Microfluidic interactions between red blood cells and drug carriers by image analysis techniques

This paper was presented at the 4th Micro and Nano Flows Conference (MNF2014), which was held at University College, London, UK. The conference was organised by Brunel University and supported by the Italian Union of Thermofluiddynamics, IPEM, the Process Intensification Network, the Institution of Mechanical Engineers, the Heat Transfer Society, HEXAG - the Heat Exchange Action Group, and the Energy Institute, ASME Press, LCN London Centre for Nanotechnology, UCL University College London, UCL Engineering, the International NanoScience Community, www.nanopaprika.eu.Blood is a complex biological fluid composed of deformable cells and platelets suspended in plasma, a protein-rich liquid. The peculiar nature of blood needs to be considered when designing a drug delivery strategy based on systemically administered carriers. Here, we report on an in vitro fluid dynamic investigation of the influence of the microcapillary flow of red blood cells (RBCs) on micron sized carriers by high speed imaging methods. The experiments were carried out in a 50μm diameter glass capillary that mimicked the hydrodynamic conditions of human microcirculation. Spherical μ particles (μ-Ps), with sizes ranging between 0.5 and 3μm, were tested. Images of the flowing RBCs and μ-Ps were acquired by a highspeed/ high-magnification microscopy. The transport and distribution of rigid particles in a suspension of RBCs under shear flow were followed for: i) the migration of RBCs towards the vessel centerline due to their deformability; ii) the cross-flow migration of μ-Ps towards the vessel wall due to their hydrodynamic interactions with RBCs; iii) the radial distribution of μ-Ps in the presence of RBCs. This study suggests that the therapeutic efficacy of μ-Ps could be ultimately affected by their interactions with the flowing RBCs in the vasculature

Tailoring the degradation kinetics of mesoporous silicon structures through PEGylation

Injectable and implantable porosified silicon (pSi) carriers and devices for prolonged and controlled delivery of biotherapeutics offer great promise for treatment of various chronic ailments and acute conditions. Polyethylene glycols (PEGs) are important surface modifiers currently used in clinic mostly to avoid uptake of particlulates by reticulo-endothelial system (RES). In this work we show for the first time that covalent attachment of PEGs to the pSi surface can be used as a means to finely tune degradation kinetics of silicon structures. Seven PEGs with varying molecular weights (245, 333, 509, 686, 1214, 3400 and 5000Da) were employed and the degradation of PEGylated pSi hemispherical microparticles in simulated physiological conditions was monitored by means of ICP-AES, SEM and fluorimetry. Biocompatibility of the systems with human macrophages in vitro was also evaluated. The results clearly indicate that controlled PEGylation of silicon microparticles can offer a sensitive tool to finely tune their degradation kinetics and that the systems do not induce release of proinflammatory cytokines IL-6 and IL-8 in THP1 human macrophages

Hyperpolarized Long-T1 Silicon Nanoparticles for Magnetic Resonance Imaging

Silicon nanoparticles are experimentally investigated as a potential hyperpolarized, targetable MRI imaging agent. Nuclear T_1 times at room temperature for a variety of Si nanoparticles are found to be remarkably long (10^2 to 10^4 s) - roughly consistent with predictions of a core-shell diffusion model - allowing them to be transported, administered and imaged on practical time scales without significant loss of polarization. We also report surface functionalization of Si nanoparticles, comparable to approaches used in other biologically targeted nanoparticle systems.Comment: supporting material here: http://marcuslab.harvard.edu/Aptekar_hyper1_sup.pd

