Open access peer-reviewed chapter

Microencapsulation for Clinical Applications and Transplantation by Using Different Alginates

Written By

Beyza Goncu and Emrah Yucesan

Submitted: 11 December 2019 Reviewed: 16 March 2020 Published: 30 April 2020

DOI: 10.5772/intechopen.92134

From the Edited Volume

Nano- and Microencapsulation - Techniques and Applications

Edited by Nedal Abu-Thabit

Chapter metrics overview

855 Chapter Downloads

View Full Metrics


Microencapsulation has been the most frequently used technique for several different disciplines such as cell-based therapies and/or transplantation. Technology is based on the idea of combining and coating a material or isolating from an external source. Microencapsulation may be performed with different materials and, among natural biocompatible materials, alginate-based microencapsulation technique is the most appropriate material for microencapsulation. The structural components of alginate materials are the derivatives of alginic acid, which is found in brown algae as an intercellular gel matrix. This alginate is preferred for clinical applications due to its safety in human studies. Therefore, the choice and the combined system need to be carefully optimized to achieve biocompatible application through cell microencapsulation especially for long term. Specifications of alginate such as primary source, isolation process, viscosity, and purity contribute to improve its biocompatibility. Clinically, cell microencapsulation is the major contribution to the field of transplantation by its technique and additionally provides local immune isolation. This chapter discusses the potential benefits of clinically suitable alginates and their applications. This promising technology may highlight its considerable potential for patients that require transplantation and/or replacement therapy in the future.


  • microencaspulation
  • alginate
  • cell therapy
  • drug delivery
  • transplantation

1. Introduction

Cell encapsulation is a process that involves immune protection of the living cell by using different polymers. The polymers can be distinguished into two main groups: natural origin (i.e., polysaccharides, polynucleotides, polypeptides) [1] and synthetic polymers (i.e., polyethylene glycol, polyvinyl alcohol, polyurethane, etc.). Several attempts have been made by scientists to use natural, synthetic, and semi-synthetic polymers in the field of encapsulation. The first approach was made in 1933 by Bisceglie et al. and used enveloped membrane to demonstrate tumor cell survival in the abdominal cavity of guinea pigs [2]. In his report, the cells survived for 12 days by diffusion of the nutrients. However, at that time immunoisolation technology was not known or understood [3]. Later, in 1943 Algire et al. reported a transparent chamber for atherapeutic approach in vivo [4]. Since this report, therapeutic demands enhanced this encapsulation technology in a way that combines the polymer source (produced synthetically or isolated from natural sources) and their functionality by using its characterization.

Several advantages and disadvantages have been reported about synthetic polymers [5]. Mechanical specifications can be more easily engineered or modified with the desired characteristics and particularly can be produced with larger amounts [6, 7, 8]. The main deficit of synthetic polymers is that they require toxic substances during the capsulation process; therefore, cell viability is a true obstacle after encapsulation [8, 9]. In this regard, synthetic polymers are frequently used in combination with different devices such as macrocapsules. Before accommodation of the encapsules, first, synthetic polymers are manufactured in the absence of living tissue/cells, and second, tissue/cells are combined with the device to preserve direct contact of the toxic solvents [1]. The most common synthetic polymers are poly(ethylene glycol) [10], polyvinyl alcohol [11], polyurethane [12], poly(ether sulfone) [13], polypropylene [14], sodium polystyrene sulfate [15], polyacrylate [16], polyphosphazene [17], AN69 [18], and lastly polytetrafluoroethylene [19].

Natural polymers have been proposed for immunoisolation based on two distinct features. First, there is no interference with the functionality of cells/tissues and second, the stability of the structure they provide during encapsulation [1, 20]. Conventionally, the most frequently used polymers from natural sources are cellulose [21], chitosan [22], collagen [23], agarose [24], and alginate [25]. The experimental success mainly depends on the application and mimicry potential of the natural polymers. Among these, in this chapter, we mainly focused on the alginate-based encapsulation and its clinical application.


