Electrical Equivalent Circuit Models of Lithium-ion Battery

*Rushali R. Thakkar*

## **Abstract**

Modelling helps us to understand the battery behaviour that will help to improve the system performance and increase the system efficiency. Battery can be modelled to describe the V-I Characteristics, charging status and battery's capacity. It is therefore necessary to create an exact electrical equivalent model that will help to determine the battery efficiency. There are different electrical models which will be discussed and examined along with the benefits and demerits. A systematic comparison and analysis using simulation will help us to select an ideal model which will suit best to a specific application.

**Keywords:** battery, lithium-ion batteries, battery modelling, state of charge, electrical equivalent, simulation

#### **1. Introduction**

Renewable energies play a major role in the power quality applications of emerging technologies. Batteries are considered as one of the most important amongst the component. Batteries are energy storage devices that can be utilised in a variety of applications and range in power from low to high. Batteries are connected in series and parallel to match the load requirements. The advantages of lithium-ion batteries include their light weight, high energy density, and low discharge rates. They're commonly seen in high-power applications like electric vehicles and hybrids. Lithium-ion batteries have a terminal voltage of 3-4.2 volts and can be wired in series or parallel to satisfy the power and energy demands of highpower applications. Battery models are important because they predict battery performance in a system, designing the battery pack and also help anticipate the efficiency of a system [1, 2].

### **2. Existing electrical equivalent battery models**

The mathematical relationship between the elements of Lithium-ion batteries and their V-I characteristics, state of charge (SOC), internal resistance, operating cycles, and self-discharge is depicted in a Lithium-ion battery model. The equivalent circuit model of a Lithium-ion battery is a performance model that uses one or more parallel combinations of resistance, capacitance, and other circuit components to construct an electric circuit to replicate the dynamic properties of Lithium-ion batteries. Time domain analysis is used to produce the most often utilised electrical

equivalent models. The simplest model equation for battery model can be represented by Open Circuit Voltage (OCV)

$$v(t) = \text{OCV} \tag{1}$$

SO0C of a cell is 100% when cell is fully charged and SOC is 0% when cell is fully discharged. The amount of charge removed from 100–0% is the total capacity measured in Ah or mAh.

Following are the models used for Lithium-ion battery to determine the performance on the system [3].

#### **2.1 Simple battery model Rint model**

**Figure 1** illustrates the most widely used battery model. It consists of an ideal battery with open circuit voltage (OCV) V0, a constant equivalent internal resistance Rint, and *v t*ð Þ as the terminal voltage. When completely charged, the terminal voltage v(t) may be determined by measuring the open circuit voltage, and Rint can be determined by connecting a load and detecting both the terminal voltage and current.

SOC is represented as z(t) of a cell is 100% when cell is fully charged and SOC is 0% when cell is fully discharged. The amount of charge removed from 100–0% is the total0 capacity (Q) measured in Ah or mAh.

$$v(t) = OCV(z(t)) - i(t)R\_{\text{int}} \tag{2}$$

$$\frac{dz}{dt} = -\frac{i(t)}{Q} \tag{3}$$

$$z(t) = z(t\mathbf{0}) - Q \int\_{t\mathbf{0}}^{t} i(T)dT\tag{4}$$

At the point when a battery is completely charged, its Open Circuit Voltage is higher than when it is discharged. The Rint model appears to be relatively simple, however it ignores the variable nature of the internal resistance related to temperature, state of charge, and electrolytic concentration.

**Figure 1.** *Resistive Thevenin battery model.*

## **2.2 Resistive Thevenin battery model**

**Figure 2** shows the circuit schematic for the resistive Thevenin battery model. This model has two types of internal resistances, R0 and R1, which are connected to the charging and discharging properties of the battery, respectively. Electrical and non-electrical losses are modelled by the internal resistances R0 and R1. Diffusion Voltages also can be closely found using1 or more RC parallel branches. The model gives better results than Rint model, however transient conditions like the capacitance effect are not considered. As a result, this model is non-dynamic and unsuitable for applications involving electric vehicles and electric hybrids [4–8].

In relaxation mode, voltage gradually reduces to zero, this is termed as diffusion voltage which can be closely approximated using parallel RC branches (**Figure 3**) [4, 5].

$$\dot{\nu}(t) = \text{OCV}(z(t)) - i(t)\text{Rint} - \text{Vc1}(t) \tag{5}$$

#### **2.3 An accurate electrical battery model**

An Accurate Electrical Battery Model, models the battery capacity, charging state, and run time using a capacitor and a current controlled source. The circuit takes into account the battery life time as well as the slow and fast transient response. A voltage controlled voltage source that is a function of state of charge is used to overcome the barrier between SOC and OCV (**Figure 4**) [1].

**Figure 2.** *Thevenin battery model with 1 RC branch.*

**Figure 3.** *Thevenin battery model with 2 RC branches.*

#### **Figure 4.**

*Accurate electrical battery model.*

#### **Table 1.**

*Comparison of electrical equivalent battery models [8].*

**Table 2.**

*Battery model specifications LIR18650 mAH.*

#### **2.4 Models of electrical equivalent batteries**

**Table 1** gives the different Electrical equivalent circuit models along with its important features so that it will be useful to predict the performance of the battery and for which application the battery can be used for.

#### **2.5 Electrical characteristics of lithium-ion battery**

Lithium-ion battery specifications used for battery model: LIR18650 mAH are given in the following **Table 2** [8].

*Electrical Equivalent Circuit Models of Lithium-ion Battery DOI: http://dx.doi.org/10.5772/intechopen.99851*

**Figure 5.** *Rate charge characteristics.*

#### **2.6 Charging and discharging characteristics**

**Figures 5** and **6** shows the rate charge and discharge characteristics of the battery Model LIR18650 2600 mAH. The battery charges with Constant Current Constant Voltage mode. The battery is charged at a constant current until it reaches 4.2 volts, then it is charged at a constant voltage until the current drops to zero [8]. The charging time of battery can be calculated as the ratio of battery Ah to the charging current.

#### **3. Simulation results and discussion**

M file is created in Matlab to simulate the model's charging and discharging curves. The generalised model for lithium-ion batteries uses the equations below [7, 8].

Discharge Model (i\*>0)

$$f1(it, i\*, i) = E0 - K.\frac{Q}{Q - it}.i\* - K.\frac{Q}{Q - it} + A.\exp\left(-B.it\right) \tag{6}$$

Charge Model (i\*<0)

$$f\mathbf{1}(it, i\*, i) = E\mathbf{0} - K. \frac{\mathbf{Q}}{it + \mathbf{0}. \mathbf{1}. \mathbf{Q}} . i\* - K. \frac{\mathbf{Q}}{\mathbf{Q} - it} + A. \exp\left(-B.it\right); \tag{7}$$

E0 is constant voltage (V), K is polarisation constant in (Ah�1 ), i\* is low frequency current dynamics, Q is maximum battery capacity (Ah), A is exponential voltage (V), B is exponential capacity (Ah�1 ), *it* is extracted capacity (Ah).

The implementation of the generalised model in MATLAB shows that the characteristics developed by mathematical electrical model of battery in Matlab and are close to the actual characteristics of Lithium-ion Battery Model LIR18650 2600 mAH [8].

#### **4. Conclusion**

Being a static model, the Rint model does not account for the battery's charging and discharging properties. Thevenin's electric model (1RC) ignores dynamic behaviour and neglects to account for state of charge dependency. 2 RC branches would be closer to match the data at the beginning of the transient. 3RC branches can be chosen as a compromise between complexity of model and its fidelity. Various electrical equivalent models are studied along with its different features in the existing models.

