Current therapeutic targets for arthritis and their effect on neutrophils.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Arthritis is an inflammatory joint disorder that can cause edema, pain, and loss of function. The most common types of arthritis are osteoarthritis, gout, and rheumatoid arthritis [1, 2]. Rheumatoid arthritis is a systemic, autoimmune disorder with an important inflammatory component in which genetic and environmental risk factors contribute to disease development. Its prevalence in the world population is between 0.3 and 1%, and it affects three times more women than men [3, 4].
\nThe pathophysiology of RA is complex and appears to be initiated when the adaptive immune system (cellular or humoral) recognizes self-joint antigens as non-self, which triggers a variety of distinct inflammatory effector mechanisms, including the recruitment of leukocytes [5–8].
\nRA is characterized by intense inflammatory processes and joint damage that are mediated by the influx of immune system cells to the synovial space such as neutrophils, macrophages, and lymphocytes [1, 2]. A critical factor that contributes to tissue damage is the excessive production of inflammatory mediators by resident and/or infiltrated cells. Among the primary mediators involved in joint damage are free radicals, enzymes that degrade the matrix, and pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, as well as chemokines such as CXCL-8, lipid mediators, such as leukotriene B4 (LTB4) [9, 10], and endothelin (ET) [11, 12]. Inflamed synovial tissue is invasive and called pannus, which can be formed by synovial cell proliferation, angiogenesis, and the accumulation of macrophages, lymphocytes, and neutrophils [13].
\nNeutrophils are crucial cells that have significant roles in diverse inflammatory diseases, including acute, chronic, autoimmune, infectious, and non-infectious conditions [14]. The most well-known effector function of neutrophils is their role in innate immunity. However, recent studies have identified neutrophils as active cells during adaptive immunity, facilitating the recruitment and activation of antigen-presenting cells or directly interacting with T cells. Neutrophils are the most abundant leukocytes in inflamed joints, and the importance of these cells in the initiation and progression of human RA as well as in murine models has been demonstrated [15–18]. Therefore, neutrophils play an essential role in joint inflammation, and the modulation of neutrophil functions is considered a potential target for pharmacological intervention in arthritis [19–21].
\nThe pharmacologic treatment options for arthritis are diverse. The current treatments are mostly symptomatic and include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying antirheumatic drugs (DMARDs), and biologic therapies. High costs and an increased risk of malignancies limit the use of these agents, in addition to the potential side effects that all therapies possess. Plant-derived products, such as polyphenols, sesquiterpenes, flavonoids, and tetranortriterpenoids, which are herbal metabolites with anti-inflammatory activity, may provide new therapeutic agents and cost-effective treatments [22, 23]. This chapter focuses on the role of neutrophils in the pathogenesis of arthritis and the action of substances from natural products as putative antirheumatic therapies.
\nNeutrophil recruitment is an important stage in the inflammatory development process, including autoimmune diseases such as RA. Among the circulating cells, neutrophils are the first ones to reach the synovium and are the most abundant cells in the synovial fluid [24]. In this section, we discuss the cascade of events that culminates in neutrophil entry into inflamed joints. The leukocyte recruitment cascade involves the following commonly recognized steps: capture, rolling, firm adhesion, and finally transendothelial migration.
\nNeutrophil release from the bone marrow to the circulating blood occurs immediately after the first signal of inflammation, serving to increase the number of neutrophils available for recruitment into the tissue in response to inflammation [25]. The mobilization of neutrophils from the bone marrow is orchestrated by the hematopoietic cytokine granulocyte colony-stimulating factor (G-CSF). G-CSF mobilizes neutrophils indirectly by shifting the balance between CXCR4 and CXCR2 ligands [26]. In response to the release of inflammatory mediators such as TNF-α and IL-17, the adjacent vascular endothelium becomes activated. Cell surface proteins of the selectin family termed E- and P-selectin and their ligands (L-selectin) mediate this initial neutrophil capture. Neutrophil rolling through the endothelium facilitates their contact with chemotactic factors that promotes neutrophil activation [27]. Chemokines (CXCR-1 or 2 ligands, such as IL-8), the C5a fragment of the complement system, and leukotriene B4 (LTB4) are responsible for neutrophil mobilization to the synovial fluid [28–30].
\nFirm adhesion is mediated by interactions between β2 integrins (LFA-1, CD11a/CD18, and MAC-1, CD11b/CD18) and their ligand (ICAM-1). Integrins are usually in an inactive state on neutrophil and become activated after the triggering of G protein-coupled receptors such as chemokine receptors [31]. The binding of integrins to their ligands activates signaling pathways in neutrophils stabilizing adhesion and initiating cell motility [32, 33]. This signaling also regulates actin polymerization, which controls the direction of neutrophil movement [34, 35]. The final stage in the adhesion cascade is the ultimate migration of the neutrophil from the vasculature into the inflamed tissue. Passage through the endothelial cell layer occurs both paracellularly (between endothelial cells) and by a transcellular route (over the endothelial cell). Paracellular migration of neutrophils is mediated by binding to endothelial proteins that target neutrophils to intercellular junctions and facilitate their passage through them. To reach the inflamed joint, neutrophils must pass over the basal membrane, which occurs through the degradation of extracellular matrix molecules by proteases stored inside the cells, such as matrix metalloproteinases (MMPs) and serine proteases [14].
\nIn inflammatory foci, neutrophils find immune complexes on the synovium that bind to Fcγ receptors on the neutrophil membrane, triggering their degranulation and reactive oxygen species (ROS) production [36]. In RA pathology, oxidative stress is a result of inadequate ROS release by neutrophils [37]. Oxygen radicals cause DNA damage and oxidation of lipids, proteins, and lipoproteins and may be involved in immunoglobulin mutations that lead to rheumatoid factor (RF) formation [38, 39]. Moreover, proteins from neutrophil degranulation are found at high concentrations in the RA synovial fluid and could be responsible for cartilage and tissue damage, activation of cytokines and soluble receptors, inhibition of chondrocyte proliferation and activation of synoviocytes proliferation and invasion [40–43]. In addition, activated neutrophils also generate chemoattractants (such as IL-8 and LTB4) that promote further neutrophil recruitment and amplify the inflammatory response (see Figure 1).
\nOverview of the role of neutrophils in arthritis. Neutrophils leave blood vessels after chemotactic signals from inflamed tissues that promote the firm adhesion of neutrophils to endothelial cells mediated by adhesion molecules, which induce neutrophil activation and actin filament formation followed by transendothelial migration toward the inflammatory foci. Immune complexes and proinflammatory molecules activate neutrophils, which then produce ROS and release enzymes responsible for cartilage destruction. Activated neutrophils communicate with other cells of the immune system through the secretion of cytokines and chemokines and by antigen presentation in conjunction with MHC class II. Neutrophils can undergo a special form of cell death called NETosis. This results in the release of a complex of nuclear and granule molecules called NETs contributing to tissue damage. Activated neutrophils also generate chemoattractants (such as IL-8 and LTB4), forming a positive-feedback loop that promotes further neutrophil recruitment and amplifies the acute inflammatory response. Finally, effective neutrophil apoptosis is required for the resolution of inflammation. However, delayed neutrophil apoptosis occurs in the inflamed joint, which results in persistent inflammation and tissue damage due to the continued release of ROS, granule enzymes, and cytokines.
Neutrophils are key cells in articular inflammation that are abundant in the synovial fluid and pannus of patients with active RA [44], a typical knee joint may have 2 × 109 cells, of which 90% are neutrophils [24]. These cells are mobilized to synovial tissue by chemoattractant mediators, such as CXCL1, CXCL2, endothelin (ET)-1, and leukotriene B4, a process in which resident macrophages play a central role [11, 45, 46].
\nFor many years, the major contribution of neutrophils to the pathology of RA was thought to be their cytotoxic potential, since neutrophils participate in the pathogenesis of arthritis by promoting the inflammatory process and cartilage degradation, as well as bone resorption. However, neutrophils are now recognized to have an active role in orchestrating the progression of inflammation through regulating the functions of other immune cells [47, 48], and current research has shown that these cells are involved in RA onset [49, 50].
