Science & Society

Commercialization of microfluidic devices

1 2

Lisa R. Volpatti and Ali K. Yetisen

1

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

2

Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QT, UK

Microfluidic devices offer automation and high-through- The market

put screening, and operate at low volumes of consum- In 2013, the microfluidics market was valued at $1.6 billion

ables. Although microfluidics has the potential to reduce [3]. With an expected compound annual growth rate

turnaround times and costs for analytical devices, par- (CAGR) of 18–29%, the market is projected to reach

ticularly in medical, veterinary, and environmental $3.6–5.7 billion by 2018 [3,4]. This high growth rate is

sciences, this enabling technology has had limited diffu- largely due to recent advances in biotechnology, including

sion into consumer products. This article analyzes the gene sequencing and in vitro diagnostics (Table 1).

microfluidics market, identifies issues, and highlights

successful commercialization strategies. Addressing Gene sequencing

niche markets and establishing compatibility with exist- With the completion of the human genome project in 2003

ing workflows will accelerate market penetration. and the advent of next-generation sequencing, microfluidic

technology has been used to increase automation and

Microfluidics is an enabling platform technology that decrease turnaround times in genomics. Key companies

allows automation and multiplexing of laboratory equip- in the field of microfluidic genotyping include Illumina Inc.

ment, drug screening technologies, and in vitro diagnostic and Fluidigm Corp. In 2013, Illumina acquired Advanced

devices [1]. Over the past two decades, several ventures Liquid Logic Inc. to gain access to their digital microflui-

have emerged to commercialize microfluidic technologies. dics platform. Their electrowetting technology manipu-

Initially, these devices were envisioned to be used in lates discrete droplets in a microfluidic device without

biological analyses and chemical syntheses so that a range pumps, valves, or channels; therefore, these devices have

of substances could be prepared and analyzed at low the potential to offer readily scalable solutions [5]. Al-

volumes in order to replace manual processing and bulky though Illumina expanded their portfolio recently to in-

benchtop equipment. Pioneering companies have argued clude microfluidic technologies, Fluidigm was founded to

that the efficient consumption of reagents, high-through- market the integrated fluidic circuit (IFC) based on a

put analyses, miniaturization of components, and the abil- pneumatic rubber valve developed in the laboratory of

ity of microfluidic devices to be produced from low-cost Stephen Quake, then at Caltech [6]. With this technology,

materials will reduce costs as compared to conventional Fluidigm became the first company to commercialize a

benchtop equipment. Although there has been a lot of digital PCR in 2006, and it held its initial public offering

promise in microfluidics, a limited number of products in 2011.

have been delivered [2]. After purchasing a commercial To facilitate sample preparation further for next-gener-

microfluidic device, end users may face difficulties in syn- ation sequencing, RainDance Technologies Inc. developed

chronization with associated hardware, such as external a single-molecule picodroplet system for digital PCR. Each

pumps and pneumatic fluid handling systems. Since addi- picodroplet is loaded with a uniform quantity of genomic

tional training may also be necessary to operate the device, DNA and primers; therefore, this system enhances repro-

many end users are not willing to change their convention- ducibility and enables the targeting of specific regions of

al practices and instruments. As a result of these hurdles, the genome [7]. Another company with single molecule

many end users are not willing to change their practices expertise is Sphere Fluidics Ltd., whose microfluidic sys-

and prefer using conventional instruments. This complica- tem can perform high-throughput analyses of single cells to

tion depreciates the value proposition of microfluidic produce their genetic, proteomic, and transcriptomic pro-

devices and diminishes the incentive to use them in the files in picoliter volume droplets [8]. These picodroplets are

laboratory or the field. There must be a significant opera- compatible with PCR machines and next-generation

tional advantage or cost reduction in order to opt for a new sequencers and can also be used in applications such as

microfluidic technology. This advantage has become ap- drug discovery and biomarker identification.

parent in two key fields of biotechnology: genomics and

point-of-care (POC) diagnostics. Point-of-care diagnostics

A second area of biotechnology that has commercially

benefited from microfluidic technologies is POC diagnos-

Corresponding author: Yetisen, A.K. ([email protected]). tics. Large pharmaceutical companies have expanded their

Keywords: commercialization; market entry; microfluidics; lab-on-a-chip.

diagnostic platforms to include POC lab-on-a-chip devices.

