally are from LMICs.85-year survival rate is 40-60% in most LMICs as compared to 80-90% in High Income Countries (HICs).2

Lack of secondary prevention programs (population based screening) and enhanced treatment, are the twomajor differentiating factors for poorer BC outcomes in LMICs. Tumors detected as a result of routinescreening tend to be smaller, well differentiated and less likely to have regional lymph- node involvementmaking treatment more effective and survival more likely.9,10,11Smaller, earlier-stage tumors are amenable tobetter, less costly treatment options. The National Cancer Institute (NCI) supported Cancer Intervention andSurveillance and Modeling Network (CISNET) suggests that 2865% (median 46%) of the observed decreasein BC mortality in the United States can be attributed to screening, with remainder attributed to treatment.

1.2 Challenges with secondary prevention and early diagnosis of breast cancer in LMICs In HICs, screening mammography and clinical breast exam (CBE) are the standards of care for BC

screening and detection. Their efficacy, cost-effectiveness and effect on survival and mortality of BC have

been well documented. However, availability and/or use of these modalities remain limited in LMICs.Organized screening mammography is expensive, resource intensive, requires stringent qualityassurance and a large, well-trained workforce of technicians and radiologists. The cost per year of life savedranges from Int.$3,468 to Int.$16,000,12,3 which is beyond the health spending capabilities of most LMICs. Interms of human resources, most LMICs simply do not have the radiology expertise capacity required for aneffective mammographic screening program. India, for example, has 10% the number of radiologists of the U.Sbut almost 4 times the population.13Clinically, mammograms are limited in women with dense breasts, whichincludes most women under 50 years of age. Culturally, in LMICs there are reservations about radiation basedsometimes painful mammogram tests.14 So even when mammography is available, it is often not utilizedMexicos Ministry of Healthreports that only 25% of the installed mammography units are in use.15

CBE.The World Health Organization and the Breast Health Global Initiative recognize CBE as a cost-effective measure to screen for BC in LMICs. In a study in Indonesia, CBE performed nearly as well as single-

view mammography.

16

In an IARC-supported, cluster-randomized controlled study in India, CBE has beenshown to enable the detection of early-stage breast cancers.17It is known however that the efficacy of CBEmay be substantially lower (28-36%) in practice than is reported in clinical trials.5Physical exams in communityhealth practice are often less systematic and poorer quality than in many organized clinical trials. 18So the truecontribution of CBE to BC detection in healthy women, and to improved survival in BC patients, has comeunder question, resulting in recent calls to standardize and lower the subjectivity of CBE administration andreporting.4

1.3 A paradigm for early detection by community health workers The American Joint Committee on Cancer (AJCC) staging system indicates prognosis based on the size

of the tumor at detection viz. stage of breast cancer. Identifying tumors at earlier stages (down-staging) canimprove survival, assuming high-quality treatment is accessible. In the U.S., approximately 40 million womenreceive mammograms annually and roughly 232,000 new cases are identified; vast majority are detected at

stage Tis and T1, for whom the 5-year survival is 100%. In the context of LMICs, where up to two-thirds ofbreast cancer cases present at late stages, systematic down-staging is required, such that majority of thecases would be identified at Stage II or earlier, where survival can be 93% or better; again, with theassumption that treatment options are available.

In LMICs, community health workers (CHWs) often represent an affordable resource for the education andprovision of preventive, primary and promotive healthcare.19Low-cost, user-friendly technology can help equipminimally trained CHWs to administer standardized breast exams without any special infrastructure, with thegoal to down-stage breast cancer (Stage II or earlier). The low-cost technology must perform with betterdetection sensitivity than CBE (higher than 50%) and equally high specificity as CBE (94%) to accurately andeffectively identify breast lumps in need of further diagnostic follow-up (diagnostic ultrasound, breast biopsy)


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without clogging the under-resourced infrastructure with false positives due to typical benign breast features(tissue variability, lumpiness and nodularity).

1.4 Proposed device and its potential to improve cancer treatment in LMICsThe product being developed by UELS, iBE (Fig. 1), is a non-invasive, hand-held, battery-powered breast

scanner that enables minimally trained CHWs to administer CBE-likebreast exams, quickly and with greaterclinical efficacy. iBE is designed to optimize and standardize any lay health workers ability to objectivelyidentify and report BCs at early stages in conditions with limited or no medical infrastructure.

iBE identifies breast tumors non-invasively andfrom the skin surface using an entirely new tactilesensor technology. It comprises an array ofpiezoelectric i sensors that electronically palpate thebreast and can differentiate between varying tissueelasticity (for a detailed description of the technology,see Section 2.1). The electronic palpationis entirelyautomated and controlled internally by the device andhence iBE requires minimal training to use. Also, sincethis palpation relies on piezoelectric sensor detection,iBE is more sensitive than physical examination byhand. iBE communicates wirelessly with a mobiledevice to display the findings in real-time, to store andshare the data digitally and to easily compare theresults with past records. iBE has the potential to optimizeCBE by improving on its overall effectiveness todetect Stage I and IIa breast cancers with minimally trained CHWs. iBE will also standardizeclinical breasexams by assisting every CHW to administer and record breast exams objectively, consistently and with theability to share the results easily using the mobile device app.

In its first commercial deployment following the completion of UH3 validation study, 2,000 local CHWsnurses or midwives appointed by NGOs and regional governmental agencies in India and Brazil will be trainedand equipped with iBE units in regions with no existing secondary prevention programs. Each iBE unit couldaccount for 20 scans per day. A UELS appointed local distributor will train existing CHWs and provide aftersales service for troubleshooting, repair and replacement of the parts. In the first year alone, 10 million womencould receive the benefit of receiving standardized breast exams for the first time.

1.5 Target LMICs: Brazil and IndiaBrazil and India are target LMICs

for several reasons: both have poorhealth outcomes related to breastcancer; UELS has strong workingrelationships with well-establishedclinical sites in both countries; there arewell-established networks by which iBEcan be deployed following validation,providing a pathway by which the devicecan have a significant impact on

womens health in these countries.Breast cancer in Brazi l and India.Both countries have a notable rising incidence of breast cancer inyounger women under age 50 (Table 1). Brazils 297 Disability Adjusted Life-Years (DALYs) lost per 100,000women is nearly double that of most countries in Latin America.24India reports that in some regions 70% of BCcases present at stage III or later, with survival rates of only 50%.23Standards of care for screening, diagnosisand treatment of BC in Brazil and India are outlined in Table 2.

Partner sites in Br azil and India.UELS is a medical device start-up focused on developing innovativeaffordable tools for womens breast health that can be operated by non-specialized individuals in low resource

iPiezoelectricity is an electrical current that is generated in certain materials in response to pressure or mechanical force. Piezoelectricmaterials, like PZT, are materials that possess this property.

TABLE 1: Breast Cancer Epidemiology in the U.S., Brazil, and India

USA Brazil,

India,

# New cases per year 232,340 42,566 115,251

# Deaths per year 39,620 12,573 53,000

Median Patient Age at Diagnosis 61 56 4447

AAR* Incidence 121 4270 2331

AAR* Mortality 22 1224 1115

% Cases detected at stage III or later 10% 3050% 4070%

5 Year Survival rate 89.2% 58% 4050%

Organized Screening Mammography Nationally Regionally None

Fig. 1: iBE Prototype v1.0


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settings. UELS first product, NoTouch BreastScanis US FDA cleared, adjunctive screening test for breastcancer detection. Under an initiative called the We Must Try campaign (www.WeMustTry.com), UELS iscollaborating with NGOs and healthcare agencies in Latin America, South Asia and the Middle East to provideNoTouch BreastScan exams to women with limited or no access to mammograms.

TABLE 2: Standards of care for screening, diagnosis, and treatment of breast cancer in Brazil and India

General healthcare, Cancer registr ies

Brazil: Healthcare expenditure per capita is $1121, up 45%

from 10 years ago.25Approximately 75% of the populationin Brazil has healthcare access through the Brazilian PublicHealth System (PHS), 26 the leading provider of breastcancer care for the majority of the country. The NationalCancer Institute of Brazil (INCA) recently released a revisedcancer report through 28 Population-Based CancerRegistries (PBCR).

India: Healthcare expenditure per capita is $59, up 25%

from 10 years ago.25 More than 80% of the populationrelies on subsidized or free healthcare, provided by locaand state governments, mandated by the Central HealthMinistry. Less than 10% of the population has healthinsurance. The National Cancer Registry Program (NCRPreports cancer epidemiology since 1982, however the vastmajority of the country remains uncovered/unreported.

Standard of breast cancer treatm ent

Brazil: Best practices for BC treatment in Brazil includebreast conservation surgery, and sentinel lymph nodedissection, however the availability of surgical oncologyexperts, waiting periods, node clearance policy and accessto breast reconstruction vary greatly across the regions andbetween public and private settings. Radiotherapyequipment and trained personnel are scarce in Brazil.27

India: 118 government and 163 private hospitals offer BCtreatment. Quality of care varies by region with privatehospitals in urban areas offering higher quality treatment. Afew centers of excellence (27) provide multimodal, protocolbased treatment, like in USA. Less than 300 operationaradiotherapy machines are available. 40 to 70% of casespresent at late stages.

