Raffaella De Vita, Ph.D. - US grants

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)."

0932024
De Vita

Sprains of the knee ligaments are among the most common orthopedic injuries. They usually occur when the knee is forced beyond its normal range of motion, such as in a fall. They also happen when the knee experiences an impact, such as in a car accident or during a football tackle. These injuries can consist of a slight over-stretch, a partial tear, or a complete disruption of the ligaments. While many investigators in biomechanics have focused on quantifying the material properties of ligaments, such as tangent modulus, tensile strength, and ultimate strain, little is know of their response to mechanical stimuli that lead to partial and complete failure. In particular, studies are needed to clarify the micro-structural changes associated with partial and complete tears. For the first time, constitutive relationships that explain the role of microstructure in the damage evolution process of ligaments will be developed. These models will be derived by integrating molecular models that provide information about collagen cross-linking and collagen molecular damage with structural continuum models. The structural models will be formulated by taking into account the components of the ligamentous tissues, their geometrical arrangement, and their interactions. They will describe the typical anisotropy, nonlinearity, and inelasticity exhibited by ligamentous tissue. Together with the theoretical study, mechanical and microscopic experiments will be performed to quantify the effect of collagen intermolecular cross-linking on the failure of ligaments. Toward this end, knee ligaments harvested from two groups of animals, one fed with a normal diet and another fed with a lathyritic diet, will be subjected to different sub-failure stretches along their physiological direction. Ligaments will be examined for microscopic structural damage, and molecular fragmentation of collagen _brils will be assessed to determine how ligament failure occurs on a molecular level. This information will, in turn, be correlated to the structural models developed based upon the mechanical data. Together, these three approaches will culminate in a more complete understanding of the structure/function relationship of the components of ligament.

Intellectual Merit. The successful completion of the proposed project requires a combined knowledge of theoretical and experimental mechanics of biological systems as well as molecular biology. The PIs will combine their expertise in continuum mechanics (R. De Vita), molecular modeling (J. W. Freeman), experimental mechanics (J. G. Barrett, R. De Vita and J. W. Freeman) and molecular biology (J. G. Barrett) to formulate novel models that together with mechanical and microscopic experiments will elucidate the relationship between damage development and material composition of ligaments. This research program will have a signifcant impact in the area of engineering materials for replacement grafts and biological scaffolds by offering a knowledge of mechanical and structural properties to target in developing replacements for ligaments. The results can also guide the design of braces or stretching routines to limit ligament strain so as prevent damage during stressful activities. Because ligaments possess a very well organized structure and a relatively simple composition, the research findings will contribute to understanding the failure mechanism of more complex biological soft tissues such as, for example, skin and arteries.

Broader Impacts. Undergraduate and graduate students will be engaged in the theoretical, numerical, and experimental components of the research project. The PIs will work with the Bioin-formatics and Bioengineering Summer Institute program and the College Bound program to attract and retain underrepresented groups to science and engineering. Research findings will be incorporated into current courses that are offered in the undergraduate, graduate and professional curricula. The results of the research will be presented at national and international conferences and published in peer-reviewed journals.

Abstract

The objective of this research is to understand how insects produce and control internal flows and to use this knowledge to create novel, highly efficient, bio-inspired fluid-transport systems. Current approaches to flow delivery and regulation in complex microsystems rely on targeted actuation and active control. In contrast, insects have evolved over millions of years to efficiently manage flows using flexible tissues, simple actuation, and passive, distributed control built into the network itself. The approach combines synchrotron x-ray imaging of internal insect dynamics, material characterization of insect vessels, fluid mechanics modeling and experiments, and advanced micromechanical fabrication technology.

The intellectual merit of the proposed research effort includes transformation of the accepted approach to fluid-based transport in small-scale systems, further development of advanced experimental and fabrication techniques, and fundamental advances in the understanding of insect physiology. The proposed research has the potential to change the paradigm for flow delivery and regulation in small-scale systems, leading to new bioengineered tissues and energy-efficient, biomedically-implantable microdevices.

