CellR4 2017; 5 (3): e2410 The as a site for pancreatic islet transplantation

M. Pellicciaro1, I. Vella1, G. Lanzoni2, G. Tisone1, C. Ricordi2 1Liver Transplant Center, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy. 2Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, FL, USA.

Corresponding Author: Marco Pellicciaro, MD student; e-mail: [email protected]

Keywords: Omentum, Greater omentum, Islet of Lang- fat tissue, and lymphoid aggregates called “milky erhans, Islet of Langerhans transplantation, T1D, Islet trans- spots”. Two monolayers of contain plantation, Pancreatic islet transplantation, Diabetes type 1, all the above cell types and structures, with the Beta cell transplantation. exception of milky spots – where the mesotheli- um is interrupted. The macroscopic presentation Abstract of the greater omentum depends on the age of The greater omentum is a highly vascularized the individual, nutrition, pathological conditions anatomical structure in the . Its and state of stimulation (such as in foreign body main components are connective, adipose and reactions, peritoneal dialysis). The right and left vascular cells, along with specialized immune Gastroepiploic arteries provide supply to cells. The omentum functions as a site for fat ac- the greater omentum. Both arteries derive from cumulation, it has adhesive properties to control the celiac trunk and pass the greater gastric cur- traumatized and inflamed tissues, and a function vature. They progressively branch out towards in local hemostasis, immune responses, and re- the and the omentum, giving terminal vascularization. Other functions include the ab- vessels for the omentum through the right and left sorption of fluids, the phagocytosis of particulate epiploic arteries. The omental margin blood supply matter, and foreign body reaction. The omentum is provided by numerous capillaries which may is catalyzing significant interest for its potential have minute anastomoses2 (Figure 3). Milky spots as a site for pancreatic islet and cell transplan- present peculiar convoluted vascular structures tation. Our knowledge about this structure, its termed omental glomeruli3. These microvascular functions, and its potential as a site for transplan- structures show a characteristic architecture at the tation is poised to grow in the coming years. lateral branches of the epiploic arteries and their terminal branches. The vascular network is usually densely packed with various cells of the reticular Anatomy and Histology system and fat cells. The outstanding feature is of the Greater Omentum that the vascular walls have many fenestrations. The greater omentum (or epiplón mayor) is an Because of the discontinuous mesothelial lining anatomical structure resembling an apron, hanging on the milky spots, the glomerulus-like vascular in the peritoneal cavity, and usually extending over structures are exposed to the peritoneal cavity4. The a large area of the abdomen1 (Figure 1, 2). It arises normal venous drainage parallels the arteries and from the greater curvature of the stomach, it cross- empties into the portal system5. The gastroepiploic es the and descends in front of ab- increases in diameter after receiving branches dominal viscera, covering the intestines. There are from stomach and omentum and empties into the two portions: the gastrocolic , from the superior mesenteric vein (83%) or in the first part stomach to the transverse colon, and an area below of the splenic portal vein6. The terminal lymphat- the colon called apron (Figure 2). The omentum is ics form a web with irregular interconnections and composed of a frame of trabecular connective tis- with bulging saccular parts. This forms an unusual sue, intermingled with arteries, , lymphatics, pattern shaped like flattened tubes7. Some of the

1 2 M. Pellicciaro, I. Vella, G. Lanzoni, G. Tisone, C. Ricordi

saccular terminals are located within the vascular system of milky spots, hence they also are exposed to the because of the gaps in the mesothelial lining8. The main cellular components of the greater omentum are adipose and connective (mesenchymal) cells. The extracellular matrix is composed of collagen, elastic and reticular fibers, connected by microfibrils. Blood vessels, vessels, and fibers pass through this mesh. The omentum loose connective tissue is areolar, as it presents fixed cells (fibroblasts, fibrocytes, fat cells, pericytes) and mobile cells (histiocytes, monocytes, plasma cells, , eosinophil- ic granulocytes, mast cells). Fat cells are the most numerous cellular population, and their mass in- creases significantly in individuals with high Body Mass Index (Figure 4)1.

