Main studies on therapeutic delivery with MNDs. Adapted from [56].
\r\n\tEqually important are the consequences deriving from the extraordinary nature of the present times. The COVID-19 pandemic and the restrictive measures to contain the infection (lockdown and "physical distancing" in primis) have revolutionized the lives, and a distortion/modification of habits, rhythms, arrangements will continue to be necessary.
\r\n\tGovernments have implemented a series of actions to mitigate the spread of infections and alleviate the consequent pressure on the hospital system. On the other hand, the Covid-19 pandemic has caused a series of other cascading effects that will probably be much more difficult to mitigate and which expose to complex consequences. The past two years have brought many challenges, particularly for healthcare professionals, students, family members of COVID-19 patients, people with mental disorders, the frail, the elderly, and more generally those in disadvantaged socio-economic conditions, and workers whose livelihoods have been threatened. Indeed, the substantial economic impact of the pandemic may hinder progress towards economic growth as well as progress towards social inclusion and mental well-being.
\r\n\t
\r\n\tAlthough in all countries the knowledge on the impact of the pandemic on mental health is still limited and mostly derived from experiences only partially comparable to the current epidemic, such as those referring to the SARS or Ebola epidemics, it is likely that the demand for intervention it will increase significantly in the coming months and years. The extraordinary growth of scientific research in the field of neuroscience now offers the possibility of a new perspective on the relationship between mind and brain and generates new scenarios in understanding the long wave of the pandemic and in the prospects for treatment. Moreover, the pandemic also has led to opportunities to implement remote monitoring and management interventions.
\r\n\t
\r\n\tOverall this volume will address the complex relationship existing between COVID-19, mental health, acquired knowledge, and possible interventions taking a highly multidisciplinary approach; from physiological and psychobiological mechanisms, and neuromodulation through medical treatment, psychosocial interventions, and self-management.
Mammalian ovulation is a fundamental physiological process involves the rupturing of follicle and releasing of the dominant follicle from the ovary into the fallopian tube where it has the potential to get fertilized if it exposed to sperm. Oocyte is covered up of four different layers namely the granulosa cells, which form a protected layer within oocyte and the extra follicular microenvironment, then theca layers of theca-interna and theca-externa, tunica albuginea and the outermost one is epithelium [1, 2]. A thin transparent layer between oocyte and follicular membrane is made up of secretions by the oocyte, termed as zona pellucida [2].
\nThe developing oocyte enclosed in a ovarian follicle which is float in a dynamic fluid i.e. Follicular fluid (FF), contain variety of signaling molecules such as polysaccharides, hormones, cytokines, chemokines, growth factors, reactive oxygen species (ROS), metabolites, antioxidant enzymes, etc. The follicular fluid formed in developing antral follicles, primarily to support the development and protection of oocytes. These molecules are also acts as communicators between somatic and germ cells [3].
\nThe duration of ovulatory process in humans, pigs, rats and rabbits takes approximately 40, 22, 12 and 10 hours respectively to complete. Substantial tissue remodeling occurs during the ovulation, the follicle increases its own size, and the layers of theca cells fuse with the tunica albuginea, resulting into thinner and permitting rupturing of follicle to release the oocyte [4]. The mature oocyte when released by the rupturing of follicle its uptake facilitated by the fingure like opening projections of fallopian tube which is known as fimbriae, if fertilization occur here then the blastocyst further transfer it towards the uterus where the pregnancy takes place [5].
\nInflammation is defensive mechanism of the cells that is crucial to health and it is delineated as a local immune response of living vascularized tissues to endogenous and exogenous stimuli and its actions is to removal of injurious stimuli with starting the healing process [6]. Inflammation is also initiated when the cells die from deficiency of nutrients or hypoxia, a condition that often is originated by the blood flow loss to the site. The chemical mediators of the inflammation generally originate from the blood plasma, platelets, white blood cells (monocytes, neutrophils, basophils, and macrophages), endothelial cells lining of the blood vessels, mast cells, and injured tissue cells. The chemical mediators responsible for the inflammation is histamine, that stimulates vasodilation and increases the vascular permeability, and lysosomal substances acting as vascular permeability enhancer which are secreted from neutrophils, and certain small proteins in the complement system, namely C3a and C5a. Various cytokines released by inflammatory cells also have vasoactive and chemotactic function. Many cells produce prostaglandins which linked to the fever and pain of inflammation; a group of fatty acids which involves in the augmentation of vascular permeability of the other substances, platelets aggregation; which is essential for coagulation [6].
\nThe objective of this review is to understand and establish a relationship between how the inflammation as well as different mediators of inflammation that influence the ovulation process that is crucial for clinical management and prediction of gynecological complications for future study.
\nInflammation is detected throughout many normal reproductive progressions, for the duration of ovulation, menstruation, implantation, as well as parturition. Ovulatory cycle is also considered as inflammatory process because the rupturing of dominant follicle undergoes the process of healing [7]. Throughout ovulation, the role of inflammation is very significant in terms of folliculogenesis and luteinization. In the course of the rupturing of follicle, there is significant surge of intra-follicular pressure which leads to weakening of follicle layer by the stimulation of gonadotropins resulted in inflammation [8]. The inflammation notably persuades in both ovulation and tissue remodeling phase which resulted in events of hyperemia, vasodilation, edema, collagenolysis, and proliferation of cells [1].