Standard of breast cancer screening and diagnosis

Brazil: Certain parts of Brazil (Sao Paolo, Rio de Janeiro,Barretos) have well-established organized mammographyscreening programs, like in USA. In early 2011, Brazilannounced a $3 billion, 4-year national plan to controlcervical and breast cancer through the outpatient andhospital network of the Brazilian Public Health System, witha strong focus on rural areas.

India: Organized secondary prevention programs viamammography or CBE are not prevalent in India at regionaor national level. In late 2012, the Indian Ministry of Health& Family Welfare (IMHFW) urged BC screening from age30, due to the increasing burden of breast cancer in youngwomen. Since 2009, the National Rural Health Mission hashired 82,000 skilled health-workers to public health system.

The Barretos Cancer Hospital (BCH) in Brazil and the Apollo Health Education and Research Foundation(AHERF) in India are supporting UELScampaign and have signed a Collaborative Research Agreement with

UELS to conduct clinical studies involving NoTouch BreastScan. Located 300 miles from the city of So PauloBCH exclusively serves rural populations to provide cancer care. BCH has a well-established breast cancerprevention and treatment program with several mobile mammography units and three fixed sites. BCHprovides healthcare services at no charge to its patients and is recognized by the National Cancer InstitutesUS Latin-America Cancer Research Network as a leading research center. The Apollo Group of Hospitals(AGH) is one of the largest private healthcare networks in India with 40 hospitals and 100+ primary care clinicsIntegrated with AGHs healthcare network is the Apollo Health Educationand Research Foundation (AHERF)a dedicated clinical research institution with experience of over 650 clinical studies, 8 clinical sites and adedicated staff of over 100 investigators and researchers. For more information on BCH and AHERF, seeSection 4.3 (Plans for collaborating with local LMIC partners) of this document andthe Facilities Section.

Brazil and India were chosen as two radically different LMIC environments in which different clinicaendpoints can be demonstrated. In Brazil, iBE will be evaluated within the context of an existing mammography

based screening program to compare both tests in their predictive value and accuracy. In India, iBE will beintroduced as the key component in a new breast cancer-screening program where screening mammographyis not available or practical. In that environment we will evaluate the ability of iBE to improve detection ratesand stage-distribution compared with historical values in the region.

2. PRELIMINARY DATA

2.1 Piezoelectric Sensor TechnologyContrast in elastic modulus between normal and abnormal breast tissue has long been recognized. 28,29

Major medical device manufacturers are developing ultrasound and magnetic resonance based elastographysolutions for breast abnormality detection and characterization. Hakki Yegingil, Ph.D. (Engineering PI) andcollaborators at Drexel University have invented a novel, low-cost, lead zirconate titanate (PZT) piezoelectric


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cantilever sensor that can accurately and non-invasively measure tissueelasticity. This sensor technology has been licensed and further developed byUELS into a manufacturable sensor array for application in BC detection. Thepiezoelectric sensor array is composed of a driving layer at the top and anarray of sensinglayers at the bottom, sandwiching a stainless steel substrate(Fig. 2).

When DC voltage is applied to the top driving layer (VDC 15 V

empirically determined by the thickness of the driving layer), reversepiezoelectric effect causes the cantilever structure to bend (Fig. 3), compressingthe bottom sensingpiezoelectric layer in which voltage is induced due to thedirect piezoelectric effect. The degree to which the cantilever is deflected islinearly proportional to the induced voltage in the sensing layer. This can bemonitored to precisely estimate the amount of deflection, which will depend onthe elasticity of the surface underneath the sensor. The effective elasticmodulus measured can be calculated using the equation;30

(1)

Where Eeff is the effective elastic modulus, AI is the indentation area, d0 is the edge displacement with nosample and dI is the edge displacement with sample, as also illustrated in Figure 3.The force (F) applied

against the tissue at the tip ( ) can also be measured by monitoring the induced voltage valueSince the tip displacement is linearly proportional tothe induced voltage, the tip displacement values (d0and dI) can be replaced by the measured Vin,0 andVin,Ivalues, where Vin,0 is the induced voltage valuewith no sample and V in,I is the induced voltage withsample, respectively.30

Differences in elastic modulus between normaland abnormal breast tissue can be accuratelydetected by comparing the degree of deflection atuniformly applied voltage in the driving layer. Thesensorsability to apply a force and measure the tip

displacement electrically, in a self-contained unit,creates an electronic palpation sensor for in-vivobreast tissue imaging with minimal operatorvariability.

2.2 Current state of development

UELS has now developed the first commercial-grade, iBE prototype (v1.0) with funding support from thePennsylvania Department of Health (C.U.R.E. grant award, August 2012) and designed for manufacturability incollaboration with Design Design Inc., a product design and development company. iBE prototype v1.0 is ahand-held, battery-powered tool that wirelessly reports to a mobile device in near real-time. All the components

PCBBattery

Piezoelectricsensor probe

Tissuecontact grid

Fig. 4: iBE Prototype v1.0; (a) Real-life picture of the iBE device at its current stage of development; (b) iBE CAD model withinternal components; (c) Sensor-Probe

(a) (b) (c)

Fig. 3: Cross-sectional view of iBE piezoelectric sensorclamped aone end creating a cantilever-like structure with plastic tip attachedat the other end; Since the force applied against the tissue at the tipcan be calculated by measuring the tip displacement value and the

known spring constant range, monitoring the induced voltageamplitude provides the resultant force magnitude at the tip. (a)Without an applied voltage, Vapp, (b) With an applied voltage, Vapp,and (c) With tissue underneath during indentation and with anapplied voltage, Vapp.

Vapp

=15V DC

Vind

=0

d0Vapp=0

Vind

=Vin,I

dIV

app=15V DC

AI

(c)V

ind=V

in,0

(a) (b)

DrivingPiezoelectric Layer

Array of SensingPiezoelectric Layer

Fig. 2: 4x4 piezoelectricsensor array

MetalSubstrate


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(electronics, sensor probe, battery) are packaged in an industrially designed ergonomic housing (Fig. 4). Foupiezoelectric sensor arrays are stacked in a step-ladder formation creating a 1.5 in2surface area sensor-probewith flush-tips to simultaneously examine elastic modulus of the breast. Although work is planned (in UH2) tofurther ready the device for deployment in LMICs, iBE prototype v1.0 already has the following attributessuitable and valuable for LMIC settings:The sensor probe, control electronics and the Bluetooth wireless communication

consume extremely low power such that the entire system can be operated for 9

hours continuously before requiring a battery recharge (3.7 V lithium-ion battery).This translates to complete breast examinations (4-5 minutes) for more than100 women, on a single charge.

With on-board processing, a single iBE scan is compressed to 100 bytes(0.1KB). A mobile device with 16GB memory can store >1 million breast exams,including demographic information for each patient.

16 sensors together can examine 1.5 in2area of the breast at any given time.The probe can be moved around from location to location (when used incontinuous mode) and the device reports the results wirelessly to a connectedmobile-device in near real-time. With a 1.5 in2 probe, each breast quadranttypically takes 30-40 seconds to examine. UELS has developed a prototypemobile app that assists breast exam data collection (Fig. 5). Each grid square

contains data from all 16 sensors. Currently, the app is under development as itdoes not yet capture patient identifier data.

2.2 Excised tissue studiesOur first set of clinical experiments involved testing one

individual PZT sensor on excised tissue collected during breastsurgeries. 71 mastectomy and lumpectomy tissue samples wereevaluated at Hahnemann University Hospital under an IRB-approved protocol. The objective was to assess the ability of iBEtechnology to identify under-lying tumors from the skin surface.The iBE operator was not informed of the location of the breastabnormality throughout the testing, and collected data bysystematically mapping the sample, collecting elastic modulusdata (during this experiment, shear modulus data were alsocollected) at each grid point (Fig. 6). The tissue samples were

then subjected tohistopathology toconfirm the locationand also to determine the type and size of each tumor. Of the 71ex-vivosamples, 38 were identified wish invasive carcinoma (IC)24 were benign and 9 were identified with ductal carcinoma insitu (DCIS) by pathological testing.

The iBE sensor could reliably detect the difference in elasticmodulus between normal breast tissue (13 3 kPa) and DCIS(62 10kPa; p


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location, the piezoelectric sensor was also capable of accurately measuring tumor size (Fig. 7). The smallestumor detected was a 2 mm satellite invasive carcinoma missed by physicians palpation, ultrasound andmammography techniques and identified by MRI and pathology.

