Magnetic Cell Targeting for Cardiovascular Tissue Engineering.

There is a critical need for novel approaches to translate cell therapy and regenerative medicine to clinical practice. Magnetic cell targeting with site specificity has started to open avenues in these fields as a potential therapeutic platform. Magnetic targeting is gaining popularity in the field of biomedicine due to its ability to concentrate and retain at a target site while minimizing deleterious effects at off-target sites.

Identification of a subpopulation of highly adherent endothelial cells for seeding synthetic vascular grafts.

Objective: There is an unmet clinical need for alternatives to autologous vessel grafts. Small-diameter (<6 mm) synthetic vascular grafts are not suitable because of unacceptable patency rates. This mainly occurs due to the lack of an endothelial cell (EC) monolayer to prevent platelet activation, thrombosis, and intimal hyperplasia.

Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net.

Objective: Here we report our preclinical, proof-of-concept testing to assess the ability of a novel device to correct mitral regurgitation. The Milwaukee Heart device aims to enable any cardiac surgeon to perform high-quality mitral valve repair using a standard annuloplasty ring with a crosshatch of microporous, monofilament suture.

Methods: Hemodynamic, echocardiographic, and videographic data were collected at baseline, following induction of mitral regurgitation, and after repair using porcine hearts in an ex vivo biosimulator model.

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

Coarctation of the aorta (CoA; constriction of the proximal descending thoracic aorta) is among the most common congenital cardiovascular defects. Coarctation-induced mechanical perturbations trigger a cycle of mechano-transduction events leading to irreversible precursors of hypertension including arterial thickening, stiffening, and vasoactive dysfunction in proximal conduit arteries. This study sought to identify kinetics of the stress-mediated compensatory response leading to these alterations using a preclinical rabbit model of CoA.

3D-bioprinting of patient-derived cardiac tissue models for studying congenital heart disease.

Introduction: Congenital heart disease is the leading cause of death related to birth defects and affects 1 out of every 100 live births. Induced pluripotent stem cell technology has allowed for patient-derived cardiomyocytes to be studied in vitro. An approach to bioengineer these cells into a physiologically accurate cardiac tissue model is needed in order to study the disease and evaluate potential treatment strategies.

Magnetic and Biocompatible Polyurethane Nanofiber Biomaterial for Tissue Engineering.

Recruitment of endothelial cells to cardiovascular device surfaces could solve issues of thrombosis, neointimal hyperplasia, and restenosis. Since current targeting strategies are often nonspecific, new technologies to allow for site-specific cell localization and capture are needed. The development of cytocompatible superparamagnetic iron oxide nanoparticles has allowed for the use of magnetism for cell targeting.

Anti-Inflammatory and Anti-Thrombogenic Properties of Arterial Elastic Laminae.

Elastic laminae, an elastin-based, layered extracellular matrix structure in the media of arteries, can inhibit leukocyte adhesion and vascular smooth muscle cell proliferation and migration, exhibiting anti-inflammatory and anti-thrombogenic properties. These properties prevent inflammatory and thrombogenic activities in the arterial media, constituting a mechanism for the maintenance of the structural integrity of the arterial wall in vascular disorders. The biological basis for these properties is the elastin-induced activation of inhibitory signaling pathways, involving the inhibitory cell receptor signal regulatory protein α (SIRPα) and Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1).

Characterization of Blood Outgrowth Endothelial Cells (BOEC) from Porcine Peripheral Blood.

The endothelium is a dynamic integrated structure that plays an important role in many physiological functions such as angiogenesis, hemostasis, inflammation, and homeostasis. The endothelium also plays an important role in pathophysiologies such as atherosclerosis, hypertension, and diabetes. Endothelial cells form the inner lining of blood and lymphatic vessels and display heterogeneity in structure and function.

Strategies for Improving Endothelial Cell Adhesion to Blood-Contacting Medical Devices.

