\r\n\tWith a history of over 50 years since their introduction into therapy and formulation of medicinal products, hydrogels remain a challenge for researchers in the field. \r\n\tVersatile, with high-water content, tunable properties, and mild processing conditions, hydrogels advanced from simple chemically or physically crosslinked networks to complex double network composites or even more sophisticated new developments as shape memory and self-healing hydrogels. \r\n\tIncreasing knowledge in hybrid or composite hydrogel materials, controlled release of sensitive drugs, or several drugs from the same hydrogel matrix could be achieved. Parallel to targeted efforts aimed to maintain drug micro- or nanoparticle’s distinct three-dimensional structure, synergistic hybrid materials with more than one type of polymer was developed.
\r\n
\r\n\tBut one of the most challenging tasks remains further and continues to improve the clinical translation of these innovative hydrogels. That is what this book intends to provide the reader: a comprehensive overview of the current state-of-the-art, recent advances, new perspectives, and applications of the hydrogels as valuable platforms for targeted delivery. Driven by the need to ensure proper patient compliance, ease of administration, along with the possibility to modulate release and degradation profiles after administration, numerous non-topical hydrogel formulations had been reported. Smart and supramolecular hydrogels, stimuli-reactive materials, that quickly respond in mild conditions, represent today an attractive approach for minimally invasive treatments.
\r\n
\r\n\tThe book will also represent an invitation to discover “new” off-the-shelf hydrogels with highly tunable properties, with low complexity of formulation (environmentally friendly processing), but with adequate features to fulfill clinical requirements and provide desired delivery platforms for therapy.
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1. Introduction
Theranostics is a portmanteau of the words therapeutics and diagnostics and is referring to a system were the modus operandi of both therapeutic and diagnostic aspects are combined. In this personalized medicine approach, patients are in the first phase non-invasively imaged to identify potential responders to a certain therapy (Figure 1) [1]. The ideal theranostic system comprises of a diagnostic and therapeutic agent, which are chemically nearly identical. In reality, the term theranostics is used in a much broader context, i.e. systems that can be used for both diagnostic and therapeutic approaches are also defined as theranostics, even if they differ in their chemical nature [2]. In this chapter, we will discuss theranostics applications mainly in the field of nuclear medicine.
Figure 1.
Personalized medicine. In the diagnostic phase, individuals from the patient cohort that are responding, measured as target accumulation of the nanomedicine, are separated from the non-responders. The responders can move on to the therapeutic phase, whereas for non-responders an alternative treatment form should be applied.
Nanomedicines, especially monoclonal antibodies (mAbs), are finding an ever widespread use in theranostic radionuclide or drug delivery approaches [3]. Unfortunately, nanomedicines typically possess slow target accumulation and excretion times resulting in unwanted and often unacceptably high radiation doses to healthy tissue or limited control in drug release combined with increased systemic toxicity [4]. Pretargeted approaches have the potential to address this challenge by separating the target accumulation process from the diagnostic or therapeutic step.
In pretargeting, a tagged nanomedicine is first administered and allowed to accumulate at its target and excrete from non-targeted tissues over the course of several hours to days. In a second step, a pretargeting agent is administered that bioorthogonally reacts with the tag of the nanomedicine, but is excreted fast from systemic circulation. As such, high and rapid accumulation at the target site can be reached while exposure of the diagnostic or therapeutic component to non-targeted tissues is minimized [5, 6]. Pretargeting is optimally suited for theranostic applications since the pretargeted vector – the nanomedicine – can initially be used for diagnostic purposes and only after having identified the feasibility of the approach, a therapeutic step is initiated (Figure 2). Especially in nuclear medicine, such strategy could be highly useful as within the diagnostic phase not only possible responders can be identified, but also the maximum tolerated radiation dose estimated and consequently, on an individual level, best therapeutic efficacy reached (Figure 1) [7].
Figure 2.
Simplified schematic overview of a typical pretargeted theranostic strategy.
2. Pretargeted theranostics
2.1 Diagnostic imaging modalities
2.1.1 Positron emission tomography (PET) and single photon emission computed tomography (SPECT)
PET or SPECT are routinely used in the clinic for diagnosis or monitoring of treatment response. Their high sensitivity (the level of detection approaches tracer concentrations of 10−12 M) combined with isotopic detection make their clinical applications unmatched [8]. Furthermore, PET can easily be applied for quantitative measurements and as such used to determine e.g. the amount of pretargeting vectors delivered to a specific target. This makes PET especially suited for personalized medicine [9]. One drawback of PET and SPECT is their limited spatial resolution, which lies within the millimeter range [10].
PET and SPECT are dependent on radionuclides that are attached to a specific ligand that is able to target e.g. a specific receptor, enzyme or protein [11]. The choice for the appropriate radionuclide depends on the context and system these diagnostic tools will be used in. For example, if diagnostic radionuclides will be attached to a nanomedicine, longer lived radionuclides are needed, as the biological half-life of the nanomedicines (accumulation or excretion) has to be matched with the physical decay half-life of the radionuclide. Typically, only after several days, nanomedicines display sufficient signal-to-background ratios for imaging purposes [4]. In case of pretargeting, radionuclides with a shorter decay half-life can be used as the good pharmacokinetic profile of small molecules results in fast accumulation and excretion [12]. This allows to use PET radionuclides such as fluorine-18, which is the most frequently used radionuclide within the clinic - due to its unique decay properties [13]. Table 1 lists several radionuclides that can be used in PET or SPECT imaging.
SPECT
PET
Isotope
T1/2 (h)
γ (keV)
Isotope
T1/2 (h)
β+ (%)
99mTc
6.01
140
11C
0.33
99.8
111In
67.3
171 and 245
18F
1.83
96.7
123I
13.3
159
64Cu
12.7
17.5
68Ga
1.13
89.1
86Y
14.7
33.0
89Zr
78.4
22.7
124I
100.2
22.8
Table 1.
Nuclear properties of common SPECT and PET radionuclides.
Their corresponding half-lives (T1/2) are noted in hours (h). For SPECT radionuclides, the energy of the gamma (γ) photon is noted in keV, for PET radionuclides, their corresponding percent (%) of positron (β+) decay is noted.
2.1.2 Fluorescence
While fluorophores are less harmful to tissue in comparison to the use of radionuclides, offer higher temporal and spatial resolution - up to tens of nanometers, fluorophores are majorly disadvantaged by their severely lower tissue penetration of only a few millimeters. This limitation prohibits their use for imaging of deeper lying tissues [14]. Nevertheless, due to their ease of use, fluorescence-based imaging probes are at least within preclinical development a commonly used imaging modality. A list of routinely used fluorophores and their absorption and emission maximum can be found in Table 2.
Fluorophore
Absorption maximum [nm]
Emission maximum [nm]
Fluorescein
495
517
AlexaFluor 488
494
519
Cyanine 5
647
665
Cyanine 5.5
672
692
Cyanine 7
753
775
Methylene Blue
665
684
CF-680
681
698
IRDye-800CW
774
789
Indocyanine Green
776
792
Dylight 800
777
794
Table 2.
Absorption and emission maxima of commonly used fluorophores in PBS.
2.1.3 Magnetic resonance imaging (MRI)
MRI is an imaging technique that does not rely on ionizing radiation and therefore has a significantly lower sensitivity (approximately 10−4 M) compared to PET or SPECT. However, it results in better spatial resolution [15]. In the context of pretargeted theranostics, a contrasting agent is often added to the pretargeting vector - in order to enhance visibility of the target. The most commonly used contrast agent is gadolinium(III) (Gd3+), in various chelated forms and works by shortening the T1 (spin–lattice) relaxation time [16]. Another T1 signal enhancer is manganese(II) (Mn2+) [17]. Several T2 (spin–spin) signal enhancers exists, but are less commonly used options. One of these are magnetic nanoparticles (MNP), such as iron oxide or iron/platinum alloys, or alternatively barium(II) (Ba2+) salts. Especially in a theranostic context, decorated MNPs are of great interest as they can simultaneously be used as passive targeting vectors - due to the enhanced permeability and retention (EPR) effect [18].
