Distribution of mean electric conductivity index frequencies.
\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
Modern academic research and clinical practice avail of various tomography systems of electrical impedance diagnostics [1–7]. Electrical impedance mammography (EIM) represents one of the most rapidly developing imaging modalities designed for breast cancer detection [8–22].
EIM belongs to noninvasive techniques of image creation. It measures electromagnetic phenomena and assesses their changes via external scanning.
Since electric current distribution is not limited by two-dimensional plane, the data obtained reflect the change of electric conductivity in three-dimensional space, thus providing for the layer-by-layer image of the object. Based on the reconstruction of internal distribution from a set of external points, EIM refers to tomography techniques of image construction.
There exist two types of techniques creating tomographic images: local and nonlocal. The local technique implies the passage of one direct ray through the body causing the creation of one pixel in the image. The pixel value depends solely on the substance that the ray meets on its way. X-ray, magnetic resonance, and positron emission all belong to local or hard-field tomography techniques.
The nonlocal technique is characterized by all points on the object affecting the measurement result. This is the so-called cross measurement. The pixel value depends both on the object structure and the structure of the surrounding tissues. Electrical impedance, ultrasound reflection, and optical tomography belong to the category of nonlocal or soft-field tomography techniques.
Thus, EIM is a noninvasive technique featuring nonlocal properties of tomographic image creation.
Modern electrical impedance mammography systems, both commercial and experimental, differ in the following characteristics: alternating current parameters, electrode number and arrangement configuration, method of data collection, and algorithm of image reconstruction. Electrical impedance mammograph, MEIKv5.6, developed and manufactured by “PKF “Sim-technika,” Russia was used for the creation of electrical impedance images [22].
The mammograph has the following significant characteristics:
Noninvasive technology of image creation
3D-tomography system
Form of “soft-field” tomography
“Nonlocal” method of tomographic image creation
50 kHz frequency and 0.5 mA amplitude alternating current
Planar positioning of electrodes
256 electrode panel
Cross-sectional approach to data collection. The cross-sectional approach is a variation of the complementary method, when all electrodes are involved in measurement pairwise.
Back-projection method as an algorithm of image reconstruction
Static image
Quantitative diagnostic information
The analysis of data obtained via the MEIKv5.6 electrical impedance mammograph allowed to pick out the following diagnostic categories:
Structural percentile limits and mammary gland structure
Age-related percentile limits and age-related electric conductivity
Outlier statistics and early detection of breast cancer
D-statistics and distorted mammographic scheme in the presence of breast cancer
Diagnostic table and EIM image evaluation
The analysis in hand is based on data acquired from 1632 electromammographic examinations of normal women of various age groups. It is essential that the test groups contained about the same number of women: 380 women aged 20–30, 428 women aged 31–40, 449 women aged 41–50, and 375 women aged 51–60. The analysis of the electrical impedance mammograms was carried out “blindly”, i.e., without taking the women\'s age into account.
The fluctuations of the electrical impedance index values made from 0.01 standard units, the lower range value, to 0.68 standard units, the upper range value. To define the structure of electric conductivity index distribution, we extracted eight property ranges with the 0.09 step and calculated the number of observations in each range (Table 1).
Electric conductivity index | Number of observations |
---|---|
0.05–0.14 | 0 |
0.15–0.24 | 67 |
0.25–0.34 | 279 |
0.35–0.44 | 471 |
0.45–0.54 | 435 |
055–0.64 | 299 |
0.65–0.74 | 75 |
0.75–0.84 | 6 |
Total | 1632 |
Distribution of mean electric conductivity index frequencies.
Figure 1 shows data distribution by the electric conductivity index. The conductivity index mean value constituted 0.29, median, and 0.26, mode.
Histogram of mean electric conductivity index frequency distribution.
A bell-shaped curve, similar mean, median, and mode values allow us to declare the quantitative variable (electric conductivity index in this case) distribution as normal. Mean value and standard deviation are generally used for normal distribution characterization. We see the implementation of the 10th, 25th, 50th, 75th, and 90th percentile as most rational since it does not require the knowledge of the variable distribution form (Figure 2).
Frequency polygon and percentile ranges.
In accordance with the proposed assessments, the values within the first range (below the 10th percentile) should be considered as distinctly low, within the second range (10th–25th percentile) as low, the third and fourth ranges (25th–75th percentile) as mean, within the fifth range (75th–90th percentile) as high, and the sixth range (above the 90th percentile) as distinctly high.
The mammary gland structure allows to distinguish a few kinds of tissues performing various functions (epithelial, connective, nerve, blood, and lymph). The age involution of the mammary gland consists in the reduction of ductal epithelium proliferation, in the substitution of the secretory epithelium by a connective tissue with different correlations of tissue elements. The electric conductivity index (IC) obtained from the electrical impedance scanning is a quantitative variable, which characterizes the mammary gland structure. A low index is typical of a gland containing a big number of cell elements and thereafter high ion concentration. This causes us to regard the mammary gland structure with the conductivity index percentile limit <10 percentile as representing the ductal type. This is confirmed by the fact that the proportion of the test-group women aged 20–30 with the ductal type of the mammary gland structure and indices fitting in the first channel (<10 percentile) exceeded 70%. A high electric conductivity index is typical of a gland containing big number of fat lobules and a lot of connective tissue and therefore low ion concentration. Thus, the mammary gland structure with the conductivity index percentile limit >90 percentile should be estimated as representing the amorphous type. This is confirmed by the fact that the proportion of women aged 51–60 with the involutive type of the mammary gland structure and indices fitting in the sixth channel (>90 percentile) also exceeded 70%. The mammary gland structure with the conductivity index percentile limit between the 25th and 75th percentile should be estimated as representing the mixed type. This is proved by the fact that this percentile channel included data of women of all age-groups. Different combinations of structures determining tissue electric conductivity produce a wide range of conductivity index values.
Table 2 presents a summary table of the mammary gland structure assessment from the perspective of EIM execution.
Structural type | Electric conductivity | Percentile limits |
---|---|---|
Amorphous | Above 0.66 | >90‰ |
Mixed with the predominance of the amorphous component | 0.57–0.65 | 75–90‰ |
Mixed | 0.30–0.56 | 25–75‰ |
Mixed with the predominance of the ductal component | 0.22–0.29 | 10–25‰ |
Ductal | Below 0.22 | <10‰ |
Types of mammary gland structure from the perspective of electrical impedance mammography.
Thus, the mammary gland structure can be assessed from the perspective of electrical impedance mammography with a view to the electric conductivity index. As is well-known, the mammary gland structure conditions its density, which is why the distinguished ranges of electric conductivity correspond to different types of breast density. The so-called dense breasts, which correlate with the ductal structural type, are characterized by low values of electric conductivity index. High index values are typical of the amorphous structure when the mammary gland chiefly consists of the adipose and connective tissues. The peculiarity of this approach to the mammary gland structure assessment is a quantitative expression of the mamma\'s anatomic and histological composition. The results of the mammary gland density assessment from the perspective of electrical impedance mammography with a view to the electric conductivity index are presented in Table 3. The assessment is done in line with the American College of Radiology (ACR) terms [23].
