Eamon G. Kavanagh

Fibrin: A Natural Biodegradable Scaffold in Vascular Tissue Engineering

Arterial occlusive disease remains a major health issue in the developed world and a rapidly growing problem in the developing world. Although a growing number of patients are now being effectively treated with minimally invasive techniques, there remains a tremendous pressure on the vascular community to develop a synthetic small-diameter vascular graft with improved long-term patency rates. The field of tissue engineering offers an exciting alternative in the search for living organ replacement structures. Several methodologies have emerged for constructing blood vessel replacements with biological functionality. Common strategies include cell-seeded biodegradable synthetic scaffolds, cell self-assembly, cell-seeded gels and xenogeneic acellular materials. A wide range of materials are being investigated as potential scaffolds for vascular tissue engineering applications. Some are commercialised and others are still in development. Recently, researchers have studied the role of fibrin gel as a three-dimensional scaffold in vascular tissue engineering. This overview describes the properties of fibrin gel in vascular tissue engineering and highlights some recent progress and difficulties encountered in the development of cell fibrin scaffold technology.

A Computational Study of the Magnitude and Direction of Migration Forces in Patient-specific Abdominal Aortic Aneurysm Stent-Grafts

OBJECTIVES Endovascular aneurysm repair for abdominal aortic aneurysm (AAA) is now a widely adopted treatment. Several complications remain to be fully resolved and perhaps the most significant of these is graft migration. Haemodynamic drag forces are believed to be partly responsible for migration of the device. The objective of this work was to investigate the drag forces in patient-specific AAA stent-grafts. METHODS CT scan data was obtained from 10 post-operative AAA patients treated with stent-grafts. 3D models of the aneurysm, intraluminal thrombus and stent-graft were created. The drag forces were determined by fluid-structure interaction simulations. A worst case scenario was investigated by altering the aortic waveforms. RESULTS The median resultant drag force was 5.46 N (range: 2.53-10.84). An increase in proximal neck angulation resulted in an increase in the resultant drag force (p = 0.009). The primary force vector was found to act in an anterior caudal direction for most patients. The worst case scenario simulation resulted in a greatest drag force of 16 N. CONCLUSIONS Numerical methods can be used to determine patient-specific drag forces which may help determine the likelihood of stent-graft migration. Anterior-posterior neck angulation appears to be the greatest determinant of drag force magnitude. Graft dislodgement may occur anteriorally as well as caudally.

Fluid-structure interaction of a patient-specific abdominal aortic aneurysm treated with an endovascular stent-graft.

BackgroundAbdominal aortic aneurysms (AAA) are local dilatations of the infrarenal aorta. If left untreated they may rupture and lead to death. One form of treatment is the minimally invasive insertion of a stent-graft into the aneurysm. Despite this effective treatment aneurysms may occasionally continue to expand and this may eventually result in post-operative rupture of the aneurysm. Fluid-structure interaction (FSI) is a particularly useful tool for investigating aneurysm biomechanics as both the wall stresses and fluid forces can be examined.MethodsPre-op, Post-op and Follow-up models were reconstructed from CT scans of a single patient and FSI simulations were performed on each model. The FSI approach involved coupling Abaqus and Fluent via a third-party software - MpCCI. Aneurysm wall stress and compliance were investigated as well as the drag force acting on the stent-graft.ResultsAneurysm wall stress was reduced from 0.38 MPa before surgery to a value of 0.03 MPa after insertion of the stent-graft. Higher stresses were seen in the aneurysm neck and iliac legs post-operatively. The compliance of the aneurysm was also reduced post-operatively. The peak Post-op axial drag force was found to be 4.85 N. This increased to 6.37 N in the Follow-up model.ConclusionIn a patient-specific case peak aneurysm wall stress was reduced by 92%. Such a reduction in aneurysm wall stress may lead to shrinkage of the aneurysm over time. Hence, post-operative stress patterns may help in determining the likelihood of aneurysm shrinkage post EVAR. Post-operative remodelling of the aneurysm may lead to increased drag forces.