2.2 Clinical studies (in-v ivo)In the first in-vivo clinical study, 40 symptomatic patients (ages 20 to 77; 15 patients were younger than

40) presenting with breast abnormalities detected by palpation or imaging were enrolled in an IRB-approvedstudy. iBE tests were performed with the patient in supine position before undergoing biopsy or surgicaexcision. The locations of the lesions detected by iBE were compared with those confirmed by imaging orpathology. For this study, an array of four sensors in a single row was used.

iBE sensors identified the majority (9 of12) of malignant lesions that were non-palpable and visible only on mammogram (Fig.8). In women under age 40, iBE identified allmammography-visible lesions (7 lesions, 2malignant); iBEs performance in youngersubjects is particularly interesting forapplication in LMICs, where the median age ofpatients with breast cancer is less than in theU.S. BC in premenopausal younger women ismore aggressive and less responsive totreatment, making earlier detection even moreimportant to clinical outcome. Overall in thisfirst in-vivo study, iBE reported 9 falsepositives (46 true positives) and 2 truepositives not originally found on imaging orpalpation (later confirmed via MRI, pathology).iBE identified 83% of the lesions reported onmammogram and did not miss detecting anyinvasive breast cancer. The results from thisstudy were published in the Journal of

American College of Surgeons.6

3. INVESTIGATORS/TEAM

Table 4 lists key team members on this project in each of the four critical functional categories andindicates their affiliation/role. Below the table is a brief description of each, as well as a description of additionaadvisors organized by affiliation (letters of support attached).

TABLE 4: Teams and Coordination of Efforts

Engineering Coord inat ion of Effor tsHakki Yegingil, PhD (co-PI)UE LifeSciencesMatthew CampisiUE LifeSciencesIan WhiteDesign Design Inc.

UH2The Engineering Team will make iBE more durable, reducsensor fabrication cost, validate specificity in breast models whideveloping and validating an operator training program

collaboration with Oncology and Global Health Delivery Team(Section 4.1: Aim 1, 2). Cultural acceptability will be assessed India using mixed methods approach and UH2 clinical study wbe undertaken (to measure efficacy to detect T1c or largcancers and other breast abnormalities) after 10 iBE v2.0 amanufactured with refinements (Section 4.1: Aim 3, 4Business Development Team will meet with LMIC stakeholderconfirm regulatory pathway and update deployment plans.

UH3 The Engineering Team will modularize the device andevelop app based self-diagnostics features, and manufactu30 iBE v3.0 units (Section 4.2.1: Aim 5). The Oncology an

OncologyAri Brooks, MD (co-PI)University of PennsylvaniaSchool of MedicineThiago Buosi, PhDBarretos Cancer Hospital, BrazilSV Prasad, MDApollo Hospitals, India

Global Healthcare Del iveryMahesh Shetty, MD (co-PI)UE LifeSciencesEdmundo Mauad, MD - Barretos Cancer Hospital, BrazilGiang Ngyuen, MD - University of Pennsylvania School

Fig. 8: Example case study showing iBE and mammogram results on the le

breast of a patient.

Nipple

Round mass in the upper outerquadrant w/ grouped finepleomorphic calcifications.Category 4 - Suspicious

4 oclock, 5 cm from nipple(Depth under skin ~ 1 cm)Non-palpable

Patient No: 007, age: 69, left breas

11 oclock, 4 cmfrom nipple.Mammo visible


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of Medicine Global Health Delivery Teams from both LMICs (India and Brazwill recruit and train CHWs in the use of iBE v3.0, obtain IRapprovals and conduct clinical studies to evaluate iBEperformance in LMIC. Business Development Team will assist teams with logistics, operations and regulatory applicatioBusiness Development Team will also expand existinpartnerships with local governments, distributors and NGOs fpost-validation commercial deployment (Section 4.2: Aim 6, 7)

Business DevelopmentMihir Shah (co-PI)UE LifeSciencesJose Pecora, BrazilBhaumik Sanghvi, India

3.1. UE LifeSciencesMihir Shah (Chief Executive Officer) has more than 8 years of entrepreneurial experience in medica

device innovation and commercialization spanning areas of multidisciplinary R&D, regulatory pathwaystrategic relationship development and product validation studies in developing countries. Mihir has helpedmove several technologies from concept-to-market like NoTouch BreastScan, InfraScan, IQ, Zoe. MrShah travels extensively to LMIC regions to develop relationships with NGOs, governmental agencies, keyopinion leaders and medical device distributors. He is also leading iBE commercialization efforts as thePrincipal Investigator in the Pennsylvania Department of Healths CUREgrant project.

Prof. Matthew Campisi (Chief Technology Officer) leads electronics design, software analytics & signaprocessing. In the past, Prof. Campisi has led the product development for other breast cancer screening toolslike Sentinel BreastScanand NoTouch BreastScandevices. As an industry professor, he teaches severacourses at the Electronics and Electrical engineering department at NYU Polytechnic Institute.

Hakki Yegingil, PhD (VP Science and Technology) is the co-inventor of the piezoelectric sensortechnology used in iBE prototype and directs iBE prototype and sensor design, fabrication and assemblyprocesses. He holds a doctorate in Materials Science and Engineering from Drexel University, where he ledthe development of the first iBE clinical prototype, as well as the preliminary ex-vivoand in-vivostudies. He isgranted multiple US and international patents for his work on piezoelectric materials and sensors. As the mainauthor, he has published peer-reviewed scientific articles in leading materials science and biomedical journals.

Mahesh Shetty, MD, FRCR, FACR (Medical Director) is a Clinical Professor of Radiology at the BaylorCollege of Medicine and the founder of the Womans Cancer Foundation, an NGO to help economicallydisadvantaged women in developing countries fight breast cancer. Dr Shetty has authored two text booksBreast and Gynecological Cancers: An Integrated approach for Screening and Early Diagnosis in DevelopingCountries (2013) and A Synopsis of Breast Cancer Screening and Diagnosis (to release in 2014) publishedby Springer. He has conducted numerous workshops and lectures in Brazil and India on the topic of secondaryprevention of BC. He's an International Visiting Professor of the Radiological Society of North America.

3.2. Pennsylvania Hospital, University of PennsylvaniaAri Brooks, MD is the Director of Endocrine and Oncologic Surgery and Director of the Integrated Breas

Center at Pennsylvania Hospital. As the Co-Primary Investigator, Dr. Brooks has led the efforts to examine iBEtechnology at the clinic, ex-vivo and in-vivo. His research findings with the proof-concept iBE device in 40women in-vivo were published in the Journal of American College of Surgeons in July 2013. In collaborationwith Susan G. Komen foundation, Dr. Brooks has helped establish a screening and treatment center for breastand cervical cancer for uninsured women. Hes named "Top Doctor" by Philadelphia Magazine (2008-2013).

Giang Nguyen, MD, MPH, MSCE is Assistant Professor of Family Medicine and Community Health at the

Hospital of the University of Pennsylvania, and an Attending Physician. He is a Senior Fellow in the LeonardDavis Institute of Health Economics, a Senior Fellow in the Center for Public Health Initiatives, and a fulmember of the Abramson Cancer Center, Cancer Prevention and Control Research Program. His researchand clinical expertise includes Asian immigrant and refugee health, preventive health, culturally competentcare, public health communication, health disparities, and cancer control.

Brian Englander, MD is the Chief of Breast Imaging at the Pennsylvania Hospital and the Director ofWomen's Imaging Center at Pennsylvania Hospital. Dr. Englander leads a dedicated team of radiologists andtechnologists with high quality interpretations and personalized care.

Yvonne Paterson, MD is the Associate Dean for Research and Professor at the University of PennsylvaniaSchool of Nursing. Dr. Paterson works closely with nursing students and teaches graduate level courses in theareas of cancer immunology and biotechnology commercialization.


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3.3. Barretos Cancer HospitalEdmundo Mauad, MD, PhD, MBA (Director of Barretos Cancer Hospital) is the Chief of Cancer Prevention

Department at Barretos Cancer Hospital. He has been directing programs of opportunistic and organizedcancer screening of Breast, Cervical, Prostate and Skin since 1994. His focus areas are cost-effectiveness,community intervention and introduction of new technologies to improve screening programs in underprivilegedpopulation in Brazil. He also serves as the Head Administrator of the Teaching and Research Institute.

Thiago Buosi, PhD (Site PI, Barretos Cancer Hospital) is a research coordinator, with experience in breast

and prostate cancer research. He coordinates the studies and protocols of the Cancer Prevention Departmentof the Barretos Cancer Hospital (Barretos, Brazil). He is the PI and sub-PI for various clinical studies involvingbreast, skin and prostate cancer prevention. Mr. Buosi is responsible for the quality control of mammographyscreening program. He teaches graduate degree courses at Barretos University and supervises scientificmultidisciplinary research.

