3 Review scientific paper  MIDEM Society Microfluidics: a review Borut Pečar, Drago Resnik, Matej Možek, Danilo Vrtačnik University of Ljubljana, Faculty of Electrical Engineering, Laboratory of Microsensor Structures and Electronics, Ljubljana, Slovenia Abstract: Microfluidics technologies have become a powerful tool in life science research laboratories over the past three decades. This review discusses three important segments of the field from origins and current status to future prospective: a) materials and microfabrication technologies from the field, b) research and development of essential microfluidic components and c) integration of components into complex microfluidic systems that will, according to some forecasts, play a key role in improving the quality of life for future generations. The most sophisticated microfluidic systems developed by now are Point-of-Care systems, that are based on Lab- on-Chip technologies. As these subfields are very extensive and go beyond the scope of this review, some carefully chosen additional review papers are provided. Keywords: microfluidics; materials; technologies; micropumps; flowmeters; microneedles; fuel steam reformers; microdosing systems; LOC; POC Mikrofluidika: pregled področja Izvleček: Mikrofluidne tehnologije so v zadnjih treh desetletjih postale nepogrešljivo orodje sodobne znanosti. Pregledni članek pokriva tri pomembne segmente področja: a) materiale in tehnologije za izdelavo mikrofluidnih naprav, b) raziskave in razvoj osnovnih mikrofluidnih komponent in c) integracijo komponent v kompleksne mikrofluidne sisteme, ki bodo po napovedi mnogih imeli ključno vlogo pri zagotavljanju višje kakovosti življenja prihodnjih generacij. Med najnaprednejše mikrofluidne sisteme uvrščamo sisteme za hitro analizo na samem mestu odvzema vzorca, ki temeljijo na tehnologijah »laboratorija na čipu«. Ker področja teh sistemov presegajo obseg tega dela, smo podali nekaj dodatnih skrbno izbranih preglednih člankov s področij. Ključne besede: Mikrofluidika; materiali; tehnologije; mikročrpalke; merilniki pretoka; mikroigle; mikroprocesorji goriva; mikrodozirni sistemi; LOC; POC * Corresponding Author’s e-mail: borut.pecar@fe.uni-lj.si Journal of Microelectronics, Electronic Components and Materials Vol. 51, No. 1(2021), 3 – 23 https://doi.org/10.33180/InfMIDEM2021.101 1 Introduction Since Richard Feynman’s thought-provoking 1959 speech “There’s Plenty of Room at the Bottom” , human- ity has witnessed the most rapid technology devel- opment in its history—the miniaturization of devices [1]. Microelectronics was one of the most significant enabling technology of the last century. Until recently, the development of miniaturized transducer and flu- idic devices lagged behind this miniaturization trend in microelectronics. In the late 1970s, silicon technology was extended to 3-D machining of mechanical micro- devices, which later came to be known as microelec- tromechanical systems (MEMS) [2]. The development of microvalves, micropumps and microflow sensors in the late 1980s dominated the early stage of microflu- idics. Since then, microfluidics is rapidly emerging as a breakthrough technology that finds applications in di- verse fields ranging from biology, chemistry, pharmacy, biomedicine to information technology and optics [3]. Microfluidics can be defined as the science and tech- nology of manipulating small amount of fluids in chan- nels with dimensions of tens to hundreds of microm- eters [4]. Due to their small scale, microfluidic devices have advantages over conventional devices. Among the advantageous properties are, large surface area to volume ratio, which lowers the diffusional distances dramatically and very low reagent consumption [4]. Consequently, they can enhance the reaction efficien- cy, reduce the analysis time, simplify procedures and provide highly portable systems [5]. Furthermore, they can be easy to use, cheap to fabricate and disposable [6]. 4 B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 The purpose of this review is to give a broad overview of the field, summarizing recent advances in materials and microfabrication technologies in relation to the field, addressing the essential microfluidic components and outlining the integration of components into wide variety of miniature-sophisticated systems capable of performing even the most demanding tasks. The re- mainder of the review paper is organized as follows: Section 2 covers relevant materials and technologies for microfluidic applications. Correspondingly, silicon, glass and polymer materials will be addressed. Focus will be on precedent research activities in the field of reactive and deep reactive ion etching of silicon, dry and wet etching of glass and polymers micromachin- ing. Since most microfluidic devices require bonding of substrates with additional functional layers to create enclosed volumes, various bonding processes such as silicon-silicon, silicon-glass and thermoplastic–polydi- methylsiloxane bonding will be reviewed. Section 3 is devoted to microfluidic components. First, an overview of micropumps, microvalves and micro- actuators will be given. Regarding micropump inte- gration into modern polydimethylsiloxane (PDMS) microfluidic systems that require miniaturization and autonomy, focus in this subsection will be on PDMS elastomeric micropumps, especially on microthrottle pumps and peristaltic micropumps. Moreover, addi- tional micropump functionalities such as bidirectional pumping and low pulsating flow will be discussed. Sec- ond, flowmeters for microfluidic applications will be outlined. Various flowmeter measurement principles and reported functional devices will be summarized. Focus will be on thermal mass microflowmeters, which have been fabricated on a wide variety of substrates. Here, past efforts which led to improvements of flow- meters sensitivity and response time, will be reviewed. Third, heaters, coolers and temperature sensors for mi- crofluidic platforms will be addressed. Temperature is a critical parameter in managing many physical, chemi- cal and biological microfluidic applications therefore many interesting approaches to this issue have been proposed. Fourth, overview of microneedles will be made. The microneedles are essential in microfluidic systems for transdermal drug delivery applications. They have been made from various materials using different fabrication processes and were applied us- ing many approaches to enhance the drug delivery through the skin. Section 4 deals with microfluidic systems, where mi- crofluidic components discussed in Section 3 are inte- grated and functionally interconnected into advanced microfluidic platforms. Such systems can execute even the most demanding tasks required by the modern sci- ence. Here, several most representative microfluidics systems will be addressed, starting with micro fuel re- formers, more specific with methanol steam reformers, which convert methanol solution into a hydrogen rich gas needed for fuel cells to generate electricity. Many different approaches related to this field and which have been reported in the last sixteen years and greatly im- proved conversing efficiency, will be reviewed. Tempera- ture control and fuel supply for micro fuel reformers will be also addressed from the microfluidic aspect. Next, microdosing systems for drug delivery, which typically comprises several integrated microfluidic components such as micropumps, microfluidic channels, reservoirs and microneedle arrays, will be suggested. In this sub- section, innovative bubble-type, shape memory alloy and other non-mechanical microdosing systems will also be tackled. At the end of the Section 4, Lab-on-Chip (LOC) and Point-of-Care (POC) systems, which are the most sophisticated microfluidic systems developed by now, will be described. As these subfields are very exten- sive and go beyond the scope of this review, we will pro- vide some additional carefully chosen review papers in conjunction with foodborne pathogens detection, drug development, stem cell analysis, cardiovascular disease prevention, infectious disease diagnostics etc. Few ex- amples of successful transformations of LOC technolo- gies into actual POC devices will follow. Our conclusions are drawn in the final Section 5. 