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Rev Diabet Stud, 2014, 11(1):84-101 DOI 10.1900/RDS.2014.11.84

Islet and Stem Cell Encapsulation for Clinical Transplantation

Rahul Krishnan1, Michael Alexander1, Lourdes Robles1, Clarence E. Foster 3rd1,2, Jonathan R.T. Lakey1,3

1Department of Surgery, University of California Irvine, Orange, CA 92868, USA
2Department of Transplantation, University of California Irvine, Orange, CA 92868, USA
3Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA
Address correspondence to: Jonathan R.T. Lakey, Director of Research and Clinical Islet Program, University of California Irvine, 333 City Blvd. West, Suite 1600, Orange, CA 92868, USA, e-mail:

Manuscript submitted June 19, 2013; resubmitted August 1, 2013; accepted August 9, 2013.

Keywords: type 1 diabetes, stem cell, encapsulation, tissue engineering, insulin-producing cell, transplantation


Over the last decade, improvements in islet isolation techniques have made islet transplantation an option for a certain subset of patients with long-standing diabetes. Although islet transplants have shown improved graft function, adequate function beyond the second year has not yet been demonstrated, and patients still require immunosuppression to prevent rejection. Since allogeneic islet transplants have experienced some success, the next step is to improve graft function while eliminating the need for systemic immunosuppressive therapy. Biomaterial encapsulation offers a strategy to avoid the need for toxic immunosuppression while increasing the chances of graft function and survival. Encapsulation entails coating cells or tissue in a semipermeable biocompatible material that allows for the passage of nutrients, oxygen, and hormones while blocking immune cells and regulatory substances from recognizing and destroying the cell, thus avoiding the need for systemic immunosuppressive therapy. Despite advances in encapsulation technology, these developments have not yet been meaningfully translated into clinical islet transplantation, for which several factors are to blame, including graft hypoxia, host inflammatory response, fibrosis, improper choice of biomaterial type, lack of standard guidelines, and post-transplantation device failure. Several new approaches, such as the use of porcine islets, stem cells, development of prevascularized implants, islet nanocoating, and multilayer encapsulation, continue to generate intense scientific interest in this rapidly expanding field. This review provides a comprehensive update on islet and stem cell encapsulation as a treatment modality in type 1 diabetes, including a historical outlook as well as current and future research avenues.

Abbreviations: ADSC - adipose-derived stem cells; a-FGF - acidic fibroblast growth factor; AN69 - acrylonitrile 69; APA - alginate poly-L-lysine alginate; CITR - Collaborative Islet Transplant Registry; EuroSPK - European Study Group in Simultaneous Pancreas and Kidney Transplantation; FGF-1- fibroblast growth factor 1; HbA1c - hemoglobin A1c; HEMA - 2-hydroxyethyl methacrylate; hESC - human embryonic stem cells; ICA - islet-like cell aggregates; IEQ - Islet equivalent; IPITA - International Pancreas and Islet Transplantation Association; iPSC - induced pluripotent stem cells; IPTR - International Pancreas Transplantation Registry; ITA - islet transplantation alone; LBL - layer-by-layer; M:G - mannuronate: guluronate: MIN6 - mouse insulinoma 6; NOD - non-obese diabetic; PAK - pancreas after kidney transplantation; PDMS - polydimethylsiloxane; PEG - polyethylene glycol; PEG-PLGA - polyethylene glycol-poly lactic-co-glycolic acid; PGA - polyglycolic acid; PLL - poly L-lysine; PPB - poly (l-lysine) - g-poly (ethylene glycol) (biotin); PTA - pancreas transplantation alone; PTFE - polytetrafluoroethylene; PU-PVP-IPN - PolyUrethane-Poly Vinyl Pyrrolidone-InterPenetrating Network; PVA - polyvinyl alcohol; SA - streptavidin; SOP - standard operating procedure; SPK - simultaneous pancreas and kidney transplantation; STZ - streptozotocin; T1D - type 1 diabetes

1. Introduction

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the rapid destruction of β-cells within the pancreas, resulting in an inexorable decline in insulin secretion, resulting in complete insulin deficiency [1]. The primary therpy concept for T1D is strict glycemic control through injectable exogenous insulin, administered subcutaneously. A surgical alternative to exogenous insulin is clinical islet transplantation, a procedure that attempts to replenish the depleted β-cell reserve by transplantation of isolated donor islets into the patient’s portal vein. Over the last decade, this procedure has undergone several modifications and refinements, such that current recipients can maintain insulin independence for prolonged periods of time. Unfortunately, the lack of organ donors of sufficient quality, the need for multiple donors per patient, inconsistent islet yields, and the need for immunosuppressive therapy continue to hamper further progress [2]. Encapsulation of islets prior to transplantation could potentially address some of these problems.

Cell encapsulation is a novel concept in which cells are encased within a biocompatible matrix. The primary role of encapsulation is to create a barrier against immune cells and cytotoxic molecules, which could potentially injure the cell, thus avoiding rejection while still allowing the active diffusion of oxygen, micro- and macronutrients, and hormones (Figure 1). Although the idea was described as early as the 1930's, no notable achievements occurred until the last decade. This review aims to provide an update on this new and rapidly evolving area of islet research while including relevant historical events, current trends in islet research, and future directions associated with the hope of ultimately utilizing islet and stem cell encapsulation to cure T1D.

Figure 1. Types of encapsulation. Two commonly used types of cell encapsulation in alginate hydrogels: microencapsulation (A) and macroencapsulation (B).


2. History of islet transplantation

In the annals of islet transplantation, the year 1894 will be recalled as the year of the first islet transplantation attempted as a treatment for T1D. That year, Dr. Williams, a British physician, attempted to cure a young diabetic by injecting a concoction of pancreatic cells obtained from sheep, under the patient's skin. Unfortunately, the treatment did not work, and the patient slipped into a diabetic coma and died two days later [3]. Following this failed attempt, no inroads were made into devising a surgical cure for T1D until the 1960s, when Dr. Kelly at the University of Minnesota attempted to transplant a segmental pancreas graft and a kidney simultaneously, from a cadaver donor into a diabetic patient with end-stage renal disease. Although the 28-year old recipient remained insulin-free for only 6 days post transplantation, rejected both grafts within 60 days of the surgery, and died of a pulmonary embolism less than two weeks after the organs were explanted, the surgical team had proven that this complicated procedure was technically feasible [4].

Unlike Dr. Kelly's pioneering surgery, where a segmental pancreatic graft was preferred, Dr. Lillehei transplanted the whole pancreas and attached duodenum either with (9 cases) or without the kidney (4 cases). This modified technique demonstrated prolonged pancreas graft function, in one case for nearly one year [5]. These trials were quickly followed by similar trials in South America [6-8], the US [7, 9], and Europe [7]. Since none of the trials demonstrated graft function for more than a year, and since the graft duodenum was noted to be robustly antigenic, techniques involving the transplant of a segmental pancreatic graft were developed in the 1970s.

The introduction of a novel immunomodulator, cyclosporin A, in clinical transplantation [10], the formation of the International Pancreas Transplantation Registry (IPTR), and the organization of scientific meetings in Spitzingsee, Germany, in the early 80's, were three major events that contributed immensely to the development of pancreas transplantation. The early meetings led to the creation of IPITA (The International Pancreas and Islet Transplantation Association) and EuroSPK (The European study group in simultaneous Pancreas and Kidney Transplantation) [11, 12], In the 1970's, surgeons at the University of Minnesota were performing pancreas after kidney (PAK) transplantations in diabetic patients, but by the 1980's, they had commenced segmental pancreas grafting for pancreas transplantation alone (PTA) [13].

In 1983, Dr. Sollinger reported a urinary drainage technique as a method for managing pancreatic exocrine secretions. The low incidence of surgical complications [14, 15] using this method, and the added advantage of being able to monitor graft rejection using urinary amylase monitoring, led to the rapid adoption of bladder drainage using whole pancreas as the standard technique for the surgical management of T1D. The whole pancreaticoduodenal transplant with enteric drainage, originally described by Lillehei [5], was perfected during the mid-80s by Starzl and associates [16], and remained the most popular technique for a decade. This technique subsequently became well established for use in simultaneous pancreas and kidney transplantation (SPK) with concomitant immunosuppressive therapy. The same technique has been modified for use in several transplantation procedures, especially in PAK transplantation and PTA. The duodeno-duodenal enteric anastomosis technique is, however, a high-risk procedure which requires the use of anti-thrombotic drugs to prevent ischemic reperfusion injuries [17].

Before 1999, results from islet transplantation alone (ITA) were poor and not comparable to survival rates for solid organ (whole or segmental pancreas) grafts. According to the 2005 Islet Transplantation Registry (ITR) report released in May 2005 at the 10th IPITA Congress, only 10% of islet transplant recipients demonstrated insulin independence at the end of one year, and even this varied depending on the center where the procedure was performed (IPITA 2005, Geneva). Since the first clinical trial where human islet allotransplantation was attempted in 1974, roughly 364 such procedures had been reported in 1999 from around 15 centers all over the world.

In March 1999, a new protocol for clinical islet transplantation using a glucocorticoid-free immunosuppressive regimen, developed in Edmonton, Alberta in 2001, demonstrated sustained insulin independence in seven human subjects for a period of almost one year [18]. When centers reported that 80% of patients treated using the steroid-free Edmonton regimen remained insulin-free after one year post transplantation, there was significant interest generated as this represented a definite improvement over previous immunosuppressive regimens, most of which included glucocorticoids which had demonstrated significant islet toxicity. Ten other centers attempted to replicate this initial success, but reported disappointingly low long-term exogenous insulin independence, with a return to hyperglycemia and insulin dependence despite immunosuppression [19]. Of the nine largest centers where human islet allotransplantation was carried out using the Edmonton protocol, only three were able to demonstrate a 65% insulin independence rate at one year after the procedure, while some centers reported success rates as low as 23% [20].

This has encouraged researchers to scout for other, non-hepatic transplant sites where presumably the early islet destruction―secondary to an intense inflammatory response, inadequate graft vascularization, and toxic levels of immunosuppressant drugs, characteristic of intra-hepatic islet allotransplantation―can be avoided [21]. A comprehensive review by Barton et al. using data obtained from the Collaborative Islet Transplant Registry (CITR), involving a total of 677 recipients who underwent allogeneic islet transplantation between 1999 and 2010 [22], has shown that exogenous insulin independence three years after transplantation improved from 27% between 1999-2002 to 44% between 2007-2010. Between 2007 and 2010, islet graft survival at 1 year (92%) and 3 years (83%) is comparable, if not slightly superior, to survival rates demonstrated with whole pancreas transplants (80% and 61% at 1 year and 3 years, respectively). Better graft survival rates noted in recent years were attributed to advanced immunosuppressive strategies which conferred greater protection to the transplanted islets.

