RESEARCH ARTICLE

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Wireless Bioelectronics for In Vivo Pressure Monitoring with

Mechanically-Compliant Hydrogel Biointerfaces
Jingsen Lin, Xingmei Chen, Pei Zhang, Yu Xue, Yinghui Feng, Zhipeng Ni, Yue Tao,
Yafei Wang, and Ji Liu*

(i.e., brain, heart, lung, or bladder), are

Recent electronics-tissues biointefacing technology has offered providing crucial diagnostic information
unprecedented opportunities for long-term disease diagnosis and treatment. for the treatment of a variety of chronic
It remains a grand challenge to robustly anchor the pressure sensing diseases.[1–7] Key enabling features are me-
bioelectronics onto specific organs, since the periodically-varying stress chanically compliant components, which
can form seamless integration between
generated by normal biological processes may pose high risk of interfacial
the bioelectronics and human skins, tis-
failures. Here, a general yet reliable approach is reported to achieve the robust sues, or even organs, thereby, the inter-
hydrogel interface between wireless pressure sensor and biological faces could provide soft mechanical cou-
tissues/organs, featuring highly desirable mechanical compliance and pling and efficient signal exchange, with
swelling resistance, despite the direct contact with biofluids and dynamic mitigated tissue damage and inflamma-
tion response.[8–11] Although physical at-
conditions. The sensor is operated wirelessly through inductive coupling,
tachment has been widely used, such strat-
characterizing minimal hysteresis, fast response times, excellent stability, and egy is generally limited to epidermal bio-
robustness, thus allowing for easy handling and eliminating the necessity for electronics, while not applicable to wet
surgical extraction after a functional period. The operation of the wireless and dynamic biointerfaces, due to the in-
sensor has been demonstrated with a custom-made pressure sensing model trinsically weak interactions (i.e., van der
and in vivo intracranial pressure monitoring in rats. This technology may be Waals interactions and/or capillary forces),
as well as potential risk of detachment dur-
advantageous in real-time post-operative monitoring of various biological
ing the long-term applications.[4,12–15] Sutur-
inner pressures after the reconstructive surgery, thus guaranteeing the timely ing has emerged as one of the most reli-
treatment of lethal diseases. able routines to construct the electronics-
tissue biointerfaces, however, it remains
challenging for certain organs with in-
trinsic fragility or dynamic shape change
1. Introduction and peristalsis (e.g., brain, heart, blood vessel, stomach, and
bladder).[2,3,5,9,16,17]
Implantable bioelectronics with capability to precisely and con- Most recently, hydrogels show a great promise as an attrac-
tinuously sense critical physiological parameters, such as pres- tive class of biointerfacing materials, since they offer intrinsically
sure, temperature, or bioelectrical signals within specific organs chemical and structural similarity to biological tissues, enable
functional and bidirectional interfaces, and also substantially
alleviate the immune responses.[8,10,18] Although recent works
J. Lin, X. Chen, P. Zhang, Y. Xue, Y. Feng, Z. Ni, Y. Tao, Y. Wang, J. Liu
Department of Mechanical and Energy Engineering on hydrogel bioadhesives have defined the routines for adhe-
Southern University of Science and Technology sion with various biological tissues, optimization of the hydrogel
Shenzhen 518055, China bioadhesives for implantable electronic biointerfacing that meet
E-mail: [email protected] specific operational requirements and long-term robustness will
J. Liu likely lead to further opportunities and improvements in those
Shenzhen Key Laboratory of Intelligent Robotics and Flexible Manufactur-
ing Systems
key features.[19–23] Shortcomings of existing hydrogel bioadhe-
Southern University of Science and Technology sives, including weak interface, swelling-induced performance
Shenzhen 518055, China deterioration and complexity in handling the adhesives, have pre-
J. Liu vented them from providing conformal yet robust integration be-
Guangdong Provincial Key Laboratory of Human-Augmentation and Reha- tween bioelectronics and wet dynamic tissues/organs.[8,24] Espe-
bilitation Robotics in Universities cially, for pressure sensing bioelectronics, it is difficult to anchor
Southern University of Science and Technology
Shenzhen 518055, China these devices onto specific organs (i.e., brain, eyes, lungs, and
bladders), since dynamic stress exerted by normal biological pro-
The ORCID identification number(s) for the author(s) of this article cesses may lead to interfacial failures and air/fluid leaking.[9,25–27]
can be found under https://doi.org/10.1002/adma.202400181 Despite the clinical utilization of non-hydrogel-based bioad-
DOI: 10.1002/adma.202400181 hesives, such as cyanoacrylate adhesives, the intrinsic high

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a b
Tissue
Suture
Intracranial pressure damage

Δf 0
Air/fluid
leakage
Intraocular pressure Time
Pressure maintaining
Polymer Wireless
hydrogel sensing
bioadhesive
Blood pressure (PHB) Mechanically
compliant

