Development of a clinically relevant ex vivo model of cardiac ablation for testing of ablation catheters.

INTRODUCTION: Reliable ex vivo cardiac ablation models have the potential to increase catheter testing throughput while minimizing animal usage. The goal of this work was to develop a physiologically relevant ex vivo swine model of cardiac ablation displaying minimal variability and high repeatability and identify and optimize key parameters involved in ablation outcomes. METHODS AND RESULTS: A root cause analysis was conducted to identify variables affecting ablation outcomes. Parameters associated with the tissue, bath media, and impedance were identified. Variables were defined experimentally and/or from literature sources to best mimic the clinical cardiac ablation setting. The model was validated by performing three independent replicates of ex vivo myocardial ablation and a direct comparison of lesion outcomes of the ex vivo swine myocardial and in vivo canine thigh preparation (TP) models. Replicate experiments on the ex vivo model demonstrated low variance in ablation depth (6.5 ± 0.6, 6.3 ± 0.6, 6.2 ± 0.4 mm) and width (10.4 ± 1.1, 9.7 ± 1.0, 9.9 ± 0.9 mm) and no significant differences between replicates. In a direct comparison of the two models, the ex vivo model demonstrated ablation depths similar to the canine TP model at 35 W (6.9 ± 1.0, and 7.0 ± 0.9 mm) and 50 W (8.0 ± 0.7, and 8.4 ± 0.7 mm), as well as similar power to depth ratios (15% and 19% for the ex vivo cardiac and in vivo TP models, respectively). CONCLUSION: The ex vivo model exhibited strong lesion reproducibility and power-to-depth ratios comparable to the in vivo TP model. The optimized ex vivo model minimizes animal usage with increased throughput, lesion characteristics similar to the in vivo TP model, and ability to discriminate minor variations between different catheter designs.

The Viscoelastic Behavior of Soft Tissues Must be Accounted for in Stapler Design and Surgeon Technique.

BACKGROUND: Since its adoption as a surgical technique over a half-century ago, stapling has continually undergone improvements, both in the devices used and in our understanding of tissue mechanics. To best design and use stapling devices, it is beneficial to have an intimate knowledge of the response of tissue to compression and stapling dynamics. This paper provides the relevant background in the field of biomechanics, and in particular addresses the viscoelastic behavior of soft tissues under compression. Biomechanics of Stapling: The change in shape of a solid, or strain, is related to the load applied, or stress. Biological tissues are known to have non-linear relationships between stress and strain, and generally the relationships are anisotropic (dependent upon direction). Further complicating matters, there is typically a time-dependency to the relationship for compression and recovery, resulting in viscoelastic behavior. Hence both the amount and rate of compressive force applied can be expected to impact the outcome of stapling. DISCUSSION: The growth of the laparoscopic use of staples has increased the difficulty of device design, as precise control of compression is problematic in extended length staplers. Progressive firing along the cartridge and multi-stage compression have both been found to be beneficial in providing the uniform force needed to produce well-formed staples. Such technical advances can reduce stresses within the stapler, preventing deformation of the stapler arm and undesirable strain in the tissue. Current research includes understanding the effects of changing the rate of compression on staple formation with the hope that further improvements can be achieved in this ever-fruitful method of tissue apposition.

Pelvic and Lower Gastrointestinal Tract Anatomical Characterization of the Average Male.