2. Alginates

The most versatile biomaterials among natural polymers are alginates, which are used in a wide range of applications including diffusion systems, drug delivery, as a wound dressing, and for encapsulation when the transplantation has to be a substitute [25, 26, 27]. Alginates are hydrophilic compounds that are naturally found in the cell wall, extracellular matrix of brown algae and some species of bacteria, for example, Pseudomonas aeruginosa and Azotobacter vinelandii [26, 27]. The most common algae source is brown seaweed. During alginate extraction, alginic acid is generally obtained and converted to a form of salt [26]. Several forms of alginates are currently approved by the Food and Drug Administration (FDA) for use, particularly in the replacement of missing/nonfunctioning endocrine-related diseases [28].

2.1 Gelling and ionic cross-linking of alginates

Alginates are linear copolymers that include two hexuronic acid residues that become dimeric blocks, which are composed of 𝛽-D-mannuronic (M) and 𝛼-L-guluronic (G) acids for building the entire molecule [29]. These blocks are known as the building blocks of alginates. Mainly, the ratio of G and M blocks depends on the source of the algae type [9]. The important feature of these building blocks is the sensitivity to binding of multivalent cations. This is the starting point of this water-soluble polysaccharide, which allows alginate to form as hydrogels. This characteristic of the hydrogel equilibrates between the environment and the relatively physiologic internal environment [29]. The divalent cations and hydrogel feature depends on the divalent ion’s affinity to alginate. Several studies reported high-rate ion affinity results in a stronger gel structure. In order to decrease the ion binding strength, divalent cations should be chosen from the following order: Pb2+>Cu2+>Cd2+>Ba2+>Sr2+>Ca2+>Co2+>Ni2+>Zn2+>Mn2+ [1, 29, 30] (Figure 1). Controlling cation addition to maintain a porous alginate structure is a critical step.

Figure 1.

Representative image for the formation of egg-box ionic cross-links between guluronic acid-rich monomer units (box) and the divalent cations (eggs). Reprinted from Baumberger and Ronsin (2009) [31], an open access article distributed under the terms of the creative commons by attribution 4.0 (CC-BY 4.0).

Successful formation of alginate spheres for delivery purposes requires suitable and selective methods. In 2006, Darrabie et al. identified gelling-cation stability by determining swelling, which contributes to colloid osmotic pressure. They suggested that Ca2+ is more hygroscopic and less prominent swelling occurs when compared with Ba2+ [32]. Protecting the conformational polymer blocks during preparation of the alginate gels for microencapsulation has been reported using different methods including conjugation of long alkyl chains [33] or dodecylamine [34], temperature (up to 60°C ± 1°C) [35, 36], emulsification by cationic agent [37], and ionotropic gelation of alginate layers [38], etc. Slow gelation utilizes the alginate solution in a more uniform structure in a gradual manner [35].

In the latter case, Lee et al. reported a degree of cross-linking of the alginate can influence a low dose of drug entrapment and unsuitable pore sizes for transplantation. In addition, the efficiency of the microcapsule size or content was found irrelevant, although the preparation step of the water-soluble alginate itself appears to be responsible for the arrangement of the polymer blocks [37]. Cross-linking capacity of the alginates can be modifiable and flexible (Figure 2). There are more than 200 types of biocompatible alginates manufactured so far [25, 26]. Moreover, due to the different cross-linking degree of various alginate types, switch in homogenous distribution of the graft/drug during the encapsulation process may occur [36].

Figure 2.

Representative image of alginate gelation process by continued calcium cations. Reprinted from Dumitru et al. [39], an open access article distributed under the terms of the creative commons by attribution 4.0 (CC-BY 4.0).

Both features of alginates promote several advantages over other polymers such as the stability of the building blocks (-G and/or/both -M repetitively); elasticity of the alginate hydrogel; surface roughness, which is related to elasticity as well, approximately 1% of the alginate can entrap a hundred times more water than its weight; and lastly permitting the ability of oxygen and nutrient permeation inside the spheres.

2.2 Biotolerability over biocompatibility

Source-dependent impurities may have detrimental effects. Safe and effective delivery of the therapeutic graft/drug with the alginate carrier is frequently mentioned as biocompatible. This naturally derived product provides immunoprotection and most of the studies reported purity of its building block structure preventing a host response when transplanted. Therefore, this makes alginate the most common material for microencapsulation. Higher water-carrying capability of alginates has been shown to directly maintain diffusion and this shows immune-safe characteristics [3]. A decade ago, Kendall et al. focused on the various components of alginate blocks and compared their purity and sphere sizes depending on the cationic agent. They reported that higher purification of alginate prevents imperfections and size/shape properties would affect immunogenicity [40]. Several other reports also demonstrated that -G and -M blocks of the alginate gel need a balance whereas the distribution of these proportions indicates the biocompatibility of the purified alginate is influenced by its viscosity [41, 42, 43]. One of the most obvious results from the studies that explains the difference between the building block’s balance in alginate gels is higher -M blocks mainly stimulate and induce an immune response [41, 44, 45, 46].