\nWissing et al. isolated differentially expressed 1186 genes in human granulosa cells (GC) before and 36 h after the administration of hCG, besides 572 genes found to be up-regulated which represented angiogenesis, inflammation, extracellular matrix and growth factors and 614 genes down-regulated which denoted cell cycle and about 72 genes which has been earlier establish linked with ovarian cancer. H19/mir675, CD24, CLDN11, ANKRD22, and FBXO32 adds as new ovulation related genes and PTGS2, an inflammatory gene heavily up-regulated [5].
\nThe release of mature oocyte relies on the expansion of cumulus oocyte complex (COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. Residual growing follicles promoted to apoptosis by the ROS [8]. Simultaneously estrogen synthesis started with the influx of catalase and Glutathione (GSH) i.e. a non-enzymatic antioxidant species exists in oocytes and embryos, in growing residual follicles for the maintenance of normal ovarian function and counter the apoptotic process. The luteal phase begins with progesterone production for the maintenance of preliminary stage of pregnancy, if fertilization did not occur then degeneration of corpus luteum starts [2]. For the induction of cell proliferation, maturation, cellular-differentiation and ovulation the physiological level of ROS is very important [9]. Augmented ROS may outcomes to DNA damage, activation of signaling cascades, and epigenetic alterations [10]. Inflammation in the course of ovulation is also responsible for the oxidative stress, damaging of DNA and moreover in the neoplastic ovarian surface epithelium (OSE) cells transformation [11].
\nElevated level of inflammation also involves in the pathogenicity of many reproductive disorder such as polycystic ovary syndrome (PCOS), characterized by biochemical hyperandrogenemia, chronic anovulation, and polycystic ovaries. About 5 to 15% of reproductive age woman are suffering with this disorder in the world. It is anticipated that the metabolic disorders associated with PCOS and the pathogenesis of PCOS due to systemic inflammation as well as dysfunctioning of mitochondria. About 33% adolescent PCOS girls are more prone to metabolic disorder are obese, which is 3 to 5 folds higher if compared with same age healthy girls and body mass index (BMI) [9]. Studies reported and found the significant increased level of monocytes, lymphocytes, CRP, interleukins IL-1, IL-6, IL-18, pro-inflammatory cytokines and TNF- α in addition to increased production of advanced oxidation protein, protein carbonylation and lipid peroxidation in PCOS patients compared with same reproductive aged healthy persons [9]. The PCOS patients suffered with chronic inflammation [12, 13]. Along with the deficiency of antioxidant i.e. Vitamin C, Vitamin E and Superoxide dismutases (SOD), this leads to cause inflammatory milieu and risk to develop the obesity, type-1 diabetes, insulin resistance, hyperandrogenism, and cardiovascular ailment [1, 14].
\nThe surge of luteinizing hormone (LH) stimulate the production of cyclic adenosine monophosphate (cAMP), steroidal hormones, histamine discharge and various mediators of inflammation e.g. prostaglandins, bradykinins, C-reactive protein (CRP), Proinflammatory cytokines, etc. [1]. Christina et al. study states that the successful folliculogenesis, oocyte maturation, and ovulation require a healthy inflammatory response.
\nThere are many findings illustrate that the importance of untroubled inflammatory response for proper folliculogenesis and ovulation, if it altered, may contribute to oocyte quality concern and reproductive dysfunctions such as anovulation, infertility, menstrual irregularities, etc. [5, 8]. It is reported that low dose of Aspirin taken by the patients suffering with higher systemic inflammation were able to reestablish the pregnancy [4, 12].
\nThe level of LH also positive correlation with release of prostaglandins and eicosanoids that are the source to trigger the fibroblasts, promotes the angiogenesis and hyperemia, collagenase activation, release of proteolytic enzymes, some of which degrade the follicular connective tissue resulting ovulation, and cause the inflammation. The gene hyaluronan (HA) synthase-2 (Has2) associated with COC matrix formation. Bradykinin play a key role in vasodilation which appears to be 10 folds increased during ovulation. The serum C- reactive protein (CRP), a marker of inflammation also raised to stimulate the production of interlukin-6 from macrophages, tumor necrosis factor α (TNFα) and the competent system of inflammatory response further activated by the adipocytes [13].
\nThe role of proinflammatory cytokines is also important throughout folliculogenesis and induction of ovulation [5]. Higher level of follicular TNF-α resulted in the poor quality of oocyte which compromised with the fertility, also the elevated level of interleukin (IL-6) associated with less chances of conceiving while the another interleukin (IL-1) found to be regulated by FSH and its higher follicular level has been resulted in the higher chance on embryo implantation [7, 15].
\nA recent finding added a new mechanism for ovulatory process regulation, suggested that the NLRP3 activation of nucleotide leukin rich polypeptide 3 (NLRP3) inflammasomes started before the ovulation lasting completion of ovulation. They induces the follicular development by 52 hours’ treatment using Pregnant mare serum gonadotropin (PMSG). It was found that the expression of NLRP3 inflammasomes and adaptor protein apoptosis-associated speck-like protein (ASC) significantly increased, and it was appeared a dramatic surge in caspase-1 activity and production of IL-1β [16].
\nGonadotropin surge trigger the ovlation with the parllel stimulation of two gens of preovulatory follicles in granulosa cells, prostaglandin-endoperoxide synthase 2 (PTGS2) and progesterone receptor (PGR). Secretion of LH stimulates the induction of both PTGS2 and PGR in preovulatory granulosa cells. Expression of PTGS2 stimulates inflammation by releasing pro-inflammatory prostaglandins wheras anti-inflammatory action through the PGR by the supression of pro-inflamatory genes or thru the stimulation of antiinflammatory genes. Higher level of PGE2 and PTGS2 are associated with the ovarian disorders such as ovarian carcinoma, ovarian hyperstimulation syndrome (OHSS) as well as polycystic ovarian syndrome (PCOS) [11].