0167-7799/ For example, Abbott Laboratories markets the i-STAT

ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tib-

system, a handheld device that integrates microfluidics

tech.2014.04.010

and electrochemical detection to analyze blood chemistry.

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Trends in Biotechnology July 2014, Vol. 32, No. 7

Table 1. Selected companies that have commercialized microfluidic technologies, their major products and applications

Company name Major products Applications Founded/ Country

acquired

Roche Diagnostics Genome Sequencer FLX System, LightCycler Genotyping, microarray 1896 Switzerland

Systems, Cedex HiRes analysis, cell analysis and US

Advanced Liquid Logic, Inc. NeoPrep Library Prep System Next-generation 1998/2013 US

(acquired by Illumina) sequencing

i-STAT Corp. (acquired by i-STAT Systems POC diagnostics 1983/2004 US

Abbott Laboratories)

Agilent Technologies 2100 Bioanalyzer Human diseases, genomics 1999 US

Danaher Corporation Original equipment manufacturer Manufacturing for life 1969 US

sciences and diagnostics

Caliper Life Sciences LabChip Systems Diagnostics, molecular testing 1995/2011 US

(acquired by PerkinElmer)

Life Technologies Corporation TaqMan Assays Genotyping, diagnostics, 1983/2013 US

(acquired by Thermo Fisher) drug discovery

Cepheid Xpert and GeneXpert Systems Diagnostics 1996 US

Fluidigm Corporation BioMark HD System, C1 System, EP1 System Genotyping and sequencing 1999 US

RainDance Technologies RainDrop System, Genotyping and 2004 US

ThunderStorm System sequencing

Claros Diagnostics Prostate-Specific Antigen (Total PSA) Test POC diagnostics 2005/2011 US

(acquired by OPKO) 4KScore Prostate Cancer Test

Gyros AB Gyrolab xP Workstation, Gyrolab Bioaffy CDs, Immunoassays, biomarker 2000 Sweden

Gyrolab Mixing CD monitoring, drug analysis

Micronit Microfluidics Microreactors, Micromixers, Droplet Manufacturing custom 1999 Netherlands

Generators, Chip Electrophoresis microfluidic devices

Dolomite Microfluidics Multiflux Manufacturing custom 2005 UK

microfluidic devices

Sphere Fluidics Ltd. Pico-Gen Picodroplet Formation Chips Human diseases, 2010 UK

drug discovery,

biomarker analyses

i-STAT can quantify analytes such as electrolytes, metab- over lateral-flow assays [13]. DFA aims to deliver low-cost

olites, and gases, while also having the capability to per- medical diagnostics, veterinary tests, and environmental

form immunoassays [9]. Similarly, OPKO Inc. acquired monitoring devices to resource-poor countries. Although

Claros Diagnostics Inc., a spinout from the laboratory of DFA serves a non-profit mission, they also generate reve-

George Whitesides at Harvard, to complement its in vitro nue through licensing agreements to supplement funding

diagnostics portfolio. Claros has developed a benchtop for further research and development.

microfluidic analyzer that reads a credit-card-sized dispos-

able cassette containing a blood sample and performs Overcoming challenges to commercialization

multiple marketed tests for urology and infectious disease Major challenges in commercializing a product involve

[10]. OPKO Health has used this technology in conjunction customer acceptance and market adoption. By specifically

with its proprietary biomarkers, such as antibody-based focusing on market entry routes, many successful startups

assays for the early diagnosis of Alzheimer’s or Parkinson’s have been able to use product development and customer

diseases [11]. development methodology in parallel. In microfluidics,

Rather than technical novelty, practical and marketable academic publications of proof-of-concept devices are abun-

devices are needed to address major clinical problems, dant, but the diffusion of this technology to consumer

particularly in the developing world. To bring high-perfor- products has been limited over the past two decades due

mance diagnostic solutions to resource-limited settings, to the absence of customer development and validation of

