**3.4 Antiphospholipid syndrome**

Primary prophylaxis with anticoagulant medication has not been shown to be beneficial for asymptomatic patients with no other risk factors, regardless of risk profile. Instead, some authors suggest daily administration of a low dose of aspirin, but this measure is not widely accepted. If other risk factors for thrombosis are associated, such as hospitalization, surgery, or concomitant autoimmune disease, prophylaxis is recommended, on a case-by-case basis [16, 34].

Secondary prophylaxis is recommended for patients with definite antiphospholipid syndrome and consists of lifelong vitamin K antagonist medication with a target INR of 2–3. In case of relapse or episodes of arterial thrombosis, the target INR should be >3. Combination with aspirin is not supported by data and is subject to controversy [16, 35].

The use of DOAC in patients with the definite antiphospholipid syndrome is not recommended, following the results of several studies that found direct oral anticoagulation to have a lower efficacy and safety profile than traditional vitamin K antagonist therapy [36].


*4.3. Distributed Algorithm*

To search the Nash equilibrium of the formulated non-cooperative game and population evolution result of the residential communities participating in DR, a distributed algorithm is proposed which is shown in Algorithm 1. In the algorithm, an interior point method is employed to solve Equation (22), which has superior performance in solving convex optimization problems. In addition, steps 2–10 are designed to search the Nash equilibrium among communities in the day-ahead bidding market, and steps 11–14 are designed to obtain the population evolution result of residential communities participating in DR.

**Algorithm 1:** Searching for Nash equilibrium and population evolution result

**Input:** Parameters *at h* , *bt h* , *Lh*,min *n* , *Lh*,max *n* , etc. **Output:** Nash equilibrium, population evolution result. **Initialization:** Number of group *N* in week 1. **1** *h* = 1; **2 Repeat 3** *n* = 1; **4 for** *n* ≤ *N*(*h*) **do 5** Initialize bidding strategy vector *Lh n*; **6** Each community *n* ∈ *N* updates *Lh n* by solving Equation (22); **7** *n* = *n* + 1; **8 end 9 Until** No community changes its strategy; **10 Return** Nash equilibrium  *Lh*∗ *n* , *Lh*∗ −*n* ; **11** Calculate transition probability α and β; **12 Update** group population with Equation (40); **13** *h* = *h* + 1; **14** Go back to step **2** until |*N*(*h*+1) − *N*(*h*)| changes in a termination criterion.


**4. Conclusions**

Although computing the Khovanov homology of links is common in the literature, no general formulae have been given for all families of knots and links. In this paper, we considered a general three-strand braid *x*1*x*2*x*1*x*2 ··· , which, depending on the powers of Garside element Δ = *x*1*x*2*x*1, is divided into six subclasses, and gave the Khovanov homology of Δ2*k*+1, Δ2*k*+1*x*2, and Δ2*k*+1*x*1 (To learn more about these classes, see Reference [23–26].) The results particularly cover the 0th, 1st, and top homology groups of these classes, and all homology groups, in general, of link Δ2*k*+1. We hope the results will help classifying links, and in studying the important properties of these links.

**Author Contributions:** Formal analysis, Y.C.K.; writing—original draft, A.R.N., Z.I., D.A., and S.M.K.; writing—review and editing, M.M.

**Funding:** This work was supported by the Dong-A University research fund.

**Acknowledgments:** We are very thankful to the reviewers for their valuable suggestions to improve the quality of this paper.

**Conflicts of Interest:** The authors declare that they have no conflicts of interest.


**1.1 Ionic liquids (ILs) and their properties**

The melting points of ILs, also known as low-melting-point organic salts, are usually below 100°C; ILs are composed of organic cations and inorganic/organic anions, as shown in **Figure 1** [1, 2]. The number of possible cation-anion combination has been estimated to be >106 [3]. ILs are most commonly abbreviated by writing the abbreviation/formula of the cation and anion in square brackets (without charges); e.g., [bmim][PF6], [bmim][Tf2N] and [emim][Cl] are the abbreviations for 1-butyl-3-methyl-imidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium bis(trifluoromethanesulphonyl)imide and 1-ethyl-3-methylimidazolium chloride, respectively. Owing to their high chemical and thermal stability, low volatility, and low toxicity, ILs have attracted much attention for applications in chemistry and industry. In addition, the properties of ILs include high conductivity, wide electrochemical window, low flammability, ability to dissolve organic and inorganic solutes and gases, and recyclability. As far as vapour pressures are concerned, several

**Figure 1.**

*Typical cationic and anionic components of ILs.*

ILs can be vaporised under a high vacuum at 200–300°C and then recondensed [4]; however, ILs indeed have negligible vapour pressures at near ambient conditions. Thus, for general reactivities or processes, they may be considered as low-volatile reaction media. ILs are generally chemically stable reaction media, but this cannot be taken as granted. The proton at the C(2)-position of imidazolium cation is acidic, and under basic conditions, deprotonation leading to carbene is possible [5]. ILs are considered as rational designable solvents that can be easily tuned by using various combinations of cations and anions to achieve ILs exhibiting appropriate properties and achieving practical applications for a desired task (so-called task-specific ILs), making it possible to introduce ILs into specific synthesis processes [6].

Because of these special properties, ILs have emerged as novel and exciting reaction media in their own right. Every year, an increasing number of papers are being published on the applications of ILs for enhancing reactivities or processes in both chemical research and industry. So far, free-radical polymerisation, polycondensation and ionic polymerisation have been successfully carried out using ILs as the reaction media. In the step polymerisation field, there is a huge interest for highperformance polymers (HPPs). Despite improved synthesis methods and commercial availability of various ILs for replacing typical organic reaction media, they are still more expensive than typical organic reaction media. Therefore, the application of ILs as reaction media for enhancing reactivities or processes is limited.