To avoid graft rejection, islet transplantation centers have implemented various immunosuppressive regimens. This treatment strategy includes lifelong drug requirement, and has been demonstrated to result in numerous deleterious effects to the patient, while also adversely impacting graft function and viability [23, 24]. Encapsulation of transplanted cellular grafts within biocompatible materials has been proposed as a viable treatment option for allogeneic human islet transplantation with the goal of eliminating the need for chronic immunosuppression, thus obviating the attendant adverse effects. Encapsulation involves enclosing tissues within immunoprotective hydrogels to achieve immunoisolation to prevent graft rejection. Various encapsulation technologies have been previously used in the management of anemia, dwarfism, neurodegenerative diseases, liver failure, chronic pain syndromes, epilepsy, and diseases of the parathyroid glands [25-29]. Despite intra-portal infusion of islets having been established as the standard of care in the treatment of T1D, maintaining long-term graft viability while avoiding toxic systemic immune therapy has only been accomplished through encapsulation [30, 31].

3. Advances in encapsulated islet technology

3.1 Animal and human trials

In 1933 Bisceglie demonstrated that a membranous polymer structure, containing mouse tumor cells, can be transplanted safely into the abdominal cavity of a guinea pig while successfully evading the immune system and simultaneously preserving the viability of the encapsulated cells for prolonged periods of time. Today, this is widely regarded as the first scientifically documented attempt to encapsulate cells in bio-artificial membranes [32].

Alginate is a commonly used term to refer to a family of complex polysaccharides commercially extracted from seaweed, including fast-growing kelp (brown algae) and certain bacteria (Pseudomonas and Azotobacter). It is composed of linear binary copolymers of β-D-mannuronic (M) and α-L-gulucorunoic (G) acid and exhibits a favorable immunologic profile after it undergoes extensive purification [33-35]. Over 30 years ago, in 1980, Lim et al. demonstrated that intra-peritoneal transplantation of 2,000-3,000 islet equivalents (IEQ) encapsulated in alginate-poly-L-lysine alginate (APA) microcapsules into diabetic rats was able to reverse STZ-induced hyperglycemia for a period of up to 21 days post transplantation. When unencapsulated islets were transplanted, there was a return to hyperglycemia after a period of only 8 days [36]. Over the last two decades, numerous studies have demonstrated that encapsulated syngeneic and xenogeneic islets continue to function for prolonged periods of time after successful transplantation into small [37-42] and large animals [43-46]. Encouraging results, including prolonged graft survival and a reduction in HbA1c levels and daily insulin requirements have even been demonstrated in a few early-phase human clinical trials [47-50]. Similar results have been obtained using various biomaterial implant devices including microcapsules made of 5% agarose [51], polyethylene glycol (PEGylated islets) [52], and polyethylene glycol-poly lactic-co-glycolic acid (PEG-PLGA) nanoparticles [53]. Alginate has become heavily favored for use in microencapsulation because of its superior biocompatibility, hydrophilicity, simple gelation process, stable architecture, abundant availability, relative ease of procurement, low manufacturing costs, and prolonged stability in vivo. Alginate microencapsulation is a technique in which each islet is individually enclosed in an alginate microcapsule (Figure 2E and F). Alginate has also been used in macroencapsulation, where the biocompatible device can contain multiple islets (Figure 2A-D).

Figure 2. Variety of encapsulation devices currently in use. Biocompatible implantable device developed at the National Autonomous University of Mexico (Mexico D.F., Mexico) [124, 125] (A). Sernova Cell Pouch System™ [182] (B). Size comparison of various theracyte models [132] (C). Alginate sheet transplanted onto the liver [183] (D). Single encapsulated islet (E). Double encapsulated islet (F) (de Vos P, personal communication). Nanoencapsulated islet (G) (Ricordi C, personal communication).


While alginate encapsulated islets have been successfully transplanted into the peritoneal cavity of canine subjects [54], under the skin and kidney capsule in non-human primate [43] and cynomolgus monkey recipients [45] with moderate success, these studies have been lacking in consistency. Regardless of this drawback, these large animal studies have paved the way for several researchers to proceed to phase one and two clinical trials in human subjects.

In 1994, the world's first clinical trial using encapsulated human islets was conducted when a 38-year old diabetic male patient suffering from end-stage kidney disease was transplanted with encapsulated human islet allografts while simultaneously being administered low-dose immunosuppression [55]. He received 10,000 islet equivalents per kilogram (IEQ/kg) body weight encapsulated within alginate microcapsules. Six months later, he received a second infusion of 5,000 islet equivalents per kilogram (IEQ/kg) body weight. After he received the first transplantation, he recovered from the surgery without any complications, and was insulin-free for 9 months [55]. Other studies were less successful. In 2006, Calafiore et al. reported significantly lower exogenous insulin requirements and improved glycemic profiles in two subjects that received encapsulated human islets. While this was encouraging, it must be noted that the subjects did not achieve insulin independence [48].

Living Cell Technologies, a company based in New Zealand, harvests pancreases from fetal pigs housed at a pathogen-free farm on Auckland Island, following which the islets are isolated in a pathogen-free facility, encapsulated within alginate microcapsules, and injected intraperitoneally into T1D human recipients. They have demonstrated significant success in the field of encapsulated islet transplantation. Several early-phase human trials have demonstrated a significant reduction in the number of hypoglycemic episodes to 40% of the pre-transplant levels. Patients also reported reduced insulin requirements and 2 of the subjects enrolled in the study reverted to insulin independence 4 months after transplantation [45, 56, 57].

Despite these promising achievements, most recipients of encapsulated islets fail to achieve sustained insulin independence and many studies demonstrate disappointing results, ranging from relapse into hyperglycemia and return to pre-transplant insulin requirements [57] to a complete failure to achieve insulin independence or even a reduction in insulin requirements, despite the presence of detectable C-peptide levels [50]. Pericapsular fibrosis seems to be a significant problem that results in increased failure rates after transplantation of microencapsulated islets [50, 58-60].

In vivo studies have consistently demonstrated that some biomaterial implants used in encapsulation impact implant survival more positively than others. King et al. demonstrated that islets encapsulated in poly L-lysine-free (PLL-free) high mannuronate alginate (high M) demonstrated prolonged periods of sustained normoglycemia (up to 8 weeks) as compared to capsules composed of high guluronate (high G) alginate [61]. However, Espevik et al. demonstrated that capsules made of high M alginate stimulated monocytes to produce TNF-α, IL-1, and IL-6, all of which are pro-inflammatory cytokines that would adversely impact islet survival [62]. On the other hand, high G alginates did not demonstrate similar pro-inflammatory characteristics [63]. Lanza et al. conducted studies comparing microcapsules of different alginate concentrations and demonstrated that improved capsule stability and prolonged graft function and survival could be achieved by simply altering the concentration of alginate (from 0.75% to 1.5%) used for encapsulation with porcine and bovine xenografts transplanted into immunocompetent rats [64].

The length and sequence of mannuronate and guluronate chains and ratio of mannuronate to guluronate (M:G ratio) in alginate hydrogels has been demonstrated to determine the mechanical strength, elasticity, durability, permeability, and swelling characteristics of the alginate [33, 65]. In addition, several chemical changes to the alginate composition have either positive or undesirable effects on its biocompatibility. The use of multivalent cations (Ca2+, Fe3+, Ba2+), polycations (poly-L-lysine or poly-L-ornithine), and poly-electrolytes in alginate synthesis as a technique of modifying its chemical properties has been extensively studied [66, 67]. APA capsules provide a high degree of permselectivity, i.e. selective blocking of antibodies from entering microcapsules [68, 69]. They also have a better stability and mechanical strength, but their use results in increased pericapsular, cellular overgrowth [70], greater antigenicity [71, 72], and macrophage activation [73, 74] resulting in a dense fibrotic overgrowth surrounding the capsules [75].

These disadvantages can be avoided by cross-linking the alginate using a multivalent cation like barium, which results in the formulation of highly elastic alginate capsules with greater stability and better mechanical strength [67, 76]. Barium cross-linking has been demonstrated to be significantly less immunogenic [77] than alginate-PLL (or other polycation-linked alginate capsules), and also provides sufficient protection from antibody- and cytokine-mediated islet-injury, despite being more permeable to IgG antibodies than alginate-PLL capsules [78]. These advantages have led to the widespread use of barium cross-linked alginate in islet encapsulation. Although alginate remains the most popular hydrogel of choice, agarose [79, 80], chitosan [81], methacrylic acid [82], methyl methacrylate [83], polyamide [82, 84], polyvinyl alcohol (PVA) [85], polyethylene glycol [86, 87], 2-hydroxyethyl methacrylate (HEMA) [88, 89], and AN69 (a copolymer of acrylonitrile and sodium-methallyl sulfonate) [90], have been used in islet encapsulation studies with limited success.

3.2 Biomaterials in transplantation

Devices used in cell encapsulation today can broadly be classified into macroscale, microscale, and nanoscale devices, the variety thereof is shown in Figure 2. These implantable devices could be implanted in intravascular or extravascular sites anywhere in the body.

Intravascular devices. Intravascular devices contain islets encapsulated within hollow biocompatible tubes or fibers attached to the recipient's vascular system [91, 92]. They present several advantages over extravascular macrocapsules, namely, better access to nutrients and oxygen, immediate recognition of changes in glucose, and higher diffusion facilitated by blood flow. However, their tendency to develop thrombi at anastomosis sites and the need for systemic anticoagulation with its attendant adverse effects [91, 92] make them poor candidates for widespread use in clinical islet transplantation.

Extravascular devices. Research into extravascular macroencapsulation devices [45, 93-100] has been progressing at a steady pace. The hemorrhagic complications seen with implantable intravascular devices are not noted with extravascular implants and consequently these devices have been studied more extensively. They may be broadly classifiable into tubular and planar devices based on their morphology.

Tubular devices. Numerous studies using islet-containing extravascular tubular chambers and sealed hollow fiber devices [99, 101-105], performed during the last two decades, have demonstrated shorter graft survival times when compared to similarly constructed intravascular devices. This was attributed to inadequate oxygen and nutrient diffusion within these devices when compared to intravascular devices. XM-50 Amicon hollow fiber macrocapsule implants (Amicon Corp, Danvers, MA), containing xenogeneic human [106] or canine islets transplanted into STZ-diabetic pigs and rodents respectively, demonstrated that the peritoneal cavity was the best transplant site with minimal fibrosis even 5 months post transplantation, despite no immunosuppression [107]. When transplanted into diabetic dogs, these devices demonstrated a 50% success rate in achieving insulin independence for a period of 51-82 days, demonstrating their efficacy in large animal models [108].