2.2 Therapy approaches
2.2.1 Radionuclide therapy
Targeted radionuclide therapy approaches have the potential to treat micrometastases and residual tumor tissue remaining after surgical resection – both of which play a major role in the mortality of cancer patients. Currently, only very few radionuclide therapies have found application in clinical practice [19]. This is likely to change in the coming decade, as radionuclide therapy may be more effective than standard therapeutic strategies, e.g. external radiation therapy or state-of-the-art chemotherapy. Two types of radiation can be used in radionuclide-based therapies, namely α- and β−-radiation. In general, α-emitting radionuclides are far more effective due to the significantly higher linear energy transfer (LET) (approx. 100 keV/μm), compared to the much lower LET of β−-emitting radionuclides (approx. 0.2 keV/mm) [4]. However, α-emitters might even be too toxic for many applications.
Just like for the diagnostic case, the choice of radionuclide is highly dependent on the context and system, these radionuclides are used in. With the exception of iodine-131 and astatine-211, all other commonly used radionuclide are radiometals and need to be chelated. As such, these radiopharmaceuticals are typically very polar (Table 3). Another factor to be considered is the limited availability of certain radionuclides, such as astatine-211, bismuth-213, lead-212 or actinium-225 [20]. Additionally, lead-212 and actinium-225 have several radioactive daughter nuclides which contribute to radiotoxicity throughout the body when released from the chelator and distributed throughout the body. Due to the high energy released after the first decay event, typically daughter nuclides are released from the chelator and not bound to the chelator any longer [21].
Isotope
T1/2 (h)
Decay
Photon energy (keV)
%
67Cu
61.8
β−
185
49
90Y
64.6
β−
1700
0.01
131I
192.5
β−
364
81
177Lu
159.5
β−
208
11
188Re
17.0
β−
155
15
211At
7.2
α
79
21.3
213Bi
0.8
α
440
26
212Pb
10.6
β− and α
a
a
225Ac
238.1
β− and α
a
a
Table 3.
Nuclear properties of common therapeutic radionuclides.
Their corresponding half-lives (T1/2) are noted in hours, the energy of the photon is noted in keV.
a. Multiple photons, at different energies, are emitted, due to multiple daughter radionuclides.
2.2.2 Chemotherapy
Chemotherapy involves the use of highly cytotoxic compounds which are supposed to kill cancer cells more efficiently than healthy cells. In the context of pretargeted approaches, these compounds work in exactly the same manner as in standard chemotherapy approaches, with the crucial difference that they are delivered from the nanomedicine to the target side and then (selectively) released e.g. using click-to-release strategies [22, 23]. A locally increased concentration of the chemotherapeutic is as such achievable, whereas the systemic concentration and its subsequent toxicity is reduced [24]. A few examples of cytotoxic compounds that have been used in conjunction with pretargeted theranostics are paclitaxel, mertansine or doxorubicin [25, 26, 27]. However, in theory any cytotoxic drug could be used.
2.3 Pretargeting strategies and their applications as potential Theranostics
2.3.1 Biotin/streptavidin binding
Pretargeting approaches based on the strong, non-covalent interaction between biotin and streptavidin, with a Kd in the order of approximately 10−14 M were among the earliest strategies to be successfully applied for pretargeted radioimmuno-imaging and –therapy [4]. In fact, several clinical studies were initiated and are ongoing [28, 29, 30]. The strong binding affinity is leveraged by most commonly attaching the tetrameric streptavidin - capable of binding up to four biotins - to a mAb and after sufficient accumulation of this pretargeting vector, radiolabeled biotin is injected as the targeting agent. Despite these successes, reports of this strategy in a theranostic setting are limited. This might be due to the observed increased levels of human anti-streptavidin antibodies, potentially leading to allergic reactions upon subsequent applications [31, 32].
2.3.2 Bispecific antibodies
Bispecific antibodies (bsAb) are artificially constructed immunoconjugates, possessing both an antigen-binding fragment (Fab) - typically targeting an over-expressed receptor on the target cell surface - and an anti-hapten Fab. This allows for targeting the cancer cell while also retaining high affinity to a hapten of choice, which can be used to bind imaging or therapeutic vectors after sufficient accumulation time of the bsAb. Antibody fragments are typically derived from the immunoglobulin G (IgG) antibody, which consists of two Fab sites and a constant fragment crystallizable (Fc) region. Digestion of IgG by pepsin yields the F(ab’)2 fragment, which can be further split into two Fab’ fragments by mild reduction. Digestion by papain on the other hand yields two Fab fragments. Removal of the two remaining constant domains and relinking them yields fusion proteins called single-chain variable fragment (scFv) (Figure 3) [33].
Figure 3.
IgG antibody and its fragments used in the construction of bispecific antibodies.
Aniline modified DOTA (DOTA-Bn, Figure 4) can act as an efficient chelator for a large variety of (radio)metals and also serve as the hapten. Haptens are small molecular entities that are used to engineer antibodies possessing high affinity to these small molecules, allowing for fragmentation into smaller hapten-binding scFv. In the case of DOTA-Bn, the scFv C825 is capable of binding DOTA-Bn chelated yttrium (Y3+) and lutetium (Lu3+) with picomolar affinity (~15 and 11 pM respectively). This allowed for construction of a IgG-scFv bsAb huA33-C825 (Figure 4) targeting GPA33-positive human colorectal cancer cell lines SW1222 [34]. Utilizing this system, SW1222 xenograft bearing mice were subjected to three treatment cycles of pretargeted immunotherapy (PRIT) consisting of injection of bsAb injection, followed by injection of a dextran-hapten clearing agent 24 hours later and injection of [177Lu]Lu-DOTA-Bn after four more hours. SPECT/CT was utilized to follow the treatment, showing high specific tumor uptake (~7% ID/g) and only low uptake (10–15 fold lower) in the liver, the spleen and the kidneys. After three cycles of treatment with 55.5 MBq activity of [177Lu]Lu-DOTA-Bn (at days 7, 14 and 21 after tumor inoculation), 100% histologic cures in 9 of 9 treated animals were achieved. Therefore, this approach allows for a theranostic platform with a single radiopharmaceutical entity, allowing for SPECT imaging and providing tumor radiation estimate by changing the amount of radioactivity administered. However, using a therapeutic radionuclide for clinical diagnosis is not optimal since only low amounts can be administered, which often result in insufficient count rates for imaging purposes.
Figure 4.
A: Schematic representation of bsAb huA33–825 and trastuzumab-C825. B: Structure of DOTA-Bn chelating M3+.
In a similar approach, the food and drug administration (FDA)-approved anti-HER2 antibody trastuzumab, modified with scFv C825 (Figure 4), was utilized to target HER2-positive human breast cancer BT-474 xenograft bearing mice [35]. Although internalizing targets like HER2 are normally not suitable for PRIT, it was found that 24 hours post injection of the bsAb around 11% of the initially bound trastuzumab-C825 remained on the cell surface. Using a clearing agent 24 hours after injection of the bsAb, followed by 5.6 MBq of [177Lu]Lu-DOTA-Bn allowed for biodistribution-based dosimetry, showing ~7% ID/g uptake in the tumor with high tumor to blood and kidney ratios (T/B: ~27, T/K: ~10). Given this, the estimated maximum tolerated activity was calculated to be 180 MBq, with blood being the dose-limiting organ. In following therapeutic studies, a single-cycle treatment with 55.5 MBq of [177Lu]Lu-DOTA-Bn was found to lead to 100% complete response (CR) in small tumors up to 30 mm3, but did not produce a high CR in medium sized tumors (100–400 mm3). The latter could be successfully treated through three cycle PRIT using 55.5 MBq of [177Lu]Lu-DOTA-Bn, showing 25% complete tumor disappearance and 75% regression to palpitation threshold. Once again, SPECT/CT was used to monitor treatment progression 24 hours p.i. of 55.5 MBq of [177Lu]Lu-DOTA-Bn.