3.4 Apollo Hospitals Educational and Research Foundation (AHERF)Jaganmani Sreekanth, MD (Site PI, AHERF) manages the Apollo Master Health Check (MHC) program at

Apollo Hospitals locations in Chennai, Hyderabad and New Delhi with 80,000 women participants thaannually visit Apollo Hospitals for a series of preventive examinations including PAP smear and clinical breastexamination. Dr. Sreekanth is a practicing internal medicine physician and has participated in multiple clinicastudies over the past 8 years.

SV Prasad, MD (Co-I, Oncology) is an eminent medical oncologist and clinical researcher with a dedicatedcareer to the treatment of hematology and oncology patients in India. He has long been an advocate ofprevention and early diagnosis of cancer in India. Dr. Prasad will advice the project in UH3 validation study inIndia to ensure proper clinical protocols are being observed and to strategically support Dr. Sreekanth managea large scale clinical study in India.

3.5. Clinical Advisory Panel (CAP) for UH2 and UH3A clinical advisory panelhas been convened to advise, mentor, evaluate and assess the creation and

progress of strategies and clinical investigations under the UH2/UH3 phases for this project. CAP members wilinclude Ben Anderson, MD (Global Health Delivery); Ari Brooks, MD (Oncology); Mahesh Shetty, MD(Secondary Prevention in LMICs, Radiology); Edmundo Mauad, MD (Cancer Prevention, LMIC Deployment inBrazil); and PK Julka, MD (Oncology, LMIC Deployment in India). The CAP has been holding at least 1 hour biweekly teleconferences with the coordinating PI (Shah) prior to the submission of this proposal. It will continue

to meet monthly, via webinar, starting with the project kick-off meeting. At these meetings, the CAP hasbeen/will be responsible for review/comment/advice on the NIH application; making recommendations onUH2/UH3 clinical study design, operational strategies for LMICs, deployment planning; Intermediateoperational, clinical, technical or research related discussion/advice; Quarterly, Annual and UH2/UH3 phaseevaluation. At the conclusion of UH2, and at least annually in UH3, the CAP will meet in session with all the PIsand with representatives of NCI/NIH to make go/no-go recommendations for UH3. Members of the CAP whohave not been described in Sections 3.1-3.4 (above) are:

PK Julka, MD is an eminent physician and the professor and head of the Department of Radiotherapyand Oncology at the All India Institute of Medical Sciences (AIIMS), New Delhi. Dr. Julka was awarded thePadmaShree Award in 2013, Indias fourth highest civilian award for his distinguished services in the field ofscience and medicine.

3.6 LMIC business advisors/consultants

Jose Pecora (Operations Manager, Brazil) has 35+ years of business experience working formultinational companies in Brazil and USA in the area of market entry, distribution channel management,regulatory and multidisciplinary team coordination. Jose is fluent in both English and Portuguese.

Bhaumik Sanghvi (Operations Manager, India) has supported UE LifeSciences activates in India since2009. Mr. Sanghvi has worked with Shah, Campisi and Sreekanth to provide support to clinical studies invarious clinical institutions spread across India. For the InfraScanner clinical study, which resulted in FDAapproval of the device, Mr. Sanghvi played a key role as the site manager and coordination between USAbased technical team and the India based clinical team. With the NTBS device, he has worked extensively with

Apollo Hospitals, NGOs in India and governmental agencies, since 2010.

3.7. Other project collaborators


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Ian White, ASME, IDSA, PDMA (President, Design Design)assists product design, CAD modeling andfabrication of iBE prototypes. Mr. White has 12 years of experience in product design and product developmenmanagement of programs for large corporations and emerging technology companies in consumer, medical,defense and industrial markets. Programs include new product development, and product design refresh withcost reduction of mature products. His design experience includes mechanical product innovation tocompliment customer driven scientific development, design for manufacturability and assembly in MCADsoftware for high/medium/low volume applications, design validation and refinement with CAE software, and

manufacturing specification (material/finish/GD&T/workmanship standards).Susan Spruill, MS, PStat (President, Applied Statistics and Consulting) is a Professional Statistician

accredited by the American Statistical Association. Susan has provided statistical analysis and consultingservices for over 29 years in areas including device development in womens health issues and oncology. Sheis an active member of International Biometrics Society, Drug Information Association, and Diversity Alliancefor Science.

3.8 Past and ongoing collaborationsThe PD/PIs share a long-term, multidisciplinary and result oriented working relationship, which ensures

that the collaborators and partners will work together effectively and complete the proposed technologyvalidation successfully: As co-inventors, Dr. Brooks and Dr. Yegingil have collaborated since early 2004 under severa

translational research grants to advance the piezoelectric sensor technology. Together, theyinvestigated early-stage clinical prototype on 71 excised lumpectomy and mastectomy breast cancertissue samples as part of Dr. Yegingils doctorate studies(Section 2.2).

Dr. Yegingil is actively working with UE LifeSciences (Mr. Shah and Prof. Campisi) since June 2012 asthe VP of Science and Technology to help develop iBE sensor technology for future commercializationas a medical device.

Mr. Shah and Dr. Shetty have visited Barretos Cancer Hospital on various occasions. Dr. Shettys bookfeatures a chapter Combined Screening for Breast and Gynecological Cancers Using Mob ile ClinicsThe Barretos Experience (Brazil). Dr. Edmundo Mauad, the Director of Barretos Cancer Hospital,serves on the medical advisory council for the Womans Cancer Foundation , founded by Dr. Shetty.

Mihir Shah has teamed with Dr. Brooks on several community based breast cancer screening camps inthe Philadelphia, PA region.

Dr. Shetty serves as the Medical Director of UELS since early 2013, to oversee and advise deploymentof UELS products and services as part of breast cancer screening programs in several developingregions including Latin America, India and the Middle East.

UE LifeSciences has worked with Apollo Hospitals, India for over three years and is now working withBarretos Cancer Hospital in Brazil regarding NoTouch BreastScan, another breast cancer screeningproduct developed by UE LifeSciences.

4. RESEARCH APPROACH

4.1 UH2 EXPLORATORY PHASEIn the two-year UH2 phase (Table 5), the iBE prototype v1.0 will be further engineered to comply with alspecific required attributes for eventual use in LMIC conditions (Aim 1). A standardized operator trainingprogram will be developed and tested (Aim 2). The resulting iBE v2.0 will be clinically validated in a preliminary

study in the U.S. (Aim 3) to compare its performance in identifying T1c or larger breast cancers and otherclinically relevant breast masses, to clinical breast exam and screening mammography. Criticacommercialization and logistical activities will also be completed, including determination of culturaacceptability of the device, and regulatory planning.

TABLE 5: UH2 Aims, Milestones, and Timeline

Aim 1: Engineering for LMIC Readiness. (1)Make iBEdurable for use in LMIC; (2)Reduce sensor fabricationcost and time; (3)Validate specificity in models.

Milestone 1: (1)Pass JISC0022 temperature and moisturetests; Pass JESD22-B111 drop test; Sensor life of 200 hours ofoperation (2,500 scans); (2)Reduce fabrication time (5 man-hour savings/unit); (3)10% false-positives.

Aim 2: Usability Validation for Operators(1)Determine and validate operator training program for

Milestone 2: (1) 6 nursing students pass the training program byscanning a breast model in 75% accuracy; (2)


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4.1.1 - Aim 1 (UH2): Engineering for LMIC ReadinessRationale and Strategy. The current iBE prototype (v1.0) readily meets most of the specific required

attributes listed in the RFA: its portable, wireless, provides rapid results at the point-of-care and is easily

operable in locations with no medical infrastructure. In this phase, we will engineer the iBE prototype v1.0further by making the sensor and device housing ruggedized for LMIC conditions and by simplifying the sensorfabrication process (to reduce complexity, cost of production). iBE v1.0 will be further developed to incorporatesignal processing and image processing algorithms to reduce false positive results and to enhance imagerepresentation. At the end of this phase, we will release a manufacturable iBE prototype (iBE v2.0), ready forusability validation (in Aim 2).