Islet-containing hollow fiber implants with smooth outer surfaces demonstrated better immunoisolation and glycemic control when implanted subcutaneously, with minimal fibrotic response and implant failure as compared to implants with rough or fenestrated outer surfaces [107-110]. Prevost et al. [111] reported that STZ- diabetic rats transplanted with AN69 hollow fiber implants containing syngeneic islets demonstrated euglycemia for 10 weeks post-transplantation. No host reaction to the implant was evident except for a thin layer of fibroblasts. Studies have also demonstrated that these fibers have neovascularization potential [112], similar to intraperitoneally transplanted, smooth surface-regenerated cellulose fibers [113]. A recent in vitro study even suggested that islets encapsulated in hollow fibers demonstrate adequate oxygenation, comparable to levels found within microcapsules [114]. Hollow fiber devices are injectable, easily retrievable, durable, and easily adaptable for subcutaneous implantation. However, they are also highly susceptible to damage after transplantation in vivo and require a large dose of islets to achieve complete insulin independence [98], which limits their widespread applicability.

Planar devices. Planar devices consist of islets encapsulated within two circular or rectangular flat sheets fastened to make a sealed chamber. It is believed that this configuration confers better stability than hollow fiber chambers and attenuates graft hypoxia by improving oxygen supply to the entire graft. These devices are implanted either in the subcutaneous tissue or in the peritoneal cavity because of their configuration and macroscopic size. In the case of prevascularized devices, the former site is preferred, as a second procedure is often needed to seed the device with islets weeks or months after the initial surgery. However, planar implants seldom remain in their original configuration after implantation [115] and studies using these devices have demonstrated graft failure secondary to the formation of a dense pericapsular fibrotic overgrowth [116, 117]. Poor oxygen and nutrient diffusion across the membranes leading to compromised islet viability, suboptimal graft function, and graft failure limit their ability to sustain insulin independence for prolonged periods of time.

Despite these disadvantages, their easy retrievability after implantation for further evaluation, and their usefulness in performing in vivo islet viability [118] and implant biocompatibility studies [119, 120] have led to their widespread use in numerous in vivo islet encapsulation studies. Certain bilayered planar devices such as the Boggs chamber and the Theracyte device (Figure 2C) can be modified to promote vascularization while simultaneously providing effective immunoisolation [92, 121].

Prevascularized devices. A 'prevascularized' device is designed to increase vascularity at the transplant site by the local administration of vascular growth or trophic factors, or by the induction of neovascularization by device pre-implantation followed by islet seeding several weeks later (Figure 2A and B). Prevascularization has been evaluated as a possible solution to overcome the diffusional limitations noted with planar devices and to mimic the native microarchitecture of the islets, where β-cells enjoy intimate contact with the surrounding microvasculature [122, 123]. Despite studies reporting successful implantation of prevascularized islet-containing devices in the omentum and other sites in the peritoneal cavity, subcutaneous implantation remains the most attractive location and represents the safer, less invasive alternative with minimal adverse effects that also allows for continuous monitoring and effortless device retrieval [124, 125].

Pore size. Choosing the appropriate pore size is vital for the success of any bio-artificial encapsulation device. An exceedingly small pore size may impede inward nutrient and oxygen diffusion and outbound insulin and metabolite diffusion from the islet-containing inner space of the planar device. In contrast, a particularly large pore size may allow unwanted immunoglobulins and other cytotoxic chemokines to enter this space, leading to islet injury and destruction. Thus, the most important criterion in designing a functional islet encapsulation device is appropriate pore size. Colton et al. studied the influence of pore-size on membrane permeability by seeding mouse insulinoma cell clusters (MIN6) encapsulated in 1% agarose, 0.005% HEMA, and 0.15 mg/ml collagen [119] into planar Nuclepore [126] membrane devices. Devices with pore sizes ranging from 0.1 mm up to 0.6 mm were transplanted intraperitoneally into diabetic Wistar rats and compared. While devices with 0.1 or 0.2 mm pore-sized membranes demonstrated sustained reversal of hyperglycemia for at least 3 months [127], those with larger pore sizes demonstrated a partial reversal that was not sustained for more than 3 weeks after implantation.

Studies have also demonstrated that membrane diffusion and permeability in planar devices can change after exposure to host defenses. Kessler et al. performed experiments where a protein coat was applied to the encapsulation device before in vitro tissue culture in an attempt to mimic an in vivo host environment [120]. Membrane permeability to glucose and insulin was assessed during culture and compared with results obtained with devices implanted intraperitoneally in rats and retrieved one week after implantation. No cellular inflammation or necrosis, cell adhesion or fibrin deposits were noted in the non-coated device implanted in vivo. However, protein adsorption onto the in-vivo-implanted membranes was greater than the amount adsorbed onto the in vitro protein coated membrane. Glucose and insulin diffusion rates were significantly lower in both pre-coated and non-coated implants, indicating that the protein coating could be a reason for the drop in permeability in vivo.

Islet sheet. The islet sheet™ (Figure 2D) is a prototype of a multi-layered islet encapsulation device constructed from alginate. The islets are inserted in a flat sheet sealed on both sides by acellular layers of purified alginate, which serve as immunoisolation layers, without any polymer reinforcement. The islet sheet thickness is maintained as small as possible (~250 µm) [115]. Like other intraperitoneally implanted encapsulation devices, this device relies primarily on passive diffusion for nutrient, oxygen, insulin, and metabolites transport. One study demonstrated fasting normoglycemia in a pancreatectomized dog, implanted with sheets containing encapsulated allogeneic islets implanted in the omentum for 84 days post transplantation [115]. A previous study using hollow fiber devices [107] has demonstrated that surface irregularities can trigger fibroblast attachment and consequently lead to fibrosis and implant failure. Thus, it is expected that a planar device like the islet sheet™ would demonstrate minimal fibroblast activation and fibrosis owing to its smooth and continuous outer membrane layers.

Vascularized devices. The idea of devising 'vascularized' devices to improve islet nutrient and oxygen supply, thus promoting improved insulin secretion and increasing the overall efficiency of encapsulation devices, was developed during the last decade. To build such a device researchers first implant a 'scaffold', usually a few days or weeks before islet implantation. This 'scaffold' promotes neovascularization―the sprouting of new capillaries around and in some instances into the implant―and helps attenuate hypoxic injury to the transplanted islets, especially during the first week immediately after transplantation when they are most vulnerable to such injury. Studies evaluating the utility of polytetrafluoroethylene (PTFE) in the formulation of a scaffold for use in islet encapsulation either alone [128], or with a coating of acidic fibroblast growth factor (a-FGF) [77] (implanted into recipient animals one month before islet seeding) concluded that, in both instances, vascularization was induced after sub-epidermal or intraperitoneal implantation. Islets were seeded within the device 4 weeks later. In successful experiments, the diabetic recipients demonstrated sustained normoglycemia for up to 6 months. When the device was retrieved at the end of the study, over half of the encapsulated islets stained positive for insulin.

Juang et al. compared the efficacy and performance of thin fibrils made of either polyvinyl alcohol (PVA) or polyglycolic acid (PGA) woven into flat sheets, within which free or encapsulated allogeneic islets were seeded, implanted at one of three sites: renal subcapsular, intraperitoneal, and subcutaneous [123]. These studies demonstrated that PGA polymer sheets transplanted subcutaneously had the best results with 80% of recipients maintaining euglycemia for 3 months after implantation. Upon retrieval, successfully implanted devices also demonstrated numerous intact islets and implant neovascularization.

Theracyte. The Theracyte device (Baxter Healthcare, Round Lake, Ill., USA) is a durable and retrievable planar macroencapsulation device that consists of a bilayer polymer membrane with a 5 µm polytetrafluoroethylene (PTFE) outer layer, laminated onto a 0.45 µm inner PTFE layer [97]. A polyester mesh is attached to the 5µm PTFE layer. At one end of the device, a polyethylene port provides access to the lumen for islet seeding (Figure 2C). This device supports neovascularization via the outer membranes while containing the engrafted cells within cell-impermeable inner membranes [97], an arrangement that avoids contact with the host immune cells and vasculature. This was demonstrated by Rafael et al. who observed that, during the first 4 weeks after implantation, the device constitutes a significant diffusion barrier with significantly lower peak glucose levels, longer times-to-peak, and smaller areas under the curve, but at 3 months, the exchange between the lumen of devices and the blood stream improved significantly.

Subsequent studies comparing Theracyte™ devices that were pre-implanted 3 months before islet seeding with devices implanted concurrently with the islets demonstrated a greater volume of viable islets, lower incidence of fibrosis, and higher proportion of insulin-positive β-cells 2 weeks post-implantation [129, 130]. One study has reported that human islets or islet-like cell clusters (ICCs) encapsulated within Theracyte™ devices remain viable and functional even after prolonged cryopreservation [131]. Allogeneic rodent islets [132] and human fetal ICCs [93], encapsulated within Theracyte™ devices and transplanted into allosensitized rats and immunodeficient mice respectively, have proved to be viable and functional for up to 6 months post transplantation.

Microencapsulation. In the case of microencapsulation, islets are immobilized inside microspheres of alginate, agarose gel, or another biocompatible material and implanted into the recipient. Compared to planar and tubular macrocapsules, alginate microcapsules (Figure 2E) are mechanically more stable, have a better surface area to volume ratio, a superior immunologic profile [133, 134], are simple to construct, and provide incredible flexibility to manipulate key parameters including wall thickness and pore size. Consequently, they remain the most commonly employed bioencapsulation devices [134-136] in islet encapsulation. Since these capsules can be mass produced by "encapsulators" using commercially developed air-jet driven droplet technology [137, 138], they are cost-effective, and can be standardized for clinical use. They have been safely tested in numerous small and large animal trials and would thus be safe for widespread application in clinical islet transplantation. Alginate microencapsulation has demonstrated graft protection from host immune attack and prolonged islet survival without immunosuppression in studies conducted in small [139] and large diabetic animal models [93].

Several stimuli-responsive hydrogels are among the most commonly used synthetic agents in encapsulation and tissue engineering including poly (vinyl methyl ether), poly acrylamide gels, poly vinyl alcohol, polyphosphazene, and other derivatives [140]. The most significant drawback with using synthetic scaffolds is the significant potential of a host inflammatory response being elicited against the foreign material leading to fibrosis and loss of the encapsulated cells. All synthetic constituents would also be required to be manufactured and purified using materials and methods that would have to be non-toxic, while also not subjecting the cells to excessive mechanical or chemical stress. They are typically also modified to be able to interact with the environment and gradually degrade under physiologic conditions. Unlike synthetic materials, naturally occurring hydrogels such as gelatin, fibrin, agarose, hyaluronate, chitosan, and alginate [141, 142] are less likely to induce a fibrotic or inflammatory host response and are hence preferred for use in microencapsulation. Alginate is the most common naturally occurring hydrogel used in the formulation of microencapsulation devices. However, naturally occurring hydrogels also have their disadvantages, namely lower tensile strength, high cost, and greater inter-batch variations, thus impeding standardization of the manufacturing process [141].

