Rachid Jellali

Amal Essaouiba

Eric Leclerc

Cécile Legallais
email: legallais@utc.fr

Dr Cécile

Chapter 4 : Membrane Bioreactors for Bio-artificial Pancreas

Designing an efficient and functional bioartificial pancreas (BAP) at human scale to treat type I diabetes remains the Holy Grail in the 2010s, although investigations started in the 1970s. Biomimetic approaches need to be performed and evaluated to offer insulin secreting cells an environment close to the native pancreas, but also accounting for the interactions between the pancreas and other organs, and more specifically liver. This chapter outlines the concept, development and recent progress of BAP technology, with specific focus on interaction between BAP and the host environment. After the introduction of pancreas anatomy and physiology and the current treatments for diabetic patients, we will study how fulfill (or not) the requirements for an efficient BAP, regarding its different components: cell types, encapsulation methods, membranes and devices dedicated to several implantation sites. We conclude with a short discussion of future directions including BAP revascularization to improve the exchanges with the host and the impact of microtechnologies on the development of next generation of BAP.

Introduction: the pancreas

The pancreas is a fundamental organ for coordination and regulation of body metabolism. The main functions of the pancreas are to control glucose homeostasis via endocrine hormones and produce exocrine enzymes necessary for digestion process. Pancreatic dysfunction is responsible for many diseases including diabetes mellitus, one of the most prevalent diseases in the world. This introduction is a brief overview of the anatomy, physiology and principal pathology associated to pancreas.

Anatomy and physiology

The pancreas is an organ with glandular structure located in the curve of duodenum just behind the stomach (Figure 1). It is divided into three regions [START_REF] Mahadevan | Anatomy of the pancreas and spleen[END_REF]: i) the head, connected to the duodenum, is the widest and most medial region of the organ; ii) the body is located behind the stomach; iii) the tapered tail region is located in the left side of the abdomen near the spleen. The vascularization of the pancreas is ensured by the anterior pancreaticoduodenal artery (head of pancreas) and multiple branches of the splenic artery (body and tail of the pancreas). Pancreatic vein joins the splenic vein to form the hepatic portal vein together with the inferior and superior mesenteric veins.

The pancreas is a heterocrine gland involved in both exocrine and endocrine regulation. The exocrine cells of the pancreas represent more than 90% of the pancreatic tissue and are grouped in structures called acini (Figure 1), whose function is the synthesis and secretion of enzymes implicated in the digestion process (pancreatic lipase and amylase, phospholipase, nucleases) [START_REF] Jouvet | The pancreas: Bandmaster of glucose homeostasis[END_REF]. Digestive enzymes are drained by the pancreatic ductal tree into the intestine where they aid in nutrient metabolism. The functional units of the endocrine system represent approximately 2% of the pancreas (2 million cells in human adults) and are made up of pancreatic islets or islets of Langerhans. They are clusters of cells whose size varies from 20 to 500 μm, with five different cell types: α-, β-, δ-, ε-, and γ (PP) cells [START_REF] Jouvet | The pancreas: Bandmaster of glucose homeostasis[END_REF][START_REF] Kumar | Pancreas specification: a budding question[END_REF] . The most abundant cells include the glucagon-producing αcells and insulin-producing ß-cells. The small proportion of δ-, ε-, and γ cells secrete somatostatin, ghrelin and pancreatic polypeptides, respectively. Despite comprising only 2% of the total mass of the pancreas, the islets receive around 15% of the pancreatic blood supply, allowing their secreted hormones ready access to the circulation [START_REF] Jansson | Pancreatic islet blood flow and its measurement[END_REF]. At the islet level, the oxygen partial pressure (PO2) is about 40 mmHg.

Figure 1 here 1.2 Mechanisms of glycemic regulation

The control of glucose levels in the blood is carried out by the interaction of two antagonistic hormones secreted by pancreatic α and β cells. Glucagon (alpha cells) increases glucose levels in the fasting period activating the glycogenolysis and gluconeogenesis in the liver in coordination with cortisol (hormone secreted by the adrenal gland). While insulin activates the uptake and storage of glucose in the muscle, fatty tissue and most importantly the liver through glycogenesis thereby decreasing blood sugar levels in postprandial (Barrett et al., 2015) (Figure 2).

The mechanism of regulation of blood glucose begins with the stimulation of insulin secretion that intensifies when blood glucose levels increase. The beta cells of the pancreas respond in a biphasic manner to this stimulus. First there is a rapid and brief rise (in the form of a peak) of insulin release, followed by a slower but constant release of the hormone (in the form of a plateau) over time [START_REF] Tortora | Principles of Anatomy and Physiology[END_REF].

The feedback loop that involves carbohydrates as an input signal and the synchronization of the insulin and glucagon release as an output allows the control of blood glucose and insulinemia to occur accurately and precisely [START_REF] Miller | Pancreatic neuroendocrinology: Peripheral neural mechanisms in the regulation of the islets of langerhans[END_REF].

The secretion of the two antagonist hormones is carried out in a pulsatile manner so that a simultaneous peak of insulin and glucagon would never occur. The synchronization of hormones is of great importance for the regulation of blood glucose by the liver.

Physiopathology & treatment

Diabetes mellitus is the most important dysfunction of the endocrine system of the pancreas affecting more than 422 million people worldwide, according to the International Diabetes Federation (IDF) and the World Health Organization (WHO) (IDF and WHO official web sites, 2018). Type I diabetes mellitus (T1DM) affects about 5-10% of diabetes patients, mostly the young population. It is a chronic pathology occurring due to the autoimmune destruction of pancreatic islet beta cells. As a result, there is a disorder in blood glucose levels caused by hyperglycemia and the inability to store glucose due to the absence of insulin. It is a pathology with a complex clinical picture. The breakdown of the control mechanism of blood glucose severely affects other organs and systems on long term basis, causing blindness, kidney failure, cardiac arrest, stroke, limb amputation due to thrombosis and even death [START_REF] Amer | Tissue engineering approaches to cell-based type 1 diabetes therapy[END_REF]WHO, global reports in diabetes, 2016).

The function in need of replacement in the case of insulin dependent diabetes is thus primarily the secretion of insulin by the pancreatic islet β cells, which has four characteristics: (a) it is continuous, even in the postabsorptive state, with rapid and transient peaks during meals: (b) it undergoes automatic regulation by blood glucose levels; (c) insulin is delivered into the portal blood system; (d) the endocrine pancreas is (of course) an internal organ placed within the body.

The most widespread treatment of T1DM is the daily and scheduled administration of insulin based on previous monitoring with a glucometer [START_REF] Klonoff | Continuous glucose monitoring: A review of the technology and clinical use[END_REF][START_REF] Stephens | Insulin therapy in type 1 diabetes[END_REF] (Table 1). In the best cases, insulin injections, glucose levels monitoring, and a restrictive diet could successfully keep the patient safe from the risks of the extreme hyperglycemia. However, the variety of the clinical profile of the patients and the age reveals the limitations of insulin injections as a treatment. On the one hand, the production of insulin usually decreases progressively as the disease progresses, so the patient continues to produce their own insulin in small quantities. This makes it difficult to estimate the amount of exogenous insulin to be administered at each moment. On the other hand, due to the nature of the pathology, it usually manifests at an early age. This makes it difficult to control certain variables such as intake and physical exercise especially in neonates and children. In addition, to correctly apply the treatment, continuous education of the patient is required to maintain glucose in the appropriate ranges [START_REF] Malik | Insulin therapy in children and adolescents with type 1 diabetes[END_REF].

