Browsing by Author "Easley, Jeremiah, committee member"

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Open Access
An evaluation of estrus suppression in the mare through the use of an altrenogest delivering intravaginal device
(Colorado State University. Libraries, 2022) Lederman, Jessica Danielle Ruth, author; Hatzel, Jennifer, advisor; Easley, Jeremiah, committee member; Hollinshead, Fiona, committee member; Bouma, Jerry, committee member
The ability to avoid adverse behavior in mares through manipulation of their reproductive cyclicity has been a desired technique for many years. The mare's sour reputation when in heat, is known by competitive professionals and hobby riders alike. As the breeding season approaches during long daylight days in the northern hemisphere, the mare will begin to transition into her regular twenty-one day interovulatory cycle. The estrus or "standing heat" phase of a mare's cycle occurs for approximately 5-7 days within a given estrous cycle. During this phase, the mare is primarily under the influence of estrogen, produced by the dominant follicle, driving signs of the sexual receptivity. Outward signs of estrus for the mare include: overt interest in other horses (especially stallions), leaning their hind end toward another horse (teasing), lifting their tail, posturing and urinating frequently. Dangerous behaviors associated with estrus such as biting, kicking, irritability, and distraction commonly persuade owners to look into estrus suppression options. Following ovulation, a corpus luteum (CL) is formed and the luteal cells begin to produce progesterone. Progesterone levels increase once again, overcoming the effects of decreasing estrogen levels for twelve to fourteen days, and often alleviating the undesirable behavior. Altrenogest, an oral and injectable synthetic progestin, is the most effective supplement for providing estrus suppression in the mare. The equine industry is in need of a reliable pharmaceutical device to suppress adverse behavior commonly associated with the estrus phase of the mare's cycle, yet allow the mare to resume normal cyclicity upon removal of the device for pursuant of reproductive procedures. A custom intravaginal ring specifically designed for the unique anatomy of the mare will provide a novel and effective method for sustained release of altrenogest administration while being safer to handle and administer. The first experiment focuses on the unique anatomy of the mare's caudal reproductive tract compared to intravaginal ring sizes in order to obtain a pilot device for experimentation. An unmedicated toroidal silicone intravaginal ring measuring 14.2 cm in diameter was selected during experiment one. The second experiment was to evaluate the vaginal ring delivering altrenogest in a trial along with a placebo intravaginal ring and control group to evaluate several parameters associated with estrus behavior suppression. Both oil-based and solid suspension-based intravaginal rings for drug administration was evaluated during experiment two. Finally, the third experiment examined the in vivo evaluation of solid suspension altrenogest IVR as well as the marketability of this product and what the future holds for novel medical devices in equine reproduction. Twelve total mares were used over the course of this study to determine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of intravaginally administered altrenogest. Variables such as: teasing behavior when presented with a stallion, ultrasonographic examination of reproductive changes throughout several cycles, uterine and vaginal cultures, and blood collections for drug hormone bioanalysis were collected and monitored to evaluate the PK and PD of this novel drug delivery device. Throughout experiment three, each mare went through three cycles in a crossover design. An oral form of the drug was administered to serve as a control group, a placebo vaginal ring control group, and therapeutic vaginal ring treatment group were used for this study. This study aims to provide horse owners and trainers an alternative method for delivering behavior modulating hormones, through an effective, therapeutic, steady-state release from a vaginal ring, and importantly enable normal reproductive cyclicity to resume upon removal.
Open Access
Determing the efficacy of Poloxamer 188 (P188) in meniscal damage prevention
(Colorado State University. Libraries, 2016) Remley, Katherine, author; Donahue, Tammy, advisor; James, Sue, committee member; Easley, Jeremiah, committee member
Meniscal injuries compose 15% of all knee injuries, most often sports-related. Due to the meniscus's avascular nature, healing is difficult and injury often results in a partial meniscectomy. Research has shown meniscectomies drastically decrease contact area between the femur and tibia and increase strains experienced by the meniscus. This additional strain predisposes the knee to developing post-traumatic osteoarthritis. Poloxamer 188 (P188) is a non-ionic, amphillic surfactant that may have the ability to prevent cell death through selective insertion into the cell membrane. This in turn may prevent damaged cell signaling and reduce overall tissue degradation. While P188 has been studied and shown promise in mitigating cell death in cartilage, the effects of P188 on the meniscus are unknown. To investigate the effects of P188 on the meniscus, the goals of this project were to: 1) create a user friendly graphical user interface for a custom bioreactor capable of displacement control for precise loading of meniscal explants to physiological and supraphysiological strains; 2) determine the efficacy of P188 in mitigating meniscal tissue damage through cell viability, mechanical data and histological analysis.
