Early Direct Injection Research Articles

Complete Correction of Severe Canine Hemophilia B By Skeletal Muscle Directed AAV-Based FIX-Padua Gene Therapy in Inhibitor-Prone Dogs

Hemophilia B (HB) is an X-linked bleeding disorder caused by a deficiency in Factor IX (FIX). Ongoing gene therapy clinical trials for HB using adeno-associated viral (AAV) vectors targeting the liver have demonstrated sustained FIX expression at therapeutic levels and improvement of the bleeding phenotype in severe HB patients. However, one of the major safety concerns is the cellular immune response directed against vector capsid antigens that can limit FIX expression if not promptly treated with transient immunosuppression. Emerging evidence suggests that this complication is vector dose dependent, occurring only at doses of 2 x 1012 vg/kg or higher. FIX-Padua, a naturally occurring hyperactive FIX variant we have preciously described (Simioni et al. NEJM 2009), which exhibits ~8-fold increase in specific activity, offers a potential way to decrease the vector dose while maintaining hemostatic efficacy. In preclinical studies, we have recently shown that in severe HB dogs with a high risk for inhibitor formation to canine FIX (cFIX) protein or with preexisting inhibitors to cFIX, liver expression after AAV-cFIX Padua gene therapy resulted in immune tolerance induction and eradication of inhibitory antibodies (Crudele et al., Blood 2015). In addition, the first description of an ongoing clinical trial with AAV-FIX-Padua reported therapeutic FIX levels without the development of FIX inhibitors. However, the success of liver-directed gene therapy approaches is not applicable to those HB patients with underlying liver disease, mostly due to HCV infection that affects >80% of adults with hemophilia treated with plasma-derived products. Thus, we sought to investigate AAV delivery to skeletal muscle as a potential alternative for these patients.Clinical trials and preclinical studies in HB dogs have demonstrated that the therapeutic vector dose for AAV muscle gene therapy was a log higher than liver GT when direct multi-site intramuscular injection was used; however, intravascular delivery to the muscle allows the vector dose to be significantly reduced to 2-3 x 1012 vg/kg. Here, we used a regional peripheral transvenular injection of AAV serotype 6 to express cFIX-Padua in the skeletal muscle of HB dogs. These dogs are at high risk for inhibitor formation due to the null mutation in their canine F9 gene resulting in no mRNA or protein expression; typically, a single injection of cFIX wild-type protein (0.5 mg) results in the formation of a high titer inhibitor. Two adult dogs received gene therapy with 3 x 1012 vg/kg of AAV6-cFIX-Padua under the control of a CMV promoter. One dog (Malani) reached a plateau of 80-100% circulating cFIX activity levels with a follow-up time of 10 months (ongoing). Sustained antigen levels are 7-10%, resulting in ~10-fold higher specific activity than wild type FIX. The second dog (Una) achieved 45-60% sustained activity with corresponding 4-5% antigen levels (~11-fold increase in specific activity) after 14 months (ongoing observation). Neither dog has developed inhibitors to cFIX. Both dogs are also negative for non-neutralizing IgG1 and IgG2 against cFIX. Whole blood clotting time and thromboelastogram parameters have also normalized in both dogs. Notably, immune tolerance has been maintained despite challenge with 0.5 mg of cFIX-wild type protein. Together, these data support the use of skeletal muscle as a target tissue for the expression of FIX Padua and, in contrast to an early direct AAV-FIX intramuscular injection trial, patients with null mutations can now be enrolled. This is the first demonstration of complete correction of HB in large animal models using AAV gene therapy targeting the skeletal muscle and supports the feasibility and safety for potential clinical studies. DisclosuresArruda:Spark Therapeutics: Patents & Royalties; Pfizer: Consultancy, Patents & Royalties, Research Funding.

Experimental measurements of n-heptane liquid penetration distance and spray cone angle for steady conditions relevant to early direct-injection low-temperature combustion in diesel engines

