Written by: Nayaonika Vasishtha
Edited by: Ryan Lee
Edited by: Ryan Lee
Pacemakers are small devices usually implanted in the chest to control patient heartbeat. They work by sending electrical impulses to help the heart beat with a normal rhythm and rate. They are an important part of medical care for patients with heart rhythm disorders and also help patients suffering from heart failure, a condition where the heart cannot pump enough blood to the body. Thus, implantable cardiac pacemakers are undoubtedly the cornerstones of therapy for bradyarrhythmias (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). Given their importance, it is no surprise that the number of permanent pacemaker implantations has been increasing due to the aging of populations worldwide and the increase in the numbers of patients with heart diseases (Saito Y, Nakamura K, Ito H. 2018).
Traditional permanent pacemakers consist of a battery-powered pulse generator that is implanted under the skin of the chest and connected to the heart via wires called leads. These pacemakers are surgically placed in the chest or abdomen and send electrical pulses to help the heart beat at a normal rate and rhythm or to help the heart chambers beat in sync. However, not all pacemaker implantations are permanent:, after heart attack or heart surgery, patients only require a temporary pacemaker for a brief period of time. These devices either act as a bridge to permanent pacing therapy (Zoll, P. M. et al. 1985) or are implemented temporarily following cardiac surgery (Curtis, J. J. et al. 1977) when postsurgical bradycardia is frequently encountered. Such temporary pacemakers work with the help of wires that are connected to a source of power outside the body.
Unfortunately, temporary and permanent pacemakers can cause complications such as infection, scar tissue formation, and damage to the heart upon their removal. Bacteria can also form biofilms on foreign materials/devices such as pacing leads (Imparato, A. M. & Kim, G. E. 1972). Since the device is not fully implanted, the externalized power supply and control system can be inadvertently dislodged when caring for or mobilizing the patient (Rog-Zielinska, Eva A et al. 2016). Finally, the removal of temporary transcutaneous devices following completion of therapy can cause laceration and perforation of the myocardium since the pacing leads can become enveloped in fibrotic tissue at the electrode–myocardium interface (Elmistekawy, E. 2019). Due to scar tissue formation grown on the heart around the device, if not careful, surgeons can rip out the scar tissue along with healthy muscles underneath it.
To combat these challenges, researchers have been working on biodegradable wireless pacemakers that bypasses a lot of the complications posed by the temporary pacemaker. This article talks specifically about the work done by researchers led by Drs. John Rogers and Rishi Arora from Northwestern University and Dr. Igor Efimov from George Washington University. Their study was partly funded by NIH’s National Heart, Lung, and Blood Institute (NHLB) and was published on June 28, 2021, in Nature Biotechnology.
The materials it is made of include magnesium, tungsten, silicon and a polymer known as PLGA, all of which are compatible with the body but which undergo chemical reactions that allow them to dissolve and be absorbed over time without the need of surgical extraction. Thus, the cardiac maker that was designed was thin, flexible, bioresorbable, and leadless. As part of the surgical implantation process, an integrated contact pad containing two dissolvable metallic electrodes attaches to the myocardium. The wireless power-harvesting part of the system, that generates electrical current from radio frequency, includes a loop antenna with a bilayer, dual-coil configuration (tungsten-coated magnesium (W/Mg); thickness ~700 nm/~50 μm), a film of a poly(lactide-co-glycolide) (PLGA) 65:35 (lactide:glycolide) as a dielectric interlayer (thickness ~50 μm) and a radiofrequency (RF) PIN diode based on a doped monocrystalline silicon nanomembrane (Si NM; thickness ~320 nm) (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). This W/Mg electrode design enables compatibility with computed tomography (CT) for noninvasive monitoring of the bioresorption process. The layout of the PIN diode allows for a capacitor-free rectifier with high efficiency power transfer to the device. The pair of exposed electrodes (2.0 × 1.4 mm2) includes adjacent holes (diameter 700 μm) as points for fixation to the heart with bioresorbable suture (Ethicon, no. MV-J451-V). A composite paste of Candelilla wax and W microparticles provides electrical interconnections (Won, S. M. et al. 2018). Two layers of PLGA 65:35 define a top and bottom encapsulation (thickness 100 μm) structure around the entire system to isolate the active materials from the surrounding biofluids during the period of implantation. The designs support stable function over a relevant timeframe with eventual complete disappearance into the surrounding biofluids and eventually, from the body itself by natural chemical/biochemical processes of hydrolysis and metabolic action (Choi, Y. S., Koo, J. & Rogers, J. A. 2020). PLGA dissolves by hydrolysis into its monomers, glycolic and lactic acid (Makadia, H. K. & Siegel, S. J. 2011). The Mg, Si NM and W disappear into nontoxic products such as magnesium hydroxide, hydrogen gas, orthosilicic acid (Si(OH4)) and tungstic acid (H2WO4) (Hwang, S. W. et al. 2014). Candelilla wax, which contains long-chain poly- and monounsaturated esters, fatty acids, anhydrides, short-chain hydrocarbons and resins, undergoes hydrolysis and resorbs into the body (Won, S. M. et al. 2018). The constituent materials largely dissolve within 5 weeks, and the remaining residues completely disappear after 7 weeks (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). By tweaking the thickness of the substance encompassing the electronic material, the time scale over which the device functions and degrades can be regulated.