Embryological development The embryonic mesoderm is a cell layer that lines the () in amniotes. The meso- derm gives rise to multiple derivatives, including Figure 1. Scheme of the main constituents of the omentum (Reprinted from “The Greater Omentum”, 1983, Edited by the mesothelium - a layer of cells that remains as D. Liebermann-Meffert and H. White – with permission a lining of the abdominal cavity, pleura, medias- from Springer-Nature). tinum, and pericardium. The mesothelium lining

Figure 2. Diagram showing peritoneal reflections and topographical relations of the omentum in the sagittal section in humans (Edited from “The Greater Omentum”, 1983, Edited by D. Lieb- ermann-Meffert and H. White – with permission from Springer-Nature). The greater omentum as a site for pancreatic islet transplantation 3

Figure 3. Vasculature of the Greater omentum in a human donor, imaged via angiography with barium gelatine. (Re- printed from “The Greater Omentum”, 1983, Edited by D. Liebermann-Meffert and H. White – with permission from Springer-Nature). the abdominal cavity is associated with a layer of connective tissue, and these tissues are collectively termed . The peritoneum forms a covering the organs in the abdominal cavity. A double fold of peritoneum constitutes the , that attaches the intestines to the wall of the (interestingly, the mesentery has been recently proposed for reclassification as an organ9). Figure 4. Adult human omentum from (a) a 36-year-old The portion of the dorsal mesentery that attaches donor with a lean omentum and (b) from a 69-year-old donor with heavy deposition of fat in the omentum. (Re- to the greater curvature of the stomach is known as printed from “The Greater Omentum”, 1983, Edited by D. the dorsal mesogastrium (Figure 5). This structure Liebermann-Meffert and H. White – with permission from subsequently expands, ‘balloons’ and then ‘deflates’, Springer-Nature). giving rise to an apron-like structure (a double layer of peritoneum) that is known as the greater unique structure of its microcirculatory system. omentum1. The rotation of the primitive stomach In pathological conditions, the omentum performs and the folding of the dorsal mesentery containing functions aimed at preserving body homeosta- the and form a dependent large in- sis12,13. The omentum absorbs particles and has an ferior recess know as the lesser sac10. The greater important role in combating abdominal infections omentum is thus one of the omenta deriving from (Morison called it the “abdominal policeman”13). the folding of the peritoneum; it is located between During episodes of , the omentum rapidly the (peritoneal cavity proper) and the clears bacteria and foreign material that have pen- lesser sac (omental bursa) of the abdominal cavity. etrated into the peritoneal cavity14. Effector mech- A fusion of the double layer of peritoneum most anisms are mediated by , neutrophils likely occurs, giving rise to the adult greater omen- and, probably, B-lymphocytes. Macrophages are tum11 (Figure 2). contained within the milky spots, and from there they can migrate into the peritoneal cavity via the Physiology, Function, and Pathophysiology openings in the mesothelial layer15. These macro- of the greater omentum phages phagocyte particles and bacteria from the The physiological function of the omentum is still peritoneal cavity. Subsequently, neutrophils can be unclear but it is believed to be connected to the recruited from the circulation, extravasate in the 4 M. Pellicciaro, I. Vella, G. Lanzoni, G. Tisone, C. Ricordi

Figure 5. Schematic of the human embryo showing the disposition of developing organs and the location of the dorsal mesogastrium, that will give rise to the greater omentum.