#### **1.2 High-performance polymers (HPPs) and their categories**

HPPs are also known as high-temperature polymers, special engineering plastics, advanced engineering materials, and heat-resistant polymers [7]. They are defined as polymers that can retain the desirable properties when exposed to very harsh conditions, including, but not limited to, a high-temperature, a high-pressure, and corrosive environment. They are well known for outstanding thermal stability and service temperatures, good mechanical properties, dimensional and environmental stability, high resistance to most chemicals, gas barrier and electrical properties, etc., under extreme conditions, even at elevated temperatures [8, 9]. To better understand the reason for their strength, one must consider the bond strength that can be quantified by bond dissociation energy. First, the higher the bond dissociation energy, the harder it is to break the polymer chain, and thus the better the resistance of the polymer to harsh environment. The bond energies of C–C and C〓C bonds are 83 and 145 kcal mol−1 , respectively; thus, it is harder to break a C〓C bond than a C–C bond. Most HPPs contain more C〓C bonds than C–C bonds. Similarly, the bond energies of C–H and C–F bonds are 99 and 123 kcal mol−1 ,

**101**

*Progress in Ionic Liquids as Reaction Media, Monomers and Additives in High-Performance…*

respectively; some of the C–H groups are also replaced with C–F groups. The resonance stabilisation is enhanced by adding aromatic components along the backbone, and it is estimated that the incorporation of resonance-stabilised units

improves their resistance and stability; thus, they can retain the desirable properties

HPPs include polysulphones (PSFs), polyimides (PIs), polyaryletherketones (PAEKs), poly(arylene sulphide)s (PASs), polyarylates (PARs), liquid crystalline polymers (LCPs), fluoroplastics (PVDFs), *p*-hydroxybenzoic acid polymers, poly(naphthalene), poly(oxadiazole), and high-temperature nylon (HTN). HPPs can be divided into amorphous polymers, semi-crystalline polymers, and LCPs; e.g., PSFs are described as amorphous polymers and polyetheretherketones are semi-crystalline polymers. The applications of HPPs span across aerospace, defence, weaponry, energy, electronics, automotive, construction, nuke industry, membrane technologies, etc. In recent years, new HPPs and materials containing HPPs with enhanced application potential in more fields have been reported, including materials obtained by the chemical modification and blending of HPPs containing ILs.

The aim of this article is to review the recent progress in the field of ILs as reaction media, monomers and additives in the synthesis, chemical modification and physical processing of HPPs based on recent literatures, with the main emphasis on possible advantages, limitations and importance of the work. The article is structured as follows: section 2 focuses on progress in IL application in HPPs. Section 2.1 focuses on ILs as reaction media in the synthesis of HPPs, including PIs, PSFs, and PAEKs, and synthesis of HPPs in ILs under microwave (MW) irradiation. Section 2.2 focuses on ILs as monomers for the chemical modification of HPPs. The last part of Section 2 focuses on ILs as additives for the physical processing of HPPs, including membranes, microcapsules, electrolytes, nanocomposites (NCs) and grease.

Most HPPs are synthesised by step polymerisation reactions. Step polymerisation is one of the main polymerisation reactions for preparing polymers, usually requiring elevated temperatures, high-boiling-point reaction solvents, high vacuum and the removal of small molecules to reach the equilibrium. Therefore, it seems to be suitable to introduce ILs into step polymerisation owing to their intrinsic properties as described above. In 2002, high-molecular-weight aromatic PIs and polyamides were synthesised for the first time, obtaining polymers with inherent viscosities from 0.52 to 1.35 dL/g in ILs 1,3-dialkylimidazolium bromides [10]. The use of ILs as novel solvents for the synthesis of other HPPs has been reported, such

In 1908, Jones et al. first synthesised PIs, but it was difficult to process and fabricate them [14]. Until the early 1960s, Du Pont, USA, made a substantial progress in the processing of PIs; thus, PIs were developed and widely utilised in various applications [15]. These polymers are known as HPPs and possess outstanding

to the bond strength. Such a molecular structure of HPPs

*DOI: http://dx.doi.org/10.5772/intechopen.86472*

**2. Progress in IL application in HPPs**

as PAEK [3, 11] and PSF [12, 13].

*2.1.1 Synthesis of PIs in ILs*

**2.1 ILs as reaction media for synthesis of HPPs**

can add 40–70 kcal mol−1

**1.3 Overview**

under very harsh conditions.

*Progress in Ionic Liquids as Reaction Media, Monomers and Additives in High-Performance… DOI: http://dx.doi.org/10.5772/intechopen.86472*

respectively; some of the C–H groups are also replaced with C–F groups. The resonance stabilisation is enhanced by adding aromatic components along the backbone, and it is estimated that the incorporation of resonance-stabilised units can add 40–70 kcal mol−1 to the bond strength. Such a molecular structure of HPPs improves their resistance and stability; thus, they can retain the desirable properties under very harsh conditions.

HPPs include polysulphones (PSFs), polyimides (PIs), polyaryletherketones (PAEKs), poly(arylene sulphide)s (PASs), polyarylates (PARs), liquid crystalline polymers (LCPs), fluoroplastics (PVDFs), *p*-hydroxybenzoic acid polymers, poly(naphthalene), poly(oxadiazole), and high-temperature nylon (HTN). HPPs can be divided into amorphous polymers, semi-crystalline polymers, and LCPs; e.g., PSFs are described as amorphous polymers and polyetheretherketones are semi-crystalline polymers. The applications of HPPs span across aerospace, defence, weaponry, energy, electronics, automotive, construction, nuke industry, membrane technologies, etc. In recent years, new HPPs and materials containing HPPs with enhanced application potential in more fields have been reported, including materials obtained by the chemical modification and blending of HPPs containing ILs.

### **1.3 Overview**

*Solvents, Ionic Liquids and Solvent Effects*

*Typical cationic and anionic components of ILs.*

**Figure 1.**

ILs can be vaporised under a high vacuum at 200–300°C and then recondensed [4]; however, ILs indeed have negligible vapour pressures at near ambient conditions. Thus, for general reactivities or processes, they may be considered as low-volatile reaction media. ILs are generally chemically stable reaction media, but this cannot be taken as granted. The proton at the C(2)-position of imidazolium cation is acidic, and under basic conditions, deprotonation leading to carbene is possible [5]. ILs are considered as rational designable solvents that can be easily tuned by using various combinations of cations and anions to achieve ILs exhibiting appropriate properties and achieving practical applications for a desired task (so-called task-specific ILs),

Because of these special properties, ILs have emerged as novel and exciting reaction media in their own right. Every year, an increasing number of papers are being published on the applications of ILs for enhancing reactivities or processes in both chemical research and industry. So far, free-radical polymerisation, polycondensation and ionic polymerisation have been successfully carried out using ILs as the reaction media. In the step polymerisation field, there is a huge interest for highperformance polymers (HPPs). Despite improved synthesis methods and commercial availability of various ILs for replacing typical organic reaction media, they are still more expensive than typical organic reaction media. Therefore, the application