OBJECTIVE: Colorectal surgeons report difficulty in positioning surgical devices in males, particularly those with a narrower pelvis. The objectives of this study were to (1) characterize the anatomy of the pelvis and surrounding soft tissue from magnetic resonance and computed tomography scans from 10 average males (175 cm, 78 kg) and (2) develop a model representing the mean configuration to assess variability. METHODS: The anatomy was characterized from existing scans using segmentation and registration techniques. Size and shape variation in the pelvis and soft tissue morphology was characterized using the Generalized Procrustes Analysis to compute the mean configuration. RESULTS: There was considerable variability in volume of the psoas, connective tissue, and pelvis and in surface area of the mesorectum, pelvis, and connective tissue. Subject height was positively correlated with mesorectum surface area (P = .028, R2 = 0.47) and pelvis volume ( P = .041, R2 = 0.43). The anterior-posterior distance between the inferior pelvic floor muscle and pubic symphysis was positively correlated with subject height ( P = .043, r = 0.65). The angle between the superior mesorectum and sacral promontory was negatively correlated with subject height ( P = .042, r = -0.65). The pelvic inlet was positively correlated with subject weight ( P = .001, r = 0.89). CONCLUSIONS: There was considerable variability in organ volume and surface area among average males with some correlations to subject height and weight. A physical trainer model created from these data helped surgeons trial and assess device prototypes in a controllable environment.

Preclinical quantification of air leaks in a physiologic lung model: effects of ventilation modality and staple design.

PURPOSE: Thoracic air leaks are a common complication following pulmonary resections. Limitations in clinical studies and preclinical models have hindered efforts to understand the pathophysiology of air leaks. With an emphasis on staple-line specific air leaks, we hypothesize that ventilation modality - intraoperative positive pressure vs postoperative negative pressure - and stapler design may play a role in air leaks. METHODS: Using a novel physiologic lung model, air leaks associated with graduated and uniform staple designs were evaluated under positive and negative pressure ventilation, simulating perioperative breathing in porcine lungs. Air leak incidence, air leak volume, and air leak rate were captured along with ventilation pressure and tidal volume. RESULTS: In all cases, negative pressure ventilation was associated with a higher occurrence of leaks when compared to positive pressure ventilation. Lungs leaked more air and at a faster rate under negative pressure ventilation compared to positive pressure ventilation. Graduated staple designs were associated with higher occurrence of leaks as well as larger leak rates when compared to uniform staples. Tissue thickness was not associated with differences in air leaks when tested with appropriate staple heights. CONCLUSION: Using a novel lung model to investigate the pathophysiology of air leaks, we have identified breathing modality and staple design as two important variables that may impact air leaks. This work will help guide device design and drive future studies in human tissue, and it may help inform clinical practice to ultimately improve patient outcomes.

Ex Vivo Modeling of Perioperative Air Leaks in Porcine Lungs.

OBJECTIVE: A novel ex vivo model is described to advance the understanding of prolonged air leaks, one of the most common postoperative complications following thoracic resection procedures. METHODS: As an alternative to in vivo testing, an ex vivo model simulating the various physiologic environments experienced by an isolated lung during the perioperative period was designed and built. Isolated porcine lungs were perfused and ventilated during open chest and closed chest simulations, mimicking intra and postoperative ventilation conditions. To assess and validate system capabilities, nine porcine lungs were tested by creating a standardized injury to create an approximately 250 cc/min air leak. Air leak rates, physiologic ventilation, and perfusion parameters were continuously monitored, while gas transfer analysis was performed on selected lungs. Segmental ventilation was monitored using electrical impedance tomography. RESULTS: The evaluated lungs produced flow-volume and pressure-volume loops that approximated standard clinical representations under positive (mechanical) and negative (physiological) pressure ventilation modalities. Leak rate was averaged across the ventilation phases, and sharp increases in leak rate were observed between positive and negative pressure phases, suggesting that differences or changes in ventilation mechanics may strongly influence leak development. CONCLUSION: The successful design and validation of a novel ex vivo lung model was achieved. Model output paralleled clinical observations. Pressure modality may also play a significant role in air leak severity. SIGNIFICANCE: This work provides a foundation for future studies aimed at increasing the understanding of air leaks to better inform means of mitigating the risk of air leaks under clinically relevant conditions.

Durability of left ventricular assist devices: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 2006 to 2011.