Daktari Diagnostics Inc. has utilized microfluidic technol- market need. Although microfluidics is a promising labo-

ogy to integrate sample preparation and analysis within ratory tool, the technology is still seeking the best applica-

one device. This device incorporates a microfluidic differ- tions. Because of the lack of a ‘killer application’

+ +

ential counter, which is able to quantify CD4 or CD8 (revenues > $100 million) in microfluidics, many investors

immune cells in a blood specimen [12]. With an accuracy have opted for other emerging technologies with well-

comparable to conventional flow cytometry, this device has defined market routes [14]. Typically, the venture capital

the potential to reduce costs in the diagnosis of HIV. industry expects a return on investment of 5–10 times for

Another company that has positioned itself for the devel- microfluidic technologies. Furthermore, funding agencies

oping world markets is Diagnostics for All (DFA). Their are increasingly interested in a tangible return on their

paper-based microfluidic devices utilize capillary forces to investments. It is in this competitive context that research-

direct the movement of fluidics and enables multiplexed ers may choose to shift their focus from innovative demon-

assays with built-in capabilities, which is an improvement strations to marketable products to maintain current

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levels of funding. In order to surmount the barriers to Concluding remarks and future perspectives

commercialization, innovators of microfluidic devices need To aid in the development of microfluidics as a widespread

to focus on two areas that currently lack sufficient atten- technology, industrial maturation should be synchronized

tion: standardization and integration. with academic efforts. Industrial partners with marketing

expertise should take an active role in discussing the

Standardization potential for a product to succeed in a given market and

Academics in microfluidic research often fail to cite repro- providing feedback on end-user requirements and expec-

ducibility statistics and quantify chip-to-chip (batch-to- tations. Academic researchers, in turn, may focus on deliv-

batch) variability within a given prototyping or fabrication ering a fully integrated product with a specific application.

method. As a result of this lack of standardization across Such an effort will also require striking a balance between

the field, novel microfluidic assays for a specific applica- academic publishing, consulting to commercial partners,

tion, including the protocols, equipment and materials are and pursuing patent protection to increase social impact

often not compatible with existing technologies in the [17].

market. For example, poly(dimethylsiloxane) (PDMS) is To market the technology at scale, the microfluidic

the dominant material of choice for use in fabricating product must far surpass the existing technology in per-

microfluidic devices in the laboratory [15]. However, most formance and capability or offer the results at a signifi-

companies in the microfluidic sector with the exception of cantly lower cost. Many current microfluidic devices,

Fluidigm refrain from using PDMS due to issues with however, only provide incremental improvements over

scaling up and manufacturability. PDMS is a relatively existing technologies and do not offer solutions to problems

high-cost material in comparison to industry-standard that are otherwise insoluble. The microfluidic community

cost-effective polymers such as poly (methyl methacrylate) should, therefore, move forward with the current pressing

(PMMA) and polycarbonate. These accessible materials needs where microfluidics is the only solution to overcome

have established high-throughput manufacturing and a challenge. This requires developers to embrace micro-

shaping methods such as injection molding, rolling, fluidic technologies as a component of a large commercial

embossing, laser-induced cutting and computer numerical technology that is compatible with existing workflows.

control (CNC) milling. However, most microfluidic capa- Rather than waiting for a killer application, targeting

bilities (e.g., displacement valves and pumps) achieved re-segmented niche markets, where existing technologies

with highly elastic polymers such as PDMS are not readily do not address specific customer needs, will reduce market

transferable to other cost-effective rigid polymers [16]. entry barriers and facilitate the commercialization of

Therefore, research efforts either need to focus on the microfluidic technologies. The combination of developing

scalable manufacture of PDMS-based devices or the fabri- technologies to solve practical problems that can be pro-

cation of microfluidic devices from other ideally low-cost duced at scale and easily integrated into any laboratory

polymers. will thus allow microfluidics to reach its full commercial potential.

