\r\n\tsustainability, financial and social investigations, and disruptive technologies. This book also covers urban resilience by considering different factors: health and wellbeing; economy and society; infrastructure and environment; leadership and strategy.
\r\n\r\n\tAs a self-contained collection of scholarly papers, the book will target an audience of practicing researchers, academics, PhD students and other scientists. Since it will be published as an Open Access publication, it will allow unrestricted online access to chapters with no reading or subscription fees.
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The most significant prognostic factors in breast cancer are the tumoral diameter, tumor grading and the status of the axillary lymph nodes. The presence of nodal metastases decreases 5-year survival by approximately 40% compared to node-negative patients, in reference [1]. Lymph node status is of particular value in choosing further therapy. Lymph node metastatic disease is an indication for skipping sentinel node biopsy (SLNB) (and proceeding to complete axillary dissection) and/or for adjuvant systemic chemotherapy, which may be of benefit if administered as preoperative treatment.
The anatomy of the axillary lymph node includes the cortex and the medulla. The high-frecquency probes allow the differentiation of the central echogenic hilum and the peripheral hypoechoic cortex. The cortex, which includes the marginal sinus and the lymphoid follicles is hypoechoic and thin, and has a fusiform shape with smooth edge. The hilum is the hyperechoic, its echogenity being attributable to multiple reflective interfaces of blood vessels, fat, and the central sinus, in reference [2,3].
Carcinoma from the breast enters the lymph node via the afferent lymphatics, penetrates the capsule, and enters the subcapsular sinus, in reference [4]. Metastatic cells firstly stop in the periphery (cortex) of the nodes, causing cortical enlargement. Then generalized cortical enlargement and destruction of the nodal architecture occurs, with compression and, eventually, loss of the hilum, in reference [2].
Grossly involvement of axillary lymph nodes can be detected by clinical examination, ultrasound or axilla MRI. However, introduction of screening mammography led to earlier diagnosis of breast cancer, in which axillary involvement is frequently absent. The challenge of imaging technique is to differentiate the normal lymph nodes from the nodes with minimal metastatic disease, which do not change the size and shape of the lymph node, in patients with small primary breast tumors.
The “golden standard” for axillary lymph node status is pathological examination of lymph nodes. There are three possibilities to obtain information regarding the axillary lymph nodes status: complete axillary lymph node dissection, biopsy of the sentinel lymph node (SLN) and pretreatment imaging of the axillary lymph nodes, associated or not with fine-needle aspiration cytology or core biopsy of the suspicious nodes.
Complete lymph node dissection represents the classic approach that allows pathological examination of all the lymph nodes in the axilla. However, complete axillary lymph node dissection is accompanied by complications like seroma formation, numbness, limitation of shoulder movement, and lymphedema, in reference [5].
SLN biopsy (SLNB) represents the biopsy of that lymph node, which first collects the lymph from the breast. It is a surgical procedure, requiring preoperative administration of a dye and/or radionuclide tracer.
Pretreatment imaging of the axillary lymph nodes must closely match the pathological findings in order to have any value for clinical decision making. Many studies suggest that patients with axillary involvement may benefit from preoperative systemic treatment. Imaging techniques for axilla include ultrasound, MRI enhanced or nonenhanced, FDG-PET scan, 99mTc-sestamibi scintigraphy.
The most available imaging technique for axilla is ultrasound. Ultrasound has two roles in visualizing the axilla: a) to characterize the abnormal lymph nodes, either identified by US or by clinical examination or other imaging technique and b) to help axillar SLN identification. In both circumstances, ultrasound helps the biopsy of the nodes.
Afferent lymphatic channels enter a node through the periphery of the cortex, so the malignant cells travelling the lymphatic vessel will first stop in the cortical region of the lymph node. Most of the US signs of lymph nodes metastasis will refer to the abnormalities of the cortex. Subtle abnormalities of the cortex can indicate early metastatic involvement.
For the assessment of a lymph node by US, quantitative or qualitative methods have been used.
The qualitative features of a metastatic lymph node on US include shape (round morphology), asymmetric cortical thickening (Figure 1), loss of central hilum, loss or compression of the hyperechoic medullary region (Figure 2), relationship with neighbouring lymph nodes, left-to-right asimetry and increased peripheral blood flow. Even more, lymph nodes can exhibit ultrasound malignancy signs characteristic to the primary breast tumor, such as angular margins, „taller than wide” (Figure 3) or they appears intensely vascularisated on Doppler ultrasound. Reactive changes associated with inflamation produce an increase of blood flux in the preexisting blood vessels, but do not generate new vessel formation or vessels that can penetrate the capsule. Metastatic disease stimulates new vessels formation, so Doppler examination can reveal an intense Doppler signal inside the lymph node or blood vessel penetrating the capsule.
Left: Metastatic lymph node, with a round shape. Invasive ductal carcinoma (primary tumor of 1.8 cm, three SLNs identified, all of them metastatic, and complete axillary dissection). Right: asymmetrical cortical thickening in a metastatic axillary lymph node (with normal the cortex-hilum area ratio).
Metastatic lymph node. Left: loss of the hyperechoic medullary region. Right: on power Doppler examination, this node is displaying both central and peripheral blood flow.
Left, metastatic lymphadenopathy, exhibiting „taller than wide” property and angular margins. Pathology showed capsular efraction. Right, gigantic metastatic lymphadenopathy with increased vascularisation and intact capsule.
The quantitative indicators of a metastatic lymph node on US include the size (Figure 4, left), maximum thickness of the cortex, in reference [6] (Figure 4, right; Figure 5), the cortex-hilum (CH) area ratio, in reference [7] (Figure 5), the longitudinal-transverse (LT) axis ratio, in reference [7], the number of peripheral blood vessels.