Another treatment based on the same principle as insulin injections, but with some improvements is the insulin pump or also called "continuous subcutaneous therapy" [START_REF] Bruttomesso | Continuous subcutaneous insulin infusion (CSII) 30 years later: still the best option for insulin therapy[END_REF]. This approach is based on the subcutaneous delivery of insulin through a catheter connected to a peristaltic pump [START_REF] Galderisi | Keeping up with the diabetes technology: 2016 endocrine society guidelines of insulin pump therapy and continuous glucose monitor management of diabetes[END_REF]. This allows the control of the insulinemia 24 hours maintaining the basal level of glucose in the blood. The control carried out by the insulin pump mimics quite well the pattern of glucose concentration given by a healthy pancreas. However, possible infections and fibrosis at the site of catheter insertion are limiting factors of the use of the insulin pump as therapy. Despite the great advances that have been made in recent years for the development of this device [START_REF] El-Khatib | Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial[END_REF], the response time is another limiting factor in terms of abrupt changes in glucose concentration [START_REF] Tauschmann | Insulin pump therapy in youth with type 1 diabetes: toward closedloop systems[END_REF].

Depending on the patient clinical profile of the T1DM, transplantation of the pancreas is sometimes chosen as a strategy to control glycemia. Since 1966, the success rates of transplantation of the pancreas have been increasing thanks to technical improvements in extraction, preservation and implantation. Up to now, more than 1500 pancreas transplants have been carried out according to the Collaborative Islet Transplant Registry (CITR) [START_REF] Shapiro | Clinical pancreatic islet transplantation[END_REF]. However, it remains an invasive intervention that is usually carried out when kidney transplantation is also required. And most importantly, it involves the submission of the patient to immunosuppressants for the rest of his life.

The transplantation of islets of Langerhans is another approach that is applied to the treatment of diabetes (Chang et al., 2017;Ludwig et al., 2013a[START_REF] Ludwig | Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist[END_REF][START_REF] Ludwig | Transplantable bioartificial pancreas devices: Current status and future prospects[END_REF]. Since the 1960s, the purification of pancreatic islets and their transplantation into different animal models have been the objects of many groups of research. Pancreatic islet transplantation is a promising therapy for patients with T1DM difficult to control [START_REF] Bertuzzi | Long-term effect of islet transplantation on glycemic variability[END_REF]. It is a technique that provides an efficient and robust control of the homeostasis of glucose against the administration of insulin. However, islet transplantation remains controversial because it requires continuous immunosuppression that is harmful to both the graft and the patient [START_REF] Nourmohammadzadeh | Microfluidic array with integrated oxygenation control for real-time live-cell imaging: Effect of hypoxia on physiology of microencapsulated pancreatic islets[END_REF].

Table 1 here 2 The concept of bioartificial pancreas (BAP)

In the above-mentioned therapeutic strategies, the objectives are to replace either the structure (transplantation) or some functions (insulin injection) to compensate organ failure. Another approach is the design of a BAP based on the two major pillars in tissue engineering: cells and scaffolds. The objectives would be to mimic as much as possible the physiology of the native organ, using the cells for the production and release of insulin, but also as "glucose sensor" and the scaffold as biocompatible environment and immunoprotection for the cells (Figure 3).

Depending on the amount of tissue to be encapsulated, there are two major configurations of pancreatic islet immunoisolation: macroencapsulation and microencapsulation [START_REF] Pandolfi | Alginate-based cell microencapsulation for tissue engineering and regenerative medicine[END_REF] (Figure 4). In addition to the amount of tissue to be encapsulated, the content of the implant also determines the type of encapsulation implemented. It is not the same to encapsulate isolated beta cells than to encapsulate cellular aggregates or islets of Langerhans. In case the islets are directly covered by a polymer, the term of nanoencapsulation is commonly employed.

Macroencapsulation consists in the assembly of a large number of islets or cells within a selectively permeable membrane forming a macrocapsule with a dimension in the centimeter range or even larger. Depending on the site of implantation, macrocapsule-based devices are classified in two categories: intravascular and extravascular ones [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF][START_REF] Kepsutlu | Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets[END_REF]. Intravascular system is directly connected to the vessels of the host via an arteriovenous shunt [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF].

Microencapsulation is the entrapment of individual or few islets of Langerhans in a polymeric matrix [START_REF] Skrzypek | Membranes for bioartificial pancreas: Macroencapsulation strategies[END_REF]. Due to optimal volume-to-surface ratio, microcapsules allow fast exchange of insulin, oxygen and nutrients. Generally, microcapsules are produced from hydrogels like alginate, chitosan, agarose, polyethyleneglycol (PEG), copolymers of acrylonitrile and polyacrylates [START_REF] De Vos | Considerations for successful transplantation of encapsulated pancreatic islets[END_REF][START_REF] Skrzypek | Membranes for bioartificial pancreas: Macroencapsulation strategies[END_REF]. The most widely used microcapsules for islet immunoisolation is the ionically crosslinked alginate system [START_REF] De Vos | Alginate-based microcapsules for immunoisolation of pancreatic islets[END_REF]. In this process, cells are mixed within alginate solution and extruded dropwise into an aqueous calcium chloride gelation solution. The droplet entrapping islets solidify to become hydrogel beads in contact with Ca 2+ divalent cations [START_REF] Pandolfi | Alginate-based cell microencapsulation for tissue engineering and regenerative medicine[END_REF]. Finally, alginate beads are coated with cationic poly-amino acid (usually poly (L-lysine)) solution, which forms a semi-permeable membrane around the microcapsule [START_REF] De Vos | Alginate-based microcapsules for immunoisolation of pancreatic islets[END_REF][START_REF] De Vos | Considerations for successful transplantation of encapsulated pancreatic islets[END_REF].

To overcome the limitations associated to micro-and macroencapsulation (size, diffusion), the use of nanoscale immune-isolation layer has been developed. This strategy called nanoencapsulation allows the immunoisolation of single islet/β-cells, and the obtained devices are less than 100 µm in diameter [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF]. Different strategies have been developed including photopolymerization of PEG and layer-by-layer deposition of polycation and polyanion [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF][START_REF] Kepsutlu | Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets[END_REF][START_REF] O'sullivan | Islets transplanted in immunoisolation devices: A review of the progress and the challenges that remain[END_REF]. The reduced distance between the implanted islet and the host enhances the diffusion of oxygen, nutrients and insulin. The BAP is an implantable device formed by endocrine tissue encapsulated by a semipermeable biomaterial that provides protection against immunological agents and allowing the mass transfer of hormones, nutrients, oxygen and waste. In the process of BAP development, it is essential to know the different variables to be considered (donor, host, material and shape of the BAP, transplantation site ...) and how to combine them to get the optimal design.

There are various requirements depending on the components of the BAP.

1. Cell functions and number: the objective is to get the same type of response (amount of insulin/glucagon synthesized, sensitivity to glucose concentration) than from the native pancreas.

Therefore, the cells have to be correctly supplied for nutrients and oxygen, and with kinetics of blood glucose concentration.

2. Immuno-isolation ensured by the material: a compromise has to be found between rapid transfer of low and medium molecular weight solutes (glucose, insulin) and sieving of immunoglobulins and cells such as macrophages and leukocytes (Figure 5).

