Towards the development of guidelines for the endovascular treatment of peripheral artery disease: a tissue characterisation approach

The femoral arteries are one of the most susceptible vascular locations for the development of atherosclerosis. The occurrence of this disease process in these vessels is the leading cause of lifestyle-limiting claudication and ischemic rest pain. Common femoral endarterectomy has been the standard treatment for focal occlusive disease of the femoral arteries for over 50 years. However, morbidity rates remain high due to its invasive nature and certain groups of patients are considered high risk for surgery. The use of Percutaneous Transluminal Angioplasty (PTA) has been advocated as a treatment alternative for patients at higher risk of surgical morbidity and mortality. Despite this, the long term results for PTA in the femoral arteries are disappointing due to uncontrolled dissections in complex lesions, inadequate luminal expansion in rigid strictures and recurrent stenosis in the dilated segment. PTA therefore requires procedural, technological, and suitable patient selection enhancements to function effectively as a treatment modality. Cutting Balloon Angioplasty (CBA) is an additional treatment alternative that employs a non-compliant balloon with radially positioned microblades to incise the plaque and propagate a controlled crack thereby reducing elastic recoil, vessel dilation, vessel injury, and subsequent restenosis. Preliminary reports have highlighted the possibility of CBA application in the peripheral arteries. However, various complications have also been reported including arterial rupture, delayed perforation and fracture of microsurgical blades. Arterial injury response to endovascular treatment varies significantly with plaque composition and it has been previously stated that the mechanisms of CBA affected by plaque composition need to be clarified. Therefore, a need exists to characterise the fracture behaviour of atherosclerotic femoral tissue and relate it to plaque biological content and structural morphology. Consequently, the research objective of this thesis is to enhance the implementation of endovascular treatments of the femoral arteries by presenting novel information regarding the characteristics of the target lesion. To achieve this, the mechanical properties and fracture behaviour of human atherosclerotic femoral tissue is characterised and related to plaque biological content and structural morphology. This will facilitate for more informed patient stratification, treatment approaches, and device design. A standardised uniaxial extension protocol is proposed and employed to characterise the mechanical behaviour of 20 endarterectomised femoral plaque samples in order to determine the tissue’s response to large circumferential deformation, the conditions induced during endovascular treatment. Guillotine testing is also employed to determine the Mode I fracture toughness of 30 sections from 5 endarterectomised femoral plaque samples to examine the tissue’s ability to resist crack propagation, the conditions induced specifically during CBA. This mechanical behaviour and fracture toughness are related to plaque biological content using Fourier transform infrared and structural morphology using scanning electron microscopy in order to determine the effect of plaque content and morphology on the mechanical response to large deformation and cut propagation. This information is then utilised to develop predictive tools and guidelines for the endovascular treatment of peripheral artery disease. Such tools can be employed to stratify patients, treatments, and devices in order to avoid endovascular treatment of lesions that are vulnerable to mechanically induced failure during PTA or that are resistant to cut propagation during CBA. Material models based on this novel mechanical and biological characterisation are also developed to better represent diseased femoral vessels numerically. Such vessel appropriate material models may lead to the production of endovascular devices and treatments that are more suited to treating atherosclerotic lesions of the femoral vessels. The characterisation of 20 human femoral atherosclerotic plaque samples revealed the identification of three plaque classifications that exhibit distinct mechanical and biological characteristics. The mechanical behaviour of the heavily calcified femoral plaque group identified suggests that femoral plaques exhibiting a ratio of calcified tissue to lipid content exceeding 2 may be vulnerable to failure during endovascular device deployment as these plaques undergo mechanically induced failure at a reduced stress and stretch. Compiling the characteristics of these 20 human femoral atherosclerotic plaque samples, with the results obtained from testing 24 carotid plaque samples in an identical manner, revealed significant differences in mechanical responses to large deformation that may aid in explaining the contrasting restenotic responses demonstrated by these vascular locations. Furthermore, the significant correlations between the biological content and the mechanical responses of both plaque groups highlights the potential to develop a tool to stratify patients based on predicted plaque mechanical response. Such a tool could stratify patients into those suitable for endovascular intervention and those that should receive open surgery or a monitoring protocol. The fracture toughness of 30 sections from 5 human femoral atherosclerotic plaque samples was characterised and related to biological content and structural morphology. A large degree of inter and intra sample variance was identified, with toughness values ranging far above and below those established for healthy arterial tissue. These results demonstrate the difficulty in effectively implementing CBA in complex atherosclerotic femoral lesions. However, the biological parameter depicting plaque calcified content correlates significantly with sample toughness. This highlights the potential to utilise this parameter as a preoperative tool for predicting the fracture response of a target lesion to CBA. Such a tool may lead to a reduction in clinically observed complications, an improvement in trial results, and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. Novel vessel appropriate material models are developed from the previously characterised mechanical behaviour of 20 femoral plaque samples. Comparing these material models to those currently employed in literature highlights the large discrepancies introduced by numerically representing femoral plaque tissue using material models based on atherosclerotic aortic plaque data. Future studies seeking to simulate endovascular treatments or device design should employ vessel-appropriate material models to represent the response of diseased femoral tissue in order to obtain more accurate numerical results

