David E. Schmidt

On the biomechanics of heart valve function

Heart valves (HVs) are fluidic control components of the heart that ensure unidirectional blood flow during the cardiac cycle. However, this description does not adequately describe the biomechanical ramifications of their function in that their mechanics are multi-modal. Moreover, they must replicate their cyclic function over an entire lifetime, with an estimated total functional demand of least 3x10(9) cycles. The focus of the present review is on the functional biomechanics of heart valves. Thus, the focus of the present review is on functional biomechanics, referring primarily to biosolid as well as several key biofluid mechanical aspects underlying heart valve physiological function. Specifically, we refer to the mechanical behaviors of the extracellular matrix structural proteins, underlying cellular function, and their integrated relation to the major aspects of valvular hemodynamic function. While we focus on the work from the authors laboratories, relevant works of other investigators have been included whenever appropriate. We conclude with a summary of important future trends.

THE ROLE OF ORGAN LEVEL CONDITIONING ON THE PROMOTION OF ENGINEERED HEART VALVE TISSUE DEVELOPMENT IN-VITRO USING MESENCHYMAL STEM CELLS

We have previously shown that combined flexure and flow (CFF) augment engineered heart valve tissue formation using bone marrow-derived mesenchymal stem cells (MSC) seeded on polyglycolic acid (PGA)/poly-L-lactic acid (PLLA) blend nonwoven fibrous scaffolds (Engelmayr, et al., Biomaterials 2006; vol. 27 pp. 6083-95). In the present study, we sought to determine if these phenomena were reproducible at the organ level in a functional tri-leaflet valve. Tissue engineered valve constructs (TEVC) were fabricated using PGA/PLLA nonwoven fibrous scaffolds then seeded with MSCs. Tissue formation rates using both standard and augmented (using basic fibroblast growth factor [bFGF] and ascorbic acid-2-phosphate [AA2P]) media to enhance the overall production of collagen were evaluated, along with their relation to the local fluid flow fields. The resulting TEVCs were statically cultured for 3 weeks, followed by a 3 week dynamic culture period using our organ level bioreactor (Hildebrand et al., ABME, Vol. 32, pp. 1039-49, 2004) under approximated pulmonary artery conditions. Results indicated that supplemented media accelerated collagen formation (approximately 185% increase in collagen mass/MSC compared to standard media), as well as increasing collagen mass production from 3.90 to 4.43 pg/cell/week from 3 to 6 weeks. Using augmented media, dynamic conditioning increased collagen mass production rate from 7.23 to 13.65 pg/cell/week (88.8%) during the dynamic culture period, along with greater preservation of net DNA. Moreover, when compared to our previous CFF study, organ level conditioning increased the collagen production rate from 4.76 to 6.42 pg/cell/week (35%). Newly conducted CFD studies of the CFF specimen flow patterns suggested that oscillatory surface shear stresses were surprisingly similar to a tri-leaflet valve. Overall, we found that the use of simulated pulmonary artery conditions resulted in substantially larger collagen mass production levels and rates found in our earlier CFF study. Moreover, given the fact that the scaffolds underwent modest strains (approximately 7% max) during either CFF or physiological conditioning, the oscillatory surface shear stresses estimated in both studies may play a substantial role in eliciting MSC collagen production in the highly dynamic engineered heart valve fluid mechanical environment.

On the mechanical role of de novo synthesized elastin in the urinary bladder wall.

The urinary bladder wall (UBW), which is composed of smooth muscle, collagen, and elastin, undergoes profound remodeling in response to changes in mechanical loading resulting from various pathologies. In our laboratory, we have observed the production of fibrillar elastin in the extracellular matrix (ECM), which makes the UBW a particularly attractive tissue to investigate smooth muscle tissue remodeling. In the present study, we explored the mechanical role that de novo elastin fibers play in altering UBW ECM mechanical behavior using a structural constitutive modeling approach. The mechanical behavior of the collagen fiber component of the UBW ECM was determined from the biaxial stress-stretch response of normal UBW ECM, based on bimodal fiber recruitment that was motivated by the UBWs unique collagen fiber structure. The resulting fiber ensemble model was then combined with an experimentally derived fiber angular distribution to predict the biaxial mechanical behavior of normal and the elastin-rich UBW ECM to elucidate the underlying mechanisms of elastin production. Results indicated that UBW ECM exhibited a distinct structure with highly coiled collagen fiber bundles and visible elastic fibers in the pathological situation. Elastin-rich UBW ECM had a distinct mechanical behavior with higher compliance, attributable to the indirect effect of elastin fibers contracting the collagen fiber network, resulting in a retracted unloaded reference state of the tissue. In conclusion, our results suggest that the urinary bladder responds to prolonged periods of high strain by increasing its effective compliance through the interaction between collagen and de novo synthesized elastic fibers.