The pacemaker is powered wirelessly through technology that is used in the wireless charging of portable electronic devices, electric toothbrushes, and contactless payments through smartphones. Electrical stimulation is delivered by the implanted device to pace the heart at various rates, stimulation strengths, and time periods by wireless power transfer according to the clinical need throughout the postoperative period (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). Alternating currents (sine wave) generated by a function generator provide a source of monophasic RF power to a transmission (Tx) antenna placed near the power harvester component of the device. The Rx coil transforms the received waveform to an approximately direct current output via the RF diode and delivers it to the interface with the myocardium as a cathodic direct current pulse through the electrode pads. An applied electrical stimulus above a threshold value initiates cardiac excitation as a result of depolarization of the transmembrane potential. This type of inductive scheme is common for wireless power transfer in implanted medical devices (Winter, K. F., Hartmann, R. & Klinke, R. A 1998) because the magnetic coupling that occurs in this megahertz frequency regime (~13.5 MHz) avoids absorption by biofluids or biological tissues (Kang, S. K. et al. 2016). Simply put, the receiver in the device converts radio frequency power that it receives from an external source into electric current that can control the heart rate. This is done through electrodes present in an encapsulating layer which connect to the heart’s surface.
The researchers want to understand and learn what happens to the biodegradable materials as they dissolve before the device begins human testing. Other concerns brought up by the researchers were regarding the dissolving process. They explained how it does not happen in a uniform way and can smaller fragments. Studies need to be done on where these fragments go before completely reabsorbing and whether there are any chances of dislodgement of the fragments in the body.
Given the scope of future testing, it is safe to say that at this stage of testing, the device has overcome a lot of the problems it sought to solve. The materials and design choices create a thin, flexible and lightweight form that maintains excellent biocompatibility and stable function throughout the desired period of use. Over a subsequent time frame following the completion of therapy, the devices disappear completely through natural biological processes. Wireless energy transfer via resonant inductive coupling delivers power to the system in a manner that eliminates the need for batteries and allows for externalized control without transcutaneous leads. These characteristics, together with a miniaturized geometry, facilitate full implantation into the body to eliminate the need for percutaneous hardware, thereby minimizing the risk of device-associated infections and dislodgement (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021).
References
Choi YS, Yin RT, Pfenniger A, Koo J, Avila R, Benjamin Lee K, Chen SW, Lee G, Li G, Qiao Y, et al. 2021 Jun 28. Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. Nature Biotechnology.:1–11. doi:https://doi.org/10.1038/s41587-021-00948-x. https://www.nature.com/articles/s41587-021-00948-x.
Saito, Y., Nakamura, K., & Ito, H. (2018). Cell-based Biological Pacemakers: Progress and Problems. Acta medica Okayama, 72(1), 1–7. https://doi.org/10.18926/AMO/55656
Rog-Zielinska, E. A., Norris, R. A., Kohl, P., & Markwald, R. (2016). The Living Scar--Cardiac Fibroblasts and the Injured Heart. Trends in molecular medicine, 22(2), 99–114. https://doi.org/10.1016/j.molmed.2015.12.006
Zoll PM, Zoll RH, Falk RH, Clinton JE, Eitel DR, Antman EM. 1985. External noninvasive temporary cardiac pacing: clinical trials. Circulation. 71(5):937–944. doi:https://doi.org/10.1161/01.cir.71.5.937.