Ruggedization.(6 months development and testing). The iBE device is likely to encounter variations ofheat and moisture in the field, which may contribute to system failure. To protect it from these conditions, aswell as from dust and contamination during installation or handling, the piezoelectric sensor array will becoated using a proprietary method that is strong enough to protect the sensors from moisture or dust, buflexible enough to enable performance. Electronics will be protected by industry standard silicone coating toprevent moisture and dust from penetrating. Sensors will be tested according to JISC0022 test, the Japanese

Industrial Standard, that establishes the best practices for conducting extreme temperature and moisturefatigue life tests.31

Drop impact is a leading cause of failure in portable electronics.32The importance that iBE be resistant todamage during rough handling is particularly acute in community health settings in LMICs, where the highvolume of patients and the mobile nature of some sites may make drops more likely, and where replacementparts or repair capabilities may be limited, meaning that a damaged unit may leave the site unable to performscreens for some time. We will evaluate (and if necessary improve) the durability of the iBE prototype v1.0 byensuring that it passes the JESD22-B111 global standard.33This standard, which is developed by the JoinElectron Device Engineering Council (JEDEC), evaluates and compares drop performance of surface mountelectronic components for handheld electronic product applications in an accelerated test environment. Ineeded to enhance usage durability, the iBE prototype enclosure may be redesigned, PCB board solderingpoints will be improved, impact-resistant cable connections will be incorporated, impact absorbers will be

installed into the enclosure and travel limiters will be designed for iBE piezoelectric sensor array safety.Fatigue resistance of iBE piezoelectric sensor array will also be crucial to ensure that the sensor-probe

can last for long periods in service particularly in field and remote environments. We will start by characterizingthe current fatigue life of the piezoelectric sensor array, which is defined by the number of cycles the sensorscan run, before the driving piezoelectric layer fails or the magnitude of the peak-to-peak induced voltagecreated on the sensing electrodes is reduced by at least 20%. Fatigue tests will be conducted on anelectromagnetic shaker. While the array is vibrated, function generators will be used to apply 15 V DCcontinuously (to mimic routine use) to the driving piezoelectric layers of the array in a square step functionmode; the generated induced voltage values will be monitored. If needed, we will improve the fatigueresistance of iBE piezoelectric sensor array by experimenting with alternative gluing mechanisms to bond thedriving and sensing electrodes to the metal substrate.

eventual use in LMIC settings; (2)Fabricate iBE v2.0units for use in UH2 study.

Manufacture 10 iBE v2.0 to design specifications.

Aim 3: Clinical validation in standard of care setting(1)Measure clinical efficacy to detect T1c or largerbreast cancers and other clinically relevant breastabnormalities; (2)Per-lesion characterization; (3)Inter-rater reliability (IRR) rate; (4) Device specificationsvalidation.

Milestone 3: (1)iBE performs with statistically better sensitivity,specificity and predictive values than CBE and similar tomammography; (2) is observational; (3)


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Piezoelectr ic Sensor Fabricat ion (4 months development and testing). Currently each piezoelectricsensor probe takes approximately ten man-hours to fabricate (two and half hours per piezoelectric sensorarray) in a time-consuming and labor-intensive manual process (Fig. 9).

Currently, industrial epoxy is manually applied and cured to attach the piezoelectric material (driving andsensing electrodes) to the substrate. Because the epoxy is applied manually, each array requires thoroughsanding and cleaning, contributing to more than 60% of the total manufacturing time. Epoxy system would bereplaced by an adhesive system which would not require sanding or cleaning, shortening the total piezoelectricsensor manufacturing to less than an hour, or more than 50% time savings over the current process.

Digital Signal Processing. (4 months development and testing). iBEs detection accuracy is a directfunction of the integrity of the data collected on the induced voltage in the sensing piezoelectric layer. Theinduced voltage is a response to a driving step function, which is created by converting an electrical stepfunction to a mechanical step function. When the step function is applied to the driving piezoelectric layer, theresulting induced voltage on the sensing piezoelectric layer includes thermal and mechanical noise, as

illustrated in Fig. 10(a). Denoising is a common signal processing technique to increase the stability andrepeatability of data measurements. Currently, the iBE prototype v1.0 utilizes a basic denoising technique (3 rd

order blurring filter) to remove the majority of the noise on the induced voltage (Fig 10(b)). However, this basic

approach, while appropriate for early prototype development, still permits errors in identifying the inducedvoltage peak value, as seen in Fig 10(d) resulting in false positive measurements (see Preliminary Data)Filters that can better estimate the desired deterministic response (Fig. 10(c)) will be designed and tested. Inorder to specify the optimal filter, cutoff frequency, Gibbs phenomena (ripple) and transition bandwidthcharacteristics need to be determined. In addition, providing real-time results at the point of care requiresminimal delay.

Lastly, the step response will be curve fitted to the desired deterministic response seen in Fig 10(c). Theknown desired step response follows a standard resistor-capacitor transient response with decay factor , where is the decay factor, R and C are the equivalent resistance and capacitance values, respectivelyand the induced voltage,

( ) (2)

Where t and are time and the induced voltage at a specific time, respectively and , are constantsThe optimum values of in (Equation 2) will be determined using least squares optimization. Thesevalues correlate with the piezoelectric sensor array tip deflection characteristics that relate to tissue elasticitymeasurements.

In addition to denoising, software algorithms can also assist in image interpretation by reducing artifactsgenerated during the positioning of the iBE device on the tissue or uneven pressure on the iBE piezoelectricsensor arrays misleading the operator and leading to false positive readings. This will be accomplished byincluding data filters that remove outliers that vary by more than two standard deviations from the average ofthe surrounding measurements. Empirical testing will further optimize filtering criteria such that only artifact iseliminated, resulting in a smoothed 4 x 4 matrix of the piezoelectric sensor measurements. Bilinear and/obicubic interpolation will further refine the data to create a smooth image visualization, removing the blocky

(a)

(b) (c) (d)

Figure 10: (a) Raw data received by piezoelectric array, (b) Low pass filtered raw data, (c) Desired response curve fitted, (d) Peakcharacteristics of (a), (b), and (c). Note the difference in peak detection (value and delay) for the different stages of processing.

Cutting Piezoelectric Material andSubstrate + Gluing & QC Check

IntermediateProcesses

Cleaning and SandingTip Attachmentand Final QC

Check

Fig. 9: Piezoelectric sensor probe (4x4) fabrication steps. Arrow length is proportional to completion time for each step.


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nature of the piezoelectric sensor geometry. Also anti-aliasing blurring will be implemented to smooth thejagged edges associated with the data. The desired goal is a smooth topological mapping of the discrete data.

To confirm successful completion of the digital signal processing refinements, 10 breast scans will beperformed on 3 different silicone breast models with inclusions of various sizes that simulate breast lesions.

Expected Outcomes and Milestones.The following metrics will be used as thresholds of success forAim 1, with risks and alternatives listed in Table 6: iBE passes the temperature and moisture test per JISC0022 standards; iBE passes the drop-test pe

JESD22-B111 std.; sensor fatigue life of min. 200 hours of operation confirmed (2,500 scans, 5 min each). 50% reduction in sensor array fabrication labor (five man-hour savings per sensor probe). No more than 10% false-positives in silicone model testing.

TABLE 6: Risks and Alternatives Aim 1 (UH2)

Risks AlternativesAmong various approaches toincrease iBEs durability andresistance to weather, thepiezoelectric sensors may not passthe drop impact test.

If the suggested travel limiter solution fails to protect the piezoelectric sensorprobe during the drop test, an accelerometer sensor will be integrated on thecircuit board, which can sense free-fall condition and trigger the circuit board toinduce 15 V DC to the piezoelectric sensor array system in a continuous mode.This measure will strengthen the sensors before the impact. Also, during theUH3 engineering phase, iBE sensor probe will be made modular ( Section 4.2,Aim 5) making it an easily removable component in case the probe is damaged

during free-fall.The conductive adhesive systemmight not provide the sameflexibility to the piezoelectric sensorarray, limiting its performance.

A screen-printing process will be used to apply the current conductive pastesystem onto the substrate, which will automate the glue application process andensure that the same amount of glue will be applied onto the substrate duringpiezoelectric sensor manufacturing.

DSP is incorporated primarily toreduce false positives andmaximize specificity. Thisoptimization may result in anincrease in false negatives.

Should the percentage of false negatives exceed 40%, the DSP algorithms canbe altered to achieve lower false negative rates while maintaining acceptable(but slightly lower) specificity.

4.1.2 - Aim 2 (UH2): Usability validation for operators (6 months)Develop Training Protocol (3 months). In order to ensure that the iBE prototype can be operated by

users with minimal healthcare training (such as might be expected in Brazil or India), we will develop a trainingprotocol, and test it, and the usability of the iBE prototype, with nursing students. Like many community CHWsin Brazil and India, nursing students possess a preliminary knowledge of the clinical environment, patientinteraction and experience and basic familiarity with biomedical equipment. An operators handbook for the iBEdevice will be drafted, including any modifications or enhancements incorporated in Aim 1. This handbook wildescribe the basis of the technology and the correct operation of iBE device, in relation to both hardware andsoftware (mobile device app). A detailed step-by-step procedure for setting up the patient for an exam toperforming a full-scan and reporting the findings will also be described in the handbook.

The handbook and training protocol will be developed so as to closely simulate the minimal commonelements that may be expected in a training environment in an LMIC. The handbook will be provided to sixnursing students from University of Pennsylvania School of Nursing, who will have the opportunity tothoroughly review the handbook and later participate in a classroom session to ask questions and observe alive demonstration of iBE prototype as specified in the handbook. When the demonstration is completed and alquestions have been addressed, each student will be given an iBE sensor, mobile device, and silicone basedbreast phantom (breast model) with spherical inclusions to simulate palpable abnormalities. Breast models wilbe made from Ecoflex-Supersoft silicone with a Shore hardness of 00-10, closely resembling elasticity similato actual breast tissue and the spherical inclusions will be made from Eager Plastics P15 silicone with a Shorehardness of 18A, representing breast abnormalities/lumps. For this experiment, the visible inclusions will be 5and 10 mm in diameter and will be located at a depth of 10 mm.