OBJECTIVES: The present study compared the interval until device exchange or death from pump-related failure in patients with pulsatile versus continuous flow left ventricular assist devices. METHODS: Data from Interagency Registry for Mechanically Assisted Circulatory Support (June 23, 2006, to March 31, 2011) compared the durability of implanted pulsatile and continuous flow left ventricular assist devices. The durability issues included pump replacement for infection, thrombosis-hemolysis, driveline failure, or pump drive unit failure, and death from driveline or pump drive unit failure. RESULTS: A total of 3302 left ventricular assist devices were implanted (486 pulsatile, 2816 continuous flow) and 98 pump exchanges or deaths from durability issues (46 pulsatile, 52 continuous flow; 3% of implants). The interval to device issue was greater for the continuous flow than for the pulsatile devices (P < .001). A comparisons of the causes for pump exchange or pump-related death showed (1) greater freedom from pump failure in the continuous flow compared with the pulsatile left ventricular assist devices (10 events/2816 continuous flow implants vs 39 events/486 pulsatile implants; P < .0001); (2) similar exchange or pump-related death for driveline failure (1/486 pulsatile vs 7/2816 continuous flow; P = .82); (3) similar exchange or pump-related death for thrombosis-hemolysis (2/486 pulsatile vs 28/2816 continuous flow; P = .25); and (4) fewer exchanges or pump-related deaths from infection in continuous flow left ventricular assist devices (4/486 pulsatile vs 7/2816 continuous flow; P = .034). Competing outcomes analysis corroborated this finding, with 54% of continuous flow versus 23% of pulsatile patients alive and receiving support at 12 months after implantation. CONCLUSIONS: The Analysis of Interagency Registry for Mechanically Assisted Circulatory Support data showed greater durability for continuous flow than for pulsatile left ventricular assist devices. Even longer durations of support can be expected if pump durability continues to improve.

Bariatric surgery for a patient with a HeartMate II ventricular assist device for destination therapy.

A patient with a HeartMate II left ventricular assist device who had a body mass index of 52 needed gastric bypass surgery in order to qualify for a heart transplant. Unlike previous experience in which the surgery was performed at the implant hospital, the gastric bypass surgery in this case was performed at a bariatric center of excellence that was a separate facility from the implant hospital. The artificial heart program of the University of Pittsburgh Medical Center worked with the bariatric center of excellence in scheduling the gastric bypass surgery using a multidisciplinary team approach at 2 hospitals to coordinate safe, high-quality patient care in a unique situation.

On the biomechanical role of glycosaminoglycans in the aortic heart valve leaflet.

While the role of collagen and elastin fibrous components in heart valve valvular biomechanics has been extensively investigated, the biomechanical role of the glycosaminoglycan (GAG) gelatinous-like material phase remains unclear. In the present study, we investigated the biomechanical role of GAGs in porcine aortic valve (AV) leaflets under tension utilizing enzymatic removal. Tissue specimens were removed from the belly region of porcine AVs and subsequently treated with either an enzyme solution for GAG removal or a control (buffer with no enzyme) solution. A dual stress level test methodology was used to determine the effects at low and high (physiological) stress levels. In addition, planar biaxial tests were conducted both on-axis (i.e. aligned to the circumferential and radial axes) and at 45° off-axis to induce maximum shear, to explore the effects of augmented fiber rotations on the fiber-fiber interactions. Changes in hysteresis were used as the primary metric of GAG functional assessment. A simulation of the low-force experimental setup was also conducted to clarify the internal stress system and provide viscoelastic model parameters for this loading range. Results indicated that under planar tension the removal of GAGs had no measureable affect extensional mechanical properties (either on- or 45° off-axis), including peak stretch, hysteresis and creep. Interestingly, in the low-force range, hysteresis was markedly reduced, from 35.96±2.65% in control group to 25.00±1.64% (p<0.001) as a result of GAG removal. Collectively, these results suggest that GAGs do not play a direct role in modulating the time-dependent tensile properties of valvular tissues. Rather, they appear to be strongly connected with fiber-fiber and fiber-matrix interactions at low force levels. Thus, we speculate that GAGs may be important in providing a damping mechanism to reduce leaflet flutter when the leaflet is not under high tensile stress.