#### **Author details**

Rushali R. Thakkar Sardar Patel Institute of Technology, Mumbai, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Electrical Equivalent Circuit Models of Lithium-ion Battery DOI: http://dx.doi.org/10.5772/intechopen.99851*


2.3.5. Results and conclusions

Despite controversy, combined orthosurgical treatment of severe maxillary excess concomitant with facial skeletal disharmony remains the only treatment option. The treatment results as seen in Figures 22–24 were remarkably promising and satisfactory.

Figure 23. Phases of treatment, pretreatment, presurgical, postsurgical, and post prosthetic replacement of extraction

Orthosurgical Correction of Severe Vertical Maxillary Excess: Gummy Smile

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139

Figure 24. Frontal and lateral photos of the face showing significant esthetic improvement and pleasing smile shaped by

spaces.

combined orthosurgical treatment.

#### 2.4. Case #4

A healthy patient (24 year and 10 month old) presented with a chief complaint "I am unhappy with my unaesthetic smile, lack of biting on my teeth, and prominent chin." The necessary data were collected and analyzed, and the patient was informed that orthodontic treatment

Figure 22. Pre and post treatment cephalometric analysis and panoramic views.

Orthosurgical Correction of Severe Vertical Maxillary Excess: Gummy Smile http://dx.doi.org/10.5772/intechopen.80384 139

Figure 23. Phases of treatment, pretreatment, presurgical, postsurgical, and post prosthetic replacement of extraction spaces.

2.3.5. Results and conclusions

138 Current Approaches in Orthodontics

2.4. Case #4

Despite controversy, combined orthosurgical treatment of severe maxillary excess concomitant with facial skeletal disharmony remains the only treatment option. The treatment results as

A healthy patient (24 year and 10 month old) presented with a chief complaint "I am unhappy with my unaesthetic smile, lack of biting on my teeth, and prominent chin." The necessary data were collected and analyzed, and the patient was informed that orthodontic treatment

seen in Figures 22–24 were remarkably promising and satisfactory.

Figure 22. Pre and post treatment cephalometric analysis and panoramic views.

Figure 21. Model surgery and diagnostic set up possible for prosthetic construction.

Figure 24. Frontal and lateral photos of the face showing significant esthetic improvement and pleasing smile shaped by combined orthosurgical treatment.

alone cannot be of benefit to you. A combined orthosurgical treatment modality was offered, and a joint meeting with the maxillofacial surgeon was arranged; details of the treatment phases, surgical risk, and cost effectiveness were explained to the patient who showed great interest in undergoing the treatment in a positive manner. The following figures reveal the steps and efforts exerted by the healthcare team and the cooperation of the patient that made the achievement possible.

plane; bilateral sagittal split osteotomy of the mandibular ramus to setback the prognathic mandible bringing narrower mandibular arch in favor of the normal transverse occlusion, anticlockwise rotation aided in correcting the open bite. Retentive means were designed to

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141

Mutual collaboration between healthcare providers allows for the proper selection of treatment modality relevant to the dentofacial deformity presented. Bimaxillary surgery helped in

Figure 26. Pretreatment lateral cephalometric and panoramic radiographs (essential diagnostic aids).

Figure 27. Pretreatment lateral ceph (McNamara) analysis and soft tissue surgical planning (prediction).

guarantee stable outcome (Figures 26–32).

2.4.4. Conclusions


**3.1. Morphological characterization of** *Bifidobacterium* **reference strains**

The basic morphologies, namely short, regular, thin cells with pointed ends, coccoidal regular cells, and long cells with slight bends or protuberances are discernible among the 2 *Bifidobacterium* reference strains (*B. adolescentis* and *B. infantis)* shown in Figures 4.1, 4.2, 4.3, 4.4 and 4.11) on modified MRS and RB media. From these micrographs alone, it is obvious to validate that individual variations of the average phenotypic morphologies of bifidobacteria are present as described earlier. The PCM also provided a rapid and clear visualization of the basic bifidobacteria cell morphology, while at the same time, allowed only broad comparisons amongst the bifid structures within a mixture of 2 other LABs (*Streptococcus thermophilus* & *Lactobacillus bulgaricus*) (see Figure 4.12).

The typical colonies of bifidobacteria are altogether round and white on RB and modified MRS media. Colonies are usually picked off of a suitable plate and may be kept sub-cultured 2 – 3 times on a freshly prepared agar as to obtain pure culture without contamination. The morphologies of the 2 reference strains and their relationship to each will now be discussed separately. When the strain of *B. adolescentis* is resuscitated and cultured on modified MRS medium (Figure 4.1) or RB medium (Figure 4.2), it may be differentiated clearly from the *B. infantis* (Figures 4.3 & 4.4) on the basis of morphology. The *B. infantis* was also resuscitated and cultured under the similar conditions. As it can be observed from Figure 4.2, *B. adolescentis* on RB displayed long and thick rod-shaped and regular coccoidal cells. The cells of *B. adolescentis*  strain on RB were almost paired and assembled, a feature which was highlighted by PCM. The existence of distinct "V"- and/or "Y"-shapes and some long cells with protuberances or slight curvature of this isolates when grown on RB agar, is a powerful diagnostic feature, particularly when distinguishing this specie from closely related *B. minimum* when grown on Trypticase-Phytone-Yeast extract (TPY) agar stabs (Biavati *et al.,* 1982). In addition, curved cells with smooth and rounded ends are the most one dominating in the micrograph. These features were not compatible with descriptions of this particular species' morphology as described by Reuter (1963), but were common to other species of the genus.

The *B. infantis* strain displayed slender, often short rod-shaped and of the typical clubshaped extremities, which cells of these species are reported to exhibit (see Figures 4.3 & 4.4). The morphology of this strain is almost the same when grown on both the MRS and RB solid growth media. Furthermore, *B. infantis* showed a distinct tendency for chain formation on RB medium. These cells often occurred in "V" and "Y"-shapes and were similar to that of many other species of the genus. Nevertheless, it was also possible to differentiate between this strain and the closely related *B. longum* GB-03 (own isolate, Fig. 4.6) on the basis of small variety of club-shaped extreme morphology.


**Meet the editors**

Dr. Nasser Sayed Awwad received his MSc in Inorganic and Radiochemistry in 1997 from Benha University, his PhD in Inorganic and Radiochemistry in 2000 from Ain Shams University and Post doctorate at Sandia National Labs, New Mexico, USA in 2004. Nasser Awwad was Associate Prof of Radiochemistry in 2006 and professor of Inorganic and Radiochemistry in 2011 at the Egyptian

Atomic Energy Authority. He has been a Professor at King Khalid University, Abha, KSA, from 2011 to the current day. He has published two chapters in the following books: "Natural Gas - Extraction to End Use" and "Advances in Petrochemicals". He has been Editor for four books: "Uranium", "New trends in Nuclear Sciences", "Dyes in Industry" and "Lanthanides". In addition to this, he has published 54 papers in ISI Journals. He has supervised 4 PhD and 16 MSc students in the field of Radioactive and Wastewater treatment. He has participated in 25 International conferences (South Korea, USA, Lebanon, KSA and Egypt). He has reviewed 2 PhD and 13 MSc papers. He has participated in 6 big projects with KACST at KSA and Sandia National Labs at USA on the conditioning of radioactive sealed sources, wastewater treatment. He is the leader of group research about utilization of nanomaterials for treatment of inorganic and organic pollutants and is a member of a research group on the influence of d- and f-block element interactions with indomethacin, bupivacaine, lidocaine, nadolol, procainamide and procaine nonsteriodal drugs on its bioactivities. He is a member of the Arab Society of Forensic Sciences and Forensic Medicine and a member of the Egyptian Society for Nuclear Sciences and its applications. He is part of the Editorial Board of the Journal of Energy and Environmental Research and Technology. He is also a member of the organizing committee of the 9th World Congress & Expo on Nanotechnology & Material science and a rapporteur of the Permanent Committee for Nuclear and Radiological Protection at King Khalid University. He is interested in utilizing the different techniques related to treatment of radioactive nuclides using nanomaterials.