\nIn the synovial cavity, activated neutrophils exhibit an increased expression of plasma membrane receptors such as major histocompatibility complex (MHC) class II molecules and present antigens to T lymphocytes, an immune function that they share with macrophages and dendritic cells (DCs) [51]. In addition, the interaction of neutrophils with other cells induces the secretion of MMP-8 and MMP-9, and a repertoire of cytokines (IL-1β, IL-12, IL-18, IL-23, and TNF-α) and chemokines (CCL-2, CCL-4, CCL-5, and CXCL-8), including TNF ligand superfamily member (RANKL) [52, 53] and TNFSF13B (also known as BLyS or BAFF) [54], which are implicated in the activation of osteoclasts and B lymphocytes, respectively, regulate the function of other immune cells [48, 55–57].
\nNeutrophils from patients with RA are functionally very different from those isolated from healthy individuals. RA blood neutrophils are already primed for ROS production [58] and striking differences in gene and protein expression exist between peripheral blood neutrophils from patients with RA and their healthy counterparts [18], including higher levels of membrane-expressed TNF and myeloblastin (also known as PR-3 or cANCA antigen) in RA [59].
\nIn RA patients, neutrophils can be activated by immune complexes, such as RF or anti-citrullinated protein antibodies (ACPAs), both within the synovial fluid and deposited on the articular cartilage surface [60]. These complexes engage Fcγ receptors and thereby trigger neutrophil activation, which release ROS and RNS [61, 62], collagenases, gelatinases, neutrophil myeloperoxidase (MPO), elastase, and cathepsin G into the synovial fluid and joints [14, 55, 56, 63] due to frustrated phagocytosis [60].
\nOne of the most prevalent symptoms of RA is the increase in sensitivity to joint pain (hyperalgesia), which causes movement limitations. Despite its clinical relevance, strategies for the treatment of arthralgia remain limited. In animal models, hyperalgesia (inflammatory pain) is defined as hypernociception (a decreased nociceptive threshold) [64]. It is broadly accepted that articular hypernociception results mainly from the direct and indirect effects of inflammatory mediators on the sensitization (increased excitability) of primary nociceptive fibers that innervate the inflamed joints [65–67]. Prostaglandins and sympathetic amines are the key mediators of this process. Furthermore, other mediators, such as the cytokines TNF-α, IL-1β, IL-6, and IL-17 play a crucial role in the pathogenesis of arthritis, increasing the recruitment of neutrophils into the joint and driving the enhanced production of chemokines and degradative enzymes [68–70]. In addition, endothelin-1 (ET-1), acting directly or indirectly, also sensitizes primary nociceptive neurons [71–74].
\nDuring the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, by mediating the release of hyperalgesic molecules (such as MPO, MMPs, hypochlorite, superoxide anion, and PGE2) capable of activating nociceptive neurons and causing pain [17, 75–78].
\nIndeed, decreased inflammation and joint destruction have been directly correlated with reduced neutrophil influx into the joints, as observed in mouse models by means of antibody blockade or the gene deletion of chemoattractant receptors such as CXCR1, CXCR2, and BLT1 (LTB4 receptor) [15, 79]. Therefore, the blockade of neutrophil migration could be a target in the development of new analgesic drugs [77].
\nCitrullination is the natural posttranslational conversion of arginine to citrulline mediated by peptidyl arginine deiminases (PADs), enzymes present in macrophages, dendritic cells, and neutrophils. Experimental evidence indicates that citrullination is involved in the breakdown of immune tolerance and may generate neoantigens (neoAgs) that become additional targets during epitope spreading [80]. Citrullinated residues stimulate the production of anti-citrullinated protein antibodies (ACPAs) in predisposed individuals. It has been observed that ACPAs can be present for several years before any clinical signs of arthritis appear [81–83]. A substantial increase in the number and titer of many antibodies against posttranslationally modified proteins is also seen shortly before the onset of arthritis. Citrullinated Ags have increased immunogenicity and arthritogenicity, and their presence in arthritic joints correlates with disease severity [80, 84–86].
\nOsteoclasts are dependent on citrullinating enzymes for their normal maturation and display citrullinated antigens on their cell surface in a non-inflamed state. In humans, the binding of ACPAs to osteoclasts in the bone compartment induces IL-8 secretion. In turn, IL-8 sensitizes and/or activates sensory neurons by binding to CXC chemokine receptor (CXCR) 1 and CXCR2 on peripheral nociceptors [87–90], producing IL 8 dependent joint pain that is associated with ACPA-mediated bone loss.
\nIL-8 release contributes to the chemoattraction of neutrophils [49], which play critical roles in initiating and maintaining joint-inflammatory processes that have been described in experimental arthritis [36, 91]. However, the exact roles that neutrophils play in the posttranslational modification of proteins and disease initiation and progression in RA remain unclear. Recent evidence suggests that, among the various mechanisms by which neutrophils cause tissue damage and promote autoimmunity, aberrant formation of neutrophil extracellular traps (NETs) could play important roles in the pathogenesis of RA [50].
\nNETs are released during a process of cellular death named NETosis. NETosis occurs with neutrophils upon contact with bacteria, fungi [92], or under several inflammatory stimuli. This process is associated with changes in the morphology of the cells, which eventually lead to cell death with extrusion of NETs [93, 94]. This process requires calcium mobilization, reactive oxygen species (ROS) produced by NADPH oxidase, neutrophil chromatin decondensation mediated by neutrophil elastase (NE) and myeloperoxidase (MPO), and chromatin modification via the citrullination of histones by peptidyl arginine deiminase 4 (PAD4) [95–99]. NETs are a network of extracellular fibers, which contain nuclear compounds as DNA and histones and that are covered with antimicrobial enzymes and granular components, such as MPO, NE, cathepsin G, and other microbicidal peptides [93, 94]. In the extracellular environment, NET fibers entrap microorganisms, and their enzymes and granular substances reach locally high concentrations and are thus able to cleave virulence factors and kill microorganisms [95, 100, 101].
\nAlthough NETs play a key role in the defense against pathogens, they may cause undesirable effects to the host, which has increased the interest in the role of neutrophils and NETs in autoimmunity. Augmented NET formation was first described in preeclampsia and ANCA-associated vasculitis and followed by the description in a series of autoimmune conditions, including psoriasis, systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), and RA [50, 100, 102–105]. Neutrophil extracellular traps are an obvious source of nuclear material. Among these are a range of cytoplasmic and extracellular citrullinated antigens, well-established targets of the ACPAs found in RA [50, 100]. The protein contents of NETs not only serve as targets for autoantibody and immune complex formation but also induce further NETosis, resulting in a harmful positive-feedback loop. These factors form an inflammatory microenvironment that may trigger a strong autoimmune response in individuals with the corresponding susceptibility [106, 107]. Pro-inflammatory cytokines, such as TNF-α and IL-17, as well as autoantibodies stimulate the formation of NETs and affect their protein composition [50]. Additionally, NETs have been shown to stimulate autoimmunity via the production of interferons and activation of the complement cascade. Interferons activate both the innate and adaptive immune systems, inducing a Th1 immune response and stimulating B cells toward the generation of autoantibodies [108]. The deposition of NETs observed in various inflammatory pathologies is associated with the circulating cell-free DNA (cfDNA) levels in biological fluids, such as plasma and serum, from patients [100, 101, 109]. Therefore, circulatory cfDNA could eventually be utilized as a marker of NETs in these pathologies, while the determination of the DNA levels might facilitate the monitoring of disease activity and assessment of the effectiveness of a selected therapeutic strategy.
\nNeutrophils have been traditionally viewed as short-lived cells that die at sites of inflammation; however, some evidence suggests that they can prolong their life span upon specific stimuli and transmigrate away from inflammatory loci [48, 110, 111]. Conditions within the synovial joint, such as hypoxia [112] and the presence of antiapoptotic cytokines (including TNF, granulocyte-macrophage colony-stimulating factor (GM CSF), and IL 8) [113, 114], can increase neutrophil survival for up to several days [115, 116], which contributes to enhanced tissue damage.
\nAs described above, neutrophils play an essential role on innate and adaptive immunity in RA physiopathology, contributing to tissue lesions in RA, and therefore represent a promising pharmacological target in RA. Pharmacological strategies that inhibit or reduce neutrophil mobilization or activation could be successful in RA treatment.
