Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Effects of implant buccal distance on peri-implant strain: A Micro-CT based finite element analysis.

Bone-implant mechanics is one of the factors that contribute to implant stability and success. In this work, voxel-based finite element models were built based on the micro-CT images of human cadaveric mandible specimens before and after implant placement. The computed results show high strain at the bone-implant contact locations and the buccal and lingual bone plates. The strain concentration in the thinner buccal plates was more substantial than that in the thicker lingual plates. The average values of maximum principal strain in the buccal and lingual ROIs were in good agreement with those measured using mechanical testing coupled with micro-CT and digital volume correlation. The implant position was then virtually changed in the models to be placed lingually or buccally. The computed strain in the buccal bone decreased when the implant was placed away from the buccal plate. The strain in lingual bone also deceased when the implant was moved from the center of the alveolar socket towards the lingual or buccal plate. The results indicate that the distance from implant to the buccal plate can affect the mechanical stimuli in bone, especially in the buccal plate, which may subsequently affect the bone remodeling process and buccal bone resorption.

Numerical Simulation of Mandible Bone Remodeling under Tooth Loading: A Parametric Study.

Bone adapts to the change of mechanical stimulus by bone remodeling activities. A number of numerical algorithms have been developed to model the adaptive bone remodeling under mechanical loads for orthopedic and dental applications. This paper examines the effects of several model parameters on the computed apparent bone density in mandible under normal chewing and biting forces. The density change rate was based on the strain energy density per unit mass. The algorithms used in this study containing an equilibrium zone (lazy zone) and saturated values of density change rate provides certain stability to result in convergence without discontinuous checkerboard patterns. The parametric study shows that when different boundary conditions were applied, the bone density distributions at convergence were very different, except in the vicinity of the applied loads. Compared with the effects of boundary conditions, the models are less sensitive to the choice of initial density values. Several models starting from different initial density values resulted in similar but not exactly the same bone density distribution at convergence. The results also show that higher reference value of mechanical stimulus resulted in lower average bone density at convergence. Moreover, the width of equilibrium zone did not substantially affect the average density at convergence. However, with increasing width, the areas with the highest and the lowest bone density areas were all reduced. The limitations of the models and challenges for future work were discussed for the better agreement between the computed results and the in vivo data.

Voxel-based micro-finite element analysis of dental implants in a human cadaveric mandible: Tissue modulus assignment and sensitivity analyses.

The success of dental implant treatment is related to the complex 3-dimensional (3D) biomechanics of the implant-bone interaction. In this work, 3D numerical models are built based on micro X-ray computed tomography (micro-CT) images of a cadaveric mandible specimen with implants placed in it. The simulation results show that the computed strain values in bone are sensitive to the uncertainties in trabecular tissue modulus and fairly insensitive to the modulus of implants and teeth and the detailed geometry of the fixed boundary condition. A bone-volume-fraction (BV/TV) based method is proposed to assign the tissue moduli of bone elements based on their BV/TV to increase the connectivity of the mesh and to improve the accuracy of the models. These models are potentially powerful for calculating the 3D full-field bone strain under implant loading, enabling in silico testing of different implant designs, but demand validation of the models. The computed results reveal high strain concentration at bone-implant contact areas and, more importantly, in the buccal (lip-side) bone that is not making contact with the implant. The computed strain concentration patterns are found to be in good agreement with the observations from our prior experiments using 3D full-field mechanical testing coupled with micro-CT and digital volume correlation. The buccal bone is thinner and less stiff than other areas of bone and is also the commonly observed area of bone resorption after dental implant treatment.