BME Seminar Series: BME Ph.D. candidates Margaret Raabe and Aaron Short

"Reduced Core Stability is Associated with Increased Biomechanical Risk Factors for Patellofemoral Pain Syndrome in Novice Runners"

Margaret Raabe 

Advisor: Ajit Chaudhari, PhD

Abstract

The annual rate of running-related injuries, including patellofemoral pain syndrome (PFPS), is reported to be as high as 65% and novice runners may be at the highest risk of developing these injuries. Previous research has shown core stability may affect lower extremity (LE) function, which has led to the popular notion that insufficient core stabilization may lead to movements that are less efficient and ultimately contribute to musculoskeletal injury. However, the role that core stability plays during running and its influence on injury risk in runners is not well understood. The purpose of this study was to investigate the effect of core stability on running mechanics that have previously been associated with running injuries. Three-dimensional running kinematics and kinetics were collected on 25 healthy, novice runners before and after they performed a core stability knockdown protocol (CSKP), designed to temporarily reduce participants’ core stability in a single testing session. In the participants (N=10) who experienced a meaningful reduction in core stability following the CSKP (≥10% from baseline level), linear mixed models demonstrated that this reduction was significantly associated with an increase in peak knee flexion moment (0.85 %BW*h, p=0.001) and peak knee abduction angle (1.22 degrees, p=0.005) during the stance phase of running. Both of these biomechanical changes have previously been associated with increased patellofemoral contact pressure during running. Therefore, when accumulated over thousands of gait cycles, this increased peak loading on a more abducted knee could lead to an increased risk of patellofemoral pain in novice runners. 

"Hydrogels: Use and Function in Cancer Migration, Infiltration, and Drug Delivery"

Aaron Short

Advisor: Dr. Jessica O. Winter

Abstract

Diseases that arise in the central nervous system (CNS) (i.e., glioblastoma) are not only devastating, but as a result of the nature and overall physiology of the CNS, are difficult to assess and treat. In order to better treat diseases like glioblastoma, a form of brain cancer, it is imperative to obtain a greater understanding of the underlining mechanisms responsible for its progression. GBM is particularly deadly because of anatomical limitations in treatment by radiation and surgery, and the eventual development of resistance to chemo-radiation therapy, which results in a highly migratory phenotype. Thus, understanding GBM migration could lead to improved therapies. In vivo models of cell migration and tumor growth allow for the most accurate representation of the physiological extracellular matrix (ECM). Unfortunately, short of expensive genetically altered animals, they have a limited capacity to study individual protein effects, which is crucial in determining how cells interact with the microenvironment during metastasis. 

To this end, substantial research has been performed to develop in vitro assays that allow for accurate recapitulation of neural microenvironment properties (i.e. physical, chemical, and mechanical), while allowing for individual components to be analyzed. To enhance simple two-dimensional co-cultures systems; a topographical biomimetic was created with electrospun nanofibers of poly (ε-caprolactone) (PCL) for use as an in vitro assay. This approach was used to assess the effects of cancerous glioblastoma cells on healthy astrocytes and vice versa. Analysis of the co-culture systems, suggests that the presence of glioma-produced ECM was a primary factor in astrocyte activation, whereas astrocytes increased glioblastoma migration rates. Interestingly, astrocyte-conditioned medium promoted glioma migration, whereas culture in the presence of fixed astrocytes was antagonistic to migration. In addition to cancer cell migration, these in vitro models show promise in achieving a better understanding in neural stem cell differentiation. Through a simple modulation of fiber diameter, morphology and migration of neural stem cells can be altered during differentiation. 

However, whereas these complex two-dimensional assays (i.e., electrospun nanofibers) are a large improvement from simple two-dimensional assays, they still fall short of the complex three-dimensional environment seen in vivo. For example, hyaluronic acid (HA) is a common protein in the CNS that is upregulated in glioblastoma tumors; creating a gradient of HA as cells leave the tumor microenvironment. Therefore, we synthesized hydrogels containing both HA and collagen to mimic physiological conditions. Interestingly, intercalated hydrogels of HA and fibril collagen showed an agnostic effect to cell migration as HA concentration increased. This raises the curious question; with glioblastoma being so highly migratory, how does a protein that is upregulated in the tumor microenvironment inhibit migration in vitro? To answer this question, new tools are needed. Through gel digestion and western blot analysis, protein quantification can be achieved. However, observing the spatial distribution of these proteins via immunofluorescence in hydrogel constructs can be difficult because of their high refractive properties. Typical methods use cryosectioning techniques to create thin hydrogel sections for staining. Unfortunately, this method creates disruption within the collagen matrix, limiting its use in understanding cell-ECM interactions. Utilizing histological processing techniques for tissues, we developed new processing methods to attenuate these artifacts, preserving the collagen matrix and permitting assessment of cell-ECM interactions. 

Ultimately developing novel assays that allow for the incorporation of multiple cues, while creating a physiologically relevant microenvironment, is crucial in further understanding cell migration in vivo. In this dissertation, we have sought to develop such models to elucidate the underlying mechanisms of brain tumor cell migration. In addition, these models may ultimately have broader applications for other cancers and within tissue engineering and regenerative medicine.