*3.2. Perform of Optimum Inundation Map by FLO-2D Model*

The overflow calculated by considering the simulated results for accumulated overflow from 342 manholes was used as the input data for the 2D hydraulic analysis program (FLO-2D model) based on the finite-difference method, as well as generated optimum inundation maps that can reflect maximum flood depth. According to the simulated total overflow results, most of the simulated maximum values of total overflow in the same year exist in different quartiles. Thus, the minimum and maximum flood occurrence maps were generated for different quantiles in the same year (Figures 7–9), using the simulated results of a 1-h minimum, and maximum total overflow for the 100 years from the 1st to the 4th quartile of the Huff method. Figure 7 shows the minimum flood occurrence map results; over the 100 years, the largest flood scale can be seen in the map of the 3rd quartile. Similarly, Figure 8 shows that over 100 years, the largest flood scale can be found in the map of the 4th quartile. Figure 9 shows the simulated results of 100-year 1-h rainfall events with different exceedance probabilities (10%, 30%, 60%, 90%) of the Huff 4th quartile. The results showed that different exceedance probabilities for Huff events also produce different flood inundation responses. This means that the temporal concentration level of storms has a strong influence on the inundation behaviors, even when they occur in the same temporal peak location.

(**c**) (**d**)

**Figure 7.** Sample minimum inundation maps applying 100-year, 1-h rainfall events with different Huff quartile distributions ((**a**–**d**): 1st, 2nd, 3rd, and 4th quartile).

**Figure 8.** Sample maximum inundation maps applying 100-year, 1-h rainfall events with different Huff quartile distributions ((**a**–**d**): 1st, 2nd, 3rd, and 4th quartile).

The results demonstrated that the same quantity of rainfall events showed considerable differences in overflow quantities with different time distribution characteristics. The difference between overflow amount and temporal distribution showed the different inundation behaviors. The rainfall event of the 4th quartile, with a 90% exceedance probability according to the Huff distribution, showed the maximum manhole overflow and widest range of inundation. The results showed that the temporal characteristics of storms, such as the temporal location of the storm peak and concentration level should be considered in order to generate the optimal inundation map to establish inundation prevention measures and conduct preliminary analysis and identification of the flood risk areas in urban drainage basins.

#### *3.3. Discussion*

Boxplots of the simulated total manhole overflow provide a visual summary of the results of 432 different rainfall scenarios reflecting the temporal characteristics of rainfall events such as the temporal concentration level and the temporal location of the storm peak. The rainfall scenarios consisted of nine different exceedance probabilities (10–90%), four different quartiles (1–4th quartile) of the Huff method, three different storm durations (1–3 h) and four different return periods (10, 50, 80, and 100-year) (Figure 10). The difference between the maximum and minimum total overflow with different temporal concentration levels of the 1, 2, and 3 h 10-year return period was 28.4 to 340.4 m3 (the maximum total overflow was 1.4 to 10.5 times larger than the minimum total overflow), the difference

between maximum total overflow and minimum with different temporal concentration levels of the 1, 2 and 3 h 100-year return period was 101 to 1323.8 m3 (the maximum total overflow was 1.5 to 4.7 times the minimum total overflow), shown according to the growth in the return period and duration, has the larger difference in overflow quantity with the same rainfall amount, and is related to temporal concentration levels. In addition, the difference between maximum total overflow and minimum in the 1st quartile of the 1, 2, and 3 h 10 to 100-year return period was 87.4 to 928.8 m3 (the maximum total overflow was 2.8 to 10.5 times larger than the minimum total overflow), whereas the difference between maximum total overflow and minimum in the 2nd quartile of the 1, 2, and 3 h 10 to 100-year return period was 28.4 to 485.9 m3 (the maximum total overflow was 1.4 to 2.6 times larger than the minimum total overflow). Furthermore, the difference between maximum total overflow and minimum in the 3rd quartile of the 1, 2, and 3 h 10 to 100-year return period was 44 to 323.6 m3 (the maximum total overflow was 1.4 to 1.7 times larger than the minimum total overflow). The difference between maximum total overflow and minimum in the 4th quartile of the 1, 2, and 3 h 10 to 100-year return period was 89.8 to 1323.8 m3 (the maximum total overflow was 3.1 to 4.9 times larger than the minimum total overflow). The simulated total overflow results for the different quartiles in the same period showed that most of the simulated maximum values of total overflow in the same year exist in different quartiles. The simulated total overflow results also showed considerable differences.