3. Biocompatible material for the cells and for the host.

4. Adequacy of the implantation site: to mimic the physiology, blood glucose should reach easily the bcells to stimulate if necessary insulin synthesis and secretion, insulin should be ideally released in the portal system. Minimally invasive surgery should be preferred, and the device should also be easily removable in case of failure.

Figure 5 here

Number and potential sources of pancreatic islets

Before addressing the cell type to use in a BAP, it is fundamental to answer the question of the number of cells/islets to implement. A human adult pancreas contains about a million and a half islets of Langerhans. However, as for other organs such as kidney or liver, they do not all operate simultaneously. To achieve normoglycemia in human, it is now widely considered that 15x10 3 islets equivalent (IEQ) per kilogram are needed in a BAP [START_REF] Kepsutlu | Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets[END_REF]. These figures come from experiments performed either in human or in small animals. In the past, our group was interested in BAP mass transfer modeling.

In a full model including glucose, insulin and O 2 transfer, we clearly outlined that O 2 was the limiting factor for BAP efficiency, and that oxygen starvation led to significant decrease in insulin release [START_REF] Dulong | What are the relevant parameters for the geometrical optimization of an implantable bioartificial pancreas?[END_REF]. In some cases, most of the implanted islets were necrosed, because their density in the implant was too high. In contrast, implementing a lower number of well oxygenated islets may lead to a better response in term of insulin release. We concluded that about 500,000 islets (i.e. 5x10 3 IEQ/kg) would be enough for human scale supply, if they maintain their functions.

Concerning primary human cells, it is reported that 2/3 of the endocrine tissue is lost in the purification stage during the pancreatic islet isolation process [START_REF] Hwang | Progress and challenges of the bioartificial pancreas[END_REF][START_REF] Ryan | Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol[END_REF][START_REF] Schweicher | Membranes to achieve immunoprotection of transplanted islets[END_REF][START_REF] Shapiro | Clinical pancreatic islet transplantation[END_REF]. Therefore, the actual availability of human donor pancreases can never fulfill the requirements for treating more than a small fraction of patients who need islet transplantation [START_REF] Kepsutlu | Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets[END_REF]. Actually, the insufficient number of human donors is the major motives for scientists to focus on exploration of other cell sources to replace the function of insulin secreting beta cells. Table 2 summarizes the advantages and limitations of different types of cells employed up to now in BAP.

The immunoisolation provided by encapsulation within semipermeable membrane indeed enabled investigation into the use of other sources of insulin-secreting cells. In the past, the use of xenogeneic porcine islets represented an interesting alternative because the close homology between porcine and human insulin (O' Sullivan et al., 2011;[START_REF] Song | An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport[END_REF][START_REF] Sykes | Clinical trial of islet xenotransplantation in Mexico[END_REF]. Several porcine islets transplantation demonstrated efficacy [START_REF] Dufrane | Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression[END_REF](Dufrane et al., , 2006a(Dufrane et al., , 2006c;;[START_REF] Dufrane | Macro-or microencapsulation of pig islets to cure type 1 diabetes[END_REF].

Studies by Dufrane et al. showed survival and function of encapsulated adult pig islets after implantation without immunosuppression into non-human primates. Diabetes was corrected up 6 months posttransplant in diabetic primates [START_REF] Dufrane | Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression[END_REF](Dufrane et al., , 2006d(Dufrane et al., , 2006b)). However, adult pig islets are expensive, fragile and difficult to maintain in culture after isolation. Alternatively, neonatal porcine islets represent an attractive source of cell for transplantation because of their ability for proliferation and differentiation, ease of isolation/purification and low cost [START_REF] Nagaraju | Islet xenotransplantation: what is the optimal age of the islet-source pig?[END_REF]. Survival and function of encapsulated neonatal porcine islets after transplantation into human and animals were reported by Elliott et al., Matsumoto et al. and Valdés-González et al. (Elliott et al., 2007, 2005b, 2005a;[START_REF] Matsumoto | Clinical porcine islet xenotransplantation under comprehensive regulation[END_REF][START_REF] Valdes-Gonzalez | Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study[END_REF]. Despite the encouraging results provided by encapsulated pig islets, new regulations, in Europe, prevent the use of such cells to avoid the risk of zoonosis [START_REF] Hwang | Progress and challenges of the bioartificial pancreas[END_REF][START_REF] Lima | Generation of functional beta-like cells from human exocrine pancreas[END_REF].

Several autologous alternatives are thus being investigated: differentiation of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) into beta cells [START_REF] Espes | MECHANISMS IN ENDOCRINOLOGY: Towards the clinical translation of stem cell therapy for type 1 diabetes[END_REF][START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF], and genetic modification of the exocrine pancreatic tissue in insulin-secreting cells [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF][START_REF] Skrzypek | Membranes for bioartificial pancreas: Macroencapsulation strategies[END_REF]. Some of these strategies are in advanced preclinical stages.

The differentiation of stem cells to insulin secreting cells represents an attractive alternative to human islets. Stem cells are able to self-renew and differentiate into specialized cell types, allowing the generation of all cell types of the human body [START_REF] Chhabra | Stem cell therapy to cure type 1 diabetes: From hype to hope[END_REF]. Among stem cells, ESCs and iPSCs are the most commonly studied for differentiation in pancreatic islets [START_REF] Amer | Tissue engineering approaches to cell-based type 1 diabetes therapy[END_REF][START_REF] Millman | Generation of stem cell-derived β-cells from patients with type 1 diabetes[END_REF]. The ideal source to obtain beta cells would be iPSCs since the tissue generated in vitro would be genetically identical to the pancreatic endocrine tissue of the patient. In the last years, several studies reporting insulin-secreting cells production from ESCs [START_REF] Cavelti-Weder | Reprogramming of pancreatic acinar cells to functional beta cells by in vivo transduction of a polycistronic construct containing Pdx1, Ngn3, MafA in Mice[END_REF][START_REF] D'amour | Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells[END_REF][START_REF] Kirk | Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape[END_REF][START_REF] Li | In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes[END_REF][START_REF] Pepper | Transplantation of human pancreatic endoderm cells reverses diabetes post transplantation in a prevascularized subcutaneous site[END_REF][START_REF] Rezania | Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells[END_REF] and iPSCs [START_REF] Bruin | Accelerated Maturation of Human Stem Cell-Derived Pancreatic progenitor cells into insulin-secreting cells in immunodeficient rats relative to mice[END_REF]Chang et al., 2017;[START_REF] Motté | Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts[END_REF][START_REF] Robert | Functional Beta Cell Mass from Device-encapsulated hESC-derived pancreatic endoderm achieving metabolic control[END_REF] have been published. Rezania et al. reported the normalization of blood glucose levels in diabetic mice after 120 days of human embryonic stem cells (hESCs) transplantation in vivo [START_REF] Rezania | Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice[END_REF]. After transplantation, the differentiation of hESCs cells was similar to human fetal pancreas development, with similar gene and protein expression profiles. Normalization of hyperglycemia in diabetic mice by hESCS, human induced pluripotent stem cells (hiPSCs) and mouse iPSCs-derived β cells was also demonstrated by Pagliuca et al. [START_REF] Pagliuca | Generation of functional human pancreatic β cells in vitro[END_REF], Yabe et al. [START_REF] Yabe | Efficient generation of functional pancreatic β-cells from human induced pluripotent stem cells[END_REF] and Alipo et al. [START_REF] Alipio | Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells[END_REF], respectively. However, there are still concerns regarding the ability of β-cells generated from stem cells to regulate insulin physiological levels in response to glucose [START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF].