2 Materials and technologies for microfluidic applications Microfluidic devices originate from microelectronics fabrication sector [7]. Silicon has been most frequently used as the base substrate material for fabrication of microfluidic devices in the past. However, silicon sub- strate is relatively expensive and optically opaque at certain wavelengths, limiting its applications in optical detection. To combat these shortcomings, glass and polymer materials have been introduced into micro- fluidic devices [7]. Polymer materials in microfluidics include polymethylmethacrylate (PMMA), polystyrene (PS), polycarbonate (PC), polyethylene terephthalate (PET), polyethylene (PE) and PDMS. Amongst these polymer materials, PDMS has been one of the most widely used materials for fabricating microfluidic de- vices due to its flexibility in moulding and stamping, optical transparency and biocompatibility [8]. The literature on microfabrication techniques for mi- crofluidic applications shows a variety of approaches. Silicon microfabrication is a process that involves the removal of silicon material using wet chemical or dry plasma etching processes such as reactive ion etch- 5 ing (RIE) or deep reactive ion etching (DRIE) in order to create 3-D silicon or non-silicon microstructures for microfluidic devices [9]. An excellent overview of tech- niques involved in advanced microfabrication of silicon was written by Resnik et al. [10]. RIE has limitations in producing deep vertical silicon structures and is more often used for etching thin inorganic and organic lay- ers. To overcome these limitations, Vrtačnik et al. [11] studied and optimized RIE of deep silicon microchan- nels for microfluidic applications. Optimal set of etch- ing parameters resulted in high silicon etching rate (2 µm/min), good anisotropy close to 90°, lateral undercut less than 6% and surface roughness of less than 1 µm. DRIE process was first introduced by Bosch in the mid- nineties and commercialized by several equipment manufactures. DRIE is capable of forming vertically smooth sidewalls at high etch rate (>10 µm min -1 ) [12]. An improved DRIE process for ultra high aspect ratio silicon trenches with reduced undercut was reported by Owen et al. [13]. By ramping process pressure, etch power and switching time, authors were able to produce 5.7 μm trenches with an aspect ratio of 70. Giang et al. [14] reported microfabrication of shallow concave pits or deep spherical cavities in PDMS using DRIE silicon molds. Effect of DRIE process parameters on the surface mor- phology and mechanical performance of silicon struc- tures were studied by Chen et al. [15]. Authors designed and performed a set of experiments to fully characterize surface morphology and mechanical behavior of silicon samples produced with different DRIE operating condi- tions. Similarly, Vrtačnik et al. [16] performed optimiza- tion of Bosch process for DRIE silicon microstructures. After optimization, directional Si etching resulted in etch rate of 3.0 µm min -1 , profile angle close to 90°, roughness of sidewalls less than 150 nm and aspect ratio higher than 10 (see test pillar structures in Fig. 1). Figure 1: SEM image of test Si pillar structures fabri- cated by optimized DRIE etching. Source: Vrtačnik et al. [16]. For glass microfabrication, three major groups of tech- niques are used: mechanical treatment, dry and wet etching. Mechanical treatments include traditional drilling, ultrasonic drilling, electrochemical discharge and powder blasting. The dry etching technique of Py- rex glass using SF 6 was reported by Li et al. [17]. Authors fabricated small through holes in Pyrex glass wafers in- tended for electrical feed-throughs. The disadvantage of glass etching by DRIE was relatively low etching rate, which extended etching time to 10 hours. Wet etching of glass is the most common method and was reported by Stjernström and Roeraade [18]. In this work, capil- lary electrophoretic chips were fabricated in glass us- ing photoresist as the mask layer. Excellent review on wet etching of glass for microfluidics was given by Ili- escu [19]. For polymers micromachining, soft lithography [20], hot embossing [21], injection molding [22], casting [23], laser micromachining [24] and milling [25] are the most commonly applied. Most microfluidic devices require bonding of substrates to create enclosed volumes for fluid handling. There- fore, various bonding processes have been developed in the last thirty years to mutually bond silicon, glass and polymer layers. Direct silicon wafer-to-wafer bond- ing without the use of intermediate adhesive layer was employed by Thompson et al. [26]. To heat silicon wa- fers above 1000 °C before they were brought into con- tact, electromagnetic induction was applied. Typical power consumption was in the range of 900 to 1300 W for silicon wafers with the diameter values between 75 and 100 mm. Low temperature direct bonding of sili- con and silicon dioxide by surface activation method was investigated by Takagi et al. [27]. Neutralized high- energy Ar beam etching (FAB 110, Atom Tech, UK) was used to create a clean surface which had strong bond- ing ability. The specimens were brought in contact and bonded in vacuum. Modified process for low tempera- ture direct silicon bonding was reported by Quenzer and Benecke [28]. After a hydrophilic pretreatment, a diluted solution of sodium silicate in water was spun onto one of the two surfaces and the two wafers were brought into contact. Resnik et al. [29,30] studied di- rect bonding of (111) and (100) oriented silicon wafers performed in the range of temperatures from 80 to 400 °C in nitrogen, oxygen and low vacuum atmosphere. Authors found that bond strengthening in nitrogen ambient exhibited about 25% higher tensile strength compared to bonding performed in vacuum or oxygen. The combination of glass and silicon is a common choice for fabrication of microfluidic systems. Glass can be bonded to silicon with fusion bonding process or anodic bonding process. Fusion bonding process B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 6 as applied by Xiao et al. [31] comprises thorough sili- con wafers cleaning during which Si–O–Si bonds of the native oxide on the silicon surface.The Si–O–Si bonds on the glass surface are cleaved by the attack of OH − and H + ions. The new Si–OH groups on wafer surfaces are formed after the