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Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus

Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for... BioscienceHorizons Volume 9 2016 10.1093/biohorizons/hzw002 Review article Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus Katie Baker* 72 Leasowe Drive, Perton, Wolverhampton WV6 7TU, UK *Corresponding author: 72 Leasowe Drive, Perton, Wolverhampton WV6 7TU, UK. Email: kbbaker@hotmail.co.uk Supervisor: Dr David Watson, School of Life Sciences, Keele University, Keele, Staffordshire, ST5 5BG. Type 1 diabetes mellitus (T1DM) is a chronic life-threatening condition whose incidence in the UK has doubled every 20 years since 1945 (Diabetes UK, 2010). Whilst intensive insulin therapy has been shown to reduce the incidence of long-term vascular complications in T1DM patients, it has also been shown to increase the risk of severe hypoglycaemia by 3-fold. Clinical islet transplantation has progressed considerably over the past decade, yet issues regarding the toxic effects of immunosuppres - sion drugs and the paucity of pancreatic donor supplies remain. To provide an effective long-term therapy for heightened glycaemic control, many studies are investigating the potential of bioartificial islet encapsulation strategies and artificial bihormonal closed-loop systems. Following consideration of the basis of pancreatic transplantation, this article takes an in- depth look at both the benefits and limitations of bioartificial and artificial therapies and compares their potential in terms of providing an effective long-term solution to patients suffering with T1DM. Key words: type 1 diabetes mellitus, pancreatic transplantation, islet encapsulation, bihormonal closed-loop system, glycaemic control, microcapsule device Submitted on 11 July 2015; accepted on 25 January 2016 Introduction When BG levels fall post-absorptive state, glucagon is released from pancreatic α cells, activating glycogen phos- Type 1 diabetes mellitus (T1DM) is an autoimmune condition phorylase to stimulate hepatic glycogenolysis and gluconeo- resulting in β-cell apoptosis of the pancreatic islets of genesis (Quesada et  al., 2008). The level of homeostatic Langerhans, which develops due to an environmental trigger in control achieved relies on the coordinated release of insulin genetically susceptible individuals (Knip and Simell, 2012). and glucagon via negative feedback. Further hormone inter- The primary soluble mediators of β cell loss are pro-inflamma - actions involve somatostatin-secreting δ cells, which respond tory cytokines interleukin-1β, interferon-γ and tumour necro- to post-prandial BG increase, acting to reduce gut motility sis factor-α; secreted by activated mononuclear cells to induce and increase nutrient absorption. Approximately 1 million differential expression of inflammatory response genes and islets are distributed throughout the healthy adult human pro-apoptotic hypoxia-inducible factor-α (Ortis et al., 2010). pancreas and each islet is then composed of ∼2000 cells; 65–80% are β cells, 15–20% are α cells and <10% are δ cells Pancreatic β-cell function is crucial for glycaemia regula- (Quesada et al., 2008). This multicellular structure enables tion; β cells act as physiological glucose sensors to detect important paracrine interactions; β cells make significant elevated blood glucose (BG) levels during the absorptive contacts with other endocrine cells, necessary for appropriate state, stimulating insulin release for the promotion of gly- insulin secretion. colysis, glycogenesis and lipogenesis (Leibiger et al., 2008). © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution and reproduction in any medium, provided the original work is properly cited. Review article Bioscience Horizons • Volume 9 2016 Progressive loss of β cell mass by apoptosis, therefore, from severe hypoglycaemia even when insulin independence causes insulinopenia, leading to hyperglycaemia and ketoaci- was not sustained (Shapiro et al., 2006). Patients now consid- dosis. The primary treatment for T1DM at present is the injec- ered for islet transplantation include those who are C-peptide tion of exogenous insulin and regular monitoring of BG levels. negative and experiencing recurrent hypoglycaemic episodes. Insulin injection has enabled successful management of diabe- This is primarily because the adverse effects of life-long tes since its first use in 1922 by Banting and Best; however, chronic immunosuppression can be justified with the risk oth - many patients develop chronic secondary complications erwise posed by hypoglycaemic unawareness. involving renal insufficiency, neuropathological problems and Limitations associated with islet impaired vision principally due to difficulty in maintaining long-term stable BG levels (Ichii and Ricordi, 2009). transplantation The challenge of achieving tight BG control is exacerbated Whilst islet allotransplantation has shown promise towards a by ‘unaware’ hypoglycemic episodes; whereby excessive circu- more effective treatment than daily insulin injections, it is lating insulin and deficient glucagon response is met with currently performed in small numbers. This can be explained impaired sympathoadrenal response, reducing warning symp- partly by the requirement for chronic immunosuppressive toms and arousal from sleep (Hovorka et al., 2014). Recurrent medication against inflammatory cytokines, enabling oppor - episodes of untreated hypoglycaemia increase patient suscep- tunistic infections such as pneumonia and herpes to invade the tibility to the development of hypoglycaemia-associated auto- host, and often causing significant adverse effects including nomic failure (HAAF) that can result in devastating immediate anaemia, leukopenia, diarrhoea, vomiting and fatigue (Shapiro neurological consequences (Unger, 2012). Clinical studies et al., 2006). According to some studies, immunosuppressants have shown that hypoglycaemic unawareness can be reversed such as tacrolimus and sirolimus may also exhibit islet toxic- in just 2–3 weeks by complete avoidance of hypoglycemic epi- ity; impairing islet viability and graft function (Drachenberg sodes (Unger, 2012), yet this requires improved therapies for et al., 1999). continuous maintenance of safe BG levels, more effective than Another major limiting factor in islet allotransplantation is that provided by insulin injection alone. the profound scarcity of healthy human donor organs (Buder et al., 2013). Over 11 000 islet equivalents per kilogram (IEQ/ Pancreatic transplantation kg) of body weight are recommended per transplant for effec- The first human whole-organ pancreatic transplantation for tive graft function, requiring 3 or 4 pancreases due to diffi - the treatment of T1DM was undertaken in 1966 by W.D. culty in separating islets from surrounding exocrine tissue Kelly; this proved effective in restoring normoglycaemia and (Sakata et al., 2012). Therefore, coupled to donor shortage is achieved insulin independence in >80% of patients beyond 1 the equally significant issue of poor islet isolation efficiency year (Sutherland et al., 2001). Whole-organ pancreatic trans- and low islet cell yield, limiting attainment of appropriate plantation is now considered the standard therapy for T1DM mass required for transplantation. The Edmonton Protocol is patients with uncontrollable BG and end-stage renal failure; typically followed as the standard procedure for isolation and however, it retains the risks associated with major surgical islet culture pre-transplant; key elements include procurement procedures and has possible complications related to exocrine of donor pancreas via controlled ductal perfusion, organ pres- tissue enzyme production (Demartines et  al., 2005). High ervation in Winconsin solution, pancreas digestion using the mortality and low islet graft survival rate chiefly explains the Ricordi system and islet purification via continuous density limited application of pancreatic transplantation. Technical gradient. Islet-cell product must then be transplanted percuta- failure rates in surgical procedure of pancreatic transplant neously into the transhepatic portal vein within 3–4 h of isola- have now decreased to ∼8%; however, vascular graft throm- tion by simply gravity infusion; most commonly, the use of at bosis, intra-abdominal infection and reperfusion pancreatitis least two fresh islet infusions are required with expected remain issues in patient and graft survival (Troppmann, purity of >30% (Shapiro et al., 2006). More recently, studies 2010). Furthermore, according to ‘NHS Blood and Transplant’ have suggested the use of an additional purification step (res - for routine whole-organ pancreatic transplantation, the wait- cue density gradient) to improve recovery of trapped islets ing time is between 1 and 2 years, calculated individually (Miki et al., 2013). based on numerous factors including total HLA mismatch, Further loss of the transplanted islet mass (up to 70%) sensitization and dialysis status. takes place immediately post-transplant due to an instant As islets represent <2% of the pancreas, experimentation blood-mediated inflammatory response (IBMIR). During an was carried out to determine the feasibility of transplanting IBMIR, platelets bind rapidly to the islet surface, contributing islets alone. In the year 2000, seven patients with T1DM to the formation of a continuous fibrin capsule surrounding received islets from multiple donors during a study known as both islets and infiltrating polymorphonuclear leucocytes. the Edmonton Protocol. The study showed the successful use This causes disruption of normal islet morphology, whilst of steroid-free immunosuppression and transplantation of activating the complement cascade which mediates βcell lysis larger islet mass for the restoration of long-term endogenous (Özmen et al., 2002). Studies have demonstrated the protec- insulin production and glycaemic stability, protecting patients tive effect of a potent caspase inhibitor, IDN-6556 in rodent 2 Bioscience Horizons • Volume 9 2016 Review article hepatic and swine intraportal islet autotransplantation, with therefore tubes with wider lumens have been used (Vos et al., markedly