*3.3. Evaluation of Wear Resistance and Long-Term Friction Behaviour*

As mentioned in Section 2.4, the determination of the wear resistance was performed only for the 3 samples having an antifriction-coating: coated benchmark, 3D microtextured (90◦) coated and 3D microtextured (45◦) coated samples. The wear resistance was determined as the wear rate (mm3/h), which was calculated from wear volume values, measured using laser optical microscopy after the tribological tests, divided by the test duration. It is worth noting that since disc specimens possess an extremely high number of micropillars (and microvalleys) on their surfaces, it is almost impossible to precisely quantify their wear volume after the wear-based tribological tests, because wear measurements were performed using a normal height threshold technique using a defined level, which also encompasses intact microvalleys that did not experience any wear during the tribological tests. Therefore, reported wear values for the disc specimens should not be interpreted as absolute, but as relative, values, which still enable a valuable comparison to be made between the investigated tribological pairings.

But first of all, before presenting the measured wear rates of the 3 aforementioned sample variations, coefficients of friction during these wear resistance tests were also monitored and are presented in Figure 13a for a direct comparison to the friction coefficients measured during the load-varying tests (short-term tests; Figure 12). For this comparison, one should bear in mind that the wear tests were performed at a normal load of 125 N; therefore, on the corresponding diagrams of Figure 12, the friction coefficient value at a load of 125 N should be used as a comparison point. Furthermore, the first values of the coefficients of friction measured and presented in Figure 13a are after a test duration of 15 min, which is about 3 times longer than the short-term load-varying tests. In order to facilitate the direct comparison of the coefficients of friction related to both tribological tests, the results of Figure 12a,c were partially combined and are presented in Figure 13b, and the corresponding coefficients of friction are listed in Table 7.

**Figure 13.** Average coefficients of friction measured: (**a**) during wear resistance tests (long-term tribological tests: 125 N, 2 h) and (**b**) during load-varying tests (short-term tribological tests: 25–200 N, 5 min. per load level) (Figure 13 = partial combination of Figure 12a,c).

**Table 7.** Comparison of coefficients of friction measured during wear resistance (long-term: 125 N, 2 h) and load-varying (short-term: 25-200 N, 5 min. per load level) tribological tests.

From Figure 13 and Table 7, it is obvious that the friction coefficients obtained either from wear resistance tests (@ 15 min) or from load-varying tests (@ 125 N) are quite similar, which gives a certain degree of validation for the friction coefficients obtained from both different tribological tests. The small discrepancy observed for the 3D microtexture with a 45◦-angle may be due to the fact that the time-range of the compared values is different (15 min for wear tests, 5 min for load-varying tests).

It is worth noting that the error bars shown in Figure 13b are larger than those in Figure 13a due to different procedures used for friction measurements. The friction values shown in Figure 13b (short-term tribological tests with varying loads) were measured and averaged for a time duration of 0.2 s at the beginning and end of each load level (*t*begin = 0 s; *t*end = 5 min.); therefore, for each load level, and due to the short time period at a new constant load value, the friction values were partially measured when the system was still in the running-in phase (in which the friction may still be relatively unstable and may relatively differ from test to test), thus resulting in larger error bars when averaging values measured from 3 short-term tribological tests. On the other hand, the friction values shown in Figure 13a (long-term tribological tests at a constant load) were measured and averaged for a time duration of 0.2 s every 15 min (*t*1 = 15 min.; *t*2 = 30 min., etc.); therefore, for the first friction measurement at t1 = 15 min., the running-in phase of the system was already finished and the system was already in a friction regime where the friction was relatively stable and relatively reproducible between different tests, resulting in smaller error bars when averaging 3 long-term tribological tests.

Typical top view pictures of wear scars after the performed wear resistance tests obtained using laser microscopy are shown in Figure 14. At first sight, one may observe that the scars of the benchmark samples are somewhat larger than those of the 3D-textured samples, with the smallest scars for the 3D-textured samples with a 90◦-angle.

For the coated benchmark samples, it is obvious that the antifriction coating was completely depleted in the center of the wear scars on the disc specimen, and thus, that the cylinder came into contact with the base material of the disc specimen, which greatly influenced the friction and wear behavior of the coated benchmark samples. At the periphery of the wear scars on the cylinder, small areas may be observed in which material transfer of the antifriction coating from the disc specimens occurred.

**Figure 14.** Typical wear scars on cylinder and disc specimens after wear resistance tests obtained using laser microscopy.

For the 3D-textured samples, the cylinder surface shows linear grooves produced by the lower 3D-texture for the samples aligned with an angle of 90◦, but no linear grooves were visually observed for the 3D-textured sample aligned at an angle of 45◦, which is simply due to the orientation angle of the 3D-texture with respect to the motion direction of the tribometer during the wear tests, as shown in Figure 15. Actually, linear grooves were also produced on the cylinders for the 3D-texture with an angle of 45◦, but the extremely small distance between each groove renders their visual observation difficult: grooves produced on the cylinders when the angle was 90◦ had a width equal to the plateau side dimensions (~ 37 μm as reported in Table 5), while grooves produced on the cylinders when the angle was 45◦ had a width equal to the plateau diagonals (~52 μm = √2 × 37 μm).

**Figure 15.** Explanation of (**a**) presence of visible linear grooves (width of grooves = sides of plateaus ~37 μm) on cylinders for the 3D-texture with an angle of 90◦ to the direction of motion and (**b**) near absence of visible linear grooves (width of grooves = diagonals of plateaus = ~52 μm) on cylinders for the 3D-texture with an angle of 45◦ to the direction of motion.

The averages of wear rates (mm3/h) of discs and cylinders measured using laser optical microscopy are shown in Figure 16a and 16b for all 3 sample variations respectively. From both diagrams shown in Figure 16, it may be seen that the use of a 3D microtexture with an orientation of 90◦ to the direction of motion in combination with an antifriction coating may reduce the overall wear rate of the tribological system (upper and lower specimens) from an average of 0.5 mm3/h to approximately 0.25 mm3/h for the discs and from an average of 0.0125 mm3/h to approximately 0.0075 mm3/h for the cylinders. By orienting the 3D microtexture at an angle of 45◦ relative to the direction of motion, the wear rate of the discs stays at a value similar to the benchmark, while the wear rate of the cylinders increased slightly above 0.02 mm3/h.

**Figure 16.** Average wear rate (mm3/h) calculated from laser microscopy measurements after long-term tribological tests (2 h) of: (**a**) discs and (**b**) cylinders.

The increase in wear rates for the 3D-textured and coated samples with an angle of 45◦ in comparison with the similar samples with an angle of 90◦ may be explained by the fact that the contact width of the plateaus having a 45◦-angle is significantly higher (~52 μm) than for a 90◦-angle (~37 μm), as shown schematically in Figure 15, and therefore, the amount of worn material through ploughing is higher for both disc and cylinder specimens. Furthermore, the lower wear resistance of the microtexture with a 45◦-angle (in comparison to the samples with a 90◦-angle) is also believed to be due to the difference in real contact pressures between these two textures. For a defined unit surface area, the number of micropillars encompassed by this area is always about 20–25% lower for the samples with a 45◦-angle than for the samples having a 90◦-angle; thus, the real contact pressures experienced by the 45◦-angle samples is 20–25% higher than the contact pressures encountered by the samples having a 90◦-angle (*p* = *F*N/*A*, where *p* = contact pressure in N/mm2, *F*N = load in N and *A* = contact surface in mm2). Table 8 gives a short overview of the formulas used for the calculation of the ratio of the contact pressures for both microtextures having different orientation angles to the direction of motion during long-term tribological tests.

**Table 8.** Calculations of ratio of real contact pressures for both microtextures with different angles to the direction of motion during long-term tribological tests.

For the textured samples with a 45◦-angle, the fact that the wear rate of the disc specimens is similar to the coated benchmark samples (Figure 16a) while the wear rate of the cylinders is significantly higher than the coated benchmark samples (Figure 16b) needs to be analyzed separately in more detail; this will be the focus of a future study and publication.


**4. Aurora kinases and cancer**

Chromosomal instability is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumor progression [73]. In fact, aberrations in chromosome number and structure, likely resulting from a combination of ineffective checkpoints and anomalous cellular divisions, occur in the majority of human cancers [74]. Given the crucial tasks of Aurora kinases in all mitotic stages, their dysfunction and/or dysregulation is believed to greatly contribute to aneuploidy. Whether Aurora kinases may have a role in cancer initiation is still a matter of debate. It has been reported that the overexpression of either Aurora-A, Aurora-B, or Aurora-C induces cell malignant transformation [75–77]. In different studies, however, the transforming ability of either Aurora-A or Aurora-B overexpression could not be confirmed [78, 79].

Aurora-A kinase has been often implicated in cancer progression, and its hyperactivation has been demonstrated to induce resistance to microtubule-targeted chemotherapy [80–82]. The *AURKA* gene is amplified in many malignancies, and its overexpression has been reported to be significantly associated with a higher tumor grade and a poor prognosis in a number of cancers, including chondrosarcoma, nasopharyngeal carcinoma, breast cancer, glioblastoma, colorectal cancer, gastric cancer, and ovarian carcinoma [83–89]. In addition, somatic mutations located within the catalytic domain of Aurora-A, altering kinase activity and subcellular localization, have been described in human cancer cells [90]. The oncogenic potential of Aurora-A derives from a sum of several spatially and temporally distinct actions. Unlike normal cells, in many cancer cells the expression of Aurora-A becomes constitutive throughout the cytoplasm, regardless of the cell cycle phase; this can trigger a plethora of improper interactions, phosphorylations, and mislocalizations. Aurora-A may also represent the downstream target of mitogenic pathways, such as MAPK/ERK (mitogen-activated protein kinases), and be overexpressed because of their constitutive activation in tumors [81]. The Aurora-A excess interferes with different cell cycle checkpoints, that is, the late G2 checkpoint, which restrains genetically aberrant cells to enter mitosis, the spindle assembly checkpoint, which blocks the metaphase–anaphase transition in cells with defective spindles, and the postmitotic G1 checkpoint, which arrests cell cycle in aneuploid cells [81, 83]. Centrosome amplification and unrestrained multinucleation, leading to abnormal mitotic spindle, are also observed in Aurora-A overexpressing cells [91]. Moreover, Aurora-A may significantly contribute to tumor progression by interacting with and inhibiting several tumor suppressor proteins such as p53, BRCA1 (breast cancer 1), and Chfr (checkpoint with forkhead and ring finger domains). Interestingly, activation of the MAPK signaling pathways has been found to induce accumulation of Aurora-A kinase in ERα+ breast cancer cells, and epithelial-tomesenchymal transition (EMT) [92, 93]. In these cells, Aurora-A has been shown to promote SMAD5 phosphorylation and nuclear translocation, upregulation of stemness gene SOX-2, and acquisition of a stem cell-like phenotype [92, 93].

