Id |
Subject |
Object |
Predicate |
Lexical cue |
T28 |
0-4 |
Sentence |
denotes |
1.1. |
T29 |
5-21 |
Sentence |
denotes |
State-of-the-Art |
T30 |
22-101 |
Sentence |
denotes |
In the past, several chip-based DNA and RNA amplification devices are reported. |
T31 |
102-209 |
Sentence |
denotes |
It goes beyond the scope of this paper to discuss the state-of-the-art of DNA amplification chips in-depth. |
T32 |
210-298 |
Sentence |
denotes |
There are several good review papers written on this topic [12,13,14,15,16,17,18,19,20]. |
T33 |
299-371 |
Sentence |
denotes |
Readers are referred to these for a comprehensive overview of the field. |
T34 |
372-562 |
Sentence |
denotes |
In this paper, the state-of-the-art is divided into several discussion points, i.e., the heating method, the temperature control method, and the substrate material and fabrication technique. |
T35 |
563-605 |
Sentence |
denotes |
These points will be discussed separately. |
T36 |
606-672 |
Sentence |
denotes |
With respect to heat supply, different methods have been employed. |
T37 |
673-785 |
Sentence |
denotes |
Almassian et al. give a comprehensive overview of different possible heating methods in their review paper [12]. |
T38 |
786-935 |
Sentence |
denotes |
Not all of the mentioned methods are easy to implement in low-cost and portable lab-on-a-chip devices due to their bulkiness or implementation costs. |
T39 |
936-1045 |
Sentence |
denotes |
Examples of these rather difficult methods are using heating via induction, infrared, or microwave radiation. |
T40 |
1046-1173 |
Sentence |
denotes |
Others are not useful due ot their challenging temperature control, like with heating up the system using exothermic reactions. |
T41 |
1174-1257 |
Sentence |
denotes |
Within the field of DNA amplification, different mechanisms of amplification exist. |
T42 |
1258-1343 |
Sentence |
denotes |
Some are based on thermo cycling processes, e.g., PCR, whereas others are isothermal. |
T43 |
1344-1431 |
Sentence |
denotes |
The use of an isothermal amplification technique puts less requirements on the heaters. |
T44 |
1432-1625 |
Sentence |
denotes |
Isothermal processes are either truly isothermal or consisting of three different temperatures, as they have a thermal denaturation step before and a termination step after the elongation step. |
T45 |
1626-1775 |
Sentence |
denotes |
The switching between these temperature steps does not have to be as fast as with thermal cycling steps in, for example, PCR amplification reactions. |
T46 |
1776-1908 |
Sentence |
denotes |
The use of less temperature variations makes it easier to maintain the set temperature as there is less heating an cooling involved. |
T47 |
1909-2033 |
Sentence |
denotes |
Furthermore, it eliminates the use of a continuous flow approach in systems with low thermal conductivities, e.g., polymers. |
T48 |
2034-2108 |
Sentence |
denotes |
Therefore, it is easier to implement within lab-on-a-chip devices [17,21]. |
T49 |
2109-2266 |
Sentence |
denotes |
Isothermal DNA amplification reactions can already be performed by putting the chip on a commercially available hotplate [22,23] or Peltier elements [24,25]. |
T50 |
2267-2328 |
Sentence |
denotes |
However, these heating systems are bulky and power-consuming. |
T51 |
2329-2416 |
Sentence |
denotes |
Therefore, they are not useful for portable equipment or operation at remote locations. |
T52 |
2417-2482 |
Sentence |
denotes |
Miniaturizing heaters lowers the bulkiness and power consumption. |
T53 |
2483-2671 |
Sentence |
denotes |
Miniaturized heaters can be integrated as integrated resistive heaters, e.g., as deposited thin-film metal [26,27,28,29] or as laminated Cu foil [30], or as micro-Peltier elements [31,32]. |
T54 |
2672-2851 |
Sentence |
denotes |
These miniaturized heaters can be implemented directly onto the microfluidic chip [28] or on a different substrate and leter incorporated onto the microfluidic chip [33,34,35,36]. |
T55 |