\nAnimal models have been extensively used in studies of RA pathogenesis. Despite the inherent limitations of all animal models, several rodent models have greatly contributed to the overall knowledge of important processes/mediators in the generation of inflammation, cartilage destruction, and bone resorption. In addition, the pharmaceutical industry has used these models for testing potential anti-arthritic agents, leading to important advances in therapeutic interventions for this destructive disease [117]. Such models include collagen-induced arthritis, collagen antibody-induced arthritis, zymosan-induced arthritis, the methylated BSA model, and genetically manipulated or spontaneous arthritis models such as the TNF-α-transgenic mouse, K/BxN mouse, and Skg mouse [118]. Many of these models show that neutrophils are the first immune cells to enter the arthritic joint, and that early measures of joint inflammation correlate with neutrophil infiltration [45, 119, 120]. In this section, we highlight pharmacological approaches targeting neutrophil recruitment and activity, which present a therapeutic benefit to patients with RA.
\nThe current treatments available to RA patients include glucocorticoids, non-steroidal anti-inflammatory drugs, and disease-modifying antirheumatic drugs. Only disease-modifying agents—and to some extent glucocorticoids—can impede or halt the inflammatory and destructive disease processes [121]. With a more complete understanding of the immune-inflammatory events that occur in the pathogenesis of RA, scientists have developed therapeutic strategies that include monoclonal antibodies and receptor constructs, which target specific soluble or cell-surface molecules of interest. Biological agents such as monoclonal antibodies and recombinant proteins that target TNF-α, CD20, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), and the IL-1 receptor as well as therapies based on the blockade of T-cell and B-cell functions have shown efficacy in controlling the physical signs and pain associated with RA [122, 123].
\nMany interventions used to treat RA exert inhibitory effects on neutrophil responses in inflammation. However, non-steroid anti-inflammatory drugs (NSAIDS), DMARDs, and biologics do not specifically target neutrophil function [124].
\nMost NSAIDs inhibit the action of the cyclo-oxygenase-1 and -2 (COX-1 and -2) enzymes, which metabolize arachidonic acid into inflammatory mediators of the prostaglandin family. NSAIDs have been shown to inhibit neutrophil adherence, decrease degranulation and oxidant production, inhibit neutrophil elastase activity, and induce neutrophil apoptosis [125–127]. Corticosteroids induce anti-inflammatory signals by several mechanisms; a major one may be to reduce the expression of cytokine-induced genes. They enter all cells and bind to the cytoplasmic steroid receptor, and then this complex translocates to the nucleus where it is recognized by specific DNA sequences. The major effect of binding to DNA is the suppression of transcription by opposing the activation of the transcription factors AP-1 and NF-κB [128]. Corticosteroids have been shown to inhibit neutrophil degranulation and ROS production, decrease production of inflammatory mediators, and prevent neutrophil adhesion and migration into RA joints [44, 129–131]. The most widely used DMARD in clinic settings is methotrexate, a compound that blocks folic acid metabolism. Its benefits in RA include the stimulation of neutrophil apoptosis [116], inhibition of the NF-κB pathway [132], and reduced adhesion molecule expression and LTB4 production [133], consequently decreasing neutrophil recruitment and ROS production [134].
\nAnti-TNF-α therapies are also widely used for the treatment of RA patients. TNF primes the neutrophil respiratory burst, upregulates the expression of adhesion molecules, cytokines and chemokines, and at high local concentrations can stimulate ROS production in adherent neutrophils [135–138]. Three different TNF inhibitors are available for RA patients who fail to respond adequately to standard DMARD therapy. Infliximab and adalimumab are monoclonal antibodies against TNF, whereas etanercept is a TNFRII fusion protein. All three drugs sequester soluble TNF [139]. Reports regarding the direct effect of anti-TNF agents on neutrophils have been published, and these drugs have been shown to decrease the mobilization of neutrophils from the peripheral blood to inflamed joints [140], decrease ex vivo neutrophil ROS production [20], and reduce neutrophil chemotactic and adhesive properties [141].
\nTocilizumab, a monoclonal antibody that blocks the soluble and tissue-expressed IL-6 receptor, is also proving to be a highly effective biologic agent in RA treatment [142]. Neutrophils are a major source of soluble IL-6 receptors, which they shed in large quantities when activated, and their accumulation in high numbers within the synovial joint could contribute significantly to IL-6 signaling within the synovium through trans-signaling [143]. In vivo therapeutic blockade of IL-6 with tocilizumab induces transient neutropenia caused by apoptosis or phagocytosis of apoptotic neutrophils but does not impair antibacterial neutrophil functions [144].
\nDespite the clinical efficacy of these therapies, many patients do not exhibit significant responses or discontinue treatment because of adverse effects. In addition, the limited availability of biological agents in developing countries, the need for parenteral administration of these products, and the high cost restrict access to such therapies for many RA patients worldwide, and this promotes a continuous search for new therapeutic targets and the development of new drugs [145]. Due to these limitations, interest has grown in the use of alternative treatments and herbal therapies for arthritis patients [146, 147] (Table 1).
\nTherapy | \nEffect on neutrophil response | \nReference |
---|---|---|
Non-steroidal anti-inflammatory drugs (NSAIDS) | \nInhibit neutrophil adherence, decrease neutrophil degranulation and ROS production, inhibit neutrophil elastase activity, and induce neutrophil apoptosis | \n[125–127] |
Corticosteroids | \nInhibit neutrophil degranulation and ROS production, decrease the production of inflammatory mediators, and prevent neutrophil adhesion and migration into RA joints | \n[44, 129–131] |
Disease-modifying antirheumatic drugs (DMARDs) | \nStimulate neutrophil apoptosis, inhibit the NF-κB pathway, and reduce adhesion molecule expression, LTB4 production, neutrophil recruitment, and ROS production | \n[116, 132–134] |
TNF-α inhibitors | \nDecrease neutrophil mobilization from the peripheral blood to inflamed joints and reduce ex vivo neutrophil ROS production and neutrophil chemotactic and adhesive properties | \n[20, 140, 141] |
IL-6 inhibitor | \nInduce transient neutropenia caused by apoptosis or phagocytosis of apoptotic neutrophils but not impair antibacterial neutrophil functions | \n[144] |
Current therapeutic targets for arthritis and their effect on neutrophils.
Current arthritis treatments result in unwanted side effects and tend to be expensive, and natural products devoid of such disadvantages offer a novel opportunity. The use of natural products represents a promising alternative to treat rheumatic diseases, in particular by acting as therapeutic adjuvants to reduce the daily doses of conventional drugs that RA patients administer [148–150]. In this section, we highlight future perspectives in the treatment of RA with natural compounds, mainly herbal compounds, to minimize the harmful effects of the over-activation of neutrophils.
\nDecreased inflammation and joint destruction have been directly correlated with reduced neutrophil influx into the joints, as observed in mouse models by means of antibody blockade or the gene deletion of chemoattractant receptors such as CXCR1, CXCR2, and BLT1 (LTB4 receptor) [15, 79]. The prospect of new drugs obtained from herbal products (or from structures of herbal products) plays a compelling role in drug discovery and development [151].
\nAs previously mentioned, pharmacologic treatment options for arthritis are diverse and present several side effects. Furthermore, the high costs and increased risk of malignancies limit the use of such agents. Because of these limitations, there is a growing interest in the use of natural products as therapies or adjunct therapies [22]. Plant-derived products such as polyphenols, sesquiterpenes, flavonoids, and tetranortriterpenoids, which are herbal metabolites, are considered to have potential activity to block inflammation, and they may provide new therapeutic agents and cost-effective treatments [22, 23]. These natural products have attracted considerable interest over the past decade because of their multiple beneficial effects, such as their antioxidant, anti-inflammatory, antiproliferative, and immunomodulatory properties. In this section, we discuss the plant-derived products that have been most studied in RA experimental models and/or clinical trials (Table 2).