Aurora-B plays a less clear role in tumorigenesis. An increased level of Aurora-B in normal cells induces premature chromosome separation and segregation errors, promotes generation of tetraploid/aneuploid cells, and potentiates Ras oncogenic activity [77, 80, 94–96]. Neither amplification nor specific mutations of *AURKB* gene have been shown to occur in human malignancies; nevertheless, Aurora-B overexpression has been demonstrated in several cancer types, including hepatocellular and oral squamous cell carcinomas, where it correlates with poor prognosis [80, 94–96].

At present, very little is known about the role of Aurora-C in cancer progression. Although Aurora-C is almost not detectable in normal somatic cells, it is highly expressed in various tumor cell lines [97–100]. One study has described the transforming potential of overexpressed Aurora-C in NIH-3T3 cells, and a correlation between the level of active kinase and tumor aggressiveness of the cells injected in nude mice [77].

#### **4.1. Aurora kinase inhibitors**

to recruit condensin proteins (**Figure 3**) [67, 68]. From early G2 phase to prophase, Aurora-B phosphorylates histone H3, but its physiological meaning remains unclear. From late prophase to metaphase CPC localizes to the inner centromere, playing a role in formation and stability of the bipolar mitotic spindle, kinetochore assembly, correction of non-bipolar chromosomespindle attachments, and control of the spindle checkpoint (**Figure 3**). In anaphase, the CPC relocates to the midzone of the mitotic spindle and to the cell cortex, remaining evident in the midbody of telophasic cells where it modulates the activity of several proteins involved in spindle dynamics, cleavage furrow formation and completion of cytokinesis (**Figure 3**) [49, 50,

Aurora-B activation requires the auto-phosphorylation and binding to INCENP, while all CPC components are necessary for its proper localization during mitosis. Several kinases, such as BubR1 and Bub1 (checkpoint kinases), monopolar spindle 1 (Mps1), checkpoint kinase 1 (Chkl), Tousled-like kinase-1, Plk1, and TD-60/RCC2 (regulator of chromosome condensation 2), have been shown to be involved in Aurora-B activation. The phosphorylation status and

The expression of Aurora-C is maximal during the G2/M phase. This kinase seems to have a prominent role in the meiotic division, as it is expressed at relative high levels in germ cells during spermatogenesis and oogenesis, and at very low levels in somatic cells. Aurora-C is highly similar to Aurora-B in sequence (61% identity), which may explain why the two kinases display similar localization patterns and share interacting proteins and substrates such as INCENP, Survivin, Borealin, and others [49, 70]. Interestingly, when ectopically expressed in cells depleted of Aurora-B, Aurora-C is capable of rescuing the Aurora-B-dependent mitotic functions [40]. It is also worth to note that Aurora-C has been shown to interact with and

Chromosomal instability is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumor progression [73]. In fact, aberrations in chromosome number and structure, likely resulting from a combination of ineffective checkpoints and anomalous cellular divisions, occur in the majority of human cancers [74]. Given the crucial tasks of Aurora kinases in all mitotic stages, their dysfunction and/or dysregulation is believed to greatly contribute to aneuploidy. Whether Aurora kinases may have a role in cancer initiation is still a matter of debate. It has been reported that the overexpression of either Aurora-A, Aurora-B, or Aurora-C induces cell malignant transformation [75–77]. In different studies, however, the transforming ability of either Aurora-A or

Aurora-A kinase has been often implicated in cancer progression, and its hyperactivation has been demonstrated to induce resistance to microtubule-targeted chemotherapy [80–82]. The

activity of Aurora-B are controlled by PP1 and PP2A phosphatases [69].

phosphorylate TACC1 in thyroid cells in the cytokinetic bridge [71, 72].

Aurora-B overexpression could not be confirmed [78, 79].

67–69].

102 Anti-cancer Drugs - Nature, Synthesis and Cell

**3.3. Aurora-C**

**4. Aurora kinases and cancer**

The overexpression of Aurora kinases in human cancers and their relevance in controlling the mitotic process have led to the development of small-molecule inhibitors as anticancer drugs. Aurora inhibition results in cytokinesis failure and generation of tetraploid cells, which, depending on the post-mitotic checkpoint activation, may be unable to proceed in a new cell cycle or rather may proliferate and become polyploid. The exit from cell cycle is likely to generate viable quiescent cells, whereas endoreplicating cells have greater tendency to undergo apoptosis. Actually, the functional inhibition of Aurora kinases is considered a promising therapeutic option against those malignancies that do not respond to the available therapies [101–108]. Up to date, about 30 small-molecule inhibitors of Aurora kinases have been developed and some of them, reported in **Table 1**, are being evaluated in Phase I-II clinical trials [101–108]. Of some interest are the preclinical observations showing the ability of different Aurora kinase inhibitors to have additive or synergist effects when combined with other anticancer therapies [109, 110]. At example, among the pan-Aurora kinase inhibitors, the AMG-900 in combination with the HDAC (histone deacetylase) inhibitor vorinostat has been shown to synergistically reduce proliferation and survival of medulloblastoma and prostate cancer-derived cell lines [111, 112]. Similarly, the SNS-314 has been shown to possess additive inhibitory effects on the HCT 116 cell line when combined with either carboplatin, gemcitabine, 5-FU, daunomycin, docetaxel, or vincristine [113]. Also the MK-0457 has revealed additive effects when combined with docetaxel on ovarian cancer cell lines or with cisplatin on the HepG2 cell line [114, 115]. Finally, the pan-Aurora kinase inhibitor CCT 137690 has been shown to sensitize SW620 colorectal cancer cells to radiotherapy [116]. In clinical trials, disease stabilization and, less frequently, partial responses in patients with solid cancers have been witnessed with the majority of Aurora kinase inhibitors, while more encouraging observations have been made in patients with hematological malignancies [101–110]. On-target toxicity observed with these drugs included grade 3/4 neutropenia, leukopenia, and myelosuppression, while off-target effects included hypertension, somnolence, mucositis, stomatitis, proctalgia, and ventricular dysfunction [101–110]. For example, the MK-0457 has been employed in different clinical trials in which patients with advanced solid tumors have been enrolled. In a Phase I dose escalation study, the most common doselimiting toxicity observed was neutropenia and herpes zoster, and major adverse events include nausea, vomiting, diarrhea, and fatigue [117]. Although no objective tumor responses were observed in this trial, 12 of 27 patients experienced stable disease with a median duration of 75.5 days (range 38–328 days). Of the latter, one patient with ovarian cancer achieved prolonged stable disease for 11 months, and one patient with rectal cancer had stable disease over 7 months [117].

The MK-0457 was found to have off-target inhibitory effects on both wild-type and mutant Abl kinases and showed to be a potent inhibitor of the BCR-ABL T315I mutant, which mediates clinical resistance to imatinib, nilotinib, and dasatinib [118]. On these bases, a phase I/II dose escalation study of MK-0457 was performed in patients with leukemias [119, 120]. Patients with refractory hematologic malignancies received 1–21 cycles of MK-0457, and maximumtolerated doses were calculated for a 5-day short infusion as 40 mg. Mucositis and alopecia were the most common drug-related adverse events observed in these patients. Forty-four percent (8/18) of patients, positive for the BCR-ABL T315I mutation, affected by chronic myelogenous leukemia (CML) had hematologic responses, and 33% (1/3) of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) obtained complete remission [119, 120].

**Table 1.** Aurora kinase inhibitors in clinical trials (adapted with permission from Ref. [14]).

Another multicenter phase II study evaluated the safety and efficacy of MK-0457 on 52 patients affected by CML or Ph+ ALL with BCR-ABL T315I mutation [121] (Seymour et al. 2014). Patients were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40, 32, or 24 mg. The most common adverse events were neutropenia and febrile neutropenia. Eight percent (4/52) of patients achieved major cytogenetic response and 6% (3/52) had a complete or a partial response. Thirteen percent (2/15) of patients with chronic phase CML achieved complete hematologic response. None of the patients with advanced CML or Ph+ ALL achieved major hematologic response [121].

A comprehensive description of clinical trials performed with the different Aurora kinase inhibitors has been recently reported [109, 110].


2. Methods

A notable bio-economic approach is applied to estimate the economic value of pollination. It has been used to estimate the economic value of pollination, and the potential relative production and agricultural sector value loss attributable to lack of or disappearance of pollinators or the production value loss attributable to a decline in pollinator [5, 10]. The total economic value of pollination (EVP) is calculated as follows:

$$EVP = \sum\_{i=1}^{n} P\_i \ast Q\_i \ast D\_i \tag{1}$$

where for each crop i€ (1:n), (where n = 38 in our study), Qi is the quantity produced, Di is the pollination dependency ratio, and Pi is the price per unit of quantity produced. The potential production value loss attributable to lack of pollinators, which is the crop vulnerability ratio (CVR), is calculated as the ratio of EVP to economic production value of the crops in our study (EV). CVR is calculated as:

$$\text{CVR} = \frac{\text{EVP}}{\text{EV}} = \frac{\sum\_{i=1}^{n} P\_i \* Q\_i \* D\_i}{\sum\_{i=1}^{n} P\_i \* Q\_i} \text{(\%)}\tag{2}$$

We calculate the pollination contribution to total farm gate value (PCV). PCV measures the potential agricultural sector production value loss attributable to lack of pollinators. It is the ratio of EVP to total farm gate value (TFGV). In our case, the total farm gate value is reported for each zone and is a summation of values of all agricultural productions (m is the whole agricultural products). We did not include services and animal products in our total farm gate value calculation. PCV is calculated as:

$$PCV = \frac{EVP}{TFGV} = \frac{\sum\_{i=1}^{n} P\_i \* Q\_i \* D\_i}{\sum\_{i=1}^{m} P\_i \* Q\_i} \text{ (\%)}\tag{3}$$

For Ethiopia, we estimate the EVP, CVR, and PCV for the period from 2003 to 2013. The spatial pattern and variation of EVP, CVR, and PCV of Ethiopia at the zone level for respective year are analyzed using geographical information systems (GIS). For a better understanding of the spatial and temporal pattern, maps were produced for the economic value of pollination, crop vulnerability ratio, and pollination contribution to total farm gate value. Spatially explicit analysis of these indices at local or national level show how pollination has fundamentally different regional significance and consequences in its absence [1].