Lymph nodes can be enlarged, either by metastatic disease or reactive changes, including fat degeneration. Reactive changes in lymph nodes increase all dimensions, keeping the eliptical shape and a normal cortical/medullar index. Metastatic disease will increase the lymph node small diameter, will replace the medullar hyperechogenic region with hypoechogenic tumoral tissue, so the maximum thickness of the cortex and cortex-hilum area ratio will increase, eventually completely destroying the hilum (absent hilum).
A small study of the author, in reference [8], evaluating 21 consecutive breast cancer patients, in which SLNB was performed, suggest that ultrasound size > 1 cm of lymph nodes correlates with invasion of SLN (Figure 4, left).
Cortical region evaluation is more important in lymph nodes assessment than size. The absolute cortical thickness is predictive for axillary metastatic disease (Figure 4, right), a cortical thickness more than 2.5 mm being associated in 70 percent of cases with lymph node metastasis (Cho N et al, 2009, in reference [6]).
Song SE et al, in reference [7], evaluated the diagnostic performance for their own positive criteria for lymph node metastasis, such as CH area ratio >2 (Figure 5), LT axis ratio <2 or peripheral type of vascularisation on power Doppler imaging. They found that the sensitivity of the CH area ratio was superior to that of the LT axis ratio (94.1% vs. 82.3%, p=0.031) and to that of the peripheral blood flow pattern (94.1% vs. 29.4%, p=0.009) (Figure 6). For specificity, all three parameters had the same high values (89.1-95.6%; NS).
Left: metastatic lymph node, showing increased size (longest dimension of 2,29 cm), in a case of advanced invasive ductal carcinoma. Core biopsy of this node showed invasive duct carcinoma. Right: maximum thickness of the cortex of 4 mm in a metastatic lymph node (invasive ductal carcinoma).
Above: reactive lymphadenopathy in patient with postpartum mastitis. There is moderate and simetrical increase of cortical thickness, but normal cortical/medullar index. Below: metastatic axillary lymph node with cortical/medullar index of 1.82 and an absolute increase of cortical thickness > 2.5 mm.
Metastatic axillary lymph node with LT axis ratio of 1.50; blood flow was absent on power Doppler.
Sonoelastography can be added to axillary lymph nodes ultrasound evaluation for further increase the precision of identification of metastatic lymph nodes. At present, there are not many studies trying to establish the place of sonoelastography in evaluation of axillary lymph nodes status. Choi (2011, 64 patients, in reference [9]), Taylor (2011, 50 patients, in reference [10]), Wojcinski (2012, 180 patients, in reference [11]) found that sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs.
Wojcinski et al (2012) found that the highest sensibility (73.3%) is obtained when cortex >3mm in B-mode OR blue cortex in the elastogram, while, when these two features are found together (cortex >3mm in B-mode AND blue cortex in the elastogram (Figure 7)), the highest specificity is obtained (99.3%).
Wojcinski et al, 2012, in reference [11]. Open Access. Example for B-mode ultrasound and elastogram of a metastatic LN. In B-mode ultrasound, the cortex of the LN is slightly enlarged (maximum ~3.5mm). The predominant color of the medulla is turquoise (to green) and the cortex is mainly blue. Meeting both criteria of cortex >3mm in B-mode AND blue cortex in the elastogram, this case would be a true-positive.
Ultrasound has a role in sentinel lymph node identification. With introduction of indocyanine green for sentinel lymph node biopsy (SLNB), Tagaya et al (2010) were able to visualize the fluorescence of lymphatic vessels on the skin. The authors performed firstly intraoperative ultrasonography to identify a SLN as the first lymph node recognized during ultrasonography scanning from the edge of the breast gland in the direction of the axilla and they marked its position on the axillary skin. After indocyanine green dye injection, lymphatic ducts were visualized towards the axilla and the fluorescence stream disappeared aproximatively 1 cm before the line marked on the skin for ultrasound SLN location. In this study, the sites of skin incision for SLNB were also identical with the LN that had been demonstrated by ultrasonography in all patients.
Ultrasound signs of SLN involvement could be very subtle, with only a minimal focal cortical thickness increase.
Above: preoperative assessment of axilla in a breast cancer patient with preoperative chemotherapy. The first lymph node during scanning towards axilla: sentinel lymph node with normal size (longest dimension 5.9 mm) and shape, but with smal focal cortical thickness. Below: intraoperative identification of SLN. After complete axillary dissection, the sentinel lymph and all the other nodes were negative.
By recognizing the first lymph node during scanning towards axilla (Figure 8), ultrasound may help SLN identification and decrease the operation time, an important fact because as the identification time increase, more SLNs are found.
However, in case of axillary metastases, identification of SLN may be impaired (Esen G, Gurses B, 2005, in [12]).
Ultrasound could have a role in imagistic staging of breast cancer. Knowledge of axillary lymph node involvement before surgery may allow for individualization of multimodal treatment. This may include preoperative chemotherapy, intraoperative breast radiotherapy or plastic surgery for immediate reconstruction.
The future protocols of breast cancer treatment will probably include ultrasound as a step in preoperative sentinel node mapping. Ultrasound may reveal abnormalities of axillary lymph nodes and guide biopsy of these nodes.
Patients with either normal or abnormal ultrasound exams, but negative cytology, underwent sentinel node mapping. Patients with abnormal ultrasound and positive cytology proceeded to complete axillary dissection, in reference [13].
There are studies trying to assess the tumoral burden in patient with positive nodes. The study of Moore A et al, in [13], indicates that abnormalities limited to the lymph node cortex (Figure 9) were indicative of N1 disease.