\nProstaglandins (PGs) are signaling molecules derived from dietary fats with clinically relevant roles in reproductive biology. PGE2, for instance, promotes ovulation downstream of the luteinizing hormone surge. Excess consumption of nonsteroidal anti-inflammatory drugs, which inhibit prostaglandin-endoperoxide synthase (cyclooxygenase or Cox), is associated with reversible female infertility, likely due to failed ovulation. On the other hand, proinflammatory cytokines increase PGF2α associated with corpus luteum development and immune cell recruitment [17].
\nA study (Bongrani et, al.) based on the adipokines roles in the pathophysiology of PCOS, they analyzed the adipokines profile in the normal-weight PCOS patients and obese women with PCOS and comparison of these with the women whose only have a Polycystic ovary morphology. Whereas they found the PCOS patient reported with lower adiponectin level in serum as well as FF, and also the lower expression in adipose tissue of AdipoR1 and AdipoR2. In granulosa cells AdipoR1 expression was positively correlated with the follicular numbers, oocytes count and embryos, on the other hand there was no significant difference in AdipoR2 reporters was found. No correlation was established among the FF adiponectin concentration and expression of its receptor, AdipoR1/AdipoR2 in GCs. Dysregulation of adiponectin may be likely mechanisms which could be responsible for impairment of insulin-sensitivity in PCOS patient, and it seems to be independent of insulin resistance severity and a potential role of adiponectin in folliculogenesis.
\nThe concentration of Omentin in FF was found to be positively correlated with BMI, higher in obese patients compared to the normal weight patients. They also point out that the omentin may possibly be controlled by means of inflammation, because the expression of omentin altered in inflammatory conditions [18].
\nROS is necessary to maintain the normal female reproductive physiology, it is involved in the oocyte maturation, corpus luteum apoptosis as well as embryonic development process. The release of mature oocyte depends on the expansion of cumulus oocyte complex (COC), where the reactive oxygen species (ROS) function as critical modulator of inflammatory reaction. The exposure of ROS may lead to undergo transformative alterations of epithelial cells in the ovary and fallopian tubes [10].
\nIt has a significant role in the process of ovulation as well as to excrete out the damaged corpous luteum from the ovarian tissue. It works by the ligand gated receptors, TNFR-I and TNFR-II [10, 19]. It is also linked with the various pathological conditions when its level elevated. It is also reported that the infertile women with PCOS reported to have higher free fatty acids and blood serum level of TNF-α when compared with the healthy patients. Oxidative stressed cells also found to release higher levels of TNF-α than the normal ovarian epithelial cells which results in an autocrine surge of TNF-α mRNA as well as in the form of expression in other pro-inflammatory cytokines, chemokines, and angiogenic factors [10, 20, 21].
\nInterleukin-15 is an important interleukin which is negatively associated with the oocyte maturation. It belongs to the cytokines family having four α-helix bundle, i.e. pleiotropic glycoprotein. It was reported to be higher in women with an unsuccessful assisted reproductive techniques outcomes (median value 1.4 pg./ml) than of the women those succeeded the clinical pregnancy (median value 0.8 pg./ml) [22]. The IL-6 is a regulator of cumulus cell-oocyte complex (COC) expansion and responsible for the quality of murine oocyte during the in-vitro fertilization.
\nThe another factor which has been found to be involved in follicular development as well as in the ovulation process are Matrix metalloproteinases (MMPs). The matrix metalloproteinases activities regulated by the specific tissue inhibitors called metalloproteinases (TIMPs) and endogenous inhibitors. The balance of both these is very essential for their activity and to maintain the normal ovarian physiology. It is well noticed that the MMP-2 and MMP-9 level increased during and before the 3 hours of ovulation if compared to 20–22 hour before the ovulation. Augmented level of MMP-9 also postulated in the PCOS pathophysiology and is also linked with progression and etiological to many other ailments such as cystic fibrosis, asthma, ulcerative colitis, cardiovascular disorders, atherosclerosis, etc. [23, 24].
\nThe Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) is established to have an ability to prevent the expression of various signaling molecules also regulates the levels of prostaglandins through regulation of cyclooxygenase-2 and differentiation of immune cells especially those which are a part of inflammation. Thereby controls ovarian function, fertilization, and ovulation. Its proinflammatory activity is linked to the formation of prostaglandin E by downregulation of COX-2 mRNA of granulosa cells whereas it is upregulated twice in PCOS [25]. It is also being proven that the PPAR-γ controls genes responsible for expression of TNF-alpha and Interleukins along with others. The study is supported by use of PPAR-γ agonist which affected the functioning of ovaries by involving signal transduction of insulin and IGF [20].
\nEarlier study reported the expression of chemokine receptor-2 (C-C motif) (CCR2) in the human ovarian cumulus-oocyte complexes, theca cells, preovulatory follicles and in feline ovarian follicle walls. This receptor is believed to be involved in folliculogenesis and determines the reproductive lifespan of female [25] (Figure 1).
\nInflammatory process in ovulation.
Inflammation is believed to be involved in triggering the process of ovulation. There are several factors, genes, receptors, proinflammatory mediators playing important but diverse role in ovulation. The extent of their role and intensity of reaction induced by them required to be studied to understand their clinical applicability.