Imparato AM. 1972. Electrode Complications in Patients With Permanent Cardiac Pacemakers. Archives of Surgery. 105(5):705. doi:https://doi.org/10.1001/archsurg.1972.04180110030009.
Elmistekawy E. 2019. Safety of temporary pacemaker wires. Asian Cardiovascular and Thoracic Annals. 27(5):341–346. doi:https://doi.org/10.1177/0218492319833276.
Won SM, Koo J, Crawford KE, Mickle AD, Xue Y, Min S, McIlvried LA, Yan Y, Kim SB, Lee SM, et al. 2018. Natural Wax for Transient Electronics. Advanced Functional Materials. 28(32):1801819. doi:https://doi.org/10.1002/adfm.201801819.
Winter K-F, Hartmann R, Klinke R. 1998. A stimulator with wireless power and signal transmission for implantation in animal experiments and other applications. Journal of Neuroscience Methods. 79(1):79–85. doi:https://doi.org/10.1016/s0165-0270(97)00160-x.
Kang S-K, Murphy RKJ, Hwang S-W, Lee SM, Harburg DV, Krueger NA, Shin J, Gamble P, Cheng H, Yu S, et al. 2016. Bioresorbable silicon electronic sensors for the brain. Nature. 530(7588):71–76. doi:https://doi.org/10.1038/nature16492. [accessed 2019 Nov 22]. https://www.nature.com/articles/nature16492.
Making a wireless, biodegradable pacemaker. 2021 Jul 12. National Institutes of Health (NIH). https://www.nih.gov/news-events/nih-research-matters/making-wireless-biodegradable-pacemaker.
Scientists develop wireless pacemaker that dissolves in body. 2021 Jun 28. the Guardian. https://www.theguardian.com/science/2021/jun/28/wireless-pacemaker-dissolves-body.
First-ever transient pacemaker harmlessly dissolves in body. newsnorthwesternedu. https://news.northwestern.edu/stories/2021/06/first-ever-transient-pacemaker-harmlessly-dissolves-in-body/.
Traditional permanent pacemakers consist of a battery-powered pulse generator that is implanted under the skin of the chest and connected to the heart via wires called leads. These pacemakers are surgically placed in the chest or abdomen and send electrical pulses to help the heart beat at a normal rate and rhythm or to help the heart chambers beat in sync. However, not all pacemaker implantations are permanent:, after heart attack or heart surgery, patients only require a temporary pacemaker for a brief period of time. These devices either act as a bridge to permanent pacing therapy (Zoll, P. M. et al. 1985) or are implemented temporarily following cardiac surgery (Curtis, J. J. et al. 1977) when postsurgical bradycardia is frequently encountered. Such temporary pacemakers work with the help of wires that are connected to a source of power outside the body.
Unfortunately, temporary and permanent pacemakers can cause complications such as infection, scar tissue formation, and damage to the heart upon their removal. Bacteria can also form biofilms on foreign materials/devices such as pacing leads (Imparato, A. M. & Kim, G. E. 1972). Since the device is not fully implanted, the externalized power supply and control system can be inadvertently dislodged when caring for or mobilizing the patient (Rog-Zielinska, Eva A et al. 2016). Finally, the removal of temporary transcutaneous devices following completion of therapy can cause laceration and perforation of the myocardium since the pacing leads can become enveloped in fibrotic tissue at the electrode–myocardium interface (Elmistekawy, E. 2019). Due to scar tissue formation grown on the heart around the device, if not careful, surgeons can rip out the scar tissue along with healthy muscles underneath it.
To combat these challenges, researchers have been working on biodegradable wireless pacemakers that bypasses a lot of the complications posed by the temporary pacemaker. This article talks specifically about the work done by researchers led by Drs. John Rogers and Rishi Arora from Northwestern University and Dr. Igor Efimov from George Washington University. Their study was partly funded by NIH’s National Heart, Lung, and Blood Institute (NHLB) and was published on June 28, 2021, in Nature Biotechnology.