In clinical practice, PET results in better spatial resolution than SPECT. In this regard, a PET tracer based hapten probe was developed [36]. Hapten [86Y]Y-DOTA-Bn was synthesized and used to image a bsAb targeting GPA33-positive cancers [37]. The biodistribution data was in line with the one determined using [177Lu]Lu-DOTA-Bn. Consequently, hapten [86Y]Y-DOTA-Bn can be used as a surrogate for the 177Lu-labeled derivative. Better diagnostic value and reduced radiation dose should be possible for clinical applications using [86Y]Y-DOTA-Bn.
While the hapten DOTA-Bn allows for straight forward incorporation of yttrium and lutetium, it comes with severe limitations to the modularity of the system as the affinity of the hapten towards scFv C825 varies depending on the chelated metal. This effect was observed in a study on the anti-DOTA antibody scFv –hu3F8-C825 (Figure 5), which bound [177Lu]Lu-DOTA-Bn with picomolar affinity, whereas [225Ac]Ac-DOTA-Bn was found to have severely decreased binding [38]. This resulted in a decreased tumor accumulation. To circumvent this problem, a novel construct bearing two DOTA-moieties called proteus-DOTA (Pr, Figure 5) was synthesized. By chelating non-radioactive, isotopologic lutetium-175 in one of the DOTA moieties, the construct is able to bind with high affinity to previously utilized scFv C825, while retaining the ability to chelate a radiometal of choice in the second DOTA chelator (Figure 5). Using this system, high tumor and relatively low normal tissue accumulation of both [111In]In-Pr and [225Ac]Ac-Pr was achieved. This approach was then successfully employed in a pretargeted therapeutic approach in treating three solid human cancer xenograft models of colorectal cancer (GPA33), breast cancer (HER2), and neuroblastoma (GD2) using the respective anti-tumor/C825 bsAb, followed by injection of a dextran clearing agent after 24 h and four hours later the radiohapten [225Ac]Ac-Pr.
Figure 5.
A: Schematic representation of bsAb hu3F8–C825. B: Structure of proteus-DOTA (Pr) chelating non-radioactive 175Lu3+ and the radiometal of choice M3+.
Another promising approach lies in changing the utilized hapten to the small peptidic sequence histamine-succinyl-glycine (HSG). In this respect, the bivalent hapten IMP288 modified with two HSG and DOTA and the trivalent bsAb TF2 were identified to be the most promising pair for clinical translation of this pretargeted system (Figure 6) [39]. The trivalent bsAb TF2 was build up through a dock-and-lock approach, linking two anti-carcinoembryonic antigen (CEA) Fabs, binding to the cancers expressing CEA, and one anti-HSG Fab linked through two disulfide bounds (Figure 6). This approach allows to label IMP288 with a set of radiometals for both therapeutic and diagnostic purposes. Subsequent preclinical studies in mice bearing CEA-expressing colonic tumors showed very low uptake in normal tissues - apart from the kidneys (~2% ID/g) – and high tumor uptake using PET or SPECT imaging with [68Ga]Ga-IMP288 (~11% ID/G) or [111In]In-IMP288 (~26% ID/G) [40]. These imaging data was successfully used for dose estimations of [177Lu]Lu-IMP288 and [213Bi]Bi-IMP288 [41, 42].
Figure 6.
A: Schematic representation of bsAb TF2. B: Structure of IMP288 chelating M3+.
Given this promising data, the IMP288/TF2 system was translated into the clinic using [111In]In-IMP288 in the imaging cycle for predictive patient-specific dosimetry and [177Lu]Lu-IMP288 as the therapeutic agent. Herein, it was shown, that the treatment of metastatic colorectal cancer patients at activity doses ranging from 2.5 to 7.4 GBq of [177Lu]Lu-IMP288 was safe, but only one of the four planned treatment cycles was carried out since all patients showed progression of the disease, 8 weeks after the first cycle [43]. Also immunogenic responses towards the humanized bsAb TF2 were observed in 11 out of 21 patients. Surprisingly, this immunogenic response was only observed to a very limited degree in one out of eight patients in another study using the same system on advanced lung cancer patients [44].
2.3.3 Oligonucleotides
A more recently employed pretargeting strategy relies on the strong interaction between complementary strands of oligonucleotides. Although unmodified desoxyribonucleic acids (DNAs,Figure 7) and ribonucleic acids (RNAs,Figure 7) are not suitable for in vivo use due to their rapid degradation by nucleases, recent developments of peptide nucleic acids (PNAs,Figure 7) have shown promise in pretargeting. PNAs increase enzymatic stability by replacing the sugar-phosphate backbone of DNAs/RNAs by a pseudo-polypeptidic backbone consisting of a N-(2-aminoethyl)-glycine units [45]. PNAs retain Watson-Crick base-pair binding to complementary PNA, DNA or RNA strands. The interaction between PNA/PNA is with greater specificity and binding affinity compared to the corresponding DNA/DNA analogs. A fourth alternative to DNAs, which is stable to enzymatic degredation are phosphorodiamidate morpholino oligomer (morpholinos, Figure 7) [46]. Here, the sugar-phosphate moiety is replaced by a methylenemorpholine ring, linked through phosphordiamidate groups.
Figure 7.
Structure of DNA, RNA, PNA and morpholino oligonucleotides.
In a pretargeted study using the PNA-affibody conjugated with ZHER2:342-SR-HP1 and a complementary PNA-based DOTA derivative (HP2), the biodistribution patterns of [68Ga]Ga-HP2 and the therapeutic PNA [177Lu]Lu-HP2 were evaluated in SKOV3 xenografts [47]. Overall, quite profound differences in biodistribution between [68Ga]Ga-HP2 (~6% ID/g tumor and ~ 9% kidney accumulation) and [177Lu]Lu-HP2 (~12% ID/g tumor and ~ 8% kidney accumulation) were found, making precise prediction of therapeutic uptake of the latter difficult [48]. This study exemplified that the choice of a theranostic pair, here gallium-68 and lutetium-177, can have an influence on the biodistribution of the labeled radiopharmaceutical. Different stability or altered dipole moments within the chelated structure are some of the possible reasons for this behavior.
2.3.4 Tetrazine/trans-cyclooctene (TCO) ligation
Another strategy for pretargeting involves the covalent bond forming ligation between an 1,2,4,5-tetrazine and a TCO [49]. The reaction is initiated with an enthalpically driven strain release of the inverse electron demand Diels-Alder (IEDDA) cycloaddition. The cycloaddition is followed by an entropically driven retro Diels-Alder reaction, in which molecular nitrogen is expelled, making this reaction irreversible (Figure 8A) [50]. Variously substituted tetrazines and TCO analogues can be used for this ligation, all differing in their corresponding speed kinetics and in vivo stability. As a general trend, with increasing in vivo stability, a decrease in speed kinetics is observed and vice versa.
Figure 8.
(A) Mechanism of the tetrazine/TCO ligation. (B) Chemical scaffold of a H-, a methyl- and a bispyridyl-tetrazine.