The students will be asked to perform a complete scan on the breast model, under the supervision of aninstructor in the laboratory environment. In the event that a student fails to perform any of the steps tosuccessfully operate the iBE device, they will be permitted to refer to the operatorshandbook and repeat thetesting. In the event that a step in the handbook cannot be completed, even while being referenced, theinstructor will query the student to address the difficulty or lack of clarity. Revising the handbook with these


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clarifications will be considered. In the event that more than half the students fail the same step, the instructowill note these findings such that device refinements to enhance usability are considered. Necessarymodifications to the operator handbook and/or the device will be made. A new group of six (6) nursing studentsthat are unfamiliar with iBE will be recruited. The above training procedure will then be repeated until everystudent can complete all tasks without referring to the handbook. This iterative process of handbook andtraining protocol development and operator testing will be repeated until an entire group of six (6) nursingstudents can complete all of the tasks successfully without having to refer the operator handbook.

Design and manufacture of iBE v2.0 (3 months). The modifications in hardware and softwaredetermined in Aim 1 and in Aim 2 (usability) will be documented and provided to collaborators at DesignDesignInc., who will develop industrial design plans that are compatible with scalable manufacturing. This moredurable, easier to operate, and more effective design will be designated as iBE prototype v2.0. DesignDesignwill manufacture and assemble ten iBE prototype v2.0 units. At least two units will be subjected to JISC0022moisture/heat testing, JESD22-B111 drop testing, fatigue testing for sensor lifespan of at least 200 hours ofoperation, and less than 10% false-positive outcome from testing in silicone models, to confirm thatperformance parameters of the final v2.0 prototypes meet expectations.

Validation o f usabi l i ty of the iBE v2.0 device (3 months). We will validate the usability of the iBEprototype v2.0 device by recruiting six nursing students who have never before used any version of the deviceEach student will be trained according to the developed training protocol, and then asked to perform a set oftasks, including scanning three breast-models, successively. The usability of the device, and the effectiveness

of the training protocol and operators handbook will be considered validated ifstudents are able to completethe evaluation in 5 minutes or less with abnormality detection and reporting accuracy of 75% or better.

Using these criteria, an operators manual and training protocol will be developed that will enable a personwith healthcare training equivalent to that of a nursing student who is new to iBE to learn to operate the deviceby reading the manual (without instructor training) and performing a reasonable number of practice scansusing one or more breast models. This protocol, including the breast models and the operators manual, will beimplemented both in the clinical study performed in the United States in UH2, and in the studies performed inBrazil (following translation into Brazilian Portuguese by a qualified healthcare translator, and independentback-translation into English to ensure linguistic equivalency prior to use) and India in UH3.

Expected outcomes and milestones.The following metrics will be considered as thresholds of success: 6 nursing students pass the training program without referencing handbook. Operators handbook will be

developed along with the training protocol, enabling minimally trained CHWs to operate the device and

perform a breast exam with iBE in less than 5 minutes, with at least 80% detection sensitivity.10 iBE v2.0 units for use in the UH2 clinical study phase (in Aim 3)

Risks and Alternatives. Unexpected iBE device malfunctions identified during the training processincluding parts failures and/or mobile device app defects will be addressed if and when they arise. As ispossible with any mobile device, software, operating system, or hardware glitches may occur unexpectedly dueto software version incompatibility, programming errors, etc. Latent defects in the engineering design ofthe device may become evident during the training process. These defects will be properly documented andpromptly addressed. There will be a spare, complete iBE system on site for training should any failure occur tominimize any delays in training.

4.1.3 Aim 3 (UH2): Clinical Validation within standard of care setting in USARationale and Strategy.Having completed the engineering and usability validation of iBE prototype v2.0

we will next validate its clinical utility by deploying it in a standard of care setting in the USA. Demonstratingsatisfactory clinical performance (sensitivity, specificity and predictive values) comparable to mammographywill provide empirical evidence of iBEs clinical effectiveness and user experience, prior to initiating larger-scaleLMIC clinical studies in Brazil and India. We will train nursing students as iBE operators (as describedpreviously), and then have them conduct iBE breast exams on subjects recruited from among patients whopresent to the study site for routine mammography or ultrasound-guided biopsy. The primary objective of thestudy is to evaluate the ability of iBE to identify breast abnormalities worthy of clinical attention (furtherdiagnostic work-up) in comparison with CBE and mammography. Our hypothesis is that iBE will performsignificantly better than CBE, and not significantly worse than screening mammography in identification oinvasive breast cancers T1c or larger and clinically relevant benign lesions worthy of additional diagnostictesting. Secondary objectives are to determine per-lesion characterization, inter-rater reliability, and device


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performance (time per test, charging, error rates), which will help to guide any further engineering work for thedevice prior to deployment in the LMICs.

Study s i te. Operators will be recruited from the University of Pennsylvanias School of Nursing, whichgraduates more than 250 nurses a year. Patients will be recruited, and procedures conducted at the WomensImaging Center at Pennsylvania Hospital. More than 11,000 screening, 3,000 diagnostic mammograms andover 1,400 needle biopsies are conducted here each year. (See Facilities for more information). Dr. ArBrooks involvement as the Principal Investigator will grant access to Pennsylvania Hospital facilities (See

Brooks Support Letter). The study will be performed under two IRB approved protocols. The first is for theprotection of patients undergoing evaluation of the device, similar to the current protocol under which iBE isbeing evaluated at the University of Pennsylvania, in symptomatic women (supported by the PA Department oHealth CURE grant award). A second protocol will be for the protection of nursing students participating in thestudy as device operators.

Operators.We will enroll female (considering LMIC requirements in India, where only female CHWs areexpected to screen women due to cultural modesty) nursing students to be iBE operators for this study. Eachstudent will undergo training in CBE and in operation of the iBE v2.0 device, as per the protocol developed inAim 2and described in the device manual. We will enroll and train 20 students during the study period, at least8 in each semester and at least 4 more for the summer term. This will provide a sufficient number of operatorsto complete the required screens (2,500 subjects) if each nursing student conducts at least 125 CBE/iBEstudies during the study period; also provides a sufficient number of students to evaluate inter-rater reliability.

Devices.The study will use 8 production prototype iBE devices (iBE v2.0). Each iBE device is providedwith a smartphone (installed with iBreastExam app) for data collection, data storage and reporting. The app wilbe enabled with a time-stamping feature to record the length of the CBE as well as iBE tests. Each device wilbe identified by a unique identifier and will be assigned to an operator until the goal of 125 CBE/iBE exams isreached, or until the operator leaves the study. To simulate LMIC conditions, each operator will be responsiblefor maintenance of her device, as outlined here, and will complete a checklist to indicate completion of routinemaintenance tasks, and to record any functional or usability observations. Each device will be charged for twohours exactly every one week, and sensor-probes will be replaced every 200 scans per iBE device. Operatorswill report error messages or hardware/software failures through the smartphone app.

Subjects. All patients between the ages of 40 and 65 presenting to the study site for routinemammography will be eligible for the study. In addition, patients between the ages of 30 and 65 presenting atthe study site for an ultrasound-guided core biopsy will also be eligible to participate in the study prior to their

biopsy. Women unwilling or unable to provide consent; or have an interfering open wound or skin pathology ineither breast; or if the examiner feels that iBE test will interfere with or be detrimental to administration ofoptimal health-care to the subject; these candidates are excluded from participating in the study. Consent willbe obtained by an individual who is not an iBE operator, so that both iBE/CBE examiner and the data analystare blinded to the reason for subjects presentation to the study site. Our power analysis (taking into accountthe expected normal presentation rate of cancers and clinically relevant benign masses, and the inclusion ofsubjects who are known to be positive) suggests that 2,500 unique subject scans will be required to achieveour primary objective (see Protection For Human Subjects).

Study d esign, procedures, and d ata col lect ion. After informed consent is obtained, the patient wilundergo a clinical breast exam in the supine position with the arm extended over the head. The exam will bedocumented on a paper grid and labeled with the study unique ID number. Next, iBE will be performed by thesame operator with the patient in the supine position, with the arm extended above the head. The data will be

stored by unique ID number in the device. The subject will then proceed to routine imaging (mammography) orbreast biopsy as scheduled in the imaging center. Data from these tests will be coded with the same unique IDfor later analysis. Data from the next yearly mammogram will be collected as well for future study. Based onthe number of enrollments at the imaging center (11,000 per year), we expect to have about 2,500 scanscompleted within one year. An institutional data safety monitoring board (DSMB) will be established atUniversity of Pennsylvania to review the results quarterly to determine if there are any adverse events relatedto the device, and also to determine if the device performance is falling outside of acceptable parameters.