The broader impacts will include integrating the findings from this project into educational programs at the K-12 and university levels. New lessons that integrate biology and engineering will be developed with under-represented students in urban and rural classrooms. The broader public will also be educated through direct involvement with new television and film productions of National Geographic. Additionally, a deeper understanding of how insect respiration and circulation work will lead to novel mechanisms for targeted biocontrol, enabling economically significant advances in agricultural, residential, and commercial pest management.

1150397
De Vita

Pelvic floor disorders (PFDs) such as urinary incontinence, fecal incontinence, and pelvic organ prolapse represent a major public health concern in the United States affecting one third of adult women. These disorders are determined by structural and mechanical alterations of the pelvic organs, their supporting muscles and connective tissues that occur mainly during pregnancy, vaginal delivery, and aging. The national cost burden imposed by PFDs is alarming in terms of direct health care costs, lost productivity, and decreased quality of life. It is projected to increase dramatically by 2050 with the increase in the aging population in the United States. New research forecasts that the number of adult women affected by PFDs will increase from to 28.1 million in 2010 to 43.8 million in 2050. The alarming cost burden and projected high incidence of PFDs emphasize the critical need for research in engineering and science that leads to the development of new treatment strategies. This CAREER project aims at determining the elastic and viscoelastic properties of two major ligaments supporting the uterus and vagina: the uterosacral ligaments (USLs) and cardinal ligaments (CLs). Rigorous mechanical experiments will be performed on USLs and CLs to completely characterize their important role as supportive structures of the uterus and vagina. Mechanical testing will be then coupled with synchrotron X-ray diffraction imaging in order to reveal the collagenous micro-structure of USLs and CLs with unprecedented details. The results of the experiments will be used to develop reliable structurally-based constitutive models for USLs and CLs and assess their predictive capabilities. These models will be derived within a nonlinear integral representation theory, which encompasses the quasi-linear viscoelasticity and the modified superposition principle, and has the potential to successfully capture expected nonlinearities in the mechanical response of the USLs and CLs.
Intellectual Merit. This project will potentially transform surgical reconstruction methods and post-operative rehabilitation protocols for female PFDs by offering new knowledge about the structural and mechanical properties of USLs and CLs. Currently, the USLs and CLs are either adjusted in ad-hoc manner or replaced using synthetic tapes for enhancing the suspension of the uterus and vagina. This innovative research will be crucial in establishing science-based guidelines and specific protocols for the treatment of PFDs ultimately providing better care for millions of adult women afflicted by these disorders. The PI has a unique blend of analytical skills and experimental prowess that makes her especially qualified to conduct the proposed research. The Biophysics Collaborative Access Team at the Argonne National Laboratory will provide the PI with the necessary expertise and training to use the synchrotron X-ray facilities. Through the collaboration with the Department of Obstetrics and Gynecology at the Walter Reed Army Medical Center, the PI will keep herself abreast of the challenges in female pelvic medicine and reconstructive surgery and contribute firsthand to the care and management of PFDs.
Broader Impact. In this project, research and education are seamlessly integrated to enhance the students' curriculum and increase the participation of underrepresented groups in science and engineering. The education program creates new partnerships between Virginia Tech and the community in the region, increasing the leadership role of the PI's home institution in the state's societal and educational initiatives. Undergraduate and graduate students will participate in the proposed research and education components of the project. A new graduate course on nonlinear mechanics of biological systems will be developed and an undergraduate course will be significantly revised to include laboratory hours in experimental biomechanics. Interactive mini-lectures complemented with hands-on activities in biomechanics, prepared in formats understandable by non-scientists, are proposed to enrich the science curriculum at the Blacksburg Middle School and engage the visitors of the Science Museum of Western Virginia. Summer camps and mentorship will be offered to high school students with disabilities in order to facilitate their transition to college. Lunch and group meetings for women faculty in engineering will be organized to create a supportive environment and mentoring relationships. The findings of these research and education efforts will be disseminated on the web, published in peer-reviewed journals, and presented at national and international conferences.

