Comparison of RFID technologies [32].
\r\n\tAnimal food additives are products used in animal nutrition for purposes of improving the quality of feed or to improve the animal’s performance and health. Other additives can be used to enhance digestibility or even flavour of feed materials. In addition, feed additives are known which improve the quality of compound feed production; consequently e.g. they improve the quality of the granulated mixed diet.
\r\n\r\n\tGenerally feed additives could be divided into five groups:
\r\n\t1.Technological additives which influence the technological aspects of the diet to improve its handling or hygiene characteristics.
\r\n\t2. Sensory additives which improve the palatability of a diet by stimulating appetite, usually through the effect these products have on the flavour or colour.
\r\n\t3. Nutritional additives, such additives are specific nutrient(s) required by the animal for optimal production.
\r\n\t4.Zootechnical additives which improve the nutrient status of the animal, not by providing specific nutrients, but by enabling more efficient use of the nutrients present in the diet, in other words, it increases the efficiency of production.
\r\n\t5. In poultry nutrition: Coccidiostats and Histomonostats which widely used to control intestinal health of poultry through direct effects on the parasitic organism concerned.
\r\n\tThe aim of the book is to present the impact of the most important feed additives on the animal production, to demonstrate their mode of action, to show their effect on intermediate metabolism and heath status of livestock and to suggest how to use the different feed additives in animal nutrition to produce high quality and safety animal origin foodstuffs for human consumer.
",isbn:"978-1-83969-404-2",printIsbn:"978-1-83969-403-5",pdfIsbn:"978-1-83969-405-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8ffe43a82ac48b309abc3632bbf3efd0",bookSignature:"Prof. László Babinszky",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10496.jpg",keywords:"Technological Feed Additives, Feed Industry, Quality of Compound Feed, Non-Antibiotic Growth Promoter, Product Quality, Additive Enzymes, Digestibility of Nutrients, NSP Enzymes, Farm Animals, Livestock, Immunity, Microbiome",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 20th 2021",dateEndFourthStepPublish:"May 11th 2021",dateEndFifthStepPublish:"July 10th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Professor Emeritus from the University of Debrecen, Hungary who authored 297 publications (papers, book chapters) and edited 3 books. Member of various committees and chairman of the World Conference of Innovative Animal Nutrition and Feeding (WIANF).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.jpg",biography:"László Babinszky is Professor Emeritus of animal nutrition at the University of Debrecen, Hungary. From 1984 to 1985 he worked at the Agricultural University in Wageningen and in the Institute for Livestock Feeding and Nutrition in Lelystad (the Netherlands). He also worked at the Agricultural University of Vienna in the Institute for Animal Breeding and Nutrition (Austria) and in the Oscar Kellner Research Institute in Rostock (Germany). From 1988 to 1992, he worked in the Department of Animal Nutrition (Agricultural University in Wageningen). In 1992 he obtained a PhD degree in animal nutrition from the University of Wageningen.He has authored 297 publications (papers, book chapters). He edited 3 books and 14 international conference proceedings. His total number of citation is 407. \r\nHe is member of various committees e.g.: American Society of Animal Science (ASAS, USA); the editorial board of the Acta Agriculturae Scandinavica, Section A- Animal Science (Norway); KRMIVA, Journal of Animal Nutrition (Croatia), Austin Food Sciences (NJ, USA), E-Cronicon Nutrition (UK), SciTz Nutrition and Food Science (DE, USA), Journal of Medical Chemistry and Toxicology (NJ, USA), Current Research in Food Technology and Nutritional Sciences (USA). From 2015 he has been appointed chairman of World Conference of Innovative Animal Nutrition and Feeding (WIANF).\r\nHis main research areas are related to pig and poultry nutrition: elimination of harmful effects of heat stress by nutrition tools, energy- amino acid metabolism in livestock, relationship between animal nutrition and quality of animal food products (meat).",institutionString:"University of Debrecen",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Debrecen",institutionURL:null,country:{name:"Hungary"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"7144",title:"Veterinary Anatomy and Physiology",subtitle:null,isOpenForSubmission:!1,hash:"75cdacb570e0e6d15a5f6e69640d87c9",slug:"veterinary-anatomy-and-physiology",bookSignature:"Catrin Sian Rutland and Valentina Kubale",coverURL:"https://cdn.intechopen.com/books/images_new/7144.jpg",editedByType:"Edited by",editors:[{id:"202192",title:"Dr.",name:"Catrin",surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"63256",title:"Novel Mechanism of Nonalcoholic Lipid Accumulation Promoting Malignant Transformation of Hepatocytes",doi:"10.5772/intechopen.77400",slug:"novel-mechanism-of-nonalcoholic-lipid-accumulation-promoting-malignant-transformation-of-hepatocytes",body:'Hepatocellular carcinoma (HCC) is one of the fifth most common malignant tumors, the third most frequent cause of cancer mortality worldwide [1, 2], and ranks the second in China among all malignancies with its mortality almost equal to its morbidity, especially in the inshore area of the Yangtze River [3, 4]. The principal treatment of HCC patient is surgical resection or liver transplantation, depending on whether the patient is a suitable transplant candidate [5, 6]. However, in most HCC patients with diagnosis at early stage is very difficult, thereby excluding the patients from definitive surgical resection. Sorafenib, the most commonly used systemic therapy, has shown to only minimally impact on patient survival by several months. Besides, neither chemotherapy nor radiotherapy are generally effective. Due to the poor prognosis of HCC patients, the early diagnosis and effective therapy of HCC are needed with several being in development, either in preclinical or clinical studies [7, 8].
The development of HCC is a complex multi-step process involved multiple genes. Major risk factors of HCC include hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcoholic or nonalcoholic fatty liver disease, nitrosamines, aflatoxin, and other harmful substances [9, 10, 11, 12]. Chronic persistent infection of nonalcoholic is still the main pathological factor of inducing cirrhosis and HCC. However, with the changes of people’s dietary structure and lifestyle, the incidence of fatty liver disease (FLD) also rose sharply [13, 14, 15]. A median prevalence of alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD) is 4.5 and 15.0%, respectively [16, 17]. It is worrying that if no interference is conducted in the treatment, nonalcoholic steatohepatitis (NASH) or alcoholic hepatitis can also be developed for liver fibrosis, cirrhosis and liver cancer (Figure 1), and its exact mechanism is worth exploring. However, the underlying molecular mechanisms that lead to malignant transformation of infected liver cells still remain to be explored. Most of HCC patients died quickly because of the rapid tumor growth, and surgical operation or liver transplantation still is the only effective treatment for HCC [18, 19]. This article summarizes new advances on relationship between NAFLD and hepatocytes malignant transformation.
NAFLD progression and clinical diagnosis. ALT: alanine aminotransferase, NAFLD: non-alcoholic fatty liver disease, NAFL: nonalcoholic fatty liver, NASH: non-alcoholic steatohepatitis, HCC: hepatocellular carcinoma, HBsAg: hepatitis B surface antigen, HCV: hepatitis C virus, ANA: antinuclear antibody.
Liver is one of the most important organs in human for maintaining energy supply and lipid metabolism [20, 21]. The peroxisomal compartment in hepatocytes hosts several essential metabolic conversions. Upon nutrient deprivation, cells metabolize fatty acids (FAs) in mitochondria to supply energy. FAs mobilization depends on triacylglycerol lipolysis, whereas autophagy feeds the lipid droplet pool for continued fueling of mitochondria. Proteome imbalance of mitochondrial electron transport chain in brown adipocytes leads to metabolic benefits [22]. Lipid metabolism are defective in peroxisomal disorders that are either caused by failure to import the enzymes such as carnitine palmitoyltransferase (CPT) in the organelle or by mutations in the enzymes or in transporters needed to transfer the substrates across the peroxisomal membrane (Figure 2). Hepatocytes specific differences have been confirmed in mitochondrial DNA maintenance and expression [23]. Hepatic pathology is one of the cardinal features in disorders of peroxisome biogenesis and peroxisomal β-oxidation, although it rarely determines the clinical fate. Besides of the morphological changes, the impact of peroxisome malfunctions on other cellular compartments includes thermal instability of carnitine palmitoyltransferase II (CPT-II) variants in mitochondria and endoplasmic reticulum (ER) [24, 25, 26]. Proteomics analysis revealed numerous enzymes expression involved with the electron transport system, the tricarboxylic acid cycle, as well as lipid and amino acid metabolism in response to anoxia exposure [27].
Fatty acid oxidation and ATP production in mitochondria. The distribution of mitochondrial CPT-I or CPT-II with regulation plays important roles in fatty acid metabolism. Fatty acid (FA) β-oxidation requires successive carnitine acyltransferases to translocate acyl-coenzyme As (acyl-CoAs) from the cytoplasm into matrix. As initial and rate-limiting CPT-I generates acylcarnitines that traverse mitochondrial membranes via specific transporters into matrix, CPT-II produces acyl-CoAs from acylcarnitines for FA β-oxidation to acetyl-CoA. Then carnitine crosses the inner membrane, binds with the endogenous or exogenous acyl CoA to prevent acyl CoA accumulation causing poisoning. ACC: acetyl CoA carboxylase, CoA: coenzyme A, TCA: tricarboxylic acid cycle, UCP: uncoupling protein, I II III IV: electron transfer complex [29].
