Publications

Sprouting angiogenesis is a core biological process critical to vascular development. Its accurate simulation, relevant to multiple facets of human health, is of broad, interdisciplinary appeal. This study presents an in-silico model replicating a microfluidic assay where endothelial cells sprout into a biomimetic extracellular matrix, specifically, a large-pore, low-concentration fibrin-based porous hydrogel, influenced by chemotactic factors. We introduce a novel approach by incorporating the extracellular matrix and chemotactic factor effects into a unified term using a single parameter, primarily focusing on modelling sprouting dynamics and morphology. This continuous model naturally describes chemotactic-induced sprouting with no need for additional rules. In addition, we extended our base model to account for matrix sensing and degradation, crucial aspects of angiogenesis. We validate our model via a hybrid in-silico experimental method, comparing the model predictions with experimental results derived from the microfluidic setup. Our results underscore the intricate relationship between the extracellular matrix structure and angiogenic sprouting, proposing a promising method for predicting the influence of the extracellular matrix on angiogenesis.Copyright © 2023 Ferre-Torres, Noguera-Monteagudo, Lopez-Canosa, Romero-Arias, Barrio, Castaño and Hernandez-Machado.

JTD Keywords: angiogenesis, biomimmetic, chemotaxis, endothelial cells, filopodia, growth, in silico model, mathematical models, mechanisms, metalloproteinase, migration, morphogenesis, phase field, pore-size, simulation, Angiogenesis, Biomimmetic, Chemotaxis, Endothelial cells, Extracellular matrix, In silico model, Mathematical models, Phase field, Tip cells

Catalytically powered micro/nanobots (MNBs) can perform active movement by harnessing energy from in situ chemical reactions and show tremendous potential in biomedical applications. However, the development of imageable MNBs that are driven by bioavailable fuels and possess multiple therapeutic functions remains challenging. To resolve such issues, we herein propose enzyme (urease) powered liquid metal (LM) nanobots that are naturally of multiple therapeutic functions and imaging signals. The main body of the nanobot is composed of a biocompatible LM nanoparticle encapsulated by polydopamine (PDA). Urease enzyme needed for the powering and desired drug molecules, e.g., cefixime trihydrate antibiotic, are grafted on external surfaces of the PDA shell. Such a chemical composition endows the nanobots with dual-mode ultrasonic (US) and photoacoustic (PA) imaging signals and favorable photothermal effect. These LM nanobots exhibit positive chemotaxis and therefore can be collectively guided along a concentration gradient of urea for targeted transportation. When exposed to NIR light, the LM nanobots would deform and complete the function change from active drug carriers to photothermal reagents, to achieve synergetic antibacterial treatment by both photothermal and chemotherapeutic effects. The US and PA properties of the LM nanoparticle can be used to not only track and monitor the active movement of the nanobots in a microfluidic vessel model but also visualize their dynamics in the bladder of a living mouse in vivo. To conclude, the LM nanobots demonstrated herein represent a proof-of-concept therapeutic nanosystem with multiple biomedical functionalities, providing a feasible tool for preclinical studies and clinical trials of MNB-based imaging-guided therapy.

JTD Keywords: cell, chemo-photothermal therapy, chemotaxis, image tracking, liquid metal nanobots, nanomotors, tracking, Chemo-photothermal therapy, Chemotaxis, Image tracking, Liquid metal nanobots, Nanomotors

Many cell therapies rely on the ability of mesenchymal stromal cells (MSCs) to diffuse and localize throughout the target tissue-such as tumoral and ischemic tissues-, in response to specific cytokine signals, rather than being concentrated at the site of implantation. Therefore, it is fundamental to engineer biomaterial carriers as reservoirs, from which cells can migrate, possibly in a controlled manner. In this work, microcarriers (μCs) made of polylactic acid are characterized as MSC delivery vehicles capable of modulating key chemotactic pathways. The effect of different functionalization strategies on MSC migratory behavior from the μCs is studied in vitro in relation to SDF-1α/CXCR4 axis,-a major actor in MSC recruitment, chemotaxis and homing. Collagen and arginine-glycine-aspartic acid (RGD) peptides were either covalently grafted or physisorbed on μC surface. While stable covalent modifications promoted better cell adhesion and higher proliferation compared to physisorption, the functionalization method of the μCs also affected the cells migratory behavior in response to SDF-1α (CXCL12) stimulation. Less stable coatings (physisorbed) showed sensibly higher number of migrating cells than covalent collagen/RGD coatings. The combination of physic-chemical cues provided by protein/peptide functionalization and stimuli induced by 3D culture on μCs improved MSC expression of CXCR4, and exerted a control over cell migration, a condition suitable to promote cell homing after transplantation in vivo. These are key findings to highlight the impact of surface modification approaches on chemokine-triggered cell release, and allow designing biomaterials for efficient and controlled cell delivery to damaged tissues.

JTD Keywords: Cell therapy, Chemotaxis, ECM (extracellular matrix), Mesenchymal stromal cells, Surface modification

Angiogenesis is a complex process regulated by many cell types and a large variety of biochemical signals such as growth factors, transcription factors, oxygen and nutrient diffusion among others. In the present study, we found out that Flk-1(+) CD34(+) progenitor cells (bone marrow resident cells with an important role in angiogenesis) were responsive to changes in extracellular calcium concentration through a membrane bound, G-protein-coupled receptor sensitive to calcium ions related to the calcium-sensing receptor (CaSR). Calcium was able to induce progenitor cell migration in Boyden chamber experiments and tubulogenesis in Matrigel assays. Addition of anti-CaSR antibodies completely blocked the effect, while CaSR agonist Mg2+ produced a similar response to that of calcium. Real time RT-PCR for a wide array of angiogenesis-related genes showed increased expression of endothelial markers and signaling pathways involved in angiogenesis. These results suggest calcium could be a physiological modulator of the bone marrow progenitor cell-mediated angiogenic response.

JTD Keywords: Endothelial progenitor cell, Calcium-sensing receptor, Angiogenesis, Chemotaxis, Calcium, Bone marrow