Exocrine pancreatic tissue is the main part of the pancreas. This tissue, about 95% of total mass of pancreas, is discarded following each islet isolation procedure. Recently, scientists have been interested in a new approach based on reprogramming of exocrine acinar and ductal cells into insulin-secreting β-cells [START_REF] Shen | Generating insulin-producing cells for diabetic therapy: Existing strategies and new development[END_REF]. Exocrine cells are close of β-cells and have similar epigenetic profiles since they arise from the same progenitor common for all pancreatic cells (Pdx1 + cells) [START_REF] Bonal | Genes controlling pancreas ontogeny[END_REF]. Moreover, pancreatic exocrine cells are known by plasticity of their phenotype. Therefore, interconversion of exocrine cells in β-cells is easily possible [START_REF] Minami | In vitro generation of insulin-secreting cells from human pancreatic exocrine cells[END_REF]. Reprogramming of exocrine cells can occur through manipulation of pancreatic transcription factors (Pdx1, Ngn3, MafA, and Pax4), in combination with growth factors (betacellulin, exendin-4 and nicotinamide) [START_REF] Lima | Generation of functional beta-like cells from human exocrine pancreas[END_REF] . In vitro and in vivo generation of insulin-secreting β-cells from pancreatic exocrine cells has been widely studied and reported in literature [START_REF] Lemper | Reprogramming of human pancreatic exocrine cells to β-like cells[END_REF][START_REF] Lima | Generation of functional beta-like cells from human exocrine pancreas[END_REF][START_REF] Minami | In vitro generation of insulin-secreting cells from human pancreatic exocrine cells[END_REF][START_REF] Zhou | In vivo reprogramming of adult pancreatic exocrine cells to β-cells[END_REF]. Nevertheless, further developments are needed to guarantee high efficacy and safety of β-cells derived from exocrine cells (O' Sullivan et al., 2011).

In addition to stem, exocrine and xenogenic cells, several other strategies of β cells generation were/are studied. Among these strategies, the most studied are the use of immortalized human pancreatic cell lines and the reprogramming of cells from other organs such as liver cells and gastrointestinal cells [START_REF] Benthuysen | Advances in β cell replacement and regeneration strategies for treating diabetes[END_REF][START_REF] Cito | The potential and challenges of alternative sources of β cells for the cure of type 1 diabetes[END_REF][START_REF] Iacovacci | The bioartificial pancreas (BAP): Biological, chemical and engineering challenges[END_REF].

Table 2 here

Mass transfer issues in BAP and implantation site

As previously described, islets of Langerhans in a native pancreas are highly vascularized, providing the cells with glucose signal (from systemic circulation), oxygen (local PO2) and releasing insulin directly in the portal system to reach the liver. In addition, in the situation of hyperglycemia, the flow rate can be multiplied by six to improve the response kinetics.

Intravascular systems combining convection and diffusion

Ideally, the BAP should be located at the same position as in the native pancreas, i.e., as a shunt between arterial and venous circulation in the portal area. In such situation, both convective and diffusive bidirectional mass transfer would occur between the blood and the isolated islets.

Local mass transfer (Js) combining diffusion and convection can be described by the following equation: Js = Jf x S x Cs + Ds x grad (Cs)

With: Js in kg.m -2 .s -1 Jf: local solvent convective flux (m.s -1 ) : Jf = UFR x ∆P, with ∆P the local transmembrane pressure and UFR the membrane ultrafiltration rate S: membrane sieving coefficient for the solute of interest Cs (kg.m -3 ): solute concentration in the compartment from which convection process is issued Ds (m.s -1 ): diffusive coefficient of the solute between both compartments (NB: this coefficient takes into account resistance in the fluids but also across the scaffold/membrane) Grad (Cs): concentration gradient between compartments

Design and limits of perfusion chambers

The Figure 6A illustrates in a simple way the exchanges that can take place between the host and the islets isolated in a perfusion chamber, and the associated governing factors. Such chambers, with various designs, have been investigated since the mid-seventies employing either flat or hollow fiber membrane, inspired from artificial kidney devices [START_REF] Chick | A hybird artifical pancreas[END_REF][START_REF] Reach | Kinetic modelling as a tool for the design of a vascular bioartificial pancreas: feedback between modelling and experimental validation[END_REF][START_REF] Scharp | Islet immuno-isolation: The use of hybrid artificial organs to prevent islet tissue rejection[END_REF][START_REF] Sun | The use, in diabetic rats and monkeys, of artificial capillary units containing cultured islets of Langerhans (artificial endocrine pancreas)[END_REF].

Based on the kinetic modelling of glucose and insulin transfer through the porous structure, the group of Reach designed a system optimizing convective fluxes across the membrane, and yielded excellent kinetics in vitro [START_REF] Reach | A U-shaped bioartificial pancreas with rapid glucoseinsulin kinetics. In vitro evaluation and kinetic modelling[END_REF] and in vivo in rats [START_REF] Reach | Kinetics of insulin delivery by a bioartificial pancreas: in vivo evaluation in conscious normal rats[END_REF] and in dogs [START_REF] Lepeintre | Ex vivo evaluation in normal dogs of insulin released by a bioartificial pancreas containing isolated rat islets of Langerhans[END_REF]. The correction of hyperglycaemia in diabetic rats with this system was demonstrated over a few hours [START_REF] Reach | Bioartificial pancreas as an approach to closed-loop insulin delivery[END_REF]. However, the system was unable to avoid blood clotting inside the fiber.

Another major effort in this field was made by the group working with Chick, who used a radically opposite approach. They focused on the haemocompatibility of the system, and reported the successful graft of a vascular device in dogs over several months in the absence of any heparinization of the animals, which only received aspirin [START_REF] Monaco | Transplantation of islet allografts and xenografts in totally pancreatectomized diabetic dogs using the hybrid artificial pancreas[END_REF][START_REF] Sullivan | Biohybrid artificial pancreas: long-term implantation studies in diabetic, pancreatectomized dogs[END_REF]. Hyperglycemia was corrected, but the authors recognize that improvements in the kinetics of insulin release by this device were still required. Last results showed that a device seeded with xenogeneic porcine islets implanted into pancreatectomized dogs allowed to reduce exogeneous insulin requirement for up to 9 months [START_REF] Maki | Treatment of diabetes by xenogeneic islets without immunosuppression. Use of a vascularized bioartificial pancreas[END_REF]. This work led to an FDA authorization to initiate clinical studies. During one of the last preclinical transplants, the device failed leading to the death of the animals and the program was cancelled.

A similar system was proposed by Calafiore et al., who implanted micro-encapsulated islets inside the wall of a Dacron-based prosthesis connected to an arterial bypass. Plasma crossed the Dacron meshes and perfused the islets, which were immunoprotected by the membrane of the microcapsules, and which released insulin into the bloodstream. This system was investigated in a small number of dogs [START_REF] Calafiore | Intravascular transplantation of microencapsulated islets in diabetic dogs[END_REF] and in two diabetic patients [START_REF] Calafiore | Transplantation of microencapsulated pancreatic human islets for therapy of diabetes mellitus. A preliminary report[END_REF].