Open Access
Development of a finite element model of supracondylar fractures stabilized with variable stiffness bone plates
(Colorado State University. Libraries, 2019) Sutherland, Conor J., author; Puttlitz, Christian M., advisor; McGilvray, Kirk, advisor; Easley, Jeremiah, committee member; James, Susan, committee member
Approximately 10% of orthopaedic fracture fixation cases lead to non-union, requiring surgical intervention. Inadequate fixation device stiffness, which causes unwanted fracture gap motion, is believed to be one of the largest factor in poor healing as it prevents ideal tissue proliferation in the callus. By altering the thickness of orthopaedic bone plates, it was theorized that the fracture gap micro-mechanics could be controlled and driven towards conditions that accommodate good healing. The first goal of the project was to create computational FEA models of an ovine femoral supracondylar fracture stabilized with a plate of varying thickness. The models were used to investigate the mechanical behavior of the plate and the callus under different physiological loading conditions. The second goal of this study was to validate the computational model with bench-top experiments using an ex-vivo ovine femoral fracture model. To achieve these goals, novel plates were designed and manufactured with different stiffnesses (100%, 85%, and 66% relative stiffness) to be used to treat a femoral supracondylar fracture model in ovine test subjects; both in-vivo and ex-vivo. The FE models were shown to accurately predict the stress/strain mechanics on both bone and plate surfaces. Micromechanics (strain and pressure) predictions in the fracture gap were reported and used to make tissue type proliferation predictions based on previously reported mechanics envelopes corresponding to bone remodeling. The results indicated that changing plate thickness successfully altered the construct stiffness and consequently, the predicted healing tissue type at the fracture site. The FE methods described could help improve patient specific fracture care and reduce non-union rates clinically. However, further in vivo testing is required to validate the clinical significance of the methods described in this thesis.
Open Access
Development of a hierarchical electrospun scaffold for ligament replacement
(Colorado State University. Libraries, 2018) Pauly, Hannah Marie, author; Haut Donahue, Tammy L., advisor; Easley, Jeremiah, committee member; Kelly, Daniel J., committee member; Palmer, Ross, committee member; Popat, Ketul C., committee member
The anterior cruciate ligament (ACL) is a dense collagenous structure that connects the femur to the tibia and is vital for joint stability. The ACL possesses complex time-dependent viscoelastic properties and functions primarily to prevent excessive translations and rotations of the tibia relative to the femur. It is estimated that 400,000 ACL tears occur in the United States annually and the monetary burden of these injuries and their subsequent treatment is approximately $1 billion annually. After injury allografts and autografts are commonly implanted to reconstruct the torn ACL in an attempt to restore joint stability, prevent pain, and limit damage to surrounding tissues. However surgical reconstructions fail to completely restore knee functionality or prevent additional injury and regardless of intervention technique radiographic osteoarthritis is present in 13% of patients 10 years after ACL rupture. Drawbacks to traditional treatments for ACL ruptures motivate the development of a synthetic ACL replacement. Tissue engineering is the use of a scaffold, cells, and signaling molecules to create a replacement for damaged tissue. The goal of this work is to develop a polymer scaffold that can be utilized as a replacement for the ACL. A tissue engineered ACL replacement should replicate the hierarchical structure of the native ACL, possess reasonable time zero mechanical properties, and promote the deposition of de novo collagenous tissue in vitro. Additionally, the scaffold should be implantable using standard surgical techniques and should maintain in situ tibiofemoral contact mechanics. Thus, four specific aims are proposed: 1) Fabricated and characterize an aligned 3-dimensional electrospun scaffold for ACL replacement. 2) Assess the in vitro behavior of ovine bone marrow-derived stems cells seeded on the scaffold in the presence of conjugated growth factor. 3) Evaluate the performance of the electrospun scaffold using uniaxial mechanical testing. 4) Assess the effect of the electrospun scaffold on ovine stifle joint contact mechanics. Development of a tissue engineered ACL replacement that mimics the structure and function of the native ACL would provide a novel treatment to improve outcomes of ACL injuries.
