Evaluating Prognostic Factors for Liver Transplantation Among United States Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis Using National Registry Data.

INTRODUCTION: Orthotopic liver transplantation has been used as a treatment for hereditary transthyretin-mediated (hATTR) amyloidosis, a rare, progressive, and multisystem disease. RESEARCH QUESTION: The objective is to evaluate survival outcomes post-liver transplantation in patients with hATTR amyloidosis in the United States and assess whether previously published prognostic factors of patient survival in hATTR amyloidosis are generalizable to the US population. DESIGN: This cohort study examined patients with hATTR amyloidosis undergoing liver transplant in the United States (N = 168) between March 2002 and March 2016 using data reported to the Organ Procurement and Transplantation Network (UNOS)/United Network for Organ Sharing (OPTN). RESULTS: A multivariable Cox hazards regression model showed among all factors tested, only modified body mass index (kg/m2 × g/L) at the time of transplant was significantly associated with survival. Higher modified BMI was associated with lower risk of death relative to a reference population (<600) with historically poor post-transplant outcomes. Patients with modified BMI 1000 to <1200 (hazard ratio [HR] = 0.27; 95% confidence interval [CI] = 0.10-0.73), 1200 to <1400 (HR = 0.20; 95% CI = 0.06-0.75), and ≥1400 (HR = 0.15; 95% CI = 0.04-0.61) exhibited improved adjusted 5-year post-transplant survival of 74%, 80%, and 85%, respectively, versus 33% in the reference population. DISCUSSION: The association between a higher modified BMI threshold at the time of transplant and improved post-transplant survival suggests that the previously published patient selection criterion for modified BMI may not be applicable to the US population.

Enhanced retention of polymer physical characteristics and mechanical strength of 70:30 poly(L-lactide-co-D,L-lactide) after ethylene oxide sterilization.

This study examined the effect of ethylene oxide (EtO) and electron beam (e-beam) irradiation on the properties of 70:30 poly(L-lactide-co-D,L-lactide). The effects of sterilization upon the polymer physical characteristics and strength retention of the material were examined, both initially and after being subjected to real time ageing. Commercially available 70:30 poly(L-lactide-co-D,L-lactide) material was fabricated into rectangular, cylindrical, screw, and sheet designs, and tested in compression, shear, or tension. Sterilization of 70:30 poly(L-lactide-co-D,L-lactide) by ethylene oxide had a nearly negligible effect on the physical properties of the polymer, regardless of specimen size or manufacturing technique. The molecular weight and inherent viscosity of the specimens decreased by approximately 3% after sterilization by EtO. However, sterilization of 70:30 poly(L-lactide-co-D,L-lactide) by e-beam irradiation resulted in immediate changes to some of the physical properties of the polymer. Specimens sterilized by e-beam irradiation displayed an immediate decrease in inherent viscosity of approximately 67% as compared to the respective nonsterile samples. The immediate decrease in inherent viscosity and molecular weight with e-beam irradiation required approximately 39 weeks of real time ageing of the EtO sterilized parts. At all time points investigated in the present study, the strength retention of the EtO sterilized devices equaled or exceeded that of the e-beam irradiated samples.

Characterization of a faster resorbing polymer after real time aging.

This study evaluated the in vitro strength retention and polymer characteristics of specimens made from commercially available 85:15 poly(D,L-lactide-co-glycolide). Test samples included dogbone tensile specimens with a nominal thickness of either 0.75 and 1.0 mm, which were machined from compression-molded sheets, and screws with a major diameter of 2.71 mm and minor diameter of 2.14 mm, which were manufactured by injection molding. All samples were sterilized by e-beam irradiation prior to in vitro aging following a standard methodology. Mechanical testing and polymer analysis were performed at time zero and weekly up to 15 weeks of real time aging. The time zero maximum tensile strength of the 0.75 mm dogbone specimens averaged 55.86 +/- 0.72 MPa. The 1.0-mm dogbone specimens tested at time zero had an average maximum tensile strength of 34.55 +/- 0.36 MPa. The 0.75-mm and 1.0-mm thick dogbone specimens exhibited a controlled decrease in their tensile strength. The initial shear strength of the injection-molded screws was 32.86 +/- 4.15 MPa. After 3 weeks of real time in vitro aging, the screws maintained approximately 70% of their initial (time zero) strength. The inherent viscosity and molecular weight (Mw) at time zero averaged approximately 0.9 dL/g and 98,000 g/mol respectively, and decreased at similar rates for both dogbones and screws. These results demonstrate a controlled, rapid degradation in the mechanical properties of 85:15 poly(D,L-lactide-co-glycolide) material, with sufficient strength for pediatric craniofacial applications.

