**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**.

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


#### **Table 1.**

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

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, 67–69, 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.

**175**

*Microencapsulation for Clinical Applications and Transplantation by Using Different Alginates*

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, 74–76]. 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].

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

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

1 Experimental Research Center, Bezmialem Vakif University, Istanbul, Turkey

\*Address all correspondence to: bsgoncu@gmail.com; bgoncu@bezmialem.edu.tr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University,

*DOI: http://dx.doi.org/10.5772/intechopen.92134*

**4. Conclusion**

encapsulated cells.

**Conflict of interest**

**Author details**

Istanbul, Turkey

Beyza Goncu1

by many different disciplines at the same time.

The authors declare no conflict of interest.

\* and Emrah Yucesan<sup>2</sup>

provided the original work is properly cited.

*Microencapsulation for Clinical Applications and Transplantation by Using Different Alginates DOI: http://dx.doi.org/10.5772/intechopen.92134*

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, 74–76]. 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].