Open Access
Development of a novel block copolymer hydrogel for meniscal replacement
(Colorado State University. Libraries, 2018) Fischenich, Kristine Marie, author; Haut Donahue, Tammy, advisor; Bailey, Travis, advisor; Easley, Jeremiah, committee member; Palmer, Ross, committee member; Goodrich, Laurie, committee member
Menisci are C-shaped fibrocartilaginous tissues responsible for distributing tibial-femoral contact pressure and are crucial for maintaining healthy joints and preventing osteoarthritis. Meniscal damage can be caused by age-related degradation, obesity, overuse from athletic activities, and trauma. Due to their primarily avascular nature, once damaged there is limited healing capacity and surgical intervention is often required. Limited technologies exist to replace damaged menisci, and standard treatment is to leave asymptomatic damage alone or perform partial meniscectomies, however, these treatment options lead to increased risk of OA. Attempts at tissue engineered meniscal scaffolds, and replacements have had mixed results due to design limitations and inability to recapitulate native tissue's material properties, shape, and pressure distribution. This project strives to create an artificial meniscus from a polystyrene-polyethylene oxide diblock copolymer. It is hypothesized that this hydrogel can be tuned to have material properties similar to those of the native meniscus. Furthermore, it is hypothesized this hydrogel can be molded into a 3D meniscal construct, implanted into the joint, and have similar pressure distribution properties as the native meniscus. Thus, the aims of this project are: 1) Mechanical comparison of a polystyrene-polyethylene oxide diblock copolymer TPE hydrogel to native meniscal tissue. 2) Develop a 3D meniscal construct which can be implanted into an ovine model and assess load distribution properties including contact area, mean pressure, and max pressure in both the medial and lateral hemijoints. If the goals of this project are met, there would exist a 3D TPE hydrogel construct that mimics the mechanical and functional properties of the native human meniscus. This meniscal replacement could provide a revolutionary addition to the field of osteoarthritis and meniscal injury.
Embargo
Immune-activated cellular therapies for osteoarthritis and the role of immune recognition of joint antigens
(Colorado State University. Libraries, 2024) Linde, Peter E., author; Dow, Steven, advisor; Pezzanite, Lynn, advisor; Regan, Dan, committee member; Easley, Jeremiah, committee member; McGilvray, Kirk, committee member
Osteoarthritis (OA) is a progressive, degenerative condition that affects over 550 million people worldwide – a 113% increase since 1990. Despite this high prevalence, there remains a lack of effective treatment options that improve quality of life without risk of adverse effects. Recent evidence supports that OA is a multifactorial condition in which the immune system plays a key role to perpetuate chronic inflammation. Cellular therapies to treat OA have emerged as an option, with mixed results reported in terms of efficacy. Heterogeneity within stromal cell populations has been proposed to be partially responsible for the observed variability in therapeutic responses, particularly in the context of variably inflamed recipient environments such as that seen in OA. Pre-activation, or 'inflammatory licensing' of mesenchymal stromal cells (MSC) through priming their respective ligands has been proposed as a means to generate a homogeneous population of immunomodulatory MSCs – thereby potentially improving their therapeutic consistency in the inflammatory environment of OA. The work in this defense addresses three primary aims: 1) to further investigation the role of the adaptive immune system in OA, investigating autoantibody production to synoviocytes and chondrocytes in OA progression, 2) to evaluate further mechanistically how innate immune pathway activation of mesenchymal stromal cell therapy modulates interactions of MSC with synovium and cartilage to mitigate OA progression, and 3) to examine alternate connective tissue sources of MSC for cell expansion as regenerative therapies. With the lifetime likelihood to develop symptomatic knee OA currently 45% and increasing, the need to develop improved strategies towards disease-modification is critical.
