The main differences between the three different illumination types in fNIRS (adopted from Ref. [20]).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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Key Part of Emerging Wearable Brain-Device Interfaces",doi:"10.5772/67457",slug:"the-nirs-cap-key-part-of-emerging-wearable-brain-device-interfaces",body:'\nNear infrared spectroscopy (NIRS) has been gaining momentum due to its unique advantages that makes it an indispensable tool in medical research. By successfully resolving certain issues of portability and data filtration, NIRS is expected to find a wide application not only in medicine but also in the gaming industry as well as any thought controlled electronic devices due to its relatively inexpensive, portable and non‐invasive nature. From a medical standpoint, the advantages of NIRS imaging, or functional NIRS (fNIRS), are quite distinct. Much like electroencephalography (EEG), its portability and non‐invasiveness make it a natural choice for imaging young children and infants [1]; however, while EEG signals are inherently noisy, non‐linear and rely on electrical signal variations on the scalp [2], NIRS offers 1–2 cm depth resolution that is capable of capturing cortical activation [3]. Additionally, NIRS offers higher temporal resolution than traditional immobile imaging devices such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), which allows the detection of transient cortical events [4]. Undoubtedly, present imaging techniques in general are bound to offer higher temporal and spatial resolution as their design develops over time, but what makes NIRS imaging an interesting contender is the combination of the previously mentioned factors which allows it to be a suitable device for long‐term cortical activity monitoring. NIRS promises a device that can be used anywhere, inside or outside of a lab or hospital setting and that can register cortical activation throughout different activities with varying degrees of freedom without particular concern towards the subject\'s age group or physical condition which can have important real‐life applications today [5–8]. Nevertheless, for NIRS to achieve its full potential the topic of its interface is yet to be properly addressed and designed.
\nThe application of NIRS imaging relies on two primary factors: the first factor is the relative transparency of human tissue to near infra‐red (NIR) light, which penetrates the skin, subcutaneous fat, skull and brain [9]. The second factor is the high attenuation of NIR light due to haemoglobin oxygenation levels [3]. More specifically, the term ‘optical window’ is used to define the range between 650 and 1350 nm where light absorption coefficients of water, melanin in addition to oxy and deoxy haemoglobin, are lowest. This allows a certain amount of light to penetrate biological tissue, where it is scattered and eventually diffused allowing for a limited amount of tissue penetration to occur. NIR imaging relies on light absorption coefficient values of key biological components, such as water, oxy and deoxy haemoglobin to measure changes in their concentration over time. For example, as shown in \nFigure 1\n, the absorption coefficients of oxy and deoxy haemoglobin intersect at around 805 nm allowing for the use of two distinct NIR wavelengths within the optical window to measure the changes in each of these elements [10–12].
\nLight absorption spectrum of oxy and deoxy‐haemoglobin, the span between 650 and 950 nm is called the ‘optical window’ due to the relatively low absorption factors in tissue [
Pigmented compounds such as chromophores of skin and hair melanin are also a high source of NIR attenuation; however, these factors are easily corrected by adjusting light intensity since their value over the period of imaging is constant [13]. The behaviour of NIR light inside tissue is also relevant, as the main mechanism of NIR light propagation is scattering, and while a part of NIR light is attenuated as it is absorbed by chromophores, the remaining scattered photons resurface back a certain distance away from the light source allowing the detection and measurement of light attenuation over time.
\nSince NIRS allows the measurement of oxy and deoxy haemoglobin changes over time, it is considered an indirect method of measuring brain activity based on the neurovascular coupling phenomenon that relates neural activation with vascular response. Neurovascular coupling refers to the increase in oxy‐haemoglobin (HbO) and simultaneous decrease in deoxy‐haemoglobin (HbR) when spatially clustered ‘cortical columns’ that share the same functional properties are stimulated. This cluster formation is what makes brain oxygenation levels detectable using optical imaging [14, 15].
\nNIRS can also provide non‐haemoglobin‐based measurements, by recording data from several wavelengths simultaneously, in order to detect tissue chromophores, including cytochrome oxidase the marker of metabolic demands [16]. While some studies suggest the use of NIRS in the detection of cell swelling as a result of neuronal firing in order to directly detect neuronal activity; however, these signals are 0.01% smaller than hemodynamic activity making it a less reliable method for detection [17–19].
\nOverall, although the special characteristics of NIR light were first published by Jobsis in 1977 [9], yet the first 10‐channel NIRS imaging system was only introduced in 1995 and actual interest in this technique was only seriously considered with the advent of multi‐channel wearable and wireless devices in 2009 [20]; since then NIRS has been used extensively in brain imaging research which is reflected in the number of publications that cover its development, use and various applications today. Nevertheless, NIRS has low reliability still in single subjects, which makes it unsuitable for clinical applications and restricts its use in large group medical research [21–24].
\nAny NIRS device can be divided into three major components: (1) a brain device interface that includes optodes and the cap stabilizing them, (2) a control module that collects, sorts registered data and provides the various illumination schemes in addition to data transfer to the (3) user interface and main software responsible for analysing data using signal processing algorithms.
\nThese three branches will be discussed briefly; however, emphasis will be on the interface and the essential role it plays on the imaging process.
\nThe term ‘optode’ refers to both the NIR light emitter and detector that ideally create a fixed and predetermined illumination scheme within the cerebral cortex. The source, or light emitter, shines light directly into the scalp, this light is scattered by head tissue causing it to deflect in all directions and only a small fraction of this light (approximately one out of 109 photons) resurfaces back to the scalp some distance away from the entry position [3]. This NIR light distribution was simulated by Okada and Delpy, their study showed the light‐scattering pattern within the scalp, skull and cerebrospinal fluid in addition to the sensitivity of each source‐detector pair to this scattering, which creates a banana‐like shape within the scalp with two narrow ends at the source‐detector locations [25]. Light attenuation can be calculated based on the Beer‐Lambert law that links the ratio of incident and reflected intensities to the absorption and diffusion phenomenon [9]. On the other hand, the distance where the NIR light resurfaces back differs from one subject to another based on age, curvature of the scalp and head size and it generally ranges from 3 to 4 cm; therefore, an ideally placed light detector at that exit position can capture it. The change in the amount of detected light overtime is used as an indicator of the absorption variation of NIR light due to cortical activation.
\nBased on this light emitter‐detector coupling, also called ‘channel’, it is clear that unlike other non‐invasive brain imaging techniques, such as EEG, the integrity of a NIRS signal relies on the assumption that the cortical illumination and detection scheme is ideal. This assumption entails that the relative position of the detector/emitter couple is constant, and that the detector, emitter operational conditions are constant throughout the imaging session. However, this is often not the case, and so far, it has been a very difficult condition to maintain, particularly for the type of experimental requirements that fNIRS is designed to meet such as imaging freely moving subjects over extended periods of time.
\nMost successful fNIRS imaging experiments are commonly conducted inside a lab, where the subject sits still on a chair and is refrained from talking, smiling or moving their head. With the advent of better signal filtration, successful use of fNIRS was also registered in rehabilitation centres with walking patients, or even cycling [5, 26, 27]; however, constrains on facial expression and subtle head movements still apply, because while certain movement artefacts such walking and running and obvious head movements are easier to isolate and/or filter out, facial expressions are far more difficult to detect. Small facial muscular fluctuations or hair resistance to NIRS optodes that are unnoticeable to outside observers can cause the entire optode holder to slide or cause slight optode inclinations. Such inclinations that fluctuate over the imaging period can cause light scattering outside the scalp, poor light detection or displacement of surrounding hair in front of optodes resulting in false attenuation values that cannot be accounted for using common artefact detection methods. Therefore, subjects with dark and voluminous hair are typically the hardest to image as any displacement of hair in front of the optodes can jeopardize the integrity of the results while voluminous hair adds resistance and counter pressure against the optode holders.