Carnitine is a physiological substance that is essential for the proper metabolism of fat and energy production that actually transports both long and medium fatty acid chains. L-carnitine attracts long and medium fatty acid chains, breaks them down, and carries them to the mitochondria of the cells where they are metabolized (burned). The L-carnitine plays important roles in the catabolism of long-chain fatty acids in the mitochondria, not only due to increased mitochondrial fatty acid oxidation reflected by increased mitochondrial biogenesis, but also to changes in plasma clearance and reduced triacylglycerol (TAG) biosynthesis [28]. The ultimate result is that you burn more fats, and in the process give your body more natural energy. In the previous study, the increasing liver weight with lipid accumulation was discovered during the course of the wild-type mice (Figure 3) in circulating carnitine analogues [3-(2,2,2-trimethyl hydrazinium) propionate dihydrate, THP] [29, 30].
Liver lipid accumulation and liver weight tissues in mice models after carnitine analogues. A–D, the mice liver tissues with Oil red O staining: A & B, the control livers; C & D, the experimental livers; E, the alterations of different tissue weight after the experimental mice with carnitine analogues [29].
Hepatic CPT-II is a mitochondrial protein which is transported to mitochondrial inner membrane. It together with CPT-I oxidizes long-chain fatty acids in mitochondria. Defects or mutation of this gene are associated with mitochondrial long-chain fatty-acid oxidation disorders. Decreasing of its activity is a disorder of mitochondrial fatty acid oxidation with autosomal recessive mode of inheritance. The variants exert a dominant-negative effect on the homotetrameric protein of the enzyme (Figure 4), with reduced activities, thermal instability, fatty acid β-oxidation decreased to 30–59%, intracellular ATP to 48–79%, a significantly decreasing of mitochondrial membrane potential with increasing temperature at 41°C, and shortening half-lives of CPT-II, and the enzyme variant proteins were polyubiquitinated and rapidly degraded by a lactacystin-sensitive proteasome pathway [24]. The very unstable CPT II variants with decreased enzymatic activities may bring mitochondrial fuel utilization below the phenotypic threshold during high fever in humans with hepatitis virus infection, and thus might be as novel potential mechanisms for NAFLD formation [31, 32].
Mutation of CPT-II gene and hepatic lipid accumulation. (A) The CPT-II gene exon 1–5. (B) The sequence fragments of CPT-II gene exon 4 were amplified on mitochondrial inner membrane. The mutation analysis of CPT-II gene exon-4 using the specific primers were designed by sequencing with 1974 nucleotides coded 658 amino acids. Compared with the original sequence from Genbank, the two substitution sites were found at 1618 (G→A) and 1858 (T→C), and code amino acids at V368I and F448L, respectively [29].
The dynamic alterations of hepatic CPT-II expression in the mitochondrial inner membrane were investigated during the malignant transformation of hepatocytes induced by abnormal fatty accumulation. After the male Sprague-Dawley (SD) rats were fed with control, high fat (HF), and HF containing 2-fluorenylaceta-mide (2-FAA) diet, respectively. The rats were divided into control, fatty liver, degeneration, pre-cancerous, and cancerous groups according to the hematoxylin and eosin staining (H&E) of liver pathological examination, hepatic lipids accumulation were confirmed with the Oil Red O staining. Massive lipid accumulation hepatocytes were seen in rats on HF and HF containing 2-FAA diets. The lipid levels in the control group were significantly lower than those in the fatty liver, degeneration, precancerous, and cancerous groups. The serum triglyceride and total cholesterol levels in the degeneration, precancerous, and cancerous groups were 2–3 times higher than those in the control group. The serum aspartate aminotransferase and alanine aminotransferase levels (Figure 5) in the degeneration, precancerous, and cancerous groups were significantly higher (4–8 times) than those in the control group. The specific concentration (μg/mg protein) of liver CPT-II expression was significantly reduced during hepatocyte malignant transformation, as confirmed by immunohistochemistry, with the CPT-II levels significantly lower in the cancerous group than in any of other groups, indicated that low hepatic CPT-II expression might lead to abnormal lipid accumulation in hepatocytes, which should promote the malignant transformation of hepatocytes [33, 34].
Rat liver tissues and their pathological examination. Liver alterations after the rats (from left to right: upper, A, B, C, D, and E; under A1, B2, C3, D4, and E5) were sacrificed at different time according to the plan schoule. (A) A representative liver from rat with normal diet; (B) a representative liver from the rat with high-fat diet (HFD) without 2-fluorenyl acetamide (2-FAA); (C) a representative liver from the rats with HFD containing 2-FAA at early stage; (D) a representative liver at interim stage; and (E) a representative liver at later stage. The liver sections were examined with hematoxylin and eosin staining and then divided into the control (A1), fatty liver (B1), degeneration (C1), precancerous (D1), and cancerous (E1) groups; A1-E1: The original magnification of the corresponding rat liver sections was ×200 [29].
Lipid accumulation in liver or HCC will cause tumor-associated molecular signaling alteration including NF-κB (nuclear factor-kappa B), JNK (c-Jun N-terminal kinase)/activation protein-1 activation, and alterations of HCC development-related genes, respectively. For example, liver unsaturated fatty acids (UFA) inhibit the expression of phosphatase and tensin homolog (PTEN) deleted on chromosome 10 (10q23.3) via activating NF-κB/mTOR (mammalian target of rapamycin) complex [35]. As a tumor suppressor gene PTEN regulates the PKB/akt (serine-threonine kinase protein kinase B) pathway, and PTEN deficiency induces the proliferation of hepatocytes by inhibiting cell apoptosis and promoting HCC formation confirmed in mice models with the PTEN deficiency in resembling non-alcoholic steatohepatitis (NASH) features with developing steatosis, and inflammation damages or fibrosis in liver tissues [36].
DNA injury affects hepatic lipid metabolism. Reactive oxygen species (ROS) is an important factor in carcinogenesis. It can be induced in NAFLD patients with contiguous DNA damage by some of hepatic inflammatory cytokines or hepatitis virus infection and react with polyunsaturated fatty acids derived from hepatocyte membrane phospholipids, and subsequently results in reactive aldehydes production as lipid oxidation (LPO) byproducts, for example, 4-hydroxynonenal (4 HNE) that can react with DNA to form mutagenic exocyclic etheno-DNA adducts. Importantly, they are preferably formed in codon 249 of TP53, resulting in inactivation of tumor suppressor p53 gene, secondary growth advantage, and anti-apoptosis [37].
Adipokine is a plethora of pro- and anti-inflammatory cytokines that secretes from adipose tissue with low-grade inflammation. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including (NAFLD) [38, 39, 40]. Adiponectin regulates the metabolism of blood glucose and hepatic fatty acid, and is decreased in NAFLD that might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance [41, 42]. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is also associated with a substantial risk for developing HCC in the non-cirrhotic stage of disease [43, 44]. Both related to liver tumorigenesis especially in preclinical models, especially in hepatic satellite cell activation with stimulating the tissue inhibitor of metalloproteinase 1 production via the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway promoting fibrogenesis [45, 46], or angiogenesis or progression from NASH to HCC that has been confirmed in mice models [47, 48].
According to the data from animal models with HCC cell lines, adiponectin could increase JNK activation and induce cell apoptosis with AMPK alteration, which could inhibit mTOR phosphorylation, xenograft growth, tumor growth and metastasis by suppression of tumor angiogenesis in nude mice. However, lower circulating adiponectin favors tumorigenesis in NASH model [49]. Adipose-derived tumor necrosis factor is a potent activator of pro-oncogenic pathways involving in mTOR, JNK, NF-κB, and extra-cellular signal-regulated kinases; Interleukin-6 (IL-6) combining with its receptors on liver or non-parenchymal cells can promote signal-transmuting receptor (gp130) complex with IL-6R activating JAK1 signaling, and STAT3 activation or phosphorylation promotes the proliferation and anti-apoptosis of cancer cells [50], indicated that adiponectin coefficient action from adipose tissues and related- cytokines affect fatty acid metabolism and hepatocyte malignant transformation via many signal molecules.
Lipid reprogramming has been considered as a crucial characteristic in HCC initiation and progression. SREBPs are the key transcription regulators of hepatic lipogenesis, and activate hepatic steatosis at the early stage. Tat-interacting protein 30 (TIP30) is a tumor suppressor protein that has been found to be expressed in a wide variety of tumor tissues that is involved in the control of cell apoptosis, growth, metastasis, angiogenesis, DNA repair, and tumor cell metabolism. TIP30 regulates lipid metabolism in human HCC by regulating SREBP1 (sterol regulatory element-binding protein 1) through the Akt/mTOR signaling pathway [51, 52]. In human HCC tissues, SREBP1 could significantly induce lipogenesis and be associated with a poor prognosis [53].
SREBP1c gene at mRNA level was up-regulated in human HCC tissues and not in their adjacent non-cancerous or non-cancerous liver tissues. The inhibition of SREBP1 expression resulted in growth arrest and apoptosis of cancerous cells, and increased the cell proliferation ability. HBx (HBV protein X) expression induces lipid accumulation in hepatic cells mediated by the induction of SREBP1, a key regulator of lipogenic genes in the liver. HBx interacts with LXRalpha (liver X receptor alpha) and enhances the binding of LXRalpha to LXRE (LXR-response element), thereby resulting in the up-regulation of SREBP1 and fatty acid synthase, suggested that HBV infection can stimulate the SREBP1-mediated control of lipid accumulation [54].