silicon and glass wafers are put together face to face in a clean room at room temperature. Resnik et al. [32,33] focused on issues ac- companied with defect free anodic bonding of multi- layer glass-Si-glass microfluidic structures. Pyrex 7740 and Borofloat 33 glass wafers were bonded to bare Si and Si/SiO2 terminated structures in the tempera- ture range 350-400 °C in the air ambient under applied anodic voltages between 800-1200 V. Authors concluded that appropriate configuration of bonding electrodes was mandatory to avoid debonding effects in multi- layer bonding process. Thermoplastic–polydimethylsiloxane assemblies in the field of microfluidics gained popularity in the last ten years [34]. Many strategies for plastic–PDMS bonding have been previously reported, such as sol–gel coating approach, chemical gluing approach and organofunc- tional silanes approach [35, 36]. First approach requires a multiple coating procedures as well as a complex technology. Second approach creates chemically robust amine–epoxy bonds at the interface at room tempera- ture, however, two silane-coupling reagents are required and both surfaces had to be oxidized prior to chemical modification. Third approach requires only one coupling agent. In this approach, the most widely used organo- functional silane is 3-amino propyltriethoxysilane (APT- ES), aminosilane frequently employed in covalent bond- ing of organic films to metal oxides [37]. Pečar et al. [38] studied, optimized and applied two room-temperature bonding processes for thermoplastic - PDMS polymer covalent bonding based on organofunctional silanes APTES and amine-PDMS linker (Fig. 2). Both bonding processes were applied on piezoelectric micropumps where glass substrate was replaced by thermoplastic substrate. Water initiated the hydrolysis of covalent bonds established via the modified APTES bonding process while micropumps employing amine- PDMS linker exhibited no deterioration in their perfor- mance after eight weeks of continuous operation. 3 Microfluidic components 3.1 Micropumps The most often encountered components in microflu- idic systems are micropumps [39]. They are incorporat- ed into the system separately as discrete components or integrated into the microfluidic platform. Division of micropumps based on Krutzch classification [40] is shown in Fig.3. Micropumps employing displacement principle ex- ert pressure forces on the working fluid through one or more moving boundaries, while the onesemploy- ing dynamic principle add energy to the working fluid in a manner that increases either its momentum or its pressure. First, reciprocating micropumps require valves for its operation. Passive valves operate based on the pressure gradient, while active valves require outside actuation. In 1988, van Linte et al. [41] intro- duced diaphragm passive check valve. Seven years latter, Carrozza et al. reported ball valve [42]. Each ball valve consisted of a cylindrical chamber connected to a hemispherical chamber, which contained a mobile ball. First cantilever flap was reported by Koch et al. in 1998 [43]. For this flap, deep boron diffusion together with KOH etching was employed. Recently, Pečar et al. [44] proposed venous-valves micropump with valves that mimic the operation of biological venous valves. Next, reciprocating micropumps require an actuator to perform pumping function. For this purpose, piezo- Figure 2: Process flow for thermoplastic (TP)-PDMS co- valent bonding via organofunctional silanes e.g. APTES or amine-PDMS linker. Formation of Si–OH groups on both surfaces is provoked by oxygen plasma. Covalent bond is established when both surfaces are brought in contact. Source: Pečar et al. [38]. B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 7 electric, electrostatic, electromagnetic, shape memory alloy and pneumatic or thermopneumatic actuators have been applied. Piezoelectric actuation with lead zirconate titanate (PZT) has been widely utilized for mi- cropump actuation due to small size, low power con- sumption, absence of electromagnetic interference and relatively low fabrication costs [45]. An effective method for reducing the excitation signal amplitudes in piezoelectric micropumps might be the use of high- ly efficient piezoelectric materials. The microcylinder pumps employing piezoelectric actuators based on relaxor-ferroelectric 0.57Pb(Sc 1/2 Nb 1/2 )O 3 –0.43PbTiO 3 (PSN–43PT) was reported by Pečar et al. [46]. The per- formance results indicate that PSN–43PT is a promising material for high performance portable, wearable, or implantable micropump applications, where operation amplitude has to be kept low for reasons of safety and smaller plus more economic driver circuits. A special subgroup of displacement micropumps are pumps without check valves (fixed geometry, throt- tle, peristaltic). Rectifying effect is accomplished (a) by geometrically asymmetric channels or structures such as diffusers [47], Tesla valves [48] or oscillating sharp- edge structures [49] shown in Fig. 4, (b) by principle of peristaltics or (c) by use of throttle rectifying elements. Over the last decade, PDMS has become virtually the default material for forming microfluidic devices due to its simplicity of casting and bonding to the glass substrate [50]. Regarding micropump integration into modern PDMS microfluidic systems that are required to be miniature and autonomous, micropumps fabri- cated on PDMS elastomer are considered as the most appropriate. Incorporation of PDMS micropumps into microfluidic systems can be found widely in the recent literature. Wang et al. [51] proposed a check valve mi- cropump for implantable drug delivery application. A magnetic nanoparticle-PDMS composite membrane is actuated in a magnetic field to release a drug. For the same application, Gadad et al. [52] reported a dual- chamber valveless PDMS micropump. It produced 1.7 ml min -1 of water flowrate at excitation frequency of 14.8 Hz. Kawun et all. [53] reported a thin PDMS noz- zle/diffuser micropump for biomedical applications. The pump comprised a cast PDMS body, a spin coated PDMS membrane and commercial silicone tubing, all bonded together with PDMS. The pump produced a peak flowrate of 135 μl min -1 and a maximum back- pressure of 2.5 mbar at excitation frequency of 12 Hz and duty cycle of 25%. Chien et al. [54] proposed a ball valve PDMS/PC micropump on LOC microfluidic devic- es. It comprised a pair of ball valves implemented by confining a micro-ball within nozzle. Micropump ex- hibited maximum flowrate of 389 ml min -1 and a maxi- mum backpressure of 41.5 mbar. Regarding advanced microfluidic systems that require additional pumping capabilities and functionalities, several solutions were recently proposed. In 2018, Ye et al. [55] reported a PDMS check valve improvement for piezoelectric PDMS pumps. Authors achieved a con- siderable increase in the micropump flowrate perfor- mance by adding a blocking edge over conventional polydimethylsiloxane (PDMS) check valve. Generally, micropumps drive the fluid in only one direction. How- Figure 3: Division of micropumps based on Krutzch classification [40] where throttle and peristaltic pumps were additionally assigned to “valves” category. Figure 4: Acoustic streaming phenomenon around the tip of a tilted oscillating sharp-edge structure in acou- stofluidic pumping