\nAs mentioned previously, optical penetration is usually 1–2 cm, which is typically half the source‐detector distance. Such penetration depth translates to 5–10 mm of outer brain tissue penetration after subtracting the thickness of the skin, subcutaneous fat and skull (which vary from one person to another and with age), this allows the detection of the outermost cortex activation [3, 10]. Most NIRS devices rely on two light wavelengths simultaneously to measure both oxy and deoxy haemoglobin changes [28–30], while three or four wavelengths might be used in some cases in order to either extract changes in other species, such as water and lipids [31, 32], or to couple with time resolved methods for additional parameters such as blood flow and absolute tissue saturation [19].
\nThere are various types of NIR light sources, the two most commonly used emitters today are laser diodes and light‐emitting diodes (LEDs). Laser diodes provide a technical advantage over LEDs as they have higher light intensity and smaller optode size, which allows for better hair penetration and scalp contact. However, they have higher energy consumption and cost, thus their use is not suitable for portable devices outside a lab environment. LEDs require simpler circuitry; they generate a light spectrum of about 30 nm and are the natural choice so far for portable fNIRS systems [19].
\nAs for light detectors, the most common choice is avalanche photodiodes (APDs) that translate the amount of detected photons into current and have low power consumption with the capacity to increase the detected light intensity. In addition, APDs are fast with more than 100 MHz speed and have a high sensitivity with the dynamic range of approximately 60 dB. Some devices rely on silicon photodiodes, however, these have a medium speed and lower sensitivity but a higher dynamic range with approximately 100 dB [19]. Modern microfabrication techniques are aiming at the creation of smaller LED and APD designs with enhanced capability, which is essential to the development of next generation portable fNIRS devices.
\nFinally, when it comes to optode holders, there are two major types of optode stabilizing methods, the cap (a soft headwear) that covers the entire head, with prefixed locations for optodes, much like an EEG cap. However, in NIRS caps, the optodes are not prefixed on the cap in order to allow for hair manipulation and tossing to take place prior to optodes installation. The other common types of optode holders are the rigid patches that cover a certain cranial zone. The term ‘rigid’ refers to the material used for stabilizing the optodes, since although they are made of silicon which allows it to bend slightly to fit the head shape at a given location, the distance between the optodes is fixed as the material itself does not stretch, unlike the cap, thus the distance between the optodes is fixed throughout the imaging session giving the patches a clear advantage over the caps. Both designs are prone for sliding, however, requiring additional restrains to keep them in place, such as attachments under the chin or to a belt that goes under the armpits and over the chest.
\nThe electronic control volume is directly connected to the optodes and therefore is the portable part of the fNIRS device in addition to the interface. This component is responsible for the illumination scheme in addition to data gathering and transmitting (in portable devices). Lighting strategies in fNIRS aim to reduce power consumption and heating of the scalp in addition to differentiating between various light emitting sources, which is essential to distinguish between the different channels when there are multiple light emitters within the range of a single detector. Therefore, the control module employs a certain method for multiplexing and/or modulating of light sources.
\nHowever, the most significant aspect of the control module is its illumination technique. There are three major types of illumination schemes used today which are shown in \nFigure 2\n. The most common type is continuous wave (CW) which measures simply the backscattered light intensity attenuation. The second type is the frequency domain (FD), which uses intensity‐modulated light in order to measure both attenuation and phase delay of returning light. The third technique is the time domain (TD), which relies on short pulses of light as an illumination source and detects the shape of the pulse after propagation through the tissue; this technique provides information about spatial specificity in addition to tissue absorption and scattering [33].
\nThe three type of fNIRS illumination techniques: (a) continuous wave, (b) frequency domain and (c) time domain (TD).
The CW scheme is relatively simple and cost effective as it relies on establishing a baseline, or a zero state, and then compares oxy and deoxy absorption changes to this initial value during a certain test or a task. However, only FD and TD methods can provide absolute characterization of tissue properties including the distinction between absorption and scattering in the tissue [20]. Nevertheless, a more complex scheme is generally associated with lower time resolution and is more susceptible to noise and movement artefacts, since determining the time of flight is effected with geometrical and contact changes. The major differences between the three techniques are summarized in \nTable 1\n.
\nMain characteristics | \nContinuous wave | \nFrequency domain | \nTime domain | \n
---|---|---|---|
Sampling rate (Hz) | \n≤100 | \n≤50 | \n≤10 | \n
Discrimination between cerebral and extra‐cerebral tissue | \nNot possible | \nFeasible | \nFeasible | \n
Measuring HbR, HbO | \nOnly changes | \nAbsolute value | \nAbsolute value | \n
Measuring scattering, absorption coefficient and pathlength | \nNo | \nYes | \nYes | \n
Measuring tissue HbO saturation (%) | \nNo | \nYes | \nYes | \n
The main differences between the three different illumination types in fNIRS (adopted from Ref. [20]).
It is important to keep in mind that as fNIRS fills a special niche for portable imaging systems, the most important qualifications in general are those related to power consumption and size, which explains why most fNIRS devices adopt the simplest illumination technique. In addition, present application of fNIRS does not require tissue characterization as it is more concerned with changes in blood oxygenation rather than absolute absorption values [3]. However, both of these aspects might change as fNIRS reliability is increased and the technology used in FD and TD systems becomes more compact and power efficient.
\nThis is where data from each illumination channel are gathered in order to be filtered, quantified and presented in a user friendly fashion. It is also where certain controls over the system in general are provided from the end user as actions and input variables. The fNIRS software package is usually provided on a computer or even a tablet with a Bluetooth connection to the control module.
\nThere are many algorithms and software dedicated to optical imaging and signal quantification based on how light behaves in tissue. The two most widely used theoretical models are the differential pathlength factor (DPF) and the diffusion approximation. Both assume that tissue is homogeneous, however, the diffusion approximation method assumes that scattering is larger than absorption; therefore, each type of tissue has a specific geometry (infinite, semi‐infinite, slab or two‐layered) [34, 35]. Still, since the two models rely on quantification over a given path, interpersonal differences such as the thickness of scalp, skull and cerebral spinal fluid in addition to hair and skin melanin concentrations are bound to create biases in spatial localization of brain activity particularly with TD and FD methods, but they are less significant in CW methods [25, 36, 37].
\nThis chapter will not cover all the various aspects related to the proper functionality of this component, it will only concentrate on aspects related to noise attenuation and filtration for their obvious relation with the signal quality obtained that is provided by the device interface and is affected by the cap design.
\nIn general, noise sources can be either instrumental, experimental or physiological. Instrumental and experimental artefacts refer to experimental errors including movement artefacts and device malfunction and have to be dealt with prior to data analysis. Physiological errors on the other hand are due to certain changes in the physiology of the subject that affect but are not part of the intended experiment. These are usually treated with filters after the conversion of raw signals to haemoglobin units either using algorithms that compensate for pulse‐related artefacts or by using additional NIRS channels that measure extra‐cortical hemodynamic variations [3, 10–12, 38]. Instrumental errors have to be dealt with prior to any testing, since they can easily overpower the measured signals. Whereas movement artefacts should be approached by carefully controlling the experimental environment whenever possible. However, since absolute control over the entirety of the experiment is not likely, not to mention that the nature of the experiment itself might produce movement artefact, such as walking or cycling, special algorithms have been developed to filter out these errors using additional data collecting methods, such as a camera [39] or an accelerometer [38, 40].
