Thin, flexible fibers made of carbon nanotubes have now proven able to bridge damaged heart tissues and deliver the electrical signals needed to keep those hearts beating.
Scientists at Texas Heart Institute (THI) report they have used those biocompatible fibers in studies that showed sewing them directly into damaged tissue can restore electrical function to hearts.
“Instead of shocking and defibrillating, we are actually correcting diseased conduction of the largest major pumping chamber of the heart by creating a bridge to bypass and conduct over a scarred area of a damaged heart,” said Dr. Mehdi Razavi, a cardiologist and director of Electrophysiology Clinical Research and Innovations at THI, who co-led the study with Rice chemical and biomolecular engineer Matteo Pasquali.
“Today there is no technology that treats the underlying cause of the No. 1 cause of sudden death, ventricular arrhythmias,” Razavi said.
“These arrhythmias are caused by the disorganized firing of impulses from the heart’s lower chambers and are challenging to treat in patients after a heart attack or with scarred heart tissue due to such other conditions as congestive heart failure or dilated cardiomyopathy.”
Results of the studies on preclinical models appear as an open-access Editor’s Pick in the American Heart Association’s Circulation: Arrhythmia and Electrophysiology. The association helped fund the research with a 2015 grant.
The research springs from the pioneering 2013 invention by Pasquali’s lab of a method to make conductive fibers out of carbon nanotubes.
The lab’s first threadlike fibers were a quarter of the width of a human hair, but contained tens of millions of microscopic nanotubes.
The fibers are also being studied for electrical interfaces with the brain, for use in cochlear implants, as flexible antennas and for automotive and aerospace applications.
The experiments showed the nontoxic, polymer-coated fibers, with their ends stripped to serve as electrodes, were effective in restoring function during monthlong tests in large preclinical models as well as rodents, whether the initial conduction was slowed, severed or blocked, according to the researchers.
The fibers served their purpose with or without the presence of a pacemaker, they found.
In the rodents, they wrote, conduction disappeared when the fibers were removed.
“The reestablishment of cardiac conduction with carbon nanotube fibers has the potential to revolutionize therapy for cardiac electrical disturbances, one of the most common causes of death in the United States,” said co-lead author Mark McCauley, who carried out many of the experiments as a postdoctoral fellow at THI.
He is now an assistant professor of clinical medicine at the University of Illinois College of Medicine.
“Our experiments provided the first scientific support for using a synthetic material-based treatment rather than a drug to treat the leading cause of sudden death in the U.S. and many developing countries around the world,” Razavi said.
Many questions remain before the procedure can move toward human testing, Pasquali said.
The researchers must establish a way to sew the fibers in place using a minimally invasive catheter, and make sure the fibers are strong and flexible enough to serve a constantly beating heart over the long term.
He said they must also determine how long and wide fibers should be, precisely how much electricity they need to carry and how they would perform in the growing hearts of young patients.
“Flexibility is important because the heart is continuously pulsating and moving, so anything that’s attached to the heart’s surface is going to be deformed and flexed,” said Pasquali, who has appointments at Rice’s Brown School of Engineering and Wiess School of Natural Sciences.
“Good interfacial contact is also critical to pick up and deliver the electrical signal,” he said. “In the past, multiple materials had to be combined to attain both electrical conductivity and effective contacts.
These fibers have both properties built in by design, which greatly simplifies device construction and lowers risks of long-term failure due to delamination of multiple layers or coatings.”
Razavi noted that while there are many effective antiarrhythmic drugs available, they are often contraindicated in patients after a heart attack. “What is really needed therapeutically is to increase conduction,” he said. “Carbon nanotube fibers have the conductive properties of metal but are flexible enough to allow us to navigate and deliver energy to a very specific area of a delicate, damaged heart.”
Tissue engineering (TE) is the study of the growth of new tissues and organs, starting from a base of cells and scaffolds.1,2
The scaffolds are used as three-dimensional (3D) structures in which cells grow, proliferate and differentiate into various cell types. Growth factors are introduced into the scaffolds to direct cell behavior toward any desired process where the eventual goal is to produce fully functional organs or tissues capable of growth and regeneration and suitable for implantation.3,4
Despite such promises, TE faces numerous limitations; transcribing these ideas into reality seems like an uphill task. The inability of engineered materials to mimic the natural properties of tissues is one of the roadblocks. Nanotechnology through customized nanoparticle engineering has the potential to solve this challenge.4,5
Nanoparticles are characterized by their nanoscale dimension, enabling them to develop critical physical and chemical characteristics that enhance their performance and therefore make them beneficial for a wide range of applications.6 In the biomedical field, nanoparticles have been used for controlled drug delivery,7,8 imaging of specific sites, probing of DNA structures,9–11biomolecular sensing, gene delivery, photothermal ablation of cells12 and, most recently, TE.13,14 Additionally, many therapies utilize nanoparticles for the treatment of cancer,15diabetes,16 allergy,17 infection18 and inflammation.19
Very recently, nanoparticles have been used in TE in order to obtain improved mechanical and biological performances.20
The surface conjugation and conducting properties of gold nanoparticles (GNPs), the antimicrobial properties of silver and other metallic nanoparticles and metal oxides, the fluorescence properties of quantum dots and the unique electromechanical properties of carbon nanotubes (CNTs) have made them very useful in numerous TE applications. In addition, magnetic nanoparticles (MNPs) have been applied in the study of cell mechanotransduction, gene delivery, controlling cell patterning and construction of complex 3D tissues.
The advantage of nanoparticles in TE stems from their small size and their associated large surface to volume ratio, which is comparable to peptides and small proteins.
