Multilayer Flow Research Articles

Degradation Phenomena on Second Generation of Explanted Aortic Textile Endografts

s 403 3 Department of Vascular and Endovascular Surgery, Manchester Royal Infirmary, United Kingdom Department of Vascular and Endovascular Surgery, University Hospital South Manchester, Manchester, United Kingdom Introduction: We previously reported our early experience using the firstgeneration multi-layer flow modulating stent (MFMS) for patients with thoraco-abdominal (TAAA) and perirenal aneurysms (PAA) who were unsuitable for conventional EVAR and unfit for open repair. We encountered continued aneurysm growth, device component dislocation and re-intervention. Our study patients have now completed at least 3 years follow-up and we report the outcomes. Methods: Patients with TAAA and PAA unfit for open surgery and with no conventional options for endovascular repair were recruited by two UK vascular units. Follow-up included CTA at 1, 3, 6, and 12 months, then annually until 3 years. Outcome measures included 30 day mortality, growth-free survival, branch vessel patency, complications, re-intervention and maximal aortic diameter. Results: MFMS were implanted in 14 patients (6 PAA, 8 TAAA) between October 2011 and March 2014 with one (7%) 30 day death and 11 (79%) surviving to 12 months. The median aneurysm growth was 9 mm in the first 12 months following implantation. At current follow-up to death or at least 3 years, eleven patients (79%) have died including four confirmed ruptures, one presumed rupture, one confirmed dissection with rupture, one MI post-op (procedure related), one multi-organ failure following re-intervention (procedure related) one myocardial infarction (MI) (out of hospital e unrelated), one pneumonia (not device or procedure related), and one decompensated liver failure (unrelated). Continued aneurysm growth occurred in all patients who suffered rupture or dissection. AAA diameter remains stable in two of the three surviving patients. Fifty of 51 covered aortic branches remained patent with no embolic episodes or symptoms of ischaemia in any patient. MFMS dislocation occurred in four patients, leading to re-intervention in two. A total of six re-interventions were performed in five patients (35%) with one post re-intervention death. Conclusion: These first-generation MFMS were unstable and dislocated frequently. It is uncertain whether MFMS implantation influenced the natural history of these aneurysms as none decreased in size, but two remain stable after a mean of 42.5 months. Although side branch patency was maintained, rupture or dissection occurred in 43% of patients and our results do not support the continued use of these first-generation devices. Further development is needed as this technology has potential as demonstrated by the control of aneurysm rupture in three and growth in two patients. Disclosure of Interest: None Declared. SESSION 4 e MISCELLANEOUS (1) THU, 29 SEPT, 8:00e9:00

Three-Year Outcomes With the Multilayer Flow Modulator for Repair of Thoracoabdominal Aneurysms

Purpose: To evaluate midterm outcomes of endovascular repair of types II and III thoracoabdominal aortic aneurysms (TAAA) using the Multilayer Flow Modulator (MFM) in patients unsuitable for open surgery or fenestrated stent-grafts. Methods: In the prospective, multicenter, nonrandomized STRATO trial (EudraCT registration: 2009-013678-42; ClinicalTrials.gov identifier NCT01756911), 23 patients (mean age 75.8 years; 19 men) with Crawford type II and III TAAA (mean diameter 6.5 cm) were implanted between April 2010 and February 2011. Outcomes included all-cause mortality and stable aneurysm thrombosis with associated branch vessel patency. Results: Through 36 months, there were 7 deaths (none confirmed as aneurysm-related), and no cases of spinal cord injury, device migration or fracture, or respiratory, renal, or peripheral complications. Three patients were lost to follow-up and 2 devices were explanted. The device was patent in the 11 remaining patients at 3 years. Stable aneurysm thrombosis was achieved for 15 of 20 patients at 12 months, 12 of 13 at 24 months, and 10 of 11 at 36 months. The rate of branch patency was 96% at 12 months (primary patency), 100% at 24 months, and 97% at 36 months. Nine patients suffered from endoleaks (attachment site or device overlap); 9 patients underwent 11 reinterventions (3 surgical). Maximum aneurysm diameter was stable for 18 of 20 patients at 12 months, 11 of 13 at 24 months, and 9 of 11 at 36 months. For 10 patients with computed tomography at 36 months, the mean ratio of aneurysm flow volume to total volume had decreased by 83%; the mean ratio of thrombus volume to total volume increased by 159%. Conclusion: Through 3 years, endovascular repair with the MFM appears to be safe and effective while successfully maintaining branch vessel patency.