Ultrasound features of axilla, suggesting metastasis in lymph nodes, combined with results of cytology or biopsy, could modify the surgical approach to the axilla, eliminating the need for sentinel node mapping in a significant proportion of patients, in reference [13].
Loss or compression of the hyperechoic medullary region, absence of fatty hilum, abnormal lymph node shape and increased peripheral blood flow are predictive of N2–3 disease, in reference [13] (Figure 10).
Preoperative ultrasound associated with ultrasound-guided biopsy can be used for preoperative axillary staging in patients who will be referred to preoperative systemic therapy. Study of Joh et al, in reference [14], showed that planning and initiation of preoperative systemic therapy can reliably be done using ultrasound axillary evaluation and biopsy.
Postoperative assessment of ultrasound. The first lymph node during scanning towards axilla: metastatic sentinel lymph node with normal size and shape, but with smal focal cortical thickness. After complete axillary dissection, the sentinel lymph node was the only metastatic lymph node.
Left and right: same case – advanced ductal carcinoma (T3 N2 M0). Three lymph nodes displaying the features of metastatic disease. Axillary metastases were confirmed by core biopsy, and the patient was referred to preoperative chemotherapy.
Unfortunetly, no imaging technique has enough reliability to attribute patients directly to complete axillary dissection, without first performing SLNB. The study of Valente SA, Sener SF et al, in [15], evaluated retrospectively 244 consecutive patients diagnosed with invasive breast carcinoma, by physical examination of the axilla, digital mammography, axillary ultrasonography, and contrast enhanced breast magnetic resonance imaging. The authors found that from the patients who had all four modalities negative, 14% were ultimately found to have histologically positive nodes at the time of surgery.
The role of ultrasound in staging breast cancer differs with stage of disease, helping treatment decisions for surgery, chemotherapy, and radiation therapy.
In operable breast cancer, ultrasound helps identification of sentinel lymph node and of suspicious nodes, that warrant biopsy. Ultrasound alone has modest accuracy in detecting axillary metastasis, not being reliable, on its own, to make a decision in surgical treatment of the axilla. Ultrasound does not provide enough information to refer patients to complete axillary dissection.
The reported a median ultrasound sensitivity, in a meta-analysis of 21 studies, including 4313 patients, made by Houssami et al, was 61.4% [51.2%-79.4%], and the median ultrasound specificity was 82.0% (76.9%-89.0%), in reference [16]. Adding a axillary biopsy procedure to ultrasound, to assess patients with abnormal or suspicious axillary nodes, leads to a good sensitivity and excellent specificity (nearly 100%). The same meta-analysis, made by Houssami et al, in [16], evaluated 1733 patients, in whom needle biopsy was added and guided by ultrasound, because of abnormal findings. In these patients, the ultrasound-guided biopsy had median sensitivity of 79.4% (68.3%-8.9%) and a median specificity of 100% (100%-100%).
The study of Holwit DM, Margenthaler JA, in [17], retrospectively performed on 256 patients with clinically node-negative breast cancer, who underwent axillary ultrasound (AUS) evaluation and ultrasound-guided FNAB/needle core biopsy only in suspicious-appearing lymph nodes, found that the sensitivity and specificity of axillary ultrasound alone were 79% and 81%, respectively. The overall combined sensitivity and specificity for AUS-guided FNAB/needle core biopsy were 71% and 99%, respectively, with a negative predictive value of 84% and a positive predictive value of 97%.
Axillary UNB has a good clinical utility, based on a meta-analysis of Houssami N, Diepstraten SCE et al, in [18], on 7097 patients, with a percent of 18.4% of patients effectively referred to axillary treatment thus avoiding SNB.
Locally advanced stages of the disease are usually associated with obvious ultrasound features of axillary node involvement, and ultrasound helps the biopsy of these nodes, in most cases reffering the patient to systemic preoperative treatment.
Ultrasound examination and US-guided biopsy may the only possibility to diagnose the breast cancer that presents with no identifiable breast tumor and clinically positive axillary metastasis only. When mammography is negative, biopsy of the clinically positive lymph node is the only way to obtain a specimen for pathology and ultrasound could help localization and guiding the procedure.
The advantages of preoperative systemic therapy include the potential downsizing of large tumors for either conversion of inoperable disease to resectable lesions or conversion of patients to breast conservation therapy, and in vivo assessment of the response of the tumor to chemotherapy, in reference [19]. Algorithms were issued for attributing patients to preoperative systemic therapy.
Patient presenting with palpable axillary lymph node. No breast tumor could be identified (mammography negative). Multiple passes were performed on the breast for core-biopsy, and the palpable node was removed by open surgery. Pathology showed axillary metastasis of invasive ductal carcinoma, with areas of mucinous carcinoma and failed to confirm the presence of the disease at the breast level.
Lee at al, in [20], consider sonographically detected axillary metastases as a clinically positive axilla, so complete ALND is recommended for patients with positive axillary biopsy, even with a clinically negative axilla, after neoadjuvant chemotherapy.
Algorithm for axillary assessment in patients with locally advanced invasive breast cancer (adapted from Lee MC et al, in [20]).
Axillary staging for breast cancer evolved from axillary lymph node dissection towards the lesser invasive sentinel lymph node biopsy. Nowadays, although SLNB remains the standard procedure for diagnosing axillar involvement, axillary ultrasonography is performed as the initial staging examination breast cancer patients.
In operable breast cancer, ultrasound helps identification and guide biopsy of sentinel lymph node, and/or other imaging suspicious-appearing lymph nodes. As axillary ultrasonography with either FNAB or core-biopsy is a far less invasive approach to diagnose lymph node metastasis, approximately 15 % of breast cancer patients will avoid an unnecessary SLNB and proceed directly to complete axillary dissection.