(**a**) (**b**)

(**c**) (**d**)

**Figure 9.** Sample inundation maps applying 100-year, 1-h rainfall events with different exceedance probabilities ((**a–d**): 10%, 30%, 60%, 90%) of Huff 4th quartile distribution.

**Figure 10.** Boxplots of the EPA-SWMM-model-simulated total overflow from 1 to 3 h for a period from 10 to 100 years ((**a**) total overflow of 1-h rainfall, (**b**) total overflow of 2-h rainfall, (**c**) total overflow of 3-h rainfall).

(**c**)

Overall, the results demonstrated that the average total overflow increases with the increase in the quartile of the storm peak location. The maximum total overflow generally occurred when the storm peak was located in the 4th quartile. The minimum total overflow generally occurred when the storm peak was located in the 1st quartile. Nevertheless, the difference between the maximum and minimum total overflow in the 1st and 4th quartile was greater than that of the 2nd and 3rd quartile. The storm concentration level effect on the total overflow is larger than that of the storm peak location. This means that accurate time distribution characteristics of rainfall events are essential for a correct understanding and response to unban flood management. Even though the results showed that the total overflow is highly related to the storm concentration level and the temporal location of the storm peak, there are limitations to generalizing the results since the results are generated by a case study of an urban drainage basin. To overcome the locality issues and to enhance the applicability, extensive further research is necessary to generalize the relationships between the characteristics of time distribution of heavy storms and manhole overflow.

#### **4. Conclusions**

The urban flood inundation impacts associated with the temporal characteristics of heavy storms were analyzed for a target drainage basin in Seoul, Korea. The total manhole overflow and the inundation behavior were simulated using the EPA-SWMM and the FLO-2D model, respectively. Rainfall scenarios reflecting the temporal characteristics of rainfall events, such as the temporal concentration level and the temporal location of the storm peak were created using the Huff method for nine different exceedance probabilities (10–90%), for four different quartiles (1–4th quartile), for three different storm durations (1–3 h) and four different return periods (10, 50, 80, and 100-years).

The simulated manhole overflow and inundation area were highly related to the temporal characteristics of storms, not only the temporal location of the storm peak but also the concentration level. The manhole overflow with different temporal concentration levels of 1, 2, and 3 h 10-year return period events showed a 4.8, 7.2 and 10.5 times difference, respectively. This means that the longer rainfall duration has the larger difference in overflow quantity with the same rainfall amount. The overflow amount with different temporal concentration levels of 1, 2, and 3 h 100-year return period events showed a 3.7, 3.8 and 2.8 times difference, respectively.

The manhole overflow with different temporal locations of the storm peak of 1, 2, and 3 h 10-year return period events showed a 29.7, 98.5 and 79.1%, difference, respectively. The manhole overflow with different temporal locations of the storm peak of 1, 2, and 3 h 100-year return period events showed a 2.17, 1.92 and 1.65 times difference, respectively. The rainfall event in the 4th quartile, with 90% exceedance in terms of Huff distribution probability, showed the maximum manhole overflow and widest inundation range. The results also illustrated that the temporal concentration level is more effective in determining the manhole overflow amount than the temporal location of the storm peak.

The results illustrate that despite the same rainfall quantity, there is a huge difference in the manhole overflow amount and the inundation area according to the difference in the time distribution characteristics. Therefore, a consideration of the temporal distribution characteristics of extreme rainfall events is essential for an accurate understanding of the rainfall–runoff response and the inundation behavior in urban areas. The results also show the possibility of establishing appropriate inundation prevention measures in urban drainage basins when rainfall forecasts including not only quantity but also time distribution characteristics are available.

**Author Contributions:** T.L., G.L. and G.K. conceived and designed the experiments; T.L. performed the experiments; G.K. provided the Huff rainfall data; T.L. ran the EPA-SWMM and FLO-2D model; T.L. analyzed the data; G.K. and G.L. supervision experiments; T.L. wrote the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Korea Environmental Industry & Technology Institute (KEITI) of the Korea Ministry of Environment (MOE) as part of the "Advanced Water Management Research Program". (79615).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Authors have the raw data readily available for presentation to the referees and the editors of the journal, if requested. Authors ensure appropriate analysis are taken so that raw data is retained in full for a reasonable time after publication.