There are many immunogenic substances such as endotoxins, proteins, and polyphenols in natural polymers including alginates. Those molecules may diffuse the outer surface from the capsules and then induce an unwanted immune response against the capsules [3]. There are highly conserved molecular motifs that are present in nature and pathogens known as pathogen-associated molecular patterns (PAMPs). PAMPs provoke pattern recognition receptors (PRRs) to enhance inflammatory response [47]. The presence of PAMPs in natural products and alginate as well is not a direct threat; however, complement activation has been reported for encapsulated islets [48]. Therefore, complement activation has a more destructive effect than the inflammatory response; it may activate and produce large quantities of cytokines to induce a stronger response.

Immunoprotective properties still require the exact characterization and preparation of the material to be used as a delivery agent. Despite giving most of the efforts to optimize the encapsulation process, the applicability of this technology has still resulted in an insufficient investigation of graft/drug delivery. In 2014, Rokstad et al. described the duration and the type of host responses and divided the whole process into three categories: acute inflammation, chronic inflammation, and the long-lasting granulation tissue phase [48]. Based on the publications from islet transplantation studies, it was reported that the granulation phase mainly refers to the “vascularized fibrous tissue containing a moderate epithelial histiocytic response” [49, 50, 51, 52]. Solely, it is important to observe these responses and that leads to the question: Why do alginate microencapsules contribute to these chain of events even when their purity, stability, and biocompatibility are comparable to most other polymers? Immunocompatibility of the alginate microencapsules should not be determined only by the features of alginate and its preparation process, but should also be evaluated for its protein absorption capability as well.

A profound impact might be introduced with the biotolerability term. Biotolerability is a term for a strategy of making biocompatible encapsulations to induce none/minimal host response. A seemingly minimal cellular overgrowth for graft provides the free diffusion of nutrients, oxygen, and some therapeutic proteins, and controlled drug release from the microcapsules. We should emphasize that the alginate microspheres are not meant to prevent an immune response yet to protect the carrier against an immune response. Therefore, the biocompatibility term not clear enough to explain the biotolerability of the carrier system.

2.3 Vascularization

The vascularization process of the microencapsules is another requirement to increase the survival of the transplanted graft. Sufficient vascularization may be achieved by improving the physical features of the spheres such as the size of the spheres or micropores and the amount/density of the graft/cells. The main argument against vascularization is hypoxia and oxidative stress whereby it develops inside the microspheres [53]. Insufficient oxygenation and nutrition occur particularly in the absence of ideal vascularization. A prerequisite is that the functional performance of the microencapsules often depends on the surface-to-volume ratio. This implies that free diffusion of nutrients and oxygen is necessary and this directly interferes with vascularization.

The majority of researchers developed different strategies to allow a fast exchange of nutrition and demonstrated several boundaries to ensure a low or no inflammatory response while supplying oxygen-nutrients inside [29, 53]. Currently, the accepted limitations of the islet transplantation are defined with three main strategies: first, the cell-to-volume ratio should not exceed 10% even if a large number of cells are required to reach curative treatment. Second, microencapsules should be kept <1 mm, once they reach the spheres they do not maintain their biphasic effect (releasing insulin after a glucose challenge) and also an immune response may be triggered. Third, direct vascular access of the microencapsules to the optimal transplantation site, for instance, glucose must pass and be observed in the transplantation site and then islets release insulin to diffuse through circulation. The whole process requires time and larger amounts to reach an effective dose to lower glucose [1, 53, 54].


3. Clinical applications

A broad range of clinical applications of the microencapsulation process have shown promising results despite encountering some biotolerability issues. Multiple disciplines have been using this alginate encapsulation technology including chemistry, protein science, and cell therapy (mostly transplantation and immunology field). The most studied and reported diseases include Type 1 diabetic patients (T1DM) [55], permanent hypoparathyroidism patients [56], scaffold systems for tissue engineering [57], bone regeneration [58, 59], leukemia (an in vivo study that uses alginate to encapsulate specialized hybridoma cells) [60], and even neurodegenerative diseases [61]. Some of the clinical studies about cell therapy are compiled in Table 1.