reduced apoptotic activity suggesting potential for 2002). However, the use of wider lumens increases the diffu- reducing islet loss (Hoglen et al., 2007; McCall et al., 2012). sion distance and decreases permeability of the macrocapsule in comparison to microcapsules, causing insufficient nutrient Overall, the rate of insulin independence in patients follow- supply and waste material accumulation. Initial studies on ing islet transplantation is known to diminish over time, with islet macroencapsulation were unsuccessful due to aggrega- ∼55% remaining insulin-free after 2 years and only ∼15% tion of the grafted tissue allowing extensive necrosis in the after 5 years (McCall et al., 2012). In order to better this prog- centre of islet clusters (Lacy et al., 1991). This was solved by nosis, the development of bioartificial and artificial pancreatic preventing contact between the tissue elements through per- transplantation has more recently shown great promise manent immobilization in a matrix such as collagen, chitosan towards heightened BG control. A comparison of these alter- or alginate (Vos et al., 2002). native strategies will be discussed to evaluate their success in overcoming the limitations associated with islet allotransplan- During microencapsulation, each islet is enveloped in its tation and to consider their potential for therapeutic interven- own spherical semi-permeable membrane ranging from tion in T1DM. 100 nm to 1 mm in size, with generally one or a few islets per capsule as shown in Fig. 1. This offers greater diffusion capac- ity and a larger surface area enabling rapid response to BG Islet encapsulation strategies fluctuation. In extravascular microencapsulation, islets are Islet encapsulation also referred to as a ‘bioartificial’ pancreas, implanted in the peritoneal cavity in a prevascularized solid- involves the envelopment of isolated islets in high polymer support system for an optimal exchange of insulin and glucose material, in order to provide a selectively permeable barrier to and improved islet nutrition (Vos and Marchetti, 2002). protect inner islets from mechanical stress and the host Alginate was the first material to be developed for use in immune system. Meanwhile, this allows the bidirectional dif- microencapsulation and now remains the favoured material fusion of nutrients, oxygen and waste and glucose-responsive of choice due to its bioneutral nature, good stability and resis- release of insulin (Sakata et al., 2012). tance to oxidative damage, and relatively low cost (Lee and Mooney, 2012). Alginate is a naturally occurring anionic Comparison of different types polymer typically obtained from brown algae (Phaeophyceae) of  encapsulation and consists of unbranched binary copolymers of β-(1-4)- There are three major approaches to islet encapsulation d-mannuronic acid and α-(1-4)-l-guluronic acid of varying including intravascular macroencapsulation, and extravascu- composition (Sakata et al., 2012). Moreover, the addition of lar macro- and microencapsulation. Intravascular devices are materials such as polyethylene glycol and poly-l-lysine have anastomosed to the vascular system, placed within a hollow been shown to reduce plasma absorption and increase mem- semi-permeable membrane separating islet clusters from the brane stability to block the diffusion of serum immunoglobu- host systemic circulation. However, thrombus formation lin, albumin and haemoglobin in vitro (Desai et al., 2000). within the device lumen along with haemorrhage and infec- A significant issue in encapsulation is total graft volume; tion has forced intravascular devices to be largely abandoned the average islet diameter is 150 µ M with the surrounding (Vos and Marchetti, 2002). capsule increasing their size 3-fold (Dufrane and Gianello, In 1916, Frederick Charles Pybus attempted the first allo - 2012). In clinical settings, viable transplant sites are unable to transplantation of pancreatic tissue; grafting cadaveric pan- naturally carry the required volume of >100 ml of capsules. creatic fragments into the abdomen of two T1DM patients To increase islet concentration relative to implant volume, without therapeutic success. Pybus understood that although alginate beads are coated with a very thin membrane of poly- transplantation was the rationale treatment, until the princi- amino acids providing capsules of ∼200 µ m while maintaining ples of grafting were established their attempts would con- a liquid core structure. Microcapsules can be implanted into tinue to fail (Pybus, 1924). Previously effective transplantation the patient by a simple injection procedure and are not easily sites were not exploited; currently islet transplants are deliv- disrupted; however, they are more difficult to remove com - ered intraportally; however, when considering encapsulation, pletely when necessary in comparison to macrocapsules (Vos the increased islet diameter and demand to accommodate et al., 2002). larger islet volume requires alternative transplant sites to pre- One of the first in vivo studies performed intraperitoneal vent blockage of small hepatic vessels and ducts. allotransplantation of alginate–polylysine microencapsulated In extravascular macrocapsules, islets are immunoisolated and unencapsulated islets in rats with streptozotocin-induced within membrane-diffusion chambers implanted with mini- diabetes without immunosuppression. Post-transplant the mal surgery in the peritoneal cavity, the subcutaneous site and encapsulated islets survived 3 weeks and remained morpho- the renal capsule and easily removal when infected. Due to logically intact over 15 weeks, whilst unencapsulated islets their shape, macrocapsules made of polysulphone hollow survived only 8 days (Lim and Sun, 1980). By 1993, micr- fibres have a tendency to bend under physiological stress and oencapsulated islet allografts injected intraperitoneally in 3 Review article Bioscience Horizons • Volume 9 2016 Figure 1 Representation of three major types of encapsulation strategy in immunoisolation devices; intravascular macrocapsule and extravascular macro- and microcapsules. Adapted from Vos and Marchetti (2002), with permission from Elsevier. spontaneous diabetic canine studies were found to survive up detectable C-peptide levels in all patients, and the absence of to 726 days evidenced by positive C-peptide release (Soon- host immune sensitization reflected long-term safety of the Shiong et al., 1993). Following promising results in large-ani- bioconstruct. Calafiore and Basta placed emphasis on the mal studies, the first human clinical trial was performed in a importance of the composition of alginate encapsulation 38-year-old male with T1DM. Cadaveric human islets encap- material. sulated in alginate microcapsules were placed intraperitoneal at 10 000 IEQ/kg with 5000 IEQ/kg booster given 6 months Nanoencapsulation has also been investigated to minimize later. The patient was able to discontinue all exogenous insu- transplant volume, using a layer-by-layer assembly technique lin at 9 months, however was on anti-rejection mediation due where islet surfaces are coated with reactive-polymer segments to renal transplantation (Soon-Shiong et al., 1994). After 25 such as the insulinotropic ligand, GLP-1, to encourage years of intense pre-clinical study on microencapsulated islet increased glucose-responsive insulin secretion (Kizilel et  al., allografts, phase 1 pilot human clinical trials with four 2010). Furthermore, nanoencapsulation is intended to allevi- patients have now been completed and followed-up 5 years ate post-transplant IBMIR; diabetic mouse models have shown post-transplant (Calafiore and Basta, 2014 ). Poly-l-ornithine- that nanoencapsulated islets with phosphorylcholine-modified coated ultrapure alginate microcapsules were grafted intraperi- polysaccharide coatings can significantly extend survival of toneally into non-immunosuppressed T1DM patients, giving a transplanted islets (Zhi et al., 2013). Nanoencapsulation is far decrease in daily insulin consumption, HbA1c levels and hypo- from clinical application; however, research suggests its poten- glycaemic unawareness. Graft function was confirmed by tial in increasing graft survival in vivo. 4 Bioscience Horizons • Volume 9 2016 Review article results described suggest that SC-β cells present an opportunity Alternative supply of donor islets for therapeutic development, yet human clinical trials are not The bio-protection provided by encapsulation against immu- likely to start for several years. Moreover, factors contributing nological responses enabled investigation into the use of xeno- to cell loss post-transplant remain including IBMIR and there- geneic porcine islets. Initial human studies transplanted fore encapsulation strategies in combination would be essential. microencapsulated neonatal porcine islets combined with ser- Another limitation faced in islet transplantation and cell- toli cells subcutaneously into the abdomen wall of 12 non- based therapies recognizes that β cells require extensive intra- immunosuppressed T1DM patients. No porcine endogenous islet communication in vivo (Bavamian et  al., 2007). The retrovirus (PERV) infection was detected nor did any signifi - expression of connexion-36 protein forms permselective cant adverse effects manifest, half of the patients showed a channels that permit diffusion of cytosolic molecules between significant reduction in exogenous insulin requirements com - adjacent β cells within individual islets, to significantly regu - pared with pre-transplant levels, and glucose-stimulated por- late biosynthesis, storage and release of insulin (Bavamian cine insulin was detected in the sera of three patients up to 4 et al., 2007). The cell surface adhesion protein epithelial (E)– years post-transplant (Valdes-Gonzalez et  al., 2005). cadherin (ECAD) also plays an essential role in allowing Unfortunately, a 7-year follow-up showed that all patients β cells to cluster into islet structures (Rogers et al., 2007). This had returned back to their pre-transplant insulin doses has been shown in mouse β cells whereby the down-regulation (Valdes-Gonzalez et al., 2010). of ECAD contributes to abnormal islet architecture and Furthermore, in