Browsing by Author "Goergen, Craig J."
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Item Activation of the Hedgehog signaling pathway leads to fibrosis in aortic valves(BMC, 2023-03-02) Gu, Dongsheng; Soepriatna, Arvin H.; Zhang, Wenjun; Li, Jun; Zhao, Jenny; Zhang, Xiaoli; Shu, Xianhong; Wang, Yongshi; Landis, Benjamin J.; Goergen, Craig J.; Xie, Jingwu; Pediatrics, School of MedicineBackground: Fibrosis is a pathological wound healing process characterized by excessive extracellular matrix deposition, which interferes with normal organ function and contributes to ~ 45% of human mortality. Fibrosis develops in response to chronic injury in nearly all organs, but the a cascade of events leading to fibrosis remains unclear. While hedgehog (Hh) signaling activation has been associated with fibrosis in the lung, kidney, and skin, it is unknown whether hedgehog signaling activation is the cause or the consequence of fibrosis. We hypothesize that activation of hedgehog signaling is sufficient to drive fibrosis in mouse models. Results: In this study, we provide direct evidence to show that activation of Hh signaling via expression of activated smoothened, SmoM2, is sufficient to induce fibrosis in the vasculature and aortic valves. We showed that activated SmoM2 -induced fibrosis is associated with abnormal function of aortic valves and heart. The relevance of this mouse model to human health is reflected in our findings that elevated GLI expression is detected in 6 out of 11 aortic valves from patients with fibrotic aortic valves. Conclusions: Our data show that activating hedgehog signaling is sufficient to drive fibrosis in mice, and this mouse model is relevant to human aortic valve stenosis.Item Assessing breast tumor margin by multispectral photoacoustic tomography(Optical Society of America, 2015-03-12) Li, Rui; Wang, Pu; Lan, Lu; Lloyd Jr., Frank P.; Goergen, Craig J.; Chen, Shaoxiong; Cheng, Ji-Xin; Department of Pathology and Laboratory Medicine, IU School of MedicineAn unmet need exists in high-speed and highly-sensitive intraoperative assessment of breast cancer margin during conservation surgical procedures. Here, we demonstrate a multispectral photoacoustic tomography system for breast tumor margin assessment using fat and hemoglobin as contrasts. This system provides ~3 mm tissue depth and ~125 μm axial resolution. The results agreed with the histological findings. A high sensitivity in margin assessment was accomplished, which opens a compelling way to intraoperative margin assessment.Item Bond-selective photoacoustic imaging by converting molecular vibration into acoustic waves(Elsevier, 2016-03) Hui, Jie; Li, Rui; Phillips, Evan H.; Goergen, Craig J.; Sturek, Michael; Cheng, Ji-Xin; Department of Cellular & Integrative Physiology, IU School of MedicineThe quantized vibration of chemical bonds provides a way of detecting specific molecules in a complex tissue environment. Unlike pure optical methods, for which imaging depth is limited to a few hundred micrometers by significant optical scattering, photoacoustic detection of vibrational absorption breaks through the optical diffusion limit by taking advantage of diffused photons and weak acoustic scattering. Key features of this method include both high scalability of imaging depth from a few millimeters to a few centimeters and chemical bond selectivity as a novel contrast mechanism for photoacoustic imaging. Its biomedical applications spans detection of white matter loss and regeneration, assessment of breast tumor margins, and diagnosis of vulnerable atherosclerotic plaques. This review provides an overview of the recent advances made in vibration-based photoacoustic imaging and various biomedical applications enabled by this new technology.Item Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction(MDPI, 2017-03-29) Wodicka, James R.; Chambers, Andrea M.; Sangha, Gurneet S.; Goergen, Craig J.; Panitch, Alyssa; Medicine, School of MedicineEndothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.Item Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy(The Company of Biologists, 2024) Earl, Conner C.; Javier, Areli J.; Richards, Alyssa M.; Markham, Larry W.; Goergen, Craig J.; Welc, Steven S.; Medicine, School of MedicineCardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD); however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. mdx and wild-type mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathological assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes and diminished cardiac reserve in mdx compared to wild-type mice. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.Item Functional cardiac consequences of β-adrenergic stress-induced injury in the mdx mouse model of Duchenne muscular dystrophy(bioRxiv, 2024-04-20) Earl, Conner C.; Javier, Areli J.; Richards, Alyssa M.; Markham, Larry W.; Goergen, Craig J.; Welc, Steven S.; Anatomy, Cell Biology and Physiology, School of MedicineCardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to enhance the cardiac phenotype in the mdx model, many methods lead to high mortality, variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. For our study, mdx and wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of low-dose isoproterenol in mdx mice as a valuable model for exploring therapies targeting DMD-associated cardiac complications.Item Murine Ultrasound-Guided Transabdominal Para-Aortic Injections of Self-Assembling Type I Collagen Oligomers(Elsevier, 2017-03-10) Yrineo, Alexa A.; Adelsperger, Amelia R.; Durkes, Abigail C.; Distasi, Matthew R.; Voytik-Harbin, Sherry L.; Murphy, Michael P.; Goergen, Craig J.; Surgery, School of MedicineAbdominal aortic aneurysms (AAAs) represent a potentially life-threatening condition that predominantly affects the infrarenal aorta. Several preclinical murine models that mimic the human condition have been developed and are now widely used to investigate AAA pathogenesis. Cell- or pharmaceutical-based therapeutics designed to prevent AAA expansion are currently being evaluated with these animal models, but more minimally invasive strategies for delivery could improve their clinical translation. The purpose of this study was to investigate the use of self-assembling type I collagen oligomers as an injectable therapeutic delivery vehicle in mice. Here we show the success and reliability of a para-aortic, ultrasound-guided technique for injecting quickly-polymerizing collagen oligomer solutions into mice to form a collagen-fibril matrix at body temperature. A commonly used infrarenal mouse AAA model was used to determine the target location of these collagen injections. Ultrasound-guided, closed-abdominal injections supported consistent delivery of collagen to the area surrounding the infrarenal abdominal aorta halfway between the right renal artery and aortic trifurcation into the iliac and tail arteries. This minimally invasive approach yielded outcomes similar to open-abdominal injections into the same region. Histological analysis on tissue removed on day 14 post-operatively showed minimal in vivo degradation of the self-assembled fibrillar collagen and the majority of implants experienced minimal inflammation and cell invasion, further confirming this material's potential as a method for delivering therapeutics. Finally, we showed that the typical length and position of this infrarenal AAA model was statistically similar to the length and targeted location of the injected collagen, increasing its feasibility as a localized therapeutic delivery vehicle. Future preclinical and clinical studies are needed to determine if specific therapeutics incorporated into the self-assembling type I collagen matrix described here can be delivered near the aorta and locally limit AAA expansion.,Item Myocardial strain imaging in Duchenne muscular dystrophy(Frontiers Media, 2022-11-23) Earl, Conner C.; Soslow, Jonathan H.; Markham, Larry W.; Goergen, Craig J.; Pediatrics, School of MedicineCardiomyopathy (CM) is the leading cause of death for individuals with Duchenne muscular dystrophy (DMD). While DMD CM progresses rapidly and fatally for some in teenage years, others can live relatively symptom-free into their thirties or forties. Because CM progression is variable, there is a critical need for biomarkers to detect early onset and rapid progression. Despite recent advances in imaging and analysis, there are still no reliable methods to detect the onset or progression rate of DMD CM. Cardiac strain imaging is a promising technique that has proven valuable in DMD CM assessment, though much more work has been done in adult CM patients. In this review, we address the role of strain imaging in DMD, the mechanical and functional parameters used for clinical assessment, and discuss the gaps where emerging imaging techniques could help better characterize CM progression in DMD. Prominent among these emerging techniques are strain assessment from 3D imaging and development of deep learning algorithms for automated strain assessment. Improved techniques in tracking the progression of CM may help to bridge a crucial gap in optimizing clinical treatment for this devastating disease and pave the way for future research and innovation through the definition of robust imaging biomarkers and clinical trial endpoints.Item Quantification of murine myocardial infarct size