**Acknowledgments:** This work was supported by the Korea Environmental Industry & Technology Institute (KEITI) of the Korea Ministry of Environment (MOE) as part of the "Advanced Water Management Research Program". (79615).

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

#### **References**


Several studies have demonstrated the significant antitumor and anticancer activities of laminarin and laminarin oligosaccharides [89]. The underlying mechanisms include apoptosis and the inhibition of cancer cell colony formation [90]. Different concentrations of laminarin have been used to treat human colon cancer LoVo cells and the intracellular reactive oxygen species (ROS), pH, intracellular calcium ion concentration, mitochondrial permeability transition pore, mitochondrial membrane potential, and Cyt-C, Caspase-9 and Caspase-3 expression levels were analyzed. The studies have found kelp polysaccharides to induce the apoptosis of human colon cancer LoVo cells through the mitochondrial pathway [91,92]. The polysaccharide did not show direct cytotoxicity, but exhibited significant antitumor activity on SK-MEL-28 human melanoma cells and it could effectively inhibit the colony formation of HT-29 cells [93,94].

Laminarin oligosaccharides can inhibit the proliferation of human tissue lymphoma cell line (U937 cells) by stimulating monocytes to produce cytokines [95]. Specific enzyme products with high content of 1,6-linked glucopyranose residues (laminarin oligosaccharides with DP 9–23) have shown significant anticancer activity and can inhibit the colony formation of melanoma and colon cancer cells [96,97]. Sulfated laminarins (LAMS) with a sulfate content of 45.92% proved to inhibit the growth of LoVo cells more significantly than laminarin, suggesting the better antitumor activity of LAMS. Accordingly, enzymatic hydrolysis and molecular modification provide new ideas for the production of laminarin derivatives with high antitumor activity [98].

The anticoagulant activity of *Laminaria* sp. extract was first reported in 1941 [99]. Although laminarin is a non-sulfated polysaccharide in seaweed, its sulfated products showed anticoagulant activity [100]. Many studies have been published on the extraction and modification of laminarin sulfate from algae in the genus *Laminaria*. If each glucose residue has an average of two sulfate groups, the anticoagulant activity of the preparation reaches 25–30% of that of standard heparin [101], while the activity of sulfonic acid derivatives appears to be higher than that of sulfate esters [102]. A derivative of laminarin with 1.83 sulfate groups per glucose unit showed 33% of the potency of heparin in rabbits, although it was extremely toxic to guinea pigs [103]. This suggests that laminarin sulphate might be effective in the prevention and treatment of cerebrovascular diseases.

#### *3.3. Anti-Inflammatory and Immunostimulatory Activity*

Studies have shown that β-glucans cause reduced recruitment of inflammatory cells and decreased secretion of inflammatory mediators in liver tissues through direct effects on immune cells or indirect effects as dietary fibers [104]. Laminarin significantly increases the release of inflammatory mediators, such as hydrogen peroxide, calcium, nitric oxide, monocyte chemoattractant protein-1, vascular endothelial growth factor, leukemia-inhibitory factor, and granulocyte colony-stimulating factor, and enhances the expression of signal transducer and transcriptional activators [86]. Recent studies have found laminarin to induce positive effect of decreasing mitochondrial activities without cytotoxicity caused by oxidative stress by regulating the interaction between glycans and receptors on the skin cell surface [105].

#### *3.4. Prebiotic Activity*

The prebiotic properties of algae polysaccharides enable them to play an important role in regulating human intestinal health [106]. For laminarin, it has been confirmed in vitro that it cannot be hydrolyzed by hydrochloric acid under physiological conditions, nor by homogenates of the human digestive system [14,107]. Since laminarin is resistant to hydrolytic enzymes in the human upper digestive tract, it can reach the intestinal flora [108]. Animal experiments have shown that adding laminarin to the diet of mice can significantly reduce the Firmicutes to Bacteroidetes ratio in the intestines, indicating that it can enhance the high-energy metabolism of the intestinal microbiota to reduce the side-effects of highfat diets [109]. In addition, laminarin oligosaccharides are beneficial for the growth of *Bifidobacterium animalis* and *Lactobacillus casei*, also increasing the production of short-chain fatty acids, such as lactic acid and acetic acid [110].

