In all accepted implantable medical accessories such as pacemakers, abysmal academician stimulators, and attack assay devices, anniversary electrode is afar affiliated to abstracted ascendancy systems. The adeptness of these accessories to sample and activate tissues is hindered by this agreement and by the rigid, collapsed attributes of the electronics and the electrode-tissue interfaces. Here, we address the development of a chic of mechanically adjustable silicon electronics for multiplexed altitude of signals in an intimate, conformal chip admission on the dynamic, three-dimensional surfaces of bendable tissues in the beastly body. We authenticate this technology in sensor systems composed of 2016 silicon nanomembrane transistors configured to almanac electrical action anon from the curved, wet apparent of a assault beefy affection in vivo. The accessories sample with accompanying submillimeter and submillisecond resolution through 288 amplified and multiplexed channels. We use this arrangement to map the advance of ad-lib and paced ventricular depolarization in complete time, at aerial resolution, on the epicardial apparent in a beefy beastly model. This affirmation is one archetype of abounding accessible uses of this technology in minimally invasive medical devices.
Conventional accoutrement for managing and alleviative cardiac arrhythmias use dispersed arrays of adamant electrodes abiding on a annular catheter that almanac electrical potentials at the apparent of cardiac tissue at one or a few spatial locations at a time. During mapping, these catheters are amid through the bank and maneuvered from abode to abode from alfresco the anatomy to almanac from detached sites on the heart. In both cases, consecutive bounded recordings are “stitched” calm with software to crop a complete representation of cardiac electrical action over a arena of interest. The accepted attributes of this admission about requires added than 1 hour in the electrophysiology lab and prevents real-time mapping of brief aberrant rhythms (1, 2). One agency to facilitate mapping and ablation is to accommodate ample numbers of broadcast sensors and electronics over the apparent of the affection to accommodate full, spatio-temporal appraisal of cardiac electrical rhythms in complete time. At present, however, all forms of high-performance electronics are congenital on the hard, rigid, and breakable surfaces of semiconductor wafers, in formats that are inherently adverse with establishing intimate, ample breadth interfaces with the angled surfaces of the body. Newer flexible, stretchable electronics accept the abeyant to abstain these limitations, but complete accessories action abandoned simple modes of functionality, afterwards the all-important levels of affiliation or achievement bare to accommodate clinically advantageous operation for real-time spatio-temporal mapping (3–13). These technologies additionally cannot yet accomplish back absorbed in biological fluids as adapted for medical use because of acute difficulties in electrically isolating the accessories to ahead arising currents that can shock the contacting tissue (3–11).
Here, we address a high-performance, conformal cyberbanking arrangement able of affectionate affiliation with dynamic, alive biological tissues. We administer this admission in a sensor arrangement configured to admeasurement cardiac electrophysiological action with aerial banausic and spatial resolution, and we validate its achievement in situ in a beefy beastly model.
Fabrication begins with benumbed distinct clear silicon nanoribbons on a silicon dent that are transfer-printed to a attenuate artificial breadth (Fig. 1, A to D). Degradation and apery of adequate dielectric and metal layers complete the anatomic electronics. Specialized designs and multilayer encapsulation schemes assure all alive apparatus from the tissue and surrounding biofluids. The completed accessory appears in Fig. 1E, and antiquity accommodation are included in Abstracts and Methods and Supplementary Material. The accessory includes an 18 × 16 arrangement of amplified electrodes to accommodate a complete of 288 altitude credibility spaced 800-μm afar and accoutrement a complete breadth of 14.4 mm by 12.8 mm (Fig. 1). Anniversary electrode consists of a gold acquaintance pad that serves as an electrical interface with the tissue, affiliated to an associated amplifier and multiplexer. A distinct amplifier, multiplexer, and electrode accomplish up a assemblage cell. Anniversary assemblage corpuscle comprises 7 n-type metal-oxide-semiconductor (nMOS) field-effect transistors for a complete of 2016. Chip multiplexing chip enables the use of abandoned 36 affairs to affix all 288 altitude credibility to alien abstracts accretion (DAQ) and ascendancy units.
Schematic illustrations and images of accomplish for architecture active, conformal electronics for cardiac electrophysiology, and photograph of a completed device. (A) Schematic analogy (left) and optical micrograph (right) of a accumulating of benumbed silicon nanomembranes in a assemblage cell. (B) Agreement afterwards antiquity of the source, drain, and aboideau contacts, with adequate interconnects and row electrodes for multiplexed addressing. (C) Agreement afterwards antiquity of the added metal layer, including the cavalcade achievement electrodes. Annotations at adapted announce the multiplexing transistor and the assorted apparatus of the amplifier. (D) Final blueprint afterwards degradation of encapsulation layers and antiquity of the tissue-contacting electrode. (E) Photograph of a completed accessory in a hardly angled state. (Inset) Abstract appearance of a brace of assemblage cells.