\nNevertheless, to date there are no methods that can provide any information regarding optode‐scalp contact ‘quality’ to ensure that the received data reflect that of an ideal illumination condition throughout the imaging session.
\nClearly, the primary objective of the NIRS cap is to stabilize the optodes, making sure that they are in constant contact with the scalp throughout the imaging period. However, in practice, there are other concerns that affect the proper functionality of the NIRS cap and its future use, namely: the installation process and subject comfort.
\nThe effect of optode stability on fNIRS signal quality was not quantified until recently, when the work presented by Yücel et al. was published in 2013 and 2014 [41, 42]. In these studies, the authors glued fibre optic optodes on the scalp using collodion, which is normally employed with EEG electrodes to monitor epilepsy patients. Using this method, the authors reported 90% reduction in signal change due to movement artefacts, a signal‐to‐noise (SNR) increase by sixfold and threefold at 690 and 830 nm wavelengths, respectively, and a statistically lower change in both oxy and deoxy haemoglobin during movement artefacts. In spite of the fact that their optode stabilizing methodology may not be practical for short‐term and off‐hospital settings. Nevertheless, this study provides an objective assessment of the effect of interface stability on the fNIRS signal, especially with moving subjects.
\nNevertheless, the task of stabilizing the optode using a mechanical device is quite elusive due to several reasons:\n
Current optode stabilization techniques rely on pressure; however, pressure is also a major source of discomfort. Thus, the more stable the optode, the more discomfort it is bound to create for patients. Such conditions might be tolerable for short‐term monitoring periods of 10–20 minutes; however, as the imaging session becomes longer these stabilizing techniques may not be acceptable. Presently, there are no studies identifying the comfort pressure threshold on the scalp, although such studies were done for other anatomical parts of the body [43]. Additionally, pressure values necessary to stabilize the optode are also unspecified yet. Preliminary results indicate that comfort pressure values on the scalp are not uniform, as the forehead and the back of the head, particularly the area behind the ears tend to be more sensitive than other areas on the scalp. More importantly, the difference between the pressure needed to provide optode stability (approximately 30–45 Pa) versus the comfort pressure margins on the head (50–60 Pa) is very small [44], therefore, designing an optode holder that relies solely on pressure is quite a challenging task. It is important to mention at this stage that both the comfort pressure as well as the pressure values necessary to stabilize the optode are tentative preliminary results and that such claims can only be established once a study on a large number of participants is conducted. In general, the results obtained from the preliminary study are in accordance with lab observations as fNIRS results tend to be better with less comfortable and higher pressure inducing headwear.
Since the importance of having a tight headwear at all cranial positions has been well clarified, one of the major obstacles in designing an ideal fNIRS cap is presented in head shape variations from one subject to another. Such variations can even be present within the same subject as differences between the right and left side of the cranium might exist. These often cause uncomfortable high pressure areas versus ‘pressure gaps’ where the optode fails to provide the necessary force to maintain scalp contact or prevent surrounding hair from covering the optode. While imaging companies try to compensate for general head shape variations by providing three (or more) headwear sizes (small, medium and large); even introducing different designs for certain markets in order to compensate for head shape differences between several ethnicities [45]. However, interpersonal head shape variations cannot be accounted for and simple caps often cannot meet the basic requirement of providing a perfect fit for all subjects. Partial head covering patches may present a reasonable solution in cases where imaging the entire head is not required, as their size allows for a certain degree of manipulation over the required imaged zone. However, such patches are prone to slippage and require extra attachments to keep them in place.
The third factor in assessing an optimal cap design is the difficulty associated with its installation. While fNIRS cap installation is considered a cumbersome task that necessitates an expert technician, it is important to keep in mind the anticipated goals of a portable brain imaging system, including its role as a brain‐device interface with applications spanning from gaming to medical devices. Therefore, unassisted single person installation is the ultimate goal for future fNIRS applications, albeit it is far from becoming reality with present designs.
Today, the installation of the fNIRS cap can be a long process that starts with taking general head measurements to identify important reference locations based on the 10/20 system. This is followed by the placement of the patch or cap and documenting the distance of the optodes from this (these) reference points, then rigorous clearing of hair at various optode locations is performed, and finally the optodes are placed. This process may take up to one hour based on the cranial area covered and the type as well as the amount of hair present. Therefore, attempts at creating easier installation of optode holders invariably address easier hair tossing or clearing methods, since this is generally the most time‐consuming part of the process. Apart from providing certain clearances around the imaged zoned to easily toss the hair (particularly when using the patches) the only solution so far seems to be in creating smaller optodes that would infiltrate hair to ensure optimal scalp contact in addition to increasing localized optode pressure by an in‐house spring. These solutions assume that optode size can eventually decrease to a point where it can become comparable to hair strands. However, this is far from the actual optode design available presently.
\nBased on these observations, it is clear that traditional fNIRS caps cannot meet the demanding requirements of portable fNIRS‐based imaging. But before proceeding to possible future solutions, the next section will focus on fNIRS cap designs that were developed so far in the literature and whether possible solutions can be based on these proposals.
\nThe design of the fNIRS cap has not received much attention in research or in the literature. This was due mostly to the fact that the fNIRS device is purely an electronic one, thus it elicited the focus of electrical and optical engineers and physicians while the optode stabilizing method itself, a mechanical device, was mostly dealt with as an accessory. The NIRS cap and the installation process were mentioned in 2009 by Huppert et al. for the first time, where the author voiced the importance of stabilizing the optodes and its effect on reducing experimental errors. The authors suggested more anchoring methods to attach the head band to the body in order to reduce the effect of the weight of the optodes on motion instability. They were also the first to mention the important dilemma of subject comfort during imaging due to the additional restrains [3].
\nThe design proposed by Huppert et al. is shown in \nFigure 3\n, and it portrays the stretchable cap that is used to stabilize a polymer patch which acts as an optode holder. Thus, the cap provides both a rigid spacing for the optodes and a flexible material to hold the patch in place, with additional Velcro attachments to stabilize the optodes and their wiring. The authors specify that even more rigorous attachments are needed for moving subjects. The design was made for in‐lab fNIRS measurements; therefore, the stability it provided with moving subject was not demonstrated.
\nStretchable cap design that holds a flexible polymer patch and stabilizes it with Velcro attachments [
Apart from this example, other attempts to create a head band for the prefrontal area were also introduced in 2009, where no complications due to hair interference can be found and the stability of the head band can be controlled by simply increasing the amount of pressure by changing the size of the head band. One such design is presented by Atsumori et al. [46]. While similar designs may be useful for gaming applications, in addition to few medical and research studies that focus on the prefrontal cortex, however, the bulky design represents additional mass that would contribute to movement artefacts, also the fact that it relies solely on pressure to ensure stability makes its use restricted to short‐term applications.
