Design of Bioartificial Pancreas with Functional Micro/Nano-Based ...

Send Orders for Reprints to [email protected] Current Pharmaceutical Biotechnology, 2014, 15, 000-000

1

Design of Bioartificial Pancreas with Functional Micro/Nano-Based Encapsulation of Islets Burcu Kepsutlu1, Caner Nazli2, Tugba Bal1 and Seda Kizilel1,2* 1

Koç University, Chemical and Biological Engineering, Istanbul, 34450, Turkey; 2Koç University, Materials Science and Engineering, Istanbul, 34450, Turkey Abstract: Type I diabetes mellitus (TIDM), a devastating health issue in all over the world, has been treated by successful transplantation of insulin secreting pancreatic islets. However, serious limitations such as the requirement of immunosuppressive drugs for recipient patients, side effects as a result of long-term use of drugs, and reduced functionality of islets at the transplantation site remain. Bioartificial pancreas that includes islets encapsulated within semi-permeable membrane has been considered as a promising approach to address these requirements. Many studies have focused on micro or nanobased islet immunoisolation systems and tested the efficacy of encapsulated islets using in vitro and in vivo platforms. In this review, we address current progress and obstacles for the development of a bioartificial pancreas using micro/nanobased systems for encapsulation of islets.

Keywords: Bioartificial pancreas, islet encapsulation, type I diabetes mellitus, immunoisolation, islet transplantation, micro/ nano-based encapsulation. INTRODUCTION Diabetes mellitus is an overwhelming health problem in the worldwide with numerous patients and immense costs [1, 2]. Currently, number of diabetics is approximately 171 million and World Health Organization (WHO) estimates that this number will double by 2030 [3]. According to International Diabetes Federation, the cost of treatment of this disease has reached $465 billion per year, with an increased annual global incidence rate of ~3% [4, 5]. Long term complications such as renal, cardiovascular, neural, ophthalmic problems, extensive morbidity rate for patients, and cost associated with the treatment are motivations for many researchers to work for the treatment of diabetes mellitus [6]. Among the treatment options, insulin therapy and pancreas transplantation have been clinically used techniques, while islet transplantation has been still considered as an experimental approach. Insulin therapy provides exogenous insulin uptake for a fair blood glucose control [7], where islet transplantation aims to replace missing beta cell function. Islet transplantation has the potential to maintain normoglycemia without the requirement of an invasive surgery [8, 9], while pancreas transplantation eliminates exogenous insulin uptake for 80% of patients through an invasive operation [9, 10]. The basic advantage of islet transplantation over whole pancreas transplantation is the possibility to avoid immunosuppressive drug uptake, through an efficient design of immunoprotective coating of islets before transplantation [11, 12]. Coating also opens up the possibility of implantation of islets into alternative sites and transplantation with xenogenic *Address correspondence to this author at the Koç University, Materials Science and Engineering, Istanbul, 34450, Turkey; Tel:/Fax: +90-212-3381548; E-mail: [email protected] 1389-2010/14 $58.00+.00

cell sources to address the limited number of donors [13, 14]. Transplantation of islets is still not the best solution for TIDM due to several limitations, such as difficulty for finding pancreatic tissue donor, requirement for life long use and deleterious effects of immunosuppressive drugs on beta cells and the immune system of the host, post-operative complications, and high expense of the method [10, 15-18]. In this paper, recent progress for the successful development of a bioartificial pancreas based on micro/nano encapsulation strategies have been reviewed and novel immunoisolation approaches to move this technology forward are discussed in detail. TREATMENT OPTIONS FOR DIABETES One of the treatment approaches for diabetes is insulin therapy (Fig. 1) [19]. Insulin therapy is applied through multiple daily injections, where patients need three or more injections per day [20]. However, insulin therapy is not sufficient to provide normoglycemia since exogenous insulin cannot fully mimic endogenous insulin [19, 21]. It may also lead to insulin resistance and severe hypoglycemia [22, 23]. Day-to-day variability of insulin requirements, fluctuating absorption profiles of insulin, the daily burden of multiple insulin injections or diet adjustments based on finger stick blood glucose determinations complicate insulin therapy [9, 24]. In addition, patients must receive lifelong education about blood glucose to keep their blood glucose levels in the targeted range [20, 25]. New combinations of insulin analogues, introduction of insulin pumps and improved home blood glucose monitoring devices may relieve the drawbacks associated with insulin therapy [19, 21, 24, 26-29]. The other approach to control blood glucose levels is the use of mechanical insulin pumps which can be applied sub© 2014 Bentham Science Publishers

2 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 6

Kepsutlu et al.

Fig. (1). Treatment options for TIDM.

cutaneously. In this therapy, exogenous insulin is delivered into the body with an insulin pump instead of syringes or pens to mimic physiological insulin release [30, 31]. The mechanical pump provides advantages over multiple injections such as overnight glycemic control, ease of administration, reduced timing and concerns about the amounts of food intake, adjustable insulin delivery pattern and achievement of basal rate [20, 30, 32]. However, the drawbacks of pumps are associated with infection at the insertion site, ketoacidosis, unexpected insulin swings, and hypoglycemia [31, 33, 34]. Moreover, patients have to carry an external pump, which may not be very convenient. Even though there exists some implantable insulin pumps, there is a possibility of formation of undesirable coating of the catheter with fibrin clots [34]. Another strategy used to control blood glucose level involves pancreas transplantation [15, 35]. Pancreas transplantation provides long term insulin independence to patients who cannot maintain normoglycemia with insulin therapy or do not want to continue a tight diet and multiple injections [36]. The International Pancreas Transplant Registry reported 95% patient survival rate between 1996-2008 for the first year, where patient survival and graft function increased after 2011 [37, 38]. Pancreas transplantation is heavily invasive and carries the highest risk of surgical complications among transplanted solid organs due to the intense immunosuppression requirement, multiple vascular and enteric anatomoses [36, 37]. The surgical complication incidence associated with pancreas transplantation is over 20 % and diabetes mellitus reoccurs in 17% of patients 5 years after transplantation [39].

Transplantation of insulin secreting islets to diabetic patients has also been developed to manage blood glucose level. The idea of transplantation of pancreatic islets was improved with Edmonton protocol for islet isolation from a guinea pig [40, 41]. Between 1960 and 1980, various clinical and animal trials of islet transplantation were performed [4144]. Since then, the success of autograft islet transplantation increased and the purity of islets was improved [45-47]. This approach allowed transplantation of well characterized, viable islets with steroid free immunosuppression [48]; however, it was still a challenge to maintain long term insulin independence [48-52]. With the progress of new immunosuppression regimens and islet isolation protocol, one-year insulin independence rate was raised to 65% by 2012 [53-56]. IMMUNOISOLATION OF ISLETS Immune rejection is still an unsolved problem of islet transplantation, although immunosuppressive agents continually evolve [57]. Hindering transplanted cells from the immune system is a must to keep transplanted cells viable and functional [58-61]. For this reason, immunoisolation is applied to coat or hide metabolically active cells within a selectively permeable membrane barrier [58, 59]. Common to various immunoisolation designs are a permselective membrane, an internal matrix and living cells [59]. These barriers constructed with either natural or synthetic materials differ in size over several orders of magnitude from small spheres, with a volume of 10-5 cm3, to large extracorporeal tools with a net volume of 10 cm3 [58]. Further, these immunoisolation systems are classified into two groups:

Design of Bioartificial Pancreas with Functional Micro/Nano-Based Encapsulation

Vascular devices and nonvascular devices [58]. Vascular devices, which can interact with blood require the use of an anticoagulant agent to prevent thrombosis. Nonvascular devices in the form of spherical microcapsules or larger polymeric macrocapsules are designed for transplantation into body cavities [59]. Macrocapsules can be fabricated as sealed cylindrical hollow fibers, flat sheet, and planar devices with one order of magnitude below 1 mm to maximize bidirectional diffusion of nutrients and cellular therapeutics. Spherical microcapsules are made of synthetic or natural polymers such as sodium alginate, poly-L-lysine (PLL), agarose, poly(ethylene glycol) (PEG), chitosan, and multilayered glycol chitosan-alginate complexes [58]. Even though macrocapsules have better mechanical strength and chemical stability than microcapsules, a large volume of the macrocapsules hinders mass transport and may cause a decrease in viability of encapsulated cells [59]. The first immunobarrier membrane for islets was employed in 1977 by Chick et al. in the form of hollow tubes from a semi-permeable acrylic copolymer [62]. Later, perm-selective microcapsules were made of alginate, PLL and poly (ethylene imine) were preferred for islet immunoisolation to overcome aforementioned limitations of macrocapsules [57]. Host Response to Materials Immune rejection is the main host reaction against cellular therapeutics such as allogenic, xenogenic or ex vivo modified autologous cells [63]. Insertion of a biomaterial into the body triggers a foreign body reaction which induces nonspecific adsorption of various proteins onto the surface of transplanted materials in native or denatured conformations, followed by migration of monocytes, leukocytes and platelets to the implant surface [64]. After activation of macrophages, biomaterial surface is exposed to cytokines, growth factors, proteolytic enzymes, and reactive oxygen and nitrogen intermediates secreted by macrophages. Leukocytes (neutrophils and monocytes) accumulate around the transplanted biomaterials during inflammation reaction. Granulation tissue grows via proliferation of fibroblasts and vascular endothelial cells around implant after the reaction with monocytes and macrophages. This new tissue consists of new small vessels and fibroblasts. Macrophages which adhere to the surface of the biomaterial change into foreign body giant cells with great number of nuclei. Final phase of immune response to biomaterials is the main fibrous capsule formation that surrounds implants and triggers severe complications [63-65]. Natural and Synthetic Materials for Islet Immunoisolation Biomaterials have been exploited as medical implants for at least 2000 years, but most of the transplanted materials broke down due to biological issues such as infection and biological reaction to the materials [64]. The properties of biomaterials such as chemical, toxicological, physical and mechanical features should be appropriate for therapeutic purposes, human health, and device performance [59, 60, 65]. The immunoisolation barrier must be biocompatible and inert to eliminate material toxicity and to inhibit host response [66]. Immunoisolation barriers are designed semipermeable, since transplanted cells can only survive if the influx and efflux rate of desired molecules such as nutrients, oxygen,

Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 6

3

therapeutic products and cellular waste are sufficiently controlled [67]. Since the purpose of islet transplantation is to recover a patient’s insulin secreting ability, transplanted islets must allow for the transport of synthesized insulin into the body. This insulin secretion could be achieved through appropriate design of membrane pore size which will also be important to prevent the diffusion of components of the immune system (Fig. 2) [58, 59, 67, 68]. Furthermore, immunoisolation barrier must withstand mechanical and osmotic stress conditions in physiological environment [69]. In their natural environment, cells are covered within extracellular matrix (ECM) which contains extracellular proteins and polysaccharides [60]. The complicated interactions between islet cells and ECM contribute to healthy development, homeostasis, and regeneration after injury or stress [70]. It can be asserted that mimicking natural environment for transplanted islets is indispensable to produce long-term viable and functional islets. In order to mimic natural ECM, various approaches have been used such as extracted biological matrix, basement proteins, short biofunctional peptide fragments, glycosaminoglycans and cell-modulating factors to improve islet function [70]. Usually, materials that are used for encapsulation of islets are in the form of hydrogel due to large hydration capability of hydrogels and similarity of those gels to the native ECM. Natural and synthetic materials (Tables 1 and 2) in the form of cross-linked structures are exploited to provide immunoisolation barriers for islets [68].

Fig. (2). Schematic illustration of islet immunoisolation.

Natural Materials Alginate, anionic polysaccharide from seaweed, has been widely studied as immunoisolation barrier due to its biocompatibility [57, 60]. Alginate-based immunobarriers have been employed in clinical trials for the treatment of TIDM [71]. Molecules of this polysaccharide (chains of mannuronic acid (M) and guluronic acid (G)) show specific binding to multivalent cations such as calcium and magnesium that induce cross-linking of alginate [71]. These electrostatically crosslinked alginate-based immunoisolation coatings do not hinder cellular function of islets; however, there exists various concerns about the interaction of alginate with cells and its mechanical stability. For example, binding of alginate to a negatively charged cellular surface is restricted due to the


Table 1.

Material

Natural materials used for the design of immunoisolation barrier. Chemical structure

Kepsutlu et al.

collagen, the material showed significant potential as an immunoisolation barrier due to the minimized harm to islets during encapsulation and homogenous coatings around islet spheroids (Fig. 3) [74]. These coated islet spheroids sustained glucose level below 200 mg/dL for 4 weeks after implantation into the intraperitoneal cavity of mice [74]. Table 2.

Alginate

Synthetic materials used for the design of immunoisolation barrier.