Data analysis and outc omes (prim ary object ives). The goal is to determine that the ability of iBE todetect T1c cancers or greater and any clinically relevant benign mass is better than CBE and similar toscreening mammography. We define this cohort to include all T1c breast cancers and greater, as well aslesions that are benign but would routinely warrant confirmation by other imaging and/or biopsy. As this is avalidation study, we make certain assumptions about the gold standard. In all cases, pathological verification


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of malignancy, when obtained, will be considered the highest level of truth. When pathology is not available (formost subjects who present for routine mammographic screening), a negative mammogram will be consideredgold standard true negative. A mammogram that identifies a lesion worthy of further evaluation such asBIRADS 3 (follow-up image in 6 months), BIRADS 4 (biopsy suggested), and BIRADS 5 (likely malignancy) wilbe considered a gold standard true positive. Of the 2,500 subjects enrolled, we expect almost 10% (200 -250to be true positives. 200 or so additional true positives will be added (biopsied subjects), resulting in a studyprevalence rate of 16%-20% (400-500) (Power Analysis in Human Subjects).

We have defined DCIS and T1a (0-5mm) and T1b (0.51-1cm) invasive cancers as not clinically relevantin LMIC settings, less than 2% of breast cancers diagnosed (in India) are DCIS or T1a; our eventual goal is tohelp enable down-staging of breast cancer from advanced (Stage III or greater in 76% of cases in Indiacurrently) to early stage. We will report the data analysis in two ways. The first is intent to treat analys iswhere all cancers including DCIS, T1a, and T1b are included in the gold standard true positive group. Thesecond is censored analysis, in which we will remove subjects found to have DCIS, T1a, and T1b tumors fromthe analysis. The reason for reporting both analyses is that it is still not clear whether the detection of theseearly-stage tumors is clinically relevant in LMICswhile we would like to keep the option open as the detectionof these early pathologies is considered favorable in the U.S., it may be beyond the scope of the planned UH3study to include them. So we would like to determine the utility of iBE both with and without this group of early-stage tumors included in the UH2 study.

For each breast, the main comparison grid is shown in Table 7. In this table, an iBE may report a positive

that is not confirmed on imaging and could be a missed malignancy. In addition, an iBE may report correctlythat there is nothing of concern in a breast that is classified as BIRADS 3,4,5 or 6. Both of these factors mayreduce the measured accuracy of iBE in this study design but are reflective of the current gold standard statefor breast screening.

The study prevalence otrue positives is expected to be16% to 20% of subjects. Theexpected detection sensitivityof mammography is 90%. IiBE detection is statistically

similar to mammography, then the sensitivity of iBE should be between 86.6% - 92.8%, and the specificity ofiBE should be between 89.1% - 90.9%. The detection rate of iBE will also be compared with that of CBE where

the proportion of true positives detected is expected to be approximately 40%. A simple rank sum test of truepositives detected for each examination method will be performed to determine if iBE is superior to CBE.

Data analysis and outcom es (secondary o bject ives). Data analyses for secondary objectives are:Per lesion characterization. A secondary endpoint will be a comparison of the characterization of

individual lesions detected.6This analysis (Table 8) will compare each lesion reported within each breast onlocation (a quadrant in the breast) and size (in mm) stored in iBE device with the data available from imaging.

Location and size datacan help optimize furthediagnostic work-up. Alsodata from this analysisincreases the number of datapoints to compare per

examination. This can exponentially increase the power of the statistical analysis to detect the true accuracy ofiBE device. However, we are not using this as a primary endpoint because in reality the information that isneeded form an iBE breast-screening test is whether or not additional work-up is indicated. Knowing that 99%of the breast is free of cancer is not clinically relevant if there is one lesion that needs to be diagnosed andtreated. Therefor what is needed is a binary output of YES, do more testing on this breast or NO, nothingfurther is needed.

Inter-rater reliability rate. We will use data from the study to determine inter-rater reliability rate to helpoptimize the clinical performance of iBE to be more consistent and reliable, intra-operator. However, since theindividual operators will not be studying the same patients, we will compare individual false negative and falsepositive rates within each of their cohorts.

TABLE 7. Comparison of iBE to Truth

Mammo negativeBIRADS 1,2

Path positive or Mammo positiveBIRADS 3,4,5

iBE negative True negative False negativeiBE positive False positive True positive

Mammo = mammography; Path = biopsy histopathology

TABLE 8. Per lesion characterizationMammo or Ultra or Pathnegative at that location

Mammo or Ultra or Pathpositive at that location

iBE negative at a location True negative False negativeiBE positive at a location False positive True positive

Mammo= mammography; Ultra = ultrasound; Path = biopsy histopathology


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Device specifications validation. Each device will be required to operate daily; performing at least 20scans without a recharge for a maximum of 3 days before charging is required. As part of the training processunder the usability phase, operators are required to switch-off the device after performing the test on a patient.iBE v2.0 uses 3.7v lithium-ion battery capable of providing 5 hours of continuous operation, or 60 patients atthe rate of 5 minutes per patient. This evaluation will practically confirm that iBE can function as per thespecifications.

Risks and alternatives for Aim 3 are shown in Table 9.

TABLE 9: Risks and Alternatives, Aim 3 (UH2)

Risks AlternativesThere is a possibility that the enrollment remainslower than 208 cases per month, required tocomplete 2500 scans in a year, during the studyperiod of 12 months. Based on historical caseloadsand the experience of physicians (Brooks,Englander) in enrolling subjects for similar studies,this is unlikely. Similarly, it may be difficult to recruit8 nursing students from Pennsylvania School ofNursings existing pool of students, as required toperform the necessary number of scans per month,during the study period.

If enrollment remains under 208 for two consecutive months,UELS will promote the study in the Philadelphia region at largeby collaborating with neighboring teaching hospitals and clinics(Hahnemann Hospital, Jefferson Hospital). These institutionshave independent breast cancer screening programs and alsohave nursing programs. They are shareholders of the UniversityCity Science Center, whose incubation program UELS isenrolled in, and the Science Center can facilitate necessarycontacts as necessary. UELS will attempt increasing enrollmentrate such as to make up for the delays.

While mammography is the established goldstandard for breast cancer screening and detection,it is clinically limited in certain conditions such as inwomen with dense breasts. In UH2, iBE results willbe compared with mammography and there ispossibility of iBE identifying abnormalities that areinvisible on routine mammogram.

In cases with breast density level 3 or higher, where densetissue makes up more than 50 percent of the breast, and posesto act as a limiting factor for mammogram, physician palpationand/or diagnostic ultrasound or MRI will be requested.

Quarterly data safety and monitoring board reviewmay identify that the iBE performance is fallingoutside the acceptable range.

NCI program manager would be notified; UELS will analyze ifthe low performance can be remedied with hardware and/orsoftware revisions and present a plan to address the issue inunder 3 months.

4.1.4 Aim 4 (UH2): Logistics for LMICsRationale and Strategy.In addition to the engineering and clinical validation of iBE, prior to progression it

will be necessary to address and confirm the feasibility of logistical aspects of the planned UH3 studies,including cultural acceptability of the testing protocol, regulatory requirements for deploying an experimentadevice in the LMICs, and confirmation of commercially-enabling partnerships (already initiated as described inTable 18) with local agencies and organizations for sustainability and growth planning.

Acceptabi l i ty in LMIC. Conducting a breast cancer screening study in a previously unscreenedpopulation (as planned in India in UH3) can pose socio-cultural challenges; a clinical study evaluating CBE inPhilippines had to be closed after the first round because of low compliance with clinical follow-up and logisticabarriers in ensuring access to diagnosis and treatment.34We plan to assess religious and cultural acceptabilityin India before enrollments begin at the LMIC sites, using a mixed methods approach. Our goal is tounderstand womens apprehensions towards using the new technology, as well as opinions about taking a test

for which they are asymptomatic, cultural reservations to enrolling in the study, and thoughts about how theywould respond to positive diagnosis or recommendation for follow-up tests. The outcomes of this study wilgreatly mitigate the risk of failure due to cultural mismatch of planned outreach and implementation activities.This assessment will not be performed in Brazil where the Barretos Cancer Hospital has been offeringorganized mammography screening in the states of Sao Paulo, Minas Gerais, Gois and Mato Grosso do Suregions for more than 10 years, screening more than 40,000 women annually since 2009. In our discussionswith BCH, the screening program has not reported any significant patient enrollment or compliance relatedissues.

