Design and development of novel self-assembled catechol-modified bile acid conjugates as pH-responsive apical sodium-dependent bile acid transporter targeting nanoparticles.

Catechol-based biomaterials demonstrate biocompatibility, making them suitable for a wide range of therapeutic applications when integrated into various molecular frameworks. However, the development of orally available catechol-based biomaterials has been hindered by significant pH variations and complex interactions in the gastrointestinal (GI) tract. In this study, we introduce a novel catechol-modified bile acid (CMBA), which is synthesized by anchoring the FDA-approved drug, ursodeoxycholic acid to the neurotransmitter dopamine. This modification could form a new apical sodium-dependent bile acid transporter (ASBT) inhibitor (ASBTi) due to the bile acid moiety. The computational analysis using the TRAnsient Pockets in Proteins (TRAPP) module, coupled with MD simulations, revealed that CMBA exhibits a strong binding affinity at residues 51-55 of ASBT with a low inhibitory constant (Ki) value. Notably, in slightly alkaline biological conditions, CMBA molecules self-assemble into carrier-free nanoparticles with an average size of 240.2 ± 44.2 nm, while maintaining their ability to bind with ASBT. When administered orally, CMBA accumulates in the ileum and liver over 24 h, exhibiting significant therapeutic effects on bile acid (BA) metabolism in a high-fat diet (HFD)-fed mouse model. This study underscores the therapeutic potential of the newly developed catechol-based, pH-responsive ASBT-inhibiting nanoparticles presenting a promising avenue for advancing therapy.

Repeatability testing of a new Hybrid III 6-year-old ATD lower extremity.

OBJECTIVE: Vehicle safety is improving, thus decreasing the number of life-threatening injuries and increasing the need for research in other areas of the body. The current child anthropomorphic test device (ATD) does not have the capabilities or instrumentation to measure many of the potential interactions between the lower extremity and the vehicle interior. A prototype Hybrid III 6-year-old ATD lower extremity (ATD-LE) was developed and contains a tibia load cell and a more biofidelic ankle. The repeatability of the device has not yet been assessed; thus, the objective was to evaluate the repeatability of the ATD-LE. Additionally, a dynamic assessment was conducted to quantify injury threshold values. METHODS: A pneumatic ram impactor was used at 2 velocities to evaluate repeatability. The ATD-LE was fixed to a table and impacted on the plantar aspect of the forefoot. Three repeated trials at 1.3 and 2.3 m/s without shoes and 2.3 m/s with shoes were conducted. The consistency of tibia force (N), bending moment (Nm), ankle range of motion (ROM, °), and stiffness (Nm/°) were quantified. A dynamic assessment using knee bolster airbag (KBA) tests was also conducted. The ATD-LE was positioned to mimic 3 worst-case scenarios: toes touching the mid-dashboard, touching the lower dashboard, and flat on the floor prior to airbag deployment. The impact responses in the femur and tibia were directly collected and compared with published injury threshold values. RESULTS: Ram impact testing indicated primarily excellent repeatability for the variables tested. For all 3 conditions the coefficients of variance (CV) were as follows: tibia force, 1.9-2.7%; tibia moment, 1.0-2.2%; ROM, 1.3-1.4%; ankle stiffness, 4.8-15.6%. The shoe-on condition resulted in a 25% reduction in tibia force and a 56% reduction in tibia bending moment. The KBA tests indicate that the highest injury risk may be when the toes touch the lower dashboard, due to the high bending moments recorded in the tibia at 76.2 Nm, which was above the injury threshold. CONCLUSIONS: The above work has demonstrated that the repeatability of the ATD-LE was excellent for tibia force, bending moment, and ankle ROM. The ATD-LE has the ability to provide new information to engineers and researchers due to its ability to directly evaluate the crash response of the ankle and leg. New information on injury mechanism and injury tolerance may lead to injury reduction and thus help advance the safety of children.