Michael R. Moreno

Stented artery biomechanics and device design optimization.

The deployment of a vascular stent aims to increase lumen diameter for the restoration of blood flow, but the accompanied alterations in the mechanical environment possibly affect the long-term patency of these devices. The primary aim of this investigation was to develop an algorithm to optimize stent design, allowing for consideration of competing solid mechanical concerns (wall stress, lumen gain, and cyclic deflection). Finite element modeling (FEM) was used to estimate artery wall stress and systolic/diastolic geometries, from which single parameter outputs were derived expressing stress, lumen gain, and cyclic artery wall deflection. An optimization scheme was developed using Lagrangian interpolation elements that sought to minimize the sum of these outputs, with weighting coefficients. Varying the weighting coefficients results in stent designs that prioritize one output over another. The accuracy of the algorithm was confirmed by evaluating the resulting outputs of the optimized geometries using FEM. The capacity of the optimization algorithm to identify optimal geometries and their resulting mechanical measures was retained over a wide range of weighting coefficients. The variety of stent designs identified provides general guidelines that have potential clinical use (i.e., lesion-specific stenting).

Effects of stent design and atherosclerotic plaque composition on arterial wall biomechanics.

Purpose: To examine the solid mechanical effects of varying stent design and atherosclerotic plaque stiffness on the biomechanical environment induced in a diseased artery wall model. Methods: Computational modeling techniques were employed to investigate the final radius of the lumen and artery wall stresses after stent implantation. Two stent designs were studied (one stiff and one less stiff). The stenotic artery was modeled as an axisymmetrical diseased vessel with a 20% stenosis by diameter. The material properties of the diseased tissue in the artery models varied. Atherosclerotic plaques half as stiff (0.5×), of equal stiffness (1.0×), or twice as stiff (2.0×) as the artery wall were investigated. Results: Final lumen radius was dependent on stent design, and the stiffer stent deformed the artery to an approximately 10% greater radius than the more compliant design. Alternatively, circumferential stress levels were dependent on both stent design and plaque material properties. Overall, the stiffer stent subjected the artery wall to much higher stress values than the more compliant design, with differences in peak values of 0.50, 0.31, and 0.09 MPa for the 2.0×, 1.0×, and 0.5× stiff plaques, respectively. Conclusion: Evidence suggests that a judicious choice of stent design can minimize stress while maintaining a patent lumen in stenotic arteries. If confronted with a rigid, calcified plaque, stent design is more important, as design differences can impose dramatically different stress fields, while still providing arterial patency. Alternatively, stent design is not as much of an issue when treating a soft, lipid-laden plaque, as stress fields do not vary significantly among stent designs.

Mechanical modeling of stents deployed in tapered arteries.

The biomechanical interaction of stents and the arteries into which they are deployed is a potentially important consideration for long-term success. Adverse arterial reactions to excessive stress and the resulting damage have been linked to the development of restenosis. Complex geometric features often encountered in these procedures can confound treatment. In some cases, it is desirable to deploy a stent across a region in which the diameter decreases significantly over the length of the stent. This study aimed to assess the final arterial diameter and circumferential stress in tapered arteries into which two different stents were deployed (one stiff and one less stiff). The artery wall was assumed to be made of a strain stiffening material subjected to large deformations, with a 10% decrease in diameter over the length of the stent. A commercially available finite element code was employed to solve the contact problem between the two elastic bodies. The stiffer stent dominated over arterial taper, resulting in a nearly constant final diameter along the length of the stent, and very high stresses, particularly at the distal end. The less stiff stent followed more closely the tapered contour of the artery, resulting in lower artery wall stresses. More compliant stents should be considered for tapered artery applications, perhaps even to the exclusion of tapered stents.