HPPs are also known as high-temperature polymers, special engineering plastics, advanced engineering materials, and heat-resistant polymers [7]. They are defined as polymers that can retain the desirable properties when exposed to very harsh conditions, including, but not limited to, a high-temperature, a high-pressure, and corrosive environment. They are well known for outstanding thermal stability and service temperatures, good mechanical properties, dimensional and environmental stability, high resistance to most chemicals, gas barrier and electrical properties, etc., under extreme conditions, even at elevated temperatures [8, 9]. To better understand the reason for their strength, one must consider the bond strength that can be quantified by bond dissociation energy. First, the higher the bond dissociation energy, the harder it is to break the polymer chain, and thus the better the resistance of the polymer to harsh environment. The bond energies of C–C and C〓C

bond than a C–C bond. Most HPPs contain more C〓C bonds than C–C bonds. Similarly, the bond energies of C–H and C–F bonds are 99 and 123 kcal mol−1

, respectively; thus, it is harder to break a C〓C

,

making it possible to introduce ILs into specific synthesis processes [6].

of ILs as reaction media for enhancing reactivities or processes is limited.

**1.2 High-performance polymers (HPPs) and their categories**

**100**

bonds are 83 and 145 kcal mol−1

The aim of this article is to review the recent progress in the field of ILs as reaction media, monomers and additives in the synthesis, chemical modification and physical processing of HPPs based on recent literatures, with the main emphasis on possible advantages, limitations and importance of the work. The article is structured as follows: section 2 focuses on progress in IL application in HPPs. Section 2.1 focuses on ILs as reaction media in the synthesis of HPPs, including PIs, PSFs, and PAEKs, and synthesis of HPPs in ILs under microwave (MW) irradiation. Section 2.2 focuses on ILs as monomers for the chemical modification of HPPs. The last part of Section 2 focuses on ILs as additives for the physical processing of HPPs, including membranes, microcapsules, electrolytes, nanocomposites (NCs) and grease.


*2.3.4 Acidisation—Tight reservoirs*

Acidisation of carbonate rocks (e.g., limestone and dolostone) to improve permeability and porosity can be successfully achieved with hydrochloric acid (HCL). Shales or sandstones containing significant proportions of carbonates can also be treated with HCL. The use of HCL becomes problematic when applied to other kinds of reservoir rocks; for instance, sandstones (chiefly composed of quartz and aluminosilicates), which are insoluble in HCL. The following are some of the problems associated with HCL [83]:

However, sandstones react favourably with hydrofluoric acid (HF). The fine particles of quartz and aluminosilicates which block the pores, especially at the near-wellbore region, are soluble in HF. HF can be introduced directly into the reservoir or produced through other chemicals like ammonium bifluoride (NH4HF2). Normally, mud acid (a blend of aqueous HCL-HF) is used to repair damages around the vicinity of the wellbore [83, 97]. Fluoride ion (F− ) is the only one of its kind that reacts with quartz in a way that repairs the damage near the wellbore [97]. Mud acid can be prepared by mixing a fluoride ion-releasing chemical, ammonium bi-fluoride salt (NH4HF2), with HCL. The reactions are expressed in Eq. (2) [98]:

$$\rm{HCl} \rightarrow \rm{H}^\* + \rm{Cl}^- \tag{2}$$

$$\rm H^{+} + \rm NH\_{4}HF\_{2} \rightarrow \rm NH\_{4}Cl + 2HF \tag{3}$$

For sandstone reservoirs, acidisation is performed in three steps: *preflush*, *main flush* and *after flush* [83]. In practice, at the preflush stage, HCL has been used for the dissolution of carbonates and positive ions (e.g., [83, 99–101]); nonetheless, its effectiveness is inconsistent and there are reported incidences of damages [102]. To circumvent this, it is possible to blend HCL with other chemicals to neutralise its adverse effects. This is demonstrated in Shafiq *et al*. [97], where HCL is combined with acetic acid (CH3COOH) to improve dissolution of carbonates and positive ions (sodium, calcium and magnesium), whilst eluding the damage that would have been triggered by pure HCL.

The second (main) stage of the acidisation process is the use of a fluoride ion (F<sup>−</sup> ) containing acid to dissolve the minerals (e.g., SiO2). HF is a commonly used acid but the fluoride ion is very reactive leading to a premature expending of the acid near the wellbore region. To decelerate the reaction rate, HF must be combined with other mineral acids. These are buffer acids, which may be, for instance, HCL or formic acid (HCOOH). The buffer acid retards the reaction rate of HF with the formation and preserves the pH of products of the reaction, which in turn prevents the precipitation of silica [97]. Other acid blends (mud acids) proposed by Shafiq et al., [97] for the main stage of acidisation include Hydrofluoric-phosphoric acid (HF-H3PO4) and fluoboric-formic acid (H3OBF4- HCOOH). In the former, H3PO4 is a substitute for HCL, while H3OBF4 replaces HF in the latter. The product of the reactions between HF and silica mineral is fluosilicic acid (H2SiF6). The reaction process is presented in Eqs. (4) and (5) [98, 103]:

$$\text{SiO}\_2 + 4\text{HF} \rightarrow \text{SiF}\_4 + 2\text{H}\_2\text{O} \tag{4}$$

*Production from Unconventional Petroleum Reservoirs: Précis of Stimulation Techniques… DOI: http://dx.doi.org/10.5772/intechopen.106318*

$$2\text{SiF}\_4 + 2HF \to H\_2\text{SiF}\_6 \tag{5}$$

Compounds such as silica gelatinous precipitate (Si(OH)4) are eventually formed when fluosilicic acid is decomposed to silicon tetrafluoride (SiF4) (Eq. (6)), which is then hydrolysed (Eq. (7)).

$$H\_2\text{SiF}\_6 \rightarrow 2HF + \text{SiF}\_4 \tag{6}$$

$$\text{SiF}\_4 + 4\text{H}\_2\text{O} \rightarrow \text{Si(OH)}\_4 + 4\text{HF} \tag{7}$$

There is also a tendency for other precipitates to form, which can be avoided by the circulation of HCL at the *preflush* stage to remove ions [97, 100]. The *after-flush* stage restores the wettability of the formation and removes the expended acids. Mutual solvents, HCL, acetic acid and other suitable chemicals are candidates for finalising the treatment process [104].