Multilayer Flow Modulator Treatment of Abdominal and Thoracoabdominal Aortic Aneurysms With Side Branch Coverage

Purpose: To evaluate endovascular repair of thoracoabdominal aortic aneurysms (TAAA) and abdominal aortic aneurysms (AAA) using the Multilayer Flow Modulator (MFM) in high-surgical-risk patients with at least one covered branch vessel. Methods: In this prospective single-center nonrandomized trial, 18 patients (mean age 61.1 years; 16 men) with TAAA (n=10, mean diameter 74.4 mm) and AAA (n=8, mean diameter 67.8 mm) were treated with the MFM between June 2009 and September 2012. The primary safety endpoints were all-cause mortality at 30 days and 12 months and neurological complications. The primary efficacy endpoint was overall procedure success, defined as patency of covered branch vessels, reductions in aneurysm diameter, and sac thrombus formation. Results: The technical success rate was 100% (53 study devices implanted, mean stented length 273 mm). Through mean follow-up of 13.4 months, all 61 covered branch vessels remained patent; there were no neurologic complications, ruptures, or instances of device migration, kinking, or fracture. Three patients died, 2 of unrelated causes and one of an undetermined cause. Only one reintervention with an additional MFM implanted at 5 years was required for a type I endoleak in a young patient with natural growth. Carefully planned and executed diameter and volume measurements demonstrated aneurysm shrinkage and progressive sac thrombus formation for both patient groups. Conclusion: Through midterm follow-up, treatment of high-surgical-risk TAAA and AAA patients with the MFM appears to be safe and effective, maintaining branch vessel patency and reducing rupture risk through reduction of aneurysm diameter and modulation of flow dynamics. Longer term follow-up is needed.

Insights from complex aortic surgery with a Streamliner device for aortic arch repair (STAR)

ObjectiveAortic arch aneurysms and thoracoabdominal aortic arch aneurysms are technically challenging to manage by established surgical and endovascular methods. The Streamliner Multilayer Flow Modulator device (Cardiatis, Isnes, Brussels, Belgium) offers an unorthodox option for these high-risk cases. The Streamliner device for aortic arch repair (STAR) study investigated complex aneurysm cases managed by the Streamliner Multilayer Flow Modulator device and offers an analytic solution for a clinical dilemma. MethodsSix cases were included, with a 1-year follow-up, comprising 4 pure arch aneurysms and 2 thoracoabdominal aortic arch aneurysms Crawford type I, from a multicenter database hosted by the Streamliner Multilayer Flow Modulator Global Registry. A total of 50% of cases were performed under instructions for use. All were American Society of Anesthesiology IV and originated from zone 0. All cases were computationally analyzed, which consisted of (1) simulating the treatment on the basis of the postoperative data, (2) repositioning the stents for the failed technical cases, and (3) assessing the effects of overlapping devices on branch patency. ResultsCorrect device placement induced aneurysm flow streamlining, which reduced the dynamic pressure by 23% to 66%, whereas incorrect placements promoted Failure Mode I with 58% and 16% dynamic pressure increases and aneurysm volume expansion up to 23%. Overlapped devices improved distal perfusion by increasing arch branch outflows from 5% to 24%. The Streamliner Multilayer Flow Modulator device does not benefit a sac volume greater than 400 cm3. ConclusionsThe Streamliner Multilayer Flow Modulator device is a new technology that can manage complex aortic arch aneurysms and thoracoabdominal aortic arch aneurysms with favorable clinical outcomes if it is performed under instructions for use. Careful procedure planning and perioperative virtual stent placement will avoid foreshortening, prevent inadequate stent overlap lengths, and provide insight into the sufficient numbers of required implanted devices.

Parametric instability of a many point-vortex system in a multi-layer flow under linear deformation

The paper deals with a dynamical system governing the motion of many point vortices located in different layers of a multi-layer flow under external deformation. The deformation consists of generally independent shear and rotational components. First, we examine the dynamics of the system’s vorticity center. We demonstrate that the vorticity center of such a multi-vortex multi-layer system behaves just like the one of two point vortices interacting in a homogeneous deformation flow. Given nonstationary shear and rotational components oscillating with different magnitudes, the vorticity center may experience parametric instability leading to its unbounded growth. However, we then show that one can shift to a moving reference frame with the origin coinciding with the position of the vorticity center. In this new reference frame, the new vorticity center always stays at the origin of coordinates, and the equations governing the vortex trajectories look exactly the same as if the vorticity center had never moved in the original reference frame. Second, we studied the relative motion of two point vortices located in different layers of a two-layer flow under linear deformation. We analyze their regular and chaotic dynamics identifying parameters resulting in effective and extensive destabilization of the vortex trajectories.

