Project description:Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer
Project description:Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer [WES]
Project description:Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer [RNA-seq]
Project description:Three-dimensionally ordered macroporous (3DOM) hydrogels prepared by colloidal crystals templating display highly reversible shape memory properties, as confirmed by indirect electron microscopy imaging of their inverse replicas and direct nanoscale resolution X-ray microscopy imaging of the hydrated hydrogels. Modifications of functional groups in the 3DOM hydrogels result in various materials with programmed properties for a wide range of applications.
Project description:Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co-culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa-osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa-osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions.
Project description:Biomaterials play an important role in the development of advancing three dimensional (3D) in vitro skin models, providing valuable insights for drug testing and tissue-specific modeling. Commercial materials, such as collagen, fibrin or alginate, have been widely used in skin modeling. However, they do not adequately represent the molecular complexity of skin components. On this regard, the development of novel biomaterials that represent the complexity of tissues is becoming more important in the design of advanced models. In this study, we have obtained aged human decellularized dermal extracellular matrix (dECM) hydrogels extracted from cadaveric human skin and demonstrated their potential as scaffold for advanced skin models. These dECM hydrogels effectively reproduce the complex fibrillar structure of other common scaffolds, exhibiting similar mechanical properties, while preserving the molecular composition of the native dermis. It is worth noting that fibroblasts embedded within human dECM hydrogels exhibit a behavior more representative of natural skin compared to commercial collagen hydrogels, where uncontrolled cell proliferation leads to material shrinkage. The described human dECM hydrogel is able to be used as scaffold for dermal fibroblasts in a skin aging-on-a-chip model. These results demonstrate that dECM hydrogels preserve essential components of the native human dermis making them a suitable option for the development of 3D skin aging models that accurately represent the cellular microenvironment, improving existing in vitro skin models and allowing for more reliable results in dermatopathological studies.
Project description:The extracellular matrix (ECM) is known to play an important role in the health of cells and tissues. Not only are chemical signals transmitted via bonds and tightly controlled diffusion, but the structure of the ECM also provides important physical signaling for the cells attached to it. The structure is composed of a mesh of fibrous proteins, such as collagen, embedded in a hydrated gel matrix of glycosaminoglycans. To study cell behavior with respect to the combined morphology and mechanics of such matrices is not currently possible with the types of 3D cell culture matrices available. Most of the cell culture matrices are single-phase bio- or polymeric hydrogels. Therefore, here we developed a continuous hybrid manufacturing process to make fiber-reinforced composite hydrogels. A far field electrospinning process was used to deposit the fibrous component with the aid of guiding electrodes; and a gravity-assisted, droplet-based system controlled the rate of addition of the cell-laden hydrogel component. The addition of the fibrous component slightly increased the elastic modulus of the pure hydrogel. The cells that were embedded into the fiber-reinforced hydrogels were viable for 8 days. The cells were randomly placed in the matrix such that some had no contact to the fibers and others were initially in proximity to fibers. The cells with no contact to fibers grew into spheroidal clusters within the hydrogel, and those in proximity to the fibers spread out and grew along the fibers showing that the fiber-reinforced hydrogels are able to control cell behavior with morphological cues.
Project description:Hydrogels have gained acceptance as biomaterials in a wide range of applications, including pharmaceutical formulations, drug delivery, and tissue sealants. However, exploiting the potential of hydrogels as scaffolds for cell transplantation, tissue engineering, and regenerative medicine still remains a challenge due to, in part, scaffold design limitations. Here, we describe a highly interconnected, macroporous poly(ethylene glycol) diacrylate hydrogel scaffold, with pores ranging from 100 to 600 microm. The scaffold exhibits rapid cell uptake and cell seeding without the need of any external force or device with high incorporation efficiency. When human mesenchymal stem cells are seeded within the porous scaffolds, the scaffolds were found to promote long-term stem cell viability, and on exposure to osteogenic medium, elicit an mineralization response as evaluated by an increased alkaline phosphatase activity (per cell) and calcium and phosphate content within the constructs. The atomic composition of the mineralized matrix was further determined by energy dispersive spectroscopy and found to be similar to calcium-deficient hydroxyapatite, the amorphous biological precursor of bone. The macroporous design of the hydrogel appears advantageous over similar porous hydrogel scaffolds with respect to ease of synthesis, ease of stem cell seeding, and its ability to support long-term stem cell survival and possible differentiation.