Ultrafast photonic PCR | Light: Science & Applications

ABSTRACT Nucleic acid amplification and quantification _via_ polymerase chain reaction (PCR) is one of the most sensitive and powerful tools for clinical laboratories, precision medicine,

personalized medicine, agricultural science, forensic science and environmental science. Ultrafast multiplex PCR, characterized by low power consumption, compact size and simple operation,

is ideal for timely diagnosis at the point-of-care (POC). Although several fast/ultrafast PCR methods have been proposed, the use of a simple and robust PCR thermal cycler remains

challenging for POC testing. Here, we present an ultrafast photonic PCR method using plasmonic photothermal light-to-heat conversion _via_ photon–electron–phonon coupling. We demonstrate an

efficient photonic heat converter using a thin gold (Au) film due to its plasmon-assisted high optical absorption (approximately 65% at 450 nm, the peak wavelength of heat source

light-emitting diodes (LEDs)). The plasmon-excited Au film is capable of rapidly heating the surrounding solution to over 150 °C within 3 min. Using this method, ultrafast thermal cycling

(30 cycles; heating and cooling rate of 12.79±0.93 °C s−1 and 6.6±0.29 °C s−1, respectively) from 55 °C (temperature of annealing) to 95 °C (temperature of denaturation) is accomplished

within 5 min. Using photonic PCR thermal cycles, we demonstrate here successful nucleic acid (λ-DNA) amplification. Our simple, robust and low cost approach to ultrafast PCR using an

efficient photonic-based heating procedure could be generally integrated into a variety of devices or procedures, including on-chip thermal lysis and heating for isothermal amplifications.

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NUCLEASES ESCALATION Article Open access 04 February 2025 INTRODUCTION After its initial invention in 1983 by Kary Mullis, polymerase chain reaction (PCR) has become an essential technique

in the fields of clinical laboratories, agricultural science, environmental science, and forensic science.1,2,3,4,5,6,7,8 PCR requires thermal cycling, or repeated temperature changes

between two or three discrete temperatures to amplify specific nucleic acid target sequences. To achieve such thermal cycling, conventional bench-top thermal cyclers generally use a metal

heating block powered by Peltier elements. Whereas commercial PCR systems have improved heating and cooling rates to reduce amplification time, they are still relatively time-consuming

(typically requiring an hour or more per amplification). This can be attributed to the larger thermal capacitance of a system that requires uniformly heating 96- or 384-well plastic PCR

plates and reaction volumes of several tens of microliters per well. Because fast/ultrafast PCR is highly desirable for applications such as timely diagnosis of infectious diseases, cardiac

diseases, cancer, neurological disorder diseases, and rapid biowarfare and pathogen identification at the point-of-care (POC) level, many academic and industrial groups have worked on

improving PCR systems,9,10,11,12,13,14,15 One commercial PCR system (LightCycler® 2.0, Roche Diagnostics USA, Indianapolis, IN, USA) using air heating/cooling and capillary tubes can perform

30 thermal cycles in 10–60 min, depending on sample volume.10 However, this system is not suitable for POC testing due to its high power consumption (800 W maximum) and heavy weight

(approximately 22 kg). For POC diagnostics for global health care in resource-limited environments, such as in developing countries, a fast/ultrafast PCR system should be portable, robust,

simple, easy to use and characterized by low power consumption through miniaturization and integration. To date, microfluidic-based fast/ultrafast PCR systems have been extensively

investigated to reduce amplification time by decreasing sample sizes as well as by increasing heat transfer rates. Resistive heating with microfabricated thin film heaters is most commonly

used to control the temperature in the static microfluidic-based PCR system, in which the PCR runs in the microfluidic chamber.11,12 However, this method requires a complicated fabrication

process to integrate the thin film heater and resistance temperature detection sensor on the chip. In the case of continuous-flow PCR on a chip, the PCR amplification occurs when the

reaction samples pass thorough three discrete temperature zones.13 This method can produce faster thermal cycling for PCR, but requires an external syringe pump for continuous-flow control

and lacks the ability to perform multiple reactions at the same time. Another approach includes infrared-mediated non-contact selective heating of water droplets (nanoliter sample volume)

for ultrafast thermal cycling using an infrared laser, which harnesses the strong absorbance of water at wavelengths over 1000 nm.14,15 However, droplet formation from the PCR mixture is a

precise process prone to human error, which is a drawback for POC testing. More recently, efforts have been made to utilize the advantages of plasmonic photothermal heating of gold

nanoparticles,16,17 using pulsed or continuous-wave laser excitation for photothermal therapy of cancer18,19 and fast PCR,20 for example. However, this arrangement is not ideal for POC

testing, as it requires not only expensive lasers and detection systems but also lacks reliable gold nanoparticles-based sample preparation. In this paper, we present a novel ultrafast

photonic PCR method that combines the use of a thin Au film as a light-to-heat converter and light-emitting diodes (LEDs) as a heat source. The strong light absorption of the thin Au film