The most common approach for pretargeting using the tetrazine ligation is based on TCO-modifications of nanomedicines, which act as pretargeting vectors [51]. These vectors can first be imaged by a tetrazine probe and followed up with a treatment phase, using a therapeutic, tetrazine based probe. For example, the CEA targeting mAb 35A7 was decorated with approximately 3–4 TCO tags and four different [177Lu]-bispyridyl-tetrazine probes used to evaluate the effectiveness of the pretargeted approach. SPECT was used to determine the in vivo biodistribution of the various tracers and gain insights about maximum tolerated dose. The most promising probe was used in a treatment approach and a projected dose of 40 MBq was applied. This resulted in a significant slow-down of tumor progression, for up to 13 days, after which the tumors started to grow again, albeit much slower as compared to the control group [52].
In a similar approach, using a human colorectal carcinoma mouse model, a transmembrane glycoprotein (the A33 antigen) targeting mAb huA33 was decorated with approximately 2–3 TCO tags. Two different tetrazine probes were administered [53]. 24 hours after administration of the huA33-TCO a [64Cu]-H-tetrazine probe was injected and used for diagnostic PET imaging. This was followed by an injection of a [177Lu]-H-tetrazine probe, after an additional 24 hours (48 hours post mAb injection). It was estimated that after the injection of the diagnostic tetrazine, roughly 64% of the TCOs on the mAb were available, for the therapeutic tetrazine probe. This study showed that the same targeting vector can be used for imaging and therapy purposes and as such for real theranostic approaches. The same group also evaluated a 67Cu-labeled H-tetrazine in the same setup for β—radiotherapy [54]. Within this study, the authors compared the therapeutic effect of pretargeted radioimmunotherapy (PRIT) to conventional radioimmunotherapy (RIT). Even though RIT achieved a comparable survival rate, at lower injected dose, compared to PRIT, it is important to note that PRIT significantly reduced the individual organ dose rates, in comparison to RIT, i.e. the radiation dose to the blood for the PRIT strategy was 5.9 cGy/MBq, compared to 71.3 cGy/MBq for the RIT strategy, highlighting the main advantage of PRIT over RIT. The authors argued that the PRIT strategy can be further optimized in regards of timing of the dosing regimen, in order to achieve optimal dose rates to the tumor.
In addition to small molecule tetrazine derivatives, also tetrazine functionalized nanocarriers, such as human serum albumin (ALB), can be used as pretargeting vectors. These structures can additionally be modified e.g. with chemotherapeutic agents or fluorophores. Such a strategy was used for trastuzumab, a human epidermal growth factor receptor 2 positive (HER2+) targeting mAb. This mAb was decorated with six TCO moieties and two CF-680 near infrared (NIR) fluorophores [55]. After eight hours, a ALB nanocarrier was injected containing approximately 2–3 paclitaxel molecules, 15 methyl-tetrazines and two DyLight 800 (DL-800) NIR fluorophores. Imaging studies revealed that the tumor uptake was twice as high in mice after two days in the pretargeted group compared to the control group. Also, treated animals only showed a relative increase of tumor volume of 3%, whereas the control group saw an increase of 14%. In another study, eight TCO’s were attached to 5D3, a prostate-specific membrane antigen (PSMA) targeting mAb, as well as eight TCO to its F(ab′)2 fragments [56]. Both moieties were additionally decorated with two AlexaFluor 488 (AF-488) fluorophores. ALB was used as the pretargeting agent and possessed 10 methyl-tetrazine handles, two rhodamine fluorophores and approximately 3–4 mertansine molecules, as a therapeutic component. Imaging studies revealed, that the F(ab′)2 fragments internalized faster compared to the whole mAb. Faster internalization is, however, disadvantageous since the internalized targeting vector is not available for the ligation with ALB. This nanocarrier cannot cross the cell membrane. Consequently, less cytotoxic drug can reach its target. No in vivo evaluation of this approach was performed.
Recently, a new click-to-release strategy was described which results in local increased drug concentration and as such increased treatment efficacy. In such an approach, the TCO component acts as a bioorthogonally click partner as well as a drug releasing component. The initial click mechanism is also based on the IEDDA (Figure 8A). However, the formed 4,5-dihydropyridazine will partly tautomerize to 1,4-dihydropyridazine which can lead to a release - via a self-immolative cascade reaction - of the chemotherapeutic drug in allylic position (attached e.g. via a carbamate to the TCO) (Figure 9). Such a TCO is also called release TCO (rTCO). This click-to-release strategy has also been employed in a theranostic context. For example, in tumor bearing mice expressing the tumor-associated glycoprotein-72 (TAG72), a CC49 diabody – targeting this glycoprotein and side-specifically conjugated to a rTCO decorated with monomethyl auristatin E (MMAE)) – was evaluated [57]. Mice were injected with the diabody 48 prior to injection of an 111In-labeled releaser bisalkyl-tetrazine. This set-up allowed to image the release via SPECT. In a different setup, [111In]bispyridyl-tetrazine was used to determine the diabody tumor uptake, as bispyridyl-tetrazines have extremely poor release capabilities for the used rTCO. The gained information was then used to design a treatment study. Four cycles, over a period of two weeks, were used in this study and extended the median survival by 34–39 days. In a different study, a PEGylated hyper-branched polymeric (HBP) nanocarrier was developed bearing rTCOs bound to the drug doxorubicin [58]. In order to achieve a modular approach, HBP was bound to a bsAb, which could selectively interact with PEGs of the HBP with one binding site, whereas the other binding site simultaneously target with the epidermal growth factor receptor (EGFR) or TAG72. A 64Cu-labeled H-tetrazine was used both as the releaser and as an imaging component. This theranostic approach was evaluated in mice bearing MCF7 and MDA-MB-468 tumors. Highest release of doxorubicin was found when the tetrazine was injected 24 hours post nanocarrier injection. Furthermore, better release was observed in non-internalizing targets compared to internalizing targets, as the polar tetrazine was not able to cross the cell membrane.
Figure 9.
Mechanism of the click-to-release reaction.
Lastly, dextran-coated iron oxide MNPs (~25 nm in size) were surface modified with methyl-tetrazines and the NIR fluorophore cyanine5.5 (Cy5.5) [59]. The MNP uptake was monitored by fluorescence, as well as by T2-weighted MRI. Targeting of these MNP was based on the EPR effect. Conceptually, selective drug release should be induced by a small molecule drug-TCO conjugate which should find the MNP-tetrazine modified targeting vector in vivo and upon reaction release the drug load. Unfortunately, the release was only in vitro, in MDA-MB-231 cells. As such, no real conclusion about the in vivo efficacy can be drawn as well as of the theranostic abilities of the system.
SPAAC has been applied in pretargeting. The reaction is based on a [3 + 2] cycloaddition between an azide and a strained alkyne (Figure 10). Opposed to the copper-catalyzed azide-alkyne cycloaddition (CuAAC), this reaction is metal free and instead entirely entropy driven. Various different constrained alkynes can be used for this biorthogonal reaction, i.e. difluorocyclooctynes (DIFO), bicyclononyne (BCN), dibenzocyclooctynes (DIBO), biarylazacyclooctynone (BARAC), among others. However, the most used alkyne is azadibenzylcyclooctyne (ADIBO/DIBAC), commonly referred to as DBCO. However, the feasibility of the SPAAC appears to be very limited due to its very slow reaction kinetics [60].
Figure 10.
Mechanism of the strain-promoted azide-alkyne cycloaddition (SPAAC).