The presence of helical flow can suppress areas of disturbed shear in parameterised models of an arteriovenous fistula

Areas of disturbed shear that develop following arteriovenous fistula (AVF) creation are believed to trigger the onset of intimal hyperplasia (IH), leading to AVF dysfunction. The presence of helical flow can suppress the flow disturbances that lead to disturbed shear in other areas of the vasculature. However, the relationship between helical flow and disturbed shear remains unevaluated in AVF. In this study, computational fluid dynamics (CFD) is used to evaluate the relationship between geometry, helical flow, and disturbed shear in parameterised models of an AVF characterised by four different anastomosis angles. The AVF models with a small anastomosis angle demonstrate the lowest distribution of low/oscillating shear and are characterised by a high helical intensity coupled with a strong balance between helical structures. Contrastingly, the models with a large anastomosis angle experience the least amount of high shear, multidirectional shear, as well as spatial and temporal gradients of shear. Furthermore, the intensity of helical flow correlates strongly with curvature (r = 0.73, P < .001), whereas it is strongly and inversely associated with taper (r = −0.87, P < .001). In summary, a flow field dominated by a high helical intensity coupled with a strong balance between helical structures can suppress exposure to low/oscillating shear but is ineffective when it comes to other types of shear. This highlights the clinical potential of helical flow as a diagnostic marker of exposure to low/oscillating shear, as helical flow can be identified in vivo with the use of ultrasound imaging

Characterising human atherosclerotic carotid plaque tissue composition and morphology using combined spectroscopic and imaging modalities

Calcification is a marked pathological component in carotid artery plaque. Studies have suggested that calcification may induce regions of high stress concentrations therefore increasing the potential for rupture. However, the mechanical behaviour of the plaque under the influence of calcification is not fully understood. A method of accurately characterising the calcification coupled with the associated mechanical plaque properties is needed to better understand the impact of calcification on the mechanical behaviour of the plaque during minimally invasive treatments. This study proposes a comparison of biochemical and structural characterisation methods of the calcification in carotid plaque specimens to identify plaque mechanical behaviour. Biochemical analysis, by Fourier Transform Infrared (FTIR) spectroscopy, was used to identify the key components, including calcification, in each plaque sample. However, FTIR has a finite penetration depth which may limit the accuracy of the calcification measurement. Therefore, this FTIR analysis was coupled with the identification of the calcification inclusions located internally in the plaque specimen using micro x-ray computed tomography (μX-CT) which measures the calcification volume fraction (CVF) to total tissue content. The tissue characterisation processes were then applied to the mechanical material plaque properties acquired from experimental circumferential loading of human carotid plaque specimen for comparison of the methods. FTIR characterised the degree of plaque progression by identifying the functional groups associated with lipid, collagen and calcification in each specimen. This identified a negative relationship between stiffness and ‘lipid to collagen’ and ‘calcification to collagen’ ratios. However, μX-CT results suggest that CVF measurements relate to overall mechanical stiffness, while peak circumferential strength values may be dependent on specific calcification geometries. This study demonstrates the need to fully characterise the calcification structure of the plaque tissue and that a combination of FTIR and μX-CT provides the necessary information to fully understand the mechanical behaviour of the plaque tissue

Simulation of human atherosclerotic femoral plaque tissue: the influence of plaque material model on numerical results