milky spots and exudate in the peritoneal cavity studies show that the exchange flows are extreme- to perform anti-microbial functions16,17. The omen- ly efficient, if not the most efficient among those tal functions of adhesiveness and cohesiveness observed in the human body22. Under steady-state are fundamental during mechanical trauma, tissue conditions, most of the fluid passing the capillary ischemia, intra-abdominal infections or reduced barrier in the omentum seems to become lymph. peristalsis18. Injury to the serosal membranes caus- Hence, the liquid originating from the omental mi- es an immediate exudation of albumin, globulin, crocirculation does not return directly to the blood and fibrinogen that, once activated, become fibrin. but passes through the . 3 hours after the exudative phase, the phase starts. This is characterized by ingrowth of Pathology fibroblasts and capillaries, and it occurs at a pace The greater omentum can present congenital ab- that is faster than adhesions observed between oth- normalities, and is susceptible to inflammatory er abdominal viscera19. The omentum also has the disease, infarction, primary tumor and tumor me- ability to reduce hemorrhage from injuries and to tastases. Omentitis in one of the most frequent absorb fluids from the peritoneal cavity. Detailed diseases of the omentum. The term omentitis in- investigation in more recent years has shown that dicates an inflammatory process of the greater it is able to encapsulate infarcted organs 20. Pirone omentum (the term epiploitis is instead used to and Wilkie observed that polymorphonuclear leu- indicate an inflammatory process involving the kocytes and mesothelial cells from the omentum greater omentum, the lesser omentum and the ap- enter the infarcted and through the ingrowth pendices epiploicae)23. Historically, omentitis has of capillaries determine its transformation into scar been classified in post-operative, post-traumatic or tissue21. The study of the chemical composition of spontaneous forms24. The spontaneous form occurs irrigation fluids indicates that exposure, micro- with bacterial infection (e.g. Mycobacterium tuber- surgical injury, and other forms of trauma in the culosis25), it can be due to visceral inflammation, omentum consistently determine an inflammatory compression, torsion, and infarction - or it can be and vasodilatory response; this can cause higher idiopathic26. Inflammatory processes and fibrosis permeability, augmented fluid filtration and - in in the omentum can be due to fungi, actinomy- creased local capillary pressures22. Microvascular cetes27 or parasites28. Actinomycetes infection can The greater omentum as a site for pancreatic islet transplantation 5 result from trauma or immunosuppression29. Par- tigators should be aware of the potential risk and asites affecting the omentum include Trematodes, should monitor recipients accordingly. Cells of Cestodes, Nematodes (e.g. filarial nematodes), Pen- the omentum can undergo benign or malignant tastomids, and Protozoa (e.g. plasmodium species transformation. When compared to other tumors, causing malaria1, amoebae30). Another cause of omental tumor has a relatively low prevalence. No inflammation that could attract the attention of systematic studies on omental benign tumors are the researchers is the reaction to the presence of available. Most of the omental benign neoplasms foreign bodies31. This reaction is usually related to are small and observed intraoperatively36. The vast the presence of needles, drains, catheters, copro- majority of malignant tumors localized at the liths, or other particulate material; it is composed omentum are metastases, frequently deriving from of macrophages and foreign body giant cells31. A , stomach and colon cancer. Less than 3% of similar foreign body reaction could occur after the malignant tumors in the omentum are primary cell transplants with encapsulation technologies omental tumors36. Mihail-Gabriel Dimofte report- used to reduce immune reactions. Fibrosis and ed a rare case of Extra-gastrointestinal stromal scar formation are frequently the final outcomes tumors (EGISTs) in the omentum; the omentum of the pathological states indicated above. The is an unusual location for this tumor (1% of the greater omentum is also subject to necrosis in EGISTs occur in the omentum)37. EGISTs have case of acute pancreatitis32. Macroscopically the features similar to Gastrointestinal stromal tu- main lesions are characterized by fat necrosis – ap- mors, they represent approximately 10% of all pearing as yellow-white and chalky foci that may stromal cancers38. The insulin-like growth factor 1 be scattered all over the omentum. During this receptor (IGF1R) and its ligands have an important pancreatic inflammatory process, the peritoneal pathophysiologic role in stromal tumors39. Islet cavity accumulates a turbid fluid, which may be- transplantation in the omentum could determine come infected. The lesions are not pathognomonic inflammation and high local insulin concentration. because they may occur after duodenal perforation Insulin at high concentration can activate IGF1R40, or traumatic injuries of . Normally, triggering cell proliferation and antiapoptotic path- chronic does not determine omental ways. Inflammation and IGF1R activation could lesions. Particular attention should be given to the