Self‐sustainable energy generation represents a new frontier to greatly extend the lifetime and effectiveness of implantable biomedical devices, such as cardiac pacemakers and defibrillators. However, there is a lack of promising technologies which can efficiently convert the mechanical energy of the beating heart to electrical energy with minimal risk of interfering with the cardiovascular functions. Here a unique design is presented based on existing pacemaker leads tailored for compact energy harvesting. This new design incorporates flexible porous polyvinylidene fluoride‐trifluoroethylene thin film within a dual‐cantilever structure, which wraps around the pacemaker lead with two free ends sticking out for harvesting energy from the heart's motion. Under various anchor methods of the lead, the maximum electrical output yields 0.5 V and 43 nA under the frequency of 1 Hz. It is found that adding a proof mass of 31.6 mg on the dual‐cantilever tip results in a 1.82 times power enhancement. The scalability of the design is also demonstrated, e.g., by connecting two such units in parallel, their simultaneous vibration can together contribute to energy conversion. Collectively, this study implies that sufficient electrical energy can be converted from the kinetic energy of a pacemaker lead especially at low frequencies to sustain operations.
Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source–sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue‐engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β‐Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace‐and‐drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.
more » « less- NSF-PAR ID:
- 10460086
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Science
- Volume:
- 6
- Issue:
- 22
- ISSN:
- 2198-3844
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Collagen is the major structural protein in myocardium and contributes to tissue strength and integrity, cellular orientation, and cell–cell and cell‐matrix interactions. Significant post‐myocardial infarction related loss of cardiomyocytes and cardiac tissue, and their subsequent replacement with fibrous scar tissue, negatively impacts endogenous tissue repair and regeneration capabilities. To overcome such limitations, tissue engineers are working toward developing a 3D cardiac patch which not only mimics the structural, functional, and biological hierarchy of the native cardiac tissue, but also could deliver autologous stem cells and encourage their homing and differentiation. In this study, we examined the utility of electrospun, randomly‐oriented, type‐I collagen nanofiber (
dia = 789 ± 162 nm) mats on the cardiomyogenic differentiation of human bone marrow‐derived mesenchymal stem cells (BM‐MSC) spheroids, in the presence or absence of 10 μM 5‐azacytidine (aza). Results showed that these scaffolds are biocompatible and enable time‐dependent evolution of early (GATA binding protein 4: GATA4), late (cardiac troponin I: cTnI), and mature (myosin heavy chain: MHC) cardiomyogenic markers, with a simultaneous reduction in CD90 (stemness) expression, independent of aza‐treatment. Aza‐exposure improved connexin‐4 expression and sustained sarcomeric α‐actin expression, but provided only transient improvement in cardiac troponin T (cTnT) expression. Cell orientation and alignment significantly improved in these nanofiber scaffolds over time and with aza‐exposure. Although further quantitativein vitro andin vivo studies are needed to establish the clinical applicability of such stem‐cell laden collagen nanofiber mats as cardiac patches for cardiac tissue regeneration, our results underscore the benefits of 3D milieu provided by electrospun collagen nanofiber mats, aza, and spheroids on the survival, cardiac differentiation and maturation of human BM‐MSCs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3303–3312, 2018. -
Cardiovascular diseases, including myocardial infarction (MI), persist as the leading cause of mortality and morbidity worldwide. The limited regenerative capacity of the myocardium presents significant challenges specifically for the treatment of MI and, subsequently, heart failure (HF). Traditional therapeutic approaches mainly rely on limiting the induced damage or the stress on the remaining viable myocardium through pharmacological regulation of remodeling mechanisms, rather than replacement or regeneration of the injured tissue. The emerging alternative regenerative medicine-based approaches have focused on restoring the damaged myocardial tissue with newly engineered functional and bioinspired tissue units. Cardiac regenerative medicine approaches can be broadly categorized into three groups: cell-based therapies, scaffold-based cardiac tissue engineering, and scaffold-free cardiac tissue engineering. Despite significant advancements, however, the clinical translation of these approaches has been critically hindered by two key obstacles for successful structural and functional replacement of the damaged myocardium, namely: poor engraftment of engineered tissue into the damaged cardiac muscle and weak electromechanical coupling of transplanted cells with the native tissue. To that end, the integration of micro- and nanoscale technologies along with recent advancements in stem cell technologies have opened new avenues for engineering of structurally mature and highly functional scaffold-based (SB-CMTs) and scaffold-free cardiac microtissues (SF-CMTs) with enhanced cellular organization and electromechanical coupling for the treatment of MI and HF. In this review article, we will present the state-of-the-art approaches and recent advancements in the engineering of SF-CMTs for myocardial repair.more » « less
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Abstract Background and Aims Fibrotic tissue formed after myocardial infarction (MI) can be as detrimental as MI itself. However, current in vitro cardiac fibrosis models fail to recapitulate the complexities of post‐MI tissue. Moreover, although MI and subsequent fibrosis is most prominent in the aged population, the field suffers from inadequate aged tissue models. Herein, an aged human post‐MI tissue model, representing the native microenvironment weeks after initial infarction, is engineered using three‐dimensional bioprinting via creation of individual bioinks to specifically mimic three distinct regions: remote, border, and scar.
Methods The aged post‐MI tissue model is engineered through combination of gelatin methacryloyl, methacrylated hyaluronic acid, aged type I collagen, and photoinitiator at variable concentrations with different cell types, including aged human induced pluripotent stem cell‐derived cardiomyocytes, endothelial cells, cardiac fibroblasts, and cardiac myofibroblasts, by introducing a methodology which utilizes three printheads of the bioprinter to model aged myocardium. Then, using cell‐specific proteins, the cell types that comprised each region are confirmed using immunofluorescence. Next, the beating characteristics are analyzed. Finally, the engineered aged post‐MI tissue model is used as a benchtop platform to assess the therapeutic effects of stem cell‐derived extracellular vesicles on the scar region.
Results As a result, high viability (>74%) was observed in each region of the printed model. Constructs demonstrated functional behavior, exhibiting a beating velocity of 6.7 μm/s and a frequency of 0.3 Hz. Finally, the effectiveness of hiPSC‐EV and MSC‐EV treatment was assessed. While hiPSC‐EV treatment showed no significant changes, MSC‐EV treatment notably increased cardiomyocyte beating velocity, frequency, and confluency, suggesting a regenerative potential.
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Abstract Biomedical self‐sustainable energy generation represents a new frontier of power solution for implantable biomedical devices (IMDs), such as cardiac pacemakers. However, almost all reported cardiac energy harvesting designs have not yet reached the stage of clinical translation. A major bottleneck has been the need of additional surgeries for the placements of these devices. Here, integrated piezoelectric‐based energy harvesting and sensing designs are reported, which can be seamlessly incorporated into existing IMDs for ease of clinical translation. In vitro experiments validate the energy harvesting process by simulating the bending and twisting motion during heart cycle. Clinical translation is demonstrated in four porcine hearts in vivo under various conditions. Energy harvesting strategy utilizes pacemaker leads as a means of reducing the reliance on batteries and demonstrates the charging ability for extending the lifetime of a pacemaker battery by 20%, which provides a promising self‐sustainable energy solution for IMDs. The additional self‐powered blood pressure sensing is discussed, and the reported results demonstrate the potential in alerting arrhythmias by monitoring the right ventricular pressure variations. This combined cardiac energy harvesting and blood pressure sensing strategy provides a multifunctional, transformative while practical power and diagnosis solution for cardiac pacemakers and next generation of IMDs.