Δf 0
hydrogel
interface
Bladder pressure
sure Time

c Gentle pressure for 10 s Robust adhesion

PLGA PLGA
Adhesive polymer brush
PHB PHB
x y n

Body fluid O NH O OH

Tissue Tissue Tissue

Poly(HEMA-NVP) Poly(AA-NHS) Covalent anchor Adhesive bonding

Hydrophobic association Chemical crosslinking NHS easter Hydrogen bond

Figure 1. Design and fabrication of hydrogel biointerface for implantable pressure sensors anchorage. a) Schematic illustration of implantable bioelec-
tronics for the in vivo biological pressure sensing within specific organs, such as brain, eyes, blood vessel, and bladder. b) Schematic illustrating the
anchorage of wireless pressure sensor with a polymer hydrogel bioadhesive (PHB), change in pressure is captured wirelessly and passively with a readout
coil adjacent to the implement site. Sharp difference in pressure signal is expected for the interface with or without robust hydrogel bioadhesion. For the
sensor anchorage through suturing, inevitable gas/liquid leaking and tissue damage may deteriorate the reliability and lifespan of the in vivo pressure
sensing. c) Schematic illustration of the PHB layer for establishing a robust biointerface between the wireless sensors and biological tissues. The hydro-
gel part of PHB dehydrates immediately upon contact with the biological tissues, and robust biointerface is built through the synergistic contribution
from both amide bond formation (NHS moieties from PHB part and amine moieties from tissue part) and hydrogen bonding.

stiffness impedes natural movement of the elastic and soft tis- deterioration,[28] despite the direct contact with biofluids. Wire-
sues, thereby, considerable mechanical mismatch may result in less operation is enabled by deploying the radio-frequency cou-
tissue damage and/or device failures.[20,27] Bioelectronic inter- pling strategy,[1,2] featuring a high sensitivity of 1 MHz mmHg−1
face, with capability to withstand a certain pressure for main- and sensing range of 0–40 mmHg. We have demonstrated the
taining the inner fluid and/or air flow, has constituted a substan- prospective utility of our hydrogel bioadhesives in forming a
tial barrier to the rapid innovation and broad application of im- seamless bioelectronic-skull biointerface, allowing for the in vivo
plantable pressure sensors.[8,18] wireless and continuous intracranial pressure sensing in a rat
Here, we report a general yet reliable approach to robustly model. This approach effectively mitigates the foreign body re-
anchor wireless pressure sensors onto the dynamical biological sponses, but also addresses interfacial mechanical mismatch,
tissues/organs with a mechanically-compliant hydrogel bioint- thereby enhancing the efficacy of wireless pressure sensing.
erface (Figure 1). The hydrogel bioadhesives are composed of Furthermore, the wireless pressure sensing devices are entirely
a sandwich structure, including a poly(HEMA-NVP) hydrogel made of biodegradable materials, thus could be biodegraded and
substrate and adhesive poly(AA-NHS) polymer brushes. The in- absorbed after several months, and eliminate the need for de-
stant and tough interfacial bioadhesion is constructed through vice removal. Our approach overcomes those key disadvantages
the well-established dry cross-linking mechanism,[20,21] while of traditional electronics-tissues biointerfaces and may serve as
swelling-resistant poly(HEMA-NVP) hydrogel substrate imparts the technical basis for the next-generation implantable bioelec-
the biointerface with long-term stability without performance tronics.