A Device to Study the Effects of Stretch Gradients on Cell Behavior

Mechanical forces are key regulators of cell function with varying loads capable of modulating behaviors such as alignment, migration, phenotype modulation, and others. Historically, cell-stretching experiments have employed mechanically simple environments (e.g., uniform uniaxial or equibiaxial stretches). However, stretch distributions in vivo can be highly non-uniform, particularly in cases of disease or subsequent to interventional treatments. Herein, we present a cell-stretching device capable of subjecting cells to controllable gradients in biaxial stretch via radial deformation of circular elastomeric membranes. By including either a defect or a rigid fixation at the center of the membrane, various gradients are generated. Capabilities of the device were quantified by tracking marked positions of the membrane while applying various loads, and experimental feasibility was assessed by conducting preliminary experiments with 3T3 fibroblasts and 10T1/2 cells subjected to 24 h of cyclic stretch. Quantitative real-time PCR was used to measure changes in mRNA expression of a profile of genes representing the major smooth muscle phenotypes. Genes associated with the contractile state were both upregulated (e.g., calponin) and downregulated (e.g., α-2-actin), and genes associated with the synthetic state were likewise both upregulated (e.g., SKI-like oncogene) and downregulated (e.g., collagen III). In addition, cells aligned with an orientation perpendicular to the maximal stretch direction. We have developed an in vitro cell culture device that can produce non-uniform stretch environments similar to in vivo mechanics. Cells stretched with this device showed alignment and altered mRNA expression indicative of phenotype modulation. Understanding these processes as they relate to in vivo pathologies could enable a more accurately targeted treatment to heal or inhibit disease, either through implantable device design or pharmaceutical approaches.

The Effect of Static and Dynamic Loading on Degradation of PLLA Stent Fibers

Understanding how polymers such as PLLA degrade in vivo will enhance biodegradable stent design. This study examined the effect of static and dynamic loads on PLLA stent fibers in vitro. The stent fibers (generously provided by TissueGen, Inc.) were loaded axially with 0 N, 0.5 N, 1 N, or 0.125-0.25 N (dynamic group, 1 Hz) and degraded in PBS at 45 °C for an equivalent degradation time of 15 months. Degradation was quantified through changes in tensile mechanical properties. The mechanical behavior was characterized using the Knowles strain energy function and a degradation model. A nonsignificant increase in fiber stiffness was observed between 0 and 6 months followed by fiber softening thereafter. A marker of fiber softening, β, increased between 9 and 15 months in all groups. At 15 months, the β values in the dynamic group were significantly higher compared to the other groups. In addition, the model indicated that the degradation rate constant was smaller in the 1-N (0.257) and dynamic (0.283) groups compared to the 0.5-N (0.516) and 0-N (0.406) groups. While the shear modulus fluctuated throughout degradation, no significant differences were observed. Our results indicate that an increase in static load increased the degradation of mechanical properties and that the application of dynamic load further accelerated this degradation.

Fabrication of macromolecular gradients in aligned fiber scaffolds using a combination of in-line blending and air-gap electrospinning ☆

Although a variety of fabrication methods have been developed to generate electrospun meshes with gradient properties, no platform has yet to achieve fiber alignment in the direction of the gradient that mimics the native tendon-bone interface. In this study, we present a method combining in-line blending and air-gap electrospinning to address this limitation in the field. A custom collector with synced rotation permitted fiber collection with uniform mesh thickness and periodic copper wires were used to induce fiber alignment. Two poly(ester urethane ureas) with different hard segment contents (BPUR 50, BPUR 10) were used to generate compositional gradient meshes with and without fiber alignment. The compositional gradient across the length of the mesh was characterized using a fluorescent dye and the results indicated a continuous transition from the BPUR 50 to the BPUR 10. As expected, the fiber alignment of the gradient meshes induced a corresponding alignment of adherent cells in static culture. Tensile testing of the sectioned meshes confirmed a graded transition in mechanical properties and an increase in anisotropy with fiber alignment. Finite element modeling was utilized to illustrate the gradient mechanical properties across the full length of the mesh and lay the foundation for future computational development work. Overall, these results indicate that this electrospinning method permits the fabrication of macromolecular gradients in the direction of fiber alignment and demonstrate its potential for use in interfacial tissue engineering. STATEMENT OF SIGNIFICANCE The native tendon-bone interface contains a gradient of properties that ensures stability of the joint. Without this transition, failure can occur due to stress concentration at the bone insertion site. Electrospinning is a method commonly used to produce fibrous grafts with gradient properties; however, no current method allows for gradients in the direction of fiber alignment. This work details a novel electrospinning method to produce gradients in the direction of fiber alignment in order to better mimic transitional zones and improve regeneration of the tendon-bone interface. In addition to the biomechanical gradients demonstrated here, this method may also be used to generate gradients of macromolecular, biochemical, and cellular cues with broad potential utility in tissue engineering.