(65%, 120 nm thick) generates heat due to the plasmonic photothermal light-to-heat conversion by photon–electron–phonon coupling at the thin Au film, followed by heating of the surrounding

solution with a maximum temperature of over 150 °C within 3 min. Thirty ultrafast thermal cycles (heating rate of 12.79±0.93 °C s−1 and cooling rate of 6.6±0.29 °C s−1) from 55 °C (point of

annealing) to 95 °C (point of denaturation) are accomplished within 5 min. Using this technique, we successfully demonstrate the amplification of λ-DNA. We propose that our PCR system would

be ideal for POC diagnostics due to its ultrafast thermal cycling capability, multiplex PCR, low power consumption (in the current set-up, up to approximately 3.5 W), low cost and simple

configuration for system level integration. Furthermore, our efficient photonic-based heating procedure could be generally integrated into a variety of devices or procedures, including

on-chip thermal lysis and heating for isothermal amplifications. MATERIALS AND METHODS FABRICATION OF THE THIN AU FILM DEPOSITED POLY(METHYL METHACRYLATE) (PMMA) PCR WELLS The 4-mm-thick

PMMA sheets were cut with a VersaLASER VL-200 laser cutting system (Universal Laser System, Inc., Scottsdale, AZ, USA) to make a reaction well with a 4-mm diameter. The 1.5-mm-thick bottom

PMMA sheet and top reaction wells were bonded together using thermal bonding performed at 84 °C with a pressure of 1.0 t after UV/ozone treatment of the PMMA sheet for 10 min. Thin Au films

of different thicknesses were deposited by electron beam evaporation under a base pressure of 2×10−7 Torr. The thin Au film was passivated with thin poly(dimethylsiloxane) by dropping 2 µL

of poly(dimethylsiloxane) into the well and curing in an oven for 2 h to prevent PCR reaction inhibition by the thin Au film and thermocouple. SIMULATION We used COMSOL Multiphysics software

(Ver. 4.3, COMSOL Inc., Burlington, MA, USA) for electromagnetic simulation. The detailed geometry and material properties for the simulation are shown in Supplementary Fig. S1 and Table

S1. A thin Au film is placed on a PMMA substrate, and then the Au film was covered with water. Different thicknesses (10, 20, 40, 80 and 120 nm) of thin Au film were applied to the

simulation to calculate the absorption of the Au films and subsequent resistive heat generation. The plane wave with an _x_-polarized electric field travels in the positive _z_ direction in

the coordinate system shown in Supplementary Fig. S1. The permittivity of Au used in this study was referred from Johnson and Christy,21 and the permittivities of PMMA and water were 3 and

1.77, respectively. ULTRAFAST PHOTONIC PCR CYCLES LEDs (Luxeon® Rebel, Lumileds, San Jose, CA, USA, royal blue with a peak wavelength of 447.5 nm, 890 mW at 700 mA injection current) were

used for plasmonic photothermal heating of the thin Au film with a Keithley 2400 source meter. To focus the light from the LEDs, a Carclo 20 mm fiber coupling optic (part number: 10356,

Carclo Optics, PA, USA) was employed. The temperature of the solution was monitored and recorded in real time by a type-K insulated thermocouple purchased from OMEGA Engineering (part

number, 5SC-TT-K-40-36) for thermal cycling. Temperature cycling using an LED, 80 mm cooling fan, source meter and thermocouple was controlled through the LabVIEW program. A National

Instruments 9213 16 channel thermocouple module with high speed mode, auto zero and cold junction compensation was used for accurate temperature acquisition from the type-K thermocouple.