**Table 1** is a summary illustration and cross-section of approaches for stimulating the production of unconventional reservoirs.

**Table 1.**

*Techniques for stimulating unconventional reservoirs.*


5.2. Pain-state models using mechanical stimuli

#### 5.2.1. Strain gauges

In this test, an increasing amount of pressure is applied to a punctiform area on the hind paw or, far less frequently, on the tail. The tail or paw is wedged between a plane surface and a blunt point mounted on top of a system of cog wheels with a cursor that can be moved in the direction of length of a graduated beam [66]. When the pressure increases, following step wise reactions occurs, i.e. the reflex removal of the paw or a complex movement of the animal to free its captured limb and at last a vocal response is noticed. Randall and Selitto with the aim of enhancing the sensitivity of the test offer comparison of thresholds seen with an inflamed paw and with a healthy paw [67].

#### 5.2.2. von-Frey filaments

The key method for the study of pain in animal models is the assessment of mechanosensitivity. This is frequently executed with the use of von-Frey filaments in an up-down testing model. This is the most commonly used method for measuring pain in animals described by Vivancos [68] for mechanosensitivity testing in rodents. Though, in this method, animals are getting a changeable amount of stimuli which may direct the animals in distinctive groups getting diverse testing experiences that affect their subsequent responses. In order to standardize the measurement of mechano-sensitivity, a simplified up-down method (SUDO) for reckoning paw withdrawal threshold (PWT) with von-Frey filaments has been developed that uses a constant number of five stimuli per test [69].

#### 5.3. Pain-state models using electrical stimuli

#### 5.3.1. Electrical stimulation of the tail

Progressively escalating strength of electrical stimuli can be applied in range (lasting for some milliseconds) through subcutaneous electrodes positioned in the tail of the mouse or the rat. One can see the following: when such slowly increasing intensities of electrical stimuli are applied from invariable voltages 40–50 V, i.e., the impulse movement of the tail, vocalization occurs at the time of stimulation, and then, utterance continuing ahead for the period of stimulation. Due to the electrical current, the animal may be died. Morphine or morphine-like drugs are useful in this model [70].


**4. Biofilms**

A consortium of microorganisms composed of cells adhering to a surface is called a biofilm [51, 52]. The physical setting for cells to adhere to a surface occurs through the intermediacy of extracellular polymeric substances (EPS) which forms a slimy extracellular matrix **Figure 1** [53]. Microbial cells in the biofilm produce the EPS which are composites of extracellular polysaccharides, proteins, lipids, and DNA [54, 55]. The cellular agglomeration of biofilms forms a three-dimensional structure as a community that offers significant protection against the forces levied by the environment [56].

### **4.1 Structure**

Microbial cells composing a biofilm are distinct from the planktonic cells of the same organism, which are single-cell organisms that are free to float or swim in an aquatic medium [57]. Biofilm structures are formed in response to a variety of different factors enabling biofilm development [58, 59]. Surface recognition is important to specific or nonspecific attachment sites, toxic materials, or antibiotics, and nutritional stress may complicate biofilm growth **Figure 2** [60]. A cell that switches to the biofilm mode of growth undergoes a shift of observable behavior of the bacteria resulting from the interaction of its genotype with the environment that is required of a microbial cell in the transition from planktonic to sessile growth in the regulation genes of the biofilm. A biofilm can mimic a hydrogel, a three-dimensional (3D) network of hydrophilic polymers complex containing a

### **Figure 1.**

*Site of biofilm interactions.*

large quantity of water, which retains its structure through chemical or physical cross-linking polymer chains [61]. Biofilm formation can lead to the formation of a coordinated functional microbial community. The bacteria composing a biofilm can share nutrients due to their proximity in the biofilm and protection from harmful factors of the environment. Biofilms usually begin to form when a free-swimming bacterium attaches to a surface [62].

Colonization of a surface requires a significant transition from the free-living planktonic existence in the bulk aquatic phase to a surface-attached state. A biofilm life cycle is portrayed in **Figure 2** [63]. This process is initiated by the reversible adhesion of a few single cells to a surface leading to a reversible attachment where weakly attached cells are sloughed to the bulk medium, or irreversible attachment where interactions of the cells and a surface are reinforced [64]. Irreversibly attached cells at a surface continue to agglomerate to form microcolonies through cellular division and can proceed to form a mature biofilm when the conditions support growth [65]. As the biofilm matures, factors that will prevent sustainable growth can be triggered by limited nutrients supply or lowered oxygen concentrations may reverse biofilm formation through the dispersal of cells from the biofilm to the bulk aquatic phase. Released cells may attach to a new surface [66]. For single-cell adhesion, three factors leading to single-cell adhesion require attention: the chemical and physical composition of the aquatic environment, the solid surface, and the transitioning microbiota [67].

### **4.2 Characteristics**

Microorganisms form from attached phase growth structures (biofilms) or multicellular microbial communities by transitioning from planktonic (freelyswimming) biota to components of a complex, surface-attached community (**Figure 1**). These communities of adhering microorganisms in the form of biofilms provide protection to the microbes participating in its development. The process begins with planktonic microorganism encountering a surface where some adsorb followed by surface release to final attachment by the secretion of exopolysaccharides which act as an adhesive for the growing biofilm (**Figure 2**) [68]. Switching from a planktonic existence to an attached-life state (sessile) requires a complex

**309**

rotating polypropylene disk.