The transistors and arrangement were formed in four layers, as illustrated in Fig. 1 (A to D). In the aboriginal step, alteration press delivers to a adjustable artificial substrate [polyimide (PI); ~25 μm thick], an organized accumulating of single-crystalline, semiconductor-grade silicon nanomembranes (260 nm) with blooming regions of n-type (phosphorus) doping (Fig. 1A). Plasma-enhanced actinic breath degradation of SiO2 (~100 nm) at a bargain temperature (~250°C) yields a aboideau dielectric through which antecedent or cesspool acquaintance openings are formed by photolithography and carving in buffered oxide etchant. Electron axle evaporation, photolithography, and wet carving ascertain the aboriginal band of metal interconnections, including source, drain, and aboideau contacts (Fig. 1B). Analogously bogus added and third metal layers anatomy the cavalcade and row acclamation electrodes (Fig. 1, C and D). A attenuate band of spin-cast PI (1.4 μm) with categorical vertical interconnect admission holes provides the interlayer dielectric amid the aboriginal and the added metal layers; a trilayer amoebic or asleep assemblage (PI/Si3N4/epoxy, 1.4 μm/80 nm/9 μm) and a distinct band of adhering (9 μm) anatomy a agnate interlayer for the added and third and third and fourth metal layers, respectively. The completed accessory appears in Fig. 1E. Accommodation are categorical in figs. S1 to S5.
This layered anatomy locates the ambit at the aloof automated alike to ahead accident from angle and to ensure reliable operation back the accessory is absorbed in acrid band-aid and biofluids, as declared below. The top metal band contains the apparent electrodes (Au pads, 250 × 250 μm) that acquaintance the cardiac tissue and affix to the basal circuits through vertical interconnect admission holes. These electrodes accept achievement impedances of 100 kilohm ± 10% at 1 kHz, as abstinent with a analogously advised acquiescent electrode arrangement absorbed in accustomed acrid (0.9%) solution. (Measuring the achievement impedance of the metal electrodes is not accessible back they are chip with the alive circuitry.) The complete accessory connects to a DAQ arrangement through an anisotropic conductive blur (ACF) adapter with 36 contacts. See fig. S6 for added accommodation and for ambit of the devices.
The adapted panels of Fig. 1C and Fig. 2A accommodate annotated images and ambit diagrams, respectively, of the amplifier and the multiplexing transistor. The amplifier uses a source-follower agreement with accepted accretion (fig. S7). The multiplexing transistor enables readout of all inputs via programmed, consecutive acclamation of anniversary row of electrodes, thereby accouterment a 16 times abridgement in the adapted cardinal of achievement affairs about to a nonmultiplexed electrode array.
Design and electrical backdrop of an active, adjustable accessory for cardiac electrophysiological mapping. (A) Ambit diagram for a assemblage cell, with annotations agnate to those in Fig. 1C. (B) Ambit diagram of four assemblage cells, advertence the arrangement for multiplexed addressing. (C) Current-voltage characteristics of a adumbrative adjustable silicon transistor. Cesspool to antecedent accepted (Ids) is advised as a action of cesspool to antecedent voltages (Vds). The aboideau to antecedent voltage (Vgs) is assorted from 0 to 4 V in 1-V steps. (Inset) Id on logarithmic (left) and beeline scales (right), as Vgs is swept from −2 to 5 V, demonstrating the beginning voltage (Vt) of the transistor. (D) Apish and abstinent abundance acknowledgment of a adumbrative amplifier with multiplexing disabled. The amplifier shows achievement backdrop affiliated with architecture targets and simulations (that is, −3 dB blow abundance of ~200 kHz). Simulations were acquired application bartering software (Cadence, Cadence Architecture Systems; see the Supplementary Actual for simulation details). (E) Adumbrative multiplexer switching response, assuming the row baddest signals, cavalcade output, and apish cavalcade output. The acknowledgment time is bound by the alien row baddest arresting bulk rate. (F) Allotment of the final voltage bulk able during the allotted clearing time, averaged beyond all of the electrodes, for accretion multiplexing frequency, advertence that the best adapted multiplexing bulk is ~200 kHz. (G) Photograph of a completed accessory with ACF interconnect absorbed in a acrid solution. (H) Sine beachcomber acknowledgment (at 10 Hz) afore and afterwards acrid captivation for 3 hours.
The schematic in Fig. 2B illustrates how the assemblage corpuscle in Fig. 2A connects to added assemblage beef to actualize the multiplexed arresting output. This basal blueprint allows the architecture to be calmly scaled up to beyond all-embracing arrangement sizes while advancement the spatial resolution of the arrangement and afterwards abacus essentially added wires. During multiplexed sampling, one row of electrodes at a time is called by alive one of the row baddest signals, such as R0 (highlighted in dejected in Fig. 2B), aerial and all of the others low (R1 … Rn, breadth R1 is accent in green). This arrangement allows the assemblage beef in the agnate row to drive the cavalcade achievement curve (C0 … Cn, breadth C0 is accent in red), which are affiliated to a accelerated analog to agenda advocate (fig. S8). Row baddest signals are rapidly cycled to sample all electrodes on the array.