EIM classification | Electric conductivity | ACR classification | |
---|---|---|---|
Type Ia | Amorphous | above 0.66 | Predominantly fat, parenchyma below 25% |
Type Ib | Mixed with the predominance of the amorphous component | 0.57–0.65 | |
Type II | Mixed | 0.30–0.56 | Fat with some fibroglandular tissue, parenchyma between 25 and 50% |
Type III | Mixed with the predominance of the ductal component, high density of the ductal component | 0.22–0.29 | Heterogeneously dense, parenchyma 50–75% |
Type IV | Ductal, extremely high density of the ductal component | below 0.22 | Extremely dense, parenchyma 75–100% |
Mammary gland structure and density types from the perspective of EIM execution in accordance with the ACR classification.
The analysis in hand is based on data acquired from over 2000 electromammographic examinations of normal women aged 20–80. The analysis of the electrical impedance mammograms was carried out using the percentile limits approach, the women\'s age taken into account. It should be noted that modern medical, biological, and clinical research has been increasingly employing the percentile approach as a method of concise description of distributions. This approach does not require the knowledge of distribution form, i.e., it is nonparametric. The use of percentile curves is routine for many diagnostic modalities, e.g., they are widely used for the assessment of fetal development in ultrasound diagnostics. 5, 50, and 95 percentile limits for the electric conductivity index were calculated in each age group, which allowed to draw percentile curves (Figure 3) and make a table summarizing percentile limits of normal age-related electric conductivity of the mammary glands (Table 4).
Percentile curves of age-related electric conductivity of the mammary gland.
Age range, years | 5 percentile | 50 percentile | 95 percentile |
---|---|---|---|
20–29 | 0.18 | 0.28 | 0.44 |
30–39 | 0.16 | 0.40 | 0.53 |
40–49 | 0.22 | 0.51 | 0.63 |
50–59 | 0.32 | 0.58 | 0.72 |
60–69 | 0.43 | 0.57 | 0.78 |
over 70 | 0.50 | 0.57 | 0.64 |
Age-related percentile limits of the mean electric conductivity index.
Percentile limits of age-related electric conductivity can be used for the formation of breast cancer risk groups. The conductivity index values below the 5th percentile must be regarded as distinctly low, whereas the values exceeding the 95th percentile as distinctly high.
The risk group for breast cancer should thus include patients exhibiting abnormally low age-related electric conductivity values, i.e., below the 5th percentile, which witnesses for extremely high density of the glandular tissue ductal component. High density of the ductal component carries potential threat since it is often conjoined by the insufficient trophic function of the connective tissue, which is known to be provided by the main substance thereof. Dyscrasia may result in dystrophic processes, including those in the basal membrane.
Abnormally high values of age-related electric conductivity, i.e., exceeding the 95th percentile, correlate with menstrual disorders, the latter standing for hormonal changes.
Unlike other tomographic modalities which only avail of visual evaluation feature, electrical impedance scanning also provides quantitative information. These unique data are used for diagnostic purposes. A detailed description thereof demands a short reference to outlier statistics.
Provided that all value variations come from a single general population, they are expected to differentiate by virtue of random causes only and stay within the range of M ± 2 standard deviation. However, we sometimes come across values, which differ dramatically from the rest of the totality. Such values are often referred to as outliers. In this case, checking the values for the presence of outliers is highly desirable. If such a difference is a result of an error or its cause is unknown, the outlier value should be excluded from the assessment. Elimination of values that are “too remote” from the center of a sample is called sample censoring.
There are two basic types of methods implemented for outlier elimination [24]:
Elimination method with the general standard deviation given.
Elimination method with the general standard square deviation not given.
In the first case, X and standard deviation are calculated with a view to the results obtained from the sample aggregate; in the second case, the sample is stripped of the suspicious results before the calculations are made. Normalized deviate, which serves a nondimensional characteristic of the variable deviation from the arithmetical mean, is one of the criteria used to determine the outliers (1).
where “t” is the outlier detection criterion, “x” is an outlier, “M” is the mean value for a variant group, and “σ” is a standard deviation. “ttable” stands for standard values of the outlier detection criterion, the values are shown in the table. The values of ttable= 2, P = 0.95 are often used for large selections.
The “three sigma” rule applied for the assessment of the measurement results distributed in accordance with the normal law is one of the simplest outlier detection methods. This rule implies the following: if Xoutlier − X > 3Sx, where Sx–is an assessment of the standard deviation measurement, the result is hardly probable and may be considered as a miss. The X and Sx values are calculated without regard to the extreme values of Xoutlier.
In this paragraph, we will comment on the results of an electrochemical test of the MEIK v5.6 electrical impedance mammograph. The figure below shows a prototype installation filled with water. The mammograph was used to acquire an electrical impedance scan of the physiological saline solution (Figure 4A). The mean electric conductivity index (IC) made 1.85, whereas the standard deviation amounted to 0.075 and three standard deviations to 0.22. Then, a metal coin was put into the water, 1 cm deeper than the mammograph panel with electrodes (Figure 4B). When overlapped, the conductivity distribution histograms (Figure 5) allow to see that the IC of the coin (dotted curve) is higher than the IC of water (continuous curve) by a value exceeding three standard deviations. This is typical of outliers; however, in this particular case, it speaks for the presence of an object whose IC value is significantly different from that of the medium, neither does the object belong to the general observation population.
Electroimpedance scans (11 mm deep) of water: A–homogeneous, B–with a metal coin in the middle, C–a 3D image.
Histograms of electric conductivity distribution of water (continuous curve) and of water with a coin (dotted curve).
The above mentioned fully applies to medical and biological measurements. Figure 6 shows an electrical impedance mammogram of a patient suffering from breast cancer, the quantitative parameters being: IC = 0.56, standard deviation–0.12. At 3 o\'clock next to the areola, we can see an indistinctly contoured focus with the IC of 0.94. Thus, the IC in the area of interest exceeds the IC of the mammogram by a value going over 3 standard deviations. On the right, we present X-ray and ultrasound images of the same case.
On 3 o\'clock next to the areola, a focus is visualized (A), highlighted–arrow (B), less than 10 mm in size. X-ray: A lesion of less than 1 cm in size with a radiant contour in the upper-outer segment. US: a lesion of an irregular shape, with nonhomogeneous structure, 9 × 9 mm without vascularization.
The given example proves that the electric properties of malignant tumors differ significantly from those of the surrounding tissue. It is a well-known fact that cancer cells exhibit an increased electrical activity. Some of the characteristic features of cancer cells that affect their electrical activity are:
Cancer cells have cell membranes that exhibit different electrochemical properties and a different distribution of electrical charges than normal tissues [25].
A change in mineral content of the cell, particularly an increase in the intracellular concentration of positively charged sodium ions and an increase in the negative charges on the cell coat (glycocalyx) are two of the major factors causing cancer cells to have lower membrane potential than normal cells [25].
Cancer cells exhibit both lower electrical membrane potentials and lower electrical impedance than normal cells [26, 27].
From Figure 7, it becomes clear that the mammary gland carcinoma has three times higher electric conductivity than the surrounding tissues [28].
Influence of the current frequency on the electric conductivity of the mammary gland tissues.
This knowledge can be applied to early detection of breast cancer. To perform this task one is to search for areas with abnormal values of IC>3 std, which is typical of an oncologic process with tumors not exceeding 1 cm. To make the search easier, the mammograph highlights abnormal conductivity areas with red (arrow) (Figure 8).
High electrical conductivity area (>3 std) outside the lactiferous sinus zone, which is highlighted (arrow).