The Global Health Delivery Team, Clinical Advisory Panel (Section 3.5) along with Mihir Shah and DrSreekanth will help design a qualitative interviewing plan to be conducted by a social worker or a graduatestudent of anthropology in 20 healthy women aged 40-65 in India who have never had breast cancer screeningWe will also enroll 20 women of similar age who have had screening (clinical breast exam and/or


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mammography) but who are nave to the new technology. The format will be one-on-one, private interviewsthat will be conducted as a general 30-45 minute conversation in community settings in Chennai, Hyderabadand New Delhi areas. Each interview will be conducted in 2 stages. In Stage 1 of the interview, participants wilbe asked to describe their thoughts about breast cancer screening in general. Interviewers will then provide adescription of the new screening technology and ask for reactions based on hearing that description. In Stage2, participants will have the opportunity to receive mock-screening using the iBE device (this will be organizedby Bhaumik Sanghvi in collaboration with NGOs in Chennai, Hyderabad and New Delhi), iiand then they will be

asked to react to the experience of screening. Finally, participants will be asked about how they might react toabnormal screening results, and what they would do in response to recommendations for follow-up. Questionsthat pertain to the new technology will be designed to elicit responses pertinent to Rogers Diffusion ofInnovations Theory,35including concepts related to Rogers 5 factors influencing an individuals decision toadopt or reject an innovation: compatibility, complexity, trialability, observability, and relative advantageInterview guides will be translated into regional languages (Hindi, Tamil, Telugu and Urdu) with the assistanceof Bhaumik Sanghvi. Independent back-translation of the interview guides into English will allow investigatorreview to ensure linguistic equivalency prior to use. The interviews will be recorded and translated in English.The Mixed Methods Research Lab (MMRL) at the Perelman School of Medicine at the University ofPennsylvania will code the English-language transcripts using NVivo qualitative software using an iterative,grounded theory approach to allow identification of themes that are most salient to the study population.

The results from the qualitative analysis will help guide the validation study in UH3 in India. Themes from

the transcripts will be used to design recruitment and marketing strategies. Coded data and summary reportswill also be used to prepare an objective, quantitative questionnaire that will also be translated and back-translated. A subset of 300 women attending the Master Health Check program at the AHERF sites will fill thequestionnaire during UH3. This will provide further evidence of cultural acceptability and feasibility. Analysis ofthe quantitative data will be descriptive in nature and will also help to identify subsets of the population whomight respond more or less favorably to the screening method.

Plans for regulatory issues at the LMIC sites, enrol lm ent of hum an subjects.Plans for regulatoryapprovals as necessary for the LMIC validation study will be pursued as described in Table 10.Premarkeregulatory approvals will be pursued as described in Section 4.4.8.

TABLE 10: Plans for regulatory issues Brazil and India

Brazil Regulatory: Non-invasive, investigational devices are importable in the country with an Institutional ReviewBoard (IRB) approval; a prerequisite condition before importation. No other regulatory clearances (ANVISA

INMETRO, ANATEL) are required for clinical research. For Risks to human subjects and Informed consenplease see Protection of Human Subjects section.

India Regulatory: Non-invasive, investigational devices are importable without requiring regulatory clearance(CDSCO, Medical Devices and Diagnostic Division). Local IRB is not required in order to import the device. FoRisks to human subjects and Informed consent, please see Protection of Human Subjects section.

Busin ess plan update and LMIC engagements.UELS has developed working relationships with NGOsgovernmental agencies and device distributors in LMICs (see Table 18in Section 4.4.9). During this projectUELS will travel to Brazil and India specifically to have introductory meetings with Site PIs, potential distributorsregulatory agencies (if required), NGOs and governmental agencies to have further discussions related to iBEThe visits are to initiate the business development and long-term growth and sustainability plans in the region.UELS current commercialization plans are described in Section 4.4. After engineering revisions and

successful clinical validation under the UH2 phase, all plans and strategies related to business developmentand deployments including manufacturing, sales, distribution and regulatory premarket approval will be revisedand updated. The UH2 clinical study (Aim 3) will offer operational and clinical insights to make changes to theUH3 LMIC validation study (Aim 6).

4.2 UH3 VALIDATION PHASE

Following successful completion of all milestones in UH2 (Table 5), and confirmation of progression toUH3 in consultation with NCI/NIH, we will progress to the UH3 (Validation) Phase. In the three-year phase UH3(Table 11), outcomes of the UH2 studies (clinical validation, cultural acceptability) will inform final engineering

iiThese are intended to be mock-screening tests and no results will be provided to the operator or the patient.


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refinements prior to manufacturing of iBE prototype v3.0 units (Aim 5). Multi-center studies in Brazil (to validateefficacy in a setting that has mammographic screening) and in India (to validate the ability to increase detectionrate and lower detection stage in a setting without existing screening programs) will be conducted ( Aim 6). Inaddition, the partnering, regulatory, and business development steps required for commercial launch in theseLMICs will be completed (Aim 7).

4.2.1 Aim 5 (UH3): Engineering refinement and manufacturingRationale and Strategy. It is expected that our experience in using the prototype v2.0 during the U.S

clinical study (Aim 3) and the subsequent acceptability testing in India (Aim 4) will be substantially instructiveas to performance, failure modes, and usability for iBE. In our final UH2 report, we will document any issuesand develop a plan for addressing each one, to be reviewed and approved by NCI/NIH prior to progression toUH3. Although at this stage of proposal development it is difficult to predict what engineering steps may berequired, beyond those outlined in our Risks and Alternatives paragraphs in Section 4.1, there are severaengineering refinements that we envision, but have chosen to defer until after initial validation in the UH2phase of the proposed project. These refinements will be integrated at the initiation of the UH3 phase.

Modularizat ion (6 months development and testing). iBE devices are designed to be used in the field(mobile or stationary community health settings) for months at a time without the need for specializedmaintenance. The component with the shortest lifespan is the sensor array (which, in UH2, will be engineeredwith at least a 2,500-scan/200-hour operational life-expectancy). Hence, this component should be fully-replaceable by operators in the field. However, in order to replace any malfunctioning sensors in the currentprototype (v1.0, and anticipated v2.0 design) it is necessary to separate the enclosure, remove the cableconnections, and then reconstruct the assembly following replacement. This requires a level of training andfamiliarity with device components that is likely to be beyond what should reasonably be expected of theCHWs. To enable the sensors to be replaceable in the field, the iBE enclosure, sensor holders, and sensorconnectors will be developed to allow a swappable design. In contrast to the current design, which requiresdismantling of the enclosure and disconnection/connection of individual iBE sensors, the new design wilintegrate all the cables from each sensor of the 4x4 array into a single connection, while not affecting the

failure modes of each individual sensor array. This will allow the replaceable sensor-probe to be easily pluggedin and out without disturbing any individual connections to any of the sensors. The swappable design will betested by trained iBE operators to ensure that they can swap sensor probes and perform the test to acceptablestandards (defined in Aim 2) successfully. The enclosed probe design will be plugged in an out of the probe 40times to ensure that the connections still work as designed. Also, the redesigned probe will be held in anenvironmental chamber at 45oC and 50% relative humidity for 200 hours to ensure that there are noconnection issues in high temperature and moisture values (as described by JISC0022).

App -based self-diagnostic s (3 months development and testing). iBE version 2.0 is comprised ofmechanical and electrical components that must function correctly to ensure the integrity and accuracy of thetest results. In the field there must be a process for validating correct function in the absence of experttechnical input. In order to meet this need, the iBE mobile device app will contain a self-diagnostic feature thatwill test each functional component of the device in real-time at the beginning of every patients breast

TABLE 11: UH3 Aims, Milestones, and Timeline

Aim 5: Engineering Refinement and Manufacturing (1)Modularization (2) Mobile app based self-diagnostics

Milestone 5: (1) 30 iBE v3.0 fabricated with swappablesensor probes and battery packs; (2) Pass error-reportingtest of the mobile app.

Aim 6:Clinical Validation in LMICs(1) Brazil:Efficacy to detect T1c or larger breast cancers andother clinical abnormalities in 24,000 subjects; (2)India:Breast cancer identification rate, stage-distribution in 90,000subjects.

Milestone 6: (1) iBE to perform with better sensitivity,specificity and predictive values better than CBE andsimilar to mammography; (2)Breast cancers detected at ahigher rate and lower stage in iBE screens compared withprior period.

Aim 7: Commercialization(1)Market;(2) Regulatory; (3) Business Plan.

Milestone 7: (1)Deployment agreements in place; (2)Obtain pre-market regulatory agreements; (3) Productlaunch in Brazil and India.

Timeline in quarters (from end of UH2) 1 2 3 4 5 6 7 8 9 10 11 12

Aim 5: Engineering M5

Aim 6: Clinical validation M6

Aim 7: Commercialization M7


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examination and alert the operator should there be any failures identified. The self-diagnostics will test thefollowing functions/components and display to the operator any failures during the procedure. The tesdiagnostics will include:

Piezoelectric sensor array fatigue: In Aim 1we described sensor fatigue over a period time, which slowlydeteriorates the sensor array performance. To ensure that iBE performs consistently over time, calibrationtrend data will be logged for each sensor array from the time of first use for real-time trend analysis. If anytrend indicates that the sensor array is fatiguing more than 0.2V from factory calibration then a sensor fatigue

error message would be displayed to the operator, requiring sensor replacement prior to continuing.Piezoelectric sensor array damage: The iBE mobile app

uels nih research plan compressed.docx

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