The biaxial mechanical behaviour of abdominal aortic aneurysm intraluminal thrombus: Classification of morphology and the determination of layer and region specific properties

Intraluminal thrombus (ILT) is present in 75% of clinically-relevant abdominal aortic aneurysms (AAAs) yet, despite much research effort, its role in AAA biomechanics remains unclear. The aim of this work is to further evaluate the biomechanics of ILT and determine if different ILT morphologies have varying mechanical properties. Biaxial mechanical tests were performed on ILT samples harvested from 19 patients undergoing open surgical repair. ILT were separated into luminal, medial and medial/abluminal layers. A total of 356 tests were performed and the Cauchy stress (σ) and tangential modulus (TM) at a stretch ratio (λ) of 1.14 were recorded for each test in both the circumferential (θ) and longitudinal (L) directions. Our data revealed three distinct types of ILT morphologies, each with a unique set of mechanical properties. All ILT layers were found to be isotropic and inhomogeneous. Type 1 (n=10) was a multi-layered ILT (thick medial/abluminal layer) whose strength and stiffness decreased gradually from the luminal to the medial/abluminal layer. Type 2 (n=6) was a multi-layered ILT (thin/highly degraded medial/abluminal layer) whose strength and stiffness decreased abruptly between the luminal and medial/abluminal layer and Type 3 (n=3) is a single layered ILT with a lower strength and stiffness than Types 1 and 2. In a sub-study, we found the luminal layer to be stronger and stiffer in the posterior than the anterior region. This work provides further insights to the biomechanical behaviour of ILT and the use of our ILT classification may be useful in future studies.

A review of the in vivo and in vitro biomechanical behavior and performance of postoperative abdominal aortic aneurysms and implanted stent-grafts.

Endovascular repair of abdominal aortic aneurysms has generated widespread interest since the procedure was first introduced two decades ago. It is frequently performed in patients who suffer from substantial comorbidities that may render them unsuitable for traditional open surgical repair. Although this minimally invasive technique substantially reduces operative risk, recovery time, and anesthesia usage in these patients, the endovascular method has been prone to a number of failure mechanisms not encountered with the open surgical method. Based on long-term results of second- and third-generation devices that are currently becoming available, this study sought to identify the most serious failure mechanisms, which may have a starting point in the morphological changes in the aneurysm and stent-graft. To investigate the “behavior” of the aneurysm after stent-graft repair, i.e., how its length, angulation, and diameter change, we utilized state-of-the-art ex vivo methods, which researchers worldwide are now using to recreate these failure modes.

Mechanical, biological and structural characterization of in vitro ruptured human carotid plaque tissue.

Recent experimental studies performed on human carotid plaques have focused on mechanical characterization for the purpose of developing material models for finite-element analysis without quantifying the tissue composition or relating mechanical behaviour to preoperative classification. This study characterizes the mechanical and biological properties of 25 human carotid plaques and also investigates the common features that lead to plaque rupture during mechanical testing by performing circumferential uniaxial tests, Fourier transform infrared (FTIR) and scanning electron microscopy (SEM) on each specimen to relate plaque composition to mechanical behaviour. Mechanical results revealed large variations between plaque specimen behaviour with no correlation to preoperative ultrasound prediction. However, FTIR classification demonstrated a statistically significant relationship between stress and stretch values at rupture and the level of calcification (P=0.002 and P=0.009). Energy-dispersive X-ray spectroscopy was carried out to confirm that the calcium levels observed using FTIR analysis were accurate. This work demonstrates the potential of FTIR as an alternative method to ultrasound forpredicting plaque mechanical behaviour. SEM imaging at the rupture sites of each specimen highlighted voids created by the nodes of calcifications in the tissue structure which could lead to increased vulnerability of the plaque.

Determining the influence of calcification on the failure properties of abdominal aortic aneurysm (AAA) tissue.