Aberrantly high expression of TRIM24 occurs in human HCC clinical samples and positively correlated with HCC tumor grade. Its knockdown inhibits proliferation and migration in HCC cells in vitro, with impeding of tumor growth in vivo [55, 56]. TRIM24 in mice is reportedly a liver-specific tumor suppressor, and appears to promote liver tumor development via AMPK signaling [57]. TRIM24 as an epigenetic co-regulator of some gene transcription that directly or indirectly inhibits mouse hepatic lipid accumulation, liver cell inflammation, liver fibrosis, and hepatocyte damage. Additionally, the global expression analyses of TRIM24−/− livers unveiled signaling pathways that closely associated with some features of NAFLD, inflammatory, cell apoptosis, and hepatocyte damage. The loss of liver TRIM24 expression could lead to the progression from patients with NAFLD to NASH or HCC in a time dependent manner [58].
According to accumulating data, human liver OPN is a multifunctional protein involved in some pathological alterations including hepatic immunity, hepatocytes inflammation, liver fibrosis, and the development of HCC. Deficiency of OPN in obese mice fed with a high-fat diet reduced hepatic steatosis and inflammation, and liver cell ballooning, portal leukocyte infiltration and macrophage accumulation were attenuated. It is induced by Hedgehog signaling, may directly promote pro-fibrogenic responses in steatohepatitis, or act as a paracrine factor secreted by bile duct or natural killer T cells (NKT), and also can be as an autocrine factor promoting fibrosis in hepatic satellite cells (HSC) [59].
The silencing OPN gene transcription by specific shRNA could result in increasing Bax, decreasing Bcl-2/Bcl-xL and X-linked inhibitor of apoptosis protein expression, and NF-κB activation, and induction of mitochondria-mediated apoptosis in HCCLM3 cells [19]. There were statistically significant differences in plasma OPN levels between the HCC group and the other groups. Regarding the validity of plasma OPN was a predictor of fatty change, with 50% diagnostic accuracy, 70% sensitivity, 45% specificity, 50% positive predictive value, and 75% negative predictive value at a cutoff value of 134 ng/mL. The data indicated that plasma OPN level could be of diagnostic potential value in NAFLD [60].
Human hepatic satellite cells (hHSC) in the perisinusoidal space between sinusoids and hepatocytes are the predominant fibrogenic cells in liver tissues, and activated by liver cell injury to transdifferentiate from a quiescent state to proliferate matrix producing myofibroblasts [61, 62, 63]. The excessive production of extra-cellular matrix might result in cirrhosis occurrence. Human amphiregulin could increase the cell proliferation via EGFR, PI3K, and p38 mitogenic signaling pathways, inducing significantly up-regulation of fibrogenic biomarkers, confirmed by the mice NASH model that exhibited rapid progression of advanced fibrosis and HCC, with mimics histological, immunological and transcriptomic features of NASH, and a useful tool for preclinical drug testing [64, 65]. In addition, fatty liver as a pro-metastasis microenvironment with hHSCs could promote HCC migration and proliferation. Fasting and specific microRNAs could inhibit hHSC activation or potentiate anti-cancer activity of Sorafenib in HCC [66, 67].
Activated immune cells interact with cells in tissues by metabolic stress will migrate to liver and drive the progression from NAFLD to HCC. The dysregulation of lipid metabolism in NAFLD from mice models or human samples causes a selective loss of intrahepatic CD4+ but not CD8+ T lymphocytes, leading to accelerated hepatocarcinogenesis via cross-talk with liver cells [68, 69]. The NKT cells primarily cause steatosis in liver tissues via secreted a type II trans-membrane protein (a TNF ligand super-family member, TNFSF14), and both of CD8+ and NKT cells cooperatively induce liver injury by feeding choline-deficient high-fat diet [70]. CD4+ T lymphocytes have greater mitochondrial mass than CD8+ T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS) [71].
Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4+ T lymphocytes. Hepatic immune cells recognize cell injury or pathogen invasion with intracellular or surface-expressed pattern recognition receptors, subsequently initiating signaling cascades that trigger the release of factors promoting inflammatory response during NAFLD progression, demonstrating that the transition from NASH to HCC through liver cell lymphotoxin-β receptor (LTβR) and NF-κB signaling. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4+ T lymphocyte decrease and delayed NAFLD-promoted HCC [72, 73].
Polyploidization is one of the most dramatic genomic changes with rarely reported. The physiological events occur in liver development or adult life. However, the pathological polyploidization takes place in NAFLD, a widespread metabolic disorder that maybe is a risk factor for HCC. The liver parenchyma in NAFLD models displayed the process alterations with a large ratio of highly polyploid mononuclear cells, but was not observed in normal liver parenchyma. Biopsies from NASH patients revealed the alterations in hepatocyte ploidy compared with tissue from controls. Hepatocytes from NAFLD mice revealed that progression through the S/G2 phases of the cell cycle was inefficient and associated with activation of a G2/M DNA damage checkpoint, which prevented activation of the cyclin B1/CDK1 complex. The oxidative stress promotes the highly polyploid cells, and antioxidant- treated NAFLD hepatocytes resumed normal cell division and returned to normal state of polyploidy, indicated that oxidative stress promote pathological polyploidization in NAFLD that might contribute to HCC [74].
NAFLD is characterized by excess lipids in hepatocytes, due to excessive fatty acid influx from adipose tissue, de novo hepatic lipogenesis, in addition to excessive dietary fat and carbohydrate intake [44, 19]. Serious imbalance was found between limited antioxidant defenses and excessive formation of reactive species produced by liver oxidative stress such as ROS or RNS (reactive nitrogen species). Obese persons could increase free fatty acids uptake, stimulates FA oxidation for compensating excessive liver fat storage, and accelerate β-oxidation leads to increased production of ROS that damage mitochondrial membrane and DNA [75, 37].
Chronic lipid overload in hepatocytes induces mitochondrial oxidative stress or hepatocytes damage leading the NAFLD developing into a more severe liver disease condition, NASH, cirrhosis or HCC. Oxidative stress may induce endoplasmic reticulum (ER) dysfunction for liver malignancy. ER plays an important role in NAFLD pathogenesis, and consecutive increasing oxidative stress, inflammation and activation of NF-κB and JNK signaling pathways lead to the accumulation of intracellular lipids [76]. Extra-cellular signal-regulated protein kinase (ERK) is highly expressed in HCC via PIK13 activation. Among others, copper is one of the main bio-metals required for the preponderance of the enzymes involved in physiological redox reactions, which primarily occurs during mitochondrial respiration. Antioxidant food agents recognized to improve NAFLD and its complications have been described in the copper-related literatures [77, 78].
NAFLD is associated with insulin resistance (IR) leading to a resistance in the antilipolytic effect of insulin in adipose tissue with an increase of FFAs. The increase of FFAs induces mitochondrial dysfunction and lipotoxicity [79]. Liver steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents. Etiologically, obesity and IR or excess alcohol intake are the most frequent causes of liver steatosis. Insulin as a key hormone regulates lipogenesis and lipolysis in adipose depots. The adipose tissue becomes resistant to the antilipolytic effect of insulin and FA release is increased with lipolysis or lipid intake, promoting triglyceride synthesis with lipid accumulation occurrence in livers [80, 81].
Liver lipid accumulation causes IR by the activation of NF-κB pathway and leads to hyperinsulinemia to activate phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, implicated the malignant transformation of hepatocytes or in hepatocarcinogenesis [82]. Hyperinsulinemia up-regulates insulin-like growth factor-1 that stimulates cell proliferation and inhibits cell apoptosis [83]. Insulin activates insulin receptor substrate-1 (IRS-1) with up-regulating expression in HCC [84]. The IRS-1-mediated related-signaling molecules may act as survival factors, promote liver cell proliferation via mitogen-activated protein kinase and PI3K, and protect against transforming growth factor β1-induced apoptosis in HCC progression [85, 86].
Liver is the main storage site for iron in the body because of its rich reticuloendothelial system [87]. Acquired hepatic iron overload is seen in a number of NAFLD patients. The dietary iron supplementation enhances experimental steatohepatitis induced by long-term high-fat diet feeding rats [88]. Excess liver iron may increase NASH risk and its progression to HCC [89, 90]. Abnormal iron deposition in liver is more frequent in NASH patients, in which necroinflammation may be the driving factor. Iron and the coexistence of hyperinsulinemia are risk factors for NASH development and together they may contribute to insulin resistance, disease progression and HCC. Iron reduction has been proposed as treatment for dysmetabolic iron overload syndrome and NAFLD or iron deprivation can suppress HCC growth in vivo and in vitro experiments [91].
While tobacco and alcohol are established risk factors for HCC, the most common type of primary liver cancer [92]. Chronic alcohol intake results in the induction of liver cytochrome P450 2E1 leads to generation of ROS with direct or indirect carcinogenic consequences [93]. Many genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis or cirrhosis. Some studies revealed that alcohol could be metabolized by oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P450 2E1. In addition, neurocan in neuronal tissue is also expressed in liver and the common polymorphism of its gene rs2228603 is associated with HCC in alcoholic liver disease [94].
Regulating control miRs are highly conserved, small non-coding RNAs (about 18–25 nucleotides in length) regulates transcription or translation of target genes and fatty acid metabolism. Both of miR-197 and miR-99 were associated with liver fibrosis in NASH patients. Altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. The over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b~25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1, phosphatase and tensin homolog, and cyclin-dependent kinase inhibitor 1. miR-93-5p, miR-221-3p, and miR-222-3p have been confirmed over-expressed in HCC. Aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC [94, 95].
