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 3×10 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 extra-cellular 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 author's laboratories, relevant works of other investigators have been included whenever appropriate. We conclude with a summary of important future trends. KeywordsHeart valves; biomechanics; soft tissue mechanics; cell mechanics; mechanobiology I -Heart Valve Physiologic Function -IntroductionHeart valves (HVs) are fluidic control components of the heart that ensure unidirectional blood flow during the cardiac cycle. Essentially, HVs are passive tissues that are directed to open and close due to inertial forces exerted by the surrounding blood. However, this description does not adequately describe the biomechanical ramifications of their function in that their mechanics are multi-modal and their loading cycle is repeated every second. For example, they must replicate this feat with each heart beat; over a period of 70 years the reader's HVs will open and close nearly 3×10 9 times.Anatomically, there are two types of valves: semilunar and atrio-ventricular (sometimes also known as "sigmodial"). The semilunar valves (pulmonary (PV) and aortic (AV)) prevent For correspondence: Michael S. Sacks, Ph.D., 100 Technology drive, Room 234, University of Pittsburgh, Pittsburgh, PA 15219, Tel: 412-235-5146, Fax: 412-235-5160, Email: msacks@pitt.edu. CONFLICT OF INTERESTThe authors have no conflict of interest, financial or otherwise, that would affect their impartiality of this work.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript retrograde flow back into the ventricles during diastole. Because of their anatomical location, they form nearly a perfec...

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 (~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 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. substantially large collagen mass production levels and rates found in our earlier CFF study. Moreover, given the fact that the scaffolds underwent modest strains (~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. NIH Public Access

The local dilation of the infrarenal abdominal aorta, termed an abdominal aortic aneurysm (AAA), is often times asymptomatic and may eventually result in rupture-an event associated with a significant mortality rate. The estimation of in-vivo stresses within AAAs has been proposed as a useful tool to predict the likelihood of rupture. For the current work, a previously-derived anisotropic relation for the AAA wall was implemented into patient-specific finite element simulations of AAA. There were 35 AAAs simulated in the current work which were broken up into three groups: elective repairs (n = 21), non-ruptured repairs (n = 5), and ruptured repairs (n = 9). Peak stresses and strains were compared using the anisotropic and isotropic constitutive relations. There were significant increases in peak stress when using the anisotropic relationship (p < 0.001), even in the absence of the ILT (p = 0.014). Ruptured AAAs resulted in elevated peak stresses as compared to non-ruptured AAAs when using both the isotropic and anisotropic simulations, however these comparisons did not reach significance (p(ani) = 0.55, p(iso) = 0.73). While neither the isotropic or anisotropic simulations were able to significantly discriminate ruptured vs. non-ruptured AAAs, the lower p-value when using the anisotropic model suggests including it into patient-specific AAAs may help better identify AAAs at high risk.

Fc-gamma receptors (FcγR) are the cellular receptors for Immunoglobulin G (IgG). Upon binding of complexed IgG, FcγRs can trigger various cellular immune effector functions, thereby linking the adaptive and innate immune systems. In humans, six classic FcγRs are known: one high-affinity receptor (FcγRI) and five low-to-medium-affinity FcγRs (FcγRIIA, -B and -C, FcγRIIIA and -B). In this review we describe the five genes encoding the low-to-medium -affinity FcγRs (FCGR2A, FCGR2B, FCGR2C, FCGR3A, and FCGR3B), including well-characterized functionally relevant single nucleotide polymorphisms (SNPs), haplotypes as well as copy number variants (CNVs), which occur in distinct copy number regions across the locus. The evolution of the locus is also discussed. Importantly, we recommend a consistent nomenclature of genetic variants in the FCGR2/3 locus. Next, we focus on the relevance of genetic variation in the FCGR2/3 locus in auto-immune and auto-inflammatory diseases, highlighting pathophysiological insights that are informed by genetic association studies. Finally, we illustrate how specific FcγR variants relate to variation in treatment responses and prognosis amongst autoimmune diseases, cancer and transplant immunology, suggesting novel opportunities for personalized medicine.

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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.