For patients with locally advanced invasive breast cancer, the recent years brought a growing practice of the routine axillary ultrasound imaging, with early referral of patients to preoperative systemic chemotherapy.
Among the Schwann cells (SCs), non-myelinating Schwann cells (NMSCs) represent an important category that was not extensively studied, although the gathered data demonstrate they are essential for axon maintenance and neuronal survival in the peripheral nervous system (PNS). Extending the knowledge on NMSCs biology could open new perspectives on the normal functioning of PNS as well as for better understanding the mechanisms underlying various pathological conditions and further on for developing new therapeutic approaches in peripheral nerve diseases.
\nThe NMSCs encompass two major cell types, according to their distribution: Schwann cells of Remak fibers and the specialized perisynaptic/terminal Schwann cells at neuromuscular junctions (NMJ). In addition in this category are also included the glial cells found in some sensory transducers, such as the Pacinian and Meissner’s corpuscles, as well as in the sensory and autonomic ganglia, where they are called satellite cells [1]. In pathological circumstances like axonal loss or demyelination, the former myelinating Schwann cells also become a class of NMSCs. Conversely, all NMSCs retain the potential to myelinate [2], if they receive the appropriate cues, most of which derive from the associated axons, along with some fate-controlling genes that act cell-autonomously within SCs [3, 4].
\nAll Schwann cells derive from multipotent progenitor cells of the neural crest (\nFigure 2\n). The fate decision mechanism of SCs to become myelinating cells or to form RSCs is not fully understood, although the plasticity of SCs in various studies is recognized. Thus, some studies proved that if myelinated nerve segments are grafted, on a nerve that contains especially unmyelinated fibers, transplanted SCs do not myelinate, and equally, RSCs can produce a myelin sheath when they are grafted onto a myelinated nerve [2, 5].
\nAfter contacting nascent nerves during embryogenesis, neural crest cells give rise to SC precursors (SCP), which further differentiate into immature Schwann cells (iSC), in late embryonic and perinatal nerves (\nFigure 1\n). After birth, iSC will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating SCs form the myelin sheath of large axons (\nFigure 2A\n). The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles (\nFigure 2B\n), or they migrate toward the neuromuscular junctions, covering the axon terminals, where they become terminal/perisynaptic/teloglia SCs (\nFigure 2C\n and \nD\n).
\nSchwann cell lineage. SCs derive from the neural crest cells, after contacting nascent nerves during embryogenesis. Neural crest cells give rise to SC precursors, in early embryonic nerves which further differentiate into immature Schwann cells, in late embryonic and perinatal nerves. Postnatally, iSch will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating cells form the myelin sheath of large axons. The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles, or they migrate toward the neuromuscular junctions, covering the axon terminals, where they become terminal/perisynaptic/teloglia Schwann cells.
Transmission electron microscopy of myelinated (mn, in A) and nonmyelinated (nn, in B) axons of peripheral nerves embedded in the cytoplasm of Schwann cell (Sch). C and D show the Schwann cells and nerve terminals (nt) in neuromuscular junction. (C) The motor end plate formed by folded sarcolemma (junctional folds, arrows) accommodates knob-like terminal buttons of the motor nerve (nt). (D) The myelin sheath (m) covering the axon ends (nt) in the vicinity of neuromuscular junction and Schwann cell extends into the synaptic cleft (arrowheads).
This chapter addresses the main types of NMSCs, in terms of biological aspects and their role, aiming to highlight their importance for a better understanding of pathological mechanisms underlying various peripheral nervous system diseases.
\nRobert Remak first described the unmyelinated nerve fibers using the nerve fiber teasing technique in 1838 [6], so, in his honor, they were named “Remak fibers.”
\nIn the PNS most nerve fibers are unmyelinated [1], formed by RSCs accommodating a variable number of small-caliber axons (less than 1 μm diameter) (\nFigure 2B\n).
\nRSCs do not produce myelin, but they are essential for normal PNS development and functioning.
\nDuring PNS formation, pockets with multiple axons within a single mesaxon can be encountered. This aspect occurs only occasionally in normal adult Remak fibers where the small diameter axons of C nerve fibers (sensory/afferent), postganglionic sympathetic fibers, and some preganglionic sympathetic or parasympathetic fibers are accommodated in separate grooves of longitudinally interconnected RSCs forming the Remak bundles. Each RSC surrounds many axons, during radial sorting, forming a mesaxon for each axon. It is uncommon for an axon to be in direct contact with the basement membrane of the Schwann cell [4].
\nThe number of axons surrounded by a RSC varies depending on the type of nerve fibers or a particular region along them. Thus, there is a higher number of axons exiting the dorsal root ganglion than in the distal segments of the peripheral nerve. In the cutaneous nerves, the number of axons per RSC decreases as they approach the skin [7], suggesting the existence of specific mechanisms regulating RSC-axons association as they approach their target. Moreover, the distribution of the axons within the Remak bundles varies along the peripheral nerve, with multiple axons within one pocket of the RSC toward the dorsal root and completely isolated axons in the distal segments [8].
\nThere are studies reporting the presence of few short, myelinated internodes along a unmyelinated fiber especially in older animals [9].
\nThus, it appears that the “ensheathment fate” of axons to either become myelinated or unmyelinated fibers relies on local/environmental cues. One of the most extensively studied is the neuregulin 1 type III signaling through ErbB receptors, an axolemmal myelin-inducing factor [3] that promotes the formation of a mesaxon for each unmyelinated axon as well as SC differentiation into myelinating cells, depending on the expression level [10].
\nAnother feature of unmyelinated nerve fibers is that axons may switch between neighboring Remak bundles along the nerve.