device actuated by piezoelectric transducer. Source: Huang et al. [49]. B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 8 ever, bidirectional capability is an important feature in the development of chemical analysis especially in the fluid handling application such as mixing, circulation and metering [56]. For instance, in a chemical analysis, to mix two chemical compounds, a single directional flow micropump needs an additional active rotational mechanism to create turbulent flow in mixing process. With the bidirectional flow functionality, the microflu- idic system can be made in more efficient and com- pact structure, which merits from reducing the chemi- cal analysis time and complexity. Recently, a research group from Malysia [57] reported a PDMS bidirectional flow dual-chamber micropump for LOC applications. Authors implemented a dispersing depth between the microchannel chamber and inlet/outlet channel in or- der to achieve a bidirectional flow. For microfluidic systems where steady, low pulsating flow is required, a PDMS micropump system with ad- ditional PDMS fluidic capacitor was proposed [58]. Two single pneumatic micropumps connected in paral- lel exhibited maximum flowrate of 496 μl min -1 . It was shown, that the PDMS structure with its elastic me- chanical properties smoothened pulsating flow with a smoothing factor of 0.6. In addition, Gidde and Pawar [59] addressed PDMS material properties and their in- fluence on PDMS micropumps performance. One sub-group of micropumps that does not employ check-valves are peristaltic micropumps. Conventional piezoelectric peristaltic micropumps comprise a series of sequentially actuated segments that deform fluidic channel on the principle of peristalsis to induce a net flow. The first piezoelectric peristaltic micropump with three piezoelectric actuators was reported by Smits in 1990 [60]. In 2003, Berg et al. [61] reported first peristal- tic micropump with two piezoelectric actuators. Here, an established mechanical traveling wave was induced by a proper signal phasing of two actuation sequences. Such provoked flow-rates were comparable to three- stage peristaltic micropumps. A two-stage micropump was patented in 2010 (U.S. 20100059127 A1). A first pi- ezoelectric peristaltic micropump with a single piezo- electric actuator was reported by Pečar et al. [62]. The fabricated prototypes featured high water / air flowrate performance (up to 0.24 ml min −1 /up to 0.84 ml min −1 ) and backpressure performance (up to 360 mbar/up to 80 mbar). Furthermore, bubble tolerance and self- priming capability have been proved, together with valve regime of operation that enables sealing of the fluidic path when appropriate dc voltage was applied. Another sub-group of micropumps that does not em- ploy check-valves are throttle micropumps [63]. Their main advantage is high tolerance to clogging caused by mechanical particles or aggregates in the pumping medium, omitting the need for filters, which introduce significant pressure drop and increase system com- plexity. Furthermore, incomplete closing of rectifying elements (throttling) prevents damage to sensitive bio- logical samples. Compared to peristaltic micropumps, microthrottle pumps exhibit superior backpressure and flowrate performance. A novel design of a strip- type microthrottle pump with a rectangular actuator geometry was proposed by Pečar et al. [64], with more efficient chip surface consumption compared to ex- isting micropumps with circular actuators. Measured characteristics proved expected micropump opera- tion, achieving maximal flow-rate 0.43 mL min −1   and maximal backpressure 12.4 kPa at 300 V excitation. In 2014, Pečar et al. [65] introduced a novel concept of microthrottle pump, named “microcylinder pump”. Improved version of microcylinder pump was embed- ded in professional housing (see Fig. 5). Novel concept offers numerous advantages over conventional micro- throttle design including self-priming ability, high level of bubble tolerance, inhibition of the cavitation occur- rence and valve regime of operation. 3.2 Flowmeters Flowmeters are prerequisite for proper operation of a wide range of microfluidics devices. Four measurement principles are frequently employed in these devices, namely thermal dilution in a flow stream, transit time measurement of a tracer injected into the flow, pres- sure difference measurement across a restriction and force measurement on an element placed in the stream [66]. Figure 5: Piezoelectric microcylinder pump in a profes- sional housing. Wang et al. [67] demonstrated an electrolytic-bubble- based approach. Authors measured pressure differ- ence (and thus flow rate) in real time by simultaneously generating two gas bubbles electrochemically along a B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 9 channel. Nezhard et al. [68] fabricated PDMS microcan- tilever flow sensor suitable for integration in LOC. The author’s attention was focused on a high aspect ratio microcantilever, which was fabricated using a multilay- er PDMS fabrication process. The device was capable of measuring flowrates as low as 35 µL min -1 . Amnache et al. [69] reported microflowmeter for moderate flow- rates of gases based on a differential pressure meas- urement. It consisted of a microfabricated silicon–glass rectangular micro-orifice plate and two pressure sen- sors. Richter et al. [70] studied microflowmeter based on the micromachined electrohydrodynamic injection pump. Method is based on the measurement of the ion transit time between two grids. Another unique ap- proach was demonstrated by Accoto et al. [71]. Their PDMS microflowmeter for closed-loop management of biological samples detected the streaming poten- tial associated with the liquid flow by means of inter- face between polymeric surfaces and polar liquids and yielded a linear response. Nie et al. [72] reported mi- croflowmeter which operated in the range of 30–250 nl min −1 for water. The principle was based on determining the evaporation rate of the liquid via reading the number of wetted pore array structures in a microfluidic system, through which continuous evaporation took place. Thermal detection principles are widely used for air and gas flow sensors. An excellent state-of-the-art review in the field of thermal mass flowmeters was given by van Oudheusden [73] with the references therein. Typically, thermal mass flowmeter comprises a heating element which creates a local temperature increase and sens- ing elements that aim to measure the distortion in the temperature profile along the channel as induced by the fluid flow [74]. Several Si-based thermal flow sen- sors are currently available for measuring gas and liq- uid flowrates [75-77]. To enhance the device sensitiv- ity and to improve corresponding response time, heat dissipation to the substrate should be minimized [78]. Due to the high thermal conductivity of the silicon substrate, various schemes have been implemented in order to achieve the thermal isolation of the sens- ing elements, such as freestanding structures, vacuum cavities and formation of porous silicon, or thin silicon nitride membranes [78]. Baek et al. [79] reported a vac- uum-isolated thermal microflowmeter for in vivo drug delivery. Flowmeter used an arsenic-doped polysili- con heater/sensor, supported on dielectric membrane over the flow channel. Heater/sensor was capped by a vacuum-sealed microchamber to minimize heating of the surrounding structure and maximize heating effi- ciency. To provide highly effective thermal isolation of the heating/sensing elements without the need for above- mentioned thermal insulation approaches and addi- tional MEMS fabrication processes, attempts have been made to substitute silicon substrate with organic ma- terials such as  epoxy-based negative photoresist SU8 [79], polyimide [80, 81], Kapton® [82] and parylene [83]. Pečar et al. [84] proposed thermal microflowmeter for microfluidic applications where a PDMS elastomer was employed as heat insulative substrate between heater/ sensor elements (Fig. 6). Device is suitable for integra- tion on common microfluidic platform with additional PDMS fluidic components. 