Oscillatory shear stress created by fluid pulsatility versus flexed specimen configurations

Oscillatory shear stress (OSS), caused by time-varying flow environments, may play a critical role in the production of engineered tissue by bone marrow-derived stem cells. This is particularly relevant in heart valve tissue engineering (HVTE), owing to the intense haemodynamic environments that surround native valves. In this study, we examined and quantified the role that (i) physiologically relevant scales of pulsatility and (ii) changes in geometry as a function of specimen flexure have in creating OSS conditions. A U-shaped bioreactor capable of producing flow, stretch and flexure was modelled with housed specimens, and computational fluid dynamic simulations were performed. We found that physiologically relevant OSS can be maximised by the application of pulsatile flow to straight, non-moving specimens in a uniform manner. This finding reduces a substantial layer of complexity in dynamic HVTE protocols in which traditionally, time-varying flow has been promoted through specimen movement in custom-made bioreactors.

Output control of da Vinci surgical system's surgical graspers

INTRODUCTION The number of robot-assisted surgeries performed with the da Vinci surgical system has increased significantly over the past decade. The articulating movements of the robotic surgical grasper are controlled by grip controls at the master console. The user interface has been implicated as one contributing factor in surgical grasping errors. The goal of our study was to characterize and evaluate the user interface of the da Vinci surgical system in controlling surgical graspers. MATERIALS AND METHODS An angular manipulator with force sensors was used to increment the grip control angle as grasper output angles were measured. Input force at the grip control was simultaneously measured throughout the range of motion. Pressure film was used to assess the maximum grasping force achievable with the endoscopic grasping tool. RESULTS The da Vinci robots grip control angular input has a nonproportional relationship with the grasper instrument output. The grip control mechanism presents an intrinsic resistant force to the surgeons fingertips and provides no haptic feedback. The da Vinci Maryland graspers are capable of applying up to 5.1 MPa of local pressure. CONCLUSIONS The angular and force input at the grip control of the da Vinci robots surgical graspers is nonproportional to the grasper instruments output. Understanding the true relationship of the grip control input to grasper instrument output may help surgeons understand how to better control the surgical graspers and promote fewer grasping errors.

Micro-Meso Scale Model of Electrospun Poly (Ester Urethane) Urea Scaffolds

Soft tissue engineering applications require accurate descriptions of native and engineered tissue microstructure and their contributions to global mechanical behavior [1–6]. Moreover, micro scale based mechanical models can be used to: (1) guide tissue engineering scaffold design, (2) provide a better understanding of cellular mechanical and metabolic response to local micro-structural deformations, and (3) investigate structural changes as a function of deformation across multiple scales. We present a novel approach to automatically collect micro-architectural data (fibers overlaps, fiber connectivity, and fiber orientation) from SEM images of electrospun poly (ester urethane) urea (PEUU) to recreate statistically equivalent scaffold mechanical models. More importantly, an appropriate representative volume element (RVE) size was selected to fully capture both critical micro-scale architectural information, as well as reproducing the larger-scale directional long fiber mechanical behavior. This approach produced material models by specifying fiber overlap density, fiber orientation, and connectivity allowing the bulk mechanical response to be determined at the meso and micro scale via FEM simulations.Copyright

Computational Prediction of Fluid Induced Stress States in Dynamically Conditioned Engineered Heart Valve Tissues