\nMoreover, a RSC can surround axons with different functions, for example, both sensitive and sympathetic axons, both axons expressing TrkA (tropomyosin receptor kinase A) receptors with a high affinity for nerve growth factor (NGF) and axons expressing RET (rearranged during transfection) receptors that respond to glial cell line-derived neurotrophic factor (GDNF) and artemin or axons derived from different dorsal ganglia [1].
\nThe RSCs differentiation is governed, at least in part, by neuronal cues, especially by the signaling pathway neuregulin 1 type III (Nrg1-III)/ErbB2/ErbB3 receptor cascades. However, a number of cell-autonomous genes also contribute to SCs differentiation toward RSCs, one of which is gamma-aminobutyric acid type B1 receptor (GABBR1) [4].
\nSCs derive from the neural crest cells, after contacting nascent nerves during embryogenesis. Neural crest cells give rise to SCP, in early embryonic nerves, which further differentiate into iSCs, in late embryonic and perinatal nerves. Postnatally, iSCs will further differentiate either toward myelinating cells or non-myelinating cells according to axon-derived signals. The myelinating cells form the myelin sheath of large axons (larger than 1 μm diameter). The non-myelinating cells ensheath small axons forming unmyelinated fibers, called Remak bundles, or they migrate toward the neuromuscular junctions, where they become terminal/perisynaptic/teloglia Schwann cells (\nFigure 3\n).
\nSchwann cell development and maturation: their role in the evolution of myelinated and unmyelinated peripheral nerve fibers. Schwann cell precursors differentiate into immature Schwann cells which start the process of “radial sorting”. A pro-myelinating Schwann cell envelops a large axon and becomes a myelinating Schwann cell. An immature Schwann cell which ensheaths many small axons becomes mature non-myelinating Schwann cell, forming a Remak bundle.
There are four distinct genes for neuregulins, but neuregulin 1 NRG1 is the best studied. NRG1, also known as glial growth factor (GGF), is a growth factor with EGF domain homology known to induce growth, differentiation, and migration of Schwann cells throughout development [10, 11]. NRG1 has three isoforms out of which type III is considered to be the most important signaling molecule for SC-axon interactions. NRG1 type III is produced by neurons and is released from axons by proteases, such as BACE1, or may remain anchored to the axonal membrane. NR1-III interacts with high-affinity tyrosine kinase receptors ErbB2/ErbB3 heterodimers, triggering the activation of downstream pathways, such as Ras/MAPK and PI3K/Akt SCs. Stimulation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade was proven to lead to the suppression of myelinating state [12] through ErbB2 and ErbB3 receptors that are expressed in Schwann cells [13]. The NRG1-ErbB signaling pathway seems to play a crucial role in the SCs lineage for both myelinating and non-myelinating SCs and promotes SCP precursor survival after birth as well as during in vitro culturing [10, 14].
\nHowever, recent studies showed that in transgenic animal models where NRG1 is conditionally ablated during postnatal life, there is no reduction in the number of sensory axons but larger, unordered Remak bundles with polyaxonal pockets, where axons are not separated by SC processes, are formed, and some large-diameter axons lose the myelin sheath. Only the sensory function was affected, without changing the survival and axonal maintenance of the neurons [15]. However, after nerve injury, RSCs re-establish normal Remak bundles, suggesting that during adulthood, after the basal lamina was established, axonal sorting is no more required [16].
\nAnother experimental in vivo study on mouse sciatic nerve showed that NRG1 type III Erb2/Erb3 signaling regulates the morphological changes of the SCs. The study used a NRG1 type III knockout mouse model (+/−) with a low expression of NRG1 type III, which produced Remak bundles with a higher number of axons and smaller spaces between axons [17].
\nA number of studies have shown that there are certain genes that control SCs fate [4, 12, 18, 19] and that they act cell-autonomously in SCs. There are genes that can trigger upregulation of NRG1 during differentiation after injury, thus stimulating remyelination and redifferentiation of SCs [20].
\nAn important genetically determining factor during SCs development is the gene for gamma-aminobutyric acid type B1 receptor (GABBR1), which is active mainly in RSCs as compared to myelinating SCs [21]. An in vivo experimental research showed that the absence of GABBR1 in embryonic SCs leads to an increased number of small-caliber axons and Remak bundles and a decreased number of the large-caliber axons [19]. Furthermore, NRG1-III expression was decreased in GABBR1 mutant animals, in correlation with lower mean diameter axons along with a compensatory gene overexpression and protein levels of ErbB2 and ErbB3. Further studies are needed to analyze the requirement and the mechanism of these cell-autonomous genes in SC fate decision.
\nDuring maturation, RSCs extend cell processes that individually encircle each axon with the plasmatic membrane and cytoplasm, separating it from surrounding axons. Naked axons, which were not completely surrounded by RSC cytoplasm and which come into direct contact with other axons, demonstrate failed RSC maturation after nerve injury [22]. Recent studies have shown that the expression level of a protein that is highly expressed in non-myelinating SCs, neuropathy target esterase (Nte), is correlated with SC developmental maturation and remyelination after neuronal injury. However, this protein is not involved in myelination [23].
\nOther proteins, such as mTOR [24, 25, 26], or G-G protein-coupled receptor Gpr126/Adgrg6, through laminin-211 and collagen type IV interactions, are required for both myelinating and non-myelinating SCs growth and function, during developmental stages as well as after nerve injury. Gpr126 controls radial sorting, myelination, SC-axon interactions, as well as Remak bundle formation [27, 28, 29, 30].