one study, a diabetic male was given an reduced insulin secretion (Yamagata et al., 2002). Following intraperitoneal xenotransplant of alginate-encapsulated por- understanding of the importance of synchronous and coop- cine islets at 15 000 IEQ/kg dosage. The patients HbA1c lev- erative activity of intact islets, the need to engineer IPS cell- els decreased from 9.3 to 7.8% within 14 months of receiving derived β cells into ‘pseudo-islet’ clusters (including other the transplant and produced detectable C-peptide for up to 11 endocrine cell types) is paramount, to allow a coordinated months (0.6 ng/ml). However, 49 weeks post-transplant, their regulatory network for fine-tuned effective insulin secretion insulin requirements returned to pre-transplant levels. In and BG stability (Hoang et al., 2014). order to understand why treatment slowly ceases to work, laparoscopy analysis was done 9.5 years post-transplantation. Issues with fibrosis and hypoxia This showed abundant nodules throughout the peritoneum, Microcapsules are designed to be immunogenically bioinvisi- containing opacified capsules with moderate insulin and gluca - ble, yet diffusion of low-molecular-weight cytotoxic molecules gon staining cells (Elliott et al., 2007). Porcine xenotransplan- due to incomplete encapsulation can successfully induce an tation is a promising approach to overcoming the shortage of instant blood-mediated inflammatory reaction ( Su et  al., human donor without the need for toxic anti-rejection ther- 2010). This leads to progressive thickening and scarring of apy; however, existing technology must improve in order for fibroproliferative connective tissue, which inhibits blood sup - therapy to be effective long-term. ply causing severe hypoxia and β-cell apoptosis (Weir, 2013). To ensure complete encapsulation, the polyionic charge of The more recent development of cell-based therapies is also islet surfaces can now be exploited as a binding site for poly- intended to alleviate issues of donor supply, exploiting the cationic coatings (Krol et al., 2006). promise offered by human stem cells produced in vitro for endogenous insulin production. In 2010 Alipio et al. demon- The ideal PO of peritoneal fluid surrounding islets for strated the reversal of hyperglycaemia in vivo using induced- optimal function has been determined at 60 mmHg, with islet pluripotent stem cells (iPSC) differentiated into mature β-like function at 50% by 27 mmHg and only 2% by 5 mmHg cells. Transplantation of iPSC in non-obese diabetic mice (Dionne et al., 1993). One approach to resolve hypoxia is to resulted in kidney engraftment and sufficient normalization of engineer an oxygen-generating biomaterial. In 2012, Pedraza BG detected via insulin secretion (Jeon et al., 2012). However, et al. used solid CaO in polydimethylsiloxane to deliver oxy- attempts for insulin-producing cells gave only β-cell like forms, gen to the encapsulated islets for 6 weeks, demonstrating lacking many functional characteristics and often of polyhor- improved islet function via increased insulin release in vitro. monal nature resembling transient endocrine cells (Bruina Studies have also shown how the temporary release of co- et  al., 2014). By October 2014, Douglas Melton’s group at encapsulated steroids such as dexamethasone can decrease Harvard reported the successful in vitro generation of func- ED-1/-2-positive macrophages and neutrophil-mediated tional human stem cell-β (SC-β) cells from human iPSC. inflammatory responses resulting in less fibrosis than those Transplantation of 5 million SC-β cells under the kidney cap- transplanted without (Bunger et al., 2005). sule of immunocompromised mice revealed that human embry- otic cells and iPSC package and secrete insulin into the host The bioengineering of a durable ‘bioartificial’ pancreas bloodstream within 2 weeks post-transplantation in glycaemic- hopes to improve long-term functionality of islets, whilst regulatory manner (Pagliuca et al., 2014). iPSC can be gener- eliminating the need for toxic immunosuppressant drugs. ated from embryonic fibroblasts or pancreas-derived epithelial However, many issues that limit its wider clinical application cells from the ultimate recipient of the transplant and are there- are still to be resolved including insufficient donor islet supply fore not faced with allo-rejection (Bruns et  al., 2013). The and total graft volume, fibrotic formation and islet hypoxia. 5 Review article Bioscience Horizons • Volume 9 2016 that provide programmed injections of insulin and glucagon Bihormonal closed-loop systems into the subcutaneous tissue. These pumps consist of refillable cartridges and have a user interface enabling patients to estab- Alternative studies have shifted their focus to improving lish a basal infusion rate and to give discrete bolus for cover- methods of BG control through enhanced exogenous delivery age of a meal or correction of hyperglycaemia (Peyser et al., of insulin with the development of an ‘artificial’ pancreas. In 2014). Perhaps, the most important component of an artificial 1974, Albisser et al. were among the first to describe an artifi - pancreas is the control algorithms incorporated into a micro- cial pancreas as a computerized control system. The system processor device, which automatically calculate real-time relied on the administration of glucose or insulin with a high insulin or glucagon (bihormonal) dosage based on data input level of complexity and could therefore only be used within from the CGM and insulin pump, to achieve specified target carefully supervised inpatient settings. Recent advances in the BG concentration. The three main algorithms include model accuracy and performance of the latest generation of closed- predictive control (MPC), which anticipates future glucose loop system components have accelerated the development of trends in insulin administration, proportional integral-deriva- devices, ultimately intended for outpatient use (Peyser et al., tive (PID) control, which continuously adjusts insulin infusion 2014). rates, and fuzzy logic, which takes into account patient char- The modern artificial pancreas is composed of three major acteristics and basal/bolus factors (Shah et al., 2014). functional components: a continuous glucose-monitoring (CGM) system, an insulin-infusion pump and a control algo- Unihormonal vs. bihormonal systems rithm (Fig. 2). The CGM is inserted subcutaneously at a depth of 8–12 mm in order to measure glucose in the interstitial There are two major level approaches to achieving closed-loop fluid rather than intravascular; recent studies have shown that BG control: unihormonal artificial pancreas systems infuse the physiological lag time between interstitial fluid and intra - only insulin to reduce BG concentration, whilst bihormonal vascular glucose is only 5–6 min (Basu et al., 2013). Insulin- systems deliver insulin during hyperglycaemia and glucagon infusion pumps are small, reliable electromechanical devices during hypoglycaemia (Peyser et al., 2014). Castle et al. (2010) Figure 2 Bihormonal closed-loop insulin and glucagon delivery system. Produced with information taken from Brown and Edelman (2010). 6 Bioscience Horizons • Volume 9 2016 Review article studied 14 T1DM patients undergoing closed-loop therapy fast-acting insulin analogue lispro and glucagon. Results with unihormonal or bihormonal control. In comparison to showed that six subjects achieved a mean BG concentration of unihormonal delivery, results showed that bihormonal delivery 140 mg/dl with no instances of hypoglycaemia, whilst five significantly reduced the time spent in the hypoglycaemic subjects did exhibit hypoglycaemia requiring carbohydrate range (15 ± 6 vs. 40 ± 10 min/day, P = 0.04) and significantly intervention due to slower lispro absorption (mean time-to- reduced the need for carbohydrate treatment (1.4 ± 0.8 vs. peak 117 ± 48 vs. 64 ± 4 min). Following preliminary results, 4 ± 1.4 treatments/day, P = 0.01). It was concluded that high- adjustment of pharmokinetic (PK) parameters prevented gain pulses of glucagon improved glycaemic control with little hypoglycaemia in all subjects, whilst still achieving a mean BG risk of hypoglycaemia; however, long-term studies are neces- concentration of 164 mg/dl (El-Khatib et al., 2010). The use sary to assess the effect of ongoing glucagon treatment. of a customized MPC algorithm provided heightened glycae- mic control, incorporating both subject weight and a PK In order to compare bihormonal and unihormonal closed- model of subcutaneous absorption and clearance of lispro loop systems in a more systematized method, Gao et al. (2013) from the blood. However, the algorithm could not anticipate used computer simulation in silico testing. Four types of insulin absorption for individuals with slower lispro PK so closed-loop control methods were compared on 10 virtual commanded further insulin doses, leading to excessive plasma hypoglycaemic subjects: insulin-only therapy, prediction insu- insulin in the late postprandial stage resulting in hypoglycae- lin-suspending therapy and insulin-glucagon dual-infusion mia. This explains intersubject variability in closed-loop therapy including proportional (P-type) and proportional- system performance (El-Khatib et al., 2010). The use of model- derivative (PD-type) switching rules. The subjects under based predictive algorithms for both insulin and glucagon can switching bihormonal systems maintained significantly lower permit dose instructions for future predicted glucose values BG indexes at 0.7 and 0.55 for P-type and PD-type, respec- and modification if secretion is inadequate; this produces a tively, in comparison to 3.43 and 3.13 for insulin-only therapy larger margin of safety for the prevention of hypoglycaemia and prediction insulin-suspending therapy, respectively (Gao (Peyser et al., 2014). et  al., 2013). Bihormonal systems also appeared to prevent hypoglycaemia (BG < 70 mg/dl) and were found to be More recently, Hovorka et al. (2014) evaluated overnight extremely robust in respect to hormone sensitivity variations, closed-loop insulin delivery in 16 young people with T1DM in measurement noises and intersubject variability (Gao et al., a free-living