Material

Chemistry

PEG

Agarose

Poly (N,Ndimethyl acrylamide)

Hydroxymethylated Polysulfone Chitosan

Poly(vinyl alcohol) (PVA)

Copolymer of D,L-lactide and glycolide (PLG) Collagen

or Polyurethane

negative charge of alginate [72]. Also alginate-polycation systems such as PLL, poly (ethylene imine), poly-Lornithine (PLO), poly-D-lysine, chitosan and poly (methylene-co-guanidine) are employed to overcome limited mechanical stability issue [72]. Lim and Sun produced alginatePLL immunobarrier with poly (ethylene imine) for islet transplantation into rats; however, alginate capsule resulted in foreign body reaction after 2-3 weeks [43]. Similarly, P. de Vos and his colleagues investigated physicochemical changes of alginate-polylysine beads in vivo, where they observed that alginate-polylysine bead was subjected to crucial physicochemical alteration, and that these changes activated immune system [73]. When alginate was used with

Agarose is another type of polysaccharide extracted from seaweed. Due to its thermosensitivity, this natural polymer has been employed for coating of islets within temperature ranges of 15-30°C [57]. Kobayashi et al. investigated immunocamuflage properties of agarose microcapsules of 100 to 400 µm in diameter (Fig. 4). The authors did not observe mononuclear cellular infiltration for more than 3 months, where efficient blood glucose could be achieved in diabetic mice that received agarose encapsulated islets [75]. However, agarose could not provide long-term immunoisolation property in physiological conditions, as was observed in another study [60]. Modification with polystyrene sulfonic acid, polybrene, carboxymethyl cellulose and combination with biological cues such as soluble domain of human complement receptor 1 were proposed as better alternatives to unmodified agarose [76, 77].



5

Fig. (3). Morphology of collagen-alginate composite coated islet spheroids: Light microscopy image of islet spheroids (a) and fluorescent microscopy images of islet spheroids (b) in 300 µm concave molds after culturing of 2 weeks. Scale bars=150 µm. A SEM image of islet spheroid (c) on day 14. Scale bar=10 µm. Top (d) and side (e) views of alginate-encapsulated spheroids separated from the concave mold. Scale bar=150 and 75 µm, respectively. (Adapted with permission from Lee, Hwang et al. 2012. Copyright 2012, Elsevier).

biocompatibility, biodegradability and natural ability to attach cells [67]. Collagen in the form of crosslinked gel has been preferred for cell encapsulation, as crosslinked form of collagen can function as a cage to retain cells [80]. Although collagen gels demonstrate lower mechanical strength, it allows reinforcement with other materials and these properties makes it an attractive tool for various devices [81]. Synthetic Materials

Fig. (4). Light microscopy image of agarose microencapsulated islets. Scale bar= 100 µm. (Adapted with permission from Kobayashi, Aomatsu et al. 2003. Copyright 2003, Wolters, Kluwer Health).

Chitin, a natural polymer, located in the shells of crustaceans and insects, is an appropriate material for biomedical applications due to its biocompatibility and easy handling. Chitin contains N-acetyl-glucosamine and N-glucosamine units, and when N-acetyl-glucosamine part becomes dominant in the structure, the polymer is named as chitosan. Chitosan is synthesized via deacetylation of chitin [57, 78]. Cross-linked chitosan has been extensively employed in diverse areas such as wound healing, plastic surgery, dental implants and islet encapsulation [60]. For example, Yang et al. encapsulated rat islets within chitosan microcapsules for immunoprotection of islets. Histological examinations demonstrated that grafted chitosan hydrogel coated islets at the renal space of mouse could secrete insulin, and that chitosan hydrogel coating could protect islets from immune cell attack for about 4 weeks (Fig. 5) [79]. Collagen is another commonly used natural polymer that is widely found in mammalian connective tissues [67]. It is extensively exploited in biomedical applications due to its

PEG is an FDA approved and commonly used synthetic material with well-known biocompatibility and low-toxicity. This polymer has extensive use in biomaterials, biotechnology, and medicine, and has exceptional features such as its linearity, non-ionic structure and hydrophilicity [82, 83]. PEG has minimum surface energy in water and due to this minimum interfacial energy, protein adhesion on PEGylated surfaces could be significantly reduced and non-specific interactions between PEG and proteins could be eliminated [83]. Due to these unique properties, PEG has also been considered for coating of insulin secreting islets and for improving the functionality of islets [84]. In one such studies, Kizilel et al. demonstrated that an insulinotropic ligand, glucagon-like peptide-1 (GLP-1), conjugated to PEG polymer could enhance viability and functionality of islets when covalently bound to pancreatic islets (Fig. 6) [84]. In addition, Lee et al. applied multiple layers of PEG coating of islets and observed that immune rejection could be delayed for 100 days in diabetic patients [85]. Long-term stability of PEGbased barrier could be achieved through synthesis of crosslinked PEG hydrogels around cells and this strategy has been used in previous studies. Photopolymerized PEG hydrogels around pancreatic islets have been observed to provide immunoprotection by limiting diffusion of immune system components through the hydrogel without compromising the function of encapsulated islets [86]. For instance, Cruise et al. coated pancreatic islets within PEG hydrogel using interfacial photopolymerization and showed that PEG hydrogel coating works as an effective immunoisolation barrier to


Kepsutlu et al.

Fig. (5). The histological studies of chitosan hydrogel encapsulated islets. The histologic sections of islets/hydrogel group show that (a) the islets were transplanted at the renal subcapsule space of mouse (The sections were stained with hematoxylin and eosin, 40×). (b) Immunohistochemical staining shows that the islets had positive insulin staining (red color, immunostain of insulin, 100×). Sections stained with antibody specific to immune cells show there was no immune cell infiltration or accumulation. (c) Negative of CD3+ T-cell lineages (40×), (d) Nor of CD68+ monocyte/macrophages (100×). (Adapted with permission from Yang, Qi et al. 2010. Copyright 2010, Elsevier).

exclude large molecules or immune cells, while allowing islets to respond to dynamic or static changes in glucose concentration by producing insulin [87, 88]. However, encapsulation of islets within nonfunctionalized PEG hydrogel is not sufficient for long-term islet viability and functionality. Hence, studies considered incorporating insulinotropic peptides such as GLP-1 and islet basal membrane derived proteins such as collagen and laminin into the gel network to enhance the function and survival of islets [89, 90]. Cross-linked poly (vinyl alcohol) (PVA) foam has also been considered as a synthetic matrix for encapsulation of islets or other cells due to low protein binding tendency, high water content and elasticity [60, 91]. Bulk encapsulation of islets in PVA hydrogel sustained normoglycemia in diabetic rats for 12 days [92]. Teramura et al. developed multilayers of PVA coating of islets through maleimide-PEG–lipid anchoring on cell membrane surface. The authors obtained ultra-thin layers of PVA around islets, and still maintained islet survival and function [93]. Another example of PVA encapsulated islets was developed by Qi et al., where the authors macroencapsulated islets within PVA and observed successful allotransplantation of PVA encapsulated islets without administration of immunosuppressive drugs. It was also reported that insulin positive islets were still present during week 4, at post transplantation and that the body weight loss was minimized in the recipients of PVA coated islet group [91]. Synthetic biodegradable copolymer of D,L-lactide and glycolide (PLG) has been considered as alternative polymer to generate 3D coating around islets [94]. This FDA approved polymer can be designed to degrade with time- rang-

ing from few weeks up to one year, where scaffolds of PLG can be considered to function as a platform for extra-hepatic islet cell transplantation. To test this hypothesis, Blomeier et al. used PLG microporous scaffold to reduce islet loss at the transplantation site due to limited blood flow. The authors observed that those islet implants were revascularized due to degradable PLG scaffold, and were found as insulin positive for 2-4 weeks [94]. Moreover, Gibly et al. designed PLG microporous scaffolds to improve cell infiltration and to provide revascularization of islets with minimum amount immune response [95]. Poly(N,N-dimethyl acrylamide) (PNNDA) synthetic hydrogels have also been considered as potential scaffolds in tissue engineering due to desirable mechanical stability, preservation of integrity during transplantation, and permeability to nutrients and oxygen with controllable pore size [96, 97]. These attractive properties have been found useful for islets macroencapsulated within PNNDA, where they remained viable and functional for about 45 days [97]. Further, modification of PNNDA with polydimethylsiloxane (PDMS) was considered to protect islets from immune attack without any prevascularization strategy or immunosuppressive therapy, where normoglycemia up to 3 weeks in pancreatectomized canines was observed [98]. Polysulfonate is another synthetic polymer that has been considered for islet encapsulation. Hydroxymethylated polysulfonate capillaries were designed by Lembert et al. for vascular tissue formation [99]. It was observed that the capillaries provided vascular growth without interfering insulin release kinetics [11, 57, 100, 101].



7

has to be adjusted among distinct membrane features to promote islet cell viability with desirable insulin secretion function in response to glucose [104]. Natural or synthetic polymers discussed above have been considered for micro-, macro-, or nano-encapsulation of pancreatic islets (Fig. 7). In addition, cellular coating has been considered as an approach to replace polymeric coating of islets. Below, these strategies have been discussed in detail.

Fig. (6). Differential interference contrast microscopy images of (a) untreated islets and (b) islets that were coated with biotin-PEGNHS/SA/biotin-PEG-GLP-1. Scale bar=200 µm. (Adapted with permission from Kizilel et al., 2010. Copyright© 2010, Mary Ann Liebert, Inc). Fig. (7). Islet encapsulation strategies for immunoisolation.

Polyurethane synthetic polymer has high strength, optically transparent and nonporous structure [102]. Dense polyurethane membranes were exploited as potential immunoisolation barrier for islets. However, significant success was not observed due to retention of molecules within the polymer. Modification of polyurethane through polytetramethylene glycol and butanediol improved biocompatibility, permeability to glucose and insulin, while islets were protected against the attack of immune system [103]. Strategies Used for Islet Encapsulation The idea of encapsulation of cells within natural or synthetic 3D scaffolds involves enclosure of viable cells or tissues within semi-permeable membranes [104]. These scaffold networks should allow for the diffusion of nutrients, oxygen and cellular waste while preventing the interaction with immune system constituents [105-107]. Encapsulation has been not only been considered for immunoisolation purposes, but can also be used to enhance cell viability and function using biomaterials at various geometries. However, for the condition of islet encapsulation, an optimal balance

Macroencapsulation involves placing of groups of islets within a selectively permeable membrane which can be designed as an intravascular or extravascular macrocapsule [105, 107, 108]. Intravascular macrocapsules refer to microporous or nanoporous perifusion chamber that is directly connected to a vein, where extravascular macrocapsules are prepared as a tube or sphere to function as a flow hollow. The inner diameter of the hollow alters from 0.5 mm to 1.5 mm, where the axial length ranges between 1 and 10 cm [86]. Qi et al. used PVA macrocapsules for transplantation of rat islets into the peritoneal cavity of C57BL/6 mouse. Although there has been decrease in insulin secretion capacity after freeze-thawing, islets encapsulated within PVA hydrogels supplemented with Euro-Collins solution (a cryoprotective solution) demonstrated comparable functionality with free islets and hyperglycemia was reversed in diabetic mice within 4 weeks [106]. The design of a bioartificial pancreas through the use of macroencapsulation approach may provide better durability than those prepared via microencapsulation. Since macroencapsulated islets can be implanted within peritoneal cavity or subcutaneous site, macroencapsu-


lation allows for the recovery of the graft with minimal surgical risk [86, 106, 109, 110]. The disadvantage of this approach is related to the large sizes of these constructs, where thick hollow platform and large capsule diameter limit the diffusion of physiologically important molecules, resulting in reduced viability and delayed insulin secretion in response to glucose [105]. Microencapsulation refers to the encapsulation of individual or few islets in a spherical capsule, where the diameter ranges between 0.02-1.5 mm [100, 104]. Various techniques have employed microencapsulation of islets using photopolymerization, double emulsion, micro-machined nanoporous microsystems and electrified coaxial liquid jets techniques [100, 104]. Soon after the first report of islet microencapsulation by Lim and Sum in 1980, scientists recognized the possibility of application of this strategy for the treatment of TIDM [111]. In the following years, various natural and synthetic materials were considered to design bioartificial pancreas in vitro or in vivo. Those studies mainly focused on elimination of immune suppression requirement with islet transplantation, and improving function and viability through vascularization of constructs [112-116]. Microencapsulation approach has various advantages compared to the other immunoisolation techniques. It results in the formation of capsules with bigger surface to volume ratio that allows relatively high diffusion rates of oxygen, insulin, nutrients and wastes simple transplantation, and retrieval of capsules [12]. The diameter of microcapsules should range between 300-400 µm in order to obtain desirable permeability property [100, 117, 118]. The microstructures have been designed to improve insulin secretion capability and to limit the diffusion of immune system components. For example, insulinotropic agents such as hypoglycemic drugs or GLP-1 have been used within the capsule to improve insulin secretion functionality of encapsulated islets [96]. In addition, high oxygenation approach was exploited via hemoglobin

Kepsutlu et al.

