Millimeter-scale bioresorbable pacemaker with optoelectronic system and powering system and applications thereof

Abstract

This invention discloses a pacemaker for stimulation‎ for a subject, comprising a phototransistor; and first and second electrodes, each electrode having a first end electrically connected to the phototransistor and a second end in communication with a target tissue of the subject for the stimulation‎. The pacemaker is self-powered with an optical control mechanism, wherein the first and second electrodes serve as both battery electrodes and pacing electrodes. The pacemaker is optically controlled by a wearable device that monitors physiological parameters and provides closed-loop, on-demand operation of the implantable pacemaker.

Description

[0001] Attorney Docket No.616146.100572 MILLIMETER-SCALE BIORESORBABLE PACEMAKER WITH OPTOELECTRONIC SYSTEM AND POWERING SYSTEM AND APPLICATIONS THEREOF STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH This invention was made with government support under grant number HL141470 awarded by the National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED PATENT APPLICATION This application claims priority to and the benefit of U.S. Provisional Application Serial No. 63 / 645,241, filed May 10, 2024, which is incorporated herein in its entirety by reference. FIELD OF THE INVENTION This invention relates generally to the field of biomedical engineering, and more particularly to a millimeter-scale, bioresorbable pacemaker with an optoelectronic system and on-board power supply, and a wireless, optical control mechanism. BACKGROUND OF THE INVENTION The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention. Temporary pacemakers are essential life-saving technologies for patients who suffer from short-lived bradycardia, typically on the order of days or weeks. Applications include postoperative care after cardiac surgery, a heart attack, or a medication overdose. Most adult patients and all pediatric patients receive a temporary pacemaker after cardiac surgery. Conventional temporary pacing requires epicardial or transvenous placements of pacing leads, which necessitates invasive Attorney Docket No.616146.100572 open-heart or endovascular surgeries. The former can lead to difficult post-surgery recovery processes, extended hospitalization times, and significant surgical scars. Endovascular surgeries are challenging for adult patients with contraindications to transvenous pacemakers and for pediatric patients with small body sizes and rapid patterns of growth. Other complications include risks of infections with the pacing leads and their percutaneous access points, lacerations, and perforations of the myocardium due to removal or replacement of these leads, and displacements of external power supplies and control systems. These circumstances create a pressing need for alternative technologies and surgical procedures. Recent work on bioresorbable devices and on materials- oriented strategies address certain challenges, but with important limitations due to their physical sizes, surgical demands, patient burdens and operating mechanisms. Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies. SUMMARY OF THE INVENTION In one aspect, this invention discloses a pacemaker for stimulation for a subject, comprising a phototransistor (PT); and first and second electrodes, each electrode having a first end electrically connected to the PT and a second end in communication with a target tissue of the subject for the stimulation. In one embodiment, the stimulation comprises cardiac pacing, brain stimulation, spinal cord stimulation, peripheral nervous system stimulation, and / or skeletal muscle stimulation. In one embodiment, the pacemaker is self-powered with an optical control mechanism, wherein the first and second electrodes serve as both battery electrodes and stimulating electrodes. In one embodiment, one of the first and second electrodes serves as an anode, and the other of the first and second electrodes serves as a cathode, and the target tissue and associated biofluids act as an electrolyte to form a galvanic battery. In one embodiment, each of the anode and the cathode comprises an electrically conductive material that is bioresorbable or biodegradable. In one embodiment, the anode comprises a bioresorbable Mg, Mg alloy, Zn, and / or Zn alloy, e.g., AZ31 (Mg96Al3Zn1), and the cathode comprises an electropositive bioresorbable Fe, Mo, W, alloys of Fe, Mo and W, e.g., FeMn, molybdenum trioxide (MoO3), iodine, and / or MnO2. In one embodiment, the PT is configured to act as the optical control mechanism to control the operation of the pacemaker with an external light source that operably emits light at tissue- penetrating wavelengths in a near-infrared (NIR) range. Attorney Docket No.616146.100572 In one embodiment, the PT comprises a bipolar junction transistor (BJT), configured to respond to illumination of the light at the tissue-penetrating wavelengths. In one embodiment, the BJT has an emitter terminal and a collector terminal electrically connected to the anode and the cathode, respectively. In one embodiment, the emitter terminal and the collector terminal are electrically connected to the anode and cathode, respectively, using a biodegradable conductive paste. In one embodiment, the stimulation are performed upon the illumination of the light to the BJT through the skin and underlying tissue. In one embodiment, in absence of the illumination of the light to the BJT, the PT has a resistance that is sufficiently high so that flow of current through the galvanic battery is prevented, whereby the pacemaker is inactive. In one embodiment, upon the illumination of the light to the BJT, the PT has a resistance that decreases to sufficiently low, thereby closing the circuit and discharging the galvanic battery through the stimulating electrodes and the adjacent tissue. In one embodiment, the fast responses of the PT and the overall optoelectronic circuit allow for precise, dynamic control over the current delivered to the target tissue. In one embodiment, the pacemaker further comprises an encapsulation layer encapsulating the entire structure, leaving the second ends of the first and second electrodes exposed to interface with the target tissue. In one embodiment, the encapsulation layer comprises a bioresorbable formulation of polyanhydride, silk, cellulose, sodium carboxymethylcellulose (Na-CMC), alginate, starch, chitosan, albumin, gelatin, keratin, shellac candelilla wax, beeswax, galactomannan, carrageenan- agar, polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), poly(3-hydroxybutyrateco-3- hydroxyvalerate) (PHBV), bioresorbable polyanhydride, polyurethane, poly(lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA), polycaprolactone (PCL), silk fibroin (SF), polyethylene glycol (PEG), polyethylene glycol diacrylate (PEGDA), polyglycolic acid (PGA), polydopamine (PDA), polybutylene adipate terephthalate (PBAT), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (PDTEC), poly(glycerol sebacate) (PGS), poly(octamethylene maleate (anhydride) citrate) (POMaC), acrylic acid (AAc), gelatin methacrylate (gelMA), acrylic acid N-hydroxysuccinimide (AAc-NHS ester), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and / or polyethylene glycol-lactide diacrylate (PEG-LA-DA). In one embodiment, the pacemaker has a size in millimeter-scales. Attorney Docket No.616146.100572 In one embodiment, the pacemaker has a footprint of about 5 mm ^ 10 mm or less, and a thickness of about 5 mm or less. In one embodiment, the pacemaker has a footprint of about 1.8 mm ^ 3.5 mm or less, and a thickness of about 1 mm or less. In one embodiment, the pacemaker is configured to be administered to a site of interest of the subject via a minimally invasive implantation procedure, wherein the minimally invasive implantation procedure comprises percutaneous injection and endovascular delivery. In one embodiment, the pacemaker is configured to fit into a small-diameter introducer for injection directly into a superficial subepicardial layer of the myocardium of the subject through skin incisions. In one embodiment, the pacemaker is configured to be administered to a site of interest of the subject via transcatheter aortic valve replacement / implantation (TAVR / TAVI) procedures. In one embodiment, one or more of a plurality of the pacemakers can be integrated with transcatheter valve devices for aortic (TAVR), pulmonary, tricuspid, and mitral valves procedures. In one embodiment, the pacemaker is implanted via catheter endocardially for pacing the conduction system for resynchronization therapy. In another embodiment, one or more of the plurality of the pacemakers are delivered via minimally invasive catheter epicardially for resynchronization therapy. In one embodiment, the pacemaker is bioresorbable and biocompatible. In one embodiment, the pacemaker is bioresorbed or biodegraded in the subject’s body after a period of bioresorption, thereby eliminating the need for surgical extraction of the pacemaker after a period of operation. In one embodiment, the period of bioresorption is at least 10 days. In one embodiment, the period of bioresorption is customizable by appropriate choices of materials and device designs. In one embodiment, the pacemaker is pairable with a soft, skin-interfaced wireless device that continuously captures electrocardiograms, performs data analytics, and optically controls the pacemaker via programming light emission in the NIR range as the basis for autonomous, on- demand closed-loop cardiac electrotherapy upon detection of arrhythmias. In one embodiment, the pacemaker is usable for pacing in a multi-site manner with a wavelength-division multiplexed (WDM) technique for time-synchronized dual-chamber and biventricular pacing, including multi-site resynchronization therapy. In one embodiment, the pacemaker is integrable onto an implantable framework including a Attorney Docket No.616146.100572 transcatheter aortic valve replacement (TAVR) frame. In one embodiment, the pacemaker is compatible with medical imaging screening of magnetic resonance imaging (MRI) and / or computed tomography (CT). In another aspect, the invention relates to a system for cardiac pacing for a subject, comprising a plurality of pacemakers implanted to different sites of interest of the subject, each pacemaker is disclosed as above; wherein each pacemaker further includes a narrow band optical filter placed atop the PT therefor to serve as the basis for a wavelength-division multiplexed (WDM) control scheme; and wherein programmable optoelectronic control of the plurality of pacemakers forms the basis for time-synchronized multi-site operation for biventricular (BiV) and dual-chamber (A&V) pacing. In one embodiment, independent operation of the plurality of pacemakers relies on illumination at wavelengths aligned with the transmission properties of the filters. In one embodiment, in operations, light emitted from light source L(X) selectively passes through optical filter F(X), illuminates phototransistor PT(X), and then activates pacemaker P(X), wherein L(X), F(X), and P(X) form a matched group, wherein X = 1, 2, ... N, N being the number of the plurality of pacemakers. In one embodiment, the light source L(X) is configured to emit the light at an intensity sufficiently high such that the output current of P(X) is sufficient to pace the heart, but sufficiently low to avoid the stimulation of any other pacemaker. In one embodiment, the system has reliable programmability of cardiac pacing at multiple sites, with timing precisely controlled by the operation of the light sources. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the like. In one embodiment, placing the two pacemakers on the RV anterior wall and LV lateral wall allows for biventricular pacing. In one embodiment, positioning at the LA lateral wall and LV lateral wall enables dual- chamber pacing. In one embodiment, programmable WDM control of both LEDs enables BiV and A&V pacing. In one embodiment, the dual-chamber pacing modality yields a physiology more consistent with normal cardiac activation than that associated with simple ventricular pacing. In one embodiment, the system is usable for cardiac resynchronization therapy. In yet another aspect, the invention relates to a system for cardiac pacing for a subject, Attorney Docket No.616146.100572 comprising at least one pacemaker implanted to at least one site of interest of the subject, wherein each pacemaker is disclosed as above; and at least one skin-interfaced module attached to a skin surface of the subject in wireless communication with the at least one pacemaker for autonomous, closed-loop, on-demand cardiac electrotherapy. In one embodiment, the at least one skin-interfaced module is configured to perform single- lead recordings of electrocardiograms (ECG); wireless data transfer to a graphical user interface on a mobile device for real-time data visualization; closed-loop analytics for automated detection of cardiac arrhythmias; and programmed operation of integrated light sources to optically control the at least one pacemaker for the cardiac pacing. In one embodiment, the at least one skin-interfaced module comprises a power management circuit, ECG sensors, light sources, an analog frontend (AFE) that amplifies, filters, and digitizes the ECG signal, and a Bluetooth-low-energy (BLE) system-on-a-chip (SoC) that collects the conditioned ECG signal and streams in real time to the graphical user interface on the mobile device, which are integrated on a flexible printed circuit board. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the like. In one aspect, the invention relates to a system for cardiac pacing for a subject, comprising a transcatheter aortic valve replacement (TAVR) frame; and a plurality of pacemakers attached onto the TAVR frame placed in a heart of the subject for delivering both rapid pacing during valve deployment and regular pacing during the post-operative period, wherein each pacemaker is disclosed as above. In one embodiment, the plurality of pacemakers is attached onto junction points of struts of the TAVR frame, wherein the TAVR frame is a self-expanding stent. In one embodiment, the plurality of pacemakers is attached with the pacing electrodes facing the septal wall for effective pacing of the myocardium. In one embodiment, the plurality of pacemakers is attached with orienting most of the pacing electrodes toward the antero-septal region of the left ventricle to ensure proximity to the heart conduction system. In one embodiment, each pacemaker is activated separately using light emitted from the light sources, starting from lower intensities, faster pacing rates, and shorter pulse widths, followed by adjusting these parameters across a range until 100% capture, or failure. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the like. Attorney Docket No.616146.100572 In one embodiment, the plurality of pacemakers is activated simultaneously by external flood illumination to ensure reliable pacing even when the orientation and precise positioning of the TAVR stent cannot be controlled during implantation. These and other aspects of the present invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the invention. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment. FIGS.1A-1I show schematically a design of injectable, self-powered, bioresorbable cardiac pacemakers with wireless, optoelectronic control according to embodiments of the invention. FIG. 1A shows an exploded view of an injectable pacemaker on the left, a schematic illustration of the injectable pacemaker and the equivalent circuit on the top right, and a cross view of a phototransistor (PT). FIG.1B shows a photograph of the pacemaker from the electrodes side. FIG. 1C shows schematic illustrations of implantation process of the pacemaker via catheter injection. FIG.1D shows a photograph of the pacemaker from the PT side. FIG.1E shows schematic illustrations of the pacemaker pairing with a skin-interfaced optoelectronic device allows autonomous, closed-loop cardiac electrotherapy. FIG.1F shows a schematic diagram of the light- controlled, self-powered pacing mechanism, with illuminating the PT and therefore reducing its electrical resistance. FIG.1G shows a FEA result reflecting the current density distribution in the heart for operation of a pacemaker current of 0.5 mA under light illumination. FIG.1H shows a schematic illustration of bioresorption of a pacemaker. FIG.1I shows a photograph and chemistries of bioresorption of a pacemaker. Scale bars, 1 mm (FIG.1B, inset in FIGS.2D, and 1I) and 1 cm (FIG.1D). Illustration of the heart in FIGS.1C, 1E and 1H was created with TurboSquid. Illustrations of the Wi-Fi signal and smartphone in FIG.1E and the ventricle in FIG.1F were created with BioRender. FIGS.2A-2H shown optoelectronic characteristics and ex vivo pacing with human / porcine hearts according to embodiments of the invention. FIG.2A shows a chart reflecting temporal response of a pacemaker under pulsed light illumination. FIG.2B shows a chart reflecting output Attorney Docket No.616146.100572 currents of a pacemaker as a function of light intensity. (Inset: equivalent circuit of the pacemaker. R1, ohmic resistance; R2, charge transfer resistance of the anode; R3, charge transfer resistance of the cathode; Q2, constant phase element of the anode; Q3, constant phase element of the cathode.) FIG.2C shows a photograph of setup for an ex vivo porcine heart pacing using the pacemaker. n = 3 biologically independent animals. FIG.2D shows a plot reflecting a strength-duration curve of the pacemaker for the embodiment in FIG.2C. FIG.2E shows ECG results of the pacemaker for the embodiment in FIG.2C. FIG.2F shows a schematic illustration of ex vivo human heart pacing at three different sites: left ventricle (i), right ventricle (ii), and Bundle of His (iii). n = 5 biologically independent individuals. FIG.2G shows a photograph of ex vivo human heart pacing at three different sites: left ventricle (i), right ventricle (ii), and Bundle of His (iii). FIG.2H shows ECG results of ex vivo human heart pacing at three different sites: left ventricle (i), right ventricle (ii), and Bundle of His (iii). Scale bars, 1 cm (FIGS.2C and 2G). Illustration of the heart in FIG.2F was created with BioRender. FIGS.3A-3H show in vivo demonstration of pacemaker injection and closed-chest pacing in canine models according to embodiments of the invention. FIG.3A shows a schematic diagram of a setup for optical simulation when illuminating the skin of the chest with NIR light (850 nm). FIG. 3B shows normalized light intensity in the body for the optical simulation of FIG.3A. FIG.3C shows a chart reflecting a percentage of light received by the PT at various depths beneath tissue. FIG.3D shows schematic illustrations (upper panel) and photographs (lower panel) of pacemaker injection process and optical stimulation. FIG.3E shows a fluoroscopy imaging of a canine heart with the pacemaker inserted in the superficial subepicardial layers of the myocardium. FIG.3F shows a photograph of the canine heart with the pacemaker inserted in the superficial subepicardial layers of the myocardium. FIG.3G shows ECG results before and during cardiac pacing underoptical stimulation. FIG. H shows ECG results before and during cardiac pacing after theimplantation of the Zn–MoO3 pacemakers. Tests extended for 20 days. Pulse width, 5 ms; pacing rate, 430 bpm. n = 4 biologically independent animals. Scale bars, 5 cm (FIGS.3A-3B), 2 cm (FIG.3E) and 1 cm (FIG. 3G). Illustrations of the human body and heart in FIG. 3A were created withTurboSquid. Illustrations of the dog, pink syringe tip and blue introducer in FIG. D were createdwith BioRender. FIGS.4A-4D show in vivo demonstration of multi-site, time-synchronized pacing in canine models according to embodiments of the invention. FIG.4A shows a schematic illustration of wavelength-division multiplexing. FIG.4B shows a schematic illustration of multi-site pacing enabled by the wavelength-division multiplexing of FIG.4A. FIG.4C shows charts reflecting Attorney Docket No.616146.100572 output currents of pacemakers P(1) and P(2) during simultaneous illumination at different intensities from LEDs (1) and (2). FIG.4D shows ECG (Lead I) in sinus rhythm and during time- synchronized cardiac pacing