Department of Biomedical Engineering Works
Permanent URI for this collection
Browse
Recent Submissions
Item Gender Differences in Histamine-Induced Depolarization and Inward Currents in Vagal Ganglion Neurons in Rats(Ivyspring, 2013-11-20) Li, Jun-Nan; Qian, Zhao; Xu, Wen-Xiao; Xu, Bing; Lu, Xiao-Long; Yan, Zhen-Yu; Han, Li-Min; Liu, Yang; Yuan, Mei; Schild, John; Qiao, Guo-Fen; Li, Bai-Yan; Biomedical Engineering, Purdue School of Engineering and TechnologyEvidence has shown gender differences regarding the critical roles of histamine in the prevalence of asthma, anaphylaxis, and angina pectoris. Histamine depolarizes unmyelinated C-type neurons without any effects on myelinated A-type vagal ganglion neurons (VGNs) in male rats. However, little is known if VGNs from females react to histamine in a similar manner. Membrane depolarization and inward currents were tested in VGNs isolated from adult rats using a whole-cell patch technique. Results from males were consistent with the literature. Surprisingly, histamine-induced depolarization and inward currents were observed in both unmyelinated C-type and myelinated A- and Ah-type VGNs from female rats. In Ah-type neurons, responses to 1.0 μM histamine were stronger in intact females than in males and significantly reduced in ovariectomized (OVX) females. In C-type neurons, histamine-induced events were significantly smaller (pA/pF) in intact females compared with males and this histamine-induced activity was dramatically increased by OVX. Female A-types responded to histamine, which was further increased following ovariectomy. Histamine at 300 nM depolarized Ah-types in females, but not Ah-types in OVX females. In contrast, the sensitivity of A- and C-types to histamine was upregulated by OVX. These data demonstrate gender differences in VGN chemosensitivity to histamine for the first time. Myelinated Ah-types showed the highest sensitivity to histamine across female populations, which was changed by OVX. These novel findings improve the understanding of gender differences in the prevalence of asthma, anaphylaxis, and pain. Changes in sensitivity to histamine by OVX may explain alterations in the prevalence of certain pathophysiological conditions when women reach a postmenopausal age.Item Viscoelastic stiffening of gelatin hydrogels for dynamic culture of pancreatic cancer spheroids(Elsevier, 2024) Nguyen, Han; Lin, Chien-Chi; Biomedical Engineering, Purdue School of Engineering and TechnologyThe tumor microenvironment (TME) in pancreatic adenocarcinoma (PDAC) is a complex milieu of cellular and non-cellular components. Pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF) are two major cell types in PDAC TME, whereas the non-cellular components are enriched with extracellular matrices (ECM) that contribute to high stiffness and fast stress-relaxation. Previous studies have suggested that higher matrix rigidity promoted aggressive phenotypes of tumors, including PDAC. However, the effects of dynamic viscoelastic matrix properties on cancer cell fate remain largely unexplored. The focus of this work was to understand the effects of such dynamic matrix properties on PDAC cell behaviors, particularly in the context of PCC/CAF co-culture. To this end, we engineered gelatin-norbornene (GelNB) based hydrogels with a built-in mechanism for simultaneously increasing matrix elastic modulus and viscoelasticity. Two GelNB-based macromers, namely GelNB-hydroxyphenylacetic acid (GelNB-HPA) and GelNB-boronic acid (GelNB-BA), were modularly mixed and crosslinked with 4-arm poly(ethylene glycol)-thiol (PEG4SH) to form elastic hydrogels. Treating the hybrid hydrogels with tyrosinase not only increased the elastic moduli of the gels (due to HPA dimerization) but also concurrently produced 1,2-diols that formed reversible boronic acid-diol bonding with the BA groups on GelNB-BA. We employed patient-derived CAF and a PCC cell line COLO-357 to demonstrate the effect of increasing matrix stiffness and viscoelasticity on CAF and PCC cell fate. Our results indicated that in the stiffened environment, PCC underwent epithelial-mesenchymal transition. In the co-culture PCC and CAF spheroid, CAF enhanced PCC spreading and stimulated collagen 1 production. Through mRNA-sequencing, we further showed that stiffened matrices, regardless of the degree of stress-relaxation, heightened the malignant phenotype of PDAC cells. STATEMENT OF SIGNIFICANCE: The pancreatic cancer microenvironment is a complex milieu composed of various cell types and extracellular matrices. It has been suggested that stiffer matrices could promote aggressive behavior in pancreatic cancer, but the effect of dynamic stiffening and matrix stress-relaxation on cancer cell fate remains largely undefined. This study aimed to explore the impact of dynamic changes in matrix viscoelasticity on pancreatic ductal adenocarcinoma (PDAC) cell behavior by developing a hydrogel system capable of simultaneously increasing stiffness and stress-relaxation on demand. This is