**4.2 Pancreatic islet cell-delivery system**

In 1933, Biscegeli implanted polymer matrix coated murine-derived tumor cells in to the abdomen of guinea pigs which remained viable without rejection, thus discovery prompted entire fields to research into microencapsulation technologies [46]. Several advances in biotechnological approaches to both cell microencapsulation and the development of drug delivery systems using alginate have been achieved for nearly 50 years [47]. When reconstituted in aqueous solution, alginate forms a hydrogel which in the presence of polyvalent cation (e.g., Ba2+, Ca2+, Sr2+) reorganizes into a rigid biomaterial [4]. Alginate hydrogels can be used to encapsulate cellular tissue and nonliving substances for therapeutic cellulardelivery as a treatment to many diseases such as Type 1 Diabetes [48]. Xenograft transplantations for type 1 diabetes heavily rely on alginate hydrogels as a source biomaterial for encapsulation of porcine pancreatic islets. Key obstacles observed with porcine islet xenograft include possible transmission of hemagglutinating

**43**

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies*

and lymphocytotoxic antigens, such as carbohydrate α-(1,3)-galactose, which are a major contributor to acute host immune rejection [49–51]. Alginate encapsulation, in contrast to other biomaterials, reduces transmission of humoral immune response elements while allowing for the transport of nutrients and export of insulin across the semipermeable barrier [52]. Recently, alginate-encapsulated APIs were transplanted intraperitoneally into STZ-induced IDDM nonhuman primates. Nonhuman primates exhibited a marked decrease in exogenous insulin demands and lower %HbA1C in addition to normalized blood glucose values for 20–70 days. However, the glycemic control was reduced over time, which they concluded was

With the application of FDA regulations and recent advances in stem cell-related technologies, there has been an increase in need for viable targeted delivery system for therapeutics [54–57]. The biocompatibility and relative ease of production of alginate hydrogels makes alginate an important candidate for production of immune-isolated stem cell delivery systems [8, 58, 59]. A major disease model currently researching stem cell-related therapies is for the treatment of type 1 diabetes, among insulin-dependent conditions. Recently, insulin-producing human SC-derived β-cells encapsulated with alginate polymers were implanted in immunecompetent mice. Multiple studies report glycemic control with immuno-isolated β-cells in mice, some resulting in up to 174 days of glycemic correction, in addition to detection of human C-peptide in mouse serum [60, 61]. A 2019 study showed similar results after transplanting human pluripotent stem cell-derived (iPSCs) β-cells into immunocompetent mice which resulted in glycemic control for more than 150 days [62]. Other disease models have also used alginate microencapsulation for therapeutic use of xenogeneic stem cell-delivery. Researchers have reported functional alginate encapsulated adrenal SCs for use in adrenal hormone insufficiency diseases [63, 64]. Successful alginate encapsulation of neural embryonic stem cells was also reported for targeted cell-delivery serving possible treatment for neural tissue repair in several neurological disorders [65]. Microencapsulation of stem cells is a very active field of research and advances with this technology have a

*DOI: http://dx.doi.org/10.5772/intechopen.87120*

due to decreased graft function and viability [53].

**4.3 Stem cell-delivery system**

wide range of clinical applications.

**4.4 Cryoprotective use of alginate microencapsulation**

Transplantations can sometimes rely heavily on transportation or storage of tissues before the procedure. Cryopreservation, known as a viable option for tissue preservation and storage, can have severe effects on the viability and function of tissues during the freezing/thawing processes and from use of cryoprotective agents [66]. Alginate microcapsules have demonstrated the ability to maintain structure, slow cooling process, reduce effects of ice crystal formation on tissue, and regulate influx of cryoprotective agents during cryopreservation [67, 68]. First used in preservation of plant cells, use of an alginate coating has been observed to have cryoprotective properties [69–72]. Success with plant cell preservation catalyzed the research into alginate cryoprotective potential with other tissue types. Alginate coatings of beneficial probiotic bacteria have demonstrated maintenance of viability and function through the cryopreservation process which has potential applications in yogurt and probiotic preservation [73–75]. An augmented necessity of tissue preservation methods has caused a rise in research related to cryopreservation for storage and distribution of animal cells. Alginate microencapsulation of cells offers significant

