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About this book

This book presents a comprehensive review of the latest advances in developing alginate-based biomaterials and derivatives as well as their biomedical and pharmaceutical applications. It covers the physiochemical properties of alginates, production and formulation methods, derivatizations and characterization methods, the fundamental work on optimizing alginate polymers for defined biomedical purposes as well as the scope and effectiveness of their applications in medicine and therapeutic approaches. The book brings together new concepts and advances in harnessing alginate-based biomaterials in combination with applied technological advances to tailor their applications to medical needs. The contributions by leading academics, clinicians and researchers not only cover the fundamentals, but also open new avenues for meeting future challenges in research and clinical applications.

Table of Contents

Frontmatter

Chapter 1. Alginate Biosynthesis and Biotechnological Production

Alginates are natural exopolysaccharides produced by seaweeds and bacteria belonging to the genera Pseudomonas and Azotobacter. Due to exhibiting unique physicochemical properties, they have been widely applied for various industrial purposes such as in food, agricultural, cosmetic, pharmaceutical, and biomedical industries. In the last two decades, they have found their way into the advanced pharmaceutical and biomedical applications, owing to their biocompatibility and non-toxicity as well as versatility in view of modifications. So far, algal alginates have been the sole commercialized products applied for various purposes, while the potential uses of bacterial alginates remain unharnessed. Importantly, algal and bacteria alginates differ substantially from each other with respect to their composition, modifications, molecular mass, viscoelastic properties, and polydispersity. Indeed, bacterial alginates may meet current needs in the field of advanced pharmaceutical and biomedical engineering. In this chapter, after a brief overview of alginate discovery, general properties, applications, and comparative assessment of algal and bacterial resources, current findings about the biosynthesis of alginates, mainly in bacteria, will be discussed. Furthermore, we will discuss the current understanding of alginate polymerizing and modifying enzymes and their structure-function relationship. Knowledge about alginate biosynthesis/modification enzymes provides foundation for rational design of cell factories for producing tailor-made alginates. As a conclusion, advanced understanding of alginate biosynthesis pathway and involved enzymes creates an opportunity for bioengineering and synthetic biology approaches toward the production of alginates exhibiting desired material properties suitable for pharmaceutical and biomedical applications.
M. Fata Moradali, Shirin Ghods, Bernd H. A. Rehm

Chapter 2. Alginate Production from Marine Macroalgae, with Emphasis on Kelp Farming

Alginates are produced industrially from marine macroalgae (also called seaweeds) belonging to the taxonomic group of brown algae (phylum Ochrophyta, class Phaeophyceae). In particular, the seaweeds commonly known as kelps (order Laminariales) are the most widely exploited worldwide as raw materials for alginate production. Alginophytes (i.e. alginate-yielding seaweeds) are mainly harvested from wild populations, although some of the raw material that is used in the alginate industry comes from the cultivation of the kelp Saccharina japonica. The demand for alginate production has increased over time, and it is likely to increase significantly in the future, particularly for the use of alginates in current and future biomedical and bioengineering applications. However, alginophyte resources are limited, and the natural kelp resources have declined worldwide in recent years. One way to meet the current and future demands of alginate-using industries is to encourage alginate production via kelp farming. The mariculture of the kelp S. japonica has already been well developed in Asia, and the cultivation of other kelp species is currently also being attempted in Europe and the Americas. This chapter provides an overview of seaweeds as a feedstock for alginate production, with emphasis on kelp farming to ensure a sustainable supply of alginates required for many applications. It describes the major stages for the cultivation of Saccharina and any other kelp, as well as the economic and environmental benefits of integrated kelp aquaculture to produce alginates, in addition to other value-added products.
César Peteiro

Chapter 3. Alginate Microcapsules for Drug Delivery

Currently, conventional drug delivery systems do not provide adequate therapeutic profiles for the management of multiple diseases. In this regard, cell encapsulation technology emerges as a suitable alternative. Undoubtedly, one of the most employed biomaterials for this purpose is alginate, since it presents multiple advantages that favor the development of this technology. Importantly, the thorough study concerning the purification and modification of the polymer has led to biocompatible alginates, a vital advancement for the correct function of the system. Furthermore, the possibility to entrap different cell types together with the plausibility of engineering cells to produce disparate therapeutic biomolecules has given rise to numerous applications. That is the case of relevant and prevalent diseases nowadays such as diabetes, cancer, or neurological diseases. Intensive research in the field has resulted in promising preclinical studies in animal models that have instigated the conduction of several clinical trials. Nonetheless, addressing some current challenges regarding aspects such as biosafety or biofunctionalization seems to be a prerequisite before the clinical translation.
Ainhoa Gonzalez-Pujana, Gorka Orive, Jose Luis Pedraz, Edorta Santos-Vizcaino, Rosa Maria Hernandez

Chapter 4. Alginate Processing Routes to Fabricate Bioinspired Platforms for Tissue Engineering and Drug Delivery