\nQuercetin (Figure 2a) is the major dietary flavonol found in fruits, vegetables, and beverages, such as tea and red wine [152]. Several epidemiological and experimental studies support the antioxidant, anti-inflammatory, antiangiogenic, antiproliferative, and proapoptotic effects of this molecule [153–155]. Preclinical studies on primary cells and animal models, as well as clinical studies, suggest an inhibitory action of quercetin in RA. Quercetin has been reported to lower the levels of IL-1β, C-reactive protein, and monocyte chemotactic protein-1 (MCP-1), and restore plasma antioxidant capacity. In addition, quercetin increased the expression of hemeoxygenase-1 in the joints of arthritic rats. Finally, quercetin inhibited the twofold increase in NF-κB activity observed in joints after arthritis induction [156].
\nChemical structure of (a) quercetin, (b) methyl gallate, (c) gedunin, (d) epigallocatechin gallate, and (e) curcumin.
Compound | \nChemical class | \nArthritis experimental model | \nReference |
---|---|---|---|
Quercetin | \nFlavonoid | \nAdjuvant-induced arthritis | \n[156] |
Methyl gallate | \nPolyphenol | \nZymosan-induced arthritis | \n[171] |
Gedunin | \nTetranortriterpenoid | \nZymosan-induced arthritis | \n[176] |
Epigallocatechin gallate | \nPolyphenol | \nCollagen-induced arthritis | \n[179] |
Curcumin | \nPolyphenol | \nCollagen-induced arthritis | \n[191] |
Herbal products that exhibit anti-arthritic potential in animal models.
There are divergent data on the effect of quercetin in neutrophils. For instance, in vitro, quercetin inhibited myeloperoxidase activity [157] but had no effect on lipopolysaccharide-induced neutrophil surface expression of the adhesion molecules L-selectin (CD62L) and β2 integrin (CD11b/Mac1), [158] which are related to rolling and firm adhesion, respectively [159]. In paw edema induced by carrageen, quercetin did not inhibit the increase in myeloperoxidase, which is used as a marker of neutrophil recruitment [160]. Therefore, it seems unlikely that quercetin would inhibit neutrophil recruitment [158]. On the other hand, quercetin inhibits the fMLP-induced increase in intracellular calcium, [158] which is necessary for actin polymerization and consequently neutrophil migration [159]. In addition, in vitro, quercetin blocked human neutrophil mobilization through the inhibition of the cellular signaling responsible for actin polymerization in association with the down-regulation of adhesion molecules [161], indicating that treatment with this flavonoid is a conceivable approach to control excessive neutrophil recruitment during inflammation and to prevent neutrophil-mediated tissue lesions [162] (Table 3).
\nCompound | \nMolecular targets/mechanisms | \nReference |
---|---|---|
Quercetin | \nInhibits IL-1β, C-reactive protein, and MCP-1 levels. Restores plasma antioxidant capacity, increases HO-1 expression, and inhibits NF-κB activity in joints Inhibits myeloperoxidase activity in neutrophils and blocks neutrophil mobilization | \n[156, 157, 161] |
Methyl gallate | \nReduces edema formation, total leukocyte accumulation, neutrophil migration and IL-6, TNF-α, CXCL-1, IL-1β, LTB4, and PGE2 production in zymosan-induced arthritis. Impairs neutrophil chemotaxis and adhesion | \n[171] |
Gedunin | \nAttenuates zymosan-induced articular edema, neutrophil migration, hypernociception, and the production of IL-6, TNF-α, LTB4, and PGE2 and prevents increases in lipid bodies. Decreases neutrophil shape changes, chemotaxis, and lipid body formation | \n[176] |
Epigallocatechin gallate | \nAmeliorates the severity of arthritis and regulates the expression of cytokines, chemokines, MMPs, ROS, NO, COX-2, and PGE2. Affects neutrophil functionality and inhibits IL-8 and MIP-3α expression | \n[179–184, 186–189] |
Curcumin | \nSuppresses collagen-induced arthritis by reducing cellular infiltration, synovial hyperplasia, cartilage destruction, and bone erosion. Blocks neutrophil recruitment | \n[191, 193] |
Major molecular targets and anti-arthritic mechanisms of herbal products.
S. terebinthifolius Raddi (Anacardiaceae) is a native plant from South America. It has been used in folk medicine as teas, infusions, or tinctures, as an anti-inflammatory, febrifuge, analgesic, and depurative agent and to treat urogenital system illnesses [163]. Scientific reports demonstrated that S. terebinthifolius extracts and fractions are rich in polyphenols and display antioxidant, antibacterial, and antiallergic properties in different experimental models [164–166]. The HPLH chromatograms of hydroalcoholic extracts from S. terebinthifolius leaves (ST-70) reveal that methyl gallate (MG, Figure 2b) is one of the major polyphenol components of the ST-70 extract [167]. Methyl gallate has been extensively studied because of its antioxidant, antitumor, and antimicrobial activities [168–170]. Pharmacological studies have shown that ST-70 and MG also have an anti-inflammatory effect and may have potential activity against arthritis. Pretreatment with ST-70 or MG markedly reduced knee-joint thickness, total leukocyte (mainly neutrophil) infiltration, and reduced the production of inflammatory mediators associated with arthritis such as CXCL-1/KC, IL-6, TNF-α, IL-1β, LTB4, and PGE2. ST-70 and MG also inhibited murine neutrophil chemotaxis induced by CXCL-1/KC in vitro, and MG impaired the adhesion of these cells to TNF-α-primed endothelial cells [167, 171]. These results provide some evidence that MG inhibits neutrophil activation and adhesion molecules expression and consequently prevents the neutrophil entry into inflammatory sites (Table 3).
\nMoreover, unlike potassium diclofenac, the long-term oral administration of ST-70 does not induce lethality or gastric damage in mice, which suggests that ST-70 could be used to treat inflammatory conditions such as arthritis with less toxicity [167].
\nC. guianensis Aublet is a member of the Meliaceae family that is widely used in folk medicine in Brazil and other countries surrounding the Amazon rainforest [172]. Anti-inflammatory and analgesic activities are among the most remarkable properties attributed by ethnopharmacological research to the oil extracted from C. guianensis seeds, mainly for rheumatic pain and arthritis [172, 173]. C. guianensis oil and six different tetranortriterpenoids (TNTP) isolated from the oil were able to significantly inhibit zymosan-induced knee joint edema formation and protein extravasation. TNTP pretreatment inhibited the increase in total leukocyte and neutrophil numbers in the synovial fluid. TNTP also impaired the production of TNF-α, IL-1β, and CXCL-8/IL-8, and significantly inhibited the expression of the NF-κB p65 subunit [174].
\nGedunin (Figure 2c) is a natural tetranortriterpenoid isolated from vegetal species of the Meliaceae family and is known to inhibit the stress-induced chaperone heat shock protein (Hsp) 90 [175]. Mouse pretreatment and posttreatment with gedunin impaired zymosan-induced edema formation and total leukocyte influx mainly due to the inhibition of neutrophil migration and reduced articular hypernociception. Gedunin also reduced the in situ expression of preproET-1 mRNA and IL-6, TNF-α, LTB4 and PGE2 production and prevented increases in the number of lipid bodies in synovial leukocytes [176]. Lipid bodies are important sites for the synthesis and storage of lipid mediators and they increase in number during inflammatory responses [177]. In neutrophils, gedunin impaired ET-1-induced shape changes, blocked ET-1- and LTB4-induced chemotaxis, decreased ET-1-induced lipid body formation and impaired neutrophil adhesion to TNF-α-primed endothelial cells [176]. The combined in vitro and in vivo effects of gedunin reveal its potential as an anti-arthritic candidate, especially its direct effect on key cells involved in articular inflammation such as neutrophils (Table 3).
\nEpigallocatechin gallate (EGCG, Figure 2d) is one of the main components of green tea [178]. It has antioxidative, anti-inflammatory, antitumor, and chemopreventive properties. The potential disease-modifying effects of green tea on arthritis have been reported; for example, in a mouse model of RA, the induction and severity of arthritis was ameliorated by the prophylactic administration of green tea polyphenols [179]. Subsequent studies suggested that EGCG possesses remarkable potential to prevent chronic diseases like OA and RA [180–184]. The anti-inflammatory and anti-arthritic effects of EGCG are supported by in vitro and in vivo data indicating that EGCG can regulate the expression of cytokines, chemokines, MMPs, ROS, nitric oxide (NO), COX-2, and PGE2 in cell types relevant to the pathogenesis of RA [179–184]. In in vivo studies, EGCG was found to inhibit inflammation in mouse models by affecting the functioning of T cells and neutrophils [185, 186]. IL-8 is the most powerful chemo-attractant for neutrophils in the target tissue. EGCG is a very effective inhibitor of IL-1β and of TNF-α-induced IL-8 and macrophage-inflammatory protein-3α (MIP-3α) expression in different cell types [187–189]. These in vitro and in vivo observations indicated the efficacy of EGCG and demonstrate that it can modulate multiple signal transduction pathways in a fashion that suppresses the expression of inflammatory mediators that play a role in the pathogenesis of arthritis (Table 3).