of sites at 150 bpm including LA only, LV only, RV only, BiV (LV+RV, 0 ms LV-RV offset), and A&V (LA+LV, 80 ms AV delay). n = 5 biologicallyindependent animals. Illustration of the heart in FIG. 4B was created with BioRender.FIGS.5A-5F show schematically a design of a wireless, skin-interfaced optoelectronic system for closed-loop cardiac electrotherapy according to embodiments of the invention. FIG.5A shows a schematic illustration of placement of a soft, skin-interfaced device for monitoring and control in a rat model. FIG.5B shows a photograph of the structure of the soft, skin-interfaced device for monitoring in FIG.5A. FIG.5C shows an exploded view of the soft, skin-interfaced device for monitoring in FIG.5A. FIG.5D shows an illustration of architecture of the device in FIG.5A, including power management circuits, a Bluetooth-low-energy (BLE) system-on-a-chip (SoC), analogue front ends and ECG sensors, and LED stimulators. FIG.5E shows a photograph illustrating a pacemaker placed on the surface of a rat heart. FIG.5F shows ECG results reflecting that detection of a heart rate lower than the bradycardic threshold (220 bpm) automatically initiates pacing (240 bpm, 2 ms pulse). GPIOs, general-purpose inputs / outputs, Scale bars, 1 cm (FIG.5B)and 2 mm (FIG. 5E). Illustration of the rat in FIG. 5A was created with BioRender.FIGS.6A-6D show ex vivo demonstration of cardiac pacing with a collection of pacemakers integrated with a TAVR valve in a human heart according to embodiments of the invention. FIG. 6A shows a schematic illustration of a deployed TAVR valve mounted with six pacemakers according to one embodiment of the invention. FIG.6B shows a photograph of the deployed TAVR valve mounted with six pacemakers of FIG.6A. FIG.6C shows a photograph showing the implantation of the valve in the aortic position of a Langendorff-perfused human heart, in which the pacemakers are color-coded and their relative locations are shown in the upper left corner. FIG.6D shows charts of ECG results during independent activation of each pacemaker. The table in the bottom summarizes the pacing abilities of these pacemakers under different stimulation conditions. NA, not applicable; VLED, voltage applied to the LED. n = 3 biologically independent subjects.Scale bars, 1 cm (FIGS. 6B-6C). Illustration of the heart in FIG. 6A was created with BioRender.FIG.7 shows comparisons of previously reported pacemakers and the technology; panel (a) shows comparisons between conventional pacemakers with leads, leadless pacemakers, bioresorbable pacemakers, and the pacemaker reported here; panel (b) shows a table showing details of previously reported leadless pacemakers and the pacemaker reported here. Illustration ofthe pacemaker with leads in panel (a) was created with BioRender. Bioresorbable pacemaker in Attorney Docket No.616146.100572panel (a) adapted from Ref. [1], Springer Nature America, Inc.FIG.8 shows plots reflecting characteristic curves of the PTs under various light intensities emitted from a NIR LED (850 nm, a) and a red LED (650 nm, b). FIG.9 shows measurement of the operational lifespan of the device. a, EIS of an agarose gel and chicken tissue. b, The output currents of the pacemaker over days. c, Output currents of the pacemaker over days under pulsed illumination. FIG.10 shows In vivo demonstration of cardiac pacing in mouse models; (a) photograph showing a pacemaker placed on the surface of a mouse heart; (b) ECG results before and during mouse heart pacing; (c) strength-duration curve when pacing at 480 bpm. n =  3 biologically independent animals. FIG.11 shows selection of LEDs and optical filters for multi-site, time-synchronized cardiac pacing; (a) emission spectra for LEDs (1) and (2); (b) transmission curves for filters (1) and (2); (c) transmitted light intensities as a function of incident intensities from LEDs (1) and (2) for filters (1) and (2). FIG.12 shows a schematic illustration showing the fabrication process (cross-section view) of the PT. FIG.13 shows an optical microscope image of a BJT-based phototransistor. FIG.14 shows a schematic diagram of light-controlled and self-powered pacing mechanism. Illuminating the phototransistor decreases its electrical resistance and thus discharges the electrochemical cell formed by the anode and cathode with surrounding tissue and biofluids as the electrolyte. During the discharge (FIGS.14-15), the Mg anode undergoes an oxidation reaction ( Mg- 2e- -> Mg2+), and the cathode undergoes a reduction reaction (Mo03+ ne- -> Mo03'). The electrons move from the anode to the cathode. The current flows from the cathode to the anode. The Mg2+ions and other cations like Na+and K+in the tissue move from the anode to the cathode, to complete the circuit. FIG.15 shows discharge profiles of the Mg-MoO3cells at constant currents of 0.1, 0.3, and 0.5 mA. FIG.16 shows CT scans of a rat with a pacemaker implanted on the surface of the heart: sagittal view (left) and coronal view (right). Red circle indicates the position of the device. FIG.17 shows MRI images of the water phantom with a pacemaker inside. FIG.18 shows MRI images of a rat with a pacemaker implanted on the surface of the heart: coronal view (top left), sagittal view (top right), axial view (bottom). Red circle indicates the position of the device. Attorney Docket No.616146.100572 FIG.19 shows saturation currents of pacemakers with fully bioresorbable MoO3 / Mo cathodes with different sizes of electrodes. FIG.20 shows Cell viability by percentages of live cells for the blank (with no sample added), PA, and pacemaker groups. Data are presented with error bars as means ± s.d. n=4 biological replicates. One-way ANOVA, P = 0.9063. FIG.21 show in vivo biocompatibility and toxicity studies in rat models. a, Weight changes of animals after the implantation of control and device groups. b, Analysis of complete blood counts and blood chemistry after implantation of control and device groups at 1-week and 4-week endpoints. RBC, red blood cell (×1,000,000 µl−1); HGB, blood haemoglobin level (g dl−1); HCT, haematocrit level (%); MCV, mean corpuscular volume (fl); MCH, mean corpuscular haemoglobin (pg); MCHC, mean corpuscular hemoglobin concentration (g dl−1); PLT, platelet count in blood (×1,000 µl−1); WBC, white blood cell (×1,000 µl−1); GLU, glucose (mg dl−1); TRIG, triglycerides (mg dl−1); ALT, alanine aminotransferase (U l−1); AST, aspartate transaminase (U l−1); ALP, alkaline phosphatase (U l−1); CHOL, cholesterol (mg dl−1); Cl, chloride (mmol l−1); Na, sodium (mmol l−1); Na / K, sodium / potassium ratio; TCO2, bicarbonate (mmol l−1); Urea, blood urea nitrogen (mg dl−1); PHOS, phosphorus (mg dl−1); Ca, calcium (mg dl−1); ALB, albumin (g dl−1); A / G, albumin / globulin; CREA, creatinine (mg dl−1); GLOB, globulin (g dl−1); K, potassium (mmol l−1); TBIL, total bilirubin (mg dl−1); TP, total protein (g dl−1). Data are presented with error bars as means ± s.d. n = 3 biologically independent animals. Two-way ANOVA, P = 0.1052 for the whole blood, P = 0.7089 for the blood serum. c, Representative images of H&E-stained cross-sectional areas near the site of implantation of control and device groups at the 1-week and 4-week endpoints. n = 3 biologically independent animals. Scale bar: 200 μm. (i) Around the cavities of the implantation site, the infiltration of varying numbers of mononuclear macrophages, lymphocytes, and plasma cells are observed. Overall, there is a mild to moderate inflammatory response, accompanied by stromal fibrous tissue hyperplasia and myxoid degeneration. (ii) Fibrous tissue hyperplasia is observed around the implantation site, with localized aggregation of macrophages (mild inflammation), some of which show pigment deposition from phagocytosed red blood cells. The proliferation of small blood vessels is present in the surrounding area, with the scattered distribution of some atypical, deeply stained cells. (iii) Localized inflammatory exudate is observed adjacent to the implantation site, with significant proliferation of macrophages. In the stroma distant from the implant site, there is fibrous tissue hyperplasia accompanied by numerous macrophages, lymphocytes, and plasma cell infiltration. Lymphocyte and plasma cell infiltration can also be seen between adjacent myocardial tissues. Overall, a moderate inflammatory response is present, with exudation and necrosis resulting from acute inflammation. (iv) After the biosorption of the Attorney Docket No.616146.100572 material, irregular cavity distribution is observed, seemingly with myxoid-like substances. There is a marked proliferation of mesothelial-like cells around the cavities, with scattered lymphocyte infiltration (mild inflammation) and proliferation of fibrous tissue and blood vessels in the stroma. FIG.22 shows technical specifications of the device. a, Output currents of a pacemaker as a function of light intensity. b, Percentage of light received by the PT at various depths beneath the skin. c, Light intensities required on the skin surface for different pacemaker outputs with the pacemaker implanted 30 mm deep beneath the skin. FIG.23 shows light intensities required on the skin surface for different pacemaker’s outputs under tissue depths of 10, 20, 30, and 40 mm. FIG.24 shows electrochemical impedance spectroscopy (EIS) of the pacemaker embedded in soft chicken muscle tissue. a, Experimental and simulated EIS plots. b, Equivalent electric circuit. c, Descriptions and values of parameters in the equivalent electric circuit. FIG.25 shows a flowchart of procedure for determining the strength-duration curve. FIG.26 shows optical simulation results. a, Normalized light intensity in the body as a function of tissue depth along two parallel trajectories in the direction of the incident light: one passing through the ribs and the other penetrating only soft tissue. b, Percentage of light received by the PT at various depths beneath the skin. c, Light intensities required on the skin surface to achieve an adequate pacing output of 0.64 mA for various implantation depths beneath the skin. FIG.27 shows photographs of pacemakers with the extended phototransistor. This modified design is for patients requiring device implantation deeper than 60 mm, in a way that ensures reliable light management. Here, the phototransistor (light-sensing component) lies close to the surface of the skin, while the pacing electrodes remain inserted into the heart. The pacing electrodes and phototransistor electrically connect through serpentine interconnects. FIG.28 shows photographs showing the injection of the pacemaker. Scale bar: 5 cm. FIG.29 shows measurement of in vivo operational lifespan of the device. a, c, Changes on the pacing threshold (minimum voltage applied on the NIR LED) after the implantation of pacemakers made of Mg-MoO3 (a) and Zn-MoO3 (c, pulse width: 5 ms) pairs. Phase I: capture under 5 ms pulse; Phase II: capture under 10 ms pulse; Phase III: loss of capture under 10 ms pulse. b, d, ECG signal before and during pacing. Pacemakers utilize Mg-MoO3(b) and Zn-MoO3(d, pulse width: 5 ms) pairs. n = 4 biologically independent animals. Zn anodes exhibit better electrochemical stability than Mg anodes. FIG.30 shows photographs for the multi-site, time-synchronized cardiac pacing experiments. a, Photographs of pacemakers P(1) and P(2) with filters (1) and (2) on top. b, Attorney Docket No.616146.100572 Photograph showing pacemakers P(1) and P(2) placed on the surface of right and left ventricles, respectively. FIG.31 shows ECG results showing transition from sinus rhythm to LV pacing in canine models (in vivo). FIG.32 shows ECG results showing transition from sinus rhythm to RV pacing in canine models (in vivo). FIG.33 shows ECG results showing transition from RV pacing to BiV pacing in canine models (in vivo). FIG.34 shows ECG results showing transition from sinus rhythm to LA pacing in canine models (in vivo). FIG.35 shows ECG results showing transitions from LA pacing to A&V pacing in canine models (in vivo). FIG.36 shows strength-duration curve (a) and ECG results (b) of ex vivo human heart pacing with pacemakers located in the TAVI valve position. The ECG were collected at two pacing conditions (1.2 Hz, 0.4 ms pulse, 1.14 mA; and 1.2 Hz, 8 ms pulse, 0.23 mA). The above results indicate that an adequate threshold can be achieved in the TAVI valve position. The strength- duration curve reveals that the pacemaker can achieve more than twice the threshold, to ensure a stable and reliable operation. FIG.37 shows a schematic illustration showing the placement of the valve in the aortic position of a Langendorff-perfused human heart. DETAILED DESCRIPTION OF THE INVENTION The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout. The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of Attorney Docket No.616146.100572 highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification. One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein. It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably. Attorney Docket No.616146.100572 It will be understood that when an element is referred to as being “on”, “attached” to, “connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature. It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention. Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below. It will be further understood that the terms “comprises” and / or “comprising”, or “includes” and / or “including”, or “has” and / or “having”, or “carry” and / or “carrying”, or “contain” and / or “containing”, or “involve” and / or “involving”, “characterized by”, and the like are to be open- ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof. Attorney Docket No.616146.100572 Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. As used in the disclosure, “around”, “about”, “approximately” or “substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated. As used in the disclosure, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. The term “flexibility” or “bendability”, as used in the disclosure, refers to the ability of a material, structure, device or device component to be deformed into a curved or bent shape without undergoing a transformation that introduces significant strain, such as strain characterizing the failure point of a material, structure, device or device component. In an exemplary embodiment, a flexible material, structure, device or device component may be deformed into a curved shape without introducing strain larger than or equal to 5%, for some applications larger than or equal to 1%, and for yet other applications larger than or equal to 0.5% in strain-sensitive regions. A used herein, some, but not necessarily all, flexible structures are also stretchable. A variety of properties provide flexible structures (e.g., device components) of the invention, including materials properties such as a low modulus, bending stiffness and flexural rigidity; physical dimensions such as small average thickness (e.g., less than 100 microns, optionally less than 10 microns and optionally less than 1 micron) and device geometries such as thin film and open or mesh geometries. The term “bending stiffness” refers to a mechanical property of a material, device or layer describing the resistance of the material, device or layer to an applied bending moment. Generally, bending stiffness is defined as the product of the modulus and area moment of inertia of the material, device or layer. A material having an inhomogeneous bending stiffness may optionally be described in terms of a “bulk” or “average” bending stiffness for the entire layer of material. The term “elastomer”, as used in the disclosure, refers to a polymeric material which can be stretched or deformed and return to its original shape without substantial permanent deformation. Attorney Docket No.616146.100572 Elastomers commonly undergo substantially elastic deformations. Useful elastomers include those comprising polymers, copolymers, composite materials or mixtures of polymers and copolymers. Elastomeric layer refers to a layer comprising at least one elastomer. Elastomeric layers may also include dopants and other non-elastomeric materials. Useful elastomers useful include, but are not limited to, thermoplastic elastomers, styrenic materials, olefenic materials, polyolefin, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, PDMS, polybutadiene, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and silicones. Exemplary elastomers include, but are not limited to, silicon containing polymers such as polysiloxanes including poly(dimethyl siloxane) (i.e., PDMS and h-PDMS), poly(methyl siloxane), partially alkylated poly(methyl siloxane), poly(alkyl methyl siloxane) and poly(phenyl methyl siloxane), silicon modified elastomers, thermoplastic elastomers, styrenic materials, olefenic materials, polyolefin, polyurethane thermoplastic elastomers, polyamides, synthetic rubbers, polyisobutylene, poly(styrene-butadiene-styrene), polyurethanes, polychloroprene and silicones. In one embodiment, a flexible polymer is a flexible elastomer. The term “encapsulate” or “encapsulation”, as used in the disclosure, refers to the orientation of one structure such that it is at least partially, and in some cases completely, surrounded by one or more other structures. “Partially encapsulated” refers to the orientation of one structure such that it is partially surrounded by one or more other structures. “Completely encapsulated” refers to the orientation of one structure such that it is completely surrounded by one or more other structures. The invention includes devices having partially or completely encapsulated electronic devices, device components and / or inorganic semiconductor components. As used in the disclosure, the term “wearable” refers to articles, adornments or items designed to be worn by a user, incorporated into another item worn by a user, act as an orthosis for the user, or interfacing with the contours of a user's body. As used in the disclosure, “biocompatible” material is a material that is compatible with living tissue or a living system by not being toxic or injurious and not causing immunological rejection. As used in the disclosure, the term “implantable” refers to an ability of a device to be positioned at a location within a body of a user, such as subcutaneously, within a body cavity, or etc. Furthermore, the terms “implantation” and “implanted” refer to the positioning of a device at a location within a body of a user, such as subcutaneously, within a body cavity, or etc. As used in the disclosure, the term “bioresorbable” refers to an ability of biodegradable, a breakdown of a compound into a simpler substance or substances that are eliminated by the body, Attorney Docket No.616146.100572 or “naturally absorbing”. The description is now made as to the embodiments of this invention in conjunction with the accompanying drawings. Various modifications to these aspects will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other aspects. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the invention. Temporary pacemakers are essential components for the care of patients with short-lived bradycardia in a postoperative and other settings. Conventional devices require invasive open-heart or less invasive endovascular surgeries, both challenging for paediatric and adult patients. Other complications include risks of infections, lacerations and perforations of the myocardium, and displacements of external power supplies and control systems. In view of the foregoing, this invention in one aspect provides a millimeter-scale, bioresorbable optoelectronic system with on-board power supply and a wireless, optical control mechanism with generalized capabilities in electrotherapy and specific application opportunities in temporary cardiac pacing. The system addresses the risks and complexities associated with conventional temporary pacemakers, such as infections and the need for surgical removal, by using a wireless, optical control mechanism and an onboard power supply. This approach aims to reduce the invasiveness of cardiac support devices and associated patient recovery time. The extremely small sizes of these devices enable minimally invasive implantation, including percutaneous injection and endovascular delivery. Experimental studies demonstrate effective pacing in mouse, rat, porcine, canine, and human cardiac models at both single-site and multi-site locations. Pairing with a skin-interfaced wireless device allows autonomous, on-demand operation upon detection of arrhythmias. The miniaturized device can be combined with other medical implants, with an example of arrays of pacemakers for individual or collective use on the frames of transcatheter aortic valve replacement systems, to provide unique solutions that address risks for atrioventricular block following surgeries. This base technology can be readily adapted for a broad range of additional applications in electrotherapy, such as nerve and bone regeneration, wound therapy, and pain management. Attorney Docket No.616146.100572 Unlike conventional pacing mechanisms that require pacing leads and separate power supplies, the novel technology directly utilizes battery electrodes as pacing electrodes. The extremely small size (1.8 mm × 3.5 mm × 1 mm) of this self-powered and leadless technology, > 2.5 times smaller than any previously reported device and > 23 times smaller than any bioresorbable alternative shown in FIG.7, minimizes device load on and risks to the patient, allows for application even with the smallest neonates and enables implantation using minimally invasive surgical techniques. Demonstrated options include percutaneous injection and endovascular delivery with additional opportunities for combined use with other medical procedures and devices, including transcatheter aortic valve replacement / implantation (TAVR / TAVI) procedures. Other distinguishing features of the invention also include the one or more abilities to: (1) pair with a soft, skin-interfaced, wireless unit that continuously captures electrocardiograms, performs data analytics, and optically controls the pacemaker as the basis for autonomous, on- demand closed-loop operation upon detection of cardiac arrhythmias; (2) pace in a multi-site manner with a wavelength-division multiplexed (WDM) technique for time-synchronized dual- chamber and biventricular pacing, including multi-site resynchronization therapy; (3) operate collections of devices directly integrated onto implantable frameworks, including TAVR stents; and (4) allow for medical imaging through compatibility with magnetic resonance imaging (MRI) and computed tomography (CT). According to the invention, the millimeter-scale, bioresorbable optoelectronic system represents a unique class of pacing technology capable of broad applications as an injectable, wireless source of electrostimulation. Broad experimental and computational studies reveal the fundamental aspects of materials science, device operation, and clinical use, the latter through optically controlled cardiac pacing in small- and large-animal models. Among other things, options for minimally invasive implantation techniques represent key features of particular value for all paediatric patients and for many adults for whom conventional, wired technologies are poorly suited. The minimized device load on and risks to the patient are also important in delivering improved outcomes. The capabilities for multi-site pacing for collections of devices follow naturally from concepts in wavelength-division multiplexing, as the basis for advanced pacing modalities such as biventricular pacing for cardiac resynchronization therapy and dual-chamber pacing for physiologically consistent responses. The compatibility with MRI and CT imaging methods allows for opportunities in advanced diagnotherapy. Many of these same engineering attributes create unique strategies, such as integration with established medical implants or temporary devices. As a specific example, results show that Attorney Docket No.616146.100572 collections of devices bonded at locations distributed across TAVR frames offer the potential for managing post-procedural TAVR conduction disturbances, such as the atrioventricular block. Successful clinical application in this context could enable same-day discharge of patients for an ambulatory procedure that, in its current form, requires intensive care unit settings. This concept foreshadows an era of cardiac care where structural and electrical support converge in a single minimally invasive procedure with seamless, patient-centric intervention, activated on demand. The invention stands out due to its focus on a fully bioresorbable form, with only a small amount (1.6% wt) of carbon black used in the cathodes unless replaced with Mo for complete bioresorption but slightly larger size for similar performance. Additionally, the use of optical mechanisms for device control and power represents a unique and innovative approach to managing and operating devices within the body. By eliminating the need for surgical intervention, this approach may also reduce the likelihood of long-term complications. This work represents significant key differences in the underlying concepts, in the engineering parameters and the clinical use cases. These differences allow for millimeter-scale pacemakers, suitable for implantation in a minimally invasive way and for unusual forms of integration within the body and / or on biomedical implants. These new platforms have particular value with paediatric patients. Currently, no pediatric pacemaker is available on the market, especially for newborns after open heart surgery for congenital heart defects. Unique opportunities are in integration with established medical implants, as demonstrated in the manuscript with first- of-a-kind pacemakers-integrated transcatheter aortic valve replacement (TAVR) systems, with additional opportunities across a wide range of applications in electrotherapy. The base technology according to the invention can be readily adapted for a broad range of additional applications in electrotherapy. Areas of particular interest are in electrical stimulation for nerve and bone regeneration, wound therapy, and pain management. Promising directions for future research in these and other areas include means for further miniaturization through materials and device design optimization, for introduction of stimulus-responsive materials for actively controlled degradation, for investigation of other mechanisms for wireless control, for enhanced safety in surgical delivery and improved fixation of devices through bioresorbable adhesivesr relatively small hearts. Important additional opportunities are in advanced clinical application of this technology and integration of this approach with other medical procedures. Without intent to limit the scope of the invention, exemplary embodiments of the invention are given below. One aspect of the invention discloses a pacemaker for stimulation for a subject, comprising Attorney Docket No.616146.100572 a phototransistor (PT); and first and second electrodes, each electrode having a first end electrically connected to the PT and a second end in communication with a target tissue of the subject for the stimulation. In one embodiment, the stimulation comprises cardiac pacing, brain stimulation, spinal cord stimulation, peripheral nervous system stimulation, and / or skeletal muscle stimulation. In one embodiment, the pacemaker is self-powered with an optical control mechanism, wherein the first and second electrodes serve as both battery electrodes and stimulating electrodes. In one embodiment, one of the first and second electrodes serves as an anode, and the other of the first and second electrodes serves as a cathode, and the target tissue and associated biofluids act as an electrolyte to form a galvanic battery. In one embodiment, each of the anode and the cathode comprises an electrically conductive material that is bioresorbable or biodegradable. the anode comprises a bioresorbable Mg, Mg alloy, Zn, and / or Zn alloy, e.g., AZ31 (Mg96Al3Zn1), and the cathode comprises an electropositive bioresorbable Fe, Mo, W, alloys of Fe, Mo and W (e.g., FeMn), molybdenum trioxide (MoO3), iodine, and / or MnO2. In one embodiment, the PT is configured to act as the optical control mechanism to control the operation of the pacemaker with an external light source that operably emits light at tissue- penetrating wavelengths in a near-infrared (NIR) range. In one embodiment, the PT comprises a bipolar junction transistor (BJT), configured to respond to illumination of the light at the tissue-penetrating wavelengths. In one embodiment, the BJT has an emitter terminal and a collector terminal electrically connected to the anode and the cathode, respectively. In one embodiment, the emitter terminal and the collector terminal are electrically connected to the anode and cathode, respectively, using a biodegradable conductive paste. In one embodiment, the stimulation are performed upon the illumination of the light to the BJT through the skin and underlying tissue. In one embodiment, in absence of the illumination of the light to the BJT, the PT has a resistance that is sufficiently high so that flow of current through the galvanic battery is prevented, whereby the pacemaker is inactive. In one embodiment, upon the illumination of the light to the BJT, the PT has a resistance that decreases to sufficiently low, thereby closing the circuit and discharging the galvanic battery through the stimulating electrodes and the adjacent tissue. In one embodiment, the fast responses of the PT and the overall optoelectronic circuit allow Attorney Docket No.616146.100572 for precise, dynamic control over the current delivered to the target tissue. In one embodiment, the pacemaker further comprises an encapsulation layer encapsulating the entire structure, leaving the second ends of the first and second electrodes exposed to interface with the target tissue. In one embodiment, the encapsulation layer comprises a bioresorbable formulation of polyanhydride, silk, cellulose, sodium carboxymethylcellulose (Na-CMC), alginate, starch, chitosan, albumin, gelatin, keratin, shellac candelilla wax, beeswax, galactomannan, carrageenan- agar, polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), poly(3-hydroxybutyrateco-3- hydroxyvalerate) (PHBV), bioresorbable polyanhydride, polyurethane, poly(lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PDLLA), poly(L-lactic acid) (PLLA), polycaprolactone (PCL), silk fibroin (SF), polyethylene glycol (PEG), polyethylene glycol diacrylate (PEGDA), polyglycolic acid (PGA), polydopamine (PDA), polybutylene adipate terephthalate (PBAT), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (PDTEC), poly(glycerol sebacate) (PGS), poly(octamethylene maleate (anhydride) citrate) (POMaC), acrylic acid (AAc), gelatin methacrylate (gelMA), acrylic acid N-hydroxysuccinimide (AAc-NHS ester), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and / or polyethylene glycol-lactide diacrylate (PEG-LA-DA). In one embodiment, the pacemaker has a size in millimeter-scales. In one embodiment, the pacemaker has a footprint of about 5 mm ^ 10 mm or less, and a thickness of about 5 mm or less. In one embodiment, the pacemaker has a footprint of about 1.8 mm ^ 3.5 mm or less, and a thickness of about 1 mm or less. In one embodiment, the pacemaker is configured to be administered to a site of interest of the subject via a minimally invasive implantation procedure, wherein the minimally invasive implantation procedure comprises percutaneous injection and endovascular delivery. In one embodiment, the pacemaker is configured to fit into a small-diameter introducer for injection directly into a superficial subepicardial layer of the myocardium of the subject through skin incisions. In one embodiment, the pacemaker is configured to be administered to a site of interest of the subject via transcatheter aortic valve replacement / implantation (TAVR / TAVI) procedures. In one embodiment, one or more of the plurality of the pacemakers can be integrated with transcatheter valve devices for aortic (TAVR), pulmonary, tricuspid, and mitral valves procedures. In one embodiment, the pacemaker is implanted via catheter endocardially for pacing the Attorney Docket No.616146.100572 conduction system for resynchronization therapy. In another embodiment, one or more of the plurality of the pacemakers is delivered via minimally invasive catheter epicardially for resynchronization therapy. In one embodiment, the pacemaker is bioresorbable and biocompatible. In one embodiment, the pacemaker is bioresorbed or biodegraded in the subject’s body after a period of bioresorption, thereby eliminating the need for surgical extraction of the pacemaker after a period of operation. In one embodiment, the period of bioresorption is at least 10 days. In one embodiment, the period of bioresorption is customizable by appropriate choices of materials and device designs. In one embodiment, the pacemaker is pairable with a soft, skin-interfaced wireless device that continuously captures electrocardiograms, performs data analytics, and optically controls the pacemaker via programming light emission in the NIR range as the basis for autonomous, on- demand closed-loop cardiac electrotherapy upon detection of arrhythmias. In one embodiment, the pacemaker is usable for pacing in a multi-site manner with a wavelength-division multiplexed (WDM) technique for time-synchronized dual-chamber and biventricular pacing, including multi-site resynchronization therapy. In one embodiment, the pacemaker is integrable onto an implantable framework including a transcatheter aortic valve replacement (TAVR) frame. In one embodiment, the pacemaker is compatible with medical imaging screening of magnetic resonance imaging (MRI) and / or computed tomography (CT). In another aspect, the invention relates to a system for cardiac pacing for a subject, comprising a plurality of pacemakers implanted to different sites of interest of the subject, each pacemaker is disclosed as above; wherein each pacemaker further includes a narrow band optical filter placed atop the PT therefor to serve as the basis for a wavelength-division multiplexed (WDM) control scheme; and wherein programmable optoelectronic control of the plurality of pacemakers forms the basis for time-synchronized multi-site operation for biventricular (BiV) and dual-chamber (A&V) pacing. In one embodiment, independent operation of the plurality of pacemakers relies on illumination at wavelengths aligned with the transmission properties of the filters. In one embodiment, in operations, light emitted from light source L(X) selectively passes through optical filter F(X), illuminates phototransistor PT(X), and then activates pacemaker P(X), wherein L(X), F(X), and P(X) form a matched group, wherein X = 1, 2, ... N, N being the number Attorney Docket No.616146.100572 of the plurality of pacemakers. In one embodiment, the light source L(X) is configured to emit the light at an intensity sufficiently high such that the output current of P(X) is sufficient to pace the heart, but sufficiently low to avoid the stimulation of any other pacemaker. In one embodiment, the system has reliable programmability of cardiac pacing at multiple sites, with timing precisely controlled by the operation of the light sources. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the like. In one embodiment, placing the two pacemakers on the RV anterior wall and LV lateral wall allows for biventricular pacing. In one embodiment, positioning at the LA lateral wall and LV lateral wall enables dual- chamber pacing. In one embodiment, programmable WDM control of both LEDs enables BiV and A&V pacing. In one embodiment, the dual-chamber pacing modality yields a physiology more consistent with normal cardiac activation than that associated with simple ventricular pacing. In one embodiment, the system is usable for cardiac resynchronization therapy. In yet another aspect, the invention relates to a system for cardiac pacing for a subject, comprising at least one pacemaker implanted to at least one site of interest of the subject, wherein each pacemaker is disclosed as above; and at least one skin-interfaced module attached to a skin surface of the subject in wireless communication with the at least one pacemaker for autonomous, closed-loop, on-demand cardiac electrotherapy. In one embodiment, the at least one skin-interfaced module is configured to perform single- lead recordings of electrocardiograms (ECG); wireless data transfer to a graphical user interface on a mobile device for real-time data visualization; closed-loop analytics for automated detection of cardiac arrhythmias; and programmed operation of integrated light sources to optically control the at least one pacemaker for the cardiac pacing. In one embodiment, the at least one skin-interfaced module comprises a power management circuit, ECG sensors, light sources, an analog frontend (AFE) that amplifies, filters, and digitizes the ECG signal, and a Bluetooth-low-energy (BLE) system-on-a-chip (SoC) that collects the conditioned ECG signal and streams in real time to the graphical user interface on the mobile device, which are integrated on a flexible printed circuit board. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the Attorney Docket No.616146.100572 like. In one aspect, the invention relates to a system for cardiac pacing for a subject, comprising a transcatheter aortic valve replacement (TAVR) frame; and a plurality of pacemakers attached onto or integrated with the TAVR frame placed in a heart of the subject for delivering both rapid pacing during valve deployment and regular pacing during the post-operative period, wherein at least one pacemaker is disclosed as above. In practice, the plurality of pacemakers may not all be of this type of pacemaker, i.e., it could be integrated with other types of pacemakers. In one embodiment, the plurality of pacemakers is attached onto junction points of struts of the TAVR frame, wherein the TAVR frame is a self-expanding stent. In one embodiment, the plurality of pacemakers is attached with the pacing electrodes facing the septal wall for effective pacing of the myocardium. In one embodiment, the plurality of pacemakers is attached with orienting most of the pacing electrodes toward the antero-septal region of the left ventricle to ensure proximity to the heart conduction system. In one embodiment, each pacemaker is activated separately using light emitted from the light sources, starting from lower intensities, faster pacing rates, and shorter pulse widths, followed by adjusting these parameters across a range until 100% capture, or failure. In one embodiment, each light source comprises a light emitting diode (LED), a laser, or the like. In one embodiment, the plurality of pacemakers is activated simultaneously by external flood illumination to ensure reliable pacing even when the orientation and precise positioning of the TAVR stent cannot be controlled during implantation. These and other aspects of the invention are further described below. Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods, and their related results according to the embodiments of the invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action. EXAMPLE: MILLIMETER-SCALE, BIORESORBABLE OPTOELECTRONIC SYSTEMS FOR MINIMALLY INVASIVE ELECTROTHERAPY Attorney Docket No.616146.100572 This exemplary study demonstrates a millimeter-scale, bioresorbable optoelectronic system with on-board power supply and a wireless, optical control mechanism with generalized capabilities in electrotherapy and specific application opportunities in temporary cardiac pacing. The extremely small sizes of the devices enable minimally invasive implantation, including percutaneous injection and endovascular delivery. Experimental studies demonstrate effective pacing in mouse, rat, porcine, canine, and human cardiac models at both single-site and multi-site locations. Pairing with a skin-interfaced wireless device allows autonomous, on-demand operation upon detection of arrhythmias. Further work illustrates opportunities in combining these miniaturized devices with other medical implants, with an example of arrays of pacemakers for individual or collective use on the frames of transcatheter aortic valve replacement systems, to provide unique solutions that address risks for atrioventricular block following surgeries. This base technology can be readily adapted for a broad range of additional applications in electrotherapy, such as nerve and bone regeneration, wound therapy, and pain management. Materials, designs, and mechanisms FIG.1A shows an explosion illustration of key design aspects according to embodiments of the invention. In one embodiment, the pacemaker has a weight of approximately 13.8 mg and dimensions of 1.8 mm ^ 3.5 mm and a thickness of 1 mm, comparable to the size of a grain of rice, as shown in FIG.1B. In one embodiment, the device exploits a self-powered mechanism, where the battery electrodes are also the pacing electrodes. Specifically, an active, bioresorbable magnesium (Mg) alloy AZ31 (Mg96Al3Zn1) foil or a zinc (Zn) composite (1.6 mm × 1.6 mm) serves as the anode, and a more electropositive bioresorbable molybdenum trioxide (MoO3) composite (1.6 mm ^ 1.6 mm) serves as the cathode. The cardiac tissue and associated biofluids act as the electrolyte to form a galvanic cell / battery (Mg-MoO3 or Zn–MoO3). As a demonstration in the example, the pacemaker utilizes the Mg–MoO3pair if not otherwise specified. In one embodiment, the two electrodes electrically interconnect through a silicon (Si) bipolar junction phototransistor (PT), as shown in FIGS.12-13, designed to respond at tissue- penetrating wavelengths in the near-infrared (NIR) range. This component provides an optical mechanism to control the operation of the device with an external light source. In particular, the anode and cathode connect to the emitter and the collector terminals of the PT, respectively, using a biodegradable conductive paste (Candelilla wax / tungsten (W) powder). In one embodiment, abioresorbable formulation of polyanhydride or wax encapsulates the entire structure, leavingregions of the electrodes exposed to interface with the cardiac tissue. These unusual materials, Attorney Docket No.616146.100572 components, and operating mechanisms serve as the basis for the pacing technology, as shown in FIGS.1B and 1D. The extremely small sizes of these devices allow for their delivery by minimally invasive percutaneous injection, as shown in FIG.1C. Specifically, the pacemakers of the invention can fit into small-diameter introducers (e.g., 8 or 9 Fr (French gauge)), as shown in FIG.1D, for injection directly into the superficial subepicardial layer of the myocardium through skin incisions with widths less than 3 mm. In one embodiment, pairing a pacemaker with a soft, skin-interfaced wireless device that supports collection of electrocardiogram (ECG) data, analysis of these data, and programmed light emission in the NIR range allows autonomous, closed-loop cardiac electrotherapy upon detection of arrhythmias, as shown in FIG.1E. Here, pacing follows from illumination through the skin and underlying tissue, as described in the following. FIGS.1F and 14 show the mechanism. In absence of illumination, the pacemaker is inactive because the high resistance of the PT (about 106Ω) prevents flow of current through the galvanic cell. Upon illumination, the resistance of the PT decreases by several orders of magnitude to about 102Ω, thereby closing the circuit and discharging the battery through the pacing electrodes and the adjacent cardiac tissue, as shown in FIG.8. During the discharge, as shown in FIGS.14 and 15, the Mg anode undergoes an oxidation reaction (Mg − 2e− → Mg2+), and the cathode undergoes a reduction reaction (MoO3 + ne− → MoO3n−). Finite element analysis (FEA) according to FIG.1G reveals the distribution of current density in the tissue for a transient pacing current of 0.5 mA cm-2. The fast responses of the PT and the overall optoelectronic circuit allow for precise, dynamic control over the current delivered to the heart. The compatibilities of the devices with MRI and CT, as shown in FIGS.15-18, provide additional benefits for patients who need routine medical imaging. In one embodiment, all materials of the invention, including the electrodes, the PT, the conductive pastes, and the packaging structure are bioresorbable except about 1.6 wt% of biocompatible carbon black as the conductive additives for cathodes. In one embodiment, replacing the carbon black with molybdenum (Mo) metal powder enables full bioresorption but results in a slightly larger size for comparable performance, as shown in FIG.19. Complete or partial bioresorption eliminates the need for surgical extraction after a period of operation, as shown in FIG.1H. FIG.1I displays results of accelerated tests of bioresorption that involve submerging a pacemaker (anode: 250 µm thick Mg alloy; cathode: 500 µm thick MoO3 composite on a 5 µm thick Mo, approximately 10 µm thick PT, and 100 µm thick PA (1:1:2.5) encapsulation) in phosphate-buffered saline (PBS) (pH 7.4) at 95 °C followed by transfer to a pH 10 buffer solution Attorney Docket No.616146.100572 to complete the process. The products of degradation are Mg(OH)2, H2MoO4, Si(OH)4, and carboxylic acids, respectively; each is water soluble and capable of excretion by the kidneys. In vitro cytocompatibility and in vivo biocompatibility studies reveal no adverse effects, as shown in FIGS.20-21. These results and additional analysis (Table 1) suggest a timescale for complete bioresorption of approximately 1.2–2.5 years. Appropriate choices of materials and device designs can enable reductions in the bioresorption timescales by about two times. Table 1. The biodegradation mechanism, rates, and degraded products of device components in this work Characteristics and ex vivo pacing As shown in FIG.2A, passing pulsed NIR light from a source located on or near the surface of the skin activates the delivery of electrical impulses to the heart, with rise and fall times aligned to those of the pulses to within less than 25 μs, far beyond the requirements for cardiac pacing. As discussed earlier, the pacing electrodes and the cardiac tissue form a battery that provides power for the pacing process. The phototransistor acts only as a passive switch, capable of activation at low intensities. Electrically connecting pacing electrodes embedded in soft chicken muscle tissue with a PT and an ammeter in series allows measurement of the output of a pacemaker under different pulsed light intensities, as shown in FIG.2B. The values are 0.02, 0.22, 0.45, and 0.64 mA at intensities of 0.001, 0.01, 0.02, and 0.05 mW mm-2, respectively. FIGS.22 and 23 show comprehensive technical specifications. Electrochemical impedance spectroscopy (EIS) of the pacemaker according to FIG.24 and measurements of PT resistance according to FIG.8 indicate that the battery resistance dominates the output current at NIR light intensities above about 0.05 mW mm-2, which explains the observed saturation behavior. The low sensitivity to intensity in this Attorney Docket No.616146.100572 regime ensures stable operation even with fluctuations that can result from body motions. Ex vivo pacing experiments on Langendorff-perfused porcine and human hearts demonstrate the functionality of pacemakers inserted into the superficial subepicardial layers of the myocardium. The illumination intensity, frequency and duty cycle control the current, rate, and pulse width of the pacing process, respectively. According to FIGS.2C, 2D, and 25, measurements of the strength- duration curve for pacing the porcine heart indicate that the rheobase and chronaxie at a current twice that of the rheobase are about 0.18 mA and about 2.8 ms, respectively. This curve confirms that the pacemaker can achieve more than twice the threshold, ensuring reliable operation post- implantation. FIG.2E shows ECG recordings before and during pacing with 2:1 and 1:1 captures at different pacing conditions. Additional experiments in FIGS.2F-2H demonstrate successful pacing on human hearts at three different sites, including left ventricle (LV), right ventricle (RV), and Bundle of His. These data demonstrate the potential for multi-site resynchronization therapy or physiological pacing in patients with heart failure who suffer from asynchronous electrical excitation and, therefore, suboptimal mechanical contraction, leading to reduced cardiac output. According to FIG.9, discharge profiles of the Mg-MoO3 pacing pairs in agarose gel at 37 °C indicate an ability to operate continuously for about 16 days at currents, rates, and pulse widths of 0.4-0.5 mA, 60 bpm, and 5 ms, respectively. These parameters exceed requirements in temporary pacing. In vivo injection and closed-chest pacing Envisioned clinical uses of the technology involve illumination through the skin. Monte Carlo analysis shown in FIG.3A captures the distribution of normalized intensity of NIR light (850 nm) in the human body associated with light emitted from an area of 4.96 × 4.96 cm2at the surface of the chest. FIG.3B shows that the ribs block more light than the soft tissue. Owing to strong light scattering within the body, differences between areas underneath the ribs and soft tissues become less pronounced with increased depth. FIG.3C presents both the simulation and experimental results of normalized light intensities on the surface of the PT implanted in the tissue. The simulation results are 28%, 3.0%, 0.49% and 0.08% at tissue depths of 10 mm, 20 mm, 30 mm and 40 mm, respectively. Experimental measurements through porcine tissues show similar trends, i.e., 8%, 1%, 0.3%, and 0.06% at tissue depths of 10 mm, 20 mm, 30 mm, and 40 mm, respectively. For adults, the average shortest distance between the surface of the skin and the surface of the heart is about 30 mm. For a pacemaker implanted at tissue depths of 10 mm, 20 mm, 30 mm and 40 mm, an output current of 0.64 mA can be achieved with light intensities of approximately 0.18 mW mm-2, Attorney Docket No.616146.100572 1.72 mW mm-2, 10.6 mW mm-2and 61.7 mW mm-2at the surface of the skin, respectively. These values are all well within a safe range for human exposure. Additional simulation results for tissue thicknesses up to 15 cm, as shown in FIG.26, and calculations for the maximum permissible exposures for skin safety indicate that the device can be reliably implanted at depths of up to about 60 mm in the body. A modified device, with the phototransistor extended closer to the skin and pacing electrodes remaining inserted into the heart, allows for pacing at deeper locations, as shown in FIG.27. In-vivo experiments in a clinically relevant canine model (adult hound dogs) follow the successful in-vivo cardiac pacing in small-animal (mouse) models, as shown in FIG.10. The canine heart anatomy (shape, size, and proportions) and electrophysiology closely resemble those of a human. Initial studies demonstrate the feasibility of minimally invasive injection of the pacemaker. FIG.3D presents a schematic outline of the procedure and corresponding intra-operative photographs. Fluoroscopy guides the procedure (FIG.3F). Direct access via lateral thoracotomy confirms the above procedures (FIG.28) and the position of the pacemaker (FIG.3G). Locating an NIR light-emitting diode (LED) on the surface of the skin at the sixth intercostal space and activating the LED in a pulsed mode successfully paces the canine heart at 240 bpm. FIG.3H shows an ECG recording with efficient left ventricle pacing and stable 1:1 capture. This technique might benefit from the development of a specialized delivery system to ensure safe and stable placement of the device, such as accessing the pericardial space from the subxiphoid region and fixing the devices through bioresorbable adhesives. In vivo experiments in rat models define the operational lifespan of pacemakers sutured onto the surfaces of the hearts, with the chest cavity closed using surgical procedures described previously. Pulsed light illumination triggers cardiac pacing daily. The results (FIGS.3H and 29) show that pacemakers made of Mg–MoO3 and Zn–MoO3 pairs can function in vivo for up to 6 days and 20 days post-implantation, respectively. This timescale exceeds requirements in temporary pacing with an average duration of 4.2 days. Pacing thresholds rise significantly from day 2 for the Mg–MoO3 and from day 19 for the Zn–MoO3 pair, possibly owing to the combined effects of local inflammation and electrode degradation. Time-synchronized multi-site pacing Programmable optoelectronic control of multiple pacemakers forms the basis for time- synchronized multi-site operation for biventricular (BiV) and dual-chamber (A&V) pacing, as shown in FIGS.4A and 4B. Narrow band optical filters (bioresorbable multilayer stacks of Attorney Docket No.616146.100572 SiNx / SiOx) placed atop the PTs allow for a WDM control scheme, to avoid the need for careful selective illumination of spatially separated devices. Specifically, independent operation relies on illumination at wavelengths aligned with the transmission properties of the filters, according to FIG. 11. In the example illustrated here, light emitted from LED (X) selectively passes through the optical filter (X), illuminates the PT(X), and activates pacemaker P(X) (X = 1 or 2). LEDs X, filters X and pacemakers PX form a matched group (where X = 1 or X = 2). As described previously, the output current of a pacemaker depends on the total resistance of the PT, the electrochemical cell, and the cardiac tissue. The ideal scenario involves illumination from LED (X) at an intensity sufficiently high such that the output current of P(X) is sufficient to pace the heart, but sufficiently low to avoid the stimulation of any other pacemaker. For the system reported here, the intensities of light emitted by LEDs (1) (850 nm) and (2) (650 nm) at the location of the PT / filter sets are below 0.035 and 0.12 mW mm-2, respectively. As shown in FIG.4C, the current of the matched pacemaker is more than 17 and more than 20 times that of the unmatched ones, for illumination from LEDs 1 and 2, respectively. This behavior ensures reliable programmability of cardiac pacing at multiple sites, with timing precisely controlled by the operation of the LEDs In vivo experiments in a canine model confirm the feasibility of this approach to multi-site pacing, further facilitated by the small sizes of the devices. Lateral thoracotomy provides access to the heart for the placement of pacemakers. Placing the two pacemakers (P1 and P2) on the right ventricle (RV) anterior wall and left ventricle (LV) lateral wall allows for biventricular pacing. Positioning at the left atrium (LA) lateral wall and LV lateral wall enables dual-chamber pacing, as shown in FIGS.4B and 30. FIGS.4D and 31-35 present ECG recordings of the intrinsic sinus rhythm (about 96 beats per minute, bpm) and of different pacing modes at 150 bpm. Initial tests confirm the ability to pace each site separately (RV, LV, LA) via illumination with a single LED. Programmable control of both LEDs enables BiV and A&V pacing. Biventricular pacing with 0 ms LV-RV pacing offset results in narrowing of the QRS complex (85±3 ms) as compared to RV- only (98±3 ms, p=0.00025) or LV-only (106±2 ms, p=0.00001) pacing. This demonstrates the potential for cardiac resynchronization therapy, an important treatment modality for patients with congestive heart failure caused by dyssynchronous ventricular activation. The right bottom panel in FIG.4D shows successful dual-chamber LA-LV pacing, tested at 80 ms atrioventricular (AV) delay. At 120 ms atrioventricular (AV) delay according to FIG.35, ECG shows fused QRS complexes due to partial activation of the ventricles through the His-Purkinje system. Reducing the AV delay to 80 ms results in a QRS morphology consistent with pure LV pacing. This dual-chamber pacing modality yields a physiology more consistent with normal cardiac activation than that associated Attorney Docket No.616146.100572 with simple ventricular pacing. Closed-loop cardiac electrotherapy As described earlier, pairing the pacemaker with a wireless, skin-interfaced optoelectronic device allows for autonomous, closed-loop, on-demand cardiac electrotherapy, as shown in FIG. 5A. In one embodiment, the technology of the invention according to FIGS.5B-5D supports (1) single-lead recordings of ECG, (2) wireless data transfer to a graphical user interface on a mobile device for real-time data visualization, (3) closed-loop analytics for automated detection of cardiac arrhythmias, (4) programmed operation of integrated LEDs to activate cardiac pacing. Examples of this combined system use in the context of bradycardia involve rat models with pacemakers fixed on the surfaces of the hearts accessed by lateral thoracotomy as shown in FIG.5E with bioresorbable adhesives. As shown in FIG.5F, detection of bradycardia (threshold of 220 bpm) automatically initiates pacing at 240 bpm. The use of bioresorbable adhesives here demonstrates a method for fixation that is well suited to small hearts, such as those of pediatric patients, as an alternative to injection of devices in the superficial subepicardial layers of the myocardium. Pacemakers-integrated TAVR platforms The widely used TAVR procedure is a minimally invasive replacement of the aortic valve in patients with severe aortic stenosis. Up to 30% of TAVR patients may, however, develop significant AV conduction disturbances, thereby necessitating the implantation of a pacemaker with its associated challenges, risks and costs. In one embodiment, the miniaturized devices of the invention introduced here offer a unique solution to this problem, through their direct, simple integration with the frame system used in the TAVR process as shown in FIG.6A, in a manner that requires minimal change in the surgical procedure. This technique can address temporary conduction disturbances and provide more time to determine whether permanent pacemakers are necessary. Collections of such integrated devices can deliver both rapid pacing during valve deployment and regular pacing during the post-operative period. This dual functionality reduces patient risks and exposures to potential complications, circumvents the need for separate pacemaker implantation, simplifies the procedure, refines the post-operative care process, and allows safe and early patient discharge. Experiments show that this integrated device placed in the area of the aortic annulus can effectively capture the ventricular myocardium in the ex vivo Langendorff perfused human heart model, as shown in FIG.36. The system, in one embodiment, includes six independent pacemakers Attorney Docket No.616146.100572 mounted on the junction points of the struts of a self-expanding stent (BD Venovo Venous Stent System), a TAVR frame, as shown in FIG.6B. Deployment into the aortic annulus area occurs with conventional delivery apparatus according to FIG.6C. Placing pacemakers with electrodes facing the septal wall allows for effective pacing of the myocardium. Orienting most of the electrodes toward the antero-septal region of the left ventricle ensures proximity to the heart conduction system. Feasibility tests use fiber-coupled LEDs to activate each pacemaker separately, starting from lower intensities, faster pacing rates, and shorter pulse widths, followed by adjusting these parameters across a range until 100% capture, or failure. FIG.6D features ECG recordings upon independent activation of each pacemaker. Pacemakers S2, S3, S5, and S6 produce reliable 100% capture, with pacing effectiveness: S6 > S3 ≈ S5 > S2, considering the conditions required for successful pacing as shown in the bottom table of FIG.6D. Pacemakers S1 and S4 located on the same edge of the stent fail to capture, likely due to their unfavorable locations – far from the conduction system, as shown in FIG.37. A plurality of pacemakers integrated in this manner and activated simultaneously by external flood illumination ensures reliable pacing even when the orientation and precise positioning of the TAVR valve cannot be controlled during implantation. Fabrication and characterization of galvanic cells and pacing electrodes Pacing electrodes used a Mg alloy AZ31 (Mg96Al3Zn1, 250 µm thick, Goodfellow) anode or a Zn anode and a MoO3cathode. Mixing 0.45 g MoO3(Sigma Aldrich), 0.05 g carbon black (MTI Corporation), and 800 µL of 300 mg / mL poly (D,L-lactide-co-glycolide) (PLGA, lactide:glycolide 65:35, molecular weight (Mw) 40-75k, Sigma Aldrich) in ethyl acetate within a planetary mixer (Thinky ARE-30) yielded a slurry for the MoO3 / C cathode. Mixing 0.9 g MoO3, 0.9 g Mo powder (Sigma Aldrich, size: 1-5 μm), and 900 µL of 200 mg / mL PLGA in ethyl acetate formed MoO3 / Mo slurry. Mo gauze (40 mesh, Alfa Aesar) or Mo foil (5 µm thick, Goodfellow) served as current collectors for the cathode materials. Applying the slurries on these current