(Hb) to promote islet viability and functionality. Kim et al. designed a rechargeable bioartificial pancreas system that included thermoreversible polymeric ECM as an immunoisolation barrier with insulinotropic agents and oxygen transporting molecules [96]. Microcapsules with Hb could improve insulin secretion and viability of islets as well as resulted in euglycemia for about 8 weeks in diabetic mice. Recently, Ma et al. proposed alginate-based microencapsulated islets with core-shell structure using droplet generator under electrostatic force [119]. Fig. (8) demonstrates that uniform core-shell microcapsules of islets could be obtained with this approach, and that these islets provided glycemic control for about 80 days after transplantation into diabetic mice [119]. The main limitation of macro and microencapsulation strategies is related to the total size of the tissue to be implanted to cure a diabetic patient. In order to reduce total graft volume and to improve glucose response time, nanothin coating strategies have been developed [57]. Krol et al. employed a multilayered nano-capsule for islet encapsulation through layer-by-layer self-assembly of polycations and polyanions on islet surface [120]. Even though it is possible to minimize the coating thicknesses through various microencapsulation strategies, the total volume of the encapsulated islets to be transplanted limits transplantation into the clinically preferred sites such as portal vein of the liver. To address this limitation of volume increase, Wilson et al. encapsulated individual islets within nano-thin membrane via layer-by-layer self-assembly of PLLg-PEG-biotin (PPB) and streptavidin (SA) (Fig. 9). The nano-thin coating did not compromise the viability, where islets in a multilayered nano-thin coating had similar survival rate and function compared to untreated islets [121]. Coating of islets within living cells have also been considered for binding of specific type of cells onto islet surface. Teramura et al. used cellular based coating approach through

Fig. (8). Alginate-based microencapsulated islets: Comparison of islets encapsulated in (a) regular capsules and (b-e) core–shell capsules. (c-e) 3D reconstructed confocal fluorescent images of islets encapsulated in core–shell capsules. The islets were stained blue, while the shell was labeled green. Scale bar=500 µm for a-b and e. Scale bar= 100 µm for c-d (Adapted with permission from Ma, Chiu et al. 2013. Copyright 2013 John Wiley and Sons).



9

Fig. (9). Nanothin membrane coated islets: (a) Islets incubated with PPB for 15 min and subsequently modified with Cy3-labeled streptavidin (Cy3-SA) showed fluorescent emission around the islet periphery. Islets incubated in only Cy3-SA demonstrated no fluorescent signal (b), and treatment of islets with nonmodified PLL prior to Cy3-SA resulted in discontinuous, concentrated domains of fluorescent emission (c). Scale bars = 50 µm. (Adapted with permission from Wilson, Cui et al. 2008. Copyright 2008, American Chemical Society).

biotin-streptavidin interaction, where HEK293 cells were immobilized on islet surfaces [122]. Fig. (10) demonstrates completely surrounded pancreatic islets within HEK293 cells after 5 days in culture. The authors also developed cellular based encapsulation of islets using PEG-conjugated phospholipid derivative and DNA hybridization approach, where PolyA20 modified HEK cells were bound on polyT20-PEGlipid incorporated islet surfaces. The authors observed cell spreading and proliferation on islet surfaces with complete coverage of islet surfaces within HEK293 cell layer in culture medium [123]. The idea of cellular based coating of pancreatic islets has been utilized to promote local immunoprotection on islet surfaces. Marek et al. used biotinstreptavidin interaction to coat islets within CD4+ CD25 high CD127– T regulatory cells. Fig. (11) shows that T regulatory cells could completely cover islet surfaces after 1 in day culture. It was observed that effective protection from effector T cell mediated reaction could be achieved without compromising insulin secretion function in response to high glucose [124]. The idea of using T regulatory cells for islet encapsulation may open up the possibility of using T regulatory cells for clinical islet transplantation, where T regulatory cells of the recipient patient could be considered for in vitro expansion and used to coat allogeneic pancreatic islets. After islet isolation, islets become avascular which causes severe hypoxia and nutrient deprivation. Since hypoxia is not desirable for cellular function and survival, islets should be rapidly revascularized. Hypoxia/reoxygenation induced injury of islets should be addressed to improve islet survival and function [125-127]. Mesenchymal stem cells may be utilized with islet grafts against hypoxia since they may inhibit cell growth and differentiation via signaling molecules and cytokines including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and leukemia inhibitory factor [126]. Alternatively, a homeostatic mechanism against reduced oxygen tension in mammals can be mimicked. Hypoxia inducible factors such as HIF-1α combined with aryl hydrocarbon receptor nuclear translocator (ARNT) regulates cellular response against hypoxia and increases vascular endothelial growth factor and antiaopototic gene secretion. Islets may be treated with deferoxamine (DFO) to increase HIF-1α production against hypoxia [128]. Other strategies have been also considered such as oxygen generating polydimetylsiloxane encapsulated

solid calcium peroxide [129], or perfluorocarbon emulsions oxygen carriers in order to address islet hypoxia. CHALLENGES ASSOCIATED WITH ISLET TRANSPLANTATION Survival rate of graft and patients, life quality and maintenance of normal metabolic state in the long run determine the success of islet transplantation [35]. Transplanted islets are expected to respond to host glucose levels by secreting insulin similar to normal pancreatic islets [130]. American Diabetes Association (ADA) defines islet transplantation as an experimental operation which is only allowed in Food and Drug Administration (FDA) controlled research centers or laboratories [6].Among the challenges of islet transplantation are loss of islets during isolation [29], loss of islet viability during or after transplantation, limited supply of islets [131], exhaustion of already limited islet mass and deleterious effects of immunosuppressive drugs [15]. In their native environment, islets of Langerhans are highly vascularized with a dense glomerular-like capillary network which enables islet communication and intra islet blood flow for normal islet function [132]. Islets contact with ECM that evokes complex cellular processes [89], and during islet isolation process, surrounding microvasculature [74] and islet-matrix interactions are destroyed. Due to these reasons, survival and function of islets and hence success of islet transplantation procedures decline [89]. In order to increase the success of islet transplantation, islet matrix interactions might be reestablished after isolation, or immunogenicity might be reduced through in vitro culturing of islets before transplantation to ameliorate islet transplantation [89, 132-135]. Source of Islets An adult human pancreas contains 0.3-1.5 x 106 islets with 2x109 beta cells [136], and a successful isolation may yield about 400,000 islets at most since only 30-50% of the islets can be isolated, where about 65% of those are viable [127]. However a standard transplant recipient requires 0.351.0 million islets since patients require around 15000 islet equivalents (IE) per kilogram of patient weight to become insulin independent. Additionally, these islets should have standard diameter of 150µm [47, 48, 50]. Therefore, there is a great gap between available source of islets and patients who need islet transplantation. This limitation highlights the


Kepsutlu et al.

Fig. (10). HEK293 cells encapsulated islets: Phase-contrast microscopy of HEK293 cell-immobilized islets in culture at 0-5 days. HEK293 cells were immobilized on the surface of the islets and cultured on a non-treated dish in Medium 199 at 37°C. Arrows indicate immobilized HEK293 cells. Scale bar=200 µm for a-c and 100 µm for d. (Adapted with permission from Teramura and Iwata 2009. Copyright 2009, Elsevier).

Fig. (11). Treg-encapsulated islets: Tregs are effectively attached to the islets. Confocal microscopy imaging after 1-day culture. (a) Three dimensional view of a human islet coated with T cells (nuclei stained with Hoechst shown in blue) reconstructed from a stack of 18 optical images with 5-µm increment. (b) Alternative viewing angle of the islet shown in A. (c) Bright field image of the human islet. (d), Cutting plane view reconstructed from T cell coordinates exposing the coating layer of T cells surrounding the unstained islet cells. (Adapted with permission from Marek, et al. 2011. Copyright 2011, Lippincott Williams & Wilkins, Inc.).


urgent need of cell sources to bring this technology closer to clinical use [136]. Islet sources from humans can be obtained from the patient himself, which is called autograft and hence, transplantation does not evoke an inflammatory reaction [132, 137]. Until 2000, 222 islet auto-transplantations were performed in the worldwide after pancreatectomy and nearly half of the patients gained insulin independence [138, 139]. Allograft islet transplantation requires islets from different individuals of the same species such as pancreas of cadaveric donors [131]. Since brain-dead donors have upregulated proinflammatory cytokines, allograft transplantation confronts immune response of the recipient [140]. Currently 65% of the diabetic patients have become insulin independent within the first year of islet allotransplantation and 5 year insulin independence rates range between 60-70% [53]. Xenotransplantation refers to primary islets or other insulin secreting tissue sources from other organisms such as porcine, rat, mouse, bovine, rabbit, trout and fish brockman bodies [35, 131, 141]. Porcine is the main alternative donor species, since human and pig insulin have structural similarity [131]. Also, pig islets efficiently proliferate in vivo and in vitro [142] and can be easily genetically manipulated compared to that of islets from primates [143]. However, xenograft islets from pig evoke hyperacute immune rejection due to the presence of nonhuman moiety, α-1,3 galactosyltransferase, on islet surface [131] and the rejection is primarily mediated by CD4+ T cells and by a minor effect of CD8 + T cells in the presence of xenoreactive antibodies through the indirect pathway of antigen presentation [144, 145] . In addition, porcine endogenous retroviruses may trigger a crossspecies infection in recipient patients [131]. Besides the possibilities of obtaining islets from autogenic, allogenic or xenogenic sources, insulin secreting cells can be obtained by genetic engineering approaches [66]. These cells or islet-like clusters easily grow under sterile conditions to high masses while allograft islets from cadaver donors hardly proliferate. This expandable and functional cell source addresses the insufficient islet problem [146, 147]. These cell sources include tumors and transformed cell lines [146], and beta-like cells derived from induced pluripotent stem cells that were shown to be effective to reverse diabetes in vivo [148, 149]. These somatic cells such as liver cells and K cells [150-152], pancreatic ductal cells [146] and fibroblasts [153] can also be reprogrammed into insulin producing cells via insulin gene delivery [150, 151]. In addition, through the use of gene therapy techniques, animal donors which lack glycosylation property can be generated to reduce xenograft rejection [143, 147, 154]. The limitation about obtaining sufficient islet source could also be addressed through stem cells which have selfrenewal and differentiation capacity [131, 155]. Embryonic stem cells, embryonic germ cells, embryonic carcinoma cells, mesenchymal stem cells, induced pluripotent cells from somatic cells [148] and adult pancreas stem cells [156158] can be utilized for islet transplantation [146, 155, 159]. These cells can be reprogrammed into beta cells if appropriate conditions for growth and differentiation are satisfied, and they can be used to normalize blood glucose levels [146, 160-165]. Adult stem cells and induced pluripotent stem cells do not evoke alloimmune rejection, but embryonic stem


11

cells do [148, 166]. Additionally, mesenchymal stem cells enhance graft survival and function when they are physically co-transplanted with islets, since they reduce required beta cell mass and promote tissue vascularization [167-173], provide anti-inflammatory and immunomodulatory properties and secrete antiapoptic paracrine factors to enhance islet viability [126, 174-176]. However, the level and induction of insulin secretion from stem cells should be quantified [177]. Risk of mutagenesis due to vectors used for reprogramming and possibility of tumorogenic properties should also be investigated in detail before stem cells can be treated as a treatment option for diabetes [152, 156, 178]. Primary beta cells as major endocrine cells to replace islets of Langerhans have been considered in cell therapy for the treatment of diabetes [179]. However, primary beta cell donation is limited and these cells have limited proliferative capacity [141, 180]. Immortalized beta cell lines may address this problem, as they are uniform, can easily proliferate and secrete insulin [141, 179, 180]. Beta cell lines may be produced from pluripotent stem cells, embryonic germ cells, embryonic carcinoma cells, bone marrow stem cells or spermatogonial stem cells via genetic and cellular engineering techniques [136, 146, 152]. RINm5F, MIN6 and HIT are some of the immortal pancreatic beta cell lines from transgenic mouse that are under experimental trials for replacement of islets to cure TIDM [179]. However, beta cell lines which contain all properties of primary beta cells have not been produced yet [179, 180]. Also, due to the carcinogenic history, beta cell lines cannot be transplanted to diabetic patients clinically. They are usually examined to understand insulin secretion and growth properties of primary beta cells according to matrix-cell interactions and cell-cell interactions [90, 136, 180]. Site of Transplantation In order to optimize islet engraftment, function and to reduce required islet mass for transplantation, researchers seek alternative sites for transplantation. An optimum transplantation site must provide sufficient blood supply, high oxygen and must have angiogenesis capacity, as beta cells cannot properly function without sufficient vasculature [181, 182]. The optimum site of transplantation must also minimize surgical complications and must require the lowest mass of islets [183]. This site must further provide portal delivery of insulin and be easily accessed to allow minimally invasive operations [184]. Spleen, epiploic pouch, peritoneal cavity, testis, thymus, kidney capsule, brain, subcutaneous tissue, pancreas, eye, lung, epididymal fat and vascularized small intestinal segments have all been studied for transplantation of islets [181, 185-189]. These sites have their own disadvantages and advantages. For instance, grafts within the lung presented poor performance [187], where liver, spleen, kidney capsule, striated muscle are highly vascularized sites, and subcutaneous and intramuscular sites are sparsely vascularized [132, 185]. Renal subcapsular space provides a fast vascular engraftment and desirable growth conditions for islets [190, 191]. However, this site is small and exocrine contamination destroys islets [182, 184]. Epididymal fat pad yields similar glycemic control efficacy to intraportal islet transplantation [188]. Testis, thymus, brain and eye are im-