There is extensive documented evidence that mechanical conditioning plays a significant role in the development of tissue grown in-vitro for heart valve scaffolds [1–3]. Modern custom made bioreactors have been used to study the mechanobiology of engineered heart valve tissues [1]. Specifically fluid-induced shears stress patterns may play a critical role in up-regulating extracellular matrix secretion by progenitor cell sources such as bone marrow derived stem cells (BMSCs) [2] and increasing the possibility of cell differentiation towards a heart valve phenotype. We hypothesize that specific biomimetic fluid induced shear stress environments, particularly oscillatory shear stress (OSS), have significant effects on BMSCs phenotype and formation rates. As a first step here, we attempt to quantify and delineate the entire 3-D flow field by developing a CFD model to predict the fluid induced shear stress environments on engineered heart valves tissue under quasi-static steady flow and dynamic steady flow conditions.Copyright

A Micro-Architectural Based Structural Model for Elastomeric Electrospun Scaffolds

Interest in electrospun polymeric nano-microfibers for tissue engineering applications has rapidly grown during the last decade. In spite of this technique’s flexibility and ability to form complex fiber assemblies, additional studies are required to elucidate how the fibrous microstructure translates into specific tissue (or meso-scale) level mechanical behavior. Deterministic structural models can quantify how key structures contribute to the mechanical response as a function of bulk deformation across multiple scales, as well as provide a better understanding of cellular mechanical response to local micro-structural deformations. Our ultimate aim is to utilize such models to assist tissue engineering scaffold design. In the current work, we present a novel approach to automatically quantify key micro-architectural descriptors (fiber overlaps, connectivity, orientation, and diameter) from SEM images of electrospun poly (ester urethane) urea (PEUU) to recreate statistically equivalent scaffold mechanical models. An appropriate representative volume element (RVE) size was determined by quantifying the point of stabilization of the architectural descriptors over image areas of increasing size. Material models were then generated specifying: fiber overlap density, fiber orientation, connectivity and fiber diameter. Macro-meso mechanical response was predicted via FEM simulations.Copyright

Characterizing the Influence of Scaffold Anisotropy on Engineered Heart Valve Leaflet Function

Tissue engineered pulmonary valves (TEPV) represent a conceptually appealing alternative to current non-viable prosthetic valves and valved conduits for the repair of congenital or acquired lesions in pediatric patients. In addition to the identification of clinically feasible cell sources, engineered soft tissues such as the TEPV require scaffolds with anisotropic mechanical properties that undergo large deformations (not possible with current PGA/PLLA non-wovens) coupled with controllable biodegradative and cell-adhesive characteristics. Electrospun PEUU (ES-PEUU) scaffolds have been produced with tensile biaxial mechanical properties remarkably similar to the native pulmonary valve (Fig. 1-a), including the ability to undergo large physiologic strains and exhibit pronounced mechanical anisotropy. Moreover, a novel cell micro-integration technique has been developed that allows for successful cell integration directly into the scaffolds at the time of fabrication, eliminating cellular penetration problems. These encouraging results suggest that ES-PEUU scaffolds micro-integrated with the appropriate cells and can serve as successful TEPV scaffolds. In the present study, we conducted a finite element based analysis of TEPV leaflets (Fig. 1-b) under quasi-static transvalvular pressure to demonstrate the impact of ES-PEUU mechanical anisotropy on scaffold strain distributions.© 2009 ASME

3D Structural Information of Soft Tissues Using Small Angle Light Scattering

Small angle light scattering (SALS) is a extensively utilized technique for the rapid quantification of the organization and structure of native fibrous soft tissues. In the present work, we developed a method to extend serial histological sections to obtain 3D distribution architectural information. This technique allows for rapid quantification and study of general trends of architectural information over large volume or areas of tissue and is beneficial to study highly heterogeneous tissue where changes in architecture, due to pathologies or stress may induce complex regional changes. An important clinical example is learning the degree of organization of abdominal aortic aneurysm (AAA) tissue. When studying the organization trend in histological sections of AAA tissue, conclusions from the SALS 2D images cannot be drawn due to the high variability of organization from section to section. This is common to diseased tissues due to the altered structure that is otherwise organized in healthy tissue.Copyright