\nAnother study for an fNIRS cap was presented by Kiguchi et al. in 2012 [47], using a cap that was made of a black rubber. This might be considered the earliest study dedicated to the fNIRS cap for ‘haired’ regions including the design of the optodes. The optodes in the helmet like cap are fixed on the inside, as an integral part of the helmet that cannot be accessed or manipulated by the end user. Instead the authors chose to stabilize the optodes surrounding hair by rubber teeth. These teeth aim also to reduce the discomfort presented by optode localized pressure that was induced by a spring. Although this study is dedicated for portable fNIRS devices, however, it does not mention neither the installation process nor present a comparative demonstration of the stability it provided to the optodes versus other cap designs. Nevertheless, the bulky design does not present a practical solution against weight‐induced movement artefacts, additionally, holding the hair in place does not guard against slippage or blocking the NIR light by hair in front of the optode.
\nRegardless of the success of the design proposed by Kiguchi et al. the idea of using a glass rod to reduce optode‐scalp contact area which results in less optode resistance by surrounding hair has been adopted in the first open‐air fNIRS study published by Piper et al. in 2014. This study also provides the first comparative look at the effect of movement artefacts on signal integrity. The imaging quality was tested under three different conditions that varied between indoor sitting on a stationary bike, indoor pedalling on a stationary bike and outdoor bicycle riding [26]. The fNIRS cap used in this study is the regular EEG‐inspired elastic cap that has been available in the market for sometime. However, innovation lies within the minimization of optode size that is further reduced by the use of a 3 mm in diameter glass rod to guide the light into and from the scalp, in addition to reducing the weight of the connecting optode wires. Although this improved design has allowed the implementation of fNIRS imaging outdoors, still movement artefacts affected the fNIRS signal visibly as demonstrated by the study. As rejected channels per person were only 5% for someone sitting on a stationary bike, but this value increases to 7.5% during indoor pedalling and reaches 35% for outdoor cycling [26]. Obviously, a different approach for designing optode holders is warranted.
\nA comprehensive study on the design of an optimal fNIRS cap was provided by the work of the Imaginc group, in order to explore several design ideas that targets the issue of patient comfort and signal stability [11, 12, 44, 48]. Their study showcased several concepts ranging from padded fNIRS caps/helmets that were geared towards patient comfort, to Velcro patches that provide a none flexible alternative to stretchable caps with an option of adding strands or adjusting for size based on the subject\'s head shape; in addition to stretchable elastic bands that provide extra space for hair tossing and ventilation, as shown in \nFigure 4\n. The study concluded that designs that focused on patient comfort as a primary goal failed completely in providing the necessary grip for optode stability. While designs that focused on optode stabilizing based on applied pressure were relatively successful and their success was a function of the amount of pressure it provided on the participant\'s scalp.
\nDifferent headwear designs for optode holders, comfortable versus stable cap designs.
The direct correlation between pressure and signal stability regardless of cap design was clearly demonstrated in a comparative experiment between different cap models that were developed by the Imaginc group. The most successful models that were tested included the Velcro cap, the elastic band cap and the neoprene cap. Movement artefacts were recorded while the subject was sitting motionless, as a baseline, then while moving the head backwards, forwards and sideways followed by a period of walking. The results obtained are shown in \nFigure 5\n, that also note the number of rejected channels in each case. Surprisingly, in spite of previous results that have restrained the use of the neoprene cap to stationary in‐lab testing, while the Velcro and elastic band caps were more successful with freely moving subjects, the neoprene cap presented surprising noise artefact reduction, even while moving the head. This was due to the fact that the cap was too tight and visibly uncomfortable for the user, which is a clear indication of the inverse relation between optode stability and comfort. On the other hand, the effect of head movement on motion artefacts was much larger than walking, even without using motion filtration methods.
\nComparative look at the various cap designs and motion artefacts under different conditions: sitting, head movements and walking.
This led the team to explore other methods to stabilize the optodes that do not rely entirely on localized pressure. These proposals will be reviewed in the following section.
\nPrevious studies conducted in the field of fNIRS cap design lead to an obvious conclusion, relying on pressure alone as a means of stabilizing the optode is not a good strategy when it comes to imaging applications. Conversely, the science of providing a perfect grip for any object is not a new one particularly in the field of robotics. Indeed, robotic arms that are being developed for several applications ranging from the industrial to the medical have already crossed several milestones in achieving gripping capabilities against slippage in addition to handling sensitive objects with speed and accuracy. In reviewing the vast literature published in this field, it is possible to find a couple of comparable solutions that can provide the required amount of grip, mould‐ability with individual head shapes and ensuring patient comfort at the same time [48].
\nWhile handling sensitive objects, a firm grip is often associated with engulfing the gripped item in order to create a distributed pressure force instead of localized ones; additionally, engulfing the gripped object creates friction, which is the horizontal force that prevents slippage [47]. The more surface area of the object is covered the better hold the gripper provides with improved protection against slippage. Technologies such as the ‘universal gripper’, for example, can firmly hold a raw egg without breaking it. While on the other end, sensor‐equipped artificial hands provide a perfect grip using accurate feedback of the amount of force applied on each point. The difference between these two technologies is vast, as the universal gripper is an extremely simple solution that relies on moulding the gripper to fit around the object, by the use of a simple grain‐filled elastic bag and a vacuum pump [49]. On the other hand, the sensor‐equipped gripper requires numerous actuators, a processor and sensors to perform properly [50].
\nSince the quality of the grip is as important as the force that is required to provide it. The two previous methods can translate into pneumatic solutions that are promising for fNIRS imaging. The sensor‐based system although costly offers an important additional feedback input that has been thus far lacking in present fNIRS systems, the quality of contact: or in other words, the amount of pressure at each optode location. Thus, defining the optimal optode pressure becomes an important factor in such systems and can help filter out signals when optode pressure values are below a certain threshold. Such a system can have the inflatable cap structure proposed in \nFigure 6\n. The two‐layered air tight cap should be made of two different polymer types, with a more elastic one at the interior in order to allow for maximum moulding and expansion on the inside of the cap rather than the outside. Additionally, the interior of the cap should be lined with pressure sensors that provide feedback to a microcontroller. Based on the return signal, the microcontroller changes the state of the valves (either open or close) in order to inflate the air pockets. It also controls the air pump that inflates the balloons and turns it off once all the valves are closed. Dividing the cap into several air pockets is also an important part of the design, since interpersonal variations in certain cranial zones are less than in other areas.
\nInflatable pneumatic cap design: a) a schematic representation of the various inflatable cap components b) a top view showing the location of the various components on the head. The cap is divided to several air pockets that are lined up with pressure sensors, once the return signal from all pressure sensors at a given air pocket are above a certain value, the microcontroller closes the valve of that air pocket, and once all air pockets valves are closed the pump is turned off too [
The inflatable pockets can help also provide optode cushioning, which not only increases its stability but also allows for overnight use of the fNIRS imaging system.
\nHowever, this solution presents technological challenges, such as the fabrication of sensors, micro‐valves, miniaturized pump and controller. In addition to ensuring that the power consumption of the added electronic components is minimal and that the cap\'s weight is low.
\nThe second pneumatic solution, on the other hand, requires a vacuum pump that is not necessarily integrated in the cap itself, and it can be considerably less challenging from a technological point of view. One example of a vacuum fNIRS cap that is an adaptation from the universal gripper concept is presented in \nFigure 7\n. As shown, the cap can be a regular fNIRS headwear that is lined with small grain‐filled balloons, or it can be made of an air tight polymer that covers the entire head also filled with small grains (the examples shown are filled with coffee or small foam grains). No embedded electronic components are necessary or required for this solution, instead, the cap can be firmly placed on the participant\'s head, then the vacuum pump is used to ‘mould’ the cap and jam the grainy material in order to create a tight grip on the head. Once this is achieved, hair can be tossed securely and the optodes can be placed in their designated sockets. The cap firmly holds the head until the imaging session is over then air is allowed back into the cap thus loosening its grip.