3.3 Heaters, coolers and temperature sensors for microfluidic platforms Modern microfluidic systems require integration of multiple functions within a compact platform. One of such functionalities is the control of temperature, either in terms of profile or accessible range [85]. The temperature is a critical parameter in managing many physical, chemical and biological microfluidic applica- tions such as Polymerase Chain Reaction (PCR), Electro- phoresis (TGF), digital microfluidics, mixing and protein crystallization. The most commonly employed heating or cooling technologies exploit Peltier element, micro- waves, pre-heated liquids, integrated wires or lasers, chemical reactions and Joule heating. Matsu et al. [86] reported application of temperature gradient concentrator in a PDMS/glass hybrid microflu- idic chip. By the combination of a temperature gradi- ent along a microchannel using two Peltie elements, an applied electric field, and a buffer with a temperature- dependent ionic strength, Oregon Green 488 carbox- ylic acid was concentrated approximately 30 times as high as the initial concentration. Kempitiya et al. [87] explored the potential of microwave heating for appli- Figure 6: Thermal microflowmeter for microfluidic ap- plications and piezoelectric micropump on common substrate by Pečar et al. [84]. PDMS elastomer is em- ployed as heat insulative substrate between heater/ sensor elements. B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 10 cations requiring parallel deoxyribonucleic acid (DNA) amplification platforms. For this purpose, authors de- livered microwave power at 6 GHz to the chamber via copper transmission line in a microstrip configuration. Temperatures up to 72 °C were achieved with less than 400 mW power consumption. An approach by using preheated and precooled liquids to generate a linear temperature gradient across a series of samples was employed by Mao et al. [88]. The three channel device (see Fig. 7 ) comprises a sandwich of glass and PDMS layers. Hot and cold fluids were introduced through the brass tubing using standard water bath circulators. The advantages of optical heating with laser are absence of the electric connections and the heating locations are more controllable comparing to the resistive elec- trodes. Optical approach was employed by Zhang et al. [89]. They used continuous wave laser induced heat to substitute microvalves and micropumps in microfluidic platform. Authors demonstrated effective blocking of microfluidic channels and bi directional pumping of fluid at a flow rate of 7.2–28.8 μl h −1 . The interesting approach to heating and cooling in mi- crofluidics, especially in PCR, was proposed by Guijt et al. [90]. In that work, chemical and physical processes were employed to locally regulate temperature. Cool- ing and heating of the microchannel was achieved by evaporation of acetone (endothermic process) and by dissolution of concentrated sulfuric acid in water (exo- thermic process), respectively. Figure 7: Three-channel device using preheated and precooled liquids by Mao et al. [88]. Reprinted with per- mission from [88]. Copyright (2019) American Chemical Society. Regarding Joule heating, Mavraki et al. [91] reported low cost microfluidic device with integrated micro- heaters on a thin flexible polymeric substrate suitable to perform DNA amplification on a chip. The heating/ sensing elements were formed on the Cu layer on the Pyralux substrate. Electrical measurements proved the functionality of the microheaters both as temperature sensors and thermal elements. Selva et al. [92] demon- strated Joule heating with electrical resistors that were fabricated by evaporating chromium (15 nm) and gold (150 nm) on the glass wafer. By applying improved op- timization algorithms, the shape of resistors was opti- mized to generate high-temperature gradients with a linear temperature profile. Hserh et al. [93] proposed a new approach to increase the temperature uniform- ity inside a microthermal cycler, especially for PCR, by using new array-type microheaters with active com- pensation units. In this study, platinum was used as material for the microheaters and the temperature sen- sors. Resnik et al. [94] reported thin film Ti/Pt heaters and integrated temperature sensors on a Si microflu- idic platform (Fig. 8). Heaters and sensors were fabri- cated by the combination of DC sputtering, lift-off process and thermal annealing of the deposited layers. Heater was able to provide vaporization of input liquid between 120 and 150 ◦C. Integrated Pt temperature sensors exhibited a typical TCR of 2200 ± 100 ppm/°C when annealed at 700 °C and proved stable during the prolonged operation. 3.4 Microneedle arrays Microneedles are essential in microfluidic systems for drug delivery application. They are used for delivering drug through the transdermal route and for overcoming the limitations of conventional drug delivery approaches [95]. Figure 8: fabricated microfluidic platform with the me- andered microchannel on the rear side (left) and a Ti/ Pt heater and sensors on the front side (right) in PTFE housing. Microneedles differ in design and composition. Cur- rently, four distinct types of microneedles exist [96]: (a) solid microneedles often used to pretreat the skin prior to the administration of bioactives; (b) drug-coated sol- id microneedles for drug dissolution in the skin; (c) hol- low microneedles for drug injections; and (d) dissolving microneedles prepared from a polymer in which the drug or vaccine is embedded in the polymer matrix for the controlled or rapid release in the skin. In the early B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 11 period microneedles used for drug delivery were made from silicon wafers through deep reactive ion etching and photolithography [97, 98]. Chen et al. [99] and Lin and Pisano [100] reported silicon microneedles with biodegradable tips and 6 mm-long silicon micronee- dles for localized chemical analysis, respectively. In the last fifteen years, various titanium [101], stainless steel [102], glass, ceramics [103] and polymeric [104-106] mi- croneedles were introduced. Since the diffusion of substances through the skin lay- ers is a gradual process, microneedles systems use vari- ous approaches to enhance the drug delivery through the skin. Common methods practice electroporation, iontophoresis, sonophoresis [107], use of chemical en- hancers [108], high velocity jet injection, ablation, tape stripping, vibratory, or impact