PREPARATION OF THE PCR REAGENT AND DNA TEMPLATE The template λ-DNA and Takara Z-TaqTM DNA polymerase (2.5 U µL−1), 10× Z-Taq Buffer (Mg2+ plus, 30 mM) and dNTP Mixture (2.5 mM each) were

purchased from Takara Bio Inc. (Otsu-shi, SHG, Japan). Forward primer (5′-CATCGTCTGCCTGTCATGGGCTGTTAAT-3′) and reverse primer (5′-TCGCCAGCTTCAGTTCTCTGGCATTT-3′) were purchased from

Integrated DNA Technologies, Inc. (Coralville, IA, USA). The reaction to amplify a 98-base pair (bp) λ-DNA target with Z-TaqTM DNA polymerase included 0.5 µL Z-Taq DNA polymerase, 5 µL of

10× Z-Taq Buffer, 4 µL of dNTP mixture, 4.5 µL of 10 µM primers (each) and 10 µL of bovine serum albumin (50 µg) and was brought to 50 µL with PCR-grade water. The final concentration of the

template λ-DNA was 0.1 ng µL−1. The 10 µL of PCR mixture was placed within Au-coated PMMA PCR wells for photonic PCR and then covered with 30 µL of mineral oil to prevent evaporation during

thermal cycling. After amplification, a mixture of 10 µL of PCR product and 10 µL of E-Gel® sample loading buffer (Invitrogen, Thermo Fisher Scientific Inc., Waltham, MA, USA) was loaded

onto E-Gel® 2% agarose gels with SYBR SafeTM DNA gel stain (Invitrogen) and run in an E-Gel base (Invitrogen) for 30 min. A 1-Kb DNA ladder was used to confirm the size of product. RESULTS

AND DISCUSSION PHOTOTHERMAL LIGHT-TO-HEAT CONVERSION FOR PCR The principle of ultrafast photonic PCR is illustrated in Figure 1a. In considering photon interaction with materials, the

absorption of photons is often treated as heat.22 When the photons from the excitation source reach the surface of the thin Au film, plasmon-assisted strong light absorption can occur. This,

in turn, excites electrons near the surface to higher energy states, generating hot electrons within 100 fs.23,24 These hot electrons can reach a temperature of several thousand degrees

Kelvin due to their small electronic heat capacity. They are also capable of rapidly diffusing throughout the thin Au film, creating a uniform distribution of hot electrons. Rapid heating is

followed by cooling to equilibrium by energy exchange between the hot electrons and the lattice phonons after 5–10 ps. Thus, overall, when thin Au films are illuminated, a large temperature

difference between the hot metal surface and the cooler surrounding solution occurs, resulting in the heating of the surrounding solution in a long time scale over 100 ps. When a light is

turned off, the fast cooling of the heated solution can also be achieved by the heat dissipation through the thin Au film with high thermal conductivity of 317 W m−1 K−1.25 A thin Au film

deposited on a PMMA well is used as a light-to-heat converter, serving as a source of plasmonic photothermal heating for the PCR thermal cycling, as shown in Figure 1b. In addition to

driving multiple PCR reactions with single LEDs, multiple well plates integrated with LED arrays could be used for multiplex PCR by modulating each LED to have unique annealing temperatures

for the various primer designs. This multiple well LED array PCR thermal cycler configuration would be ideal for multiplex ultrafast PCR for POC diagnostics because it could perform multiple

tests at once. We performed a set of electromagnetic simulations to theoretically characterize the plasmonic photothermal light-to-heat conversion of our Au films. We calculated the

electromagnetic field and resistive heat distributions for 10-nm- and 120-nm-thick Au films on a PMMA substrate. As expected from the skin depth, where _ω_ is the angular frequency, _μ_ is

the permeability and _σ_ is the conductivity; the thickness of the thin Au film determines the amount of light to heat conversion. Upon a normal incidence of a 450 nm wavelength light

source, the 10 nm thick Au film transmits an enormous amount of electromagnetic energy (Figure 2a), and the heat conversion energy is saturated along the film depth (Figure 2c). However, the

120-nm thick Au film absorbs most of the incident light (Figure 2b) and subsequently, generates more heat in the Au film by converting light into heat (Figure 2d). Figure 2e shows that an

increase in thickness of thin Au film, in the range of 10–120 nm, corresponds to an increase in the optical absorption. A significant increase of the optical absorption below the 540-nm

wavelength could be attributed to the plasmonic electron resonance of gold.26 As a result, the averaged light-to-heat conversion efficiency over the emission wavelength from each LED

increases with increasing Au film thickness for three different LEDs, as shown in Figure 2f (see Supplementary Fig. S2). It is noteworthy that the blue LEDs with peak emission wavelength of