Alginate is a water-soluble polymer which has gained much attention in the last 20 years as suitable biomaterial for numerous applications in biomedical science and engineering. The strong biocompatibility in cell microenvironment and the possibility to process alginate solution by safe conditions to reach a stable form after polymer gelation – via ionic, chemical, or thermal route – make them useful to design different types of devices (i.e., injectable gels, porous scaffolds, micro-/nanoparticles) which are attractive for wound healing, cell transplantation, drug delivery, and three-dimensional scaffolds for tissue engineering applications.
In this chapter, current potential applications of alginates in biomedical science, tissue engineering, and drug delivery will be discussed. After a brief overview of general properties of polymer and its hydrogels, we will focus on the processing techniques mainly used for their manufacturing, also suggesting, in the last part, potential uses and future perspectives for their novel applications in biomedical field.
Vincenzo Guarino, Rosaria Altobelli, Francesca della Sala, Assunta Borzacchiello, Luigi Ambrosio

Chapter 5. Alginate Utilization in Tissue Engineering and Cell Therapy

Due to the structural similarity to the extracellular matrix, nowadays, hydrogels are widely used for tissue engineering applications. Among the various hydrogels, alginate is considered a very useful biomaterial that has found numerous applications in the biomedical field due to its favorable properties, including biocompatibility and ease of gelation. It has been used to design tissue engineering constructs of various structures, such as porous scaffolds, microspheres, films, and microcapsules for drug and cell delivery and various tissue engineering applications particularly for bone, cartilage, muscle, and vascular tissue engineering. This chapter will provide a comprehensive overview of the applications of alginate-based hydrogels as various forms of constructs and scaffolds for tissue engineering.
Bapi Sarker, Aldo R. Boccaccini

Chapter 6. Alginate-Based Three-Dimensional In Vitro Tumor Models: A Better Alternative to Current Two-Dimensional Cell Culture Models

The conventional two-dimensional (2D) cell culture models, although providing considerable information about the cellular dynamics, often fail in vivo. In the area of oncology drug discovery and development process, the tumor microenvironment poses a significant challenge owing to the complexity of tumor stroma, and the traditional 2D in vitro systems fail to mimic the extracellular matrix (EC) and cell-to-cell interaction-based modulations. Three-dimensional (3D) cell culture systems/matrices, also designated as scaffolds, offer an excellent platform to study the tumor microenvironment in a more realistic way. Alginate matrices are widely used for cellular encapsulation, cell transplantation, and tissue engineering. Alginate-based 3D gels and scaffolds have emerged as a prime matrix to simulate tumor microenvironment closer to physiological condition. Alginate being hydrophilic provides uniform matrix for growth and proliferation. The alginate scaffolds and hydrogels have been used to investigate the cytotoxicity, apoptosis, and penetration of conventional drugs as well as various formulations into the in vitro tumor scaffolds/spheroids. Another advantage of alginate-based matrices for 3D cultures is that the cancer stem cell (CSC) niches can be better understood owing to the inherent 3D nature of CSCs. Moreover, the use of 3D systems gives a better impression of the physiological architecture; unique cellular interactions can occur and improve the functional properties. In this chapter, initially we compare and contrast 2D and 3D cell culture systems and the pitfalls of the conventional in vitro tumor models. Then a brief introduction of alginate-based 3D scaffolds is provided. Various in vitro models based on alginate scaffolds (AlgiMatrix™) and hydrogels are briefed with the parameters studied and the associated advantages. Future improvements in the 3D cell culture based on alginate matrices are thought through, and the possible future directions are provided. In conclusion, results from different studies give an indication that high-throughput in vitro 3D tumor models based on alginate can be prepared to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations.
Amit Khurana, Chandraiah Godugu

Chapter 7. Alginate Application for Heart and Cardiovascular Diseases

Alginate biomaterial has been extensively investigated and used for many biomedical applications due to its biocompatibility, low toxicity, relatively low cost, and ease of use. Its use toward cardiovascular application is no exception. Alginate is approved by the Food and Drug Administration (FDA) for various medical applications, such as a thickening, gel forming, and as a stabilizing agent for dental impression materials, wound dressings, and more. In this chapter, we describe the versatile biomedical applications of alginate, from its use as supporting extracellular matrices (ECM) in patients after acute myocardial infarction (MI), to its employment as a vehicle for stem cell delivery, to controlled delivery of multiple combinations of bioactive molecules. We also cover the application of alginate in creating solutions for treatment of other cardiovascular diseases by capitalizing on the natural properties of alginate to improve creation of heart valves, blood vessels, and drug and stem cell delivery vehicles.
Zhengfan Xu, Mai T. Lam