2.3.6 Miscellaneous
Besides the previously mentioned strategies, some lesser known and underexplored strategies exist. These are all based on high affinity interactions. One such set of interaction partners is based on the high affinity (~5 × 104 M−1) between β-cyclodextrin, as the host and an adamantine derivative as the guest molecule [61]. This approach has been used in hepatic radioembolization where a macro ALB aggregate (MAA) was decorated with approximately 108 adamantane derivatives and used as the pretargeting vector. Poly(isobutyl methacrylate) (PIMBA) functionalized with 10 β-cyclodextrin handles was used as the pretargeting agent (Table 4) [62].
Pretargeting system
Rate constants [M−1 s−1]
In vivo stability
Clinical studies
Benefits and limitations
bsAb
103–5
High
Yes
+ Highly specific binding to variety of cellular targets + Straight forward accessibility through dock-and-lock approach - Reversible binding between hapten and bsAb - Lower tumor uptake compared to other methods
PNA
105
High
No
+ Stable to enzymatic degradation + Potentially allows for administering two different complementary strands - Increased complexity to incorporate clearing agents - Challenging preparation
SPAAC
10−1–10−2
Low
No
+ Easy access to pretargeting pairs - Low reactivity requires high molar ratios between pretargeting pairs
Comparison of the pretargeting strategies utilized in pretargeted theranostics [4].
2.3.7 Comparison of the pretargeting strategies
3. Conclusion
The recently seen rapid increase in development of novel pretargeted conjugation strategies allowed for pretargeted PET imaging and α/β−-therapy resulting in lower off-target toxicity and overall radiation doses. Despite preclinical successes, the increased complexity of the pretargeting approach still hampers further clinical translation, resulting in only few pretargeted theranostics being clinically investigated. Since the required multicomponent approach comes with high entry barriers of current good manufacturing practice (cGMP) production, the pretargeting approach must result in undoubtful benefits over more traditional imaging or treatment options. Although theranostics come with the large benefit of combining imaging and therapeutic agents, allowing for optimized treatment parameters, still more clinical trials need to be initiated and deliver prove of increased efficacy and decreased off-target toxicity to justify the inherently increased treatment challenges.
Acknowledgments
C.B.M.P acknowledges funding by the BRIDGE – Translational Excellence Programme at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (grant agreement no. NNF18SA0034956). Further, this project has received funding from the European Union’s EU Framework Programme for Research and Innovation Horizon 2020, under grant agreement no. 668532.
Conflict of interest
The authors declare no competing financial interest.
\n',keywords:"radionuclide therapy, PET, SPECT, MRI, radiopharmaceuticals, bispecific antibodies, oligonucleotides, tetrazine/TCO ligation, pretargeting",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74944.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74944.xml",downloadPdfUrl:"/chapter/pdf-download/74944",previewPdfUrl:"/chapter/pdf-preview/74944",totalDownloads:230,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 29th 2020",dateReviewed:"December 21st 2020",datePrePublished:"February 1st 2021",datePublished:"September 29th 2021",dateFinished:"January 27th 2021",readingETA:"0",abstract:"Personalized medicine is becoming an integral part of our healthcare system, in which theranostics play a fundamental role. Nanomedicines such as monoclonal antibodies are a commonly used targeting vector in such approaches due to their outstanding targeting abilities as well as their capabilities to function as drug delivery vehicles. However, the application of nanomedicines in a clinical setting is connected with several challenges. For example, nanomedicines typically possess slow pharmacokinetics in respect to target accumulation and excretion. For targeted radionuclide therapy, this results in high radiation burden to healthy tissue. For drug delivery systems, long circulation and excretion times of the nanomedicine complicate site-specific release approaches and limit as such the usability of these strategies. One way to circumvent these challenges is the use of pretargeting strategies, which allow to separate the accumulation and excretion of nanomedicines from the actual diagnostic or therapeutic application. As such, pretargeting allows to use theranostic concepts utilizing the same nanomedicine and determine the success chances with diagnostic measures before initiating therapy. This chapter will explain the concept of pretargeted theranostics, which pretargeting systems have thus far been developed and compare how these systems performed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74944",risUrl:"/chapter/ris/74944",signatures:"Markus Staudt, Matthias M. Herth and Christian B.M. Poulie",book:{id:"10232",type:"book",title:"Theranostics",subtitle:"An Old Concept in New Clothing",fullTitle:"Theranostics - An Old Concept in New Clothing",slug:"theranostics-an-old-concept-in-new-clothing",publishedDate:"September 29th 2021",bookSignature:"Elisabeth Eppard",coverURL:"https://cdn.intechopen.com/books/images_new/10232.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83962-788-0",printIsbn:"978-1-83962-783-5",pdfIsbn:"978-1-83962-789-7",isAvailableForWebshopOrdering:!0,editors:[{id:"245845",title:"Dr.",name:"Elisabeth",middleName:null,surname:"Eppard",slug:"elisabeth-eppard",fullName:"Elisabeth Eppard"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"328435",title:"Associate Prof.",name:"Matthias M.",middleName:null,surname:"Herth",fullName:"Matthias M. Herth",slug:"matthias-m.-herth",email:"matthias.herth@sund.ku.dk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"328436",title:"Dr.",name:"Markus",middleName:null,surname:"Staudt",fullName:"Markus Staudt",slug:"markus-staudt",email:"markus.staudt@sund.ku.dk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Copenhagen",institutionURL:null,country:{name:"Denmark"}}},{id:"328437",title:"Dr.",name:"Christian Bernard Matthijs",middleName:null,surname:"Poulie",fullName:"Christian Bernard Matthijs Poulie",slug:"christian-bernard-matthijs-poulie",email:"christian.poulie@sund.ku.dk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Copenhagen",institutionURL:null,country:{name:"Denmark"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Pretargeted theranostics",level:"1"},{id:"sec_2_2",title:"2.1 Diagnostic imaging modalities",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_3_3",title:"Table 2.",level:"3"},{id:"sec_4_3",title:"2.1.3 Magnetic resonance imaging (MRI)",level:"3"},{id:"sec_6_2",title:"2.2 Therapy approaches",level:"2"},{id:"sec_6_3",title:"Table 3.",level:"3"},{id:"sec_7_3",title:"2.2.2 Chemotherapy",level:"3"},{id:"sec_9_2",title:"2.3 Pretargeting strategies and their applications as potential Theranostics",level:"2"},{id:"sec_9_3",title:"2.3.1 Biotin/streptavidin binding",level:"3"},{id:"sec_10_3",title:"2.3.2 Bispecific antibodies",level:"3"},{id:"sec_11_3",title:"2.3.3 Oligonucleotides",level:"3"},{id:"sec_12_3",title:"2.3.4 Tetrazine/trans-cyclooctene (TCO) ligation",level:"3"},{id:"sec_13_3",title:"2.3.5 Strain-promoted azide-alkyne cycloaddition (SPAAC)",level:"3"},{id:"sec_14_3",title:"Table 4.",level:"3"},{id:"sec_15_3",title:"2.3.7 Comparison of the pretargeting strategies",level:"3"},{id:"sec_18",title:"3. Conclusion",level:"1"},{id:"sec_19",title:"Acknowledgments",level:"1"},{id:"sec_22",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'S. Jeelani, R. Jagat Reddy, T. Maheswaran, G. Asokan, A. Dany, and B. Anand, “Theranostics: A treasured tailor for tomorrow,” J. Pharm. Bioallied Sci., vol. 6, no. 5, p. 6, 2014, doi: 10.4103/0975-7406.137249'},{id:"B2",body:'S. Shrivastava, S. Jain, D. Kumar, S. L. Soni, and M. Sharma, “A Review on Theranostics: An Approach to Targeted Diagnosis and Therapy,” Asian J. Pharm. Res. Dev., vol. 7, no. 2, pp. 63-69, Apr. 2019, doi: 10.22270/ajprd.v7i2.463'},{id:"B3",body:'E. J. L. Stéen et al., “Pretargeting in nuclear imaging and radionuclide therapy: Improving efficacy of theranostics and nanomedicines,” Biomaterials, vol. 179, pp. 209-245, Oct. 2018, doi: 10.1016/j.biomaterials.2018.06.021'},{id:"B4",body:'E. J. L. 