As the disease connected by the breakup of the epithelium basal membrane progresses, various phenomena can occur in the tumor and the surrounding tissues. These processes are always accompanied by alterations of electrical properties of the tumor mass. Increased vascularization leads to electrical conductivity increase due to ionic conduction. Replacement of dead tumor cells by collagen fibers leads to electrical conductivity decrease. While purulent inflammation areas emerge, permittivity decreases as a result of the cell membranes death. Lymphocytic infiltration causes the tumor and the surrounding tissues impedance to increase, because of a significant local concentration of cell membranes. Thus, tumor growth is regularly accompanied by the alteration of the electrical properties both of the tumor and the surrounding tissues.
As noted previously, the electrical impedance approach enables to conduct a quantitative analysis of the image involving the assessment of the following parameters: mean electric conductivity index, histogram of electric conductivity distribution, comparison of the electric conductivity distribution histogram with the referent values.
To refer the patient to the norm or pathology category, the divergence in the distribution form criterion, also known as the λ-criterion or the Kolmogorov-Smirnov criterion [29], is used in Eq. (2).
where N1 stands for observation quantities within the ranges, n1–within the sample aggregate, A1; and N2 and n2–the same for A2.
Dx statistics, to be more exact, a subaggregate when calculating the Kolmogorov-Smirnov criterion Eq. (3).
where N1 stands for observation quantities within the ranges, n1–within the sample aggregate, A1; N2 and n2–the same for A2.
This nonparametric criterion enables to determine the statistical significance of divergences in the distribution of any characteristic of norm or pathology including the distribution of electric conductivity on electrical impedance tomograms.
The Dx statistics allows to define the area of one of the distributions, which is not shared by the other (Figure 9). The Dx value reflects the proportion of observations or data, which distinguishes experiment (patient) from control (norm). This value is essential for substantiation of diagnosis as well as for assessing the parameter information capacity.
Assessment of distribution divergence by their area.
High information capacity of the divergences revealed enables to refer the patient to this or that category (e.g., norm or cancer) with great probability. To determine the informative value of distribution divergence Kulback\'s information measure is applied Eq. (4).
where J = information value of the range, P1–probability of patients\' suffering from disease A1 getting into the range, P2–the same for disease A2.
It shows how informative the Dx statistics applied is, how this parameter contributes to diagnosing the disease, e.g., cancer. The assessment of distribution divergence (Dx) produced results standing in direct relationship with the information capacity, according to Kulback (Table 5). This relationship must be recognized as fairly regular and consistent [29].
Distribution divergence | Information capacity | Reliability |
---|---|---|
below 20% | Very low | No |
20–30% | Relatively low | Yes |
30–50% | Good | Yes |
50–65% | High | Yes |
Distribution divergence and information capacity.
In the presence of cancer, the histogram of the affected gland is shifted. Table 6 sums up data on comparative electric conductivity obtained from patients suffering breast cancer, benign changes of the mammary gland as well as from normal women with different types of mammary gland structure.
Number of patients | Comparative electric conductivity (affected–normal gland) | ||||||
---|---|---|---|---|---|---|---|
<20% | 20–30% | 30–40% | 40–50% | 50–60% | >60% | ||
Cancer | 310 | 101 (33%) | 67 (22%) | 44 (14%) | 37 (12%) | 26 (8%) | 35 (11%) |
Healthy | 161 | 157 (98%) | 4 (2%) | 0 | 0 | 0 | 0 |
Healthy acinar-ductal type | 20 | 18 (90%) | 1 (5%) | 1 (5%) | 0 | 0 | 0 |
Healthy amorphous type | 32 | 28 (88%) | 2 (6%) | 2 (6%) | 0 | 0 | 0 |
Benign | 68 | 59 (87%) | 7 (10%) | 2 (3%) | 0 | 0 | 0 |
Comparative electric conductivity of the mammary glands, data acquired from patients suffering from breast cancer, benign lesions, and normal women.
In the course of oncologic process development, general and local electric conductivity naturally tends to change. The distortion of the mammographic scheme can be observed as early as at onset of the disease that is why this criterion was added to the EIM breast cancer diagnostic scale (Table 7). Below (Figure 10), we provide examples of the distorted mammographic scheme from three patients with breast cancer.
Diagnostic criteria | Electrical impedance mammography points |
---|---|
Shape | |
| 1 |
| 2 |
Contour | |
| 0 |
| 1 |
| 2 |
Surrounding tissues | |
| 0 |
| 1 |
| 2 |
Internal electrical structure | |
| 0 |
| 1 |
| 2 |
| 3 |
Comparative electrical conductivity | |
| 0 |
| 1 |
| 2 |
| 3 |
Diagnostic criteria for differentiation of volumetric lesions in electroimpedance mammography.
Electroimpedance mammographic scheme distortion (the top images show the affected gland, the bottom line contains images of the normal breast).
A volumetric lesion is an extensional involvement detected on several scan planes. Image analysis implies the assessment of the lesion shape, contour, internal electric structure, and changes in the surrounding tissues.
A diagnostic table was made to regularize the description of volumetric lesions. Table 7 presents assessment parameters each being given a certain set of points.
Using the numerical score for the assessment of volumetric lesions in electrical impedance mammography allows to compare this information to BI-RADS ACR categories (Table 8).
EIM | ACR |
---|---|
Common scale | BI-RADS categories |
No score | BI-RADS 0 poor image |
0–1 | BI-RADS 1 lesion is not defined |
2–3 | BI-RADS 2 benign tumors–routine mammography |
4 | BI-RADS 3 probably benign findings |
5–7 | BI-RADS 4 suspicious abnormality–biopsy |
>8 | BI-RADS 5 highly suggestive of malignancy–treatment/biopsy |
EIM scale and ACR BI-RADS.
The EIM point scale enables to standardize the description of volumetric lesions when carrying out electrical impedance mammography examination as well as use the algorithm of patients\' supervision worked out by the specialists of the American College of Radiology.
EIM diagnostic system is a clear and logical system involving determination of the mammary gland structure and density, allowing for cancer diagnostics for various types of breast as well as formation of breast cancer risk groups.
There are a number of factors that influence patient outcome in trauma and orthopedic surgery in relation to hemorrhage. These can include patient factors, for example anticoagulant and antiplatelet medications, coagulopathies and other conditions, as well as surgical factors such as bony bleeding, large surgical incisions, diffuse venous bleeding and unseen sources of bleeding [1, 2].
Trauma still remains a leading worldwide cause of morbidity and mortality [3] and despite various developments over the years, hemorrhagic shock from trauma continues to form one part of the terrible triad contributing to mortality in both the military and civilian settings [4].
Effective hemostasis during surgery is advantageous to the surgeon as it prevents diffuse bleeding from capillaries and venules obscuring the surgical field and adding to operation time and infection risk [5, 6].
Significant blood loss has been associated with increased need for allogeneic and autologous blood transfusion [2, 7, 8]. These are associated with attendant risks including nosocomial infections [9], transfusion-related injury and fluid overload [10, 11]. In fact blood transfusion is an independent risk factor for infection, respiratory complications and the need for critical care support in traumatic injuries and resulted in a twofold increase in complications and critical care admissions, with more than two units of blood transfusion [7]. The risk of major perioperative complications is also increased with high intraoperative blood loss [2, 12, 13]. Therefore, patient outcome is optimal when the balance between bleeding and clotting is maintained during surgery such that tissue perfusion is adequate without excessive blood loss [5, 6].
