LOCALIZED DELIVERY OF EPIDERMAL GROWTH-FACTOR IMPROVES THE SURVIVAL OF TRANSPLANTED HEPATOCYTES

Hepatocyte transplantation may provide a new approach for treating a v ariety of liver diseases if a sufficient number of the transplanted ce lls survive over an extended time period. In this report, we describe a technique to deliver growth factors to transplanted hepatocytes to i mprove their engraftment. Epidermal growth factor (EGF) was incorporat ed (0.11%) into microspheres (19 +/- 12 mu m) fabricated from a copoly mer of lactic and glycolic acid using a double emulsion technique. The incorporated EGF was steadily released over 1 month in vitro, and it remained biologically active, as determined by its ability to stimulat e DNA synthesis, cell division, and long-term survival of cultured hep atocytes. EGF-containing microspheres were mixed with a suspension of hepatocytes, seeded onto porous sponges, and implanted into the mesent ery of two groups of Lewis rats. The first group of animals had their portal vein shunted to the inferior vena cava prior to cell transplant ation (portal-caval shunt = PCS), and the second group of animals did not (non-PCS). This surgical procedure improves the survival of transp lanted hepatocytes. The engraftment of transplanted hepatocytes in PCS animals was increased twofold by adding EGF microspheres, as compared to adding control microspheres that contained no growth factors. Devi ces implanted into non-PCS animals had fewer engrafted hepatocytes tha n devices implanted into PCS animals, regardless of whether blank or E GF-containing microspheres were added. These results first indicate th at it is possible to design systems which can alter the microenvironme nt of transplanted hepatocytes to improve their engraftment. They also suggest that hepatocyte engraftment is not improved by providing sing le growth factors unless the correct environment (PCS) is provided for the transplanted cells. (C) 1996 John Wiley & Sons, Inc.