*3.3. People*

Based on the employees' perspective, the qualitative analysis identified people as one theme, including both employees and customers. Employees were central actors in relation to keeping the level of waste down due to their knowledge, experience, mandate, awareness of product-specific causes and meeting customers' requirements. Customers affected the waste through their behaviour, demands and careless handling.


Collaboration methodologies used in HRC research

**Figure 4.** Collaboration methods used in selected human–robot collaboration in the period 2009–2018: In blue, hand guiding (HG); in orange, safety-rated monitored stop (SMS); in gray, speed and separation monitoring (SSM); in yellow, power and force limiting (PFL).

As stated previously, the collaborative mode depends on the considered application. Figure 5 depicts the considered tasks over the last decade. The most studied task is assembly, likely due to the required flexibility in the task, which makes traditional robotic systems too expensive or difficult to implement. However, the task of production also requires flexibility, and could greatly benefit from collaborative applications. Likely, until the fundamental challenges of setting up collaborative workcells are solved for the easier tasks of assembly, we will not see many case studies targeting production.

**Figure 5.** Tasks assigned to the robot in selected collaborative applications in research in the period 2009–2018: In blue, assembly tasks; in orange, the tasks used to assist the operator, e.g., handover of parts, quality control tasks, or machine tending, i.e., loading and/or unloading.

In our review, 35 papers presented unique case studies of industrial applications. Two industries seem to drive this research—the automotive industry accounted for 22.85% of studies, and the electronics industry a further 17.14%. Interestingly, research for the automotive industry only began after 2015, and will likely continue to drive research in this area.

HRC studies present several objectives that can be grouped into three main topics. Figure 6 depicts the focus of HRC studies in the last decade. It is interesting to note that the first phase of HRC study [37–41] was more focused on increasing the production and safety aspects of HRC, at least in a manufacturing context. As the research progressed, an increasing number of studies were focused on HRI methodologies, becoming a predominant objective in 2017. The ostensible reduction in 2018 should not mislead us to believe that HRI studies were abandoned in that year: As stated before, the presented classification is not univocal, thus studies such as [42–44] could also be considered HRI studies.

**Objective in HRC research**

**Figure 6.** Main topics or objectives in HRC studies. The objectives were divided into productivity studies (blue), safety studies (orange), e.g., ergonomics and collision avoidance, HRI (Human–Robot Interaction) studies (gray), e.g., development or improvement of HRI methodologies.

The key findings of these studies highlight challenge areas that research has successfully addressed, or even solved, when cobots are used for industrial tasks. Multiple studies reported an increase in task performance—e.g., by reducing completion time and minimizing error[25,37,38,43] as well as a better understanding of the operator space [29,31,32,41] and higher precision of workpiece manipulation [28,30,45]. Thematic areas of research intent can be identified, such as increasing and quantifying the trust of the operator in the robotic system [29,46,47], as well as improving safety by minimizing collisions [40].

The directions of future work identified in literature are summarized in Figure 7. Historically, researchers aimed to increase the HRI relevance of their work, also with a focus on higher safety requirements and more complex tasks. In recent years, the scope of future work has expanded, with researchers focusing on more complex methods that improve the performance of their systems whether this is by applying their method to different application fields or more complex tasks. This is likely due to the prevalence of new cobots and sensing methodologies coming onto the market, maturing algorithms, and experience in designing collaborative workcells.

Future work directions in HRC studies

**Figure 7.** Future work topics from HRC studies. The work was divided into directions of HRI (dark blue), safety (orange), task complexity (gray), applicability (yellow), method (light blue), and productivity (green).

Many of the reviewed works highlight future work in terms of the method they used, whether it be by increasing the complexity of their modeling of the operator and/or environment [48], or using different metrics to evaluate performance [33,49,50] and task choice [51]. Others believe that expanding their research setup to other application areas is the next step [31,45,52]. In our view, these works can be achieved without any step change in existing technology or algorithms; rather, it requires more testing time. To increase safety, productivity, and task performance, researchers will need to improve planners, [39,53], environment and task understanding [28,40,54,55], operator intention understanding [38], and ergonomic cell setups [37,56]. To improve HRI systems, common future work focuses on increasing the robots' and operators' awareness of the task and environment by object recognition [44] and integrating multi-modal sensing in an intuitive manner for the operator [3,32,36].

In essence, this future direction focuses on having better understanding of the scene—whether this is what the operator intends to do, what is happening in the environment, or the status of the task. Researchers propose solving this by using more sensors and advanced algorithms, and fusing this information in a way that is easy to use and intuitive for the operator to understand. These systems will inherently lead to better safety, as unexpected motions will be minimized, leading consequently to more trust and uptake. We can expect that many of these advances can come from other areas of robotics research, such as learning by demonstration through hand-guiding or simulation techniques that make it easy to teach a robot a task, and advances in computer vision and machine learning for object recognition and semantic mapping. Other reviews, such as [8], identify similar trends, namely those of improved modeling and understanding, better task planning, and adaptive learning. It will be very interesting to see how this technology is incorporated into the industrial setting to take full advantage of the mechanics and control of cobots and the HRI methodologies of task collaboration.

#### *4.2. Trend of the Market*

We believe that the current market should also be presented in order to better place our literature review in the manufacturing context. According to [57], the overall collaborative robot market is estimated to grow from 710 million USD in 2018 to 12,303 million USD by 2025 at a compounded annual growth rate (CAGR) of 50.31% during the forecasted period. However, the International Federation of Robotics (IFR), acknowledging an increase in the robot adoption with over 66% of new sales in 2016, expects that market adoption may proceed at a somewhat slower pace over the forecasted timeframe [58]. However they suggest that the fall in robot prices [59] has led to a growing market

for cobots, especially considering that small- and medium-sized enterprises (SMEs), which represent almost 70% of the global number of manufacturers [60] and could not afford robotic applications due to the high capital costs, are now adopting cobots, as they require less expertise and lower installation expenses, confirming a trend presented in scientific works [3].

Finally, [57] highlights that cobots, presenting different payloads, were preferred with up to 5 kg payload capacity; indeed, they held the largest market size in 2017, and a similar trend is expected to continue from 2018 to 2025. This preference of the market towards lightweight robots, which are safer but do not present the high speed and power typically connected with industrial robots [36,61], restrains the HRC possibilities in the current manufacturing scenario. However, we believe that without proper regulation, the current market will continue to mark a dividing line between heavy-duty tasks and HRC methods.

## **5. Conclusions**

Human–robot collaboration is a new frontier for robotics, and the human–robot synergy will constitute a relevant factor in industry for improving production lines in terms of performances and flexibility. This will only be achieved with systems that are fundamentally safe for human operators, intuitive to use, and easy to set up. This paper has provided an overview of the current standards related to Human–Robot Collaboration, showing that it can be applied in a wide range of different modes. The state of the art was presented and the kinematics of several popular cobots were described. A literature analysis was carried out and 41 papers, presenting 35 unique industrial case studies, were reviewed.

Within the context of manufacturing applications, we focused on the control systems, the collaboration methodologies, and the tasks assigned to the cobots in HRC studies. From our analysis, we can identify that the research is largely driven by the electronics and automotive industries, but as cobots become cheaper and easier to integrate into workcells, we can expect SMEs from a wide range of industrial applications to lead their adoption. Objective, key findings and future research directions are also identified, the latter highlighting ongoing challenges that still need to be solved. We can expect that many of the advances needed in the identified directions could come from other areas of robotics research; how these will be incorporated into the industrial setting will lead to new challenges in the future.

**Author Contributions:** Conceptualization, E.M. and G.R.; Methodology, E.M. and G.R.; Formal analysis, E.M., R.M., and E.G.G.Z.; Investigation, E.M., R.M. and E.G.G.Z.; Data curation, E.M., R.M., and E.G.G.Z.; Writing—original draft preparation, E.M., R.M., and E.G.G.Z.; Writing—review and editing, M.F., E.M., R.M., G.R., and E.G.G.Z.; Supervision, M.F. and G.R.; Project administration, M.F. and G.R.; Funding acquisition, G.R.

**Funding:** This research was funded by University of Padua—Program BIRD 2018—Project no. BIRD187930, and by Regione Veneto FSE Grant 2105-55-11-2018.

**Conflicts of Interest:** The authors declare no conflict of interest.

**A1.**Listofcharacteristicsofsomeofthemostusedcobotsfordifferentkinematics.

**Appendix A. Tables**

**Table 2.** Denavit–Hartenberg parameters and singularity configurations for the considered kinematic schemes.

**Table 3.** Literature review analysis.


*4.7. Behavioral Correlates Mental Health and Cardiovascular Measurements*

Correlation analysis through all the components suggests functional interactions between NPS and cognitive impairment with amygdala and HPA axis. The vascular function correlated with activity, while the left and right hemispheres' asymmetry of rCBF with NPS and cognitive impairments. Increased activation of the amygdala in 3xTg-AD mice [55] could explain the specific correlation between amygdala CBF and body weight. Corticosterone level correlations agree with our first report on the increase in glucocorticoid levels concomitantly to increased anxiety and peripheral immune dysfunction [12] and recent work of other laboratories [77]. Systolic blood pressure correlated positively with the number of half-buried marbles and negatively correlated with latency to cross the T-intersection and TM test, which are indicators of a worse neuro-immunoendocrine function, accelerated aging, and premature death in mice [53]. These correlates agree with mice chronically subjected to high blood pressure being more active in the openfield and faster in a spontaneous alternation test [78]. Recently, we demonstrated the correlation between peripheral small vessel properties and anxiety in both NTg and 3xTg-AD mice, mostly in females [21]. Here, we show that the animals with lower endothelialindependent vasodilatations to sodium nitroprusside (i.e., lower muscle relaxation capacity) were the most active in the open-field test, in both non-goal- (horizontal activity) and goaldirected (rearing) behaviors [79,80]. The correlation was consistent, as also observed in the repeated test**.** Regarding relative cerebral blood flow and neuropsychiatric and cognitive impairment, the cortex was the better area correlated with behavior. Cortex hemisphere asymmetry correlated with risk assessment (stretch attendance), neophobia in the corner test, and worse memory performance in the T-maze test. Correlation between asymmetry and neophobia was also observed in the hippocampus and amygdala. Since testing the pairwise correlations between dozens of variables without multiple comparison correction may involve a high risk of type-1 error, only those which are meaningful, obtained a maximum statistical significance (p < 0.001), and could be verified with closerelated variables were considered. Despite our aim to highlight and explore the sex-based differences, the statistical power of the sample size per sex did not allow to compare whether the correlations between these variables were different between male and female mice and thus modulated by the sex. Overall, this correlation analysis allows for finding meaningful functional correlations between behavioral responses related to the levels of anxiety, cognition and locomotor activity, and cardiovascular measurements. Especially, the present work provides pieces of evidence of the brain regions' asymmetry of both males and females with normal and AD-neurodegenerative aging correlation with neuropsychiatric symptoms and cognitive deficits.