Some studies found that miR-122 is a key regulator of glucose and lipid metabolism in livers [96] and significantly higher circulating miR-122, miR-34a, and miR-16 expression were found in NAFLD. During the development of NAFLD patients with simple steatosis to steatohepatitis, the serological levels of miR-122 and miR-34a were positively correlated with disease severity, liver enzyme activities, fibrosis staging, active inflammation, and silencing of microRNA-122 is an early event during hepatocarcinogenesis from NASH [97], suggesting that the alteration of circulating miR-122 could be an early event from NASH to hepatocarcinogenesis..
The development and progression of NAFLD are determined by environmental and genetic factors [10, 98]. The effect of genetic factors has been demonstrated by familial studies, twin studies and several cross-sectional studies. The data from the genome-wide association studies (GWAS) have shown that patatin-like phospholipase domain-containing protein 3 (PNPLA3) involved in metabolism of triglyceride on chromosome 22 is a genetic factor that promotes NASH development, and PNPLA3 gene variant I148M showed a strong relationship with the development and progression of NAFLD, NASH, and NAFLD-related HCC. Single nucleotide polymorphism (SNP, rs738409) is closely related to fatty liver involved in fibrosis progression of NAFLD. The C<G variation in SNP rs738409 also increases HCC risk in NAFLD patients [99, 100].
The whole exome sequencing finds that apolipoprotein B mutations (c.6718A>T, K2240X) represent a paradigm of rare variant influencing liver fat content and HCC risk. Besides, the Patatin-like phospholipase domain-containing 3 [the trans-membrane 6 superfamily member 2 (TM6SF2)] genes variant E167K was associated with NAFLD [101, 102]. Telomerase reverse transcriptase (TERT) mutations have been associated with hepatic steatosis. The deficiency of TERT can reduce the response to liver damage inducing the formation of steatosis and fibrosis. In conclusion, the occurrence of NAFLD-HCC seems to be influenced by common genetic variants as PNPLA3 and by rare genetic variants. Several genes have been proposed as candidate genes to be associated with NAFLD based on case–control studies [103].
NAFLD has become the most common chronic liver disease worldwide and is well-accepted that gut dysbiosis is associated with NAFLD [103]. The gut-liver axis has been proposed as a key player in the pathogenesis of NAFLD, as the passage of bacteria-derived products into the portal circulation could lead to a trigger of innate immunity, which in turn leads to liver inflammation. In intestine, there are trillions of microorganisms including bacteria, archaea, yeasts and viruses collectively called intestinal ecosystem through energy harvesting and fat storage [78, 104]. The relationship between gut microbiota and NAFLD is dependent on levels of choline, bile acid, larger production of endogenous ethanol, higher prevalence of intestinal dysbiosis, higher prevalence of increased intestinal permeability, bacterial translocation, pro-inflammatory molecules, endotoxemia, and cytokines. The hepatic manifestation of the dysregulation of insulin-dependent pathways leads to IR and adipose tissue accumulation in NAFLD patients with liver injury, indicated that the gut liver-axis is the way by which the bacteria and their potential hepatotoxic products (LPS, DNA, RNA, etc.) can easily reach liver [105, 106].
The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of ROS. The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis [78]. Recently, a new isoform of human manganese superoxide dismutase (MnSOD) has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by cirrhosis [107]. Primary bile acids which derived from cholesterol become secondary bile acids under the action of intestinal microbes. If the bile acids bind to G-protein-coupled cell surface receptor (TGR5), it could inhibit inflammation via suppressing NF-κB pathway in macrophages. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms might be the issue of further investigations [108, 109].
NAFLD has been implicated in some conditions such as IR, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Dietary or genetic obesity induces alterations of gut microbiota, thereby increasing the levels of deoxycholic acid, a gut bacterial metabolite known to cause DNA damage [78, 110]. Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) are the predominant components of toxic AGEs (TAGE). More data suggested that TAGE with its receptor might change intracellular signaling, pro-inflammatory molecules gene expression, and also elicited the oxidative stress generation in liver cells including hHSCs. Circulating TAGE levels were significantly higher in NASH patients than those with simple steatosis or healthy subjects. Moreover, their TAGE levels inversely correlated with adiponectin. Increased lipid availability in livers might provide ATP and structural support for cancerous cell proliferation [111, 112].
Recent epidemiological studies have identified NASH, a progressive form of NAFLD, as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention [97, 113].
Liver derangements in lipid metabolism, importing FFA and manufacturing, storing, and exporting lipids could lead to NAFLD development [114]. The dysregulation of hormonal axes, mitochondrial carnitine palmitoyltransferase-II inactivity, and cytokines in NAFLD promotes a worse cycle between metabolic and inflammatory stimulus lead to malignant transformation of hepatocytes [33, 71]. The majority of NAFLD patients had steatosis about 20% present as NASH that was defined by microscopic finding, and consists of liver injury, steatosis, parenchymal and portal inflammation, and different fibrosis. Alterations of miRNA in hepatocarcinogenesis were associated with TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling pathways. Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. Aberrant expression of miRNAs might have mechanistic significance in NASH-associated liver carcinogenesis and serve as an indicator for the development of NASH-derived HCC [115, 116].
Hepatic lipid accumulation is accompanied by distinct patterns of perilipin expression, suggested that abnormality of hepatic lipid accumulation might promote hepatocyte malignant transformation [33]. The levels of high leptin and low adiponectin are hallmarks of obesity and involved in NAFLD and carcinogenesis [117]. Obesity-promoted HCC occurrence was dependent on increasing IL-6 and TNF levels, which resulted in liver inflammation and oncogenic STAT3 activation. The long-term chronic inflammatory in obesity plus higher IL-6 and TNF might be the risk factor for HCC [118]. The prospective studies (25,337 patients with HCC) demonstrated that both of excess body weight and obesity in males or females are related to an increased risk factor for HCC occurrence [119]. The prospective studies with longer follow-up periods should screen the malignant transformation of hepatocytes with specific biomarkers among NASH or NAFLD populations [3, 120].
In the past decade, the discussion of substantially NAFLD increased by hypernutrition and HCC had become a cocktail party cliché, and its impact on public health cannot be dismissed. With both relationship gradually deepening, more and more evidences have supported that NAFLD might promote the malignant transformation of hepatocytes because of liver lipid accumulation, its toxicity, endoplasmic reticulum dysfunction, IR, and abnormal fat metabolism. Although the exact mechanisms from NAFLD tumor-promoting mechanism triggered by hypernutrition remain to be explored [121], however, the patients with the excessive fat deposition feeds this tumor-promoting inflammatory flame and should be treated in time to avoid the occurrences of hepatocyte malignant transformation [7, 122].
This work was supported by the part grants from the Key Program of Jiangsu Province (BE2016698), the Projects from the National Natural Science Foundations (31872738, 81673241, 81702419), and the International Science & Technology Cooperation Program (2013DFA32150) of China.
CPT | carnitine palmitoyltransferase |
HBV | hepatitis B virus |
HCV | hepatitis C virus |
HSC | hepatic satellite cell |
IL-6 | interleukin-6 |
NAFLD | non-alcoholic fatty liver disease |
NASH | nonalcoholic fatty hepatitis |
NF-κB | nuclear factor kappa B |
MiR | microRNA |
OPN | osteopontin |
HCC | hepatocellular carcinoma |
PNPLA | patatin-like phospholipase domain-containing protein |
ROS | reactive oxygen species |
SREBP | sterol regulatory element-binding protein |
TAGE | toxic advanced glycation end-products |
In recent years, radio identification (RFID) technology [1, 2] has grown extraordinarily. Initially, it came to replace barcodes for product identification [3]. Nowadays, there are several frequency bands and a number of applications [2]. RIFD can be classified depending on the frequency band used: low frequency (LF), high frequency (HF), ultrahigh frequency (UHF), or microwave bands [2]. Another classification refers to the power source: tags can be passive if they harvest the energy from the RF interrogating signal of the reader or active if the energy to feed the electronics is obtained from a battery. The communication in passive tags is based on backscattering communication and consists on modulating the load that modifies the radar cross section of the antenna [4, 5]. Although UHF readers are expensive (1–2 k$), the inlays designed for traceability are cheap, and the return on investment (ROI) is possible due to the large number of units involved. The read range can be increased by improving the IC sensitivity (e.g., −22 dBm for Impinj Monza R6) allowing to reach several meters (about 10–15 m). There exist also semi-passive or battery-assisted tags (BAP) that use battery to feed only the electronics needed to improve the sensitivity, but the communication is based on backscattering as in the passive tags [6, 7, 8]. The cost of UHF BAP tags is often lower than active tags based on transceivers such as Bluetooth low energy (BLE), Zigbee, etc. Recently, several UHF BAP transponders have appeared in the market such as the AMS-SL900A IC [7, 9]. This chip integrates a 10-bit ADC and an internal temperature sensor. However, the sensitivity in passive mode (without battery) is lower (−6.9 dBm) than the BAP mode (−15 dBm) that allows a longer rad range and data logging [7]. Semi-passive tags are microwave frequencies, or zero power tags are recently under intense research for sensing [10, 11].
