REVIEWS

Hydrogel interfaces for merging

humans and machines
Hyunwoo Yuk 1,3 ✉, Jingjing Wu 1
and Xuanhe Zhao 1,2 ✉

Abstract | The last few decades have witnessed unprecedented convergence between humans
and machines that closely operate around the human body. Despite these advances, traditional
machines made of hard, dry and abiotic materials are substantially dissimilar to soft, wet and
living biological tissues. This dissimilarity results in severe limitations for long-​term, reliable and
highly efficient interfacing between humans and machines. To bridge this gap, hydrogels have
emerged as an ideal material candidate for interfacing between humans and machines owing to
their mechanical and chemical similarities to biological tissues and the versatility and flexibility
in designing their properties. In this Review, we provide a comprehensive summary of functional
modes, design principles, and current and future applications for hydrogel interfaces towards
merging humans and machines.

Capacitance
In the last century, advances in the understanding and The main challenges of human–machine interfaces
C=q/V, where q is the charge engineering of the human body were made possible stem from materials. Existing machines largely employ
held on the conductor and V through interdisciplinary efforts in modern medicine, conventional materials, such as metals, silicon, glass,
is the electric potential of the biology and biomedical engineering. In parallel, com­ ceramics and plastics, to communicate and interact
conductor. Unit: F.
plex and ever more capable machines, such as compu­ with human bodies. However, the hard, dry and abiotic
ters, mobile devices, sensors, actuators and robots, nature of these conventional materials is intrinsically
have transitioned from science fiction into daily real­ contradictory with the soft, wet and living nature of
ities. Despite these advances, artificial interfaces — biological tissues. In recent decades, intensive efforts
facilitating communication and interactions between have been devoted to transforming these conventional
humans and machines — are still largely primitive, materials into flexible and stretchable structures to con­
leading to short-​term and inefficient interfacing between formally interface with soft and curvilinear biological
humans and machines. These shortcomings are espe­ tissues1,13–17. However, these structural designs do not
cially apparent in the emerging fields of brain–machine alter the materials’ intrinsic properties, which may still
interfaces, neuroprosthetics, clinical equipment, medical hamper their communication and interactions with
implants, wearable and ingestible devices, and virtual or biological tissues. For example, the integration of con­
augmented reality. Long-​term, efficient, biocompatible ventional materials with tissues usually relies on phys­
and seamless communication and interactions between ical attachment or surgical suturing, methods that face
humans and machines could lead to breakthroughs in challenges such as non-​conformal contact, unstable
these emerging sectors and other technological fields adhesion, tissue damage and/or scar formation15,18,19. As
but have not been achieved due to lingering challenges. another example, the properties of metallic electrodes,
1
Department of Mechanical
For example, conventional probes and arrays used for such as their high rigidity, low interfacial capacitance
Engineering, Massachusetts
Institute of Technology, brain–machine interfaces and neuroscientific studies, and low charge injection capacity, make them far from
Cambridge, MA, USA. such as the Michigan probes and Utah arrays, com­ ideal for the electrical recording and stimulation of soft
2
Department of Civil and monly induce substantial foreign-​body responses, such neural tissues1,2,5,17,20–22. In addition, biological tissues
Environmental Engineering, as gliosis and scar formation, severely hampering the often recognize these materials, even when in flexible
Massachusetts Institute long-​term reliability and functionality of brain–machine and stretchable structures, as foreign bodies due to their
of Technology, Cambridge,
interfaces1–6. As another example, implantable glucose inherently disparate properties, resulting in an adverse
MA, USA.
sensors and insulin pumps for diabetic monitoring and foreign-​body response, biofouling, and fibrotic encap­
3
Present address: SanaHeal,
Inc., Cambridge, MA, USA.
management often face substantially limited efficacy in sulation or fibrosis2,23,24. Such foreign-​body response
✉e-​mail: [email protected]; the long term owing to fibrotic encapsulation induced and subsequent fibrotic isolation from the surrounding
[email protected] by a foreign-​b ody response and subsequent loss of tissues can severely compromise the long-​term reliabil­
https://doi.org/10.1038/ the functional interfaces for sensing and delivery to the ity and efficacy of the communication and interactions
s41578-022-00483-4 surrounding tissues7–12. between humans and machines10,23,25–29.