Hemostasis in regard to trauma and surgery is a highly regulated process, maintaining flow through vessels at the same time as the thrombotic response to tissue damage is occurring [14], thereby ensuring tissue perfusion and limiting blood loss. The process is a complex interaction between vascular endothelium, platelets, the coagulation and fibrinolytic systems [15, 16].
Following injury, a temporary vascular smooth muscle contraction occurs in an attempt to stem blood flow. Endothelial disruption exposes the subendothelial layer and circulating Von Willebrand factor attaches to the site of injury. Surface glycoproteins also adhere to platelet surfaces. The subendothelial collagen activates adhering platelets and their surface receptors then bind circulating fibrinogen, forming a soft platelet plug comprising aggregated platelets and fibrinogen [14]. The adhering platelets secrete humoral factors including serotonin, prostaglandins and thromboxane that maintain a reduced blood flow, creating an environment that is conducive to clot formation at the site of bleeding. At the same time, circulating coagulating factors produced by the liver are activated in a series of precisely controlled sequential and dependant reactions [14, 17].
The final common pathway is the activation of thrombin that leads to conversion of soluble plasma fibrinogen to insoluble fibrin. The complex of activated factor XIII and fibrin results in cross-linking of fibrin monomers to form a stable clot [17].
Broadly speaking, there are mechanical, thermal, pharmacological and topical methods of hemorrhage control [2, 6, 8, 17, 18, 19, 20].
Mechanical methods include direct pressure, ligating clips and staples, sutures, fabric pads and gauze while hemostatic scalpels and lasers also reduce bleeding during surgery [6, 7, 17]. However, these methods have their drawbacks with respect to certain situations. The location of bleeding is particularly important with respect to orthopedics and in particular trauma. Bony surface bleeding and bleeding from the intramedullary canals are almost impossible to control with mechanical methods. Inflamed or friable tissues may contain a dense network of friable capillaries may prove a challenge [1, 2, 7]. Junctional bleeding in trauma may be potentially catastrophic and its control may not be amenable to the above methods.
The use of pharmacological methods can be a useful adjunct to other methods in these circumstances [7]. These may include epinephrine, desmopressin, tranexamic acid, vitamin K, aminocaproic acid and others.
In some situations though, even the above methods are ineffective or impractical [15] and hence the development of topical hemostatic agents. These are a diverse group of agents of varying composition and mechanisms of action. They can be versatile in the sense that when blood loss is minimal, they can be used sparingly and when there is severe blood loss then more liberal application could be an option [2]. They may be applied directly to the bleeding site and prevent or reduce continuous and unrelenting bleeding intraoperatively and postoperatively [2] and their topical nature broadly avoids the systemic adverse effects associated with systemic hemostatic medications including thrombosis [8].
Topical hemostasis is defined as a process that acts locally to stop bleeding from damaged vessels [21]. Recent and continuing developments have focused on agents that can be used as adjuncts to control bleeding during surgical procedures and control residual problematic bleeding if conventional methods fail. Broadly speaking, topical hemostats can be divided into three types [17, 20].
Passive—where the mechanism of action is to provide a physical scaffold around which platelets can aggregate. These act through contact activation and promote platelet aggregation so a clot can form. Examples include collagen, cellulose and gelatins.
Active—these have biological activity and their mechanism of action is actively influencing the clotting cascade to promote clot formation [17, 20]. These usually contain thrombin in one form or another [14].
Combined—combination of passive product with thrombin.
Contact activation occurs between receptors on platelets and collagen, promoting platelet aggregation [15, 17]. Preparation includes collagen sponges, pastes and powders [15, 17] and is obtained mainly from bovine sources [15], making it potentially immunogenic. In fact a 2–4% allergy in the total population to bovine collagen has been reported in the literature [22] (Table 1).
Hemostatic agent | Examples | Manufacturer |
---|---|---|
Collagen-based products | Avitene | Davol/BD BARD |
Helistat/Helitene | Integra Lifesciences | |
Instat/Ultrafoam | Ethicon. Johnson & Johnson | |
Oxidized cellulose | Surgicel Fibrillar | Ethicon, Johnson & Johnson |
Surgicel Nu-Knit | Ethicon, Johnson & Johnson | |
Gelatin-based products | Gelfoam | Pharmacia Corp, Pfizer |
Surgifoam | Johnson & Johnson | |
Polysaccharide spheres | Arista AH | BD BARD |
Passive hemostats.
The active ingredient in this product is oxidized regenerated cellulose (ORC). Its exact mechanism of action is poorly understood but contact activation is thought to play a part [15]. Often at reoperation, previously used ORC is visible, indicating reduced absorption and poor biodegradability, although this may be related to the amount used and the site of implantation [8]. For this reason, only the minimum possible amount to be used is indicated and it is recommended that the product be removed once hemostasis is achieved and before definitive closure [6, 8].
Their mechanism of action involves swelling while in contact with blood, providing a tamponade effect in confined spaces and restoring blood flow, and thereby producing a stable scaffold around which clots can form [17]. This does make it suitable for irregular wounds [6] and confined spaces [17]. However, it tends to stick to instruments when soaked with blood, making it difficult to handle and does not form a tight bond with the bleeding surface and can hence easily be dislodged [17].
Active agents have biological activity and actively participate in the coagulation cascade to induce clot formation at the site of bleeding [20]. They include thrombin, which comes into play in the last stages of the clotting cascade, converting circulating fibrinogen to a fibrin clot [17, 23]. Hence a significant advantage of thrombin is that its action is less susceptible to coagulopathies caused by clotting factor or platelet dysfunction [17]. Its activity constitutes the final steps in the clotting cascade and therefore it bypasses the initial steps in the cascade. Therefore, other aspects of the clotting cascade can be dysfunctional without significantly impairing the local hemostatic activity of thrombin [20].
Thrombin-based products are therefore excellent adjuncts in the presence of congenital and acquired coagulation and platelet disorders and in the presence of pharmacological and antiplatelet agents that are increasingly being used in the general population [5, 17]. Circulating fibrinogen is necessary for hemostasis to occur by active agents as thrombin converts it into insoluble fibrin that forms part of the clot. Therefore in rare cases of fibrinogen deficiency, clotting by thrombin-based products is impaired [17, 23].
These accomplish their action by bypassing the coagulation cascade to the final steps and converting fibrinogen to fibrin [24]. A fibrin precursor and thrombin stored in two separate adjacent syringes (dual syringe kit) with a single lumen enables delivery and mixing of these agents in the lumen and onto the surgical site, causing thrombin to cleave the fibrin precursor, resulting in fibrin monomers that polymerize at the site into a soluble mesh stabilized into a stable clot by factor XIII at the tissue surface [25]. Previously, bovine thrombin was used, which has recently been replaced by human thrombin [26] and more recently autologous human thrombin. Autologous fibrin sealants overcome the risk of allogeneic blood products, for example one is a patient-derived fibrin sealant utilizing the patient’s own blood as a source of fibrinogen and prothrombin and mixing it with an alkaline buffer solution to lower the pH, activating endogenous prothrombin [24] (Table 2).