It is obvious that the development of these systems was hindered by the need for vascular access and by its thrombotic risk: indefinite prevention of clotting represents a formidable challenge. This may be one reason why the intravenous route for insulin delivery by implantable pumps has been almost abandoned in the late 90's. More recently, Prochorov et al. revisited the concept using an intravascular device that contains around 6000 IEQ/kg isolated from fetal rabbit [START_REF] Prochorov | Treatment of insulin dependent diabetes mellitus with intravascular transplantation of pancreatic islet cells without immunosuppressive therapy[END_REF]. 19 patients with T1DM received a nylon microporous device into the arteria profunda femoris (APF) using autovenous angioplastics [START_REF] Prochorov | Treatment of insulin dependent diabetes mellitus with intravascular transplantation of pancreatic islet cells without immunosuppressive therapy[END_REF]. After 18 months, the patients showed no complications related to the transplantation. Although insulin secreted was not enough to reestablish normoglycemia, it helps to reduce the insulin dose injected per day and protect against episodes of hyperglycemia or hypoglycemia.

Direct perfusion of encapsulated islets implanted in vascularized organs

This approach is inspired from the first transplantation of pancreatic islets into the portal vein of the liver which had been carried out successfully in the 90s [START_REF] Scharp | Insulin independence after islet transplantation into type I diabetic patient[END_REF]. Choosing the liver as a site of implantation of the BAP is driven by physiology, since liver is the first organ through which the hormones secreted by the pancreas pass. In addition, liver is a major site for glucose storage (glycogenesis) and release (gluconeogenesis). Finally, thanks to the last advances in minimally invasive surgery, BAP implantation could be carried out easily by percutaneous transhepatic portal embolization technique [START_REF] Goss | Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center[END_REF][START_REF] Ryan | Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol[END_REF][START_REF] Scharp | Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients[END_REF]. This site required to deploy microencapsulation of the islets, due to the size of the vessels. To overcome mass transfer limitations leading to cell necrosis, several groups even attempted to reduce the thickness of the encapsulating material by surface treatment of the islets directly instead of creating a continuous barrier around them (antibodies, heparin, cells…) [START_REF] Arifin | Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites[END_REF][START_REF] Cabric | Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet transplantation[END_REF][START_REF] Giraldo | The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model[END_REF][START_REF] Lau | Surface coating of pancreatic islets with neural crest stem cells improves engraftment and function after intraportal transplantation[END_REF][START_REF] Teramura | Bioartificial pancreas: Microencapsulation and conformal coating of islet of Langerhans[END_REF] or by using new improved biomaterials [START_REF] Mooranian | Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic β-cells[END_REF]Teramura andIwata, 2011, 2009), leading to so-called nano-encapsulation.

The coating or superficial treatment of the islets presents some very promising results after its implantation in rodents. The superficial treatment significantly reduces the size of the implant, allowing its insertion in highly vascularized organs as well as increasing postoperative survival up to 78% (Fotino et al., 2015;[START_REF] Teramura | Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers[END_REF]Teramura andIwata, 2010, 2009;[START_REF] Tomei | Device design and materials optimization of conformal coating for islets of Langerhans[END_REF]. But despite the good glycemic control obtained in diabetic subjects, the long-term stability of this encapsulation technique is quite questionable [START_REF] Arifin | Magnetoencapsulated human islets xenotransplanted into swine: a comparison of different transplantation sites[END_REF]. The deterioration of the protective layer exposes the islets to the attack of the immune system [START_REF] Giraldo | The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model[END_REF].

However, the liver as an implantation site presents some drawbacks. First, the space available is rather small for the size of the graft; it is necessary to consider that the microencapsulated islets in spheres of material containing one or two islets have a diameter of 400 μm each one. Secondly, microspheres hosting pancreatic islets generate problems of embolization and thrombosis of the small blood vessels around the implantation site induced by the instant blood-mediated inflammatory responses (IBMIR). The third drawback of the intraportal implantation is the partial pressure of oxygen to which the pancreatic islets will be exposed [START_REF] Zhu | Selection of implantation sites for transplantation of encapsulated pancreatic islets[END_REF]. The partial pressure of oxygen in the liver portal system is considerably lower than in the pancreas (5-10 against 40 mmHg) [START_REF] Carlsson | Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site[END_REF][START_REF] Olsson | Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation[END_REF][START_REF] Zhu | Selection of implantation sites for transplantation of encapsulated pancreatic islets[END_REF]: the islets are permanently in hypoxia, which affect significantly their viability. Usually, a large amount of IEQ islet per kilogram is needed for the pancreatic islets transplantation, considering that half of them die in a few hours after the intervention [START_REF] Shapiro | Clinical pancreatic islet transplantation[END_REF].

At first sight, the spleen could be also a good candidate as a BAP implantation site. It is a very vascularized organ with similar characteristics to the portal vein without the risk of hypertension induced after intraportal transplantation. The limited number of publications about intrasplenic transplantation in rodents and dogs shows that it is safe and feasible as a procedure. However, there are not enough studies to corroborate the suitability of the site for the BAP. The lake of studies is due to the small space available to place the majority of the devices, the risk of hemorrhage during surgery, the concentration of the immune system cells that could activate easily the IBMIR and the difficulty to remove the graft in case of failure [START_REF] Aoki | Intrasplenic transplantation of encapsulated genetically engineered mouse insulinoma cells reverses streptozotocin-induced diabetes in rats[END_REF][START_REF] Gores | Pancreatic islet transplantation: Is purification necessary?[END_REF][START_REF] Itoh | The spleen is an ideal site for inducing transplanted islet graft expansion in mice[END_REF].

Figure 6 here

Diffusion based extravascular systems

If perfusion cannot be considered, the alternative option is to enhance/promote diffusion, since the substances to exchange present relatively low molecular weight. In this case, the limiting parameter is the diffusion capacity of the solute, which is mostly governed by the diffusivity within the scaffold (Figure 6B). Mass transfer can thus be enhanced either by increasing the porosity of the structure, or by reducing the diffusion length. The diffusion length can be defined as the mean distance between islets and surrounding blood: it can thus be decreased either by decreasing the scaffold/device thickness, or by promoting neovascularization of the implant.

We will see in the following subchapter that these different strategies have been investigated in various implantation sites.

Omental pouch and intraperitoneal transplantation

Intraperitoneal transplantation is the most common site for the BAP in the clinical setting [START_REF] Basta | Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: Four cases[END_REF][START_REF] Calafiore | Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases[END_REF]Jacobs-Tulleneers-Thevissen et al., 2013a;[START_REF] Soon-Shiong | Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation[END_REF][START_REF] Tuch | Safety and viability of microencapsulated human islets transplanted into diabetic humans[END_REF]. One major advantage is the ease and safety of implantation through minimally invasive surgery and accessibility to the graft. It is an ideal choice for macroencapsulation systems due to the space available for the placement of the device. It benefits from appropriate environment considering that the encapsulated cells are in contact with the surrounding fluids allowing the exchange of insulin and nutrients.

