TECHNICAL PAPER

Polymerase chain reaction compatibility of adhesive transfer tapebased microfluidic platforms

Pulak Nath • Tuhin S. Maity • Frida Pettersson •

Jesse Resnick • Yuliya Kunde • Noelle Kraus •

Nicolas Castano

Received: 25 May 2013 / Accepted: 13 August 2013 / Published online: 28 August 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract Laser patterned adhesive transfer tapes are a

rapid, versatile, and low cost option to fabricate microflu-

idic platforms. In this work, we examined the compatibility

with polymerase chain reaction (PCR) of different types of

adhesive tape materials patterned with a CO2 laser cutter.

Acrylic, polyimide, and silicone-based tapes were consid-

ered. We performed a systematic study on off-the-shelf

adhesive tapes with respect to fluid handling, PCR inhibi-

tion, reagent loss, and on-chip PCR reaction. A novel

microfluidic PCR approach was implemented that com-

bines the advantages of previously reported systems. It uses

a thermal gradient from a single heating element and the

thermocycling was carried out by passing the reaction

mixture back and forth in a microfluidic channel strategi-

cally placed along the thermal gradient. Only the silicone-

based tapes were compatible with on-chip PCR. The

overall fabrication process takes less than 30 min, uses

only off-the-shelf finished or semi-finished materials, and

is amenable to large-scale reel-to-reel processing.

1 Introduction

Fabrication of microfluidic devices were first derived from

the integrated circuits manufacturing techniques with the

idea that mass production of proven platforms would be

simple and cost-effective. However, there are significant

differences in the application of integrated circuits and

microfluidic devices. While lowering the cost of manu-

facturing is a common goal, the challenges are quite dif-

ferent. Integrated circuits are seldom required to be

disposable or be exposed to harsh fluidic environments.

Whereas microfluidic platforms, which largely target the

medical diagnostics industry, have a large demand to be

disposable or one-time-use, and are exposed to complex

biological fluids such as blood. As a result, fabrication of

microfluidic devices has come away from common inte-

grated circuit fabrications methods. Now a day, there are

many ways to fabricate microfluidic devices. However,

since the introduction of soft lithography (Xia and White-

sides 1998), Polydimethylsiloxane (PDMS) has become the

predominant material of choice for fabricating microfluidic

platforms (Whitesides et al. 2001). Nevertheless, there are

major obstacles in transforming research-scale microfluidic

technologies into commercial-scale production (Blow

2009; Mukhopadhyay 2007; Becker 2010). Many of the

processes developed with PDMS are difficult to realize

outside a controlled laboratory environment. A good pro-

totyping method for microfluidics should not only be

suitable for fabricating versatile platforms to develop

intended applications, but also be transformable into viable

commercial products (Focke et al. 2010).

Fabrication of microfluidic platforms based on finished

or semi-finished thin films, also known as Lab on a Foil

(Velten et al. 2008; Focke et al. 2010; Lutz et al. 2010), has

the potential to become a low-cost reel-to-reel manufac-

turing method for large-scale production of microfluidic

platforms. Among other applications, the flexible circuit

industry is driving innovations in reel-to-reel manufactur-

ing for low cost, high throughput production of compo-

nents used in consumer electronics. Several fabrication

techniques such as lamination, laser ablation, or hot

P. Nath (&) � F. Pettersson � J. Resnick � N. Kraus � N. Castano

Applied Modern Physics, Los Alamos National Laboratory,

Los Alamos, NM 88545, USA

e-mail: pulakn@lanl.gov

T. S. Maity � Y. Kunde

Bioscience Division, Los Alamos National Laboratory,

Los Alamos, NM 88545, USA

123

Microsyst Technol (2014) 20:1187–1193

DOI 10.1007/s00542-013-1901-1

embossing are amenable to reel-to-reel processing (Velten

et al. 2010; Khan Malek et al. 2009; Focke et al. 2010),

which can make large-scale production of microfluidic

devices more economical. Previously, we have developed a

versatile rapid prototyping technique that used polymer

substrates, adhesive transfer tapes, CO2 laser ablation, and

lamination to fabricate microfluidic platforms (Nath et al.