mune-privileged, and the iris of the eye is also highly vascularized with a rich autonomic nerve network and provides easy imaging [181, 186]. In vascularized small intestinal segments, vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor-2 and transforming growth factor-β are expressed which accelerate islet graft revascularization [189].An optimal site for islet transplantation has not yet been reported; however, currently, intraportal islet transplantation is the predominant method, because insulin is intrinsically metabolized in liver [42, 192, 193]. Between 1990 and 2000, 92% of the clinical islet transplantation cases were performed into the liver via portal vein injection or infusion [55]. Liver provides oxygen plus nutrient rich environment, hepatic uptake of nutrients and hormones, simple and cheap access to the transplantation site and portal insulin drainage with a normal rate. Therefore, it reduces hyperinsulinemia risk and insulin secretion delay [35, 66, 183, 192, 194]. However, liver has many disadvantages such as insufficient islet vascularization and the risk of various complications [132, 183, 194]. Intense immune rejection, instant blood mediated inflammatory reaction, immunosuppressive drug and toxin accumulation may cause graft loss [46, 94, 132, 182, 195]. Intraperitoneal site has a large volume to accommodate encapsulated islets; however, it provides relatively low oxygen and blood supply to islets, and contains many macrophages. Also, the peritoneal cavity retards insulin release, as it is not a regular insulin delivery route [69, 194]. Many studies have conflict about the efficacy of intraperitoneal transplantation of islets to achieve insulin independence for patients [94, 196, 197]. Pancreas is the intrinsic location of native islets. The transplanted islets maintain their functionality and anatomy better in the pancreas than in the liver through intraportal transplantation [198]. This site has an insulin delivery to the portal vein and a high angiogenesis potential [198, 199]. The omentum pouch provides portal venous drainage, easy access for clinical follow-up, high vascular density and neoangiogenesis capacity [192]. However, omental islet transplantation has not been clinically studied yet and requires a higher amount of islet mass than intraportal and splenic transplantation [183, 192, 200]. Subcutaneous space is easily accessible for biopsy, guarantees maximum patient safety [201-203]. However, poor vascularization and low oxygen concentration in this site is the major challenge [185]. In order to address this issue, subcutaneous tissue or islets are prevascularizated, transplanted with fibroblasts [201-205]. Immunosuppressive Drugs When an allograft or xenograft is transplanted into a host, genetic inconsistency initiates numerous cellular, molecular and humoral immunological events. These events are induced by T and B cells, macrophages, and dendritic cells to reject foreign tissue [131]. Nonspecific inflammatory reactions respond to foreign tissue first; immune mediated destruction occurs later [35] (Fig. 12a). Especially, intraportally transplanted islets experience instant blood mediated inflammatory response (IBMIR). IBMIR involves complement and coagulation cascade activation and neutrophil infiltration [154]. It is a thrombotic reaction caused by direct contact of islets with ABO-compatible blood. In this process,

Kepsutlu et al.

activated platelets rapidly bind to the surface of the islets and a clot is formed around the islets that initiates thrombotic and complement activation cascades. Leukocytes infiltrate and islets suffer morphological defects [206, 207] (Fig. 12b). Along with these inflammatory reactions, T cells and other immune cell types are activated to evoke a cytokinecoordinated rejection. In allotransplantation, the rejection occurs through a direct pathway. When T cells recognize the represented antigens by donor MHC class II cells, CD4 + helper Th1 cells are generated. These cells produce cytokines which expand cytotoxic CD8+ T cells. CD8+ T cells are called primary effector cells against allogenic cells (Fig. 12c). In xenotransplantation, rejection occurs through antigen-antibody reaction pathway and in this pathway, professional antigen presenting cells of the host represents donor antigens [131] (Fig. 12d). In order to avoid immune rejection and autoimmune islet destruction, immunosuppressive drug uptake is crucial after pancreas and islet transplantation [19, 131]. Between 1999 and 2003, 80% of immunosuppression regimens were composed of IL2R antagonists. Therefore, recipients predominantly took calcineurin and mTOR inhibitor combinations. Later, until 2009, usually a combination of calcineurin inhibitor and IMPDH inhibitor was preferred after islet transplantation. Between 2007 and 2009, agents which induce T cell depletion regardless of the presence of TNF antagonists supplemented the immunosuppressive regimens [53]. Although immunosuppressive drugs inhibit acute rejection, they have many detrimental side effects such as increased malignancy elevated levels of reactive oxygen species in the host, cardiovascular problems, nephro- and neuro-toxicity, renal dysfunction, allergies, dermatologic diseases, inhibition of wound healing, mouth ulcers and alteration of the menstrual cycle in women [15, 19, 63, 131, 208-214]. During immunosuppressive drug therapy, a balance between toxicity and efficacy should be established [48, 66, 130, 181, 206]. Therefore, a personal dosage and schedule arrangement covering optimum timing and best fitting drug option is required. This procedure is very time consuming and difficult, as it depends on trial and error procedure [208, 215]. Immunosuppressive drugs may also have deleterious effects on beta cell function and structure while decreasing insulin gene expression and causing glucose mechanism abnormalities [216-220]. They can reduce host’s ability to -fight disease by impairing immune system. Moreover, in spite of all envisaged risks, immunosuppresive agents may fail to prevent allo- and auto- immunity against transplanted islets. Therefore, new techniques to prevent immunosuppressive drug uptake are necessary. Hence, immunoisolation strategies have emerged to hinder allogenic and xenogenic islet grafts from host antibodies [15, 66, 136, 221]. The basic drawbacks of immunoisolation techniques are mass transport limitations and inflammatory responses to device materials [66]. CONCLUSION TIDM is a common health problem affecting many people worldwide. To address this problem, many treatment options are developed such as insulin therapy, pancreas or islet transplantation. The treatment techniques are continuously improved to obtain the best method, which provides the most strict glycemic control. There is not an established



13

Fig. (12). Immune reaction against transplanted islets. a) Islet Graft Rejection: Upon contact of islets with ABO-incompatible blood, coagulation cascade (blue arrow) and complement cascade (pink arrow) starts. As a result of complement cascade, leukocytes are recruited to the region to perform allograft rejection via donor APC recognition (green circle) or xenograft rejection via host/donor APC recognition pathways (pink circle). b) Instant Blood Mediated Inflammation Reaction: IBMIR is a thrombotic reaction caused by direct contact of islets with ABO-incompatible blood. It involves complement and coagulation cascade activation and neutrophil infiltration. In coagulation cascade, the activated platelets rapidly bind to the surface of the islets resulting in clot formation around the islets. c) Allograft Rejection: Through direct pathway, as T cells recognize those represented antigens by donor MHC class II cells, CD4+ helper Th1 cells are developed which produce cytokines for expansion of cytotoxic CD8+ T cells as primary effector cells against allogenic cells. d) Xenograft Rejection: Light region (Direct Pathway): Donor antigen presenting cells are stimulated and host compatibility complex molecules (class II) are presented to T cells. MHCs displayed on donor xenotransplants may not effectively interact with host T-cells and may not mediate direct pathway. Dark Region (Indirect Pathway): Antigen-antibody reaction pathway, the antigens of the donor tissue are represented by the host professional antigen presenting cells which are macrophages and dendritic cells. Upon interaction of donor antigen representing cells and host T cells, CD4+ helper Th1 cells are developed which produce cytokines for expansion of cytotoxic CD8+ T cells as primary effector cells against xenogenic cells.


method or chemical regimen which completely cures diabetes mellitus; however, islet transplantation stands out as a novel and has potential to be improved through immunoisolation options which hinder islets from host immune rejection, possibility to exploit various sources of islets and various transplantation sites. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

Kepsutlu et al.

[18] [19] [20]

[21]

ACKNOWLEDGEMENTS This work was supported by the funds from the EU-FP7IRG- Marie Curie-DMIOL 239471, Istanbul Rotary Club, Turkish Scientific and Research Council (TUBITAK)-MAG113M232.

[22] [23] [24]

REFERENCES [1] [2] [3] [4] [5] [6] [7]

[8]

[9] [10]

[11] [12] [13] [14] [15]

[16] [17]

Drury, P.L.; Bodansky, H.J. The relationship of the reninangiotensin system in type I diabetes to microvascular disease. Hypertension, 1985, 7(6 Pt 2), II84-89. Kleinman, K.S.; Fine, L.G. Prognostic implications of renal hypertrophy in diabetes mellitus. Diabet.Metab. Rev., 1988, 4(2), 179-189. Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes care, 2004, 27(5), 1047-1053. IDF, IDF Diabetes Atlas, 6th Ed. 6 ed.; 2011. IDF, Global Diabetes Plan, 2011-2021. 2011. Jahansouz, C.; Kumer, S.C.; Brayman, K.L. Evolution of beta-Cell Replacement Therapy in Diabetes Mellitus: Islet Cell Transplantation. J. Transplant., 2011, 2011, 247959. Ido, Y.; Vindigni, A.; Chang, K.; Stramm, L.; Chance, R.; Heath, W.F.; DiMarchi, R. D.; Di Cera, E.; Williamson, J.R. Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science, 1997, 277(5325), 563-566. Korsgren, O.; Lundgren, T.; Felldin, M.; Foss, A.; Isaksson, B.; Permert, J.; Persson, N.H.; Rafael, E.; Ryden, M.; Salmela, K.; Tibell, A.; Tufveson, G.; Nilsson, B. Optimising islet engraftment is critical for successful clinical islet transplantation. Diabetologia, 2008, 51(2), 227-232. Sutherland, D.E.; Gruessner, R.W.; Gruessner, A.C. Pancreas transplantation for treatment of diabetes mellitus. World J. Surg., 2001, 25(4), 487-496. Venstrom, J.M.; McBride, M.A.; Rother, K.I.; Hirshberg, B.; Orchard, T.J.; Harlan, D. M. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA, 2003, 290(21), 2817-2823. Lanza, R.P.; Langer, R.S.; Vacanti, J. Principles of tissue engineering. 3rd ed.; Elsevier / Academic Press: Amsterdam; Boston, 2007. Lanza, R.P.; Hayes, J.L.; Chick, W.L. Encapsulated cell technology. Nat. Biotechnol., 1996, 14(9), 1107-1111. Juang, J.H.; Bonner-Weir, S.; Ogawa, Y.; Vacanti, J.P.; Weir, G.C. Outcome of subcutaneous islet transplantation improved by polymer device. Transplantation, 1996, 61 (11), 1557-1561. van Schilfgaarde, R.; de Vos, P. Factors influencing the properties and performance of microcapsules for immunoprotection of pancreatic islets. J. Mol. Med., (Berl), 1999, 77 (1), 199-205. Frank, A.; Deng, S.; Huang, X.; Velidedeoglu, E.; Bae, Y.S.; Liu, C.; Abt, P.; Stephenson, R.; Mohiuddin, M.; Thambipillai, T.; Markmann, E.; Palanjian, M.; Sellers, M.; Naji, A.; Barker, C.F.; Markmann, J.F. Transplantation for type I diabetes: Comparison of vascularized whole-organ pancreas with isolated pancreatic islets. Ann. Surg., 2004, 240(4), 631-640; discussion 640-633. Gunnarsson, R. The pathogenesis of type II diabetes mellitus. A brief survey. Ann. Clin. Res., 1983, 15(Suppl 37), 6-11. Kleinman, R.; Ohning, G.; Wong, H.; Watt, P.; Walsh, J.; Brunicardi, F.C. Regulatory role of intraislet somatostatin on

[25] [26]

[27]

[28] [29] [30]

[31] [32]

[33]

[34] [35] [36]

[37]

