There is significant need for effective medical adhesives that function reliably on wet tissue surfaces with minimal inflammatory insult. To address these performance characteristics, we have generated a synthetic adhesive biomaterial inspired by the protein glues of marine mussels. In-vivo performance was interrogated in a murine model of extrahepatic syngeneic islet transplantation, as an alternative to standard portal administration. The adhesive precursor polymer consisted of a branched poly(ethylene glycol) (PEG) core, whose endgroups were derivatized with catechol, a functional group abundant in mussel adhesive proteins. Under oxidizing conditions, adhesive hydrogels formed in less than one minute from catechol-derivatized PEG (cPEG) solutions. Upon implantation, the cPEG adhesive elicited minimal acute or chronic inflammatory response in C57BL6 mice, and maintained an intact interface with supporting tissue for up to one year. In-situ cPEG adhesive formation was shown to efficiently immobilize transplanted islets at the epididymal fat pad and external liver surfaces, permitting normoglycemic recovery and graft revascularization. These findings establish the use of synthetic, biologically-inspired adhesives for islet transplantation at extrahepatic sites.
Eight manufacturing facilities participating in the National Institutes of Health–sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.
The involvement of cytokines derived from ovarian and hematopoietic cells have been suggested in the cyclic events of the ovary. In the present study the effects of two cytokines, interleukin-1 beta (IL-1 beta) and IL-2, on ovulation, steroidogenesis, and prostaglandin (PG) production were explored in rat ovaries perfused in vitro. Ovaries of equine CG (20 IU)-primed immature rats were perfused in a recirculating system for 20 h, and samples were taken for analysis of progesterone, estradiol, prostaglandin E (PGE), and PGF2 alpha. The number of ovulations was estimated by counting the number of oocytes released into the ovarian bursae. Unstimulated ovaries did not ovulate, whereas the addition of LH (100 ng/ml) resulted in 3.4 +/- 0.6 ovulations/treated ovary. The addition of human recombinant IL-1 beta (4 ng/ml) induced ovulation (1.6 +/- 0.4) and increased the LH-induced ovulation rate 3-fold (9.8 +/- 0.5). The addition of human recombinant IL-2 (40 ng/ml) did not induce ovulation and did not affect the LH-induced ovulation rate. Ovarian release of progesterone and PGF2 alpha was increased by IL-1 beta, but estradiol and PGE release was not affected. IL-2 did not affect steroidogenesis or PG release. To elucidate whether the IL-1 beta-stimulated ovarian synthesis of PGF2 alpha was crucial for the ovulatory effect of IL-1 beta, experiments were performed in the presence of indomethacin (5 micrograms/ml), an inhibitor of PG synthesis. Indomethacin (5 micrograms/ml) inhibited LH-induced ovulation almost completely (one ovulation in one of the five treated ovaries), but did not affect the IL-1 beta-induced ovulation rate (1.4 +/- 0.2). The number of ovulations in the group treated with LH and IL-1 beta was significantly reduced (3.2 +/- 0.6) in the presence of indomethacin. These data demonstrate that IL-1 beta induces ovulation in the rat ovary, and this effect may be partly mediated by the increased production of the ovulatory mediator progesterone.
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