The materials it is made of include magnesium, tungsten, silicon and a polymer known as PLGA, all of which are compatible with the body but which undergo chemical reactions that allow them to dissolve and be absorbed over time without the need of surgical extraction. Thus, the cardiac maker that was designed was thin, flexible, bioresorbable, and leadless. As part of the surgical implantation process, an integrated contact pad containing two dissolvable metallic electrodes attaches to the myocardium. The wireless power-harvesting part of the system, that generates electrical current from radio frequency, includes a loop antenna with a bilayer, dual-coil configuration (tungsten-coated magnesium (W/Mg); thickness ~700 nm/~50 μm), a film of a poly(lactide-co-glycolide) (PLGA) 65:35 (lactide:glycolide) as a dielectric interlayer (thickness ~50 μm) and a radiofrequency (RF) PIN diode based on a doped monocrystalline silicon nanomembrane (Si NM; thickness ~320 nm) (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). This W/Mg electrode design enables compatibility with computed tomography (CT) for noninvasive monitoring of the bioresorption process. The layout of the PIN diode allows for a capacitor-free rectifier with high efficiency power transfer to the device. The pair of exposed electrodes (2.0 × 1.4 mm2) includes adjacent holes (diameter 700 μm) as points for fixation to the heart with bioresorbable suture (Ethicon, no. MV-J451-V). A composite paste of Candelilla wax and W microparticles provides electrical interconnections (Won, S. M. et al. 2018). Two layers of PLGA 65:35 define a top and bottom encapsulation (thickness 100 μm) structure around the entire system to isolate the active materials from the surrounding biofluids during the period of implantation. The designs support stable function over a relevant timeframe with eventual complete disappearance into the surrounding biofluids and eventually, from the body itself by natural chemical/biochemical processes of hydrolysis and metabolic action (Choi, Y. S., Koo, J. & Rogers, J. A. 2020). PLGA dissolves by hydrolysis into its monomers, glycolic and lactic acid (Makadia, H. K. & Siegel, S. J. 2011). The Mg, Si NM and W disappear into nontoxic products such as magnesium hydroxide, hydrogen gas, orthosilicic acid (Si(OH4)) and tungstic acid (H2WO4) (Hwang, S. W. et al. 2014). Candelilla wax, which contains long-chain poly- and monounsaturated esters, fatty acids, anhydrides, short-chain hydrocarbons and resins, undergoes hydrolysis and resorbs into the body (Won, S. M. et al. 2018). The constituent materials largely dissolve within 5 weeks, and the remaining residues completely disappear after 7 weeks (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). By tweaking the thickness of the substance encompassing the electronic material, the time scale over which the device functions and degrades can be regulated.
The pacemaker is powered wirelessly through technology that is used in the wireless charging of portable electronic devices, electric toothbrushes, and contactless payments through smartphones. Electrical stimulation is delivered by the implanted device to pace the heart at various rates, stimulation strengths, and time periods by wireless power transfer according to the clinical need throughout the postoperative period (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021). Alternating currents (sine wave) generated by a function generator provide a source of monophasic RF power to a transmission (Tx) antenna placed near the power harvester component of the device. The Rx coil transforms the received waveform to an approximately direct current output via the RF diode and delivers it to the interface with the myocardium as a cathodic direct current pulse through the electrode pads. An applied electrical stimulus above a threshold value initiates cardiac excitation as a result of depolarization of the transmembrane potential. This type of inductive scheme is common for wireless power transfer in implanted medical devices (Winter, K. F., Hartmann, R. & Klinke, R. A 1998) because the magnetic coupling that occurs in this megahertz frequency regime (~13.5 MHz) avoids absorption by biofluids or biological tissues (Kang, S. K. et al. 2016). Simply put, the receiver in the device converts radio frequency power that it receives from an external source into electric current that can control the heart rate. This is done through electrodes present in an encapsulating layer which connect to the heart’s surface.