\nWe acknowledge the financial help received from Grant4Target.
\nThe authors declare no conflict of interest.
A new type of biomedical devices was born when technologies and facilities for Micro and Nano Electro Mechanical Systems (MEMS and NEMS) fabrication have met medical and biological issues. These new kinds of biomedical devices are able to easily control physical and chemical parameters at a very small scale, down to nanomolar concentrations and nanometric sizes [1, 2, 3]. Moreover, the integration of such a device in wearable and/or mobile systems gave them popularity among commercial devices. In this technological frame, Microneedles based devices (MNDs) were born. Their height is sufficiently large to overcome the outer natural barrier of the human body, the stratum corneum of the skin, but not enough to reach the nerves, resulting in a lack of pain [4]. Usually, MN height is ranging from 10 to 1000 μm, depending on the application and how deep in the epidermis is the specific target analyte. Then, MNs based devices act as an interface between the body of the patient and a biomedical device, whose applications can range from fluid extraction for ex-situ analysis to drug and gene delivery, from
(A) Sketch of different MNDs for sensing purposes together with their working conditions into the human skin. Starting from the right, they are characterized by the locus of probe-analyte interaction: Swelling bulk MNs sensors (BMNDs), where probe-analyte interaction is inside the volume of MN; hollow MNs sensors (HMNDs), where a small material sampling of ISF is analyzed on or offline; coated MNs sensors (CMNDs), whose surface is the locus of the interaction between analytes and bioprobes; planar MNs sensors (PMNDs), where the probe–analyte interaction is on a specific zone of a flat MNs surface. (B) some configurations for MNs for drugs delivery: (from left) hollow MNs present a inner cavities to immediately administration of high dose and high MW drugs; soluble and hybrid MNs for fast administration with a high doses and medium MW; coated MNs for fast administration of low doses and any MW; swelling MNs for very slow administration of high doses of smaller molecules. Reproduced with permission of Ref. [
Moreover, microneedle-based devices (MNDs) can combine diagnostic sensing and therapeutic administration of drugs in one single tool. From this point of view, more than a painless door to the human body, a MND represents the a perfect example of theranostic instrument, since a single device could quantify the real value of a relevant biomolecule, such as glucose, and accurately deliver a drug, the insulin, if needed. MNDs are particularly interesting as simple drug administration tools, too. In fact, the transdermal route for drug administration is a very fascinating way, not only for the very low invasiveness and the easiness of self-administration, but also for the absence of first pass metabolism. However, the intercellular lipid matrix of the epidermis consists of ceramides, free fatty acids, and cholesterol, a complex mixture of neutral lipids arranged as bilayers with hydrophobic chains facing each other (lipophilic bimolecular leaflet) [9]. Transdermal delivery works only for lipophilic uncharged drugs with low MW (<500 Da), which need low dose and continuous delivery. Moreover, components, formulations and drugs must be non-irritating and non-sensitizing. MNs can be used with both lipophilic and hydrophilic formulations, both charged and uncharged drugs, both small and oversized molecules.
For all these cases, MN configurations are illustrated in Figure 1B, where the possibility to use solving or hybrid soluble/insoluble MNs are considered.
MNDs could be integrated on printed circuit boards, flexible electronics and microfluidic channels, thus allowing a continuous monitoring of the physiological parameters with very low invasiveness, together with sustained and localized administration of drugs. MNDs can be designed for very specific applications, from the detection of skin cancer to the monitoring of metabolic pathways.
Technologies, skills and facilities for Micro and Nano Electro Mechanical Systems (MEMS and NEMS) fabrication are the key elements for the development of new biomedical devices [1, 2, 3, 10]. Fabrication methods for Microneedles (MNs) strongly depend on the MNs shape, tip model, length, density of the MNs matrix, and the material of which they are made of.
Moreover, structural characteristics of the MNs matrix in turn depend on the specific application considered [11]. In fact, MNDs are exploited in fluid extraction [12] and
At first, Silicon and silicon-based nanostructured materials, such as porous silicon, were largely employed in MNDs fabrication due to the well-established functionalization chemistry protocols and fabrication techniques, extenseively used in microelectronics, which simplified the integration into more complex systems [14]. However, silicon revealed to be a non-biocompatible material, due to its fragility and to the local inflammations (silicosis) it could provoke; for this reason its use has been limited in cell applications [15].
To overcome limitations on the use of silicon, polymers have been extensively proposed as alternative materials in many applications. Poly Dimethyl Siloxane (PDMS) is one of the most used materials in microfluidics to design biomedical devices, due to its well-known biological compatibility [16]. Usually, PDMS is employed as mold to fabricate MNDs by replica molding (see Figure 2). In case of PDMS molding, the fabrication involves the following steps: female PDMS mold fabrication by means of standard photolithography or laser drilling; patterned MNs in PDMS mold filling with liquid polymers in vacuum conditions; curing of the polymers by temperature and/or UV exposure; mold removal; eventually, an additional curing step [16]. Biodegradable polymers have been largely employed in MNDs for drugs delivery application [20, 21, 22, 23, 24], but the biodegradability is not required for biosensing.