assisted approaches [109]. Resnik et al. [110] reported investigation of skin penetration efficacy by a silicon microneedle array. When impact assisted penetration of microneedle ar- ray was applied instead of incremental increase of ap- plied force, a significant impedance reduction of up to 50% on animal skin and 95% on human skin was ob- tained, which was a strong evidence of successful skin penetration. Several publications have appeared in recent years documenting many successful microneedle arrays ap- plications. In recent study, Deng et al. [111] for the first time evaluated the ability of solid silicon micronee- dle array for punching holes to deliver cholesterol- modified housekeeping gene (GAPDH) siRNA to the mouse ear. Such development of siRNA therapies has significant potential for the treatment of skin condi- tions (alopecia, allergic skin diseases, hyperpigmenta- tion, psoriasis, skin cancer, pachyonychia congenital) caused by aberrant gene expression. In 2020, Kim et al. [112] delivered coronaviruses-S1 subunit vaccines by dissolving microneedle array. MERS-S1 subunit vac- cines elicited strong and long-lasting antigen-specific antibody responses in mice, implyingthat it is a prom- ising immunization strategy against coronavirus infec- tion. For diabetic patients, insulin delivery using hollow microneedle array is very desirable. In experimental study of in vivo insulin delivery conducted by Resnik et al. [113], two types of fast-acting insulin were used to provide evidence of efficient delivery by hollow mi- croneedle array to a human subject (Fig. 9). Results of in vivo insulin delivery proved successful infusion of fast- acting insulin as shown by blood analyses. Recently, a new cell transplantation method to inject donor cells into tissues to treat certain diseases using an array of ultrathin microneedles was reported by Iliescu et al. [114]. Here, an array of silicon microneedles was suc- cessfully employed to inject fluorescently labeled Mar- din–Darby canine kidney cells into rat liver tissue. Figure 9: SEM image of hollow Si microneedles array fabricated by DRIE etching (a) and assembled microin- jection device with 100 microneedles (b) view from the rear side, showing fluidic connection, distribution cav- ity and through holes. Source: Resnik et al. [113]. 4 Microfluidic systems 4.1 Micro fuel reformers With the rapid advancement in technology, everyday application of electronic devices such as laptops, cell phones, music players and other portable devices has become inevitable. Li-ion batteries are good options for providing the required energy for such devices. However, they require time-consuming recharging and are generally difficult to be recycled [115]. In contrast, liquid hydrocarbon fuels contains enormous energy per volume and weight compared to the best existing batteries, refueling is more convenient than recharging and recyclable fuel cartridges are more environmental- ly friendly. From the above reasons, various approaches were proposed to convert liquid hydrocarbon fuels to electrical power at micro-scale, such as using miniature gas turbine generators, fuel cells, thermo electric gen- erators, a thermophotovoltaic generator and a thermi- B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 12 onic generator [116]. Among them, a miniature hydro- gen fuel cell system combined with a microfluidic fuel reformer seems one of promising candidates to power mobile devices. Microfluidics technologies enabled fabrication of catalyst coated microchannels with large surface area to volume ratio, which greatly increased fuel conversion efficiency. Methanol is one of the best choices for the hydrogen production since it is a liquid at room temperature and can be easily stored in small cartridges premixed with water. In 2004, Pacific Northwest National Laboratory devel- oped a micro integrated methanol reformer, which was equipped with a microcombustor, an evaporator and a CO methanizer [117]. It was small enough for port- able electronics but limited to 3.55 ml min -1 hydrogen production. Kamura et al. [118] reported a miniaturized methanol reformer with Cu/ZnO/Al 2 O 3 catalyst-based microreactor shown in Fig. 10. The microreactor (25 × 17 × 1.3 mm 3 ) was constructed from glass and silicon substrates. The use of the high-performance catalyst allowed for higher hydrogen production rates than us- ing a commercial Cu/ZnO catalyst. The microreactor was demonstrated to be capable maintaining a hydro- gen production rate suitable for powering 1 W-class devices. Hsueh et al. [119] presented a numerical investigation of the transport phenomena and performance of a plate methanol steam micro-reformer with serpentine flow field as a function of wall temperature, fuel ratio and Reynolds number. Jeong et al. [120] studied hydro- gen production by steam reforming of methanol  over Cu/Zn-based catalysts. Among the catalysts tested, Cu/ZnO/ZrO 2 /Al 2 O 3   exhibited the highest methanol conversion and the lowest CO concentration in the outlet gas. Figure 10: Individual glass wafers of MEMS methanol reformer heated by decomposition of hydrogen perox- ide. Source: Kim et al. [121]. Kim et al. [121] proposed micro methanol reformer with a heat source. The micro system consists of the metha- nol steam-reforming reactor, the hydrogen peroxide catalytic decomposition reactor and a heat exchanger between the two reactors. Catalyst loaded supports were inserted in the cavity made on the glass wafer. The total hydrogen production rate was 23.5 ml min -1 . This amount of hydrogen can produce 1.5 W of power on a typical proton-exchange membrane fuel cells. To improve the energy conversion of a  micro-chan- nel reactor, Mei et al. [122] proposed and fabricated an innovative microchannel catalyst support with a micro- porous surface. Results showed that the microchannel catalyst support with micro-porous and non-porous sur- faces had a hydrogen production rate of 18.07 ml min-1 and 9.65 m min-1, respectively at 573 K under the inlet flowrate of 30 μl min-1. Huang et al. [123] studied the fractal channel pattern design and the gradient catalyst layer in relation to their effects on the performance of a methanol micro steam reformer. Compared to a uniform catalyst layer, the fractal design effectively increased the conversion ratio by 8.5% and decrease CO by 11% when the inlet liquid flow rate was fixed at 1.0 cc min-1. Recently, Sarafraz et al. [124] conducted series of experi- ments for the hydrogen production via steam reforming of methanol with Cu–SiO2 porous catalyst coated on the internal walls of a micro-reactor with parallel micro- passages. Wang et al. [125] proposed a partial oxidation methanol micro reformer with finger-shaped channels for low operating temperature and high conversing effi- ciency. Micro reformer supplied hydrogen to fuel cells by generating 2.23 J min-1 for 80% H2 utilization and 60% fuel cell efficiency at 2 ml min-1 of supplied reactant gas. Figure 11: Si based micro catalytic methanol–oxy- gen combustor with thin  film nanostructured Pt/ CeO 2 catalyst in microchannels. To maintain the required reactions taking place in micro reformer unit, a micro combustor is commonly B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 13 employed. The most convenient approach is to uti- lize the same energy source (methanol) for