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Item Biomechanics and Biomaterials Research Center(Office of the Vice Chancellor for Research, 2013-04-05) Yokota, Hiroki; Xie, DongThe Biomechanics and Biomaterials Research Center (BBRC) was founded in 1991 and reactivated in the current form in 2012. Through a collaborative effort from School of Engineering and Technology, School of Dentistry, School of Medicine, School of Science, and School of Health and Rehabilitation Sciences, the Center is to strengthen a national presence in the emerging areas of Mechanobiology, Tissue Engineering, and Biomaterials. The main aim of BBRC is to enhance our competitiveness for research grants by fostering new research collaborations among established investigators as well as new investigators. In particular, we coordinate efforts to obtain multi-PI research grants from federal agencies including NIH, NSF, NASA, and DOD, as well as center grants, and training programs. Funds at BBRC are used to seed pilot projects, support students, provide shared equipment, and invite seminar speakers for developing multidisciplinary and multi-school research programs. The following pilot projects were funded (95K in total) in 2013. • Development of NIAMS P30 • Development of novel oral stable dental resin composite • FRET-based analysis of mechanotransduction of joint cells • Stat3 and mitochondrial activity in mechanotransduction • Synthetic niche for in vitro culture of pancreatic cancer cells • Mechanical stimulation, fracture resistance and fracture healing in bone • Integration of spatial and temporal respiratory motion in adaptive proton therapy deliveryItem Decreased SIRT1 Activity Is Involved in the Acute Injury Response of Chondrocytes to Ex Vivo Injurious Mechanical Overload(MDPI, 2023-03-30) Karnik, Sonali; Noori-Dokht, Hessam; Williams, Taylor; Joukar, Amin; Trippel, Stephen B.; Sankar, Uma; Wagner, Diane R; Mechanical and Energy Engineering, School of Engineering and TechnologyA better understanding of molecular events following cartilage injury is required to develop treatments that prevent or delay the onset of trauma-induced osteoarthritis. In this study, alterations to SIRT1 activity in bovine articular cartilage explants were evaluated in the 24 h following a mechanical overload, and the effect of pharmacological SIRT1 activator SRT1720 on acute chondrocyte injury was assessed. SIRT1 enzymatic activity decreased as early as 5 min following the mechanical overload, and remained suppressed for at least 24 h. The chondrocyte injury response, including apoptosis, oxidative stress, secretion of inflammatory mediators, and alterations in cartilage matrix expression, was prevented with pharmacological activation of SIRT1 in a dose-dependent manner. Overall, the results implicate SIRT1 deactivation as a key molecular event in chondrocyte injury following a mechanical impact overload. As decreased SIRT1 signaling is associated with advanced age, these findings suggest that downregulated SIRT1 activity may be common to both age-related and injury-induced osteoarthritis.Item Design and biofabrication of dermal regeneration scaffolds: role of oligomeric collagen fibril density and architecture(Future Science Group, 2020-02) Sohutskay, David O.; Buno, Kevin P.; Tholpady, Sunil S.; Nier, Samantha J.; Voytik-Harbin, Sherry L.; Surgery, School of MedicineAim: To evaluate dermal regeneration scaffolds custom-fabricated from fibril-forming oligomeric collagen where the total content and spatial gradient of collagen fibrils was specified. Materials & methods: Microstructural and mechanical features were verified by electron microscopy and tensile testing. The ability of dermal scaffolds to induce regeneration of rat full-thickness skin wounds was determined and compared with no fill control, autograft skin and a commercial collagen dressing. Results: Increasing fibril content of oligomer scaffolds inhibited wound contraction and decreased myofibroblast marker expression. Cellular and vascular infiltration of scaffolds over the 14-day period varied with the graded density and orientation of fibrils. Conclusion: Fibril content, spatial gradient and orientation are important collagen scaffold design considerations for promoting vascularization and dermal regeneration while reducing wound contraction.Item In Vitro Multitissue Interface Model Supports Rapid Vasculogenesis and Mechanistic Study of Vascularization across Tissue Compartments(ACS Publications, 2016-08-31) Bruno, Kevin P.; Chen, Xuemei; Weibel, Justin A.; Thiede, Stephanie N.; Garimella, Suresh V.; Yoder, Mervin C.; Voytik-Harbin, Sherry L.; Department of Pediatrics, IU School of MedicineA significant challenge facing tissue engineers is the design and development of complex multitissue systems, including