[38]

insulin secretion in the isolated perfused human pancreas. Pancreas, 1994, 9(2), 172-178. Teramura, Y.; Iwata, H. Bioartificial pancreas microencapsulation and conformal coating of islet of Langerhans. Adv. Drug Deliv. Rev., 2010, 62(7-8), 827-840. Atkinson, M.A.; Eisenbarth, G.S. Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet, 2001, 358(9277), 221-229. Bode, B.W.; Sabbah, H.T.; Gross, T.M.; Fredrickson, L.P.; Davidson, P.C. Diabetes management in the new millennium using insulin pump therapy. Diabet. Metab. Res. Rev., 2002, 18(Suppl 1), S14-20. Hermansen, K.; Fontaine, P.; Kukolja, K.K.; Peterkova, V.; Leth, G.; Gall, M.A. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia, 2004, 47(4), 622-629. Cleland, S.J.; Fisher, B.M.; Colhoun, H.M.; Sattar, N.; Petrie, J.R. Insulin resistance in type 1 diabetes: what is 'double diabetes' and what are the risks? Diabetologia, 2013, 56(7), 1462-1470. Fowler, M.J. Hypoglycemia. Clinical Diabetes, 2008, 26, 170-173. Lepore, M.; Pampanelli, S.; Fanelli, C.; Porcellati, F.; Bartocci, L.; Di Vincenzo, A.; Cordoni, C.; Costa, E.; Brunetti, P.; Bolli, G.B. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes, 2000, 49(12), 2142-2148. Ellen Toth, D.P. Hypoglycemia: Understanding the enemy. Canadian Diabetes, 2002, 15(3), 1-2. Ratner, R.E.; Hirsch, I.B.; Neifing, J.L.; Garg, S.K.; Mecca, T.E.; Wilson, C.A. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care, 2000, 23(5), 639-643. Raskin, P.; Klaff, L.; Bergenstal, R.; Halle, J.P.; Donley, D.; Mecca, T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care, 2000, 23(11), 1666-1671. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The DCCT Research Group. Am. J. Med., 1991, 90(4), 450-459. Noguchi, H. Pancreatic islet transplantation. World J. Gastrointest. Surg., 2009, 1(1), 16-20. Scheiner, G.; Sobel, R.J.; Smith, D.E.; Pick, A.J.; Kruger, D.; King, J.; Green, K. Insulin pump therapy: Guidelines for successful outcomes. Diabetes Educ, 2009, 35(Suppl 2), 29S-41S; quiz 28S, 42S-43S. Lenhard, M.J.; Reeves, G.D. Continuous subcutaneous insulin infusion: a comprehensive review of insulin pump therapy. Arch. Intern. Med., 2001, 161(19), 2293-2300. Weintrob, N.; Benzaquen, H.; Galatzer, A.; Shalitin, S.; Lazar, L.; Fayman, G.; Lilos, P.; Dickerman, Z.; Phillip, M. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens in children with type 1 diabetes: a randomized open crossover trial. Pediatrics, 2003, 112(3 Pt 1), 559-564. Pickup, J.; Mattock, M.; Kerry, S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. BMJ, 2002, 324(7339), 705. Renard, E. Implantable closed-loop glucose-sensing and insulin delivery: the future for insulin pump therapy. Curr. Opin. Pharmacol., 2002, 2(6), 708-716. Inoue, K.; Miyamoto, M. Islet transplantation. J. Hepatobiliary Pancreat. Surg., 2000, 7(2), 163-177. Banga, N.; Hadjianastassiou, V.G.; Mamode, N.; Calder, F.; Olsburgh, J.; Drage, M.; Sammartino, C.; Koffman, G.; Taylor, J. Outcome of surgical complications following simultaneous pancreas-kidney transplantation. Nephrol.Dial. Transplant, 2012, 27(4), 1658-1663. Gruessner, A.C. 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. Gruessner, A.C.; Sutherland, D. E. Pancreas transplant outcomes for United States (US) cases as reported to the United Network for


[39]

[40] [41] [42] [43] [44] [45] [46] [47] [48]

[49]

[50]

[51]

[52]

[53] [54] [55] [56] [57]

[58] [59]

Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Clin Transpl, 2008, 45-56. Reddy, K.S.; Stratta, R.J.; Shokouh-Amiri, M.H.; Alloway, R.; Egidi, M.F.; Gaber, A. O. Surgical complications after pancreas transplantation with portal-enteric drainage. J. Am. Coll. Surg., 1999, 189(3), 305-313. Moskalewski, S. Beginning of pancreatic islet isolation by collagenase digestion (personal reminiscences). Ann. Transplant, 1997, 2(3), 6-7. Gaba, R.C.; Garcia-Roca, R.; Oberholzer, J. Pancreatic islet cell transplantation: an update for interventional radiologists. J. Vasc. Interv. Radiol., 2012, 23(5), 583-594; quiz 594. Ballinger, W.F.; Lacy, P.E. Transplantation of intact pancreatic islets in rats. Surgery, 1972, 72(2), 175-186. Lim, F.; Sun, A.M. Microencapsulated islets as bioartificial endocrine pancreas. Science, 1980, 210 (4472), 908-910. Robertson, R.P. Pancreatic islet cell transplantation: Likely impact on current therapeutics for type 1 diabetes mellitus. Drugs, 2001, 61(14), 2017-2020. Ricordi, C.; Lacy, P.E.; Finke, E.H.; Olack, B.J.; Scharp, D.W. Automated method for isolation of human pancreatic islets. Diabetes, 1988, 37(4), 413-420. Robertson, R.P. Islet transplantation a decade later and strategies for filling a half-full glass. Diabetes, 2010, 59(6), 1285-1291. Paget, M.; Murray, H.; Bailey, C.J.; Downing, R. Human islet isolation: semi-automated and manual methods. Diab. Vasc. Dis. Res., 2007, 4(1), 7-12. Shapiro, A.M.; Lakey, J.R.; Ryan, E.A.; Korbutt, G.S.; Toth, E.; Warnock, G.L.; Kneteman, N.M.; Rajotte, R.V. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med., 2000, 343(4), 230-238. Ryan, E.A.; Lakey, J.R.; Rajotte, R.V.; Korbutt, G.S.; Kin, T.; Imes, S.; Rabinovitch, A.; Elliott, J.F.; Bigam, D.; Kneteman, N.M.; Warnock, G.L.; Larsen, I.; Shapiro, A.M. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes, 2001, 50(4), 710-719. Ryan, E.A.; Paty, B.W.; Senior, P.A.; Bigam, D.; Alfadhli, E.; Kneteman, N.M.; Lakey, J.R.; Shapiro, A.M. Five-year follow-up after clinical islet transplantation. Diabetes, 2005, 54(7), 20602069. Froud, T.; Ricordi, C.; Baidal, D.A.; Hafiz, M.M.; Ponte, G.; Cure, P.; Pileggi, A.; Poggioli, R.; Ichii, H.; Khan, A.; Ferreira, J.V.; Pugliese, A.; Esquenazi, V.V.; Kenyon, N.S.; Alejandro, R. Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience. Am. J. Transplant, 2005, 5(8), 2037-2046. Shapiro, A.M.; Ricordi, C.; Hering, B.J.; Auchincloss, H.; Lindblad, R.; Robertson, R.P.; Secchi, A.; Brendel, M.D.; Berney, T.; Brennan, D.C.; Cagliero, E.; Alejandro, R.; Ryan, E.A.; DiMercurio, B.; Morel, P.; Polonsky, K.S.; Reems, J.A.; Bretzel, R.G.; Bertuzzi, F.; Froud, T.; Kandaswamy, R.; Sutherland, D.E.; Eisenbarth, G.; Segal, M.; Preiksaitis, J.; Korbutt, G.S.; Barton, F.B.; Viviano, L.; Seyfert-Margolis, V.; Bluestone, J.; Lakey, J.R. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med., 2006, 355(13), 1318-1330. CITR Coordinating Center, T. E. C., Rockville CITR(2010) Seventh Annual Report; Collaborative Islet Transplant Registry: December 30, 2011, 2011. Registry, I. T. ITR 1999 Newsletter #8 Draft; Islet Transplant Registry: August 1999, 1999; pp 1-20. Registry, I. I. T. ITR 2001 Newsletter # 9; International Transplant Registry: June 2001, 2001. Alejandro, R.; Barton, F.B.; Hering, B.J.; Wease, S. 2008 Update from the Collaborative Islet Transplant Registry. Transplantation, 2008, 86(12), 1783-1788. O'Sullivan, E.; Vegas, A.; Anderson, D.; Weir, G. Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain. Endocr. Rev., 2011, 32 (417520b41f08-46cb-ea8d-531123ec8b22), 827-871. Lanza, R.P.; Langer, R.S.; Vacanti, J. Principles of tissue engineering. 3rd ed.; Elsevier Academic Press: Amsterdam; Boston, 2007. Ratner, B.D. Biomaterials science: an introduction to materials in medicine. 2nd ed.; Elsevier Academic Press: Amsterdam; Boston, 2004.

[60] [61]

[62]

[63] [64] [65] [66] [67] [68] [69]

[70] [71]

[72] [73]

[74]

[75]

[76]

[77]

[78] [79]

[80]


15

Li, R.H. Materials for immunoisolated cell transplantation. Adv. Drug Deliv. Rev., 1998, 33(1-2), 87-109. Orive, G.; Hernandez, R.M.; Gascon, A.R.; Calafiore, R.; Chang, T.M.; De Vos, P.; Hortelano, G.; Hunkeler, D.; Lacik, I.; Shapiro, A.M.; Pedraz, J.L. Cell encapsulation: promise and progress. Nat. Med., 2003, 9(1), 104-107. Chick, W.L.; Perna, J.J.; Lauris, V.; Low, D.; Galletti, P.M.; Panol, G.; Whittemore, A.D.; Like, A.A.; Colton, C.K.; Lysaght, M.J. Artificial pancreas using living beta cells:. effects on glucose homeostasis in diabetic rats. Science, 1977, 197(4305), 780-782. Mikos, A.G.; McIntire, L.V.; Anderson, J.M.; Babensee, J.E. Host response to tissue engineered devices. Adv. Drug Deliv. Rev., 1998, 33(1-2), 111-139. Ratner, B.D.; Bryant, S.J. Biomaterials: where we have been and where we are going. Annu. Rev. Biomed. Eng., 2004, 6, 41-75. Anderson, J. Biological responses to materials. Annu Rev Mater Res, 2001, 31, 81-110. Wilson, J.T.; Chaikof, E.L. Challenges and emerging technologies in the immunoisolation of cells and tissues. Adv. Drug Deliv. Rev., 2008, 60(2), 124-145. Hernandez, R.M.; Orive, G.; Murua, A.; Pedraz, J.L. Microcapsules and microcarriers for in situ cell delivery. Adv. Drug Deliv. Rev., 2010, 62(7-8), 711-730. Sakata, N.; Sumi, S.; Yoshimatsu, G.; Goto, M.; Egawa, S.; Unno, M. Encapsulated islets transplantation: Past, present and future. World J. Gastrointest. Pathophysiol., 2012, 3(1), 19-26. King, A.; Andersson, A.; Strand, B.L.; Lau, J.; Skjak-Braek, G.; Sandler, S. The role of capsule composition and biologic responses in the function of transplanted microencapsulated islets of Langerhans. Transplantation, 2003, 76(2), 275-279. Cheng, J.Y.; Raghunath, M.; Whitelock, J.; Poole-Warren, L. Matrix components and scaffolds for sustained islet function. Tissue Eng. Part B Rev., 2011, 17(4), 235-247. Soon-Shiong, P.; Heintz, R.E.; Merideth, N.; Yao, Q.X.; Yao, Z.; Zheng, T.; Murphy, M.; Moloney, M.K.; Schmehl, M.; Harris, M.; et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet, 1994, 343(8903), 950951. de Vos, P.; Faas, M.M.; Strand, B.; Calafiore, R. Alginate-based microcapsules for immunoisolation of pancreatic islets. Biomaterials, 2006, 27(32), 5603-5617. de Vos, P.; Spasojevic, M.; de Haan, B.J.; Faas, M.M. The association between in vivo physicochemical changes and inflammatory responses against alginate based microcapsules. Biomaterials, 2012, 33(22), 5552-5559. Lee, B.R.; Hwang, J.W.; Choi, Y.Y.; Wong, S.F.; Hwang, Y.H.; Lee, D.Y.; Lee, S. H. In situ formation and collagen-alginate composite encapsulation of pancreatic islet spheroids. Biomaterials, 2012, 33(3), 837-845. 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(5), 619-625. Tun, T.; Inoue, K.; Hayashi, H.; Aung, T.; Gu, Y.J.; Doi, R.; Kaji, H.; Echigo, Y.; Wang, W. J.; Setoyama, H.; Imamura, M.; Maetani, S.; Morikawa, N.; Iwata, H.; Ikada, Y. A newly developed threelayer agarose microcapsule for a promising biohybrid artificial pancreas: rat to mouse xenotransplantation. Cell Transplant, 1996, 5(5 Suppl 1), S59-63. Luan, N.M.; Teramura, Y.; Iwata, H. Immobilization of the soluble domain of human complement receptor 1 on agarose-encapsulated islets for the prevention of complement activation. Biomaterials, 2010, 31(34), 8847-8853. Khor, E.; Lim, L.Y. Implantable applications of chitin and chitosan. Biomaterials, 2003, 24(13), 2339-2349. Yang, K.C.; Qi, Z.; Wu, C.C.; Shirouza, Y.; Lin, F.H.; Yanai, G.; Sumi, S. The cytoprotection of chitosan based hydrogels in xenogeneic islet transplantation: An in vivo study in streptozotocininduced diabetic mouse. Biochem. Biophys. Res. Commun., 2010, 393(4), 818-823. Senuma, Y.; Franceschin, S.; Hilborn, J.G.; Tissieres, P.; Bisson, I.; Frey, P. Bioresorbable microspheres by spinning disk atomization as injectable cell carrier: from preparation to in vitro evaluation. Biomaterials, 2000, 21(11), 1135-1144.