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Rondon et al., “Pretargeted radioimmunotherapy and SPECT imaging of peritoneal carcinomatosis using bioorthogonal click chemistry: probe selection and first proof-of-concept,” Theranostics, vol. 9, no. 22, pp. 6706-6718, 2019, doi: 10.7150/thno.35461'},{id:"B53",body:'O. Keinänen et al., “Dual Radionuclide Theranostic Pretargeting,” Mol. Pharm., vol. 16, no. 10, pp. 4416-4421, 2019, doi: 10.1021/acs.molpharmaceut.9b00746'},{id:"B54",body:'O. Keinänen et al., “Harnessing 64 Cu/67 Cu for a theranostic approach to pretargeted radioimmunotherapy,” Proc. Natl. Acad. Sci., p. 202009960, Oct. 2020, doi: 10.1073/pnas.2009960117'},{id:"B55",body:'S. Hapuarachchige, Y. Kato, and D. Artemov, “Bioorthogonal two-component drug delivery in HER2(+) breast cancer mouse models,” Sci. Rep., vol. 6, no. 1, p. 24298, Jul. 2016, doi: 10.1038/srep24298'},{id:"B56",body:'S. Hapuarachchige et al., “Cellular Delivery of Bioorthogonal Pretargeting Therapeutics in PSMA-Positive Prostate Cancer,” Mol. Pharm., vol. 17, no. 1, pp. 98-108, Jan. 2020, doi: 10.1021/acs.molpharmaceut.9b00788'},{id:"B57",body:'R. Rossin et al., “Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice,” Nat. Commun., vol. 9, no. 1, p. 1484, Dec. 2018, doi: 10.1038/s41467-018-03880-y'},{id:"B58",body:'G. R. Ediriweera et al., “Targeted and modular architectural polymers employing bioorthogonal chemistry for quantitative therapeutic delivery,” Chem. Sci., vol. 11, no. 12, pp. 3268-3280, 2020, doi: 10.1039/D0SC00078G'},{id:"B59",body:'I. Khan, P. F. Agris, M. V. Yigit, and M. Royzen, “In situ activation of a doxorubicin prodrug using imaging-capable nanoparticles,” Chem. Commun., vol. 52, no. 36, pp. 6174-6177, 2016, doi: 10.1039/C6CC01024E'},{id:"B60",body:'B. L. Oliveira, Z. Guo, and G. J. L. Bernardes, “Inverse electron demand Diels–Alder reactions in chemical biology,” Chem. Soc. Rev., vol. 46, no. 16, pp. 4895-4950, 2017, doi: 10.1039/C7CS00184C'},{id:"B61",body:'M. R. Eftink, M. L. Andy, K. Bystrom, H. D. Perlmutter, and D. S. Kristol, “Cyclodextrin inclusion complexes: studies of the variation in the size of alicyclic guests,” J. Am. Chem. Soc., vol. 111, no. 17, pp. 6765-6772, Aug. 1989, doi: 10.1021/ja00199a041'},{id:"B62",body:'S. J. Spa et al., “A Supramolecular Approach for Liver Radioembolization,” Theranostics, vol. 8, no. 9, pp. 2377-2386, 2018, doi: 10.7150/thno.23567'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Markus Staudt",address:null,affiliation:'
Department of Drug Design and Pharmacology, University of Copenhagen, Denmark
'},{corresp:"yes",contributorFullName:"Matthias M. Herth",address:"matthias.herth@sund.ku.dk",affiliation:'
Department of Drug Design and Pharmacology, University of Copenhagen, Denmark
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University Hospital, Denmark
Department of Drug Design and Pharmacology, University of Copenhagen, Denmark
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We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
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We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
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Our platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
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Our reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
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"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
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Unfortunately, the comorbidities of aging have created a large economic and health burden on society. Osteoporosis is the most prevalent age-related disease. It is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. These fractures lead to disproportionally high mortality rate and a drastic decline in quality of life for those affected. While estrogen loss is one known trigger of osteoporosis, a number of recent studies have shown that osteoporosis is a multifactorial condition in both humans and rodent models. The presence or absence of certain factors are likely to determine which subset of the population develop osteoporosis. In this chapter, we review the factors that contribute to osteoporosis with an emphasis on its multifactorial nature and the therapeutic consequences.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Di Wu, Anna Cline-Smith, Elena Shashkova and Rajeev Aurora",authors:[{id:"339667",title:"Associate Prof.",name:"Rajeev",middleName:null,surname:"Aurora",slug:"rajeev-aurora",fullName:"Rajeev Aurora"},{id:"347366",title:"Mr.",name:"Di",middleName:null,surname:"Wu",slug:"di-wu",fullName:"Di Wu"},{id:"347367",title:"Ms.",name:"Anna",middleName:null,surname:"Cline-Smith",slug:"anna-cline-smith",fullName:"Anna Cline-Smith"},{id:"347579",title:"Dr.",name:"Elena",middleName:null,surname:"Shashkova",slug:"elena-shashkova",fullName:"Elena Shashkova"}]},{id:"75660",doi:"10.5772/intechopen.96487",title:"Bone Quality of the Dento-Maxillofacial Complex and Osteoporosis. 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Therefore, the objective of this chapter is to describe the use of these parameters as an auxiliary mechanism in the detection of low bone mineral density, as well as to characterize the radiographic findings of patients with osteoporosis.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Plauto Christopher Aranha Watanabe, Giovani Antonio Rodrigues, Marcelo Rodrigues Azenha, Michel Campos Ribeiro, Enéas de Almeida Souza Filho, Rafael Angelo Soares Vieira and Fabio Santos Bottacin",authors:[{id:"76171",title:"Prof.",name:"Plauto C. A.",middleName:null,surname:"Watanabe",slug:"plauto-c.-a.-watanabe",fullName:"Plauto C. A. 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Anti-inflammatory diet is designed to improve health and prevent the occurrence and development of chronic diseases associated with inadequate diet. Proper nutrition is based on the anti-inflammatory pyramid and changes in poor eating habits are the long-term strategy for preventing inflammation and chronic diseases. Inflammatory factors from food may play a role in the development of osteoporosis and an anti-inflammatory diet may be a way to control and reduce long-term inflammation and prevent bone loss. Pro-inflammatory cytokines from the fat tissue, through activation of the RANKL/RANK/OPG system could intervene with bone metabolism in a way of increased bone loss. Therefore the special attention need to be given to obese patients due to twofold risk, one related to pro-inflammatory cytokines release and the other related to the deprivation of the vitamin D in the fat tissue.