Biosurgical | Examples | Manufacturer |
---|---|---|
Liquid fibrin adhesives | Tiseel | Baxter |
Evicel | Ethicon, Johnson & Johnson | |
Crosseal | Ethicon, Johnson & Johnson | |
Floseal | Baxter | |
Fibrin patches | Tachosil | Takeda |
Platelet gels | Vitagel | Orthovita |
Glutaraldehyde cross-linked albumin | BioGlue | Cryolife |
Sealants and adhesives.
These are a combination of thrombin, calcium and platelet-rich plasma, usually obtained from autologous sources using centrifugation systems that produce platelet-rich plasma. Platelets provide growth factors to stimulate wound healing and contribute to the strength of the clot [27].
These systems however rely on an intact coagulation system and may not be as effective in patients on antiplatelet or anticoagulant medications [27]. Also the extraction systems are expensive and there is a risk of contamination.
In addition to not requiring normal clotting mechanisms to work as mentioned before, active hemostats may offer other advantages. With many passive hemostatic agents, degeneration and reabsorption are a problem. This necessitates their removal from the surgical site prior to closure. With thrombin, this is not the case as degeneration and resorption of the resulting fibrin clot is achieved as part of wound healing [1, 8]. Thrombin and combination products also have a rapid onset of action with hemostasis being achieved within 10 min in most patients [7, 17, 28, 29]. Studies have shown that combining an active hemostat within a hemostatic product accelerates clotting. In a comparison of collagen-based products at different bleeding sites after surgical tumor resection, the combination of a collagen-thrombin product (n = 23) achieved complete hemostasis three times faster than the collagen sponge alone (n = 30). The median time to hemostasis was 78 seconds versus 243 seconds respectively (p < 0.001) [30]. Furthermore, approximately 80% achieved complete hemostasis within 2 min with an active topical hemostatic agent compared with only one-third of patients receiving a passive topical hemostatic agent [31]. Active hemostats are also very versatile and can come in various forms. These include sprays that can be advantageous in covering large bleeding surfaces quickly without the need for tamponade [31], and the concentration of thrombin in the formulation can also be varied depending on the severity and type of bleeding. Surgeons can use them in multiple ways during a single procedure due to their flexibility and range of delivery options [20]. Although bovine sources of thrombin may induce antibodies in hosts, this has not manifest itself as a major problem in the clinical setting [1, 32].
It has been shown that the terrible triad of hypothermia, coagulopathy and acidosis are associated with increased mortality in multiple trauma patients and that infection and multiple organ failure are other potential complications arising from severe blood loss [33, 34]. About a quarter of patients presenting to trauma centers have an established coagulopathy secondary to hemorrhage [35] with attendant risks of significant complications. Multiple defects in hemostasis can occur in combat injuries and as such, conventional methods of hemostasis may not be possible. Time is of the essence in these situations and non-transfusional approaches to hemostasis and the use of biosurgicals may be indicated [36, 37, 38, 39].
The combat setting has proved a challenging environment in many different ways in terms of management of hemorrhage. The tissue available for controlling life-threatening hemorrhage may be limited, the wound severity and the possibility of multiple injuries make the situation uniquely challenging [40]. Most combat injuries are penetrating in nature and a large proportion are limb wounds. Mortality from hemorrhage from these kinds of wounds is potentially preventable [36, 41, 42].
In the combat setting, the three principal sites of lethal hemorrhage are truncal (67%), junctional (19%) and extremity (14%). A report from the National Trauma Database suggests that the mortality from isolated lower limb extremity trauma with arterial injury is 2.8% with a 6.6% amputation rate [38]. Tourniquets can be used for these isolated injuries and their use in the military and civilian setting is supported by the Hartford consensus [39] and by the American College of Surgeons Committee on Trauma [38].
Junctional injuries (neck, axilla, groin and perineum) form a significant proportion of trauma in a combat setting and may damage the large vascular structures. These types of injuries are difficult to compress and are not amenable to tourniquet control [43, 44]. Topical hemostatic agents that have been developed in the last two decades [36, 45] can play a vital role in controlling severe bleeding in these situations and increase survival [33, 46] and have thus been listed as optional basic equipment for ambulances [39]. In addition, in a combat setting, more complex types of wound patterns are encountered than in a civilian setting, including blast injuries, which may be more amenable to topical hemostasis.
In 2003, USAIR [47] introduced guidelines of what should constitute the perfect hemostatic agent for use in the prehospital and battlefield settings [33, 41, 47, 48, 49] that included the following: being able to stop large vessel and arterial bleeding within 2 min of application, ability to be delivered through a pool of blood when applied, ready to use with no need for on-site preparation, simple enough to use by the wounded victim or a paramedic with minimal training, light weight and durable with a minimum 2-year shelf life in extreme environmental conditions, safe to use with no risk of injury to tissues or transmission of infection and inexpensive [41, 45, 50, 51]. In addition, hemostatic dressings need to be conformable and flexible enough due to the irregular shape, depth and wound configurations caused by modern explosive devices [40, 48].
These include gelatin [52], oxidized cellulose [53] and collagen and plant-derived polysaccharide spheres [54]. These agents are not biologically active and rely on the patients’ endogenous fibrin production for hemostasis. They provide a scaffold for platelet activation and aggregation, absorbing fluid several times their own weight to form a matrix at the site of hemorrhage, activating the extrinsic coagulation pathway and allowing clotting to occur. This makes them suitable only for patients in whom the coagulation system is intact [55, 56]. In fact in the absence of some coagulation factors, these agents may not be effective [53, 56]. They can be used as first line due to their ready availability and favorable cost-effectiveness, mostly as adjuncts with direct pressure at bleeding sites to control minimal residual hemorrhage [56].
These agents act by forming a physical matrix that stimulates platelet aggregation and degranulation to release factors that encourage clot formation [55].
Cellulose is a homopolysaccharide made by polymerization of glucopyranose molecules through glucosidic bonds. Surgical oxidized cellulose is either regenerated where organized fibers are formed prior to oxidation (regenerated ORC), or non-regenerated, with unorganized fibers prior to oxidation [55]. ORC conforms more rapidly to the surrounding environment. Surgical oxidized cellulose offers several favorable properties in hemostasis including bactericidal activity, good biocompatibility and ease of use [55]. It is usually resorbed but can take anywhere between 2 and 6 weeks depending on the amount used, the degree of saturation with blood and the tissue bed. The excess material may also cause foreign body reactions and granuloma formation without biodegradation and complicate radiological and clinical diagnoses of abscess, residual or recurrent tumor and granuloma [55, 57, 58]. For this reason, the minimal effective amount should be used and excess material removed prior to definitive closure. In addition, these products should not be used or left in place close to nerves, ureters, intestinal and vascular structures due to the risk of local inflammatory reactions and ischemia [55].
These can be used in combination with active agents such as thrombin in adhesives, or in a stand-alone manner. They are usually of bovine or porcine origin and act at the terminal stages of clotting to facilitate fibrin clot formation and are highly absorptive, forming a mechanical matrix for the clot to adhere to [55, 59]. They are quite versatile and available as sponges, powders or granules and are usually completely resorbed in 4–6 weeks [59]. It is important to use the minimum amount necessary to achieve hemostasis and to remove excess because part of the mechanism of action is swelling to cause a tamponade effect and this could potentially cause compression and necrosis in surrounding tissues if packed in tight spaces. This is particularly important around neural tissue and in bony spaces [59]. They are also useful in irregular wounds and surgical cavities as they can expand and fill these irregular spaces.