\nCurcumin (Figure 2e) is a yellow-colored polyphenol found in the rhizome of turmeric. It has antioxidant, anti-inflammatory, antiapoptotic, and anticarcinogenic properties [190]. Oral administration of curcumin suppressed type II collagen-induced arthritis (CIA) in mice by reducing cellular infiltration, synovial hyperplasia, cartilage destruction, and bone erosion. Moreover, the production of MMP-1 and MMP-3 was inhibited by curcumin in CIA and in TNF-α-stimulated RA fibroblast-like synoviocytes (RA-FLS) and chondrocytes [191].
\nIn vitro, it has been reported that curcumin decreases IL-1β-induced expression of the pro-inflammatory cytokine IL-6 and vascular endothelial growth factor (VEGF) in RA-FLS [192]. In addition, curcumin blocks neutrophil recruitment through the inhibition of cellular signaling responsible for actin polymerization in association with the down-regulation of adhesion molecules [193]. It has also been shown to induce apoptosis of RA-FLS (which are resistant to apoptosis) by increasing the expression of the proapoptotic protein Bax and down-regulating the expression of the antiapoptotic protein Bcl-2 [190]. Some molecular mechanisms related to curcumin have been identified. In a human synovial fibroblast cell line (MH7A) stimulated with IL-1β, curcumin blocked the activation of the NF-κB pathway and induced deactivation of the ERK-1/2 pathway [192]. In addition, this polyphenol inhibited activating phosphorylation of protein kinase Cδ (PKCδ) in CIA, RA-FLS, and chondrocytes. Curcumin also suppressed JNK and c-Jun activation in those cells [191].
\nIn a clinical trial with RA patients, curcumin reduced reported pain, tenderness, and swelling of joints [194]. A curcumin-based medicine, Meriva®, demonstrated efficacy in clinical trials with patients with osteoarthritis by reducing reported pain [195]. In another clinical trial, treatment with Meriva® reduced stiffness and physical signs of RA (treadmill test) along with IL-1, IL-6, and VCAM-1 production [196] (Table 3).
\nIn RA, neutrophils are key cells that are recognized to play an active role in orchestrating the progress of inflammation, through the release of pro-inflammatory cytokines, ROS, RNS, and NETs, which potentially affect the activities of both neutrophils and other cell types, such as resident mononuclear cells and chondrocytes. In addition, neutrophils participate in the cascade of events leading to mechanical hypernociception. Therefore, neutrophils participate in the pathogenesis of arthritis by promoting the inflammatory process, degradation of cartilage, and bone resorption. The modulation of neutrophil migration and functions in RA can be considered a potential target for pharmacological intervention in arthritis. The pharmacologic treatment options for arthritis are diverse. High costs and an increased risk of malignancies limit the use of these agents, in addition to the potential for side effects that all therapies possess. Nevertheless, herbal metabolites with anti-inflammatory activity and inhibitory action in neutrophils may provide new therapeutic agents and cost-effective treatments.
\nThis work was supported by Brazilian grants from Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). L. B. Correa is a student of the post-graduation Program in Cellular and Molecular Biology from Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
\nNowadays, long working stroke precision positioning systems with micro-to-nano resolution are significantly demanded in many scientific studies and industrial fields [1, 2, 3]. Most of the conventional actuators can hardly satisfy the requirements on positioning resolution for precision positioning systems, such as hydro-motors, direct/alternating current motors, pneumatic elements, et al., even with the merits of large output capability, fast response, and long working stroke [4, 5, 6].
\nThe piezoelectric actuator is one of the potential alternatives for high-resolution precision positioning systems [7, 8, 9, 10]. Up to now, various of piezoelectric-driven positioning systems with flexure hinge-based compliant mechanisms have been developed and widely applied in many scientific and industrial applications, such as atomic force microscopy (AFM) [11, 12, 13], fast tool servo (FTS) single-point diamond turning [14, 15, 16] and optical adaptive mirror [17, 18, 19], et al. Generally, restricted by the inverse piezoelectric effect of current piezoelectric materials, the displacement of a single piezoelectric element is limited within tens of nanometers to several micrometers [20]. The applications of such positioning stages are only employed within limited scopes due to micro-scale working stroke. In order to extend the working stroke of piezoelectric elements, several methods have been proposed and investigated [21, 22, 23], which can be classified according to the motion principle into the direct-driven principle, ultrasonic principle, and stepping principle. Direct-driven principle is the initial application in piezoelectric actuators. With the assistance of flexure hinge-based compliant mechanisms, it is found that the working stroke can be amplified up to several times of the original displacement of a single piezoelectric element. The maximum working stroke is extended to tens of micrometers [24, 25, 26]. However, it is still not long enough for most of the applications, and furthermore complicated flexure hinge-based compliant mechanisms deteriorate the static and dynamic characteristics of the piezoelectric actuators, reducing structural stiffness and intrinsic resonant frequency. Therefore, the direct-driven principle gradually loses its popularity in the recent years. Ultrasonic principle utilizes the resonance of stators to drive the slider/rotor. However, the interfacial wear and heat generation are lack of adequate solution to date, especially in high-speed & full-load motion [27, 28]. Stepping principle realizes the long working stroke by step displacement accumulation. By this way, high-precision positioning accuracy can be achieved in long working stroke. Hence, stepping principle has attracted much attention in the piezoelectric actuator development in the recent decades.
\nVarious of stepping piezoelectric actuators can be further classified into three motion types, involving inchworm type, friction-inertia type, and parasitic type [3, 29, 30, 31]. Inchworm type, as a kind of bionic driving type, mimics the motion principle of inchworms in nature, which alternates the clamping and driving units to move forward and backward. Thus, its control strategy, structural assembly and the motion sequence are generally complicated. Friction-inertia type refers to a kind of spontaneous jerking motion that can occur, while two mass blocks alternate between sticking to each other and sliding over each other, with a corresponding tuning the friction and inertia forces. Compared with the inchworm type, the basic structure and control system of friction-inertia type are largely simplified but associated with loss on loading capability.
\nParasitic type is a new solution to acquire both long working stroke and large output capability by adopting the parasitic motion of flexure hinge-based compliant mechanisms, which is commonly restricted in previous designs [32, 33]. Up to now, tens of PMP piezoelectric actuators based on various of flexure hinge-based compliant mechanisms have been developed with great success and achievement on improving working stroke and output capability. The purpose of this chapter is to introduce the basic parasitic motion principle, review the developments and achievements in recent years, and finally point out some potential issues and current challenges in this research.
\nDifferent from other kinds of motion principles, the parasitic principle belongs to a kind of dependent motion, which generally accompanies with an independent motion, as illustrated in Figure 1(a). When a load F is applied at the end of a cantilever beam, it will be bent with two motion components in x and y directions. The motion component in y direction is the major motion, which is directly induced by the load F, while the motion component in x direction is called as the parasitic motion. It simultaneously occurs with the major motion, which is generally regarded as an undesired motion component in previous studies. In general, the parasitic motion is much smaller than the major motion, but this dependent motion may deteriorate positioning accuracy and lead to more issues in calibration. On the other hand, if the parasitic motion of flexure hinge-based compliant mechanisms can be appropriately adopted in the design of piezoelectric actuators, it can be employed as a motion task by utilizing lower degree of freedom (DOF) with easier control, lower cost, less complexity of kinematics and simple structure. By employing specially designed control signal, for instance, the saw-tooth wave as shown in Figure 1(b), applied to the piezoelectric element, the relative displacement is realized, and thus the stepping motion is achieved. Therefore, the PMP piezoelectric actuator becomes popular since its emergence in recent years.