Assessment of Minimally Invasive Device That Provides Simultaneous Adjustable Cardiac Support and Active Synchronous Assist in an Acute Heart Failure Model

One of the major maladaptive changes after a major heart attack or cardiac event is an initial decline in pumping capacity of the heart leading to activation of a variety of compensatory mechanisms, and subsequently a phenomenon known as cardiac or left ventricular remodeling, i.e., a geometrical change in the architecture of the left ventricle. Evidence suggests that the local mechanical environment governs remodeling processes. Thus, in order to control two important mechanical parameters, cardiac size and cardiac output, we have developed a minimally invasive direct cardiac contact device capable of providing two actions simultaneously: (1) adjustable cardiac support to modulate cardiac size and (2) synchronous active assist to modulate cardiac output. As a means of enabling experiments to determine the role of these mechanical parameters in reverse remodeling or ventricular recovery, the device was further designed to (1) be deployed via minimally invasive surgical procedures, (2) allow uninhibited motion of the heart, (3) remain in place about the heart via an intrinsic pneumatic attachment, and (4) provide direct cardiac compression without aberrantly inverting the curvature of the heart. These actions and features are mapped to particular design solutions and assessed in an acute implantation in an ovine model of acute heart failure (esmolol overdose). The passive support component was used to effectively shift the EDPVR leftward, i.e., counter to the effects of disease. The active assist component was used to effectively decompress the constrained heart and restore lost cardiac output and stroke work in the esmolol failure model. It is expected that such a device will provide better control of the mechanical environment and thereby provide cardiac surgeons a broader range of therapeutic options and unique intervention possibilities.

Biomimetic collagen/elastin meshes for ventral hernia repair in a rat model

Ventral hernia repair remains a major clinical need. Herein, we formulated a type I collagen/elastin crosslinked blend (CollE) for the fabrication of biomimetic meshes for ventral hernia repair. To evaluate the effect of architecture on the performance of the implants, CollE was formulated both as flat sheets (CollE Sheets) and porous scaffolds (CollE Scaffolds). The morphology, hydrophylicity and in vitro degradation were assessed by SEM, water contact angle and differential scanning calorimetry, respectively. The stiffness of the meshes was determined using a constant stretch rate uniaxial tensile test, and compared to that of native tissue. CollE Sheets and Scaffolds were tested in vitro with human bone marrow-derived mesenchymal stem cells (h-BM-MSC), and finally implanted in a rat ventral hernia model. Neovascularization and tissue regeneration within the implants was evaluated at 6weeks, by histology, immunofluorescence, and q-PCR. It was found that CollE Sheets and Scaffolds were not only biomechanically sturdy enough to provide immediate repair of the hernia defect, but also promoted tissue restoration in only 6weeks. In fact, the presence of elastin enhanced the neovascularization in both sheets and scaffolds. Overall, CollE Scaffolds displayed mechanical properties more closely resembling those of native tissue, and induced higher gene expression of the entire marker genes tested, associated with de novo matrix deposition, angiogenesis, adipogenesis and skeletal muscles, compared to CollE Sheets. Altogether, this data suggests that the improved mechanical properties and bioactivity of CollE Sheets and Scaffolds make them valuable candidates for applications of ventral hernia repair. STATEMENT OF SIGNIFICANCE Due to the elevated annual number of ventral hernia repair in the US, the lack of successful grafts, the design of innovative biomimetic meshes has become a prime focus in tissue engineering, to promote the repair of the abdominal wall, avoid recurrence. Our meshes (CollE Sheets and Scaffolds) not only showed promising mechanical performance, but also allowed for an efficient neovascularization, resulting in new adipose and muscle tissue formation within the implant, in only 6weeks. In addition, our meshes allowed for the use of the same surgical procedure utilized in clinical practice, with the commercially available grafts. This study represents a significant step in the design of bioactive acellular off-the-shelf biomimetic meshes for ventral hernia repair.