using 2-D and 4-D high-frequency ultrasound(American Physiological Society, 2022) Dann, Melissa M.; Clark, Sydney Q.; Trzaskalski, Natasha A.; Earl, Conner C.; Schepers, Luke E.; Pulente, Selena M.; Lennord, Ebonee N.; Annamalai, Karthik; Gruber, Joseph M.; Cox, Abigail D.; Lorenzen-Schmidt, Ilka; Seymour, Richard; Kim, Kyoung-Han; Goergen, Craig J.; Mulvihill, Erin E.; Medicine, School of MedicineIschemic heart disease is the leading cause of death in the United States, Canada, and worldwide. Severe disease is characterized by coronary artery occlusion, loss of blood flow to the myocardium, and necrosis of tissue, with subsequent remodeling of the heart wall, including fibrotic scarring. The current study aims to demonstrate the efficacy of quantitating infarct size via two-dimensional (2-D) echocardiographic akinetic length and four-dimensional (4-D) echocardiographic infarct volume and surface area as in vivo analysis techniques. We further describe and evaluate a new surface area strain analysis technique for estimating myocardial infarction (MI) size after ischemic injury. Experimental MI was induced in mice via left coronary artery ligation. Ejection fraction and infarct size were measured through 2-D and 4-D echocardiography. Infarct size established via histology was compared with ultrasound-based metrics via linear regression analysis. Two-dimensional echocardiographic akinetic length (r = 0.76, P = 0.03), 4-D echocardiographic infarct volume (r = 0.85, P = 0.008), and surface area (r = 0.90, P = 0.002) correlate well with histology. Although both 2-D and 4-D echocardiography were reliable measurement techniques to assess infarct, 4-D analysis is superior in assessing asymmetry of the left ventricle and the infarct. Strain analysis performed on 4-D data also provides additional infarct sizing techniques, which correlate with histology (surface strain: r = 0.94, P < 0.001, transmural thickness: r = 0.76, P = 0.001). Two-dimensional echocardiographic akinetic length, 4-D echocardiography ultrasound, and strain provide effective in vivo methods for measuring fibrotic scarring after MI. NEW & NOTEWORTHY: Our study supports that both 2-D and 4-D echocardiographic analysis techniques are reliable in quantifying infarct size though 4-D ultrasound provides a more holistic image of LV function and structure, especially after myocardial infarction. Furthermore, 4-D strain analysis correctly identifies infarct size and regional LV dysfunction after MI. Therefore, these techniques can improve functional insight into the impact of pharmacological interventions on the pathophysiology of cardiac disease.Item Regenerative tissue filler for breast conserving surgery and other soft tissue restoration and reconstruction needs(Springer Nature, 2021-02-01) Puls, Theodore J.; Fisher, Carla S.; Cox, Abigail; Plantenga, Jeannie M.; McBride, Emma L.; Anderson, Jennifer L.; Goergen, Craig J.; Bible, Melissa; Moller, Tracy; Voytik‑Harbin, Sherry L.; Surgery, School of MedicineComplete removal of cancerous tissue and preservation of breast cosmesis with a single breast conserving surgery (BCS) is essential for surgeons. New and better options would allow them to more consistently achieve this goal and expand the number of women that receive this preferred therapy, while minimizing the need for re-excision and revision procedures or more aggressive surgical approaches (i.e., mastectomy). We have developed and evaluated a regenerative tissue filler that is applied as a liquid to defects during BCS prior to transitioning to a fibrillar collagen scaffold with soft tissue consistency. Using a porcine simulated BCS model, the collagen filler was shown to induce a regenerative healing response, characterized by rapid cellularization, vascularization, and progressive breast tissue neogenesis, including adipose tissue and mammary glands and ducts. Unlike conventional biomaterials, no foreign body response or inflammatory-mediated “active” biodegradation was observed. The collagen filler also did not compromise simulated surgical re-excision, radiography, or ultrasonography procedures, features that are important for clinical translation. When post-BCS radiation was applied, the collagen filler and its associated tissue response were largely similar to non-irradiated conditions; however, as expected, healing was modestly slower. This in situ scaffold-forming collagen is easy to apply, conforms to patient-specific defects, and regenerates complex soft tissues in the absence of inflammation. It has significant translational potential as the first regenerative tissue filler for BCS as well as other soft tissue restoration and reconstruction needs.