Takeuchi and his group succeeded in restoring blood glucose level of diabetic rodents by the transplantation of different hydrogel-based microfibers [START_REF] Onoe | Metre-long cellladen microfibres exhibit tissue morphologies and functions[END_REF]Ozawa et al., 2017aOzawa et al., , 2017b;;[START_REF] Sugimoto | Implantable hydrogel microfiber encapsulating pancreatic beta-cells for diabetes treatment[END_REF]. Hollow fiber devices have been explored since early in the 80's. They give a good responsiveness to changes in glucose blood levels [START_REF] Jun | Microfluidicsgenerated pancreatic islet microfibers for enhanced immunoprotection[END_REF]. However, they had some drawbacks such the little amount of tissue that could be encapsulated in a fiber, requesting to consider significant lengths to be implanted [START_REF] Lacy | Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets[END_REF]. Takeuchi's group proposed an innovative technique based on microtechnology to produce fibers with small diameters without compromising the viability of the tissue (Ozawa et al., 2017b).

Alginate beads as a microencapsulated device seems to be more suitable device for intraperitoneal transplantation than macrodevices in terms of long term viability and performance [START_REF] Elliott | Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation[END_REF], 2005b, 2005a[START_REF] Matsumoto | Clinical benefit of islet xenotransplantation for the treatment of type 1 diabetes[END_REF][START_REF] Schweicher | Membranes to achieve immunoprotection of transplanted islets[END_REF][START_REF] Ryan | Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol[END_REF][START_REF] Valdes-Gonzalez | Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study[END_REF]. However, microbeads injected in the peritoneal cavity move from their original implantation site and end up in the lower part of the pelvis due to the upright position adopted by human and non-human primates (Dufrane et al., 2006a;[START_REF] Jacobs-Tulleneers-Thevissen | Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient[END_REF][START_REF] Lanza | Biohybrid artificial pancreas. Long-term function of discordant islet xenografts in streptozotocin diabetic rats[END_REF][START_REF] Omer | Macrophage depletion improves survival of porcine neonatal pancreatic cell clusters contained in alginate macrocapsules transplanted into rats[END_REF][START_REF] Sun | Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression[END_REF][START_REF] Vegas | Long-term glycemic control using polymerencapsulated human stem cell-derived beta cells in immune-competent mice[END_REF]ClinicalTrials.gov NCT01739829).

The peritoneal cavity has also certain drawbacks that do not fully meet to the requirements of the BAP. On the one hand, due tots anatomy and physiology, it has small or null revascularization capacity around the implant, which hinders the exchange of oxygen and nutrients and submits the encapsulated islets to hypoxia. On the other hand, not being in direct contact with the bloodstream limits the ability of the implanted device to respond to changes in glucose concentration is slow and delayed, which subjects the body constantly to hypoglycemia or hyperglycemia.

To mitigate the hypoxia, polydimethylsiloxane (PDMS) based materials with high oxygen permeability have been used for the graft encapsulation [START_REF] Coronel | Mitigating hypoxic stress on pancreatic islets via in situ oxygen generating biomaterial[END_REF][START_REF] Mcquilling | Methods for incorporating oxygen-generating biomaterials into cell culture and microcapsule systems[END_REF][START_REF] Pedraza | Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials[END_REF]. But the most representative device with an effective mechanism to improve the oxygen supply for islets survival is the β-air [START_REF] Barkai | Enhanced oxygen supply improves islet viability in a new bioartificial pancreas[END_REF]Ludwig et al., 2013b[START_REF] Ludwig | Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist[END_REF][START_REF] Neufeld | The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs[END_REF] or its new version beta-O 2 [START_REF] Ludwig | Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes[END_REF]. β-air is a disk diffusion chamber where the islets are loaded in an alginate-based core and a polytetrafluoroethylene (PTFE) based semipermeable membrane. But the most important characteristic is the central oxygen module connected with the outside of the host body that provides more O 2 than the blood transporters.

To improve the neovascularization of the graft, devices in development like Sernova cell pouch [START_REF] Kriz | A novel technique for the transplantation of pancreatic islets within a vascularized device into the greater omentum to achieve insulin independence[END_REF]ClinicalTrials.gov NCT01652911) and Viacyte (ClinicalTrials.gov NCT02239354) have made interesting progresses in recent years. Both devices are currently in phases I or II of the clinical study.

Sernova cell pouch has shown that omental transplantation with a subcutaneous access point (for the subsequent replacement of the islets) can induce a good neovascularization of the device thanks to the close position of the portal vein and the microenvironment that provides the great omentum. The omental pouch can be stimulated by neoangiogenic factors to create new blood vessels in a short time. 70% of the rodents involved in Kriz et al. study have shown long-term normoglycemia [START_REF] Kriz | A novel technique for the transplantation of pancreatic islets within a vascularized device into the greater omentum to achieve insulin independence[END_REF]. Several studies corroborated the suitability of the omentum as a site for the transplantation of encapsulated pancreatic islets [START_REF] Harrington | Hyaluronic acid/collagen hydrogel as an alternative to alginate for long-term immunoprotected islet transplantation[END_REF][START_REF] Opara | Design of a bioartificial pancreas[END_REF][START_REF] Pareta | Long-term function of islets encapsulated in a redesigned alginate microcapsule construct in omentum pouches of immune-competent diabetic rats[END_REF].

Kidney capsule

The renal subcapsular site is the most widely used for islet transplantation in experimental studies, especially in rodents. Islet transplantation into the kidney is easy and has been reported to restore normoglycemia [START_REF] Zhu | Selection of implantation sites for transplantation of encapsulated pancreatic islets[END_REF]. Kidney subcapsular space offers good vascular network and desirable growth conditions for islets [START_REF] Kepsutlu | Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets[END_REF]. Previous studies reported that mice and human islets transplanted in kidney subcapsular present better morphology and function, compared with islets implanted in liver, lung and spleen of mice [START_REF] Hayek | Experimental transplantation of human fetal and adult pancreatic islets[END_REF][START_REF] Mellgren | The renal subcapsular site offers better growth conditions for transplanted mouse pancreatic islet cells than the liver or spleen[END_REF]. In comparative study between intraportal and kidney subcapsular transplantation in mice, Sakata et al., demonstrated that two hundred islets yielded normoglycemia in renal subcapsular grafts, while minimum 800 islets are required for normoglycemia with intraportal transplantation [START_REF] Sakata | Efficacy comparison between intraportal and subcapsular islet transplants in a murine diabetic model[END_REF].

Transplantations of encapsulated islets with different shapes into kidney subcapsular space were also studied and have shown their ability to correct glycemia. Dufrane et al. investigated transplantation of pig islets microencapsulated with alginates into Kidney subcapsular space of monkey. The results demonstrated the functionality of alginate microcapsules and the absence of capsule fibrosis (Dufrane et al., 2006a). In other study, the same group has shown that alginate microcapsules transplanted under kidney capsule of rat demonstrate better biocompatibility than capsules transplanted in the peritoneum. In addition, due to restricted mobility of the grafts, alginate microcapsules integrity was preserved to a greater extent in the kidney, compared to peritoneal cavity (Dufrane et al., 2006d). Rat islet cells encapsulated within alginate microfibers and mice islets protected by PEGylation were also transplanted in kidney subcapsular of mice. Islets into alginate microfibers normalized blood glucose concentrations for two weeks in diabetic mice [START_REF] Onoe | Metre-long cellladen microfibres exhibit tissue morphologies and functions[END_REF]. Concerning PEGylated islets, the transplanted diabetic mice exhibited long term normoglycemia (>100 days) [START_REF] Giraldo | The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model[END_REF].