\nIn SCs, both deletion and overexpression of mTOR complex I adapter (Raptor) disrupts Remak bundle formation by increasing the number of axons in Remak bundles, with many naked axons [26], or decreasing the number of axons in Remak bundles and aberrant wrapping of multiple membrane-layered axons by RSCs, respectively [24, 31].
\nThe absence of myelin gives Remak fibers a certain plasticity, sprouting, and growth abilities that exceed that of myelinated fibers. That is why they are found especially in PNS, where the risk of physical injuries is much higher than in the CNS.
\nAlthough Remak fibers are found mainly in the PNS, they are also found in the CNS, associated with unmyelinated fibers in the parallel fiber system of the cerebellum and nigrostriatal pathway [1, 32].
\nNMSCs, like other SCs, can also function as immunocompetent cells playing an essential contribution in mounting and modulating of immune response in certain conditions, by antigen presentation and cytokine secretion, as well as by their direct interaction with immune cells. Moreover, NMSCs express specific pattern recognition receptors (PRR) for the detection of pathogens, such as Toll-like receptors (TLRs) and the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family [33, 34, 35].
\nThe crosstalk between immune- and peripheral nerve SCs through a large array of molecules either expressed or recognized by SCs build up the base for nervous-immune system interactions. The subject was extensively reviewed by Tzekova et al. [34]. Moreover, Hu et al. showed that NMSCs located in the thymus develop correlations with thymocytes, lymphocytes, and dendritic cells under normal and pathological conditions. They concluded that NMSCs are highly suitable for studying the local interactions of the PNS and primary lymphoid tissues or organs [36]. The same observations were made by Ma et al. studying the mouse spleen and the interactions between NMSCs and leukocytes [37].
\nAnother role for NMSCs was concluded by the study of Yamazaki et al. which showed that NMSCs maintain hematopoietic stem cell hibernation in the bone marrow niche. They demonstrated that NMSCs proved responsible for activation of TGF-beta latent form. These glial cells, ensheathing autonomic nerves, get in contact with hematopoietic stem cells and maintain them in hibernation by regulating activation of latent TGF-beta [38].
\nTransection of a nerve fiber initiates Wallerian degeneration of the distal stump. As opposed to oligodendrocytes, SCs maintain the ability to dedifferentiate to an immature phenotype in response to nerve injury or disease, and they can actively promote the repair and functional recovery. The repair SCs express inflammatory mediators, such as interleukins and TNFα, as well as anti-inflammatory cytokines (IL-10, Epo, or TGFβ) and growth factors shown to promote Wallerian degeneration, macrophage attraction, and axonal regeneration upon nerve injury [34].
\nA number of molecules have been shown to play important roles in modulating SC behavior after nerve injury.
\nLDL receptor-related protein 1 (LRP1) is a significant factor involved in the development and maintenance of Schwann Cells, both myelinating and NMSCs [39]. LRP1 is one of the molecules upregulated after various types of peripheral nerve injury.
\nThe study of Campana et al. proved that LPR1 upregulation was directly correlated with local production of TNFα and TNFα/LPR1 signaling is one of the survival mechanisms for SC migration and survival observed in in vitro studies [40].
\nAnother signaling receptor that plays an important role in regulation of Schwann cell-axon interactions is fibroblast growth factor receptor (FGFR). Fibroblast growth factor 2 (FGF2) is one of the essential regulators of peripheral nerve regeneration after injury [41]. Three of its receptors, expressed by Schwann cells and dorsal root ganglia neurons, are FGFR1, FGFR2, and FGFR3 which are all upregulated after nerve injury [42].
\nOne day after nerve transection, all SCs start to proliferate within the basal lamina. One week post-injury, RSCs double in length, and after 4 weeks they are three-fold longer and were called repair-supportive Schwann cells. About 50% of repair cells derive from RSCs. The loss of axonal contact determines cells to branch. They form branches lying parallel to the main cell axis, building cellular columns and Bungner bands distal to injury site and offering the support of regenerating sprouts. They will further differentiate to myelinating cells after regeneration [43].
\nMost unmyelinated C-fibers ensheathed by Remak cells are nociceptors [39]. They transmit pain information to the brain. Thus, the dysfunction of RSC induces an altered transmission of the nociceptive stimuli, which leads to severe neuropathic pain.
\nThe specific loss of GABBR1 in SCs results in an increased number of C-unmyelinated fibers, leading to a hypersensitivity to thermal and mechanical stimuli. There is also an alteration of the locomotor coordination, without any injury. It is not known whether these consequences are caused only by the modification of the unmyelinated axon number [19].
\nOther in vivo studies showed that after injury, in LRP1 knockout animals, the resulting hypomyelination and impaired RSCs ensheathment lead to motor dysfunction and mechanical allodynia [39] without any traumatic injury. These pathological changes can cause notable painful symptoms such as mechanical allodynia [39]. In a model with partial nerve injury, the LRP-negative mice have a higher degree of RSC apoptosis, an accelerated degeneration, and further more severe pain in the LRP than the nonmutant mice [39]. These findings suggest the involvement of RSC in the pathophysiology of neuropathic pain and the importance of LRP1 in the physiology of RSC and open the possibility of using RSC as a new therapeutic target in the treatment of neuropathic pain.
\nIn an experimental study in vivo on FGFR1 and FGFR2 single and FGFR1/FGFR2 double conditional knockout mice, Furusho et al. showed that lack of FGFR1 and FGFR2 signaling in NMSCs resulted in sensory axonal neuropathy in unmyelinated C-fibers and the impairment of thermal pain sensitivity [42]. Another study by Chen et al. performed on transgenic mice that postnatally express a dominant-negative ErbB receptor in NMSCs but not in the myelinating ones led to a progressive peripheral neuropathy with loss of unmyelinated axons and heat/cold pain [44]. Altogether, such data suggest the important role of RSCs in in the modulation of pain sensitivity in peripheral sensory neuropathies.
