Abstract
Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver’s vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.
| Original language | English (US) |
|---|---|
| Article number | eadk3081 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jun 7 2024 |
Funding
This research was supported by the Integrated Molecular Structure Education and Research Center (IMSERC) at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF grant no. ECCS-1542205); the State of Illinois and the International Institute for Nanotechnology (IIN); the Northwestern University Center for Advanced Molecular Imaging (CAMI), which is supported by NCI grant no. CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center; the MRSEC program (NSF grant no. DMR-1720139) at the Materials Research Center; the IIN; and the State of Illinois, through the IIN. This work was supported by Department of Defense (W81XWH-19-1-0230, to G.A.A.), Center for Advanced Regenerative Engineering (to G.A.A.), National Science Foundation Graduate Research Fellowship Program (DGE-1842165, to J.A.B.), and Dr. John N. Nicholson Fellowship (to J.A.B.). Acknowledgments: this research was supported by the integrated Molecular Structure education and Research center (iMSeRc) at northwestern University, which has received support from the Soft and hybrid nanotechnology experimental (Shyne) Resource (nSF grant no. eccS-1542205); the State of illinois and the international institute for nanotechnology (iin); the northwestern University center for Advanced Molecular imaging (cAMi), which is supported by nci grant no. ccSG P30 cA060553 awarded to the Robert h. lurie comprehensive cancer center; the MRSec program (nSF grant no. dMR-1720139) at the Materials Research center; the iin; and the State of illinois, through the iin. Funding: this work was supported by department of defense (W81XWh-19-1-0230, to G.A.A.), center for Advanced Regenerative engineering (to G.A.A.), national Science Foundation Graduate Research Fellowship Program (dGe-1842165, to J.A.B.), and dr. John n. nicholson Fellowship (to J.A.B.). Author contributions: conceptualization: J.A.B., Y.Z., and G.A.A. Methodology: J.A.B., Y.Z., X.Z., P.d.R., i.J., d.l., h.n., S.R., Q.R., J.M., d.c., J.O., and X.l. investigation: J.A.B., Y.Z., and G.A.A. visualization: J.A.B. and Y.Z. Funding acquisition: G.A.A. Project administration: J.A.B., Y.Z., and P.d.R. Supervision: J.O., X.l., and G.A.A. Writing\u2014original draft: J.A.B., Y.Z., and G.A.A. Writing\u2014review and editing: J.A.B. and G.A.A. Competing interests: celltrans (employees): P.d.R., i.J., d.l., h.n., S.R., Q.R., J.M., d.c., and J.O. celltrans (financial holdings): P.d.R., i.J., J.M., d.c., and J.O. Snc therapeutics (position of influence): J.A.B. vesseltek BioMedical, llc (vtB) (financial holdings): G.A.A. Pct patent application: US/2012/023293, ePO application 12741537.0, \u201Cinjectable thermoresponsive polyelectrolytes,\u201Dissued June 2018, inventor: G.A.A. vesseltek BioMedical, llc (vtB) licensing rights to patent US/2012/023293. the other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General