increase the risk of development of omental tu- omental torsion and infarction. Omental torsion is mors. This risk should be taken into consideration. classified into primary (due to intrinsic causes)33 and secondary (due to extrinsic causes). Despite Surgical Use being a rare condition, secondary torsion may oc- The rich vascularization and the vascular plasticity cur much more frequently than primary. Torsion is of the greater omentum have attracted the attention frequently recorded as a secondary finding during of many surgeons. The omentum has been used for abdominal surgery. Omental torsion can determine protective and reconstructive surgery in conditions the throttling and strangulation of vessels. The such as stomach and intestinal perfurations1. The sequelae resulting from this could be localized or omentum is currently being studied as a site for generalized omentum necrosis. with hemorrhagic pancreatic islet transplantation. exudation and aseptic inflammation33. Scar tissue formation is usually observed if the foci of ne- Sites for Pancreatic Islet Transplantation crosis are small, whereas larger areas of necrosis It is estimated that 4% of the world population is lead to abscess formation34. Necrotic areas can affected by diabetes mellitus and that 10% of dia- form after appendectomy. The typical and gold betic patients have type 1 diabetes41. The prevalence standard treatment of omental infarction is the of this disease is increasing. Insulin is the primary surgical resection of the necrotic areas associated treatment method for diabetes. Insulin is a life-sav- with appendectomy35. As discussed in a separate ing intervention, but it can determine hypoglycemic paragraph, pancreatic islet transplantation in the events. Approximately 5-10% of patients experience omentum is currently performed by “rolling-up” multiple, severe and unexpected episodes of hypogly- (or “folding-up”) the greater omentum. Omental cemia, which can have serious and life-threatening infarction secondary to this surgical procedure consequences. In such cases, pancreas transplanta- has never been reported, but surgeons and inves- tion is an alternative treatment option that is already 6 M. Pellicciaro, I. Vella, G. Lanzoni, G. Tisone, C. Ricordi in clinical use and remains the gold standard therapy and reaching insulin independence was reported for diabetes mellitus associated with end-stage kid- in 199055. This procedure is considered uninvasive, ney failure. A more recent alternative option is islet or minimally invasive. Bleeding, portal venous transplantation, which is less invasive than pancreas thrombosis, and puncturing remain transplantation42. The manufacture of the islet cell potential risks56 but they are minimized by close product with an automated method43, 44 and islet adherence to the standard protocols for hepariniza- transplantation in T1D patients45 are currently in tion, obliteration of the catheter tract, and use of Phase 3 clinal trials in the U.S.A46. Up to 80% of ultrasound guidance57. At 5 years post-transplan- recipients of islet transplantation were reported to tation, most of the patients that receive intraportal be insulin independent in the first year post-treat- islets infusions maintain functioning islet grafts ment. The long-term survival rate of transplanted in the , but only 10% of them remain insulin islets remains low, although certain pharmacological independent (data from the CITR - Clinical Islet treatments appear to be associated with significantly Transplant Registry58,59). Insulin independence at prolonged islet graft survival47. A set of obstacles 3 years after transplant improved from 27% in will have to be overcome in order to enable a wide- the early era (1999-2002) to 37% in the mid era spread use of islet transplantation, including: the low (2003-2006) and to 44% in a more recent era of number of available and suitable donor , islet transplantation (2007-2010)59. Besides this, the substantial cost of the islet isolation procedure, the function of transplanted islets has the highly technical difficulties in recovering large numbers of beneficial effect of abating the risk of severe hy- islets, limited engraftment, limited duration of insulin poglycemic events – even when islet function is independence, allograft rejection, and autoimmunity. limited46. Nevertheless, the efficiency in yielding For these reasons, as of today only a limited number and maintaining insulin independence is certainly of islet transplantations can be carried out48. It will be suboptimal. This limited efficiency is partly due essential to identify a high-yield source of beta cells, to the loss of islet mass early after infusion. The durable over the time and that can be transplanted causes of this important loss, approximately 60% with little or no immunosuppression49. Moreover, of cells immediately after injection60, are connect- the transplantation strategy will have to be improved ed to the intraportal transplant method and to the with the aim of maximizing engraftment and func- target site – the liver61. IBMIR, thrombosis into tion. The implantation site of choice impacts islet the liver sinusoid, and hepatic tissue ischemia are engraftment and function50. Ideally, the transplant frequently observed61. Transient mild increases of site should reduce or avoid the instant blood-medi- alanine transaminase