achieved by crosslinking two gelatin-based macromers through orthogonal thiol-norbornene photochemistry and post-gelation stiffening with mushroom tyrosinase. The results revealed that higher matrix stiffness, regardless of the degree of stress relaxation, exacerbated the malignant characteristics of PDAC cells.Item Numerical Simulation and Clinical Implications of Stenosis in Coronary Blood Flow(Hindawi, 2014) Zhang, Jun-Mei; Zhong, Liang; Luo, Tong; Huo, Yunlong; Tan, Swee Yaw; Wong, Aaron Sung Lung; Su, Boyang; Wan, Min; Zhao, Xiaodan; Kassab, Ghassan S.; Lee, Heow Pueh; Khoo, Boo Cheong; Kang, Chang-Wei; Ba, Te; Tan, Ru San; Biomedical Engineering, Purdue School of Engineering and TechnologyFractional flow reserve (FFR) is the gold standard to guide coronary interventions. However it can only be obtained via invasive angiography. The objective of this study is to propose a noninvasive method to determine FFRCT by combining computed tomography angiographic (CTA) images and computational fluid dynamics (CFD) technique. Utilizing the method, this study explored the effects of diameter stenosis (DS), stenosis length, and location on FFRCT. The baseline left anterior descending (LAD) model was reconstructed from CTA of a healthy porcine heart. A series of models were created by adding an idealized stenosis (with DS from 45% to 75%, stenosis length from 4 mm to 16 mm, and at 4 locations separately). Through numerical simulations, it was found that FFRCT decreased (from 0.89 to 0.74), when DS increased (from 45% to 75%). Similarly, FFRCT decreased with the increase of stenosis length and the stenosis located at proximal position had lower FFRCT than that at distal position. These findings are consistent with clinical observations. Applying the same method on two patients' CTA images yielded FFRCT close to the FFR values obtained via invasive angiography. The proposed noninvasive computation of FFRCT is promising for clinical diagnosis of CAD.Item Orthogonally crosslinked gelatin-norbornene hydrogels for biomedical applications(Wiley, 2024) Lin, Chien-Chi; Frahm, Ellen; Afolabi, Favor O.; Biomedical Engineering, Purdue School of Engineering and TechnologyThe thiol-norbornene photo-click reaction has exceptionally fast crosslinking efficiency compared with chain-growth polymerization at equivalent macromer contents. The orthogonal reactivity between norbornene and thiol/tetrazine permits crosslinking of synthetic and naturally derived macromolecules with modularity, including poly(ethylene glycol) (PEG)-norbornene (PEGNB), gelatin-norbornene (GelNB), among others. For example, collagen-derived gelatin contains both cell adhesive motifs (e.g., Arg-Gly-Asp or RGD) and protease-labile sequences, making it an ideal macromer for forming cell-laden hydrogels. First reported in 2014, GelNB is increasingly used in orthogonal crosslinking of biomimetic matrices in various applications. GelNB can be crosslinked into hydrogels using multi-functional thiol linkers (e.g., dithiothreitol (DTT) or PEG-tetra-thiol (PEG4SH) via visible light or longwave ultraviolet (UV) light step-growth thiol-norbornene reaction or through an enzyme-mediated crosslinking (i.e., horseradish peroxidase, HRP). GelNB-based hydrogels can also be modularly crosslinked with tetrazine-bearing macromers via inverse electron-demand Diels-Alder (iEDDA) click reaction. This review surveys the various methods for preparing GelNB macromers, the crosslinking mechanisms of GelNB-based hydrogels, and their applications in cell and tissue engineering, including crosslinking of dynamic matrices, disease modeling, and tissue regeneration, delivery of therapeutics, as well as bioprinting and biofabrication.Item Degradable and Multifunctional PEG-Based Hydrogels Formed by iEDDA Click Chemistry with Stable Click-Induced Supramolecular Interactions(American Chemical Society, 2024-02-16) Dimmitt, Nathan H.; Lin, Chien-Chi; Biomedical Engineering, Purdue School of Engineering and TechnologyThe inverse electron demand Diels-Alder (iEDDA) reactions are highly efficient click chemistry increasingly utilized in bioconjugation, live cell labeling, and the synthesis and modification of biomaterials. iEDDA click reactions have also been used to cross-link tetrazine (Tz) and norbornene (NB) modified macromers [e.g., multiarm poly(ethylene glycol) or PEG]. In these hydrogels, Tz-NB adducts exhibit stable supramolecular interactions with a high hydrolytic stability. Toward engineering a new class of PEG-based click hydrogels with highly adaptable properties, we previously reported a new group of NB-derivatized PEG macromers via reacting hydroxyl-terminated PEG with carbic anhydride (CA). In this work, we show that c cross-linked by PEGNBCA or its derivatives exhibited fast and tunable hydrolytic degradation. Here, we show that PEGNBCA (either mono- or octafunctional) and its dopamine or tyramine conjugated derivatives (i.e., PEGNB-D and PEGNB-T) readily cross-link with 4-arm PEG-Tz to form a novel class of multifunctional