Main fabrication strategies for MNs fabrication. Replica molding [
A direct method for MNDs fabrication is the so-called drawing lithography [19]. Drawing lithography is a fabrication method, which does not need light irradiation and a mask, since it is based on the use of a thermosetting polymer directly drawn from a 2D solid surface (see Figure 2). In drawing lithography, commercial photoresist is usually spin coated or drop casted onto the substrate and cooled down. Drills are fixed in an array on a PDMS frame and used as pillars contacted with the photoresist. Conical-shaped bridges between the substrate and the pillars appear when their relative distance is increased by drawing (elongation). The bridges are cured to generate a rigid structure. Finally, the separation of the bridges produces the desired MND.
However, drawing method lacks in flexibility and the curing at high temperature of the polymers encapsulating biopharmaceutical molecules can cause their denaturation or inactivation. In fact, MNDs encapsulating drugs or bioprobes must be fabricated in a controlled environment to preserve the biological activity.
The increasing demand for simple methods that preserve the biological activity by utilizing the natural properties of polymers has conducted to the idea of centrifugal lithography [17]. In [17], centrifugal lithography was used for the fabrication of MNDs in a single centrifugation, by exploiting the self-shaping properties of hyaluronic acid (HA). Briefly, fabrication involves the following steps: HA drops encapsulating drugs molecules are casted onto the substrate; centrifugal force is applied under refrigerated conditions (4°C) to the droplets in order to shape in hourglass microstructures; finally, the mirroring shapes are separated to form MNs. Also in the case of HA, drug delivery is successfully obtained, but biosensing is unavailable due to its biodegradability.
On the other hand, hydrogel polymers are very attractive materials for MNDs and, generally, for biomedical devices, since a hydrated gel provides near physiological conditions. These gels are excellent encapsulation matrices for biological probes, such as enzymes and peptides [18, 20, 25, 26]. Moreover, the standard photolithographic processes can be employed to fabricate micrometric devices based on polymeric hydrogels [materials] (Figure 2). In [6, 18, 27, 28], authors proposed procedures of standard direct photolithography, where a mixture of Poly(ethylene glycol) diacrylate (PEGDA) and a commercial photoinitiator were used as an ordinary photoresist, without any etching step being required. In fact, PEGDA is a biocompatible polymer that solidifies at room temperature in presence of a photoinitiator after exposure to ultraviolet (UV) light for few seconds. In case of photolithographic process, the fabrication involves the following steps: the liquid photosensitive polymeric mixture is casted onto a UV-transparent substrate and exposed to ultraviolet radiation, in order to fabricate the MNDs base; a vessel is fulfilled with a second quantity of liquid mixture and the MNDs base is put on; a second exposure through a mask, whose pattern is an array of holes, is applied; finally the structure is developed by simply washing in deionized water. The PEGDA mixture can be customized to encapsulate a variety of drugs or sensing probes as biological molecules or inorganic nanoparticles [29, 30, 31].
Comparing the fabrication methods, all produced MNs have demonstrated high quality in indentation proof and a good grade of reproducibility, with some critical issues during the mold removal step in replica molding method.
Finally, we highlight that the photolithographic approach allows the fabrication of MNDs for a wide range of applications. In fact, this process allows the design of a wide range of MN types with different shape, length and tip, simply by adjusting the exposure parameters or shape photolithographic masks [18, 28]. In Figure 3, the whole range of possibilities enabled by photolithographic method are summarized: mask type 1 (simple circle) enables MNs with several heights depending on time exposure; mask type 2 (ring) enables hollow MNs with height and closure depending on time exposure; mask type 3 (mismatched concentric ring) enables in a single exposure the fabrication of hollow MNs with a lateral oblique aperture as in hypodermic syringes. Also in this case, lateral aperture is smaller as the exposure time increases.
The photolithographic methods offer a wide range of solutions for MNDs. Changing time exposure and/or photolithographic mask several configurations and arrays of MNs for both therapeutics and biosensing can be fabricated. From above: Mask type 1 (simple circle) enables MNs with several heights depending on time exposure; mask type 2 (ring) enables hollow MNs with height and closure depending on time exposure; mask type 3 (mismatched concentric ring) enables in one only exposure hollow MNs with a lateral oblique aperture, which is smaller as the exposure time increases.
MNs represent actually a flexible technological platform, which enables innovative diagnostic solutions and breakthrough therapeutic issues in biomedicine [1, 2, 3]. First, finding a painless alternative to hypodermic injections has driven researchers to the development of MNDs. In fact, belonephobia, which is the unreasonable fear of needles, affects up to 10% of the population and has implications for treatment and follow up, especially in the pediatric patients [32]. In reverse, the sensation caused by MNs has proved to be statistically indistinguishable from a smooth surface and the pain caused by a hypodermic needle has been perceived substantially more than MNs [4]. Moreover, as previously stated, the transdermal route for drug administration is a very fascinating way, not only for the very low invasiveness and the easiness of self-administration, but also for the absence of first pass metabolism. However, the intercellular lipid matrix of the epidermis consists of ceramides, free fatty acids, and cholesterol, a complex mixture of neutral lipids arranged as bilayers with hydrophobic chains facing each other (lipophilic bimolecular leaflet) [9]. Transdermal delivery works only for lipophilic uncharged drugs with low MW (<500 Da), which need low dose and continuous delivery. Moreover, components, formulations and drugs must be non-irritating and non-sensitizing. MNs can be used with both lipophilic and hydrophilic formulations, both charged and uncharged drugs, both small and oversized molecules. In fact, currently, interesting MNDs are involved in clinical trials both for some topical applications, as analgesic compounds, anti-inflammatory or anesthetic drugs, and for some traditional systemic drugs, such as anticancer drugs, vaccines, insulin or hormones [33].