Early direct-injection is a diesel-engine combustion strategy in which fuel is injected early in the compression stroke when in-cylinder temperature and density are both much lower than for conventional operation, increasing the potential for impingement and wall wetting due to slower vaporization of fuel. Quantitative understanding of liquid-phase fuel penetration and dispersion, therefore, is necessary for these conditions in order to avoid problems such as impingement that are counterproductive to advanced combustion strategies. This work reports liquid penetration distances and spray cone angles of n-heptane measured using high-speed imaging of elastic light scattering in a constant-pressure flow vessel. Air temperatures in the constant-pressure flow vessel included well below, near, and well above saturation temperatures of n-heptane, which should provide insight into spray behavior of diesel fuel components for early-injection conditions that also potentially range from below to above saturation. Maximum liquid penetration distances and spray angles were found to be essentially independent of injection pressure and injection duration, as well as air flow velocity, but strongly dependent on thermodynamic properties of the flowing air. Maximum liquid penetration trends with respect to temperature and spray angle trends with respect to density were in qualitative agreement with model predictions, but did not agree with expected quantitative values. In addition, trends of maximum liquid penetration versus density and spray angle versus temperature were either non-existent or in direct opposition to model predictions. Results strongly suggest that well-accepted models, based on mixing-limited vaporization of fuel and ignoring heat and mass transfer of individual droplets, are insufficient for these conditions relevant to early direct-injection.

Combustion and emission characteristics of a diesel engine with DME as port premixing fuel under different injection timing

This work dealt with the combustion and exhaust performance of a DME premixed charge compression ignition diesel engine. With the port premixing DME, the heat-release process was made up of the premixed charge homogeneous charge compression ignition combustion and diffusion combustion. The in-cylinder fuel injection timing and port premixing DME quantity played the important roles in combustion and emission control. They had little impact on the peak position of heat-release rate (HRR) during LTR phase. However, they had great effects on the peak values and the crank-angle positions corresponding to the HRR peaks during HTR and diffusion combustion phase. The peak value of HRR increased and the crank-angle corresponding to the HRR peak advanced with an incremental DME quantity or an early injection during HTR phase. However, the peak value of HRR dropped with an incremental DME quantity or a late injection during the diffusion combustion phase. pmax and Tmax increased with an incremental DME quantity or an early injection. At the fixed direct-injection timing, BSFC decreased slightly with a rise of DME quantity due to CA50 closer to TDC. At a fixed DME quantity, BSFC was lowest when diesel was injected into cylinder at 7°CA BTDC. Moreover, as more DME was aspirated from port, NOx emissions decreased firstly but this decreasing trend ceased later. Smoke reduced, but CO and HC increased with a rise of DME quantity. Meanwhile, like the conventional DICI operation, NOx increased, but smoke, CO and HC declined with an early direct-injection.

Predicting auto-ignition characteristics of RCCI combustion using a multi-zone model

The objective of new combustion concepts is to meet emission standards by improving fuel air mixing prior to ignition. Since there is no overlap between injection and ignition, combustion is governed mainly by chemical kinetics and it is challenging to control the phasing of ignition. Reactivity Controlled Compression Ignition (RCCI) combustion aims to control combustion phasing by altering the fuel ratios of the high- and low octane fuel and injection timings. In this study the dual fuel blend is prepared with gasoline and diesel fuels. The applied injection timings of the diesel are very early (90 to 60° CA bTDC). In the detailed reaction mechanism, n-heptane and iso-octane represent diesel and gasoline fuel, respectively. A multi-zone model approach is implemented to perform RCCI combustion simulation. Ignition characteristics are analyzed by using CA50 as the main parameter. In the experiments for the early direct injection (DI) timing advancing the injection time results in a later ignition. Qualitatively, the trend effect of the diesel injection timing and the effect of the ratio gasoline/diesel are captured accurately by the multi-zone model.

Multi-zone modelling of PCCI combustion

Early Direct Injection Premixed Charge Compression Ignition (EDI PCCI) combustion is a promising concept for the diesel combustion. Although EDI PCCI assures very low soot and NOx emission levels, the injection is uncoupled from combustion, which narrows down the operating conditions. The main purpose is to analyse the effect of mixing. A multi-zone model is presented with the use of detailed chemical models. The paper presents the effects of parameters, like number of zones and chemical model, on emissions and ignition delay. A dedicated set of experiments is also utilised to assess the quality of the model.

Effects of Fuel Volatility on Early Direct-Injection, Low-Temperature Combustion in an Optical Diesel Engine

The effect of fuel volatility on early direct-injection, low-temperature combustion (LTC) was investigated using an optically accessible diesel engine. Five blends of conventional no. 2 diesel fuel and a high-volatility (HV) fuel mixture of n-heptane and toluene having approximately the same ignition quality were tested over a range of injection timings at steady-state speed-load operating conditions. Diagnostics included conventional heat-release analysis, the measurement of spatially integrated broadband light emitted during the combustion process (natural luminosity), and high-speed, in-cylinder imaging of both natural luminosity and laser light elastically scattered from liquid-phase fuel in the charge gas. Engine-out emissions of nitrogen oxides (NOx), smoke, unburned hydrocarbons (HC), and carbon monoxide (CO) also were monitored. Results show that, as the injection timing is advanced during LTC operation, liquid-fuel films on in-cylinder surfaces are likely to form because of low in-cylinder gas an...