\nVacuum fNIRS cap design (a) an airtight latex cap covering the entire head and filled with granular foam balls, (b) a regular fNIRS cap lined with tube balloons filled with coffee grains [
With such gripping methods, the cap is expected to be worn without the need for additional attachments connecting the cap to a belt under the arms or to the chin. However, without an actual demonstration of the stability of these designs, such expectations remain speculative. Preliminary results from the vacuum cap design indicate that the complete head wear provides a tighter grip than the balloon‐lined design due to the increase in the gripped surface area.
\nSo far, the topic of future fNIRS caps focused on user\'s comfort and optode stability. However, cap installation is an important part of anticipated fNIRS imaging applications, not to mention its present day relevance for medical research considering the time and effort it requires from experts in the field of imaging. This has been generally due to the assumption that once smaller optodes were designed, the need for hair clearing would diminish; therefore, no mechanical methods would be necessary to clear the hair and ensure optode/scalp contact. Additionally, as optode holders generally provide a very small space (0.7–1.2 mm in diameter) to place the optodes, this complicates the design of a mechanical hair tossing device to operate in. Consequently, designing a hair clearing optode holder can be a very expensive endeavour. So far, the best caps or optode holders from installation point of view were considered the ones that provided a clearing around the optode location to help with the hair tossing process. Therefore, small polymer patches or the elastic band cap in addition to the adjustable Velcro strips cap in \nFigure 4\n are preferable to other complete head covering models. Still, the installation process even with the help of adjustable patches or additional spaces around the optode requires the help of an expert technician, as the only advantage they provide thus far is that of reduced installation time.
\nAlthough the topic of the importance of a hair clearing optode holder is debatable given its complexity, clearing and holding the hair in place can potentially help in stabilizing the optode holder itself. Therefore, the basic concepts for such a device will be mentioned here for future references. As shown in \nFigure 8\n, hair tossing can be performed using either a double hair tossing pins, a single hair tossing pin or multiple pins directing hair from the middle of the opening outwards. Such mechanisms can be added to the socket, which is the locking mechanism used to place the optode on the cap. Integrating a hair clearing mechanism that can be activated by simply placing the optode inside the opening can potentially allow for single user installation, without the need for an expert technician.
\nThe various components of the optode housing and how it connects to the socket that is attached to the cap, a spring located inside the optode housing provides an additional pressure to maintain optode/scale contact. Hair clearing can be achieved via the development of socket designs that can play a dual role, by adding a hair clearing mechanism to it. Possible hair parting methods are: (a) dual parting pins, (b) single parting pin and (c) multiple parting [
Applying these clearing techniques on hair is faced with certain complications, such as hair directionality; therefore, for a socket that has two pins, parting the hair from the middle cannot be helpful at locations where hair direction is not parallel to the pins. This is even more complicated with one pin parting designs, therefore ‘adjusting’ methods for pin directionality are necessary, such as designing a pin that can be placed in any of three placement combinations. Ideally, parting the hair from the middle is the best method, as it eliminates all difficulties associated with the other two methods. From a practical standpoint, the size of such pins would be in the millimetre range (maximum a centimetre); therefore, any concept needs to be tested on various levels, mechanical design, machining and implantation in order for it to be viable. Preliminary results obtained from the study presented by Kassab [48] shows that a collet‐based pin concept that parts the hair from the middle by a simple twist of the optode holder can provide an interesting solution for single user applications. Such a design can be very simple to use, would not require knowledge about hair directionality and is not affected by a hair type. More importantly, it can potentially lock the hair around the optode holder thus providing additional cap stabilizing mechanism.
\nThe aim of this chapter is to demonstrate the importance of fNIRS caps or optode holders as an interface, and how the imaging signal and ergo the future use of fNIRS can be affected by its efficiency and performance. The major challenges of an efficient imaging cap were articulated as well as present available models and possible future solutions. In general, the field of fNIRS imaging has not been generous when it comes to studies aimed at the interface itself, albeit designing an ideal imaging cap can potentially be a major factor in solidifying the marketability of fNIRS imaging as an inexpensive medical device by increasing its reliability and creating a user friendly and practical system.
\nIn preparing this study on fNIRS caps, it was obvious that several areas were in need of proper documentation, including basic definitions or guidelines, such as the pressure values for optode stability versus pressure values for patient comfort on the head. Such design parameters are important for any tight headwear and medical device designs. On the other hand, while there are numerous studies on movement artefact algorithms and how to filter out or control them, studies on optode inclination and detachment as a movement artefact associated with facial expressions or head movement, and how it affects the imaged signal is not yet approached. With long‐term imaging, issues pertaining to the effect of sweat and heat on the imaged signal is also an important one, and when considering freely moving subjects, pressure fluctuation with motion, or the dynamic pressure, on the head and how it correlates with motion artefacts can also present an important feedback defining sources of error and isolating factors that have affected the reliability of fNIRS imaging for the past couple of decades.
\nFinally, when it comes to testing the efficiency of fNIRS cap designs, there are no protocols or standards that define its proper use and limitations. For example, some patches can be very practical with motionless subjects for finger tap testing or visual stimulation; however, they might fail with freely moving subjects. Therefore, establishing a proper testing mechanism for fNIRS caps can also aid workers and end users in understanding the limitations of each device and thus avoid possible errors in application.
\nThe authors like to express their gratitude for the Imaginc team for their vital role in making this work possible, special thanks to Mr. Le Lan for his support and resourcefulness. The Imaginc group is supported by the Canadian Institutes of Health Research (CIHR) and the Institute of Circulatory and Respiratory Health.
\n\n
APD | \nAvalanche photodiodes | \n
CW | \nContinuous wave | \n
DPF | \nDifferential path length factor | \n
EEG | \nElectroencephalography | \n
FD | \nFrequency domain | \n
fNIRS | \nFunctional near infrared spectroscopy | \n
HbO | \nOxyhaemoglobin | \n
HbR | \nDeoxyhaemoglobin | \n
LED | \nLight‐emitting diodes | \n
MRI | \nMagnetic resonance imaging | \n
NIR | \nNear infrared | \n
NIRS | \nNear infrared spectroscopy | \n
PET | \nPositron emission tomography | \n
SNR | \nSignal‐to‐noise ratio | \n
TD | \nTime domain | \n
The entrance of induced Pluripotent Stem Cells (iPSCs) in the stem cell scene represents a novel approach for studying human diseases and a promising tool for regenerative medicine. [1]
The compelling need to overcome ethical and technical issues related to the production and utilization of Embryonic Stem Cells (ESCs) has prompted to search for a method to induce the pluripotency in terminally differentiated cells pushing them to an embryonic-like state.