Among the topical applications, MNDs can replace very invasive methods for warts therapy, such as electrocautery and cryotherapy. A MND developed by Ryu et al. for warts treatment resulted to be innovative and effective [34]. In this study, quite 40 patients with wart lesions were enrolled and referred less pain than cryotherapy, as well as more tolerability with respect to electrocautery. Other skin diseases have been treated by means of MNDs, as melasma in [35], where authors fabricated biocompatible polymeric MNs based on methacrylic acid and polyvinyl pyrrolidone (PVP) to locally administer tranexamic acid, an innovative molecule that inhibits excessive melanin production by acting on melanocytes.
Acne vulgaris is another common inflammatory skin disease, affecting both physiologically and psychologically on patients. Barrier properties of skin strongly limit the usual antibiotic drug creams used to cure acne, but the use of MNs can overcome this limits, by using a reactive oxygen species–responsive [36]. In some
On the other hand, also administration of systemic drugs by means of MNDs showed good results in effectiveness, safe and economic efficiency as disposal devices. A wide range of molecules has been proven to be compatible with MNDs and each category of drug showed specific advantages compared to the use of oral or hypodermic administration.
First of all, vaccine delivery is probably the most involved health issue in MN technology, due to the large number of people involved each year. Nguyen and Park recently reviewed MNDs enrolled in human studies and reported the progress of MNDs in the clinical trials [38]. Finally, the use of MNs in therapy for clinical vaccine was recognized as very important, but further tests are recommended.
When MNDs is used to deliver vaccines based on DNA, some studies show that the gene expression is improved with respect to the results of conventional hypodermic injection. Consequently, the use of MNs to administrate DNA based vaccine results in an improvement of the immune responses [38, 39]. In [39], Authors hypothesized that the improvement of the immune response by delivering DNA vaccine by means of MNs could be due to the enhancement of the protein expression of the encoded gene.
Another important issue of vaccine administration improved by MNDs is the stability of the active ingredients into dissolving or swellable MNs. Encapsulation of inactivated polio vaccine (IPV) into dissolving MNs gains a better thermal stability with respect to that of the conventional liquid formulation of IPV [40]. The greater thermostability of the MN patches can generally enable a mass distribution with less constrains on cold chain storage resulting in a great reduction of costs, since global vaccination strategies require large immunization coverage. Moreover, new MNDs have been proposed as an alternative solution to the standard needle injections, for the advantage of self-vaccination.
Further studies have been done to elucidate the interactions between polymers and vaccines, as in the case of hydrogel based MNs and dissolving MNs. In these cases, the antigen ovalbumin was used as a model protein interaction with polymers and the consequences on the immune response [40, 41].
Hollow MNs have the advantage of overcoming the skin barrier imposed by the stratum corneum and delivering bigger molecules, such as macromolecules or nanoparticle systems, in the fastest possible way. Polymeric nanoparticles encapsulating the model antigen ovalbumin have been intradermal delivered by means of hollow MNDs by Niu et al., reporting that this kind of delivery is a promising approach to improve the effectiveness of vaccine formulations [42]. Among the dissolving devices, MNs based on hyaluronic acid (HA) resulted a promising encapsulation method of high content of antigen molecules in intradermal vaccination [43].
Also anticancer drugs belong to an important field of application of MNDs: two research groups have investigated on DOX administration by means of MNs in [44] and in [45]. Nguyen et al. found
Moreover, lipophilic drugs found a lot of benefits from the use of MNs: poorly soluble drugs were encapsulated and easily administrated by MNDs, as in the case of the widely used specific 5-HT3 receptor antagonist, namely granisetron, that prevents nausea and vomiting during emetogenic chemotherapy in cancer patients [46].
An innovative pharmaceutical solution involving a MND in the field of HIV treatment has been proposed by Yavuz et al. in [47]. Also in this case, the self-injection route of administration represents the key issue for care improvement, since it limited the risks of contamination of the personnel involved in therapy and guaranteed a painless delivery for the patients via patches of microneedles.
New drugs and innovative therapies have been put in place with the help of MNDs. In particular, polymeric MNs have been widely exploited for their porous nature, which is expressed both by soluble MNs and by simply biocompatible ones. In [48, 49], anti-obesity substances have been successfully administered. These substances modified the metabolic process by increasing the energy consumed and transforming the white fat that stores calories into brown fat that burns calories [48]. While in [49], gelatin MNDs were used to induce lipolysis and suppress adipocyte lipogenesis in fatty rats.
Particular attention has to be paid on insulin delivery, since diabetes is one of the most common diseases, not only in elder patients, but also in obesity-affected patients.
Avoiding use of enzymes, a polymeric MND has been developed for on-demand insulin delivery by Chen et al. [50]. Continuous and acute glycemic control was realized with a long-acting, safe, stable, economically efficient and on-demand insulin delivery by MND, without depending on patient compliance. Thus, this technology opens to next generation of diabetes therapies.
In the same field, the treatment of individuals with type II diabetes mellitus has been successfully obtained with metformin HCl, the most widely used drug for this disease, delivered by means of hydrogel MNs [51].
In [52], authors proposed a temperature-independent MND for glucose-responsive insulin release. The rapid and sustained regulation is enabled through a “skin layer” of Phenylboronic acid (PBA), formed on the surface of MNs. PBA is a synthetic hydrogel with reversible binding capability with glucose. Compared to other glucose-responsive MNDs based on nanoparticles or glucose oxidase, the proposed patch overcomes the safety concerns and provides a good sustainability for large-scale production. In Figure 4, a sketch of the proposed glucose-responsive insulin dispensing MND is presented together with main results in on-demand insulin release at physiological temperature.