Pelvic floor disorders (PFDs) encompass a number of medical conditions including stress urinary and fecal incontinence, and pelvic organ prolapse. Although not often discussed, these conditions are extremely common, with more than 50% of parous women having some degree of a PFD during their lifetime and 11% of women requiring surgery. These disorders severely alter the quality of life of women often leading to isolation and depression. To someone not entirely familiar with internal female pelvic anatomy, it may appear that the vagina is no more important than the rectum or urethra in the development of these disorders. However, the vagina is the primary support structure for the urethra, bladder, uterus, and rectum. The vagina is, in turn, supported by a combination of muscle and connective tissues. A direct insult to the vagina and/or its supportive muscles and tissues compromises the function of other pelvic organs. Thus, it should come as no surprise that excessive stretching and tearing of the vagina during labor and vaginal delivery are predisposing factors for the development of PFDs. It is still unclear, however, which of the structural and mechanical alterations that occur in vaginal tissue during pregnancy predispose women to the development of PFDs.

This collaborative project aims to characterize, for the first time, the mechanisms of stretch induced damage and tear propagation in virgin and pregnant rat vaginal tissue. A comprehensive set of ring tests will be conducted to determine the functional role of the tissue?s constituents (collagen, elastin, and smooth muscle cells) on both the active and passive mechanics of the vagina. Planar biaxial tests will be performed to study the tear propagation process. The results of these tests will guide the development of a new constitutive model that will capture the active and passive mechanical response of the vaginal tissue, including stretch-induced damage. The constitutive model will be implemented into a finite element code especially developed to simulate damage and tear propagation of vaginal tissue. For validation, three-dimensional in-vivo experimental data, which are collected by conducting inflation tests that simulate a birth injury within a state-of-the-art 7T micro-MRI, will be utilized.

Pelvic organ prolapse (POP), which occurs when a pelvic organ--such as the bladder or uterus--drops from its normal place in the lower belly and pushes against the walls of the vagina, is a very common disorder, affecting half of all women over the age of 50. The quality of life of women with POP is severely compromised: depression, anxiety, social isolation, and sexual dysfunction are serious consequences. Treatment options vary from physical therapy to surgical interventions, but the overall success rates are low. Given the high incidence and low success rates of current procedures for POP, new interventional methods are required. By far, the most important supportive tissues of the uterus, cervix, and vagina complex are the uterosacral ligaments (USLs). These are not true ligaments as their name suggests, but they are membrane-like structures that are primarily composed of collagen and smooth muscle. Despite the crucial supportive role of the USLs and their extensive use in surgical procedures for prolapses, the contractile properties of the USLs remain unknown. This project focuses on filling this gap by providing the first mechanical characterization of the contractile properties of the USL. Toward this end, state-of-the-art mechanical testing and advanced light-based imaging methods will be integrated. The new data will guide the development of high fidelity mathematical models that capture the active mechanics of the USLs at the cell and tissue levels. Progress towards understanding the function of the USLs for the prevention and treatment of POP inevitably depends on the development and use of advanced engineering methods for mechanical characterization. Using computer simulations based on the new mathematical models for the USLs, this project can radically change current conservative methods and surgical procedures for POP, ultimately improving the quality of life of many women. The learning experiences of undergraduate and graduate students working on this project will be enhanced by exchange visits with La Sapienza University, Rome, Italy. The students will acquire unique skills, build professional networks, and gain cross-cultural experiences, thus becoming more competitive in the global workplace. Summer camps, called STEMABILITY, will be organized to serve, train, empower, and mentor high school students with disabilities while also exposing them to science, technology, mathematics, and engineering.