The multiplexing transistors display on-off ratios of ~105 and electron mobilities of ~490 cm2/Vs, affected from the arrangement of best and minimum accepted outputs and the slopes of the alteration curves (inset), respectively, by application accepted field-effect transistor models (14) (Fig. 2C). The aerial advancement of single-crystalline silicon, about to organics or added abstracts for adjustable electronics, enables the amplifier to accept a aerial bandwidth (Fig. 2D), and the multiplexer to about-face bound (Fig. 2E), alike for the almost base ambit of the accessories appear actuality (channel lengths of ~40 μm). The switching time (~5 μs) is limited, however, by the bulk bulk of the alien row baddest signals provided to the array, as apparent in dejected and blooming in Fig. 2E. We additionally angled the allotment of the final voltage bulk able during the allotted clearing time, averaged beyond all of the electrodes, with accretion multiplexing abundance (Fig. 2F). Multiplexing ante up to 200 kHz were measured, acquiescent accessible sampling ante up to 12.5 kHz per electrode. The signal-to-noise arrangement (SNR) for the arrangement charcoal affiliated up to 200 kHz multiplexing abundance (fig. S9). The SNR adding corresponds to arresting to babble and baloney (SINAD) for a 50-mV peak-to-peak sine beachcomber at 20 Hz. The aerial bulk for SINAD indicates that there is actual little nonlinear baloney alien by the device. The SNR abstracts (fig. S9) and the voltage accouterment amid adjoining channels (Fig. 2E) announce that cantankerous allocution is negligible for archetypal arresting levels.
In abstracts declared below, the 16 row baddest signals were cycled at 10 kHz, acquiescent a sampling bulk of 625 Hz per alive electrode, with all 16 electrodes in a accustomed row appropriately sampled sequentially. The multiplexed analog signals were synchronously sampled at 50 kHz, with bristles times oversampling per about-face breach to advance the SNR. If the bulk bulk of the row baddest signals is added via improvements in the DAQ system, the multiplexing bulk can be added increased.
We acclimated analytic mechanics clay to analyze the bending-induced strains in all layers of the accessories acclimated in our beastly experiments. For angle radii of ~5 cm, archetypal of those acclimated in commercially accessible electrophysiology catheter designs, best strains in Si and SiO2 are begin to be 0.001% and 0.0001%, respectively. These ethics are three to four orders of consequence beneath the breach ache for Si and SiO2 (~1%), and they are additionally appreciably beneath than those accepted to adapt their electrical achievement (15). The induced strains abide beneath the breach banned to radii of curvature as baby as 500 μm (fig. S10), thereby enabling, in principle, the arrangement to be formed into a catheter of abandoned a few millimeters in bore and unrolled already delivered to the ambition tissue. Bound folding tests, to radii as baby as 500 μm, accepted that the circuits abide operational beneath such altitude alike afterwards several days.
We additionally activated whether the angle acerbity of the ambit is abundantly low to acquiesce conformal wrapping on the clammy apparent of the cardiac tissue. These mechanics can be modeled by comparing the arrangement activity for a ambit in a collapsed agreement to one in a captivated accompaniment (fig. S11). The aftereffect is that wrapping is agilely advantaged back γ > B / 2R2, breadth γ is the adherence activity amid the ambit and the tissue, R is the ambit of curvature, and B is the angle acerbity of the circuit. By application R of ~2.5 cm and a computed bulk of B, one finds that wrapping is the adopted agreement for cases breadth γ > 34.7 mJ/m2. The appear bulk of adherence activity amid two wet surfaces is ~75 to 150 mJ/m2 (16–18). Our archetypal accordingly predicts that the circuits will artlessly blanket about the partially wet apparent of the cardiac tissue afterwards any abstracted apparatus to ensure adhesion. This aftereffect was authentic in our abstracts in the beefy model.
For use in analytic settings, the ambit allegation accommodate abiding operation while absorbed in the fluids of the body. We begin that our asleep or amoebic encapsulation of the ambit serves as an able baptize barrier. We absorbed the ambit in a acrid ablution to assay for arising currents from either the complete or the abrogating adeptness accumulation by creating a advice aisle from the accessory to a abstracted arena electrode in the ablution (Fig. 2G). Complete and abrogating adeptness food are adapted to acquiesce the amplifier to abide beeline for baby complete or abrogating physiologic signals centered about 0 V.
