RESUMO
In this study, a mixed porcine-human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research.
RESUMO
Management of post-surgical pain following herniorrhaphy remains a clinical challenge and novel methods to deliver analgesic compounds could be of great benefit. Because there is great interest in the use of natural biomaterials for hernia repair, we investigated the biocompatibility of a natural biomaterial, porcine small intestinal submucosa (SIS), which was impregnated with bupivacaine (SIS-B) via immersion in a solution of poly(lactic-co-glycolic acid) (PLGA). Groups of Sprague Dawley rats underwent surgical creation of a ventral abdominal wall defect with subsequent repair using either SIS or SIS-B. Analysis of serial blood samples showed peak bupivacaine levels (83 ng/mL) were achieved 16 h after implantation of SIS-B. One month after surgery, the rats were euthanized and implant sites harvested for mechanical strength testing and histological analysis. At the time of necropsy, adhesion extent and tenacity was greater in SIS-B rats, with 90% of SIS-B rats have adhesion to the implant site compared to only 75% of SIS rats. Microscopically, SIS implant sites were characterized by small amounts of residual SIS surrounded by mild-to-moderate chronic inflammation. In contrast, rats treated with SIS-B, residual SIS-B was surrounded by a ring of acute inflammatory cells and an outer ring of chronic inflammatory cells, possibly due to bupivacaine or residual PLGA. Mechanical strength testing of the harvested implant sites showed no significant (p ≤ 0.05) difference between SIS and SIS-B implants. In summary, bupivacaine is readily elaborated from SIS-B; and impregnation of SIS with bupivacaine does not substantially alter the biocompatibility of the biomaterial or its mechanical strength following implantation.