Medically Biodegradable Hydrogenated Amorphous Silicon Microspheres

[EN] Hydrogenated amorphous silicon colloids of low surface area (<5 m(2)/g) are shown to exhibit complete in-vitro biodegradation into orthosilicic acid within 10-15 days at 37 degrees C. When converted into polycrystalline silicon colloids, by high temperature annealing in an inert atmosphere, microparticle solubility is dramatically reduced. The data suggests that amorphous silicon does not require nanoscale porosification for full in-vivo biodegradability. This has significant implications for using a-Si:H coatings for medical implants in general, and orthopedic implants in particular. The high sphericity and biodegradability of submicron particles may also confer advantages with regards to contrast agents for medical imaging.This work has been partially supported by the Spanish CICyT projects, FIS2009-07812, Consolider CSD2007-046, MAT2009-010350 and PROMETEO/2010/043.Shabir, Q.; Pokale, A.; Loni, A.; Johnson, DR.; Canham, L.; Fenollosa Esteve, R.; Tymczenko, MK.... (2011). Medically Biodegradable Hydrogenated Amorphous Silicon Microspheres. Silicon. 3(4):173-176. https://doi.org/10.1007/s12633-011-9097-4S17317634Salonen J, Kaukonen AM, Hirvonen J, Lehto VP (2008) J Pharmaceutics 97:632–53Anglin EJ, Cheng L, Freeman WR, Sailor MJ (2008) Adv Drug Deliv Rev 60:1266–77O’Farrell N, Houlton A, Horrocks BR (2006) Int J Nanomedicine 1:451–72Canham LT (1995) Adv Mater 7:1037, PCT patent WO 97/06101,1999Park JH, Gui L, Malzahn G, Ruoslahti E, Bhatia SN, Sailor MJ (2009) Nature Mater 8:331–6Cullis AG, Canham LT, Calcott PDJ (1997) J Appl Phys 82:909–66Canham LT, Reeves CR (1996) Mat Res Soc Symp 414:189–90Edell DJ, Toi VV, McNeil VM, Clark LD (1992) IEEE Trans Biomed Eng 39:635–43Fenollosa R, Meseguer F, Tymczenko M (2008) Adv Mater 20:95Fenollosa R, Meseguer F, Tymczenko M, Spanish Patent P200701681, 2007Pell LE, Schricker AD, Mikulec FV, Korgel BA (2004) Langmuir 20:6546Xifré-Perez E, Fenollosa R, Meseguer F (2011) Opt Express 19:3455–63Fenollosa R, Ramiro-Manzano F, Tymczenko M, Meseguer F (2010) J Mater Chem 20:5210Xifré-Pérez E, Domenech JD, Fenollosa R, Muñoz P, Capmany J, Meseguer F (2011) Opt Express 19–4:3185–92Rodriguez I, Fenollosa R, Meseguer F, Cosmetics & Toiletries 2010;42–49Ramiro-Manzano F, Fenollosa R, Xifré-Pérez E, Garín M, Meseguer F (2011) Adv Mater 23:3022–3025. doi: 10.1002/adma.201100986Iler RK (1979) Chemistry of silica: solubility, polymerization, colloid & surface properties & biochemistry. Wiley, New YorkTanaka K, Maruyama E, Shimado T, Okamoto H (1999) Amorphous silicon. Wiley, New York, NYPatterson AL (1939) Phys Rev 56:978–82Canham LT, Reeves CL, King DO, Branfield PJ, Gabb JG, Ward MC (1996) Adv Mater 8:850–2Iler RK In: Chemistry of silica: solubility, polymerization, colloid & surface properties &Biochemistry. Wiley, New York, NYFinnie KS, Waller DJ, Perret FL, Krause-Heuer AM, Lin HQ, Hanna JV, Barbe CJ (2009) J Sol-Gel Technol 49:12–8Zhao D, Huo Q, Feng J, Chmelka BF, Stucky GD (1998) J Am Chem Soc 120:6024–36Fan D, Akkaraju GR, Couch EF, Canham LT, Coffer JL (2010) Nanoscale 1:354–61Tasciotti E, Godin B, Martinez JO, Chiappini C, Bhavane R, Liu X, Ferrari M (2011) Mol Imaging 10:56–