randomized clinical trial. Participants underwent 2013). Overall, the results suggested the superiority of two 21-day periods of sensor-augmented pump therapy with PD-type switching rule maintaining stable BG levels (Gao and without overnight closed-loop. Every 12 min, the treat- et al., 2013). to-target algorithm calculated insulin-infusion rate using a compartment model of glucose kinetics, accounting for MPC algorithms ‘control to zone’ design has recently been patient weight, total daily insulin dose and carbohydrate con- reported in several publications, where the objective is to tent of meals. The closed-loop system significantly increased bring glycaemic levels into an acceptable zone or range, rather the time of glucose in target range during both day and night than a strict and artificial target ( Gondhalekar et al., 2013). with fewer episodes of nocturnal hypoglycaemia. Compared Furthermore, eventually multiparametric MPC algorithms with control conditions, closed-loop therapy reduced mean may be adapted for personalized models available to each overnight glucose by a mean of 14 mg/dl and almost halved individual subject (Dassau et al., 2013). the number of nights when glucose was <63 mg/dl for at least 20 min (Hovorka et al., 2014). Moreover, numerous clinical trials have shown that the amylin analogue pramlintide acetate significantly reduces Closed-loop studies have revealed substantial night-to- postprandial hyperglycaemia by slowing gastric emptying, night variability in insulin requirements, with the amount and so can decrease insulin requirements by 30–50% (Ratner ranging between 50 and 200% from that given during control et al., 2005). Weinzimer et al. (2012) studied eight T1DM sub- (Hovorka et al., 2014). Difficulty in achieving consistent noc - jects using a closed-loop system with an insulin feedback algo- turnal glucose levels with insulin pump therapy alone con- rithm; allowing 24 h on closed-loop control alone and 24 h on firms the potential for closed-loop approaches. Results closed-loop plus 30 µ g pre-meal pramlintide injection. The indicate that integration of closed-loop therapy into a normal use of pramlintide significantly delayed time-to-peak BG and living routine with varied diet and sleeping patterns is feasible, significantly reduced glycaemic excursion from target 120 mg/ and conclude that unsupervised home-use of overnight closed- dL compared with control. It has been widely suggested that loop systems is safe (Hovorka et al., 2014). in order to provide further improvement in glycaemic control, the bihormonal approach may be expanded to include pram- Obstacles to overcome lintide (Micheletto et al., 2013). Despite promising results, there are no large-scale clinical trials Pharmokinetics in clinical studies on fully implanted bihormonal closed-loop systems at the pres- Clinical studies carried out by El-Khatib et  al. in 2010 fol- ent time. This is because a number of challenges must be solved lowed up 11 subjects with T1DM; the effect of bihormonal before the successful development of commercially viable arti- closed-loop systems was investigated for 27 h using the ficial pancreas devices. Firstly the functional components of 7 Review article Bioscience Horizons • Volume 9 2016 the artificial pancreas must be maintained; sensors of the Nonetheless, the physiological attractiveness of β-cell encapsula- CGM must be replaced every 7 days and require frequency tion is beset by challenges including paucity of islet transplants, calibration (Shah et al., 2014), the device must be recharged instant blood-mediated inflammatory responses and the inevi - regularly and insulin pumps refilled every 3 days ( Brown and table confinement by fibrotic overgrowth. Comparatively, Edelman, 2010). The insertion of CGM subcutaneously is an bihormonal closed-loop delivery systems have shown promise invasive procedure and thus results in an inflammatory in small clinical trials particularly with the use of pramlintide response at the insertion site that may produce inaccurate and PK customised algorithms but are behind in terms of CGM data (Shah et al., 2014) whilst catheter blockage may development due to a number of limitations. These include the prevent insulin delivery. Secondly, changes in insulin sensitiv- invasive procedure of device transplantation causing inflam - ity can occur based on concurrent illness, unusual levels of mation that gives inaccurate CGM data, the requirement for physical activity and medication taken by the patient. frequent maintenance and changing of system components, the inadequate formulations of insulin and glucagon and the sub- Improved formulations of insulin and glucagon are optimal accuracy and reliability of CGM with transient devia- required before bihormonal closed-loop systems can enter an tions including sensor overestimation. outpatient setting. The time from subcutaneous delivery to peak action of rapid-acting insulin analogues is around Recent work in human stem cell systems is promising; 90 min; in addition to this, the individual variability of however, a major goal will be using these cells to produce absorption and clearance of insulin analogues makes it pseudo-islets capable of the same level of bihormonal control increasingly difficult to imitate normal human physiological offered in islet systems. Conclusively bioartificial encapsula - conditions where insulin action is immediate (Shah et  al., tion is more effective in maintaining normoglycaemia com- 2014). A review by Cengiz (2013) discusses the different pared with closed-loop bihormonal artificial systems and is approaches for producing insulin with more favourable phar- more widely accepted as a natural, safer therapy. However, the mokinetics to facilitate quicker treatment of hyperglycaemia, scarcity of donor supplies and the long-term effectiveness of including localized heating, inhaled insulins and interperito- this approach remain significant challenges. Following the neal delivery. Glucagon is chemically and physically unstable positive outcomes in terms of capsule material qualification, and therefore a new solution must be prepared every 8 h; it is solving these two prominent issues should result in islet also sparingly soluble and has a tendency to fibrillate in solu - encapsulation displacing conventional naked islet treatment tion which can induce an immunogenic response in patients for the possible cure of T1DM. (Brown and Edelman, 2010). Acknowledgements Another significant limitation is the suboptimal accuracy and reliability of commercially available CGM systems, which Special thanks to my supervisor Dr David Watson for his sup- can give a relative absolute difference between sensor and ref- port and encouragement throughout my project. erence glucose measurements of up to 15% (Thabit and Hovorka, 2012). These deviations often relate to sensor over- Author biography estimation or mechanical perturbation; erroneous calibration or inappropriate algorithms (Thabit and Hovorka, 2012). In summer 2015 I graduated from Keele University, having Such a persistent deviation may cause insulin over-delivery achieved a first class honours degree in Biomedical Science. I and so increased risk of hypoglycaemia, posing the greatest have always had a personal interest in diabetes, experiencing challenge to closed-loop insulin delivery. Additional technical family members and friends diagnosed with the disease con- problems include the challenge of integrating CGMs, insulin stantly striving to manage their condition. Following my desire pumps and system algorithms from different commercial enti- to continue to learn about the treatment of different diseases ties, and there is also not currently a single insulin pump with and the safety of pharmaceutical drugs, I am currently study- a dual-cartridge system capable of continuous subcutaneous ing for an MSc in Toxicology at the University of Birmingham. infusion of both insulin and glucagon as its creation would be costly and time-consuming (Peyser et al., 2014). References Albisser, A. M., Leibel, B. S., Ewart, T. G. et al. (1974) An artificial endocrine Conclusion pancreas. Diabetes, 23 (5), 389–396. Current progress in capsule biocompatibility has brought Alipio, Z., Liao, W., Roemer, E. J. et al. 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(2010) Complications after pancreas transplantation. Current opinion in organ transplantation, 15 (1), 112–118. Pedraza, E., Coronel, M. M., Fraker, C. A. et al. (2012) Preventing hypoxia- induced cell death in beta cells and islets via hydrolytically activated, Unger, J. (2012) Uncovering undetected hypoglycemic events. Journal of oxygen-generating biomaterials. Proceedings of the National Diabetes, Metabolic Syndrome and Obesity, 5, 57–74. Academy of Science USA, 109 (11), 4245–4250. Valdes-Gonzalez, R. A., Dorantes, L. M., Garibay, G. N. et al. (2005) Peyser, T., Dassau, E., Breton, M. et al. (2014) The artificial pancreas: Xenotransplantation of porcine neonatal islets of Langerhans and current status and future prospects in the management Sertoli cells: a 4-year study. European Journal of Endocrinology, 153 of  diabetes. Annals of the New York Academy of Sciences, 1311, (3), 419–427. 102–123. Valdes-Gonzalez, R., Rodriguez-Ventura, A. L., Whitem, D. J. et al. (2010) Long- Pybus, F. C. (1924) Notes on suprarenal and pancreatic grafting. term follow-up of patients with type 1 diabetes transplanted with neo- The Lancet, 204 (5272), 550–551. natal pig islets. Clinical & Experimental Immunology, 162 (3), 537–542. Quesada, I., Tuduri, E., Ripoll, C. et al. (2008) Physiology of the pancreatic Vos, P. and Marchetti, P. (2002) Encapsulation of pancreatic islets for alpha-cell and glucagon secretion: role in glucose homeostasis and transplantation in diabetes: the untouchable islets. Trends in diabetes. Journal of Endocrinology, 199 (1), 5–19. Molecular Medicine, 8 (8), 363–366. Ratner, R., Whitehouse, F., Fineman, M. S. et al. (2005) Adjunctive therapy Vos, P., Hamel, A. F. and Tatarkiewicz, K. (2002) Considerations for success- with pramlintide lowers HbA1c without concomitant weight gain ful transplantation of encapsulated pancreatic islets. Diabetologia, and increased risk of severe hypoglycaemia in patients with type 1 45, 159–173. diabetes approaching glycaemic targets. Experimental and Clinical Weinzimer, S. A., Sherr, J. L., Cengiz, E. et al. (2012) Effect of pramlintide on Endocrinology and Diabetes 113 (4), 199–204. prandial glycaemic excursions during closed-loop control in adoles- Rogers, G. J., Hodgkin, M. N. and Squires, P. E. (2007) E-cadherin and cell cents and young adults with type 1 diabetes. Diabetes Care, 35 (10), adhesion: a role in architecture and function in the pancreatic islet. 