Salem A. AlFaify (S. AlFaify) is currently an associate professor of physics, leader of the "quantum functional materials for advanced applications" (QFMAA) research group and a leading researcher at the advanced functional materials and optoelectronics laboratory (AFMOL) at the department of physics faculty of sciences, King Khalid University (KKU). He was President of the Saudi

Physical Society (SPS) from 2013-2016. He obtained his Ph.D. in condensed matter physics/nano-materials in 2011 from the Western Michigan University, USA. He was awarded a thesis

appointment scholarship from the department of energy DOE-USA to conduct his Ph.D research project in the center for nano-scale material (CNM) at Argonne National Laboratory (ANL), one of the dominant national laboratories of the DOE-USA operated and managed by the University of Chicago. He has authored and co-authored more than 150 articles in peer-reviewed and highly reputed ISI journals. He works with collaborators/researchers with mutual interest from many institutes and universities around the world. His research interests are primarily in the area of the condensed matter physics at the nano-scale, in particular, the correlation nature of the nano-quantum structures and their properties and applications. In addition to the growth of varying forms of nanostructured materials and their basic characterization by XRD, SEM, TEM etc., he is interested in utilizing the powerful techniques related to accelerators physics such as ion beam analysis (IBA) and synchrotron radiation to fundamentally investigate the essence of the nanomaterials/fine matters and understand/ engineer their novel properties for modern and futuristic applications.

Contents

**Preface VII**

**Nuclear Science 1**

Chapter 2 **Nuclear Reactor Simulation 5**

Toru Aoki

Joji M. Otaki

Thomas W. Grimshaw

Edmundo del Valle-Gallegos

Chapter 1 **Introductory Chapter: Introduction to New Trends in**

Andrés Rodríguez Hernández, Armando Miguel Gómez-Torres and

Olena Maslyanchuk, Stepan Melnychuk, Volodymyr Gnatyuk and

**the Field-Laboratory Paradox: Multifaceted Biological Effects**

Chapter 3 **Mechanisms of Charge Transport and Photoelectric Conversion in CdTe-Based X- and Gamma-Ray Detectors 27**

Chapter 4 **Understanding Low-Dose Exposure and Field Effects to Resolve**

Chapter 5 **Integrated Policymaking for Realizing Benefits and Mitigating**

**from the Fukushima Nuclear Accident 49**

**Secondary Impacts of Cold Fusion 73**

Salem A. AlFaify and Nasser S. Awwad


**4.6 Treatment of ADHD**

For patients with tics and ADHD without response to behavioral therapies, options of treatment including the use of the norepinephrine reuptake inhibitor atomoxetine. This drug has documented efficacy for ADHD and has been associated with either no change or a slight reduction in tics49. Stimulants remain the most potent and most predictably effective medications for treating ADHD in children with tics and they are well tolerated by the majority of patients. It does seem that upon initiation of therapy stimulants can worsen tics in some patients but this effect is temporary and tic severity usually returns to baseline or even declines from baseline within a few weeks50. The efficacy and good tolerability of the stimulant methylphenidate in children with tics and ADHD has been well documented in placebo-controlled trials51. Methylphenidate may be less likely to exacerbate tics than some other stimulant preparations, such as mixed amphetamine salts and dextroamphetamine52. Newer extended release preparations of methylphenidate tend to provide good coverage of ADHD during the school day and have been very well tolerated by patients with tics. Supplemental use of short-acting methylphenidate formulations can be useful, particularly for college students who have unpredictable study hours.

etiological role in causing tics. Children with documented streptococcal infections be treated with an appropriate course of antibiotics, but that treatment with chronic antibiotics or immune-modifying therapies like plasma exchange or intravenous immuneglobulin are not

Tic disorders secondary to CNS lesions or infection may improve with antipsychotic drug therapy. Tics are not commonly a disabling feature of neurodegenerative diseases such as Huntington's disease and antipsychotics have the potential to worsen overall motor function. In tardive phenomena patients including tics, discontinuation of the offending agent is suggested as first-line treatment and improvement can be attained with use of

Behavioral therapies have not been particularly beneficial for patients with disabling tics. Behavioral approaches have included operant conditioning models, rewarding tic suppression and discouraging disruptive tics and massed practice, repeated, voluntarily performance of a tic until fatigue occurs. Habit reversal therapy (HRT) can be considered if a single tic or small subset of tics is unduly disruptive or causing self-injury or pain. HRT trains patients to recognize their tics and to perform a volitional movement different from the tic each time a problem tic occurs. Open-label assessments have identified sustained benefit from HRT for up to 10months48. However, current trials will include raters blinded

In the school setting, approaches often include preferential classroom seating, extra time for tests, an opportunity to take tests in a separate quiet room and assistance with organizing schoolwork. An alpha-2-agonist, such as guanfacine, is a good first choice medication for patients experiencing problematic tics and ADHD because this type of drug can improve

For patients with tics and ADHD without response to behavioral therapies, options of treatment including the use of the norepinephrine reuptake inhibitor atomoxetine. This drug has documented efficacy for ADHD and has been associated with either no change or a slight reduction in tics49. Stimulants remain the most potent and most predictably effective medications for treating ADHD in children with tics and they are well tolerated by the majority of patients. It does seem that upon initiation of therapy stimulants can worsen tics in some patients but this effect is temporary and tic severity usually returns to baseline or even declines from baseline within a few weeks50. The efficacy and good tolerability of the stimulant methylphenidate in children with tics and ADHD has been well documented in placebo-controlled trials51. Methylphenidate may be less likely to exacerbate tics than some other stimulant preparations, such as mixed amphetamine salts and dextroamphetamine52. Newer extended release preparations of methylphenidate tend to provide good coverage of ADHD during the school day and have been very well tolerated by patients with tics. Supplemental use of short-acting methylphenidate formulations can be useful, particularly

clonazepam, clozapine, an alpha-2-agonist46 or reintroduction of an antipsychotic47.

justified based on existing evidence.

**4.5 Behavioral treatment**

both conditions.

**4.6 Treatment of ADHD**

**4.4 Treatment of secondary tic disorders**

to treatment assignment lacking in previous trials.

for college students who have unpredictable study hours.


**3. Discussion**

CD38 [5] is a transmembrane glycoprotein that is highly expressed on multiple myeloma cells and on normal lymphoid and myeloid cells albeit at low levels.

**89**

*Pleural Effusion Secondary to Multiple Myeloma: Is Daratumumab an Effective Treatment?…*

The mechanism of action is that of an ectoenzyme involved in the regulation of the intracytoplasmic concentration of calcium and of the catabolism of extracel-

The anti-CD38 fully human IgG1-k monoclonal antibody, daratumumab, carries out its cytotoxic effect through a series of mechanisms following binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct induction of apoptosis, which are its main mechanisms of action. Another effect of daratumumab recently described is its immunomodula-

A phase I/II dose escalation study in 104 patients with relapsed or refractory

Two phase [5] III studies are evaluating patients with relapsed or refractory disease; one of these studies is comparing daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone and the other is comparing daratumumab plus lenalidomide and dexamethasone versus lenalidomide and

Pending the final results of these studies, however, we want to underline how the CASTOR study (Velcade/dex vs. Dara/Velcade/dex) was interrupted early because at an interim analysis the study reached its final point with a ratio of very impressive risk of 0.39 in favor of the daratumumab arm. The POLLUX study (Rev/dex vs. Dara/Rev/dex) also showed similarly impressive results with a hazard ratio of 0.37 in favor of the Dara arm. Two further phase III studies are ongoing in patients with previously untreated multiple myeloma; one is comparing daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan, and prednisone), and the other is evaluating daratumumab plus lenalidomide and dexamethasone

We wanted to report this clinical case only to hypothesize a possible role of daratumumab in the treatment of extramedullary recurrences and above all its possible

The selection of resistant clones is known in the course of myeloma recurrence, but the negativity/masking of CD 38 in the pleural fluid could demonstrate the

Obviously we have no previous data, but the phenotypic analysis of the marrow

But to date, the treatment of extramedullary plasmacytoma remains a therapeu-

Despite significant progress in the treatment of multiple myeloma, the disease

The approval of promising new agents will undoubtedly improve outcomes for

Most likely, we should have performed a PET/CT at the onset of staging for a better evaluation of any extramedullary localization and perhaps choose different

Molecular biology studies certainly in the near future will help us better understand which forms are most at risk and perhaps will guide us better in

The most common adverse events were grade 3 or 4 pneumonia and

multiple myeloma evaluated the safety of daratumumab.