collectors and baking at 80 ℃ for 1 hour completed the process. Mixing 0.5 g Zn powder (Sigma-Aldrich, size 40–60 nm), 0.04 g carbon black and 800 µl of 300 mg ml-1PLGA in ethyl acetate formed a Zn slurry. Zn foil (50 µm thick, Goodfellow) served as current collectors for the Zn anode materials. The Zn slurry was applied on both sides of the Zn current collectors, followed by baking at 120 °C for 50 min. The Zn anodes were then sintered in 5 wt% acetic acid aqueous solution at room temperature for 30 min and dried in the air. An ultraviolet laser prototyping system (LPKF U4) defined the shapes of the Mg alloy anodes, Zn anodes and MoO3cathodes from Mg alloy AZ31 foil, Zn foil, Mo foil and Mo gauze. The discharge behaviors of Mg-MoO3batteries formed from Mg alloy anodes and Attorney Docket No.616146.100572 MoO3 cathodes in PBS electrolyte were tested under constant current discharge (CCD) using a Landt battery tester. EIS under potentiostatic mode relied on a Metrohm system, used a frequency range of 500 kHz to 0.1 Hz, with a voltage amplitude of 10 mV. Fabrication and characterization of PTs Thin (100) silicon wafers (100 μm thick; boron doped; 1–10 Ω·cm) were cleaned with RCA cleaning procedures including SC-1 (NH4OH:H2O2:H2O = 1:1:5) and SC-2 (HCl:H2O2:H2O = 1:1:6). Dry oxidation at 1000 °C for 7 hr formed a 200 nm thick oxide layer as a mask for the doping process. Photolithographic patterns defined base doping regions (i.e., the photosensitive region of the PT) and a combination of CH4 / O2 dry etching and 6:1 BOE wet-etching processes removed the oxide layer to expose areas for base (n) doping. After cleaning the wafer again with SC-1 and SC-2, 120 keV phosphorus (P) ions were implanted with a dose of 6×1012ions·cm-2into Si to form n base area. The remaining oxide mask was removed in BOE (6:1), followed by dry oxidation at 1000 °C for 7 hr to activate implanted ion dopants and create a second oxide mask. Photolithographic patterns defined each doping region for emitter and collector electrode, respectively. After RCA cleaning again, highly concentrated boron doping (p+) was performed in a tube furnace with solid boron source at 1000 °C for 20 minutes under N2 atmosphere. The remaining oxide mask was removed in BOE (6:1), followed by 100 nm thick SiO2 deposition using PECVD to fully encapsulate BJT-based PTs. Photolithographic patterns defined metal contact holes for emitter (E) and collector (C) area. The exposed SiO2 layer was removed in BOE (6:1) to open contact areas for E / C metals. E / C metal electrodes were patterned with AZ nLoF 2035, followed by sputter-deposition of tungsten (100 nm thick) and lift-off in acetone. A laser cutting system defined the rectangular geometries of the PTs. Mechanical polishing processes thinned the PTs (down to approximately 10 µm thick). The characteristic responses of the PTs under various light intensities were determined by linear sweep voltammetry (LSV) using a PalmSens4 system. Fabrication and characterization of optical filters Alternating SiOx and SiNy layers were deposited onto 100 µm thick Si substrates using PECVD. Drop casting PLGA (lactide:glycolide 65:35, Mw40-75k, Sigma Aldrich) solution (7 wt% in ethyl acetate) on the above multilayers and baking at 70 ºC yielded 10 µm thick PLGA films attached to the multilayers. Etching the Si substrates from the backside under a vapor of XeF2 completed the fabrication. The Perkin Elmer LAMBDA 1050 spectrophotometer measured the transmission spectra of the filters. A Thorlabs’ PM200 Optical Power and Energy Meter recorded Attorney Docket No.616146.100572 the intensities of light from LEDs (Digi-Key, LED (1): LZ4-00R408; LED (2): MTPS7065MT2- BK) before and after passing through the filters. Fabrication and characterization of pacemakers Bioresorbable pacing electrodes including a Mg alloy AZ31 anode or a Zn composite anode and a MoO3cathode were electrically connected to a bioresorbable PT through a biodegradable conductive paste (Candelilla wax / W powder). Bioresorbable optical filters placed atop the phototransistors provided a wavelength selective response. Polybutanedithiol 1,3,5-triallyl-1,3,5- triazine-2,4,6(1H,3H,5H)-trione pentanoic anhydride (polyanhydride) or a mixture of natural wax (candelilla wax and beeswax, mass ratio 3:2) served as the encapsulation material (total size of 3.5 mm^1.8 mm^1 mm). To measure the output current of a pacemaker in tissue under pulsed light, the pacing electrodes (placed within tissue), the PT, and a current measurement module (National Instruments CompactDAQ NI-9208, configured in Reference Single-Ended (RSE) mode) were electrically connected in series. A function generator (Rigol) powered the LEDs and generated pulsed light with various light intensities on the PT. Optical control systems for activation of pacemakers LED (1): NIR LED (850 nm), Digi-Key, LZ4-00R408; LED (2): Red LED (650 nm), Digi- Key, MTPS7065MT2-BK (biventricular and dual-chamber pacing); and Thorlabs, M660FP1 (pacemakers-integrated TAVR system) are used in this study. The SparkFun FemtoBuck LED Driver served as a mechanism to control the LEDs. Replacing the Sense Resistor of the internal AL8860 DC-DC step-down converter of the LED driver with a 0.05 ohm shunt resistor bypassed the low default output (330 mA) and enabled a nominal average output of up to 2 A. Finite element analysis The three-dimensional FEA used commercial software (Ansys Maxwell) to define the distributions of current density in the heart under electrical stimulation. Use of an adaptive mesh (tetrahedron elements) ensured computational accuracy. The pacemaker was inserted 1 mm deep into a 3D heart model (TurboSquid). The relative permittivity (εr) and bulk conductivity (σ) were2.36^107 and 0.0537 S⋅m-1 for the heart tissue, 12.6 and 2.3 S⋅m-1 for the MoO3 composite, and 3and 6.7^10-16S⋅m-1for polyanhydride. The electromagnetic parameters of other materials relied on the material library in the Ansys Maxwell software package. Attorney Docket No.616146.100572 Optical simulation The Monte Carlo method was used to simulate the light transport within the human body. The body, with bones and the heart, was voxelated, creating a simulation space of 700×200×566 voxels, each with a side length of 0.62 mm. A total of 5^109photons were simulated to ensure accuracy. The light was passed through the front of the body across a square region of 49.6 mm×49.6 mm, with the incident direction along the negative axis. The light has a wavelength of850 nm. The absorption coefficient (μa) and the reduced scattering coefficient (^^′^^) are 0.008 mm-1and 1.2 mm-1for bones, and 0.006 mm-1and 1.3 mm-1for other tissue. The refractive indices (n) for these tissues is 1.4. In addition, a pacemaker occupying 3×2×5 voxels was placed in the heart wall, with μa = 53.5 mm-1, ^^′^^ = 0 mm-1, and n = 3.65.Fabrication and operation of the soft, skin-interfaced optoelectronic controller Electrical components. The system was assembled on a double-layer flexible printed circuit board (fPCB; Cu (18 μm): Polyimide (PI, 75 μm): Cu (18 μm)]. A lithium polymer battery (PowerStream Technology) powered the device. The output voltage of the battery was converted to a constant voltage (2.5 V) by a low-dropout linear voltage regulator (ADP7112, Analog Devices Inc.) in 6-pin wafer-level chip-scale package (WLCSP) (1.2 mm × 1 mm) to power the system. A BLE SoC (nRF52832-CIAA, Nordic Semiconductor, Norway) with a footprint of 3.0 mm × 3.2 mm served as the microcontroller and wireless communication module. An ultra-low-power (180 μW), high common-mode rejection (>100 dB) biopotential AFE (MAX30003, Analog Devices Inc.) with a footprint of 2.74 mm × 2.9 mm amplified, filtered and digitized the ECG signal and transmitted the digital data to the BLE SoC via the SPI interface. The BLE SoC streamed the ECG signal in real time to a custom Python script on a laptop. The BLE SoC directly controlled the LEDs via general purpose inputs / outputs (GPIOs). The BLE SoC used a miniaturized (3.2 mm × 1.6 mm) ceramic 2.45 GHz antenna (2450AT18A100, Johanson Technology Inc.). Passive components with the smallest packaging, such as 0201 (imperial), were used to minimize the overall size of the system. Assembly and encapsulation of the device. Electrical components were soldered to the flexible printed circuit board (fPCB) by hot-air soldering. An epoxy adhesive (Loctite 3621, Henkel, Rocky Hill, CT) was applied to the BLE SoC and MAX30003 and cured at 95 °C for 25 min to provide mechanical protection for the chips. Casting of a silicone gel (Silbione RT GEL 4717 A&B, Elkem) into the gap of milled aluminium core and cavity molds (Roland MDX 540) and curing at 75oC for 90 min formed the top encapsulation layer. Spin coating of the silicone gel Attorney Docket No.616146.100572 on a thin acrylic plate at 180 rpm for 1 min and curing at 75oC for 90 min formed the bottom encapsulation layer. Filling the cavity between the top and bottom encapsulation layers with Ecoflex 0030 and curing at 60oC for 30 min ensured full coverage of the components. Data collection and data analysis. The ECG data was collected at 512 Hz. Custom Python code with Python 3.8.10 and Bleak 0.12.1, Scipy 1.7.3, Numpy 1.20.2, Pandas 1.2.5 and Matplotlib 3.3.4 was used to receive and analyze ECG data. The algorithm analyzed the latest 1 s ECG data every 1 s. For each 1 s window, the algorithm started with a Butterworth low-pass filter (cut-off: 50 Hz, order: 4) to remove high-frequency noise, followed by finding QRS complexes using the find_peaks function of Scipy. Peaks were rejected if the corresponding RR intervals were not within ^30% of the mean of the RR intervals of the window. Next, the heart rate of the window was calculated based on the mean of valid RR intervals. If the heart rate is below the threshold, the Python script sends a command with predefined pacing rate and duty cycle to the BLE SoC. The BLE SoC subsequently drives the LED following the parameters in the command. In vivo demonstration of cardiac pacing in small-animal models All experimental animal procedures and protocols were approved by Northwestern University Institutional Animal Care and Use Committee and in compliance with suggestions from the panel of Euthanasia of the American Veterinary Medical Association and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. In vivo rodent study was performed on mice (15–25 weeks old; C57BL / 6J; Jackson Laboratory; male and female) and rats (12-14 weeks old; Sprague–Dawley; Charles Rivers Laboratory; male). The procedure for pacemaker implantation via open thoracotomy was adapted from the standard technique in a previous report. All procedures were performed under general anaesthesia using inhaled isoflurane vapor (1–3%). The animal was ventilated using a VentElite Small Animal Ventilator (Harvard Apparatus, Holliston, MA). Subdermal ECG leads were connected for intraoperative cardiac monitoring (lead II configuration) using PowerLab 4 / 26 and PowerLab FE234 Quad Bio Amp and LabChart ECG Recording software (ADInstruments, Sydney, Australia). The heart was exposed via left thoracotomy. In acute studies, the pacemaker was secured (with the electrode side facing down) onto the epicardial surface using non-absorbable monofilament 6-0 polypropylene suture (Ethicon, 8705H) or photocurable bioresorbable adhesives. In long-term studies, steroids (15 mg dexamethasone acetate, Sigma) were added into 800 µl of 300 mg ml-1PLGA in ethyl acetate while fabricating Zn and MoO3composite electrodes. The photocurable hydrogel was applied on the surfaces of the Attorney Docket No.616146.100572 electrodes, followed by curing under ultraviolet light. Pacemakers were sterilized in an ethylene oxide sterilizer (AN74i sterilizer) for 24 h before implantation. The pacemaker was sutured onto the epicardial surface using non-absorbable monofilament 6-0 polypropylene suture (Ethicon, 8705H). After surgical implantation, pacemakers were tested daily. Illuminating the anterior chest with an NIR LED activated the pacemaker. The illumination intensity, frequency and duty cycle controlled the current, rate and pulse width of the pacing process, respectively. The minimum voltage required to successfully pace the heart was recorded as the pacing threshold. Local inflammation can lead to a significant increase in the threshold following the implantation of the pacemaker. Therefore, maintaining a safety margin of at least two times the sensing threshold is necessary to ensure stable and reliable operation, a standard practice in clinical settings to counteract post-implantation threshold increases. Ex vivo demonstration of cardiac pacing with the whole human and porcine hearts Donor human hearts rejected for organ transplant were procured from the Gift of Hope Organ & Tissue Donor Network as deidentified discarded tissue not involving human individuals. Porcine hearts were acquired from the Center of Comparative Medicine of Northwestern Universityas post-euthanasia tissue transfer. At the time of tissue procurement, the left and right coronaryarteries of the heart were perfused with cold University of Wisconsin cardioplegic solution and were then cannulated separately. The heart was then transferred to a Langendorff perfusion system with a custom tissue chamber and was perfused with a modified Tyrode’s solution (128.2 mM NaCl, 4.7 mM KCl, 1.05 mM MgCl2, 1.3 mM CaCl2, 1.19 mM NaH2PO4, 20 mM NaHCO3, 11.1 mM glucose) and bubbled with 95% O2 / 5% CO2. The pressure of the heart was maintained between 60 mm Hg and 80 mm Hg by regulating the perfusion flow rate through roller-pumps. The temperature of the perfusion system was maintained at 37 °C throughout the experiment. Far-field ECG signals were acquired and recorded by using LabChart software (AD Instruments) with two sensing electrodes placed on the myocardium surface and one ground electrode placed in the tissue bath around the heart. For cardiac pacing, a 2-mm dissection was made at an angle to the myocardial surface of the ventricles to create a pocket for the pacemaker insertion with the electrode side facing down and the phototransistor side facing up. For TAVR pacing, mounting six pacemakers with epoxy onto the junctions of the struts of the TAVR valve stent (BD Venovo Venous Stent System) formed the pacemaker-integrated TAVR stent, which was then deployed and expanded in the annulus of the aortic valve with electrode side facing the septal wall and the phototransistor part facing the opposite side to be excited by illumination from a fibre-coupled LED Attorney Docket No.616146.100572 (Thorlabs, M660FP1). In vivo demonstration of pacemaker injection and cardiac pacing in large-animal models Retired breeder female and male hound dogs (age 1.6–4.5 years, weight 39-53 kg) used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no.85–23, revised 1996) as approved by the IACUC of Northwestern University. Before surgery, the animals were premedicated with acepromazine (0.01–0.02 mg / kg) and induced with propofol (3–7 mg / kg). All experiments were performed under general anaesthesia (inhaled) with isoflurane (1-3 %). Adequacy of anaesthesia was assessed by toe pinch and palpebral reflex. Surface electrodes that were applied to the limbs allowed continuous six-lead ECG recording at a sampling rate of 977 Hz (Prucka CardioLab). The pacemakers were implanted through lateral thoracotomy or minimally invasive injection approaches. In the lateral thoracotomy, the heart was exposed by pericardiectomy. The pacemakers were placed on the myocardial surface or inserted in the superficial subepicardial layers of the myocardium. The NIR LED was placed above the pacemaker location. For long-range optical stimulation, the chest was closed. The NIR LED was positioned on the skin surface in the projection of the pacemaker location. For the minimally invasive injection approach, an 18-gauge needle (1.27 mm in outer diameter) accessed the border of the heart from the eighth intercostal space, followed by subsequent advancement of a guidewire into the pericardial space. Next, a 9 F percutaneous sheath introducer advanced over the wire and reached the epicardial surface of the left ventricle. A dilator pushed the pacemaker through the sheath, under the guidance of fluoroscopy, until the device reached the surface of the heart and entered a pre-made pocket in the superficial subepicardial layer of the myocardium. Activating an NIR LED on the surface of the skin at the sixth intercostal space (in the projection of the pacemaker device location) paced the heart. Upon finishing the in vivo portion of the study and after confirming a very deep plane of anaesthesia, the heart was removed. No complications or unscheduled deaths occurred. In vitro cytocompatibility In vitro cytocompatibility studies of the pacemaker against mouse cells (L929, ATCC) were performed through the indirect contact method. A mixture of Eagle's Minimum Essential Medium (Gibco™, Catalog # 11095080), 10 vol.% fetal bovine serum (Thermo Fisher Scientific) and 1 vol.% penicillin–streptomycin (Thermo Fisher Scientific) served as the cell culture medium. Attorney Docket No.616146.100572 Incubating samples in cell medium for 24 h resulted sample extracts (ISO 10993-12), which were centrifuged at 14,000 rpm for 10 min. Supernatants were 1:100 diluted and added into the cell- seeded wells for 24 h. Cell proliferation was assessed using the CellTiter 96® AQueous One Solution Cell Proliferation Assay (Promega, Catalog # G3580). The absorbance of the plate was measured at 490 nm. Blank controls (medium alone without cells) were subtracted from the absorbance values in all assays. In vivo biocompatibility tests All procedures were performed in accordance with the ethical standards and protocols of Northwestern University. Each male Sprague–Dawley rat (12–14 weeks) was placed under isoflurane anaesthesia (1–3%), then given pre-operative analgesia (0.5–1.0 mg kg−1 buprenorphine). Studies involve a device group (n = 3) and a control group of high-density polyethylene (US Food and Drug Administration-approved non-toxic material; n = 3), each sutured onto the surface of the heart. Animals were weighed every 3 days to monitor weight loss and health status post-surgery. Blood and heart tissues adjacent to the implants were collected at 1- and 4-week endpoints. Heart tissues were fixed in 10% neutral-buffered formalin and embedded in paraffin. Cross-sectional samples were stained with haematoxylin and eosin for histological analysis. Fabrication of polyanhydride encapsulation Polybutanedithiol 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione pentanoic anhydride (PA)(Choi et al., 2020) served as the encapsulation material (total size of 3.5 mm^1.8 mm^1 mm), synthesized through thiol-ene click reactions of three compounds: 4-pentenoic anhydride (4PA, Sigma Aldrich), 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TTT, Sigma Aldrich), and 1,4- butanedithiol (Sigma Aldrich).4-PA, TTT, and 1,4-butanedithiol mixed with a molar ratio of 1:1:2.5 (for accelerated aging test) or 1:4:7 (for all other experiments) in Ecoflex 35 molds, followed by exposure to ultraviolet (UV, wavelength of 365 nm) light with 2,2-dimethoxy-2- phenylacetophenone (Sigma Aldrich) as the photoinitiator (total mass of 0.5%). Design of a wireless, skin-interfaced electronic controller The system module is integrated on a flexible printed circuit board based on a middle polyimide support layer with rolled, annealed copper on the top and bottom surfaces, and plated gold on the copper surface. The circuit structure integrates electric components including an ultra- low-power, high-precision biopotential analog frontend (AFE) that amplifies, filters, and digitizes Attorney Docket No.616146.100572 the ECG signal at 512 Hz, and a Bluetooth-low-energy (BLE) system-on-a-chip (SoC) that collects the conditioned ECG signal via the serial peripheral interface (SPI) and streams in real time to a custom Python script on a laptop. A lithium polymer battery powers the device. In vivo demonstration of cardiac pacing in small-animal models All experimental animal procedures and protocols were approved by Northwestern University Institutional Animal Care and Use Committee and in compliance with suggestions from the panel of Euthanasia of the American Veterinary Medical Association and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. In vivo rodent study