16 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 6 [81] [82] [83] [84]

[85]

[86] [87]

[88]

[89] [90] [91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

Wallace, D.G.; Rosenblatt, J. Collagen gel systems for sustained delivery and tissue engineering. Adv. Drug Deliv. Rev., 2003, 55(12), 1631-1649. Kizilel, S.; Perez-Luna, V.H.; Teymour, F. Photopolymerization of poly(ethylene glycol) diacrylate on eosin-functionalized surfaces. Langmuir, 2004, 20(20), 8652-8658. Lee, J.H.; Lee, H.B.; Andrade, J.D. Blood compatibility of poly(ethylene oxide) surfaces. Prog. Polym. Sci., 1995, 20, 10431079. Kizilel, S.; Scavone, A.; Liu, X.; Nothias, J.M.; Ostrega, D.; Witkowski, P.; Millis, M. Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion. Tissue Eng. Part A, 2010, 16(7), 2217-2228. Lee, D.Y.; Park, S.J.; Lee, S.; Nam, J.H.; Byun, Y. Highly poly(ethylene) glycolylated islets improve long-term islet allograft survival without immunosuppressive medication. Tissue Eng., 2007, 13(8), 2133-2141. Kizilel, S.; Garfinkel, M.; Opara, E. The bioartificial pancreas: Progress and challenges. Diabetes Technol. Ther., 2005, 7(6), 968985. Cruise, G.M.; Hegre, O.D.; Scharp, D.S.; Hubbell, J.A. A sensitivity study of the key parameters in the interfacial photopolymerization of poly(ethylene glycol) diacrylate upon porcine islets. Biotechnol. Bioengin., 1998, 57(6), 655-665. Wyman, J.L.; Kizilel, S.; Skarbek, R.; Zhao, X.; Connors, M.; Dillmore, W.S.; Murphy, W.L.; Mrksich, M.; Nagel, S.R.; Garfinkel, M.R. Immunoisolating pancreatic islets by encapsulation with selective withdrawal. Small, 2007, 3(4), 683-690. Weber, L.M.; Anseth, K.S. Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion. Matrix Biol, 2008, 27(8), 667-673. Lin, C.C.; Anseth, K.S. Glucagon-like peptide-1 functionalized PEG hydrogels promote survival and function of encapsulated pancreatic beta-cells. Biomacromolecules, 2009, 10(9), 2460-2467. Qi, Z.; Yamamoto, C.; Imori, N.; Kinukawa, A.; Yang, K.C.; Yanai, G.; Ikenoue, E.; Shen, Y.; Shirouzu, Y.; Hiura, A.; Inoue, K.; Sumi, S. Immunoisolation effect of polyvinyl alcohol (PVA) macroencapsulated islets in type 1 diabetes therapy. Cell Transplant, 2012, 21(2-3), 525-534. Inoue, K.; Fujisato, T.; Gu, Y. J.; Burczak, K.; Sumi, S.; Kogire, M.; Tobe, T.; Uchida, K.; Nakai, I.; Maetani, S.; et al. Experimental hybrid islet transplantation: application of polyvinyl alcohol membrane for entrapment of islets. Pancreas, 1992, 7(5), 562-568. Teramura, Y.; Kaneda, Y.; Iwata, H. Islet-encapsulation in ultrathin layer-by-layer membranes of poly(vinyl alcohol) anchored to poly(ethylene glycol)-lipids in the cell membrane. Biomaterials, 2007, 28(32), 4818-4825. Blomeier, H.; Zhang, X.; Rives, C.; Brissova, M.; Hughes, E.; Baker, M.; Powers, A.C.; Kaufman, D.B.; Shea, L.D.; Lowe, W.L., Jr. Polymer scaffolds as synthetic microenvironments for extrahepatic islet transplantation. Transplantation, 2006, 82(4), 452-459. Gibly, R.F.; Zhang, X.; Graham, M.L.; Hering, B.J.; Kaufman, D.B.; Lowe, W.L., Jr.; Shea, L.D. Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models. Biomaterials, 2011, 32(36), 9677-9684. Kim, Y.Y.; Chae, S.Y.; Kim, S.; Byun, Y.; Bae, Y.H. Improved phenotype of rat islets in a macrocapsule by co-encapsulation with cross-linked Hb. J. Biomat. Sci. Polym. Ed., 2005, 16(12), 15211535. Isayeva, I.S.; Kasibhatla, B.T.; Rosenthal, K.S.; Kennedy, J.P. Characterization and performance of membranes designed for macroencapsulation/implantation of pancreatic islet cells. Biomaterials, 2003, 24(20), 3483-3491. Grundfest-Broniatowski, S.F.; Tellioglu, G.; Rosenthal, K.S.; Kang, J.; Erdodi, G.; Yalcin, B.; Cakmak, M.; Drazba, J.; Bennett, A.; Lu, L.; Kennedy, J.P. A new bioartificial pancreas utilizing amphiphilic membranes for the immunoisolation of porcine islets: a pilot study in the canine. ASAIO J, 2009, 55(4), 400-405. Lembert, N.; Wesche, J.; Petersen, P.; Doser, M.; Zschocke, P.; Becker, H. D.; Ammon, H.P. Encapsulation of islets in rough surface, hydroxymethylated polysulfone capillaries stimulates VEGF release and promotes vascularization after transplantation. Cell Transplant, 2005, 14(2-3), 97-108.

Kepsutlu et al. [100] [101]

[102]

[103] [104] [105] [106]

[107] [108] [109]

[110]

[111] [112]

[113] [114]

[115] [116] [117] [118]

[119]

[120]

[121]

Beck, J.; Angus, R.; Madsen, B.; Britt, D.; Vernon, B.; Nguyen, K.T. Islet encapsulation: strategies to enhance islet cell functions. Tissue Eng., 2007, 13(3), 589-599. Petersen, P.; Lembert, N.; Zschocke, P.; Stenglein, S.; Planck, H.; Ammon, H.P.T.; Becker, H. D. Hydroxymethylated polysulphone for islet macroencapsulation allows rapid diffusion of insulin but retains PERV. Transplant P., 2002, 34(1), 194-195. Ward, R.S.; White, K.A.; Wolcott, C.A.; Wang, A.Y.; Kuhn, R.W.; Taylor, J.E.; John, J.K. Development of a hybrid artificial pancreas with a dense polyurethane membrane. ASAIO J., 1993, 39(3), M261-267. George, S.; Nair, P.D.; Risbud, M.V.; Bhonde, R.R. Nonporous polyurethane membranes as islet immunoisolation matrices-biocompatibility studies. J. Biomater. Appl., 2002, 16(4), 327-340. Uludag, H.; De Vos, P.; Tresco, P.A. Technology of mammalian cell encapsulation. Adv. Drug Deliv. Rev., 2000, 42(1-2), 29-64. Lanza, L., Vacanti, Principles of Tissue Engineering. 3 ed.; Elsevier: 2007. Qi, M.; Gu, Y.; Sakata, N.; Kim, D.; Shirouzu, Y.; Yamamoto, C.; Hiura, A.; Sumi, S.; Inoue, K. PVA hydrogel sheet macroencapsulation for the bioartificial pancreas. Biomaterials, 2004, 25(27), 5885-5892. Mikos, A.G.; Papadaki, M.G.; Kouvroukoglou, S.; Ishaug, S.L.; Thomson, R.C. Mini-review: Islet transplantation to create a bioartificial pancreas. Biotechnol. Bioengin., 1994, 43(7), 673-677. Hou, Q.P.; Bae, Y.H. Biohybrid artificial pancreas based on macrocapsule device. Adv. Drug Deliv. Rev., 1999, 35(2-3), 271287. Tatarkiewicz, K.; Hollister-Lock, J.; Quickel, R.R.; Colton, C.K.; Bonner-Weir, S.; Weir, G.C. Reversal of hyperglycemia in mice after subcutaneous transplantation of macroencapsulated islets. Transplantation, 1999, 67(5), 665-671. Wang, W.; Gu, Y.; Hori, H.; Sakurai, T.; Hiura, A.; Sumi, S.; Tabata, Y.; Inoue, K. Subcutaneous transplantation of macroencapsulated porcine pancreatic endocrine cells normalizes hyperglycemia in diabetic mice. Transplantation, 2003, 76(2), 290296. Chang, T.M. Pharmaceutical and therapeutic applications of artificial cells including microencapsulation. Europ. J. Pharmaceut.Biopharmaceut. 1998, 45(1), 3-8. Sawhney, A.S.; Pathak, C.P.; Hubbell, J.A. Modification of islet of langerhans surfaces with immunoprotective poly(ethylene glycol) coatings via interfacial photopolymerization. Biotechnol. Bioengin., 1994, 44(3), 383-386. Dupuy, B.; Gin, H.; Baquey, C.; Ducassou, D. In situ polymerization of a microencapsulating medium round living cells. J. Biomed. Mater. Res., 1988, 22(11), 1061-1070. Koo, S.K.; Kim, S.C.; Wee, Y.M.; Kim, Y.H.; Jung, E.J.; Choi, M.Y.; Park, Y.H.; Park, K.T.; Lim, D.G.; Han, D.J. Experimental microencapsulation of porcine and rat pancreatic islet cells with air-driven droplet generator and alginate. Transplant Proc., 2008, 40(8), 2578-2580. Brissova, M.; Powers, A.C. Revascularization of transplanted islets: can it be improved? Diabetes, 2008, 57(9), 2269-2271. Opara, E.C.; Mirmalek-Sani, S.H.; Khanna, O.; Moya, M.L.; Brey, E.M. Design of a bioartificial pancreas. J. Investig. Med., 2010, 58(7), 831-837. Renken, A.; Hunkeler, D. Microencapsulation: a review of polymers and technologies with a focus on bioartificial organs. Polimery-W, 1998, 43(9), 530-539. Sugiura, S.; Oda, T.; Izumida, Y.; Aoyagi, Y.; Satake, M.; Ochiai, A.; Ohkohchi, N.; Nakajima, M. Size control of calcium alginate beads containing living cells using micro-nozzle array. Biomaterials, 2005, 26(16), 3327-3331. Ma, M.L.; Chiu, A.; Sahay, G.; Doloff, J.C.; Dholakia, N.; Thakrar, R.; Cohen, J.; Vegas, A.; Chen, D.L.; Bratlie, K.M.; Dang, T.; York, R.L.; Hollister-Lock, J.; Weir, G.C.; Anderson, D.G. Coreshell hydrogel microcapsules for improved islets encapsulation. Adv. Healthc. Mater., 2013, 2(5), 667-672. 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(9), 1933-1939. Wilson, J.T.; Cui, W.; Chaikof, E.L. Layer-by-layer assembly of a conformal nanothin PEG coating for intraportal islet transplantation. Nano Lett., 2008, 8(7), 1940-1948.



[122]