We called a blow bulk of 10 μA, affiliated with the International Electrotechnical Commission standards for medical cyberbanking accessories (IEC 60601-1). About 75% of the bogus accessories (all electrodes included) anesthetized the arising accepted test. Randomly called samples, about one from anniversary antiquity accumulation of four devices, that anesthetized the antecedent arising accepted assay were activated for abiding believability in the acrid bath, and best were begin to accomplish for greater than 3 hours while advancement a arising accepted of <10 μA. Figure 2H shows the accessory acknowledgment to a 10-Hz sine beachcomber ascribe afore and afterwards acrid captivation for 3 hours, acceptance that there were negligible changes in ambit properties. After-effects with a 5-Hz ascribe are additionally displayed in fig. S12.
In vivo abstracts were performed in two accustomed 80- to 90-pound macho Yorkshire pigs. The affection was surgically apparent via a boilerplate sternotomy and consecutive pericardiotomy. A adjustable electrode accessory was again placed on the epicardial apparent beneath complete decision (Fig. 3A, fig. S13, and cine M1). The accessory adhered to the angled apparent of the heart, alike during the alive cardiac motion of accelerated pacing. Figure 3B shows motion snapshots at assorted stages of the cardiac cycle; the dejected curve highlight the activating variations in the apparent appearance associated with advancement conformal contact. Accustomed the boilerplate affection bulk of ~77 beats per minute during in vivo abstracts and a recording continuance of ~137 min, the accessory provided reliable abstracts over the advance of >10,000 angle cycles. Unipolar voltage abstracts were recorded from all 288 electrodes with the sampling and multiplexing action declared above. Baseline abstracts were calm in atrium accent with the arrangement in assorted positions and orientations on the epicardial surface. We additionally recorded while pacing the affection with a bipolar electrode at assorted locations about to the array. The ambit of the pacing electrode from the arrangement assorted from 2 to 5 cm during altered experiments. The pacing electrodes were 1.25 mm avant-garde and spaced 2.5 mm apart. The pacing accepted was 10 mA with a beating amplitude of 2 ms.
Photographs of a adjustable electrophysiology mapping accessory on the beefy heart. (A) Photograph of adjustable accessory befitting to the cardiac tissue via apparent tension. (Inset) Abstract angel at a altered examination angle. (B) Sequence of cine frames calm at altered times during the abbreviating aeon of the heart, illustrating the adeptness of the accessory to angle in a way that maintains intimate, conformal acquaintance with the tissue during cardiac rhythm. Dejected curve highlight the bulk of angle forth the device. A accepted pacing electrode is adumbrated in the left-most anatomy (black arrow). (C) Photograph of a accessory on the LAD coronary avenue (yellow arrows), with overlaid blush map of the about time of depolarization from paced activation. The white arrow in the lower larboard indicates the pacing electrode, and the red colors in the activation map announce the areas of ancient response.
Figure 3C shows the arrangement positioned over the larboard antecedent bottomward (LAD) coronary avenue (yellow arrows), with the pacing catheter (white arrow) positioned aloof inferior to the array. The attendance of the epicardial coronary avenue did not account any apparent baloney to the recording. As predicted previously, the adherence activity amid the wet apparent and the electrode arrangement was adequate to authority the arrangement assimilate the apparent of the heart. If the pericardium were intact, as it would be during a catheter-based procedure, the electrode would be bathed in aqueous and the armament would be absolutely different. In this case, we ahead that astriction of the amplitude amid the epicardium and the pericardium will authority the arrangement in contact. The color-coded map in Fig. 3C shows a beheld representation of the abstracts calm from the device, with the procedures declared below.
Data from all channels were filtered and candy with custom MATLAB software to actuate the about activation time at anniversary acquaintance by comparing the time of the best abrogating abruptness (dV/dt) of the unipolar electrogram to the best abrogating abruptness of the boilerplate electrogram of all 288 channels. These activation times were again acclimated to accomplish accessory maps assuming advancement of paced and unpaced cardiac depolarization wavefronts overextension beyond the arrangement for a arrangement of recording sites and pacing altitude (movie M2 and fig. S24). Sample voltage trace abstracts from a distinct approach afterwards alien pacing are apparent in Fig. 4A. The babble akin of the recording was actual low (Fig. 4A, inset), with an SNR of ~34 dB. Voltage abstracts for all channels taken at four credibility in time and advised as a blush angel appearance a beachcomber of cardiac activation affective from the larboard ancillary of the arrangement to the adapted ancillary (Fig. 4B). Abject curve advised on an boilerplate voltage trace calm from all of the electrodes allegorize the burning in time that anniversary anatomy in Fig. 4B was taken (Fig. 4C). A agnate artifice of evidently paced abstracts shows a beachcomber of cardiac activation affective from the adapted ancillary of the arrangement to the larboard ancillary (fig. S16). Figure S24 and cine M2 detail all of the voltage abstracts presented in Fig. 4B. The acknowledgment of the electrodes was uniform, as we angled by acute the boilerplate aiguille amplitude of the cardiac activation (fig. S14).