Strength retention of 70:30 poly(L-lactide-co-D,L-lactide) following real-time aging.

This study evaluated the in vitro strength retention and polymer characteristics of plates and screws made from commercially available 70:30 poly(L-lactide-co-D,L-lactide) over a 2-year time period. Test samples included three routine manufacturing lots each of plates (1.2 mm thick, 41.70 mm long, with 2.5-mm holes), which were machined from compression-molded sheets, and screws (2.4-mm major diameter and 1.86-mm minor diameter), which were manufactured by injection molding. All samples were sterilized by e-beam irradiation prior to in vitro aging following a standard methodology. Mechanical testing and polymer analysis was performed after 0, 6, 13, 26, 39, 52, 65, 78, and 104 weeks. The initial (time zero) tensile strength of the plates averaged 33.2+/-1.9 MPa; the plates retained 100% of this strength at 6 weeks, 84% at 13 weeks, and 34% at 39 weeks. The screws had an initial (time zero) shear strength of 29.8+/-4.2 MPa, and maintained 97% of this strength at 26 weeks and 73% of this strength at 39 weeks. The inherent viscosity and molecular weight (M(w)) at time zero averaged approximately 1.4 dL/g and 165,000 g/mol, respectively, and decreased at similar rates for both the plates and screws. These results demonstrate excellent strength retention of devices fabricated from 70:30 poly(L-lactide-co-D,L-lactide) over time periods exceeding those associated with normal bone healing.

Evaluation of cytocompatibility and bending modulus of nanoceramic/polymer composites.

In an attempt to simulate the microstructure and mechanical properties of natural bone, novel nanoceramic/polymer composite formulations were fabricated and characterized with respect to their cytocompatibility and mechanical properties. The bending moduli of nanocomposite samples of either poly(L-lactic acid) (PLA) or poly(methyl methacrylate) (PMMA) with 30, 40, and 50 wt % of nanophase (<100 nm) alumina, hydroxyapatite, or titania loadings were significantly (p < 0.05) greater than those of pertinent composite formulations with conventional, coarser grained ceramics. The nanocomposite bending moduli were 1-2 orders of magnitude larger than those of the homogeneous, respective polymer. For example, compared with 0.06 GPa for the 100% PLA, the bending modulus of 50/50 nanophase alumina/PLA composites was 3.5 GPa. Osteoblast adhesion on the surfaces of the nanophase alumina/PLA composites increased as a function of the nanophase ceramic content. Most importantly, osteoblast adhesion on the 50/50 nanophase alumina/PLA substrates was similar to that observed on the 100% nanophase ceramic substrates. Similar trends of osteoblast adhesion were observed on the surfaces of the nanophase titania/polymer and nanophase hydroxyapaptite/polymer composites that were tested. In contrast, fibroblast adhesion on the nanophase composites was either similar or lower than that observed on the conventional composites with either PLA or PMMA and minimum on all tested neat nanophase substrates. The calcium content in the extracellular matrix of cultured osteoblasts was also enhanced on the nanoceramic/PLA composite substrates tested as a function of the nanophase ceramic loading and duration of cell culture. The results of the present in vitro study provide evidence that nanoceramic/polymer composite formulations are promising alternatives to conventional materials because they can potentially be designed to match the chemical, structural, and mechanical properties of bone tissue in order to overcome the limitations of the biomaterials currently used as bone prostheses.