450 nm show the highest light-to-heat conversion efficiency using the thin Au film. LED-DRIVEN PHOTONIC PCR THERMAL CYCLER The optical absorption spectra of thin Au films with different

thicknesses deposited on PMMA substrates are shown in Figure 3a (see Supplementary Fig. S3). Our simulation results can help us determine when the strongest light absorption occurs, as this

is critical to maximizing photothermal heating. As the thickness of the thin Au film increases, the optical absorption also increases, showing 65 % absorption at the peak wavelength (450 nm)

of the excitation LEDs in the 120-nm-thick Au film. Our photonic PCR thermal cycler uses LEDs as a heating source, PMMA PCR wells deposited with thin Au films, and a lens to focus the

excitation light (see Supplementary Fig. S3). The light from the LEDs is continuous-wave and randomly polarized. Therefore, the efficiency of light-to-heat conversion would be lower in this

case than using a pulsed laser because as electrons are excited to higher energy states, the probability of further excitation decreases. Despite its possibly lower light-to-heat conversion

efficiency than a pulsed light source, however, LEDs require minimal power consumption and are extremely low in cost compared with laser sources, making them an ideal PCR heating source for

POC testing. The component cost of the instruments for our ultrafast photonic PCR thermal cycle (see Supplementary Fig. S3b) could be less than US$100 including the LEDs, focus lens and

driver, if the LabVIEW and data acquisition board for temperature control are integrated into a microcontroller module. The maximum power consumption of an LED is approximately 3.5 W at a 1

A injection current. Figure 3b shows the temperature profiles of 10 µL volumes of solution (here, glycerol was used to show the maximum heating temperatures) upon thin Au films of different

thicknesses at a fixed injection current of 500 mA. The maximum temperatures increased as the thickness of the thin Au film increases from 10 nm to 120 nm due to the increasing optical

absorption. The photothermal heating of the 120-nm-thick Au film was further characterized as a function of the injection current, as shown in Figure 3c, because the heating rate is

determined by the amount of dissipated power (i.e., the injection current of the LEDs). Figure 3d summarizes the temperature of a solution after 3-min heating with Au films of different

thickness and varying injection currents (see Supplementary Table S2). These results clearly indicate that the maximum temperature increases with an increase of Au film thickness to 120 nm

and an increase of injection current to 1 A. Complete PCR thermal cycling, consisting of three representative temperatures (94 °C for denaturation, 60 °C for annealing and 72 °C for

extension), is demonstrated using an LED-driven photonic PCR thermal cycler, as shown in Figure 3e. To prevent evaporation during thermal cycling, 10 µL of PCR buffer was covered with 30 µL

of mineral oil. The averages and standard deviations at each temperature were obtained from the temperature profile, and the results are 94.09±0.17 °C at 94 °C, 59.94±0.13 °C at 60 °C and

72.02±0.12 °C at 72 °C, respectively, showing excellent temperature accuracy and stability. The initial temperature fluctuation before reaching the setting temperature could be further

reduced by optimizing the proportional-integral-derivative controller value in LabVIEW. ULTRAFAST THERMAL CYCLING AND NUCLEIC ACID AMPLIFICATION To determine maximum heating and cooling

rates, a thermal cycle was performed whereby the solution (here, 5 µL of PCR mixture covered with 30 µL of mineral oil) temperature was rapidly cycled between 55 °C and 95 °C, mirroring the

denaturation (95 °C) and annealing (55 °C) temperatures. Figure 4a shows the 30 ultrafast photonic cycles within 5 min. Using the thermal cycling result, heating and cooling rates were

calculated by measuring the temperature difference between successive temperature maxima and minima and then dividing by the time interval between them. The average rates and sample standard

deviations were obtained as shown in Figure 4b. The average heating and cooling rates obtained are 12.79±0.93 °C s−1 and 6.6±0.29 °C s−1, respectively. The amplification of λ-DNA was

performed to verify our photonic PCR method. After running PCR reactions as shown in Figure 4c, the amplicons were visualized by E-Gel® 2% agarose gels with SYBR SafeTM. Lane 1 represents

the 1 kb DNA marker, lanes 2 and 3 are the PCR products from ultrafast photonic PCR with different cycle numbers (94 °C for 0 s, 62 °C for 0 s), and lanes 4 and 5 contain positive controls

produced from standard thermal cycling condition (94 °C for 1 s, 62 °C for 1 s, 60 cycles) by a bench-top thermocycler (Bio-Rad C1000TM Thermal Cycler, Bio-Rad Laboratories Inc., Hercules,