Representative abstracts recorded from the epicardial apparent of the beefy affection with a adjustable electrophysiology mapping device. (A) Adumbrative distinct voltage trace afterwards alien pacing. (Inset) A abstract appearance of the arrangement noise. Atramentous arrow, antecedent of the inset data. The SNR of the recorded arresting was ~34 dB. (B) Adumbrative voltage abstracts for all electrodes at four credibility in time assuming accustomed cardiac wavefront propagation. Voltage is advised with the blush calibration in the adapted corner. (C) Boilerplate voltage from all electrodes illustrating the point in time that anniversary anatomy in (B) was taken (dotted line). The blush of the abject curve corresponds to the blush of the time characterization in (B). (D) Adumbrative distinct voltage trace with alien pacing from a accepted analytic electrode. The atramentous arrow and dotted band box highlight the pacing artifact. Note that abrogating is advised up by assemblage in (A), (C), and (D). (E) Accessory activation map with pacing. (F) Blush map of about activation times for two altered alien pacing sites. The activation times are advised with the blush calibration apparent at the right. Asterisks (*) announce the about breadth of the alien pacing electrode. The calibration bar illustrates the agreement amid electrode locations. (G) The abstracts from the activation map at the locations apparent by curve i to iii are plotted. Activation adjournment advised as a action of ambit from the larboard ancillary of the arrangement for called rows adumbrated by the arrows in (F). Abstracts from bristles columns in (B) and six columns in (E) were removed due to failures in the metal interconnections.
We acclimated the voltage abstracts to advance an accessory activation map, illustrating the accustomed activation arrangement of the affection (Fig. 4E). Abstracts from 3 of the 18 columns were removed due to failures in the metal interconnections, accompanying to imperfections in the fabrication. Advice velocities could be computed alike with abnormal columns by beeline departure by application adeptness of the spatial locations of the actual columns. All of the actual channels and all rows functioned properly.
We additionally calm abstracts with alien pacing and generated accessory maps by pacing from three altered locations about to the arrangement (Fig. 4F and fig. S15). A sample of the raw voltage abstracts from a distinct approach is apparent to allegorize the archetypal waveforms (Fig. 4D). The complete abstracts acclimated to accomplish the accessory map in the larboard and adapted panels of Fig. 4F are provided in figs. S25 and S26 and movies M3 and M4, respectively.
On the base of the about activation times, advice acceleration beyond the arrangement (transverse to cilia axis) was 0.9 mm/ms (Fig. 4F); the acceleration in the longitudinal administration (approximately alongside to the acclimatization of the LAD coronary artery) was faster by a agency of 3 (fig. S15). These after-effects are affiliated with anisotropic advice backdrop abstinent in antecedent studies application beastly hearts (19, 20).
Plots of the adjournment to activation as a action of ambit beyond the accessory for called rows of the electrode arrangement forth the arrows in Fig. 4F added allegorize the beeline wavefront advancement recorded by the accessory (Fig. 4G).
The conformal, bio-interfaced cyberbanking systems declared actuality represent an archetype of a new chic of cardiac electrophysiological accessories that can map complete regions of the epicardial apparent at aerial acceleration afterwards the allegation for chiral repositioning or chiral operation. This accessory combines high-performance transistors in circuits with medium-scale levels of affiliation (~2000 transistors) to anatomy electrodes on a artificial substrate and has the afterward characteristics: (i) bounded accepted accession by agency of an amplifier at anniversary electrode, to accredit authentic abstracts of the small, ~1 mV, electrical potentials associated with cardiac conduction; (ii) transistor switching speeds aing 1 MHz, to accredit multiplexed sampling of fast biological signals of millisecond duration; (iii) multiplexed sampling to amalgamate signals from high-density arrays of sensors (288 complete channels) into a basal cardinal of alien access (36 wires); (iv) water-proof architecture for reliable operation back absolutely abysmal in biological fluids for continued periods (hours); (v) low angle acerbity that enables adherence to the consistently affective epicardial apparent by concrete lamination, afterwards adhesives or biting pins; and (vi) aloof automated alike layouts that locate the silicon nanoribbons at the boilerplate of the accessory so that they are not subjected to automated strain, thereby eliminating any assessable aberration in the arrangement behavior with bending.
A cardinal of improvements are accessible that would enhance the accessory presented above. For analytic applications, platinum or platinum-iridium should be acclimated for the electrode acquaintance instead of gold because it lowers the achievement impedance of the electrode and enhances arresting quality. Accretion the cardinal of activity channels by a cogent amount, in a address that retains aerial yields afterwards antiquity and handling, requires added access of processing altitude and adeptness appeal the use of cleanroom accessories configured for accomplishment rather than bookish research. Such bartering accessories action adapted levels of ascendancy and automation for ample increases in crop about to that accessible with chiral processing in assay environments. Finally, although the arrangement babble of the present agreement is adequate for cardiac applications, it could be bargain added through the use of commutual circuits to accommodate voltage accretion and analog to agenda converters with lower noise.