**Figure 2.** *Biofilm life cycle.*

**4.3 Plastic colonization and plastisphere communities**

*The Importance of Biofilms to the Fate and Effects of Microplastics*

process composed of several factors derived from biological, chemical, and physical properties of the environment, the surface, and the bacterial cell (**Figure 2**) [69]. Initial weak, reversible interactions between a bacterium and a surface lead to irreversible adhesion. New phenotypic characteristics are exhibited by the bacteria of a biofilm in response to environmental signals. Initial cell-polymer surface interactions, biofilm maturation, and the return to the planktonic mode of growth have regulatory circuits and genetic elements controlling these diverse functions. Studies have been conducted to explore the genetic basis of biofilm development with the development of new insights. Compositionally, these films have been found to be a single microbial species or multiple microbial species with attachment to a range of biotic and abiotic surfaces [70]. Mixed-species biofilms are generally encountered in most environments. With proper nutrient and carbon substrate provided, biofilms can grow to massive sizes. A biofilm can achieve large film structures that may be sensitive to physical forces such as agitation. Such energy regimes can lead to biofilm detachment. An example of biofilm attachment and utility can be found in the wastewater treatment sector where large polypropylene disks are rotated through industrial or agriculture wastewater and then exposed to the atmosphere to treat pollutants through the intermediacy of cultured biofilms attached to the

Plastic's role in freshwater and marine systems is poorly understood from many perspectives especially microbiology. Microscopic scrutiny and next-generation sequencing of PMD from locations in the North Atlantic were used to characterize attached microbial communities. A microbial community having a high degree of diversity was identified as the "Plastisphere" from the pitting of the debris surface which suggested bacterial shapes engaged in the utilization of the polymer by enzymatic means [71]. Opportunistic pathogens were observed as specific members of the genus *Vibrio* [72, 73]. Attached plastisphere communities were found to be distinct from surrounding surface water, suggesting that PMD could be a novel ecological habitat in the open ocean. Most natural floating marine substrates have shorter half-lives than PMD which is enhanced by a hydrophobic surface that assists

*DOI: http://dx.doi.org/10.5772/intechopen.92816*

*The Importance of Biofilms to the Fate and Effects of Microplastics DOI: http://dx.doi.org/10.5772/intechopen.92816*

*Bacterial Biofilms*

**Figure 1.**

*Site of biofilm interactions.*

large quantity of water, which retains its structure through chemical or physical cross-linking polymer chains [61]. Biofilm formation can lead to the formation of a coordinated functional microbial community. The bacteria composing a biofilm can share nutrients due to their proximity in the biofilm and protection from harmful factors of the environment. Biofilms usually begin to form when a free-swimming

Colonization of a surface requires a significant transition from the free-living planktonic existence in the bulk aquatic phase to a surface-attached state. A biofilm life cycle is portrayed in **Figure 2** [63]. This process is initiated by the reversible adhesion of a few single cells to a surface leading to a reversible attachment where weakly attached cells are sloughed to the bulk medium, or irreversible attachment where interactions of the cells and a surface are reinforced [64]. Irreversibly attached cells at a surface continue to agglomerate to form microcolonies through cellular division and can proceed to form a mature biofilm when the conditions support growth [65]. As the biofilm matures, factors that will prevent sustainable growth can be triggered by limited nutrients supply or lowered oxygen concentrations may reverse biofilm formation through the dispersal of cells from the biofilm to the bulk aquatic phase. Released cells may attach to a new surface [66]. For single-cell adhesion, three factors leading to single-cell adhesion require attention: the chemical and physical composition of the aquatic environment, the solid

Microorganisms form from attached phase growth structures (biofilms) or multicellular microbial communities by transitioning from planktonic (freelyswimming) biota to components of a complex, surface-attached community (**Figure 1**). These communities of adhering microorganisms in the form of biofilms provide protection to the microbes participating in its development. The process begins with planktonic microorganism encountering a surface where some adsorb followed by surface release to final attachment by the secretion of exopolysaccharides which act as an adhesive for the growing biofilm (**Figure 2**) [68]. Switching from a planktonic existence to an attached-life state (sessile) requires a complex

bacterium attaches to a surface [62].

surface, and the transitioning microbiota [67].

**4.2 Characteristics**

**308**

process composed of several factors derived from biological, chemical, and physical properties of the environment, the surface, and the bacterial cell (**Figure 2**) [69]. Initial weak, reversible interactions between a bacterium and a surface lead to irreversible adhesion. New phenotypic characteristics are exhibited by the bacteria of a biofilm in response to environmental signals. Initial cell-polymer surface interactions, biofilm maturation, and the return to the planktonic mode of growth have regulatory circuits and genetic elements controlling these diverse functions. Studies have been conducted to explore the genetic basis of biofilm development with the development of new insights. Compositionally, these films have been found to be a single microbial species or multiple microbial species with attachment to a range of biotic and abiotic surfaces [70]. Mixed-species biofilms are generally encountered in most environments. With proper nutrient and carbon substrate provided, biofilms can grow to massive sizes. A biofilm can achieve large film structures that may be sensitive to physical forces such as agitation. Such energy regimes can lead to biofilm detachment. An example of biofilm attachment and utility can be found in the wastewater treatment sector where large polypropylene disks are rotated through industrial or agriculture wastewater and then exposed to the atmosphere to treat pollutants through the intermediacy of cultured biofilms attached to the rotating polypropylene disk.

### **4.3 Plastic colonization and plastisphere communities**

Plastic's role in freshwater and marine systems is poorly understood from many perspectives especially microbiology. Microscopic scrutiny and next-generation sequencing of PMD from locations in the North Atlantic were used to characterize attached microbial communities. A microbial community having a high degree of diversity was identified as the "Plastisphere" from the pitting of the debris surface which suggested bacterial shapes engaged in the utilization of the polymer by enzymatic means [71]. Opportunistic pathogens were observed as specific members of the genus *Vibrio* [72, 73]. Attached plastisphere communities were found to be distinct from surrounding surface water, suggesting that PMD could be a novel ecological habitat in the open ocean. Most natural floating marine substrates have shorter half-lives than PMD which is enhanced by a hydrophobic surface that assists

microbial colonization and biofilm formation. The adhesion of individual bacteria to a surface-initiated biofilm formation is supported by a collection of factors arising from initial adhesion to the growth of a mature biofilm [74].

Bacteria communicate with one another using chemical signal molecules [75]. This process, termed quorum sensing, allows bacteria to monitor the environment to adjust community behavior at a population-wide scale in response to community changes in the number and species present [76]. The information conveyed by these molecules works to synchronize activities for a wide group of cells. This cell-to-cell communication is used by bacteria to coordinate population density-dependent changes in behavior. Quorum sensing involves the production of and response to diffusible or secreted signals, which can vary substantially across different types of bacteria and important to the first stage of encounter between a bacterium and a solid surface [77].