*DOI: http://dx.doi.org/10.5772/intechopen.95659*

lular nucleotides.

tory action.

thrombocytopenia.

dexamethasone.

with lenalidomide and dexamethasone.

overcoming of the pleural barrier by daratumumab.

or more aggressive therapeutic treatments.

tic challenge even in the era of new drugs.

remains incurable in a vast majority of patients.

therapeutic choices.

**4. Conclusion**

myeloma patients.

and peripheral blood is the same for the other antigens evaluated.

overcoming of the pleural barrier.

*Pleural Effusion Secondary to Multiple Myeloma: Is Daratumumab an Effective Treatment?… DOI: http://dx.doi.org/10.5772/intechopen.95659*

The mechanism of action is that of an ectoenzyme involved in the regulation of the intracytoplasmic concentration of calcium and of the catabolism of extracellular nucleotides.

The anti-CD38 fully human IgG1-k monoclonal antibody, daratumumab, carries out its cytotoxic effect through a series of mechanisms following binding to CD38, including antibody-dependent cell-mediated cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), antibody-dependent cell-mediated phagocytosis (ADCP), and direct induction of apoptosis, which are its main mechanisms of action.

Another effect of daratumumab recently described is its immunomodulatory action.

A phase I/II dose escalation study in 104 patients with relapsed or refractory multiple myeloma evaluated the safety of daratumumab.

The most common adverse events were grade 3 or 4 pneumonia and thrombocytopenia.

Two phase [5] III studies are evaluating patients with relapsed or refractory disease; one of these studies is comparing daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone and the other is comparing daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone.

Pending the final results of these studies, however, we want to underline how the CASTOR study (Velcade/dex vs. Dara/Velcade/dex) was interrupted early because at an interim analysis the study reached its final point with a ratio of very impressive risk of 0.39 in favor of the daratumumab arm. The POLLUX study (Rev/dex vs. Dara/Rev/dex) also showed similarly impressive results with a hazard ratio of 0.37 in favor of the Dara arm. Two further phase III studies are ongoing in patients with previously untreated multiple myeloma; one is comparing daratumumab plus bortezomib, melphalan, and prednisone with bortezomib, melphalan, and prednisone), and the other is evaluating daratumumab plus lenalidomide and dexamethasone with lenalidomide and dexamethasone.

We wanted to report this clinical case only to hypothesize a possible role of daratumumab in the treatment of extramedullary recurrences and above all its possible overcoming of the pleural barrier.

The selection of resistant clones is known in the course of myeloma recurrence, but the negativity/masking of CD 38 in the pleural fluid could demonstrate the overcoming of the pleural barrier by daratumumab.

Obviously we have no previous data, but the phenotypic analysis of the marrow and peripheral blood is the same for the other antigens evaluated.

Most likely, we should have performed a PET/CT at the onset of staging for a better evaluation of any extramedullary localization and perhaps choose different or more aggressive therapeutic treatments.

Molecular biology studies certainly in the near future will help us better understand which forms are most at risk and perhaps will guide us better in therapeutic choices.

But to date, the treatment of extramedullary plasmacytoma remains a therapeutic challenge even in the era of new drugs.

#### **4. Conclusion**

Despite significant progress in the treatment of multiple myeloma, the disease remains incurable in a vast majority of patients.

The approval of promising new agents will undoubtedly improve outcomes for myeloma patients.

*Multiple Myeloma*

restriction = 13%

*Phenotypic analysis on bone marrow blood.*

chains kappa and lambda

*Phenotypic analysis of pleural effusion.*

\*Therapy with Daratumumab

*Phenotypic analysis of pleural effusion.*

**Table 4.**

**Table 5.**

**Table 6.**

After one cycle of Dara Rd. therapy, for new reappearance of pleural effusion,

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence**

Result Mature lymphocytes = 20% Clonal myeloma plasma cells: CD 138+ CD 38++CD19-CD56+ bright, CD 45 low with kappa clonal

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence** Antigens studied: CD3, CD3/4, CD 3/CD8, CD19, CD16–56, CD117, CD 138, CD38, CD45, intracytoplasmatic

> Result Mature lymphocytes = 60%

**Immunophenotypic study in flow cytometry Method used direct immunofluorescence**

> RESULT Mature lymphocytes = 40%

Clonal myeloma plasma cells: CD 138+ CD 38-, CD56+, CD 45 + heterogeneous, cy kappa + = 10%

Antigens studied: CD19, CD 138, CD38, CD 56, chains kappa and lambda

While the plasma cells are absent for the reevaluation of the phenotypic study on

the patient underwent thoracentesis, this time by performing the phenotypic

Clonal myeloma plasma cells: CD 138+ CD 38-\*, CD56 + bright, cyvs38c+, CD 19- = 7.5%

After four cycles of therapy, we repeated PET/CT that was unfortunately

The PET/CT showed persistence of a large area of hyperaccumulation of the tracer in coincidence of pathological tissue from D3 to L5 that incorporates the

Persistence of pathological accumulation in the anterior mediastinum, in the pleuro-pericardial region in increase compared to the previous examination, extending from the xiphoid to the anterior costophrenic recess, area of hyperaccumulation in the right parasternal and at the level of the mediastinal pleura close to the ascending aorta. Despite the progression of disease, the CD38 negativity remained to the pheno-

CD38 [5] is a transmembrane glycoprotein that is highly expressed on multiple

myeloma cells and on normal lymphoid and myeloid cells albeit at low levels.

peripheral blood, we continued the treatment until the fourth cycle.

**88**

**3. Discussion**

analysis (**Table 5**).

compatible with persistence of disease.

posterior mediastinal structures in its course.

Daratumumab is a monoclonal antibody that is now approved for treatment of multiple myeloma patients and has shown significant response in the real-world setting.

Our case illustrates the potential to overcome the pleural membrane and therefore a possible role also in the treatment of extramedullary localizations of multiple myeloma.


**2.1 Virtual verses real environments**

Milgram's Reality-Virtuality Continuum defined in 1994 describes a continuum that spans space from the real environment into a pure virtual environment. In between those end points there are spaces of augmented reality that are closer to the real environment and /or augmented virtuality that are closer to the fully virtual environment (Milgram & Kishino, 1994). From the virtual reality perspective an environment is presented to the end user that can either contain totally virtual (computer-generated) content or be somewhere in between thereby containing relative levels of realism or actual existent artefacts not computer generated.

There is a natural merging (see Figure 1) of the two concepts where the purely virtual environment meets the natural or real environment. In essence, virtual reality evolves from systematically-generated environmental content that is presented to the end-user and gradually adds real world content while augmented reality (from an opposing perspective) evolves from the real world and gradually infuses digital content into the end-users presentation.

Fig. 1. Converging Realities: Real vs. Virtual

In a real environment we might have a live meeting with all the participants in the room in the same place at the same time to discuss or work on some kind of business problem. Of course this has become more and more impractical as people are geographically farther and farther apart because of workforce globalization and decentralization. To respond to the need to communicate across geographic boundaries we saw the introduction of technologies like Skype, live meetings online, instant message usage or even some kinds of social networking that involved either synchronous or asynchronous communications. The use of these tools has now become ubiquitous in the workplace as businesses find one or more combinations of these communications tools, which can be used to smooth and speed up communication and business processes.