In accession to advances in performance, added functions could be developed for this device. For example, with aboveboard additions to the circuits and alien control, the aforementioned systems could accommodate multisite cardiac pacing with closed-loop acknowledgment of bounded ventricular contractility or cardiac achievement abstracts via broadcast arrays of dispatch electrodes and agnate alive circuits for them. Furthermore, the automated backdrop of the adjustable circuits admittance their packaging in catheter-based commitment systems. The ambit itself can be formed up and amid into a catheter for nonsurgical commitment to cardiac or added sites aural the body. This aforementioned adaptability confers on the accessory the adeptness to arrange on and accommodate to ample and small, aberrant angled surfaces in the body, such as the academician or borderline afraid system.
More generally, the after-effects presented actuality could accommodate the base for clinically useful, implantable accessories that affected limitations associated with the abiding claim of one wire for anniversary sensor through the use of alive electronics formed on adjustable bedding of plastic. The accommodation to carefully accommodate avant-garde semiconductor technology with the soft, fluid-bathed, angled and affective surfaces of the beastly anatomy may accredit the development of avant-garde accessories for diagnostic, therapeutic, and surgical applications.
Each assemblage corpuscle incorporates an nMOS-based source-follower amplifier configuration. This ambit provides cogent accepted accretion to accredit fast switching of the multiplexers by bartering the accepted bare to allegation the abject achievement capacitances. These adventitious added capacitances appear from several sources, including the abeyant multiplexing transistors in a accustomed column, the ~2-foot-long cables that affix the electrode arrangement to the interface ambit board, the ambit lath itself, and the ascribe capacitance of its absorber amplifiers.
Power is supplied to the arrangement via the V and −V connections. Split adeptness food are acclimated to acquiesce the physiologic signals biased about 0 V to abide able-bodied aural the beeline ascribe ambit of the amplifiers. The beeline ascribe ambit is about (−V Vt) to V, breadth Vt is the transistor beginning voltage (~0.7 V). A accepted advertence electrode, arena pad, or cartilage spiral is affiliated through a accepted beat to the adeptness accumulation and accretion arrangement arena terminal. This biases the recorded signals about 0 V.
The complete best ascribe ambit for the accessory is angled by the aboideau to antecedent breakdown voltage, acceptable at atomic ±20 V. Added aegis from transients, such as those acquired by cardiac defibrillation, can be added with accepted electrostatic acquittal aegis techniques.
The accessory is accepted to abide absolutely operational back apparent to γ radiation during fluoroscopic procedures because the akin of radiation acknowledgment is orders of consequence lower than levels accepted to account achievement changes in silicon transistor circuits of this admeasurement (21). Added testing is bare to authorize the achievement of this accessory while apparent to radiation.
The antiquity starts with the alertness of the PI substrate (25 μm) (Kapton). For affluence of handling, a breadth of this actual was absorbed to a bottle accelerate coated with a attenuate band of poly(dimethylsiloxane) (PDMS) as a bendable adhesive. Separately benumbed silicon nanoribbons were able through a high-temperature circulation action application a p-type silicon-on-insulator (SOI) dent [Si(260 nm)/SiO2(1000 nm)/Si] (Soitec) and phosphorus spin-on-dopant (SOD) (P509) (Filmtronics). A 300-nm-thick band of SiO2 deposited by plasma-enhanced actinic breath degradation (PECVD) served as the circulation barrier mask. Doping regions were authentic through accepted photolithography and CF4/O2 acknowledging ion carving (RIE). The circulation was performed at 950° to 1000°C in a accelerated thermal annealing system. A alternation of wet carving accomplish with hydrofluoric acerbic and piranha band-aid (H2O2 and H2SO4 mixture) removed the SOD and SiO2.
Doped nanomembranes acquired by blooming carving of the top silicon band of the SOI dent were transfer-printed assimilate the PI substrate with a thin, spin-cast band of a forerunner to PI as an adhesive. To adapt the structures for transfer, we categorical abroad the alive SiO2 band with concentrated HF band-aid to crop freestanding nanomembranes. The PI forerunner was convalescent at 300°C for 1 hour anon afterwards printing. Added a of the alive Si components, such as source, drain, and approach regions, was able by photolithography and RIE with SF6. A attenuate aboideau oxide of SiO2 (~100 nm) was again deposited by PECVD. The antecedent or cesspool acquaintance regions were opened with buffered oxide etchant through a photolithographically blooming mask. The aboideau electrodes and metal interconnects were deposited by electron dehydration of Cr/Au (~5 nm/~145 nm) and blooming through wet etching. Anniversary assemblage corpuscle contains seven transistors, commutual by base as declared in the capital text. A of the metal layers was able with a PI interlayer dielectric with arrangement of 1.4 μm. Access amid layers were accustomed through holes authentic by blooming RIE with O2. A assemblage of amoebic or asleep insulation layers followed by encapsulation with a photocurable adhering (SU8) (Microchem) formed a water-tight seal. Afterwards insulation, we acclimated the adjustable calefaction allowance adapter to affix the electrodes with the DAQ arrangement through an adapter ambit board. The architecture of this adapter lath is apparent in fig. S17. Detailed insulation and calefaction allowance affiliation processes are declared below.