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2. Results and Discussion lation was only detected within the circular area. Remarkably,
upon application of the pressure, the interface separation re-
2.1. Fabrication of Hydrogel Bioadhesives mained below 0.0005 mm, indicating a completely bonded state.
The resilient stability of the interface can be ascribed to the ex-
Thanks to the established biocompatibility and robust interfa- istence of phase segregation facilitated by hydrophobic associa-
cial adhesion, hydrogel adhesives have been widely adopted as tion, coupled with inherent van der Waals interactions and hy-
a versatile platform to anchor wearable and implantable devices drogen bonds.[30,31] The measured burst pressure for our PHB
onto the wet and dynamic tissues.[20,24,29] In our study here, adhesives reached as high as 15 kPa (113 mmHg, Figure 2h;
we fabricated an adhesive hydrogel layer onto a poly(lactic-co- Figure S8, Supporting Information), surpassing that of previ-
glycolic acid) (PLGA) substrate, which is widely used as a bio- ously reported hydrogel bioadhesives, such as GelMA.[32] Ad-
compatible and biodegradable encapsulation material for bioelec- ditionally, the burst pressure of the PHB bioadhesive signif-
tronics (Figure 1c).[12] A poly(2-hydroxyethyl methacrylate-co-N- icantly exceeded the critical value of physiological pressures,
vinylpyrrolidone) (poly(HEMA-NVP)) hydrogel layer was formed such as severe intracranial pressure (20−25 mmHg) and in-
through radical copolymerization, while chemical anchorage traocular pressure (≈24 mmHg),[33,34] and such superior adhe-
of the poly(HEMA-NVP) chain onto an acrylate-functionalized sion performance is particularly desirable for clinical pressure
PLGA substrate led to the PLGA/poly(HEMA-NVP) hybrid struc- sensing. Different from the sandwiched structure (bioelectron-
ture with robust interface (Figure 2a).[28] We then chemically ics/hydrogel/biological tissues),[19–23] we elaborately integrated
grafted the adhesive polymer brushes, poly(acrylic acid-co-N- the hydrogel bioadhesives (poly(HEMA-NVP)/poly(AA-NHS))
hydroxysuccinimide acrylate ester) (poly(AA-NHS)), onto the with the PLGA substrate (commonly-used encapsulation mate-
poly(HEMA-NVP) hydrogel substrate, resulting in our polymer rial for implantable bioelectronics). Therefore, the PLGA/PHB
hydrogel adhesives (PHB for abbreviation, Figure S1, Support- hybrid could be readily used for various implantable bioelectron-
ing Information). Optical microscopic image evidenced the dis- ics, enabling the formation of a more robust biointerface than the
tinct three-layer geometry of the PHB samples (Figure 2b), sandwiched geometry (Figure S9, Supporting Information).
with the poly(AA-NHS) polymer chains penetrated within the We also co-cultured the NIH3T3 cell line with our PHB sam-
poly(HEMA-NVP) hydrogel substrate (Figure S2, Supporting In- ples to evaluate the in vitro biocompatibility and cell behav-
formation). Gradual decrease in both modulus and strength of iors during culturing. No difference in quantitative cell viability
the PHB/PLGA hybrid structure was detected during the three- (through CCK-8 assay) could be detected between the PHB bioad-
step fabrication process (Figure 2c), thanks to the incorpora- hesive samples (Figure 2i). We also observed a uniform mono-
tion of hydrogel layer. The resulting PHB bioadhesive reached layer of the NIH3T3 cells on the PHB substrate, featuring nor-
its equilibrium state after a 9-h immersion in PBS buffer (pH mal cell morphologies. Additionally, nearly no dead cells (red flu-
7.4, 100 mM), maintaining a substantial water content of 80.2% orescence) were observed upon live/dead cell staining, and the
(Figure 2d), with a tissue-like Young’s modulus of ca. 100 kPa NIH3T3 cells substantially proliferated over tenfold within five
(Figures S3 and S4, Supporting Information). To achieve an in- days (Figure 2j).
stant and tough bioadhesion, our PHB hybrid structure adopted
the well-established dry cross-linking mechanism, exploiting
the synergetic contribution from non-covalent interactions (i.e., 2.2. Wireless Sensing
hydrogen bonding and electrostatic interactions) and covalent
bonding between the NHS (hydrogel adhesive side) and amine Currently, most implantable bioelectronics require wire connec-
moieties (tissue side).[20,21,28] Figure 2e and Movie S1 (Support- tions and battery supplies, and these tethered solutions may
ing Information) demonstrated that the adhered joint between cause undesirable discomforts and high risk of infection, tissue
the PHB and porcine skin can endure significant deformation, damage, and complications stemming from dislocation, leaking,
exhibiting a finger-like pattern before the initiation of interfacial and/or blocking.[8] Wireless bioelectronic devices, typically based
crack propagation. Obviously, the PHB adhesive exhibited supe- on the inductor-capacitor (LC) circuits, possess the potential to
rior bioadhesion capability to porcine skin, with an interfacial circumvent these disadvantages.[2,10,17] Specifically, wireless sen-
toughness of 50 J m−2 and shear stress of 60 kPa. It is deserved sors made of constituent materials, which can be decomposed
to mention that the presence of a PLGA substrate did not notably into biologically benign end-products within the biofluids over
affect the adhesive performance of the hydrogel adhesive layer a predesignated period, could effectively eliminate the devices
(Figure S5, Supporting Information). The magnified microstruc- after a functional period, thereby bypassing the need for sur-
tures corroborated the formation of conformal interface between gical extraction.[6,12,21] In our study here, components used for
the PHB and porcine tissue, thereby, resulting in a robustly ad- the wireless devices were completely made of those commonly-
hered biointerface (Figure 2f). used and biodegradable materials and could be easily processed,
To quantify the interfacial toughness and shear stress, we while a bench-top process involving laser cutting and physical
soaked the adhered joints within PBS buffer till equilibrium, lamination was adopted. The sensor assembly incorporated two
followed by quantitative lap shear and peeling tests (Figure 2g; 50-μm-thick Mg coils for the LC circuit, a 150-μm-thick PLGA
Figure S6, Supporting Information). The adhered interface ex- film serving dual roles as the dielectric layer and packaging
hibited a shear stress over 30 kPa even after 36-h soaking in layer, a 100-μm-thick poly(1,8-octanediol-co-citrate) (POC) layer
PBS buffer. We reconstructed the adhesion interface in Abaqus as the deformable support for the capacitor, and the PHB as
(Figure S7, Supporting Information), with the PHB adhesives the bioadhesive hydrogel interface (Figure 3a). Each constituent
layer reaching its swelling-equilibrium state, and stress accumu- was meticulously designed in light of the biodegradability and

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a b
Stage 1 Stage 2 Stage 3 PHB PHB cross-section
+ Double bond + Poly(HEMA-NVP) hydrogel + Poly(AA-NHS) brushes

Adhesive hydrogel

PLGA PLGA

Poly(HEMA-NVP) Chemical crosslinking Hydrophobic association

10 mm 100 µm
Silane coupling Poly(AA-NHS) NHS easter

c Modulus Strength
d 100 Water content Swelling ratio 600
e
200 16
500
80

Swelling ratio (%)

Water content (%) Stretching
Strength (MPa)
PHB
Modulus (MPa)