Despite the promising results observed in animal experiments, clinical transplantation into renal subcapsular would be difficult given the limited space within this site. It is impossible to implant devices with the islets number necessary to correct human glycemia. In addition, renal cortex has an oxygen tension of 15 mmHg, which represents an hypoxic environment for islets (the oxygen partial pressure in pancreas is about 40 mmHg).

Subcutaneous tissues

The first clinical trial of subcutaneous transplantation of a BAP has been carried out by [START_REF] Scharp | Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects[END_REF] The islets has been encapsulated by semi-permeable membrane in the form of hollow fiber [START_REF] Scharp | Protection of encapsulated human islets implanted without immunosuppression in patients with type I or type II diabetes and in nondiabetic control subjects[END_REF]. In an attempt to verify the biocompatibility and survival of human pancreatic islets, the results were quite promising. Although not surprisingly, the response time to the stimulus of insulin secretion was slow.

Subcutaneous transplantation is usually carried out for the macroencapsulated devices in the form of hollow fiber, planar or when an external oxygenation mechanism is integrated, like in the β-Air device [START_REF] Barkai | Enhanced oxygen supply improves islet viability in a new bioartificial pancreas[END_REF][START_REF] Ludwig | Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes[END_REF]Ludwig et al., , 2013a[START_REF] Ludwig | Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist[END_REF][START_REF] Neufeld | The efficacy of an immunoisolating membrane system for islet xenotransplantation in minipigs[END_REF]. The advantages of the subcutaneous transplantation are the easy access and monitoring of the graft, the good biocompatibility and the high viability of the islets in the postoperative period [START_REF] Pepper | A prevascularized subcutaneous device-less site for islet and cellular transplantation[END_REF]. However, the difficulty of neovascularization of the macrodevices and the low partial pressure of oxygen remain the major drawbacks in the subucutaneous transplantation.

The most representative device of subcutaneous transplantation is the Theracyte System ™ or its new generations Viacyte and Encaptra® [START_REF] Robert | Functional Beta Cell Mass from Device-encapsulated hESC-derived pancreatic endoderm achieving metabolic control[END_REF]. The first was initiated by Baxter Healthcare in the late 1990's as a planar device of two composite membranes sealed at all sides with a loading port or ports [START_REF] Cañibano-Hernández | Current advanced therapy cell-based medicinal products for type-1-diabetes treatment[END_REF]. The outside of the device is designed for strength and to encourage host tissue to incorporate into its outer portions. The other sections are a teflon-based membrane (PTFE) to encourage capillary ingrowth and a hydrogel semipermeable membrane (alginate based) for allograft immune protection. Theracyte has evolved in parallel with the safety level of experiments, from rodents to large animals implementing different cell sources including human cells [START_REF] Bruin | Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice[END_REF][START_REF] Elliott | Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation[END_REF][START_REF] Kirk | Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape[END_REF][START_REF] Kumagai-Braesch | The TheraCyte TM device protects against islet allograft rejection in immunized hosts[END_REF][START_REF] Motté | Composition and function of macroencapsulated human embryonic stem cell-derived implants: comparison with clinical human islet cell grafts[END_REF].The latest innovation provided by the manufacturers of Viacyte is the device-less character in its new trials thanks to the implemented prevascularization technique whose objective is the preparation of a suitable microenvironment for grafting before the cells implantation to improve the viability and the sensibility of the graft [START_REF] Kroon | Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo[END_REF][START_REF] Pepper | Transplantation of human pancreatic endoderm cells reverses diabetes post transplantation in a prevascularized subcutaneous site[END_REF][START_REF] Pepper | A prevascularized subcutaneous device-less site for islet and cellular transplantation[END_REF].

Another original approach has been described by Farina et al. They implemented a prevascularized polylactic acid (PLA) scaffold printed in 3D [START_REF] Farina | 3D printed vascularized device for subcutaneous transplantation of human islets[END_REF]. The porous biomaterial was tested in nude mice with human pancreatic islets. The islets were injected into the device 4 weeks after its transplantation. The angiogenesis of the islets was demonstrated, but it was necessary a second injection of islets to get the same amount of insulin secreted in the positive because of the slow neovascularization.

Subcutaneous transplantation remains controversial regardless the problem of angiogenesis and the mechanical requirements of the BAP. The superficial location of a graft so sensitive and so important for the control of metabolism can suffer irreversible damage due to temperature variations or physical trauma [START_REF] Zhu | Selection of implantation sites for transplantation of encapsulated pancreatic islets[END_REF].

Porous Scaffolds -Membranes

Table 3 here

Different materials have been employed as "membrane" structure. In intravascular devices, islets are encapsulated within hollow semipermeable tubes or fibers made of polymeric materials such as polyacrylonitrile-polyvinylchloride copolymer, polyethylene-vinyl alcohol, polycarbonate and nylon [START_REF] De Vos | Considerations for successful transplantation of encapsulated pancreatic islets[END_REF][START_REF] Skrzypek | Membranes for bioartificial pancreas: Macroencapsulation strategies[END_REF][START_REF] Song | Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices[END_REF]. In extravascular devices, two main geometries are used: tubular and planar devices. Various polymeric or inorganic biomaterials have been investigated. However, polymeric materials are the most commonly used. These include alginate, 2hydroxy-ethyl methacrylate (HEMA), nitro-cellulose acetate, acrylonitrile, sodium-methallylsulfonate, and PTFE [START_REF] De Vos | Considerations for successful transplantation of encapsulated pancreatic islets[END_REF].

Micro or macroencapsulation using alginate as basic material is probably the best response to biocompatibility since alginate is an inert polysaccharide. However, as material from natural origin, it may contain impurities promoting fibrosis. Alginate, when jellified with calcium or other divalent cations, is also not very stable over time and might lose its polymeric state. Therefore, crosslinking agents or additional layers have been added, changing the overall mass transfer and interactions with the host tissue [START_REF] Basta | Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: Four cases[END_REF][START_REF] Calafiore | Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases[END_REF][START_REF] Jacobs-Tulleneers-Thevissen | Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of mice leading to a pilot study in a type 1 diabetic patient[END_REF][START_REF] Soon-Shiong | Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation[END_REF][START_REF] Tuch | Safety and viability of microencapsulated human islets transplanted into diabetic humans[END_REF][START_REF] Veiseh | Size-and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates[END_REF]. Strand et al. reviewed the progress that have been made in alginate encapsulated pancreatic islets [START_REF] Strand | Current and future perspectives on alginate encapsulated pancreatic islet[END_REF]. The lack of long-term trials and cohort studies plus the fibrosis of the alginate-based capsules are the most important drawbacks to overcome.

According to the BAP requirements, all the scaffolds/membranes entrapping the insulin secreting cells or the islets are designed with the same objectives in term of sieving: allow the exchange of oxygen, nutrients, insulin and waste products and prevent immune response from the host (Fotino et al., 2015).

If this second point is fulfilled by the membrane-based devices, there is no need for immunosuppressive therapy after the implantation. Describing in detail the rejection process of a graft and the factors involved is far beyond the scope of this review. Briefly, this immune response, in the case of type I diabetic patients, can be of two different types : i) allogenic or xenogenic response of the host to the transplanted tissue, leading to the activation of the innate immune system due the detection of foreign cells by the host; ii) auto-immunity (following the same mechanisms than those inducing the pathology in the native pancreas [START_REF] Scharp | Encapsulated islets for diabetes therapy: History, current progress, and critical issues requiring solution[END_REF]. The first response is mainly supported by cells (lymphocytes B and T) but can also be mediated by immunoglobulins.