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Olga Cvijanović Peloza, Sandra Pavičić Žeželj, Gordana Kenđel Jovanović, Ivana Pavičić, Ana Terezija Jerbić Radetić, Sanja Zoričić Cvek, Jasna Lulić Drenjak, Gordana Starčević Klasan, Ariana Fužinac Smojver and Juraj Arbanas",authors:[{id:"339281",title:"Associate Prof.",name:"Olga",middleName:null,surname:"Cvijanović Peloza",slug:"olga-cvijanovic-peloza",fullName:"Olga Cvijanović Peloza"},{id:"346420",title:"Prof.",name:"Sandra",middleName:null,surname:"Pavičić Žeželj",slug:"sandra-pavicic-zezelj",fullName:"Sandra Pavičić Žeželj"},{id:"346421",title:"BSc.",name:"Ivana",middleName:null,surname:"Pavičić",slug:"ivana-pavicic",fullName:"Ivana Pavičić"},{id:"346423",title:"Prof.",name:"Ana Terezija",middleName:null,surname:"Jerbić Radetić",slug:"ana-terezija-jerbic-radetic",fullName:"Ana Terezija Jerbić Radetić"},{id:"346424",title:"Prof.",name:"Sanja",middleName:null,surname:"Zoričić Cvek",slug:"sanja-zoricic-cvek",fullName:"Sanja Zoričić Cvek"},{id:"346426",title:"MSc.",name:"Jasna",middleName:null,surname:"Lulić Drenjak",slug:"jasna-lulic-drenjak",fullName:"Jasna Lulić Drenjak"},{id:"346427",title:"Prof.",name:"Gordana",middleName:null,surname:"Starčević Klasan",slug:"gordana-starcevic-klasan",fullName:"Gordana Starčević Klasan"},{id:"346428",title:"MSc.",name:"Ariana",middleName:null,surname:"Fužinac Smojver",slug:"ariana-fuzinac-smojver",fullName:"Ariana Fužinac Smojver"},{id:"346429",title:"Prof.",name:"Juraj",middleName:null,surname:"Arbanas",slug:"juraj-arbanas",fullName:"Juraj Arbanas"},{id:"350011",title:"Dr.",name:"Gordana",middleName:null,surname:"Kenđel Jovanović",slug:"gordana-kendjel-jovanovic",fullName:"Gordana Kenđel Jovanović"}]},{id:"76351",doi:"10.5772/intechopen.97416",title:"Glucocorticoid-Induced Osteoporosis",slug:"glucocorticoid-induced-osteoporosis",totalDownloads:246,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The use of glucocorticoids (GC) in the medium and long term, causes several considerable side effects, being one of the main ones the reduction of bone mineral density (BMD). Prolonged corticosteroid therapy reduces BMD by up to 20% in trabecular bone and approximately 2–3% in cortical bone in the first year of use. This loss rate declines and stabilizes at approximately 2% in subsequent years. Therefore, there is a considerable increase in the incidence of pathological fractures, whether clinically symptomatic or asymptomatic (detected as a radiological finding), which varies between 30 and 50% of patients who use GC for more than three months. In view of the above, it is essential to prevent fractures and treat osteoporosis in patients using glucocorticoids for long periods (in particular, greater than or equal to 3 months), which may or may not be associated with clinical risk factors or previous fractures. The guidelines for the treatment and prevention of this comorbidity are well established for postmenopausal women and men over 50 years of age. However, for patients below this range, studies are still lacking.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"José Renan Vieira da Costa Júnior and Sérgio Luchini Batista",authors:[{id:"164388",title:"Prof.",name:"Sergio",middleName:null,surname:"Luchini Batista",slug:"sergio-luchini-batista",fullName:"Sergio Luchini Batista"},{id:"354032",title:"Dr.",name:"José Renan",middleName:null,surname:"Vieira Da Costa Júnior",slug:"jose-renan-vieira-da-costa-junior",fullName:"José Renan Vieira Da Costa Júnior"}]},{id:"76677",doi:"10.5772/intechopen.97760",title:"Introductory Chapter: Osteoporosis Overview",slug:"introductory-chapter-osteoporosis-overview",totalDownloads:169,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Luis Rodrigo",authors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}]}],mostDownloadedChaptersLast30Days:[{id:"75660",title:"Bone Quality of the Dento-Maxillofacial Complex and Osteoporosis. 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Therefore, the objective of this chapter is to describe the use of these parameters as an auxiliary mechanism in the detection of low bone mineral density, as well as to characterize the radiographic findings of patients with osteoporosis.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Plauto Christopher Aranha Watanabe, Giovani Antonio Rodrigues, Marcelo Rodrigues Azenha, Michel Campos Ribeiro, Enéas de Almeida Souza Filho, Rafael Angelo Soares Vieira and Fabio Santos Bottacin",authors:[{id:"76171",title:"Prof.",name:"Plauto C. A.",middleName:null,surname:"Watanabe",slug:"plauto-c.-a.-watanabe",fullName:"Plauto C. A. Watanabe"},{id:"337631",title:"Dr.",name:"Giovani Antonio",middleName:null,surname:"Rodrigues",slug:"giovani-antonio-rodrigues",fullName:"Giovani Antonio Rodrigues"},{id:"350577",title:"Dr.",name:"Fabio",middleName:null,surname:"Santos Bottacin",slug:"fabio-santos-bottacin",fullName:"Fabio Santos Bottacin"},{id:"350578",title:"Dr.",name:"Rafael Angelo",middleName:null,surname:"Soares Vieira",slug:"rafael-angelo-soares-vieira",fullName:"Rafael Angelo Soares Vieira"},{id:"350579",title:"Dr.",name:"Enéas de Almeida",middleName:null,surname:"Souza Filho",slug:"eneas-de-almeida-souza-filho",fullName:"Enéas de Almeida Souza Filho"},{id:"350580",title:"Dr.",name:"Michel",middleName:null,surname:"Campos Ribeiro",slug:"michel-campos-ribeiro",fullName:"Michel Campos Ribeiro"},{id:"350581",title:"Dr.",name:"Rodrigues Azenha",middleName:null,surname:"Rodrigues Azenha",slug:"rodrigues-azenha-rodrigues-azenha",fullName:"Rodrigues Azenha Rodrigues Azenha"}]},{id:"76677",title:"Introductory Chapter: Osteoporosis Overview",slug:"introductory-chapter-osteoporosis-overview",totalDownloads:170,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Luis Rodrigo",authors:[{id:"73208",title:"Prof.",name:"Luis",middleName:null,surname:"Rodrigo",slug:"luis-rodrigo",fullName:"Luis Rodrigo"}]},{id:"76507",title:"Osteoporosis: A Multifactorial Disease",slug:"osteoporosis-a-multifactorial-disease",totalDownloads:195,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"A great achievement of modern medicine is the increased lifespan of the human population. Unfortunately, the comorbidities of aging have created a large economic and health burden on society. Osteoporosis is the most prevalent age-related disease. It is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. These fractures lead to disproportionally high mortality rate and a drastic decline in quality of life for those affected. While estrogen loss is one known trigger of osteoporosis, a number of recent studies have shown that osteoporosis is a multifactorial condition in both humans and rodent models. The presence or absence of certain factors are likely to determine which subset of the population develop osteoporosis. In this chapter, we review the factors that contribute to osteoporosis with an emphasis on its multifactorial nature and the therapeutic consequences.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Di Wu, Anna Cline-Smith, Elena Shashkova and Rajeev Aurora",authors:[{id:"339667",title:"Associate Prof.",name:"Rajeev",middleName:null,surname:"Aurora",slug:"rajeev-aurora",fullName:"Rajeev Aurora"},{id:"347366",title:"Mr.",name:"Di",middleName:null,surname:"Wu",slug:"di-wu",fullName:"Di Wu"},{id:"347367",title:"Ms.",name:"Anna",middleName:null,surname:"Cline-Smith",slug:"anna-cline-smith",fullName:"Anna Cline-Smith"},{id:"347579",title:"Dr.",name:"Elena",middleName:null,surname:"Shashkova",slug:"elena-shashkova",fullName:"Elena Shashkova"}]},{id:"75742",title:"Osteoporosis and Dietary Inflammatory Index",slug:"osteoporosis-and-dietary-inflammatory-index",totalDownloads:230,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Healthy bones are constantly being renewed and proper nutrition is an important factor in this process. Anti-inflammatory diet is designed to improve health and prevent the occurrence and development of chronic diseases associated with inadequate diet. Proper nutrition is based on the anti-inflammatory pyramid and changes in poor eating habits are the long-term strategy for preventing inflammation and chronic diseases. Inflammatory factors from food may play a role in the development of osteoporosis and an anti-inflammatory diet may be a way to control and reduce long-term inflammation and prevent bone loss. Pro-inflammatory cytokines from the fat tissue, through activation of the RANKL/RANK/OPG system could intervene with bone metabolism in a way of increased bone loss. Therefore the special attention need to be given to obese patients due to twofold risk, one related to pro-inflammatory cytokines release and the other related to the deprivation of the vitamin D in the fat tissue.