1994–1999. Cellular Physiology and Biochemistry 19, 987–994. Weir, G. C. (2013) Islet encapsulation: advances and obstacles. Sakata, N., Sumi, S., Yoshimatsu, G. et al. (2012) Encapsulated islets trans- Diabetologia, 56 (7), 1456–1461. plantation: past, present and future. World Journal of Gastrointestinal Yamagata, K., Nammo, T., Moriwaki, M. et al. (2002) Overexpression of Pathophysiology, 3 (1), 19–26. dominant-negative mutant hepatocyte nuclear factor-1 alpha in Shah, V. N., Shoskes, A., Tawfik, B. et al. (2014) Closed-loop systems in the pancreatic beta-cells causes abnormal islet architecture with management of diabetes: past, present and future. Diabetes decreased expression of E-cadherin, reduced beta cell proliferation Technology and Therapeutics, 16 (8), 477–490. and diabetes. Diabetes, 51, 114–123. Shapiro, J., Ricordi, C., Hering, B. et al. (2006) International trial of the Zhi, Z. L., Khan, F. and Pickupm, J. C. (2013) Multilayer nanoencapsula- Edmonton protocol for islet transplantation. New England Journal of tion: a nanomedicine technology for diabetes research and manage- Medicine, 355, 1318–1330. ment. Diabetes Research and Clinical Practice, 100 (2), 162–169. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioscience Horizons Oxford University Press

Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus

Bioscience Horizons , Volume 9 – Mar 10, 2016

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BioscienceHorizons Volume 9 2016 10.1093/biohorizons/hzw002 Review article Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus Katie Baker* 72 Leasowe Drive, Perton, Wolverhampton WV6 7TU, UK *Corresponding author: 72 Leasowe Drive, Perton, Wolverhampton WV6 7TU, UK. Email: kbbaker@hotmail.co.uk Supervisor: Dr David Watson, School of Life Sciences, Keele University, Keele, Staffordshire, ST5 5BG. Type 1 diabetes mellitus (T1DM) is a chronic life-threatening condition whose incidence in the UK has doubled every 20 years since 1945 (Diabetes UK, 2010). Whilst intensive insulin therapy has been shown to reduce the incidence of long-term vascular complications in T1DM patients, it has also been shown to increase the risk of severe hypoglycaemia by 3-fold. Clinical islet transplantation has progressed considerably over the past decade, yet issues regarding the toxic effects of immunosuppres - sion drugs and the paucity of pancreatic donor supplies remain. To provide an effective long-term therapy for heightened glycaemic control, many studies are investigating the potential of bioartificial islet encapsulation strategies and artificial bihormonal closed-loop systems. Following consideration of the basis of pancreatic transplantation, this article takes an in- depth look at both the benefits and limitations of bioartificial and artificial therapies and compares their potential in terms of providing an effective long-term solution to patients suffering with T1DM. Key words: type 1 diabetes mellitus, pancreatic transplantation, islet encapsulation, bihormonal closed-loop system, glycaemic control, microcapsule device Submitted on 11 July 2015; accepted on 25 January 2016 Introduction When BG levels fall post-absorptive state, glucagon is released from pancreatic α cells, activating glycogen phos- Type 1 diabetes mellitus (T1DM) is an autoimmune condition phorylase to stimulate hepatic glycogenolysis and gluconeo- resulting in β-cell apoptosis of the pancreatic islets of genesis (Quesada et  al., 2008). The level of homeostatic Langerhans, which develops due to an environmental trigger in control achieved relies on the coordinated release of insulin genetically susceptible individuals (Knip and Simell, 2012). and glucagon via negative feedback. Further hormone inter- The primary soluble mediators of β cell loss are pro-inflamma - actions involve somatostatin-secreting δ cells, which respond tory cytokines interleukin-1β, interferon-γ and tumour necro- to post-prandial BG increase, acting to reduce gut motility sis factor-α; secreted by activated mononuclear cells to induce and increase nutrient absorption. Approximately 1 million differential expression of inflammatory response genes and islets are distributed throughout the healthy adult human pro-apoptotic hypoxia-inducible factor-α (Ortis et al., 2010). pancreas and each islet is then composed of ∼2000 cells; 65–80% are β cells, 15–20% are α cells and <10% are δ cells Pancreatic β-cell function is crucial for glycaemia regula- (Quesada et al., 2008). This multicellular structure enables tion; β cells act as physiological glucose sensors to detect important paracrine interactions; β cells make significant elevated blood glucose (BG) levels during the absorptive contacts with other endocrine cells, necessary for appropriate state, stimulating insulin release for the promotion of gly- insulin secretion. colysis, glycogenesis and lipogenesis (Leibiger et al., 2008). © The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution and reproduction in any medium, provided the original work is properly cited. Review article Bioscience Horizons • Volume 9 2016 Progressive loss of β cell mass by apoptosis, therefore, from severe hypoglycaemia even when insulin independence causes insulinopenia, leading to hyperglycaemia and ketoaci- was not sustained (Shapiro et al., 2006). Patients now consid- dosis. The primary treatment for T1DM at present is the injec- ered for islet transplantation include those who are C-peptide tion of exogenous insulin and regular monitoring of BG levels. negative and experiencing recurrent hypoglycaemic episodes. Insulin injection has enabled successful management of diabe- This is primarily because the adverse effects of life-long tes since its first use in 1922 by Banting and Best; however, chronic immunosuppression can be justified with the risk oth - many patients develop chronic secondary complications erwise posed by hypoglycaemic unawareness. involving renal insufficiency, neuropathological problems and Limitations associated with islet impaired vision principally due to difficulty in maintaining long-term stable BG levels (Ichii and Ricordi, 2009). transplantation The challenge of achieving tight BG control is exacerbated Whilst islet allotransplantation has shown promise towards a by ‘unaware’ hypoglycemic episodes; whereby excessive circu- more effective treatment than daily insulin injections, it is lating insulin and deficient glucagon response is met with currently performed in small numbers. This can be explained impaired sympathoadrenal response, reducing warning symp- partly by the requirement for chronic immunosuppressive toms and arousal from sleep (Hovorka et al., 2014). Recurrent medication against inflammatory cytokines, enabling oppor - episodes of untreated hypoglycaemia increase patient suscep- tunistic infections such as pneumonia and herpes to invade the tibility to the development of hypoglycaemia-associated auto- host, and often causing significant adverse effects including nomic failure (HAAF) that can result in devastating immediate anaemia, leukopenia, diarrhoea, vomiting and fatigue (Shapiro neurological consequences (Unger, 2012). Clinical studies et al., 2006). According to some studies, immunosuppressants have shown that hypoglycaemic unawareness can be reversed such as tacrolimus and sirolimus may also exhibit islet toxic- in just 2–3 weeks by complete avoidance of hypoglycemic epi- ity; impairing islet viability and graft function (Drachenberg sodes (Unger, 2012), yet this requires improved therapies for et al., 1999). continuous maintenance of safe BG levels, more effective than Another major limiting factor in islet allotransplantation is that provided by insulin injection alone. the profound scarcity of healthy human donor organs (Buder et al., 2013). Over 11 000 islet equivalents per kilogram (IEQ/ Pancreatic transplantation kg) of body weight are recommended per transplant for effec- The first human whole-organ pancreatic transplantation for tive graft function, requiring 3 or 4 pancreases due to diffi - the treatment of T1DM was undertaken in 1966 by W.D. culty in separating islets from surrounding exocrine tissue Kelly; this proved effective in restoring normoglycaemia and (Sakata et al., 2012). Therefore, coupled to donor shortage is achieved insulin independence in >80% of patients beyond 1 the equally significant issue of poor islet isolation efficiency year (Sutherland et al., 2001). Whole-organ pancreatic trans- and low islet cell yield, limiting attainment of appropriate plantation is now considered the standard therapy for T1DM mass required for transplantation. The Edmonton Protocol is patients with uncontrollable BG and end-stage renal failure; typically followed as the standard procedure for isolation and however, it retains the risks associated with major surgical islet culture pre-transplant; key elements include procurement procedures and has possible complications related to exocrine of donor pancreas via controlled ductal perfusion, organ pres- tissue enzyme production (Demartines et  al., 2005). High ervation in Winconsin solution, pancreas digestion using the mortality and low islet graft survival rate chiefly explains the Ricordi system and islet purification via continuous density limited application of pancreatic transplantation. Technical gradient. Islet-cell product must then be transplanted percuta- failure rates in surgical procedure of pancreatic transplant neously into the transhepatic portal vein within 3–4 h of isola- have now decreased to ∼8%; however, vascular graft throm- tion by simply gravity infusion; most commonly, the use of at bosis, intra-abdominal infection and reperfusion pancreatitis least two fresh islet infusions are required with