3D bioprinting of collagen to rebuild components of the human heart

Science ◽  
2019 ◽  
Vol 365 (6452) ◽  
pp. 482-487 ◽  
Author(s):  
A. Lee ◽  
A. R. Hudson ◽  
D. J. Shiwarski ◽  
J. W. Tashman ◽  
T. J. Hinton ◽  
...  
Keyword(s):  
Human Heart ◽  
Primary Component ◽  
Patient Specific ◽  
Wall Thickening ◽  
Micro Computed Tomography ◽  
Collagen Scaffolds ◽  
Human Cardiomyocytes ◽  
Porous Microstructure ◽  
Cardiac Ventricles ◽  
And Function

Collagen is the primary component of the extracellular matrix in the human body. It has proved challenging to fabricate collagen scaffolds capable of replicating the structure and function of tissues and organs. We present a method to 3D-bioprint collagen using freeform reversible embedding of suspended hydrogels (FRESH) to engineer components of the human heart at various scales, from capillaries to the full organ. Control of pH-driven gelation provides 20-micrometer filament resolution, a porous microstructure that enables rapid cellular infiltration and microvascularization, and mechanical strength for fabrication and perfusion of multiscale vasculature and tri-leaflet valves. We found that FRESH 3D-bioprinted hearts accurately reproduce patient-specific anatomical structure as determined by micro–computed tomography. Cardiac ventricles printed with human cardiomyocytes showed synchronized contractions, directional action potential propagation, and wall thickening up to 14% during peak systole.

scholarly journals Modeling the heart with Novoheart’s MyHeart™ platform

2020 ◽  
Vol 2 (2) ◽  
pp. FDD32
Author(s):  
Gabriel K Y Wong ◽  
Kevin D Costa ◽  
Bernard Fermini ◽  
Ronald A Li
Keyword(s):  
Human Heart ◽  
Animal Testing ◽  
Cardiac Tissues ◽  
Drug Discovery And Development ◽  
Human Cardiomyocytes ◽  
Effective Models ◽  
And Function ◽  
2D And 3D ◽  
Human Specific

Reliable and predictive human-specific in vitro heart models can revolutionize drug discovery and development. With the advent of pluripotent stem cell technologies, human cardiomyocytes can now be readily produced in large quantities. Using tissue engineering techniques, they can be further assembled into cardiac tissues of specific 2D and 3D configurations, to create models that behave and function like the native human heart. Novoheart (BC, Canada) uniquely offers the MyHeartTM Platform of bioengineered human heart constructs, designed to provide researchers with effective models of either healthy or diseased human hearts. As in vitro, human-based assays become more widely accepted, the next decade could witness a shift away from animal testing towards more accurate and scalable human assays like the MyHeartTM Platform.

scholarly journals Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Angad Malhotra ◽  
Matthias Walle ◽  
Graeme R. Paul ◽  
Gisela A. Kuhn ◽  
Ralph Müller
Keyword(s):  
Mechanical Loading ◽  
Bone Defect ◽  
Bone Healing ◽  
Three Dimensional ◽  
Patient Specific ◽  
Dependent Manner ◽  
Micro Computed Tomography ◽  
Computed Tomography Images ◽  
Bone Defect Healing ◽  
Subject Specific

AbstractMethods to repair bone defects arising from trauma, resection, or disease, continue to be sought after. Cyclic mechanical loading is well established to influence bone (re)modelling activity, in which bone formation and resorption are correlated to micro-scale strain. Based on this, the application of mechanical stimulation across a bone defect could improve healing. However, if ignoring the mechanical integrity of defected bone, loading regimes have a high potential to either cause damage or be ineffective. This study explores real-time finite element (rtFE) methods that use three-dimensional structural analyses from micro-computed tomography images to estimate effective peak cyclic loads in a subject-specific and time-dependent manner. It demonstrates the concept in a cyclically loaded mouse caudal vertebral bone defect model. Using rtFE analysis combined with adaptive mechanical loading, mouse bone healing was significantly improved over non-loaded controls, with no incidence of vertebral fractures. Such rtFE-driven adaptive loading regimes demonstrated here could be relevant to clinical bone defect healing scenarios, where mechanical loading can become patient-specific and more efficacious. This is achieved by accounting for initial bone defect conditions and spatio-temporal healing, both being factors that are always unique to the patient.

scholarly journals A feasibility study of a novel, task-specific movement training intervention for women with patellofemoral pain