At LF and HF, the radio link is established by near-field communication (NFC) because the distance is smaller than the wavelength. Therefore, the tag is in the near-field region, and the magnetic field decays proportionally to the square of the distance. Therefore, the communication between the loop antennas of the reader and the tag is produced by inductive coupling. However, at UHF and microwave bands, the communication is based on the modulation of the far fields, and hence the electromagnetic fields decrease and become inversely proportional to the distance. As a result, the read range of these tags is higher than those based on near-field communication [2, 4, 5].
Another recent approach to radio identification is the one known as chipless RFID [12, 13]. In these tags, the identification is done without a chip by a permanent modification of the structure that determines a specific electromagnetic signature in the frequency domain [12, 13, 14, 15] or in the time domain [16, 17]. Initially, the main research efforts have been oriented to increase the number of bits that the electromagnetic structure can encode [13]. In frequency-coded chipless RFID, the number of bits is limited by the number of resonators with high-quality factors that can be integrated and detected in the bandwidth [13]. In time-coded chipless RFID, the number of bits is encoded in the length of the line, and it is limited by the time domain resolution of the radar that depends on its bandwidth and the losses of the lines [5]. The most important drawback of this technology is the detection of the tags. The change in the radar cross section (RCS) introduced by the chipless tag in frequency domain or in time domain is small compared with the clutter and objects in which the tag is attached. Therefore, in order to detect the tag, the background subtraction technique is often used in the literature. This technique consists of the subtraction of the background from the measurements using a previous saved measurement without the presence of the tag. In addition, the small perturbations introduced for the tag requires highly sensitive receivers; therefore, expensive vector network analyzers (VNAs) are often used as readers [18]. Another important drawback is the detection of several chipless tags in a small area due to the inexistence of an anti-collision protocol. The tags can only be identified by time gating if their spacing is higher than the spatial radar resolution [19] that is the function of the reader bandwidth. In order to mitigate these important issues, depolarizing tags [20] that reduce the clutter contribution and improve detection techniques have been developed in the literature [5, 21, 22]. In spite of these advances, the read range in frequency-coded chipless RFID is about 0.5–1 and 2–3 m for time-coded chipless tags. The inexistence of standardized readers in the market [18] and the limitations in the number of identification codes [13], in the read range, and in the cost (because it often uses high-frequency substrates, much more expensive than the substrates used in the inlay tags) are nowadays the challenges of this approach compared to UHF or other well-established RFID technologies. However, the interest of sensors based on chipless technology [23, 24, 25, 26] is recently growing in those cases in which the robustness to harsh environments [26, 27] and the cost may be competitive with other sensor technologies. In sensor applications, the anti-collision issues are not critical in those applications in which the number of sensors is small, and few bits can be used for identification or other techniques can be employed. Small number of resonators can be used for identification, and other resonators can be dedicated for sensing. The small number of resonators in chipless sensors simplifies its detection too and the bandwidth requirements [28].
Near-field communication technology at 13.56 MHz [29] is massively used for payment systems using NFC cards. Consequently, most smartphones include an NFC reader as it is shown in the exponential growing of number of NFC-enabled mobile devices depicted in Figure 1 [30]. NFC employs electromagnetic induction between two loop antennas; therefore the range of these tags is constrained by the rapid drop of the magnetic field with the distance. However, enough energy can be harvested to feed low-power microcontrollers and sensors. As a consequence, the interest in the market of NFC-based sensors [31] is growing. Recently several manufacturers of NFC integrated circuits include the possibility of using energy harvesting (EH) in these integrated circuits. These components provide up to 3 mA at 2–3 V to feed low-power sensors [32]. These battery-less sensors can be interesting in numerous applications for short-range wireless reading of low-cost sensors. The use of mobiles as a reader for standardized tags enables a fast introduction of these sensors in the market. On the other hand, batteries contain toxic components that can contaminate foods and release waste pollutants to the environment [33]. Therefore, the use of battery-less sensors is a preferable choice in applications in which the devices are in contact with food or implanted in the body. In addition, in this last case, the replacement of the batteries is an important drawback.
Number of NFC-enabled mobile devices worldwide from 2012 to 2018 (in million units) [30].
Nowadays, besides the traditional applications of identification, the interest of RFID technology in applications such as sensing [34] and localization [35, 36] (e.g., for robot guidance) is growing. Table 1 summarizes the main properties of passive RFID used for sensing (chipless RFID, NFC, UHF, and RFID) and a BLE as a representative wireless technology used in modern wearable applications. The key features of RFID technologies over active wireless technologies (such as Bluetooth or Zigbee) are the cost and the short setup time due to simpler communication protocol. The absence of battery, or its long lifetime in the case of BAP tags, is another valuable feature of the RFID technology. Depending on the read range required, NFC or UHF can be used. Nowadays, chipless RFID is a promising technology for short-range sensing. However, it is not mature enough for commercial use yet. Advanced sensors require additional processing; therefore, active wireless communication technologies with integrated microcontroller are needed. For wearable applications, BLE is a good option because this technology is available in smartphones. The cost of the reader is another important point that determines the selection of the technology. While the NFC and Bluetooth are low cost because most of the smartphones are equipped with NFC and Bluetooth modules, UHF readers are expensive, and therefore this technology is used in professional or logistic users but not for personal applications. In sensing applications where the read range of the Bluetooth is limiting, other wireless communication technologies such as Wi-Fi, Zigbee networks for medium range, or GPRS, Sigfox, LoRa, or NB-IoT for long range can be considered [37].
Feature | Chipless RFID | NFC | UHF RFID | BLE |
---|---|---|---|---|
Communication method | Backscattering far field | Backscattering near field | Backscattering far field | Transceiver far field |
Read range | Typically, <50 cm for frequency-coded 2–3 m for time-coded UWB | 1–2 cm for proximity cards with energy harvesting, 0.5 m for vicinity cards | Up to 15 m with inlay tags with −22 dBm read IC sensitivity Up to 3 m UHF sensors (with −9 dBm read IC sensitivity) Up to 30 m BAP | About 10 m |
Energy source | Passive | Passive or semi-passive | Passive or semi-passive | Active |
Tag price | Moderate | Low | Low | High |
Reader cost | High, no commercial | Low, smartphone | High 1–2 k$ | Low, smartphone |
Standard | No | Yes | Yes | Yes |
Universal frequency regulation | No, often used UWB | Yes, ISM | No, by regions | Yes, ISM |
Tag size | Large | Medium | Medium | Small |
Memory capacity | <40 bits | <64 kbits | 96bits EPC, typically 512 bits for users (<64kbytes) | Several Kbytes depending on the microcontroller |
ID rewritable | No | Yes | Yes | Yes |
Setup time | — | Less than 0.1 s | Less than 0.1 s | Approx. 6 s |
Energy harvesting | No | Approx. 10 mW | Few μW | No |
Tag substrate | Low-loss microwave substrates | Low cost or FR4 | Low cost or FR4 | FR4 |
Tag flexibility | Depends on the substrate | Depends on the substrate | Depends on the substrate | No |
Tag robustness | High | Low (inlays) | Low (inlays) | Moderate |
Comparison of RFID technologies [32].
NFC employs electromagnetic induction between two loop antennas. It operates within the globally available unlicensed radio frequency ISM band of 13.56 MHz on ISO/IEC 18000-3 air interface at rates ranging from 106 to 424 kbit/s [2]. The communication between reader and tag is briefly described in Figure 2. Firstly, the reader transmits an unmodulated carrier to activate the tag (Figure 2a). The receiver antenna at the tag is connected to the internal rectifier, which takes energy from the RF field to power up the tag electronics. After that, the reader sends commands by ASK modulating the carrier (Figure 2b), and the internal logic at the transponder demodulates the message. The tag transponder (which is assumed to be passive) responds using the passive load modulation technique (Figure 2c), by changing its antenna impedance [2, 29]. The passive load modulation spectrum consists of the RF carrier, two subcarriers at 12.712 and 14.408 MHz, and modulated sidebands on these two subcarrier signals (Figure 3). All the transmitted data are carried in the two sidebands.
Scheme of the communication between reader and tag: (a) power up the tag by the reader, (b) modulation of the carrier by the reader for transmission of the commands from the reader to the tag, (c) transmission the data from the tag to the reader by load modulation.
A typical spectrum of an NFC system illustrating the reader command around the carrier frequency and the load modulation at the sidebands.
An NFC tag IC is composed by two main blocks connected to the antenna ports (see Figure 4): the wireless power transfer unit that is responsible of harvesting the energy and powering the IC and the communication unit block that demodulates the messages and generates the clock for the transmission of data back to the reader. An RF limiter to protect the IC from a high-input voltage that could damage it, a rectifier, and a shunt regulator compose the WPT unit. The load modulator can be modeled as a shunt capacitance with the antenna. The IC impedance depends on the received power mainly due to the nonlinear behavior of the rectifier and the RF limiter. Therefore, a simplified model for the tag IC consisting of a nonlinear resistance RIC in parallel with a capacitance CIC that includes the parasitic elements is considered.
Block diagram of NFC IC.