expected remain issues in patient and graft survival (Troppmann, purity of >30% (Shapiro et al., 2006). More recently, studies 2010). Furthermore, according to ‘NHS Blood and Transplant’ have suggested the use of an additional purification step (res - for routine whole-organ pancreatic transplantation, the wait- cue density gradient) to improve recovery of trapped islets ing time is between 1 and 2 years, calculated individually (Miki et al., 2013). based on numerous factors including total HLA mismatch, Further loss of the transplanted islet mass (up to 70%) sensitization and dialysis status. takes place immediately post-transplant due to an instant As islets represent <2% of the pancreas, experimentation blood-mediated inflammatory response (IBMIR). During an was carried out to determine the feasibility of transplanting IBMIR, platelets bind rapidly to the islet surface, contributing islets alone. In the year 2000, seven patients with T1DM to the formation of a continuous fibrin capsule surrounding received islets from multiple donors during a study known as both islets and infiltrating polymorphonuclear leucocytes. the Edmonton Protocol. The study showed the successful use This causes disruption of normal islet morphology, whilst of steroid-free immunosuppression and transplantation of activating the complement cascade which mediates βcell lysis larger islet mass for the restoration of long-term endogenous (Özmen et al., 2002). Studies have demonstrated the protec- insulin production and glycaemic stability, protecting patients tive effect of a potent caspase inhibitor, IDN-6556 in rodent 2 Bioscience Horizons • Volume 9 2016 Review article hepatic and swine intraportal islet autotransplantation, with therefore tubes with wider lumens have been used (Vos et al., markedly reduced apoptotic activity suggesting potential for 2002). However, the use of wider lumens increases the diffu- reducing islet loss (Hoglen et al., 2007; McCall et al., 2012). sion distance and decreases permeability of the macrocapsule in comparison to microcapsules, causing insufficient nutrient Overall, the rate of insulin independence in patients follow- supply and waste material accumulation. Initial studies on ing islet transplantation is known to diminish over time, with islet macroencapsulation were unsuccessful due to aggrega- ∼55% remaining insulin-free after 2 years and only ∼15% tion of the grafted tissue allowing extensive necrosis in the after 5 years (McCall et al., 2012). In order to better this prog- centre of islet clusters (Lacy et al., 1991). This was solved by nosis, the development of bioartificial and artificial pancreatic preventing contact between the tissue elements through per- transplantation has more recently shown great promise manent immobilization in a matrix such as collagen, chitosan towards heightened BG control. A comparison of these alter- or alginate (Vos et al., 2002). native strategies will be discussed to evaluate their success in overcoming the limitations associated with islet allotransplan- During microencapsulation, each islet is enveloped in its tation and to consider their potential for therapeutic interven- own spherical semi-permeable membrane ranging from tion in T1DM. 100 nm to 1 mm in size, with generally one or a few islets per capsule as shown in Fig. 1. This offers greater diffusion capac- ity and a larger surface area enabling rapid response to BG Islet encapsulation strategies fluctuation. In extravascular microencapsulation, islets are Islet encapsulation also referred to as a ‘bioartificial’ pancreas, implanted in the peritoneal cavity in a prevascularized solid- involves the envelopment of isolated islets in high polymer support system for an optimal exchange of insulin and glucose material, in order to provide a selectively permeable barrier to and improved islet nutrition (Vos and Marchetti, 2002). protect inner islets from mechanical stress and the host Alginate was the first material to be developed for use in immune system. Meanwhile, this allows the bidirectional dif- microencapsulation and now remains the favoured material fusion of nutrients, oxygen and waste and glucose-responsive of choice due to its bioneutral nature, good stability and resis- release of insulin (Sakata et al., 2012). tance to oxidative damage, and relatively low cost (Lee and Mooney, 2012). Alginate is a naturally occurring anionic Comparison of different types polymer typically obtained from brown algae (Phaeophyceae) of  encapsulation and consists of unbranched binary copolymers of β-(1-4)- There are three major approaches to islet encapsulation d-mannuronic acid and α-(1-4)-l-guluronic acid of varying including intravascular macroencapsulation, and extravascu- composition (Sakata et al., 2012). Moreover, the addition of lar macro- and microencapsulation. Intravascular devices are materials such as polyethylene glycol and poly-l-lysine have anastomosed to the vascular system, placed within a hollow been shown to reduce plasma absorption and increase mem- semi-permeable membrane separating islet clusters from the brane stability to block the diffusion of serum immunoglobu- host systemic circulation. However, thrombus formation lin, albumin and haemoglobin in vitro (Desai et al., 2000). within the device lumen along with haemorrhage and infec- A significant issue in encapsulation is total graft volume; tion has forced intravascular devices to be largely abandoned the average islet diameter is 150 µ M with the surrounding (Vos and Marchetti, 2002). capsule increasing their size 3-fold (Dufrane and Gianello, In 1916, Frederick Charles Pybus attempted the first allo - 2012). In clinical settings, viable transplant sites are unable to transplantation of pancreatic tissue; grafting cadaveric pan- naturally carry the required volume of >100 ml of capsules. creatic fragments into the abdomen of two T1DM patients To increase islet concentration relative to implant volume, without therapeutic success. Pybus understood that although alginate beads are coated with a very thin membrane of poly- transplantation was the rationale treatment, until the princi- amino acids providing capsules of ∼200 µ m while maintaining ples of grafting were established their attempts would con- a liquid core structure. Microcapsules can be implanted into tinue to fail (Pybus, 1924). Previously effective transplantation the patient by a simple injection procedure and are not easily sites were not exploited; currently islet transplants are deliv- disrupted; however, they are more difficult to remove com - ered intraportally; however, when considering encapsulation, pletely when necessary in comparison to macrocapsules (Vos the increased islet diameter and demand to accommodate et al., 2002). larger islet volume requires alternative transplant sites to pre- One of the first in vivo studies performed intraperitoneal vent blockage of small hepatic vessels and ducts. allotransplantation of alginate–polylysine microencapsulated In extravascular macrocapsules, islets are immunoisolated and unencapsulated islets in rats with streptozotocin-induced within membrane-diffusion chambers implanted with mini- diabetes without immunosuppression. Post-transplant the mal surgery in the peritoneal cavity, the subcutaneous site and encapsulated islets survived 3 weeks and remained morpho- the renal capsule and easily removal when infected. Due to logically intact over 15 weeks, whilst unencapsulated islets their shape, macrocapsules made of polysulphone hollow survived only 8 days (Lim and Sun, 1980). By 1993, micr- fibres have a tendency to bend under physiological stress and oencapsulated islet allografts injected intraperitoneally in 3 Review article Bioscience Horizons • Volume 9 2016 Figure 1 Representation of three major types of encapsulation strategy in immunoisolation devices; intravascular macrocapsule and extravascular macro- and microcapsules. Adapted from Vos and Marchetti (2002), with permission from Elsevier. spontaneous diabetic canine studies were found to survive up detectable C-peptide levels in all patients, and the absence of to 726 days evidenced by positive C-peptide release (Soon- host immune sensitization reflected long-term safety of the Shiong et al., 1993). Following promising results in large-ani- bioconstruct. Calafiore and Basta placed emphasis on the mal studies, the first human clinical trial was performed in a importance of the composition of alginate encapsulation 38-year-old male with T1DM. Cadaveric human islets encap- material. sulated in alginate microcapsules were placed intraperitoneal at 10 000 IEQ/kg with 5000 IEQ/kg booster given 6 months Nanoencapsulation has also been investigated to minimize later. The patient was able to discontinue all exogenous insu- transplant volume, using a layer-by-layer assembly technique lin at 9 months, however was on anti-rejection mediation due where islet surfaces are coated with reactive-polymer segments to renal transplantation (Soon-Shiong et al., 1994). After 25 such as the insulinotropic ligand, GLP-1, to encourage years of intense pre-clinical study on microencapsulated islet increased glucose-responsive insulin secretion (Kizilel et  al., allografts, phase 1 pilot human clinical trials with four 2010). Furthermore, nanoencapsulation is intended to allevi- patients have now been completed and followed-up 5 years ate post-transplant IBMIR; diabetic mouse models have shown post-transplant (Calafiore and Basta, 2014 ). Poly-l-ornithine- that nanoencapsulated islets with phosphorylcholine-modified coated ultrapure alginate microcapsules were grafted intraperi- polysaccharide coatings can significantly extend survival of toneally into non-immunosuppressed T1DM patients, giving a transplanted islets (Zhi et al., 2013). Nanoencapsulation is far decrease in daily insulin consumption, HbA1c levels and hypo- from clinical application; however, research suggests its poten- glycaemic unawareness. Graft function was confirmed by tial in increasing graft survival in vivo. 4 Bioscience Horizons • Volume 9 2016 Review article results described suggest that SC-β cells present an opportunity Alternative supply of donor islets for therapeutic development, yet human clinical trials are not The