On the in vivo deformation of the mitral valve anterior leaflet: effects of annular geometry and referential configuration.

Alteration of the native mitral valve (MV) shape has been hypothesized to have a profound effect on the local tissue stress distribution, and is potentially linked to limitations in repair durability. The present study was undertaken to elucidate the relation between MV annular shape and central mitral valve anterior leaflet (MVAL) strain history, using flat annuloplasty in an ovine model. In addition, we report for the first time the presence of residual in vivo leaflet strains. In vivo leaflet deformations were measured using sonocrystal transducers sutured to the MVAL (n = 10), with the 3D positions acquired over the full cardiac cycle. In six animals a flat ring was sutured to the annulus and the transducer positions recorded, while in the remaining four the MV was excised from the exsanguinated heart and the stress-free transducer positions obtained. In the central region of the MVAL the peak stretch values, referenced to the minimum left ventricular pressure (LVP), were 1.10 ± 0.01 and 1.31 ± 0.03 (mean ± standard error) in the circumferential and radial directions, respectively. Following flat ring annuloplasty, the central MVAL contracted 28% circumferentially and elongated 16% radially at minimum LVP, and the circumferential direction was under a negative strain state during the entire cardiac cycle. After valve excision from the exsanguinated heart, the MVAL contracted significantly (18 and 30% in the circumferential and radial directions, respectively), indicating the presence of substantial in vivo residual strains. While the physiological function of the residual strains (and their associated stresses) are at present unknown, accounting for their presence is clearly necessary for accurate computational simulations of MV function. Moreover, we demonstrated that changes in annular geometry dramatically alter valvular functional strains in vivo. As levels of homeostatic strains are related to tissue remodeling and homeostasis, our results suggest that surgically introduced alterations in MV shape could lead to the long term MV mechanobiological and microstructural alterations that could ultimately affect MV repair durability.

Modification of infarct material properties limits adverse ventricular remodeling.

BACKGROUND: Infarct expansion after myocardial infarction (MI) is an important phenomenon that initiates and sustains adverse left ventricular (LV) remodeling. We tested the hypothesis that infarct modification by material-induced infarct stiffening and thickening limits infarct expansion and LV remodeling. METHODS: Anteroapical infarction was induced in 21 sheep. Sheep were randomized to injection of saline (2.6 mL) or tissue filler material (2.6 mL) into the infarct within 3 hours of MI. Animals were monitored for 8 weeks with echocardiography to assess infarct expansion and global LV remodeling. Morphometric measurements were performed of excised hearts to quantify infarct thickness. Regional blood flow was assessed with colored microspheres. Infarct material properties were measured using biaxial tensile testing. RESULTS: Compared with controls at 8 weeks, treatment animals had less infarct expansion, reduced LV dilatation (LV systolic volumes: 60.8±4.3 vs 80.3±6.9 mL; p<0.05), greater ejection fraction (0.310±0.026 vs 0.276±0.013; p<0.05), thicker infarcts (5.5±0.2 vs 2.2±0.3 mm; p<0.05), and greater infarct blood flow (0.22±0.04 vs 0.11±0.03 mL/min/g; p<0.05). The longitudinal peak strain in the treatment group was less (0.05014±0.0141) than the control group (0.1024±0.0101), indicating increased stiffness of the treated infarcts. CONCLUSIONS: Durable infarct thickening and stiffening can be achieved by infarct biomaterial injection, resulting in the amelioration of infarct expansion and global LV remodeling. Further material optimization will allow for clinical translation of this novel treatment paradigm.

Three-dimensional quantitative micromorphology of pre- and post-implanted engineered heart valve tissues.