Nowadays, the most important manufactures offer NFC IC with energy-harvesting capabilities. These ICs have access to the internal output of the rectifier to feed external circuits such as microcontrollers or sensors. Some commercial NFC ICs with energy-harvesting mode are listed in Table 2. Most of them are compatible with standards ISO14443-3 or ISO15693 and can be connected to external microcontrollers using the I2C bus or serial-to-parallel interface (SPI). The internal EEPROM memory size to store the NFC Data Exchange Format (NDEF) message varies between 4 and 64 kbit. Although most NFC ICs are designed to be connected to a microcontroller, some models such as the MLX90129 from Melexis, the SL13 from AMS, and the SIC43x from Silicon Craft integrate an A/D for autonomous sensor acquisition without an external microcontroller, reducing the part count. In addition, the model RF430FRL152H from TI integrates a low-power microcontroller (MSP430) and a 14-bit A/D. The maximum sink current that can be drawn to power external devices connected to the EH output such as sensors or microcontrollers varies with the IC model and operation mode. Most of the models can configure different current levels depending on the range of magnetic field. The current to be provided depends on field strength, antenna size, and Q factor, but it is typically limited to the order of 5 mA with output voltages between 2 and 3 V for magnetic fields of the order of 3.5–5 A/m [32].
IC model (manufacturer) | Energy harvesting Max. sink current and typical voltage | Standard | ADC | Interface bus | Memory and other comments |
---|---|---|---|---|---|
M24LR-E-R ST25DV-I2C (STMicro-electronics) | 6 mA/3 V | ISO15693 | No | I2C | 4–64kBit |
NT3H1101 NT3H1201 (NXP) | 5 mA/2 V | ISO14443-3 | No | I2C | 8kBit/16kBit |
NF4 (EM Microelectronics) | 5 mA/3.6 V | ISO14443A | No | SPI | 8kBit/32kBit/64KBit |
GT23SC6699–1/2 (Giantec Semiconductor) | NA/3.2 V | ISO14443-3 | No | I2C | 8kBit/16kBit |
SIC4310 SIC4340 SIC4341 (Silicon Craft) | 10 mA/3.3 V | ISO14443A | No Yes | UART | 220 bytes EEPROM |
AS3953A (AMS AG) | 5 mA/2 V | ISO14443A-4 | No | SPI | 1KBit |
SL13 (AMS AG) | 4 mA/3.4 V | ISO15693 | Yes | SPI | 8 kBit temperature sensor integrated |
MLX90129 (Melexis) | 5 mA/3 V | ISO15693 | Yes | SPI | 4kBit |
RF430FRL152H (Texas Inst.) | NA/3 V | ISO15693 | Yes | I2C/SPI | MSP430 2kB FRAM |
Main features of some commercial NFC ICs with energy harvesting [32].
A simplified model of the RF front-end of an NFC reader transceiver is shown in Figure 5. The topology of the transmitter usually presents differential output, and it is connected to the loop antenna through a matching network to obtain the maximum transmitted power. The output resistance (Rout) is a function of the transmitter power, and the DC voltage determines the current consumption of the transmitter. The matching network is composed of a differential L matching network (Cs and Cp). The current that flows through the loop antenna produces the magnetic field. In order to fulfill the emission regulations, a low-pass LC filter to reduce the spurious emission at the second harmonic is included. The receiver shares the loop antenna with the transmitter; therefore, two series resistances Rx are often added to attenuate the signal, avoiding the AC voltage at the receiver input to exceed a limit value and saturating it. Sometimes, a capacitive splitter is used for that purpose. The input impedance of the receiver is mainly capacitive, and it is modeled with the capacitance Cin in Figure 5. Although the overall impedance of the Rx and Cin is high, the effect of the receiver impedance must be considered in the design of the matching network. The steps to design this matching network can be found in [32]. In addition, recently, modern transceivers such as the ST25R391x incorporate an automatic antenna tuning method, enabling the matching network design in which Cp may be modified by switching an external bank of capacitors [38].
Model of the reader including the matching network, EMI filter, and antenna model and the simplified equivalent circuit model (right).
Printed loop antennas are used in NFC reader designs. There is a great variety of them depending on the reader type, but they are often designed to maximize the coupling with a payment card. Therefore, relatively large antennas between 4 and 5 cm square loops are integrated. The quality factor of these printed antennas is often high (more than 70). As the quality factor of the transmitter determines its bandwidth B (B = fc/Q), the quality factor (QT) must be reduced to allow the transmission of the sidebands of the carrier. To this end, two series resistances RQ are added at the input. The maximum quality factor of the transmitter is limited by the duration of the pause Tp in the modified Miller bit coding (see Figure 2):
The quality factor is limited to 40 and 128, for standards ISO 14443 and ISO 15693, respectively (35 and 100 considering design tolerances). Condition (1) represents an additional restriction for energy harvesting compared with other WPT systems for battery charging (with or without very small communication rate) where high Q coils can be used in the transmitter and receiver to increase the power efficiency.
Despite the transmitter’s complexity, it can be modeled using a simplified Thevenin equivalent circuit tuned at fc = 13.56 MHz, used for circuit analysis (see Figure 5, right). The parasitic capacitance of the transmit antenna is included within the equivalent circuit. The relatively low-quality factor of the coils simplifies the antenna reader design. Antenna inductance varies typically between 1 and 3.5 μH. Several formulas for inductance calculation can be found depending on the shape of the printed antenna [39, 40]. In addition, the inductance and the equivalent resistance (or quality factor) can be analyzed using electromagnetic simulators such as Keysight ADS, HFSS, or CST studio, among others. The main challenge in the antenna design arises when it must be integrated into the reader case, since the proximity of metallic parts or other components (e.g., displays, batteries, or PCB boards) can modify the inductance and the parasitic capacitance. The worst case is the presence of NFC transceiver in modern smartphones, due to space limitations. Figure 6 considers three different types of reader antennas including the typical locations of the NFC antenna into the smartphone [41]. Table 3 compares the main parameters analyzed. Antenna 1 corresponds to a simple printed antenna over a PCB such as used on readers connected to PC through the USB port. Antenna 2 corresponds to a typical smartphone with a plastic case in which the antenna is attached to the battery pack of the mobile. A sheet of ferrite isolates the traces from the metal on the bottom plane. Antenna 3 is known as Murata solution [42], and it is based on the integration of the loop antenna around the hole of the camera. The magnetic field generated or collected by a coil over or close to a metallic surface is almost parallel to this surface. Hence the magnetic flux is concentrated in the proximity of the coil [43], whereas it is zero in its center because of the cancelation of the field produced by the image currents with opposite sign. The effect is a considerable reduction in the read range and the increasing of the losses. A layer of ferrite material is placed under the coil, in order to isolate the antenna in the presence of metal. Modern sintered ferrite sheets with Re(μr) between 100 and 190 and Im(μr) losses typically of 5–10 at 13.56 MHz can be found in the market (e.g., MHLL12060-000 from Laird). As it can be appreciated in Table 3, the high magnetic permeability (μr) increases the inductance depending on the thickness of the ferrite foil. The effect of the ferrite loss produces an increasing of the antenna resistance and therefore a reduction of the antenna quality factor as it can be seen in Table 3. This is not an inconvenience so that it will only be necessary to readjust the matching network. Consequently, the inclusion of a ferrite layer modifies the field boundary conditions, making the magnetic field almost perpendicular, creating a scenario similar to the case of free space [32, 44].
Typical NFC reader antennas [41]: Antenna over a PCB (antenna 1), antenna on top of a mobile battery (antenna 2), and antenna around the camera hole (antenna 3).
Parameter | Antenna 1 | Antenna 2 | Antenna 3 |
---|---|---|---|
Loop area (mm × mm) | 50 × 50 | 50 × 50 | 25 × 25 |
Trace width (mm) | 0.7 | 0.7 | 0.25 |
Spacing between traces (mm) | 0.7 | 0.7 | 0.25 |
Number of turns | 6 | 6 | 8 |
Substrate relative permittivity | 4.7 | 4.7 | 3 |
Substrate thickness (mm) | 0.8 | 0.8 | 0.1 |
Ferrite relative permeability* | — | 150-j5 | 150-j5 |
Inductance (μH) | 2.68 | 3.92 | 3.63 |
Self-resonance frequency (MHz) | 77.0 | 37.4 | 79.05 |
Quality factor at 13.56 MHz | 153 | 132 | 74 |
Dimensions and simulated parameters of the reader antennas of Figure 6.
100 μm thickness with 50 μm of adhesive plastic sheet of MHLL12060-200 from Laird (with μr = 150-j5) is considered.
Antenna 1 and Antenna 2 have the same dimensions, but Antenna 2 has a sheet of ferrite.
Figure 7 shows a simplified equivalent circuit of the NFC system. The transmitter and the IC are modeled with the Thevenin model of Figure 5 and its equivalent input impedance (Figure 4), respectively. The tag antenna is modeled with an inductance L2, its equivalent resistance R2 that takes into account the antenna losses, and its parasitic capacitance Cp. The coupling between the transmitter and receiver coils allows the transfer of energy between the transmitter and the tag. In order to achieve high efficiency, the resonance frequency of the tag must be adjusted to the operation frequency (13.56 MHz).
Wireless power transfer model between the reader and the tag.
The design of an NFC tag is relatively easy. The resonance frequency is obtained from the simplified equivalent circuit of Figure 4, and it is given by:
where L2 is the inductance of the tag antenna, CIC is the equivalent capacitance of the NFC IC, Cp is the parasitic capacitance of the antenna and interconnections, and Ctun is an additional tuning capacitance connected in parallel at the input, used to adjust the resonance frequency. CIC is nonlinear and varies about 5% with the received power. The typical values of CIC provided by the IC manufactures vary between 20 and 50 pF when low-input levels are applied on them.
