Hepatotrophic factor

Liver bioactivation hepatotrophic factors complement proteins... 

After resolving the issue of matrix design, the next step was to determine a desirable anatomical location. Several considerations were used in determining possible implant sites. The first is the size of the implant and the requirement that it be placed in juxtaposition to well-vascularized tissue. A transplant matrix constructed as a porous sheet-like structure could be at most 200 mm thick, based on estimates of nutrient transport limitations (66). The size of a device required to replace about 5% of the mass of an adult liver would then be about 0.5 m2. Surgical trauma must be avoided when implanting the device, because such trauma produces fibrin clots and hematoma formation around the wounded area, which creates a poor environment for cell survival. Also, the implant may behave better if supplied by the portal circulation rather than the systemic, because the portal circulation contains potential hepatotrophic factors. For these reasons, the mesentery—the vascularized membrane which secures the intestines—was selected as the best potential site (Fig. 15). 

We found that artificial cells containing hepatocytes increased the survival time of fulminant hepatic failure rats. Xenografts of rat hepatocytes in artificial cells were not immunorejected in mice. Instead, the viability of the enclosed liver cells increased after intraperitoneal implantation. This was because the hepatotrophic factor secreted by the encapsulated hepatocytes accumulates in the artificial cells. ° After implanfafion, hepatocytes in artificial cells can lower the high bilirubin level in the Gunn rats. Reports by another group also support this finding. ... 

We found that the addition of either PCS or partial hepatectomy increased cell survival. The group of animals that received both a PCS and partial hepatectomy demonstrated a marked increase in overall cellularity with acinar and tubule formation evident. The increase in cellularity was evaluated using image analysis and morphometric quantification and demonstrated a 1-2 fold increase with hepatectomy alone, and a sixfold increase when hepatectomy was combined with PCS. We have made substantial progress in our efforts to restore liver function with our approach however, to apply this technology as replacement therapy we may need to expand Ae cell population in vivo. We hope to stimulate transplanted cells with controlled release of hepatotrophic factors at the implantation site using previously described techniques (34). 

It is clear from the transplant literature that graft survival requires portal blood flow and the hepatotrophic effect of hepatectomy is well established(33). To take full advantage of circulating hepatotropic factors, we created portocaval shunts (PCS) in the recipient rats to eliminate first pass clearance of these factors by the native liver. We therefore repeated the studies with prevascularized polymeric foams, but additionally created a PCS in one group of animals, a 70% hepatectomy in another group of animals, and both a PCS and hepatectomy in yet another group studied. 

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