Engineering Vascular Bioreactor Systems to Closely Mimic Physiological Forces In Vitro.

In vitro models of the vasculature play an important role in biomedical discovery research, with diverse applications in vascular biology, drug discovery, and tissue engineering. These models aim to replicate the conditions of the human vasculature including physical geometry, employing appropriate vascular cells exposed to physiological forces. However, vessel biology is complex, with multiple relevant cell types, precise three-dimensional (3D) architectural arrangement, an array of biological cues and pressure, flow rate, and shear stress stimulation that are difficult to replicate outside of the body. Vessel bioreactors typically comprise core modules, common to most systems: a 3D tubular scaffold to support cells, media and nutrient exchange for cell viability, a pumping module, and sensor arrays for monitoring. In our comprehensive review of the literature, foundational elements such as maintenance of cell viability, nutrient exchange with flow, use of 3D scaffolds, and basic sensing capabilities are well established. However, most bioreactor systems fail to adequately replicate combinations of physiologically relevant stimuli-including pressure, shear stress, and flow rate-independently, as system input parameters. At the root of this deficiency is the field's reliance on simple pumping systems designed for other applications, making it necessary to add resistors and compliance chambers to even approach human vascular conditions. As vascular biology research rapidly progressed it became increasingly clear that combinations of physical forces strongly influence cell phenotype, gene expression, and in turn can be drivers of pathology. We highlight the need for renewed innovation in vascular bioreactor development with a focus on the importance of providing appropriate physiological forces in the same system. Impact statement In vitro systems modeling aspects of the human vasculature are increasingly important in tissue engineering and biomedical research. Current systems maintain basic cell viability and facilitate nutrient exchange but poorly replicate physiological forces, reliant on simplistic pumping systems. Our review highlights the need to more accurately mimic arterial pressure, flow rate, and shear stress in the same system. Innovation in this area would improve in vitro modeling of the vasculature, significantly impacting tissue engineering and vascular biology in this area.

Plasma polymerized nanoparticles effectively deliver dual siRNA and drug therapy in vivo.

Multifunctional nanocarriers (MNCs) promise to improve therapeutic outcomes by combining multiple classes of molecules into a single nanostructure, enhancing active targeting of therapeutic agents and facilitating new combination therapies. However, nanocarrier platforms currently approved for clinical use can still only carry a single therapeutic agent. The complexity and escalating costs associated with the synthesis of more complex MNCs have been major technological roadblocks in the pathway for clinical translation. Here, we show that plasma polymerized nanoparticles (PPNs), synthesised in reactive gas discharges, can bind and effectively deliver multiple therapeutic cargo in a facile and cost-effective process compatible with up scaled commercial production. Delivery of siRNA against vascular endothelial growth factor (siVEGF) at extremely low concentrations (0.04 nM), significantly reduced VEGF expression in hard-to-transfect cells when compared with commercial platforms carrying higher siRNA doses (6.25 nM). PPNs carrying a combination of siVEGF and standard of care Paclitaxel (PPN-Dual) at reduced doses (< 100 µg/kg) synergistically modulated the microenvironment of orthotopic breast tumors in mice, and significantly reduced tumor growth. We propose PPNs as a new nanomaterial for delivery of therapeutics, which can be easily functionalised in any laboratory setting without the need for additional wet-chemistry and purification steps.