2010). The use of adhesive transfer tapes provides flexi-

bility in the range of materials that can be exploited. Laser

ablation enables quick adoption of design changes at the

early stages of developments. Lamination eliminates the

need for sophisticated tools for bonding. These character-

istics result in a rapid and versatile laboratory prototyping

approach that is at least an order of magnitude lower in cost

than common microfabrication techniques. More impor-

tantly, the technology and materials are both compatible

with reel-to-reel manufacturing methods, and, therefore,

prototypes can be mass-produced with little or no modifi-

cation of the laboratory-scale fabrication steps.

Different types of lasers are available for fabricating

microfluidic devices (Li et al. 2012; Kim et al. 2005;

Kim and Xu 2003). However, CO2 based laser engraving

tools are most common and accessible due to their large

applications in the engraving industry and low cost. The

cost of adhesive transfer tapes is also very low due their

large market in the consumer electronics and the pack-

aging industry. In this work, we investigate the bio-

compatibility of several CO2 laser-cut adhesive tapes for

microfluidic Polymerase Chain Reaction (PCR). PCR is a

complex, thermally regulated, enzymatic process that can

be very sensitive to contamination, reagent loss, and

chemical inhibition (Zhang and Xing 2007). Other

reports of successful tape-based PCR platforms used

double-sided tapes patterned with much slower, shear-

based methods such as Xurography (Pjescic et al. 2010;

Shen et al. 2005). We used adhesive transfer tapes,

which differ from conventional double-sided tapes in that

the tape is made of the adhesive material alone and does

not involve a carrier material. This reduces the number

of materials that may interact unfavorably with the fab-

rication process and with biological samples. It also

allows flexible use of custom carrier materials, as dem-

onstrated in this work. Since microfluidic devices have

high surface to volume ratio, material interactions can

lead to unfavorable outcomes, especially for biological

applications. CO2 laser-based fabrication was selected

over shear-based methods (e.g. Xurography) because

CO2 lasers can cut/engrave a wide range of materials

and are readily available at a low cost. However, burn

residues may occur on the cut surfaces. The residues can

be difficult to remove depending on the type of materials

cut and may cause biocompatibility issues for lab-on-a-

chip applications. In this work, we systematically

examined the compatibility of our fabricated platforms

with PCR as a central test for their compatibility with

sensitive biochemical applications.

2 Experimental

2.1 Materials and fabrication

Commercially available adhesive tapes were primarily

chosen based on their thermal stability for PCR reactions.

The tapes that were considered were (1) 200 double-sided

polyimide tape (PPTDE-2, http://www.kaptontape.com);

(2) ARcare 90880 double coated PSA tape (Adhesive

Research, Inc., Glen Rock, PA); (3) High performance

acrylic based 200MP adhesive transfer tape (3M, St. Paul,

MN, USA); and (4) Silicone adhesive transfer tape (SiATT

9122, 3M, St. Paul, MN, USA). The thickness of the

double-sided tapes varied between 50 and 100 lm. Our

intended channel thickness was in the order of 250–300 lm

range that could accommodate PCR reaction volume

comparable to common bench-top systems.

To achieve the desired thickness of the channel layer,

we either laminated multiple layers (2–4) of the double-

sided tapes or laminated them on both sides of a carrier

layer with desirable thickness. Hybrislip Sheets (Product

I.D. 440610, Grace Biolabs, Bend, OR) and Culture well

Silicone sheets (Product I.D. CWS-S-0.25, Grace Biolabs,

Bend, OR) were chosen as the carrier layers. Hybrislip

sheets were used as the supporting substrate (top and bot-

tom laminate) material for fabrication. The adhesive layers

were patterned using a CO2 laser cutter (M-360, Universal

Laser Systems, Scottsdale, AZ). The side walls of the laser-

cut parts were cleaned only with high-pressure air; no

organic solvent-based cleaning was used. The patterned

adhesives were then laminated with Hybrislip sheets from

the top and bottom to enclose the channels. The fabrication

steps are described in more detail in Nath et al. (2010). The

platforms were then attached to pre-cut Acrylic sheets

(Plaskolite Optix, 1/1600 thick, Columbus, Ohio) before

placing them on a heater. The overall fabrication process

takes less than 30 min.

Different combinations of materials can be used as the

adhesive layers. The combinations were chosen based on

the adhesion properties of the tapes onto the carrier mate-

rials. For example, 200MP adhesives had poor adhesion to

silicone sheets and, therefore, were not considered for

fabricating the platform. The following combinations were

used for the final study:

1. Three layers of Polyimide tape laminated with each

other

2. Two layers of ARcare tape laminated with each other

1188 Microsyst Technol (2014) 20:1187–1193

123

3. 200MP adhesive transfer tapes laminated on both sides

of Hybrislip sheets

4. Silicone adhesive transfer tapes laminated on both

sides of silicone sheets

Figure 1 shows an example of the different layers

involved in the fabrications process. The finished PCR

channels were washed with RNAse free water at a flow rate

of 100 lL/min for about 10 min for all platforms made

with the different tape materials.