Endovascular management of renal artery aneurysms using the multilayer flow modulator

ObjectiveOur aim was to describe our experience of the Multilayer Flow Modulator (MFM, Cardiatis, Isnes, Belgium) used in the treatment of type III renal artery aneurysms (RAA).MethodsThis is a single-centre...

An integrated numerical study of coextrusion flow inside and outside the die

ABSTRACTThe three‐dimensional coextrusion flow of two polymer melts is solved over the die‐extrudate region using the finite element method. As elastic recovery is known to be the main source of extrudate swelling, a viscoelastic constitutive model (the Phan‐Thien‐Tanner or PTT model) is adopted to characterize the rheological behavior of the elastomers. A major challenge in the simulation of multilayer flow inside and outside the die is to update multiple moving surfaces (material interface and extrudate free surface) simultaneously. This difficulty is resolved by introducing a two‐step updating algorithm which decouples the iterations of the interface and the free surface. The effects of extrudate swelling and bending on interface deformation are investigated herein, together with the interface shape dependency on flow elasticity. The numerical method is also applied to an industrial profile and the simulation result is in quantitative agreement with the experimental coextrusion data. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43522.

Multi-layer Flow-modulating Stents for Thoraco-abdominal and Peri-renal Aneurysms: The UK Pilot Study

There remains a population of patients with aortic aneurysms that cannot be treated by conventional endovascular means. Multi-layer flow modulating stents (MFMS) are a novel approach for the treatment of aortic aneurysm; this study reports outcomes of a UK pilot study of first-generation MFMS in thoraco-abdominal (TAAA) and perirenal aneurysms (PAA) in patients who were also unfit for open surgery. Patients with TAAA and PAA unfit for open surgery and with no conventional options for endovascular repair were recruited. Follow-up included CTA at 1, 3, 6, and 12 months, then annually. Outcome measures included 30 day mortality, growth-free survival, branch vessel patency, complications, re-intervention, and maximal aortic diameter. MFMS were implanted in 14 patients (6 PAA, 8 TAAA) between October 2011 and March 2014 with one (7%) 30 day death and 11 (79%) surviving to 12 months. The median aneurysm growth was 9 mm in the first 12 months following implantation. On mean follow-up of 22.8 months, seven (50%) patients had died including one confirmed rupture. AAA diameter remained stable in only two of the surviving patients. Fifty of 51 covered aortic branches remained patent with no embolic episodes or symptoms of ischaemia in any patient. MFMS dislocation occurred in four patients, leading to re-intervention in two. A total of six re-interventions were performed in five patients (35%) with one post-re-intervention death. These first-generation MFMS were unstable and dislocated frequently. It is uncertain whether MFMS implantation influenced the natural history of these aneurysms as none decreased in size, but two remain stable after a mean of 22.8 months. Although side branch patency was maintained, our results do not support the continued use of these first-generation devices. Further development is needed if this technology is to have a role in treatment of aortic aneurysm.

Dynamics of the removal of viscoplastic fluids from inclined pipes

The dynamics of the removal of a viscoplastic fluid by a Newtonian fluid is investigated experimentally and theoretically in an inclined pipe based on our previous studies on near-horizontal and highly inclined configurations. The fluids are miscible. The displacing Newtonian fluid is heavier than the displaced viscoplastic one i.e. the configuration is density-unstable. In our earlier work it was found that two major flow regimes, namely center-type and slump-type, might occur depending on the density difference. These flows are explored in great details through measurements of the displacement speeds and hydraulic Reynolds numbers. The residual viscoplastic layer unevenness is characterized revealing that the flows are in the range of large roughness regimes. Through an integrated experimental-theoretical approach, estimates of the interfacial and wall shear stresses are given which is of great importance in designing the displacement and cleaning processes involving fluids with yield stress. Accompanied by Ultrasonic Doppler Velocimetry (UDV) data, the dynamics of the removal of the viscoplastic fluid from a pipe is elucidated suggesting three distinct phases in the displacement process namely a plug flow, inertial multi-dimensional flow at the displacing front and steady multi-layer developed flow. Finally, the viscoplastic displacement flow results are compared against the predictions of the closure model, previously proved successful for Newtonian and shear-thinning fluids displacement in pipe. It is found that in the case of viscoplastic fluids the closure model always over predicts the displacing front velocity due to the inertial stresses present at the front not captured in the model.