2017 ◽  
Vol 32 (2) ◽  
pp. 179-190 ◽  
Author(s):  
Gretchen B Salsich ◽  
Barbara Yemm ◽  
Karen Steger-May ◽  
Catherine E Lang ◽  
Linda R Van Dillen
Keyword(s):  
Weight Bearing ◽  
Knee Kinematics ◽  
Frontal Plane ◽  
Patellofemoral Pain ◽  
Patient Specific ◽  
Training Intervention ◽  
Specific Training ◽  
Intervention Effects ◽  
And Function ◽  
Treatment Credibility

Objective: To investigate whether a novel, task-specific training intervention that focused on correcting pain-producing movement patterns was feasible and whether it would improve hip and knee kinematics, pain, and function in women with patellofemoral pain. Design: Prospective, non-randomized, within-group, double baseline, feasibility intervention study. Subjects: A total of 25 women with patellofemoral pain were enrolled. Intervention: The intervention, delivered 2×/week for six weeks, consisted of supervised, high-repetition practice of daily weight-bearing and recreational activities. Activities were selected and progressed based on participants’ interest and ability to maintain optimal alignment without increasing pain. Main measures: Primary feasibility outcomes were recruitment, retention, adherence, and treatment credibility (Credibility/Expectancy Questionnaire). Secondary outcomes assessing intervention effects were hip and knee kinematics, pain (visual analog scale: current, average in past week, maximum in past week), and function (Patient-Specific Functional Scale). Results: A total of 25 participants were recruited and 23 were retained (92% retention). Self-reported average daily adherence was 79% and participants were able to perform their prescribed home program correctly (reduced hip and knee frontal plane angles) by the second intervention visit. On average, treatment credibility was rated 25 (out of 27) and expectancy was rated 22 (out of 27). Hip and knee kinematics, pain, and function improved following the intervention when compared to the control phase. Conclusion: Based on the feasibility outcomes and preliminary intervention effects, this task-specific training intervention warrants further investigation and should be evaluated in a larger, randomized clinical trial.

scholarly journals S ‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

2016 ◽  
Vol 30 (5) ◽  
pp. 1849-1864 ◽  
Author(s):  
Konstantina Stathopoulou ◽  
Ilka Wittig ◽  
Juliana Heidler ◽  
Angelika Piasecki ◽  
Florian Richter ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein C ◽  
Human Heart ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Human Heart Failure ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
And Function

Abstract P392: The Effect Of Cell Sex On Magnetic Nanoparticle Uptake Of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Morteza Mahmoudi ◽  
Vahid Serpooshan ◽  
Phillip C Yang ◽  
Mahyar Heydarpour
Keyword(s):  
Heart Failure ◽  
Actin Filaments ◽  
Electromechanical Coupling ◽  
Critical Role ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
P Value ◽  
Male And Female ◽  
Cell Therapies ◽  
Human Cardiomyocytes

Introduction: It is well understood that the occurrence, progress, and treatment of heart failure, which is a leading cause of death worldwide, is sex-specific. Over the past decade, the majority of efforts in myocardial regeneration have been centered on cell-based cardiac repair. A promising cell source for these efforts is patient-specific human cardiomyocytes (CMs) differentiated from human inducible pluripotent stem cells (hiPSCs). However, successful use of hiPSC-CMs faces a major limitation, the poor engraftment and electromechanical coupling of transplanted cells with the host myocardial tissue. Magnetic nanoparticles (NPs) demonstrate great potential to address this challenge for treating heart failure via cell therapies. In particular, superparamagnetic iron oxide NPs (SPIONs) have been used to label hiPSC-CMs and, with the aid of external magnetic field, improve their engraftment and electromechanical coupling in the heart tissue. However, the critical role of cell sex in the uptake and labeling efficacy of NPs has not been evaluated. Hypothesis: Significant differences in the molecular and structural (e.g., actin structures and distribution) characteristics of male and female hiPSC-CMs affect their labeling efficacy with SPIONs. Methods and Results: To test our hypothesis, we first performed RNA-Seq analysis on three male and three female (healthy) hiPSC-CM lines. The normalized outcomes were analyzed by edgeR package. We next calculated gene-expression differential between male and female CMs. The results revealed 58 genes with significant differences between the male and female cells (p-value < 0.01). The highest observed sex-specific variation in genes was related to tophit gene (MEG3: logFC = 7.32, P-value = 5.63e -06 ), which is the maternally expressed imprinted gene with a great role in cardiac angiogenesis. Among the identified genes, a number of those were related to the cellular cytoskeletal structures including actin. We probed possible structural differences between actin filaments organization and distribution of male and female hiPSC-CMs using the stochastic optical reconstruction microscopy (STORM) technique. The results demonstrated substantial differences in organization, distribution, and morphology of actin filaments between male and female CMs. Incubation of SPIONs with male and female hiPSC-CMs revealed higher uptake of NPs (~ 3 folds) in female cells as compared to the male cells. The significant differences in the uptake of SPIONs by male vs. female cells could be attributed to the distinct organization, distribution, and morphology of actin in male vs. female cells. Conclusions: Our results indicate that male and female hiPSCs-CMs respond differently to the labeling SPIONs.

