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Review
. 2022 Aug 18;25(9):104986.
doi: 10.1016/j.isci.2022.104986. eCollection 2022 Sep 16.

Disposable paper-based microfluidics for fertility testing

Misagh Rezapour Sarabi  1 , Defne Yigci  2 , M Munzer Alseed  3 , Begum Aydogan Mathyk  4 , Baris Ata  2   5 , Cihan Halicigil  6 , Savas Tasoglu  1   3   7   8   9
Affiliations
Review

Disposable paper-based microfluidics for fertility testing

Misagh Rezapour Sarabi et al. iScience. .

Abstract

Fifteen percent of couples of reproductive age suffer from infertility globally and the burden of infertility disproportionately impacts residents of developing countries. Assisted reproductive technologies (ARTs), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have been successful in overcoming various reasons for infertility including borderline and severe male factor infertility which consists of 20%-30% of all infertile cases. Approximately half of male infertility cases stem from suboptimal sperm parameters. Therefore, healthy/normal sperm enrichment and sorting remains crucial in advancing reproductive medicine. Microfluidic technologies have emerged as promising tools to develop in-home rapid fertility tests and point-of-care (POC) diagnostic tools. Here, we review advancements in fabrication methods for paper-based microfluidic devices and their emerging fertility testing applications assessing sperm concentration, sperm motility, sperm DNA analysis, and other sperm functionalities, and provide a glimpse into future directions for paper-based fertility microfluidic systems.

Keywords: Biodevices; Biotechnology; Medical device in health technology.

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Conflict of interest statement

The authors declare the following competing financial interest(s): S.T. is a co-founder of and has equity interest in GetDeHealth, a company that is developing microfluidic technologies for point-of-care diagnostic and wellness solutions. The interests of S.T. were viewed and managed in accordance with the conflict of interest policies. Author S.T. is a member of the iScience Editorial Board. B.A. is a member of ART Fertility Clinics, a company working on human reproductive medicine. The interests of B.A. were viewed and managed in accordance with the conflict of interest policies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

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Graphical abstract
Figure 1
Figure 1
An overview of disposable microfluidics for fertility testing Applications of paper-based microfluidic devices in male fertility can be enabled by tests based on (A) sperm concentration, (B) sperm motility, (C) sperm DNA or sperm mitochondrial DNA analysis, and (D) sperm morphology and fertility-related hormones. (E and D) Use of paper-based microfluidic technologies has emerged at home or in clinics for male fertility testing and/or sperm sorting. (E) Convenient, inexpensive, effective in-home male fertility testing using small sample volumes. Ease of application through fast analysis, potentially using smartphones. (F) Use of microfluidics for sperm sorting for better outcomes in assisted reproductive technologies (ARTs) such as intra-cytoplasmic sperm injections (ICSI) and/or point-of-care male sperm fertility testing with small sample volumes. (G) Potential integration of artificial intelligence (AI), lens-free imaging, or digital holography in future applications to achieve higher quality and accuracy in microfluidics-based fertility tests.
Figure 2
Figure 2
A general view of analytical capabilities employed in paper-based assays Analytical capabilities employed in paper-based assays include fluid and analyte handling (investigating the effects of the geometry, surface chemistry, physical actuation, and external fields), sample processing and analysis (investigating the effects of the surface chemistry, membranes, and external fields), and quantification (investigating the user interface and consumer technology). Adapted from ref. (Gong and Sinton, 2017) with permission from American Chemical Society.
Figure 3
Figure 3
Mechanism of and use for point-of-care, smartphone- and colorimetric-paper-based semen analysis (A) The mechanism of color change of yellow MTT into purple formazan used to assess mitochondria content in sperm. (B) Potential applications of the MTT test strip, which can be used either at home, at clinics, or in resource-limited developing countries. Upon collecting a semen sample, men can easily determine results using a smartphone or color indicator chart (within 15 min). Adapted from ref. (Tsao et al., 2020) in accordance with the Creative Commons 4.0 International (CC BY 4.0) license.
Figure 4
Figure 4
Smartphone-based semen analysis (A) Illustration of smartphone-based semen analysis system displaying lens, 3D printed housing, switch, battery, slide holder, and LED. (B–D) Comparison of manual conventional method of analysis and smartphone estimation. (B) Linear regression analysis showed agreement (n = 31). (C) Passing-Bablok analysis on sperm viability assessments showed strong linear relationship (n = 103). (D) Band-Altman analysis (n = 20) on DNA fragmentation scores. Adapted from ref. (Dimitriadis et al., 2019) in accordance with the Creative Commons 4.0 International (CC BY 4.0) license.
Figure 5
Figure 5
Paper-based device operating with ion concentration polarization (ICP) technique (A) Paper-based ICP device design illustrating reservoir, sample channel, and Nafion-coated region. (B) Diagram representing ICP enrichment and depletion upon voltage application. As a result of local electric field strength, E, net movements of analytes are determined by electrophoretic migration (EPH) and electroosmotic flow (EOF). (C) %DFI results were compared between paper-based ICP and clinical results for patients and donors, producing a correlation of R2 = 0.98. Threshold of 30% for %DFI was used to determine clinical outcome. Error bars for the device reflect one standard deviation of normal fits and error bars for clinical results, average of two measurements, represent one standard deviation. Adapted from ref. (Gong et al., 2015) with permission from American Chemical Society.
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