\nSchematic diagrams of the parasitic motion principle: (a) generation of parasitic motion when bending a cantilever, (b) saw-tooth wave control signal, and (c) motion principle of the PMP piezoelectric actuator in one step [23].
\nFigure 1(c) shows the motion principle in one step of the PMP piezoelectric actuator. This kind of actuators is generally consisted of two sections, the stator and the slider/rotor. At the initial step (1), the stator and the slider are in separated state with an initial gap δ between each other. Then, in step (2), with a moment/force slowly applied to the flexure hinge-based compliant mechanism, the initial gap δ is filled, leading to an initial contact between the stator and the slider/rotor. Afterwards, in step (3), both the major motion and parasitic motion increase with deformation of the flexure hinge-based compliant mechanism. The slider/rotor moves in the same direction with the parasitic motion. Finally, after the slider/rotor moves to the forward displacement/angle in one step, the moment/force is suddenly removed, and the flexure hinge-based compliant mechanism recovers to its initial state and gets ready for the next cycle. In this process, as the stator still contacts with the slider/rotor, a backward motion would generally appear in the final step. Therefore, the PMP piezoelectric actuator could move with one-step displacement ΔS, the one-step maximum displacement minus the backward motion. By cycling from step (1) to step (4), the long working stroke can be easily achieved.
\nInchworm type, friction-inertia type, and parasitic type are three main kinds of motion types in stepping principle to realize long working stroke. Inchworm type, as a kind of bionic principle, employs the driving units and clamping units to obtain long working stroke. The utilization of clamping units facilitates the enhancement on output capability for piezoelectric actuators. In general, the inchworm type actuator consists of three separate parts, one driving unit and two clamping units. The moving processes of the inchworm type piezoelectric actuator are presented in Figure 2.
\nMotion principle of the inchworm type actuator: (a) moving principle of inchworm in nature [34], and (b) bionic stepping motion principle of inchworm type piezoelectric actuators.
\nFigure 3 shows the schematic diagram of friction-inertia type motion principle. The motion principle for the friction-inertia type follows the law of momentum conservation. A piezoelectric stack or piezoelectric bimorph, between two objects with different weights, is driven by a special control signal. At the initial step (1), the piezoelectric element is in its original status and connects two blocks. Then, in the step (2), the piezoelectric element extends gradually with the increase of driving voltage, and one block follows the movement of the piezoelectric element due to the static friction. In this process, there is no relative motion between the two objects. Afterwards, in step (3), the driving voltage suddenly drops to zero and the piezoelectric element loses power. It quickly recovers to the initial status, but the moving block remains in its position due to the inertial force. Following these steps, a small displacement occurs in this process. Based on the moving process, the friction-inertia actuator involves two motion types: impact-friction type and stick–slip type [3]. The main difference from impact-friction type is that, in stick–slip type, one end of the driving element is connected to the base and the other end drives the mass block by surface friction.
\nMotion principles of two friction-inertia types actuators: (a) impact-drive type, and (b) stick–slip type [3].
These three motion principles have some similarities and differences. According to the previous research, the performance comparison of these three motion types of stepping principle piezoelectric actuators is listed in Table 1. From the list, the inchworm type piezoelectric actuators dominate the high resolution and large output capability, but the free-load motion velocity is lower than its counterparts. Whereas, the friction-inertia type and parasitic type piezoelectric actuators have superiorities on motion speed and control system but deficiency on the output capability.
\nType | \nPositioning resolution | \nCarrying capability | \nMotion speed | \nControl strategy | \n
---|---|---|---|---|
Inchworm | \nHigh | \nHigh | \nSlow | \nComplex | \n
Friction-inertia | \nMiddle | \nlow | \nFast | \nSimple | \n
Parasitic | \nMiddle | \nMiddle | \nFast | \nSimple | \n
Performance comparison of three motion types of stepping principle piezoelectric actuators.
Compared with the inchworm type piezoelectric actuator, the structure of the PMP piezoelectric actuator is compact and its control strategy is quite simple. The parasitic motion completes the actions of clamping and driving in inchworm type motion. The re-clamping in the inchworm type is neglected in the parasitic type motion. Therefore, the difficulty and complexity on control system drop down but the output load capability is sacrificed to some extent. As a similar motion like friction-inertia type, the main difference is on the interaction between the driver and the slider/rotor. In PMP piezoelectric actuators, the normal clamping force, as well as the friction, between the driver and the slider/rotor becomes large as the voltage increases, while the forces are generally maintained the same in friction-inertia type piezoelectric actuator. All in all, the parasitic motion principle can be treated as a combination of inchworm principle and friction-inertia principle to some extent. It simplifies the structures and control strategy of inchworm principle, and exceeds the output capability of friction-inertia motion principle by increasing the clamping force.
\nIn 2012, Huang et al. was the first one proposing the PMP piezoelectric actuator by using two microgrippers [23]. The three-dimension (3D) model of the actuator is shown in Figure 4(a). A slider is parallelly placed between two elastic clampers. In most cases, the micro-gripper is employed to precisely manipulate micro/nano-scale objects. However, with the major motion Δx clamping the objects, a parasitic motion Δy pulls the slider to move a minor distance being vertical to the clamping direction. Driven by the saw-tooth wave, a long working stroke was accumulated by step-by-step motion. Various of experiments were conducted with 25 V ~ 100 V driving voltages and 1 Hz ~ 5 Hz driving frequencies to prove the practicability of the proposed driving mechanism. In another research, as shown in Figure 4(b), a more compact linear parasitic motion positioning stage consisting of one compact micro-gripper and one piezoelectric element was developed by Huang et al. [35]. The experiments indicated the linear positioning stage can achieve forward and reverse movements with different driving saw-tooth waves, as well as movement velocities and stepping displacement.
\nPMP piezoelectric actuators proposed by Huang et al. [23, 35]. (a) using two microgrippers and (b) using only one microgripper.
By utilizing various of flexure hinge-based compliant mechanisms, some novel kinds of piezoelectric actuators based on parasitic motion are developed. Figure 5 illustrates novel PMP piezoelectric actuators with bridge-type flexure hinge-based compliant mechanism. This type of flexure hinge-based compliant mechanism is a novel kind of structure used in piezoelectric actuators, which not only amplifies the output displacement but generates coupled motion component as well. The motion principle of the bridge-type flexure hinge-based compliant mechanism is shown in Figure 5(a). Li et al. introduced both linear and rotary PMP piezoelectric actuators based on such mechanism [36, 37], as shown in Figure 5(b) and (c). The parasitic motion of the bridge-type flexure hinge-based compliant mechanism was theoretically analyzed and numerically simulated by the elastic-beam theory (EBT), rigid-body method (RBM) and finite element method (FEM), respectively. Dual-servo control strategy was introduced to achieve long working stroke and nano-scale resolution positioning within one single step. Experiments showed that the maximum velocity of 7.95 mm/s was achieved for the linear actuator with the driving voltage of 100 V at a driving frequency of 1000 Hz, while the rotary actuator can reach 32000 μrad/s with the driving voltage of 100 V at a driving frequency of 100 Hz. Wang et al. proposed a bidirectional complementary-type actuator, which utilized parasitic motion in the longitudinal deformation for driving and clamping [38]. Compared with the current existing prototypes, it reduced the motion coupling to 4%, and optimized the step consistency and driving capability to a large extent.
\nPMP piezoelectric actuators designed by using the bridge-type flexure hinge-based compliant mechanism: (a) working principle, (b) bidirectional linear actuator by Li et al. [37], and (c) rotary actuator by Li et al. [36].