3.3 Current advances in encapsulation technology

Although encapsulation should theoretically ensure immune isolation and free oxygen and nutrient diffusion across the matrix (Figure 3), in reality, graft rejection and necrosis have been observed [143, 144], which have led researchers to believe that hypoxic injury and apoptosis is to blame. Some researchers have addressed these issues by employing layer-by-layer coating (Figure 2F), which involves the generation of a complex of nanocoatings by adding additional layers surrounding the islets to achieve adequate immunoisolation while preserving optimum diffusion parameters.

Figure 3. Schematic figure of a bioencapsulated islet. A schematic demonstrating the advantages of alginate microencapsulation. The capsule acts as an immunoisolation device which restricts the entry of immune cells and antibodies while allowing for the passive diffusion of nutrients, oxygen, and glucose into the capsules and insulin out of the capsules into the body. Encapsulation design by Islet Science, LLC. Picture provided by Dr. Jonathan RT Lakey, UCI.


Nanoencapsulation. Nanoencapsulation is achieved by creating an efficient and biocompatible nanoscale immunoisolation layer adjacent to the cell surface (Figure 2G), thus eliminating diffusion barriers, while also allowing for implantation of the encapsulated islets into sites normally suitable only for non-encapsulated islets [145]. This technique confers several advantages over conventional micro- and macroencapsulation techniques, especially enhanced glucose response time, superior nutrient access, and the possibility of 'tuning' permeability by controlling layer thickness and composition without a significant increase in the size of the islet or the protective envelope. In addition, enhanced biocompatibility and islet survival could also be achieved by incorporation of immunosuppressive drugs into the capsule for sustained release into the tissue interstitium.

Several methods of nanoencapsulation have been used in islet encapsulation, of which 'PEG'ylation, or nanocoating islets with polyethylene glycol (PEG) is the most popular [146]. Exposure of PEG to ultraviolet or visible light triggers cross-linking which results in the formation of a 'nanocapsule' around the islet with minimal tissue damage [53]. However, PEG is less biocompatible than many hydrogels currently being studied for use in islet encapsulation and it cannot effectively protect the encapsulated cells against cytokine attack [147]. Layer-by-layer (LBL) nanoencapsulation with multiple layers of polyelectrolyte [148], polyvinyl alcohol conjugated to a single layer of PEG-phospholipid [149], or the incorporation of biological factors like FGF-1 [150], anti-coagulants [151], or anti-inflammatory molecules [152-156] are being investigated to address this issue. LBL encapsulation has also been attempted in novel areas such as delayed-release pharmacotherapy, antioxidants, and even oxygen-generating biomaterials (PolyDiMethylSiloxane (PDMS)-encapsulated solid calcium peroxide) [157] in an attempt to address encapsulation induced hypoxia. Alginate-chitosan nanolayers [158], polylysine/polyglutamic acid membranes [159], poly (l-lysine)-g-poly (ethylene glycol) (biotin) (PPB) and streptavidin (SA) [160], complement receptor 1 and heparin [161], and PEG lipid and PVA [149, 162] are some of the many biomaterials currently being studied for use in islet nanoencapsulation.

3.4 Stem cells

Stem cells are an attractive alternative to human islets, as the limited availability of transplant-worthy human cadaveric donors, the need for multiple donors per recipient, and low islet yields remain an obstacle to the widespread application of human islet allotransplantation in achieving a long term cure for T1D. Viable insulin-producing β-cells can be sourced from various kinds of stem cells (human embryonic, induced pluripotent, mesenchymal etc.) for transplantation. Although several in vivo studies have been conducted in this field, the results have not been consistently encouraging.

Viacyte LLC (San Diego, CA), a pioneer in the area of encapsulated stem cell-related transplants, has demonstrated the feasibility of encapsulating human embryonic stem cells (hESC) within the Theracyte™ device and efficiently directing the encapsulated cells down a pancreatic endocrine lineage, despite not having any direct contact with the host environment. In one study, diabetic host mice transplanted with these cells encapsulated within the Theracyte™ device demonstrated euglycemia within three months after receiving the aforementioned device [163]. In another study, although initial glucose-stimulated insulin responses and plasma C-peptide levels remained low 12 weeks after transplantation, after 5 months, both parameters improved remarkably, suggesting that differentiation continued after encapsulation [93]. It has even been demonstrated that human insulin-expressing cells, encapsulated using the Theracyte device, can be safely cryopreserved and thawed, and they still retain their function [131]. However, such positive outcomes were not always observed [164]; there were instances of devices becoming walled off within fibrotic tissue and failing to stain positive for endocrine cells after retrieval. It has been demonstrated that the stiffness of the alginate substrate can affect stem cell differentiation.

Candiello et al. demonstrated that hESC gene expression was sensitive to changes in the stiffness of the alginate hydrogel substrate used. Endodermal gene expression demonstrated the greatest sensitivity to changes in substrate stiffness and could be manipulated in conjunction with chemical signals to guide stem cell lineage fates toward endodermal lines [165]. Alternatively, mesenchymal stem cells derived from human amnion have demonstrated the ability to transform into functional islet-like clusters which, when encapsulated in polyurethane-polyvinyl pyrrolidone or alginate microcapsules and transplanted into diabetic mice, resulted in a return to normoglycemia two weeks post transplantation. The changes were sustained until approximately 30 days after transplantation [166, 167].

Davis et al. demonstrated that silk-based encapsulation devices are versatile, provide an excellent encapsulation milieu for islets, and maintain islet viability and function in vitro. When murine islets were co-encapsulated with mesenchymal stem cells (MSCs) and extra cellular matrix (ECM) proteins within these devices, graft function and survival improved. If these results could be reproduced in small and large animal in vivo studies, the device could potentially represent a breakthrough in the search for a cure for T1D [168].

Another study using adipose-derived stem cells (ADSCs) reported that islet-like cell aggregates (ICas) derived from ADSCs expressed pancreatic endocrine hormones, co-expressed insulin and somatostatin (similar to fetal pancreatic cells), and demonstrated human C-peptide secretion in response to in vitro glucose stimulation in a dose-dependent manner. When these ICAs were allowed to mature, encapsulated within biocompatible Polyurethane-poly vinyl pyrrolidone-Interpenetrating network (PU-PVP-IPN) microcapsules and transplanted into the peritoneal cavity of STZ-induced diabetic mice, a sustained lowering of blood glucose levels was noted within 3 weeks of transplantation. These results were sustained up to two months after surgery [169].

Mason et al. demonstrated that dissociated embryonic pancreatic precursor cells photoencapsulated and cultured within a synthetic PEG hydrogel selectively differentiated into insulin-secreting β-cells. The results of this study seem to suggest that embryonic pancreatic precursor cells could be exposed to specific chemical environments to encourage targeted cell proliferation and differentiation to generate a population of primarily glucose responsive β-cells [170].

Induced pluripotent stem cells (iPSCs) are another important source of stem cells that are being studied for use in islet transplantation. These cells have demonstrated the ability to differentiate into functional β-cells, in vitro, as demonstrated by a partial C-peptide release response after glucose stimulation [171-173]. Furthermore, iPSCs derived from mice and rhesus monkeys have demonstrated the ability to differentiate into glucose-responsive insulin-positive cells, resulting in a complete reversal of experimentally induced hyperglycemia after transplantation in diabetic mice (type 1 and type 2) [174]. In addition to all the aforementioned cell types, pancreatic epithelial cells, ductal cells, and even α-cells have been demonstrated to be able to differentiate into β-cells under appropriate conditions [174].

It is still a matter of concern that no research group has achieved the vital breakthrough of sustained insulin independence using β-cells generated from stem cells. New research developments in the field of stem cell differentiation are being reported and will hopefully improve upon the method pioneered by Blyszczuk [175]. Even if researchers achieved controlled stem cell differentiation into functional β-cells with long-term insulin independence after transplantation into non-human diabetic primates, diabetic human subjects would not be able to benefit from these achievements immediately. Similar, reproducible results from multi-center, multidisciplinary, randomized, controlled, clinical trials would be required to translate their findings into an established treatment modality for patients with T1D. Although the protocols and standard operating procedures (SOPs) for the isolation, proliferation, in-vitro culture, differentiation, and maturation of stem cells derived from human embryos and induced pluripotent stem cells have been established, tested, and standardized, several significant milestones need to be reached before studies can be commenced in diabetic human subjects.
The two principal issues of concern are:

1. The inherent ability of hESC/iPSCs to proliferate rapidly in an unpredictable manner by undergoing malignant transformation.
2. The risk that the implanted stem cells are recognized as foreign by the host immune system and subsequently attacked and destroyed, leading to graft failure and a relapse into the diabetic state.

However, if hESC or iPSC-derived insulin-producing cells are enclosed in a protective, bioinert, biocompatible layer or capsule and implanted at an appropriate site, tumor formation and immune attack can be prevented, and adequate insulin secretion for long-term maintenance of euglycemia can be achieved [176].

4. Conclusions

Islet and stem cell encapsulation is a rapidly expanding field that attempts to challenge conventionally accepted treatment paradigms and revolutionize the field of islet transplantation [177]. Stem cell therapy has established itself as a rapidly expanding and potentially limitless source of β-cells to arrive at a cure for T1D, but the issue of recognition of these foreign cells by the host immune system and subsequent destruction via either a humoral or cellular immune response remains unaddressed. Although new developments in the field of biomaterial encapsulation provide several solutions to eliminate the need for toxic immunosuppressive therapy while promoting implant engraftment, several challenges still remain [178-181]. Improvements in graft viability, encapsulation techniques, biomaterial manufacturing, and purification procedures, identification of the safest, most reliable and scalable tissue source, and refinement of islet and stem cell isolation and culture techniques are vital to translate bench research into successful clinical islet transplantation with a prolonged period of insulin independence.

Disclosures: The authors report no conflict of interests.

Acknowledgments: This work was supported by the Department of Surgery, University of California Irvine. We are grateful to Drs. Paul de Vos, Camillo Ricordi, and Jonathan R.T. Lakey for the provision of images on multi-layer alginate capsules and nanoencapsulated islets.