Initial bacterial adhesion to a surface, bacterial mass transport, the role of substratum surface properties in initial adhesion and the transition from reversible to irreversible adhesion have been analyzed through a physiochemical lens to yield great insight. Surface thermodynamics and Derjaguin Landau Verwey Overbeek analyses can describe bacterial support using smooth, inert colloidal particles to estimate bacterial cells. A depiction of initial bacterial adhesion to surfaceprogrammed biofilm growth was found to have four major stages: bacterial mass transport towards a surface, reversible bacterial adhesion, conversion to irreversible adhesion, cell wall deformation, and associated developing properties [78]. The production of EPS can be surface-programmed [79]. Initial bacterial adhesion to surfaces and biofilm growth at the solid surface is driven by aspects of physicochemistry [80].

Bacterial adhesion is important to the fate and transport of plastics in aquatic environments. There has been no systematic investigation of bacterial adhesion to different types of plastics. A limited evaluation of short-term and long-term adhesion for different types of bacteria and four types of plastics, polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), and polyvinyl chloride (PVC), was conducted [81]. The target physicochemical factors of surface charge, hydrophobicity/hydrophilicity, roughness, and plastic hardness were characterized. Surface hardness of the plastics was identified as a major factor dominating the adhesion of bacteria onto plastic surfaces in contrast to the other factors [82]. There were significant differences in bacterial cell adhesion for the types of plastics. The different plastic types influenced the bacterial adhesion due to intrinsic surface properties in both short- and long-term studies [83]. Generally, surface roughness, topography, surface free energy, surface charge, electrostatic interactions, and surface hydrophobicity are anticipated to be important to the process of biofilm attachment [84].


**4. Evolving controversies**

## **4.1 Stroke**

There is a common misconception that trans-catheter therapies are inherently associated with fewer strokes. This is an observation that has not been demonstrated in many of the high-profile studies. Furthermore, there are growing concerns that the neurologic events that patients experience after trans-catheter therapies occur after the index hospitalization in which the procedure is performed. For example, one study exploring a Medicare database of over 44,000 patients suggested an 86% greater risk of ischemic stroke and a six-fold increase risk of hemorrhagic stroke after trans-catheter therapies when compared to conventional surgery, with many of the events occurring in subsequent readmissions to the hospital within the first year [19]. In fact, the 90-day readmission rate for neurologic events after TAVR was substantially higher than many other cardiac and non-cardiac procedures, including left ventricular assist device placement, cardiac catheterization, surgical aortic valve replacement, and coronary artery bypass procedures [20]. Clearly, the risk of neurologic events after catheter-based valvular interventions requires further objective review.

Such concerns have resulted in a substantial increase in the development and utilization of cerebral protection devices during TAVR. Despite the inherent appeal and considerable cost associated with these protection devices, definitive data demonstrating a clinical improvement and reduction in neurologic events is still lacking [21, 22]. Nevertheless, this is an area of tremendous research and development [23, 24].

### **4.2 Pacemaker rates**

There is no doubt, as demonstrated in almost every major study of TAVR, that this procedure is associated with a much greater risk for needing a permanent pacemaker when compared to conventional surgery. While conduction abnormalities are not uncommon after valve surgery, there is growing concern that the need for a pacemaker after TAVR is neither trivial nor benign. Some large-scale studies suggest a four-fold increase in the need for permanent pacemaker after TAVR [25]. While the long-term consequences of needing a pacemaker are still unclear, especially since the short and long-term natural history of conduction problems after valve replacement is variable, there is evidence to suggest that the need for a pacemaker is associated with worse long-term survival in these patients [26]. Considering the growing emphasis on early discharge and the concern that some of the conduction abnormalities might be physiologically significant and not present until after the index hospitalization, the consequences of such events is still unclear [27].

### **4.3 Paravalvular leaks**

Unlike surgical valve replacement in which the existing stenotic calcified valve is physically removed, TAVR inserts and expands against the existing valve. This fundamental difference in the two procedures can explain why TAVR is still associated with a significantly higher rate of paravalvular leaks – especially in those with eccentric valve pathology or bicuspid valves [28]. Again, the long-term significance of paravalvular leaks is incompletely defined, but without a doubt, those patients with at least moderate leaks have a much worse survival at 2 years than those with mild or less leaks. The PARTNER 2 study, as previously discussed

**7**

*Introductory Chapter: The Evolution of Complex Valve Pathology - The Surgeon's Perspective*

above, demonstrated a 34% risk of mortality in patients with moderate to severe paravalvular leaks, when compared to the 13-14% risk in those with none, trace, or

Durability and cost remain a considerable concern regarding catheter-based therapies. Although costs vary significantly depending on the intrinsic structure of a health-care system, conflicting evidence regarding the short- and long-term costs of different types of therapy for valvular disease exists. Without a doubt, a surgical valve is substantially less expensive than a catheter-based valve, but the overall costs of the hospitalization and short-term rehabilitation needs might be more. However, factoring in the needs for pacemakers, stroke management, and concomitant coronary disease, there is growing concern surrounding the real-world costs for catheter-based therapies – especially as an increasing number of patients with advanced comorbidities, age, and poor functional status are being treated prior to

Especially with patients who are older and have multiple comorbidities, the incidence of coronary artery disease further challenges clinical decision-making. Again, despite the appeal of catheter-based solutions to treat both obstructive coronary disease and aortic valve pathology, definitive data directing one therapeutic option over another is lacking. In fact, many of the initial studies exploring the outcomes of one approach over another specifically excluded concomitant coronary procedures or those patients with significant obstructive disease. Nevertheless, criticism of some of the more recent low risk trials is that the surgical patients had a much higher intrinsic risk profile because of the need for concomitant coronary revascularization. In addition, structural characteristics of artificial valves also raises concerns regarding difficulties in coronary access in patients with previous valve replacements (both surgical and TAVR) and further suggests the importance of complete revascularization at the time of definitive valve therapies. As mentioned, many studies specifically excluded patients with combined aortic stenosis and coronary artery disease, and current guidelines tend to favor surgery considering the limitations of the data [32, 33]. Preliminary data also suggests that patients undergoing coronary stenting prior to TAVR may have worse outcomes and increased need for re-interventions due to major adverse cardiac and cerebrovascu-

The area of aortic valve disease that probably is the most supportive of transcatheter therapies is in patients that have had previous valve replacement, either with a previous surgical valve or a trans-catheter valve. Many patients underwent surgical replacement with a biologic valve, despite established guidelines and a potential survival advantage advocating the use of a mechanical valve under the promise that their next intervention would be a trans-catheter valve [36, 37]. While the appeal of this approach is undeniable and logical, the practical applications are still under considerable study. Conflicting data regarding the best approach for the management of a failing biologic valve is substantial. Even though repeat surgery is not without risks, many experienced centers can offer re-operative surgery with a risk profile similar to first-time valve replacement. Furthermore, there are concerns

*DOI: http://dx.doi.org/10.5772/intechopen.95049*

mild leaks [29]

dying [30, 31].

lar events [34, 35].