Chapter 8. Alginates in Dressings and Wound Management

This chapter considers how wound dressings are used in the treatment of wounds identifying the ideal properties of a wound dressing. Changes in the treatment of wounds with dressings since 1980 are discussed highlighting the current availability of a wide range of advanced wound dressings that clinicians have to select from for each wound they treat. Alginate wound dressings are introduced with their chemistry briefly considered and their indications and contraindications for clinical use reported. The clinical evidence supporting the use of alginate wound dressings is discussed highlighting the generally weak evidence underpinning the use of all advanced wound dressings. Recent reviews of the effectiveness of alginate dressings noted that across all the studies, there were no statistically significant differences between the outcomes achieved using the alginate dressings and the comparison groups. It is concluded that alginate dressings are currently not in widespread use in the UK National Health Service and may now be considered as comparisons against which new technologies may be compared.
Michael Clark

Chapter 9. Alginates in Metabolic Syndrome

Alginates extracted from seaweeds are widely used for nutrition, but they are underutilised for the prevention or reversal of human disease. Alginates are long chains of α-L-guluronic acid and β-D-mannuronic acid from brown seaweeds that act as readily available, low cost, non-toxic and biodegradable biopolymers. Sodium alginates are primarily used for the management of gastrointestinal tract disorders, but they are of potential use to attenuate the components of the metabolic syndrome including obesity, type 2 diabetes, hypertension, non-alcoholic fatty liver disease and dyslipidaemia. As prebiotics, alginates changed the gut microbiome to increase production of short-chain fatty acids as substrates for Bifidobacteria. Alginates inhibited pancreatic lipases and so decreased triacylglycerol breakdown and uptake. Treatment with alginates decreased food intake by inducing satiety and increased weight loss in patients on a calorie-restricted diet. Both glucose and fatty acid uptake were reduced. In rat models of hypertension, alginates decreased blood pressure. An alginate-antacid combination is an effective treatment of gastric reflux disease by forming a raft on the gastric contents. Alginates are important as drug carriers in microparticles and nanoparticles to increase drug bioavailability, for example, in drugs used for treatment of metabolic syndrome. Alginates are also used to protect cells during transplantation from immune responses of the host, allowing potential long-term control of some endocrine disorders such as type 1 diabetes and increased thermogenesis by brown adipocytes in obesity. There are many potential uses for these versatile biopolymers in the treatment of human disease.
Senthil Arun Kumar, Lindsay Brown

Chapter 10. Alginate Oligomers and Their Use as Active Pharmaceutical Drugs

Alginate oligomers retain most of the chemical and physical properties of the higher molecular weight commercial alginates, retaining affinity towards monovalent and divalent ions, which is dependent on the chemical composition of the oligomer. However, due to their low molecular weight, they will normally not form gels in the presence of divalent cations. This property is exploited in biological systems to chelate multivalent ions and disrupt Ca2+-mediated cross-linking. Studies have also identified interactions between alginate oligomers and complex mucin polymer systems, bacteria and extracellular polymeric substance (EPS), which suggests that these interactions are not simply the result of cationic chelation. By virtue of their low molecular weight, alginate oligomers stay in solution at high concentration without significant increase in viscosity and can be tailor-made to precisely defined chemical composition and molecular weight. This affords the opportunity to design effective formulations with precisely defined properties and biological effects. The properties now being identified for alginate oligomers represent a promising new approach in the management of chronic lung diseases, biofilm infections and antibiotic use. This chapter outlines the research performed to date, highlighting the excellent safety profile and novel chemical characteristics of alginate oligomers that emphasize their potential in multiple therapeutic applications.
P. D. Rye, A. Tøndervik, H. Sletta, M. Pritchard, A. Kristiansen, A. Dessen, D. W. Thomas

Chapter 11. Mannuronic Acid as an Anti-inflammatory Drug

Alginic acid is a linear polymer forming of β-D-mannuronic acid and α-L-guluronic acid residues that are present in the polymer chain in blocks. The D-mannuronic acid represents a newly designed nonsteroidal anti-inflammatory drug (NSAID) that has also immunosuppressive effects together with antioxidant property. D-mannuronic acid has been studied as an anti-inflammatory and novel immunosuppressive agent in several experimental models such as animal models of immune complex glomerulonephritis, nephrotic syndrome, multiple sclerosis, and rheumatoid arthritis. Both molecular mechanism and therapeutic efficacy of this new drug are based, in particular, on its inhibitory effects on matrix metalloproteinase-2 activity, immune cell infiltration in inflammatory foci, decrease of inflammatory cytokine IL-6 level, a reduction in antibody production, and induction of apoptosis. Several literature data reported no gastro-nephrotoxicity and therapeutic effects in several inflammatory diseases; for this reason it is strongly recommended as the safest drug for decreasing anti-inflammatory reactions. Moreover, recently many clinical trials were performed; results obtained support the idea that D-mannuronic acid is characterized by potent anti-inflammatory and immunosuppressive properties.
Rosalia Crupi, Salvatore Cuzzocrea
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