Background: Due to the limited number of experimental studies that mechanically characterise human atherosclerotic plaque tissue from the femoral arteries, a recent trend has emerged in current literature whereby one set of material data based on aortic plaque tissue is employed to numerically represent diseased femoral artery tissue. This study aims to generate novel vessel-appropriate material models for femoral plaque tissue and assess the influence of using material models based on experimental data generated from aortic plaque testing to represent diseased femoral arterial tissue. Methods: Novel material models based on experimental data generated from testing of atherosclerotic femoral artery tissue are developed and a computational analysis of the revascularisation of a quarter model idealised diseased femoral artery from a 90% diameter stenosis to a 10% diameter stenosis is performed using these novel material models. The simulation is also performed using material models based on experimental data obtained from aortic plaque testing in order to examine the effect of employing vessel appropriate material models versus those currently employed in literature to represent femoral plaque tissue. Results: Simulations that employ material models based on atherosclerotic aortic tissue exhibit much higher maximum principal stresses within the plaque than simulations that employ material models based on atherosclerotic femoral tissue. Specifically, employing a material model based on calcified aortic tissue, instead of one based on heavily calcified femoral tissue, to represent diseased femoral arterial vessels results in a 487 fold increase in maximum principal stress within the plaque at a depth of 0.8 mm from the lumen. Conclusions: Large differences are induced on numerical results as a consequence of employing material models based on aortic plaque, in place of material models based on femoral plaque, to represent a diseased femoral vessel. Due to these large discrepancies, future studies should seek to employ vessel-appropriate material models to simulate the response of diseased femoral tissue in order to obtain the most accurate numerical results

The influence of composition and location on the toughness of human atherosclerotic femoral plaque tissue

The toughness of femoral atherosclerotic tissue is of pivotal importance to understanding the mechanism of luminal expansion during cutting balloon angioplasty (CBA) in the peripheral vessels. Furthermore, the ability to relate this parameter to plaque composition, pathological inclusions and location within the femoral vessels would allow for the improvement of existing CBA technology and for the stratification of patient treatment based on the predicted fracture response of the plaque tissue to CBA. Such information may lead to a reduction in clinically observed complications, an improvement in trial results and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. This study characterises the toughness of atherosclerotic plaque extracted from the femoral arteries of ten patients using a lubricated guillotine cutting test to determine the critical energy release rate. This information is related to the location that the plaque section was removed from within the femoral vessels and the composition of the plaque tissue, determined using Fourier Transform InfraRed spectroscopy, to establish the influence of location and composition on the toughness of the plaque tissue. Scanning electron microscopy (SEM) is employed to examine the fracture surfaces of the sections to determine the contribution of tissue morphology to toughness. Toughness results exhibit large inter and intra patient and location variance with values ranging far above and below the toughness of healthy porcine arterial tissue (Range: 1330–3035 for location and 140–4560 J/m2 for patients). No significant difference in mean toughness is observed between patients or location. However, the composition parameter representing the calcified tissue content of the plaque correlates significantly with sample toughness (r = 0.949, p < 0.001). SEM reveals the presence of large calcified regions in the toughest sections that are absent from the least tough sections. Regression analysis highlights the potential of employing the calcified tissue content of the plaque as a preoperative tool for predicting the fracture response of a target lesion to CBA (R2 = 0.885, p < 0.001)

Cryopreservation of porcine urethral tissue: storage at − 20◦C preserves the mechanical, failure and geometrical properties

Cryopreservation is required to preserve the native properties of tissue for prolonged periods of time. In this study, we evaluate the impact that 4 different cryopreservation protocols have on porcine urethral tissue, to identify a protocol that best preserves the native properties of the tissue. The cryopreservation protocols include storage in cryoprotective agents at − 20 ◦C and − 80 ◦C with a slow, gradual, and fast reduction in temperature. To evaluate the effects of cryopreservation, the tissue is mechanically characterised in uniaxial tension and the mechanical properties, failure mechanics, and tissue dimensions are compared fresh and following cryopreservation. The mechanical response of the tissue is altered following cryopreservation, yet the elastic modulus from the high stress, linear region of the Cauchy stress – stretch curves is unaffected by the freezing process. To further investigate the change in mechanical response following cryopreservation, the stretch at different tensile stress values was evaluated, which revealed that storage at − 20 ◦C is the only protocol that does not significantly alter the mechanical properties of the tissue compared to the fresh samples. Conversely, the ultimate tensile strength and the stretch at failure were relatively unaffected by the freezing process, regardless of the cryopreservation protocol. However, there were alterations to the tissue dimensions following cryopreservation that were significantly different from the fresh samples for the tissue stored at − 80 ◦C. Therefore, any study intent on preserving the mechanical, failure, and geometric properties of urethral tissue during cryopreservation should do so by freezing samples at − 20 ◦C, as storage at − 80 ◦C is shown here to significantly alter the tissue properties