**Table 1.**

*Comparison Burago's and Kárman-Tsien methods.*

method is observed. For the values of the relative coordinate along the major axis of the ellipse 0*:*1≤*x*≤ 0*:*5, there is a significant discrepancy between the Kárman-Tsien results and the Burago method. However, it can be noted that the calculations of other authors are in good agreement with the calculations by the Kárman-Tsien formula (34). The calculation according to this method approaches the value of the pressure coefficient, indicated in **Figure 4** as *C*∗ *p* , which corresponds to the critical Mach number. As can be seen from **Figure 4**, the values determined in the article [16] and by the author practically coincide. **Figure 4** also shows the distribution of the pressure-drop coefficient *C*0 *p* for an incompressible fluid. **Figure 4** shows the strong influence of the compressibility factor. Of greatest interest to researchers is the value of the critical Mach number for a cylinder in a transverse flow. In **Figure 5 (a, b)**, the results of calculations of the relative velocity on the surface of the cylinder, obtained using the proposed approximate technique, are compared with the calculations of other authors performed by other methods.

Pai [6]) are compared in **Figure 5**. The results of Simisaki's calculations were taken from [17]. The calculations were carried out for the Mach number almost equal to the critical Mach number *M*∞ ≈ 0.372 (**Table 2**). It can be noted that in **Figure 5**, the author's calculation is in good agreement with the data of other authors for velocities

0.390 Calculations by I. Imei. Z. Hashimoto 5 0.37170¤0.00001 author's calculation —

*M***\* Method and authors of calculation results** *δ* **%** 0.415 C. Jacob's calculation [7] 10 0.409 Poggi method. Calculations by S. Kaplan [12] 9 0.404 I. Imei's calculation 8 0.400 Rayleigh-Janzen method. T. Simisaki's calculations 7

*Comparison of the calculated values of the pressure drop coefficient on the surface of the ellipse (relative*

*Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies*

*DOI: http://dx.doi.org/10.5772/intechopen.94981*

*thickness 20%) (a); for a biconvex airfoil (relative thickness 6%) (b).*

0.3983¤0.0002 The Rayleigh-Janzen method. Hoffman's calculations 7

calculations by P.I. Chushkin

Dorodnitsyn. calculations by R. Melnik and D. C. Ives

G. A. Dombrovsky

A. Dombrovsky

Calculations by M. Holt and B. Messon

7

7

6

5

5

0.399 The method of integral relations by A.A. Dorodnitsyn.

0.39853¤0.00002 The multi-layer method of integrated relations by A.A.

0.396 The method of approximation of adiabat. Approximation A4.

0.390 The method of approximation of adiabat. A3 approximation. G.

*Comparison of the calculated values for the critical Mach number on the surface of the cylinder.*

0.390 The method of integral relations by A.A. Dorodnitsyn.

Let us consider the numerical values of the critical Mach numbers *M*\* for a flow around a circular cylinder obtained by different authors. **Table 1** shows a comparison of the results of calculating the critical Mach numbers by different methods. The value *δ* denotes the relative error of comparing the values of the critical Mach

on the cylinder surface, taking into account the compressibility factor.

numbers calculated by different methods and by this method.

**Table 2.**

**181**

**Figure 4.**

Integral relationship method [17], method of Legendre transformations [10], method approximation of adiabat [7], Rayleigh-Janzen method (Simisaki [17]; Shih-I *Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies DOI: http://dx.doi.org/10.5772/intechopen.94981*

#### **Figure 4.**

*Comparison of the calculated values of the pressure drop coefficient on the surface of the ellipse (relative thickness 20%) (a); for a biconvex airfoil (relative thickness 6%) (b).*

#### **Table 2.**

method is observed. For the values of the relative coordinate along the major axis of the ellipse 0*:*1≤*x*≤ 0*:*5, there is a significant discrepancy between the Kárman-Tsien results and the Burago method. However, it can be noted that the calculations of other authors are in good agreement with the calculations by the Kárman-Tsien formula (34). The calculation according to this method approaches the value of the

*p* **Mach number** *M***∞ Cp Kárman-Tsien Cp Burago** *δ* **%** 0.1 0.3 0.1051 0.1048 0.29

0.5 0.3 0.5305 0.5315 0.18

1.0 0.3 1.0742 1.0796 0.5

1.5 0.3 1.6315 1.6474 1.0

2.0 0.3 2.2029 2.2389 1.6

2.5 0.3 2.7890 2.8618 2.5

3.0 0.3 3.3904 3.5221 3.7

3.5 0.3 4.0076 4.2352 5

4.0 0.3 4.6414 5.0245 8

4.5 0.3 5.2922 5.9404 11

0.6 0.1266 0.1269 0.24 M\* = 0.886 0.2289 0.2165 6

0.6 0.6667 0.7042 5.0 M\* = 0.679 0.7489 0.8696 14

0.4 1.1432 1.1659 2.0 M\* = 0.558 1.3427 1.5874 15

0.4 1.7566 1.8320 4 M\* = 0.486 1.9245 2.2790 16

0.4 2.4009 2.6067 8 M\* = 0.437 2.5034 2.9683 16

M\* = 0.400 3.0782 3.6432 16

M\* = 0.371 3.6515 4.3127 15

M\* = 0.348 4.2265 4.9949 15

M\* = 0.329 4.8020 5.6830 15

M\* = 0.312 5.3714 6.3339 15

Mach number. As can be seen from **Figure 4**, the values determined in the article [16] and by the author practically coincide. **Figure 4** also shows the distribution of

strong influence of the compressibility factor. Of greatest interest to researchers is the value of the critical Mach number for a cylinder in a transverse flow. In **Figure 5 (a, b)**, the results of calculations of the relative velocity on the surface of the cylinder, obtained using the proposed approximate technique, are compared with

Integral relationship method [17], method of Legendre transformations [10], method approximation of adiabat [7], Rayleigh-Janzen method (Simisaki [17]; Shih-I

*p* , which corresponds to the critical

*p* for an incompressible fluid. **Figure 4** shows the

pressure coefficient, indicated in **Figure 4** as *C*∗

*Comparison Burago's and Kárman-Tsien methods.*

the calculations of other authors performed by other methods.

the pressure-drop coefficient *C*0

**Table 1.**

**180**

*C***0**

*Aerodynamics*

*Comparison of the calculated values for the critical Mach number on the surface of the cylinder.*

Pai [6]) are compared in **Figure 5**. The results of Simisaki's calculations were taken from [17]. The calculations were carried out for the Mach number almost equal to the critical Mach number *M*∞ ≈ 0.372 (**Table 2**). It can be noted that in **Figure 5**, the author's calculation is in good agreement with the data of other authors for velocities on the cylinder surface, taking into account the compressibility factor.

Let us consider the numerical values of the critical Mach numbers *M*\* for a flow around a circular cylinder obtained by different authors. **Table 1** shows a comparison of the results of calculating the critical Mach numbers by different methods. The value *δ* denotes the relative error of comparing the values of the critical Mach numbers calculated by different methods and by this method.

to other methods. Holt and Messon [17] point out that "symmetric flows (in which a shock does not occur) were calculated only up to the Mach number of the freestream flow *M*∞=0.37". This circumstance indirectly confirms that the exact value of the critical Mach number is closer to that determined by the Burago method than

*Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies*

An important question is the question: how does the viscosity of the medium affect the value of the critical Mach number? **Figure 6** shows a comparison of the calculated data for the flow around the biconvex airfoil using the ideal gas and viscous models. **Figure 6** also shows the experimental results that can be observed

Calculations for viscous gas are performed in a computational package Flow Simulation (SolidWorks). The calculations in the Flow Simulation software are based on solving the Navier–Stokes equations. The calculation domain and the grid used in the calculations Flow Simulation are shown in **Figure 7(a)** and **(b)**. The flow velocity was calculated at a distance equal to the thickness of the boundary

by other methods.

*DOI: http://dx.doi.org/10.5772/intechopen.94981*

also in **Figure 4(b)**.

**Figure 7.**

**183**

*The calculation domain and grid used in package flow simulation.*

**Figure 5.** *The velocity on the cylinder surface vs. Mach number.*

If we exclude from the comparison the early work of Kaplan [12] in which the adiabatic exponent for air was taken equal *κ* = 1.408 which affected the value of the calculated critical Mach number and the work of Jacob (see [7]) then based on the data in **Table 1** it can be argued that the accuracy of calculating the critical Mach number on the surface of the circular cylinder by the Burago's method in comparison with other methods on average approximately corresponds to a relative error of 5%. From **Table 1** it can be seen that the critical Mach number on the surface of the circular cylinder calculated by Burago's method is the smallest of the data presented in the **Table 1**. This does not mean that this value is the most inaccurate compared

**Figure 6.** *Critical Mach number vs. relative thickness of the biconvex airfoil.*

## *Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies DOI: http://dx.doi.org/10.5772/intechopen.94981*

to other methods. Holt and Messon [17] point out that "symmetric flows (in which a shock does not occur) were calculated only up to the Mach number of the freestream flow *M*∞=0.37". This circumstance indirectly confirms that the exact value of the critical Mach number is closer to that determined by the Burago method than by other methods.