*Current Perspective and Advancements of Alginate-Based Transplantation Technologies DOI: http://dx.doi.org/10.5772/intechopen.87120*

and lymphocytotoxic antigens, such as carbohydrate α-(1,3)-galactose, which are a major contributor to acute host immune rejection [49–51]. Alginate encapsulation, in contrast to other biomaterials, reduces transmission of humoral immune response elements while allowing for the transport of nutrients and export of insulin across the semipermeable barrier [52]. Recently, alginate-encapsulated APIs were transplanted intraperitoneally into STZ-induced IDDM nonhuman primates. Nonhuman primates exhibited a marked decrease in exogenous insulin demands and lower %HbA1C in addition to normalized blood glucose values for 20–70 days. However, the glycemic control was reduced over time, which they concluded was due to decreased graft function and viability [53].

### **4.3 Stem cell-delivery system**

*Alginates - Recent Uses of This Natural Polymer*

and 3-D cell culture matrices.

**4. Current biotechnological uses**

**4.1 Food industry applications**

of alginate in the future.

**4.2 Pancreatic islet cell-delivery system**

a risk of hydrolysis [36]. Amphiphilic alginate derivatives that are water soluble have also been developed using cholesteryl groups which are synthesized using N,N′-dicyclohexylcarbodiimide as a coupling agent and 4-(N,N′-dimethylamino) pyridine as a catalyst at room temperature [37]. Other derivatives include cellinteractive alginates which are composed of cell-adhesive peptides. To prepare these, carbodiimide chemistry is used to combine peptide side-chains with carboxylic groups on sugar molecules [36]. This is important because alginate must acquire the proper ligands to participate in cell-to-cell interactions since it does not innately have cell-adhesivity to mammalian cells [36]. The peptide sequence arginineglycine-aspartic acid (RGD) has been studied widely due to the copious integrin receptors for this ligand on a variety of cell types [38]. This, among other types of cell-interactive alginates, has been used for scaffolds for tissue engineering and 2-D

The alginate industry saw increases in production in response to the scientific advancements in the study of alginate properties and potential uses [39]. Currently, the FDA classifies alginate as meeting the guidelines of the Food Chemical Codex and lists over seven different uses of it in the food industry [40]. The primary market for alginate in the processed food market where they serve as texturing agents and food stabilizers [41]. The gel-like chemical properties, which are safe for consumption, also allow for several other uses such as increasing storage life of potatoes, immobilization of banana enzymes, immobilization of lactic acid bacteria, and fillers in meat and fish products [39, 42]. The ability of alginate hydrogel to be polymerized, or gelled, into a microcapsule with a hollow core has led to the development of food encapsulation technologies aimed at food preservation [42]. Recently, researchers have shown that application of an alginate coating on egg shells has led to the elimination of cross-contamination from *Salmonella enteritidis* for up to 42 days [43]. Currently in the beverage industry, alginate is used as an emulsifying agent to maintain the stability of foam within beverages like beer [44, 45]. Continued use in the food industry will likely increase the commercial demand

In 1933, Biscegeli implanted polymer matrix coated murine-derived tumor cells in to the abdomen of guinea pigs which remained viable without rejection, thus discovery prompted entire fields to research into microencapsulation technologies [46]. Several advances in biotechnological approaches to both cell microencapsulation and the development of drug delivery systems using alginate have been achieved for nearly 50 years [47]. When reconstituted in aqueous solution, alginate forms a hydrogel which in the presence of polyvalent cation (e.g., Ba2+, Ca2+, Sr2+) reorganizes into a rigid biomaterial [4]. Alginate hydrogels can be used to encapsulate cellular tissue and nonliving substances for therapeutic cellulardelivery as a treatment to many diseases such as Type 1 Diabetes [48]. Xenograft transplantations for type 1 diabetes heavily rely on alginate hydrogels as a source biomaterial for encapsulation of porcine pancreatic islets. Key obstacles observed with porcine islet xenograft include possible transmission of hemagglutinating