Mechanical and morphological characterisation of porcine urethras for the assessment of paediatric urinary catheter safety

Paediatric urinary catheters are often necessary in critical care settings or to address congenital anomalies  affecting the urogenital system. Iatrogenic injuries can occur during the placement of such catheters, highlighting  the need for a safety device that can function in paediatric settings. Despite successful efforts to develop devices  that improve the safety of adult urinary catheters, no such devices are available for use with paediatric catheters.  This study investigates the potential for utilising a pressure-controlled safety mechanism to limit the trauma  experienced by paediatric patients during inadvertent inflation of a urinary catheter anchoring balloon in the  urethra. Firstly, we establish a paediatric model of the human urethra using porcine tissue by characterising the  mechanical and morphological properties of porcine tissue at increasing postnatal timepoints (8, 12, 16 and 30  weeks). We identified that porcine urethras harvested from pigs at postnatal week 8 and 12 exhibit morpho?logical properties (diameter and thickness) that are statistically distinct from adult porcine urethras (postnatal  week 30). We therefore utilise urethra tissue from postnatal week 8 and 12 pigs as a model to evaluate a pressure-controlled approach to paediatric urinary catheter balloon inflation intended to limit tissue trauma during  inadvertent inflation in the urethra. Our results show that limiting catheter system pressure to 150 kPa avoided  trauma in all tissue samples. Conversely, all of the tissue samples that underwent traditional uncontrolled urinary  catheter inflation experienced complete rupture. The findings of this study pave the way for the development of a  safety device for use with paediatric catheters, thereby alleviating the burden of catastrophic trauma and life  changing injuries in children due to a preventable iatrogenic urogenital event.  </p

In vivo ureteroscopic intrarenal pressures and clinical outcomes: a multi-institutional analysis of 120 consecutive patients

  Objectives To evaluate the pressure range generated in the human renal collecting system during ureteroscopy (URS), in a large patient sample, and to investigate a relationship between intrarenal pressure (IRP) and outcome. Patients and Methods A prospective multi-institutional study was conducted, with ethics board approval; February 2022–March 2023. Recruitment was of 120 consecutive consenting adult patients undergoing semi-rigid URS and/or flexible ureterorenoscopy (FURS) for urolithiasis or diagnostic purposes. Retrograde, fluoroscopy-guided insertion of a 0.036-cm (0.014″) pressure guidewire (COMET™ II, Boston Scientific, Marlborough, MA, USA) to the renal pelvis was performed. Baseline and continuous ureteroscopic IRP was recorded, alongside relevant operative variables. A 30-day follow-up was completed. Descriptive statistics were applied to IRP traces, with mean (sd) and maximum values and variance reported. Relationships between IRP and technical variables, and IRP and clinical outcome were interrogated using the chi-square test and independent samples t-test.   Results A total of 430 pressure traces were analysed from 120 patient episodes. The mean (sd) baseline IRP was 16.45 (5.99) mmHg and the intraoperative IRP varied by technique. The mean (sd) IRP during semi-rigid URS with gravity irrigation was 34.93 (11.66) mmHg. FURS resulted in variable IRP values: from a mean (sd) of 26.78 (5.84) mmHg (gravity irrigation; 12/14-F ureteric access sheath [UAS]) to 87.27 (66.85) mmHg (200 mmHg pressurised-bag irrigation; 11/13-F UAS). The highest single pressure peak was 334.2 mmHg, during retrograde pyelography. Six patients (5%) developed postoperative urosepsis; these patients had significantly higher IRPs during FURS (mean [sd] 81.7 [49.52] mmHg) than controls (38.53 [22.6] mmHg; P  Conclusions A dynamic IRP profile is observed during human in vivo URS, with IRP frequently exceeding expected thresholds. A relationship appears to exist between elevated IRP and postoperative urosepsis.</p