islet mass in autotransplants. Transplantation, 2011, 91(3), 367372. Prokop, A. Bioartificial pancreas: Materials, devices, function, and limitations. Diabet. Technol. Therapeut., 2001, 3(3), 431-449. Korbutt, G.S.; Ao, Z.; Flashner, M.; Rajotte, R.V. Neonatal porcine islets as a possible source of tissue for humans and microencapsulation improves the metabolic response of islet graft posttransplantation. Ann. NY Acad. Sci., 1997, 831, 294-303. Bucher, P.; Morel, P.; Buhler, L.H. Xenotransplantation: an update on recent progress and future perspectives. Transpl. Int., 2005, 18(8), 894-901. Troppmann, C.; Gruessner, A.C.; Papalois, B.E.; Nakhleh, R.E.; Gruessner, R.W. Discordant xenoislets from a large animal donor undergo accelerated graft failure rather than hyperacute rejection: impact of immunosuppression, islet mass, and transplant site on early outcome. Surgery, 1997, 121(2), 194-205. Thompson, P.; Badell, I.R.; Lowe, M.; Cano, J.; Song, M.; Leopardi, F.; Avila, J.; Ruhil, R.; Strobert, E.; Korbutt, G.; Rayat, G.; Rajotte, R.; Iwakoshi, N.; Larsen, C.P.; Kirk, A.D. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Amer. J. Transplantat., 2011, 11(12), 2593-2602. Soria, B.; Skoudy, A.; Martin, F. From stem cells to beta cells: new strategies in cell therapy of diabetes mellitus. Diabetologia, 2001, 44(4), 407-415. Moore, D. J.; Markmann, J. F.; Deng, S. Avenues for immunomodulation and graft protection by gene therapy in transplantation. Transpl Int., 2006, 19(6), 435-445. Alipio, Z.; Liao, W.; Roemer, E.J.; Waner, M.; Fink, L.M.; Ward, D.C.; Ma, Y. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc. Natl. Acad. Sci. USA, 2010, 107(30), 13426-13431. Jeon, K.; Lim, H.; Kim, J.H.; Thuan, N.V.; Park, S.H.; Lim, Y.M.; Choi, H.Y.; Lee, E. R.; Lee, M.S.; Cho, S.G. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells Develop., 2012, 21(14), 2642-2655. Vitoria, J.C.; Castano, L.; Rica, I.; Bilbao, J.R.; Arrieta, A.; GarciaMasdevall, M.D. Association of insulin-dependent diabetes mellitus and celiac disease: a study based on serologic markers. J. Pediatr. Gastroenterol. Nutr., 1998, 27(1), 47-52. Savilahti, E.; Simell, O.; Koskimies, S.; Rilva, A.; Akerblom, H.K. Celiac disease in insulin-dependent diabetes mellitus. J. Pediatr., 1986, 108(5 Pt 1), 690-693. Godfrey, K.J.; Mathew, B.; Bulman, J.C.; Shah, O.; Clement, S.; Gallicano, G.I. Stem cell-based treatments for Type 1 diabetes mellitus: bone marrow, embryonic, hepatic, pancreatic and induced pluripotent stem cells. Diabet. Med., 2012, 29(1), 14-23. Tateishi, K.; He, J.; Taranova, O.; Liang, G.; D'Alessio, A.C.; Zhang, Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J. Biol. Chem., 2008, 283(46), 3160131607. Thompson, P.; Badell, I.R.; Lowe, M.; Cano, J.; Song, M.; Leopardi, F.; Avila, J.; Ruhil, R.; Strobert, E.; Korbutt, G.; Rayat, G.; Rajotte, R.; Iwakoshi, N.; Larsen, C.P.; Kirk, A.D. Islet xenotransplantation using gal-deficient neonatal donors improves engraftment and function. Am. J. Transplant, 2011, 11(12), 25932602. Miszta-Lane, H.; Mirbolooki, M.; James Shapiro, A.M.; Lakey, J.R. Stem cell sources for clinical islet transplantation in type 1 diabetes: embryonic and adult stem cells. Med. Hypotheses, 2006, 67(4), 909-913. Huangfu, D.; Osafune, K.; Maehr, R.; Guo, W.; Eijkelenboom, A.; Chen, S.; Muhlestein, W.; Melton, D.A. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat. Biotechnol., 2008, 26(11), 1269-1275. Timper, K.; Seboek, D.; Eberhardt, M.; Linscheid, P.; Christ-Crain, M.; Keller, U.; Muller, B.; Zulewski, H. Human adipose tissuederived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem. Biophys. Res. Commun., 2006, 341(4), 1135-1140. Ulrich, A.B.; Schmied, B.M.; Standop, J.; Schneider, M.B.; Pour, P.M. Pancreatic cell lines: a review. Pancreas, 2002, 24(2), 111120. Baetge, E.E. Production of beta-cells from human embryonic stem cells. Diabet. Obes. Metab., 2008, 10(Suppl 4), 186-194.

[123] [124]

[125] [126]

[127] [128]

[129]

[130]

[131] [132]

[133]

[134]

[135]

[136]

[137] [138] [139]

[140]

Teramura, Y.; Iwata, H. Islet encapsulation with living cells for improvement of biocompatibility. Biomaterials, 2009, 30(12), 2270-2275. Teramura, Y.; Minh, L.N.; Kawamoto, T.; Iwata, H. Microencapsulation of islets with living cells using polyDNAPEG-lipid conjugate. Bioconjug Chem, 2010, 21(4), 792-796. Marek, N.; Krzystyniak, A.; Ergenc, I.; Cochet, O.; Misawa, R.; Wang, L.J.; Golab, K.; Wang, X.; Kilimnik, G.; Hara, M.; Kizilel, S.; Trzonkowski, P.; Millis, J.M.; Witkowski, P. Coating human pancreatic islets with CD4(+)CD25(high)CD127(-) regulatory T cells as a novel approach for the local immunoprotection. Ann. Surg., 2011, 254(3), 512-518; discussion 518-519. Carlsson, P.O.; Palm, F.; Mattsson, G. Low revascularization of experimentally transplanted human pancreatic islets. J.Clin. Endocrinol. Metabol., 2002, 87(12), 5418-5423. Lu, Y.; Jin, X.; Chen, Y.; Li, S.; Yuan, Y.; Mai, G.; Tian, B.; Long, D.; Zhang, J.; Zeng, L.; Li, Y.; Cheng, J. Mesenchymal stem cells protect islets from hypoxia/reoxygenation-induced injury. Cell Biochem. Funct., 2010, 28(8), 637-643. Hatziavramidis, D.T.; Karatzas, T.M.; Chrousos, G.P. Pancreatic islet cell transplantation: an update. Ann. Biomed. Engin., 2013, 41(3), 469-476. Stokes, R.A.; Cheng, K.; Deters, N.; Lau, S.M.; Hawthorne, W.J.; O'Connell, P.J.; Stolp, J.; Grey, S.; Loudovaris, T.; Kay, T.W.; Thomas, H.E.; Gonzalez, F.J.; Gunton, J.E. Hypoxia-inducible factor-1alpha (HIF-1alpha) potentiates beta-cell survival after islet transplantation of human and mouse islets. Cell Transplantation, 2013, 22(2), 253-266. Pedraza, E.; Coronel, M.M.; Fraker, C.A.; Ricordi, C.; Stabler, C.L. Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc. Natl. Acad. Sci. USA, 2012, 109(11), 4245-4250. Gimi, B.; Kwon, J.; Kuznetsov, A.; Vachha, B.; Magin, R.L.; Philipson, L.H.; Lee, J. B. A nanoporous, transparent microcontainer for encapsulated islet therapy. J. Diabet. Sci. Technol., 2009, 3(2), 297-303. Narang, A.S.; Mahato, R.I. Biological and biomaterial approaches for improved islet transplantation. Pharmacol. Rev., 2006, 58(2), 194-243. Christoffersson, G.; Henriksnas, J.; Johansson, L.; Rolny, C.; Ahlstrom, H.; Caballero-Corbalan, J.; Segersvard, R.; Permert, J.; Korsgren, O.; Carlsson, P.O.; Phillipson, M. Clinical and experimental pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in native islets. Diabetes, 2010, 59(10), 2569-2578. Pinkse, G.G.; Bouwman, W.P.; Jiawan-Lalai, R.; Terpstra, O.T.; Bruijn, J. A.; de Heer, E. Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans. Diabetes, 2006, 55(2), 312-317. Nikolova, G.; Jabs, N.; Konstantinova, I.; Domogatskaya, A.; Tryggvason, K.; Sorokin, L.; Fassler, R.; Gu, G.; Gerber, H.P.; Ferrara, N.; Melton, D.A.; Lammert, E. The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Development. Cell, 2006, 10(3), 397-405. Xiaohui, T.; Wujun, X.; Xiaoming, D.; Xinlu, P.; Yan, T.; Puxun, T.; Xinshun, F. Small intestinal submucosa improves islet survival and function in vitro culture. Transplant. Proc., 2006, 38(5), 15521558. Zhi, Z.L.; Liu, B.; Jones, P.M.; Pickup, J.C. Polysaccharide multilayer nanoencapsulation of insulin-producing beta-cells grown as pseudoislets for potential cellular delivery of insulin. Biomacromolecules, 2010, 11(3), 610-616. Sutherland, D.E.; Matas, A.J.; Goetz, F.C.; Najarian, J.S. Transplantation of dispersed pancreatic islet tissue in humans: autografts and allografts. Diabetes, 1980, 29(Suppl 1), 31-44. Lee, M.K.; Bae, Y.H. Cell transplantation for endocrine disorders. Advanced drug delivery reviews, 2000, 42(1-2), 103-120. Wahoff, D.C.; Papalois, B.E.; Najarian, J.S.; Kendall, D.M.; Farney, A.C.; Leone, J. P.; Jessurun, J.; Dunn, D.L.; Robertson, R.P.; Sutherland, D.E. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann. Surg., 1995, 222(4), 562575; discussion 575-569. Bellin, M.D.; Sutherland, D.E.; Beilman, G.J.; Hong-McAtee, I.; Balamurugan, A.N.; Hering, B.J.; Moran, A. Similar islet function in islet allotransplant and autotransplant recipients, despite lower

[141] [142]

[143] [144]

[145]

[146] [147] [148]

[149]

[150]

[151] [152]

[153]

[154]

[155]

[156]

[157]

[158] [159]

17

18 Current Pharmaceutical Biotechnology, 2014, Vol. 15, No. 6 [160]

[161]

[162]

[163]

[164]

[165] [166]

[167]

[168]

[169] [170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

Raikwar, S.P.; Zavazava, N. Spontaneous in vivo differentiation of embryonic stem cell-derived pancreatic endoderm-like cells corrects hyperglycemia in diabetic mice. Transplantation, 2011, 91(1), 11-20. Hori, Y.; Rulifson, I.C.; Tsai, B.C.; Heit, J.J.; Cahoy, J.D.; Kim, S.K. Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. Proc. Natl. Acad. Sci. USA, 2002, 99(25), 16105-16110. Wang, H.S.; Shyu, J.F.; Shen, W.S.; Hsu, H.C.; Chi, T.C.; Chen, C.P.; Huang, S.W.; Shyr, Y.M.; Tang, K.T.; Chen, T.H. Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplant, 2011, 20(3), 455-466. Kadam, S.; Muthyala, S.; Nair, P.; Bhonde, R. Human placentaderived 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(2), 168-182. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science, 1999, 284(5411), 143-147. Kodama, S.; Kuhtreiber, W.; Fujimura, S.; Dale, E.A.; Faustman, D.L. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science, 2003, 302(5648), 1223-1227. Hess, D.; Li, L.; Martin, M.; Sakano, S.; Hill, D.; Strutt, B.; Thyssen, S.; Gray, D.A.; Bhatia, M. Bone marrow-derived stem cells initiate pancreatic regeneration. Nat. Biotechnol., 2003, 21(7), 763-770. Ding, Y.; Xu, D.; Feng, G.; Bushell, A.; Muschel, R.J.; Wood, K.J. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes, 2009, 58(8), 1797-1806. Sakata, N.; Chan, N.K.; Chrisler, J.; Obenaus, A.; Hathout, E. Bone marrow cell cotransplantation with islets improves their vascularization and function. Transplantation, 2010, 89(6), 686693. Sordi, V.; Piemonti, L. Mesenchymal stem cells as feeder cells for pancreatic islet transplants. Rev. Diabet. Stud., 2010, 7(2), 132-143. Ohmura, Y.; Tanemura, M.; Kawaguchi, N.; Machida, T.; Tanida, T.; Deguchi, T.; Wada, H.; Kobayashi, S.; Marubashi, S.; Eguchi, H.; Takeda, Y.; Matsuura, N.; Ito, T.; Nagano, H.; Doki, Y.; Mori, M. Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice. Transplantation, 2010, 90(12), 1366-1373. Trivedi, H.L.; Vanikar, A.V.; Thakker, U.; Firoze, A.; Dave, S.D.; Patel, C.N.; Patel, J.V.; Bhargava, A.B.; Shankar, V. Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin. Transplant Proc., 2008, 40(4), 1135-1139. Golocheikine, A.; Tiriveedhi, V.; Angaswamy, N.; Benshoff, N.; Sabarinathan, R.; Mohanakumar, T. Cooperative signaling for angiogenesis and neovascularization by VEGF and HGF following islet transplantation. Transplantation, 2010, 90(7), 725-731. Bal, T.; Nazli, C.; Okcu, A.; Duruksu, G.; Karaöz, E.; Kizilel, S. Mesenchymal stem cells (MSCs) and ligand incorporation in biomimetic peg hydrogels significantly improve insulin secretion from pancreatic islets. J. Tissue Engin. Regenerat. Med. in revision, 2014. Berman, D.M.; Willman, M.A.; Han, D.; Kleiner, G.; Kenyon, N.M.; Cabrera, O.; Karl, J.A.; Wiseman, R.W.; O'Connor, D.H.; Bartholomew, A.M.; Kenyon, N.S. Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates. Diabetes, 2010, 59(10), 2558-2568. Longoni, B.; Szilagyi, E.; Quaranta, P.; Paoli, G.T.; Tripodi, S.; Urbani, S.; Mazzanti, B.; Rossi, B.; Fanci, R.; Demontis, G.C.; Marzola, P.; Saccardi, R.; Cintorino, M.; Mosca, F. Mesenchymal stem cells prevent acute rejection and prolong graft function in pancreatic islet transplantation. Diabet. Technol. Therapeut., 2010, 12(6), 435-446. Jung, E.J.; Kim, S.C.; Wee, Y.M.; Kim, Y.H.; Choi, M.Y.; Jeong, S.H.; Lee, J.; Lim, D.G.; Han, D.J. Bone marrow-derived mesenchymal stromal cells support rat pancreatic islet survival and insulin secretory function in vitro. Cytotherapy, 2011, 13(1), 19-29. D'Amour, K.A.; Bang, A.G.; Eliazer, S.; Kelly, O.G.; Agulnick, A.D.; Smart, N.G.; Moorman, M.A.; Kroon, E.; Carpenter, M.K.;

Kepsutlu et al.

