SBIR-STTR Award

Despite aggressive public health campaigning and strict guidelines for diagnosis and treatment, the estimated incidence of severe hyperbilirubinemia (defined as serum bilirubin levels greater than 99th percentile) is 1:70. Severe hyperbilirubinemia can cause a spectrum of neurologic dysfunction of which kernicterus is the most concerning. Kernicterus manifests as a life-long movement disorder with occulomotor and auditory dysfunction. The subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP) has proposed guidelines to reduce the frequency of severe neonatal hyperbilirubinemia and bilirubin encephalopathy. These include the recommendation to measure total serum bilirubin level or cutaneous bilirubin level of all infants with jaundice in the first 24 hours of life. The committee also identified the need for screening for hereditary causes such as G6PD deficiency and congenital hypothyroidism, which if present can change the treatment completely. Early identification and initiation of treatment can prevent acute bilirubin encephalopathy and kernicterus. Currently testing for hyperbilirubinemia is often available at the point of care, but results are usually returned after patient discharge. Tests for G6PD and CH are usually done only if the patient does not respond to therapy. In this proposal, we describe a new technology that has the potential to dramatically simplify the testing process and expedite the availability of test results. Time is of the essence in diagnosis of these newborn conditions as significant brain injury can be prevented by prompt treatment. This new technology will require minimal resources, will be low cost, and will be suitable for use in hospitals, outpatient clinics, and rural communities. Availability of portable and multiplex devices for on-site screening will enable rapid diagnosis of at-risk infants. Development of a device that could perform multiple assays for common newborn disorders at the point-of-care with rapid turnaround is an initial step in the development of multiplex testing with an on-site portable device.

Public Health Relevance:
Advanced Liquid Logic, Inc. is developing a lab-on-a-chip on its proprietary digital (droplet-based) microfluidic platform for clinical diagnostics. The proposed project aims to demonstrate a near-patient platform for screening neonates with very high levels of bilirubin (hyperbilirubinemia). The device would be greatly useful in rapid identification and enable early treatment.

Public Health Relevance Statement:
Advanced Liquid Logic, Inc. is developing a lab-on-a-chip on its proprietary digital (droplet-based) microfluidic platform for clinical diagnostics. The proposed project aims to demonstrate a near-patient platform for screening neonates with very high levels of bilirubin (hyperbilirubinemia). The device would be greatly useful in rapid identification and enable early treatment.

NIH Spending Category:
Bioengineering; Biotechnology; Brain Disorders; Digestive Diseases; Health Services; Hematology; Liver Disease; Mental Retardation (Intellectual and Developmental Disabilities (IDD)); Neurosciences; Pediatric; Pediatric Research Initiative; Perinatal Period - Conditions Originating in Perinatal Period; Prevention; Rural Health