Homogeneous charge compression ignition (HCCI) combustion of diesel fuel with external mixture formation

Abstract HCCI (Homogeneous Charge Compression Ignition) has been touted for many years as the alternate technology of choice for future engines, preserving the inherent efficiency of CIDI (Compression Ignition Direct Injection) engines while significantly reducing emissions. The current direction for all published diesel HCCI research is mixture preparation using the direct injection – system, referred to as internal mixture formation. The benefit of internal mixture formation is that it utilizes an already available direct injection system. Direct injected diesel HCCI can be divided into two areas, early injection (early in the compression stroke) and late injection (usually after Top Dead Center (aTDC)). Early direct injection HCCI requires carefully designed fuel injector to minimize the fuel wall-wetting that can cause combustion inefficiency and oil dilution. Late direct injection HCCI requires a long ignition delay and rapid mixing rate to achieve the homogeneous mixture. The ignition delay is extended by retarding the injection timing and rapid mixing rate was achieved by combining high swirl with toroidal combustion-bowl geometry. There is a compromise between Direct Injection (DI) and HCCI combustion regimes. Even under ideal conditions, it can prove difficult to form a truly homogeneous charge, which leads to elevated emissions when compared to true homogenous charge combustion and also strongly contribute to the high sensitivity of the combustion phasing to external parameters. The alternative to the internal mixture formation is, predictably, external mixture formation. By introducing the fuel external to the combustion chamber one can use the turbulence intake process to create a homogeneous charge regardless of engine conditions. This eliminates the need for combustion system changes which were necessary for the internal mixture formation method. With this method, the combustion system remains fully optimized for direct injection and also capable of running in HCCI combustion mode with nearly ideal mixture preparation. The key to the external mixture formation with diesel fuel is proper mixture preparation. In the present investigation a fuel vapouriser was used to achieve excellent HCCI combustion in a single cylinder air-cooled direct injection diesel engine. No modifications were made to the combustion system. In this study a vaporized diesel fuel was mixed with air to form a homogeneous mixture and inducted into the cylinder during the intake stroke. To control the early ignition of diesel vapour–air mixture, cooled (30 °C) Exhaust Gas Recirculation (EGR) technique was adopted. Experiments were conducted with diesel vapour induction without EGR and diesel vapour induction with 10%, 20% and 30% EGR and results are compared with conventional diesel fuel operation (DI @ 23° before Top Dead Center (bTDC) and 200 bar injection pressure).

Early Direct-Injection, Low-Temperature Combustion of Diesel Fuel in an Optical Engine Utilizing a 15-Hole, Dual-Row, Narrow-Included-Angle Nozzle

Low-temperature combustion of diesel fuel was studied in a heavy-duty, single-cylinder optical engine employing a 15-hole, dual-row, narrow-included-angle nozzle (10 holes x 70/mD and 5 holes x 35/mD) with 103-/gmm-diameter orifices. This nozzle configuration provided the spray targeting necessary to contain the direct-injected diesel fuel within the piston bowl for injection timings as early as 70/mD before top dead center. Spray-visualization movies, acquired using a high-speed camera, show that impingement of liquid fuel on the piston surface can result when the in-cylinder temperature and density at the time of injection are sufficiently low. Seven single- and two-parameter sweeps around a 4.82-bar gross indicated mean effective pressure load point were performed to map the sensitivity of the combustion and emissions to variations in injection timing, injection pressure, equivalence ratio, simulated exhaust-gas recirculation, intake temperature, intake boost pressure, and load. High-speed movies of natural luminosity were acquired by viewing through a window in the cylinder wall and through a window in the piston to provide quasi-3D information about the combustion process. These movies revealed that advanced combustion phasing resulted in intense pool fires within the piston bowl, after the end of significant heat release. These pool fires are a result of fuel-filmsmore » created when the injected fuel impinged on the piston surface. The emissions results showed a strong correlation with pool-fire activity. Smoke and NO/dx emissions rose steadily as pool-fire intensity increased, whereas HC and CO showed a dramatic increase with near-zero pool-fire activity.« less

COMBUSTION AND EMISSION CHARACTERISTICS OF A PARTIAL HOMOGENEOUS CHARGE COMPRESSION IGNITION ENGINE WHEN USING TWO-STAGE INJECTION

The focus of this study was an investigation for the realization of a partial homogeneous charge compression ignition (HCCI) combustion as a control mechanism for HCCI combustion. Premixed fuel was supplied using an in-cylinder early direct injection, and the second injection was made near the TDC to control the ignition and combustion rates of the premixed fuel. In order to obtain the optimal injection timing for the premixed fuel, combustion, and emission characteristics with respect to DI fuel injection timing was investigated in various operational ranges, from conventional diesel combustion to HCCI combustion. The results showed that two-stage injection was very effective in reducing NOx emissions from a DI diesel engine. Additionally, at an optimized injection timing, the ignition of premixed fuel can be controlled by the main injection without premature autoignition. Based on the experimental results, the effect of the premixed ratio and timings of the first and main injections on the combustion characteristics and exhaust emissions in a direct injection diesel engine were discussed.