Open Access
Optimization of overhead enclosure monitoring software in a rodent model of osteoarthritis
(Colorado State University. Libraries, 2022) Helbling, Joel E., author; Santangelo, Kelly, advisor; Easley, Jeremiah, committee member; Kendall, Lonnie, committee member
Osteoarthritis (OA) is a degenerative joint disease characterized by pain, inflammation, and decreased range of motion, leading to impaired activities of daily living and reduced quality of life. OA affects between 250 and 500 million people worldwide, contributing to a substantial and sustained economic burden. Given the global pervasiveness of this poorly understood disease process, in vivo OA research relies on both naturally occurring and induced animal models for its study. The Dunkin Hartley guinea pig spontaneously develops degenerative joint disease as early as 3 months of age and represents a well-characterized animal model of primary OA with pathological progression similar to humans. In contrast, secondary OA is caused by non-idiopathic factors, including trauma, and animal models of secondary OA rely on chemical, surgical and non-surgical induction of instability. Open-field testing (OFT) is a behavioral tool which provides objective measurements of mobility outcomes for animals enrolled in musculoskeletal studies and can be paired with overhead monitoring software to non-invasively track voluntary animal movement through the designated arena. However, established protocols for OFT have not been published in the guinea pig. The overarching goal of this project was to optimize OFT in the guinea pig to reduce environmental variability in behavioral testing conditions. The results of this project provided a framework to ensure accurate and reproducible data collection in subsequent studies involving therapeutic interventions to both spontaneous OA and traumatic OA. A hallmark symptom of OA is pain and, as such, the second portion of this work was dedicated to researching cannabidiol (CBD) as an alternative interventional therapeutic to analgesia. Specifically, mobility outcomes assessments were performed during a pharmacokinetic safety study as well as a chronic oral CBD dosing study. Significant differences were analyzed both on baseline (pre-treatment) and on treatment intervention in each phase of this two-part study pertaining to OFT. The results of these studies identified time-of-day effects exist when testing guinea pigs in the open-field and provided preliminary evidence that no adverse short-term behavioral effects exist after oral administration of CBD. The final goal of this project was to design of bioreactor to establish a non-surgical animal model of post-traumatic osteoarthritis (PTOA) in the guinea pig through precision rupture of the anterior cruciate ligament (ACL) by tibial compression and displacement. While this model has been characterized in other rodents, it has not been described in guinea pigs. Work from this portion of the project helped produce a functional bioreactor which will be used initially on cadavers and will ultimately promote in vivo research of interventional treatments for PTOA by establishing reproducible ligament lesions with subsequent degenerative joint pathology.
Open Access
The path from injury to degeneration: multi-modal characterization of chronic rotator cuff degeneration
(Colorado State University. Libraries, 2021) Johnson, James W., author; McGilvray, Kirk C., advisor; Puttlitz, Christian, committee member; Ghosh, Soham, committee member; Easley, Jeremiah, committee member
Rotator cuff tendon tears are a prevalent issue worldwide; tears to these tendons can reduce arm mobility, cause pain, and decrease quality of life. Unfortunately, rotator cuff tendon tear repair surgeries experience unacceptable failures rates, with comorbidities such as age, chronic rotator cuff degeneration, or osteoporosis exacerbating these failures. The etiology of chronic degeneration is not fully understood, and there are no therapies or treatment capable of reversing or healing that condition. Furthermore, research is hindered due to the inability of current large animal translational models to faithfully recapitulate the wide range of changes noted in chronic degeneration. With that in mind, this work sought to improve the understanding of chronic rotator cuff degeneration through development of a clinically translatable large animal model and study of the injury and degeneration cascade. Specifically, this work has five components that will contribute to this body of knowledge. The first aim was to generate a model through transection of one half of the width of the tendon; unfortunately, this was found to result in differential changes on the two halves of the tendon that did not match the embodiment of changes seen clinically. The inadequacy and learnings from this model led to the generation of aims two and three. It has been hypothesized that chronic degeneration can result from untreated partial tears that are not diagnosed or treated with any conservative treatment. Aim 2 was focused on generating a chronic degeneration model through a clinically relevant bursal-side partial tear. Whereas Aim 3 was focused on creating a similar model without damaging the tendon insertion, providing the opportunity to screen therapies intended at halting or reversing the degeneration cascade. Aim 4 involved assessing tendons in an ovine model of osteoporosis for signs of degeneration as a means of determining the underlying cause for increased prevalence of rotator cuff repair failure in patients with osteoporosis. Aim 5 included characterization of the biomechanical, histological, and gene expression changes in cadaveric human rotator cuff tendons across a spectrum of ages as a means of better understanding the manifestation of chronic degeneration with the human rotator cuff. This aim was utilized as positive validation of the ovine models and as a means to generate design targets for repair scaffold mechanical properties. Aim 6 entailed generating a preliminary design of a scaffold capable of recapitulating the biomechanical properties of the healthy human supraspinatus tendons tested in Aim 5. Together, these proposed Aims provide new models of chronic rotator cuff degeneration, unique and novel data illuminating the multifactorial degeneration cascade in humans, and a prototype scaffold aimed at improving repair prognosis.