Alginate typeGraft survivalGraftYearReference
Alginate high in guluronic acid9 monthsBeta-cells (Islets)1994[49]
Ultrapure alginate (68% glucuronic acid)3 monthsBeta-cells (Islets)2013[50]
Barium alginateVarious duration for four recipientsBeta-cells (Islets)2009[51]
poly-l-ornithine-sodium alginate<1 yearBeta-cells (Islets)2006[62]
Ultra-purified sodium alginate3 yearsBeta-cells (Islets)2011[63]
Alginate-Poly-L-Ornithine<8 monthsBeta-cells (Islets)2010[64]
Collagen/Alginaten/aBeta-cells (Islets)2010[65]
Sodium alginate3 monthsParathyroid cells1997[66]
Amitogenic alginate<3 monthsParathyroid cells2001[43]
n/a1 yearParathyroid tissue particles2001[67]
n/an/aParathyroid cells2004[68]
Sodium alginate<20 monthsParathyroid cells2009[69]
Ultrapure-low viscosity high guluronic acid-rich alginate>1 yearParathyroid cells2019[56]

Table 1.

Some of the examples of alginate derivates used in microencapsulation studies.

Based on the current experience with alginate, most of the studies have already performed transplantation of beta-cells (islets). The first and well-known clinical trial with islet transplantation was performed in 1994 by Soon-Shiong et al. They reported 9 months of survival of the microencapsules, which were prepared with high guluronic acid containing alginate [49]. Another case reported how islet transplantation was prepared with alginate- poly-l-ornithine and that the patient’s need for insulin decreased after transplantation [62]. Following two case reports, Tuch et al. used barium alginate to encapsulate islets and transplanted these into four recipients. In their report, grafts showed various survival rates and did not restore insulin requirements [51]. Considering the last case reports, several companies took the stage and initiated clinical trials to overcome T1DM by using macro- and microencapsulation with alginate and other polymers. In 2014, Scharp and Marchetti evaluated the outcomes of islet encapsulation from companies with larger clinical studies, respectively. The increased interest in islet transplantation reached its most popular level between 2010 and 2012 [54]. For the last 2 years, researchers provided detailed in vivo experiments and defined an alginate encapsulation strategy in a more enhanced way [52, 60, 70, 71] . The vast majority of attempts have been made to treat T1DM and the critical requirements remain to be elucidated in the future.

Another endocrine replacement therapy performed for hypoparathyroidism by encapsulated parathyroid tissue/cell transplantation (PTX) was described only in seven case reports for 12 recipients [43, 56, 67, 68, 69, 72, 73] between 1997 and 2019. Six of these case studies used alginate for encapsulation. In 1997, Hasse et al. performed the first microencapsulated PTX for two recipients and reported 3 months of graft survival [72]. The second one, performed by Zimmerman et al. in 2001 for one recipient showed no trace of parathyroid tissue particles nor microcapsules, after 3 months, from histological samples from the implantation site of the recipient [43]. The third transplantation case reported up to 1 year graft survival by Tibell et al. and they had macroencapsulated the parathyroid tissue particles and transplanted into four recipients [67]. Another case by Ulrich et al. reported two PTX recipients had elevations in PTH levels and reduced the supplementation requirement into half dose [68]. In 2009, Cabane et al. microencapsulated the enzymatically isolated parathyroid cells in one recipient and reported the longest follow-up data with 20 months of graft survival [69]. The last and seventh case performed by Yucesan et al. in 2019 microencapsulated parathyroid cell transplantation for one recipient reported and the results followed for a year with success [56]. Despite these achievements, the necessity of immunoisolation for parathyroid allotransplantation requires more case studies with long-term follow-up data.