The Multilayer Flow Modulator stent for the treatment for arterial aneurysms: Concept, Indications and Contraindications

The Multilayer Flow Modulator stent for the treatment for arterial aneurysms: Concept, Indications and Contraindications

The use of multilayer flow modulators in the endovascular treatment of complex aortic aneurysms and aortic dissections

The use of multilayer flow modulators in the endovascular treatment of complex aortic aneurysms and aortic dissections

Streamliner Multilayer Flow Modulator stents as a therapeutic option in the management of complex thoraco-abdominal aortic pathology report from Global SMFM Registry

Complex thoraco-abdominal aortic aneurysm (TAAA) patients remain a challenge irrespective of treatment choice. The Streamliner Multilayer Flow Modulator (SMFM) is an alternative modality of treatment and it is conceptually at variance with conventional treatment modes.Preliminary results show that treatment of infra-renal AAA, juxta-renal AAA, Stanford Type B dissection and Crawford Type V by the SMFM device were most successful. Large volumes of more than 450cm3 in pathologies such as Crawford Type II and Type IV, should be labelled as a contraindication for use of the SMFM. C-reactive protein, haemoglobin, aneurysm volume and maximum diameter all play major roles in successful treatment. The greater the length of the aorta to be covered and the greater the number of stents utilized, the greater the risk of adverse events and mortality. Patient requiring a reintervention with an additional SMFM(s) within 200 days of primary treatment increases mortality. Both length of the pathology and rate of reintervention indicate a severe aortic pathology burden and its aggressive nature.The SMFM harnesses the body's innate physiological processes to modulate the aneurysm, with no risk of critical shuttering or loss of native side branches. The SMFM offers less operative trauma, shorter procedure times and reduced hospital stays. It offers simplicity, consistency and reproducibility in one treatment. However, the SMFM is not a solution for patients living on borrowed time. It is a promising disruptive technology, only in safe hands and must be utilized under strict instructions for use.

Efficacy of Multilayer Flow Modulator in treatment of thoracic aortic pseudoaneurysm in a case of Behçet's disease

Behçet's disease (BD) is a multi-systemic, autoimmune primitive vascularity of unknown aetiology. It is common around the Mediterranean basin and in south-east Asia. Arterial lesions are relatively rare but when they involve the aorta, and they become life-threatening. The classic treatment for pseudoaneurysms combines surgery and double therapy with an immunosuppressant and steroids. The risk of recurrence and the life-threatening risk of surgical treatment have led to a preference for endovascular treatment for the complex aortic localisations linked to BD.We report an original observation of a symptomatic distal thoracic aortic pseudoaneurysm with haemothorax which revealed BD. We treated it with the implantation of a Multilayer Flow Modulator combined with double therapy: immunosuppressants and steroids.Two years after the procedure, the patient is in good condition with a follow-up CT scan showing total disappearance of aneurysmal sac and patent visceral arteries.

Abstract 19579: An Experimental Evaluation of the Compliance Mismatch Effects for Four Stent-graft Devices and a Multi-layer Flow Modulator (MFM) Device for the Treatment of Abdominal Aortic Aneurysms

Purpose: To experimentally investigate the arterial wall/device compliance mismatch of four stent-graft devices and a multi-layer flow modulator within the supra- and infra-renal locations for the treatment of Abdominal Aortic Aneurysms (AAA). Methods: Five devices were tested under physiologically flow conditions within a flow simulator system comprising of a patient-specific thin-walled flexible AAA model with replicated intraluminal thrombus (ILT) supported by the spinal column. Arterial pressure/diameter measurements were monitored and recorded at the supra- and infra-renal regions and various hemodynamic indicators were obtained to assess the effects of compliance mismatch. Results: At the suprarenal region, all devices except the Excluder™, significantly decreased the compliance by 10 - 21% (p<0.002) and increased the stiffness values by 5 - 21% (p<0.001). At the infrarenal region, three devices (Endurant™ and Excluder™) significantly decreased the compliance by 13 - 26% (p<0.001), while the other three devices (MFM™, Zenith™ and Fortron™) did not significantly change the aortic compliance (p>0.057). There was a variation of 10.9 - 16.0 m/s in pulse wave velocities with an increase of 8 - 238% (p<0.001) in the reflection coefficient for all devices. The Excluder™ and Endurant TM devices doubled the infrarenal unstented median elastic modulus value (p<0.001). Conclusions: Commercially available endovascular devices lower the arterial wall compliance and increase the wall stiffness at the stent/arterial wall interface by varying amounts. The Excluder™ was found to be the most compliant in the surprarenal region, while the MFM™ device was the most compliant in the infrarenal region.