#### **4. Fucoidan**

Fucoidan is a sulfated polysaccharide that consists mainly of fucose repeating units besides several other monosaccharide residues. It is commonly found in brown seaweed [111,112], and has also been reported in echinoderms and some lower plants [113]. Fucoidan typically acts as a structural polysaccharide in the cell walls of brown macroalgae, with its relative amount ranging between 4 and 8% of the total dry weight [114]. Since fucoidan was first isolated in 1913, the structure of fucoidans from different brown seaweeds has been studied. Seaweed fucoidan is a heterogeneous material, with varying composition of carbohydrate units and non-carbohydrate substituents [115]. Fucoidan is mainly composed of fucose and sulfate groups (Figure 4). For example, the fucoidan from bladder wrack (*Fucus vesiculosus*) has a simple composition and contains only fucose

and sulfate groups (44.1% fucose, 26.3% sulfate) [116]. In addition, it might also contain other monosaccharides (mannose, galactose, glucose, xylose, etc.), uronic acid, and even acetyl groups and proteins. For example, the fucoidan from *Fucus vesiculosus* contains 84% fucose, 6% xylose, 7.3% galactose, and 2% mannose [117]. The fucoidan found in *Fucus distichus* is composed of 51.6% fucose, 2.7% xylose, 1.5% galactose, 0.7% mannose, and 0.2% glucose [118]. Comprehensive analysis concluded that the fucose content of fucoidans is in the range of 4.45–84%, besides 1.44–49% galactose, 0.2–45% glucose, and 0.3% to 16% xylose and mannose. As a heterogeneous polymer, fucoidan exhibits considerable structural diversity that makes it difficult to draw general conclusions. Moreover, its structure cannot be described solely based on monosaccharide composition.

**Figure 4.** Structure and biological effects of fucoidan (A: *Ascophyllum nodosum* and *Fucus vesiculosus*; B: *Saccharina japonica*, adapted from literature [119–121]).

The structural variety of fucoidans is to a large extent related to the different types of brown algae they are found in. Generally, α (1→3) and/or (1→4) glycosidic bonds constitute the main chain of the macromolecules, dominating in most backbone structures. The presence of sulfate groups at the C-2, C-4 and or C-3 position is another important feature [94,122–127]. Due to the structural heterogeneity of fucoidans, the degradation of fucoidan requires a large set of enzymes of different activities and specificities [128]. Fucoidanase are mainly from marine bacteria, invertebrates and sometimes fungi. Similar to the above mentioned polysaccharide-degrading enzymes, endo-type fucoidanase produce fuco-oligosaccharides while exo-type fucosidase leads to the formation of mono- or oligosaccharides with a small degree of polymerization [129]. Natalie et al. purified a new fucoidanase and hydrolyzed fucoidan without desulfation to form oligosaccharides ranging from 10 to 2 fucose units plus fucose [130]. Dong et al. discovered a new α-L-fucosidase from marine bacterium *Wenyingzhuangia fucanilytica*, and found that Alf1\_Wf was capable of hydrolyzing α-1,4-fucosidic linkage and synthetic substrate. Besides, Alf1\_Wf could act on partially degraded fucoidan [131]. Compared to other brown polysaccharides, there are few studies on the enzymatic degradation of fucoidan and the function of fucooligosaccharides, whereas the functional investigation of biological activities, such as anti-obesity, antivirus, antitumor, antidiabetic, and antioxidative effects has been widely proven. It is generally believed that fucoidan can become an important substance in the functional food and nutrition and health industries [132,133].

#### *4.1.  The underlying mechanism includes the inhibition of tumor cell proliferation, stimulating tumor cell apoptosis, blocking tumor cell metastasis, and enhancing various immune responses [136,139–141]. Low molecular weight fucoidan (LMWF), for instance, triggers G1-block and apoptosis in human colon cancer cells (HCT116 cells) through ap53-independent mechanisms [142]. Through the assessment of microtubule-associated proteins and the accumulation of Beclin-1, fucoidan is also found to induce autophagy in human gastric cancer cells (AGS cells) [143]. The polysaccharide induces the apoptosis of HTLV-1-infected T-cell lines mediated by cytostatics that downregulate apoptosis protein-2. The use of fucoidan in vivo thus severely inhibits the tumor growth of subcutaneously transplanted HTHT-1-infected T-cell lines in immunodeficient mice [138]. In addition, fucoidan activates the caspase-independent apoptotic pathway in MCF-7 cancer cells by activating ROS-mediated MAP kinase and regulating the mitochondrial pathway mediated by Bcl-2 family proteins [144]. Similarly, fucoidan has shown antitumor activity against PC-3 (prostate cancer), HeLa (cervical cancer), A549 (alveolar cancer), and HepG2 (hepatocellular carcinoma) cells [145].