steam re- forming process and for catalytic combustion. In this case the methanol–air or methanol–oxygen mixture should be provided for combusting process. Corre- spondingly, Resnik et al. [126] studied Si based micro catalytic methanol–oxygen combustor with thin film nanostructured  Pt/CeO 2  catalyst (Fig. 11). The goal of the study was to reduce the catalyst load and to maxi- mize the catalyst effectiveness through better mass transfer by implementing of the new high performance mesoporous Pt/CeO 2 catalyst with multiple layer depo- sition method and by the proposed micro combustor design. For proper operation of methanol fuel microreactor, precise temperature control and uninterrupted fuel supply is mandatory. Temperature control of metha- nol fuel microreactor for hydrogen production was re- ported by Peruško et al. [127]. The temperature control was achieved by on-off control with an adjustable hys- teresis. The heater actuation circuit comprised a boost converter, controlled by pulse width modulated signal from the microcontroller. The output of the boost con- verter was applied to the platinum (Pt) heater in the microreactor evaporation stage. To pump the fuel into microreformer, a fuel supply system is required. Pečar et al. [128] proposed a low cost, energy efficient flow- generator for hydrogen production in microreactors. The proposed approach is energy efficient and suit- able for implementation into a compact hybrid device, small enough to fit on microreactor housing. 4.2 Micro dosing systems for drug delivery A typical microdosing system comprises micropump, microsensor, microfluidic channel, reservoir and elec- tronics. It is mainly aimed at serious chronic diseases, such as diabetes, melancholia, malignant lymphoma, etc., or abrupt life threats, such as heart attack, stroke, septicaemia etc. [129]. With the automatic dosing sys- tem, the patients are protected from sudden death or irregular/incorrect taking medicine. Microdosing sys- tems are fabricated using bio-compatibile materials such as poly methyl methacrylate, poly-pimethylsilox- ane, SU-8 photo resist, or parylene C [129].  Bubble-type and other non-mechanical microdos- ing systems need no physical actuation components but its effectiveness, due to long time delay and slow response, are much devalued [129]. Bohm et el. [130] proposed a closed-loop controlled micromachined dosing system for accurate manipulation of liquids in microsystems down to the nanoliter range via ex- panding electrochemically generated gas bubbles. Another solution was described by Reynaerts et al. [131]. An implantable drug-delivery system based on shape memory alloy micro-actuation was based on a precisely controlled discontinuous release from a pres- surized reservoir by using a shape memory actuated microwave system. One dose can be controlled with accuracy up to 5 μl. However, shape memory alloys dosing systems suffer from a relatively low flowrate and insufficient bio-compatibility [129]. A microdosing de- vice comprising a dosing chamber, dispensing opening and vibration unit was patented by Koerner et al. [132]. Vibration unit was connected to at least one boundary surface of the dosing chamber. Consequently, bound- ary surface oscillated for the purpose of a dispensing operation. A plastic micro drug delivery system was successfully demonstrated by Ianchulev et al. [133], utilizing the principle of osmosis without any electri- cal power consumption. The system had an osmotic microactuator and a polydimethylsiloxane (PDMS) mi- crofluidic cover compartment consisting of a reservoir, a microfluidic channel and a delivery port. Induced osmotic pressure could extend up to 25 MPa to over- come possible blockages caused by cells or tissues dur- ing drug delivery operations. Than et al. [134] reported a strategy using an eye patch equipped with an array of detachable microneedles. Microneedles penetrated the ocular surface tissue, and served as implanted mi- croreservoirs for controlled drug delivery. System com- prised micro-seized membrane in sealed microfluidic reservoir, piezoelectric microcylinder pump and array of hollow Si microneedles. Biocompatible components were covalently bonded to each other to form a com- pact wearable system. Complete emptying of 590 µl sealed reservoir needed suction pressure of less than 50 millibars which minimized power consumption that is crucial for long device autonomy. Figure 12: Wearable integrated microdosing system for transdermal drug delivery by Vrtačnik et al. [136,137]. Kabata et al. [135] fabricated insulin pump using the volume change of hydrogen bubbles and conducted experiments using rats. To monitor the blood glu- B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 14 cose level, a glucose sensor was employed. Recently, Vrtačnik et al. [136, 137] proposed and patented wear- able integrated microdosing system with a micronee- dle array for transdermal drug delivery (Fig. 12). 4.3 Lab-on-Chip and Point-of-Care systems One of the main objectives of microfluidic technolo- gies is to provide a total solution, from sample input to display of the analyzed results [138]. Complete ana- lytical protocols, from sample pretreatment through to sample and reagent manipulation, separation, reaction and detection can be performed automatically on well- designed and integrated miniaturized devices such as LOC systems. LOC devices are a subset of MEMS devices and often indicated by “Micro Total Analysis Systems” (µTAS) as well [139]. LOC devices comprise microchan- nels, integrated pumps, electrodes, valves, sensors and electronics to perform required tasks [140]. The term “Lab on Chip” was probably first used [141] by Moser et al. from Technical University Vienna [142] to describe the miniaturized thin film glutamate and glutamine bi- osensors developed by them. Research on LOC focuses on several applications including human diagnostics, DNA analysis and synthesis of chemicals [140]. The miniaturization of biochemical operations normally handled in a laboratory has numerous advantages, such as cost efficiency, parallelization, ergonomics, di- agnostic speed and sensitivity. LOC systems offer advantages for pathogen, toxin and virus detection. A review by Yoon et al. [143] summa- rized the requirements of LOCs for foodborne patho- gens detection and gave an overview on immunoassay and PCR-based LOC biosensors. A review by Weigl et al. [144] highlights LOCs for drug development, advances in LOC technology for flow-injection analysis, electro- kinesis, cell manipulation, proteomics, sample pre- conditioning, immunoassays, electrospray ionization mass spectrometry, and polymerase chain reaction. Overview on LOC technologies for stem cell analysis was presented by Ertl et al. [145]. Authors focused on the advantages of the microfluidic devices to over- come most of the challenges associated with stem cell identification, expansion and differentiation. Por et al. [146] focused on the latest developments in environ- mental LOC monitoring devices and provided future perspectives to overcome the challenges using print- ing technologies. Wu et al. [147] made a short review on LOC platforms for detection of cardiovascular dis- ease and cancer biomarkers. Ai et al. [148] summarized recent progress in LOCs for pharmaceutical analysis and pharmacological/toxicological tests. Authors gave insight into the challenges and possible breakthrough of Pharm-LOCs development. POC diagnostic systems are instruments that can rap- idly provide in vitro diagnostic results by non-trained personnel at a patient site, in the physician’s office, in the field, at home, in an ambulance, or in a hospi- tal [149]. There has been a growing need to provide diagnostic results at the point of care, for prompt treat- ment of acute diseases such as acute myocardial infarc- tion and for home-care diagnostics such as diabetes monitoring. In many ways, the features of microfluidics and LOC technologies are a natural fit for POC diagnos- tics devices [150]. Bringing the LOC technology to life through POC devices is a challenging task. So far, there have been only a few successes in the transformation of LOC technology to the actual POC devices with a real life application [151]. A review of POC diagnostic sys- tems using microfluidic LOC technologies was recently given by Sia at al.