Mucoporous polysaccharide hemispheres are among a relatively new class of hemostatic agents derived from plant starch. Their mechanism of action includes absorbing water and the low-molecular weight components of blood, hence concentrating platelets and clotting factors in the vicinity, thereby enhancing local clotting processes [58, 60]. They have been used safely in cardiothoracic and neurospinal surgery.
These are active formulations containing mostly two agents—human purified fibrinogen and thrombin. They may also have added other compounds such as factor XIII, fibronectin and antifibrinolytics such as aprotinin used previously and tranexamic acid currently [61]. However, formulations without tranexamic acid or aprotinin are available to avoid hypersensitivity associated with aprotinin and neurotoxicity associated with tranexamic acid [62, 63] (Table 2).
These products are available in liquid or low-viscosity forms (fibrin glues) or as part of stiff collagen fleece (fibrin patches) [55]. Once applied, their mechanism of action is cleavage of fibrinogen to fibrin monomers by thrombin, which also activates factor XIII and the complex fibrin matrix forms the clot [55]. Calcium is required in both these steps and then the clot is eventually resorbed via the fibrinolytic pathway [25]. Generally, they connect atraumatically to tissues and form a barrier to leakage and bleeding through covalent polymerization between themselves and adjacent tissue [55]. Chiara et al. set out the properties of an sealant as being strong, rapid to adhere, flexible, sterile, without toxicity, biologically inert, biocompatible and able to be used in relatively wet environments with low thrombogenicity [55].
True sealants are of two types: synthetic (PEG-based or cyanoacrylates) [53, 60, 64, 65, 66, 67] or semisynthetic glutaraldehyde [68] (Table 2).
True sealants are cross-linking sealants that polymerize through nonenzymatic reactions, free of the need for the presence of blood or coagulation factors although some do have some coagulation factors within them. Both can be used to control residual ooze [53, 67].
PEG sealants are composed of polyethylene glycol and come in both flowing form as well as pads or fleeces. They should be avoided in kidney disease due to the renal clearance of polyethylene glycol and may contain allergenic components such as human albumin that can also lead to the theoretical risk of disease transmission [55].
Cyanoacrylates are products generally used for skin closure or lacerations in areas of low skin tension, for example scalp wounds. They are synthetic sealants that rapidly polymerize with water acting as the catalyst. There are two formulations: octyl-2-cyanocrylate and N-Butyl-2-cyanoacrylate. In a systematic review looking at octyl-2-cyanoacrylate, there were no differences in infections, wound dehiscence or cosmetic appearance when compared with other methods of closure [65]. Polymerization generates heat and therefore the amount used should be just enough and should certainly be avoided in delicate areas such as the spinal canal and neural tissue [55, 65]. Below the skin, a foreign body reaction may occur [65] and intravascular use is contraindicated due to the risk of systemic embolization [55].
Semisynthetic sealants otherwise known as bioglues are compounds of semisynthetic glutaraldehyde—bovine albumin-based sealant. Proteins on the surface of bleeding human tissue link with those of bovine albumin in the bioglue, causing a sealant effect [55]. Within synthetic graft materials, bioglue permeates interstices within the graft matrix [69], making it suitable for sealing anastomotic sites and decreasing postop bleeding [70].
These can be used as an adjunct to surgical hemostasis to improve residual moderate bleeding [55]. They are usually applied by double syringe systems. Each component is located in a separate section of the syringe, which then combine in a single lumen. They subsequently are applied using a blunt needle or spray tips in cases of large bleeding surface areas to the bleeding surgical site [25, 61]. Since the components bypass the initial steps in the extrinsic coagulation pathway, they can be used in achieving hemostasis in patients with congenital or acquired bleeding disorders such as hemophilia and patients on anticoagulants or antiplatelet medications [25, 62, 71] (Table 2).
They do have some drawbacks including the risk of thrombosis if injected intravascularly, hypotension and death and the risk of air embolization with the use of gas-driven sprayers [55]. In addition, the cost of sealants is significant and hence they are not recommended for use except in particular situations where indicated, for example in those with coagulation disorders [61]. One cost-effectiveness analysis done in the United Kingdom in patients undergoing total knee replacement on Quixil, one of the commercial brands, in addition to conventional hemostatic agents estimated that the use of a 5-ml dose of Quixil in addition to conventional hemostatic methods was cost saving in comparison to conventional methods alone. But the use of a 10-ml dose increased the cost substantially and they recommended that liquid fibrin adhesives only be used in selected cases [25]. They have however been found to be effective. Echave et al. [59] carried out a systematic review of 27 studies on the effectiveness of human gelatin-thrombin matrix sealant in different surgical fields including orthopedics. All 27 studies demonstrated that this sealant was associated with a significantly higher rate of successful hemostasis, and a shorter time to achieve it (p < 0.001) in comparison to other alternatives when conventional methods failed.
These products are also available as patches, for example Tachosil. They may have slightly different components but all of them have essentially the same mechanism of action, offering mechanical support with either collagen, oxidized cellulose/polyglactin 910 matrix, binding coagulation factors, allowing better adherence to bleeding tissue even in the presence of brisk bleeding, preventing the so-called “streaming effect” observed with fluid adhesives [72, 73, 74]. Tachosil is a ready-to-use fixed combination of equine collagen patch on one side and coated with coagulation factors, human fibrinogen and human thrombin on the other side [55]. Fibrin-pad and PGA-felt are absorbable hemostats composed of polyglactin 910, oxidized regenerated cellulose, thrombin and fibrinogen shown to be effective in a variety of tissue types [25, 72] and can rapidly achieve hemostasis in brisk bleeding in the retroperitoneum and pelvis, compared with the standard of care [72, 73] (Table 2).
Junctional hemorrhage is a significant problem in major trauma especially on the battlefield and often conventional methods such as tourniquets are ineffective [55]. In this respect, science has led to the development of products that are effective options in these circumstances and they can be divided into factor concentrators [75], procoagulants [76] and mucoadhesives [77] (Table 3).
Biosurgical | Examples | Manufacturer |
---|---|---|
Zeolite dressings | QuikClot & QuikClot ACS | Z-Medica |
Smectite dressings | WoundStat | TraumaCure Inc. |
Kaolin dressings | QuikClot Combat Gauze | Z-Medica |
Rapid Deployment Hemostat | Marine Polymer Technologies | |
Celox | Med Trade Products, UK | |
Trauma Stat | OreMedix | |
Fibrin dressings | Dry fibrin sealant dressing (DFSD) | American Red Cross |
Hemostatic dressings.
These are compounds of either zeolite (microporous crystalline aluminum silicate) or smectite (a nonmetallic clay mineral sodium, calcium and aluminum silicate). Examples include QuikClot (Z-Medica LLC, CT,USA) and QuikClot ACS (advanced clotting sponge), Traumadex (Medafor Inc., MN, USA) and self-expanding hemostatic polymer (SEHP) [35]. As the group name suggests these agents rapidly absorb the fluid content of blood. The resulting effect is an increase in relative concentration of its cellular and protein content and therefore clot formation. Water molecules are held in its pores by hydrogen bonds and this results in a relative local increase in concentration of platelets and clotting factors [35]. The first generation of QuikClot was designed as granules that were poured onto the bleeding wound. A high efficiency rate of 92% was demonstrated in a series of 103 patients in the military and civilian setting. There were eight patients in which hemorrhage was not effectively controlled with QC in coagulopathic patients where it was used as a last resort [75]. There were also some side effects of QC including intense exothermic reaction and scar formation from foreign body reaction [75]. Animal and early human studies on QC revealed thermal injury, poor biodegradability and foreign body reactions as the main drawbacks of QC [78, 79, 80]. In fact temperature generated by QuikClot in contact with aqueous components of blood at bleeding wounds has been measured to reach and average of 61°C with a potential rise to 76°C [78].