The endothelium is a critical mediator of homeostasis on blood-contacting surfaces in the body, serving as a selective barrier to regulate processes such as clotting, immune cell adhesion, and cellular response to fluid shear stress. Implantable cardiovascular devices, including stents, vascular grafts, heart valves, and left ventricular assist devices, are in direct contact with circulating blood and carry a high risk for platelet activation and thrombosis without a stable endothelial cell (EC) monolayer. Development of a healthy endothelium on the blood-contacting surface of these devices would help ameliorate risks associated with thrombus formation and eliminate the need for long-term antiplatelet or anticoagulation therapy.

Cardiac Valve Bioreactor for Physiological Conditioning and Hydrodynamic Performance Assessment.

Purpose: Tissue engineered heart valves (TEHV) are being investigated to address the limitations of currently available valve prostheses. In order to advance a wide variety of TEHV approaches, the goal of this study was to develop a cardiac valve bioreactor system capable of conditioning living valves with a range of hydrodynamic conditions as well as capable of assessing hydrodynamic performance to ISO 5840 standards.

Methods: A bioreactor system was designed based on the Windkessel approach.

Biomaterial characterization of off-the-shelf decellularized porcine pericardial tissue for use in prosthetic valvular applications.

Fixed pericardial tissue is commonly used for commercially available xenograft valve implants, and has proven durability, but lacks the capability to remodel and grow. Decellularized porcine pericardial tissue has the promise to outperform fixed tissue and remodel, but the decellularization process has been shown to damage the collagen structure and reduce mechanical integrity of the tissue. Therefore, a comparison of uniaxial tensile properties was performed on decellularized, decellularized-sterilized, fixed, and native porcine pericardial tissue versus native valve leaflet cusps.

Nanoparticle-Mediated Cell Capture Enables Rapid Endothelialization of a Novel Bare Metal Stent.

Incomplete endothelialization of intracoronary stents has been associated with stent thrombosis and recurrent symptoms, whereas prolonged use of dual antiplatelet therapy increases bleeding-related adverse events. Facilitated endothelialization has the potential to improve clinical outcomes in patients who are unable to tolerate dual antiplatelet therapy. The objective of this study was to demonstrate the feasibility of magnetic cell capture to rapidly endothelialize intracoronary stents in a large animal model.

Recellularization of a novel off-the-shelf valve following xenogenic implantation into the right ventricular outflow tract.

Current research on valvular heart repair has focused on tissue-engineered heart valves (TEHV) because of its potential to grow similarly to native heart valves. Decellularized xenografts are a promising solution; however, host recellularization remains challenging. In this study, decellularized porcine aortic valves were implanted into the right ventricular outflow tract (RVOT) of sheep to investigate recellularization potential.

Xenoantigenicity of porcine decellularized valves.

Background: The xenoantigenicity of porcine bioprosthetic valves is implicated as an etiology leading to calcification and subsequent valve failure. Decellularization of porcine valves theoretically could erase the antigenicity of the tissue leading to more durable prosthetic valves, but the effectiveness of decellularization protocols in regard to completely removing antigens has yet to be verified. Our hypothesis was that decellularization would remove the more abundant α-gal antigens but not remove all the non α-gal antigens, which could mount a response.

Supercritical carbon dioxide-based sterilization of decellularized heart valves.

Objective: The goal of this research project encompasses finding the most efficient and effective method of decellularized tissue sterilization.

Background: Aortic tissue grafts have been utilized to repair damaged or diseased valves. Although, the tissues for grafting are collected aseptically, it does not eradicate the risk of contamination nor disease transfer.

Magnetizable stent-grafts enable endothelial cell capture.

Emerging nanotechnologies have enabled the use of magnetic forces to guide the movement of magnetically-labeled cells, drugs, and other therapeutic agents. Endothelial cells labeled with superparamagnetic iron oxide nanoparticles (SPION) have previously been captured on the surface of magnetizable 2205 duplex stainless steel stents in a porcine coronary implantation model. Recently, we have coated these stents with electrospun polyurethane nanofibers to fabricate prototype stent-grafts.

Fabrication of Small Caliber Stent-grafts Using Electrospinning and Balloon Expandable Bare Metal Stents.