An important question is the question: how does the viscosity of the medium affect the value of the critical Mach number? **Figure 6** shows a comparison of the calculated data for the flow around the biconvex airfoil using the ideal gas and viscous models. **Figure 6** also shows the experimental results that can be observed also in **Figure 4(b)**.

Calculations for viscous gas are performed in a computational package Flow Simulation (SolidWorks). The calculations in the Flow Simulation software are based on solving the Navier–Stokes equations. The calculation domain and the grid used in the calculations Flow Simulation are shown in **Figure 7(a)** and **(b)**. The flow velocity was calculated at a distance equal to the thickness of the boundary

**Figure 7.** *The calculation domain and grid used in package flow simulation.*

If we exclude from the comparison the early work of Kaplan [12] in which the adiabatic exponent for air was taken equal *κ* = 1.408 which affected the value of the calculated critical Mach number and the work of Jacob (see [7]) then based on the data in **Table 1** it can be argued that the accuracy of calculating the critical Mach number on the surface of the circular cylinder by the Burago's method in comparison with other methods on average approximately corresponds to a relative error of 5%. From **Table 1** it can be seen that the critical Mach number on the surface of the circular cylinder calculated by Burago's method is the smallest of the data presented in the **Table 1**. This does not mean that this value is the most inaccurate compared

**Figure 5.**

*Aerodynamics*

**Figure 6.**

**182**

*Critical Mach number vs. relative thickness of the biconvex airfoil.*

*The velocity on the cylinder surface vs. Mach number.*

layer. In the calculations, the free-stream velocity varied, and as soon as the local flow velocity at the boundary of the layer boundary became equal to the sound velocity, the critical Mach number was calculated.

Based on **Figure 6**, it can be concluded that viscosity has practically no effect on the value of the critical Mach number.

Another two-dimensional body, the flow around which is well studied is an ellipse. **Figure 8** shows the calculated results for the critical Mach number depending on the degree of compression (relative thickness, *p* = *a*/*b*) of the ellipse. **Figure 8** also shows the value of the critical Mach number for a two-dimensional body formed by two contacting cylinders. Calculations of the critical Mach number for such a 2-D body were first performed by the author [1].

We have looked at comparing calculations for two-dimensional bodies. The high accuracy of the calculation of the critical Mach numbers by the Burago method is shown.

Let us now consider the applicability of the Burago method for axisymmetric flows. It is also of interest to compare the critical Mach numbers for two-dimensional and axisymmetric flows. Ellipses and ellipsoids of revolution (spheroids) with various factor of compression *δ* are chosen. For calculations the well-known potential models for ellipses and spheroids [21] were used. It is obvious that the maximal error will correspond to flow around thick bodies (*δ* ! 1.0) and for the case *M*∞ = *M*\*. In **Table 3** and in **Figure 9(a)** results of calculation of critical Mach number for ellipses and spheroids with an offered method and with Dorodnitsyn method of integral relations executed by Chushkin [14, 15] are compared.

elliptical contour to the velocity at infinity as a function of the Mach number (symmetric flow). **Figure 9(b)** uses the relative ellipse thickness *δ* = 0.1. Here, along with the calculations by the proposed method, the results of calculations obtained by the theory of small perturbations and by the Hantz and Wendt second approximation (see the Book [7]), as well as the results of calculations obtained by the Dombrovsky method [7] are shown. It can be noted that the results of calcula-

*δ* **Ellipses Ellipsoids**

*Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies*

**Relative difference %**

0.05 0.103 0.869 0.884 1.8 0.014 0.984 0.980 0.4 0.10 0.210 0.803 0.807 0.5 0.042 0.957 0.945 1.3 0.15 0.323 0.752 0.748 0.5 0.080 0.929 0.905 2.6 0.20 0.440 0.709 0.700 1.3 0.122 0.899 0.868 4.0 0.40 0.960 0.588 0.566 3.7 0.337 0.783 0.742 5 0.60 1.560 0.506 0.480 5 0.602 0.692 0.648 6 0.80 2.240 0.447 0.418 6 0.908 0.620 0.576 7 1.00 3.000 0.399 0.372 7 1.250 0.563 0.519 8

*C***0**

*p* **min Chushkin [14]** *M***\***

**Calculation** *M***\***

**Relative difference %**

**Calculation** *M***\***

*Critical Mach number at a flow around ellipses and spheroids.*

tions using the proposed method practically coincided with the results of Dombrovsky. The critical Mach number equal to *M\** ≈ 0.807 (**Figure 9(b)**) was obtained by the Dombrovsky method of approximation of the adiabat. This is in very good agreement with Lighthill's data (see Book [7]) and Dombrovsky's result [7] *M*\* ≈ 0.81 and Chushkin's result *M\** ≈ 0.803 (**Table 2**). Kaplan's result [12] *M\** ≈ 0.857 should be considered less accurate, but the relative error does not

Also, it follows from **Figure 9(a)** that critical Mach number for the twodimensional case is always less than for axisymmetric case for bodies with the same

*(a) Critical Mach number vs. relative thickness of an ellipse and ellipsoid; (b) relative maximal velocity of the*

exceed 7%.

**Table 3.**

*C***0**

*p* **min Chushkin [14]***M***\***

*DOI: http://dx.doi.org/10.5772/intechopen.94981*

cross-section.

**Figure 9.**

**185**

*flow around ellipse vs. Mach number.*

**Table 3** and **Figure 9(a)** shows a comparison of the results of calculating the critical Mach numbers by two different methods. **Table 3** and **Figure 9(a)** shows a good agreement. It is necessary to notice that calculations in a range of ð Þ 0*:*4≤*δ*≤0*:*8 were executed by Chushkin only for the second approximation and each subsequent approximation resulted in reduction the value of critical Mach number. Therefore, some additional error can be explained by this fact. It can be noted that the relative difference in values of the critical Mach numbers increases with increasing *δ* for both ellipses and spheroids.

However, the maximum relative difference in values of the critical Mach numbers for the elliptic cylinder does not exceed 7% and for the sphere 8%. **Figure 9(b)** shows a comparison of the ratio of the maximum velocity at the surface of an

**Figure 8.** *Critical Mach number vs. relative thickness of the ellipse.*

*Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies DOI: http://dx.doi.org/10.5772/intechopen.94981*

#### **Table 3.**

layer. In the calculations, the free-stream velocity varied, and as soon as the local flow velocity at the boundary of the layer boundary became equal to the sound

Another two-dimensional body, the flow around which is well studied is an

depending on the degree of compression (relative thickness, *p* = *a*/*b*) of the ellipse. **Figure 8** also shows the value of the critical Mach number for a two-dimensional body formed by two contacting cylinders. Calculations of the critical Mach number

We have looked at comparing calculations for two-dimensional bodies. The high accuracy of the calculation of the critical Mach numbers by the Burago method is

Let us now consider the applicability of the Burago method for axisymmetric flows. It is also of interest to compare the critical Mach numbers for two-dimensional and axisymmetric flows. Ellipses and ellipsoids of revolution (spheroids) with various factor of compression *δ* are chosen. For calculations the well-known potential models for ellipses and spheroids [21] were used. It is obvious that the maximal error will correspond to flow around thick bodies (*δ* ! 1.0) and for the case *M*∞ = *M*\*. In **Table 3** and in **Figure 9(a)** results of calculation of critical Mach number for ellipses and spheroids with an offered method and with Dorodnitsyn method of integral

**Table 3** and **Figure 9(a)** shows a comparison of the results of calculating the critical Mach numbers by two different methods. **Table 3** and **Figure 9(a)** shows a

ð Þ 0*:*4≤*δ*≤0*:*8 were executed by Chushkin only for the second approximation and each subsequent approximation resulted in reduction the value of critical Mach number. Therefore, some additional error can be explained by this fact. It can be noted that the relative difference in values of the critical Mach numbers increases

However, the maximum relative difference in values of the critical Mach numbers for the elliptic cylinder does not exceed 7% and for the sphere 8%. **Figure 9(b)** shows a comparison of the ratio of the maximum velocity at the surface of an

good agreement. It is necessary to notice that calculations in a range of

ellipse. **Figure 8** shows the calculated results for the critical Mach number

Based on **Figure 6**, it can be concluded that viscosity has practically no effect on

velocity, the critical Mach number was calculated.

for such a 2-D body were first performed by the author [1].

relations executed by Chushkin [14, 15] are compared.

with increasing *δ* for both ellipses and spheroids.

*Critical Mach number vs. relative thickness of the ellipse.*

the value of the critical Mach number.

shown.

*Aerodynamics*

**Figure 8.**

**184**

*Critical Mach number at a flow around ellipses and spheroids.*

elliptical contour to the velocity at infinity as a function of the Mach number (symmetric flow). **Figure 9(b)** uses the relative ellipse thickness *δ* = 0.1. Here, along with the calculations by the proposed method, the results of calculations obtained by the theory of small perturbations and by the Hantz and Wendt second approximation (see the Book [7]), as well as the results of calculations obtained by the Dombrovsky method [7] are shown. It can be noted that the results of calculations using the proposed method practically coincided with the results of Dombrovsky. The critical Mach number equal to *M\** ≈ 0.807 (**Figure 9(b)**) was obtained by the Dombrovsky method of approximation of the adiabat. This is in very good agreement with Lighthill's data (see Book [7]) and Dombrovsky's result [7] *M*\* ≈ 0.81 and Chushkin's result *M\** ≈ 0.803 (**Table 2**). Kaplan's result [12] *M\** ≈ 0.857 should be considered less accurate, but the relative error does not exceed 7%.

Also, it follows from **Figure 9(a)** that critical Mach number for the twodimensional case is always less than for axisymmetric case for bodies with the same cross-section.

#### **Figure 9.**

*(a) Critical Mach number vs. relative thickness of an ellipse and ellipsoid; (b) relative maximal velocity of the flow around ellipse vs. Mach number.*

proposed method is shown. The method allows one to determine the parameters of a compressible flow from the values of the flow of an incompressible fluid up to a speed corresponding to the critical Mach number. This method does not depend on the means determination parameters of the incompressible flow. The calculation in software Flow Simulation was shown that the viscosity factor does not affect the value critical Mach number. It was found that with an increase in the relative thickness of the body, the value of the critical Mach number decreases. It was also found that the value of the critical Mach number for the two-dimensional case is always less than for the axisymmetric case for bodies with the same cross-section.

*Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies*

**Conflict of interest**

**Acronyms and abbreviations**

TM Technical Memorandum

**Appendices and nomenclature**

HSH High Speed Hydrodynamics

TR Technical Report

The author declares no conflict of interest.

*DOI: http://dx.doi.org/10.5772/intechopen.94981*

AMM Applied Mechanics and Materials

TsAGI Central Aerohydrodynamic Institute

*ρ* local density of gas; *τ*, *σ* special functions (Eq. (2));

*p* the static pressure;

*h* the enthalpy;

*c*0

**187**

*κ* the ratio of specific heats; *P(p)* the pressure function;

*M*∞ the Mach number at infinity; *M* the local Mach number; *u* ¼ *u=U*∞, *v* ¼ *v=U*∞ dimensionless velocities; *E(M)* the function (Eq. (11)); *a* the sound speed;

*ε* given accuracy of calculation;

*G(M), F(M)* the functions (Eq. (30)).

*U* local total relative velocity (Eq. (23));

(Eq. (28));

NACA National Advisory Committee for Aeronautics

*u*, *v* velocity components along axis *x* и *r*;

**V** the vector of full local velocity of flow;

∞ subscript indicates flow parameters at infinity;

*ηc* the compressibility factor of the flow (Eq. (15));

*p* the pressure-drop coefficient for an incompressible flow

0 lower index, specifies parameters of the flow in the stag-

the flow of the incompressible liquid;

nation point or upper index and specifies parameters of

#### **Figure 10.**

*Maximal velocities on surface of the ellipse and spheroid vs. Mach number.*

#### **Figure 11.**

*Influence of Mach number of compressible flow on pressure-drop coefficient on the surface of the an ellipse and spheroid.*

The effect of compressibility is shown in **Figure 10**, which shows the ratio of the relative maximum velocities *U*max ¼ *U*max*=U*∞ for compressible and incompressible flows on the surface of 2D ellipses and 3D spheroids.

It follows from **Figure 10** that the effect of compressibility for two-dimensional ellipses at the same Mach number is greater than for 3D-spheroids. **Figure 11** shows the results of calculating the pressure-drop coefficient for compressible and incompressible flows on the surfaces of two- and three-dimensional bodies.

As seen in **Figure 11**, the compressibility effect has a stronger effect on 2D bodies than on axisymmetric bodies.

## **4. Conclusions**

This paper presents the results of calculating the critical Mach numbers of the flow around two-dimensional and axisymmetric bodies. A sufficiently high accuracy of calculating the critical Mach numbers for engineering calculations using the *Critical Mach Numbers of Flow around Two-Dimensional and Axisymmetric Bodies DOI: http://dx.doi.org/10.5772/intechopen.94981*

proposed method is shown. The method allows one to determine the parameters of a compressible flow from the values of the flow of an incompressible fluid up to a speed corresponding to the critical Mach number. This method does not depend on the means determination parameters of the incompressible flow. The calculation in software Flow Simulation was shown that the viscosity factor does not affect the value critical Mach number. It was found that with an increase in the relative thickness of the body, the value of the critical Mach number decreases. It was also found that the value of the critical Mach number for the two-dimensional case is always less than for the axisymmetric case for bodies with the same cross-section.


**Meet the editor**

Shimon Rumelt received his medical degree and a diploma in ophthalmology from the Tel Aviv University, Israel. He completed his ophthalmology residency program at Western Galilee Medical Center in Nahariya, Israel, and then an oculoplastics fellowship at Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, and vitreoretinal fellowship at Boston University. He earned a master degree

in Public Administration (Health Systems) from Clark University, Worcester, MA. Shimon Rumelt is a senior ophthalmologist at the Western Galilee Medical Center, Nahariya, and is engaged with various fields in ophthalmology. He is engaged with clinical activities, surgery, research, and teaching medical students, residents, and fellows. Shimon Rumelt edited 4 books and is the author and coauthor of approximately 100 scientific articles and book chapters. He is a member of the editorial board of Evidence-Based Ophthalmology and a reviewer for multiple professional journals. He is an associate clinical professor at the Faculty of Medicine, Bar-Ilan University, Zefat, Israel.


*4.1. Experimental Design*

In addition to intelligently choosing the model parameters, one should verify that the data used for the learning phase accurately represent the domain malware's real-world distribution. Hence, the dataset was constructed such that 75% were benign domains, and the remaining 25% were malicious domains (~5000 benign URLs and ~1350 malicious domains, respectively) [65].

There are many ways to define the efficiency of a model. A broad set of metrics was extracted to account for most of them, including accuracy, recall, F1-score, and training time. Note that for each model, the dataset was split into train and test sets where 75% of the data (both benign and malicious) were assigned to the train set, and the remaining domains were assigned to the test set. Note that the entire dataset included 75% benign samples. Later, when we trained a model, we used 75% of the dataset for the training process and 25% for the evaluation (i.e., test set).

The evaluation measured the efficiency of the different models while varying the robustness of the features included in the model. Specifically, four classical models (i.e., Logistic Regression, SVM, ELM, and ANN) were trained using the following feature sets:


**5.1 Marking techniques**

Preoperative reference and axis marking techniques could be broadly categorized as manual methods, image-guided systems, and intraoperative aberrometrybased methods.

The three-step manual technique is at present most commonly used [47], which is fairly accurate [48]. The first step is preoperative marking of the reference axis, which is commonly placed in the horizontal 3'o and 9'o clock positions. The second step is intraoperative alignment of the reference mark. The marking may be performed with a skin marking pen or needle. The patient should be sitting erect in a straight-ahead gaze while marking the reference axis. A change in patient position from sitting to supine may induce significant cyclotorsion; studies reported up to 28° of cyclotorsion in 68% of cases [49]. The manual marking methods have been limited by smudging of the dye, irregular, and broad marks.

Image-guided systems and intraoperative aberrometry have advantages compared with manual marking. The image-guided system based on the concept of landmarks to place the axis marks [50], which could be iris crypts, nevi, brush fields, etc. The systems capture a preoperative reference image and calculated the location of these marks and their distance in degrees from the target IOL axis. Then the system generated a final plan which provides simple angular directions from each reference mark to the planned axis of IOL placement.

There are a few image-guided systems at present such as CALLISTO Eye and Z Align (Carl Zeiss Meditec, Jena, Germany), VERION (Alcon, Fort Worth, Texas), TrueGuide (TrueVision 3D Surgical System, Santa Barbara, Calif), Osher Toric Alignment System (OTAS, Haag-Streit, Koeniz, Switzerland), and iTrace System (Tracey Technologies, Houston, Tx). Besides alignment, image-guided systems also contribute to planning the incisions, capsulorhexis size, and optimal IOL centration.

### **5.2 Intraoperative toric IOL alignment**

Intraoperative IOL positioning is the key procedure to sustain rotation stability. During IOL alignment, the IOL should be left about 3–5° anticlockwise of the final desired lens position, followed by complete OVD removal and hydration of the wounds. Most open-loop IOLs can be rotated only clockwise, and a complete rerotation will be needed if the IOL rotates further clockwise of the target axis.

The image-guided systems and intraoperative aberrometry could be definitely more useful than manual alignment. As mentioned above, the image-guided systems capture a preoperative reference image and an intraoperative image and then match the two images with respect to each other using landmarks. During the operation, a graphic overlay is then superimposed on the surgical field along the target axis, which provides a guide for toric IOL alignment. The image-guided systems and intraoperative aberrometry have improved the precision of toric IOL alignment, with <5° of deviation from the intended axis in the majority of cases.

(Rayner 600S IOL) was reported to have excellent rotational stability: average

[62]. In a study by Oshika et al., 6431 eyes are implanted with toric IOLs, and realignment was performed in 0.653% of cases [63]. An early repositioning performed after 1 week of primary cataract surgery had optical outcomes.

surgery, an IOL exchange, piggyback IOLs procedures may be considered.

undergoing multifocal IOLs may not tolerate residual astigmatism of <1 D, and multifocal IOLs without toric design perform best with less than 0.75 D of

(FineVision POD F) [73] also showed great performance.

interfere with the postoperative outcomes.

**7. Multifocal toric IOLs**

*Toric Intraocular Lenses*

*DOI: http://dx.doi.org/10.5772/intechopen.90153*

cylinder [67].

**8. Special cases**

and expanding.

**41**

In cases with more than 10° of rotation, realignment of the toric IOL is needed

IOL tilt could also induce astigmatism: tilting toric IOLs aligned at 180° would decrease with-the-rule astigmatism, bringing in undercorrection, while aligned at 90° increased against-the-rule astigmatism, bringing in overcorrection [64].

Meanwhile, LASIK, customized surface ablation, or femtosecond laser-assisted intrastromal keratotomies could also be used to correct residual astigmatism [65]. Some toric rotation check, such as https://www.astigmatismfix.com/, could help determine the amount of IOL rotation, and the expected residual refraction. When the large residual cylinder not amenable to correction by rotation alone or refractive

Toric designs are even more required in multifocal IOLs [66] because patients

In previous studies [68–72], toric multifocal IOLs achieved good visual performance, with UDVA better than 20/40 in more than 97% of patients, uncorrected near visual acuity better than 20/40 in 100% of patients, spectacle independence in more than 80% of patients, and residual refractive astigmatism lower than 0.50 D in 38–79% of patients. Toric trifocal IOLs such as a trifocal spherical hydrophilic IOL

But on the other hand, the selection of multifocal toric IOLs should be more restricted than monofocal toric IOLs, especially for the following candidates: (1) patients who had unrealistic expectations of visual quality when having related ocular comorbidities; (2) patients who may not tolerate dysphoric symptoms such

multifocal IOLs, such as abnormal κ or α angle, etc. Thus, a comprehensive ocular examination should be undertaken to rule out any ocular comorbidities that may

Normally, cases with irregular astigmatism, corneal ectatic disorders, postrefractive surgery, post-keratoplasty, and high myopia are not ideal candidates for toric IOL implantation, partly because they are unlikely to achieve complete refractive correction with toric IOLs. However, the amount of astigmatism may be partly reduced, decreasing spectacle dependence. And such cases may be considered for surgery after adequate counseling. As a consequence, the applications of toric IOLs are expanding to include special cases such as pellucid marginal degeneration [74, 75], mild keratoconus with cataract [76], astigmatism after keratoplasty [77–80], and high astigmatism [81]; even toric trifocal IOLs were used in high astigmatism cases [82]. In general, the indications of toric IOL are still controversial

as glare and halos; and (3) patients who had specific contraindications for

1.83° 1.44° at 6 months and no lens rotated more than 5° [61].