and aspartate transaminase ated inflammatory reaction (IBMIR), it should be levels have been reported in about 50% patients well-vascularized, favor islet revascularization, have undergoing intraportal islet transplant: these are an appropriate oxygen tension, a suitable pH, an ap- probably associated with liver thrombosis and isch- propriate clearance of toxic metabolites, and access emia, and usually normalize in 1 month62. More to nutrients. Also, it should enable islet function and than 20% of recipients show hepatic microsteato- good glycemic control, possibly using a low number sis on ultrasonography, MRI and liver biopsy63. of cells. Ideally, it should also protect the graft from The islets transplanted into the liver are definitely the cellular immune response51. Desirably the trans- exposed to higher concentrations of immunosup- plant site should be easily accessible, to enable min- pressive drugs. Many of these agents can inhibit imally invasive procedure. Furthermore, the islets angiogenesis and are toxic for β-Cells, impairing should not be dispersed, so that they could be easily their engraftment and function64,65. The awareness studied and eventually removed. of these limitations has stimulated the search for alternative sites for pancreatic islet transplantation. Pancreatic Islet Transplantation in the Liver Currently, the liver is the site of choice for pan- Alternative Sites for Pancreatic creatic islets transplantation. The technique of Islet Transplantation intraportal islet transplantation for engraftment Several sites alternative to the liver have been into the liver was pioneered by Paul Lacy in investigated. Some of them enable extravascular 197350,52-54. The first case of a diabetic patient re- transplantation, others could be immune privileged. ceiving allogeneic islet transplantation in the liver Alternative sites considered for islet transplan- The greater omentum as a site for pancreatic islet transplantation 7 tation include: thymus66, bone marrow67, testis68, transplantation. A prevascularized site engineered the anterior chamber of the eye69, pancreas70, gas- in the intermuscular space enabled the efficient tric submucosa71, muscle72, subcutaneous space72, engraftment and function of islets in rats87. In 1997, spleen73, capsule74,75, and omentum76-78. De- Stegall reported the findings in three T1D patients spite the success of experiments in animals, only that received pancreatic islet allografts in the fore- a few alternative sites have been tested into the arm, under the muscle fascia. The islet dose was clinical setting: the muscle of the forearm79, the subtherapeutic, and the biopsies of the grafts were bone marrow67, and the omentum78. explanted at 7 and 14 days after transplantation. The pancreas should offer the most appropriate Two of the three grafts showed a mononuclear cell environment for islet transplantation. Injection in- infiltrate suggestive of recurrence of autoimmuni- to the pancreatic parenchyma showed that, when ty79. To reduce immunogenicity and recurrence of compared to , a lower number autoimmunity against islet grafts, transplantation of islets was sufficient to revert diabetes80. Islets into an immune-privileged site would be desirable. transplanted in the pancreas receive a better ox- The site should also have a sufficient volume to ygenation and were found to be metabolically enable transplantation of a clinically relevant num- superior to those transplanted into the liver81. The ber of islets without substantial damage to normal problems of transplantation into this site remain function. Interesting studies found that co-trans- the invasiveness of the procedure, the risk of pan- plant of islets with Sertoli cells delayed rejection creatitis, and the recurrence of autoimmunity. The in the absence of immunoppression88, 89. first could be overcome by minimally invasive en- doscopic approaches. Pancreatitis can be extremely Pancreatic Islet Transplantation dangerous. Moreover, autoimmunity may recur in the Omentum more rapidly at this site. Islet transplantation into Ferguson and Scothorne proposed the strategy of the gastrointestinal wall was found to be superior islet transplantation in the greater omentum in when compared to intra-liver transplantation in 197776. Free floating islets were directly positioned hamsters71. , pancreas and gastroin- onto the surface of the omentum, and the omen- testinal wall certainly merit further investigation. tum was subsequently folded76. The investigators Pancreatic islets transplanted in the spleen would observed that islets transplanted in the omentum be exposed to an environment similar to that of the survived longer than islets transplanted in the liv- pancreas. Despite good oxygenation and insulin er76. The first studies in patients were performed drainage in the portal system, islets transplanted by the group of Drs. Altman, Bethoux, Cugnenc, into the spleen did not show particular advantages and Chretien in 1988-198990, 91. Three T1D patients over the liver in primates82. The kidney subcap- received allogeneic islet transplantation via em- sular site can be considered the gold-standard site bolization in a branch of the right gastroepiploic for islet transplantation in rodents83. This site has artery irrorating the omentum. De novo insulin a relatively poor oxygenation and nutrition supply. production