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"Olga Cvijanović Peloza, Sandra Pavičić Žeželj, Gordana Kenđel Jovanović, Ivana Pavičić, Ana Terezija Jerbić Radetić, Sanja Zoričić Cvek, Jasna Lulić Drenjak, Gordana Starčević Klasan, Ariana Fužinac Smojver and Juraj Arbanas",authors:[{id:"339281",title:"Associate Prof.",name:"Olga",middleName:null,surname:"Cvijanović Peloza",slug:"olga-cvijanovic-peloza",fullName:"Olga Cvijanović Peloza"},{id:"346420",title:"Prof.",name:"Sandra",middleName:null,surname:"Pavičić Žeželj",slug:"sandra-pavicic-zezelj",fullName:"Sandra Pavičić Žeželj"},{id:"346421",title:"BSc.",name:"Ivana",middleName:null,surname:"Pavičić",slug:"ivana-pavicic",fullName:"Ivana Pavičić"},{id:"346423",title:"Prof.",name:"Ana Terezija",middleName:null,surname:"Jerbić Radetić",slug:"ana-terezija-jerbic-radetic",fullName:"Ana Terezija Jerbić Radetić"},{id:"346424",title:"Prof.",name:"Sanja",middleName:null,surname:"Zoričić Cvek",slug:"sanja-zoricic-cvek",fullName:"Sanja Zoričić Cvek"},{id:"346426",title:"MSc.",name:"Jasna",middleName:null,surname:"Lulić Drenjak",slug:"jasna-lulic-drenjak",fullName:"Jasna Lulić Drenjak"},{id:"346427",title:"Prof.",name:"Gordana",middleName:null,surname:"Starčević Klasan",slug:"gordana-starcevic-klasan",fullName:"Gordana Starčević Klasan"},{id:"346428",title:"MSc.",name:"Ariana",middleName:null,surname:"Fužinac Smojver",slug:"ariana-fuzinac-smojver",fullName:"Ariana Fužinac Smojver"},{id:"346429",title:"Prof.",name:"Juraj",middleName:null,surname:"Arbanas",slug:"juraj-arbanas",fullName:"Juraj Arbanas"},{id:"350011",title:"Dr.",name:"Gordana",middleName:null,surname:"Kenđel Jovanović",slug:"gordana-kendjel-jovanovic",fullName:"Gordana Kenđel Jovanović"}]},{id:"76351",title:"Glucocorticoid-Induced Osteoporosis",slug:"glucocorticoid-induced-osteoporosis",totalDownloads:248,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The use of glucocorticoids (GC) in the medium and long term, causes several considerable side effects, being one of the main ones the reduction of bone mineral density (BMD). Prolonged corticosteroid therapy reduces BMD by up to 20% in trabecular bone and approximately 2–3% in cortical bone in the first year of use. This loss rate declines and stabilizes at approximately 2% in subsequent years. Therefore, there is a considerable increase in the incidence of pathological fractures, whether clinically symptomatic or asymptomatic (detected as a radiological finding), which varies between 30 and 50% of patients who use GC for more than three months. In view of the above, it is essential to prevent fractures and treat osteoporosis in patients using glucocorticoids for long periods (in particular, greater than or equal to 3 months), which may or may not be associated with clinical risk factors or previous fractures. The guidelines for the treatment and prevention of this comorbidity are well established for postmenopausal women and men over 50 years of age. However, for patients below this range, studies are still lacking.",book:{id:"10323",slug:"osteoporosis-recent-advances-new-perspectives-and-applications",title:"Osteoporosis",fullTitle:"Osteoporosis - Recent Advances, New Perspectives and Applications"},signatures:"José Renan Vieira da Costa Júnior and Sérgio Luchini Batista",authors:[{id:"164388",title:"Prof.",name:"Sergio",middleName:null,surname:"Luchini Batista",slug:"sergio-luchini-batista",fullName:"Sergio Luchini Batista"},{id:"354032",title:"Dr.",name:"José Renan",middleName:null,surname:"Vieira Da Costa Júnior",slug:"jose-renan-vieira-da-costa-junior",fullName:"José Renan Vieira Da Costa Júnior"}]}],onlineFirstChaptersFilter:{topicId:"1414",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"April 24th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. 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Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. 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She holds a Ph.D. from the University of Oulu, Finland.',institutionString:"Swedish Association for Distance Education, Sweden",institution:null},editorTwo:null,editorThree:null},{id:"94",title:"Climate Change and Environmental Sustainability",coverUrl:"https://cdn.intechopen.com/series_topics/covers/94.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"95",title:"Urban Planning and Environmental Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/95.jpg",isOpenForSubmission:!0,annualVolume:11979,editor:{id:"181079",title:"Dr.",name:"Christoph",middleName:null,surname:"Lüthi",slug:"christoph-luthi",fullName:"Christoph Lüthi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHSqQAO/Profile_Picture_2022-04-12T15:51:33.png",biography:"Dr. Christoph Lüthi is an urban infrastructure planner with over 25 years of experience in planning and design of urban infrastructure in middle and low-income countries. 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He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. 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He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. 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Ost",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}},{id:"325029",title:"Dr.",name:"Prem Chand",middleName:null,surname:"Jain",slug:"prem-chand-jain",fullName:"Prem Chand Jain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Shiv Nadar University",country:{name:"India"}}},{id:"357275",title:"Dr.",name:"Thomas",middleName:null,surname:"Mih",slug:"thomas-mih",fullName:"Thomas Mih",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Buea",country:{name:"Cameroon"}}},{id:"305305",title:"Dr.",name:"Arturo Yosimar",middleName:null,surname:"Jaen-Cuellar",slug:"arturo-yosimar-jaen-cuellar",fullName:"Arturo Yosimar Jaen-Cuellar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}},{id:"305315",title:"Dr.",name:"David Alejandro",middleName:null,surname:"Elvira-Ortiz",slug:"david-alejandro-elvira-ortiz",fullName:"David Alejandro Elvira-Ortiz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}},{id:"344374",title:"Dr.",name:"Manuel",middleName:null,surname:"Toledano-Ayala",slug:"manuel-toledano-ayala",fullName:"Manuel Toledano-Ayala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}}]}},subseries:{item:{id:"40",type:"subseries",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
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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:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"May 7th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:3,numberOfPublishedChapters:96,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. Osma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDv7QAG/Profile_Picture_1626602531691",institutionString:null,institution:{name:"Universidad de Los Andes",institutionURL:null,country:{name:"Colombia"}}},{id:"69697",title:"Dr.",name:"Mani T.",middleName:null,surname:"Valarmathi",fullName:"Mani T. Valarmathi",profilePictureURL:"https://mts.intechopen.com/storage/users/69697/images/system/69697.jpg",institutionString:"Religen Inc. | A Life Science Company, United States of America",institution:null},{id:"205081",title:"Dr.",name:"Marco",middleName:"Vinícius",surname:"Chaud",fullName:"Marco Chaud",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSDGeQAO/Profile_Picture_1622624307737",institutionString:null,institution:{name:"Universidade de Sorocaba",institutionURL:null,country:{name:"Brazil"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/187376",hash:"",query:{},params:{id:"187376"},fullPath:"/profiles/187376",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)}()