Several studies, therefore, have been focused on characterizing and isolating unique transcriptional factors expressed by ESCs, presuming that their expression was sufficient to confer to adult cells the peculiar features of pluripotent cells. [2] The hypothesis that genome is not irreversibly modified during the differentiation and that some factors residing in ESCs can confer pluripotency to terminally differentiated nuclei has given a boost to bypass both the practical and ethical concerns related to the use of ESCs and has paved the way for the development of cutting-edge approaches for tissue regeneration, like cellular reprogramming by artificially inducing the pluripotency. [3]
Cell reprogramming consists in converting adult somatic cells in undifferentiated cells defined by an acquired pluripotency, typically showed by ESCs. Many techniques have been developed to achieve the goal since in 2006 Yamanaka and colleagues succeeded in the undertaking challenge of identifying four specific transcription factors (Oct4, SOX2, c-Myc, and KLF4) capable of reprogramming murine or human fibroblasts to embryonic-like cells, and termed them “induced pluripotent stem cells”. [4] The four factors recognized by Yamanaka are involved in multiple mechanisms and are pivotal for the pluripotency of embryonic stem cells, for embryonic development and to determine cell fate. [5]
The great potential residing in iPSCs was soon noticeable, primarily for the possibility to obtain stem cell lineages customized for each patient, able to give rise to the needed cell type, then, for the chance to overcome organ shortage difficulties and to avoid invasive medical procedures to treat degenerative diseases. [6]
Additionally, iPSCs share several features with ESCs showing similarities for morphology and culturing conditions: they both grow arranging in dome-shaped colonies (Figure 1) and need to be cultured in presence of a layer of feeder cells and/or specific cytokines. [7] Furthermore, iPSCs express equal stemness markers showed by ESCs, a common proliferation potential, the capability to self-renew and differentiate into the three fundamental germ layers. [8]
Skin fibroblast reprogrammed by mRNAs codifying for Oct4, SOX2, c-Myc, KLF4, Nanog, LIN28. Representative images of iPSCs arranging after 24 hours to form a colony (A) that appeared clearly visible ten days later (B). Scale bar is 250 μm.
It is considerably relevant that iPSCs can also provide effective disease models to investigate cellular and molecular mechanisms involved in the development of pathologies and a platform for toxicological and pharmacological screening. [9]
Until the sprawl of cell reprogramming, ESCs were considered the most promising and innovative tool for the research and clinical application in the field of regenerative medicine. Due to their ability to grow indefinitely and to differentiate into cells of the three germ layers while maintaining the pluripotency, ESCs rapidly gained the attention of the scientific community. [10] Despite the tremendous potential they hold for tissue and organ regeneration, at now, the clinical application of ESCs is limited and still faces many obstacles. The use of ESCs, in fact, raises several controversies and the studies focused on the understanding of their biology are strictly regulated or even forbidden in many countries. The reason of such restraint primarily resides in their origin and isolation techniques, as ESCs derive from the inner cell mass of mammalian blastula, the early stage of embryonic development, and common methods for their isolation require the destruction of the embryo, triggering ethical concerns. [11]
Beside the ethical issue, several other hurdles limit the concrete employment of ESCs, such as the risk of rejection related to their immunogenicity, the challenging conditions to culture and expand ESC lines and then to maintain the undifferentiated state ensuring their stability. [12, 13, 14] Additionally, there is a risk for tumor formation if ESCs are not fully addressed into a specific differentiated cell type prior to implantation. [15] Finally, about the therapeutic application of ESCs in human studies, another major concern is the use of non-human and xenogenic materials such as fetal bovine serum for cell culture. [16]
However, the pluripotency makes ESCs unique, and this astonishing differentiation capability renders them very attractive to research studies, to the extent that a big effort has been put recently into the search for methods to artificially reproduce their pluripotency (Figure 2).
Human iPSC technology allows, through the introduction of reprogramming factors into adult somatic cells, to obtain pluripotent cells capable of differentiating towards several mature cells which can be used for providing cells for regenerative medicine, for in vitro or in vivo disease modeling, and for screening and developing new drugs. (The figure was prepared with the support of Servier Smart Medical Art,
Nonetheless, the efficiency of cell reprogramming remains low, hence, the reprogramming techniques are under intense investigation so as to generate induced pluripotent stem cells ameliorating the efficiency of the process, the quality and safety of the derived cells. [17] The improvement generally targets several aspects of the reprogramming methods: primarily the source of somatic cells, as many studies suggest that some cells are more prone than others to be reprogrammed into certain cell types; [18] reprogramming factor cocktail; [19] the conditions to culture and maintain the iPSCs and, above all, the technique to introduce the reprogramming factors. [20]
A major issue related to the production of iPSCs, in fact, is the use of retroviruses to obtain a permanent integration of the reprogramming factors in the host cell genome, leading to teratoma formation due to the residual expression of oncogenes like c-Myc and KLF4. [21]
Different methods are known, at the present, to induce the expression of the reprogramming factors, classified in two major categories: non-viral and viral vector-based methods. [22] Viral-based methods include integrating viruses like Retrovirus and Lentivirus and non-integrating viruses, such as Adenovirus, Sendai virus. [23]
According to several studies, all these methods provide good results in terms of effectiveness of cell reprogramming, hence, the choice of the suitable method strictly depends on the cell type used and on the subsequent applications of the iPSCs obtained. [24]
Since from the first studies on reprogramming programs the most common method to generate iPSCs included the employment of retroviruses or lentiviruses to deliver Yamanaka factors. [25, 26, 27] Retroviruses integrate into host’s genome allowing a satisfying expression of reprogramming factors. The first retrovirus used to deliver specific transcription factors into mouse and human fibroblasts was the Moloney Murine Leukemia Virus (MMLV), capable to infect only actively dividing cells and silent in immature cells such as ESCs. [22, 28]
Conversely, the most common lentivirus used as a delivery vector derives from HIV. Usually lentiviruses have higher cloning capacities and infection efficiency than retroviruses. Unlike MMLV based retroviruses, lentiviruses could replicate both in dividing and non-dividing cells. Lentiviruses, with the respect to retroviruses have two safety advantages, the lack of integration near the transcription site of start and the capacity to deliver simultaneously different reprogramming factors in a single construct. [29]
However both vectors made of retrovirus and lentivirus carry significant risk of insertion mutagenesis during transfection related to their genomic integration; [26] therefore, even if they are properly silenced, viral transgenes can eventually be reactivated during differentiation or during the maturation of iPSCs, with high risk for tumorigenicity. [6]
Therefore, while they represent a valuable research tools, they cannot be safely employed in the clinical application (Figure 3).
The scheme summarizes the major advantages and disadvantages of integrating vs non-integrating methods currently employed for adult somatic cells reprogramming. (The figure was prepared with the support of Servier Smart Medical Art,
The efficiency and safety of generating and using iPSCs show a negative balance, and thus clinical employment of iPSC technology is still waiting for an effective protocol better poising these two fundamental features. [30]
Even though the integration of reprogramming factors in iPSCs generated using viral methods offers high efficiency and a good yield, it is risky and represents a strong limitation for further clinical applications. Indeed, the residual expression of Yamanaka factors in the derived cells, such as the oncogene c-Myc, causes several genetic and epigenetic mutations, along with transcriptional abnormalities, despite the silencing of these genes during reprogramming. The integration of the reprogramming factors, in fact, is responsible for disruption of coding regions, promoters, and enhancers/repressors causing the instability of the gene network of the iPSCs obtained. Genetic aberrations are strongly related to cancer onset, hence, the maintenance of genomic stability of iPSCs without dragging integrating viral vectors sequences is highly desirable (Figure 3). To overcome all these relevant safety issues newer protocols are currently under development for deriving iPSCs without any integration while addressing the low efficiency showed by earlier reprogramming methods. [31]
In order to fulfill the above-mentioned requirements several integration-free methods have been developed, many of them employing viruses. It is important to underline that, even if all these methods are classified as “non-integrating”, avoiding even a partial and negligible integration of viral genome into the host cells is not possible (Figures 2 and 3).