150 12 400
60
Backing 300
100 8
40
200 PHB Tissue
50 4
20 100 10 mm

0 0 0 0
PLGA Stage 1 Stage 2 Stage 3 0 3 6 9 12 24 48
Time (h)
f g
80

Shear stress
PLGA Swelling
PLGA Equilibrium
60

(kPa)
40

Adhesive hydrogel 10 µm 20
Adhesive hydrogel
0
toughness (J m-2)
60
Adhesive hydrogel
Interfacial

45
30
Tissue 15
Tissue 100 µm 20 µm
0
0 4 10 22 36
Time (h)

h GelMA PHB i Control PHB j

Porcine skin PHB 100
Burst pressure (mmHg)

Cell viability (%)

80
150

120 Air flow 60

90 Barometer
40
60
20
30 100 µm

0 0
0 12 Day 1 Day 3 Day 5 Day 1 Day 3 Day 5
Time (h)

Figure 2. Structure characteristics and bioadhesion performance of the PHB. a) Schematic illustration of engineering the PLGA substrate with a polymer
hydrogel bioadhesion (PHB) layer. The PLGA film was first functionalized with double bond, following by chemical grafting a conformal and swelling-
resistant poly(HEMA-NVP) hydrogel layer. Subsequently, poly(AA-NHS) polymer brushes were introduced onto PLGA-poly(HEMA-NVP) hybrid structure,
leading to the PHB structure. b) Images of PHB with a distinct three-layer structure. Scale bar: 10 mm (left); 100 μm (right). c) Evolution of the Young’s
modulus and strength of the PHB samples at different fabrication stages. A significant reduction in Young’s modulus was observed during the transition
from Stage 1 to Stage 2, attributed to the substantially high volume ratio of the hydrogel layer. d) Evolution of water content and swelling ratio of the PHB
samples (dry state, 0 h) upon hydration within PBS buffer during 48 h. The equilibrium state is detected within 9 h. e) Images of peeling an adhered PHB
sample from a porcine skin substrate. Structural deformation of the porcine skin corroborates the formation of a tough and mechanically conformal
biointerface. Scale bar: 10 mm. f) SEM images of the adhered interface between the PHB and a biological tissue (porcine skin) upon lyophilization.
Magnified image shows the distinct three-layer structure of the PHB, and also seamless and conformable interface between biological tissue and PHB.
Scale bars are100, 10, and 20 μm, respectively. g) Evolution of interfacial shear strength and toughness for the adhered joints between PHB and porcine
skins, during the 36-h soaking within PBS buffer. h) Summary of the burst pressure of the PHB and GelMA for sealing a hole in porcine skin model, before
and after soaking in PBS buffer for 12 h. The burst pressure of PHB samples is two times higher than that of severe intracranial hypertension (human,
40 mmHg), thus satisfying the purpose of intracranial pressure monitoring. i) Quantitative cell viability of NIH3T3 cells against the PHB samples after
an incubation period of 1, 3, and 5 days. j) Representative fluorescent images of the NIH3T3 cells culturing on the surface of PHB samples, following
the live (green) and dead (red) cell staining assay on Day 1, 3, and 5. Scale bar of 100 μm. Data in (c, d, g, h, i) are means ± S.D., n = 3.

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Figure 3. Design and performance of the wireless pressure sensor. a) Exploded view of the fully-encapsulated wireless pressure sensor. The sensor
is completely composed of biocompatibile and biodegradable materials, including Mg, PLGA, POC, and PHB. b) In vitro degradation of a wireless
pressure sensor in PBS buffer with lipase from porcine pancreas at 37 °C on the Day 0, 18, and 48. Scale bar of 10 mm. c) Functional composition of the
wireless sensor. The sensing function is enabled by the capacitor, which is composed of S-shaped and rectangle Mg plates. The outer double-layer coils
constitute the inductor of the LC circuit, thus enabling the wireless signal sensing and transmission. The pressure of the fluid is sequentially converted
into capacitance (C/C0 ) and resonance frequency (f0 ), which are simultaneously monitored through the readout coil. d) Capacitor and sensor response
to an applied pressure within the range of 0 to 40 mmHg. Superior sensitivity is corroborated in this working range. e) Measured real pressure, C/C0
and f0 under stepwise pressure from 0 to 50 mmHg (50 s per step). The increase in pressure directly leads to the rise of C/C0 and fall of f0 . f) Measured
S11 of the wireless sensors with different number of coils at a sensing distance ranging from 0 to 7 mm in air. All data were measured at the same time.
Data in (d, f) are means ± S.D., n = 3.