2.2 Instrumentation

The PCR platform consisting of a channel network with

three zones (Fig. 2) was placed on a heater (WS-640/240V,

Omega Engineering, Stamford, CT) at a constant temper-

ature. The heater was controlled by a PID controller

(CSC32 Series, Omega Engineering, Stamford, CT). The

PCR platform was placed such that only a portion of the

platform was in contact with the heater (Fig. 3a), creating a

thermal gradient across the platform. Based on the tem-

perature gradient on the platform, the channel network was

designed such that the three zones were established with

constant temperatures of 88 �C (Denaturation), 68 �C

(extension) and 58 �C (annealing), respectively. Figure 3b

illustrates the temperature stability of the temperature

zones on the PCR platform. The channels were designed to

accommodate variable PCR reaction volumes (20 lL or

less). The channels were interfaced with a syringe pump

using world-to-chip interfaces reported in our previous

work (Nath et al. 2010). The samples were passed back-

and-forth between zones by manually controlling the

injection/withdraw mode of the syringe pump via the

control console. Samples were loaded by withdrawing

15 lL of PCR mix from a PCR tube using the syringe

pump. To improve fluid-handling, mineral oil was used as

the carrier fluid within the syringes and the channels. A

description of the fluid handling protocol is presented in

Table 1.

2.3 PCR reaction

For the PCR reaction, the lactose operon repressor (LacI)

coding region was amplified from E. coli-K12 DNA using

forward and reverse primers, 50-G ATC GGA TCC GTG

AAA CCA GTA ACG TTA TAC GAT GTC GC-30 and 50-GAT CCA TGG TCA CTG CCC GCT TTC CAG TCG

GGA AAC C-30, respectively. This PCR product

(1,192 bp) was used as template in all successive PCR

reactions. The final optimized PCR reaction mixture con-

tained *50 ng template/100 lL of reaction volume,

0.4 lM Forward Primer, 0.4 lM Reverse Primer, 1X PCR

reaction buffer, 0.4 mM dNTPs, 2 mM MgSO4, and

0.2 units/lL Platinum Taq DNA polymerase (Invitrogen).

The PCR mix was spiked with REDTaq� DNA polymerase

(Sigma) (1/100 lL of reaction vol.) to facilitate visualiza-

tion of the reaction solution inside the microfluidic plat-

forms. Additionally, 10 % glycerol and 2.0 mg/mL BSA

(NEB) were added to the PCR reaction mixture for

reducing evaporation and for dynamic passivation,

respectively. All PCR reactions on the microfluidic plat-

forms were carried out as illustrated in Table 1 for 25

cycles. A commercial bench top thermocycler (S1000,

BioRAD) was used to carry out off-chip analysis and as a

comparative standard. PCR reactions in bench top

Fig. 1 Schematic showing different layers of a PCR microfluidic

platform made with silicone adhesive transfer tapes laminated on both

sides of a silicone sheets

Tem

perature Gradient

Heater

92°C

70°C

58°C

Fig. 2 Schematic showing the design of the microfluidic PCR

platform

Microsyst Technol (2014) 20:1187–1193 1189

123

thermocycler were performed for 25 cycles (denaturing,

92 �C, 30 s; annealing, 60 �C, 30 s; extension, 68 �C,

1 min). A standard final 10 min extension step was incor-

porated at the end of the PCR cycle to ensure reaction

completion. All PCR amplification products were analyzed

on 1 % agarose gel and visualized using EtBr staining.

3 Results and discussion

We have used a systematic approach to eliminate the tape

based materials that were not suitable to perform on-chip

PCR. The systematic approach involved studying the dif-

ferent materials for their compatibility with the fluid han-

dling methods, inhibition of PCR reactions, and loss off

reagents.

3.1 Fluid handling and additives

Several methods have been developed to carry out micro-

fluidic PCR (Zhang and Xing 2007). In continuous flow

method, the reaction mixtures are passed through a ser-

pentine channel placed on three thermal elements with

constant temperatures. This method eliminates the cooling

requirements in conventional PCR, but limits amplification

to a fixed number of cycles based on the channel layout.