As indicated in Table 3, most of the synthetic polymer based membranes/scaffolds present pore size average 0.2-0.4 µm [START_REF] Colton | Implantable biohybrid artificial organs[END_REF][START_REF] Schweicher | Membranes to achieve immunoprotection of transplanted islets[END_REF], which is a sieve for cells only and not immunoglobulins. So far, immune rejection seems to be effective on relatively short-term basis. In these cases, the membrane demonstrated a very high porosity, and the diffusive transport is not hindered. Only the thickness of the device and the seeding density of the islets/cells influenced the mass transfer. In such case, Dulong and Legallais [START_REF] Dulong | A theoretical study of oxygen transfer including cell necrosis for the design of a bioartificial pancreas[END_REF] demonstrated that a too high density may lead to islet necrosis in case of implantation in poorly oxygenated sites.

Besides the sieving effect, in most of the case, one has to consider that the membrane is in contact with the host tissues. One major problem in biocompatibility for implanted device is the development of a fibrous and inert structure around the device. It represents an additional resistance to mass transfer and increases the risk of islets' necrosis due to oxygen starvation. A way to circumvent this issue would be to use materials that can promote neovascularization.

Conclusions and Future Trends

Pancreatic islet transplantation can successfully controls glucose levels and has been validated as a treatment for type 1 diabetes on short periods. The development of BAP that consists of islets encapsulation within semi-permeable membrane is considered as a promising strategy to overcome some obstacles of classical islet transplantation. Despite the significant progress in the lab, clinical applications of BAP are few. To increase the impact of the BAP translation from the bench to the bed side, it appears necessary to combine the progress made in different disciplines such as nanotechnology, biomaterials, immunology and tissue engineering.

Hypoxia adversely affects the functionality of encapsulated islets and represents a major limitation in the development of efficient BAP devices. Limited oxygen supply causes apoptosis and reduces the capacity of islets to secrete insulin [START_REF] Barkai | Enhanced oxygen supply improves islet viability in a new bioartificial pancreas[END_REF]. In the last years, different strategies including prevascularization and in situ oxygen supply have been investigated to improve encapsulated islet oxygenation. The combination of conformal coating and extravascular microencapsulation has shown some promising results. Other studies reported the use of proangiogenic factors (vascular endothelial growth factor (VEGF)) to induce BAP prevascularization [START_REF] Pileggi | Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device[END_REF][START_REF] Trivedi | Improved vascularization of planar membrane diffusion devices following continuous infusion of vascular endothelial growth factor[END_REF]. Several researchers are working on the co-encapsulation of insulin-secreting cells with another cell type in order to improve viability and stimulate graft neovascularization without compromising immunological safety [START_REF] Valdes-Gonzalez | Xenotransplantation of porcine neonatal islets of Langerhans and Sertoli cells: a 4-year study[END_REF][START_REF] Vériter | Improvement of subcutaneous bioartificial pancreas vascularization and function by coencapsulation of pig islets and mesenchymal stem cells in primates[END_REF]. Johansson et al. provided evidence that the coculture of MSCs and endothelial cells with human islets in vitro before transplantation initiated the formation of vessel-like structures that may promote further neovascularization [START_REF] Johansson | Formation of composite endothelial cell-mesenchymal stem cell islets: A novel approach to promote islet revascularization[END_REF]. In other approach, Barkai et al. developed a device that can be refueled with oxygen via subdermally implanted access ports. The transplantation of this device normalized glucose levels in diabetic rats for 6 months. The authors demonstrated that the functionality of the device was dependent on oxygen supply [START_REF] Barkai | Enhanced oxygen supply improves islet viability in a new bioartificial pancreas[END_REF].

In recent years, microfluidic technology has emerged as a valuable tool for a wide range of applications such as biotechnology, tissue engineering and analytical applications. This technology has been used to generate precise micro-scaled encapsulation. Onoe et al. developed microfibers encapsulating ECM proteins and islets cells using microfluidic device [START_REF] Onoe | Metre-long cellladen microfibres exhibit tissue morphologies and functions[END_REF]. The fabricated microfibres reconstitute intrinsic morphologies and functions of living tissues. In other study, Tomei et al. developed an encapsulation method that allows conformal coating of islets through microfluidics and minimizes capsule size, capsule thickness and graft volume. The reduction of capsule thickness improves oxygen and insulin exchange [START_REF] Tomei | Device design and materials optimization of conformal coating for islets of Langerhans[END_REF]. Microfluidic devices can be used in differentiation of stem cells, which can be alternative sources of islets for transplantation to solve the critical problem of the shortage of human islet donors. Indeed, the destiny of stem cells is highly regulated by microenvironment. Such devices provide a new support of cells culture with unique advantages to mimic complex physiological microenvironments in vivo [START_REF] Zhang | Stem cell culture and differentiation in microfluidic devices toward organ-on-a-chip[END_REF]: high oxygenation, 3D tissue reorganisation, dynamic stimulation, continuous nutrient supply and waste removal. Microsystems can be also used to assess islets or beta cells functionality before transplantation, in an environment close to in vivo conditions.

In conclusion, the interactions between the graft and its microenvironment still remain a huge challenge for the BAP. It is well known that the structural organization of the pancreatic beta cells and its interaction with the host cells influences the amount of insulin secreted [START_REF] Desai | Advances in islet encapsulation technologies[END_REF]. Tables Table 1: Summary of the different treatment available for type I diabetic patients.

List of symbols

  Figure 2 here

  Figure 3 here

FiguresFigure 1 .

 1 Figures

Figure 2 .

 2 Figure 2. Mechanisms of glycemia regulation by the pancreas and other tissues (liver, adipose, muscle).

Figure 3 .

 3 Figure 3. Concept of implantable bioartificial pancreas.

Figure 4 .

 4 Figure 4. Different concept of islet encapsulation, from macro to nano scale.

Figure 5 .

 5 Figure 5. Classification of the elements implicated in BAP inmuno-isolation by their molecular weight (adapted from Schweicher et al., 2014). (R) free radicals; (N) nitrogen metabolites; (+) cation; (-) anion; (Cyt) cytokines; (GF) growth factors; (C1q) complement component 1q.

Figure 6 .

 6 Figure 6. Schematic representation of intravascular BAP (A) and diffusion chamber (B).

Table 2 :

 2 Cells' sources, pros and cons to be used in BAP.

Table 3 :

 3 in vivo studies of some bioartificial pancreas in development.

	Cells source	With/without	Recipient	Inmuno-	Material	Transplantation site	Characteristics		Success	Reference
		immunosuppre		isolation
		ssants
	Porcine			No		Kidney	Fetal	porcine	Partially.	Groth MD
							islet-like clusters (ICC)	cell	Presence of porcine	et 1994 35	al.
										peptide-C
	Porcine			No		Kidney	Fetal	porcine	Yes	Reinholt
							islet			et al. 1998
	Porcine			yes		subcutaneous	porcine			Yes	Valdés-
						autologous	neonatal islets	González
							of Langerhans	et al. 2005
							and Sertoli cells
	Porcine			yes		Peritoneal cavity	neonatal			Yes	Matsumot
							porcine islets	o et al.
										2014
	Porcine			yes		Peritoneal cavity	neonatal			No,	Elliott et
										immuno-