  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004. 27(Suppl 1):S5-S10. [DOD] 
  2. Shenkman RM, Chalmers JJ, Hering BJ, Kirchhof N, Papas KK. Quadrupole magnetic sorting of porcine islets of Langerhans. Tissue Eng Part C Methods 2009. 15:147-156. [DOD] [CrossRef]
  3. Langer RM. Islet transplantation: lessons learned since the Edmonton breakthrough. Transplant Proc 2010. 42:1421-1424. [DOD] [CrossRef]
  4. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 1967. 61:827-837. [DOD] 
  5. Lillehei RC, Ruix JO, Aquino C, Goetz F. Transplantation of the pancreas. Acta Endocrinol Suppl (Copenh) 1976. 205:303-320. [DOD] 
  6. Chapo Bortagaray M, Zelasco JF, Bava A, Baun P, Cassin E, Crouzel G, Justo J, Lori R, Maquieira N, Mathov E, et al. Partial hemotransplant of the pancreas in the diabetic patient. Physiopathological basis for its location in the neck. 2 cases. Prensa Med Argent 1970. 57:220-224. [DOD] 
  7. Sutherland DE. Pancreas and islet transplantation. II. Clinical trials. Diabetologia 1981. 20:435-450. [DOD] [CrossRef]
  8. Teixeira E, Monteiro G, De Cenzo M, Teixeira A, Bergan JJ. Transplantation of the isolated pancreas: report on the first human case. Bull Soc Int Chir 1970. 29:337-344. [DOD] 
  9. Connolly JE, Martin DC, Steinberg T, Gwinup G, Gazzaniga AB, Bartlett RH. Clinical experience with pancreaticoduodenal transplantation. Arch Surg 1973. 106:489-494. [DOD] [CrossRef]
  10. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Henderson RG, Aziz S, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979. 2:1033-1036. [DOD] [CrossRef]
  11. Segmental pancreatic transplantation. International workshop, Munich/Spitzingsee. Horm Metab Res Suppl, 1983, 1-104. [DOD] 
  12. Squifflet JP, Malaise J, Van Ophem D, Marcelis V, Land WG, Euro SPKSG. The history of the EuroSPK - Study Group. Acta Chir Belg 2008. 108:67-69. [DOD] 
  13. Sutherland DE, Gruessner RW, Dunn DL, Matas AJ, Humar A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Robertson RP, et al. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg 2001. 233:463-501. [DOD] [CrossRef]
  14. Sollinger HW, Stratta RJ, D'Alessandro AM, Kalayoglu M, Pirsch JD, Belzer FO. Experience with simultaneous pancreas-kidney transplantation. Ann Surg 1988. 208:475-483. [DOD] [CrossRef]
  15. Sollinger HW, Cook K, Kamps D, Glass NR, Belzer FO. Clinical and experimental experience with pancreaticocystostomy for exocrine pancreatic drainage in pancreas transplantation. Transplant Proc 1984. 16:749-751. [DOD] 
  16. Starzl TE, Iwatsuki S, Shaw BW Jr, Greene DA, Van Thiel DH, Nalesnik MA, Nusbacher J, Diliz-Pere H, Hakala TR. Pancreaticoduodenal transplantation in humans. Surg Gynecol Obstet 1984. 159:265-272. [DOD] 
  17. Squifflet JP, Gruessner RW, Sutherland DE. The history of pancreas transplantation: past, present and future. Acta Chir Belg 2008. 108:367-378. [DOD] 
  18. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000. 343:230-238. [DOD] [CrossRef]
  19. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes 2005. 54:2060-2069. [DOD] [CrossRef]
  20. Ault A. Edmonton's islet success tough to duplicate elsewhere. Lancet 2003. 361:2054. [DOD] 
  21. Hardy MA, Witkowski P, Sondermeijer H, Harris P. The long road to pancreatic islet transplantation. World J Surg 2010. 34:625-627. [DOD] [CrossRef]
  22. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012. 35:1436-1445. [DOD] [CrossRef]
  23. Hafiz MM, Faradji RN, Froud T, Pileggi A, Baidal DA, Cure P, Ponte G, Poggioli R, Cornejo A, Messinger S, et al. Immunosuppression and procedure-related complications in 26 patients with type 1 diabetes mellitus receiving allogeneic islet cell transplantation. Transplantation 2005. 80:1718-1728. [DOD] [CrossRef]
  24. Niclauss N, Bosco D, Morel P, Giovannoni L, Berney T, Parnaud G. Rapamycin impairs proliferation of transplanted islet beta cells. Transplantation 2011. 91:714-722. [DOD] [CrossRef]
  25. Bachoud-Levi AC, Deglon N, Nguyen JP, Bloch J, Bourdet C, Winkel L, Remy P, Goddard M, Lefaucheur JP, Brugieres P, et al. Neuroprotective gene therapy for Huntington's disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum Gene Ther 2000. 11:1723-1729. [DOD] [CrossRef]
  26. Eriksdotter-Jonhagen M, Linderoth B, Lind G, Aladellie L, Almkvist O, Andreasen N, Blennow K, Bogdanovic N, Jelic V, Kadir A, et al. Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's disease. Dement Geriatr Cogn Disord 2012. 33:18-28. [DOD] [CrossRef]
  27. Fernandez M, Barcia E, Fernandez-Carballido A, Garcia L, Slowing K, Negro S. Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson's disease. Int J Pharm 2012. 438:266-278. [DOD] [CrossRef]
  28. Huber A, Padrun V, Deglon N, Aebischer P, Mohler H, Boison D. Grafts of adenosine-releasing cells suppress seizures in kindling epilepsy. Proc Natl Acad Sci U S A 2001. 98:7611-7616. [DOD] [CrossRef]
  29. Jeon Y. Cell based therapy for the management of chronic pain. Korean J Anesthesiol 2011. 60:3-7. [DOD] [CrossRef]
  30. Hering BJ. Islet transplantation for patients with type 1 diabetes; results, research priorities, and reasons for optimism. Graft 1999. 2:12-27. [DOD] 
  31. Shapiro AM, Nanji SA, Lakey JR. Clinical islet transplant: current and future directions towards tolerance. Immunol Rev 2003. 196:219-236. [DOD] [CrossRef]
  32. Bisceglie V. Uber die antineoplastische Immunität; heterologe Einpflanzung von Tumoren in Hühner-embryonen. Ztschr f Krebsforsch 1933. 40:122-140. [DOD] [CrossRef]
  33. O'Sullivan ES, Johnson AS, Omer A, Hollister-Lock J, Bonner-Weir S, Colton CK, Weir GC. Rat islet cell aggregates are superior to islets for transplantation in microcapsules. Diabetologia 2010. 53:937-945. [DOD] [CrossRef]
  34. Kim AR, Hwang JH, Kim HM, Kim HN, Song JE, Yang YI, Yoon KH, Lee D, Khang G. Reduction of inflammatory reaction in the use of purified alginate microcapsules. J Biomater Sci Polym Ed 2013. 24:1084-1098. [DOD] [CrossRef]
  35. Langlois G, Dusseault J, Bilodeau S, Tam SK, Magassouba D, Halle JP. Direct effect of alginate purification on the survival of islets immobilized in alginate-based microcapsules. Acta Biomater 2009. 5:3433-3440. [DOD] [CrossRef]
  36. Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science 1980. 210:908-910. [DOD] [CrossRef]
  37. Cui W, Barr G, Faucher KM, Sun XL, Safley SA, Weber CJ, Chaikof EL. A membrane-mimetic barrier for islet encapsulation. Transplant Proc 2004. 36:1206-1208. [DOD] [CrossRef]
  38. Lamb M, Storrs R, Li S, Liang O, Laugenour K, Dorian R, Chapman D, Ichii H, Imagawa D, Foster C 3rd, et al. Function and viability of human islets encapsulated in alginate sheets: in vitro and in vivo culture. Transplant Proc 2011. 43:3265-3266. [DOD] [CrossRef]
  39. Lum ZP, Tai IT, Krestow M, Norton J, Vacek I, Sun AM. Prolonged reversal of diabetic state in NOD mice by xenografts of microencapsulated rat islets. Diabetes 1991. 40:1511-1516. [DOD] [CrossRef]
  40. Veriter S, Mergen J, Goebbels RM, Aouassar N, Gregoire C, Jordan B, Leveque P, Gallez B, Gianello P, Dufrane D. In vivo selection of biocompatible alginates for islet encapsulation and subcutaneous transplantation. Tissue Eng Part A 2010. 16:1503-1513. [DOD] [CrossRef]
  41. Yang H, O'Hali W, Kearns H, Wright JR Jr. Long-term function of fish islet xenografts in mice by alginate encapsulation. Transplantation 1997. 64:28-32. [DOD] [CrossRef]
  42. Zhi ZL, Kerby A, King AJ, Jones PM, Pickup JC. Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes. Diabetologia 2012. 55:1081-1090. [DOD] [CrossRef]
  43. 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. 90:1054-1062. [DOD] [CrossRef]
  44. Dufrane D, Goebbels RM, Saliez A, Guiot Y, Gianello P. Six-month survival of microencapsulated pig islets and alginate biocompatibility in primates: proof of concept. Transplantation 2006. 81:1345-1353. [DOD] [CrossRef]
  45. Elliott RB, Escobar L, Tan PL, Garkavenko O, Calafiore R, Basta P, Vasconcellos AV, Emerich DF, Thanos C, Bambra C. Intraperitoneal alginate-encapsulated neonatal porcine islets in a placebo-controlled study with 16 diabetic cynomolgus primates. Transplant Proc 2005. 37:3505-3508. [DOD] [CrossRef]
  46. Gianello P, Dufrane D. Correction of a diabetes mellitus type 1 on primate with encapsulated islet of pig pancreatic transplant. Bull Mem Acad R Med Belg 2007. 162:439-449. [DOD] 
  47. Basta G, Montanucci P, Luca G, Boselli C, Noya G, Barbaro B, Qi M, Kinzer KP, Oberholzer J, Calafiore R. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 2011. 34:2406-2409. [DOD] [CrossRef]
  48. Calafiore R, Basta G, Luca G, Lemmi A, Montanucci MP, Calabrese G, Racanicchi L, Mancuso F, Brunetti P. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 2006. 29:137-138. [DOD] [CrossRef]
  49. Calafiore R, Basta G, Luca G, Lemmi A, Racanicchi L, Mancuso F, Montanucci MP, Brunetti P. Standard technical procedures for microencapsulation of human islets for graft into nonimmunosuppressed patients with type 1 diabetes mellitus. Transplant Proc 2006. 38:1156-1157. [DOD] [CrossRef]
  50. Tuch BE, Keogh GW, Williams LJ, Wu W, Foster JL, Vaithilingam V, Philips R. Safety and viability of microencapsulated human islets transplanted into diabetic humans. Diabetes Care 2009. 32:1887-1889. [DOD] [CrossRef]
