Pregnancy produces rapid, non-pathological volume-overload in the maternal circulation due to the demands of the growing fetus. Using a bovine model for human pregnancy, previous work in our laboratory has shown remarkable pregnancy-induced changes in leaflet size and mechanics of the mitral valve. The present study sought to relate these changes to structural alterations in the collagenous leaflet matrix. Anterior mitral valve leaflets were harvested from non-pregnant heifers and pregnant cows (pregnancy stage estimated by fetal length). We measured changes in the thickness of the leaflet and its anatomic layers via Verhoeff-Van Gieson staining, and in collagen crimp (wavelength and percent collagen crimped) via picrosirius red staining and polarized microscopy. Collagen concentration was determined biochemically: hydroxyproline assay for total collagen and pepsin-acid extraction for uncrosslinked collagen. Small-angle light scattering (SALS) assessed changes in internal fiber architecture (characterized by degree of fiber alignment and preferred fiber direction). Pregnancy produced significant changes to collagen structure in the mitral valve. Fiber alignment decreased 17% with an 11.5° rotation of fiber orientation toward the radial axis. Collagen fiber crimp was dramatically lost, accompanied by a 53% thickening of the fibrosa, and a 16% increase in total collagen concentration, both suggesting that new collagen is being synthesized. Extractable collagen concentration was low, both in the non-pregnant and pregnant state, suggesting early crosslinking of newly-synthesized collagen. This study has shown that the mitral valve is strongly adaptive during pregnancy, with significant changes in size, collagen content and architecture in response to rapidly changing demands.

Pregnancy produces rapid, dramatic volume-overload changes to the maternal circulation. This paper examines pregnancy-induced structural-mechanical changes in bovine aortic and mitral heart valve leaflets. Valve leaflets were harvested from non-pregnant heifers and pregnant cows. Dimensions, biaxial extensibility and creep resistance were assessed and related to changes in the collagen network: histological leaflet and anatomic layer thicknesses plus collagen crimp, and biochemical collagen content. Collagen stability and crosslinking were assessed thermomechanically. Pregnancy altered both aortic and mitral valve leaflets. Both valves demonstrated biphasic changes in leaflet stretch, decreasing in early pregnancy and recovering by late pregnancy. Creep in leaflets from both valves was minimal and decreased even further with pregnancy in the mitral valve. There were valve-specific changes in preconditioning areal extension with pregnancy: increasing in the aortic valve and decreasing in the mitral valve. Leaflet area increased dramatically (84% aortic, 56% mitral), with thickening mainly in the fibrosa, accompanied by increases in collagen content (8% aortic, 16% mitral): together suggesting synthesis of new collagen. Collagen crimp was almost completely lost in pregnancy, with the denaturation temperature decreased by approximately 2 °C. Mature and total crosslinking increased, curiously without a significant increase in immature crosslinking. Mature aortic and mitral heart valve leaflets in the maternal cardiovascular system remodel substantially and similarly-despite their different embryological origins.

There is growing evidence that heart valves are not passive structures but can remodel with left ventricular dysfunction. To determine if these tissues remodel under nonpathological conditions, we examined the mirtal valve anterior leaflet during the volume loading and cardiac expansion of pregnancy using a bovine model. We measured leaflet dimensions, chordal attachments, and biaxial mechanical properties of leaflets collected from never-pregnant heifers and pregnant cows (pregnancy duration estimated from fetal length). Hydrothermal isometric tension (HIT) tests were performed to assess the denaturation temperature (T(d)) associated with collagen molecular stability and the load decay half-time (t(1//2)) associated with intermolecular cross-linking. Histological changes were examined using Verhoeff-van Gieson and picrosirius red staining with polarized light. We observed striking changes to the structure and material properties of the mitral anterior leaflet during pregnancy. Leaflet area was increased 33%, with a surprising increase (nearly 25%) in chordae tendinae attachments. There was a biphasic change in leaflet extensibility: it rapidly decreased by 30% and then reversed to prepregnant values by late pregnancy. The 2°C decrease in T(d) in pregnancy was indicative of collagen remodeling, whereas the 70% increase in HIT t(1/2) indicated an increase in collagen cross-linking. Finally, histological results suggested transient increases in leaflet thickness and transient decreases in collagen crimp. This remodeling may compensate for the increased loading conditions associated with pregnancy by normalizing leaflet stress and maintaining coaptation. Understanding the mechanisms of mitral valve physiological remodeling in pregnancy could contribute to alternative treatments of pathological remodeling associated with left ventricular dysfunction.

Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves. HEART VALVES ARE COMPLEX and dynamic biological structures. They play important roles toward efficient cardiac pumping, ensuring unidirectional blood flow while opening and closing 3 billion times in a lifetime. The extent and the mechanisms via which the valves may adapt to changing loading conditions in either physiology or pathology remain unclear. Many investigations of valve adaptation have focused on physiological development (8,20,(51)(52)(53) or pathological conditions such as left ventricular (LV) dysfunction (10), mitral valve regurgitation (58), myxomatous degeneration (19), or heart failure (17). Recent studies from our laboratory, however, have demonstrated the capacity of maternal heart valve leaflets to remodel under the altered hemodynamics of pregnancy, a nonpathological condition (38,39,60). Pregnancy is accompanied by an increase in blood volume and cardiac output of ϳ50%, as the maternal circulation accommodates the developing fetoplacental unit. This volume overload produces cardiac enlargement (21, 45, 60) with expansion of valve orifices (areas increasing from 12-53% in humans; see Refs. 9 and 43). These changes in geometry then elevate...

Borate glasses have shown promising potential as bioactive materials. With recent research demonstrating that glass properties may be modulated by appropriate compositional design. This may provide for indication specific material characteristics and controlled release of therapeutic inorganic ions (i.e., strontium); controlling such release is critical in order to harness the therapeutic potential. Within this sub-chronic pilot study, a rabbit long-bone model was utilized to explore the safety and efficacy of a high borate glass (LB102: 70B O -20SrO-6Na O-4La O ) particulate (90 - 710 μm) for bone regeneration. Six bilateral full-thickness defects (Ø = 3.5 mm; L = 8 mm) were created in three white New Zealand rabbits. Longitudinal non-decalcified sections of each defect site were produced and stained with Goldner's Trichrome. Histopathological examination revealed that LB102 demonstrated osteoconductive and osseointegrative properties with greater new bone being formed within and surrounding LB102 particles, when compared to the sham control. The inflammatory cell infiltration was observed to be slightly higher in the control when compared to LB102 defect sites, while no significant difference in fibrosis and neovascularization was determined, indicating that healing was occurring in a normal fashion. These data further suggest the possible utility of high borate glasses with appropriate compositional design for medical applications, such as bone augmentation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1818-1827, 2017.

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