A different therapy for using microencapsulation is cell therapy for neurodegenerative diseases. The development of a delivery strategy is limited due to the blood–brain barrier; however, principle studies in animal models may offer new approaches including gene delivery, cell-based delivery, and also biomaterial drug delivery [61]. In the past year, several in vivo studies have been reported for neurodegenerative diseases [71, 74, 75, 76]. Galli et al. used alginate-poly-L-lysine-alginate (APA) microcapsules and cross-linked the spheres with both Ca2+ and Ba2+. They have used this system as a transporter to carry a specialized cell clone for codon optimization of the cerebral dopamine neurotrophic factor gene. According to their recent data, this system has the potential to deliver polymer-encapsulated-drug conjugates for the treatment of Parkinson’s and Alzheimer’s diseases [76].


4. Conclusion

Immunoisolating construct tuning may be achieved by defining the mechanical properties, molecular weight, cross-linking density of the polymer, and the concentration balance between the therapeutic graft/drug and the biomaterial. These proportions still require optimal decisions even with the known performances of encapsulated cells.

Significant efforts have been made so far by ongoing studies from research laboratories and biotechnology companies, which continue to encounter microencapsulation strategies at every step. The future perspective is strong enough to overcome the current limitations. Nevertheless, alginate is the best natural product to be used by many different disciplines at the same time.


Conflict of interest

The authors declare no conflict of interest.


