TRANSPLANTATION OF MICROENCAPSULATED PANCREATIC ISLETS IN NONIMMUNOSUPPRESSED DIABETIC RECIPIENTS.
Bibliographic record
Abstract
P449 Aims: We aimed to bring our microencapsulated islet transplant system into human pilot clinical trials. To achieve this goal, we have addressed and thoroughly fulfilled a number of safety and efficacy issues, as far as both, chemical formulation and physics of the microcapsules, and the whole product (islets in microcapsules) were concerned, either in vitro or in vivo, post-transplant into pre-clinical animal models of diabetes. Methods: a) Microcapsules - Na alginate (AG), prevalently composed of mannuronic acid, underwent stepwise, multiple purification and ultrafiltration process, in order to remove endotoxins as well as other pyrogens and foreign microparticles. Poly-L-ornithine (PLO), at low molecular weight, as uniquely shown by our laboratory, was used to coat the initially formed AG gel beads. The latter, upon previous, careful mixing with the islet suspension, were obtained by a microdroplet generator, not involving use of electrostatic forces, but simply air shears and mechanical pressure; b) Islets – we separated/purified islets from the pancreas of either neonatal pigs (NPCC), or humans, by the classical collagenase digestion and COBE 2991 gradient purification, according to protocols developed by the Edmonton group, University of Alberta, Canada. The isolated islets were culture-maintained in HAM F12 for at least 24 hrs., prior to encapsulation, and underwent both morphologic (integrity, viability and immunocytochemistry) and functional (in vitro glucose stimulated insulin release) quality control testing; c) Experimental design – nonimmunosuppressed NOD mice and dogs with spontaneous, insulin-dependent diabetes were enrolled in the pre-clinical trials and were grafted intraperitoneally with microencapsulated either NPCC (NOD mice, dogs) or human (NOD) islets, with the post-TX blood glucose levels as well as daily insulin consumption rates being carefully monitored. Results: Our method resulted in endotoxin-free, highly purified AG. AG/PLO empty microcapsules did not provoke any inflammatory cell reaction upon intraperitoneal TX in NOD mice, with the microcapsules retaining full morphologic integrity and mechanical strenght, and containing viable islet cells. The transplanted NOD mice, with either human or NPCC encapsulated islets showed full remission of hyperglycemia that was sustained for at least 60 throughout 180 days. Transplanted dogs with NPCC showed remission of hyperglycemia coupled to substantial evidence of peripheral serum porcine C-peptide levels. Exogenous insulin withdrawal was achieved in one animal for 50 days, while its prolonged and sustained reduction was accomplished in all recipients. Conclusions: We have provided evidence that microencapsulated islets may represent a safe tool for transplantation with no recipient’s pharmacological immunosuppression. In vitro and preliminary in vivo pre-clinical results have warranted us permission, from the Italian Ministry of Health to embark on clinical trials of microencapsulated human islet allografts tha now are ready to begin.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".