Similar to the transmitter, the loaded quality factor of the tag (Q2L) must be low enough to achieve the communication bandwidth, avoiding the attenuation of the modulation of the subcarrier in the backscattering link. Therefore, the maximum value of Q2L is approximately Q2L = 8π ≈ 25 [29]. The loaded quality factor (Q2L) is the hyperbolic average of the quality factor of the tag’s antenna (Q2) and the loaded quality factor of the IC (QL). Therefore, for typical values of printed loop antennas (Q2 > 50), the loaded quality factor is approximately QL:
Consequently, the tag quality factor Q2L < Q2Lmax if the following condition is fulfilled:
RIC is highly nonlinear and decreases with the input level. RIC takes typical values between 1500 and 400 in commercial ICs for the activation input level [45]. Therefore, condition (5) can be easily fulfilled for tag inductances higher than 0.7 μH, and in consequence, tag design is simple because it only is necessary to tune the resonance frequency with the capacitance Ctun for the desired loop antenna.
To this end, it is important to know the environment in which the tag will be used. The presence of high-permittivity materials such as the body or, for example, on wearable or implanted applications can detune the tag. These materials are nonmagnetic; therefore, they do not modify the loop inductance, but change the parasitic capacitance, reducing the resonance frequency and increasing losses. Figure 8a shows the measured results of an implanted antenna in a phantom that consists of a piece of pork steak. The antenna is a 15 × 15 mm square coil consisting of six loops, printed in duplicates on each of the layers of a FR4 board whose thickness is 0.8 mm. The introduction of a low-permittivity cover (e.g., silicone, εr = 3) allows to reduce the losses of the phantom when the thickness is larger than 1 mm. Similar results are found for a coil close to the body surface (Figure 8b) considering a low-permittivity spacer (εr = 3) located between the coil and the body. Here the coil is a 25 × 25 mm square consisting of four loops printed on a thin flexible substrate (Ultralam 3000, thickness 100 μm).
(a) Measured quality factor of a coil in the air and inside of a phantom for different coating thickness, (b) measured quality factor of a thin coil over the skin as a function of the spacer thickness.
Another typical situation is the detuning due to the presence of nearby metal surfaces. If the NFC sensor is going to work on a metallic surface, the antenna can be isolated using a ferrite foil as in the case of the reader. But the typical situation takes place in the tags that will be read by smartphones with a metallic case. In this case, the inductance of the tag will be reduced by the presence of the metal due to the opposite image currents induced on it. The result is a detuning of the tag as can be shown in Figure 9. In order to check if a tag is correctly tuned, a test coil can be connected to the port 1 of a vector network analyzer. An absorption peak will be observed at the resonance frequency if the test coil is located close to the tag (but sufficiently spaced to avoid strong coupling between the coils). Figure 10 shows the inductance of a coil as a function of the metal distance. A considerable reduction of its value is observed. Therefore, the tag must be tuned depending on the application and the desired read range of the tag.
Measured S11 of the test antenna as a function of frequency for different distances between the tag and the mobile [32].
Simulated and measured antenna inductance as a function of the distance to a ground plane for a 50 × 50 mm loop antenna with 0.7 mm trace width and six turns, manufactured on a 0.8-mm-thick FR4 [32].
The area available for the antenna depends on the application. For example, Table 4 shows the design of a tag sensor using the coil of Figure 10 and an M24LR04E-R IC from ST for short range (5 mm) and long range (15 mm). For long ranges (distances higher than 15 mm), the inductance and the other antenna parameters (resistance and capacitance) are nearly constant and close to the values of the free space case. The tuning capacitor (Ctun) that must be mounted in parallel at the input of the NFC IC is obtained from (2), and it is approximately 25 pF. However, for short read range applications in the presence of metal, the values of inductance for a distance of 5 mm must be considered. In this case, the tuning capacitance must be increased up to 36 pF. The inductance for each case is obtained from the measured impedance with the VNA, and the parasitic capacitance (Cp) is obtained from the self-resonance frequency of the antenna (without considering the tuning capacitor). If the antenna cannot be measured, e.g., due to the lack of laboratory instruments, the tuning capacitance can be obtained considering that the nominal inductance (value measured or computed in free space) decreases about 16% for short-range case. For very short ranges, the coupling coefficient k between the transmitter and tag antennas is very high (typically k > 0.1). Therefore, the input impedance at the transceiver increases (see Figure 7) due to the loading effect of the tag, and it is detuned because the matching network is designed considering that it is far from the reader and hence uncoupled to it. This is the reason why sometimes the tags are read worse when are on contact or very close to the reader than when are more spaced.
Parameter | Tuning for short range (5 mm) | Tuning for long range (15 mm) |
---|---|---|
Loop area (mm × mm) | 50 × 50 | 50 × 50 |
Trace width (mm) | 0.7 | 0.7 |
Spacing between traces (mm) | 0.7 | 0.7 |
Number of turns | 6 | 6 |
FR4 substrate thickness (mm) | 0.8 | 0.8 |
Metal thickness (μm) | 34 | 34 |
Chip capacitance CIC(pF) | 27.5 | 27.5 |
Inductance L2 (μH) | 2.68 | 3.92 |
Self-resonance frequency (MHz) | 52.9 | 55.7 |
Antenna quality factor Q2 | 87 | 118 |
Parasitic capacitance Cp (pF) | 2.3 | 1.7 |
Tuning capacitance Ctun (pF) | 36 | 25 |
Example of design for short-range application (5 mm) and long-range application (15 mm).
The communication in an NFC system can be limited by the uplink (reader to tag) when the tag does not receive enough energy to power the transponder IC or by the downlink (tag to reader) if the backscattered level received at the NFC reader is not sufficiently high to demodulate the message. For an NFC IC equipped with energy harvesting, the main limitation is the WPT in the uplink because it is necessary to provide higher energy than in a conventional NFC IC without energy harvesting. Thus, the read range in NFC tags with the EH mode activated is lower than the range for reading a previously stored data in the memory.
At this point it is interesting to take into account the factors that limit the read range of an EH NFC sensor. To this end, the wireless power transfer between the reader and tag can be analyzed considering the circuit of Figure 7. Analytical formulas found in the literature or a circuit simulator such as Keysight ADS can be used. In this model, L1 is the reader antenna inductance and R1 is its losses. C1 is the equivalent series capacitance that allows the circuit to resonate at 13.56 MHz. L1 and R1 can be obtained from the measurement of the antenna impedance or from electromagnetic simulations. Rs is the Thevenin output resistance, and it is chosen to achieve the maximum loaded Q factor in the transmitter to ensure the communication. As the reader in the smartphone is designed to read both ISO 14443A and ISO 15693 standards, the QT is often limited to 35. Therefore, Rs is obtained from the loaded quality factor of the transmitter at 13.56 MHz (Rs = ωL1/QT-R1). The inductance L2 in series with a loss resistance R2 is used to model the tag antenna.
A key parameter is the mutual inductance M between the coils, as a function of the distance. The coupling coefficient k is obtained from the Z parameters from electromagnetic simulations or S parameters measurements performed with VNA:
Figure 11 compares the simulated coupling coefficient for each reader antenna as a function of the distance between the tag and reader antenna. Antenna 1 has been used as the tag antenna since it has a size similar to a smart card. The simulations have been done using Keysight Momentum. The coupling coefficient is obtained using (6) from the simulated Z parameters. Figure 11 shows a similar coupling coefficient for Antennas 1 and 2 (see Figure 6). Therefore, the introduction of the ferrite foil effectively mitigates the effect of the metal. On the other hand, the coupling coefficient of Antenna 3 (Figure 6) is smaller than in the previous cases because its area is the smallest.
Simulated coupling coefficient between a tag using antenna 1 and different reader antennas of Figure 6.
The circuit of Figure 7 can be analyzed both analytically [46] or using a circuit simulator (e.g., Keysight ADS). In any case, the NFC IC is considered linear and modeled with its equivalent circuit. The values of RIC and CIC depend on the power. In addition, the manufacturer does not often give RIC. This equivalent circuit can be measured using a VNA. However, the output level of commercial VNA does not achieve the typical level in a tag under real conditions. A modified high-power VNA with an external reflectometer and a power amplifier can be used, as it is proposed in Refs. [45, 47]. An alternative setup with an oscilloscope has been recently presented in [48]. However, these setups are not often available for the users interested in the design of NFC-based sensors. In order to estimate the maximum read range, the value of RIC at that distance must be known. It can be estimated from the minimum average magnetic field, Hmin. This is the threshold average magnetic field that ensures the RF to DC conversion at the read range and can be computed from Ref. [45]:
where fr is the resonance frequency of the tag, A is the loop area, N is the number of loops, and Umin is the minimum AC threshold voltage at the IC input required for the NFC IC operation. Therefore, Hmin depends only on the tag parameters, and it can be considered a figure of merit of the tag. It can be experimentally found measuring the average magnetic field generated by the reader as a function of the distance between the tag and reader. A measurement procedure can be found in [32, 41]. Umin can be measured with an oscilloscope using a probe with low capacitance at the maximum distance where EH is activated.
Taking into account the coupling coefficients of Figure 11, Figure 12 compares simulated results for the antennas considered in Figure 6. It is assumed that the transmitter power is 20 dBm and that EH output is activated if the AC voltage at the input of the rectifier is high enough. In these conditions, the average field is equal to Hmin. Considering Umin = 4.8 V, Hmin = 1.2 ARMS/m, and RIC = 550 Ω, a distance between 12 and 18 mm is obtained. This estimation is in agreement with measurements of received Hav for a tag using the same antenna than in the simulation. Experimentally, a value of Hmin ≈ 1.1 ARMS/m (see Figure 13) corresponding to an EH range of 10 and 17 mm has been obtained, depending on the mobile used.