**42**

With the application of FDA regulations and recent advances in stem cell-related technologies, there has been an increase in need for viable targeted delivery system for therapeutics [54–57]. The biocompatibility and relative ease of production of alginate hydrogels makes alginate an important candidate for production of immune-isolated stem cell delivery systems [8, 58, 59]. A major disease model currently researching stem cell-related therapies is for the treatment of type 1 diabetes, among insulin-dependent conditions. Recently, insulin-producing human SC-derived β-cells encapsulated with alginate polymers were implanted in immunecompetent mice. Multiple studies report glycemic control with immuno-isolated β-cells in mice, some resulting in up to 174 days of glycemic correction, in addition to detection of human C-peptide in mouse serum [60, 61]. A 2019 study showed similar results after transplanting human pluripotent stem cell-derived (iPSCs) β-cells into immunocompetent mice which resulted in glycemic control for more than 150 days [62]. Other disease models have also used alginate microencapsulation for therapeutic use of xenogeneic stem cell-delivery. Researchers have reported functional alginate encapsulated adrenal SCs for use in adrenal hormone insufficiency diseases [63, 64]. Successful alginate encapsulation of neural embryonic stem cells was also reported for targeted cell-delivery serving possible treatment for neural tissue repair in several neurological disorders [65]. Microencapsulation of stem cells is a very active field of research and advances with this technology have a wide range of clinical applications.

#### **4.4 Cryoprotective use of alginate microencapsulation**

Transplantations can sometimes rely heavily on transportation or storage of tissues before the procedure. Cryopreservation, known as a viable option for tissue preservation and storage, can have severe effects on the viability and function of tissues during the freezing/thawing processes and from use of cryoprotective agents [66]. Alginate microcapsules have demonstrated the ability to maintain structure, slow cooling process, reduce effects of ice crystal formation on tissue, and regulate influx of cryoprotective agents during cryopreservation [67, 68]. First used in preservation of plant cells, use of an alginate coating has been observed to have cryoprotective properties [69–72]. Success with plant cell preservation catalyzed the research into alginate cryoprotective potential with other tissue types. Alginate coatings of beneficial probiotic bacteria have demonstrated maintenance of viability and function through the cryopreservation process which has potential applications in yogurt and probiotic preservation [73–75]. An augmented necessity of tissue preservation methods has caused a rise in research related to cryopreservation for storage and distribution of animal cells. Alginate microencapsulation of cells offers significant

degree of cryoprotection during cryo processing [76, 77]. Transplantation research has particularly benefited from use of alginate technologies during cryopreservation. Recent studies in pancreatic islet transplantation have demonstrated that use of alginate microencapsulation helps maintain islet viability during preservation and improves islet secretory function during transplantation [67, 78, 79]. A 10 years study using encapsulated rat, pig, human islets showed that alginate encapsulated islets maintained significantly higher viability, secretory function, and yield compared to nonencapsulated islets after cryopreservation for 10 years [80]. Like pancreatic islets grafts, cryopreservation is also used for preservation of stem cells before transplantation. Alginate encapsulation has been shown repeatedly to improve both yield and function of multiple stem cell lines, including human stem cells [81, 82]. Recently, the use of alginate microcapsules improved viable recovery of human adipose-derived stem-cells after 72-h storage in hypothermic conditions [83]. The overall benefits of cryoprotection via alginate encapsulation will ensure relevance in future research of cell preservation and transplantation.