We have rapidly developed beyond even these latest technologies now and are seeing rapidly evolving; newer ones emerge that include virtual reality and augmentation tools. While these new virtual reality and augmentation tools, allow for more depth and

and/or augmented reality use then is to better understand the characteristics between the two extremes of 3D virtual reality and real world reality with augmented reality spanning

Milgram's Reality-Virtuality Continuum defined in 1994 describes a continuum that spans space from the real environment into a pure virtual environment. In between those end points there are spaces of augmented reality that are closer to the real environment and /or augmented virtuality that are closer to the fully virtual environment (Milgram & Kishino, 1994). From the virtual reality perspective an environment is presented to the end user that can either contain totally virtual (computer-generated) content or be somewhere in between thereby containing relative levels of realism or actual existent artefacts not computer

There is a natural merging (see Figure 1) of the two concepts where the purely virtual environment meets the natural or real environment. In essence, virtual reality evolves from systematically-generated environmental content that is presented to the end-user and gradually adds real world content while augmented reality (from an opposing perspective) evolves from the real world and gradually infuses digital content into the end-users

In a real environment we might have a live meeting with all the participants in the room in the same place at the same time to discuss or work on some kind of business problem. Of course this has become more and more impractical as people are geographically farther and farther apart because of workforce globalization and decentralization. To respond to the need to communicate across geographic boundaries we saw the introduction of technologies like Skype, live meetings online, instant message usage or even some kinds of social networking that involved either synchronous or asynchronous communications. The use of these tools has now become ubiquitous in the workplace as businesses find one or more combinations of these communications tools, which can be used to smooth and speed up

We have rapidly developed beyond even these latest technologies now and are seeing rapidly evolving; newer ones emerge that include virtual reality and augmentation tools. While these new virtual reality and augmentation tools, allow for more depth and

the spectrum in between.

generated.

presentation.

**2.1 Virtual verses real environments**

Fig. 1. Converging Realities: Real vs. Virtual

communication and business processes.

expression in communication thereby facilitating increasingly effective communication processes like training programs and client communications, users are finding that they are often costly to implement and fraught with more risk factors than the earlier technologies like Skype and instant messaging (IM). For example, there is a steeper learning curve for use in VR technologies and there are risks associated with storage of information that may be considered meeting or business communications required by law to be housed and accessible. Additionally there may be significant upfront costs for software development or implementation that businesses don't anticipate. This does not mean that use of VR technologies should be avoided by businesses as effective implementation can have far more advantages then disadvantages when they are properly planned and implemented.

We are now beginning to see more extensive adoption by Universities, hospitals and medical companies as well as industry of these VR environments and augmented reality technologies. However, there seems to be little consideration given to the actual choice and implementation of the technologies with regard to their place on the continuum, their longterm viability and evolution, and the requisite return on investment (ROI) of implementation and use. By placing technologies on the proposed ROTATOR continuum and evaluating the goals and needs of an organization, companies can better plan and more efficiently use limited resources for implementation and adoption of VR and augmented technologies in business applications. Additionally, use of the ROTATOR model should aid in illuminating any potential risks associated with their implementation depending on the company and application. Use of the ROTATOR model can also shed light on possible risks associated with use and maintenance of VR and should help minimize risks based on planned and appropriate implementation policies and procedures.


**1. Introduction**

Fibre metal laminates (FML) are hybrid materials comprised of alternating metal sheet and fibre composite layers, that can be bonded in distinct sequences. Unlike hybrid multi-material stacks, in which thicker composite and metal layers are simply stacked and fastened by means of rivets, adhesive joints or bolted connections, the FML layers' thickness is typically less than 1 mm and consolidated through hot-curing cycles [1,2]. The superior performance of the laminate combination when compared to the isolated composite and metallic materials is highly relevant in structural applications, such as the transportation sector, where high specific strength is required, while also maintaining good impact and bending resistance [3,4]. Moreover, when such materials are adopted in the aviation industry, energy savings of approximately 30% are achieved [5,6]. Effectively illustrating the FML expression in aircraft applications and its increasing adoption [7] is the excellent fatigue strength, damage tolerance and overall durability of these materials, due to fibres acting as a barriers, thus delaying metal crack propagation [8]. Furthermore, worth mentioning is the good thermal insulation, corrosion and flame resistance properties of such materials [7,9].

FML can be currently manufactured in near-net shape geometries, such as large fuselage panels and stringers in aeronautics and also complex-shaped floor assemblies in the automotive industry [10]. Nonetheless, the fastening of multiple components relies

**Citation:** Marques, F.; Silva, F.G.A.; Silva, T.E.F.; Rosa, P.A.R.; Marques, A.T.; de Jesus, A.M.P. Delamination of Fibre Metal Laminates Due to Drilling: Experimental Study and Fracture Mechanics-Based Modelling. *Metals* **2022**, *12*, 1262. https:// doi.org/10.3390/met12081262

Academic Editor: Francisco J. G. Silva

Received: 30 May 2022 Accepted: 23 July 2022 Published: 27 July 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

mostly on mechanical joints, such as rivets or bolts, which can amount up to 3 million in a commercial aircraft [11]. Hole-making is, therefore, intensively performed for parts assembly, enabling riveting of aircraft panels such as the fuselage, wings and stabilizers [12,13] and despite the existent non-conventional feasible alternatives, such as laser machining and water-jet cutting, drilling remains the most employed technique [14]. The heterogeneity of FML allied to the highly abrasive properties of fibre reinforcement make drilling operations a challenging task. Their success may be compromised by simultaneous occurrence of (i) the well-known entry (peel-up) and exit (push-out) delamination, matrix thermal damage, fibre pull out and formation of abrasive fibre particles in composite layers as well as (ii) strain-hardening, continuous chip formation and thermal softening in the metal layers [15–17].

The lack of research regarding drilling operations on FML is evidenced by Bonhin et al. [16], especially in what concerns aluminium alloy (AA) and carbon-fibrereinforced polymers (CFRP) configurations with thermoset matrices. To the authors' knowledge, no studies have been performed in AA-CFRP laminates with thermoplastic matrices. The enhanced sustainability of the thermoplastic polymers (promoted by their improved recyclability) has encouraged the increasing usage of thermoplastic-based FML in relevant sectors, such as the aeronautical industry. Ekici et al. [18] experimentally analysed hole quality and delamination on AA-CFRP material samples, using Physical Vapour Deposition (PVD)-coated and uncoated drills. Despite the little number of holes each drill performed, the authors found that the uncoated condition (carbide) outperforms (PVD) coated drills in terms of entry delamination and hole nominal size. Sridhar et al. [19] systematically analysed the influence of operative conditions on drilling performance indicators such as thrust force and roughness, being able to identify ideal cutting parameters for AA-CFRP laminates using a conventional drill geometry. Despite the more intricate process kinematics of helical milling when compared to drilling, Bolar et al. [20] report advantages of the former, concerning cutting load, thermal impact, chip evacuation and hole nominal size. The implementation of analytic/numerical models capable of delamination prediction is of key relevance for both FML processing/assembly and drill tool manufacturers. Although some work can be found for CFRP materials, no data are available regarding these novel AA-CFRP material configurations. Feito et al. [21] compare the predictability of both complete simulation of a drilling operation with a simplistic model, in which the drill acts as a punch that pierces the laminate. The latter yields very reasonable cost-effective results with slight overestimation of delamination factor, setting upper limits that are highly valuable as support decision techniques.