iEDDA click hydrogels. Through modularly adjusting the macromers with unstable and stable iEDDA click-induced supramolecular interactions (iEDDA-CSI), we achieved highly tunable degradation, with full degradation in less than 2 weeks to over two months. We also show that secondary enzymatic reactions could dynamically stiffen these hydrogels. These hydrogels could also be spatiotemporally photopatterned through visible light-initiated photochemistry. Finally, the iEDDA-CSI hydrogels post ester hydrolysis displayed shear-thinning and self-healing properties, enabling injectable delivery.Item Left atrial reservoir strain as a predictor of cardiac dysfunction in a murine model of pressure overload(Wiley, 2025) Salvas, John P.; Moore-Morris, Thomas; Goergen, Craig J.; Sicard, Pierre; Biomedical Engineering, Purdue School of Engineering and TechnologyAim: Left atrial (LA) strain is emerging as a valuable metric for evaluating cardiac function, particularly under pathological conditions such as pressure overload. This preclinical study investigates the predictive utility of LA strain on cardiac function in a murine model subjected to pressure overload, mimicking pathologies such as hypertension and aortic stenosis. Methods: High-resolution ultrasound was performed in a cohort of mice (n = 16) to evaluate left atrial and left ventricular function at baseline and 2 and 4 weeks after transverse aortic constriction (TAC). Acute adaptations in cardiac function were assessed in a subgroup of mice (n = 10) with 3 days post-TAC imaging. Results: We report an increase in LA max volume from 11.0 ± 4.3 μL at baseline to 26.7 ± 16.7 μL at 4 weeks (p = 0.002) and a decrease in LA reservoir strain from 20.8 ± 5.4% at baseline to 10.2 ± 6.9% at 4 weeks (p = 0.001). In the acute phase, LA strain dysfunction was present at 3 days (p < 0.001), prior to alterations in LA volume (p = 0.856) or left ventricular (LV) ejection fraction (p = 0.120). LA reservoir strain correlated with key indicators of cardiac performance including left ventricular (LV) ejection fraction (r = 0.541, p < 0.001), longitudinal strain (r = -0.637, p < 0.001), and strain rate (r = 0.378, p = 0.007). Furthermore, markers of atrial structure and function including LA max volume (AUC = 0.813, p = 0.003), ejection fraction (AUC = 0.853, p = 0.001), and strain (AUC = 0.884, p < 0.001) all predicted LV dysfunction. Conclusion: LA strain and function assessments provide a reliable, non-invasive method for the early detection and prediction of cardiac dysfunction in a model of pressure overload.Item Preparation and evaluation of a high-strength biocompatible glass-ionomer cement for improved dental restoratives(IOP, 2008) Xie, D.; Zhao, J.; Yang, Y.; Park, J.; Chu, T. M.; Zhang, J. T.; Biomedical Engineering, Purdue School of Engineering and TechnologyWe have developed a high-strength light-cured glass-ionomer cement (LCGIC). The polymer in the cement was composed of the 6-arm star-shape poly(acrylic acid) (PAA), which was synthesized using atom-transfer radical polymerization. The polymer was used to formulate with water and Fuji II LC filler to form LCGIC. Compressive strength (CS) was used as a screening tool for evaluation. Commercial glass-ionomer cement Fuji II LC was used as control. The results show that the 6-arm PAA polymer exhibited a lower viscosity in water as compared to its linear counterpart that was synthesized via conventional free-radical polymerization. This new LCGIC system was 48% in CS, 77% in diametral tensile strength, 95% in flexural strength and 59% in fracture toughness higher but 93.6% in shrinkage lower than Fuji II LC. An increasing polymer content significantly increased CS, whereas an increasing glass filler content increased neither yield strength nor ultimate CS except for modulus. During aging, the experimental cement showed a significant and continuous increase in yield strength, modulus and ultimate CS, but Fuji II LC only showed a significant increase in strength within 24 h. The experimental cement was very biocompatible in vivo to bone and showed little in vitro cytotoxicity. It appears that this novel LCGIC cement will be a better dental restorative because it demonstrated significantly improved mechanical strengths and better in vitro and in vivo biocompatibilities as compared to the current commercial LCGIC system.Item Digital Light Processing 3D Bioprinting of Gelatin-Norbornene Hydrogel for Enhanced Vascularization(Wiley, 2023) Duong, Van Thuy; Lin, Chien-Chi; Biomedical Engineering, Purdue School of Engineering and TechnologyDigital light processing (DLP) bioprinting can be used to fabricate volumetric scaffolds with intricate internal structures, such as perfusable vascular channels. The successful implementation of DLP bioprinting in tissue fabrication requires using suitable photo-reactive bioinks. Norbornene-based bioinks have emerged as an attractive alternative to (meth)acrylated macromers in 3D bioprinting owing to their mild and rapid reaction kinetics, high cytocompatibility for in situ cell encapsulation, and adaptability for post-printing modification or conjugation of bioactive motifs. In this contribution, the development of gelatin-norbornene (GelNB) is reported as a photo-cross-linkable bioink for DLP 3D bioprinting. Low concentrations of GelNB (2-5 wt.