was observed in all cases. In one of Other intra-vascular infusion experiments have these patients, islet transplantation was combined been performed, including transplantation into the with liver transplantation. This case was a remark- lung (systemic venous circulation), and infusion in- able success: with insulin independence gained at to the celiac artery. Although the arterial infusion 7 months and maintained at 15 months post-trans- should offer increased oxygenation and nutrition plant, this was one of the first cases of long-term to the transplanted islets, islet survival was found insulin withdrawal after an islet graft91. After these to be superior after infusion in the portal system84. pioneering studies, other surgical approaches have Islet grafts in the lung showed a good graft sur- been developed for islet implantation in the omental vival in animals85 but the risk of thrombosis and site. One strategy utilized a sequential approach: 1) IBMIR remain considerably high. Experiments in a cell pouch device was wrapped in the omentum, rats showed a long-term β-cell survival using the 2) the device received vascularization, 3) pancre- femoral bone marrow as a transplant site, with C- atic islets were implanted in the preimplanted cell peptide control for more than 30 days86. The intra- pouch92. Another strategy termed omental roll-up muscular site is easy to access and easy to monitor, was developed. This technique consists in the and it has already been tested for parathyroid auto- preparation of a coagulum of autologous plasma 8 M. Pellicciaro, I. Vella, G. Lanzoni, G. Tisone, C. Ricordi with islets and vascular endothelial growth factor Advantages and Limitations of (VEGF), and in the positioning of this coagulum Islet Transplantation in the Omentum onto the omentum. The omentum and the is- Preliminary observations suggest that islet trans- lets-containing coagulum are subsequently rolled plantation in the omentum could be simpler than up to present the islet layer with two omental sur- islet transplantation in other sites. Clinical trials faces for engraftment and to prevent the spreading will provide information about the safety and of islet cells into the abdominal cavity93. Another efficacy of this strategy. Animal experiments strategy was developed and tested in non-human have shown that islet grafts survive longer in the primates: islets were seeded on a synthetic scaf- omentum, compared to islets grafts in the liver76. fold and transplanted in an omental pouch. Islet Rapid correction of diabetes and good glycemic engrafted in the omentum and survived for long control have been observed78. Compared with the periods of time94. Islet engrafted in the omentum intraportal infusion technique, this procedure is were found to release insulin (c-peptide) at levels expected to circumvent the IBMIR reaction76. The comparable to those of islets transplanted in the omentum has a high vascular density and good liver94. The team of the Diabetes Research Institute arterial supply, but further studies will be required at the University of Miami started testing a strat- in order to understand how long transplanted is- egy based on creating a resorbable scaffold com- lets will remain in hypoxic conditions, and how prising autologous plasma, islets, and thrombin77. rapidly islets will be revascularized. The level of An evolution of these initial preclinical findings oxygenation of islets transplanted in the omentum was recently tested in the clinical setting and the is still debated. Some authors have proposed that first clinical case of islet transplantation onto the the revascularization in the omentum is delayed omentum was reported, as part of an ongoing clin- and that this could interfere with the metabolic ical trial (ClinicalTrials.gov ID: NCT02213003)78. outcome97; the initial islets loss is mainly due to In August 201595, a 43 years old T1D patient the hypoxia secondary to the delayed revascular- underwent transplantation of allogenic islet in ization, and it is independent of an inflammatory a degradable biologic scaffold onto the greater or immune-mediate reaction. Espes and colleagues omentum78. Allogeneic islets were combined with reported contrasting findings: the initial hypoxia autologous plasma and laparoscopically layered could stimulate the engraftment, the angiogenesis onto the omentum. The omentum was subsequent- and the innervation of the islets yielding a supe- ly folded over to avoid distribution of the islets in rior functionality when the newly formed vessels the abdominal cavity. Recombinant thrombin and are fully functional98. Additional studies will be another layer of autologous plasma were layered required to clarify the aspects of hypoxia and ox- over the islets. The induction immunosuppression ygenation in islet grafts in the omentum. Unknown regimen consisted of anti-thymocyte globulin and is also the potential effect of recipient BMI and etanercept, and the maintenance immunosuppres- amount of adipose tissue present in the omentum sion regimen consisted of mycophenolate sodium on islet engraftment and function (see Figure 4). and tacrolimus. Tacrolimus was switched to siro- The abundance of adipose tissue could impact limus 8 months after transplantation due to a side negatively the oxygenation and revascularization effect. The patient was followed up for 1 year. The