Compared with manual marking, Elhofi et al. had observed more precise alignment with VERION image-guided system [51], which offers comprehensive astigmatism management, the incision location optimization, toric IOL power calculation, as well as decreasing SIA.

However, Solomon et al. claimed that, compared with the surgeon's standard of care, the use of the VERION combined with intraoperative aberrometry (Optiwave Refractive Analysis system with VerifEye) did not significantly optimize the outcomes [52]. The accuracy of CALLISTO Eye is also very effective [53], and it also assists in planning the position of limbal relaxing incisions.

### **6. Complications**

Postoperative toric IOL misalignment is the major complication after toric IOL implantation. Toric IOL misalignment could harm visual quality. In a recent experimental study, 5° IOL axis rotation from the intended position determined a decay in the image quality of 7.03%, 10° of IOL rotation caused 11.09% decay, and 30° rotation caused 45.85% decay [54].

Toric IOL misalignment may be attributed to three factors: (1) inaccurate preoperative prediction of the axis of IOL alignment; (2) inaccurate intraoperative alignment; and (3) postoperative IOL rotation. IOL rotation may be observed as early as 1 hour after surgery, and a majority of rotations occur within the initial 10 days [18]. Early IOL rotation likely results from incomplete OVD removal, whereas late postoperative rotation is influenced by the IOL architecture, design, and axial length. In a recently published case report, the toric IOL was rotated more than 115° shortly after a neodymium: YAG (Nd:YAG) laser posterior capsulotomy [55].

Rotational stability of the IOL varies with design and material and strength of IOL capsular bag adhesions. Maximum rotational stability has been observed with hydrophobic acrylic lenses, followed by Hydrophobic acrylic, hydrophilic acrylic, PMMA and silicone. Loop haptic IOLs are better than plate-haptic IOLs on postoperative rotation stability when using silicone IOL, but they are similar when using acrylic IOL. A study of AT TORBI 709 M, which had one-piece hydrophilic acrylic with hydrophobic surface and a supporting four-haptic design, had rotation of more than 5° in 10% cases in 6 months [56]. Another study of AT TORBI 709 M reported 13% eyes had rotation of more than 10° [57], while another study reported 100% rotation of more than 10° [58]. Scialdone et al. found similar results in rotation stability between AT TORBI 709 M and AcrySof toric IOLs [59]. A long-term of 2-year study of AcrySof toric IOLs (hydrophobic acrylic IOL with Flexible loop haptic) reported postoperative rotation of more than 10° in 1.68% eyes, more than 5° in 23.3% eyes [18]. A recent cohort study [60] of 1273 eyes showed that AcrySof toric IOL was less likely to rotate, with 91.9% of eyes rotated 5° in AcrySof toric IOL eyes compared with 81.8% in TECNIS Toric IOL eyes (P < 0.0001); rotation 10° (97.8% Acrysof vs. 93.2% TECNIS, P = 0.0002) and 15° (98.6% Acrysof vs. 96.4% TECNIS, P = 0.02). Furthermore, a hydrophilic IOL with C-flex design

The image-guided systems and intraoperative aberrometry could be definitely more useful than manual alignment. As mentioned above, the image-guided systems capture a preoperative reference image and an intraoperative image and then match the two images with respect to each other using landmarks. During the operation, a graphic overlay is then superimposed on the surgical field along the target axis, which provides a guide for toric IOL alignment. The image-guided systems and intraoperative aberrometry have improved the precision of toric IOL alignment, with <5° of deviation from the intended axis in the majority of cases. Compared with manual marking, Elhofi et al. had observed more precise alignment with VERION image-guided system [51], which offers comprehensive astig-

However, Solomon et al. claimed that, compared with the surgeon's standard of care, the use of the VERION combined with intraoperative aberrometry (Optiwave Refractive Analysis system with VerifEye) did not significantly optimize the outcomes [52]. The accuracy of CALLISTO Eye is also very effective [53], and it also

Postoperative toric IOL misalignment is the major complication after toric IOL implantation. Toric IOL misalignment could harm visual quality. In a recent experimental study, 5° IOL axis rotation from the intended position determined a decay in the image quality of 7.03%, 10° of IOL rotation caused 11.09% decay, and 30°

Toric IOL misalignment may be attributed to three factors: (1) inaccurate preoperative prediction of the axis of IOL alignment; (2) inaccurate intraoperative alignment; and (3) postoperative IOL rotation. IOL rotation may be observed as early as 1 hour after surgery, and a majority of rotations occur within the initial 10 days [18]. Early IOL rotation likely results from incomplete OVD removal, whereas late postoperative rotation is influenced by the IOL architecture, design, and axial length. In a recently published case report, the toric IOL was rotated more than 115° shortly after

Rotational stability of the IOL varies with design and material and strength of IOL capsular bag adhesions. Maximum rotational stability has been observed with hydrophobic acrylic lenses, followed by Hydrophobic acrylic, hydrophilic acrylic, PMMA and silicone. Loop haptic IOLs are better than plate-haptic IOLs on postoperative rotation stability when using silicone IOL, but they are similar when using acrylic IOL. A study of AT TORBI 709 M, which had one-piece hydrophilic acrylic with hydrophobic surface and a supporting four-haptic design, had rotation of more than 5° in 10% cases in 6 months [56]. Another study of AT TORBI 709 M reported 13% eyes had rotation of more than 10° [57], while another study reported 100% rotation of more than 10° [58]. Scialdone et al. found similar results in rotation stability between AT TORBI 709 M and AcrySof toric IOLs [59]. A long-term of 2-year study of AcrySof toric IOLs (hydrophobic acrylic IOL with Flexible loop haptic) reported postoperative rotation of more than 10° in 1.68% eyes, more than 5° in 23.3% eyes [18]. A recent cohort study [60] of 1273 eyes showed that AcrySof toric IOL was less likely to rotate, with 91.9% of eyes rotated 5° in AcrySof toric IOL eyes compared with 81.8% in TECNIS Toric IOL eyes (P < 0.0001); rotation 10° (97.8% Acrysof vs. 93.2% TECNIS, P = 0.0002) and 15° (98.6% Acrysof vs. 96.4% TECNIS, P = 0.02). Furthermore, a hydrophilic IOL with C-flex design

matism management, the incision location optimization, toric IOL power

assists in planning the position of limbal relaxing incisions.

a neodymium: YAG (Nd:YAG) laser posterior capsulotomy [55].

calculation, as well as decreasing SIA.

rotation caused 45.85% decay [54].

**6. Complications**

*Intraocular Lens*

**40**

(Rayner 600S IOL) was reported to have excellent rotational stability: average 1.83° 1.44° at 6 months and no lens rotated more than 5° [61].

In cases with more than 10° of rotation, realignment of the toric IOL is needed [62]. In a study by Oshika et al., 6431 eyes are implanted with toric IOLs, and realignment was performed in 0.653% of cases [63]. An early repositioning performed after 1 week of primary cataract surgery had optical outcomes.

IOL tilt could also induce astigmatism: tilting toric IOLs aligned at 180° would decrease with-the-rule astigmatism, bringing in undercorrection, while aligned at 90° increased against-the-rule astigmatism, bringing in overcorrection [64].

Meanwhile, LASIK, customized surface ablation, or femtosecond laser-assisted intrastromal keratotomies could also be used to correct residual astigmatism [65]. Some toric rotation check, such as https://www.astigmatismfix.com/, could help determine the amount of IOL rotation, and the expected residual refraction. When the large residual cylinder not amenable to correction by rotation alone or refractive surgery, an IOL exchange, piggyback IOLs procedures may be considered.


4.2 Power generation

2. Flexible sizing of the microgrid: Depending on local regulations, neighboring entities could also be enlisted into the microgrid. Although not modeled herein, if such entities include vital facilities such as hospitals or fire stations, the microgrid facility may be eligible for non-interruptible status with respect to

3.Maximization of renewable energy assets: Buildings would be designed from the outset to maximize both solar and wind generations, thereby decreasing

the carbon footprint of the development overall and the cost of fuel.

A model is presented which incorporates a microgrid utilizing renewable energy assets into a development consisting of three 32-story residential towers and one 57-story commercial tower. The scale of the development is in keeping with current large-scale developments. The model is run in each of the eight cities of interest using local data on environmental conditions, construction costs (exclusive of real estate purchase), and income levels based upon local rents and power rates. Analyses of the benefits of including the microgrid, as opposed to the same scale conventional development, are performed on three

1.Infrastructure impact: Electric load is presented with and without the

2. Economic: Construction cost, anticipated revenue, and time to repay are

3.Ecological: Greenhouse emissions are compared with and without the

Actual hourly electrical usage data and building specifications of one 32-story residential tower and one 57-story commercial tower located in New York City were generously provided by GridMarket LLC, New York City, NY. The dimensions of each tower, given in square feet (sq. ft.) and number of apartments (apts.), are given in Table 5. Rentable area for the entire four-tower development is calculated, per industry standard, at 50% of total square footage, with the remaining 50% designated for hallways, stairwell, elevator shafts, and other such types of general-

Floors Retail

Res. 1916 94 80,333 938,324 32 26,805 0 879,019 608 Comm. 1972 165 127,966 2,689,635 57 216,912 2,319,046 0 0

(sq. ft)

Office (sq. ft)

Res. (sq. ft) Apts.

presented with and without the microgrid.

natural gas supply.

Micro-Grids - Applications, Operation, Control and Protection

4. The development model

levels:

microgrid.

microgrid.

4.1 The buildings

use areas.

Table 5.

8

Built ES Lot

area

Internal area (sq. ft)

Specifications for buildings to be used in the model (provided by GridMarket LLC).

