A Research Platform for Singapore

CellFACE

Executive Summary

CellFACE aims to establish imaging flow cytometry as a label-free platform technology for routine cellular diagnostics at the point-of-care. To assure success of the interdisciplinary CellFACE project, back-to-back teams between Munich and Singapore are formed. Using co-creational principles engineers and life scientists at TUM-CREATE, NTU, and A*STAR cooperate with clinicians at National University Hospital to develop a workflow solution for blood cell analysis to improve acute care diagnostics.

 

Research

Clinical and diagnostic challenges

Approximately 5% of all adult presentations and up to 15% of visits from elderly patients to emergency rooms (ER) are for fever [1]. Clinicians face several dilemmas because it is the initial symptom presenting for a range of illnesses, from a simple viral infection to meningitis or malignancy. For instance, in Singapore fever constituted 21.6% of all unscheduled patient return visits to the ER of which 28.3% had a wrong or delayed diagnosis [2] - in particular elderly patients [3-5]. Depending on the complexity of the case, inadequate patient management leads to extra costs and ineffective allocation of clinical resources at ERs, the intensive care/acute medical units (ICUs/AMUs), and wards. Time-to-results for a correct differential diagnosis for the cause of fever adds on average of 10.000 S$ for in vitro diagnostics (IVD), medical imaging per hospitalized NUH patient, and unnecessary application of antibiotics.

Blood cells are of highest importance as biomarkers in the clinical routine due the unique properties of cellular biomarkers. Today, automated hematological analysis is in fact one of the most requested in vitro diagnostic tests worldwide providing complete blood counts (CBC) as well as leukocyte differentials (Diff). Despite the availability of automated analyzers in the central laboratory, the gold standard for the routine diagnosis of hematological disorders is the tedious Giemsa stained blood smear and is always required when analyzer report a flagged result. In the central laboratory, flagged results are a break of automation and are cost drivers. The analysis of thin blood films require personnel, suffer from inter-observer variations due to low statistical power. Most importantly, a CBC/Diff only provides information on blood cell concentrations but lacks functional cell information.

Scientific and technical goals

Imaging flow cytometry based on a highly defined microfluidic flow of blood samples and digital holographic microscopy (DHM) allows to perform high-throughput cell analysis at physiological conditions. Due to the label- and reagent-free imaging approach we can visualize cell morphologies, differentiate cells based on phase information [6] and - most importantly - have access to hidden functional biomarker. The value of these new classes of biomarkers will be observed in longitudinal clinical studies at NUHS. In this way, we hope to support rapid stratification of patients with fever using functional hematology biomarkers related to immune system, hemostasis, and organ function. 

Cartridge-based workflow integration with industry partner and artificial intelligence algorithm will be explored to reduce workflow complexity and computational effort. Robust analysis of hidden biomarker will demonstrate the realization potential of future point-of-care (POC) applications with time-to-results in a few minutes. To ensure reproducible clinical testing, CellFACE will develop additional standardization and calibration methods for this next generation POC hematology analyzer. The results of CellFACE could potentially revolutionize patient care, producing many benefits ranging from improved antimicrobial stewardship to prevention of unnecessary hospital admissions during uncertainty of diagnosis, and help save costs by focusing investigations to rapidly identify the underlying causes of fever.

Figure 1. Microfluidic channel for highly parallelized blood cell imaging (© Richard Koh)

Figure 2. CellFACE prototype operated in a Biosafety Level 2 laboratory at CREATE (© Richard Koh

Members

 

OrganizationNameDesignation

TUM

Diepold, Klaus

PI, Professor

NA

Hayden, Oliver

PI, Professor

NA

Knolle, Percy

PI, Professor

NA

Prazeres da Costa, Clarissa

PI, Professor

NA

Schneider, Gerhard

PI, Professor

NA

Hamway, Youssef

Postdoc

NA

Irl, Hedwig

Physician

NA

Klenk, Christian

PhD

NA

Röhrl, Stefan

PhD

TUM CREATE

Chen, Qianyu

Research Associate

NA

Delikoyun, Kerem

Research Associate
 

Alperen Yildiz

Research Assistant
   

A*Star

Renia, Laurent

PI, Professor

NA

Lee, Hwee Kuan

PI, Adjunct Associate Professor

NA

Wei, Liu

Postdoc

NA

Wang Wei, Charles

Supplier

NTU

Hou, Han Wei

Assistant Professor

NUHS

Chew, Ka Lip

PI

NA

Chng, Wee Joo

PI, Professor

NA

Cove, Matthew Edward

PI, Assistant Professor

NA

Kuan, Win Sen

PI, Assistant Professor

NA

Soong, John Tshon Yit

PI, ​Assistant Professor

Sunningdale Tech Ltd

Goh, Yew Guan

Industry Collaborator

Dracoon GmbH

Schieder, Marc

Industry Collaborator

Duke-NUS

Bertoletti, Antonio

Adviser

 

Contact

For any enquiry on CellFACE project, please contact us at:

Email: cellface@tum-create.edu.sg

Phone: +65 9784 9125

 

Publications

[1]

S. DeWitt, S. A. Chavez, J. Perkins, B. Long, and A. Koyfman, “Evaluation of fever in the emergency department,” Am. J. Emerg. Med., vol. 35, no. 11, pp. 1755–1758, Nov. 2017, DOI: 10.1016/j.ajem.2017.08.030.

[2]

C. H. W. Soh et al., “Risk Factors for Emergency Department Unscheduled Return Visits,” Medicina, vol. 55, no. 8, p. 457, Aug. 2019, DOI: 10.3390/medicina55080457.

[3]

G. Gavazzi and K.-H. Krause, “Ageing and infection,” The Lancet Infectious Diseases, vol. 2, no. 11, pp. 659–666, Nov. 2002, DOI: 10.1016/S1473-3099(02)00437-1.

[4]

K. P. High et al., “Clinical Practice Guideline for the Evaluation of Fever and Infection in Older Adult Residents of Long-Term Care Facilities: 2008 Update by the Infectious Diseases Society of America,” Clinical Infectious Diseases, vol. 48, no. 2, pp. 149–171, Jan. 2009, DOI: 10.1086/595683.

[5]

M. A. Horan and N. Pendleton, “The relationship between aging and disease,” Rev. Clin. Gerontol., vol. 5, no. 2, pp. 125–141, May 1995, DOI: 10.1017/S0959259800004093.

[6]

M. Ugele et al., “Label-Free High-Throughput Leukemia Detection by Holographic Microscopy,” Adv. Sci., vol. 5, no. 12, p. 1800761, Dec. 2018, DOI: 10.1002/advs.201800761.

 

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