After that, several different PMP piezoelectric actuators are proposed by employing different flexure hinge-based compliant mechanisms, i.e. asymmetric flexure hinge-based compliant mechanism, parallelogram flexure hinge-based compliant mechanism and trapezoid flexure hinge-based compliant mechanism. In comparison with the bridge-type flexure hinge-based compliant mechanism, the asymmetric flexure hinge-based compliant mechanism has simple structure with high stiffness. Li et al. proposed an asymmetric flexure hinge-based compliant mechanism, as shown in Figure 6(a), to amplify the parasitic motion in the PMP piezoelectric actuator [39]. By introducing the asymmetric flexure hinge-based compliant mechanism, the resolution of the proposed linear PMP piezoelectric actuator was improved to 0.68 μm. The maximum speed can reach 4.676 mm/s and the maximum output load was enhanced to 91.3 g. Another linear actuator was proposed by Li et al., as shown in Figure 6(b). The lever-type piezoelectric actuator could achieve bidirectional motion driven by a single piezoelectric element [40]. Under the symmetry of 20% and 80%, the maximum forward velocity was 7.69 mm/s and maximum reverse velocity was 7.12 mm/s, respectively. Gao et al. presented a PMP piezoelectric actuator based on an asymmetrical flexure hinge-based compliant mechanism [41], as shown in Figure 6(c). The authors designed four bars with different thickness right-circle flexure hinges to achieve improvement on output speed and efficiency. Simulations were employed to optimize the structure parameters and the experimental results indicated that the maximum velocity of the proposed piezoelectric actuator reached 15.04 mm/s under the driving voltage of 100 V at a driving frequency of 490 Hz.
\nPMP piezoelectric actuators with the asymmetric flexure hinge-based compliant mechanism developed by (a) Li et al. [39], (b) Li et al. [40], and (c) Gao et al. [41].
Parallelogram flexure hinge-based compliant mechanism is another widely used structure in PMP piezoelectric actuators. Due to its simple structure and flexible design, it gains popularity in studies. Li et al. first introduced the parallelogram flexure hinge-based compliant mechanism in the PMP piezoelectric actuators and characterized the performance of the proposed actuator [42], as shown in Figure 7(a). In the case, the maximum free-load motion speed of the proposed PMP piezoelectric actuator was 14.25 mm/s under the driving voltage of 100 V at a driving frequency of 2000 Hz. Some modified parallelogram structures were also proposed with improved driving capability by Li et al. [43, 44]. By combining the parallelogram flexure hinge-based compliant mechanism and asymmetrical flexure hinge-based compliant mechanism, several different PMP piezoelectric actuators were developed, as shown in Figure 7(b) and (c). The parasitic motion was characterized by EBT and FEM, and the experiments proved the feasibility of the proposed piezoelectric actuator and simplification of walking type for piezoelectric actuators. Furthermore, Gao et al. developed another modified parallelogram flexure hinge-based compliant mechanism in PMP piezoelectric actuators. [45]. By adopting different stiffness flexure hinges, parasitic motion displacement was amplified, and the working performance was investigated by a prototype, as shown in Figure 7(d).
\nPMP piezoelectric actuators designed with the parallelogram flexure hinge-based compliant mechanism developed by (a) Li et al. [42], (b) Wen et al. [43], (c) Wan et al. [44], and (d) Gao et al. [45].
The special mechanical properties of the trapezoid flexure hinge-based compliant mechanism attract the attention from researchers. By adjusting the structural parameters, various kinds of trapezoid flexure hinge-based compliant mechanism with different mechanics characteristics can be obtained. Some of them can easily bring in the parasitic motion in the deformation. Li et al. investigated the possibility of introducing trapezoid flexure hinge-based compliant mechanism into PMP piezoelectric actuators [46], and manufactured a prototype to study the kinematic properties of the proposed PMP piezoelectric actuator. The design of the PMP piezoelectric actuator is shown in Figure 8(a). The right-circular flexure hinges with different thickness were employed in the prototype design of the trapezoid flexure hinge-based compliant mechanism, which had the capability to achieve the parasitic motion. The moving process was characterized and verified by theoretical calculation, numerical simulation and experiments. The experimental results indicated that the maximum speed was 180 μm/s with the driving voltage of 100 V at a driving frequency of 220 Hz. Cheng et al. analyzed the trapezoid flexure hinge-based compliant mechanism and applied such structure into the development of PMP piezoelectric actuators [47]. They attempted to optimize the asymmetrical flexure hinge-based compliant mechanism to achieve large static friction force in slow extension phase while low kinetic friction force in quick backward phase. The prototype was fabricated to confirm the proposed structure. The maximum speed and maximum output load were 5.96 mm/s and 3 N under the driving voltage of 100 V at a driving frequency of 500 Hz. Another research employing a modified trapezoid flexure hinge-based compliant mechanism was developed by Lu et al. [48], which achieved high speed at lower driving frequency.
\nPMP piezoelectric actuators with trapezoid flexure hinge-based compliant mechanism: (a) equilateral triangle flexure structure by Li et al. [46], and (b) right-circular flexure structure by Cheng et al. [47].
Apart from the most used flexure hinge-based compliant mechanism in PMP piezoelectric actuators, some other structures are also introduced to enhance the parasitic motion. The symmetrical flexure hinge-based compliant mechanism was applied into the PMP piezoelectric actuator by Yao et al. [49]. The design of the actuator is shown in Figure 9(a). The structural characteristics and motion displacement were theoretically analyzed and predicted by FEM. The motion principle of the coupled symmetrical flexure hinge-based compliant mechanism is shown in Figure 9(b). With the assistance of the coupled symmetrical flexure hinge-based compliant mechanism, the developed PMP piezoelectric actuator achieved notable improvement on kinematic performance and large output capability. The experiments showed that the minimum step displacement was 0.495 μm under the input driving voltage of 30 V at a driving frequency of 1 Hz and the maximum speed was 992.4 μm/s with the input driving voltage of 120 V at a driving frequency of 400 Hz. Lu et al. developed another kind of coupled symmetrical flexure hinge-based compliant mechanism for linear PMP piezoelectric actuators [50]. The FEM simulation under static load is shown in Figure 9(c). The feasibility of the designed structure was confirmed by the numerical simulation and experiment.
\nPMP piezoelectric actuators with coupled symmetrical flexure hinge-based compliant mechanism: (a) linear piezoelectric actuator by Yao et al. [49], (b) motion principle of the symmetrical flexure hinge-based compliant mechanism, and (c) FEM simulation by Lu et al. [50].
Besides the aforementioned PMP piezoelectric actuators, Li et al. investigated a “Z-shaped” symmetric flexure hinge-based compliant mechanism in the PMP piezoelectric actuator [51]. Since the symmetric flexure hinge-based compliant mechanisms were rotated with an angle of θ = ±20° to the slider, coupled motion could be achieved in x and y directions. Figure 10(a) shows the 3D model of the PMP piezoelectric actuator. In this case, the system statics and kinetic models were established for better understanding the static and dynamic performances of the proposed linear PMP piezoelectric actuator. Furthermore, a triangular structure with flexure hinge-based compliant mechanism was proposed by Zhang et al. [52], as shown in Figure 10(b). Compared to the existing actuators with similar motion principle, the proposed triangular flexure hinge-based compliant mechanism had the capability to amplify the clamping force as well as the driving force. The proposed actuator achieved several times larger driving force and higher free-load motion speed with similar or even lower driven voltage. Besides these linear PMP piezoelectric actuators, several kinds of rotary PMP piezoelectric actuators with triangular structure were proposed by Zhang et al. to confirm the possibility of the proposed flexure hinge-based compliant mechanism in PMP piezoelectric actuators [53]. To enhance the load capability for both forward and backward motions, a shared driving foot flexure hinge-based compliant mechanism, equipped with two piezoelectric stacks, was proposed by Zhang et al. [54]. The 3D model and the working principle are shown in Figure 10(c). Experimental results indicated that the actuator could achieve a free-load maximum forward and backward speed up to 18.6 mm/s and 16.0 mm/s, respectively. The output capacity was largely improved to 2.0 kg for the both driving directions. Zhang et al. developed a linear piezoelectric actuator with mode conversion flexure hinge-based compliant mechanism [55], as shown in Figure 10(d). The mode conversion flexible hinge with a structure of chutes achieved lateral motion and constant phase difference with symmetrical waveform. Different parameters of the chutes were analyzed by FE simulation and experiment. The experimental results showed good agreement with the simulation analysis.
\nPMP piezoelectric actuators designed by using (a) a “Z-shaped” flexure hinge-based compliant mechanism by Li et al. [51], (b) triangular-type flexure hinge-based compliant mechanism by Zhang et al. [52], (c) shared driving foot mechanism by Zhang et al. [54], and (d) mode conversion flexure hinge-based compliant mechanism by Zhang et al. [55].