[152]. This review covers advances in POC technologies, commercially available POC diag- nostic systems and microfluidic LOC technologies. Park et al. [153] summarized advances in microfluidic PCR for POC infectious disease diagnostics. In this review, authors discussed practical issues and perspectives related to implementing microfluidic PCR technolo- gies into infectious disease diagnostics. Further on, in recent years, paper-based microfluidics has emerged as a multiplexable POC platform [154]. Paper-based microfluidics is considered a low-cost, lightweight, and disposable technology [155].  A review on paper-based microfluidic POC diagnostic devices was given by Yeti- sen et al. [156], covering fabrication of paper-based microfluidic devices, functionalization of microfluidic components and quantitative readouts via handheld devices and camera phones. Examples of successful transformations of the LOC technologies into an actual POC devices are encourag- ing. Ahn et al. [157] demonstrated a disposable plastic biochip incorporating smart passive microfluidics with embedded on-chip power sources and integrated bio- sensor array for applications in clinical diagnostics and POC testing. Neuzil et al. [158] demonstrated a high performance polymerase chain reaction system in port- able LOC for POC. Sun et al. [159] designed, fabricated, and tested miniature 96 sample ELISA-LOC for immuno- logical detection of Staphylococcal Enterotoxin B. Their simple POC system is useful for carrying out various immunological assays and other complex medical assays without a laboratory. Upaassana et al. [160] re- ported highly sensitive LOC immunoassay for protein biomarker that causes lung inflammation (see Fig. 13). Authors drastically reduced analysis time to about 30 min as opposed to hours in conventional methods. Recently, several authors demonstrated an integrated POC solution for noninvasive diagnosis and therapy monitoring of heart failure patients [161]. KardiaPOC™ is an easy to use portable device with a disposable LOC B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 15 for the rapid, accurate, non-invasive and simultaneous quantitative assessment of four heart failure related biomarkers from saliva samples. Figure 13: Schematic diagram of the highly sensitive LOC for POC immunoassay for protein biomarker that causes lung inflammation by Upaassana et al. [160]. On-chip reservoirs store assay reagents. Air gaps iso- late reagents and prevent mixing while in storage and during the assay. Reprinted with permission from [160]. Copyright (2019) American Chemical Society. 5 Conclusions: Future perspective of the field The field of microfluidics has grown into a mature tech- nology capable of producing the most complex micro- fluidics systems that push the boundaries of today’s scientific and technological advances. Many challenges still lie ahead, but the main challenge remains how to translate a wide variety of successful microfluidic con- cepts from laboratory prototypes to robust end-user products in order to be more accessible. Many fabrica- tion processes currently employed in laboratory envi- ronment, including manually performed PDMS soft lithography techniques, are inappropriate for mass pro- duction of microfluidic devices due to speed and cost concerns. There is a need to overcome these limitations in the future. Advances in bioinspired smart materials are leading to next-generation fabrication technolo- gies for microfluidic devices such as 4-D printing, which adds a time dimension to the conventional 3-D print- ing and offer the capability to control size, shape and structure post-manufacture [162]. With the continuous development of novel fabrication technologies includ- ing 4-D printing, it is expected that the future micro- fluidic devices, will be less expensive, more integrated, more customizable and will incorporate a higher level of quality control [163]. Given the current state of the field, we can expect that future advances, particularly in POC systems, will have a transformative impact on the global health care system, which will improve the quality of life especially for elder people and people in developing countries [164]. Some exciting futuristic as- pects for the field of microfluidics was given by Tian et al. [165] as follows: »Microfluidics will provide autonomous distributed monitors for public health and surveillance for biothreats. The aging population will use health kits to provide preventive medicine. Medical checkups will be performed daily. Healthcare costs will be reduced due to the availability of microfluidics instruments. Chronic disease patients will possess home diagnostics systems and high risk patients (e.g. post surgical) will enjoy the comfort of being at home knowing that LOC de- vices will be monitoring risks of infection, blood clots, etc. Microfluidic devices will increase the efficacy and safety of medical treatments by assisting in the pre- scription and administration of drugs. Artificial cells, synthetic hybrid biomolecules and synthetic biomate- rials will require the development of sophisticated mi- crofluidic platforms down to the true nanometer scale dimensions.« 6 Acknowledgments The authors would like to thank the Slovenian Research Agency/ARRS and the Ministry of Education, Science, Culture and Sport for their support of this work (Grant No P2-0244). 7 Conflict of Interest The authors declare no conflict of interest. 8 Permission statement The authors declare they have permission from the rightsholders to re-use the material. 9 References 1. R. P . Feynman, “There’s plenty of room at the bot- tom” , Journal of Microelectromechanical Systems, B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 16 Vol. 1, Issue 1 , pp. 60-66, Mar 1992, https://doi.org/10.1109/84.128057. 2. K. E. Petersen, “Silicon as a mechanical material” , Proc.IEEE, Vol. 70, No. 5, pp. 420-457, 1982, https://doi.org/10.1109/PROC.1982.12331. 3. P. S. Dittrich and A. 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Arrived: 04. 12. 2021 Accepted: 19. 03. 2021 B. Pečar et al.; Informacije Midem, Vol. 51, No. 1(2021), 3 – 23 Copyright © 2021 by the Authors. This is an open access article dis- tributed under the Creative Com- mons Attribution (CC BY) License (https://creativecom- mons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.