**4. Application to coal-to-liquids**

A sensible polygeneration facility, as described earlier [1] where both power generation and liquid fuels/chemicals are made, requires that the co-gasification process produce a syngas that is typically rich in H2 and CO only. A portion of this syngas would be directed to an IGCC unit for power generation and the rest to a gas-toliquids process. This was shown above that possible operational regions would be on the line connecting thermally balanced point G and the exothermic partial oxidation of methane (r1) – refer to **Figure 3**. Along this line of operation, the gasification reactions are inherently exothermic and it is preferred to operate closer to point G as the reactions are not highly exothermic (for temperature control in the gasifier) and less CH4 (more coal) is used overall. However, this also means the syngas composition does not have a high H2-content for the downstream gas-to-liquids conversion. This section covers some of the strategies employed to obtain a syngas feed composition suitable for methanol production as given by Higman & van der Burgt [10] as an example and the details are provided in **Table 3** below. It is noted that this syngas requires the presence of up to 3.5% CO2 for the catalyst to operate optimally. While traditional methods would deploy an additional Water-Gas-Shift reactor to correct the H2:CO ratio, in this work it is not implemented due to the additional equipment cost, raising of additional steam and the CO2 byproduct created directly by the WGS reaction and indirectly by raising steam.

The thermally balanced point at G represents the maximum H2 that can be produced from the co-gasification process where the syngas product temperature equals the feed temperature. Generally, a real gasification process will operate just off of this point and into the "hot" exothermic side [2]. The methanol feed, point S, is shown in the ternary diagram, **Figure 4**. The task for the designer is to obtain this feed point starting from point G and requires either the addition of excess hydrogen and or the removal of CO2 to obtain the final methanol feed composition. Several scenarios are provided and discussed where the choice of additional equipment for WGS was avoided.

#### **4.1 Excess hydrogen from electrolysis**

To achieve the methanol feed point (see **Figure 4**) from point G, the addition of H2 and CO2 is necessary. Microsoft Excel's solver tool is used to calculate the amount of

**Table 3.** *Methanol synthesis feed composition [2].*

**Figure 4.** *Target co-gasification points (P, Q) and methanol feed (S).*

H2 and CO2 required to achieve the correct H2:CO ratio and CO2 composition. The target co-gasification reaction (including additional steam for equilibrium consideration – See Section 3.2) is thus determined to be:

$$\begin{aligned} &\text{2CH}\_{0.75}\text{O}\_{0.16} + \text{1.4285O}\_{2} + \text{1.7118CH}\_{4} + \text{1.6543H}\_{2}\text{O} \\ &\rightarrow 2.406\text{5CO} + \text{3.7986}H\_{2} + 0.3053\text{CO}\_{2} + \text{1.6543H}\_{2}\text{O} \end{aligned} \tag{6}$$

This output is represented by point P on **Figure 4** and represents the syngas operating point from the exit of the co-gasification process. The final methanol feed is obtained by the addition of excess H2 (such that H2:CO = 2.44 as required in **Table 3**) obtained from a CO2-free source such as solar-electrolysis of water. The choice of CO2-free H2 introduces the possibility of including renewable resources, to minimise additional CO2 production, into existing fossil fuel based facilities and in this particular case indicates the minimum amount of renewable H2 needed for a co-gasification process to exist. For this Bosjesspruit coal the amount of H2 needed, to obtain the final methanol feed from point P, represents the minimum amount of renewable H2 needed for co-gasification with methane. Point P may also be implemented for IGCC application as it has a relatively high HHV and is lowest CO2 in the syngas.

### **4.2 Obtaining methanol feed by removal of CO2 from Co-gasification process**

Another possibility of obtaining the methanol feed from point G, excluding water electrolysis, is by operating the co-gasification process such that some CO2 is allowed to be formed allowing the H2:CO to correct itself internally (no external WGS reactor). This is represented by the point Q on **Figure 4**. From this point, after cleaning the syngas for contaminants (Sulphur, particulates etc) some CO2 (1.05) is removed to obtain the final methanol feed composition as required. The balanced reaction from the co-gasification process (including additional steam for equilibrium) is thus:

$$\begin{aligned} &2\,\text{CH}\_{0.75}\text{O}\_{0.16} + 2.52\,\text{65O}\_{2} + 2.8549\,\text{CH}\_{4} + 12\,\text{H}\_{2}\text{O} \\ &\to 2.4967\text{CO} + 6.0848\,\text{H}\_{2} + 1.3582\,\text{CO}\_{2} + 12\,\text{H}\_{2}\text{O} \end{aligned} \tag{7}$$

#### **4.3 Methanol from traditional gasification of Bosjesspruit coal**

The analysis for traditional gasification of Bosjesspruit with steam and oxygen has been done elsewhere [8] and the important thermally balanced reactions are provided in **Table 4** below:

**Table 4.**

*Thermally balanced reactions for traditional Bosjesspruit gasification [8].*

Reaction M and N are used as basis to determine the gasification operation point that is exothermic and lies on the line that connects the final methanol feed and CO2 point. This is required as the final step requires the removal of CO2. **Figure 4** shows the line M-N as well as the gasification point R for the coal only system. The Gibbs Free reactor was used on Aspen Plus at 1700 K and 50 bar to determine the equilibrium reaction (amount of H2O needed for equilibrium). The resulting overall reaction, represented by R (including excess steam for equilibrium), is as follows:

$$\begin{aligned} &\text{CH}\_{0.75}\text{O}\_{0.16} + 0.665\text{O}\_{2} + 0.2528\text{H}\_{2}\text{O} + 6.1\text{H}\_{2}\text{O} \\ &\rightarrow 0.2576\text{CO} + 0.6278\text{H}\_{2} + 0.7424\text{CO}\_{2} + 6.1\text{H}\_{2}\text{O} \end{aligned} \tag{8}$$

### **5. Comparison of processes for poly-generation operation**

The three methods to produce syngas for the poly-generation system was described where the H2:CO ratio required for methanol production was obtained either by co-gasification of coal and methane then adding H2 from electrolysis using renewable energy (4.1), or from co-gasification with CO2 removal (4.2) or from the traditional steam-oxygen gasification (4.3) of the same Bosjesspruit coal from a South African mine.

The process reactions are summarised below normalised (per mol of CO) in the syngas produced:

Co-gasification with H2 addition from Electrolysis

$$\begin{aligned} &0.4156 \text{CH}\_{0.75} \text{O}\_{0.16} + 0.5936 \text{O}\_2 + 0.7112 \text{CH}\_4 + 0.6875 \text{H}\_2\text{O} \\ &\rightarrow \text{CO} + 2.4371 \text{H}\_2 + 0.1269 \text{CO}\_2 + 0.6875 \text{H}\_2\text{O} \end{aligned} \tag{9}$$

Co-gasification with CO2 removal:

$$\begin{aligned} &0.4005CH\_{0.75}O\_{0.16} + 1.0119O\_2 + 1.1435CH\_4 + 4.806H\_2O \\ &\rightarrow CO + 2.4371H\_2 + 0.5441CO\_2 + 4.806H\_2O \end{aligned} \tag{10}$$

#### **Table 5.**

*H2O required and CO2 produced (per Mol of CO) for various processes.*

Traditional CTL:

$$\begin{aligned} &3.8819CH\_{0.75}O\_{0.16} + 2.5815O\_2 + 0.9814H\_2O + 23.68H\_2O \\ &\rightarrow CO + 2.437H\_2 + 2.8819CO\_2 + 23.68H\_2O \end{aligned} \tag{11}$$

**Table 5** compares the various processes (per mol of CO) against the amount of excess steam required for equilibrium and the excess CO2 produced.

As seen in **Table 5**, the best case scenario which requires minimal steam and does not produce excess CO2 is from the co-gasification of coal with methane with the addition of H2 from renewable-electrolysis. It is noted that the small amount of CO2 in the methanol feed (or gasification product) is a requirement for optimal catalyst performance and requires the co-gasification process to operate away from the preferred H2-CO line where equilibrium is favoured. Hence all operations in the ternary diagram that operate away from the H2-CO line will invariably require excess steam and hence produce excess CO2 – albeit without a separate WGS reactor.