Integration

Past research has focused on the invention of individual References

1 Sackmann, E.K. et al. (2014) The present and future role of

lab-on-a-chip (LOC) components, leaving the integration

microfluidics in biomedical research. Nature 507, 181–189

of these components as an afterthought. However, issues

2 Blow, N. (2009) Microfluidics: the great divide. Nat. Methods 6, 683–

with standardization preclude the possibility of easily 686

stitching together these innovative components to form 3 Markets and Markets (2013) Microfluidics market by materials

functional, fully integrated devices. In order to realize (polymers, silicon, glass), pharmaceuticals (microreactors, toxicity

screening, lab on chip, proteomic & genomic analysis) drug delivery

the potential of LOC devices, researchers must consider

devices (microneedles, micropumps), IVD (POC) – global trends &

the final commercial application from the early design

forecast to 2018

stages and ensure that each component is mutually

4 Yole Development, Research and Markets (2013) Microfluidic

compatible. For example, many devices require pumps applications in the pharmaceutical, life sciences, in-vitro diagnostic

or a voltage supply to operate the device and specific and medical device markets report.

5 Pamula, V.K. et al. Advanced Liquid Logic, Inc, a wholly owned

computer software that the user must learn to analyze

subsidiary of Illumina, Inc. Methods and apparatus for

and interpret the results. Furthermore, many biological

manipulating droplets by electrowetting-based techniques, WO

assays require sample pretreatment. If sample prepara-

2004030820 A2

tion is the rate-limiting step and must be done off-chip, 6 Chou, H.P. et al. Fluidigm Corporation. Microfabricated elastomeric

then customers would be unlikely to use the device. valve and pump systems, WO 2001001025 A3

7 Ismagilov, R.F. et al. RainDance Technologies, Inc. Method for obtaining

Therefore, successful performance of technically complex

a collection of plugs comprising biological molecules, US 8273573 B2;

analyses on-chip requires the procedures to be run si-

Ismagilov, R.F. et al. RainDance Technologies, Inc. Method for

multaneously, seamlessly moving from one step to the conducting an autocatalytic reaction in plugs in a microfluidic system,

next. Moreover, the integrated product should be self- US 8304193 B2; Ismagilov, R.F. et al. RainDance Technologies, Inc.

Method for conducting reactions involving biological molecules in plugs

contained, ideally not requiring prior sample treatment,

in a microfluidic system, US 8329407 B2

preparation, or amplification. It should be fully automat-

8 Abell, C. et al. Sphere Fluidics Limited. Method of providing a chemical

ed to reduce errors and facilitate use for operators with-

or biological material in quantised form and system therefor, WO

out microfluidics expertise. The results should be clearly 2012022976 A1

displayed to minimize the need for subjective user inter- 9 Davis, G. et al. Abbott Laboratories. Apparatus and methods for

pretation. analyte measurement and immunoassay, WO 2003076937 A3

349

Science & Society

Trends in Biotechnology July 2014, Vol. 32, No. 7

10 Linder, V. et al. Claros Diagnostics, Inc (OPKO, Inc). Liquid 13 Yetisen, A.K. et al. (2013) Paper-based microfluidic point-of-care

containment for integrated assays, WO 2009038628 A3; Linder, V. diagnostic devices. Lab Chip 13, 2210–2251

et al. Claros Diagnostics, Inc (OPKO, Inc). Feedback control in 14 Blow, N. (2007) Microfluidics: in search of a killer application. Nat.

microfluidic systems, WO 2011130625 A1; Tan, E. et al. Claros Methods 4, 665–670

Diagnostics, Inc (OPKO, Inc). Fluid mixing and delivery in 15 Nge, P.N. et al. (2013) Advances in microfluidic materials, functions,

microfluidic systems, WO 2011066361 A1 integration, and applications. Chem. Rev. 113, 2550–2583

11 Chin, C.D. et al. (2011) Microfluidics-based diagnostics of infectious 16 Berthier, E. et al. (2012) Engineers are from PDMS-land, biologists are

diseases in the developing world. Nat. Med. 17, 1015–1019 from polystyrenia. Lab Chip 12, 1224–1237

12 Watkins, N.N. et al. (2013) Microfluidic CD4+ and CD8+ T lymphocyte 17 Yetisen, A.K. et al. (2014) Patent protection and licensing in

counters for point-of-care HIV diagnostics using whole blood. Sci. microfluidics. Lab Chip http://dx.doi.org/10.1039/c4lc00399c

Transl. Med. 5, 214ra170

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