  51. Kobayashi T, Aomatsu Y, Iwata H, Kin T, Kanehiro H, Hisanaga M, Ko S, Nagao M, Nakajima Y. Indefinite islet protection from autoimmune destruction in nonobese diabetic mice by agarose microencapsulation without immunosuppression. Transplantation 2003. 75:619-625. [DOD] [CrossRef]
  52. Lee DY, Park SJ, Lee S, Nam JH, Byun Y. Highly poly(ethylene) glycolylated islets improve long-term islet allograft survival without immunosuppressive medication. Tissue Eng 2007. 13:2133-2141. [DOD] [CrossRef]
  53. Dong H, Fahmy TM, Metcalfe SM, Morton SL, Dong X, Inverardi L, Adams DB, Gao W, Wang H. Immuno-isolation of pancreatic islet allografts using pegylated nanotherapy leads to long-term normoglycemia in full MHC mismatch recipient mice. Plos One 2012. 7:e50265. [DOD] [CrossRef]
  54. Soon-Shiong P, Feldman E, Nelson R, Heintz R, Yao Q, Yao Z, Zheng T, Merideth N, Skjak-Braek G, Espevik T, et al. Long-term reversal of diabetes by the injection of immunoprotected islets. Proc Natl Acad Sci USA 1993. 90:5843-5847. [DOD] [CrossRef]
  55. Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M, et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 1994. 343:950-951. [DOD] [CrossRef]
  56. Elliot RB, Garkavenko O, Tan P, Skaletsky NN, Guliev A, Draznin B. Transplantation of microencapsulated neonatal porcine islets in patients with type 1 diabetes: safety and efficacy. 70th Scientific Sessions, American Diabetes Association. Orlando, Florida, USA, 2010. [DOD] 
  57. Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 2007. 14:157-161. [DOD] [CrossRef]
  58. Duvivier-Kali VF, Omer A, Lopez-Avalos MD, O'Neil JJ, Weir GC. Survival of microencapsulated adult pig islets in mice in spite of an antibody response. Am J Transplant 2004. 4:1991-2000. [DOD] [CrossRef]
  59. Suzuki K, Bonner-Weir S, Trivedi N, Yoon KH, Hollister-Lock J, Colton CK, Weir GC. Function and survival of macroencapsulated syngeneic islets transplanted into streptozocin-diabetic mice. Transplantation 1998. 66:21-28. [DOD] [CrossRef]
  60. Tze WJ, Cheung SC, Tai J, Ye H. Assessment of the in vivo function of pig islets encapsulated in uncoated alginate microspheres. Transplant Proc 1998. 30:477-478. [DOD] [CrossRef]
  61. King A, Lau J, Nordin A, Sandler S, Andersson A. The effect of capsule composition in the reversal of hyperglycemia in diabetic mice transplanted with microencapsulated allogeneic islets. Diabetes Technol Ther 2003. 5:653-663. [DOD] [CrossRef]
  62. 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. Eur J Immunol 1993. 23:255-261. [DOD] [CrossRef]
  63. Otterlei M, Ostgaard K, Skjak-Braek G, Smidsrod O, Soon-Shiong P, Espevik T. Induction of cytokine production from human monocytes stimulated with alginate. J Immunother (1991) 1991. 10:286-291. [DOD] [CrossRef]
  64. Lanza RP, Jackson R, Sullivan A, Ringeling J, McGrath C, Kuhtreiber W, Chick WL. Xenotransplantation of cells using biodegradable microcapsules. Transplantation 1999. 67:1105-1111. [DOD] [CrossRef]
  65. Zimmermann U, Thurmer F, Jork A, Weber M, Mimietz S, Hillgartner M, Brunnenmeier F, Zimmermann H, Westphal I, Fuhr G, et al. A novel class of amitogenic alginate microcapsules for long-term immunoisolated transplantation. Ann N Y Acad Sci 2001. 944:199-215. [DOD] [CrossRef]
  66. Sakai S, Ono T, Ijima H, Kawakami K. Modification of porous aminopropyl-silicate microcapsule membrane by electrically-bonded external anionic polymers. J Biomater Sci Polym Ed 2003. 14:643-652. [DOD] [CrossRef]
  67. Zimmermann H, Zimmermann D, Reuss R, Feilen PJ, Manz B, Katsen A, Weber M, Ihmig FR, Ehrhart F, Gessner P, et al. Towards a medically approved technology for alginate-based microcapsules allowing long-term immunoisolated transplantation. J Mater Sci Mater Med 2005. 16:491-501. [DOD] [CrossRef]
  68. Kulseng B, Thu B, Espevik T, Skjak-Braek G. Alginate polylysine microcapsules as immune barrier: permeability of cytokines and immunoglobulins over the capsule membrane. Cell Transplant 1997. 6:387-394. [DOD] [CrossRef]
  69. Morch YA, Donati I, Strand BL, Skjak-Braek G. Effect of Ca2+, Ba2+, and Sr2+ on alginate microbeads. Biomacromolecules 2006. 7:1471-1480. [DOD] [CrossRef]
  70. King A, Sandler S, Andersson A. The effect of host factors and capsule composition on the cellular overgrowth on implanted alginate capsules. J Biomed Mater Res 2001. 57:374-383. [DOD] [CrossRef]
  71. Rokstad AM, Brekke OL, Steinkjer B, Ryan L, Kollarikova G, Strand BL, Skjak-Braek G, Lacik I, Espevik T, Mollnes TE. Alginate microbeads are complement compatible, in contrast to polycation containing microcapsules, as revealed in a human whole blood model. Acta Biomater 2011. 7:2566-2578. [DOD] [CrossRef]
  72. Vandenbossche GM, Bracke ME, Cuvelier CA, Bortier HE, Mareel MM, Remon JP. Host reaction against alginate-polylysine microcapsules containing living cells. J Pharm Pharmacol 1993. 45:121-125. [DOD] [CrossRef]
  73. Juste S, Lessard M, Henley N, Menard M, Halle JP. Effect of poly-L-lysine coating on macrophage activation by alginate-based microcapsules: assessment using a new in vitro method. J Biomed Mater Res A 2005. 72:389-398. [DOD] [CrossRef]
  74. Pueyo ME, Darquy S, Capron F, Reach G. In vitro activation of human macrophages by alginate-polylysine microcapsules. J Biomater Sci Polym Ed 1993. 5:197-203. [DOD] [CrossRef]
  75. Strand BL, Ryan TL, In't Veld P, Kulseng B, Rokstad AM, Skjak-Brek G, Espevik T. Poly-L-Lysine induces fibrosis on alginate microcapsules via the induction of cytokines. Cell Transplant 2001. 10:263-275. [DOD] 
  76. Omer A, Duvivier-Kali V, Fernandes J, Tchipashvili V, Colton CK, Weir GC. Long-term normoglycemia in rats receiving transplants with encapsulated islets. Transplantation 2005. 79:52-58. [DOD] [CrossRef]
  77. Kulseng B, Skjak-Braek G, Ryan L, Andersson A, King A, Faxvaag A, Espevik T. Transplantation of alginate microcapsules: generation of antibodies against alginates and encapsulated porcine islet-like cell clusters. Transplantation 1999. 67:978-984. [DOD] [CrossRef]
  78. De Vos P, De Haan BJ, Wolters GH, Strubbe JH, Van Schilfgaarde R. Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets. Diabetologia 1997. 40:262-270. [DOD] [CrossRef]
  79. Jain K, Asina S, Yang H, Blount ED, Smith BH, Diehl CH, Rubin AL. Glucose control and long-term survival in biobreeding/Worcester rats after intraperitoneal implantation of hydrophilic macrobeads containing porcine islets without immunosuppression. Transplantation 1999. 68:1693-1700. [DOD] [CrossRef]
  80. Iwata H, Takagi T, Amemiya H. Agarose microcapsule applied in islet xenografts (hamster to mouse). Transplant Proc 1992. 24:52. [DOD] 
  81. Yang KC, Qi Z, Wu CC, Shirouza Y, Lin FH, Yanai G, Sumi S. The cytoprotection of chitosan based hydrogels in xenogeneic islet transplantation: An in vivo study in streptozotocin-induced diabetic mouse. Biochem Biophys Res Commun 2010. 393:818-823. [DOD] [CrossRef]
  82. Isayeva IS, Kasibhatla BT, Rosenthal KS, Kennedy JP. Characterization and performance of membranes designed for macroencapsulation/implantation of pancreatic islet cells. Biomaterials 2003. 24:3483-3491. [DOD] [CrossRef]
  83. Jones KS, Sefton MV, Gorczynski RM. In vivo recognition by the host adaptive immune system of microencapsulated xenogeneic cells. Transplantation 2004. 78:1454-1462. [DOD] [CrossRef]
  84. Lhommeau C, Toillon S, Pith T, Kessler L, Jesser C, Pinget M. Polyamide 4,6 membranes for the encapsulation of Langerhans islets: preparation, physico-chemical properties and biocompatibility studies. J Mater Sci Mater Med 1997. 8:163-174. [DOD] [CrossRef]
  85. Qi Z, Yamamoto C, Imori N, Kinukawa A, Yang KC, Yanai G, Ikenoue E, Shen Y, Shirouzu Y, Hiura A, et al. Immunoisolation effect of polyvinyl alcohol (PVA) macroencapsulated islets in type 1 diabetes therapy. Cell Transplant 2012. 21:525-534. [DOD] [CrossRef]
  86. Nadithe V, Mishra D, Bae YH. Poly(ethylene glycol) cross-linked hemoglobin with antioxidant enzymes protects pancreatic islets from hypoxic and free radical stress and extends islet functionality. Biotechnol Bioeng 2012. 109:2392-2401. [DOD] [CrossRef]
  87. Aghajani-Lazarjani H, Vasheghani-Farahani E, Shojaosadati SA, Hashemi-Najafabadi S, Zahediasl S, Tiraihi T, Atyabi F. The effect of two different polyethylene glycol (PEG) derivatives on the immunological response of PEG grafted pancreatic islets. J Artif Organs 2010. 13:218-224. [DOD] [CrossRef]
  88. Sefton MV. The good, the bad and the obvious: 1993 Clemson Award for Basic Research - Keynote Lecture. Biomaterials 1993. 14:1127-1134. [DOD] [CrossRef]
  89. Klomp GF, Ronel SH, Hashiguchi H, D'Andrea M, Dobelle WH. Hydrogels for encapsulation of pancreatic islet cells. Trans Am Soc Artif Intern Organs 1979. 25:74-76. [DOD] [CrossRef]
  90. Kessler L, Pinget M, Aprahamian M, Dejardin P, Damge C. In vitro and in vivo studies of the properties of an artificial membrane for pancreatic islet encapsulation. Horm Metab Res 1991. 23:312-317. [DOD] [CrossRef]
  91. Maki T, Lodge JP, Carretta M, Ohzato H, Borland KM, Sullivan SJ, Staruk J, Muller TE, Solomon BA, Chick WL, et al. Treatment of severe diabetes mellitus for more than one year using a vascularized hybrid artificial pancreas. Transplantation 1993. 55:713-717. [DOD] [CrossRef]