CA, USA). Photonic PCR yielded a single 98-bp major band (lanes 2 and 3), indicating that the λ-DNA was successfully amplified using our ultrafast photonic PCR method. The weak band

intensity from the PCR product amplified by photonic PCR could be attributed to the lower amplification efficiency compared with a traditional bench-top thermal cycler. Currently, only the

thin Au film acts as a two-dimensional photothermal heater, leading to a temperature gradient in the solution and a potentially lower amplification efficiency. This limitation can be

improved by utilizing a three-dimensional substrate in the PCR chamber for uniform photothermal heating of the PCR mixture. Amplification time as well as reagent consumption could be further

reduced, simultaneously improving the efficiency of the PCR reaction by faster molecular diffusion and uniform solution temperature. CONCLUSION In conclusion, we demonstrated a novel

ultrafast photonic PCR through plasmonic photothermal heating of thin Au films driven by LEDs. We designed and fabricated a thin Au film-based light-to-heat converter to heat a PCR solution

over 150 °C by harnessing gold plasmon-assisted high optical absorption. We achieved ultrafast thermal cycling from 55 °C (annealing) to 95 °C (denaturation) within 5 min for 30 cycles with

ultrafast heating (12.79±0.93 °C s−1) and cooling (6.6±0.29 °C s−1) rates. Nucleic acid (λ-DNA) amplification using our ultrafast photonic PCR thermal cycler was successfully demonstrated.

We propose that this simple, robust and low-cost photonic PCR technique with ultrafast thermal cycling capability would be ideal for POC molecular diagnostics, because the photonic PCR

technique can meet the ‘ASSURED’ criteria:27 (i) Affordable: inexpensive system with a LED and lens; (ii) Smaller: compact and light PCR system without a heating block; (iii) Simple step

with disposable PCR chip; (iv) User-friendly interface with an LED driver and display; (v) Rapid and robust PCR without environmental stress; (vi) Equipment-free: consists of only an LED and

microcontroller modules with a cellphone camera; and (vii) Durable in harsh environments and power consumption is low. As the current set-up is based on only one PCR well, future work will

focus on integrating more wells and an LED array to allow high-throughput and multiplexed amplification, as well as optimizing the PCR reaction chamber for uniform heating. REFERENCES *

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16: 1062–1069. Article  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported in part by a grant from the Bill & Melinda Gates Foundation (Global Health Grant:

OPP1028785) and in part by the Global Research Lab Program (2013-050616) through the National Research Foundation of Korea funded by the Ministry of Science, ICT (Information and

Communication Technologies) and Future Planning. We thank Karthik R. Prasad and Nusrat J. Molla for helping with the LabVIEW programming for the photonic PCR thermal cycler. _NOTE: ACCEPTED

ARTICLE PREVIEW ONLINE 29 JUNE 2015_ AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Bioengineering, University of California, Berkeley, 94720, CA, USA Jun Ho Son, Byungrae Cho, 

SoonGweon Hong, Sang Hun Lee, Ori Hoxha, Amanda J Haack & Luke P Lee * Berkeley Sensor and Actuator Center, University of California, Berkeley, 94720, CA, USA Jun Ho Son, Byungrae Cho, 

SoonGweon Hong, Sang Hun Lee & Luke P Lee * Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, 94720, CA, USA Luke P Lee * Biophysics

Graduate Program, University of California, Berkeley, 94720, CA, USA Luke P Lee Authors * Jun Ho Son View author publications You can also search for this author inPubMed Google Scholar *

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this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Luke P Lee. ADDITIONAL INFORMATION Note: Supplementary Information for this article can be found on the _Light:

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_Light Sci Appl_ 4, e280 (2015). https://doi.org/10.1038/lsa.2015.53 Download citation * Received: 17 November 2014 * Revised: 21 January 2015 * Accepted: 28 January 2015 * Published: 31

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light-emitting diodes (LEDs) * molecular diagnostics * personalized medicine * plasmonics * point-of-care (POC) diagnostics * polymerase chain reaction (PCR)