**4.6 Repeat interventions**

**4.5 Coronary artery interventions**

**4.4 Durability and cost**

*Introductory Chapter: The Evolution of Complex Valve Pathology - The Surgeon's Perspective DOI: http://dx.doi.org/10.5772/intechopen.95049*

above, demonstrated a 34% risk of mortality in patients with moderate to severe paravalvular leaks, when compared to the 13-14% risk in those with none, trace, or mild leaks [29]


**1. Introduction**

Nanotechnology-enabled drug delivery systems (NDDS) are associated with high expectations regarding their economic and societal value. NDDS are expected to contribute to important issues in healthcare such as enabling novel pharmaceutical therapies which only target the site of the disease and help to reduce costs of healthcare. To date, more than two dozen NDDS have been developed into marketed products and many more are under development [1]. Market forecasts have estimated that the market for these technologies will grow from US\$ 1 billion in 2010 to US\$ 136 billion in 2021 [2, 3].

The pronounced expectations surrounding nanotechnology-enabled drug delivery applica‐ tions and its claimed market potential suggest that the path toward market introduction is clear. This is however not the case, as is often with newly emerging technologies. While for instance claims have been made about NDDS contributing to a reduction of undesirable side effects of drugs (compared to conventional delivery systems), to date limited clinical data is available to actually support such claims. Uncertainties about the application of regulatory regimes and which methodologies to apply in order to assess novel nanotechnology-enabled drug carriers have created further challenges for firms to introduce new products on the market.

Making promises is almost inevitable in order to attract attention and mobilize resources. However, too broad promises may make sponsors such as large pharmaceutical companies and venture capitalists reluctant. Uncertainties about the performance of specific future drug delivery systems, the demand for such technologies and how they will be evaluated by

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

regulatory authorities have contributed to impasses, 'waiting games' as we have called them [1, 4] which constrain development and potential market introduction of NDDS.

new technologies become embedded is difficult in itself, due to uncertainties regarding how new products will eventually look like and their impacts. Anticipation of how other involved actors perceive and cope with parts of the embedding process and what this means for individual actors' strategies then introduces further complexities. Yet, taking into account these perspectives and strategies is exactly what is important in the case of the drug delivery sector, which consists of an intersection of different value chains with a large number of mutually dependent actors. Then how to anticipate future market introduction and embedding of nanotechnology-enabled drug delivery systems? How to support articulation of anticipa‐ tory strategies and decision making of, say academic and business entrepreneurs, taking into

Anticipating Market Introduction of Nanotechnology-Enabled Drug Delivery Systems

http://dx.doi.org/10.5772/57180

503

The question of anticipation of future introduction and embedding of NDDS is a common challenge of emerging technologies. Within the field of technology assessment a number of approaches have been developed to deal with uncertainties of emerging technologies empha‐ sizing interactive anticipatory approaches such as real-time technology assessment [7], anticipatory governance [8], interaction research in lab-settings [9] and constructive technol‐ ogy assessment [10]. Such approaches are devised to support stakeholders in their anticipatory competences and to support strategies and decision making. These approaches differ in terms of scope, i.e. which dynamics and actors are taken into account, and in their main target

In this chapter I will focus on the approach of Constructive Technology Assessment (CTA) which has a particular emphasis on exploring future developments with stakeholders in a domain and feeding insights back to researchers and technology developers. This approach is by now well established and has been applied for different nanotechnologies and their applications. I will describe the methodology of CTA scenario workshops and demonstrate the approach by offering the results of a study [11] where this approach was used to map and support anticipation of opportunities and challenges of nanotechnology-enabled drug

In section 2 I will start with offering a general perspective on how different types of actors perceive and assess emerging technologies. This is important to recognize when interacting with a variety of involved actors and forms the backdrop against which I position the meth‐ odology and approach of Constructive Technology Assessment and its scenario workshops. I will describe the CTA methodology and discuss how to organize and prepare for such interactive workshops. In section 3 I will set the scene for the workshops by briefly describing the main actors involved in the drug delivery sector and the promises of NDDS. In section 4 I will report on the preparation of the workshops and discuss in detail the main lines of discussion in the workshop and participants' assessments of the situation in which the drug delivery sector finds itself regarding emerging nanotechnologies. In section 5 I will conclude by summarizing main findings and reflecting on the merits of the CTA approach for antici‐ pating, and supporting anticipation of, market introduction of nanotechnology-enabled drug

account other actors' perspectives in the domain of drug delivery systems?

audience, i.e. whose strategy articulation and assessment is actually supported.

delivery technologies.

delivery systems.

In such uncertain and ambiguous situations actors need to make sense of what is happening already and what might happen [5], before taking a specific course of action. There are two main strategies available to developers of NDDS to handle this challenging situation. Aca‐ demic entrepreneurs and firms interested in developing and introducing NDDS on the market may view uncertainties regarding performance and value inevitable and/or postpone such discussions until a later stage and wait for the 'invisible hands' of the market to do its proverbial work. Or, they can anticipate reception of new products and interact with the broader environment to work towards the market introduction of what they consider to be desirable products.

Pro-active interactions will have to go beyond the promotion of promises of nanotechnologyenabled drug delivery systems in anticipation of the opening up of new markets. Market success of newly introduced NDDS products involves more than attractive sales figures. Deuten et al. [6] argued for broadening the notion of market success by thinking in terms of what they call 'societal embedding'. They characterized societal embedding by three dimen‐ sions (p. 132): (1) Integration: new technologies need to be integrated in industries and markets; that is, within business practices and repertoires of users, in this case clinicians and patients. (2) Admissibility: new products need to be acceptable according to rules and standards within the sector or set by the government. Think for instance of good manufacturing practices, preclinical testing and clinical trials. (3) Acceptance: new products have to be accepted by the public. That is, societal concerns should not be too strong, there should be sufficient articulation in order to make well-informed choices by clinicians and patients, and the product should actually be used.

