**2. History of animal and human trials of islet encapsulation**

The first encapsulated islet transplants occurred in 1980, where islets in an alginate hydrogel transplanted intraperitoneally into diabetic rats achieved normoglycemia for 3 weeks, compared to 8 weeks for nonencapsulated islets [12]. Currently, there are a number of achievements in encapsulating islets seen in small and large animal studies, as well as in early phase clinical trials. A syngeneic transplant of nonobese diabetic (NOD) into prediabetic islets diabetic NOD recipients, using 5% agarose encapsulating 1500–2000 islet equivalents (IEq), showed that intraperitoneal implantation as well as omental pouch transplants demonstrated prolonged euglycemia for a period of 100 days compared to 8 days for unencapsulated islet transplants [13]. This study was repeated in 2006, where the same period of normoglycemia was observed in transplant recipients. In addition, when the devices were removed after 400 days, viable islets were recovered with a small percentage of necrotic cells [14]. Aside from agarose, polyethylene glycol-poly lactic-co-glycolic acid (PEG-PLGA) has been used to encapsulate 500–600 IEq islets for syngeneic transplant into streptozotocin (STZ) induced diabetic BALB/c mice, where over half of the recipients achieved normal glucose levels for up to 100 days [15].

**1. Introduction**

220 Challenges in Pancreatic Pathology

not the underlying disease.

transplant rejection and autoimmunity.

the use of immunosuppression [10, 11].

Over 25 million people in the United States (USA) suffer from diabetes, with approximately 5% characterized as type 1 diabetes (T1DM). Diabetes is ranked as the seventh leading cause of death in the USA. T1DM is characterized by the autoimmune-mediated destruction of the β-cells of the pancreas, resulting in insulin deficiency [1]. The current method of treatment for T1DM is insulin injection to maintain blood glucose control, which treats the symptoms but

With the invention of the Edmonton protocol in 2000, islet transplantation has become an attractive treatment for T1DM. As a treatment option, islet transplantation meets the goal of treating the disease rather than the symptoms. The end goal of islet transplantation in patients is the elimination of exogenous insulin dependence, allowing for those with T1DM to return to normal lives without constant monitoring of their blood glucose levels. There have been a total of 677 islet transplant recipients from 2000 to 2010. The success of the treatment has improved as well, where 27% of recipients achieved 3 years of insulin independence before 2007. After 2007 that rate has increased to 44%. Compared to insulin injection regimen, islet transplanta-

Islet transplantation faces two challenges from the host immune system: the rejection of the transplanted islets as foreign body and the existing autoimmunity against β-cells. Immunosuppressive drugs such as sirolimus and rapamycin used in the Edmonton protocol has toxic side effects on islets [3, 4]. As such, there is an impetus to move away from the use of immunosuppressive therapy and instead shift toward developing physical barriers against

Cell encapsulation to provide physical barrier has been tested in treating other diseases such as neurodegenerative diseases, pain, and epilepsy to name a few. So far, encapsulation has been used primarily to treat T1DM [5–9]. By providing a physical barrier to immune rejection, islet encapsulation has been shown to allow transplanted islet to function normally and avoid

The first encapsulated islet transplants occurred in 1980, where islets in an alginate hydrogel transplanted intraperitoneally into diabetic rats achieved normoglycemia for 3 weeks, compared to 8 weeks for nonencapsulated islets [12]. Currently, there are a number of achievements in encapsulating islets seen in small and large animal studies, as well as in early phase clinical trials. A syngeneic transplant of nonobese diabetic (NOD) into prediabetic islets diabetic NOD recipients, using 5% agarose encapsulating 1500–2000 islet equivalents (IEq), showed that intraperitoneal implantation as well as omental pouch transplants demonstrated prolonged euglycemia for a period of 100 days compared to 8 days for unencapsulated islet transplants [13]. This study was repeated in 2006, where the same period of normoglycemia was observed in transplant recipients. In addition, when the devices were removed after 400 days, viable

tion resulted in significant reduction in episodes of hypoglycemia unawareness [2].

**2. History of animal and human trials of islet encapsulation**

Results in large animal studies have mostly mirrored that of the small animal trials. Diabetic canine recipients, receiving 15,000–20,000 IEq islets/kg in alginate microcapsule into the intraperitoneal cavity, were able to maintain normoglycemia without insulin injection for up to 110 days, with c-peptide detectable in the blood for more than 1 year [16]. In 2010, allogeneic transplant in nonhuman primate was tested using subcutaneous and kidney capsule transplants of alginate micro and macroencapsulated islets, at a dose of 30,000 IEQ/kg. In this study, normoglycemia was observed for 28 weeks [17]. In a xenotransplant study of neonatal porcine islets into diabetic cynomolgus monkey, 10,000 IEq/kg of alginate encapsulated islets resulted in more than 40% reduction in injectable insulin dose compared to preimplantation [18].

The first human clinical trial of encapsulated islets transplant in T1DM was reported in 1994. In a type 1 diabetes patient, a postoperative kidney transplant maintained on low dose immunosuppression initially received 10,000 IEQ/kg of cadaver human islets encapsulated in an alginate microcapsule followed by a repeat infusion of 5000 IEQ/kg 6 months later. The patient's insulin requirements were reduced to 1–2 insulin units per day, and eventually he was able to discontinue all exogenous insulin after 9 months [19]. In 2006, human cadaveric islets (400,000–600,000 IEQ) were encapsulated into sodium alginate beads and placed intraperitoneally into two diabetic patients. The patients showed improved daily glucose levels and a decline in daily exogenous insulin intake. However, neither patient became insulin independent [20].

Living Cell Technologies Ltd. an Australia company has achieved the best outcomes for encapsulated islet transplants. The company, which owns a pathogen-free pig farm in New Zealand, performed xenotransplantation of alginate encapsulated fetal pig islets in several human clinical trials. The most significant achievement has been in the reduction of hypoglycemic episodes to around 40%. Several patients achieved improvements in daily glucose levels and a reduction in exogenous insulin dosing, while two patients became insulin independent after 4 months [21, 22].

Unfortunately, there is a lack of consistency in the human clinical results. For example, a human clinical trial by Tuch et al. used alginate encapsulated human islets and tracked the presence of plasma C-peptide levels for up to 2.5 years, ultimately resulting in no change in insulin requirements for the recipients [23]. While these early phase clinical trials aim to ensure safety and determine optimal islet dose, most of the trial patients do not achieve sustainable insulin independence.
