Microenvironment-mediated cancer dormancy: Insights from metastability theory.

Dormancy is an evolutionarily conserved protective mechanism widely observed in nature. A pathological example is found during cancer metastasis, where cancer cells disseminate from the primary tumor, home to secondary organs, and enter a growth-arrested state, which could last for decades. Recent studies have pointed toward the microenvironment being heavily involved in inducing, preserving, or ceasing this dormant state, with a strong focus on identifying specific molecular mechanisms and signaling pathways. Increasing evidence now suggests the existence of an interplay between intracellular as well as extracellular biochemical and mechanical cues in guiding such processes. Despite the inherent complexities associated with dormancy, proliferation, and growth of cancer cells and tumor tissues, viewing these phenomena from a physical perspective allows for a more global description, independent from many details of the systems. Building on the analogies between tissues and fluids and thermodynamic phase separation concepts, we classify a number of proposed mechanisms in terms of a thermodynamic metastability of the tumor with respect to growth. This can be governed by interaction with the microenvironment in the form of adherence (wetting) to a substrate or by mechanical confinement of the surrounding extracellular matrix. By drawing parallels with clinical and experimental data, we advance the notion that the local energy minima, or metastable states, emerging in the tissue droplet growth kinetics can be associated with a dormant state. Despite its simplicity, the provided framework captures several aspects associated with cancer dormancy and tumor growth.

Optical quantification of intracellular mass density and cell mechanics in 3D mechanical confinement.

Biophysical properties of cells such as intracellular mass density and cell mechanics are known to be involved in a wide range of homeostatic functions and pathological alterations. An optical readout that can be used to quantify such properties is the refractive index (RI) distribution. It has been recently reported that the nucleus, initially presumed to be the organelle with the highest dry mass density (ρ) within the cell, has in fact a lower RI and ρ than its surrounding cytoplasm. These studies have either been conducted in suspended cells, or cells adhered on 2D substrates, neither of which reflects the situation in vivo where cells are surrounded by the extracellular matrix (ECM). To better approximate the 3D situation, we encapsulated cells in 3D covalently-crosslinked alginate hydrogels with varying stiffness, and imaged the 3D RI distribution of cells, using a combined optical diffraction tomography (ODT)-epifluorescence microscope. Unexpectedly, the nuclei of cells in 3D displayed a higher ρ than the cytoplasm, in contrast to 2D cultures. Using a Brillouin-epifluorescence microscope we subsequently showed that in addition to higher ρ, the nuclei also had a higher longitudinal modulus (M) and viscosity (η) compared to the cytoplasm. Furthermore, increasing the stiffness of the hydrogel resulted in higher M for both the nuclei and cytoplasm of cells in stiff 3D alginate compared to cells in compliant 3D alginate. The ability to quantify intracellular biophysical properties with non-invasive techniques will improve our understanding of biological processes such as dormancy, apoptosis, cell growth or stem cell differentiation.

Electrophoretic deposition: a versatile tool against biomaterial associated infections.

Biomaterial-associated infections (BAIs) are today considered as one of the most withering complications of orthopedic implant surgery. Even though BAIs occur relatively infrequently in primary joint replacement surgeries (incidence rates around 1-2%), revision arthroplasties carry up to 40% risk of infection recurrence, with devastating consequences for the patient and significant associated cost. Once the responsible pathogens, mainly bacteria, attach to the surface of the biomaterial, they start creating layers of extracellular matrix with complex architectures, called biofilms. These last mentioned, encapsulate and protect bacteria by hindering the immune response and impeding antibiotics from reaching the pathogens. To prevent such an outcome, the surface of the biomaterials, in particular implants, can be modified in order to play the role of inherent drug delivery devices or as substrates for antibacterial/multifunctional coating deposition. This paper presents an overview of novel electrochemically-triggered deposition strategies, with a focus on electrophoretic deposition (EPD), a versatile and cost-effective technique for organic and inorganic material deposition. Other than being a simple deposition tool, EPD has been recently employed to create novel micro/nanostructured surfaces for multi-purpose antibacterial approaches, presented in detail in this review. In addition, a thorough comparison and assessment of the latest antibacterial and multifunctional compounds deposited by means of EPD have been reported, followed by a critical reflection on current and future prospects of the topic. The relative simplicity of EPD's application, has, by some means, undermined the fundamental requirement of rationality of multifunctional coating design. The demanding practical needs for a successful clinical translation in the growing fields of tissue engineering and antibacterial/multifunctional implant coatings, calls for a more systematic in vitro experimental design rationale, in order to make amends for the scarcity of significant in vivo and clinical studies.

Direct covalent attachment of silver nanoparticles on radical-rich plasma polymer films for antibacterial applications.

Prevention and treatment of biomaterial-associated infections (BAI) are imperative requirements for the effective and long-lasting function of orthopedic implants. Surface-functionalization of these materials with antibacterial agents, such as antibiotics, nanoparticles and peptides, is a promising approach to combat BAI. The well-known silver nanoparticles (AgNPs) in particular, although benefiting from strong and broad-range antibacterial efficiency, have been frequently associated with mammalian cell toxicity when physically adsorbed on biomaterials. The majority of irreversible immobilization techniques employed to fabricate AgNP-functionalized surfaces are based on wet-chemistry methods. However, these methods are typically substrate-dependent, complex, and time-consuming. Here we present a simple and dry strategy for the development of polymeric coatings used as platforms for the direct, linker-free covalent attachment of AgNPs onto solid surfaces using ion-assisted plasma polymerization. The resulting coating not only exhibits long-term antibiofilm efficiency against adherent Staphylococcus aureus (S. aureus), but also enhances osteoblast adhesion and proliferation. High resolution X-ray photoelectron spectroscopy (XPS), before and after sodium dodecyl sulfate (SDS) washing, confirms covalent bonding. The development of such silver-functionalized surfaces through a simple, plasma-based process holds great promise for the fabrication of implantable devices with improved tissue-implant integration and reduced biomaterial associated infections.