bio-protection provided by encapsulation against immu- likely to start for several years. Moreover, factors contributing nological responses enabled investigation into the use of xeno- to cell loss post-transplant remain including IBMIR and there- geneic porcine islets. Initial human studies transplanted fore encapsulation strategies in combination would be essential. microencapsulated neonatal porcine islets combined with ser- Another limitation faced in islet transplantation and cell- toli cells subcutaneously into the abdomen wall of 12 non- based therapies recognizes that β cells require extensive intra- immunosuppressed T1DM patients. No porcine endogenous islet communication in vivo (Bavamian et  al., 2007). The retrovirus (PERV) infection was detected nor did any signifi - expression of connexion-36 protein forms permselective cant adverse effects manifest, half of the patients showed a channels that permit diffusion of cytosolic molecules between significant reduction in exogenous insulin requirements com - adjacent β cells within individual islets, to significantly regu - pared with pre-transplant levels, and glucose-stimulated por- late biosynthesis, storage and release of insulin (Bavamian cine insulin was detected in the sera of three patients up to 4 et al., 2007). The cell surface adhesion protein epithelial (E)– years post-transplant (Valdes-Gonzalez et  al., 2005). cadherin (ECAD) also plays an essential role in allowing Unfortunately, a 7-year follow-up showed that all patients β cells to cluster into islet structures (Rogers et al., 2007). This had returned back to their pre-transplant insulin doses has been shown in mouse β cells whereby the down-regulation (Valdes-Gonzalez et al., 2010). of ECAD contributes to abnormal islet architecture and Furthermore, in one study, a diabetic male was given an reduced insulin secretion (Yamagata et al., 2002). Following intraperitoneal xenotransplant of alginate-encapsulated por- understanding of the importance of synchronous and coop- cine islets at 15 000 IEQ/kg dosage. The patients HbA1c lev- erative activity of intact islets, the need to engineer IPS cell- els decreased from 9.3 to 7.8% within 14 months of receiving derived β cells into ‘pseudo-islet’ clusters (including other the transplant and produced detectable C-peptide for up to 11 endocrine cell types) is paramount, to allow a coordinated months (0.6 ng/ml). However, 49 weeks post-transplant, their regulatory network for fine-tuned effective insulin secretion insulin requirements returned to pre-transplant levels. In and BG stability (Hoang et al., 2014). order to understand why treatment slowly ceases to work, laparoscopy analysis was done 9.5 years post-transplantation. Issues with fibrosis and hypoxia This showed abundant nodules throughout the peritoneum, Microcapsules are designed to be immunogenically bioinvisi- containing opacified capsules with moderate insulin and gluca - ble, yet diffusion of low-molecular-weight cytotoxic molecules gon staining cells (Elliott et al., 2007). Porcine xenotransplan- due to incomplete encapsulation can successfully induce an tation is a promising approach to overcoming the shortage of instant blood-mediated inflammatory reaction ( Su et  al., human donor without the need for toxic anti-rejection ther- 2010). This leads to progressive thickening and scarring of apy; however, existing technology must improve in order for fibroproliferative connective tissue, which inhibits blood sup - therapy to be effective long-term. ply causing severe hypoxia and β-cell apoptosis (Weir, 2013). To ensure complete encapsulation, the polyionic charge of The more recent development of cell-based therapies is also islet surfaces can now be exploited as a binding site for poly- intended to alleviate issues of donor supply, exploiting the cationic coatings (Krol et al., 2006). promise offered by human stem cells produced in vitro for endogenous insulin production. In 2010 Alipio et al. demon- The ideal PO of peritoneal fluid surrounding islets for strated the reversal of hyperglycaemia in vivo using induced- optimal function has been determined at 60 mmHg, with islet pluripotent stem cells (iPSC) differentiated into mature β-like function at 50% by 27 mmHg and only 2% by 5 mmHg cells. Transplantation of iPSC in non-obese diabetic mice (Dionne et al., 1993). One approach to resolve hypoxia is to resulted in kidney engraftment and sufficient normalization of engineer an oxygen-generating biomaterial. In 2012, Pedraza BG detected via insulin secretion (Jeon et al., 2012). However, et al. used solid CaO in polydimethylsiloxane to deliver oxy- attempts for insulin-producing cells gave only β-cell like forms, gen to the encapsulated islets for 6 weeks, demonstrating lacking many functional characteristics and often of polyhor- improved islet function via increased insulin release in vitro. monal nature resembling transient endocrine cells (Bruina Studies have also shown how the temporary release of co- et  al., 2014). By October 2014, Douglas Melton’s group at encapsulated steroids such as dexamethasone can decrease Harvard reported the successful in vitro generation of func- ED-1/-2-positive macrophages and neutrophil-mediated tional human stem cell-β (SC-β) cells from human iPSC. inflammatory responses resulting in less fibrosis than those Transplantation of 5 million SC-β cells under the kidney cap- transplanted without (Bunger et al., 2005). sule of immunocompromised mice revealed that human embry- otic cells and iPSC package and secrete insulin into the host The bioengineering of a durable ‘bioartificial’ pancreas bloodstream within 2 weeks post-transplantation in glycaemic- hopes to improve long-term functionality of islets, whilst regulatory manner (Pagliuca et al., 2014). iPSC can be gener- eliminating the need for toxic immunosuppressant drugs. ated from embryonic fibroblasts or pancreas-derived epithelial However, many issues that limit its wider clinical application cells from the ultimate recipient of the transplant and are there- are still to be resolved including insufficient donor islet supply fore not faced with allo-rejection (Bruns et  al., 2013). The and total graft volume, fibrotic formation and islet hypoxia. 5 Review article Bioscience Horizons • Volume 9 2016 that provide programmed injections of insulin and glucagon Bihormonal closed-loop systems into the subcutaneous tissue. These pumps consist of refillable cartridges and have a user interface enabling patients to estab- Alternative studies have shifted their focus to improving lish a basal infusion rate and to give discrete bolus for cover- methods of BG control through enhanced exogenous delivery age of a meal or correction of hyperglycaemia (Peyser et al., of insulin with the development of an ‘artificial’ pancreas. In 2014). Perhaps, the most important component of an artificial 1974, Albisser et al. were among the first to describe an artifi - pancreas is the control algorithms incorporated into a micro- cial pancreas as a computerized control system. The system processor device, which automatically calculate real-time relied on the administration of glucose or insulin with a high insulin or glucagon (bihormonal) dosage based on data input level of complexity and could therefore only be used within from the CGM and insulin pump, to achieve specified target carefully supervised inpatient settings. Recent advances in the BG concentration. The three main algorithms include model accuracy and performance of the latest generation of closed- predictive control (MPC), which anticipates future glucose loop system components have accelerated the development of trends in insulin administration, proportional integral-deriva- devices, ultimately intended for outpatient use (Peyser et al., tive (PID) control, which continuously adjusts insulin infusion 2014). rates, and fuzzy logic, which takes into account patient char- The modern artificial pancreas is composed of three major acteristics and basal/bolus factors (Shah et al., 2014). functional components: a continuous glucose-monitoring (CGM) system, an insulin-infusion pump and a control algo- Unihormonal vs. bihormonal systems rithm (Fig. 2). The CGM is inserted subcutaneously at a depth of 8–12 mm in order to measure glucose in the interstitial There are two major level approaches to achieving closed-loop fluid rather than intravascular; recent studies have shown that BG control: unihormonal artificial pancreas systems infuse the physiological lag time between interstitial fluid and intra - only insulin to reduce BG concentration, whilst bihormonal vascular glucose is only 5–6 min (Basu et al., 2013). Insulin- systems deliver insulin during hyperglycaemia and glucagon infusion pumps are small, reliable electromechanical devices during hypoglycaemia (Peyser et al., 2014). Castle et al. (2010) Figure 2 Bihormonal closed-loop insulin and glucagon delivery system. Produced with information taken from Brown and Edelman (2010). 