3D Bone Morphology Alters Gene Expression, Motility, and Drug Responses in Bone Metastatic Tumor Cells.

Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell-cell and cell-microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo.

Altering adsorbed proteins or cellular gene expression in bone-metastatic cancer cells affects PTHrP and Gli2 without altering cell growth.

The contents of this data in brief are related to the article titled "Matrix Rigidity Regulates the Transition of Tumor Cells to a Bone-Destructive Phenotype through Integrin β3 and TGF-β Receptor Type II". In this DIB we will present our supplemental data investigating Integrin expression, attachment of cells to various adhesion molecules, and changes in gene expression in multiple cancer cell lines. Since the interactions of Integrins with adsorbed matrix proteins are thought to affect the ability of cancer cells to interact with their underlying substrates, we examined the expression of Integrin β1, β3, and β5 in response to matrix rigidity.

Fabrication of 3D Scaffolds with Precisely Controlled Substrate Modulus and Pore Size by Templated-Fused Deposition Modeling to Direct Osteogenic Differentiation.

Scaffolds with tunable mechanical and topological properties fabricated by templated-fused deposition modeling promote increased osteogenic differentiation of bone marrow stem cells with increasing substrate modulus and decreasing pore size. These findings guide the rational design of cell-responsive scaffolds that recapitulate the bone microenvironment for repair of bone damaged by trauma or disease.

Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin β3 and TGF-β receptor type II.

Cancer patients frequently develop skeletal metastases that significantly impact quality of life. Since bone metastases remain incurable, a clearer understanding of molecular mechanisms regulating skeletal metastases is required to develop new therapeutics that block establishment of tumors in bone. While many studies have suggested that the microenvironment contributes to bone metastases, the factors mediating tumors to progress from a quiescent to a bone-destructive state remain unclear.

Wnt signaling induces gene expression of factors associated with bone destruction in lung and breast cancer.

Parathyroid hormone-related protein (PTHrP) is an important regulator of bone destruction in bone metastatic tumors. Transforming growth factor-beta (TGF-β) stimulates PTHrP production in part through the transcription factor Gli2, which is regulated independent of the Hedgehog signaling pathway in osteolytic cancer cells. However, inhibition of TGF-β in vivo does not fully inhibit tumor growth in bone or tumor-induced bone destruction, suggesting other pathways are involved.

Cell protective, ABC triblock polymer-based thermoresponsive hydrogels with ROS-triggered degradation and drug release.

A combination of anionic and RAFT polymerization was used to synthesize an ABC triblock polymer poly[(propylenesulfide)-block-(N,N-dimethylacrylamide)-block-(N-isopropylacrylamide)] (PPS-b-PDMA-b-PNIPAAM) that forms physically cross-linked hydrogels when transitioned from ambient to physiologic temperature and that incorporates mechanisms for reactive oxygen species (ROS) triggered degradation and drug release. At ambient temperature (25 °C), PPS-b-PDMA-b-PNIPAAM assembled into 66 ± 32 nm micelles comprising a hydrophobic PPS core and PNIPAAM on the outer corona. Upon heating to physiologic temperature (37 °C), which exceeds the lower critical solution temperature (LCST) of PNIPAAM, micelle solutions (at ≥2.

A porous tissue engineering scaffold selectively degraded by cell-generated reactive oxygen species.

Biodegradable tissue engineering scaffolds are commonly fabricated from poly(lactide-co-glycolide) (PLGA) or similar polyesters that degrade by hydrolysis. PLGA hydrolysis generates acidic breakdown products that trigger an accelerated, autocatalytic degradation mechanism that can create mismatched rates of biomaterial breakdown and tissue formation. Reactive oxygen species (ROS) are key mediators of cell function in both health and disease, especially at sites of inflammation and tissue healing, and induction of inflammation and ROS are natural components of the in vivo response to biomaterial implantation.

Injectable foams for regenerative medicine.

The design of injectable biomaterials has attracted considerable attention in recent years. Many injectable biomaterials, such as hydrogels and calcium phosphate cements (CPCs), have nanoscale pores that limit the rate of cellular migration and proliferation. While introduction of macroporosity has been suggested to increase cellular infiltration and tissue healing, many conventional methods for generating macropores often require harsh processing conditions that preclude their use in injectable foams.

Synthetic and tissue-derived models for studying rigidity effects on invadopodia activity.

Invasion by cancer cells through the extracellular matrix (ECM) of tissues is a critical step in cancer progression and metastasis. Actin-rich subcellular protrusions known as invadopodia are thought to facilitate this process by localizing proteinases which degrade the ECM and allow for cancer cell penetration. We have shown in vitro that invadopodia activity is regulated by the rigidity of the ECM, which suggests that matrix remodeling in vivo may also be regulated by the mechanical properties of tissues.

Design and development of reactive injectable and settable polymeric biomaterials.

Injectable and settable biomaterials are a growing class of therapeutic technologies within the field of regenerative medicine. These materials offer advantages compared to prefabricated implants because of their ability to be utilized as part of noninvasive surgical procedures, fill complex defect shapes, cure in situ, and incorporate cells and other active biologics. However, there are significant technical barriers to clinical translation of injectable and settable biomaterials, such as achieving clinically relevant handling properties and benign reaction conditions.

Elucidation of adhesion-dependent spontaneous apoptosis in macrophages using phase separated PEG/polyurethane films.

Circulating monocytes undergo spontaneous apoptosis when there is no activation stimulus, which is critical to population control for proper host response to implants. As activation and apoptosis of monocytes/macrophages are regulated by cell-cell and cell-matrix interactions, their regulatory mechanism was investigated in this study using polyethylene glycol (PEG)-containing polyurethane films in which PEG-rich and polyester-rich domains were phase separated. Human blood monocyte-derived macrophages (HBMs) preferentially adhered to PEG domains (cell-matrix interaction) due to the low molecular weight (600 g mol⁻¹), resulting in increased HBM density (cell-cell interaction).

Biocompatibility and chemical reaction kinetics of injectable, settable polyurethane/allograft bone biocomposites.

Injectable and settable bone grafts offer significant advantages over pre-formed implants due to their ability to be administered using minimally invasive techniques and to conform to the shape of the defect. However, injectable biomaterials present biocompatibility challenges due to the potential toxicity and ultimate fate of reactive components that are not incorporated in the final cured product. In this study the effects of stoichiometry and triethylenediamine (TEDA) catalyst concentration on the reactivity, injectability, and biocompatibility of two component lysine-derived polyurethane (PUR) biocomposites were investigated.