%) and poly(ethylene glycol)-tetra-thiol (PEG4SH) are DLP-printed with a wide range of stiffness (G' ≈120 to 4000 Pa) and with perfusable channels. DLP-printed GelNB hydrogels are highly cytocompatible, as demonstrated by the high viability of the encapsulated human umbilical vein endothelial cells (HUVECs). The encapsulated HUVECs formed an interconnected microvascular network with lumen structures. Notably, the GelNB bioink permitted both in situ tethering and secondary conjugation of QK peptide, a vascular endothelial growth factor (VEGF)-mimetic peptide. Incorporation of QK peptide significantly improved endothelialization and vasculogenesis of the DLP-printed GelNB hydrogels, reinforcing the applicability of this bioink system in diverse biofabrication applications.Item Simulating Subject-Specific Aortic Hemodynamic Effects of Valvular Lesions in Rheumatic Heart Disease(ASME, 2023) Cebull, Hannah L.; Aremu, Olukayode O.; Kulkarni, Radhika S.; Zhang, Samuel X.; Samuels, Petronella; Jermy, Stephen; Ntusi, Ntobeko A. B.; Goergen, Craig J.; Biomedical Engineering, Purdue School of Engineering and TechnologyRheumatic heart disease (RHD) is a neglected tropical disease despite the substantial global health burden. In this study, we aimed to develop a lower cost method of modeling aortic blood flow using subject-specific velocity profiles, aiding our understanding of RHD's consequences on the structure and function of the ascending aorta. Echocardiography and cardiovascular magnetic resonance (CMR) are often used for diagnosis, including valve dysfunction assessments. However, there is a need to further characterize aortic valve lesions to improve treatment options and timing for patients, while using accessible and affordable imaging strategies. Here, we simulated effects of RHD aortic valve lesions on the aorta using computational fluid dynamics (CFD). We hypothesized that inlet velocity distribution and wall shear stress (WSS) will differ between RHD and non-RHD individuals, as well as between subject-specific and standard Womersley velocity profiles. Phase-contrast CMR data from South Africa of six RHD subjects with aortic stenosis and/or regurgitation and six matched controls were used to estimate subject-specific velocity inlet profiles and the mean velocity for Womersley profiles. Our findings were twofold. First, we found WSS in subject-specific RHD was significantly higher (p < 0.05) than control subject simulations, while Womersley simulation groups did not differ. Second, evaluating spatial velocity differences (ΔSV) between simulation types revealed that simulations of RHD had significantly higher ΔSV than non-RHD (p < 0.05), these results highlight the need for implementing subject-specific input into RHD CFD, which we demonstrate how to accomplish through accessible methods.Item Passage dependent changes in nuclear and cytoskeleton structures of endothelial cells under laminar shear stress or cyclic stretch(Medip Academy, 2021) Jiang, Yizhi; Witt, Nathaniel; Ji, Julie Y.; Biomedical Engineering, Purdue School of Engineering and TechnologyBackground: The ability of vascular endothelium to sense and respond to the mechanical stimuli generated by blood flow is pivotal in maintaining arterial homeostasis. A steady laminar flow tends to provide athero-protective effect via regulating endothelial functions, vascular tone, and further remodeling process. As arterial aging appeared to be an independent risk factor of cardiovascular diseases, it is critical to understand the effects of cell senescence on endothelial dysfunction under dynamic mechanical stimuli. Methods: In this study, we investigated the morphological responses of aortic endothelial cells toward laminar flow or cyclic stretch. Automated image recognition methods were applied to analyze image data to avoid bias. Differential patterns of morphological adaptations toward distinct mechanical stimuli were observed, and the shear-induced changes were found to be more associated with cell passages than that of cyclic strain. Results: Our results demonstrated that the cytoskeleton and nuclear structural adaptations in endothelial cells toward laminar flow were altered over prolonged culture, suggesting that the failure of senescent endothelial cells to adapt to the applied shear stress morphologically could be one of the contributors to endothelial dysfunctions during vascular aging. Conclusions: Results indicated that cells were able to adjust their cytoskeleton and nuclear alignment and nuclear shapes in response to the applied mechanical stimuli, and that the shear-induced changes were more dependent on PD levels, where cells with higher PDL were more responsive to external forces.