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Box 1 | Similarities between hydrogels and biological tissues

High water content
The human body contains few organs with a relatively low water content (such as bone, ~25% of weight) and many organs
with a high water content (such as muscle, ~70% of weight, and brain, ~85% of weight), resulting in an average water
content of ~70% of body weight270 (see the figure, part a). By contrast, most engineering materials, such as silicon, metals,
ceramics, plastics and elastomers, are dry and contain little or no water5. Because water in biological tissues serves criti-
cal roles in diverse biological, chemical and physical processes, including nutrient and waste transportation, intercellular
signalling by waterborne chemicals, and ionic electrophysiological communication, hydrogels with a tissue-​like high
water content can closely mimic physiological interactions and minimize potential issues caused by dry foreign materials.
Mechanical softness
The human body is largely composed of soft tissues with few exceptions such as teeth and bone. Soft tissues in the human
body have Young’s moduli typically in the range of 1 Pa to 1 MPa, whereas most conventional solids, such as elastomers,
plastics, inorganics and metals, exhibit Young’s moduli several orders of magnitude higher2,13 (see the figure, part b).
This stark difference in mechanical properties is one of the major sources of tissue damage, foreign-​body response and
scar tissue formation around the rigid devices interfacing with the human body1–3,5. By contrast, hydrogels can have
Young’s moduli similar to those of biological tissues owing to their structural and compositional similarities as highly
hydrated polymer networks.
Biocompatibility
Biocompatibility is one of the most crucial requirements for interfacing with the human body while avoiding adverse bio-
logical interactions and outcomes. Owing to their non-​toxic and biocompatible nature, hydrogels have been widely stud-
ied and adopted in tissue engineering31, regenerative medicine29,32 and biomedical devices41 in both academic research and
commercial products. Furthermore, hydrogels can offer antifouling64,66–68 functions and reduce foreign-​body responses69–78
when in contact with physiological environments.
Biofunctionality
Both biological tissues and hydrogels are water-​based polymer systems, and a broad range of biopolymers and synthetic
polymers with biologically important functional groups can be used as constituents for hydrogels31,33,80,81. For example,
various extracellular matrix components (such as collagen, gelatin and hyaluronic acid) as well as chemically modified
biopolymers and synthetic polymers (such as arginyl-​glycyl-​aspartic acid (RGD) peptide-​modified alginate and polyethyl-
ene glycol) have been adopted in hydrogels to facilitate biological functionalities (such as cell adhesion253 and tissue
engineering29,31).

a
Blood, ~50% Lung, ~80%
Heart, ~75%
Bone, ~25%
Muscle, ~70%
Teeth, ~10% Skin, ~70% Brain, ~85%

0% 30% 60% 90%

Water content

b Elastomers Plastics
Silicones, polyurethanes, Polyimide, polycarbonate,
Soft tissues epoxy, natural rubbers PMMA, parylene, PETE
Skin, muscle, GI organs,
neural tissues, lung, heart, Hydrogels Inorganics and metals
blood vessels Synthetic polymer hydrogels, Silicon, glass, ceramic,
biopolymer hydrogels gold, platinum, titanium

1 Pa 1 kPa 1 MPa 1 GPa

Young’s modulus
GI, gastrointestinal; PMMA, poly(methyl methacrylate); PETE, poly(ethylene terephthalate).

Because of their unique similarities to biological hydrogels have been commercialized and have become
tissues30–33 (Box 1) and the versatility and flexibility in the standard interfaces between ultrasound equipment
tailoring their properties5,33–37, hydrogels have naturally and human skin for various medical imaging and ther­
emerged as a promising material candidate to act as apeutic applications37–42. Similarly, commercially avail­
an alternative or adjunct to conventional materials for able skin-​adhesive hydrogels have become the main
bridging humans and machines. Hydrogel interfaces — candidates for epidermal electrodes used in clinical bio­
both explored in academic research and as commercial electronic recordings, such as in electrocardiography,
products — are rapidly emerging in a broad range of electromyography (EMG) and electroencephalo­
applications (Fig. 1). For instance, ultrasound-​coupling graphy, and in clinical bioelectronic stimulation such as