  92. Sun AM, Parisius W, Healy GM, Vacek I, Macmorine HG. The use, in diabetic rats and monkeys, of artificial capillary units containing cultured islets of Langerhans (artificial endocrine pancreas). Diabetes 1977. 26:1136-1139. [DOD] [CrossRef]
  93. Lee SH, Hao E, Savinov AY, Geron I, Strongin AY, Itkin-Ansari P. Human beta-cell precursors mature into functional insulin-producing cells in an immunoisolation device: implications for diabetes cell therapies. Transplantation 2009. 87:983-991. [DOD] [CrossRef]
  94. Sorenby AK, Kumagai-Braesch M, Sharma A, Hultenby KR, Wernerson AM, Tibell AB. Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation: studies in a rodent model. Transplantation 2008. 86:364-366. [DOD] [CrossRef]
  95. Geller RL, Loudovaris T, Neuenfeldt S, Johnson RC, Brauker JH. Use of an immunoisolation device for cell transplantation and tumor immunotherapy. Ann N Y Acad Sci 1997. 831:438-451. [DOD] [CrossRef]
  96. Brauker J, Martinson LA, Young SK, Johnson RC. Local inflammatory response around diffusion chambers containing xenografts. Nonspecific destruction of tissues and decreased local vascularization. Transplantation 1996. 61:1671-1677. [DOD] [CrossRef]
  97. Brauker JH, Carr-Brendel VE, Martinson LA, Crudele J, Johnston WD, Johnson RC. Neovascularization of synthetic membranes directed by membrane microarchitecture. J Biomed Mater Res 1995. 29:1517-1524. [DOD] [CrossRef]
  98. Colton CK. Implantable biohybrid artificial organs. Cell Transplant 1995. 4:415-436. [DOD] [CrossRef]
  99. Scharp DW, Swanson CJ, Olack BJ, Latta PP, Hegre OD, Doherty EJ, Gentile FT, Flavin KS, Ansara MF, Lacy PE. Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects. Diabetes 1994. 43:1167-1170. [DOD] [CrossRef]
  100. Scharp DW, Mason NS, Sparks RE. Islet immuno-isolation: the use of hybrid artificial organs to prevent islet tissue rejection. World J Surg 1984. 8:221-229. [DOD] [CrossRef]
  101. Hoesli CA, Luu M, Piret JM. A novel alginate hollow fiber bioreactor process for cellular therapy applications. Biotechnol Prog 2009. 25:1740-1751. [DOD] 
  102. Silva AI, Mateus M. Development of a polysulfone hollow fiber vascular bio-artificial pancreas device for in vitro studies. J Biotechnol 2009. 139:236-249. [DOD] [CrossRef]
  103. Dulong JL, Legallais C, Darquy S, Reach G. A novel model of solute transport in a hollow-fiber bioartificial pancreas based on a finite element method. Biotechnol Bioeng 2002. 78:576-582. [DOD] [CrossRef]
  104. Zekorn T, Renardy M, Planck H, Zschocke P, Bretzel RG, Siebers U, Federlin K. Experiments on a new hollow fiber membrane for immuno isolated transplantation of islets of Langerhans. Horm Metab Res Suppl 1990. 25:202-206. [DOD] 
  105. Altmah JJ. The bioartificial pancreas: macroencapsulation of insulin secreting cells in hollow fibers. J Diabet Complications 1988. 2:68-74. [DOD] [CrossRef]
  106. Icard P, Penfornis F, Gotheil C, Boillot J, Cornec C, Barrat F, Altman JJ. Tissue reaction to implanted bioartificial pancreas in pigs. Transplant Proc 1990. 22:724-726. [DOD] 
  107. Lanza RP, Borland KM, Staruk JE, Appel MC, Solomon BA, Chick WL. Transplantation of encapsulated canine islets into spontaneously diabetic BB/Wor rats without immunosuppression. Endocrinology 1992. 131:637-642. [DOD] 
  108. Lanza RP, Borland KM, Lodge P, Carretta M, Sullivan SJ, Muller TE, Solomon BA, Maki T, Monaco AP, Chick WL. Treatment of severely diabetic pancreatectomized dogs using a diffusion-based hybrid pancreas. Diabetes 1992. 41:886-889. [DOD] [CrossRef]
  109. Lanza RP, Butler DH, Borland KM, Harvey JM, Faustman DL, Solomon BA, Muller TE, Rupp RG, Maki T, Monaco AP, et al. Successful xenotransplantation of a diffusion-based biohybrid artificial pancreas: a study using canine, bovine, and porcine islets. Transplant Proc 1992. 24:669-671. [DOD] 
  110. Lacy PE, Hegre OD, Gerasimidi-Vazeou A, Gentile FT, Dionne KE. Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 1991. 254:1782-1784. [DOD] [CrossRef]
  111. Prevost P, Flori S, Collier C, Muscat E, Rolland E. Application of AN69 hydrogel to islet encapsulation: evaluation in the streptozotocin-induced diabetic rat model. Transplant Proc 1995. 27:3393-3395. [DOD] 
  112. Rivereau AS, Darquy S, Chaillous L, Maugendre S, Gouin E, Reach G, Sai P. Reversal of diabetes in non-obese diabetic mice by xenografts of porcine islets entrapped in hollow fibres composed of polyacrylonitrile-sodium methallylsulphonate copolymer. Diabetes Metab 1997. 23:205-212. [DOD] 
  113. Schrezenmeir J, Gero L, Laue C, Kirchgessner J, Muller A, Huls A, Passmann R, Hahn HJ, Kunz L, Mueller-Klieser W, et al. The role of oxygen supply in islet transplantation. Transplant Proc 1992. 24:2925-2929. [DOD] 
  114. Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro- and macroencapsulation on oxygen consumption by pancreatic islets. Cell Transplant 2009. 18:195-201. [DOD] [CrossRef]
  115. Storrs R, Dorian R, King SR, Lakey J, Rilo H. Preclinical development of the Islet Sheet. Ann N Y Acad Sci 2001. 944:252-266. [DOD] [CrossRef]
  116. Chick WL, Perna JJ, Lauris V, Low D, Galletti PM, Panol G, Whittemore AD, Like AA, Colton CK, Lysaght MJ. Artificial pancreas using living beta cells:. effects on glucose homeostasis in diabetic rats. Science 1977. 197:780-782. [DOD] [CrossRef]
  117. Whittemore AD, Chick WL, Galletti PM, Mannick JA. Function of hybrid artificial pancreas in diabetic rats. Surg Forum 1977. 28:93-97. [DOD] 
  118. Tatarkiewicz K, Sitarek E, Sabat M, Orlowski T. Long-term culture of non-purified rat islets embedded in hydrogel matrix. Transplant Proc 1996. 28:831-832. [DOD] 
  119. Ohgawara H, Miyazaki J, Karibe S, Katagiri N, Tashiro F, Akaike T. Assessment of pore size of a semipermeable membrane for immunoisolation on xenoimplantation of pancreatic B cells using a diffusion chamber. Transplant Proc 1995. 27:3319-3320. [DOD] 
  120. Kessler L, Aprahamian M, Keipes M, Damge C, Pinget M, Poinsot D. Diffusion properties of an artificial membrane used for Langerhans islets encapsulation: an in vitro test. Biomaterials 1992. 13:44-49. [DOD] [CrossRef]
  121. Whittemore AD, Chick WL, Galletti PM, Like AA, Colton CK, Lysaght MJ, Richardson PD. Effects of the hybrid artificial pancreas in diabetic rats. Trans Am Soc Artif Intern Organs 1977. 23:336-341. [DOD] [CrossRef]
  122. De Vos P, Hillebrands JL, De Haan BJ, Strubbe JH, Van Schilfgaarde R. Efficacy of a prevascularized expanded polytetrafluoroethylene solid support system as a transplantation site for pancreatic islets. Transplantation 1997. 63:824-830. [DOD] [CrossRef]
  123. Juang JH, Bonner-Weir S, Ogawa Y, Vacanti JP, Weir GC. Outcome of subcutaneous islet transplantation improved by polymer device. Transplantation 1996. 61:1557-1561. [DOD] [CrossRef]
  124. Pileggi A, Molano RD, Ricordi C, Zahr E, Collins J, Valdes R, Inverardi L. Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device. Transplantation 2006. 81:1318-1324. [DOD] [CrossRef]
  125. Valdes R, Martin S, Cravioto A, Tenopala J. Biological encapsulation as a new model for preservation of islets of Langerhans. Transplant Proc 1998. 30:481. [DOD] [CrossRef]
  126. Colton CK, Avgoustiniatos ES. Bioengineering in development of the hybrid artificial pancreas. J Biomech Eng 1991. 113:152-170. [DOD] [CrossRef]
  127. Hirotani S, Ohgawara H, Agishi T, Akaike T, Miyazaki S. A bio-artificial endocrine pancreas for the treatment of diabetes. Transplant Proc 1998. 30:485-489. [DOD] [CrossRef]
  128. Andersson A, Eizirik DL, Hellerstrom C, Johnson RC, Pipeleers DG. Morphology of encapsulated human pancreatic islets transplanted into nude mice. Transplant Proc 1994. 26:802-803. [DOD] 
  129. Rafael E, Wernerson A, Arner P, Wu GS, Tibell A. In vivo evaluation of glucose permeability of an immunoisolation device intended for islet transplantation: a novel application of the microdialysis technique. Cell Transplant 1999. 8:317-326. [DOD] 
  130. Rafael E, Wu GS, Hultenby K, Tibell A, Wernerson A. Improved survival of macroencapsulated islets of Langerhans by preimplantation of the immunoisolating device: a morphometric study. Cell Transplant 2003. 12:407-412. [DOD] [CrossRef]
  131. Yakhnenko I, Wong WK, Katkov II, Itkin-Ansari P. Cryopreservation of human insulin expressing cells macro-encapsulated in a durable therapeutic immunoisolating device theracyte. Cryo Letters 2012. 33:518-531. [DOD] 
  132. Kumagai-Braesch M, Jacobson S, Mori H, Jia X, Takahashi T, Wernerson A, Flodstrom-Tullberg M, Tibell A. The TheraCyt device protects against islet allograft rejection in immunized hosts. Cell Transplant 2013. 22:1137-1146. [DOD] [CrossRef]
  133. Borg DJ, Bonifacio E. The use of biomaterials in islet transplantation. Curr Diab Rep 2011. 11:434-444. [DOD] [CrossRef]
  134. Krishnamurthy NV, Gimi B. Encapsulated cell grafts to treat cellular deficiencies and dysfunction. Crit Rev Biomed Eng 2011. 39:473-491. [DOD] [CrossRef]
  135. Khanna O, Larson JC, Moya ML, Opara EC, Brey EM. Generation of alginate microspheres for biomedical applications. J Vis Exp 2012. 66:pii3388. [DOD] 