A 2 � 1 (two gas turbines 7.9 MW powering 1 MW steam turbine) was the optimal configuration for the cogeneration plant. This would be supplemented by power provided by 10,500 solar panels and 295 1 kW vertical drum-type wind turbines. The number of solar panels was estimated by covering the entire roof area of the four proposed buildings with standard 77 inch by 39 inch panels, while the number of wind turbines was estimated by placing a turbine every 10 feet around the periphery of each roof. It is recognized that whole-roof coverage with solar panels is impracticable; however, the estimate is valid because some amount of appropriately facing surface area would be available for additional panels. Also, it is assumed for these calculations that the buildings will be boring rectangles. As this is neither likely nor desirable, setbacks will create additional space for more wind turbines. Energy storage devices will be included in the design from the outset in order to balance generated power between times of low load and high load.


*3.6. Quantification of Inflammatory Cytokine*

Osteoblasts can produce bone-active cytokines such as tumor necrosis factor-α and IL-6 [21,38]. In bone metabolism, these cytokines act as potent factors for osteoclast formation and bone resorption because they can mediate the effects of many stimulators of bone resorption, i.e., parathyroid hormone and IL-1 [22,23,40]. Among these cytokines, IL-6—the most potent osteoclastogenic factor—promotes the activation of osteoclast precursors and their subsequent differentiation into mature osteoclasts, leading to the bone resorption. In addition, a significant release of IL-6 can suppress cell viability. Thus, we determined the expression of IL-6 in cell cultures to evaluate the bone-forming ability and cytocompatibility of the PVDF composite nanofibers.

It was found that PVDF and PO06 promoted the expression of the IL-6 markedly due to the contamination by LPS and subsequent macrophage activation (Figure 11). However, all composite nanofibers containing the POSS–EGCG conjugate exhibited considerably decreased levels of IL-6 expression compared with the pure PVDF nanofiber. In particular, PE06 exhibited only a very small amount of IL-6 secretion, suggesting that the POSS–EGCG conjugate can downregulate the production of bone-active cytokines and improve the cytocompatibility of the composite nanofibers via the anti-inflammatory effect of EGCG [22,23,40]. Therefore, the content of the POSS–EGCG conjugate present was an essential factor in decreasing IL-6 production on the PVDF composite nanofibers.

**Figure 11.** Levels of IL-6 expression by RAW 264.7 cells on the PVDF composite nanofibers (*n* = 5). Significant difference from the pure PVDF nanofiber at each time point was denoted as *p*\* < 0.05.


**Author details**

Aimann Surak Department of Paediatrics, University of Alberta, Edmonton, Alberta, Canada

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## IntechOpen Book Series Veterinary Medicine and Science Volume 5

Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. Catrin completed her degree, Masters, and then PhD (University of Derby, Technische Universität München and University of Nottingham), undertook post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. She has also achieved her MMedSci (Medical Education) and PGC-

HE. Catrin is an author of 43 peer-reviewed journal articles, 11 books/book chapters, and 93 research abstracts. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, Fellow of the Galton Institute, and Senior Fellow of the Higher Education Academy. She has also written popular science books for the public. Orcid: https://orcid.org/0000-0002-2009-4898. Website https:// www.nottingham.ac.uk/vet/people/catrin.rutland

Albert A. Rizvanov is a Professor and Director of the Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology, Kazan Federal University (KFU), Russia. He is the Head of the Center of Excellence "Regenerative Medicine" and Vice-Director of Strategic Academic Unit "Translational 7P Medicine". Albert completed his Ph.D. at the University of Nevada, Reno, USA and Dr.Sci. at KFU. He is a corresponding member of the

Tatarstan Academy of Sciences, Russian Federation. Albert is an author of more than 300 peer-reviewed journal articles and 22 patents. He has supervised 11 Ph.D. and 2 Dr.Sci. dissertations. Albert is the Head of the Dissertation Committee on Biochemistry, Microbiology, and Genetics at KFU. ORCID https://orcid.org/0000-0002-9427-5739

Website https://kpfu.ru/Albert.Rizvanov?p\_lang=2

**Editors of Volume 5: Dr Catrin Sian Rutland** University of Nottingham, UK

**Professor Albert Rizvanov** Kazan Federal University, Russia

#### **Book Series Editor: Rita Payan-Carreira** University of Évora, Portugal

### Scope of the Series

Contents

**Section 1**

**Section 2**

in the Mare

*by David A. Trundell*

*and Catrin Sian Rutland*

Targets for Cartilage Health

*by Sinan Kandir*

*by Jasmine Dum-Tragut*

Medieval Equine Medicine from Armenia

Tendinitis and Desmitis in Horses

*Catrin Sian Rutland and Albert Rizvanov*

**Preface XI**

Medieval Medicine to Gene Therapy **1**

**Chapter 1 3**

**Chapter 2 17**

**Chapter 3 27**

Reproduction, Locomotion and Skin **51**

**Chapter 4 53**

**Chapter 5 71**

**Chapter 6 91**

Gene Therapy as a Modern Method of Treating Naturally Occurring

*by Rachael Levings, Andrew Smith, Padraic P. Levings, Glyn D. Palmer,*

*by Elena Zakirova, Kovac Milomir, Margarita Zhuravleva,*

Gene Therapy for the Treatment of Equine Osteoarthritis

*Anthony Dacanay, Patrick Colahan and Steven C. Ghivizzani*

Equine Reproduction: Seasonality, Endometritis, and Twinning

Investigation into Whether Proximal Suspensory Desmitis of the

ADAMTS Proteases: Potential Biomarkers and Novel Therapeutic

*by Anne Skivington, Milomir Kovac, Elena Zakirova, Albert A. Rizvanov*

Hindlimb Could Predispose Horses to Sacroiliac Disease

Paralleling similar advances in the medical field, astounding advances occurred in the Veterinary Medicine and Science in recent decades, fostering a better support to animal health and more humane animal production, a better understanding of the physiology of endangered species, to improve the assisted reproductive technologies or the pathogenesis of certain diseases, where animals can be used as models for human diseases (like cancer, degenerative diseases or fertility), and even as a guarantee of public health. Bridging the Human, Animal and Environmental health, the holistic and integrative "One Health" concept intimately associates the developments within those fields, projecting its advancements into practice. This book series aims to tackle a variety of fields in the animal-related medicine and sciences, providing thematic volumes, high quality and significance in the field, directed to researchers and postgraduates. It aims to give us a glimpse into the new accomplishments in the Veterinary Medicine and Science field. By addressing hot topics in veterinary sciences, we aim to gather authoritative texts within each issue of this series, providing in-depth overviews and analysis for graduates, academics and practitioners and foreseeing a deeper understanding of the subject. Forthcoming texts, written and edited by experienced researchers from both industry and academia, will also discuss scientific challenges faced today in Veterinary Medicine and Science. In brief, we hope that books in this series will provide accessible references for those interested or working in this field and encourage learning in a range of different topics.

## Contents

Preface

Understanding equine medicine, anatomy, physiology, nutrition, and behaviors is essential for horse and donkey welfare. This book contains both literature reviews and recent research into topics ranging from reproduction and locomotion through to ancient and modern treatments. The book investigates both healthy and pathological conditions at differing stages of life. The importance of each cell and tissue through to the whole organism is explored alongside the methodologies used to

As editors, we are both practicing gene therapy, anatomy, and physiology researchers and teachers, therefore we have strived to ensure that every chapter is accessible to everyone. Whether you are a veterinary professional, student, researcher, animal owner, or simply have an interest in horses and donkeys, we

The 'Medieval Medicine to Gene Therapy' section starts with an interesting chapter showing strategies used in Armenia, where East meets West in both traditions and medicines. This fascinating chapter bridges science and history, kings and physicians, to guide the reader through a topic rarely written about. The next two chapters show the brilliant advances being made in gene therapy used to treat lameness caused by tendinitis, desmitis, and osteoarthritis. These techniques rely on knowledge of not only how and why genes and proteins are expressed, but also on the best methods to introduce gene therapies and then the effects on healing, the

The next section concentrates on 'Reproduction, Locomotion, and Skin'. The first chapter reviews seasonality and the effect of photoperiod on mares, shows improvements in reproductive efficiency in mares, and also explores endometritis and twin pregnancies. The next chapter looks at proximal suspensory desmitis of the hindlimb and whether this can predispose horses to sacroiliac disease. By asking owners and bringing together published evidence and information, the authors cover both disorders. The next chapter investigates cartilage health, looking in detail at potential biomarkers for diagnosis and novel therapeutic targets, concentrating on equine joints and lameness causing issues. The final chapter delves into equine sarcoid, which is the most common skin neoplasia in the horse and also affects other equids. This chapter describes what equine sarcoid is, how and why it presents and

develops, clinical and pathological diagnosis, and potential treatments.

The final section covers the digestive system, diet, and finishes with a chapter on behavior. The first chapter covers the gastrointestinal system, looking at decades of experiences diagnosing and treating horses with postoperative ileus using different methods. It explores the difficulties, outcomes, and makes recommendations based not only on a large study but also on the published literature. Continuing the theme, a morphophysiological study of the gastrointestinal tract of the donkey is presented. Although the donkey is very similar to the horse, the chapter highlights the key attributes of the digestive system in the donkey, bringing together the vast literature on the subject into one chapter. Following information on the digestive system, it

hope you will find a number of interesting chapters in this book.

understand these vital structures and functions.

cells, tissues, and the whole animal.


**Acknowledgements**

We express sincere votes of thanks to the management of the International Medical & Technological University (IMTU) for guidance and promotion of this research activity. We also aknowledge I-Katch technology Ltd through its *Coffeeshop clinical research & scientific writing programme*. Moreover, we hereby express our thanking note to Café aroma in Dar es Salaam, Tanzania. Café aroma provided a near perfect environment (coffee, free-wifi and wonderful caloric-burning standing office tables) through which most of our meetings during study research question formulation, early study designs and data analysis were done, at times in their busiest business hours. *Dr Godfrey Ruben Swai* of The Registered Trustees of Ultimate Family Healthcare in Dar es salaam, Tanzania is credited for timely peer review, and insightful opinion on the quality of the final draft. Lastly but most important, we wish to eternally recognize the willingness of all women who consented wholeheartedly to be part of the primary study.