biocompatibility, alleviating concerns related to inflammation The device was consisted of a parallel-plate capacitive sensor
and the necessity for extraction through secondary surgery. that was sensitive to any kinds of pressure, together with a bilayer
Figure 3b illustrated the in vitro degradation process in a coil structure for the wireless transmission of the radio-frequency
PBS/lipase buffer solution at 37 °C. The sensor progressively dis- data. Once the capacitor plate was deformed under external pres-
integrated, dissolved, and yielded small-sized fragments that per- sure, it√was accompanied with a shift in resonant frequency
sisted after a period of 48 days. While complete degradation may (f0 = 1/ (LC)) of the LC circuit. Real-time S11 spectrum was mon-
extend over a longer period, the material mass substantially di- itored wirelessly with a vector network analyzer (VNA) through
minished within the initial two weeks (Figures S10 and S11, Sup- a readout coil. Thereby, change in pressure can be wirelessly
porting Information). By elaborately tuning the thickness, size, monitored through a battery-free approach (Figure 3c). The wire-
and composition of the pressure sensor, the device’s lifespan can less pressure sensor was further simulated and analyzed through
be precisely regulated within any desired ranges. The complete FEM analysis, integrating both the mechanical and electrostatic
LC circuits were formed by two overlapped yet separated laser- simulations. As shown in Figure S13 (Supporting Information),
cut Mg coils (Figure S12, Supporting Information).[35] During the shift of simulated f0 upon compressing perfectly met our ex-
the assembly, a crucial consideration was to ensure that the ro- pectations for the in vivo physiological pressure monitoring.
tation direction of the two coils was consistent, and the circuits The sensors were then characterized in a model that mimicked
was precisely aligned, thereby, it could successfully prevent the the change of in vivo physiological pressure (Figures S14–16,
significant baseline shifts of f0 (resonant frequency of the LC cir- Supporting Information). Both the sensing capacitors and wire-
cuit). This design intricately circumvented the need for intricate less pressure sensors were covered and sealed on a hole of a plas-
electrical connections, offering benefits in terms of process opti- tic box, which was equipped with an air pump and a barometer
mization and low-cost fabrication, as illustrated in Figure 3c. on each side (Movie S2, Supporting Information). The capacitors

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were connected to a LCR meter to measure the capacitance, while and the porcine skin could sustain a dramatic structural deforma-
the readout coil was linked to a VNA for wireless measurement tion without interfacial failure (Figure 4b). It was also deserved
of the f0 . Remarkable sensitivity to the change in capacitance to mention that no gas leaking was detected during the measure-
(≈0.01 pF mmHg−1 ) and f0 (1 MHz mmHg−1 ) was evidenced in ment, corroborating the robust interface constructed through our
Figure 3d. For even higher sensitivity, a larger size of the hole in hydrogel bioadhesion technology.
dielectric layer could be used (Figure S16c, Supporting Informa- The device was then placed within a simulated body fluid (PBS,
tion). To further mimic the practical detection of inner biological pH = 7.4) to evaluate the signal attenuation (Figure 4c) with in-
pressure, the capacitors and sensors were applied with stepwise creased sensing distance. S11 reached ≈ -6.5 dB at a distance of
pressure (Figure 3e). Both capacitance and f0 were highly con- 1.5 mm in PBS buffer, which was slightly larger than the corre-
sistent with the applied pressure, showing great promise in real- sponding value in air (Figure S19, Supporting Information). Dur-
time practical monitoring. With variation in the applied pressure, ing the continuous pressure loading (Figure 4d), the measured f0
the sensing curves were characterized with accurate and prompt remained constant at any fixed pressure and synchronously in-
response with ignorable baseline shifting. Similar sensing per- duced the changes in pressure, corroborating the robust adhe-
formance was also detected with applied pressure with various sion interface with PHB and promise in long-term in vivo pres-
frequencies and amplitudes (Figure S16d,e, Supporting Informa- sure monitoring. The device was characterized by simultaneously
tion). In our work here, wireless pressure sensors with various sensing the simulated pressure in vitro exerted by applied pulsed
turns of coils were also fabricated, by taking into consideration air with various frequencies and amplitudes (Figure 4e), demon-
the in vivo implant size and implantation depth for various appli- strating performances comparable to those commercially avail-
cation scenarios (Figure 3f; Figure S17, Supporting Information). able pressure sensors. A high sensitivity of 1 MHz mmHg−1 and
Despite the attenuation of S11 intensity as the distance increased, sensing range of 0–40 mmHg were quantified. In addition to the
the sensing performance could be improved significantly by in- pulsed air purging, we also programmed the pressure in a step-
creasing the turns of the coils. For example, by adding another wise manner (Figure 4f), and the synergistic change in f0 corrob-
one turn of coil, the S11 value of a four-turn device gained an- orated the sensitivity of our wireless sensor.
other 3.5-dB increase at a fixed sensing distance of 2 mm. As
shown in the Figure S18a (Supporting Information), the simula-
tion results was completely in consistence with the experimental 2.4. In Vivo Intracranial Pressure (ICP) Monitoring
curve in Figure 3f after subtracting the thickness of the encap-
sulation layer (≈ 1 mm). The appearance of peak value might be Continuous monitoring of inner pressures in those closed com-
associated with the decrease in mutual inductance, which was partments of the human body, such as in the intracranial, blood
caused by the mismatch between the readout coil and the sensor vessel, and abdominal cavities, can provide crucial diagnostic and
(Figure S18b,c, Supporting Ifnformation).[27] therapeutical information for various life-threatening diseases.
For example, increase in intracranial pressure (ICP) by 5–10
mmHg after traumatic brain injuries results in ischemias where
2.3. In Vitro Wireless Sensing Performance immediate medical intervention is indispensable.[36] Thereby,
to avoid the un-timely treatment of lethal intracranial hyper-
By virtue of the significant differences in physical and chemical tension, it is necessary to conduct the continuous monitoring
characteristics between electronic devices and biological tissues, of the patients’ ICP after craniocerebral surgery. Having estab-
deploying hydrogel bioadhesive to construct the seamless bioint- lished the robust biointerface between the wireless pressure sen-
erface has emerged as the most promising strategy in current im- sor and biological tissues, as well as the biological decomposi-
plantable bioelectronics. Our PHB adhesive was initially bonded tion of the pressure sensors and PHB layer, we further validated
onto a PLGA substrate, which is widely used as the encapsulation the potential for in vivo ICP monitoring with in a rat model
substrate, in light of its superior biocompatibility, biodegradabil- (Figure 5a). A three-turn sensor with dimension of 6.4 mm (L) ×
ity, and also flexibility. For the fabrication of wireless pressure 6.4 mm (W) was implanted over a burr hole drilled through the
sensor, the PLGA side was further exploited for device encapsu- skull, which directly connected the cranial cavity and the pres-
lation, while the hydrogel side for bioadhesion. We then tested sure sensing devices (Figure 5b; Movie S3, Supporting Informa-
the in vitro wireless pressure sensing performance by assem- tion). The interface between the ICP sensor and the skull tissue
bling a model with porcine skins to mimic the internal biolog- was build with the hydrogel biointerface through the dry cross-
ical pressures (Figure 4a), where robust interfacial sealing was linking mechanism,[20] allowing for wireless measurements of
perquisite. In the wireless sensing configuration, a sensor with ICP (Figure 5c). Some drift of the baseline occurred upon in vivo
three-turn coil and PHB (15 mm in diameter) layer was bonded implantation (Figure S20, Supporting Information), which was
onto a piece of porcine skin (a pre-cut hole of 4.5 mm in diam- likely due to transient flow of the interstitial and cerebrospinal
eter) through the hydrogel adhesion. Another piece of porcine fluids, accompanied with changes in the corresponding dielec-
skin with a thickness of 1.5 mm was then laminated onto the tric environment around the capacitor. Therefore, a re-calibration
pressure sensor (without interfacial adhesion), while the inner was indispensable for the in vivo wireless sensing (see Experi-
pressure was tuned by gradually purging air into the hole with mental Section for more details).
an air pump. The readout coil, which was connected to a VNA, Squeezing the flank of the rat induced obvious changes in
was put over the top of the porcine skin, allowing for the wire- ICP across an expected range (Figure 5d; Figure S21, Sup-
less and continuous pressure monitoring. Thanks to the robust porting Information). This operation mimicked the increases
hydrogel biointerface, the adhered joint between wireless sensor in ICP due to intra-abdominal hypertension: compressing the

