* The Ovine Model for Meniscus Tissue Engineering: Considerations of Anatomy, Function, Implantation, and Evaluation.

Meniscus injuries represent one of the most-common intra-articular knee injuries. The current treatment options include meniscectomy and allograft transplantation, both with poor long-term outcomes. Therefore, there is a need for regenerative techniques to restore meniscal function. To preclinically test scaffolds for meniscus replacement, large animal models need to be established and standardized. This review establishes the anatomical and compositional similarities between human and sheep menisci and provides guidance for implantation and evaluation of such devices. The ovine meniscus represents a scaled-down version of the human meniscus, with only slight structural differences that can be addressed during device fabrication. Implantation protocols in sheep remain a challenge, as the meniscus cannot be visualized with the arthroscopic-assisted procedures commonly performed in human patients. Thus, we recommend the appropriate implantation protocols for meniscus visualization, ligamentous restoration, and surgical fixation of both total and partial meniscus replacement devices. Last, due to the lack of standardization in evaluation techniques, we recommend a comprehensive battery of tests to evaluate the efficacy of meniscus replacement implants. We recommend other investigators utilize these surgical and testing techniques to establish the ovine model as the gold standard for preclinical evaluation of meniscus replacement devices.

A hydrogel prepared by in situ cross-linking of a thiol-containing poly(ethylene glycol)-based copolymer: a new biomaterial for protein drug delivery.

A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH) groups was cross-linked in situ to form a polymer hydrogel under mild conditions. No organic solvent, elevated temperature, or harsh pH is required in the formulation or patient administration processes, making it particularly useful for delivery of fragile therapeutics, such as proteins. The in vitro release of fluorescein-labeled bovine serum albumin and the in vivo release of the model proteins, erythropoietin, RANTES and three PEG-conjugated RANTES derivatives showed sustained release for 2-4 weeks and demonstrated prolonged biological activity of the released proteins in animals.

Differentiation of gut and hepatic first pass metabolism and secretion of saquinavir in ported rabbits.

The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1-5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged Cmax but prolonged Tmax and t(1/2), P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS.

Differentiation of gut and hepatic first-pass loss of verapamil in intestinal and vascular access-ported (IVAP) rabbits.

Low and varied oral bioavailability (BA) of some drugs has been attributed to extraction by the intestine and liver. However, the role of the intestine is difficult to directly assess. We recently developed an in vivo intestinal and vascular access-ported (IVAP) rabbit model that allows for a direct assessment of the contributions of the gut and the liver to the first-pass loss of drugs. The current studies validate the utility of the IVAP rabbit model using verapamil (VL). VL pharmacokinetics (PK) were determined after intravenous (i.v.), portal venous (PV), and upper small intestinal (USI) administration. In the i.v. dose range studied, VL exhibited linear PK. The PV concentration of VL was significantly lower than systemic concentrations after i.v. administration, suggesting significant intestinal second-pass extraction. The intestinal and hepatic extraction of VL, calculated directly from area under the curve measurements, were 79% and 92%, respectively, and are in contrast to our previous dog results that showed VL intestinal extraction to be negligible. Assessing the role of intestinal extraction using an "indirect" method was not predictive, further showing the utility of this direct measurement model. The BA of VL after USI administration was 1.65%, much lower than that reported for rats, dogs, or humans. However, humans and rabbits behave similarly in that the contribution of intestinal extraction for VL is high. In conclusion, the current results demonstrate the utility of the rabbit IVAP model in studying the first- and second-pass intestinal and hepatic loss of drugs and other xenobiotics.