2852-2975 |
Sentence |
denotes |
The geometry of such a heater contributes significantly to the uniformity of the heat distribution within the chip [26,37]. |
T56 |
2976-3102 |
Sentence |
denotes |
One method to accurately control the temperature is the use of a proportional-integral-derivative (PID) controlled thermostat. |
T57 |
3103-3235 |
Sentence |
denotes |
These PID controllers are coupled to the electrical heaters and use a thermocouple as feedback-loop to the controller [22,23,24,25]. |
T58 |
3236-3345 |
Sentence |
denotes |
There are various materials that can be used to fabricate lab-on-a-chip devices for DNA or RNA amplification. |
T59 |
3346-3481 |
Sentence |
denotes |
In the past 15 years, more than ten polymers, ceramic materials, and metals have successfully been used to fabricate such devices [15]. |
T60 |
3482-3561 |
Sentence |
denotes |
The major property playing a role here is the biocompatibility of the material. |
T61 |
3562-3650 |
Sentence |
denotes |
The surface of the microfluidic structure should not inhibit the amplification reaction. |
T62 |
3651-3804 |
Sentence |
denotes |
This biocompatibility can be an intrinsic property of the material or the surface can be modified or coated to achieve this [12,13,14,15,16,17,18,19,20]. |
T63 |
3805-3935 |
Sentence |
denotes |
One often used material is polydimethylsiloxane (PDMS) [22,23,31,32,34,35,38], which can be processed using soft lithography [39]. |
T64 |
3936-4053 |
Sentence |
denotes |
However, this is a fabrication technology used in academia and is not suitable for upscaling to mass production [40]. |
T65 |
4054-4157 |
Sentence |
denotes |
Fabrication methods suitable for mass production are thermoforming/embossing or injection molding [41]. |
T66 |
4158-4377 |
Sentence |
denotes |
One of the materials which is biocompatible and suitable for both industrial scale fabrication technologies is cyclic olefin copolymer (COC) [42], which is one of the materials used in the past as well [28,36,43,44,45]. |
T67 |
4378-4558 |
Sentence |
denotes |
Guckenberger et al. estimates the costs of injection molding of only 50 simple microfluidic devices on $47, but this becomes cheaper when the mass production stage is reached [41]. |
T68 |
4559-4632 |
Sentence |
denotes |
Another benefit of COC is the possibility to shape it using micromilling. |
T69 |
4633-4746 |
Sentence |
denotes |
This technique is a rapid prototyping technology and therefore very useful within proof-of-concept projects [41]. |
T70 |
4747-4835 |
Sentence |
denotes |
Integrating resistive metal tracks onto a COC substrate have also been done in the past. |
T71 |
4836-5055 |
Sentence |
denotes |
Some papers describe the use of a surface modification step done before metal deposition in order to enhance adhesion between the COC and the metal layer, like a pretreatment with plasma [46] or an organic solvent [47]. |
T72 |
5056-5138 |
Sentence |
denotes |
Other papers describe the direct deposition of metal onto the COC surface [28,48]. |
T73 |
5139-5238 |
Sentence |
denotes |
Chung et al. specifically, fabricated an amplification chip in COC with integrated Au heaters [28]. |
T74 |
5239-5369 |
Sentence |
denotes |
However, their system required heating from both sides as the used grade of COC has a glass transition temperature (Tg) of 130 °C. |
T75 |
5370-5473 |
Sentence |
denotes |
This COC could not withstand the required heater temperatures to have enough heat flux into the system. |
T76 |
5474-5608 |
Sentence |
denotes |
They had to heat up the heater to temperatures above 130 °C, which caused cracking of the heater tracks due to deformation of the COC. |
T77 |
5609-5713 |
Sentence |
denotes |
With their double-sided heating they ensured that the reaction mixture had the desired PCR temperatures. |
T78 |
5714-5868 |
Sentence |
denotes |
However, double-sided heating doubles the amount of metal required, increases the amount of fabrication steps, and therefore increases the price per chip. |