A Single-Center Experience of Aortic and Iliac Artery Aneurysm Treated with Multilayer Flow Modulator

The aim of this study was to analyze our series of endovascular treatments using a multilayer flow modulator (MFM) and to show the midterm results. At our institution, 8 patients were treated with an MFM. Four patients presented with an aortic aneurysm (2 type II thoracoabdominal aortic aneurysms [TAAAs], 1 type IV TAAA, and 1 juxtarenal abdominal aortic aneurysm) and 4 with an aneurysm involving the common iliac artery. Mortality, rupture and secondary intervention, major complications, patency of collateral vessels, and volume analysis were evaluated. Treated patients were followed up with computed tomography angiography at 1, 3, 6, and 12 months. Results showed no 30-day mortality or major complications; technical success was achieved in 87.5% of patients, patency of collateral vessels was reached in all cases at intraoperative completion angiography. Mean follow-up was 22.1 months (range, 18-30), survival rate was 87.5%, and one case of death unrelated to MFM treatment was reported. During follow-up, MFM and collateral vessel patency were observed in all cases. Secondary endovascular or open surgical procedures were not needed during follow-up. Volume analysis showed a slight increase in patients with aortic aneurysm, and an overall trend to increase in thrombosis was observed in all cases. Endovascular treatment of aneurysms with MFM seems to have encouraging midterm results. Should our results be confirmed by larger series and longer follow-up studies, MFM may become a viable alternative to other endovascular approaches.

Multi-layer Flow-modulating Stents for Thoraco-abdominal and Peri-renal Aneurysms: The UK Pilot Study

There remains a population of patients with aortic aneurysms that cannot be treated by conventional endovascular means. Multi-layer flow modulating stents (MFMS) are a novel approach for the treatment of aortic aneurysm; this study reports outcomes of a UK pilot study of first-generation MFMS in thoraco-abdominal (TAAA) and perirenal aneurysms (PAA) in patients who were also unfit for open surgery. Patients with TAAA and PAA unfit for open surgery and with no conventional options for endovascular repair were recruited. Follow-up included CTA at 1, 3, 6, and 12 months, then annually. Outcome measures included 30 day mortality, growth-free survival, branch vessel patency, complications, re-intervention, and maximal aortic diameter. MFMS were implanted in 14 patients (6 PAA, 8 TAAA) between October 2011 and March 2014 with one (7%) 30 day death and 11 (79%) surviving to 12 months. The median aneurysm growth was 9 mm in the first 12 months following implantation. On mean follow-up of 22.8 months, seven (50%) patients had died including one confirmed rupture. AAA diameter remained stable in only two of the surviving patients. Fifty of 51 covered aortic branches remained patent with no embolic episodes or symptoms of ischaemia in any patient. MFMS dislocation occurred in four patients, leading to re-intervention in two. A total of six re-interventions were performed in five patients (35%) with one post-re-intervention death. These first-generation MFMS were unstable and dislocated frequently. It is uncertain whether MFMS implantation influenced the natural history of these aneurysms as none decreased in size, but two remain stable after a mean of 22.8 months. Although side branch patency was maintained, our results do not support the continued use of these first-generation devices. Further development is needed if this technology is to have a role in treatment of aortic aneurysm.