Scaling behaviour for the water transport in nanoconfined geometries

The transport of water in nanoconfined geometries is different from bulk phase and has tremendous implications in nanotechnology and biotechnology. Here molecular dynamics is used to compute the self-diffusion coefficient D of water within nanopores, around nanoparticles, carbon nanotubes and proteins. For almost 60 different cases, D is found to scale linearly with the sole parameter theta as D(theta)=DB[1+(DC/DB-1)theta], with DB and DC the bulk and totally confined diffusion of water, respectively. The parameter theta is primarily influenced by geometry and represents the ratio between the confined and total water volumes. The D(theta) relationship is interpreted within the thermodynamics of supercooled water. As an example, such relationship is shown to accurately predict the relaxometric response of contrast agents for magnetic resonance imaging. The D(theta) relationship can help in interpreting the transport of water molecules under nanoconfined conditions and tailoring nanostructures with precise modulation of water mobility

Bioresponsive Mesoporous Silica Nanoparticles for Triggered Drug Release

Mesoporous silica nanoparticles (MSNPs) have garnered a great deal of attention as potential carriers for therapeutic payloads. However, achieving triggered drug release from MSNPs in vivo has been challenging. Here, we describe the synthesis of stimulus-responsive polymer-coated MSNPs and the loading of therapeutics into both the core and shell domains. We characterize MSNP drug-eluting properties in vitro and demonstrate that the polymer-coated MSNPs release doxorubicin in response to proteases present at a tumor site in vivo, resulting in cellular apoptosis. These results demonstrate the utility of polymer-coated nanoparticles in specifically delivering an antitumor payload.National Science Foundation (U.S.) (grant R01-CA124427)National Science Foundation (U.S.) (grant U54-CA119349)National Science Foundation (U.S.) (grant U54-CA119335

Silicon particles as trojan horses for potential cancer therapy

[EN] Background: Porous silicon particles (PSiPs) have been used extensively as drug delivery systems, loaded with chemical species for disease treatment. It is well known from silicon producers that silicon is characterized by a low reduction potential, which in the case of PSiPs promotes explosive oxidation reactions with energy yields exceeding that of trinitrotoluene (TNT). The functionalization of the silica layer with sugars prevents its solubilization, while further functionalization with an appropriate antibody enables increased bioaccumulation inside selected cells. Results: We present here an immunotherapy approach for potential cancer treatment. Our platform comprises the use of engineered silicon particles conjugated with a selective antibody. The conceptual advantage of our system is that after reaction, the particles are degraded into soluble and excretable biocomponents. Conclusions: In our study, we demonstrate in particular, specific targeting and destruction of cancer cells in vitro. The fact that the LD50 value of PSiPs-HER-2 for tumor cells was 15-fold lower than the LD50 value for control cells demonstrates very high in vitro specificity. This is the first important step on a long road towards the design and development of novel chemotherapeutic agents against cancer in general, and breast cancer in particular.The authors acknowledge financial support from the following projects FIS2009-07812, MAT2012-35040, PROMETEO/2010/043, CTQ2011-23167, CrossSERS, FP7 MC-IEF 329131, and HSFP (project RGP0052/2012) and Medcom Tech SA. Xiang Yu acknowledges support by the Chinese government (CSC, Nr. 2010691036).Fenollosa Esteve, R.; Garcia-Rico, E.; Alvarez, S.; Alvarez, R.; Yu, X.; Rodriguez, I.; Carregal-Romero, S.... (2014). Silicon particles as trojan horses for potential cancer therapy. 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Does electrification spur the fertility transition? evidence from Indonesia

We analyze various pathways through which access to electricity affects fertility in Indonesia, using a district difference-in-difference approach. The electrification rate increased by 65 % over the study period, and our results suggest that the subsequent effects on fertility account for about 18 % to 24 % of the overall decline in fertility. A key channel is increased exposure to television. Using in addition several waves of Demographic and Health Surveys, we find suggestive evidence that increased exposure to TV affects, in particular, fertility preferences and increases the effective use of contraception. Reduced child mortality seems to be another important pathway