This limitation can be overcome using a back-and-forth

flow of the reaction mixture over three constant tempera-

ture zones. Furthermore, the design with three heating

elements can be simplified by using only one heating ele-

ment and the thermal gradients generated from the heating

surface (Crews et al. 2008). In this work, we combined a

thermal gradient heating scheme with back-and-forth flow

arrangements to develop a unique microfluidic PCR plat-

form that uses only one heating element and is not limited

to a fixed number of PCR cycles.

The success of a PCR reaction in our microfluidic

devices greatly depended on the ability to reproducibly

control the movement of sample between different tem-

perature zones. Initially, we investigated air to actuate the

sample mixture between zones. However, air was found to

be unsuitable medium for sample control, especially at

elevated temperatures. Air expands as it reaches 88 �C

degrees and contracts when it is at 58 �C. Due to the small

volume of the channels, the expansion of the air in the

88 �C zone caused the liquids to be expelled out of the

desired location erratically, which made it impossible to

reproducibly control sample temperature cycling. To

address this problem, the sample mixture (*15 lL) was

pushed back and forth inside the channels with an immis-

cible liquid, such as PCR compatible mineral oil (BioRAD)

(Wang and Burns 2009).

50

60

70

80

90

100

0 20 40 60

Tem

per

atu

re (C

)

Time (Minutes)

Tape58 oC68 oC88 oC

Heating block at constant temperature (92 oC)

Acrylic (a)

(b)

Fig. 3 a Schematic showing the cross-section of the heater/chip

arrangements; b temperature distribution on different zones over an

hour

Table 1 Fluid handling steps for on-chip PCR

Steps Description

1. Rinse chip with RNAse free water for 10 min at 100 lL/min

2. Fill channels and pump line with mineral oil

3. Withdraw sample into channel at 100 lL/min

4. Stop pump when sample is located on 88 �C zone

5. Wait 10 min

6. Turn on pump in infuse mode

7. Stop pump when sample is located on 58 �C zone

8. Wait 30 s

9. Turn on pump in infuse mode

10. Stop pump when sample is located on 68 �C zone

11. Wait 60 s

12. Turn on pump in withdraw mode

13. Stop pump when sample is located on 88 �C zone

14. Wait 30 s

15. Repeat steps 6–14 twenty four times

16. Turn on pump in infuse mode

17. Stop pump when sample is located on 58 �C zone

18. Wait 10 min

19. Turn on pump in infuse mode

20. Collect products in PCR tubes

1190 Microsyst Technol (2014) 20:1187–1193

123

We also observed evaporation of the sample forming

bubbles that expanded and contracted based on their

location on a temperature zone, especially when the sam-

ples were moved using just air. When mineral oil was used,

surface tension between the oil and channel wall resulted

into encapsulation of the aqueous sample by the oil. It

changed the vapor pressure on the sample and resulted in

reduced evaporation. Nevertheless, it was not possible to

entirely eliminate evaporative droplet formation, and

optimized additives (Zhang and Xing 2007) were necessary

to keep evaporation under control. Microfluidic PCR

reactions have been shown to remain unaffected with

glycerol additives up to 20 % (Trung et al. 2010). We used

10 % glycerol in a sample volume of 10–20 lL to elimi-

nate evaporation during on-chip thermocycling.

The use of mineral oil to push the sample inside the

microchannels introduces a new variable—the compati-

bility of the adhesive materials with the mineral oil. It was

found that all platforms, except the ones that were made

with ARcare, were stable at the operating conditions of the

PCR reaction. We tested three platforms from each type of

materials described earlier. The platforms made with AR-

care consistently began to leak within 10–15 cycles when

used with mineral oils. Therefore, the platforms made with

ARcare adhesive tapes were eliminated from all follow on

experiments.

3.2 Study of PCR inhibition

One of our objectives was to simplify the fabrication steps

such that the prototyping is more amenable to reel-to-reel

mass manufacturing. Therefore, no washing step was

incorporated until the fabrication of enclosed channels was

completed. Since the channels were cleaned only with

high-pressure air, it may leave burn products inside the

channels that could cause PCR inhibition.

