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SCI 발표논문

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Proc Natl Acad Sci U S A. 2023;120(51):e2315824120.

Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

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제1저자 김민지, 김초림 · 교신저자 이승표, 최영빈

소속 (9)
  1. Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Republic of Korea.
  2. Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
  3. Center for Nanoparticle Research, Institute for Basic Science, Seoul 08826, Republic of Korea.
  4. Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea.
  5. Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  6. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  7. Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
  8. Innovative Medical Technology Research Institute, Seoul National University Hospital, Seoul 08826, Republic of Korea.
  9. ToBIOs Inc., Seongbuk-gu, Seoul 02880, Republic of Korea.

Abstract

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Keywords

antihypertensionautomatic drug deliverybatteryless deviceimplantable devicetimed drug administration

Figures

Fig. 1.
Fig. 1. Schematic of the assembly procedure of the IDC and constituent units.
Fig. 2.
Fig. 2. Working principle of the IDC. Using the preexisting clockwork mechanism, the drug can be infused at precise 12-h intervals.
Fig. 3.
Fig. 3. In vitro drug infusion profiles of the metoprolol-loaded IDC. During the experiments, the IDC is recharged (A) manually by pressing the button in the manual charger 30 times consecutively (n = 3) every 24 h and (B) automatically by mechanical agitation of the whole IDC (n = 3). For mechanical agitation, the IDC is shaken at 100 rpm for 30 min every 24-h. The amount of infused metoprolol is measured at the expected infusion times as well as 10 min before the infusion for a duration of 72 h, while the IDC is fully immersed in 50 mL of pH 7.4 PBS at 37 °C. At each sampling time, 5 mL of the medium is extracted and the same volume of fresh medium is added back. (C) The IDC is tested under accelerated environments (n = 3). For this, we pull out the crown and intentionally rotate the hour axis for multiple turns, as we do when setting the clock, to accelerate the rotation. The amount of infused metoprolol is measured after every 10 turns, while the IDC is fully immersed in pH 7.4 PBS at 37 °C. Data are presented as means ± SD.
Fig. 4.
Fig. 4. In vivo pharmacokinetic profiles obtained from the four different animal groups: Oral-PBS (n = 5), Oral-MP (n = 5), IDC-PBS (n = 5), and IDC-MP (n = 5). (A) Profiles of Cmax measured 7, 14, 21, and 28 d after the onset of experiments. On each scheduled day, the measurement was performed at a strictly scheduled time with an allowable difference of less than 5 min. Short-term pharmacokinetic profiles of Oral-MP and IDC-MP obtained on (B) 7 d and (C) 28 d. The AUC was calculated using the trapezoidal rule. Data are presented as means ± SD. (n.s.: not significantly different).
Fig. 5.
Fig. 5. In vivo pharmacodynamics profiles obtained from the four different animal groups: Oral-PBS (n = 5), Oral-MP (n = 5), IDC-PBS (n = 5), and IDC-MP (n = 5). (A) Profiles of systolic, diastolic, and mean blood pressures. (B) Heart weight and ratio of heart/body weight measured at the end of experiments (28 d). Data are presented as means ± SD. (Red *indicates that Oral-MP significantly differs from Oral-PBS; Blue *indicates that IDC-MP significantly differs from Oral-PBS; Red #indicates that Oral-MP significantly differs from IDC-PBS; Blue # indicates that IDC-MP significantly differs from IDC-PBS. *P < 0.05, **P < 0.01, #P < 0.05, and ##P < 0.01).
Fig. 6.
Fig. 6. Histological analysis on tissues surrounding the IDC, which are biopsied on 0 (n = 5) and 28 d (n = 5) after the onset of experiments (i.e., 14 and 42 d after IDC implantation, respectively). Representative images of the H&E-stained tissues are obtained at (A) 200× and (B) 40× magnification, using an optical microscope. (Scale bars are 100 µm.) The asterisk (*) indicates the location of the implanted IDC. Arrows show the capsule thickness. Data are presented as means ± SD. (n.s.: not significantly different).

그림 출처: PubMed Central 공개 논문 (PMC10741381)

Conflict of interest statement

Competing interests statement:Min Ji Kim, C.R.K., and Y.B.C. are listed as inventors on the patent application (KR 10-2022-0087244, PCT/KR2023/009827) filed by Seoul National University Research & Development Business (SNU R&DB) for the device described in this article. The other authors declare no conflicts of interest.

그 밖의 정보
출판 형태
Journal Article, Research Support, Non-U.S. Gov't
저널
Proceedings of the National Academy of Sciences of the United States of America · eISSN 1091-6490
전자 출판
2023-12-14
MeSH
Animals · Humans · Pharmaceutical Preparations · Electric Power Supplies*
Substances
Pharmaceutical Preparations
연구비
National Research Foundation of Korea (NRF) 2021R1A2B5B03001914 · Seoul National University Hospital (SNUH) 04-2021-2020
참고문헌
48편