vascularized tissue-tissue interfaces. While conventional in vitro models focus on either vasculogenesis (de novo formation of blood vessels) or angiogenesis (vessels sprouting from existing vessels or endothelial monolayers), successful therapeutic vascularization strategies will likely rely on coordinated integration of both processes. To address this challenge, we developed a novel in vitro multitissue interface model in which human endothelial colony forming cell (ECFC)-encapsulated tissue spheres are embedded within a surrounding tissue microenvironment. This highly reproducible approach exploits biphilic surfaces (nanostructured surfaces with distinct superhydrophobic and hydrophilic regions) to (i) support tissue compartments with user-specified matrix composition and physical properties as well as cell type and density and (ii) introduce boundary conditions that prevent the cell-mediated tissue contraction routinely observed with conventional three-dimensional monodispersion cultures. This multitissue interface model was applied to test the hypothesis that independent control of cell-extracellular matrix (ECM) and cell-cell interactions would affect vascularization within the tissue sphere as well as across the tissue-tissue interface. We found that high-cell-density tissue spheres containing 5 × 10(6) ECFCs/mL exhibit rapid and robust vasculogenesis, forming highly interconnected, stable (as indicated by type IV collagen deposition) vessel networks within only 3 days. Addition of adipose-derived stromal cells (ASCs) in the surrounding tissue further enhanced vasculogenesis within the sphere as well as angiogenic vessel elongation across the tissue-tissue boundary, with both effects being dependent on the ASC density. Overall, results show that the ECFC density and ECFC-ASC crosstalk, in terms of paracrine and mechanophysical signaling, are critical determinants of vascularization within a given tissue compartment and across tissue interfaces. This new in vitro multitissue interface model and the associated mechanistic insights it yields provide guiding principles for the design and optimization of multitissue vascularization strategies for research and clinical applications.Item Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates(The Company of Biologists, 2018-09-25) Klymenko, Yuliya; Wates, Rebecca B.; Weiss-Bilka, Holly; Lombard, Rachel; Liu, Yueying; Campbell, Leigh; Kim, Oleg; Wagner, Diane; Ravosa, Matthew J.; Stack, M. Sharon; Mechanical and Energy Engineering, School of Engineering and TechnologyEpithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. EOC dissemination is predominantly via direct extension of cells and multicellular aggregates (MCAs) into the peritoneal cavity, which adhere to and induce retraction of peritoneal mesothelium and proliferate in the submesothelial matrix to generate metastatic lesions. Metastasis is facilitated by the accumulation of malignant ascites (500 ml to >2 l), resulting in physical discomfort and abdominal distension, and leading to poor prognosis. Although intraperitoneal fluid pressure is normally subatmospheric, an average intraperitoneal pressure of 30 cmH2O (22.1 mmHg) has been reported in women with EOC. In this study, to enable experimental evaluation of the impact of high intraperitoneal pressure on EOC progression, two new in vitro model systems were developed. Initial experiments evaluated EOC MCAs in pressure vessels connected to an Instron to apply short-term compressive force. A Flexcell Compression Plus system was then used to enable longer-term compression of MCAs in custom-designed hydrogel carriers. Results show changes in the expression of genes related to epithelial-mesenchymal transition as well as altered dispersal of compressed MCAs on collagen gels. These new model systems have utility for future analyses of compression-induced mechanotransduction and the resulting impact on cellular responses related to intraperitoneal metastatic dissemination.This article has an associated First Person interview with the first authors of the paper.Item Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy(American Heart Association, 2022) Riaz, Muhammad; Park, Jinkyu; Sewanan, Lorenzo R.; Ren, Yongming; Schwan, Jonas; Das, Subhash K.; Pomianowski, Pawel T.; Huang, Yan; Ellis, Matthew W.; Luo, Jiesi; Liu, Juli; Song, Loujin; Chen, I-Ping; Qiu, Caihong; Yazawa, Masayuki; Tellides, George; Hwa, John; Young, Lawrence H.; Yang, Lei; Marboe, Charles C.; Jacoby, Daniel L.; Campbell, Stuart G.; Qyang, Yibing; Pediatrics, School of MedicineBackground: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.Item The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health(Elsevier, 2021-11-22) Priddy, Carlie; Li, Jiliang; Biology, School of ScienceIn conjunction with advancements