The researchers want to understand and learn what happens to the biodegradable materials as they dissolve before the device begins human testing. Other concerns brought up by the researchers were regarding the dissolving process. They explained how it does not happen in a uniform way and can smaller fragments. Studies need to be done on where these fragments go before completely reabsorbing and whether there are any chances of dislodgement of the fragments in the body.
Given the scope of future testing, it is safe to say that at this stage of testing, the device has overcome a lot of the problems it sought to solve. The materials and design choices create a thin, flexible and lightweight form that maintains excellent biocompatibility and stable function throughout the desired period of use. Over a subsequent time frame following the completion of therapy, the devices disappear completely through natural biological processes. Wireless energy transfer via resonant inductive coupling delivers power to the system in a manner that eliminates the need for batteries and allows for externalized control without transcutaneous leads. These characteristics, together with a miniaturized geometry, facilitate full implantation into the body to eliminate the need for percutaneous hardware, thereby minimizing the risk of device-associated infections and dislodgement (Choi, Y.S., Yin, R.T., Pfenniger, A. et al. 2021).
References
Choi YS, Yin RT, Pfenniger A, Koo J, Avila R, Benjamin Lee K, Chen SW, Lee G, Li G, Qiao Y, et al. 2021 Jun 28. Fully implantable and bioresorbable cardiac pacemakers without leads or batteries. Nature Biotechnology.:1–11. doi:https://doi.org/10.1038/s41587-021-00948-x. https://www.nature.com/articles/s41587-021-00948-x.
Saito, Y., Nakamura, K., & Ito, H. (2018). Cell-based Biological Pacemakers: Progress and Problems. Acta medica Okayama, 72(1), 1–7. https://doi.org/10.18926/AMO/55656
Rog-Zielinska, E. A., Norris, R. A., Kohl, P., & Markwald, R. (2016). The Living Scar--Cardiac Fibroblasts and the Injured Heart. Trends in molecular medicine, 22(2), 99–114. https://doi.org/10.1016/j.molmed.2015.12.006
Zoll PM, Zoll RH, Falk RH, Clinton JE, Eitel DR, Antman EM. 1985. External noninvasive temporary cardiac pacing: clinical trials. Circulation. 71(5):937–944. doi:https://doi.org/10.1161/01.cir.71.5.937.
Imparato AM. 1972. Electrode Complications in Patients With Permanent Cardiac Pacemakers. Archives of Surgery. 105(5):705. doi:https://doi.org/10.1001/archsurg.1972.04180110030009.
Elmistekawy E. 2019. Safety of temporary pacemaker wires. Asian Cardiovascular and Thoracic Annals. 27(5):341–346. doi:https://doi.org/10.1177/0218492319833276.
Won SM, Koo J, Crawford KE, Mickle AD, Xue Y, Min S, McIlvried LA, Yan Y, Kim SB, Lee SM, et al. 2018. Natural Wax for Transient Electronics. Advanced Functional Materials. 28(32):1801819. doi:https://doi.org/10.1002/adfm.201801819.
Winter K-F, Hartmann R, Klinke R. 1998. A stimulator with wireless power and signal transmission for implantation in animal experiments and other applications. Journal of Neuroscience Methods. 79(1):79–85. doi:https://doi.org/10.1016/s0165-0270(97)00160-x.
Kang S-K, Murphy RKJ, Hwang S-W, Lee SM, Harburg DV, Krueger NA, Shin J, Gamble P, Cheng H, Yu S, et al. 2016. Bioresorbable silicon electronic sensors for the brain. Nature. 530(7588):71–76. doi:https://doi.org/10.1038/nature16492. [accessed 2019 Nov 22]. https://www.nature.com/articles/nature16492.
Making a wireless, biodegradable pacemaker. 2021 Jul 12. National Institutes of Health (NIH). https://www.nih.gov/news-events/nih-research-matters/making-wireless-biodegradable-pacemaker.
Scientists develop wireless pacemaker that dissolves in body. 2021 Jun 28. the Guardian. https://www.theguardian.com/science/2021/jun/28/wireless-pacemaker-dissolves-body.
First-ever transient pacemaker harmlessly dissolves in body. newsnorthwesternedu. https://news.northwestern.edu/stories/2021/06/first-ever-transient-pacemaker-harmlessly-dissolves-in-body/.
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