Adapted with permission from ACS Appl. Polym. Mater. 2020, 2, 7, 2781–2790. Copyright (2020) American Chemical Society. Sketch of device and
Finally, we cite the engage of MNDs in effective administration of small peptides, vitamin K and mRNA administered, both
In Table 1, main studies on therapeutic delivery with MNDs are summarized. Another important issue is the integration of MNs in optical, microelectronic or microfluidic devices. In [6], authors present the proof-of-concept of an optical integrated MNDs based on polymeric MNs and porous silicon (PSi) for transdermal drug delivery (Figure 5). Since its surface can be chemically modified, PSi is one of the most popular porous material used in drug administration [57]. Moreover, PSi structures have a tunable refractive index that depends on their porosity [58]. The MND presented in [6] is based on PEGDA hydrogel MNs and includes a PSi free-standing membrane with a Bragg mirror optical structure, i.e. an optical structure that reflects a specific wavelength (color) in the visible spectrum. Furthermore, the Psi membrane not only acts as a drug/biomolecules reservoir, but also it can be used to optically monitor the released drug, since the reflected wavelength changes with the emptying of pores (Figure 5). In [6], the integrated-chip optical device guarantees the optimum disposable MND, which can be self-administrated and self-wasted, once the drug has been all delivered by only looking at the color variation at naked-eye.
MN type | Disease | Experiments | Refs. |
---|---|---|---|
Swelling | Acne vulgaris | [36] | |
Swelling | Diabetes | [50] | |
Swelling | Diabetes | [51] | |
Swelling | Immunity (vaccines) | [40] | |
Swelling | Nausea and vomiting | [46] | |
Swelling | Keloid scar | [53] | |
Swelling/hybrid | — | [6] | |
Hollow | Immunity (vaccines) | [42] | |
Dissolving | Melasma | [35] | |
Dissolving | Ocular infection | [37] | |
Dissolving | Cancer | [44] | |
Dissolving | Cancer | [45, 54] | |
Dissolving | Immunity (vaccines) | [41, 43] | |
Dissolving | Obesity | [48, 49] | |
Dissolving | Vitamin K deficiency | [55] | |
Coated | Warts | [34] | |
Coated | Immunity (vaccines) | [39] | |
hybrid | Diabetes | [52] |
Main studies on therapeutic delivery with MNDs. Adapted from [56].
The optical integrated MND presented in [
Human interstitial fluid (ISF) is on average between 9 and 13.5 L [59, 60]. Fluid moves from the lymphatic vasculature into the interstitium, among the endothelial walls of cells, then to the blood plasma, and finally returns to the lymphatic vasculature. Analytes enter into the ISF through three paths: first, by transcellular path, through the capillaries; secondly, by paracellular path, through the cell walls; finally, by vesicular path, from the cells to the ISF [61, 62]. ISF moves within a network of glycosaminoglycans, elastin, and collagen and transports electrolytes and metabolites to muscle cells, bone cells, cartilage, tissues, organs and so on [60, 63].
Dermal ISF is localized in the extracellular spaces between the vasculature, connective tissues and the cells. A lot of research efforts have been done to develop extraction methods of ISF in order to obtain an analytical composition and understand the relationship between plasma and ISF. Table 2 summarizes the main ISF constituents, measured concentrations, and typical concentration ranges for healthy people [63].
ISF constituent | Measured concentration | Typical concentration ranges |
---|---|---|
Glucose | 4–8 mM | 4.5–8 mM |
Cortisol | 24–40 nM | Morning: 1–50 nM Afternoon: 27–42 nM |
Lactate | 1.17 ± 0.23 mM | 1–2 mM |
Lipids | 1.5 ± 0.3 μM | Not reported |
Na+ | 141 mM | 135–150 mM |
K+ | 4.4 mM | 3.8–4.9 mM |
Cl− | 110 mM | 99–117 mM |
Main ISF constituents, measured concentrations and typical concentration ranges for healthy people [63].
Since its location just under human skin (the largest human organ) and its relationship with the vasculature system, analysis of ISF has received interest for the realization of new wearable devices.
On the other hand, new diagnostic methods can sensitively, rapidly and accurately detect, analyze and monitor relevant diseases of social interest, and can lead to an effective management of healthcare. Biomarkers and biosensors research receive, then, a constantly increasing thrust.
Despite the transduction method used, innovation in standard sensing technologies is continuously pursued. Although several optical techniques, such as fluorescence, surface plasmon resonance and surface enhanced Raman spectroscopy have been exploited, electrochemical methods, based either on voltammetry or impedance spectroscopy, have been demonstrated to quantify analytes in ISF with high sensitivity and easily integration into a MND [8].
Standard electrochemical sensors are realized confining bioprobes onto an electrode surface directly immersed in a solution, as the ISF. A key issue in the innovation of electrochemical devices is the design of the so-called working electrode, that can increase the performance of the whole biosensor. The development of electrochemical engineered biosensors has been recently the focus of many research groups, which provided several fabrication strategies [64].
