In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release.

Neuroinflammation due to glial activation has been linked to many CNS diseases. We developed a computational model of a microglial cytokine interaction network to study the regulatory mechanisms of microglia-mediated neuroinflammation. We established a literature-based cytokine network, including TNFα, TGFβ, and IL-10, and fitted a mathematical model to published data from LPS-treated microglia. The addition of a previously unreported TGFβ autoregulation loop to our model was required to account for experimental data. Global sensitivity analysis revealed that TGFβ- and IL-10-mediated inhibition of TNFα was critical for regulating network behavior. We assessed the sensitivity of the LPS-induced TNFα response profile to the initial TGFβ and IL-10 levels. The analysis showed two relatively shifted TNFα response profiles within separate domains of initial condition space. Further analysis revealed that TNFα exhibited adaptation to sustained LPS stimulation. We simulated the effects of functionally inhibiting TGFβ and IL-10 on TNFα adaptation. Our analysis showed that TGFβ and IL-10 knockouts (TGFβ KO and IL-10 KO) exert divergent effects on adaptation. TFGβ KO attenuated TNFα adaptation whereas IL-10 KO enhanced TNFα adaptation. We experimentally tested the hypothesis that IL-10 KO enhances TNFα adaptation in murine macrophages and found supporting evidence. These opposing effects could be explained by differential kinetics of negative feedback. Inhibition of IL-10 reduced early negative feedback that results in enhanced TNFα-mediated TGFβ expression. We propose that differential kinetics in parallel negative feedback loops constitute a novel mechanism underlying the complex and non-intuitive pro- versus anti-inflammatory effects of individual cytokine perturbations.

Objective The purpose of the present study is to model the dynamics of lobular Ca2+ wave propagation induced by an extracellular stimulus and to analyze the effect of spatially systematic variations in cell-intrinsic signaling parameters on sinusoidal Ca2+ response. Methods We developed a computational model of lobular scale Ca2+ signaling that accounts for receptor-mediated initiation of cell-intrinsic Ca2+ signal in hepatocytes and its propagation to neighboring hepatocytes through gap junction-mediated molecular exchange. Results Analysis of the simulations showed that a pericentral-to-periportal spatial gradient in hormone sensitivity and/or rates of IP3 synthesis underlies the Ca2+ wave propagation. We simulated specific cases corresponding to localized disruptions in the graded pattern of these parameters along a hepatic sinusoid. Simulations incorporating locally altered parameters exhibited Ca2+ waves that do not propagate throughout the hepatic plate. Increased gap junction coupling restored normal Ca2+ wave propagation when hepatocytes with low Ca2+ signaling ability were localized in the mid-lobular or the pericentral region. Conclusion Multiple spatial patterns in intracellular signaling parameters can lead to Ca2+ wave propagation that is consistent with the experimentally observed spatial patterns of Ca2+ dynamics. Based on simulations and analysis, we predict that increased gap junction-mediated intercellular coupling can induce robust Ca2+ signals in otherwise poorly responsive hepatocytes, at least partly restoring the sinusoidally oriented Ca2+ waves. Significance Our bottom-up model of agonist-evoked spatial Ca2+ patterns can be integrated with detailed descriptions of liver histology to study Ca2+ regulation at the tissue level.