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Figure 4. Validation of wireless pressure sensing with PHB in a simulated environment. a) Schematic illustration of the set-up for in vitro experiment.
The in vitro equipment mimicks the wet environment under the skin, supplemented with a programmed air flow. After adhering the wireless pressure
sensor to the hole (4.5 mm in diameter) and covered with a piece of porcine skin (1.5 mm in thickness), a readout coil connected to VNA is placed
adjacent to the sensor for pressure monitoring. b) Images of the assembled sensor adhered onto a piece of biological tissue (i.e., porcine skin). The
wireless pressure sensor could be robustly adhered onto the tissue under a large deformation (e.g., crimping). Scale bar: 10 mm. c) Wirelessly measured
S11 of the pressure sensor within PBS buffer at a distance range from 0 to 5 mm using a 10-mm readout coil. d) Measured f0 of the sensor under
a continuous pressure loading for 3,000 s. The small deviation of f0 corroborates the robust interface with PHB hydrogel bioadhesives and potential
long-term in vivo pressure monitoring. e) Measured f0 of the wireless pressure sensor under programmed pulse pressure. PHB offers a robust interface
to maintain the inner pressure and prevent the potential air or fluid leaking. f) Measured f0 of the sensor under stepwise pressure loading, featuring
highly-desirable sensing robustness. Real pressure loaded is also monitored simultaneously and presented at the bottom of the chart in (d–f). Data in
(c) are means ± S.D., n = 3.

abdominal cavity increased the intra-abdominal pressure, which not be achieved with sutures or adhesive systems with weak
in turn increased the ICP.[9] As demonstrated in Movie S4 (Sup- interfaces.
porting Information), upon squeezing and pressure releasing Both the wireless sensor and hydrogel bioadhesive were fabri-
the flank of the rat, the VNA could track a significant shift in cated with biodegradable materials, which could be decomposed
resonance point (f0 ). This shift was highly synchronized with into biologically benign end-products within the biofluids over a
the applied pressure, thus played an important role in dis- predesignated period of time; therefore, further surgical extrac-
ease diagnosis, assessment and therapies. In contrast, with- tion could be effectively avoided. As per Micro-CT result, the Mg
out an adhesive interface, the sensor was incapable to detect circuits within the device were predominantly decomposed on
any changes in ICP (Movie S5, Supporting Information). Mean- Day 14 (Figure 5e). A parallel degradation test was also conducted
while, the leakage of cranial contents would directly threaten with the wireless sensor implanted subcutaneously with rats. On
lives of the rats. All these in vivo data demonstrated the crucial Day 21, remarkable millimetre-scale pores were detected on the
role of PHB adhesion to maintain inner pressure, which could surface due to the degradation of PLGA layer, with only fractional