Abstract WMP34: Multimodal Evaluation of Unruptured Intracranial Aneurysm Wall

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yukishige Hashimoto ◽  
Kazuhiro Furukawa ◽  
Koji Shimonaga ◽  
Hiroki Takahashi ◽  
Chiaki Ono ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Three Dimensional ◽  
Fast Spin Echo ◽  
Maximum Diameter ◽  
Patient Specific ◽  
Wall Thickening ◽  
Hemodynamic Parameters ◽  
Aneurysm Wall ◽  
Unruptured Intracranial Aneurysms ◽  
Morphological Variables

Background and Purpose: Recent studies have suggested that MR-vessel wall imaging (VWI) or computational fluid dynamics (CFD) could evaluate aneurysm wall features in unruptured intracranial aneurysms (UIAs). The combination of these modalities might be comprehensive and help better understanding of the pathophysiology of aneurysm wall. This study was performed to disclose the relationship between VWI and hemodynamic characteristics evaluated by CFD. Methods: From April 2017 through May 2019, a total of 36 microsurgically-treated UIAs preoperatively underwent VWI and CFD were reviewed. Three-dimensional T1-weighted fast spin-echo sequences were obtained before and after injection of contrast medium, and aneurysm wall enhancement (AWE) was evaluated. CFD was carried out using patient specific geometry models from three-dimensional CT angiography. Morphological variables, intraoperative inspection and hemodynamic parameters were statistically analyzed between enhanced and nonenhanced wall of UIAs. Fourteen UIAs were available for histopathological examination. Results: In morphological variables, maximum diameter and irregularity were associated with AWE (p=0.02, respectively). AWE lesions corresponded to intraoperatively inspected atherosclerotic lesions of UIAs (sensitivity, 0.90; specificity, 0.79). Among hemodynamic parameters, oscillatory velocity index that suggests the directional changes of the flow velocity was significantly higher in UIAs with AWE (p=0.02). Histopathologic studies revealed that wall thickening accompanied by atherosclerosis, neovascularization, and macrophage infiltration corresponded to AWE lesions, while UIAs without AWE demonstrated various histopathological findings such as myointimal hyperplasia or thinning wall with loss of mural cells and wall degeneration. Conclusions: Pathophysiology of AWE could be explained as atherosclerotic changes with inflammation presumably associated with aberrant flow conditions in irregular UIAs. VWI and CFD are complementarily valuable imaging techniques to understand an aneurysm wall pathophysiology.

Structural and functional remodeling of the female Apoe-/- mouse aorta due to chronic cigarette smoke exposure

2021 ◽  
Author(s):  
Yasmeen M. Farra ◽  
Jacqueline Matz ◽  
Bhama Ramkhelawon ◽  
Jessica M. Oakes ◽  
Chiara Bellini
Keyword(s):  
Cigarette Smoking ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Wall Thickening ◽  
Cross Sectional ◽  
Fibrous Cap ◽  
Cardiovascular Morbidity And Mortality ◽  
Chronic Smoking ◽  
And Function ◽  
Thoracic And Abdominal

Despite a decline in popularity over the last several decades, cigarette smoking remains a leading cause of cardiovascular morbidity and mortality. Yet, the effects of cigarette smoking on vascular structure and function are largely unknown. To evaluate changes in the mechanical properties of the aorta that occur with chronic smoking, we exposed female Apolipoprotein E-deficient mice to mainstream cigarette smoke daily for 24 weeks, with room air as control. By the time of sacrifice, cigarette-exposed mice had lower body mass, but experienced larger systolic/diastolic blood pressure when compared to controls. Smoking was associated with significant wall thickening, reduced axial stretch, and circumferential material softening of the aorta. While this contributed to maintaining intrinsic tissue stiffness at control levels despite larger pressure loads, the structural stiffness became significantly larger. Furthermore, the aorta from cigarette-exposed mice exhibited decreased ability to store elastic energy and augment diastolic blood flow. Histological analysis revealed a region-dependent increase in the cross-sectional area due to smoking. Increased smooth muscle and extracellular matrix content led to medial thickening in the ascending aorta, while collagen deposition increased the thickness of the descending thoracic and abdominal aorta. Atherosclerotic lesions were larger in exposed vessels and featured a necrotic core overlaid by a thinned fibrous cap and macrophage infiltration, consistent with a vulnerable phenotype. Collectively, our data indicate that cigarette smoking decreases the mechanical functionality of the aorta, inflicts morphometric alterations to distinct segments of the aorta, and accelerates the progression of atherosclerosis.