Adenovirus is DNA virus that can reprogram cellular metabolism in a variety of ways, like increasing glucose uptake in cells and stimulating the synthesis of lactate, and produce many other metabolic changes related to cancer. Several studies have shown the effectiveness of the adenovirus as a vector to deliver specific differentiation factors to generate iPSCs without integration into host’s genome.
The use of Adenovirus as a delivering method for reprogramming factors shows a certain effectiveness, allowing, at the same time, the production of quite safe and integration-free iPSCs. As a matter of fact, Stadtfeld and colleagues have demonstrated that human iPSCs generated from adenovirus are pluripotent and can be differentiated into all three germ layers in vitro and in vivo. [32] Zhou and Freed produced iPSCs from human embryonic fibroblasts using adenoviral vectors expressing c-Myc, KLF4, Oct4, and SOX2, and the iPSCs obtained expressed ESCs specific markers, showed a great differentiation potential and were free of any viral or transgene integration. [33] However, despite the employment of the adenovirus method eliminate the risk for malignant transformation associated with retrovirus or lentivirus, it shows disadvantages, such as the lower efficiency and the shorter expression kinetics requiring repeated transductions to maintain an adequate level of transgene expression. [33]
Additionally, not all the cell types are capable to generate iPSCs with this method alone as shown by Okita and colleagues in their studies they were unable to obtain murine hepatocyte iPSCs clones introducing the four reprogramming factors in the adenoviral vector alone, but the entire process required additional transfections of Oct3/4 and KLF4 or Oct3/4 and SOX2 by retrovirus. [34]
Sendai virus is an RNA virus that can infect a wide range of cell types either proliferating or quiescent and does not enter the nucleus of host cells. RNA virus-derived vectors are considered an attractive tool to vehicle Yamanaka factors, as they show a low risk of genomic insertion and are commonly used to reprogram neonatal and adult fibroblasts, and blood cells. The virus, while replicating, remains in the cytoplasm after infection and can be washed out of the host cells by several passages. Sendai virus shows a high transduction efficiency as confirmed by the expression of transgenes delivered yet detectable within a few hours after transduction, with a maximum expression after 24 hours after transduction. Sendai virus vectors have been largely studied and have emerged for their capability of successfully produce iPSCs with a non- detectable presence of viral RNA reprogramming adult human fibroblasts and circulating T cells. [35]
As Sendai virus is an RNA virus it holds the great advantage that does not enter the nucleus of the host cells and allows a highly efficient reprogramming. [36] Further, Sendai virus-based vectors are replication deficient, and their copies became diluted during cell divisions, and eventually virus-free iPSCs are available after about 10 passages. Thus, this reprogramming technique works to obtain iPSCs without introducing changes to genome. However, their relatively short expression strongly limits their use in biological and research application that require long-term manipulation for somatic cell reprogramming.
Due to the highlighted safety issues, it is necessary to develop efficient non-viral reprogramming methods. To generate iPSCs completely free from any viral contamination, researchers have modified and used DNA-based vectors, such as plasmids, episomal vectors, minicircle vectors, piggyBac transposons and non-DNA-based methods to deliver Yamanaka factors as mRNAs, microRNAs and proteins, as well as the direct reprogramming by exosomes (Figure 2). [37]
The common denominator of these methods is a much lower reprogramming efficiency as compared to lentiviral vectors-based reprogramming (Figure 3).
They require the use of elements composed of DNA to induce the expression of the reprogramming factors into the target cells. The most used elements include circular DNA vectors of different sizes (episomal vectors and minicircles) and mobile DNA sequences able to move and integrate to different locations within the genome by a cut and paste mechanism (PiggyBac).
One of the first integration-free techniques used for cell reprogramming includes the employment of non-replicating or replicating episomal vectors. This method is a quite simple technique not requiring special skills by the operators performing the experiments. Beside these advantage, reprogramming by the means of episomal vectors produces iPSCs still containing fragments of plasmidic DNA, due to the low transfection power that requires multiple transfections to obtain an appropriate expression level of the desired genes in the derived cells. Due to such a low transfection efficacy, the possibility of DNA fragments integration is highly increased, and it is crucial to improve the technique focusing on the reduction of transfection frequency and genetic fragments integration. Reprogramming by episomes is an excellent choice if employing blood cells but needs modification of standard culture conditions to reprogram fibroblasts into iPSCs. [34]
Minicircle vectors were first developed as smaller alternates to episomal vectors with a higher efficiency of transfection. They are circular, non-viral DNA elements that have been freed from a prokaryotic vector containing sequences of interest i.e. Oct3/4, SOX2, Nanog, LIN28, Green Fluorescent Protein (GFP). Expression of minicircle-coded genes occurs in both dividing and non-dividing cells with high efficiency, and typically yield higher expression levels of desired proteins, as they are less likely to be inactivated and silenced by cellular mechanisms targeting foreign nucleic acids. [38, 39]
In PiggyBac transposon reprogramming, transgene sequence can be removed from integration site without changing host’s DNA. It requires only the inverted terminal repeats, flanking a transgene and transient expression of the transposase to catalyze insertion or excision events. [40] All the mentioned methods show disadvantages, for example, the Sendai virus is effective on all cell types, but requires a lot of passages to obtain iPSCs. The PiggyBac method could represent an attractive alternate but studies in human cells are still limited and weak. [40]
Most common reprogramming strategies are based on the use of DNA. All these techniques are effective in achieving a successful reprogramming of the somatic cell, but they are considered less safe as some fragments of the DNA employed can integrate into the host cells genome due to the repeated treatments required to obtain the appropriate expression level of the desired genes. To avoid this safety issues, several groups focused on the development of protocols including non-DNA based methods for reprogramming, such as the use of mRNAs, microRNAs, or recombinant proteins (Figures 2 and 3).
Beside reprogramming, and subsequent differentiation into desired cell type, several authors have recently reported the possibility of trans-differentiation, or conversion of one cell type to another one, while bypassing the iPSC-state. An example is the direct conversion of myocardial scar fibroblasts (MSFs) to cardiomyocytes by infection of human MSFs with a lentivirus vector encoding the potent cardiogenic transcription factor myocardin. [41]
The direct reprogramming, in fact, is a procedure by which a mature, fully differentiated cell is converted into another cell type, completely or partially bypassing an intermediate pluripotent state. The direct reprogramming is an interesting new approach of regenerative medicine allowing to overcome the numerous problems related to the use of stem cells. Additionally, it has a low risk for genetic alterations and tumor development, as the reprogramming by this technique avoids risky genetic manipulation and the use of viruses or other strategies causing the residual integration of exogenous genetic material.