(a) Simulated voltage at the input of the tag at 13.56 MHz (VAC), (b) efficiency, and (c) average magnetic field Hav, as a function of the distance for 20 dBm of transmitted power. The threshold limit is shown in dashed line.
Measured average magnetic field Hav(ARMS/m) for a tag using antenna 1 as a function of the tag-to-reader distance for two mobile models.
Figure 14 shows the block diagram of an NFC-based data logger assisted with a complementary (optional) energy source (e.g., a solar cell). It is composed of an antenna that receives the interrogation signal emitted from a reader, usually, a mobile equipped with an NFC reader, an NFC integrated circuit, a microcontroller, and the sensor and its conditioning electronics. Table 2 shows that there are several commercial NFC ICs with energy-harvesting capabilities available in the market. These devices can operate in two modes: battery-assisted (semi-passive) and battery-less (passive). Battery-assisted devices are used in data logger applications where stand-alone continuous and autonomous monitoring is necessary. The NFC sensor is fed from a battery or assisted from an additional harvesting source. These devices can communicate with external microcontrollers using I2C or SPI interface. In the passive operation mode, the integrated NFC circuit is in charge of capturing the energy from the RF signal, rectifying it and extracting energy for the electronic circuits, microcontroller, or sensors. Sensors based on NFC IC with energy harvesting may operate in both modes: in semi-passive mode until the battery is exhausted and thereafter in passive mode. Data are stored in the EEPROM of the NFC IC to be read when the user taps the sensor. It should be highlighted that for tags in battery-less mode, data can only be updated with a new sensor reading in the presence of field from the reader. Another challenge is the amount of power that can be harvested from the RF signal. According to market research summarized in Table 2, commercial ICs can provide up to 15 mW. Despite this figure, battery-less sensors based on NFC have a wide range of applications. The most important key is that a specific reader is not required because the own smartphone equipped with NFC can be used as reader, and the data can be uploaded to cloud services using the Internet connectivity of the mobile. This fact is probably the important factor for the diffusion of this technology as can be derived from the large number of battery-less sensors based on NFC that are recently reported in the literature. Next section will review some examples.
Block diagram of a green NFC-based sensor system.
Several temperature sensors based on NFC have been proposed in the literature for different applications. In the pioneering works, based on NFC-WISP [49, 50] due to the inexistence of commercial NFC IC with energy harvesting, the rectification was performed with an external full-wave rectifier with discrete diodes. NFC-WISP communicated using the ISO-14443 protocol implemented in a low-power microcontroller (TI MSP430). As an option, the data could be shown in an E-ink display.
The monitoring of environment temperature in a cold chain or body temperature without using batteries that contain toxic products has aroused great interest. Several temperature sensors based on commercial IC such as MLX90129 [51] or RF430FRL152H [52, 53] have been reported in the literature for these applications. Other physical magnitudes can be measured with NFC sensors. For example, [54] reports a wireless tire pressure sensor based on a custom ASIC compatible with ISO14443 protocol.
A soil moisture battery-less NFC sensor for low-cost irrigation control at home, in a greenhouse, or at a garden center has been presented in [55]. The tag is based on an M24LR04E-R from ST connected to a low-cost microcontroller (ATtiny85 from Atmel). Volumetric water content of soil is obtained from capacitance measurement based on a low-power timer 555 working as an oscillator and a diode detector whose output is measured by the ADC of the microcontroller. Additionally, the temperature is measured using an I2C temperature sensor (LM75A), while air humidity is detected by reading the analog output from the HIH-5030 humidity sensor from Honeywell. The external circuitry requires less than 1 mA at 3 V to operate. Figure 15 shows an image of the soil volumetric water content sensor inserted in a flower pot, the mobile app that shows the information in the screen and a comparison between the measured and the real volumetric water content (soil moisture) [55].
Comparison of the volumetric water content (VWC) obtained with the sensor and real [55].
A second example is a smart diaper [56]. The tag is based on the M24LR04E-R from ST and an ATtiny85 from Atmel. The microcontroller senses the capacitance between two electrodes based on the discharge time of an RC circuit. The capacitance changes as a function of the urine level, as it is shown in Figure 16. Chemical sensors inserted in NFC-based tags have also been proposed. The presence of gas sensors based on functionalized CWNT that change the resonance frequency of an NFC has also been proposed in [57].
(a) Photograph of the layout of the tag and the screen of the mobile app. (b) NFC reading as a function of the level of saline water for two diapers (adult for night and day and baby size 2).
Another advantage of NFC technology over other types of RFID working at UHF frequencies is that the NFC antennas can be designed to be compatible with the body. The effect of the body on NFC antennas is lower than at UHF band, where a considerable reduction of antenna efficiency and therefore the read range is experienced. Therefore, although the body losses reduce the quality factor of the coil and can detune the resonance frequency, the introduction of a small spacer can mitigate these effects, as shown in the previous section. Several wearable NFC-based sensors can be found in the literature that exploits this fact. In addition, the short read range inherent in the NFC technology provides a degree of privacy and security over undesired access to sensible information by nearby third parties [58, 59]. Prototypes of patches to perform measurements of body temperature based on commercial NFC IC can be found in [52, 53]. Another example is a prototype for monitoring the degree of hydration based on Melexis MLX90129 [60]. This sensor measures the concentration of NaCl in sweat, reading the surface temperature and sensing the potential difference between two electrodes. A noninvasive, NFC pH sensing system for monitoring wound healing and identifying the possibility of early-stage infection is reported in [61]. A low-power CMOS ISFET array for pH sensing is inductively powered using SIC4310 from Silicon Craft NFC IC in [62].
The authors have demonstrated that colorimetric measurements can be done with battery-less NFC. The advantage over other methods based on cameras is that the illumination conditions are similar, and therefore the measurements have higher repeatability and accuracy. A prototype of NFC colorimeter with a low-cost color light-to-digital TCS3472 converter from TAOS is integrated with an ST M24LR04E-R NFC IC and a microcontroller (see Figure 17). It is used to measure the change in color of pH tires [41]. The same method can be used for other sensors based on the measurement of the color changes due to another sensitive chemical component (e.g., urine tests). Figure 17 shows an image of the prototype and a comparison of the measured hue component as a function of the pH, showing that a simple linear model can be employed for pH calibration. The same NFC colorimeter is adapted to the design of a color-based classification system for grading the ripeness of fruit in [63] (Figure 18).
Photograph of an NFC PH sensor from the measurement of the color of a strip with the android application and relation between the measured hue and the pH [41].
Photograph of the NFC tag within the 3D printed enclosure in real application to detect apple ripeness and top/bottom photographs of the prototype.
Finally, another application of NFC sensors is implantable medical devices (IMDs). Long-term implantable continuous glucose monitoring based on custom ASIC has been reported in [64, 65]. Wireless communication with IMDs is fundamental for monitoring and the reconfiguration of these devices to reduce the surgical operations [58]. Due to the size of the implanted coil, the coupling coefficient with the antennas integrated into the mobile is small, resulting in a short read range. One method to improve the readability with a modern smartphone and to increase the energy-harvesting range is including a relay coil on the body surface integrated on a patch. Figure 19a shows the setup for measuring the average magnetic field and a prototype of implanted NFC sensor integrating a LED, a temperature sensor, and a microcontroller as proof of concept (Figure 19b). Figure 20 shows the measurements with a commercial mobile of the average magnetic field as a function of the distance of an implanted coil of 15 × 15 mm within a phantom of pork steak for different depths of the implanted tag. Two systems are compared: the conventional two-coil system and a three-coil system where a relay resonant coil is on a patch over the skin. Using the last system, implanted NFC sensors can be powered by conventional smartphones at a depth up to 16 mm and read at distance between 1 and 2 cm from the skin.
(a) Setup used for the measurement of the average magnetic field, (b) photograph of a designed tag for testing: Top view (left) and bottom view (right).
Measured average magnetic field as a function of the mobile to skin distance for an implanted tag in a phantom at different depths between 4 and 16 mm for the two-coil system (a) and the three-coil system with a resonant relay loop on the skin (b). The threshold Hmin is shown in dashed line.
The availability in the market of low-cost near-field communication devices with energy-harvesting capabilities allows to feed small sensors enabling the development of low-cost battery-less sensors. One important advantage over other RFID is that additional readers are not required since most of the modern smartphones incorporate NFC readers. The limited read range for a selected number of applications is an advantage rather than a drawback because it ensures the privacy and improves the security under undesired access to sensible information by nearby third parties. In this chapter, an overview of recent advances in the field of battery-less NFC sensors at 13.56 MHz is provided, and it also briefly compares these sensors to other short-range RFID technologies. After reviewing power transfer in NFC, recommendations are made for the practical design of NFC-based sensor tags and NFC readers. A list of commercial NFC integrated circuits with energy-harvesting capabilities is also provided. A survey of recent battery-less NFC-based sensors for different applications has been done showing that conventional low-power sensors can be integrated within NFC tags for the new generation of IoT devices.
This work was supported by grant BES-2016-077291 and Spanish Government Project RTI2018-096019-B-C31.
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