in modern medicine, bone health is becoming an increasingly prevalent concern among a global population with an ever-growing life expectancy. Countless factors contribute to declining bone strength, and age exacerbates nearly all of them. The detrimental effects of bone loss have a profound impact on quality of life. As such, there is a great need for full exploration of potential therapeutic targets that may provide antiaging benefits and increase the life and strength of bone tissues. The Keap1-Nrf2 pathway is a promising avenue of this research. The cytoprotective and antioxidant functions of this pathway have been shown to mitigate the deleterious effects of oxidative stress on bone tissues, but the exact cellular and molecular mechanisms by which this occurs are not yet fully understood. Presently, refined animal and loading models are allowing exploration into the effect of the Keap1-Nrf2 pathway in a tissue-specific or even cell-specific manner. In addition, Nrf2 activators currently undergoing clinical trials can be utilized to investigate the particular cellular mechanisms at work in this cytoprotective cascade. Although the timing and dosing of treatment with Nrf2 activators need to be further investigated, these activators have great potential to be used clinically to prevent and treat osteoporosis.Item The Role of Wnt Signaling in Bone Mechanotransduction(2019-11) Bullock, Whitney Ann; Robling, Alexander; Bidwell, Joseph; Plotkin, Lilian; Sankar, Uma; White, KennethThe aging US population is experiencing a growing incidence of osteoporosis, characterized by increased fracture risk and low bone mass. In skeletal tissue, canonical Wnt signaling is a critical regulator of bone mass, and dysregulation of the Wnt pathway has been implicated in numerous skeletal displasias. Some components of the Wnt signaling pathway have a clear role in bone homeostasis, particularly in the response of bone to altered mechanical environment. Other pathway components are more poorly defined. One important intracellular signal transduction node in the Wnt cascade is β- catenin, which modulates gene expression and cell-cell junctions, among other functions. During periods of disuse, β-catenin is degraded, leading to inhibition of Wnt targets. Here, I characterize the role of β-catenin in bone during a disuse challenge, using a genetic mouse model expressing an inducible constitively-active mutant form of β- catenin in the osteocyte population. I hypothesize that prevention of β-catenin degradation during disuse will prevent the bone wasting effects of mechanodeprivation. As a second goal, I focus on upstream (membrane-bound) modulation of Wnt. Here, I investigate the low-density lipoprotein receptor-related receptor 4 (Lrp4), in the regulation of bone mass and mechanotransduction. I generated an Lrp4 knockin mouse model harboring a missense mutation found among human patients with abnormally high bone mass. I hypothesize that the mutation compromises sclerostin action on bone cells. Understanding how each of these components of the Wnt signaling pathway interact, may lead to novel therapeutic targets for treatment of bone diseases.Item Sizing it up: The mechanical feedback hypothesis of organ growth regulation(Elsevier, 2014) Buchmann, Amy; Alber, Mark; Zartman, Jeremiah J.; Medicine, School of MedicineThe question of how the physical dimensions of animal organs are specified has long fascinated both experimentalists and computational scientists working in the field of developmental biology. Research over the last few decades has identified many of the genes and signaling pathways involved in organizing the emergent multi-scale features of growth and homeostasis. However, an integrated model of organ growth regulation is still unrealized due to the numerous feedback control loops found within and between intercellular signaling pathways as well as a lack of understanding of the exact role of mechanotransduction. Here, we review several computational and experimental studies that have investigated the mechanical feedback hypothesis of organ growth control, which postulates that mechanical forces are important for regulating the termination of growth and hence the final physical dimensions of organs. In particular, we highlight selected computational studies that have focused on the regulation of growth of the Drosophila wing imaginal disc. In many ways, these computational and theoretical approaches continue to guide experimental inquiry. We demonstrate using several examples how future progress in dissecting the crosstalk between the genetic and biophysical mechanisms controlling organ growth might depend on the close coupling between computational and experimental approaches, as well as comparison of growth control mechanisms in other systems.