was performed on mice (15–25 weeks old; C57BL / 6J; Jackson Laboratory; male and female) and rats (12-14 weeks old; Sprague–Dawley; Charles Rivers Laboratory; male). The procedure for pacemaker implantation via open thoracotomy was adapted from the standard technique in a previous report2. The sterilized surgical space included the intubation equipment, anaesthesia equipment, ECG recording computers, ventilator, sterilized surgical instruments, regulated heading bed, and adjustable spotlight. General anaesthesia was induced by inhaling isoflurane vapours with 1–3% isoflurane in an induction chamber until the loss of consciousness was confirmed with toe pinch. The path of vaporized isoflurane was then switched to an intubation stand. The animal’s tongue was gently retracted using forceps to visualize the vocal cords. Supported by a blunt curved stylet, a 16-gauge cannula was blindly passed through the vocal cords into the trachea. The proper placement of the endotracheal tube was confirmed by checking the presence of condensation on the mirror, in addition to auscultation of respiratory sounds with a stethoscope. The animal was ventilated using a VentElite Small Animal Ventilator (Harvard Apparatus, Holliston, MA). The ventilation was regulated by pressure control mode with ventilation rate of 80 breaths per minute and peak inspiratory pressure limit of 14 cm H2O. Subdermal ECG leads were connected for intraoperative cardiac monitoring (lead II configuration) using PowerLab 4 / 26 and PowerLab FE234 Quad Bio Ampand LabChart ECG Recording software (ADInstruments, Sydney, Australia). The intubated animal was placed on a regulated heating bed and prepared for the implantation surgery. A 4 × 4 cm area in the left lateral chest was shaved and prepped using a 10% povidone-iodine solution and alcohol wipes. The animal was then covered with a sterile drape, exposing the surgical site. Surgical scissors were used to make a curvilinear dissection through the skin and subcutaneous tissue across the chest wall into the thoracic cavity. A surgical retractor was applied to open the intercostal space to better visualize the heart surface. After the left thoracotomy, cotton swabs were applied to retract the lung and expose the heart, further excising the pericardium. The pacemaker was secured (with electrode side facing down) onto the epicardial surface using non-absorbable monofilament 6-0 Attorney Docket No.616146.100572 polypropylene suture (Ethicon, 8705H) or photocurable bioresorbable adhesives. In long-term studies, the photocurable PEG-LA-DA / alginate double network hydrogel was applied on the surfaces of the electrodes, followed by curing under UV light (365 nm, 20 mW cm-2, 5 minutes). The hydrogel was prepared by mixing of solutions A and B as described in the previous study3. Here, 0.3% (w / w) of N,N′-methylenebisacrylamide (Sigma Aldrich) and 3% (w / w) NaCl was added in the solution A. Steroids were introduced to the hydrogel by dissolving 5% (w / w) dexamethasone sodium phosphate (Sigma Aldrich) in solution B. Pacemakers were then sterilized in an ethylene oxide sterilizer (AN74i sterilizer) for 24 hours before implantation. The pacemaker was sutured onto the epicardial surface using non-absorbable monofilament 6-0 polypropylene suture (Ethicon, 8705H). The thoracic cavity, muscle layer, and skin were closed by interrupted stitches using non-absorbable 4-0 nylon monofilament suture. (Oasis, MV-1629-V). At the end of the surgical procedure, pacemakers were tested by applying NIR stimulation on the chest to verify proper pacing function and electrode placement. Animals were then withdrawn from anaesthesia and allowed to recover until self-ambulation. Appropriate post-operative monitoring and care were provided following surgery. An intraperitoneal dose of buprenorphine (0.5– 1.0 mg / kg) was administered as analgesia before incision and once every 12 h for 48 h following surgery. Data analysis The following software were used in this study: ^PSTrace (v5.9): analysis of results collected using a PalmSens4 system,^ Prism (v10, GraphPad): analysis of results from biocompatibility studies,^ OriginLab (v2019b): analysis and plotting of experimental results,^ EC-Lab (V11.36): analysis of EIS results,^ Labchart (v8): analysis of ECG signals collected using PowerLab 4 / 26 and PowerLabFE234 Quad Bio Amp, and ^MATLAB (R2023b): analysis of ECG signals collected using the skin-interfaced patch.Compatibilities of the devices with MRI and CT. We performed high-field medical imaging (MRI, CT) tests with various sequences on a rat model with a pacemaker implanted on the surface of the heart. We observed minor artifacts from the metallic / conductive part of the pacemaker for both MRI and CT. The entity of the artifacts suggests that it does not in all likelihood affect the surrounding tissue. In conclusion, the pacemaker does not create large susceptibility artifacts in all imaging modalities and has optimal compatibility with MRI Attorney Docket No.616146.100572 and CT. Therefore, our device possesses additional benefits for patients who need routine medical imaging screening. The skin-interfaced patch is an essential part of the pacing system. It does not contain coils, previously used for wireless power transfer in other studies, thereby avoiding interference with MRI systems. Although Bluetooth communication may be disrupted in an MRI environment, the LED used for pacemaker illumination remains functional, allowing the pacemaker to be activated as needed. To develop an MRI-compatible patch, one solution is to use the MRI-compatible LED, controlled by MRI-compatible electronic components, and powered by the MRI-compatible battery. Discussion on the device's biocompatibility Weights of animals and analysis of complete blood counts and blood chemistry tests (FIG.21, panels a and b) show no statistically significant differences between the control and the device groups (significance level P < 0.05, One-Way ANOVA), suggesting the biocompatibility of the device. FIG. 21, panel c, shows representative images of the stained cross-sectional areas near the site of implantation. Animals euthanized and examined at the end of 1 and 4 weeks exhibited mild to moderate inflammatory cell infiltration, consisting of macrophages, lymphocytes, and plasma cells at the implantation site. The epicardial mixed-cell inflammation was comparable for control and device groups. At the end of 1 week, moderate inflammatory responses are observed in the device group with localized inflammatory exudate and noticeable proliferation of macrophages. At the end of 4 weeks, the device group shows alleviated inflammation, likely due to the natural healing process of the body and the attenuation of the initial inflammatory response. Control and device groups show comparable mild responses at the end of 4 weeks. Bioresorption of the pacemaker The main components of the device are Mg / Zn, Mo, MoO3, Si, and polyanhydride (PA). The biodegradation mechanisms and rates of these materials are summarized in Table 1. The products of degradation of Mg / Zn, Mo, MoO3, Si, and PA are Mg(OH)2 / Zn(OH)2, H2MoO4, H2MoO4, Si(OH)4, and carboxylic acids, respectively. Each of these products is water soluble and can be harmlessly excreted in the urine. H2, as an additional degradation product of Mg / Zn and Si, dissolves into the adjacent tissues, diffuses through these tissues and blood vessels, and can pass through the skin. The pacing process involves the electrochemical oxidation of the Mg anode and the reduction of the MoO3cathode. As a result, this process increases the rate of bioresorption of these electrodes. Degradation reactions for the other components including the phototransistor, the Attorney Docket No.616146.100572 conductive paste, and the polyanhydride (PA) encapsulation are relatively unaffected by the pacing process. FIG.1I indicates that the dissolution of the about 10 µm thick Si-based phototransistor (PT) is the rate-limiting step of complete bioresorption. The Si-based PT is mainly the Si doped with boron and phosphorus. Previous works report the dissolution rates being about 11 nm / day for both boron-doped and phosphorus-doped Si and about 23 nm / day for pure Si, respectively, in artificial cerebrospinal fluid (pH 7.4) at physiological temperature (37 °C), which indicates timescales for complete bioresorption of about 1.2-2.5 years. Appropriate choices of materials and device designs can enable decreases of bioresorption timescales. One option is to fabricate Si micro / nanomembrane-based phototransistors on silicon-on- insulator wafers followed by releasing the devices via back-side etching and transfer printing manners. Reducing the thickness of the PT to about 5 µm can decrease the timescale by 2 times. Discussion on the device's technical specifications Energy requirements: FIG.22, panel a, shows the relationship between the light intensity and the output current of the pacemaker. FIG.22, panel b, plots the simulated normalized light intensity received by the phototransistor part of the device at various tissue depths beneath the skin. For adults, the average shortest distance between the surface of the skin and the surface of the heart is ~30 mm. For device implanted at this depth, the light intensities required on the skin surface for different pacemaker outputs are plotted in FIG.22, panel c. These results suggest that the required light intensity increases with increasing pacemaker output. For example, a current of 0.64 mA from the pacemaker requires an intensity of about 10.6 mW mm-2at the surface of the skin, well within a safe range for human exposure. Efficiency of the optical control mechanism: As shown in FIG.22, panel b, the lightintensity drops to 28%, 3.0%, 0.49%, and 0.08% at tissue depths of 10, 20, 30, and 40 mm,respectively. FIG. 2A shows the temporal response of a pacemaker under pulsed light illumination.The rise and fall times are less than 25 μs, far beyond the requirements for cardiac pacing. Range of operable conditions: To provide a comprehensive range of operable conditions, we plotted the required light intensities on the skin surface for different pacemaker outputs at tissue depths of 10, 20, 30, and 40 mm, as shown in FIG.23. These results suggest that the required light intensity increases with increasing pacemaker output at a specific implantation depth. In addition, increasing the depth of implantation increases the required light input on the surface of the skin, for a given pacemaker output. Attorney Docket No.616146.100572 Discussion on the device's operational lifespan In benchtop experiments, we conducted electrochemistry impedance spectroscopy (EIS) measurements on fresh chicken tissue and agarose gel (1 wt% agarose, 0.9 wt% NaCl and 0.5 wt% glycerol) to evaluate their impedance across a frequency range from 1 Hz to 10 kHz. The impedances of the agarose gel and chicken tissue are similar, ~500 Ohm at 1 kHz, corresponding to a ~ 1 ms pulse width during cardiac pacing. This result indicates that the agarose gel can serve as a phantom tissue to mimic the physiological impedance. We then sandwiched the pacing electrodes in the agarose gel at 37 °C. The pacing electrodes, the phototransistor, and a current measurement module (PalmSens4) were electrically connected in series. A function generator (Rigol) powered the LEDs and generated pulsed illumination with a frequency of 1 Hz and a pulse width of 5 ms on the phototransistor. The output current of the pacemaker was measured every 6 h. As shown in FIG.9, the pacemaker can maintain a stable output for up to 16 days. Calculations on the maximum permissible exposures for skin safety According to the American National Standard for Safe Use of Lasers Guidelines ANSI Z136.1, we calculated the maximum permissible exposures (MPE) for skin safety for 850 nm light when pulsed at a frequency of 1 Hz with a duration of 2 ms. In this work, we utilized multiple- pulsed (repetitive-pulsed) light. Two rules apply for the case of the skin safety. The exposure is evaluated according to each rule to determine a set of possible MPEs, and the most restrictive MPE in the set is taken as the MPE for the exposure. The wavelength correction factor CAfor 850 nm is CA= 100.002(^^−700)= 100.002(850−700)= 1.995 where λ is the wavelength of the light. Rule 1: Single-Pulse MPE: e exposure from any single pulse in a train of pulses shall not exceed the MPE for the duration of the pulse. Rule 1 protects against injury from any single pulse having greater than average energy. The MPE:H for a single 2 ms pulse is MPE: H = 1.1 × ^^^^ × ^^0.25 = 1.1 × 1.995 × 0.0020.25 = 0.464 ^^ ^^^^−2where t is the duration of exposure, MPE:H is radiant exposure for a single pulse or exposure (J cm-2). In terms of peak irradiance, ^^^^^^: ^^ =^^^^^^:^^ 0.464= -2^^^^ = 0.002232 W cm Attorney Docket No.616146.100572 where tp is the pulse duration, MPE:E is the maximum permissible irradiance (W cm-2). Rule 2: Average-Power MPE for Thermal and Photochemical Hazards: e exposure from any grouping of pulses within the train of pulses shall not exceed the MPE for the duration of the grouping. Rule 2 protects against cumulative injury from photochemical damage mechanisms and also against heat buildup. Consider the MPE for a 10 s exposure, ^^^^^^: ^^^^^^^^^^^^ = 1.1 × ^^^^ × ^^0.25 = 1.1 × 1.995 × 100.25 = 3.9 ^^ ^^^^−2where MPE:HGroup is the radiant exposure for the summation of all the energy in a group of pulses (J cm-2). The MPE:H / pulse based on a 10 s exposure is ^^^^^^: ^^ / ^^^^^^^^^^ = 3.9 ^^ cm−2 -210 ^^^^^^^^^^^^ = 0.39 J cm In terms of peak irradiance, ^^^^^^: ^^ =^^^^^^:^^ / ^^^^^^^^^^ 0.39-2^^^^ = 0.002= 195 W cmThe lower MPE value for the exposure. Therefore, the peak irradiance must be kept within 195 W cm-2(1950 mW mm-2). This result indicates that the device can reliably be implanted up to about 60 mm deep in the body, with the light magnitude manageable. Multi-site stimulation strategy In the example illustrated in this work, light emitted from LED (X) selectively passes through the optical filter (X), illuminates the PT(X), and activates pacemaker P(X) (X = 1 or 2). In this sense, LED (X), filter (X), and P(X) form a matched group. As described previously, the output current of a pacemaker depends on the total resistance of the PT, the electrochemical cell, and the cardiac tissue. The ideal scenario involves illumination from LED (X) at an intensity sufficiently high such that the output current of P(X) is sufficient to pace the heart, but sufficiently low to avoid the stimulation of any other pacemaker. For the system reported here, the intensities of light emitted by LEDs (1) (850 nm) and (2) (650 nm) at the location of the PT / filter sets are below 0.035 and 0.12 mW mm-2, respectively. Pacing technique during TAVR implantation To ensure stable and reliable pacing during TAVI implantation, a conventional commercial Attorney Docket No.616146.100572 cardiac pacemaker may be used temporarily. After the procedure, this temporary pacing lead can be removed, as tissue will not have grown around the lead in such a short period. Our device can then take over pacing duties during the post-operative period, which allows safe and early patient discharge. Discussion on the illumination strategy for pacemakers integrated with TAVR The distances between the skin surface and the aortic root / LVOT junction (where the TAVR sits) for six patients evaluated by CT or MRI are between 5 to 10 cm. For effective stimulation at these distances, the required emitted light on the surface of the skin is 1.54 - 980 W mm-2. For skin safety, the peak irradiance needs to be kept within 1950 mW mm-2at 0.2% duty cycle (2 ms pulse, 60 bpm). Thus, for distance larger than 60 mm, the modified design (FIG.27) needs to be used. Another illumination strategy using optical fibers to deliver light directly on the phototransistor at low and safe intensity levels can also help. Key conceptual differences and associated engineering advances of this platform compared to previously reported bioresorbable electrostimulators The millimeter-scale, bioresorbable optoelectronic system introduced here represents significant key differences in the underlying concepts, in the engineering parameters and the clinical use cases compared to previously reported bioresorbable electrostimulators. These differences allow for millimeter-scale pacemakers, suitable for implanted in a minimally invasive way and for unusual forms of integration. These new platforms have a particular value with paediatric patients. Unique opportunities are in integration with established medical implants, as demonstrated in the main text with first-of-a-kind pacemakers-integrated transcatheter aortic valve replacement (TAVR) systems, with additional opportunities across a wide range of applications in electrotherapy. Comparisons of our pacemaker with previously reported bioresorbable pacemakers (Table 2) highlight key conceptual differences and associated engineering advances. The self-powered design, where asymmetric electrodes with different electrochemical potentials directly serve as the pacing electrodes, enables the realization of pacemakers with millimeter-scale dimensions, more than 21 times lighter by weight, 4.2 times shorter in length, and 5.5 times narrower in width than previously reported alternatives. This ultraminiaturized design allows for minimally invasive procedures for surgical implantation, including those based on transvenous catheters or injections. The technology also creates unique opportunities for integration with established medical implants. Furthermore, the optical control strategies support wavelength-division multiplexed (WDM) Attorney Docket No.616146.100572 techniques for operation, to allow time-coordinated multi-site pacing, not achievable with other types of devices. Table 2. Comparison between this work and previously reported bioresorbable pacemakers. Additional comparisons involve previously reported bioresorbable electrostimulators (Table 3). As before, the operating principles in devices reported here allow for size scales that are orders of magnitude smaller than these alternatives, with similar consequent increases in options for implantation and clinical use. Table 3. Comparison between this work and previously reported bioresorbable electronics. Attorney Docket No.616146.100572 The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described to explain the principles of the invention and their practical application to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the invention pertains without departing from its spirit and scope. Accordingly, the scope of the invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein. Some references, which may include patents, patent applications, and various publications, are cited and discussed in the description of this invention. The citation and / or discussion of such references is provided merely to clarify the description of the invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference. LIST OF REFERENCES[1]. Choi, Y. S. et al. Fully implantable and bioresorbable cardiac pacemakers without leads orbatteries. Nat Biotechnol 39, 1228–1238 (2021).[2]. Zhang, Y. et al. Advances in Bioresorbable Materials and Electronics. Chem Rev 123, Attorney Docket No.616146.100572 11722–11773 (2023).[3]. Choi, Y. S. et al. A transient, closed-loop network of wireless, body-integrated devices forautonomous electrotherapy. Science 376, 1006–1012 (2022).[4]. Lumia, F. J. & Rios, J. C. Temporary Transvenous Pacemaker Therapy: An Analysis ofComplications. Chest 64, 604–608 (1973).[5]. Wood, M. A. & Ellenbogen, K. A. Cardiac Pacemakers From the Patient’s Perspective.Circulation 105, 2136–2138 (2002).[6]. Bar-Cohen, Y. et al. Minimally Invasive Implantation of a Micropacemaker Into thePericardial Space. Circ Arrhythm Electrophysiol 11, (2018).[7]. Zhao, J. et al. Permanent epicardial pacing in neonates and infants less than 1 year old: 12-year experience at a single center. Transl Pediatr 11, 825–833 (2022).[8]. Wildbolz, M., Dave, H., Weber, R., Gass, M. & Balmer, C. Pacemaker Implantation inNeonates and Infants: Favorable Outcomes with Epicardial Pacing Systems. Pediatr Cardiol 41, 910–917 (2020).[9]. Wilhelm, M. J. et al. Cardiac Pacemaker Infection: Surgical Management With and WithoutExtracorporeal Circulation. Ann Thorac Surg 64, 1707–1712 (1997).