#### *4.2. Antiviral and Anti-Inflammatory Activity*

Fucoidans isolated from different seaweed species have potential antiviral activity. For instance, they can inhibit the replication of enveloped viruses, including the human immunodeficiency virus (HIV) and the herpes simplex virus (HSV) [146]. According to Queiroz et al. [147], fucoidans from *Dictyota mertensii*, *Lobophora variegata*, *Spatoglossum schroederi*, and *Fucus vesiculosus* inhibit the HIV reverse transcriptase (RT) enzyme, while other studies have shown that they also reduce the amount of the HIV-1 p24 antigen [148]. Compared with other antiviral drugs currently used in clinical medicine, the inhibitory effect of fucoidan is accompanied by lower cytotoxicity. According to one potential mechanism, fucoidan prevents viruses from entering the cells by changing the characteristics of the cell surface. The polysaccharide may also directly interact with viral enzymes or viral proteins on the surface of the pathogen.

Many studies have reported the blocking effect of fucoidan on HSV infection. Fledman et al. isolated different fucoidan components from *Leathesia difformis* and verified the selective antiviral activity of different components against HSV-1 and HSV-2 [149]. Fucoidan extracted from *Undaria pinnatifida* has shown antiviral activity against 32 HSV clinical strains, including 12 ACV-resistant (4 HSV-1 and 8 HSV-2) and 20 ACV-susceptible ones. Judging by the survival rate and lesion score, oral fucoidan can protect mice from HSV-1 infection by stimulating cytotoxic T lymphocytes, natural killer activity, and neutralizing antibodies [150].

The above findings clearly indicate the potential antiviral activity of seaweed fucoidans, which can also strengthen the immune response of the host and achieve multichannel and multi-level regulation of the immune system [151,152]. The polysaccharide is

able to prevent virus transmission by directly inhibiting virus replication and stimulating innate and adaptive immune defense functions. The immunomodulatory activity of fucoidan is another hot research topic. Numerous studies have already confirmed fucoidan to exhibit an anti-inflammatory effect through immune regulation (Table 1). This involves the polysaccharide binding to different receptors, e.g., the Toll-like receptors (TLRs) of monocytes, such as dendritic cells (DCs) and macrophages, and thereby initiating the release of pro-inflammatory factors: cytokines and chemokines. They also suppress the expression of NO synthase (iNOS) and cyclooxygenase (COX)-2 at the protein level, and dose-dependently inhibit the production of nitric oxide (NO) and prostaglandin E2 (PGE2).

**Table 1.** Monosaccharide composition, molecular weight, concentration, sulfation degree and anti-inflammatory mechanism of different fucoidans.

Fucoidan can enhance the various beneficial effects of lactic acid bacteria on immune function by improving Th1/Th2 immune balance [162], and can also treat gastric mucosal damage caused by oral aspirin through its ability to regulate immune response and reduce ulcers' inflammation [163]. During in vivo experiments, Li et al. evaluated the potential inhibitory activity of fucoidan on the myocardial ischemia-reperfusion (I/R) model in rats. The results showed a significant effect by modulating the inflammatory response through the inactivation of high mobility group box 1 (HMGB1) and nuclear factor kappa B (NF-κB) [164].

It has been reported that the destruction of connective tissue during inflammatory diseases such as chronic wounds, chronic inflammation, or rheumatoid arthritis is a result of a continuous supply of inflammatory cells and increased production of inflammatory cytokines and matrix proteases [165]. Selectins expressed on endothelial cells, leukocytes, and platelets contribute to the interaction of leukocytes and platelets on the side of vascular injury, thereby enhancing the inflammatory response during the arterial response to injury [166]. Fucoidan can effectively inhibit the interaction between selectins and their ligands leading to reduced inflammation at an early stage. Therefore, fucoidan use seems beneficial for treating certain inflammations accompanied by uncontrolled extracellular matrix degradation. The above studies have laid the preclinical foundation for the development of fucoidans as a new generation of polysaccharide immunomodulators.