The traditional CTL process is by far the worst in performance as it produces the most CO2 and requires the most excess steam. When comparing the two nonelectrolysis (for high H2) processes it is evident that the co-gasification of coal with methane is also superior to the traditional CTL process. Here, the excess steam required for co-gasification process is about 5 times less and up to 7 times less CO2 is emitted than the traditional CTL process. This is an important result for re-looking at the way traditional CTL is done in South Africa and other developing countries intending to use low grade coal for power generation and or liquids fuel/chemicals production.

### **6. Conclusions**

The co-gasification of coal and methane has been studied from a fundamental understanding of basic mass and energy balances for the purposes of producing syngas for polygeneration facilities where power and liquid fuels are required. Here a South African coal from Bosjesspruit mine is studied in various process routes, namely co-gasification with methane with H2 addition from water electrolysis using renewable energy, co-gasification with CO2 removal and the traditional gasification of coal using steam and oxygen. An important result showed that the poor quality of the Bosjesspruit coal requires the co-feeding of methane in the gasification and polygeneration process to produce a syngas rich in H2-CO ready for IGCC purposes or further treated for liquid fuels/chemicals production. This coal would otherwise be only used for liquid fuels production resulting in high CO2 emissions and with large requirements for water in the process.

Moreover, a technique of graphical analysis for co-gasification of coal with methane was presented forming the basis for decision making in poly-generation facilities. This allows for the quick screening of coal types as well as strategies required to design co-gasification processes. Lastly, this analysis is independent of the gasification reactor type allowing designers to narrow the options required for their purposes.


**3. Results and Discussion**

## *3.1. Morphologies of Nanofibrous Films*

Figure 1 shows the pictures of each film and the morphologies and diameter distributions of the solution blowing spun GA, PA66 films and GA/PA66 films with various weight ratios (2/1, 1/1 and 1/2 *w*/*w*). The average diameter of pure GA fibers was over 1000.0 nm, and the average diameter of pure PA66 fibers was 223.2 nm; with the weight ratio of PA66 increased from 1:2 to 2:1, the diameters increased from 172.3 nm to 322.1 nm. It can be observed that the addition of PA66 resulted in a significant reduction in fiber diameter, thus creating a denser network structure, which could improve the water vapor barrier performance. This was probably due to the fact that the addition of PA66 reduced the viscosity of the solution and promoted the elongation of the nanofibers, resulting in a thinner diameter [12]. In a similar study of modification of gelatin by Meng et al. [22], they found the average diameter of GA/poly (lactic-co-glycolic acid) (PLGA) nanofibers also decreased with the addition of PLGA. Moreover, the pure GA fibers were straight, while after the addition of PA66, the GA/PA66 composite fibers showed a curly appearance. In addition, the usage of pure gelatin solution for spinning resulted in a large number of droplets, so the film had hard lumps, leading to low solution utilization; while after the introduction of PA66, the droplets were significantly reduced and the phenomenon of hard lump formation disappeared, making the solution utilization improve. Therefore, this indicates that the addition of PA66 led to the improvement of GA spinnability during the SBS fabrication of nanofiber films. Like other spinnable polymers, nylon may increase the viscoelasticity of the gelatin-containing precursor solution, allowing for easier fiber formation [35].


**7. The usefulness of transthyretin in the human clinical practice**

#### **7.1. Nutritional marker**

Transthyretin may be used as important diagnostic tool for various disease conditions in humans, but is more often used as an indicator of malnutrition [62]. Several studies have shown a correlation between the concentrations of TTR and nutritional status [63, 64]. According to Ingenbleek and Young [14], low TTR concentrations are associated with inadequate protein calorie consumption or malnutrition. However, TTR may not serve as a reliable nutritional marker in patients with high concentrations of C-reactive protein (CRP), because of the activation of inflammatory responses [65]. This may complicate the use of TTR as an indicator of nutritional status, since inflammatory processes can lead to the decrease of serum TTR concentrations (negative acute phase protein) [66]. The CRP/TTR ratio may be a useful index in these cases to differentiate inflammatory states from protein malnutrition [67]. Very high ratios (>20) are indicative of acute phase response rather than protein malnutrition, while mild inflammatory processes may be accompanied by approximately a 10-fold increase in the concentrations of CRP and in CRP/TTR index values [6]. However, an inflammatory and nutrition index in animals was not yet established.

Surprisingly, extreme cases of starvation, including anorexia nervosa, have not been associated with a decrease of TTR concentrations. Nova et al. [68] reported normal values of transthyretin in patients with anorexia nervosa, which were comparable to values found in controls and did not differ after nutritional intervention. Barbe et al. [69] stated also that transthyretin concentrations in the majority of anorectic patients did not differ from those in control subjects, even in the presence of severe cachexia, but increased after weight gain. On the other hand, Gendall et al. [70] found lower concentrations of TTR in women with bulimia nervosa. These contradictory data indicate that further studies are needed to determine the effect of the aforementioned generalized malnutrition states on the values of transthyretin.

#### **7.2. Disease marker**

As transthyretin (prealbumin) belongs to negative acute phase proteins, its serum concentrations may be affected by many disease conditions, including trauma, inflammatory diseases, infections or malignancy (**Table 1**). Patients with severe sepsis or multiple injuries often have very low concentrations of TTR, related to severe acute phase response [71]. Studies have suggested that TTR may be a sensitive marker for the diagnosis of patients with liver cell damage, liver cirrhosis or hepatocellular carcinoma, reflecting the impaired liver synthetic function [72, 73]. Hutchinson et al. [74] and Yasmin et al. [75] found significantly lower concentrations of TTR in various types of chronic liver diseases when compared with controls with no impairment of liver functions. Moreover, Liu et al. [72] reported significantly lower TTR values in patients who died compared to survivors suggesting its role in predicting the prognosis of patients with decompensated liver cirrhosis.

In humans, for the measurement of concentrations of TTR, it was recommended to take blood samples after 15–20 min in the sitting position [6]. Lower values are expected in bedridden patients, while standing position prior to blood sampling may result in higher concentrations.

Transthyretin may be used as important diagnostic tool for various disease conditions in humans, but is more often used as an indicator of malnutrition [62]. Several studies have shown a correlation between the concentrations of TTR and nutritional status [63, 64]. According to Ingenbleek and Young [14], low TTR concentrations are associated with inadequate protein calorie consumption or malnutrition. However, TTR may not serve as a reliable nutritional marker in patients with high concentrations of C-reactive protein (CRP), because of the activation of inflammatory responses [65]. This may complicate the use of TTR as an indicator of nutritional status, since inflammatory processes can lead to the decrease of serum TTR concentrations (negative acute phase protein) [66]. The CRP/TTR ratio may be a useful index in these cases to differentiate inflammatory states from protein malnutrition [67]. Very high ratios (>20) are indicative of acute phase response rather than protein malnutrition, while mild inflammatory processes may be accompanied by approximately a 10-fold increase in the concentrations of CRP and in CRP/TTR index values [6]. However, an inflam-

Surprisingly, extreme cases of starvation, including anorexia nervosa, have not been associated with a decrease of TTR concentrations. Nova et al. [68] reported normal values of transthyretin in patients with anorexia nervosa, which were comparable to values found in controls and did not differ after nutritional intervention. Barbe et al. [69] stated also that transthyretin concentrations in the majority of anorectic patients did not differ from those in control subjects, even in the presence of severe cachexia, but increased after weight gain. On the other hand, Gendall et al. [70] found lower concentrations of TTR in women with bulimia nervosa. These contradictory data indicate that further studies are needed to determine the effect of the

As transthyretin (prealbumin) belongs to negative acute phase proteins, its serum concentrations may be affected by many disease conditions, including trauma, inflammatory diseases, infections or malignancy (**Table 1**). Patients with severe sepsis or multiple injuries often have very low concentrations of TTR, related to severe acute phase response [71]. Studies have suggested that TTR may be a sensitive marker for the diagnosis of patients with liver cell damage, liver cirrhosis or hepatocellular carcinoma, reflecting the impaired liver synthetic function [72, 73]. Hutchinson et al. [74] and Yasmin et al. [75] found significantly lower concentrations of TTR in various types of chronic liver diseases when compared with controls with no impairment of liver functions. Moreover, Liu et al. [72] reported significantly lower

aforementioned generalized malnutrition states on the values of transthyretin.