[0010] . Donovan, K. D. & Lee, K. Y. Indications for and Complications of Temporary TransvenousCardiac Pacing. Anaesth Intensive Care 13, 63–70 (1985).

[0011] . BRAUN, M. U. et al. Percutaneous Lead Implantation Connected to an External Device inStimulation-Dependent Patients with Systemic Infection—A Prospective and Controlled Study. Pacing and Clinical Electrophysiology 29, 875–879 (2006).

[0012] . Donovan, K. D. & Lee, K. Y. Indications for and Complications of Temporary TransvenousCardiac Pacing. Anaesth Intensive Care 13, 63–70 (1985).

[0013] . Ouyang, H. et al. Symbiotic cardiac pacemaker. Nat Commun 10, 1821 (2019).

[0014] . Lyu, H. et al. Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Modelbased on Wirelessly Powered Leadless Pacemakers. Sci Rep 10, 2067 (2020).

[0015] . Ho, J. S. et al. Wireless power transfer to deep-tissue microimplants. Proceedings of theNational Academy of Sciences 111, 7974–7979 (2014).

[0016] . Wang, S. et al. A self-assembled implantable microtubular pacemaker for wireless cardiacelectrotherapy. Sci Adv 9, (2023).

[0017] . Prominski, A. et al. Porosity-based heterojunctions enable leadless optoelectronicmodulation of tissues. Nat Mater 21, 647–655 (2022).

[0018] . Liu, Z. et al. Photoelectric Cardiac Pacing by Flexible and Degradable Amorphous Si Radial Attorney Docket No.616146.100572 Junction Stimulators. Adv Healthc Mater 9, 1901342 (2020).

[0019] . Wang, L. et al. A fully biodegradable and self-electrified device for neuroregenerativemedicine. Sci Adv 6, 1–16 (2020).

[0020] . Zhang, Y. et al. Self-powered, light-controlled, bioresorbable platforms for programmeddrug delivery. Proceedings of the National Academy of Sciences 120, (2023).

[0021] . Huang, I. et al. High performance dual-electrolyte magnesium–iodine batteries that canharmlessly resorb in the environment or in the body. Energy Environ Sci 15, 4095–4108(2022).

[0022] . Koo, J. et al. Wireless bioresorbable electronic system enables sustainednonpharmacological neuroregenerative therapy. Nat Med 24, 1830–1836 (2018).

[0023] . Choi, Y. S. et al. Biodegradable Polyanhydrides as Encapsulation Layers for TransientElectronics. Adv Funct Mater 30, 2000941 (2020).

[0024] . 24. Song, G. Control of biodegradation of biocompatable magnesium alloys. Corros Sci49, 1696–1701 (2007).

[0025] . Schauer, A. et al. Biocompatibility and Degradation Behavior of Molybdenum in an In VivoRat Model. Materials 14, 7776 (2021).

[0026] . Yin, L. et al. Dissolvable Metals for Transient Electronics. Adv Funct Mater 24, 645–658(2014).

[0027] . Yu, K. J. et al. Bioresorbable silicon electronics for transient spatiotemporal mapping ofelectrical activity from the cerebral cortex. Nat Mater 15, 782–791 (2016).

[0028] . Kang, S.-K. et al. Bioresorbable silicon electronic sensors for the brain. Nature 530, 71–76(2016).

[0029] . Li, G. et al. Flexible Transient Phototransistors by Use of Wafer‐Compatible TransferredSilicon Nanomembranes. Small 14, (2018).

[0030] . Li, G. et al. Silicon nanomembrane phototransistor flipped with multifunctional sensorstoward smart digital dust. Sci Adv 6, (2020).

[0031] . López Ayerbe, J. et al. Temporary Pacemakers: Current Use and Complications. RevistaEspañola de Cardiología (English Edition) 57, 1045–1052 (2004).

[0032] . Yu, L., Nina-Paravecino, F., Kaeli, D. & Fang, Q. Scalable and massively parallel MonteCarlo photon transport simulations for heterogeneous computing platforms. J Biomed Opt 23, 1 (2018).

[0033] . Fang, Q. & Boas, D. A. Monte Carlo Simulation of Photon Migration in 3D Turbid MediaAccelerated by Graphics Processing Units. Opt Express 17, 20178 (2009). Attorney Docket No.616146.100572

[0034] . Taroni, P., Pifferi, A., Torricelli, A., Comelli, D. & Cubeddu, R. In vivo absorption andscattering spectroscopy of biological tissues. Photochemical & Photobiological Sciences 2,124–129 (2003).

[0035] . Khan, R., Gul, B., Khan, S., Nisar, H. & Ahmad, I. Refractive index of biological tissues:Review, measurement techniques, and applications. Photodiagnosis Photodyn Ther 33,102192 (2021).

[0036] . Green, M. A. & Keevers, M. J. Optical properties of intrinsic silicon at 300 K. Progress inPhotovoltaics: Research and Applications 3, 189–192 (1995).

[0037] . Rahko, P. S. Evaluation of the Skin-To-Heart Distance in the Standing Adult by Two-Dimensional Echocardiography. Journal of the American Society of Echocardiography 21,761–764 (2008).

[0038] . Chen, R. et al. Deep brain optogenetics without intracranial surgery. Nat Biotechnol 39,161–164 (2021).

[0039] . Yin, R. T. et al. Open thoracic surgical implantation of cardiac pacemakers in rats. NatProtoc (2022) doi:10.1038 / s41596-022-00770-y.

[0040] . Yang, Q. et al. Photocurable bioresorbable adhesives as functional interfaces betweenflexible bioelectronic devices and soft biological tissues. Nat Mater 20, 1559–1570 (2021).

[0041] . Shea, J. B. & Sweeney, M. O. Cardiac Resynchronization Therapy A Patient’s Guide.Circulation 108, (2003).

[0042] . Connolly, S. J., Kerr, C., Gent, M. & Yusuf, S. Dual-Chamber Versus Ventricular Pacing.Circulation 94, 578–583 (1996).

[0043] . Rodés-Cabau, J., Muntané-Carol, G. & Philippon, F. Managing Conduction DisturbancesAfter TAVR: Toward a Tailored Strategy. JACC Cardiovasc Interv 14, 992–994 (2021).