High-efficiency, synthetic mRNA-based reprogramming was recently described. [42] Synthetic mRNAs codifying for Yamanaka factors are modified to overcome innate antiviral responses. Since mRNA is translated to protein in the cytoplasm, it does not enter the nucleus, minimizing chance of unwanted modifications of hosts DNA. This method appears to work fast and efficiently, but the major disadvantage is that mRNA is degraded in few days. As such, repeated transfection is required for successful reprogramming. [42, 43]
The direct delivery of synthetic mRNAs for the conversion of adult mature cells into iPSCs is an example of direct reprogramming. An effective protocol including the employment of this method was proposed by Warren et al. The idea of delivering mRNA directly raised from the possibility of random DNA fragment integration when DNA is used to derive iPSCs. This procedure is based on the in vitro transcription by the means of templates previously amplified by molecular biology techniques to encode the four Yamanaka reprogramming factors. A strong limitation related to the employment of this procedure is due to the multiple administrations required to gain an adequate protein expression levels, therefore the entire reprogramming process consists in a daily mRNA transfection and the derivation of iPSCs can take up to 18 days. Nonetheless, the transfection of human dermal fibroblast with Yamanaka’s reprogramming factors combined with Nanog and LIN28, from Thomson’s approach, have been reported as inducing the arrangement of cells in colonies as early as 24 h after the first transfection (Figure 1). [18, 19] To increase the efficiency of the technique, the delivery of mRNAs is combined with hypoxic culture conditions that seem to double the efficiency of reprogramming. However, direct cell reprogramming mediated by mRNA is risky, as the numerous and repeated administrations of them to ensure a high expression level of proteins of interest can eventually trigger the activation of c-Myc, with a high risk for tumor development. A pivotal improvement for this procedure could target the frequency of mRNAs administration and the activation of the oncogene c-Myc.
MicroRNAs are small molecules of non-coding RNA primarily involved in gene expression regulation at both transcriptional and post-transcriptional level; in particular, they are responsible for gene silencing. Several studies have reported that including microRNAs in the traditional procedures employed for reprogramming can positively impact the efficiency of the process. Equally to other procedures not requiring DNA, reprogramming by microRNAs produces iPSCs free from exogenous DNA integration, but the needing of multiple administrations makes the procedure complicated and time consuming. [44]
To overcome the issue related to the introduction of exogenous DNA into derived iPSCs, another approach consists in the employment of recombinant proteins as reprogramming factors. Protein-based reprogramming carries the advantage that it does not cause any genetic changes. As already mentioned, current methods of protein-based reprogramming are less efficient that lentiviral delivery of Yamanaka factors. [42, 45] Typically, synthesized in bacteria, Yamanaka factors are modified so that they express basic amino acids or other transport peptides enabling to cross the cell membrane. [4]
Some studies have led to the development of different methods to isolate, purify, and then deliver reprogramming factors in form of recombinant proteins. [33, 45]
The reprogramming mediated by recombinant proteins is challenging and need several improvements. The synthesis of a consistent amount of proteins is quite hard and requires specific skills that make the technique ineffective for a number of laboratories.
The modern trend for cell reprogramming consists in the direct conversion of a cell into another by the means of exosomes containing a cocktail of reprogramming factors for a specific purpose, named reprosomes. With the respect to the iPSCs, reprogramming cells by exosomes seems to be more likely for clinical applications, as it requires easier procedures and the risk for tumor formation and mutations is low. [46]
Exosomes are nanovesicles with a size ranging between 30 and 200 nm. They are secreted by all cell types and circulate in many body fluids, from where they can be easily isolated. After the discovery that exosomes are able to transfer molecules of biological relevance, like mRNA, miRNA and proteins to one cell to another eliciting phenotypical changes, several studies are ongoing to define their potential as an integration-free method for cellular reprogramming. Despite several advantages offered by the use of exosomes, like the easy extraction method, the reduction of immunological host response and the possibility to reprogram cells without genetical manipulation, their effective employment is still under investigation and the procedures for their isolation and characterization are still limited by a low efficiency and a poor specificity. [47, 48]
The improvement of non-integrating methods is now the target for cell reprogramming to derive iPSCs. In fact, these methods do not require the incorporation of viral genome into the host cells, avoiding the risk of tumor development. The safety of these methods, that makes the derived cells more appealing for clinical applications, is a common strong point, although beside the above-mentioned specific issues related to each method, the common major weakness is represented by a general low efficiency respect to the traditional integrating approaches. The original protocol proposed by Yamanaka for generating iPSCs from adult somatic cells was based on the insertion of only four factors: octamer-binding transcription factor-3/4 (OCT3/4), SRY-related high-mobility group (HMG)-box protein-2 (SOX2), Myc, and Kruppel-like factor-4 (KLF4), or Nanog and LIN28 instead of Myc and KLF4 [4]. A major obstacle in cellular reprogramming, beside the risk of tumor formation due to the integrating methods, is the very low efficiency of the reprogramming procedure, strictly related to several factors, such as the type of cell to be reprogrammed, the method of delivering the reprogramming factors and culture conditions. Although the non-integrating methods offer a safer way to produce iPSCs for further clinical application, it is crucial to focus on the enhancement of the efficiency of the existing and ongoing protocols. In this respect, several strategies have been developed, such as the employment of promoters or enhancers boosting the reprogramming of somatic cells have being developed. Regulatory genes involved in proliferation and cell cycle modulators represent a valid example among the approaches proposed, although if on one side they allow a better yield, on the other they have the disadvantage of being potentially tumorigenic. [49, 50]
Additional candidates investigated for their ability to increase up to 100 folds the efficiency of reprogramming, due to their capability of remodeling chromatin, are small molecules and inhibitor factors, such as valproic acid (VPA) and histone deacetylase (HDAC) inhibitor. Further, the use of VPA together with hypoxic conditions greatly boosts the efficiency of reprogramming. [51, 52, 53] The remodeling of chromatin induces a dynamic modification of chromatin architecture that allows the access to the condensed DNA by proteins involved in transcriptional regulation mechanism and responsible for the modulation of the gene expression in the cells. [54]
Other factors heavily impacting on the efficiency of reprogramming are culture conditions, the possible employment of supporting feeder cells, and the composition of culture medium. [55, 56] It is well documented that reprogramming under hypoxic conditions of 5% O2 instead of the atmospheric 21% O2 increases the reprogramming efficiency of mouse embryonic fibroblasts (MEFs) and human dermal fibroblasts. The presence of a layer of feeder cells is extremely important to support cells during the reprogramming procedures, as feeder cells are responsible for the secretion of growth factors essential for cell survival. Usually, mouse feeder cells are used to support the growth and culture of iPSCs, but they must be removed before the use in clinical applications. Basically, feeder cells consist in a layer of growth-arrested cells unable to divide, which provides extracellular secretions to help other cells to proliferate. However, the use of animal derived feeder cells rises safety issues for the clinical applications due to the contamination of pathogens cross-transfer. To overcome this limitation, the use of Matrigel, a mixture of extracellular matrix proteins such as laminin, collagen and fibronectin, and supplemented with a medium conditioned by feeder cells, as substitute supporting layer is widely popular to produce and support iPSCs. [19, 57, 58]
A successful reprogramming also depends on the choice of the proper cell type to reprogram. The original protocol proposed by Yamanaka included the use of fibroblasts, first from mouse, then from humans, and these cells still remain the favorite cell type, primarily for the easiness of harvesting by skin biopsy. However, even among the different types of fibroblasts several studies highlighted that they are not reprogrammable with the same efficiency [18]; hence, other cell sources need to be found. In fact, the specific promptness of cell to be reprogrammed is strictly related to the endogenous expression of some reprogramming factors and from the starting differentiation state. Currently, there are different strategies, which allow choosing the appropriate cell source, the delivery method, and the system to boost the efficiency of cell reprogramming to derive iPSCs in the safer manner. Nevertheless, all these techniques need to be strongly boosted in order to be considered useful for a clinical application of the derived iPSCs.:
The authors declare no conflict of interest.
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