\nCharcot-Marie-Tooth type 1A (CMTA1A) is a genetic disease of the peripheral nervous system in which demyelination and further aberrant remyelination occur in a repeated cycle, with an “onion bulb” appearance in microscopy. From the clinical point of view, CMT1A is characterized by weakness and muscle atrophy in the lower limbs and later on by sensory loss. Myelinating Schwann cells are classically known to be impaired in CMT1A, but it seems that there is also an impairment of the RSC [45]. A proliferation of RSC takes place as a response to the degeneration of the myelinated axons that appear to secrete mitogenic factors [45]. Unexpectedly, no degeneration occurs in the unmyelinated fibers [45]. These findings reveal that RSC are altered in CMT1A, but without any impact on the unmyelinated fibers, in comparison to the relation between myelinating SCs alteration and degenerated myelinated axons. Further studies need to elucidate the contribution of RSC to the pathogenesis of CMT1A.
\nPSC, also known as teloglia or terminal Schwann cell, is a type of non-myelinating Schwann cell which is found above the presynaptic nerve terminal at the level of the NMJ. Louis-Antoine Ranvier described in 1878 the presence of a type of cell in the NMJ distinct from the axon terminal or the muscle fiber. He named this cells “arborization nuclei” because of their widespread projections along the NMJs. Later on, with improved histology techniques and in the era of electron microscopy, several studies identified the presence of this specific type of cell in the NMJ (\nFigure 2C\n).
\nPSCs express several markers that are used to highlight them in situ. The most common approach used is anti-S100b immunolabeling [46]. S100b is a nonspecific marker for all types of SCs, either myelinating or non-myelinating ones. In amphibians only, to distinguish PSCs from myelinating SCs, two specific antibodies are used, peanut agglutinin (PNA) [47] and 2A12 monoclonal antibody [48], which mark the extracellular matrix and the cells’ surface, respectively. Interestingly, PSCs express several myelin proteins such as myelin-associated glycoprotein (MAG), galactocerebroside, protein zero (P0), and 2′,3′-cyclic nucleotide 3′-phosphodiesterase [49]. The cells are not involved in the process of myelination, though the presence of these proteins proves the common origin of the two types of Scs. Additionally, PSCs express on their surface several receptors such as acetylcholine receptors, ATP, purinergic receptors, and L-type voltage-dependent calcium channels that usually take part in the synaptic transmission [50, 51, 52, 53] supporting the hypothesis that PSCs play an active role in the NMJ rather than having only a structural role.
\nSeveral studies determined that the number of PSCs gradually increase after birth [54]. Adult NMJ may contain one up to five PSCs [55, 56, 57], and their number is modulated by PSC-muscle cross talk through neurotrophins [58].
\nPSCs tend to be positioned at the presynaptic side, on top of the motor axon terminal, without the intervention of a basal lamina [55, 56]. Recently a new population of fibroblast-like cells named kranocytes—NMJ-capping cells—was detected on the other side, above the basal lamina of the PSC, covering all other cells of the NMJ. They are thought to have important roles in the NMJ repair after nerve injury [59, 60]. Kranocytes appear to communicate with PSCs via neuregulin signaling pathway to act synergistically after nerve damage [59].
\nMost studies about PSCs were performed either on amphibian (frog) or rodent (mouse) samples [53]. A peculiarity of the frog’s NMJ, where the unmyelinated nerve terminal is completely surrounded by PSCs and does not form dilated terminal buttons and the synaptic contact is formed all along, is that PSCs send finger-like projections into the synaptic cleft, on the presynaptic side, which separate, at a regular distance, active areas where the neurotransmitters are released from covered areas [52, 61]. These active areas correspond on the opposite side to the folds of the sarcolemma, the postsynaptic element of the NMJ, which are rich in nicotinic acetylcholine receptors [52, 61]. In mammals, PSC projections do not reach the synaptic cleft (\nFigure 2D\n).
\nPSCs are involved in the growth and maintenance of the NMJ during development.
\nAlthough these cells do not take part in the initial formation of the axon-muscle junction, PSCs have key contributions in the next stages of NMJ development. In animal models lacking SCs, the axon reaches the muscle in the initial step of the NMJ formation, but only for a brief time [62, 63]. In the absence of SCs, the NMJ gets disrupted, suggesting the vital role of PSCs in the NMJ maintenance during development [64]. Soon after the contact between the axon and the muscle, PSCs intensively divide, sprout, and are primarily involved in the growth of the synapse [64].
\nPSCs are also involved in the physiological processes of polyneuronal innervation and synapse elimination. PSCs are involved in the multiple innervation process of the muscles and suffer a regression in parallel with the axonal withdrawal [1, 65, 66]. After the process of axonal withdrawal, PSCs are engaged in the removal of nerve debris, through phagocytosis [67].
\nThe signaling pathway which facilitates the survival and growth of PSCs and the tight communication between PSCs and motor axons is the neuregulin1-ErbB pathway [1].
\nPSCs have important roles in the maintenance of the NMJ during the adult life as the structural support. Ablation in PSCs on the adult NMJ does not impede the immediate structure and function of the synapse, but after a period of time, the motor axon terminals retract, and the NMJ collapses [64, 68]. Thus PSCs have a significant contribution to the structural maintenance of the synapse under the action of physical factors such as the intense tractions between the nerve and the muscle [53].
\nThese cells dynamically participate in the process of synaptic transmission of information between the motor axons and the muscles, having an important role in the modulation of NMJ activity [53, 57, 69]. Not only PSCs can alter the synaptic transmission, but PSC activity can also be modified by synaptic transmission. Or, as some authors like to say, PSCs can both “talk” and “listen” in the synapse [53, 69].