More recently, some compact flexure hinge-based compliant mechanisms are introduced into the PMP piezoelectric actuators to enhance the performances. Wang et al. reported a rotary piezoelectric actuator with centrosymmetric flexure hinge-based compliant mechanism [56]. The structure of the proposed piezoelectric actuator is presented in Figure 11(a). The motion principle was analyzed by FEM, which was further confirmed by the experiment. Both the output capability and moving resolution of the proposed actuator were improved, and the clockwise and anticlockwise rotations can be switched by adjusting the driving voltage waveform. Besides the rotary PMP piezoelectric actuator, another linear PMP piezoelectric actuator was then introduced to confirm the feasibility of bidirectional PMP piezoelectric actuator [57]. The structure of the bidirectional piezoelectric actuator is illustrated in Figure 11(b). Furthermore, by employing two lever-type flexure hinge-based compliant mechanism, Li et al. developed a 2-DOF piezoelectric-driven precision positioning stage by using parasitic motion [58]. As shown Figure 11(c), the stage consisted of two layers with the same driven structures and the L-shape flexure hinges made the structure compact with piezoelectric stacks being parallel to the slider. The prototype achieved relatively large output displacement over 1,600 μm with good linearity. Wang et al. developed a high-velocity rotary parasitic type piezoelectric positioner [59]. A compact rotational symmetric flexure mechanism with self-centering function was employed to generate parasitic motion to drive the rotor, as shown in Figure 11(d). The experimental results showed the proposed positioning stage achieved the maximum speed of 151.4 mrad/s, which was much greater than most of the current reported non-resonant piezoelectric positioner.
\nPMP piezoelectric actuators designed by using (a) centrosymmetric flexure hinge-based compliant mechanism for rotary actuator [56], (b) two lever-type flexure hinge-based compliant mechanism for linear actuator [57], (c) “L-shape” compact 2-DOF actuator [58], and (d) rotational symmetric flexure hinge-based compliant mechanism for rotary actuator [59].
In order to obtain better understanding of the motion characteristics, some in-depth research is conducted to clarify the nature in some phenomena, such as backward motion and interfacial interaction. Huang et al. firstly investigated the non-linearity and backward motion in one step of a rotary PMP piezoelectric actuator [60], as shown in Figure 12(a). The analysis indicated that the non-linearity in one step was due to the fit-up gap of the bearing and the self-deformation of the flexible micro-gripper when contacted with the slider, while the backward motions was attributed to the non-ideal driving wave. Furthermore, the characteristics of a linear PMP piezoelectric actuator were also investigated [61], and a dynamics model was provided for system control and optimization. Taking some potential factors, such as the coupling angle, the driving signal symmetry, the mover mass and the preload force, into consideration, the model analyzed the influences of these factors on the output, such as the step length, the backward ratio and the maximum load. Based on the characterization and analysis of the PMP piezoelectric actuators, some strategies were introduced to suppress the backward motion. Huang et al. employed two piezoelectric stacks to realize the synergic motion principle [62]. One of the piezoelectric stacks was used for driving and the other was used for lifting, as shown in Figure 12(b). By theoretical analysis and experiments, the actuator could achieve stepping displacement without backward motion with the aid of synergic driving principle. Another strategy on suppression of backward motion in PMP piezoelectric actuators was by means of the sequential control method [63]. As shown in Figure 12(c), two flexure-based hinge mechanisms with different displacement amplification rates in x and y directions were responsible for driving and lifting, respectively. Compared with some conventional PMP piezoelectric actuators, the backward motion was suppressed under the sequential control method.
\nMechanism investigations and further improvement on (a) non-linear and backward motion in rotary actuator [60], (b) synergic motion principle by two piezoelectric stacks [62], and (c) sequential control method to suppress the backward motion [63].
Up to now, more detailed phenomena in PMP piezoelectric actuators are focused and analyzed to enhance the performances. Wang et al. investigated the influence of initial gap on the one-stepping characteristics of PMP piezoelectric actuators [64]. The experimental results showed that the initial gap significantly affected the output characteristics. As shown in Figure 13(a), the previous sudden return (backward motion) transformed into sudden jump, and between them, there was a transition stage, i.e. smooth motion. Another study on preloading was conducted by Yang et al. [65]. By varying the preloading between the flexure hinge-based compliant mechanism and slider, the piezoelectric actuator worked under two different motion modes. Under the new motion mode, the output performances were studied with different initial gaps, driving voltages, driving frequencies, and vertical loads. In addition, the contact force was also measured in PMP piezoelectric actuator by Xu et al. [66], as shown in Figure 13(b). Since the contact force has never been quantitatively detected, it is difficult for keeping the performance uniformity of such actuator in previous studies. By integrating a cantilever beam into the driving unit for measuring the contact force, the actuator could optimize the loading capacity and motion stability by adjusting driving voltage and frequency. The experiments verified the feasibility, and the corresponding actuator was applicable.
\nMechanical and mechanism investigations on (a) initial gap for one-stepping characteristics [64], and (b) measuring the contact force [66].
Parasitic type piezoelectric actuator is a novel member in the family of stepping actuators. Thus, there is still a lot of research to be done to make the underlying mechanism clear, optimize the structure & control strategy, and enhance the output performances. Although several potential issues have been solved and some achievements have been obtained, the PMP piezoelectric actuators are still far from mass production and wide applications in industry. For example, the nature of the interfacial interaction, compact & simple structures to suppress the backward motion and many related issues are still the stumbling blocks on the way to completion.
\nWith the introduction of stepping motion principle into piezoelectric actuators, positioning systems are capable to achieve long working stroke and micro-to-nano positioning resolution. Three motion types of stepping piezoelectric actuators are mostly utilized, inchworm type, friction-inertia type and parasitic type. As one of the most important types, parasitic type showcases the flexibility and massive potential in practical applications in future research and industry. In comparison with the inchworm type piezoelectric actuator, the structure and control strategy of the system are simpler, and it is much easier to obtain high free-load speed. Therefore, further research and efforts should be made to overcome the existing issues in PMP piezoelectric actuators, i.e. backward motion, to satisfy the requirements from general and specific applications, and enhance their adaptation in different conditions.
\nFor the PMP piezoelectric actuators, which have superiorities on simple structure and control system, the low output load and intrinsic backward motions are long-existing issues due to the motion principle. Although some studies attempt to address these issues, some other issues come with the solution. For example, the suppression of backward motion came with increasing complexity of structure and control system. It is now still far from the complete to overcome these issues. Therefore, the studies on improvement of output capability and deep understanding on suppression of backward motion should be further conducted. Furthermore, since the relative motion exists in the parasitic type motion, the wear and tear damages can not be neglected, which will reduce the reliability and stability of the actuator in service. So, the deep understanding and optimization of the interfacial interaction between the flexure and the slider/rotor is another topic in future research. Finally, the multi-direction, integration and minimization of PMP piezoelectric actuators become vital for future applications. Only those which combine long stroke, large load, compact size and integrated system will gain popularity in the future precision-actuator market.
\nThis chapter reviews the recent developments and achievements on PMP piezoelectric actuators. Combined with stepping motion principle, the PMP piezoelectric actuator acquires the capabilities on long working stroke and relatively large output capability, which breaks through the long-standing obstacles on micrometric working stroke of single piezoelectric element. In addition, some novel flexure-based hinge mechanisms are introduced to enhance the performances of the parasitic type motion, which not only extend the motion displacement in one step but also improve the motion stability in long working stroke. In addition, the underlying potential issues, i.e. backward motion and contact force, are investigated to understand the nature of the mechanism. By utilizing theoretical analysis and FE simulation, novel structures and driving strategies are applied to suppress the backward motion and improve the motion speed by adjusting interfacial interaction. These prototypes demonstrate better performances than previous parasitic type actuators, verifying the feasibility of the proposed methods. However, further studies should be conducted for improving the performances and overcoming current issues to satisfy the increasing demands for precision positioning and related applications.
\nThis work was supported by the National Natural Science Foundation of China (Grant No. 52075221), the Young Elite Scientists Sponsorship Program by CAST (YESS) (Grant No. 2017QNRC001), and the Fundamental Research Funds for the Central Universities (2019-2021).
\nThe authors declare no conflict of interest.
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