Development of a Non-Blood Contacting Cardiac Assist and Support Device: An In Vivo Proof of Concept Study

One of the maladaptive changes following a heart attack is an initial decline in pumping capacity, which leads to activation of compensatory mechanisms, and subsequently, a phenomenon known as cardiac or left ventricular remodeling. Evidence suggests that mechanical cues are critical in the progression of congestive heart failure. In order to mediate two important mechanical parameters, cardiac size and cardiac output, we have developed a direct cardiac contact device capable of two actions: (1) adjustable cardiac support to modulate cardiac size and (2) synchronous active assist to modulate cardiac output. In addition, the device was designed to (1) remain in place about the heart without tethering, (2) allow free normal motion of the heart, and (3) provide assist via direct cardiac compression without abnormally inverting the curvature of the heart. The actions and features described above were mapped to particular design solutions and assessed in an acute implantation in an ovine model of acute heart failure (esmolol overdose). A balloon catheter was inflated in the vena cava to reduce preload and determine the end-diastolic pressure-volume relationship with and without passive support. A Millar PV Loop catheter was inserted in the left ventricle to acquire pressure-volume data throughout the experiments. Fluoroscopic imaging was used to investigate effects on cardiac motion. Implementation of the adjustable passive support function of the device successfully modulated the end-diastolic pressure-volume relationship toward normal. The active assist function successfully restored cardiac output and stroke work to healthy baseline levels in the esmolol induced failure model. The device remained in place throughout the experiment and when de-activated, did not inhibit cardiac motion. In this in vivo proof of concept study, we have demonstrated that a single device can be used to provide both passive constraint/support and active assist. Such a device may allow for controlled, disease specific, flexible intervention. Ultimately, it is hypothesized that the combination of support and assist could be used to facilitate cardiac rehabilitation therapy. The principles guiding this approach involve simply creating the conditions under which natural growth and remodeling processes are guided in a therapeutic manner. For example, the passive support function could be incrementally adjusted to gradually reduce the size of the dilated myocardium, while the active assist function can be implemented as necessary to maintain cardiac output and decompress the heart.

A Biomechanical Comparison of Fifth Metatarsal Jones Fracture Fixation Methods

Background: Fifth metatarsal base fractures of the metaphyseal-diaphyseal watershed junction (Jones fracture) are commonly treated with surgical fixation in athletes. Intramedullary screw fixation remains the most utilized construct, although plantar-lateral plating is an alternative. Purpose/Hypothesis: The purpose was to compare the mechanical strength of fracture fixation between an intramedullary screw and plantar-lateral plating. The hypothesis was that plantar-lateral plate fixation would allow for more cycles and higher peak loads before failure, as well as less fracture gapping, than would an intramedullary screw in cadaveric foot specimens with simulated Jones fractures exposed to cantilever bending. Study Design: Controlled laboratory study. Methods: Twelve pairs of male cadaver feet were separated into 2 groups (plate or screw) to conduct contralateral comparative testing of 2 devices with equally numbered right and left feet. For each fifth metatarsal, an osteotomy with a microsagittal saw was created to simulate a Jones fracture. The plate group underwent fixation with a 3.0-mm 4-hole low-profile titanium plate placed plantar-laterally with 3 locking screws and 1 nonlocking screw. The screw group underwent fixation with a 40- or 45-mm × 5.5-mm partially threaded solid titanium intramedullary screw. After fixation, the metatarsals were excised for biomechanical testing. Cyclic cantilever failure testing was conducted with a gradient-cycle method. Sinusoidal loading forces were applied, increasing by 5.0-pound-force increments per 10 cycles, until each specimen experienced mechanical failure of implant or bone. Failure mode, number of cycles to failure, peak failure load, gap width at the last mutual prefailure loading, and video data were recorded. Paired 2-tailed t test (α = 0.05) was used to compare groups (P < .05 set for significance). Results: Failure mode in both groups occurred predominantly at the bone-implant interface. Plate fixation resulted in significantly higher mean ± SD values for cycles to failure (63.9 ± 27.0 vs 37.3 ± 36.9, P = .01) and peak failure load (159.2 ± 60.5 N vs 96.5 ± 45.8 N, P = .01), with a significantly lower mean gap width (0.0 ± 0.0 mm vs 3.2 ± 2.4 mm, P < .01). Conclusion: As compared with intramedullary screw fixation, plantar-lateral plating allowed for greater cycles to failure and peak load before failure, as well as less gap width, when applied to cadaver foot specimens with simulated Jones fractures exposed to cantilever bending in a load frame. Clinical Relevance: Early return to play among athletes before Jones fracture union is associated with increased risk of failure. This study introduces a plantar-lateral plating construct that performed more favorably than intramedullary screw fixation when applied to simulated Jones fractures in cadaveric foot specimens. Further clinical comparative studies are needed to assess the clinical use of this construct.