  1. 1. de Vos P, Lazarjani HA, Poncelet D, Faas MM. Polymers in cell encapsulation from an enveloped cell perspective. Advanced Drug Delivery Reviews. 2014;67-68:15-34
  2. 2. Bisceglie V. Über die antineoplastische Immunität. Zeitschrift für Krebsforschung. 1934;40(1):141-158
  3. 3. David A, Day J, Shikanov A. Immunoisolation to prevent tissue graft rejection: Current knowledge and future use. Experimental Biology and Medicine (Maywood, N.J.). 2016;241(9):955-961
  4. 4. Algire GH. An Adaptation of the Transparent-Chamber Technique to the Mouse. JNCI: Journal of the National Cancer Institute. 1943;4(1):1-11
  5. 5. Song R, Murphy M, Li C, Ting K, Soo C, Zheng Z. Current development of biodegradable polymeric materials for biomedical applications. Drug Design, Development and Therapy. 2018;12:3117-3145
  6. 6. Piskin E. Biodegradable polymers as biomaterials. Journal of Biomaterials Science. Polymer Edition. 1995;6(9):775-795
  7. 7. Gill I, Ballesteros A. Bioencapsulation within synthetic polymers (Part 1): sol-gel encapsulated biologicals. Trends in Biotechnology. 2000;18(7):282-296
  8. 8. Gill I, Ballesteros A. Bioencapsulation within synthetic polymers (Part 2): non-sol-gel protein-polymer biocomposites. Trends in Biotechnology. 2000;18(11):469-479
  9. 9. de Vos P, van Schilfgaarde R. Biocompatibility Issues. In: Kühtreiber WM, Lanza RP, Chick WL, editors. Cell Encapsulation Technology and Therapeutics. Boston, MA: Birkhäuser Boston; 1999. pp. 63-75
  10. 10. Zalipsky S, Mullah N, Harding JA, Gittelman J, Guo L, DeFrees SA. Poly(ethylene glycol)-grafted liposomes with oligopeptide or oligosaccharide ligands appended to the termini of the polymer chains. Bioconjugate Chemistry. 1997;8(2):111-118
  11. 11. Emerich DF, Hammang JP, Baetge EE, Winn SR. Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum. Experimental Neurology. 1994;130(1):141-150
  12. 12. Seymour RB, Kauffman GB. Polyurethanes: A class of modern versatile materials. Journal of Chemical Education. 1992;69(11):909
  13. 13. Abe T, Kato K, Fujioka T, Akizawa T. The blood compatibilities of blood purification membranes and other materials developed in Japan. International Journal of Biomaterials. 2011;2011:375390
  14. 14. Coates GW, Waymouth RM. Oscillating stereocontrol: A strategy for the synthesis of thermoplastic elastomeric polypropylene. Science. 1995;267(5195):217-219
  15. 15. Brown LF, Detmar M, Claffey K, Nagy JA, Feng D, Dvorak AM, et al. Vascular permeability factor/vascular endothelial growth factor: A multifunctional angiogenic cytokine. EXS. 1997;79:233-269
  16. 16. Young TH, Yao NK, Chang RF, Chen LW. Evaluation of asymmetric poly(vinyl alcohol) membranes for use in artificial islets. Biomaterials. 1996;17(22):2139-2145
  17. 17. Teasdale I, Bruggemann O. Polyphosphazenes: Multifunctional, biodegradable vehicles for drug and gene delivery. Polymers (Basel). 2013;5(1):161-187
  18. 18. Prevost P, Flori S, Collier C, Muscat E, Rolland E. Application of AN69 hydrogel to islet encapsulation. Evaluation in streptozotocin-induced diabetic rat model. Annals of the New York Academy of Sciences. 1997;831:344-349
  19. 19. Buder B, Alexander M, Krishnan R, Chapman DW, Lakey JR. Encapsulated islet transplantation: Strategies and clinical trials. Immune Netw. 2013;13(6):235-239
  20. 20. Paredes Juarez GA, Spasojevic M, Faas MM, de Vos P. Immunological and technical considerations in application of alginate-based microencapsulation systems. Frontiers in Bioengineering and Biotechnology. 2014;2:26
  21. 21. Miyamoto T, Takahashi S, Ito H, Inagaki H, Noishiki Y. Tissue biocompatibility of cellulose and its derivatives. Journal of Biomedical Materials Research. 1989;23(1):125-133
  22. 22. Chandy T, Mooradian DL, Rao GH. Evaluation of modified alginate-chitosan-polyethylene glycol microcapsules for cell encapsulation. Artificial Organs. 1999;23(10):894-903
  23. 23. Lee CH, Singla A, Lee Y. Biomedical applications of collagen. International Journal of Pharmaceutics. 2001;221(1-2):1-22
  24. 24. Iwata H, Amemiya H, Matsuda T, Takano H, Hayashi R, Akutsu T. Evaluation of microencapsulated islets in agarose gel as bioartificial pancreas by studies of hormone secretion in culture and by xenotransplantation. Diabetes. 1989;38(Suppl 1):224-225
  25. 25. Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug Development and Industrial Pharmacy. 2002;28(6):621-630
  26. 26. Jost A, Sapra A. Alginate. Treasure Island (FL): StatPearls; 2019
  27. 27. Sánchez P, Hernández RM, Pedraz JL, Orive G. Encapsulation of cells in alginate gels. In: Guisan JM, editor. Immobilization of Enzymes and Cells. Third ed. Totowa, NJ: Humana Press; 2013. pp. 313-325