\nWhen the nerve terminal increases its firing rate and a large amount of neurotransmitter is released in the synaptic cleft, a simultaneous increase of intracellular calcium occurs in PSCs [70, 71]. A similar effect is obtained by applying exogenous acetylcholine and ATP, molecules normally released by the synaptic vesicles, to PSCs [51]. Moreover, the levels of intracellular calcium vary depending on the type of the nerve firing rate, either burst or continuous [72]. These events do not occur in the myelinating SCs and emphasize the detection of synaptic activity by PSCs and the modification of their cellular behavior secondary to the synaptic transmission [69]. This is similar to a decoding process of the synaptic activity. Thereby, the events correspond to the “listening” ability of PSCs in the synapse.
\nThe increase of the PSC intracellular calcium levels does not play only a “decoder” role. This transient raising modulates the synapse by intensifying the neuromuscular transmission. PSCs are expressed on the surface of several G protein-coupled receptors with contributions in the modulation of the synapse activity [73]. Evidences suggest that different ligands of these G protein-coupled receptors determine different changes in the neuromuscular transmission, as follows: a GTP analogue decreased the neurotransmitter release, while a GDP analogue reduced the synaptic depression [73]. These events correspond to the “talking” ability of PSCs in the synapse.
\nTherefore, PSCs are not only a structural, passive component of the NMJ, but an active one. These evidences confirm that the NMJ is a tripartite synapse.
\nPSCs induce and guide the growth of nerve sprouts to re-establish the NMJ after nerve injury.
\nAll the actions that PSCs perform in an attempt to regain the activity of the NMJ appear to be mediated by neuregulin1-ErbB signaling pathway [74].
\nFirst of all, after nerve degeneration, PSCs develop phagocytic traits for the clearance of the debris from the nerve terminals [75].
\nSecond of all, PSCs are involved in the guiding of reinnervation. A few days after the nerve injury, PSCs from the altered NMJ begin to abundantly sprout, and these new processes reach adjacent undamaged synapses [76]. In this manner, “bridges” are established between the innervated and the dennervated NMJs. The role of the newly formed bridges is to facilitate the nerve pathway to find the altered NMJ and to regenerate the synapse more rapidly [69, 76]. However, satellite NMSCs seem to play a role in nerve regeneration after insult as well and might be involved in pathogenic pathways of neuropathic pain [77].
\nMiller Fisher syndrome is a Guillain-Barré syndrome variant with antibodies against GQ1b ganglioside that is clinically characterized by ataxia, ophthalmoplegia, and areflexia. Studies on mouse models revealed that PSCs represent an important target of the autoimmune process, the cellular destruction is complement dependent, and this pathogenic mechanism might be relevant for the human disease [68, 78].
\nAmyotrophic lateral sclerosis (ALS) is a challenge for both the clinician and the researcher due to the obscure pathological mechanisms that are still not completely understood. The role of glial cells in the pathophysiology of the disease is not clear yet. Most probably the SC modifications are a consequence of the neurodegeneration process. However in human patients with ALS, PSCs have abnormal features with cellular processes that extend into the synaptic cleft [79]. Additionally, in ALS mouse models, PSCs have abnormal intracellular levels of calcium, causing a flaw in the synaptic “decoding” function [80].
\nAnother neuromuscular disease in which PSCs appear to be involved is spinal muscular atrophy (SMA). In an ultrastructural study on SMA mouse models, PSCs in the diaphragmatic muscle show changes in their morphology such as vacuole-like translucent profiles and an electron-dense cytoplasm [81]. Another study on SMA mouse models revealed that in the evolution of the disease, there is a progressive loss of PSCs, leading to an improperly remodeling and regeneration of the NMJ [82].
\nAlthough little is known on the NMSC, they are very important players for normal PNS function. Recent studies showed that RSCs play a very important role in the development of peripheral nerves and regeneration after injury. RSCs are also involved in the modulation of pain sensitivity in peripheral sensory neuropathies. Even in the absence of injury, disturbance in axonal-RSC interaction is followed by neuropathic pain.
\nAdditionally, PSCs are mandatorily involved not only in synaptogenesis but also in the growth and maintenance of the normal synapse as well as after denervation. Morphological changes of PSCs were detected in various pathological conditions suggesting their potential involvement in the pathogenic mechanism of such diseases.
\nA better understanding of the molecular mechanisms that govern the development and functioning of NMSCs could broaden the perspective on the pathogenesis and potential therapeutic targets for neuropathy and peripheral nerve injuries.
\nThis work was funded by Ministry of Education and Research in Romania under grants no. 7PFE/16.10.2018 and PN 1N/2019_19.29.01.02.
\nThe authors declare no conflict of interest.
SCs | Schwann cells |
RSC | Remak Schwann cells |
NMSCs | nonmyelinated Schwann cells |
NGF | nerve growth factor |
GGF | glial growth factor |
ERK | extracellular signal-regulated kinase |
Nte | neuropathy target esterase |
FGFR | fibroblast growth factor receptor |
NRG1 | neuregulin 1 |
Nrg1-III | neuregulin 1 type III |
GDNF | glial cell line-derived neurotrophic factor |
GABBR1 | gamma-aminobutyric acid type B1 receptor |
SCP | SC precursors |
iSch | immature Schwann cells |
PSCs | perisynaptic Schwann cells |
NMJ | neuromuscular junction |
PNA | peanut agglutinin |
ALS | amyotrophic lateral sclerosis |
CMT1A | Charcot-Marie-Tooth type 1A |
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
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",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
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\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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