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Figure 5. In vivo wireless monitoring of the intracranial pressure (ICP). a) Schematic illustration of the wireless in vivo measurement of the ICP. The
flank of a rat is manually squeezed (5 s time−1 ), in order to simulate the sharp changes in ICP. The capacitance of sensor increases and causes the
decrease of f0 , which is simultaneously captured by VNA via a readout coil. b) The surgical operation of implanting a wireless pressure sensor for ICP
measurement. The tissue on the surface of the skull was removed by a skin punch, and then a 5-mm diameter hole is created with an electric drill.
After opening the dura, the wireless ICP sensor is quickly adhered to the tissue, allowing the sensor to directly contact with fluids in the intracranial
space. Scale bar: 10 mm. c) Schematic illustration of the cross-section of the implanted ICP sensor with hydrogel biointerface. d) Measurements of
f0 while squeezing and releasing the flank of a rat. The rate of rise and fall of f0 perfectly matches the frequency of squeezing and releasing the flank,
evidencing the robust interface. e) Micro CT images of a three-turn ICP sensor subcutaneously implanted on the skull of a rat model at Day 0 and Day
14. The circuits of the sensor (marked in blue) became fragmented at Day 14, indicating the decomposition and adsorption of the constitute material
(Mg). Scale bar: 5 mm. f) Images of the ICP sensors with PHB during the subcutaneous implantation at Day 0, 21, and 60. Compared to Day 0, the
implanted sensor with PHB exhibits obvious signs of corrosion at Day 21, while the traces of the circuits are completely invisible at Day 60. Scale bar:
1 mm. g) Representative histological images stained with HE for the subcutaneously implanted wireless pressure sensor with PHB at 21, 60, and 90
days after implantation. Scale bar: 1 mm (top), 250 μm (bottom). h) Blood chemistry analysis of control (healthy animal without surgery) and animals
with subcutaneously implanted wireless pressure sensor with PHB at 21, 60, and 90 days post-implantation. Liver function parameters include ALT
(alanine transaminase), AST (aspartate transaminase), TP (total protein) and ALB (albumin). Renal function parameters include Urea, UA (uric acid),
and CR (creatinine). Data in (h) are means ± S.D., n = 3. One-way analysis of variance (One-way ANOVA) is employed to determine the significance
level between multiple groups, where p > 0.05 represents no significant difference.