of the graft, potentially causing partial graft loss or patient showed a rapid gain of glycemic control, functional alterations. A potential advantage of the became insulin-independent at day 17 post trans- omental site could be that islets would be exposed plantation, and remained insulin-free at 12 months to lower levels of diabetogenic immunosuppressive post transplantation. Glycemic control remained drugs, since orally administered immunosuppres- stable at 6 months post-transplant, and showed a sion produces relatively higher concentrations of minor deterioration at 12 month post-transplant. potentially beta cell toxic drugs in the liver99. No episodes of hypoglycemia were observed in Additional studies will be required to test vari- the post-transplant period78. Multiple clinical trials ables involved in islet engraftment and long-term are currently testing safety and efficacy of islet function in the omentum, to optimize the strategy transplantation into the omentum (NCT02213003, in this alternative transplant site. As we indicated NCT0282106, NCT02803905, and NCT00798785) in previous paragraphs, the omentum has a natu- (see ClinicalTrials.gov96). ral disposition to respond to foreign bodies with The greater omentum as a site for pancreatic islet transplantation 9 a strong inflammatory reaction. Such reactions function of transplanted islets will have to be ana- may occur if certain scaffolding or encapsulating lyzed in long-term studies, in order to characterize materials are combined with pancreatic islets. Is- in depth this alternative transplantation site. When let hormones released into the venous system of compared to the liver, this alternative site for islet the omentum would have an action similar to the transplantation has advantages and disadvantages. physiological one, due to venous drainage in the Ongoing and future studies will clarify whether portal system. Regeneration of β-cells innervation or not the advantages outweigh the disadvantages. could also occur. Espes et al98 observed a higher density of innervation and lower regeneration time Conflict of Interest in nude rats receiving human islets transplants. The Authors declare that they have no conflict of interests. This innervation could make the release of insulin more similar to the physiologic one. In addition to References this, unpublished preliminary reports suggest that 1. Liebermann-Meffert D, White H. The Greater Omentum. β-cells maintain their differentiated state more New York: Springer-Verlag Berlin Heidelberg GmbH: 1983. efficiently when transplanted into the omentum, 2. Alday ES, Goldsmith HS. Surgical technique for omental compared to the liver. This could contribute to the lengthening based on arterial anatomy. Surg Gynecol Ob- long-term function of β-cells. Patients with liver stet 1972; 135: 103-107. disease could definitely benefit from this type of 3. Shimotsuma M, Shields JW, Simpson-Morgan MW, transplantation. The procedure that is currently Sakuyama A, Shirasu M, Hagiwara A, et al. Mor- tested in clinical trials is minimally invasive. The pho-physiological function and role of omental milky spots as omentum-associated lymphoid tissue (OALT) in surgeon has an easy access to the anatomical re- the peritoneal cavity. Lymphology 1993; 26: 90-101. gion of interest, laparoscopically drips the islets 4. Borisov AV. Lymphatic capillaries and blood vessels of and the scaffold, and folds over an omental flap78. milky spots in the human greater omentum. Fed Proc This maneuver is done to create a pouch that can Transl Suppl 1964; 23: 150-154. protect the graft and avoid dissemination of islets 5. Bouchet A. Aspects nouveaux sur la structure et la vasculari- sation du grand epiploon. Strasbourg: Alsatie: 1962; pp. 3-31. in the peritoneal cavity. Islets could be easily 6. Netter FH. Blood supply of stomach and . In: removed for analysis. Unfortunately, the current Edited by Netter FH. Digestive system. New York: Ciba imaging techniques do not enable non-invasive Coll Med Illustr; pp. 56-65. imaging of the transplanted islet tissue. Beta cell 7. Nylander G, Tjernberg B. The lymphatics of the greater function (insulin, c-peptide), glycemia and related omentum. An experimental study in the dog. Lympholo- parameters (glycated HbA1c, required exogenous gy 1969; 2: 3-7. 8. Zweifach BW, Prather JW. Micromanipulation of pres- insulin dose, frequency of hypoglycemic events) sure in terminal lymphatics in the mesentery. Am J indirectly indicate that islets transplanted in the Physiol 1975; 228: 1326-1335. omentum can control human T1D78. 9. Coffey JC, O’Leary DP. The mesentery: structure, func- tion, and role in disease. Lancet Gastroenterol Hepatol Conclusions 2016; 1: 238-247. 10. Meckel JF. Bildungsgeschichte des Darmakanals der The omentum represents one of the most inter- Saugethiere und namentilich des menschen. Meckel’s esting sites for islet transplantation, an alternative Arch Anat Physiol 1817; pp. 1-84. to the liver. Additional studies will be required to 11. Toldt C. Die Darmgekröse und Netze im gesetzmässigen clarify whether islet transplantation in the omen- und im gesetzwidrigen Zustand. Dekschr Adad Wiss tum is superior to transplantation into the liver. Wien: K.K. Hof-und Staatsdruckere 1889; pp. 1-46. Factors such as details of the surgical strategy 12. 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