Project Terms:
0-6 weeks old; 21H-Biline-8,12-dipropanoic acid, 2,17-diethenyl-1,10,19,22,23,24-hexahydro-3,7,13,18-tetramethyl-1,19-dioxo-; Academy; Acquired brain injury; Acute; Ambulatory Care Facilities; American; Assay; Auditory; Bilirubin; Bilirubin Encephalopathy; Bilirubin IX alpha; Bilirubin, total; Bilirubin, total measurement; Bilirubinemia; Bioassay; Biologic Assays; Biological Assay; Blood; Blood Sample; Blood Serum; Blood specimen; Brain Injuries; Chemistry; Clinical; Clinical Chemistry; Congenital Hypothyroidism; Cretinism; Cretinisms; Cutaneous; D-Glucose-6-phosphate[{..}]NADP+ 1-oxidoreductase; Development; Development and Research; Devices; Diagnosis; Diagnostic; Discharge from Healthcare Facility; Disease; Disorder; Dysfunction; Dyskinesia Syndromes; EC 1.1.1.49; Early identification; Early treatment; Frequencies (time pattern); Frequency; Functional disorder; G6PD; G6PD deficiency; GPD Deficiency; Glucose-6-Phosphate Dehydrogenase; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Goals; Guidelines; HOSP; Health Campaign; Hereditary; Hospitals; Hour; Human Resources; Hyperbilirubinemia; Hyperbilirubinemic Encephalopathy; Icterus; Immunoassay; Incidence; Infant; Infant, Newborn; Inherited; Jaundice; Kernicterus; Lab On a Chip; Laboratories; Life; Liquid substance; Logic; Manpower; Measurement; Measures; Microfluidic; Microfluidics; Movement Disorder Syndromes; Movement Disorders; Myxedema, Congenital; Myxedemas, Congenital; Neonatal Jaundice; Neurologic Dysfunctions; Newborn Infant; Newborns; Outpatient Clinics; Patient Discharge; Patients; Pediatrics; Phase; Phlebotomy; Physiopathology; Process; Public Health; R & D; R&D; Recombinant TSH; Recombinant Thyroid-Stimulating Hormone; Recommendation; Refractory; Research Resources; Resources; Reticuloendothelial System, Blood; Risk; Rural Community; Science of Chemistry; Screening procedure; Serum; Services; Side; Site; Speed; Speed (motion); Systems Integration; TBILI; Technology; Test Result; Testing; Thyreotropin; Thyroid Stimulating Hormone; Thyroid-Stimulating Hormone; Thyrotropin; Time; Total Bilirubin; Translating; Translatings; Venous blood sampling; WHBLOOD; Whole Blood; assay development; base; brain damage; brain lesion (from injury); cost; design; designing; digital; disease/disorder; fluid; glucose 6 phosphate dehydrogenase deficiency; instrument; language translation; liquid; micro-total analysis system; mu-TAS; neonatal hyperbilirubinemia; neonate; neurological dysfunction; new technology; newborn human (0-6 weeks); pathophysiology; personnel; point of care; prevent; preventing; public health medicine (field); public health relevance; rapid diagnosis; research and development; screening; screenings; total measurement Bilirubin

Severe hyperbilirubinemia (defined as serum bilirubin levels greater than 99th percentile) can cause a spectrum of neurologic dysfunction, of which kernicterus has the most devastating neurologic consequences. Kernicterus manifests as a life-long movement disorder with occulomotor and auditory dysfunction. In developing countries such as India, 5%-12% of all newborns are reported to develop severe hyperbilirubinemia in the newborn period. Among premature infants, incidence of hyperbilirubinemia warranting treatment has been reported to be as high as 78%. In China, 35% of full term newborns were noted to have significant hyperbilirubinemia. Even in light of incidence that is much higher than noted in the United States and the detrimental consequences associated, universal screening for hyperbilirubinemia is not currently available to the newborns in these developing nations. In cases of prolonged jaundice, measurement of total bilirubin alone does not suffice. Underlying causes such as glucose-6-phosphate dehydrogenase (G6PD) deficiency and congenital hypothyroidism (CH) should be strongly considered. Infants with jaundice secondary to these conditions may not respond to traditional modes of therapy (such as phototherapy) until the underlying illness is addressed. The challenges of implementing a successful population-based newborn screening program in developing countries such as India and China are very different from countries with established programs. The paradigm of centralized newborn screening that works well in developed countries is quite challenging to implement in highly populated developing countries such as India or China. This is due to larger number of births, lower percentage of hospital births, and lack of logistical infrastructure to transport samples. There is therefore a compelling need for an inexpensive, scalable, and distributable newborn screening platform for use in these countries. Building upon successful results from phase I, we propose to build a laboratory prototype of a highly distributable low cost newborn screening platform suitable for use in India and China (Aim 1). We will design a low cost digital microfluidic cartridge to perform assays for total bilirubin, G6PD and TSH and verify analytical performance (Aim 2) and clinical performance (Aim 3).

Public Health Relevance:
Advanced Liquid Logic, Inc. is developing a lab-on-a-chip on its proprietary digital microfluidic platform for newborn screening. The proposed project aims to demonstrate a near-patient platform for screening neonates for hyperbilirubinemia which, if not detected in time, could lead to kernicterus leaving the child developmentally challenged for entire life. This inexpensive device would be greatly useful in rapid identification and to enable early treatment.