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residues of the Mg circuits, while sensor circuit was completely pressure, while the PLGA film with thickness of 30 μm was used as the
decomposed on Day 60 (Figure 5f). Additionally, the degradation packing materials to shape the Mg fixed wires. Each deformable coil was
mechanism of PHB alone was also identified, showing that the encapsulated with two pieces of low-modulus POC elastomer (100 μm).
The fixed layer and deformable layer were separated by the dielectric layer
PHB materials was decomposed into small fragments after 90
and precisely aligned with each other. Finally, laser-cut PHB was seam-
days (Figures S22 and S23, Supporting Information). The com- lessly connected to the sensor by dissolving the PLGA layers with CH2 Cl2 .
plete degradation of these components of the device is expected to In order to completely evaporate the solvent, the fully assembled wireless
occur over another several months. Histological evaluation of the sensor was placed within a ventilated condition for 12 h.
implanted sensor showed a notable degradation and fragmenta- Wireless Pressure Sensing: Circuit of the test equipment was mainly
tion after a 90-day implantation (Figure 5g; Figure S24, Support- consisted of a cavity, connected to a controllable pressure supplier and
a measuring equipment (Figure S10, Supporting Information). The con-
ing Information). To evaluate the potential systemic toxicity of
trollable pressure supply was realised by tuning the constant air flow with
the decomposed by-products, liver, and renal functional analyses manual valve and electronic valve, which was controlled with a micro-
were then conducted. Over a 90-day implantation, the liver and controlle unit (Arduino UNO). By control the on/off periods of the elec-
renal functions were comparable to those of healthy animals, in- tronic valve, the pressure with variable frequencies or amplitudes could
dicating no marked signs of systematic toxicity (Figure 5h). be rationally tailored. Meanwhile, change of the pressure within the cav-
ity was monitored in real time with a barometer (Krand, NP-15C030R).
Changes in capacitance and f0 could be continuously monitored with a
3. Conclusion LCR meter (Tonghui, TH2826) and benchtop VNA (Keysight, E5071C), re-
spectively. The capacitance was recorded at a frequency of 100 kHz, and
By creating a design strategy that synergistically combines the the data collected with VNA was further processed and analyzed with the
mechanically compliant hydrogel bioadhesion interface and the software MATLAB.
wireless sensing platform, we presented an implantable pressure The pressure supply for in vitro pressure sensing experiment was the
sensor with highly desirable interfacial robustness, superior pres- same as the sensing test, as mentioned above. The only difference of the
sure sensitivity, fast response speed and repeatability, as well as in vitro experiment was that the sensors were placed in a home-designed
set to simulate the in vivo environment (Figure 4a). To evaluate the sens-
in vivo biodegradability. Enabled by these properties, collectively, ing capability, the purging pressure frequency and/or amplitude was ra-
our wireless pressure device can continuously monitor the pres- tionally tuned, while change in f0 was monitored with a VNA through the
sure change, which has also been demonstrated by quantitatively readout coil.
measuring the intracranial pressure in a rat model. Such hydro- Experiments on Animal Subjects: All animal surgeries were reviewed
gel adhesives-based biointerfacing technology offers an effective and approved by the Committee on Animal Care at the Southern Univer-
routine for constructing tissue-bioelectronics interfaces, and also sity of Science and Technology (Protocol Number: SUSTech-JY202201005).
All biological porcine tissues and organs for ex vivo experiments were pur-
potentially be used for real-time physiological and clinical investi-
chased from a meat production and processing company (Linyi Xincheng
gations in a next-generation personal health monitoring system. Jinluo Meat Products Group Co. LTD).
In Vivo Intracranial Pressure (ICP) Monitoring: SD rats (≈200–250 g)
were first anaesthetised in a chamber (3 vol.% isoflurane in oxygen).[9,27]
After the induction of anesthesia, the rat was transferred into a stereo-
4. Experimental Section taxic frame and maintained being anesthetized with a face mask (2 vol.%
Preparation of the poly(HEMA-NVP)/poly(AA-NHS) Hydrogel Adhesives: isoflurane in oxygen). A 2-cm incision on the skull was created to expose
The hydrogel adhesives were fabricated by chemically forming a thin the thin tissue on skull. A craniectomy with 5-mm diameter on the head
poly(HEMA-NVP) hydrogel layer (0.72 mm in thickness) on a PLGA film was made with an electric drill, and then a three-turn wireless ICP sen-
(0.08 mm in thickness), followed by chemically growing another poly(AA- sor was implanted on the skull. The PHB part was bonded onto the tis-
NHS) polymer brushes onto the poly(HEMA-NVP) hydrogel substrate. sue under slight pressure (≈1 kPa) for 10 s, forming a tough adhesion
Briefly, the PLGA film was treated with oxygen plasma, then soaked into an interface and ensuring the sensor’s capbility of monitoring. To induce a
ethanol/water solution (90/10 vol.%) of MSPMA silane, in order to anchor change in the ICP, the flank of the rat under anaesthesia was squeezed
the methylacrylate moieties onto the PLGA substrate. The poly(HEMA- by hand for 5 s, and then the compression was unloaded for another for
NVP) hydrogel layer was then formed through photopolymerization of 5 s. The body temperature of the rat was kept at 40 °C with a heating pad.
HEMA/NVP precursor solution, and the PLGA/poly(HEMA-NVP) joints The change in f0 was collected via a readout coil at a working distance
were formed through the chemical chain anchorage. After that, poly(AA- of ≈2 mm.
NHS) polymer brushes were chemically grafted into the poly(HEMA- Histological Analysis: Histological analysis was carried out to evaluate
NVP) hydrogel through the well-established protocol for surface initiated the inflammation response. Biological tissue samples collected from the
polyermization.[28] Finally, the as-formed hybrid sample was rinsed with animal models were fixed with 4 vol.% paraformaldehyde solution, dehy-
acetic acid solution (2 wt%, Adamas) to remove excessive small molecules drated in sequence using gradient ethanol (75%–90%–95%–100%), and
and free polymer chains, followed by air drying to yield a hybrid poly- embedded in paraffin afterwards. The sample sectioning was conducted
mer film. with a Leica RM2016 Cryostat (Leica, Germany) into slides of 4 μm in
Assembly of the Wireless Sensors: The materials for the fabrication of thickness, followed by hematoxylin and eosin (HE) and Masson trichrome
biodegradable wireless pressure sensors were consisted of Mg, PLGA, staining. All the images were taken with an optical microscope (Panno-
POC, and PHB. Mg foil (50 μm) was cut into fixed and deformable wires ramic DESK, 3D HISTECH, Hungary).
according to the 3D models obtained form FEM simulation. Mg wires Statistical Analysis: All results were presented as the mean ± standard
were soaked into ethanol/water solution (50/50 vol.%) and treated with deviation (S.D.). All experiments were repeated for at least three times
an ultrasonic bath for 2 min, and then stored in a sealed container af- and each condition was analyzed in triplicate. Data distribution was as-
ter air drying. The PLGA film (75:25, Mw = 87,000–106,000 Da) was pre- sumed to be normal for all parametric tests, two-sided t test and One-way
pared by solvent casting a PLGA/CH2 Cl2 solution within a glass mould analysis of variance (One-way ANOVA) were used to determine the sig-
at room temperature. PLGA films of two different thicknesses, 150 and nificance level between two groups and multiple groups, respectively. The
30 μm, were fabricated by tuning the overall volume. The PLGA film with significance levels were considered as p > 0.05 represents no significant
thickness of 150 μm was laser-cut into a ring shape and used as the di- difference. All statistical analyzes were carried out with the Origin soft-
electric layer to determine f0 of the wireless pressure sensor under zero ware package.

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the author. D. S. Yang, Y. Park, R. Caldwell, A. Banks, S. Xu, Y. Huang, S. Fatone,
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Haney, W. Spees, Y. Lee, M. Choi, J. Ko, H. Ryu, J.-K. Chang, M.
J.S.L and X.M.C. contributed equally to this work. J.L. acknowledged
the financial support by National Natural Science Foundation of Pezhouh, S.-K. Kang, S. M. Won, K. J. Yu, J. Zhao, Y. K. Lee, M. R.
China (52373139), STI 2030-Major Projects (2022ZD0209500), Nat- MacEwan, S.-K. Song, Y. Huang, W. Z. Ray, J. A. Rogers, Nat. Biomed.
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