  136. Zimmermann H, Shirley SG, Zimmermann U. Alginate-based encapsulation of cells: past, present, and future. Curr Diab Rep 2007. 7:314-320. [DOD] [CrossRef]
  137. Fiszman GL, Karara AL, Finocchiaro LM, Glikin GC. A laboratory scale device for microencapsulation of genetically engineered cells into alginate beads. Electron J Biotechnol 2002. 5:23-24. [DOD] 
  138. Sun AM. Microencapsulation of pancreatic islet cells: a bioartificial endocrine pancreas. Methods Enzymol 1988. 137:575-580. [DOD] [CrossRef]
  139. Duvivier-Kali VF, Omer A, Parent RJ, O'Neil JJ, Weir GC. Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane. Diabetes 2001. 50:1698-1705. [DOD] [CrossRef]
  140. Nguyen MK, Lee DS. Injectable biodegradable hydrogels. Macromol Biosci 2010. 10:563-579. [DOD] [CrossRef]
  141. Lee KY, Mooney DJ. Hydrogels for tissue engineering. Chem Rev 2001. 101:1869-1879. [DOD] [CrossRef]
  142. Nicodemus GD, Bryant SJ. Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng Part B Rev 2008. 14:149-165. [DOD] [CrossRef]
  143. De Vos P, Van Straaten JF, Nieuwenhuizen AG, de Groot M, Ploeg RJ, De Haan BJ, Van Schilfgaarde R. Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth? Diabetes 1999. 48:1381-1388. [DOD] 
  144. Xin ZL, Ge SL, Wu XK, Jia YJ, Hu HT. Intracerebral xenotransplantation of semipermeable membrane- encapsuled pancreatic islets. World J Gastroenterol 2005. 11:5714-5717. [DOD] 
  145. Wilson JT, Chaikof EL. Challenges and emerging technologies in the immunoisolation of cells and tissues. Adv Drug Deliv Rev 2008. 60:124-145. [DOD] [CrossRef]
  146. Lee DY, Yang K, Lee S, Chae SY, Kim KW, Lee MK, Han DJ, Byun Y. Optimization of monomethoxy-polyethylene glycol grafting on the pancreatic islet capsules. J Biomed Mater Res 2002. 62:372-377. [DOD] [CrossRef]
  147. Jang JY, Lee DY, Park SJ, Byun Y. Immune reactions of lymphocytes and macrophages against PEG-grafted pancreatic islets. Biomaterials 2004. 25:3663-3669. [DOD] [CrossRef]
  148. Krol S, del Guerra S, Grupillo M, Diaspro A, Gliozzi A, Marchetti P. Multilayer nanoencapsulation. New approach for immune protection of human pancreatic islets. Nano Lett 2006. 6:1933-1939. [DOD] [CrossRef]
  149. Teramura Y, Kaneda Y, Iwata H. Islet-encapsulation in ultra-thin layer-by-layer membranes of poly(vinyl alcohol) anchored to poly(ethylene glycol)-lipids in the cell membrane. Biomaterials 2007. 28:4818-4825. [DOD] [CrossRef]
  150. Khanna O, Moya ML, Opara EC, Brey EM. Synthesis of multilayered alginate microcapsules for the sustained release of fibroblast growth factor-1. J Biomed Mater Res A 2010. 95:632-640. [DOD] [CrossRef]
  151. Teramura Y, Iwata H. Improvement of graft survival by surface modification with poly(ethylene glycol)-lipid and urokinase in intraportal islet transplantation. Transplantation 2011. 91:271-278. [DOD] [CrossRef]
  152. Baruch L, Benny O, Gilert A, Ukobnik M, Ben Itzhak O, Machluf M. Alginate-PLL cell encapsulation system Co-entrapping PLGA-microspheres for the continuous release of anti-inflammatory drugs. Biomed Microdevices 2009. 11:1103-1113. [DOD] [CrossRef]
  153. Campo GM, Avenoso A, Campo S, D'Ascola A, Traina P, Sama D, Calatroni A. Glycosaminoglycans modulate inflammation and apoptosis in LPS-treated chondrocytes. J Cell Biochem 2009. 106:83-92. [DOD] [CrossRef]
  154. Leung A, Lawrie G, Nielsen LK, Trau M. Synthesis and characterization of alginate/poly-L-ornithine/alginate microcapsules for local immunosuppression. J Microencapsul 2008. 25:387-398. [DOD] [CrossRef]
  155. Senzolo M, Coppell J, Cholongitas E, Riddell A, Triantos CK, Perry D, Burroughs AK. The effects of glycosaminoglycans on coagulation: a thromboelastographic study. Blood Coagul Fibrinolysis 2007. 18:227-236. [DOD] [CrossRef]
  156. Bunger CM, Tiefenbach B, Jahnke A, Gerlach C, Freier T, Schmitz KP, Hopt UT, Schareck W, Klar E, de Vos P. Deletion of the tissue response against alginate-pll capsules by temporary release of co-encapsulated steroids. Biomaterials 2005. 26:2353-2360. [DOD] [CrossRef]
  157. Pedraza E, Coronel MM, Fraker CA, Ricordi C, Stabler CL. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc Natl Acad Sci U S A 2012. 109:4245-4250. [DOD] [CrossRef]
  158. Mansouri S, Merhi Y, Winnik FM, Tabrizian M. Investigation of layer-by-layer assembly of polyelectrolytes on fully functional human red blood cells in suspension for attenuated immune response. Biomacromolecules 2011. 12:585-592. [DOD] [CrossRef]
  159. Pickup JC, Zhi ZL, Khan F, Saxl T, Birch DJ. Nanomedicine and its potential in diabetes research and practice. Diabetes Metab Res Rev 2008. 24:604-610. [DOD] [CrossRef]
  160. Wilson JT, Cui W, Chaikof EL. Layer-by-layer assembly of a conformal nanothin PEG coating for intraportal islet transplantation. Nano Lett 2008. 8:1940-1948. [DOD] [CrossRef]
  161. Luan NM, Teramura Y, Iwata H. Layer-by-layer co-immobilization of soluble complement receptor 1 and heparin on islets. Biomaterials 2011. 32:6487-6492. [DOD] [CrossRef]
  162. Tatsumi K, Ohashi K, Teramura Y, Utoh R, Kanegae K, Watanabe N, Mukobata S, Nakayama M, Iwata H, Okano T. The non-invasive cell surface modification of hepatocytes with PEG-lipid derivatives. Biomaterials 2012. 33:821-828. [DOD] [CrossRef]
  163. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008. 26:443-452. [DOD] [CrossRef]
  164. Matveyenko AV, Georgia S, Bhushan A, Butler PC. Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats. Am J Physiol Endocrinol Metab 2010. 299:E713-E720. [DOD] [CrossRef]
  165. Candiello J, Singh SS, Task K, Kumta PN, Banerjee I. Early differentiation patterning of mouse embryonic stem cells in response to variations in alginate substrate stiffness. J Biol Eng 2013. 7:9. [DOD] [CrossRef]
  166. Kadam S, Muthyala S, Nair P, Bhonde R. Human placenta-derived mesenchymal stem cells and islet-like cell clusters generated from these cells as a novel source for stem cell therapy in diabetes. Rev Diabet Stud 2010. 7:168-182. [DOD] [CrossRef]
  167. Ngoc PK, Phuc PV, Nhung TH, Thuy DT, Nguyet NT. Improving the efficacy of type 1 diabetes therapy by transplantation of immunoisolated insulin-producing cells. Hum Cell 2011. 24:86-95. [DOD] [CrossRef]
  168. Davis NE, Beenken-Rothkopf LN, Mirsoian A, Kojic N, Kaplan DL, Barron AE, Fontaine MJ. Enhanced function of pancreatic islets co-encapsulated with ECM proteins and mesenchymal stromal cells in a silk hydrogel. Biomaterials 2012. 33:6691-6697. [DOD] [CrossRef]
  169. Chandra V, Swetha G, Muthyala S, Jaiswal AK, Bellare JR, Nair PD, Bhonde RR. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. Plos One 2011. 6:e20615. [DOD] [CrossRef]
  170. Mason MN, Mahoney MJ. Selective beta-cell differentiation of dissociated embryonic pancreatic precursor cells cultured in synthetic polyethylene glycol hydrogels. Tissue Eng Part A 2009. 15:1343-1352. [DOD] [CrossRef]
  171. Zhu FF, Zhang PB, Zhang DH, Sui X, Yin M, Xiang TT, Shi Y, Ding MX, Deng H. Generation of pancreatic insulin-producing cells from rhesus monkey induced pluripotent stem cells. Diabetologia 2011. 54:2325-2336. [DOD] [CrossRef]
  172. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, Leibel RL, Melton DA. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A 2009. 106:15768-15773. [DOD] [CrossRef]
  173. Tateishi K, He J, Taranova O, Liang G, D'Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 2008. 283:31601-31607. [DOD] [CrossRef]
  174. Lysy PA, Weir GC, Bonner-Weir S. Concise review: pancreas regeneration: recent advances and perspectives. Stem Cells Transl Med 2012. 1:150-159. [DOD] [CrossRef]
  175. Blyszczuk P, Czyz J, Kania G, Wagner M, Roll U, St-Onge L, Wobus AM. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci U S A 2003. 100:998-1003. [DOD] [CrossRef]
  176. Korsgren O, Nilsson B. Improving islet transplantation: a road map for a widespread application for the cure of persons with type I diabetes. Curr Opin Organ Transplant 2009. 14:683-687. [DOD] [CrossRef]
  177. Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud 2011. 8(1):6-16. [DOD] [CrossRef]
  178. Shapiro JA. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev Diabet Stud 2012. 9(4):385-406. [DOD] [CrossRef]
  179. Vaithilingam V, Oberholzer J, Guillemin GJ, Tuch BE. The humanized NOD/SCID mouse as a preclinical model to study the fate of encapsulated human islets. Rev Diabet Stud 2010. 7(1):62-73. [DOD] [CrossRef]
  180. Vaithilingam V, Tuch BE. Islet transplantation and encapsulation: an update on recent developments. Rev Diabet Stud 2011. 8(1):51-67. [DOD] [CrossRef]
  181. Parkinson J. Developing a comprehensive system to protect islet cells and deliver transplants to all with insulin dependence. 2012. Accessed July 30, 2013. [DOD] 
  182. Hanuman Medical Foundation. An Example of Academic Research Presented as A Path to the Cure. 2009. Accessed July 30, 2013. [DOD] 
  183. Mao GH, Chen GA, Bai HY, Song TR, Wang YX. The reversal of hyperglycaemia in diabetic mice using PLGA scaffolds seeded with islet-like cells derived from human embryonic stem cells. Biomaterials 2009. 30:1706-1714. [DOD] [CrossRef]

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