#### *4.3. Antidiabetic Activity*

Studies have shown that fucoidan can also exhibit antidiabetic effects by reducing postprandial hyperglycemia and pancreatic β-cell damage, increasing insulin secretion, and regulating glucose metabolism to reduce blood sugar [167,168]. Fucoidan has a significant inhibitory effect on the three starch-hydrolyzing enzymes; it is a non-competitive inhibitor of α-amylase and amyloglucosidase, while being a competitive inhibitor of αglucosidase [169]. Its inhibitory mechanism lies in the formation of hydrogen bonds [170]: the hydroxyl groups of fucoidan, especially the ones at the C-terminus that may be connected to fucose, can easily form hydrogen bonds with the amino acids of the two enzymes. The negatively charged oxygens of the sulfated groups of the polysaccharide (and the ones connected to C-2 and/or C-3 in particular) further facilitate the formation of hydrogen bonds or salt bridges with the proteins, resulting in strong interactions, thereby inhibiting the enzyme. Furthermore, inhibition of dipeptidyl peptidase-IV (DPP-IV) is one of the possible mechanisms involved in the antihyperglycemic activity of fucoidan. Dipeptidyl peptidase-IV (DPP-IV) is an enzyme that is involved in the inhibition of the rapid degradation of incretin hormones, which prevents postprandial hyperglycemia. Inhibiting DPP-IV prolongs the action of incretins, which reduces glucose production and increases insulin production [171]. Fucoidan can be used as a dipeptidyl peptidase-IV (DPP-IV) inhibitor to block DPP-IV action thereby prolonging the half-life and biological activity of incretin hormones [172], which play a crucial role in glucose homeostasis by promoting α and β cell function [173]. It also downregulates the gastric emptying and gastric acid secretion to reduce the postprandial glucose level [174,175]. Olga N. Pozharitskaya et al. have found a concentration-dependent inhibition of the enzyme DPP-IV by fucoidan at the concentration range of 0.02–200 μg/mL, The IC50 was 11.1 μg/mL and the maximum inhibition degree was 60–75% [176].

In addition, fucoidan may have a positive effect on antidiabetics by reducing β cell damage in the pancreas and increasing insulin secretion. According to a complex mechanism, the polysaccharide enhances the activity of sirtuin 1, thereby inducing deacetylation and upregulation of FOXA2 and p-FOXO-1 to promote the expression of PDX-1 and its regulation of insulin synthesis, thereby reducing β cell apoptosis and dysfunction in mice [177]. Furthermore, fucoidan is able to prevent the occurrence of diabetic nephropathy (DN) associated with spontaneous diabetes by inhibiting the NF-κB signaling pathway and lowering blood sugar in a non-toxic way [178]. It has also been found that a combination

of fucoidan and traditional Chinese medicine has a beneficial effect on hyperglycemia and DN in rats [179].

#### *4.4. Other Biological Activities*

Heparin is a highly sulfated polysaccharide found in mammalian tissues and has been used as an anticoagulant for more than 50 years [180]. However, the clinical use of heparin is known to cause various side effects, such as excessive bleeding, thrombocytopenia, mild transaminase elevation, and hyperkalemia [181]. Therefore, it is necessary to find alternative drugs with safe and effective anticoagulant properties. It is worth noting that fucoidan has shown effectiveness for blood clotting, and many studies suggest it as an alternative to heparin [182,183]. Through studying the anticoagulant activity of fucoidans isolated from nine species of brown seaweed, the ones from *Ecklonia kurome* and *Hijikia fusiforme* were found to have the strongest effect in terms of thromboplastin time (TT) and activated partial thromboplastin time (aPTT) [184]. The mechanism of fucoidan action differs from that of heparin since it can be used in the cases where the application of heparin itself, for some reason or other, is ineffective. The anticoagulant action of fucoidans (as well as that of heparin) can be quickly blocked by the intravenous introduction of biocompatible cationic polymers such as protamine sulfate and VIM-DEMC (a synthetic copolymer of 1-vinylimidazole with diethyl maleate) [185]. Fucoidans may inhibit thrombin activity by directly acting on the enzyme or through the activation of thrombin inhibitors, including antithrombin III and heparin cofactor II [186].The position of the sulfate group on the sugar residues was found to be an important factor, with the concentration of C-2 sulfated and C-2,3 disulfated residues considerably affecting anticoagulant activity [123].

