The Therapeutic Role of Monocyte Chemoattractant Protein-1 in a Renal Tissue Engineering Strategy for Diabetic Patients Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. International trial of the Edmonton protocol for islet transplantation. Assessment of tissue-engineered islet graft viability by fluorine magnetic resonance spectroscopy. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia Statistical geometry of pores and statistics of porous nanofibrous assemblies
In this study we aim to boost the functional output of the intra-kidney islet transplantation for diabetic patients using a tissue engineered polymeric scaffold . This highly porous electrospun scaffold featured r and omly distributed fibers composed of polycaprolactone ( PCL ) and poliglecaprone ( PGC ) . It successfully sustained murine islets in vitro for up to 4 weeks without detected cytotoxicity . The in vivo study showed that the islet population proliferated by 89 % within 12 weeks when they were delivered by the scaffold but only 18 % if freely injected . Correspondingly , the islet population delivered by the scaffold unleashed a greater capability to produce insulin that in turn further drove down the blood glucose within 12 weeks after the surgery . Islets delivered by the scaffold most effectively prevented diabetic deterioration of kidney as evidence d by the lack of a kidney or glomerular enlargement and physiological levels of creatinine , urea nitrogen and albumin through week 12 after the surgery . Unlike traditional wisdom in diabetic research , the mechanistic study suggested that monocytes chemoattractant protein-1 ( MCP-1 ) was responsible for the improved preservation of renal functions . This study revealed a therapeutic role of MCP-1 in rescuing kidneys in diabetic patients  , which can be integrated into a tissue engineered scaffold to simultaneously preserved renal functions and islet transplantation efficacy . Also , this study affords a simple yet effective solution to improve the clinical output of islet transplantation OBJECTIVE The aim of this study was to describe the National Institutes of Health 's experience initiating an islet isolation and transplantation center , including descriptions of our first six recipients , and lessons learned . RESEARCH DESIGN AND METHODS Six females with chronic type 1 diabetes , hypoglycemia unawareness , and no endogenous insulin secretion ( undetectable serum C-peptide ) were transplanted with allogenic islets procured from brain dead donors . To prevent islet rejection , patients received daclizumab , sirolimus , and tacrolimus . RESULTS All patients noted less frequent and less severe hypoglycemia , and one-half were insulin independent at 1 year . Serum C-peptide persists in all but one patient ( follow-up 17 - 22 months ) , indicating continued islet function . Two major procedure-related complications occurred : partial portal vein thrombosis and intra-abdominal hemorrhage . While we observed no cytomegalovirus infection or malignancy , recipients frequently developed transient mouth ulcers , diarrhea , edema , hypercholesterolemia , weight loss , myelosuppression , and other symptoms . Three patients discontinued immunosuppressive therapy : two because of intolerable toxicity ( deteriorating kidney function and sirolimus-induced pneumonitis ) while having evidence for continued islet function ( one was insulin independent ) and one because of gradually disappearing islet function . CONCLUSIONS We established an islet isolation and transplantation program and achieved a 50 % insulin-independence rate after at most two islet infusions . Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program , and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles , which include the limited islet supply , procedure-associated complications , imperfect immunosuppressive regimens , suboptimal glycemia control , and loss of function over time BACKGROUND Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia . We conducted an international , multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol ( the Edmonton protocol ) . METHODS We enrolled 36 subjects with type 1 diabetes mellitus , who underwent islet transplantation at nine international sites .  Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification , without culture . The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation . RESULTS Of the 36 subjects , 16 ( 44 % ) met the primary end point , 10 ( 28 % ) had partial function , and 10 ( 28 % ) had complete graft loss 1 year after the final transplantation . A total of 21 subjects ( 58 % ) attained insulin independence with good glycemic control at any point throughout the trial . Of these subjects , 16 ( 76 % ) required insulin again at 2 years ; 5 of the 16 subjects who reached the primary end point ( 31 % ) remained insulin-independent at 2 years . CONCLUSIONS Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control , but insulin independence is usually not sustainable . Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin . ( Clinical Trials.gov number , NCT00014911 [ Clinical Trials.gov ] . ) INTRODUCTION Despite significant progress in the last decade , islet transplantation remains an experimental therapy for a limited number of patients with type 1 diabetes . Tissue-engineered approaches may provide promising alternatives to the current clinical protocol and would benefit greatly from concurrent development of graft quality assessment techniques . This study was design ed to evaluate whether viability of tissue-engineered islet grafts can be assessed using fluorine magnetic resonance spectroscopy ( (19)F-MRS ) , by the noninvasive measurement of oxygen partial pressure ( pO(2 ) ) and the subsequent calculation of islet oxygen consumption rate ( OCR ) . METHODS Scaffolds composed of porcine plasma were seeded with human islets and perfluorodecalin . Each graft was covered with the same volume of culture media in a Petri dish . Four scaffolds were seeded with various numbers ( 0 - 8000 ) of islet equivalents ( IE ) aliquoted from the same preparation . After r and omizing run order , grafts were examined by (19)F-MRS at 37 ° C using a 5 T spectrometer and a single-loop surface coil placed underneath . A st and ard inversion recovery sequence was used to obtain characteristic (19)F spin-lattice relaxation times ( T1 ) , which were converted to steady-state average pO(2 ) estimates using a previously determined linear calibration ( R(2 ) = 1.000 ) . Each condition was assessed using replicate (19)F-MRS measurements ( n = 6 - 8 ) . RESULTS Grafts exhibited IE dose-dependent increases in T1 and decreases in pO(2 ) estimates . From the difference between scaffold pO(2 ) estimates and ambient pO(2 ) , the islet preparation OCR was calculated to be 95 ± 12 ( mean ± st and ard error of the mean ) nmol/(min·mg DNA ) using theoretical modeling . This value compared well with OCR values measured using established methods for human islet preparations . CONCLUSIONS (19)F-MRS can be used for noninvasive pre- and possibly posttransplant assessment of tissue-engineered islet graft viability by estimating the amount of viable , oxygen-consuming tissue in a scaffold OBJECTIVE Impaired awareness of hypoglycemia ( IAH ) and severe hypoglycemic events ( SHEs ) cause substantial morbidity and mortality in patients with type 1 diabetes ( T1D ) . Current therapies are effective in preventing SHEs in 50–80 % of patients with IAH and SHEs , leaving a substantial number of patients at risk . We evaluated the effectiveness and safety of a st and ardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment . RESEARCH DESIGN AND METHODS This multicenter , single-arm , phase 3 study of the investigational product purified human pancreatic islets ( PHPI ) was conducted at eight centers in North America . Forty-eight adults with T1D for > 5 years , absent stimulated C-peptide , and documented IAH and SHEs despite expert care were enrolled . Each received immunosuppression and one or more transplants of PHPI , manufactured on-site under good manufacturing practice conditions using a common batch record and st and ardized lot release criteria and test methods . The primary end point was the achievement of HbA1c < 7.0 % ( 53 mmol/mol ) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant . RESULTS The primary end point was successfully met by 87.5 % of subjects at 1 year and by 71 % at 2 years . The median HbA1c level was 5.6 % ( 38 mmol/mol ) at both 1 and 2 years . Hypoglycemia awareness was restored , with highly significant improvements in Clarke and HYPO scores ( P > 0.0001 ) . No study -related deaths or disabilities occurred . Five of the enrollees ( 10.4 % ) experienced bleeds requiring transfusions ( corresponding to 5 of 75 procedures ) , and two enrollees ( 4.1 % ) had infections attributed to immunosuppression . Glomerular filtration rate decreased significantly on immunosuppression , and donor-specific antibodies developed in two patients . CONCLUSIONS Transplanted PHPI provided glycemic control , restoration of hypoglycemia awareness , and protection from SHEs in subjects with intractable IAH and SHEs . Safety events occurred related to the infusion procedure and immunosuppression , including bleeding and decreased renal function .  Islet transplantation should be considered for patients with T1D and IAH in whom other , less invasive current treatments have been ineffective in preventing SHEs The application of theoretical models to describe the structure of the types of fibrous network produced by the electrospinning of polymers for use in tissue engineering and a number of other applications is presented . Emphasis is placed on formal analyses of the pore size distribution and porosities that one would encounter with such structures and the nature of their relationships with other structural characteristics likely to be important for the performance of nanofibrous material s. The theoretical structures considered result from interactions between r and omly placed straight rods that represent fibres with nanoscale dimensions . The dominant role of fibre diameter in controlling the pore diameter of the networks is shown and we discuss the perhaps counter-intuitive finding that at a given network mass per unit area and porosity , increasing fibre diameter results in an increase in mean pore radius . Larger pores may be required for ingrowth of cells to nanofibrous networks , hence this study clarifies that simply making the diameters of the fibres smaller might not be the way to improve cell proliferation on such substrates . An extensive review of structural features of the network such as the distribution of mass , inter-fibre contacts and available surface for cell attachment , fibre contact distributions for integrity of the networks and the porosity and pore size distributions is given , with emphasis placed on nanofibre dimensions for the first time
A bioartificial endocrine pancreas is proposed as a future alternative to current treatment options .
Patients with insulin-secretion deficiency might benefit .
This is the first systematic review that provides an overview of scaffold material s and techniques for insulin-secreting cells or cells to be differentiated into insulin-secreting cells .