They can easily diffuse across membranes and facilitate uptake by cells. Moreover, one is not limited by a predetermined size for nanoparticles, since they can be made in customized sizes and surface characteristics in order to suit any purpose. Nanoparticles also mimic the natural nanometer size scale of extracellular matrix (ECM) components of tissues themselves.
In one sense, nanoscale structures can be considered as an integral part of our body where the components of organs and tissues such as ECM and cells comprise various atoms, molecules, nanostructures, microstructures and macroscale structures hierarchically.
On the other hand, there are numerous external nanoparticles that enter and exit our body frequently through the inhaled air or oral and topical routes, which depending on the toxicity or nature of the particle may or may not be harmful to the body. A third source of nanoparticles in our body could be the release or secretion of elements from biomedical prosthetics and implants transplanted in our body.
As reported in several studies,21–23 metal nanoparticles, namely, Ag, Cr, Fe, Mo, Ni, Ta, Cr, Co, Sb and Sc,22 were formed both in tissues adjacent to the implants and distant to the implantation sites after implementation of bioprosthetics in the body.
A high accumulation of metallic elements was found in the brain and lungs of patients with hip endoprosthesis, while hip arthroplasty patients were found to exhibit high concentrations of Cr, Co and Mo ions in their hair as well.24 These three types of nanoparticles mentioned earlier are beyond the scope of this review.
In this review, we present an overview of the diverse applications of various types of nanoparticles in TE applications.
This review addresses the applications of magnetic, metallic, ceramic and metal oxide nanoparticles in TE. They are advantageous, as they tend to be biocompatible and have low immunogenicity.
The specific intrinsic properties of each material may hold the answer to overcoming the current hurdles in TE, where the use of materials engineering has not been exploited to its full potential. The insights provided in this review will be beneficial for material scientists and tissue engineers working with nanoparticles, allowing them to navigate through applications that best fit their need.
Brief background of nanoparticles
Nanoparticles are entities of any shape with a size range of 1–100 nm in any one dimension.25Such a unique size gives these particles the properties of both bulk materials and molecular structures. As such, nanoparticles are viewed as the “bridge” between the macroscopic and microscopic structures.
Their small size gives them one of their most attractive intrinsic properties: a high surface to volume ratio. Nanoparticles are highly mobile when they are in a free state, causing them to have tremendously slow sedimentation rates (Figure 1).
In addition, they are characterized by a wide range of compositions ranging from soft to hard materials depending on their use and may exhibit what is known as the quantum effect. This quantum effect allows one to have extreme control over the surface energy of these particles, which in turn can control initial protein adsorption to dictate cellular interactions.26
Interaction of bacteria and mammalian cells with nanoparticles.
Notes: (A) Schematics of the effects of nanoparticles on bacterial cells. (B and C) Representative electron microscopy images showing the interaction of E. coli with the samples of cerium oxide nanoparticles at different magnifications. (D) Programmable nanomaterial synthesis using GNPs under different deposition parameters. (E) Effects of CeO2 nanoparticles on cardiac progenitor cell morphology and growth. CeO2-untreated (a) or CeO2-treated cells 10 μg/mL (b), 25 μg/mL (c) and 50 μg/mL (d). (A–C) Republished with permission of American Society for Microbiology, from Effects of engineered cerium oxide nanoparticles on bacterial growth and viability. Pelletier DA, Suresh AK, Holton GA, et al. Appl Environ Microbiol. 76(24):7981–7989. Copyright 2010.167 (D) Reprinted by permission from Springer Nature: Nat Nanotechnol. Programming the detection limits of biosensors through controlled nanostructuring. Soleymani L, Fang Z, Sargent EH, Kelley SO. Copyright 2009.168 (E) Reprinted with permission from Pagliari F, Mandoli C, Forte G, et al. Cerium oxide nanoparticles protect cardiac progenitor cells from oxidative stress. ACS Nano. 2012;6(5):3767–3775. Copyright 2012 American Chemical Society.169
Abbreviations: E. coli, Escherichia coli; GNP, gold nanoparticle; ROS, reactive oxygen species.
Depending on the shape, nanoparticles can be of 0D, 1D, 2D or 3D structure types.27,28
Based on their source or type of materials, they can be divided into different categories such as carbon-based, metal-based, ceramic-based, polymeric-based, semiconductor-based and lipid-based nanoparticles.28
Nanoparticles can be synthesized by using two main methods such as
1) bottom-up and
2) top-down approaches.29
Furthermore, these methods can be divided into mechanical, chemical and biological syntheses,30 and these include chemical vapor deposition, physical vapor deposition, a sol–gel method, radio frequency (RF) plasma method, pulsed laser method, thermolysis and solution combustion method. Various characterization methods used to characterize the nanoparticles depend on the property of the materials.
The morphology of the nanoparticles has been analyzed using polarized optical microscopy (POM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), infrared (IR), X-ray diffraction (XRD), Raman spectroscopy, Brunauer–Emmett–Teller (BET) and Zeta size analyzer.30,31
These properties provide unique applications of nanoparticles in a wide variety of research fields, eg, biomedical sciences, electronics, optics and more.
While significant progress has been made for numerous nanoparticle applications in these fields, their applications in TE are still in their infancy stage hindered by some significant challenges.
Here, we aim to review the application of nanoparticles in TE along with the challenges associated with them and address how such challenges can be tackled widening the application of nanoparticles in a broad range of TE applications.
More information: Mark D. McCauley et al. In Vivo Restoration of Myocardial Conduction With Carbon Nanotube Fibers, Circulation: Arrhythmia and Electrophysiology (2019). DOI: 10.1161/CIRCEP.119.007256
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