There is a significant gap in our knowledge of engineered heart valve tissue (EHVT) development regarding detailed three-dimensional (3D) tissue formation and remodeling from the point of in vitro culturing to full in vivo function. As a step toward understanding the complexities of EHVT formation and remodeling, a novel serial confocal microscopy technique was employed to obtain 3D microstructural information of pre-implant (PRI) and post-implant for 12 weeks (POI) EHVT fabricated from PGA:PLLA scaffolds and seeded with ovine bone-marrow-derived mesenchymal stem cells. Custom scaffold fiber tracking software was developed to quantify scaffold fiber architectural features such as length, tortuosity, and minimum scaffold fiber-fiber separation distance and scaffold fiber orientation was quantified utilizing a 3D fabric tensor. In addition, collagen and cellular density of ovine pulmonary valve leaflet tissue were also analyzed for baseline comparisons. Results indicated that in the unseeded state, scaffold fibers formed a continuous, oriented network. In the PRI state, the scaffold showed some fragmentation with a scaffold volume fraction of 7.79%. In the POI specimen, the scaffold became highly fragmented, forming a randomly distributed short fibrous network (volume fraction of 2.03%) within a contiguous, dense collagenous matrix. Both PGA and PLLA scaffold fibers were observed in the PRI and POI specimens. Collagen density remained similar in both PRI and POI specimens (74.2 and 71.5%, respectively), though the distributions in the transmural direction appeared slightly more homogenous in the POI specimen. Finally, to guide future 2D histological studies for large-scale studies (since acquisition of high-resolution volumetric data is not practical for all specimens), we investigated changes in relevant collagen and scaffold metrics (collagen density and scaffold fiber orientation) with varying section spacing. It was found that a sectioning spacing up to 25 µm (for scaffold morphology) and 50 µm (for collagen density) in both PRI and POI tissues did not result in loss of information fidelity, and that sectioning in the circumferential or radial direction provides the greatest preservation of information. This is the first known work to investigate EHVT microstructure over a large volume with high resolution and to investigate time evolving in vivo EHVT morphology. The important scaffold fiber structural changes observed provide morphological information crucial for guiding future structurally based constitutive modeling efforts focused on better understanding EHVT tissue formation and remodeling.

In vivo dynamic deformation of the mitral valve annulus.

Though mitral valve (MV) repair surgical procedures have increased in the United States [Gammie, J. S., et al. Ann. Thorac. Surg. 87(5):1431-1437, 2009; Nowicki, E. R., et al. Am. Heart J. 145(6):1058-1062, 2003], studies suggest that altering MV stress states may have an effect on tissue homeostasis, which could impact the long-term outcome [Accola, K. D., et al. Ann. Thorac. Surg. 79(4):1276-1283, 2005; Fasol, R., et al. Ann. Thorac. Surg. 77(6):1985-1988, 2004; Flameng, W., P. Herijgers, and K. Bogaerts. Circulation 107(12):1609-1613, 2003; Gillinov, A. M., et al. Ann. Thorac. Surg. 69(3):717-721, 2000]. Improved computational modeling that incorporates structural and geometrical data as well as cellular components has the potential to predict such changes; however, the absence of important boundary condition information limits current efforts. In this study, novel high definition in vivo annular kinematic data collected from surgically implanted sonocrystals in sheep was fit to a contiguous 3D spline based on quintic-order hermite shape functions with C(2) continuity. From the interpolated displacements, the annular axial strain and strain rate, bending, and twist along the entire annulus were calculated over the cardiac cycle. Axial strain was shown to be regionally and temporally variant with minimum and maximum values of -10 and 4%, respectively, observed. Similarly, regionally and temporally variant strain rate values, up to 100%/s contraction and 120%/s elongation, were observed. Both annular bend and twist data showed little deviation from unity with limited regional variations, indicating that most of the energy for deformation was associated with annular axial strain. The regionally and temporally variant strain/strain rate behavior of the annulus are related to the varied fibrous-muscle structure and contractile behavior of the annulus and surrounding ventricular structures, although specific details are still unavailable. With the high resolution shape and displacement information described in this work, high fidelity boundary conditions can be prescribed in future MV finite element models, leading to new insights into MV function and strategies for repair.