Fucoidan also has a positive effect in treating and preventing obesity.  Furthermore, *Fucus vesiculosus*-derived fucoidan was found to hinder fat accumulation in 3T3-L1 adipocytes by stimulating lipolysis through increased hormone-sensitive lipase expression and reduced glucose uptake [188].

At present, there is limited information available regarding the antiallergic effect of fucoidan. Recent studies have shown that the orally administered polysaccharide suppresses allergic symptoms by promoting the expression of galectin-9 mRNA and serum galectin-9 levels, thereby preventing immunoglobulin E (IgE) binding to mast cells [189].

#### **5. Conclusions**

This review summarized the physicochemical and structural properties of polysaccharides and oligosaccharides derived from brown algae. Their structure and composition determine their biological activity and thereby their nutritional and therapeutic potentials. Although more is now known regarding their biological activities in vitro and significant advance has been made in their extraction from natural sources and modifications, further structural-activity investigation is necessary. Sustainable technologies must be established for the purification of the polysaccharides and the production of oligosaccharides, minimizing energy and chemical consumption while allowing upscaling of consistent quality and freedom from side-effect causing impurities. Lastly, research on catalytic enzymes, including alginate lyase, laminarinase, fucoidanase, and fucosidase, with high stability and desired substrate specificity is needed to enable the production of high-purity oligosaccharides with uniform structure and degrees of polymerization. Progress in enzyme and metabolic engineering will further promote the utilization of brown algae polysaccharides in the food and pharmaceutical industries.

**Author Contributions:** D.W. and Y.S.Y.H. conceived and designed the project. Y.L., Y.Z. (Yuting Zheng), A.C.Y.W. and B.I. wrote the article. Y.Z. (Ye Zhang), Y.Y. and P.W. collected the literature. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by "the Fundamental Research Funds for the Central Universities, Southwest University" (No. SWU019034), Chongqing Science and Technology Bureau (cstc2020jcyjmsxmX0463), "Innovation and entrepreneurship project for returned overseas talents in Chongqing" (CX2019016), Postgraduate mentor team-building program of Southwest University (XYDS201905), Knut and Alice Wallenberg Foundation, and the Swedish Foundation for International Cooperation in Research and Higher Education (KO2018-7936).

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

#### **References**

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ISBN 978-3-0365-2469-6


Contents

### **Preface XIII**

### **Part 1 Introduction 1**

### **Part 2 Materials 147**

Contents VII

**Part 4 Infection 411**

Chapter 19 **Infection in Primary Hip and Knee Arthroplasty 413**

Chapter 20 **Infections in Hip and Knee Arthroplasty: Challenges to**

**Part 5 Arthroplasty of Spine and Upper Extremity 497**

Chapter 24 **Lumbar Spinal Arthroplasty: Clinical Experience 515**

**in Proximal Humerus Fractures 533** José Hernández Enríquez, Xavier A. Duralde

**After Shoulder Arthroplasty 603**  Michael W. Maier and Philip Kasten

**for Metacarpophalangeal Arthroplasty 565**

Chapter 27 **Humeral Hemiarthroplasty with Spherical Glenoid Reaming:**

**Theory and Technique of The Ream and Run Procedure 577**

and Antonio J. Pérez Caballer

Nicola Massy-Westropp

Chapter 28 **Development of Proprioception**

Chapter 22 **Arthroplasty in HIV/SCD Carriers 485**

Chapter 23 **Cervical Disc Arthroplasty 499** Bruce V. Darden

Fred H. Geisler

Chapter 25 **Shoulder Hemiarthroplasty**

Chapter 26 **Postoperative Therapy**

Moby Parsons

Michelle M. Dowsey, Trisha N. Peel and Peter F.M. Choong

**and Chances for the Microbiological Laboratory 439** Peter Schäfer, Bernd Fink, Dieter Sandow and Lars Frommelt

J. Bahebeck, D. Handy Eone, B. Ngo Nonga and T. Kingue Njie

Chapter 21 **Staphylococcus Infection Associated with Arthroplasty 459** Weisheng Ye, Wei Shang and Yaqiong Yang