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a Epidermal and wearable applications In this Review, we first provide a comprehensive sum­
Ultrasound probe Hydrogel
Hydrogel Hydrogel Hydrogel mary of recent advances in hydrogel interfaces using
Hydrogel examples from both academic literature and commercial
products. Based on the nature of the communication and
Sweat interactions between humans and machines, the func­
Wound
Skin tions of hydrogel interfaces can be broadly categorized
into mechanical, acoustic, electrical, optical, chemical and
Epidermal Ultrasonic Wound Sweat sensor Contact lens
electrode couplant dressing biological modes. Thereafter, we systematically discuss
the property requirements for hydrogel interfaces to ena­
b Implantable applications ble various functional modes and provide the design prin­
Hydrogel Hydrogel
Hydrogel
Hydrogel ciples to achieve such properties. We conclude with future
Drug Hydrogel
perspectives on next-​generation hydrogel interfaces and
the remaining challenges and opportunities.
Delivered
Implant light Applications of hydrogel interfaces
Implantable
Along with various devices and machines in contact and
Tissue adhesive Drug-delivery Anti-FBR Optical
electrode carrier coating waveguide interacting with human bodies, hydrogel interfaces have
emerged and have been adopted in diverse applications
c Ingestible and minimally invasive applications
Hydrogel Hydrogel in both academic and commercial settings (Table 1). The
current applications of hydrogel interfaces can be largely
categorized based on the invasiveness of their inter­
Hydrogel
actions with various parts of the human body (Fig. 1).
Blood Hydrogel Hydrogel interfaces for epidermal and wearable appli­
vessel
cations (Fig. 1a) provide non-​invasive communication,
Ingestible device Catheter Guidewire Stent whereas hydrogel interfaces for implantable applications
(Fig. 1b) are invasive and often provide long-​term contact
Fig. 1 | Current applications of hydrogel interfaces. Various examples of hydrogel inter-
faces for epidermal and wearable (part a), implantable (part b), and ingestible and minimally with internal organs and tissues. Hydrogel interfaces are
invasive (part c) applications around the human body. FBR, foreign-​body response. also increasingly adopted in ingestible and minimally
invasive applications within body cavities (such as tho­
racic and abdominal cavities) or tubular organs (such as
transcutaneous electrical nerve stimulation5,41–45. Besides intestines and blood vessels) (Fig. 1c). In this section, we
their application as ultrasound-​coupling agents and bio­ review current applications of hydrogel interfaces from
electrodes, hydrogels have also been intensively explored each category using examples from the literature and
as sensors, actuators and drug reservoirs in wearable commercially available products (Tables 1 and 2).
devices such as sweat sensors46–48, contact lenses49–52,
and wound dressings and bandages53–56. In addition, Epidermal and wearable applications. Skin is the largest
taking advantage of their edible, food-​like proper­ organ in the human body and forms the body’s outer­
ties and tunable swelling and degradation properties, most interface to external environments15. The facile
hydrogels have recently emerged as a promising carrier and non-​invasive nature of epidermal interfacing has
for ingestible sensors and devices capable of long-​term encouraged the development of a wide range of epi­
retention and functions in the gastrointestinal tract57–59. dermal and wearable devices, many of which have been
Furthermore, hydrogels with designed mechanical prop­ commercialized and adopted as the standard of care
erties and chemical compositions have been shown to in clinical practice. Despite its environment-​exposed
substantially enhance the biocompatibility of implant­ nature, skin possesses starkly different properties than
able devices by providing highly lubricious surfaces60–65, conventional materials used in devices and machines.
reducing biofouling64,66–68 and alleviating foreign-​body To bridge these dissimilarities and allow stable function­
responses69–78. This enhanced biocompatibility paves the ality, diverse hydrogel interfaces have been adopted in
way for various implantable devices to form long-​term epidermal and wearable applications (Fig. 1a).
reliable and functional interfaces with the human body. Epidermal electrodes are an essential component
Despite the great promise and recent advances in for various electrical sensing and stimulation devices in
hydrogel interfaces, to the best of our knowledge, there health monitoring15, diagnostic5,15, therapeutic45,89 and
is no systematic discussion on hydrogel interfaces for human–machine interfacing90 applications. The efficacy
the merging of humans and machines. The literature of epidermal electrical communications is influenced
on hydrogels as scaffolds for tissue engineering31,32,79–83, by several factors, including conformal mechanical
carriers for drug delivery84–87 and emerging materials contact with skin and the degree of skin hydration5,43,91.
for soft machines34,88 has been extensively reviewed, but Conventional metallic electrodes are dry and mechan­
existing reviews usually do not account for the appli­ ically stiff; therefore, they face various limitations, such
cations of hydrogels as bridging interfaces between as poor interfacial contact with dehydrated skin tissues,
humans and machines nor do they provide the require­ resulting in high skin–electrode interfacial impedance and
ments or principles for the design of hydrogel interfaces. ineffective electrical communication5. To address these
Such a systematic discussion is central for the future limitations, hydrogel interfaces were introduced as coat­
development of this nascent yet impactful field. ings on metal electrodes and have become the standard