QuikClot has been compared to other hemostatic agents including HemCon (HemCon Medical Technologies Inc., OR, USA) in a military setting in multiple patients injured after explosions and gunshot wounds [81]. In this study, QC was effective but thermal injury was an issue. This has also been investigated in other studies by McMannus et al. [82] in the combat setting and evidence suggests that the greater the amount of blood and the more the QC applied, the greater is the risk of thermal injury. Thus currently it is only recommended for external use and the minimum amount required to achieve effective hemostasis is recommended.
QuikClot ACS is a newer generation of product made by larger zeolite beads packaged into mesh bags. This makes it easier to pack into cavities and irregular wounds often found on the battlefield and at junctional sites of hemorrhage and in cavities [55] and is claimed to produce much less of an exothermic reaction [75, 78] although there is a lack of studies with sufficient numbers to confirm this unequivocally [41].
Self-expanding hemostatic polymer (SEHP) is a dual action factor concentrator. Its mechanism of action results from its extremely potent absorptive capacity following absorption of the fluid component of blood and its ability to expand to conform to large irregular cavities and spaces, exerting a tamponade effect [35]. The other action is the effect of the polymer absorbing the liquid phase of blood into its matrix, thereby leading to a relative increase in concentration of platelets and coagulation factors at the site of bleeding, thereby promoting clotting [83, 84].
Woundstat is a compound of smectite granules that come in granular form. Its mechanism of action is absorption of the aqueous phase of blood, forming a clay substance that adheres to bleeding tissue and acts as a sealant and also concentrates clotting factors and blood cells locally, contributing to hemostasis. Granules are negatively charged and activate the intrinsic pathway as well [85, 86, 87].
These are products where the basic component is chitosan, which is a polymer derived from crustacean chitin. It is a complex biodegradable carbohydrate [55]. The mechanism of action appears to be related to highly positively charged chitosan interacting electronically with negatively charged cell membranes of erythrocytes. The product adheres strongly to tissues and seals bleeding wounds [77, 88, 89]. Examples include HemCon (HemCon Med Tech, Portland, OR) and Celox (Med. Trade Products, UK).
Celox is a chitosan-based adhesive, which is biodegradable and causes absorption of the aqueous phase and the advancement of red blood cell bonding. The positively charged Celox binds negatively charged red blood cells independently of the body’s clotting system, resulting in clot formation without the exothermic reaction associated with certain factor concentrators like QuikClot [35]. Its action is independent of the body’s clotting system, a property that makes it useful in patients requiring antiplatelet or anticoagulant medications or in the presence of coagulopathy and its local action means that it is not associated with distant clot formation. It is also reported to be very versatile, being available in granular and bandage forms and easy to remove from the wound after its clot formation activity is complete [49, 90, 91, 92]. HemCon, however, does have a hard consistency and is made in a square shape. Therefore, it works best on flat bleeding surfaces rather than deep irregular wounds [79, 83]. Wedmore et al. [77] looked at a series of patients with prehospital combative injuries where chitosan-based products had been used externally in chest, groin, buttock and abdominal wounds in 25 patients, 35 extremity wounds and neck and facial wounds in 4 cases. In about two-thirds of cases, the chitosan dressings were used following failure of hemostasis using only gauze with 100% success. In 97% of cases, bleeding stopped or hemostasis was improved, with failure only occurring in two cases attributed to blind stuffing of bandages into large cavitational injuries [77].
Trauma Stat is another chitosan-based derivative that was developed in collaboration with the United States Army, in which the mechanism of action involves positive charges in the amine groups on the chitosan molecule interacting with negative charges on the red blood cell membranes and in addition the adsorption of chitosan for fibrinogen and plasma proteins [79, 93].
Te Grotenhuis carried out a study of 66 patients in which conventional treatment with gauze and compression failed to control excessive bleeding or where conventional treatment was unlikely to achieve hemostasis. Complete cessation of hemorrhage including arterial hemorrhage occurred in 70% using the HemCon ChitoGauze, and reduction in hemorrhage occurred in 20% of patients despite 21 patients being on anticoagulants or having a clotting disorder and no adverse events occurred [88].
Due to the fact that chitosan is derived from crustaceans, there is a theoretical risk of allergenic reactions in patients allergic to shellfish. However in a study of 19 patients who had a positive IgE test to shellfish, none of the patients demonstrated a positive skin prick test to chitosan powder or expressed a reaction to HemCon bandage during serial bandage challenges, indicating favorable but not completely risk-free use of these products [94].
Chitosan-based dressings are also easy to remove after hemostasis has been achieved [41] and are known to have some antimicrobial properties [41, 95].
Their mechanism of action is mainly to deliver factors that promote coagulation into the bleeding wound. Examples are dry fibrin sealant dressing (DFSD) and QuikClot Combat Gauze (QCG) [70, 96, 97]. QCG is a surgical gauze coated with kaolin. On contact with injured endothelium, kaolin activates the extrinsic pathway, enhancing coagulation and promoting hemostasis. It is not degradable and needs to be removed from the wound following achievement of hemostasis [76].
Kaolin-based products have been used in a military setting and have demonstrated good results in both junctional and non-junctional hemorrhage [76]. In the above study, Shina et al. retrospectively reviewed 133 kaolin-based dressings applied to 122 military patients. 27% were for junctional hemorrhage with a success rate of 88% while the rest were extremity trauma where the success rate was 92%.
In addition to problems specific to certain types of hemostatic agents, there are also general drawbacks.
The hemostats that contain biological agents, usually the active hemostats, can be associated with the risk of disease transmission. For example, DFSD has the theoretical risk of viral disease transmission and hence has not achieved FDA approval.
Some agents have handling characteristics that are beneficial in certain situations. For example agents that have a granular nature can be used for complex irregular wounds with multiple bleeding points. However, the handling characteristics are difficult and they are difficult to apply in combat situations [89]. In addition, many agents are nonabsorbable and need to be removed after hemostasis is achieved. This may be difficult with some agents and require multiple washouts. Granular agents also have the potential to enter the vascular system and occlude the distal parts of vessels, causing endothelial injury and intravascular coagulation [41]. This has been demonstrated by Kheirabadi et al. [89] in their study, and for these reasons a bandage/gauze form of hemostatic agent is preferable as being safer for hemorrhage control, avoiding intravascular complications [38].
Any chapter on hemostasis in trauma and orthopedics is incomplete without the mention of tranexamic acid. This drug has been shown to be effective in reducing mortality due to bleeding in both the military and civilian setting.