Varying degrees of calcification are present in most abdominal aortic aneurysms (AAAs). However, their impact on AAA failure properties and AAA rupture risk is unclear. The aim of this work is evaluate and compare the failure properties of partially calcified and predominantly fibrous AAA tissue and investigate the potential reasons for failure. Uniaxial mechanical testing was performed on AAA samples harvested from 31 patients undergoing open surgical repair. Individual tensile samples were divided into two groups: fibrous (n=31) and partially calcified (n=38). The presence of calcification was confirmed by fourier transform infrared spectroscopy (FTIR). A total of 69 mechanical tests were performed and the failure stretch (λf), failure stress (σf) and failure tension (Tf) were recorded for each test. Following mechanical testing, the failure sites of a subset of both tissue types were examined using scanning electron microscopy (SEM)/energy dispersive X-ray spectroscopy (EDS) to investigate the potential reasons for failure. It has been shown that the failure properties of partially calcified tissue are significantly reduced compared to fibrous tissue and SEM and EDS results suggest that the junction between a calcification deposit and the fibrous matrix is highly susceptible to failure. This study implicates the presence of calcification as a key player in AAA rupture risk and provides further motivation for the development of non-invasive methods of measuring calcification.

The Biaxial Biomechanical Behavior of Abdominal Aortic Aneurysm Tissue

Rupture of the abdominal aortic aneurysm (AAA) occurs when the local wall stress exceeds the local wall strength. Knowledge of AAA wall mechanics plays a fundamental role in the development and advancement of AAA rupture risk assessment tools. Therefore, the aim of this study is to evaluate the biaxial mechanical properties of AAA tissue. Multiple biaxial test protocols were performed on AAA samples harvested from 28 patients undergoing open surgical repair. Both the Tangential Modulus (TM) and stretch ratio (λ) were recorded and compared in both the circumferential (ϴ) and longitudinal (L) directions at physiologically relevant stress levels, the influence of patient specific factors such as sex, age AAA diameter and status were examined. The biomechanical response was also fit to a hyperplastic material model. The AAA tissue was found to be anisotropic with a greater tendency to stiffen in the circumferential direction compared to the longitudinal direction. An anisotropic hyperelastic constitutive model represented the data well and the properties were not influenced by the investigated patient specific factors however, a future study utilizing a larger cohort of patients is warranted to confirm these findings. This work provides further insights on the biomechanical behavior of AAA and may be useful in the development of more reliable rupture risk assessment tools.

New Pulsatile Hydrostatic Pressure Bioreactor for Vascular Tissue‐engineered Constructs

Mechanical conditioning represents a potential means to enhance the biochemical and biomechanical properties of tissue-engineered cell constructs. Bioreactors that can simulate physiologic conditions can play an important role in the preparation of tissue-engineered constructs. Although various forms of bioreactor systems are currently available, these have certain limitations, particularly when these are used for the creation of vascular constructs. The aim of the present report is to describe and validate a novel pressure bioreactor system for the creation of vascular tissue. Here, we present and discuss the design concepts, criteria, as well as the development of a novel pressure bioreactor. The system is compact and easily housed in an incubator to maintain sterility of the construct. Moreover, the proposed bioreactor, in addition to mimicking in vivo pressure conditions, is flexible, allowing different types of constructs to be exposed to various physiologic pressure conditions. The core bioreactor elements can be easily sterilized and have good ergonomic assembly characteristics. This system is a fundamental tool, which may enable us to make further advances in bioreactor technology and tissue engineering. The novel system allows for the application of pressure that may facilitate the growth and development of constructs needed to produce a tissue-engineered vascular graft.

On the influence of patient‐specific material properties in computational simulations: A case study of a large ruptured abdominal aortic aneurysm

Patient-specific modelling of abdominal aortic aneurysm has been shown to have clinical potential. This paper examines a large ruptured abdominal aortic aneurysm where the tissue from the diseased wall and the intraluminal thrombus was excised during open surgical repair and experimentally characterised. The mechanical data were used to develop material parameters that were incorporated into finite element models with measured nonuniform wall thickness. Implementation of the material data into the numerical model increased peak wall stress by 67%, wall strain by 320% and displacement by 177%, when compared with simulations based on material properties available in the literature. Distributions of numerical results were similar for both material data. Magnitudes of numerical results can differ significantly when using patient-specific material properties and therefore, care should be taken when interpreting numerical results derived from population-based data.