Membrane barrier of a porcine hepatocyte bioartificial liver

Abstract

Pores in the membrane of a bioartificial liver (BAL) allow it to function as a semipermeable barrier between its contents (i.e., liver cells) and components of the recipient's immune system. This study is designed to assess the influence of pore size on immune response to a BAL containing porcine hepatocytes. Sixteen healthy dogs were divided into four groups (four dogs per group) based on pore size of the BAL membrane and level of exposure to porcine hepatocytes. Group 1 dogs were administered porcine hepatocytes by intraperitoneal injection and served as positive controls. Group 2 dogs were exposed to porcine hepatocytes in a large-pore (200-nm) BAL, and group 3 dogs were exposed to porcine hepatocytes in a small-pore (10-nm) BAL. Group 4 dogs were exposed to a no-cell (unloaded) BAL and served as negative controls. Intraperitoneal injection of hepatocytes or 3 hours of BAL hemoperfusion was performed day 0 and 3 weeks later on day 21. Biochemical, humoral, and cellular measures of immune response were collected until day 44. The initiation of BAL hemoperfusion was associated with a rapid decline in CH 50 levels of complement and transient neutropenia and thrombocytopenia during all BAL exposures. Xenoreactive antibody response to BAL was increased by use of membranes with large pores and secondary exposures. Skin testing on day 42 showed a delayed-type hypersensitivity response to porcine hepatocytes that also correlated with level of previous antigen exposure. BAL

A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes

“…On the other hand, de novo donor-specific antibodies that develop after transplantation are capable of triggering insidious graft injury in the late phase of post-transplantation. Protection against hyperacute rejection and chronic rejection are vital to BAL systems [27,28], as well as to organ transplantation and to cell transplantation [29]. …”

“…Mass transfer rates are mainly determined by membrane permeability [24,30]. Larger pore size enables more efficient exchange of substances via the membrane of the module [28]. Conversely, a membrane with a large pore size may permit permeation of immunoglobulins that can cause antibody-mediated rejection of embedded hepatocytes.…”

Pig-to-Baboon Liver Xenoperfusion Utilizing GalTKO.hCD46 Pigs and Glycoprotein Ib Blockade.

“…These studies have been in pre-clinical large animal models utilizing both hepatocyte-based devices [12,13] and whole-organ liver perfusion [14], as well as in limited clinical applications using porcine hepatocytes or whole livers [2,[15][16][17][18]. In our present report, we utilize a genetically modified GalTKO.hCD46 porcine liver designed to eliminate hyperacute rejection while simultaneously attempting to interfere with the constitutive activation between VWF and the GPIb receptor by administering D-arginine vasopressin (DDAVP) and αGPIb antibody.…”

Optimization of mass transfer for toxin removal and immunoprotection of hepatocytes in a bioartificial liver

“…In one report, liver failure patients developed a significant xenoreactive antibody response after exposure to pig hepatocytes in a BAL employing an apheresis membrane of 200 nm permeability (Baquerizo et al, 1999). Studies involving healthy animals have indicated that a membrane permeability of 150–400 kDa (~10–20 nm) served as an effective barrier to the patient's cytotoxic immune response against hepatocytes within the BAL (Nyberg et al, 2003, 2004). Less studied is the influence of the BAL's membrane permeability on mass transfer rate, detoxification, and removal of other waste products that accumulate in liver failure (Patzer, 2006).…”