Thesaurus Terms:
0-11 Years Old;0-6 Weeks Old;21h-Biline-8,12-Dipropanoic Acid, 2,17-Diethenyl-1,10,19,22,23,24-Hexahydro-3,7,13,18-Tetramethyl-1,19-Dioxo-;Actinotherapy;Address;Adrenal Gland Hyperplasia;Assay;Auditory;Bilirubin;Bilirubin Encephalopathy;Bilirubin Ix Alpha;Bilirubin, Total;Bilirubin, Total Measurement;Bilirubinemia;Bioassay;Biologic Assays;Biological Assay;Biotinidase Deficiency;Birth;Birth Centers;Birthing Centers;Blood Serum;Capital;Child;Child Youth;Children (0-21);China;Clinical;Computer Programs;Computer Software;Congenital Hypothyroidism;Consumption;Country;Cretinism;Cretinisms;Cystic Fibrosis;D-Glucose-6-Phosphate[{..}]nadp+ 1-Oxidoreductase;Detection;Developed Countries;Developed Nations;Developing Countries;Developing Nations;Development;Devices;Disease;Disorder;Drugs, Nonproprietary;Dysfunction;Dyskinesia Syndromes;Ec 1.1.1.49;Early Treatment;Electronics;Environment;Functional Disorder;G6pd;G6pd Deficiency;Gpd Deficiency;Galactosemia;Galactosemias;Generic Drugs;Glucose-6-Phosphate Dehydrogenase;Glucosephosphate Dehydrogenase;Glucosephosphate Dehydrogenase Deficiency;Hosp;Hospitals;Human, Child;Hyperbilirubinemia;Hyperbilirubinemic Encephalopathy;Icterus;Incidence;India;Industrialized Countries;Industrialized Nations;Infant;Infant, Newborn;Infant, Premature;Infrastructure;Investigators;Jaundice;Kernicterus;Lab On A Chip;Laboratories;Lead;Left;Less-Developed Countries;Less-Developed Nations;Letters;Life;Light;Light Therapy;Liquid Substance;Logic;Mainland China;Maintenance;Maintenances;Marketing;Maternity Hospitals;Mechanics;Methods;Microfluidic;Microfluidics;Movement Disorder Syndromes;Movement Disorders;Mucoviscidosis;Multiple Carboxylase Deficiency, Late-Onset;Myxedema, Congenital;Myxedemas, Congenital;Neonatal Screening;Neonatology;Neurologic;Neurologic Dysfunctions;Neurological;Newborn Infant;Newborn Infant Screening;Newborns;Parturition;Patients;Pb Element;Performance;Phase;Photoradiation;Photoradiation Therapy;Phototherapy;Physiopathology;Premature Infant;Programs (Pt);Programs [publication Type];Reader;Reagent;Recombinant Tsh;Recombinant Thyroid-Stimulating Hormone;Reporting;Research Infrastructure;Research Personnel;Research Resources;Researchers;Resources;Risk;Sampling;Savings;Screening Procedure;Secondary To;Serum;Site;Software;Specificity;System;System, Loinc Axis 4;Tbili;Technology;Testing;Texas;Third-World Countries;Third-World Nations;Thyreotropin;Thyroid Stimulating Hormone;Thyroid-Stimulating Hormone;Thyrotropin;Time;Total Bilirubin;Translating;Translatings;Under-Developed Countries;Under-Developed Nations;United States;Universities;Validation;Work;Adrenal Hyperplasia;Base;Children;Computer Program /Software;Computer Program/Software;Cost;Design;Designing;Digital;Disease /Disorder;Disease/Disorder;Fluid;Generic;Glucose 6 Phosphate Dehydrogenase;Glucose 6 Phosphate Dehydrogenase Deficiency;Heavy Metal Pb;Heavy Metal Lead;Innovate;Innovation;Innovative;Instrument;Language Translation;Liquid;Mass Spectrometer;Micro-Total Analysis System;Mu-Tas;Neonatal Hyperbilirubinemia;Neonate;Neurological Dysfunction;New Technology;Newborn Human (0-6 Weeks);Newborn Screening;Pathophysiology;Population Based;Portability;Premature Baby;Premature Infant Human;Preterm Baby;Preterm Infant;Preterm Infant Human;Preterm Neonate;Programs;Prototype;Screening;Screenings;Total Measurement Bilirubin;University;Youngster