Electrochemical sensors based on MNs can analytically monitor biomarkers, drug release, metabolites, electrolytes and other chemical species present in dermal ISF and involved in biological functions. Recently, in [65] authors gave a proteomic characterization of the dermal ISF, extracted by means of a hollow MND. In this work, 407 proteins have been found and quantified [65]. Moreover, less than 1% of these proteins have been identified only into the ISF, confirming that the ISF is strictly connected to both plasma and serum. Then, the MNDs can be minimally invasive alternative devices to blood-derived fluids sensors with potential for real-time monitoring applications. In addition, in [66] an extremely small quantity (<1 nL) of the ISF was extracted by means of a hollow MN to measure drug concentrations and the typically painful blood drawn was avoided. In [66], the inner cavity of a hollow MN was derivatized to bind vancomycin. Optical absorbance is used as off-line transducer method, after extracting ISF with an integrated optofluidic device. The optofluidic MND detected the vancomycin in a sample volume of 0.6 nL with a limit of detection (LoD) of less than 100 nM.
Before being widely adopted into clinical practice, MNDs used as biosensors have to pursuit some general issues: a low cost fabrication; continuous monitoring and/or long-lasting working time; the possibly of integration in MEMS; the protection of the bioprobe, critical in enzyme-based detection; a good electrical conductivity (EC) for electrochemical sensing [67]. Moreover, the biofouling at the tissue–device interface must be avoided to successfully realize a wearable MND sensor [68]. According to Da Silva et al., currently, wearable sensors are still not yet ready for commercial develop, but within a few years MNDs biosensors will conquer the market [69].
In the field of MNDs for diagnostics, as well as for therapy, the approach can drastically vary with shapes and materials; Figure 1A shows a sketch of different MNDs for sensing purposes together with their working conditions into the human skin. Starting from the right, Figure 6 reports: swelling bulk MNs sensors (BMNDs), whose diagnostic approach includes a volume effect in the probe-analyte interaction that will be considered separately; hollow MNs sensors (HMNDs), where a small material sampling of ISF is analyzed on or offline [70, 71, 72]; coated MNs sensors (CMNDs), whose surface is the locus of the interaction between analytes and bioprobes [73, 74, 75, 76, 77, 78, 79, 80, 81]; planar MNs sensors (PMNDs), where the probe–analyte interaction is on a specific zone of a flat MNs surface [82].
Design of the working electrode, optical images with and without metal coating and sketch of working of the MNDs. Experimental data for glucose and lactate acid dose–response. Reproduced with permission of Ref. [
The bulk volume of solid MNs (BMNDs) is often exploited in electrochemical biosensing. Usually, hydrogels and swelling polymers are employed in the fabrication of BMN. Examples are polyethylene glycol diacrylate (PEGDA), polyvinyl pyrrolidone (PVP), polyvinyl alcohol, poly(acrylic acid), poly-l-lactide, poly(lactide-coglycolide acid) and poly-N-isopropylacrylamide [83, 84]. These types of polymers can be processed by several fabrication techniques, such as replica molding, photolithography, drawing lithography and more [85]. Usually, probes and enhancers of transduction mechanisms are directly embedded in the porous polymer matrix during the fabrication. This environment protects probes without avoiding interaction between target analytes and bioprobes.
Caliò et al. trapped enzymes with vinyl-ferrocene mediator into a polymeric matrix of PEGDA in order to detect glucose and lactate exploiting the volume effect of the hydrogel matrix [27]. After being in contact with the ISF, the PEGDA matrix swells and the analytes solved into ISF enter the volume of the MNs, where a large number of probe molecules (enzymes) can be stored. The redox reaction takes place inside the volume and is transmitted to the electrode. The fabrication of the electrochemical MN biosensor only required a single further step (metal coating) in addition to the direct photolithographic process. The hybrid device traps GOx and LOX enzymes to enable the electrochemical detection of glucose and lactic acid, respectively, in physiological solution. The sensing MND showed a linear response from 0 to 4 mM for glucose, and from 0 to 1 mM for lactic acid (Figure 6) and a LoD of about 1 μM was found for both cases. Figure 6 shows design of the MN based working electrode, optical images with and without metal coating and a sketch of the working principle of the swelling MNDs. Moreover, experimental data for glucose and lactate acid dose–response are reported.
Appeared on scene as a painless alternative to syringes, MNDs have conquered the biomedicine. The flexibility of these innovative devices makes these technological platforms really attractive for even new fields of application. Almost all materials can be used in the fabrication of MNDs: noble metals (gold and silver), semiconductors (silicon), plastics (polymers and hydrogels), amorphous materials (ceramics) and artificial nanostructured materials (porous silicon). MNDs have been used for drug delivery, cosmetic industry or biosensing, where the MN microstructures have been used as electrodes for electrochemical transduction. For biosensing systems, pros and cons have been highlighted for each device type in terms of analytical performances such as LoD, detection time, sensitivity and so on. In all the application cases, considerations about the safety of MNDs is due, since MNDs are conceived for being in contact with the human body. Then, inert, biocompatible, or physiologically dissolvable materials have to be engaged for device fabrication, even if they show lower analytical or delivery performances. After the overcoming of the skin natural barrier, MNs are directly in contact with human ISF. Hollow, coated, and swelling MNDs are all used in two ways: sensing of analytes and delivery of drugs; biosensing and administration; therapy and diagnosis.
The authors declare no conflict of interest.
The Authors would like to thank all the Materias s.r.l. staff for supporting. In particular, Caterina Meglio, Aniello Cammarano, Maria Emilia Mercurio and Maria Grazia Ramaglia, those continuously help our research with their work.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. 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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. 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Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment"},{id:"5",title:"Parasitic Infectious Diseases",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/450741",hash:"",query:{},params:{id:"450741"},fullPath:"/profiles/450741",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()