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Table 1 | Current applications, functional modes and translation statuses of hydrogel interfaces
Applications Examples Functional mode Translation status Refs.
Epidermal Epidermal hydrogel electrodes Mechanical, electrical Academic and commercial 5,15,45,89,157

and wearable
applications Hydrogel wound dressing Mechanical, chemical, Academic and commercial 53–56,99

biological
Hydrogel drug-​delivery patch Mechanical, chemical, Academic and commercial 53,97,98

biological
Hydrogel ultrasound couplants Mechanical, acoustic Academic and commercial 38,93,94,170

Hydrogel contact lenses Mechanical, optical Academic and commercial 49–52,108–110

Hydrogel glucose sensors Electrical, optical, chemical Academic 262,263

Hydrogel pH sensors Electrical, chemical Academic 54

Implantable Tissue adhesives and sealants Mechanical, chemical, Academic and commercial 113–117,264

applications biological
Hydrogel electrode coatings Mechanical, electrical Academic 5,76–78

Hydrogel waveguides Mechanical, optical Academic 110,141–144

Drug-​eluting hydrogels Chemical, biological Academic and commercial 42,84–87,167

Tissue scaffolds Chemical, biological Academic and commercial 29,31,259,265

Hydrogel glucose sensors Chemical, biological Academic 266,267

Anti-​FBR hydrogel coatings Mechanical, biological Academic 64,66–68,147

Ingestible Ingestible hydrogels for drug Mechanical, chemical, Academic 57–59

and minimally delivery or sensing biological

invasive
applications Ingestible hydrogels for weight Mechanical, chemical, Academic and commercial 58,150,268

control biological
Low-​friction hydrogel coatings Mechanical, biological Academic and commercial 64,151–154

for minimally invasive devices

FBR, foreign-​body response.

electrode coatings in various clinical diagnostic (such Beyond skin, hydrogel interfaces have been widely
as electrocardiography, electromyography and electro­ utilized in ophthalmic wearable devices to interface
encephalography) and therapeutic (such as transcutane­ with the eye. The soft, wet and transparent nature of
ous electrical nerve stimulation) applications. The soft hydrogels and their optical properties, such as their
and adhesive properties of hydrogel epidermal electrodes tunable refractive index, are highly desirable for oph­
provide conformal contact with skin, and their high water thalmic interfacing. The majority of contact lenses,
content and high electrical conductivity offer low tissue– including clinically approved products based on
electrode impedance, synergistically leading to effective poly(2-​hydroxyethyl methacrylate) (Acuvue, J&J) and
electrical sensing and stimulation. Notably, the majority polyvinyl alcohol hydrogels (Dailies, CIBA Vision)
of commercially available and clinically approved epider­ (Table 2), have been based on hydrogels since the first
mal electrodes are composed of ionic hydrogel interfaces commercial launch of hydrogel-​based soft contact lenses
consisting of crosslinked hydrophilic polymers, such as in the 1970s108,109. More recently, various health monitor­
polyacrylate copolymers, which have a high water content, ing and diagnostic functions have been introduced to
good skin adhesiveness and dissolved ions (for example, ophthalmic hydrogel interfaces to create smart contact
potassium chloride) for electrical conductivity5,92 (Table 2). lenses49–52,108,110.
Furthermore, epidermal diagnostic imaging tech­
niques, such as ultrasonography, rely on hydrogel cou­ Implantable applications. In order for devices or
plants at the tissue–ultrasound probe interface, owing to machines to interface over the long term with internal
Electrical conductivity the tissue-​like mechanical and acoustic characteristics tissues and organs, they often need to be implanted
For an ideal conductor, the
electrical conductivity is
of hydrogels38,93–96. Hydrogel interfaces have also been into the human body. Unlike non-​invasive epidermal
σ = L / RA, where L is the widely adopted for the treatment of injured skin in the interfacing, implantable applications involve invasive
length, A is the cross-​sectional form of wound dressings or epidermal bandages owing surgical procedures and introduction of foreign objects
area and R is the electrical to their unique capabilities for promoting wound healing within the human body. As a result, implantable appli­
resistance of the material.
through dehydration prevention, antimicrobial protec­ cations face various challenges, including tissue dam­
The reciprocal of electrical
conductivity is electrical tion and transdermal drug delivery53,55,56,97–99 (Table 2). age, foreign-​body responses and subsequent functional
resistivity. Unit: Sm-1. In addition, hydrogel interfaces have been used in many failure of the implants. These challenges often originate
epidermal health monitoring and diagnostic applica­ from and are substantially exacerbated by disparate
Refractive index tions100. For example, the high water absorption of vari­ properties between biological tissues and the implants.
n=c/v, where c is the speed of
light in a vacuum and v is the
ous chemical-​sensing hydrogels enables their use as Hydrogel interfaces have been adopted for diverse
speed of light in the material. diagnostic devices based on epidermally collected body implantable applications to resolve or alleviate these
Unitless. fluids such as sweat51,101–107. challenges (Fig. 1b).