6 Bioscience Horizons • Volume 9 2016 Review article studied 14 T1DM patients undergoing closed-loop therapy fast-acting insulin analogue lispro and glucagon. Results with unihormonal or bihormonal control. In comparison to showed that six subjects achieved a mean BG concentration of unihormonal delivery, results showed that bihormonal delivery 140 mg/dl with no instances of hypoglycaemia, whilst five significantly reduced the time spent in the hypoglycaemic subjects did exhibit hypoglycaemia requiring carbohydrate range (15 ± 6 vs. 40 ± 10 min/day, P = 0.04) and significantly intervention due to slower lispro absorption (mean time-to- reduced the need for carbohydrate treatment (1.4 ± 0.8 vs. peak 117 ± 48 vs. 64 ± 4 min). Following preliminary results, 4 ± 1.4 treatments/day, P = 0.01). It was concluded that high- adjustment of pharmokinetic (PK) parameters prevented gain pulses of glucagon improved glycaemic control with little hypoglycaemia in all subjects, whilst still achieving a mean BG risk of hypoglycaemia; however, long-term studies are neces- concentration of 164 mg/dl (El-Khatib et al., 2010). The use sary to assess the effect of ongoing glucagon treatment. of a customized MPC algorithm provided heightened glycae- mic control, incorporating both subject weight and a PK In order to compare bihormonal and unihormonal closed- model of subcutaneous absorption and clearance of lispro loop systems in a more systematized method, Gao et al. (2013) from the blood. However, the algorithm could not anticipate used computer simulation in silico testing. Four types of insulin absorption for individuals with slower lispro PK so closed-loop control methods were compared on 10 virtual commanded further insulin doses, leading to excessive plasma hypoglycaemic subjects: insulin-only therapy, prediction insu- insulin in the late postprandial stage resulting in hypoglycae- lin-suspending therapy and insulin-glucagon dual-infusion mia. This explains intersubject variability in closed-loop therapy including proportional (P-type) and proportional- system performance (El-Khatib et al., 2010). The use of model- derivative (PD-type) switching rules. The subjects under based predictive algorithms for both insulin and glucagon can switching bihormonal systems maintained significantly lower permit dose instructions for future predicted glucose values BG indexes at 0.7 and 0.55 for P-type and PD-type, respec- and modification if secretion is inadequate; this produces a tively, in comparison to 3.43 and 3.13 for insulin-only therapy larger margin of safety for the prevention of hypoglycaemia and prediction insulin-suspending therapy, respectively (Gao (Peyser et al., 2014). et  al., 2013). Bihormonal systems also appeared to prevent hypoglycaemia (BG < 70 mg/dl) and were found to be More recently, Hovorka et al. (2014) evaluated overnight extremely robust in respect to hormone sensitivity variations, closed-loop insulin delivery in 16 young people with T1DM in measurement noises and intersubject variability (Gao et al., a free-living randomized clinical trial. Participants underwent 2013). Overall, the results suggested the superiority of two 21-day periods of sensor-augmented pump therapy with PD-type switching rule maintaining stable BG levels (Gao and without overnight closed-loop. Every 12 min, the treat- et al., 2013). to-target algorithm calculated insulin-infusion rate using a compartment model of glucose kinetics, accounting for MPC algorithms ‘control to zone’ design has recently been patient weight, total daily insulin dose and carbohydrate con- reported in several publications, where the objective is to tent of meals. The closed-loop system significantly increased bring glycaemic levels into an acceptable zone or range, rather the time of glucose in target range during both day and night than a strict and artificial target ( Gondhalekar et al., 2013). with fewer episodes of nocturnal hypoglycaemia. Compared Furthermore, eventually multiparametric MPC algorithms with control conditions, closed-loop therapy reduced mean may be adapted for personalized models available to each overnight glucose by a mean of 14 mg/dl and almost halved individual subject (Dassau et al., 2013). the number of nights when glucose was <63 mg/dl for at least 20 min (Hovorka et al., 2014). Moreover, numerous clinical trials have shown that the amylin analogue pramlintide acetate significantly reduces Closed-loop studies have revealed substantial night-to- postprandial hyperglycaemia by slowing gastric emptying, night variability in insulin requirements, with the amount and so can decrease insulin requirements by 30–50% (Ratner ranging between 50 and 200% from that given during control et al., 2005). Weinzimer et al. (2012) studied eight T1DM sub- (Hovorka et al., 2014). Difficulty in achieving consistent noc - jects using a closed-loop system with an insulin feedback algo- turnal glucose levels with insulin pump therapy alone con- rithm; allowing 24 h on closed-loop control alone and 24 h on firms the potential for closed-loop approaches. Results closed-loop plus 30 µ g pre-meal pramlintide injection. The indicate that integration of closed-loop therapy into a normal use of pramlintide significantly delayed time-to-peak BG and living routine with varied diet and sleeping patterns is feasible, significantly reduced glycaemic excursion from target 120 mg/ and conclude that unsupervised home-use of overnight closed- dL compared with control. It has been widely suggested that loop systems is safe (Hovorka et al., 2014). in order to provide further improvement in glycaemic control, the bihormonal approach may be expanded to include pram- Obstacles to overcome lintide (Micheletto et al., 2013). Despite promising results, there are no large-scale clinical trials Pharmokinetics in clinical studies on fully implanted bihormonal closed-loop systems at the pres- Clinical studies carried out by El-Khatib et  al. in 2010 fol- ent time. This is because a number of challenges must be solved lowed up 11 subjects with T1DM; the effect of bihormonal before the successful development of commercially viable arti- closed-loop systems was investigated for 27 h using the ficial pancreas devices. Firstly the functional components of 7 Review article Bioscience Horizons • Volume 9 2016 the artificial pancreas must be maintained; sensors of the Nonetheless, the physiological attractiveness of β-cell encapsula- CGM must be replaced every 7 days and require frequency tion is beset by challenges including paucity of islet transplants, calibration (Shah et al., 2014), the device must be recharged instant blood-mediated inflammatory responses and the inevi - regularly and insulin pumps refilled every 3 days ( Brown and table confinement by fibrotic overgrowth. Comparatively, Edelman, 2010). The insertion of CGM subcutaneously is an bihormonal closed-loop delivery systems have shown promise invasive procedure and thus results in an inflammatory in small clinical trials particularly with the use of pramlintide response at the insertion site that may produce inaccurate and PK customised algorithms but are behind in terms of CGM data (Shah et al., 2014) whilst catheter blockage may development due to a number of limitations. These include the prevent insulin delivery. Secondly, changes in insulin sensitiv- invasive procedure of device transplantation causing inflam - ity can occur based on concurrent illness, unusual levels of mation that gives inaccurate CGM data, the requirement for physical activity and medication taken by the patient. frequent maintenance and changing of system components, the inadequate formulations of insulin and glucagon and the sub- Improved formulations of insulin and glucagon are optimal accuracy and reliability of CGM with transient devia- required before bihormonal closed-loop systems can enter an tions including sensor overestimation. outpatient setting. The time from subcutaneous delivery to peak action of rapid-acting insulin analogues is around Recent work in human stem cell systems is promising; 90 min; in addition to this, the individual variability of however, a major goal will be using these cells to produce absorption and clearance of insulin analogues makes it pseudo-islets capable of the same level of bihormonal control increasingly difficult to imitate normal human physiological offered in islet systems. Conclusively bioartificial encapsula - conditions where insulin action is immediate (Shah et  al., tion is more effective in maintaining normoglycaemia com- 2014). A review by Cengiz (2013) discusses the different pared with closed-loop bihormonal artificial systems and is approaches for producing insulin with more favourable phar- more widely accepted as a natural, safer therapy. However, the mokinetics to facilitate quicker treatment of hyperglycaemia, scarcity of donor supplies and the long-term effectiveness of including localized heating, inhaled insulins and interperito- this approach remain significant challenges. Following the neal delivery. Glucagon is chemically and physically unstable positive outcomes in terms of capsule material qualification, and therefore a new solution must be prepared every 8 h; it is solving these two prominent issues should result in islet also sparingly soluble and has a tendency to fibrillate in solu - encapsulation displacing conventional naked islet treatment tion which can induce an immunogenic response in patients for the possible cure of T1DM. (Brown and Edelman, 2010). Acknowledgements Another significant limitation is the suboptimal accuracy and reliability of commercially available CGM systems, which Special thanks to my supervisor Dr David Watson for his sup- can give a relative absolute difference between sensor and ref- port and encouragement throughout my project. erence glucose measurements of up to 15% (Thabit and Hovorka, 2012). These deviations often relate to sensor over- Author biography estimation or mechanical perturbation; erroneous calibration or inappropriate algorithms (Thabit and Hovorka, 2012). In summer 2015 I graduated from Keele University, having Such a persistent deviation may cause insulin over-delivery achieved a first class honours degree in Biomedical Science. I and so increased risk of hypoglycaemia, posing the greatest have always had a personal interest in diabetes, experiencing challenge to closed-loop insulin delivery. Additional technical family members and friends diagnosed with the disease con- problems include the challenge of integrating CGMs, insulin stantly striving to manage their condition. Following my desire pumps and system algorithms from different commercial enti- to continue to learn about the treatment of different diseases ties, and there is also not currently a single insulin pump with and the safety of pharmaceutical drugs, I am currently study- a dual-cartridge system capable of continuous subcutaneous ing for an MSc in Toxicology at the University of Birmingham. infusion of both insulin and glucagon as its creation would be costly and time-consuming (Peyser et al., 2014). References Albisser, A. M., Leibel, B. S., Ewart, T. G. et al. (1974) An artificial endocrine Conclusion pancreas. Diabetes, 23 (5), 389–396. Current progress in capsule biocompatibility has brought Alipio, Z., Liao, W., Roemer, E. J. et al. 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Bioscience HorizonsOxford University Press

Published: Mar 10, 2016

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