  28. 28. Montanucci P, Terenzi S, Santi C, Pennoni I, Bini V, Pescara T, et al. Insights in behavior of variably formulated alginate-based microcapsules for cell transplantation. BioMed Research International. 2015;2015:965804
  29. 29. Lopes M, Abrahim B, Veiga F, Seica R, Cabral LM, Arnaud P, et al. Preparation methods and applications behind alginate-based particles. Expert Opinion on Drug Delivery. 2017;14(6):769-782
  30. 30. Poojari R, Srivastava R. Composite alginate microspheres as the next-generation egg-box carriers for biomacromolecules delivery. Expert Opinion on Drug Delivery. 2013;10(8):1061-1076
  31. 31. Baumberger T, Ronsin O. From thermally activated to viscosity controlled fracture of biopolymer hydrogels. The Journal of Chemical Physics. 2009;130(6):061102
  32. 32. Darrabie MD, Kendall WF, Opara EC. Effect of alginate composition and gelling cation on microbead swelling. Journal of Microencapsulation. 2006;23(6):613-621
  33. 33. Pelletier S, Hubert P, Payan E, Marchal P, Choplin L, Dellacherie E. Amphiphilic derivatives of sodium alginate and hyaluronate for cartilage repair: Rheological properties. Journal of Biomedical Materials Research. 2001;54(1):102-108
  34. 34. Leonard M, De Boisseson MR, Hubert P, Dalencon F, Dellacherie E. Hydrophobically modified alginate hydrogels as protein carriers with specific controlled release properties. Journal of Controlled Release. 2004;98(3):395-405
  35. 35. Lee KY, Mooney DJ. Alginate: Properties and biomedical applications. Progress in Polymer Science. 2012;37(1):106-126
  36. 36. Whelehan M, Marison IW. Microencapsulation using vibrating technology. Journal of Microencapsulation. 2011;28(8):669-688
  37. 37. Lee HY, Chan LW, Heng PW. Influence of partially cross-linked alginate used in the production of alginate microspheres by emulsification. Journal of Microencapsulation. 2005;22(3):275-280
  38. 38. Ehrhart F, Mettler E, Bose T, Weber MM, Vasquez JA, Zimmermann H. Biocompatible coating of encapsulated cells using ionotropic gelation. PLoS One. 2013;8(9):e73498
  39. 39. Dumitru LM, Manoli K, Magliulo M, Ligonzo T, Palazzo G, Torsi L. A hydrogel capsule as gate dielectric in flexible organic field-effect transistors. APL Materials. 2014;3(1):014904
  40. 40. Kendall WF Jr, Darrabie MD, El-Shewy HM, Opara EC. Effect of alginate composition and purity on alginate microspheres. Journal of Microencapsulation. 2004;21(8):821-828
  41. 41. Tam SK, Dusseault J, Bilodeau S, Langlois G, Halle JP, Yahia L. Factors influencing alginate gel biocompatibility. Journal of Biomedical Materials Research. Part A. 2011;98(1):40-52
  42. 42. Klock G, Pfeffermann A, Ryser C, Grohn P, Kuttler B, Hahn HJ, et al. Biocompatibility of mannuronic acid-rich alginates. Biomaterials. 1997;18(10):707-713
  43. 43. Zimmermann U, Cramer H, Jork A, Thürmer F, Zimmermann H, Fuhr G, et al. Microencapsulation-based cell therapy. Biotechnology. 2001:547-571
  44. 44. Otterlei M, Ostgaard K, Skjak-Braek G, Smidsrod O, Soon-Shiong P, Espevik T. Induction of cytokine production from human monocytes stimulated with alginate. Journal of Immunotherapy. 1991;10(4):286-291
  45. 45. Espevik T, Otterlei M, Skjak-Braek G, Ryan L, Wright SD, Sundan A. The involvement of CD14 in stimulation of cytokine production by uronic acid polymers. European Journal of Immunology. 1993;23(1):255-261
  46. 46. Kulseng B, Skjak-Braek G, Ryan L, Andersson A, King A, Faxvaag A, et al. Transplantation of alginate microcapsules: Generation of antibodies against alginates and encapsulated porcine islet-like cell clusters. Transplantation. 1999;67(7):978-984
  47. 47. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clinical Microbiology Reviews. 2009;22(2):240-273
  48. 48. Rokstad AM, Lacik I, de Vos P, Strand BL. Advances in biocompatibility and physico-chemical characterization of microspheres for cell encapsulation. Advanced Drug Delivery Reviews. 2014;67-68:111-130
  49. 49. Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet. 1994;343(8903):950-951
  50. 50. Jacobs-Tulleneers-Thevissen D, Chintinne M, Ling Z, Gillard P, Schoonjans L, Delvaux G, et al. Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient. Diabetologia. 2013;56(7):1605-1614
  51. 51. Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, et al. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care. 2009;32(10):1887
  52. 52. Bochenek MA, Veiseh O, Vegas AJ, McGarrigle JJ, Qi M, Marchese E, et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nature Biomedical Engineering. 2018;2(11):810-821
  53. 53. Colton CK. Oxygen supply to encapsulated therapeutic cells. Advanced Drug Delivery Reviews. 2014;67-68:93-110