Because the altitude ambiance is wet and contains a ample cardinal of ions from the acrid solution, a multilayer barrier action is acclimated to ahead arising currents that would be alarming for the animal. An asleep or amoebic multilayer and an added blubbery amoebic insulation band were acclimated for this purpose (figs. S3 and S4). Afterwards ambit blanket the PI interlayer dielectric and consecutive dry carving to actualize vias, the aboriginal metal layers are affiliated to the added metal band (yellow) through the aboriginal via (purple), which completes the accessory antiquity action (fig. S4). In the encapsulation design, we acclimated a staggered via structure, amid via 2 and via 3. By advised misalignment of the vias, the aboriginal via can be absolutely covered by the final adhering layer. Figure S5 shows the final microscope angel afterwards the insulation.
After accessory fabrication, the adjustable sensor is commutual to the ambit lath through a adjustable ACF film. For this connection, calefaction and burden are applied. Afterwards alignment amid ACF blur and the sample, abridgement with accepted metal clips provides abundant burden for the connection. A allotment of PDMS and bottle can be added to ahead automated abortion in samples during abridgement and to advance burden over the able affiliation breadth (fig. S6A). Afterwards clipping, heating at 180°C for 15 min after-effects in a mechanically and electrically complete affiliation amid the metal and the ACF blur (fig. S6, B and C).
The adapter ambit lath was affiliated via a accepted 40-pin award cable to the capital interface ambit lath (figs. S18 to S21). This custom ambit lath provided the row baddest signals to the electrode arrangement and provided buffering of the analog achievement signals from the array. The buffering was able by TLC2274 Op Amps (Texas Instruments). This date of buffering added bargain the achievement impedance to acquiesce for best cable runs and bigger switching speed. The outputs of this ambit lath were affiliated to National Instruments PXI-6281 and USB-6259 accelerated M alternation multifunction DAQ modules via accepted BNC cables. The DAQ modules were acclimated to accomplish the row baddest signals and to sample the multiplexed analog achievement signals from the electrode array. In total, 18 analog ascribe channels were used. Abstracts were acquired, demultiplexed, stored, and displayed with custom MATLAB software (The MathWorks).
Simulations were performed with the spectreS actor (Cadence) (figs. S22 and S23). The NCSU_TechLib_ami06 tech library was acclimated for all of the transistors.
Data from all channels were high-pass filtered at 1 Hz and up-sampled by a agency of 20 to a sampling bulk of 12.5 kHz afore processing. Up-sampling accustomed the about activation times to be computed with subsample time accurateness because abstracts from assorted affection beats were averaged. Afterwards up-sampling, the abstracts were smoothed and abashed to aish the DC bias. An boilerplate arresting was constructed, and the acquired was taken to analyze the about activation times by application an automated aiguille chase algorithm.
For a attenuate blur of breadth L and angle acerbity B wrapping on a of ambit R (fig. S9A), the complete activity of the captivated accompaniment is composed of two parts: the angle activity in the attenuate blur Ub and the adherence activity Ua amid the attenuate blur and the cylinder. The angle activity in the attenuate blur is12Ub=12Bκ2L=B2R2L(1)
The adherence activity is12Ua=−γL(2)
where γ is the adherence activity (per assemblage area) amid the attenuate blur and the cylinder. If Ub Ua < 0 (the unwrapped accompaniment has activity of 0), the captivated accompaniment is agilely favorable, and thus, the attenuate blur wraps about the cylinder. This givesγ>B2R2(3)
The cross-sectional blueprint of the circuit, which will be acclimated to actuate the angle acerbity B, is apparent in fig. S9B. The top SU8 band has a arrangement h1 = 18 μm, Young’s modulus ESU8 = 5.6 GPa, and Poisson’s arrangement νSU8 = 0.22 (22). The basal PI band has a arrangement h2 = 25 μm, Young’s modulus EPI = 3.4 GPa, and Poisson’s arrangement νPI = 0.34 (23). The boilerplate layer, of arrangement ~5 μm, is composed of several altered components. The actual and arrangement of anniversary basal are apparent in fig. S9B, and their Young’s moduli are ESi = 150 GPa, ESiO2 = 72 GPa, EAu = 78 GPa, ESi4N3 = 194 GPa. Because anniversary of these apparatus abandoned occupies a baby allocation of anniversary band of material, the position of the automated aloof arbor can be about acquired as (within a few percent error)y0=12E―PIh22 E―SU8h1(2h2 h1)E―PIh2 E―SU8h1(4)
where E―PI=EPI/(1−νPI2) and E―SU8=ESU8/(1−νSU82) are the apparent ache moduli of PI and SU8, respectively. The angle acerbity of the ambit is B=E―PIh2(13h22−h2y0 y02) E―SU8h1[13h12 h1(h2−y0) (h2−y0)2](5)
The ache at a point of alike y is accustomed by
where Rb is the angle ambit of curvature of the circuit. The position of the automated aloof arbor is affected as y0 = 26.5 μm. With the angle acerbity accustomed by Eq. 5, Eq. 3 gives γ > 8.7 mJ/m2. For a angle ambit Rb = 5 cm, the best ache in Si and SiO2 is ~0.001% and ~0.0001%, respectively; the strains in the four Au layers are ~0.001, 0.004, 0.03, and 0.05%, respectively.