[178] [179]

[180] [181] [182] [183] [184] [185] [186]

[187] [188] [189]

[190] [191]

[192]

[193]

[194]

[195]

[196] [197]

Baetge, E.E. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol., 2006, 24(11), 1392-1401. Sipione, S.; Eshpeter, A.; Lyon, J.G.; Korbutt, G.S.; Bleackley, R.C. Insulin expressing cells from differentiated embryonic stem cells are not beta cells. Diabetologia, 2004, 47(3), 499-508. Miyazaki, J.; Araki, K.; Yamato, E.; Ikegami, H.; Asano, T.; Shibasaki, Y.; Oka, Y.; Yamamura, K. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology, 1990, 127(1), 126-132. Weber, L.M.; Hayda, K.N.; Anseth, K.S. Cell-matrix interactions improve beta-cell survival and insulin secretion in threedimensional culture. Tissue Eng. Part A, 2008, 14(12), 1959-1968. Espes, D.; Eriksson, O.; Lau, J.; Carlsson, P.O. Striated muscle as implantation site for transplanted pancreatic islets. J. Transplant, 2011, 2011, 352043. Christoffersson, G.; Carlsson, P.O.; Phillipson, M. Intramuscular islet transplantation promotes restored islet vascularity. Islets, 2011, 3(2), 69-71. Merani, S.; Toso, C.; Emamaullee, J.; Shapiro, A.M. Optimal implantation site for pancreatic islet transplantation. Br. J. Surg., 2008, 95(12), 1449-1461. Kin, T.; Korbutt, G.S.; Rajotte, R.V. Survival and metabolic function of syngeneic rat islet grafts transplanted in the omental pouch. Am. J. Transplant., 2003, 3(3), 281-285. Juang, J.H.; Hsu, B.R.; Kuo, C.H. Islet transplantation at subcutaneous and intramuscular sites. Transplant Proc., 2005, 37(8), 3479-3481. Speier, S.; Nyqvist, D.; Cabrera, O.; Yu, J.; Molano, R.D.; Pileggi, A.; Moede, T.; Kohler, M.; Wilbertz, J.; Leibiger, B.; Ricordi, C.; Leibiger, I. B.; Caicedo, A.; Berggren, P. O. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat. Med., 2008, 14(5), 574-578. Hayek, A.; Beattie, G.M. Experimental transplantation of human fetal and adult pancreatic islets. J. Clin. Endocrinol. Metab., 1997, 82(8), 2471-2475. Chen, X.; Zhang, X.; Larson, C.; Chen, F.; Kissler, H.; Kaufman, D.B. The epididymal fat pad as a transplant site for minimal islet mass. Transplantation, 2007, 84(1), 122-125. Kakabadze, Z.; Gupta, S.; Brandhorst, D.; Korsgren, O.; Berishvili, E. Long-term engraftment and function of transplanted pancreatic islets in vascularized segments of small intestine. Transpl. Int., 2011, 24(2), 175-183. Olsson, R.; Olerud, J.; Pettersson, U.; Carlsson, P.O. Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation. Diabetes, 2011, 60(9), 2350-2353. Mellgren, A.; Schnell Landstrom, A.H.; Petersson, B.; Andersson, A. The renal subcapsular site offers better growth conditions for transplanted mouse pancreatic islet cells than the liver or spleen. Diabetologia, 1986, 29(9), 670-672. Berman, D.M.; O'Neil, J.J.; Coffey, L.C.; Chaffanjon, P.C.; Kenyon, N.M.; Ruiz, P., Jr.; Pileggi, A.; Ricordi, C.; Kenyon, N.S. Long-term survival of nonhuman primate islets implanted in an omental pouch on a biodegradable scaffold. Am. J. Transplant, 2009, 9(1), 91-104. Jindal, R.M.; Sidner, R.A.; McDaniel, H.B.; Johnson, M.S.; Fineberg, S.E. Intraportal vs kidney subcapsular site for human pancreatic islet transplantation. Transplant Proc., 1998, 30(2), 398399. Motomura, T.; Maeda, T.; Kawahito, S.; Matsui, T.; Ichikawa, S.; Ishitoya, H.; Kawamura, M.; Shinohara, T.; Sato, K.; Kawaguchi, Y.; Taylor, D.; Oestmann, D.; Glueck, J.; Nose, Y. Development of silicone rubber hollow fiber membrane oxygenator for ECMO. Artif. Organs, 2003, 27(11), 1050-1053. Rafael, E.; Tibell, A.; Ryden, M.; Lundgren, T.; Savendahl, L.; Borgstrom, B.; Arnelo, U.; Isaksson, B.; Nilsson, B.; Korsgren, O.; Permert, J. Intramuscular autotransplantation of pancreatic islets in a 7-year-old child: a 2-year follow-up. Am. J. Transplant, 2008, 8(2), 458-462. Kemp, C.B.; Knight, M.J.; Scharp, D.W.; Ballinger, W.F.; Lacy, P.E. Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats. Diabetologia, 1973, 9(6), 486-491. Korbutt, G.S.; Mallett, A.G.; Ao, Z.; Flashner, M.; Rajotte, R.V. Improved survival of microencapsulated islets during in vitro


[198]

[199] [200] [201]

[202]

[203]

[204]

[205] [206] [207]

[208] [209]

culture and enhanced metabolic function following transplantation. Diabetologia, 2004, 47(10), 1810-1818. Lau, J.; Mattsson, G.; Carlsson, C.; Nyqvist, D.; Kohler, M.; Berggren, P.O.; Jansson, L.; Carlsson, P.O. Implantation sitedependent dysfunction of transplanted pancreatic islets. Diabetes, 2007, 56(6), 1544-1550. Stagner, J.I.; Rilo, H.L.; White, K.K. The pancreas as an islet transplantation site. Confirmation in a syngeneic rodent and canine autotransplant model. JOP, 2007, 8(5), 628-636. Ao, Z.; Matayoshi, K.; Lakey, J.R.; Rajotte, R.V.; Warnock, G.L. Survival and function of purified islets in the omental pouch site of outbred dogs. Transplantation, 1993, 56(3), 524-529. Perez-Basterrechea, M.; Briones, R.M.; Alvarez-Viejo, M.; GarciaPerez, E.; Esteban, M.M.; Garcia, V.; Obaya, A.J.; Barneo, L.; Meana, A.; Otero, J. Plasma-fibroblast gel as scaffold for islet transplantation. Tissue Engin. Part A, 2009, 15(3), 569-577. Lamb, M.; Storrs, R.; Li, S.; Liang, O.; Laugenour, K.; Dorian, R.; Chapman, D.; Ichii, H.; Imagawa, D.; Foster, C., 3rd; King, S.; Lakey, J. R. Function and viability of human islets encapsulated in alginate sheets: in vitro and in vivo culture. Transplant Proc., 2011, 43 (9), 3265-3266. Kawakami, Y.; Iwata, H.; Gu, Y.J.; Miyamoto, M.; Murakami, Y.; Balamurugan, A. N.; Imamura, M.; Inoue, K. Successful subcutaneous pancreatic islet transplantation using an angiogenic growth factor-releasing device. Pancreas, 2001, 23(4), 375-381. Kawakami, Y.; Iwata, H.; Gu, Y.; Miyamoto, M.; Murakami, Y.; Yamasaki, T.; Cui, W.; Ikada, Y.; Imamura, M.; Inoue, K. Modified subcutaneous tissue with neovascularization is useful as the site for pancreatic islet transplantation. Cell Transplant, 2000, 9(5), 729-732. Hiscox, A.M.; Stone, A.L.; Limesand, S.; Hoying, J.B.; Williams, S.K. An islet-stabilizing implant constructed using a preformed vasculature. Tissue Engin. Part A, 2008, 14(3), 433-440. Hering, B.J. Achieving and maintaining insulin independence in human islet transplant recipients. Transplantation, 2005, 79(10), 1296-1297. Bennet, W.; Sundberg, B.; Groth, C.G.; Brendel, M.D.; Brandhorst, D.; Brandhorst, H.; Bretzel, R.G.; Elgue, G.; Larsson, R.; Nilsson, B.; Korsgren, O. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes, 1999, 48(10), 1907-1914. Allison, A.C. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology, 2000, 47(2-3), 63-83. Coelho, T.; Tredger, M.; Dhawan, A. Current status of immunosuppressive agents for solid organ transplantation in children. Pediatr. Transplant., 2012, 16(2), 106-122.

Received: March 04, 2014

Revised: April 15, 2014

Accepted: June 27, 2014

[210] [211]

[212]

[213] [214]

[215] [216] [217]

[218] [219]

[220]

[221]


19

Chen, A. M.; Scott, M. D. Current and future applications of immunological attenuation via pegylation of cells and tissue. BioDrugs, 2001, 15(12), 833-847. Rezzani, R.; Rodella, L.; Buffoli, B.; Giugno, L.; Stacchiotti, A.; Bianchi, R. Cyclosporine A induces vascular fibrosis and heat shock protein expression in rat. Int. Immunopharmacol., 2005, 5(1), 169-176. Basso, M.S.; Subramaniam, P.; Tredger, M.; Verma, A.; Heaton, N.; Rela, M.; Mieli-Vergani, G.; Dhawan, A. Sirolimus as renal and immunological rescue agent in pediatric liver transplant recipients. Pediatr. Transplant., 2011, 15(7), 722-727. Berney, T.; Secchi, A. Rapamycin in islet transplantation: friend or foe? Transpl. Int., 2009, 22(2), 153-161. Cure, P.; Pileggi, A.; Froud, T.; Norris, P.M.; Baidal, D.A.; Cornejo, A.; Hafiz, M.M.; Ponte, G.; Poggioli, R.; Yu, J.; Saab, A.; Selvaggi, G.; Ricordi, C.; Alejandro, R. Alterations of the female reproductive system in recipients of islet grafts. Transplantation, 2004, 78(11), 1576-1581. Calne, R.Y. Prope tolerance--the future of organ transplantation from the laboratory to the clinic. Int. Immunopharmacol., 2005, 5(1), 163-167. Dean, P.G.; Kudva, Y.C.; Larson, T.S.; Kremers, W.K.; Stegall, M.D. Posttransplant diabetes mellitus after pancreas transplantation. Am. J. Transplant, 2008, 8(1), 175-182. Drachenberg, C.B.; Klassen, D.K.; Weir, M.R.; Wiland, A.; Fink, J.C.; Bartlett, S. T.; Cangro, C.B.; Blahut, S.; Papadimitriou, J.C. Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation, 1999, 68(3), 396-402. Hirano, Y.; Fujihira, S.; Ohara, K.; Katsuki, S.; Noguchi, H. Morphological and functional changes of islets of Langerhans in FK506-treated rats. Transplantation, 1992, 53 (4), 889-894. Tanemura, M.; Ohmura, Y.; Deguchi, T.; Machida, T.; Tsukamoto, R.; Wada, H.; Kobayashi, S.; Marubashi, S.; Eguchi, H.; Ito, T.; Nagano, H.; Mori, M.; Doki, Y. Rapamycin causes upregulation of autophagy and impairs islets function both in vitro and in vivo. Am. J. Transplant., 2012, 12(1), 102-114. Zhang, N.; Su, D.; Qu, S.; Tse, T.; Bottino, R.; Balamurugan, A. N.; Xu, J.; Bromberg, J. S.; Dong, H. H. Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes, 2006, 55(9), 2429-2436. Cheung, C.Y.; Anseth, K.S. Synthesis of immunoisolation barriers that provide localized immunosuppression for encapsulated pancreatic islets. Bioconjug. Chem., 2006, 17(4), 1036-1042.

Design of Bioartificial Pancreas with Functional Micro/Nano-Based ...

Design of Bioartificial Pancreas with Functional Micro/Nano-Based ...

Suggest Documents

The Bioartificial Pancreas - KU

Photosynthetic Oxygen Generator for Bioartificial Pancreas - CiteSeerX

Improvement of islet function in a bioartificial pancreas by enhanced ...

morphological and functional discrepancies in endocrine pancreas ...

Bioartificial liver support - Hindawi

Cholecystitis Associated with Heterotopic Pancreas

Development of a hybrid bioartificial liver.

SOFTWARE DESIGN MODELLING WITH FUNCTIONAL PETRI NETS

Solid pseudopapillary tumor of pancreas with ...

Agenesis of dorsal pancreas associated with pancreatic ...

Mucinous cystadenocarcinoma of the pancreas with anaplastic ...

Bioartificial Polymeric Materials Based on

Perspective of Bioartificial Uterus as Gynecological Regenerative ...

Development of Bioartificial Myocardium by ...

Achievements and challenges in bioartificial kidney ... - CiteSeerX

Functional algorithm design - ScienceDirect

FUNCTIONAL REQUIREMENTS AND DESIGN

Annular pancreas concurrent with ... - Semantic Scholar

PDF DOWNLOAD Bioartificial Organs - Google Sites

Mediastinal Ectopic Pancreas with Abundant Endocrine Cells ...

Case Study: Pancreas cancer with Whipple's operation

Case Study: Pancreas cancer with Whipple's operation

Pearson bone marrow-pancreas syndrome with ...

Ampullary Carcinoma Associated with an Annular Pancreas