Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis.

Solid cancers frequently relapse with distant metastasis, despite local and systemic treatment. Cellular dormancy has been identified as an important mechanism underlying drug resistance enabling late relapse. Therefore, relapse from invisible, minimal residual cancer of seemingly disease-free patients call for in vitro models of dormant cells suited for drug discovery.

3D osteocyte lacunar morphometry of human bone biopsies with high resolution microCT: From monoclonal gammopathy to newly diagnosed multiple myeloma.

Osteocytes are mechanosensitive, bone-embedded cells which are connected via dendrites in a lacuno-canalicular network and regulate bone resorption and formation balance. Alterations in osteocyte lacunar volume, shape and density have been identified in conditions of aging, osteoporosis and osteolytic bone metastasis, indicating patterns of impaired bone remodeling, osteolysis and disease progression. Osteolytic bone disease is a hallmark of the hematologic malignancy multiple myeloma (MM), in which monoclonal plasma cells in the bone marrow disrupt the bone homeostasis and induce excessive resorption at local and distant sites.

Phase diagrams of bone remodeling using a 3D stochastic cellular automaton.

We propose a 3D stochastic cellular automaton model, governed by evolutionary game theory, to simulate bone remodeling dynamics. The model includes four voxel states: Formation, Quiescence, Resorption, and Environment. We simulate the Resorption and Formation processes on separate time scales to explore the parameter space and derive a phase diagram that illustrates the sensitivity of these processes to parameter changes.

Dynamic 3D lung models: applications of inorganic nanoparticles for model development and characterization.

Being a vital organ exposed to the external environment, the lung is susceptible to a plethora of pathogens and pollutants. This is reflected in high incidences of chronic respiratory diseases, which remain a leading cause of mortality world-wide and pose a persistent global burden. It is thus of paramount importance to improve our understanding of these pathologies and provide better therapeutic options.

From breast cancer cell homing to the onset of early bone metastasis: The role of bone (re)modeling in early lesion formation.

Breast cancer often metastasizes to bone, causing osteolytic lesions. Structural and biophysical changes are rarely studied yet are hypothesized to influence metastasis. We developed a mouse model of early bone metastasis and multimodal imaging to quantify cancer cell homing, bone (re)modeling, and onset of metastasis.

Nonspecific membrane-matrix interactions influence diffusivity of lipid vesicles in hydrogels.

The diffusion of extracellular vesicles and liposomes in vivo is affected by different tissue environmental conditions and is of great interest in the development of liposome-based therapeutics and drug-delivery systems. Here, we use a bottom-up biomimetic approach to better isolate and study steric and electrostatic interactions and their influence on the diffusivity of synthetic large unilamellar vesicles in hydrogel environments. Single-particle tracking of these extracellular vesicle-like particles in agarose hydrogels as an extracellular matrix model shows that membrane deformability and surface charge affect the hydrogel pore spaces that vesicles have access to, which determines overall diffusivity.

Hydrogels with stiffness-degradation spatial patterns control anisotropic 3D cell response.

In nature, tissues are patterned, but most biomaterials used in human applications are not. Patterned biomaterials offer the opportunity to mimic spatially segregating biophysical and biochemical properties found in nature. Engineering such properties allows to study cell-matrix interactions in anisotropic matrices in great detail.

Convergence of scaffold-guided bone regeneration principles and microvascular tissue transfer surgery.

A preclinical evaluation using a regenerative medicine methodology comprising an additively manufactured medical-grade ε-polycaprolactone β-tricalcium phosphate (mPCL-TCP) scaffold with a corticoperiosteal flap was undertaken in eight sheep with a tibial critical-size segmental bone defect (9.5 cm, M size) using the regenerative matching axial vascularization (RMAV) approach. Biomechanical, radiological, histological, and immunohistochemical analysis confirmed functional bone regeneration comparable to a clinical gold standard control (autologous bone graft) and was superior to a scaffold control group (mPCL-TCP only).

Curvature in Biological Systems: Its Quantification, Emergence, and Implications across the Scales.

Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed.

Effect of capillary fluid flow on single cancer cell cycle dynamics, motility, volume and morphology.

From primary tumours and disseminating to secondary organs, cancer cells experience a wide variety of fluid flow profiles when passing through blood vessels or the lymphatic system before extravasation. Sinusoidal capillaries are a common site for extravasation. Therefore, we aim to investigate how metastatic cancer cells react to a biophysical cue such as capillary fluid flow by quantifying its effect on metastatic cell cycle progression, motility, cell and nuclear volume, and morphology.

FUCCItrack: An all-in-one software for single cell tracking and cell cycle analysis.