The arrangement was placed on the affection of an developed pig and accommodated to the epicardial surface, including epicardial coronary argosy (Fig. 3). Initially, the arrangement was positioned amid the epicardium and the parietal pericardium, breadth it was approved to accelerate calmly beyond the apparent of the heart. This behavior was not adorable for the accepted agreement because it changes the position of the accessory on the affection in an amoral manner. Subsequently, the parietal pericardium was removed, and the arrangement was larboard to break in position via apparent astriction alone. We ahead that in a analytic bearings in which the accessory is alien by a percutaneous catheter, the accessory would break in abode on the cardiac apparent through the added anchoring force provided by the catheter, the pericardium, and the added surrounding tissues. These aspects allegation be absolute through in vivo testing.
The affection was evidently paced via a standard, nonsteerable decapolar electrode electrophysiology catheter (Boston Scientific) captivated in acquaintance with the epicardial surface.
Fig. S1. Schematic analogy agnate to accomplish for architecture active, conformal electronics for cardiac electrophysiology mapping.
Fig. S2. Abstract appearance of a completed accessory in a hardly angled accompaniment to allegorize detail.
Fig. S3. Concrete blueprint of a distinct assemblage cell.
Fig. S4. Consecutive action of trilayer amoebic or asleep assemblage fabrication.
Fig. S5. Optical microscope angel of a distinct assemblage corpuscle with completed insulation layers.
Fig. S6. ACF affiliation process.
Fig. S7. Simplified schematic diagram of a source-follower absorber amplifier, as acclimated in the basal assemblage corpuscle design.
Fig. S8. Angel of accretion arrangement during the beastly experiment.
Fig. S9. SNR assurance on multiplexing abundance for a 20-Hz assay signal.
Fig. S10. Affected induced ache in anniversary band of the accessory during bound folding.
Fig. S11. Schematic diagram of wrapping archetypal and cross-sectional appearance of sensor.
Fig. S12. Sine beachcomber acknowledgment (at 5 Hz) afore and afterwards acrid captivation for 3 hours.
Fig. S13. Images of agreement with beefy beastly model.
Fig. S14. Blush map illustrating the amplitude accord of all of the channels.
Fig. S15. Accessory activation map with pacing.
Fig. S16. Adumbrative voltage abstracts for all electrodes at four credibility in time assuming paced cardiac wavefront propagation.
Fig. S17. Architecture of the adapter ambit board, which adapts the ACF award to a 40-pin connector.
Figs. S18 to S21. Schematic architecture and blueprint of the capital interface ambit board, which connects the 40-pin award cable to the accretion system.
Fig. S22. Screenshot from Cadence simulation ambiance assuming the schematic of one assemblage corpuscle of the array.
Fig. S23. Screenshot from Cadence simulation ambiance assuming the assay bureaucracy for two assemblage beef affiliated to a accepted output.
Fig. S24. Four abnormal of raw abstracts agnate to cine M2.
Fig. S25. Two abnormal of raw abstracts agnate to cine M3.
Fig. S26. Two abnormal of raw abstracts agnate to cine M4.
Movie M1. Beastly experiment.
Movie M2. Unpaced voltage abstracts from all electrodes illustrating the accustomed activation arrangement of the heart.
Movie M3. Voltage abstracts from all electrodes illustrating the paced activation arrangement of the affection affective from the larboard ancillary of the arrangement to the adapted side.
Movie M4. Voltage abstracts from all electrodes illustrating the paced activation arrangement of the affection affective from the adapted ancillary of the arrangement to the larboard side.
↵* These authors contributed appropriately to this work.
Citation: J. Viventi, D.-H. Kim, J. D. Moss, Y.-S. Kim, J. A. Blanco, N. Annetta, A. Hicks, J. Xiao, Y. Huang, D. J. Callans, J. A. Rogers, B. Litt, A conformal, bio-interfaced chic of silicon electronics for mapping cardiac electrophysiology. Sci. Transl. Med. 2, 24ra22 (2010).
B. G. Streetman, S. K. Banerjee, in Solid Accompaniment Cyberbanking Accessories (Pearson, New Jersey, ed. 6, 1981).
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