  54. 54. Scharp DW, Marchetti P. Encapsulated islets for diabetes therapy: history, current progress, and critical issues requiring solution. Advanced Drug Delivery Reviews. 2014;67-68:35-73
  55. 55. Vaithilingam V, Bal S, Tuch BE. Encapsulated islet transplantation: Where do we stand? The Review of Diabetic Studies. 2017;14(1):51-78
  56. 56. Yucesan E, Basoglu H, Goncu B, Akbas F, Ersoy YE, Aysan E. Microencapsulated parathyroid allotransplantation in the omental tissue. Artificial Organs. 2019;43(10):1022-1027
  57. 57. Reakasame S, Boccaccini AR. Oxidized alginate-based hydrogels for tissue engineering applications: A review. Biomacromolecules. 2018;19(1):3-21
  58. 58. Nabavinia M, Khoshfetrat AB, Naderi-Meshkin H. Nano-hydroxyapatite-alginate-gelatin microcapsule as a potential osteogenic building block for modular bone tissue engineering. Materials Science & Engineering. C, Materials for Biological Applications. 2019;97:67-77
  59. 59. Zhou X, Liu P, Nie W, Peng C, Li T, Qiang L, et al. Incorporation of dexamethasone-loaded mesoporous silica nanoparticles into mineralized porous biocomposite scaffolds for improving osteogenic activity. International Journal of Biological Macromolecules. 2020;149:116-126
  60. 60. Lang MS, Hovenkamp E, Savelkoul HF, Knegt P, Van Ewijk W. Immunotherapy with monoclonal antibodies directed against the immunosuppressive domain of p15E inhibits tumour growth. Clinical and Experimental Immunology. 1995;102(3):468-475
  61. 61. Emerich DF, Orive G, Thanos C, Tornoe J, Wahlberg LU. Encapsulated cell therapy for neurodegenerative diseases: From promise to product. Advanced Drug Delivery Reviews. 2014;67-68:131-141
  62. 62. Calafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: First two cases. Diabetes Care. 2006;29(1):137-138
  63. 63. Basta G, Montanucci P, Luca G, Boselli C, Noya G, Barbaro B, et al. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: Four cases. Diabetes Care. 2011;34(11):2406-2409
  64. 64. Tan PL. Company profile: Tissue regeneration for diabetes and neurological diseases at living cell technologies. Regenerative Medicine. 2010;5(2):181-187
  65. 65. Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90(10):1054-1062
  66. 66. An D, Wang LH, Ernst AU, Chiu A, Lu YC, Flanders JA, et al. An atmosphere-breathing refillable biphasic device for cell replacement therapy. Advanced Materials. 2019;31(52):e1905135
  67. 67. Tibell A, Rafael E, Wennberg L, Nordenstrom J, Bergstrom M, Geller RL, et al. Survival of macroencapsulated allogeneic parathyroid tissue one year after transplantation in nonimmunosuppressed humans. Cell Transplantation. 2001;10(7):591-599
  68. 68. Ulrich F, Klupp J, Thürmer F, Rayes N, Seehofer D, Tullius S, et al. Allotransplantation of encapsulated human parathyroid tissue in patients with permanent hypoparathyroidism. Transplantation. 2004;78:79
  69. 69. Cabane P, Gac P, Amat J, Pineda P, Rossi R, Caviedes R, et al. Allotransplant of microencapsulated parathyroid tissue in severe postsurgical hypoparathyroidism: A case report. Transplantation Proceedings. 2009;41(9):3879-3883
  70. 70. Safley SA, Kenyon NS, Berman DM, Barber GF, Willman M, Duncanson S, et al. Microencapsulated adult porcine islets transplanted intraperitoneally in streptozotocin-diabetic non-human primates. Xenotransplantation. 2018;25(6):e12450
  71. 71. Liu Q, Chiu A, Wang LH, An D, Zhong M, Smink AM, et al. Zwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation. Nature Communications. 2019;10(1):5262
  72. 72. Hasse C, Klock G, Schlosser A, Zimmermann U, Rothmund M. Parathyroid allotransplantation without immunosuppression. Lancet. 1997;350(9087):1296-1297
  73. 73. Khryshchanovich V, Ghoussein Y. Allotransplantation of macroencapsulated parathyroid cells as a treatment of severe postsurgical hypoparathyroidism: Case report. Annals of Saudi Medicine. 2016;36(2):143-147
  74. 74. Emerich DF, Kordower JH, Chu Y, Thanos C, Bintz B, Paolone G, et al. Widespread striatal delivery of GDNF from encapsulated cells prevents the anatomical and functional consequences of excitotoxicity. Neural Plasticity. 2019;2019:6286197
  75. 75. Paolone G, Falcicchia C, Lovisari F, Kokaia M, Bell WJ, Fradet T, et al. Long-term, targeted delivery of GDNF from encapsulated cells is neuroprotective and reduces seizures in the pilocarpine model of epilepsy. The Journal of Neuroscience. 2019;39(11):2144-2156
  76. 76. Galli E, Lindholm P, Kontturi LS, Saarma M, Urtti A, Yliperttula M. Characterization of CDNF-secreting ARPE-19 cell clones for encapsulated cell therapy. Cell Transplantation. 2019;28(4):413-424

Written By

Beyza Goncu and Emrah Yucesan

Submitted: 11 December 2019 Reviewed: 16 March 2020 Published: 30 April 2020