Beyond the more conventional single-cell segmentation and tracking, single-cell cycle dynamics is gaining a growing interest in the field of cell biology. Thanks to sophisticated systems, such as the fluorescent ubiquitination-based cell cycle indicator (FUCCI), it is now possible to study cell proliferation, migration, changes in nuclear morphology and single cell cycle dynamics, quantitatively and in real time. In this work, we introduce FUCCItrack, an all-in-one, semi-automated software to segment, track and visualize FUCCI modified cell lines.

In vivo microCT-based time-lapse morphometry reveals anatomical site-specific differences in bone (re)modeling serving as baseline parameters to detect early pathological events.

The bone structure is very dynamic and continuously adapts its geometry to external stimuli by modeling and remodeling the mineralized tissue. In vivo microCT-based time-lapse morphometry is a powerful tool to study the temporal and spatial dynamics of bone (re)modeling. Here an advancement in the methodology to detect and quantify site-specific differences in bone (re)modeling of 12-week-old BALB/c nude mice is presented.

An in silico model predicts the impact of scaffold design in large bone defect regeneration.

Large bone defects represent a clinical challenge for which the implantation of scaffolds appears as a promising strategy. However, their use in clinical routine is limited, in part due to a lack of understanding of how scaffolds should be designed to support regeneration. Here, we use the power of computer modeling to investigate mechano-biological principles behind scaffold-guided bone regeneration and the influence of scaffold design on the regeneration process.

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.

Role of extracellular matrix structural components and tissue mechanics in the development of postoperative pancreatic fistula.

Radical resection remains the only curative treatment option in pancreatic cancer. Postoperative pancreatic fistulas (POPF) occur in up to 30% of patients leading to prolonged hospital-stay, increased cost of care and morbidity and mortality. Mechanical properties of the pancreas are associated with POPF.

Osmotic pressure modulates single cell cycle dynamics inducing reversible growth arrest and reactivation of human metastatic cells.

Biophysical cues such as osmotic pressure modulate proliferation and growth arrest of bacteria, yeast cells and seeds. In tissues, osmotic regulation takes place through blood and lymphatic capillaries and, at a single cell level, water and osmoregulation play a critical role. However, the effect of osmotic pressure on single cell cycle dynamics remains poorly understood.

A humanised rat model of osteosarcoma reveals ultrastructural differences between bone and mineralised tumour tissue.

Current xenograft animal models fail to accurately replicate the complexity of human bone disease. To gain translatable and clinically valuable data from animal models, new in vivo models need to be developed that mimic pivotal aspects of human bone physiology as well as its diseased state. Above all, an advanced bone disease model should promote the development of new treatment strategies and facilitate the conduction of common clinical interventional procedures.

Dynamic Mechanical Control of Alginate-Fibronectin Hydrogels with Dual Crosslinking: Covalent and Ionic.

Alginate is a polysaccharide used extensively in biomedical applications due to its biocompatibility and suitability for hydrogel fabrication using mild reaction chemistries. Though alginate has commonly been crosslinked using divalent cations, covalent crosslinking chemistries have also been developed. Hydrogels with tuneable mechanical properties are required for many biomedical applications to mimic the stiffness of different tissues.

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.

Dual alginate crosslinking for local patterning of biophysical and biochemical properties.

Hydrogels with patterned biophysical and biochemical properties have found increasing attention in the biomaterials community. In this work, we explore alginate-based materials with two orthogonal crosslinking mechanisms: the spontaneous Diels-Alder reaction and the ultraviolet light-initiated thiol-ene reaction. Combining these mechanisms in one material and spatially restricting the location of the latter using photomasks, enables the formation of dual-crosslinked hydrogels with patterns in stiffness, biomolecule presentation and degradation, granting local control over cell behavior.

An Early Myeloma Bone Disease Model in Skeletally Mature Mice as a Platform for Biomaterial Characterization of the Extracellular Matrix.

Multiple myeloma (MM) bone disease is characterized by osteolytic bone tissue destruction resulting in bone pain, fractures, vertebral collapse, and spinal cord compression in patients. Upon initial diagnosis of MM, almost 80% of patients suffer from bone disease. Earlier diagnosis and intervention in MM bone disease would potentially improve treatment outcome and patient survival.

Alginate Hydrogels for Bone Regeneration: The Immune Competence of the Animal Model Matters.

Biomaterials with tunable biophysical properties hold great potential for tissue engineering. The adaptive immune system plays an important role in bone regeneration. Our goal is to investigate the regeneration potential of cell-laden alginate hydrogels depending on the immune status of the animal model.