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Charge injection capacity

The surgical repair of injured tissues and implanta­ reliable bioelectronic communication and modula­
Amount of charge that the tion of devices on targeted organs commonly requires tion over extended periods of time. However, conven­
electrode can inject per unit establishing robust mechanical interfaces between the tional metallic implantable electrodes can elicit adverse
area without causing injured tissues and between the devices and organs, responses such as fibrosis and scar formation from the
irreversible electrochemical
respectively. Conventional techniques to form mechani­ target and surrounding tissues, resulting in functional
reactions or tissue damage.
cal interfaces, such as sealing and fixation, rely on sutures loss owing to a decrease in signal-​to-​noise ratios dur­
Young’s modulus and surgical staples111. However, sutures and surgical ing recording and a decrease in charge injection capacity
The Young’s modulus of a staples commonly damage tissues, and their substan­ during stimulation2,4,6,21. To address these issues, hydrogel
material in the linear elastic
tial mismatch with tissue properties can cause various interfaces have been introduced as adjunct or alternatives
region is E=S/ε, where S is
the engineering stress and ε
adverse outcomes and complications, including scar to metallic electrodes to provide improved biocompati­
is the engineering strain of the formation, impaired healing and leakages112. In recent bility69,76,136,137 due to their tissue-​matching Young’s modulus
material. Unit: Pa. decades, tissue adhesives and sealants have been devel­ and lower bending stiffness as well as improved electrical
oped to address the limitations of sutures and surgical properties5,77,78,138,139 resulting from their lower impedance
staples113–115. Because hydrogels provide robust, biocom­ and higher charge injection capacity.
patible and tissue-​matching adhesive interfaces, a broad Optical interfacing has also been utilized in implant­
range of hydrogels based on synthetic polymers116,117 able applications for photomedicine in photothermal ther­
(such as polyethylene glycol) and biopolymers118,119 apy, photodynamic therapy and photobiomodulation110
(such as fibrin or gelatin) have been adopted in implant­ as well as for the modulation of neural activities in
able tissue adhesives for tissue repair114 and integrated optogenetics21,140, where optical communication with
in devices both in academic studies and in clinically the target tissue commonly relies on implanted wave­
approved products19 (Table 2). guides110. However, conventional optical waveguides
Implantable electrodes for neurological treatment are made of silica or plastics and their mechanical mis­
(such as deep brain stimulation)120–122, for rehabilitation match with biological tissues can cause various adverse
(such as spinal cord stimulation)123–127 and for functional outcomes and deterioration of functionalities110. To
augmentation involving, for example, pacemakers128–131, avoid these limitations, hydrogel-​based implantable
cochlear implants132 or neuroprosthetics2,133–135, require optical waveguides with tissue-​matching mechanical

Table 2 | A representative list of clinically approved materials for hydrogel interfaces