The goal of this project is to characterize the active and passive properties of the uterosacral ligaments (USLs) in a rat model and then use that information to develop a new constitutive model incorporating tissue and cell-level properties that can be used for accurate finite element modeling of the pelvic floor. The Research Plan is organized under 3 objectives. The first objective is to determine the active and passive mechanical properties of smooth muscle cells isolated from the rat USL by conducting uniaxial tests and measuring three-dimensional deformations using high sensitivity spectral modulation interferometry (SMI) and spectral-domain phase gradient (SDPG) optical methods. The optical imaging techniques are uniquely capable of quantifying minute (subnanometer) cellular morphological changes during contraction. The second objective is to quantify the active and passive mechanical properties of the rat USL tissue by performing biaxial tests and measuring three-dimensional deformations using state-of-the-art digital image correlation (DIC) and optical tomographic imaging (OPT) methods. The third objective is to describe and predict empirical results by formulating and validating a new constitutive framework that accounts for the active mechanical response of the USL. The first step is deriving new constitutive laws and equations that consider the smooth muscle contribution to the overall mechanical behavior. Mechanisms to be considered include: nonlinearity, anisotropy, elasticity, viscoelasticity and active and passive behavior. The format features three configurations: 1) a reference stress-free state, 2) an active(due to electrical or chemical stimulation) without stress state and 3) an active and passive response with stress state. The evolution law will be derived starting from the description of microscopic mechanisms, e.g., actin-myosin filament sliding, that lead to muscle activation. The parameters of the constitutive equations will be obtained via curve-fitting to experimental data. The resulting set of nonlinear equations will be solved within a finite element computational framework. The new modeling framework will be used to provide scientific-based recommendations for both conservative management and surgical intervention for vaginal vault prolapse and uterine prolapse; for example, findings have implications for planning pelvic floor exercises, for improving mesh grafts for POP repair and for designing surgical interventions that preserve the active and passive mechanical properties of the USL.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Around 80 percent of women experience vaginal tears during labor, when the diameter of the vagina has to increase from 2.5 cm to 9.5 cm in order to allow the passage of a full-term baby. Complications associated with vaginal tears include postpartum hemorrhaging, fecal incontinence, urinary incontinence, and dyspareunia. Current evaluation methods of vaginal tears after childbirth are qualitative and rely on the expertise and training of obstetricians and midwives. This reliance upon subjective assessments often leads to incorrect diagnosis and inadequate treatment that severely compromise the quality of life of women. In order to establish new quantitative metrics for evaluating vaginal tears, a seamless experimental, theoretical, and computational characterization of the mechanical properties of the vagina -- including the tear resistance properties -- will be studied. This project will examine fundamental mechanical properties and response of this very under-studied tissue. The knowledge gained will support improved understanding of the response of vaginal tissue to the natural stretch that occurs during childbirth, and this will then support improved diagnostic, assessment, and treatment methods. Undergraduate and graduate students, mostly from underrepresented groups, will be recruited to participate in this highly interdisciplinary research and education program, which involves synergistic exchanges between the medical and STEM fields. In addition, in order to inspire, prepare, and empower undergraduate women to pursue graduate studies in engineering and help close the gender gap, a new one-day workshop offering preparatory information about graduate school will be organized at Virginia Tech.

In order to meet these project goals, entire vaginal canals from virgin and late pregnant rats will be subjected to inflation tests to induce tearing, and the resulting large inhomogeneous deformations will be measured using the digital image correlation technique. By using multi-photon microscopy and second harmonic generation imaging, the collagen fiber organization in the near- and far-fields of the tears will be measured. The experimental data will guide the development of new microstructurally-based constitutive models for the vaginal wall that are validated using a highly efficient data-driven reduced order modeling approach. Finally, new mechanics-based metrics for vaginal tear evaluation will be established following the theory of critical distances approach, using both the experimental data and data-driven models. This will include markers for levator ani trauma, predictors for maternal trauma, and protocols for pelvic floor trainer devices.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.