scholarly journals Human iPSC-Cardiomyocytes as an Experimental Model to Study Epigenetic Modifiers of Electrophysiology

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 200
Author(s):  
Maria R. Pozo ◽  
Gantt W. Meredith ◽  
Emilia Entcheva
Keyword(s):  
Experimental Model ◽  
Histone Deacetylases ◽  
Human Heart ◽  
Transcriptional Control ◽  
Rapid Development ◽  
Hdac Inhibitors ◽  
Induced Pluripotent Stem Cell ◽  
New Drugs ◽  
Patient Specific ◽  
Cardiac Events

The epigenetic landscape and the responses to pharmacological epigenetic regulators in each human are unique. Classes of epigenetic writers and erasers, such as histone acetyltransferases, HATs, and histone deacetylases, HDACs, control DNA acetylation/deacetylation and chromatin accessibility, thus exerting transcriptional control in a tissue- and person-specific manner. Rapid development of novel pharmacological agents in clinical testing—HDAC inhibitors (HDACi)—targets these master regulators as common means of therapeutic intervention in cancer and immune diseases. The action of these epigenetic modulators is much less explored for cardiac tissue, yet all new drugs need to be tested for cardiotoxicity. To advance our understanding of chromatin regulation in the heart, and specifically how modulation of DNA acetylation state may affect functional electrophysiological responses, human-induced pluripotent stem-cell-derived cardiomyocyte (hiPSC-CM) technology can be leveraged as a scalable, high-throughput platform with ability to provide patient-specific insights. This review covers relevant background on the known roles of HATs and HDACs in the heart, the current state of HDACi development, applications, and any adverse cardiac events; it also summarizes relevant differential gene expression data for the adult human heart vs. hiPSC-CMs along with initial transcriptional and functional results from using this new experimental platform to yield insights on epigenetic control of the heart. We focus on the multitude of methodologies and workflows needed to quantify responses to HDACis in hiPSC-CMs. This overview can help highlight the power and the limitations of hiPSC-CMs as a scalable experimental model in capturing epigenetic responses relevant to the human heart.

scholarly journals MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3152
Author(s):  
Naveen Mekala ◽  
Jacob Kurdys ◽  
Alexis Paige Vicenze ◽  
Leana Rose Weiler ◽  
Carmen Avramut ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Protein Trafficking ◽  
Cardiac Contractility ◽  
Metabolic Stress ◽  
Mitochondrial Translation ◽  
Human Cardiomyocytes ◽  
Bioenergetic Metabolism ◽  
Mitochondrial Defects ◽  
And Function ◽  
High Albumin

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

Amentoflavone Inhibits Osteoclastogenesis and Wear Debris-Induced Osteolysis via Suppressing NF-κB and MAPKs Signaling Pathways

Planta Medica ◽  
2018 ◽  
Vol 84 (11) ◽  
pp. 759-767 ◽  
Author(s):  
Zhen Zhang ◽  
Shuai Zhao ◽  
Xiaolei Li ◽  
Xiaoqi Zhuo ◽  
Wu Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Aseptic Loosening ◽  
Wear Debris ◽  
Mitogen Activated Protein Kinase ◽  
Micro Computed Tomography ◽  
Computed Tomography Scanning ◽  
Mitogen Activated Protein ◽  
And Function

AbstractWear debris-induced osteolysis is one of the major reasons for subsequent aseptic loosening after cementless hip arthroplasty. Increasing evidence suggests that receptor activator of nuclear factor kappa-B (NF-κB) ligand-mediated osteoclastogenesis and osteolysis are responsible for wear debris-induced aseptic loosening. In the present study, we explored the effect of amentoflavone (AMF) on inhibiting osteoclast generation and wear debris-induced osteolysis in vitro and in vivo. Twenty-four male C57BL/J6 mice were randomly divided into four groups: a sham group and groups with titanium wear debris treatment followed by intraperitoneal injection of various concentrations of AMF (0, 20, and 40 mg/kg/day). The micro computed tomography scanning and histological analysis were performed. Bone marrow-derived macrophages were cultured to investigate the effect of AMF on osteoclast generation and function. The results showed that AMF suppressed osteoclastogenesis, F-actin ring formation, and bone absorption without cytotoxicity. AMF prevented titanium wear debris-induced osteolysis in mice. AMF suppressed the relative proteins of NF-κB and mitogen-activated protein kinase (MAPKs) signaling pathways. Thus, the present study suggests that AMF derived from plants could inhibit osteoclastogenesis and titanium wear debris-induced osteolysis via suppressing NF-κB and MAPKs signaling pathways.

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