A computational study of an HCCI engine with direct injection during gas exchange

We present a new probability density function (PDF)-based computational model to simulate a homogeneous charge compression ignition (HCCI) engine with direct injection (DI) during gas exchange. This stochastic reactor model (SRM) accounts for the engine breathing process in addition to the closed-volume HCCI engine operation. A weighted-particle Monte Carlo method is used to solve the resulting PDF transport equation. While simulating the gas exchange, it is necessary to add a large number of stochastic particles to the ensemble due to the intake air and EGR streams as well as fuel injection, resulting in increased computational expense. Therefore, in this work we apply a down-sampling technique to reduce the number of stochastic particles, while conserving the statistical properties of the ensemble. In this method some of the most important statistical moments (e.g., concentration of the main chemical species and enthalpy) are conserved exactly, while other moments are conserved in a statistical sense. Detailed analysis demonstrates that the statistical error associated with the down-sampling algorithm is more sensitive to the number of particles than to the number of conserved species for the given operating conditions. For a full-cycle simulation this down-sampling procedure was observed to reduce the computational time by a factor of 8 as compared to the simulation without this strategy, while still maintaining the error within an acceptable limit. Following the detailed numerical investigation, the model, intended for volatile fuels only, is applied to simulate a two-stroke, naturally aspirated HCCI engine fueled with isooctane. The in-cylinder pressure and CO emissions predicted by the model agree reasonably well with the measured profiles. In addition, the new model is applied to estimate the influence of engine operating parameters such as the relative air–fuel ratio and early direct injection timing on HCCI combustion and emissions. The qualitative trends observed in the parametric variation study match well with experimental data in literature.

Improvements in premixed charge compression ignition combustion and emissions with lower distillation temperature fuels

The charge mixture in a premixed charge compression ignition (PCCI) engine with direct in-cylinder injection early in the compression stroke is still heterogeneous even at the compression end. Direct injection of a low-volatility fuel, such as diesel fuel, early in the compression stroke results in adhesion of unevaporated fuel on the cylinder liner wall. It may be possible to improve both mixture formation and homogeneity, and decrease wall wetting by using higher-volatility fuels with distillation temperatures lower than the in-cylinder gas temperature early in the compression stroke. This research addressed the potential for improvements in early direct injection type PCCI combustion with a higher-volatility fuel, experimentally and computationally. A normal heptane + isooctane blended fuel with ignitability similar to diesel fuel in PCCI operation was used as the higher-volatility fuel. The experimental results showed that the deterioration in thermal efficiency that occurs with advanced injection timings with ordinary diesel fuel could be eliminated with the higher-volatility fuel without significantly altering the total hydrocarbons (THC) and CO emissions. With early injection timings, the rate of heat release with diesel fuel is smaller than with higher-volatility fuels. This result suggests that with diesel fuel there is significant fuel adhesion to the cylinder liner wall and also absorption into the lubricating oil.

Mixture formation and controlled auto-ignition combustion in four-stroke gasoline engines with port and direct fuel injections

Controlled auto-ignition (CAI) combustion, also known as homogeneous charge compression ignition (HCCI) can be achieved by trapping residuals with early exhaust valve closure in both port and direct fuel injection four-stroke gasoline engines. A multi-cycle three-dimensional engine simulation program has been developed and applied to study the effect of injection on in-cylinder mixing and CAI combustion. The full engine cycle simulation, including complete gas exchange and combustion processes, was carried out over several cycles in order to obtain the stable cycle for analysis. The combustion models used in the present study are based on the Shell auto-ignition model and the characteristic-time combustion model, both of which have been modified to take the high level of residual gas into consideration. A liquid sheet break-up spray model was used for the droplet break-up processes. The analyses show that the injection timing plays an important role in affecting the in-cylinder air/fuel mixing and mixture temperature, which in turn affects the CAI combustion and engine performance. In comparison with the port fuel injection case, an early direct injection at exhaust valve closure can lead to higher load and lower fuel consumption.