[0044] . Urena, M. & Rodés-Cabau, J. Conduction Abnormalities: The True Achilles’ Heel ofTranscatheter Aortic Valve Replacement? JACC Cardiovasc Interv 9, 2217–2219 (2016).

[0045] . Pagnesi, M. et al. Incidence, Predictors, and Prognostic Impact of New PermanentPacemaker Implantation After TAVR With Self-Expanding Valves. JACC Cardiovasc Interv 16, 2004–2017 (2023).

[0046] . Reiter, C. et al. Delayed Total Atrioventricular Block After Transcatheter Aortic ValveReplacement Assessed by Implantable Loop Recorders. JACC Cardiovasc Interv 14, 2723–2732 (2021).

[0047] . Muntané-Carol, G. et al. Ambulatory Electrocardiographic Monitoring FollowingMinimalist Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 14, 2711– Attorney Docket No.616146.100572 2722 (2021).

[0048] . Krishnaswamy, A. et al. Feasibility and Safety of Same-Day Discharge FollowingTransfemoral Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 15, 575–589 (2022).

[0049] . Choi, Y. S. et al. Biodegradable Polyanhydrides as Encapsulation Layers for TransientElectronics. Adv Funct Mater 30, 2000941 (2020).

[0050] . Yin, R. T. et al. Open thoracic surgical implantation of cardiac pacemakers in rats. NatProtoc 18, 374–395 (2023).

[0051] . Yang, Q. et al. Photocurable bioresorbable adhesives as functional interfaces betweenflexible bioelectronic devices and soft biological tissues. Nat Mater 20, 1559–1570 (2021).

[0052] . Yin, L. et al. Dissolvable Metals for Transient Electronics. Adv Funct Mater 24, 645–658(2014).

[0053] . Song, G. Control of biodegradation of biocompatable magnesium alloys. Corros Sci 49,1696–1701 (2007).

[0054] . Zhang, Y. et al. Self-powered, light-controlled, bioresorbable platforms for programmeddrug delivery. Proceedings of the National Academy of Sciences 120, (2023).

[0055] . Huang, X. et al. A Fully Biodegradable Battery for Self-Powered Transient Implants. Small14, 1800994 (2018).

[0056] . He, Q., Shi, J., Zhu, M., Chen, Y. & Chen, F. The three-stage in vitro degradation behaviorof mesoporous silica in simulated body fluid. Microporous and Mesoporous Materials 131, 314–320 (2010).

[0057] . Kuhlmann, J. et al. Fast escape of hydrogen from gas cavities around corroding magnesiumimplants. Acta Biomater 9, 8714–8721 (2013).

[0058] . Yu, K. J. et al. Bioresorbable silicon electronics for transient spatiotemporal mapping ofelectrical activity from the cerebral cortex. Nat Mater 15, 782–791 (2016).

[0059] . Kang, S.-K. et al. Bioresorbable silicon electronic sensors for the brain. Nature 530, 71–76(2016).

[0060] . Li, G. et al. Flexible Transient Phototransistors by Use of Wafer‐Compatible TransferredSilicon Nanomembranes. Small 14, (2018).

[0061] . Li, G. et al. Silicon nanomembrane phototransistor flipped with multifunctional sensorstoward smart digital dust. Sci Adv 6, (2020).

[0062] . Chen, R. et al. Deep brain optogenetics without intracranial surgery. Nat Biotechnol 39,161–164 (2021). Attorney Docket No.616146.100572

[0063] . Aly, I. et al. Cardiac ultrasound: An Anatomical and Clinical Review. TranslationalResearch in Anatomy 22, 100083 (2021).

[0064] . Choi, Y. S. et al. Fully implantable and bioresorbable cardiac pacemakers without leads orbatteries. Nat Biotechnol 39, 1228–1238 (2021).

[0065] . Choi, Y. S. et al. A transient, closed-loop network of wireless, body-integrated devices forautonomous electrotherapy. Science (1979) 376, 1006–1012 (2022).

[0066] . Liu, Z. et al. Photoelectric Cardiac Pacing by Flexible and Degradable Amorphous Si RadialJunction Stimulators. Adv Healthc Mater 9, 1901342 (2020).

[0067] . Lee, G. et al. A bioresorbable peripheral nerve stimulator for electronic pain block. Sci Adv8, (2022).

[0068] . Koo, J. et al. Wireless bioresorbable electronic system enables sustainednonpharmacological neuroregenerative therapy. Nat Med 24, 1830–1836 (2018).

[0069] . Yao, G. et al. A self-powered implantable and bioresorbable electrostimulation device forbiofeedback bone fracture healing. Proceedings of the National Academy of Sciences 118, (2021).

[0070] . Wu, P. et al. Ultrasound-driven in vivo electrical stimulation based on biodegradablepiezoelectric nanogenerators for enhancing and monitoring the nerve tissue repair. Nano Energy 102, 107707 (2022).

[0071] . Zheng, Q. et al. Biodegradable triboelectric nanogenerator as a life-time designedimplantable power source. Sci Adv 2, (2016).

Claims

Attorney Docket No.616146.100572 CLAIMS What is claimed is:

1. A pacemaker for stimulation for a subject, comprising:a phototransistor (PT); and first and second electrodes, each electrode having a first end electrically connected to the PT and a second end in communication with a target tissue of the subject for the stimulation.

2. The pacemaker of claim 1, being self-powered with an optical control mechanism, whereinthe first and second electrodes serve as both battery electrodes and stimulating electrodes.

3. The pacemaker of claim 2, wherein one of the first and second electrodes serves as an anode,and the other of the first and second electrodes serves as a cathode, and the target tissue and associated biofluids act as an electrolyte to form a galvanic battery.

4. The pacemaker of claim 3, wherein each of the anode and the cathode comprises anelectrically conductive material that is bioresorbable or biodegradable.

5. The pacemaker of claim 4, wherein the anode comprises a bioresorbable Mg, Mg alloy, Zn,and / or Zn alloy, and the cathode comprises an electropositive bioresorbable Fe, Mo, W, alloys of Fe, Mo and W, molybdenum trioxide (MoO3), iodine, and / or MnO2.

6. The pacemaker of claim 3, wherein the PT is configured to act as the optical controlmechanism to control the operation of the pacemaker with an external light source that operably emits light at tissue-penetrating wavelengths in a near-infrared (NIR) range.

7. The pacemaker of claim 6, wherein the PT comprises a bipolar junction transistor (BJT),configured to respond to illumination of the light at the tissue-penetrating wavelengths.

8. The pacemaker of claim 7, wherein the BJT has an emitter terminal, and a collector terminalAttorney Docket No.616146.100572 electrically connected to the anode and the cathode, respectively.

9. The pacemaker of claim 8, wherein the emitter terminal and the collector terminal areelectrically connected to the anode and cathode, respectively, using a biodegradable conductive paste.

10. The pacemaker of claim 8, wherein the stimulation are performed upon the illumination ofthe light to the BJT through the skin and underlying tissue.

11. The pacemaker of claim 10, wherein in absence of the illumination of the light to the BJT,the PT has a resistance that is sufficiently high so that flow of current through the galvanic battery is prevented, whereby the pacemaker is inactive.

12. The pacemaker of claim 10, wherein upon the illumination of the light to the BJT, the PT hasa resistance that decreases to sufficiently low, thereby closing the circuit and discharging the galvanic battery through the stimulating electrodes and the adjacent tissue.

13. The pacemaker of claim 12, wherein the fast responses of the PT and the overalloptoelectronic circuit allow for precise, dynamic control over the current delivered to the target tissue.

14. The pacemaker of claim 1, further comprising an encapsulation layer encapsulating the entirestructure, leaving the second ends of the first and second electrodes exposed to interface with the target tissue.

15. The pacemaker of claim 14, wherein the encapsulation layer comprises a bioresorbableformulation of polyanhydride, silk, cellulose, sodium carboxymethylcellulose (Na-CMC), alginate, starch, chitosan, albumin, gelatin, keratin, shellac candelilla wax, beeswax, galactomannan, carrageenan-agar, polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), poly(3-hydroxybutyrateco-3-hydroxyvalerate) (PHBV), bioresorbable polyanhydride, polyurethane, poly(lactic-co-glycolic acid) (PLGA), poly(D,L-lactic acid) (PDLLA), poly(L-Attorney Docket No.616146.100572 lactic acid) (PLLA), polycaprolactone (PCL), silk fibroin (SF), polyethylene glycol (PEG), polyethylene glycol diacrylate (PEGDA), polyglycolic acid (PGA), polydopamine (PDA), polybutylene adipate terephthalate (PBAT), poly(trimethylene carbonate) (PTMC), poly(desaminotyrosyl-tyrosine ethyl ester carbonate) (PDTEC), poly(glycerol sebacate) (PGS), poly(octamethylene maleate (anhydride) citrate) (POMaC), acrylic acid (AAc), gelatin methacrylate (gelMA), acrylic acid N-hydroxysuccinimide (AAc-NHS ester), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), and / or polyethylene glycol- lactide diacrylate (PEG-LA-DA)16. The pacemaker of claim 1, having a size in millimeter-scales.

17. The pacemaker of claim 16, having a footprint of about 5 mm ^ 10 mm or less, and athickness of about 5 mm or less.

18. The pacemaker of claim 17, having a footprint of about 1.8 mm ^ 3.5 mm or less, and athickness of about 1 mm or less.

19. The pacemaker of claim 16, being configured to be administered to a site of interest of thesubject via a minimally invasive implantation procedure, wherein the minimally invasive implantation procedure comprises percutaneous injection and endovascular delivery.

20. The pacemaker of claim 19, being configured to fit into a small-diameter introducer forinjection directly into a superficial subepicardial layer of the myocardium of the subject through skin incisions.

21. The pacemaker of claim 19, being configured to be administered to a site of interest of thesubject via transcatheter aortic valve replacement / implantation (TAVR / TAVI) procedures.

22. The pacemaker of claim 19, being configured such that one or more pacemakers areintegrable with transcatheter valve devices for aortic (TAVR), pulmonary, tricuspid, and mitral valves procedures.Attorney Docket No.616146.10057223. The pacemaker of claim 19, wherein the pacemaker is implanted via catheter endocardiallyfor pacing the conduction system for resynchronization therapy.

24. The pacemaker of claim 19, wherein a plurality of pacemakers is delivered via minimallyinvasive catheter epicardially for resynchronization therapy.

25. The pacemaker of claim 1, being bioresorbable and biocompatible.

26. The pacemaker of claim 25, being bioresorbed or biodegraded in the subject’s body after aperiod of bioresorption, thereby eliminating the need for surgical extraction of the pacemaker after a period of operation.

27. The pacemaker of claim 26, wherein the period of bioresorption is at least 10 days.

28. The pacemaker of claim 26, wherein the period of bioresorption is customizable byappropriate choices of materials and device designs.

29. The pacemaker of claim 1, being pairable with a soft, skin-interfaced wireless device thatcontinuously captures electrocardiograms, performs data analytics, and optically controls the pacemaker via programming light emission in the NIR range as the basis for autonomous, on-demand closed-loop cardiac electrotherapy upon detection of arrhythmias.

30. The pacemaker of claim 1, being usable for pacing in a multi-site manner with a wavelength-division multiplexed (WDM) technique for time-synchronized dual-chamber and biventricular pacing, including multi-site resynchronization therapy.

31. The pacemaker of claim 1, being integrable onto an implantable framework including atranscatheter aortic valve replacement (TAVR) frame.

32. The pacemaker of claim 1, being compatible with medical imaging screening of magneticAttorney Docket No.616146.100572 resonance imaging (MRI) and / or computed tomography (CT).

33. The pacemaker of claim 1, wherein the stimulation comprises cardiac pacing, brainstimulation, spinal cord stimulation, peripheral nervous system stimulation, and / or skeletal muscle stimulation.

34. A system for cardiac pacing for a subject, comprising:a plurality of pacemakers implanted to different sites of interest of the subject, wherein each pacemaker is according to any one of claims 1-33; wherein each pacemaker further includes a narrow band optical filter placed atop the PT therefor to serve as the basis for a wavelength-division multiplexed (WDM) control scheme; and wherein programmable optoelectronic control of the plurality of pacemakers forms the basis for time-synchronized multi-site operation for biventricular (BiV) and dual- chamber (A&V) pacing.

35. The system of claim 34, wherein independent operation of the plurality of pacemakers relieson illumination at wavelengths aligned with the transmission properties of the filters.

36. The system of claim 35, wherein in operations, light emitted from light source L(X)selectively passes through optical filter F(X), illuminates phototransistor PT(X), and then activates pacemaker P(X), wherein L(X), F(X), and P(X) form a matched group, wherein X = 1, 2, ... N, N being the number of the plurality of pacemakers.

37. The system of claim 36, wherein the light source L(X) is configured to emit the light at anintensity sufficiently high such that the output current of P(X) is sufficient to pace the heart, but sufficiently low to avoid the stimulation of any other pacemaker.

38. The system of claim 37, having reliable programmability of cardiac pacing at multiple sites,with timing precisely controlled by the operation of the light sources.Attorney Docket No.616146.10057239. The system of claim 38, wherein each light source comprises a light emitting diode (LED), alaser, or the like.

40. The system of claim 34, wherein placing the two pacemakers on the RV anterior wall andLV lateral wall allows for biventricular pacing.

41. The system of claim 34, wherein positioning at the LA lateral wall and LV lateral wallenables dual-chamber pacing.

42. The system of claim 34, wherein programmable WDM control of both LEDs enables BiVand A&V pacing.

43. The system of claim 34, wherein the dual-chamber pacing modality yields a physiology moreconsistent with normal cardiac activation than that associated with simple ventricular pacing.

44. The system of claim 34, being usable for cardiac resynchronization therapy.

45. A system for cardiac pacing for a subject, comprising:at least one pacemaker implanted to at least one site of interest of the subject, wherein each pacemaker is according to one of claims 1-33; and at least one skin-interfaced module attached to a skin surface of the subject in wireless communication with the at least one pacemaker for autonomous, closed-loop, on- demand cardiac electrotherapy.

46. The system of claim 44, wherein the at least one skin-interfaced module is configured toperform: single-lead recordings of electrocardiograms (ECG); wireless data transfer to a graphical user interface on a mobile device for real-time data visualization; closed-loop analytics for automated detection of cardiac arrhythmias; and programmed operation of integrated light sources to optically control the at least oneAttorney Docket No.616146.100572 pacemaker for the cardiac pacing.

47. The system of claim 46, wherein the at least one skin-interfaced module comprises a powermanagement circuit, ECG sensors, light sources, an analog frontend (AFE) that amplifies, filters, and digitizes the ECG signal, and a Bluetooth-low-energy (BLE) system-on-a-chip (SoC) that collects the conditioned ECG signal and streams in real time to the graphical user interface on the mobile device, which are integrated on a flexible printed circuit board.

48. The system of claim 47, wherein each light source comprises a light emitting diode (LED), alaser, or the like.

49. A system for cardiac pacing for a subject, comprising:a transcatheter aortic valve replacement (TAVR) frame; and a plurality of pacemakers attached onto or integrated with the TAVR frame placed in a heart of the subject for delivering both rapid pacing during valve deployment and regular pacing during the post-operative period, wherein at least one of the pacemaker is according to one of claims 1-33.

50. The system of claim 49, wherein the plurality of pacemakers is attached onto junction pointsof struts of the TAVR frame, wherein the TAVR frame is a self-expanding stent.

51. The system of claim 49, wherein the plurality of pacemakers is attached with the pacingelectrodes facing the septal wall for effective pacing of the myocardium.

52. The system of claim 51, wherein the plurality of pacemakers is attached with orienting mostof the pacing electrodes toward the antero-septal region of the left ventricle to ensure proximity to the heart conduction system.

53. The system of claim 49, wherein each pacemaker is activated separately using light emittedfrom the light sources, starting from lower intensities, faster pacing rates, and shorter pulse widths, followed by adjusting these parameters across a range until 100% capture, or failure.Attorney Docket No.616146.10057254. The system of claim 52, wherein each light source comprises a light emitting diode (LED), alaser, or the like.

55. The system of claim 49, wherein the plurality of pacemakers is activated simultaneously byexternal flood illumination to ensure reliable pacing even when the orientation and precise positioning of the TAVR stent cannot be controlled during implantation.

Images