	- **Part 3 Loosening 273**

### **Part 4 Infection 411**

VI Contents

**Part 2 Materials 147**

Chapter 9 **Titanium as a Biomaterial for Implants 149** Carlos Oldani and Alejandro Dominguez

Chapter 11 **The Use of PEEK in Spine Arthroplasty 211**

Chapter 12 **The Biology of Bone Grafts 235**

**Part 3 Loosening 273**

Chapter 13 **Cross-Linked Gelatin Microcapsules for**

Chapter 14 **Risk Factors for Aseptic Loosening**

Chapter 10 **The Bearing Surfaces in Total Hip Arthroplasty –**

T. Brown, Qi-Bin Bao and Hansen A. Yuan

**Drug Delivery in a Arthritic TMJ 255**

**Following Total Hip Arthroplasty 275**

**Aseptic Loosening of Hip Arthroplasty 295**

Jiri Gallo, Yrjö T. Konttinen, Stuart B. Goodman, Jacob P. Thyssen, Emmanuel Gibon, Jukka Pajarinen, Yuya Takakubo, Peter Schalock, Zygmunt Mackiewicz,

Eemeli Jämsen, Martin Petrek, Rihard Trebse,

**Could Improve Diagnostic Accuracy 363**  Cathérine Ruther, Ulrich Timm, Hartmut Ewald, Wolfram Mittelmeier, Rainer Bader, Rico Schmelter,

**Revision Knee Replacement Surgery 387** Matteo Fosco, Rida Ben Ayad, Luca Amendola,

Chapter 17 **Current Possibilities for Detection of Loosening of**

Chapter 15 **Evidence Linking Elevated Oxidative Stress and**

Chapter 16 **Aseptic Loosening of Total Hip Arthroplasty as**

Plamen Kinov and Peter Tivchev

Andrei Coer and Michiaki Takagi

Armin Lohrengel and Daniel Kluess

Dante Dallari and Domenico Tigani

Chapter 18 **Management of Bone Loss in Primary and**

Carlos Roberto Galia and Luis Fernando Moreira

**Options, Material Characteristics and Selection 163**

Hamid Reza Seyyed Hosseinzadeh, Alireza Eajazi and Ali Sina Shahi

P. R. Kramer, Brian Windsor, Kenneth Carson and Larry Bellinger

Scott J. MacInnes, Andrew Gordon and J. Mark Wilkinson

**a Result of Local Failure of Tissue Homeostasis 319**

**Total Hip Replacements and How Intelligent Implants**

	- **Part 5 Arthroplasty of Spine and Upper Extremity 497**

Preface

quality of life.

field.

special chapters on loosening and materials.

The purpose of this book is to offer an exhaustive overview of the recent insights into the state-of-the-art in arthroplasty. The tremendous long-term success of Sir Charnley's total hip arthroplasty has encouraged many researchers, physicians, surgeons, and technicians to search for new applications, designs, technology, and surgical exposures to treat pain, improve function and create solutions for higher

Indeed, the success story was repeated very soon with knee arthroplasty. Moreover, the number of knee arthroplasties has shown almost exponential growth worldwide and has exceeded the number of total hip arthroplasties in many clinics in the Western countries in the past decade. Besides, and as described in a special chapter of this book, arthroplasty of the upper extremity joints and spine is an emerging

However, there are complications involved in bringing any foreign design into the unique and wonderful system of the human body. First, opportunistic germs try to win the ever-ongoing war with their host in the cover of the prosthesis. In the chapter on infections we endeavor to provide a comprehensive, up-to-date analysis and description of the surgical and medical management of this difficult problem. Secondly, the immune system is suddenly faced with a strange material coming in huge amounts of micro-particles from the tribology code for an extended period of time. Therefore, great attention has been given to the problem of aseptic loosening in

Each chapter includes an extensive review of the literature as well as current techniques and philosophies. We have been as fortunate as to have an outstanding group of arthroplasty specialists from all over the world contributing to this publication. Some current topics have been discussed by several authors; therefore some repetition has been inevitable. However, as the problems are illuminated from

We especially wish to acknowledge the contributing authors, without whom a work of this magnitude would clearly not be realizable. We thank them for allocating much of

different points of view, this only brings an added value to the book.