The CRASH-2 (Clinical Randomization of an Antibrinolytic in Severe Hemorrhage-2) trial was a multicenter trial involving 40 centers looking at 20,211 adult trauma patients with significant bleeding who were randomized to two arms. One arm received TA within the first 3 hours of trauma and the other received placebo. The study demonstrated a reduction in mortality risk due to any cause from 14.5% compared with 16% in the placebo group (p < 0.001), with no increase in vasoocclusive events such as pulmonary embolism or myocardial infarction (0.3% versus 0.5% p-0.096) [98].
The MATTER (Military Application of Tranexamic Acid in Trauma) study looked at 896 patients with severe combat injuries and demonstrated a 6.5% absolute risk reduction in mortality in these patients with the use of tranexamic acid [99].
Both these studies have recommended incorporation of intravenous tranexamic acid into clinical practice [24].
Joint replacements are major procedures in elective orthopedics and can be associated with significant blood loss and increased transfusion requirements if appropriate steps are not taken to mitigate against this. In addition to the conventional methods of blood management including preoperative optimization, tourniquets if appropriate, intraoperative techniques such as cell saver and cauterization, topical and pharmacological hemostats and biosurgicals may offer some excellent solutions to reduce the transfusion requirements and achieve hemostasis.
A few studies have looked at human-derived fibrin sealants in total knee replacement [100, 101, 102]. A multicenter randomized control trial looking at 58 patients who underwent total knee replacement demonstrated a reduced postoperative blood loss, reduced postoperative decrease in hemoglobin and calculated blood loss in patients in whom fibrin sealant was used compared with that in the standard group (20% compared with the standard 83% p = 0.004) [100]. Another study that showed benefit was done by Dhillon et al. [25]. Results from other studies have been equivocal and have not demonstrated any clear difference.
In total hip arthroplasty, the use of fibrin sealants has been associated with reducing blood loss but inconsistent results have been demonstrated with regard to reduction in postoperative transfusion requirements [24, 103, 104, 105].
Multiple studies have looked at platelet gels in arthroplasty surgery. The evidence has been inconsistent in many. One randomized control trial looking at 100 total knee replacements did demonstrate significantly lower transfusion requirements in patients in whom platelet gels were used [106].
Desmopressin is a synthetic analog of anti-diuretic hormone. Its mechanism of action is to increase the levels of factor VIII and Von Willebrand factor, thereby enhancing primary hemostasis and platelet aggregation and adherence. This makes it suitable as a blood management strategy in patients with platelet dysfunction or other clotting disorders such as Von Willebrand’s disease and hemophilia A [107, 108]. It has also been used in healthy individuals for reducing postoperative bleeding in total hip and knee replacement surgery [109]. Six randomized placebo-controlled trials addressing the use of desmopressin in total hip and knee arthroplasty have been undertaken [110, 111, 112, 113, 114, 115]; however, evidence suggests that desmopressin is not significantly effective in reducing blood loss or transfusion requirements in these patients [24].
There are a number of good-quality randomized control trials that support the use of tranexamic acid in reducing blood loss and transfusion requirements in both knee and hip arthroplasty surgery [24]. There is however considerable amount of heterogeneity between the trials with regard to methods of delivery including single intravenous bolus dose, repeated boluses, prolonged infusion or intraarticular injection [116], and also differing dosing regimes [117]. In total knee arthroplasty, it has been shown that one intraoperative dose is sufficiently effective in reducing transfusion requirements and postoperative bleeding [118]. With the theoretical risk of intravascular thrombosis, intraarticular injection of tranexamic acid was investigated and compared to placebo and the studies showed reduction in blood loss but no reduction in transfusion rates [101, 119, 120]. Only one RCT by Seo et al. [121] showed a reduction in transfusion requirements with intraarticular (20%) rather than intravenous (34%) or placebo (94%). The evidence in total hip replacement with regard to intraarticular tranexamic acid is less convincing than in knee arthroplasty and more studies are needed.
With regard to aminocaproic acid, three RCTs did demonstrate benefit in hip and knee replacement surgery in terms of reducing blood loss in comparison with placebo. However, with regard to reducing transfusion requirements the evidence is much less convincing [24, 122, 123, 124].
Spine surgery presents a few unique challenges that limit the products that can be used for hemostasis in these situations. One of them is the friability of neural tissue and secondly the fact that the spinal cord and nerve roots are enclosed in rigid bony spaces that limit the kinds of hemostats that can be used due to the potential of swelling and compression of neural tissue in a rigid space. In addition, there is the potential for neurotoxicity with certain agents.
Cerebrospinal fluid leaks are a common source of postoperative morbidity in patients who have undergone spinal surgery. The morbidity burden includes severe postural headaches, vomiting, dizziness, photophobia, tinnitus, pseudomeningoceles and the risk of meningitis. It is therefore important that when dural tears occur or when an iatrogenic durotomy is created a water tight repair is essential. PEG hydrogel sealant has been found to be a safe effective way to augment dural closure and prevent these complications. A prospective study by Kim et al. [66] demonstrated that augmentation of standard dural closure techniques with this sealant in patients had significantly higher rates of watertight closure than with controls (100% and 64.3% respectively), without statistical differences in cerebrospinal fluid leaks, infections or wound healing. Complications due to swelling of polyethylene glycol and nerve compression were not demonstrated in this study but this remains a possibility. This led to the development of low-swell PEG hydrogel sealant (Duraseal) [55] and has been found to be safe and effective in a 3-to-1 randomized single-blind multicenter trial in which 100% of patients who had this low-swell formulation achieved watertight dural closure. Another study has also shown that BioGlue (semisynthetic glutaraldehyde-bovine albumin sealant) is safe and cost-effective in proximity to neurological structures despite previous concerns. Miscusi et al. [125] demonstrated a watertight dural closure in 23 patients requiring dural repair, with no incidence of neurological or infection related complications.
Collagen and gelatin-based products can be used to achieve hemostasis in spinal surgery. Xu et al. [64] carried out a study on 92 patients undergoing spinal fusion surgery and concluded that collagen-based products are superior to gelatin-based products in achieving hemostasis in spine surgery, with lower blood loss and postoperative drain volume.
Oxidized regenerated cellulose has been used for hemostasis in spine surgery. However when used around or in foramina with rigid bony walls, the swelling of small portions of the cellulose material may lead to significant mass effect and neural compression 1 day after surgery as demonstrated by Menovsky et al. [126] and may lead to rapid neurological deterioration. Therefore this material should be removed after hemostasis has been achieved prior to closure.
As mentioned before, liquid fibrin sealants can be used in spine surgery for hemostasis, but those containing tranexamic acid may be associated with neurotoxicity and should not be used if CSF leak or dural tear is present [55].
Topical hemostats and biosurgicals are a diverse group of compounds that have been developed and can be used in different situations as part of a comprehensive blood management program to limit the amount of blood loss. Trauma and orthopedics as a specialty also presents some unique challenges, with operations having significant blood loss and in trauma, junctional injuries on the battlefield with hemorrhage that is hard to control by conventional means. In addition, patients may be complex and frequently have platelet or coagulation disorders that preclude the use of certain classes of hemostatic agents. As mentioned before, these compounds are diverse, with different mechanisms of actions and indications, both in an elective and an emergency trauma setting. A comprehensive knowledge of these products is essential in modern-day trauma and orthopedic practice.
Despite recent developments, the perfect hemostatic or biosurgical agent still remains elusive and each of these products has their own drawbacks, side effects and unique indications and future research will hopefully continue to improve on these.
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\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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