**7. The usefulness of transthyretin in the human clinical practice**

matory and nutrition index in animals was not yet established.

**7.1. Nutritional marker**

56 Pathophysiology - Altered Physiological States

**7.2. Disease marker**

Pneumonia in children caused by *Mycoplasma pneumonia* was also associated with lower TTR concentrations compared to a healthy control group [76]. Similarly, Luo et al. [77] recorded reduced TTR values in patients with tuberculosis and lung cancer, while the serum concentrations of TTR were lower in patients suffering from tuberculosis than in patients with lung cancer. Moreover, the changes in TTR values were in accordance with the therapeutic effects of anti-tuberculosis drugs, which may be useful by the monitoring of therapy in these patients. However, seeing that nutritional imbalance is very common in patients with tuberculosis and after chemotherapy in subjects with lung cancer, poor performance status should be taken into consideration when interpreting serum TTR values in these patients and should be further investigated.

The concentrations of transthyretin may be altered also by thyroid diseases, especially endemic goitre [6]. Low concentrations of TTR were found by Vergani et al. [78] in patients with untreated thyrotoxicosis, but the values recorded in the majority of cases with untreated hypothyroidism were within normal range. The concentrations of transthyretin were measured also by Ishida et al. [79] in patients with various thyroidal states. In patients with untreated hyperthyroidism, markedly low serum TTR values were found, but were normalized by treating with anti-thyroid drug. Similarly, the aforementioned authors observed markedly low TTR concentrations in patients with subacute thyroiditis, but in patients with hypothyroidism the TTR values were within the normal range.

Changes in the concentrations of TTR were evaluated also in subjects affected by proteinlosing enteropathy, which is characterized by marked losses of serum proteins through the bowel wall into the gastrointestinal tract resulting in hypoproteinaemia [80]. Despite hypoproteinaemia, Takeda et al. [81] observed TTR values within the normal range in patients with protein-losing gastroenteropathy. This phenomenon may be explained by the slightly increased production of rapidly turned-over proteins (including TTR) by the liver in response to the gastrointestinal losses.

**Table 1.** Abnormalities in the serum concentrations of transthyretin and associated diseases (adapted from Ref. [6]).

Increased serum concentrations of transthyretin are typically associated with chronic renal failure, presumably due to the decreased tubular uptake and degradation of RBP [82]. Cano [83] stated also that chronic renal failure may result in an increase of serum TTR concentrations, but these elevated TTR values during renal insufficiency are secondary to the lack of RBP degradation in renal tubules and to the subsequent increase in TTR. The concentrations of TTR may rise also during corticosteroid therapy and administration of anabolic steroids, as well as in patients using anti-inflammatory agents [6, 84]. Young et al. [85] found increased concentrations of TTR in ill-surgical patients receiving anabolic steroids, which may enhance amino acid and water uptake by tissues and increase the utilization of fat. Increased TTR concentrations may be seen in acute alcohol intoxication, caused by the leakage of proteins from damaged hepatic cells [86]. Transthyretin was shown to be upregulated also in Hodgkin´s lymphoma and pancreatic cancer [11, 87].

dodecyl-polyacrylamide gel electrophoresis with subsequent Western blot analysis [98]. Piechotta et al. [99] investigated the serum concentrations of TTR in dogs with nonthyroidal illness (including neoplasia, allergy, cardiac disease, gastrointestinal disease, parasitism and hepatic disease) and low T4 concentrations compared with those in healthy dogs and dogs with primary hypothyroidism. They found significantly decreased serum concentrations of TTR in dogs with nonthyroidal illness (24.8 mg/L) compared with its concentration in hypothyroid dogs (41.1 mg/L). On the other hand, significant differences in TTR values were not found between hypothyroid and healthy dogs, or between dogs with nonthyroidal illness and healthy dogs. In the study presented by Raila et al. [100], low concentration of TTR was found in a young dog with chronic renal failure, probably caused by its increased urinary excretion. Changes in the serum concentrations of TTR were observed also in rats during proteinenergy malnutrition [62]. The mean value of transthyretin in healthy pig serum obtained by Campbell et al. [54] was 302 ± 8 mg/L, but following *Streptococcus suis* type 2 infection the concentrations markedly decreased. In horses, transthyretin was identified using immunodiffusion technique, but the study was performed many years ago [101]. Establishing a quantitative method, such as an enzyme immunoassay, to measure the concentrations of TTR may be useful also in horses. In cattle, there are very little published reports about the usefulness of transthyretin in the diagnosis of diseases. Our preliminary results suggest lower concentrations of TTR in diarrhoic calves at the age of 1 month compared with healthy animals at the same age. Similarly, *Mycobacterium avium paratuberculosis* seropositive cows showed lower TTR values than those obtained in healthy cattle (unpublished data). Chang et al. [102] have isolated and sequenced transthyretin not only in humans and other mammalian species but also in birds, including emu, chicken, ostrich and pigeon. This study showed that TTR has greater than 98% homology and has a very similar binding pattern across species. However, additional studies should be done to determine the effect of various diseases on the serum

Transthyretin in the Evaluation of Health and Disease in Human and Veterinary Medicine

http://dx.doi.org/10.5772/intechopen.68725

59

Presented data suggest that transthyretin may contribute to the evaluation of health state and diagnosis of some diseases also in animals. Changes in serum concentrations of TTR may be indicative of inadequate nutrient intake and may serve as an additional diagnostic tool for clinicians in the evaluation of some pathological conditions. It may be used as an integral part of the overall health assessment or in hospitalized animals to evaluate their nutritional status during the treatment and recovery. Low serum TTR concentrations may be considered a sign

This work was supported by Scientific Grant Agency of Ministry of Education SR Nos.

of increased risk of malnutrition, requiring further nutritional assessment.

concentrations of TTR in animals.

**9. Conclusions**

**Acknowledgement**

1/0154/15 and 1/0486/17.

#### **7.3. Prognostic indicator**

Several studies evaluated the significance of TTR as a prognostic biomarker and suggested that low concentrations may be associated with poor prognosis [88, 89]. Transthyretin was found as a prognostic factor for treatment outcomes and/or nutritional status of colon, oesophagus, ovarian and lung cancers [90–92]. In these studies, the concentrations of TTR correlated with response to treatment and clinical outcomes. Ho et al. [93] reported that low values of TTR may serve as prognostic factor for overall survival in cancer patients. However, the interpretation of its values in patients with systemic inflammatory response may be challenging. In these conditions, further clinical assessments and laboratory assays may be helpful, including markers of inflammation such as C-reactive protein, erythrocyte sedimentation rate or white blood cell number.

According to Cheng et al. [94], TTR has also been identified as a significant predictor of clinical outcomes after surgical intervention. Therefore, it may be used as part of the blood screening completed before surgery to determine pre-surgery health. Low TTR values before surgery may be associated with an increased risk of complications, including infections or pneumonia. Devakonda et al. [88] reported that surgery patients with low preoperative TTR values had significantly longer hospital duration of stay and longer intensive care unit duration of stay. Moreover, low concentrations of transthyretin were associated with higher rates of infectious complications, mortality and other surgical complications [95, 96].