TCT-778 Renal Artery Aneurysms. First Human Treatment With The Multilayer Flow Modulator

TCT-778 Renal Artery Aneurysms. First Human Treatment With The Multilayer Flow Modulator

An Experimental Evaluation of Device/Arterial Wall Compliance Mismatch for Four Stent-Graft Devices and a Multi-layer Flow Modulator Device for the Treatment of Abdominal Aortic Aneurysms

To investigate experimentally the arterial wall/device compliance mismatch of four stent-graft devices and a multilayer flow modulator within the supra- and infrarenal locations for the treatment of abdominal aortic aneurysms (AAA). Five devices (MFM, EndurantII, Excluder, Zenith, and Fortron) were tested under physiological flow conditions within a flow simulator system comprising of a patient-specific thin-walled flexible AAA perfusion model with replicated intraluminal thrombus, supported by the spinal column. Devices were submitted to circumferential force tests and implanted in the perfusion model for circumferential arterial pressure/diameter measurements. Parameters, including radial resistive force, supra-/infrarenal compliance, pulsatile arterial energy loss (PAEL), pulse wave velocity (PWV), and wave reflection coefficient (Γ), were computed to characterise the devices' performance. The Zenith and EndurantII devices had the highest radial resistive force (up to 3 N/cm), while the Fortron device had the lowest (0.11 N/cm). Supra- and infrarenal compliance varied between 6.9-5.1 × 10(-4)/mmHg and 4.8-5.4 × 10(-4)/mmHg, respectively. Two devices (EndurantII and Excluder) significantly decreased infrarenal compliance by 13-26% (p < .001). Four devices increased the PAEL by 13-44% (p < .006). The PWV ranged from 10.9 m/s (MFM; p = .164) to 15.1 m/s (EndurantII; p < .001). There was an increase of 8-238% (p < .001) in the reflection coefficient for all devices. Commercially available endovascular devices lower the aortic wall compliance after implantation. The MFM was found to be the most compliant in the suprarenal region, while the Fortron device was the most compliant in the infrarenal region. Choosing the most compliant devices for treating AAAs produces positive gains in the aortic elastic recoil, thus minimising the device related complications.

Influence of Copolymer Architecture on Generation of Defects in Reactive Multilayer Coextrusion

Several polymers can be combined in one multilayer structure by reactive coextrusion. Tie-layers are often used to compatibilize adjacent layers and may reduce or suppress interfacial instabilities and defects in multilayer coextrusion flow. However, a new additional defect defined as “grainy” defect can be observed. In our best of knowledge, no study in literature has been dedicated to understand its origin. The phenomena are quite complex due to the coupling of the effects of flow and the physico-chemical mechanisms at the interface. The aim of this work is to understand the relationship between the instabilities and defects encountered in multilayer coextruded films and the role of the copolymer formed in-situ between tie and barrier layers. Polyamide 6 (PA6) and ethylene-vinyl alcohol copolymer (EVOH) were used as barrier layers sandwiched in polypropylene (PP) with or without tie-layer based on polypropylene grafted maleic anhydride (PP-g-MA). Influence of process parameters and nature of the polymer pair on the generation of “grainy” defect has been assessed and related to the rheological and the physico-chemical properties of layers. These experiments showed that this defect appeared mainly in the compatibilized EVOH system and could be distinguished from the usual coextrusion instabilities. Interfacial properties between tie and barrier layers have been investigated. Shear stress relaxation experiments have been carried out on reactive tie/barrier bilayers. Due to the interphase generated in-situ, the relaxation behavior was altered by extending the relaxation time. Investigation of interfacial morphology highlighted that the copolymer architecture significantly affected the interface/interphase development and interface roughness. Hence, relationships between relaxation process, interfacial morphology and copolymer structure were correlated with the generation of grainy defects in coextrusion.

A mixed integer programming model for optimizing multi-level operations process in railroad yards

A typical railroad hump yard contains multiple layers of complex operations. The railcars coming with inbound trains through the yard need to be humped into different classification tracks according to the destination, and then assembled to generate the desired outbound trains. During this complex procedure, the processing time of railcars and various resource constraints at different railroad yard facilities could significantly affect the overall performance of yard operations, individually and in combination. It is theoretically challenging to represent a large number of practical operation rules through tractable mathematical programming models. This paper first presents a time-expanded multi-layer network flow model to describe the connection between different layers of yard operations. A mixed integer programming model is developed to optimize the overall performance by jointly considering tightly interconnected facilities. We adopt a cumulative flow count representation to model the spatial capacity constraints in terms of the number of railcars in classification yards. A novel lot-sizing modeling framework and related valid inequality formulations are introduced to model the assembling jobs for outbound trains. We also develop an aggregated flow assignment model and earliest due date-based heuristic rules to determine the humping jobs sequence for reducing the search space. Numerical experiments are conducted to examine the solution quality and computational efficiency under different types of formulation strategies.