Pro-active action then requires taking a broader perspective than that of a single actor, saying an academic researcher or a start-up firm with a patent in the field of NDDS. Societal embed‐ ding involves a variety of issues which create openings for different actors - who have different interests in, and perspectives on, emerging NDDS - to engage in strategic actions and interac‐ tions. In the drug delivery sector, firms, governmental bodies, health insurers, scientists, clinicians and patient organizations are all more or less involved in interactions with respect to one or more dimensions of societal embedding. Thus, important dynamics related to the market introduction of NDDS exist at the level of the drug delivery sector rather than at the level of individual academic or business entrepreneurs. Put differently, for the market introduction of NDDS entrepreneurial individuals and organizations are dependent on interactions with other players in the sector which is beyond their full control. Pro-active action then requires understanding of what happens at the level of the domain and feeding back such insights into individual or collective strategies to further development and market introduc‐ tion of NDDS.

Anticipation on future market introduction and embedding may seem the wiser option compared to trial-and-error strategies, but is also difficult and precarious. Anticipation on how new technologies become embedded is difficult in itself, due to uncertainties regarding how new products will eventually look like and their impacts. Anticipation of how other involved actors perceive and cope with parts of the embedding process and what this means for individual actors' strategies then introduces further complexities. Yet, taking into account these perspectives and strategies is exactly what is important in the case of the drug delivery sector, which consists of an intersection of different value chains with a large number of mutually dependent actors. Then how to anticipate future market introduction and embedding of nanotechnology-enabled drug delivery systems? How to support articulation of anticipa‐ tory strategies and decision making of, say academic and business entrepreneurs, taking into account other actors' perspectives in the domain of drug delivery systems?

regulatory authorities have contributed to impasses, 'waiting games' as we have called them

In such uncertain and ambiguous situations actors need to make sense of what is happening already and what might happen [5], before taking a specific course of action. There are two main strategies available to developers of NDDS to handle this challenging situation. Aca‐ demic entrepreneurs and firms interested in developing and introducing NDDS on the market may view uncertainties regarding performance and value inevitable and/or postpone such discussions until a later stage and wait for the 'invisible hands' of the market to do its proverbial work. Or, they can anticipate reception of new products and interact with the broader environment to work towards the market introduction of what they consider to be desirable

Pro-active interactions will have to go beyond the promotion of promises of nanotechnologyenabled drug delivery systems in anticipation of the opening up of new markets. Market success of newly introduced NDDS products involves more than attractive sales figures. Deuten et al. [6] argued for broadening the notion of market success by thinking in terms of what they call 'societal embedding'. They characterized societal embedding by three dimen‐ sions (p. 132): (1) Integration: new technologies need to be integrated in industries and markets; that is, within business practices and repertoires of users, in this case clinicians and patients. (2) Admissibility: new products need to be acceptable according to rules and standards within the sector or set by the government. Think for instance of good manufacturing practices, preclinical testing and clinical trials. (3) Acceptance: new products have to be accepted by the public. That is, societal concerns should not be too strong, there should be sufficient articulation in order to make well-informed choices by clinicians and patients, and the product should

Pro-active action then requires taking a broader perspective than that of a single actor, saying an academic researcher or a start-up firm with a patent in the field of NDDS. Societal embed‐ ding involves a variety of issues which create openings for different actors - who have different interests in, and perspectives on, emerging NDDS - to engage in strategic actions and interac‐ tions. In the drug delivery sector, firms, governmental bodies, health insurers, scientists, clinicians and patient organizations are all more or less involved in interactions with respect to one or more dimensions of societal embedding. Thus, important dynamics related to the market introduction of NDDS exist at the level of the drug delivery sector rather than at the level of individual academic or business entrepreneurs. Put differently, for the market introduction of NDDS entrepreneurial individuals and organizations are dependent on interactions with other players in the sector which is beyond their full control. Pro-active action then requires understanding of what happens at the level of the domain and feeding back such insights into individual or collective strategies to further development and market introduc‐

Anticipation on future market introduction and embedding may seem the wiser option compared to trial-and-error strategies, but is also difficult and precarious. Anticipation on how

[1, 4] which constrain development and potential market introduction of NDDS.

products.

502 Application of Nanotechnology in Drug Delivery

actually be used.

tion of NDDS.

The question of anticipation of future introduction and embedding of NDDS is a common challenge of emerging technologies. Within the field of technology assessment a number of approaches have been developed to deal with uncertainties of emerging technologies empha‐ sizing interactive anticipatory approaches such as real-time technology assessment [7], anticipatory governance [8], interaction research in lab-settings [9] and constructive technol‐ ogy assessment [10]. Such approaches are devised to support stakeholders in their anticipatory competences and to support strategies and decision making. These approaches differ in terms of scope, i.e. which dynamics and actors are taken into account, and in their main target audience, i.e. whose strategy articulation and assessment is actually supported.

In this chapter I will focus on the approach of Constructive Technology Assessment (CTA) which has a particular emphasis on exploring future developments with stakeholders in a domain and feeding insights back to researchers and technology developers. This approach is by now well established and has been applied for different nanotechnologies and their applications. I will describe the methodology of CTA scenario workshops and demonstrate the approach by offering the results of a study [11] where this approach was used to map and support anticipation of opportunities and challenges of nanotechnology-enabled drug delivery technologies.

In section 2 I will start with offering a general perspective on how different types of actors perceive and assess emerging technologies. This is important to recognize when interacting with a variety of involved actors and forms the backdrop against which I position the meth‐ odology and approach of Constructive Technology Assessment and its scenario workshops. I will describe the CTA methodology and discuss how to organize and prepare for such interactive workshops. In section 3 I will set the scene for the workshops by briefly describing the main actors involved in the drug delivery sector and the promises of NDDS. In section 4 I will report on the preparation of the workshops and discuss in detail the main lines of discussion in the workshop and participants' assessments of the situation in which the drug delivery sector finds itself regarding emerging nanotechnologies. In section 5 I will conclude by summarizing main findings and reflecting on the merits of the CTA approach for antici‐ pating, and supporting anticipation of, market introduction of nanotechnology-enabled drug delivery systems.