Stent-grafts are widely used for the treatment of various conditions such as aortic lesions, aneurysms, emboli due to coronary intervention procedures and perforations in vasculature. Such stent-grafts are manufactured by covering a stent with a polymer membrane. An ideal stent-graft should have a biocompatible stent covered by a porous, thromboresistant, and biocompatible polymer membrane which mimics the extracellular matrix thereby promoting injury site healing.

Cell Labeling and Targeting with Superparamagnetic Iron Oxide Nanoparticles.

Targeted delivery of cells and therapeutic agents would benefit a wide range of biomedical applications by concentrating the therapeutic effect at the target site while minimizing deleterious effects to off-target sites. Magnetic cell targeting is an efficient, safe, and straightforward delivery technique. Superparamagnetic iron oxide nanoparticles (SPION) are biodegradable, biocompatible, and can be endocytosed into cells to render them responsive to magnetic fields.

Low-Dose Gamma Irradiation of Decellularized Heart Valves Results in Tissue Injury In Vitro and In Vivo.

Background: Decellularized heart valves are emerging as a potential alternative to current bioprostheses for valve replacement. Whereas techniques of decellularization have been thoroughly examined, terminal sterilization techniques have not received the same scrutiny.

Methods: This study evaluated low-dose gamma irradiation as a sterilization method for decellularized heart valves.

Ferromagnetic Bare Metal Stent for Endothelial Cell Capture and Retention.

Rapid endothelialization of cardiovascular stents is needed to reduce stent thrombosis and to avoid anti-platelet therapy which can reduce bleeding risk. The feasibility of using magnetic forces to capture and retain endothelial outgrowth cells (EOC) labeled with super paramagnetic iron oxide nanoparticles (SPION) has been shown previously. But this technique requires the development of a mechanically functional stent from a magnetic and biocompatible material followed by in-vitro and in-vivo testing to prove rapid endothelialization.

Design and validation of a novel ferromagnetic bare metal stent capable of capturing and retaining endothelial cells.

Rapid healing of vascular stents is important for avoiding complications associated with stent thrombosis, restenosis, and bleeding related to antiplatelet drugs. Magnetic forces can be used to capture iron-labeled endothelial cells immediately following stent implantation, thereby promoting healing. This strategy requires the development of a magnetic stent that is biocompatible and functional.

Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia.

Myocardial ischemia (MI) activates innate cardioprotective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we report a MI-activated liver-dependent mechanism for myocardial protection. In response to MI in the mouse, hepatocytes exhibited 6- to 19-fold upregulation of genes encoding secretory proteins, including α-1-acid glycoprotein (AGP)2, bone morphogenetic protein-binding endothelial regulator (BMPER), chemokine (C-X-C motif) ligand 13, fibroblast growth factor (FGF)21, neuregulin (NRG)4, proteoglycan 4, and trefoil factor (TFF)3.

Cardioprotective mechanisms activated in response to myocardial ischemia.

Myocardial ischemia, a disorder causing myocardial infarction and malfunction, can activate various adaptive mechanisms that protect cardiomyocytes from ischemic injury. During the early hours post myocardial ischemia, injured cardiac cells can release several molecules, including adenosine, opioids, and bradykinin, which promote myocardial survival by activating the G protein signaling pathways. During a later phase about several days, myocardial ischemia induces upregulation of growth factors and cytokines, including VEGF, ILGF, HGF, and SDF-1, in the injured myocardium, contributing to cardioprotection.

Formation of smooth muscle alpha actin filaments in CD34+ bone marrow cells on arterial elastic laminae: potential role of SH2 domain-containing protein tyrosine phosphatase-1.

Arterial smooth muscle cells (SMCs) are present in the elastic lamina-containing media, suggesting that the elastic laminae may regulate the development of SMCs. Here, we investigated the role of elastic laminae in regulating the formation of SM alpha actin filaments in mouse CD34+ bone marrow cells and the role of a protein tyrosine phosphatase, SH2 domain-containing protein tyrosine phosphatase (SHP)-1, in the mediation of this process. Mouse CD34+ bone marrow cells were isolated by magnetic separation and used for assessing the influence of elastic laminae and collagen matrix on the formation of SM alpha actin filaments.