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The Efficacy of a Prevascularized, Retrievable Poly(D,L,-lactide-co-e-caprolactone) Subcutaneous Scaffold as Transplantation Site for Pancreatic Islets

Smink, Alexandra M. PhD; Li, Shiri MSc; Hertsig, Don T. MSc; de Haan, Bart J. BSc; Schwab, Leendert PhD; van Apeldoorn, Aart A. PhD; de Koning, Eelco PhD; Faas, Marijke M. PhD; Lakey, Jonathan R.T. PhD; de Vos, Paul PhD

doi: 10.1097/TP.0000000000001663
Original Basic Science—General

Background The liver as transplantation site for human pancreatic islets is a harsh microenvironment for islets and it lacks the ability to retrieve the graft. A retrievable, extrahepatic transplantation site that mimics the pancreatic environment is desired. Ideally, this transplantation site should be located subdermal for easy surgical-access but this never resulted in normoglycemia. Here, we describe the design and efficacy of a novel prevascularized, subcutaneously implanted, retrievable poly (D,L-lactide-co-ε-caprolactone) scaffold.

Method Three dosages of rat islets, that is, 400, 800, and 1200, were implanted in immune compromised mice to test the efficacy (n = 5). Islet transplantation under the kidney capsule served as control (n = 5). The efficacy was determined by nonfasting blood glucose measurements and glucose tolerance tests.

Results Transplantation of 800 (n = 5) and 1200 islets (n = 5) into the scaffold reversed diabetes in respectively 80 and 100% of the mice within 6.8 to 18.5 days posttransplant. The marginal dose of 400 islets (n = 5) induced normoglycemia in 20%. The glucose tolerance test showed major improvement of the glucose clearance in the scaffold groups compared to diabetic controls. However, the kidney capsule was slightly more efficacious because all 800 (n = 5) and 1200 islets (n = 5) recipients and 40% of the 400 islets (n = 5) recipients became normoglycemic within 8 days. Removal of the scaffolds or kidney grafts resulted in immediate return to hyperglycemia. Normoglycemia was not achieved with 1200 islets in the unmodified skin group.

Conclusions Our findings demonstrate that the prevascularized poly (D,L-lactide-co-ε-caprolactone) scaffold maintains viability and function of islets in the subcutaneous site.

Rat pancreatic islets were implanted in diabetic nude mice either in a scaffold that had been vascularized after subcutaneous implantation or under the kidney capsule. Although the kidney capsule was superior to revert diabetes, the scaffold also allowed control of diabetes using higher numbers of islets. Supplemental digital content is available in the text.

1 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

2 Department of Surgery, University of California Irvine, Orange, CA.

3 Polyganics, Groningen, The Netherlands.

4 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

5 Department of Developmental BioEngineering, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.

6 Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

7 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

8 Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

9 Department of Biomedical Engineering, University of California Irvine, Irvine, CA.

10 Department of Surgery, University of California Irvine, Orange, CA.

11 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Received 19 August 2016. Revision received 9 December 2016.

Accepted 4 January 2017.

This research is part of the Diabetes Cell Therapy Initiative (DCTI) (FES 2009 program, Dutch ministry of welfare and sports, and the Dutch diabetes research foundation). It is also supported by a JDRF short-term fellowship for discovery consortia grant (March 2015) and a JDRF research grant (May 2016).

The authors declare no conflicts of interest.

A.M.S., S.L., and B.d.H. conducted the data collection and analysis. They and the other academical authors (A.A.v.A., E.d.K., M.M.F., J.L., P.d.V.) are responsible for the study design, decision to publish, and preparation of the article. The private partners have contributed to the project through regular discussion (D.T.H., L.S.).

Correspondence: Alexandra M. Smink, PhD, Pathology and Medical Biology, Section Immunoendocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA11, 9713 GZ, Groningen, The Netherlands. (a.m.smink@umcg.nl).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

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