To investigate the compatibility of the laser cut mate-

rials (that were only cleaned with high pressure air) with

PCR, 15 lL of the RNAse free water was first passed

through the chip according to the fluid handling protocols

described in Table 1. We hypothesized that if any burn

residue is left after air-cleaning, they will be washed into

the water. These water samples from different chips were

collected (in triplicates), mixed with other necessary PCR

reagents, and amplified on the bench-top thermocycler to

investigate if the use of only air cleaning affects the overall

PCR outcome. Water samples collected from the channels

made with 200MP adhesive/Hybrislip structures showed

signs of PCR inhibition, indicating that inhibitory residues

were introduced into the water during its on-chip thermo-

cycling. Channels made with the polyimide tapes and the

silicone adhesive transfer tape/silicone sheets however, did

not show any inhibition, suggesting that platforms made

from these two materials would not inhibit on-chip PCR

reactions. Therefore, 200MP adhesive/Hybrislip based

PCR platforms were eliminated form all subsequent

experiments.

3.3 Study of reagent loss

Due to the large surface to volume ratio in microfluidic

platforms, interaction (e.g. adsorption) of the PCR com-

ponents with the channel walls can cause the PCR to fail.

To check the loss of any PCR component, five samples

were prepared that contained RNAse free water and only

one of the five following PCR reagents: dNTPs, Primers,

Taq polymerase, Buffers, and Templates, respectively. The

volume ratio of these components was kept the same as

what is commonly recommended for a bench top PCR

reaction. Each sample was passed back-and-forth through

the microfluidic platforms in cold conditions 25 times and

then collected in a PCR tube. The remainders of the PCR

reagents were then added to the samples and the final

reaction mixtures were amplified in the conventional

thermocycler. The objective of this exercise was to

experimentally determine if reagent loss occurs in any of

the platforms. If reagent loss occurs, that would be

reflected as a failure of PCR amplification reaction in the

bench-top system. Based on gel electrophoresis analysis of

three different experiments for each PCR component, it

was found that only Taq polymerase was getting adsorbed

on the surface of the channels. Protein adsorption is com-

mon in microfluidic devices. There are several ways to

passivate the surface to reduce such absorption (Zhang and

Xing 2007). We chose to add BSA to the PCR reaction

mixture to provide dynamic passivation. After testing dif-

ferent concentrations of BSA it was found that 2.0 mg/mL

BSA was sufficient for dynamic passivation. These tests

were only performed on platforms that were made with the

polyimide tapes and the silicone adhesive transfer tape/

silicone sheets. The other candidate materials were previ-

ously eliminated based on flow optimization studies and

inhibition analysis.

3.4 On-chip PCR

The platforms made with the polyimide tapes and the sil-

icone adhesive transfer tapes were used to investigate on-

chip PCR amplification using our custom heater/control

arrangements. Experiments were performed according to

Table 1 in triplicates to ensure reproducibility. PCR

products were successfully and reproducibly amplified only

on the platforms made with silicone adhesive transfer tapes

(Fig. 4).

Microsyst Technol (2014) 20:1187–1193 1191

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4 Conclusions

The use of double-sided tapes is becoming more and

more popular for microfluidic applications (Schaff and

Sommer 2011; Siegrist et al. 2010). Based on our sys-

tematic approach we demonstrate that it is very impor-

tant to select the right tape material when fabricating

microfluidic platforms that incorporates PCR based

analysis. We found that silicone based adhesive transfer

tapes are suitable to fabricate rapid, low cost prototypes

for PCRs using CO2 laser-based cutting and lamination.

We also demonstrated a novel microfluidic PCR platform

that combines the benefits of several existing microflu-

idic PCR platforms. The rapid prototyping method con-

sidered here does not use any organic solvent based

processing (e.g. developing, dissolution, cleaning, etc.)

during the fabrication steps. While platforms can be

fabricated form different types of adhesive transfer tapes,

only CO2 laser cut silicone based adhesive transfer tapes

are suitable for developing microfluidic platforms that

are compatible with very sensitive biochemical reactions

such as PCR. The rapid nature, low cost, compatibility

with reel-to-reel manufacturing, and PCR biocompatibil-

ity of the fabrication approach provides a new and ver-

satile option to make lab-on-a-chip platforms for

biological applications.

Acknowledgments This work was funded by a Department of

Energy Laboratory Directed Research and Development Grant

(20070010-DR) at Los Alamos National Laboratory. The authors

thank Michelle Espy, Momchilo Vuyisich, Scott White, Andrew

Badbury, Ahmet Zeytun, Alina Deshpande, and John Dunbar for

valuable discussions.

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