Hydrogel material Product/company Application Approved indication
Epidermal and wearable applications
Polyacrylate copolymer (with Red Dot/3M Hydrogel skin electrodes Electrocardiograph electrodes (FDA
dissolved potassium chloride) approved)
Polyacrylate copolymer (with Self-​Adhesive Electrodes/Philips Hydrogel skin electrodes Cutaneous electrodes for TENS (FDA
dissolved potassium chloride) approved)
Polyethylene glycol Aquaflo/Covidien Hydrogel wound dressings Wound dressings for first- and
second-​degree burns (FDA approved)
Polyacrylic acid Aquasonic/Parker Laboratories Hydrogel ultrasound couplants Coupling medium for ultrasound
transmission (FDA approved)
Poly(2-​hydroxyethyl methacrylate) Acuvue/J&J Hydrogel contact lenses Daily wear contact lens (FDA approved)
Polyvinyl alcohol Dailies/CIBA Vision Hydrogel contact lenses Daily wear contact lens (FDA approved)
Implantable applications
Polyethylene glycol CoSeal/Baxter Tissue adhesives Adjunct haemostasis for vascular
reconstitution (FDA approved)
Fibrin Evicel/J&J Tissue adhesives Adjunct haemostasis (FDA approved)
Gelatin LifeSeal/LifeBond Tissue adhesives Staple-​line reinforcement in
gastrointestinal surgery (CE marked)
Poly(2-​hydroxyethyl methacrylate) Vantas/Endo Pharmaceuticals Drug-​eluting hydrogels Palliative treatment of prostate cancer
(FDA approved)
Hyaluronic acid Euflexxa/Ferring Pharmaceuticals Tissue scaffolds Knee osteoarthritis (FDA approved)
Alginate Algisyl-​LVR/LoneStar Heart Tissue scaffolds Advanced heart failure (CE marked)
Ingestible and minimally invasive applications
Cellulose Plenty/Gelesis Ingestible hydrogels Ingestible hydrogels to aid in weight
management (FDA approved)
Polyvinylpyrrolidone SpeediCath/Coloplast Low-​friction hydrogel coatings Urinary catheters (FDA approved)
Poly(methyl vinyl ether/maleic Radifocus/Terumo Corporation Low-​friction hydrogel coatings Cardiovascular guidewires (FDA approved)
anhydride)
Vortek/Coloplast Low-​friction hydrogel coatings Ureteral stents (FDA approved)
Date of search: December 2021. CE, Conformité Européenne (European Conformity); TENS, transcutaneous electrical nerve stimulation.

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properties have been developed as a promising alternative guidewires (in particular, poly(methyl vinyl ether/
to conventional stiff optical waveguides110,141–144. maleic anhydride) hydrogels) and stents (in particular,
Sustained delivery of pharmacological substances poly(methyl vinyl ether/maleic anhydride) hydrogels) in
from implanted reservoirs is one of the major strategies the form of thin coatings to provide soft, low-​friction and
for the treatment of various diseases145. Hydrogels have antifouling interfacing with the endoluminal surface of
played an important role in the development and transla­ tubular organs64,151–156 (Table 2).
tion of implantable drug delivery systems owing to their
favourable characteristics, including high water content, Functional modes of hydrogel interfaces
ease of chemical modification and incorporation of Machines and the human body can interact and com­
drugs, biocompatibility, and biodegradability84,87,146. As municate via diverse functional modes depending on the
a result, various hydrogels, such as poly(2-​hydroxyethyl desired applications and the characteristics of the target
methacrylate), hyaluronic acid and alginate, have been tissues and organs. Hence, hydrogel interfaces bridging
adopted in clinically approved products as implant­ machines and the human body also need to incorporate
able drug reservoirs or tissue scaffolds31,42,87 (Table 2). a wide range of functional modes. We classify the func­
In implantable applications, such as for sustained drug tional modes of hydrogel interfaces into six categories:
delivery, the foreign-​body response and subsequent mechanical, acoustic, electrical, optical, chemical and
blockage of drug release by biofouling and fibrosis biological (Table 3 and Fig. 2).
around the implanted devices is a critical issue ham­ In addition, because a machine can interface with
pering long-​term efficacy9. To alleviate this challenge, the human body via multiple functional modes simul­
diverse anti-​foreign-​b ody response hydrogel inter­ taneously, hydrogel interfaces often need to be multi­
faces have been adopted in implantable machines and functional (Table 1). For example, epidermal electrodes
devices in academic studies to minimize the formation require hydrogel interfaces to function not only in the
of fibrotic encapsulation (by reducing protein absorption electrical mode through electrical conduction but also
and inflammatory reactions) and to preserve long-​term in the mechanical mode exploiting skin-​matching
functional efficacy64,66–68,147. mechanical properties and adhesiveness5,157. Therefore,
the rationally guided design and development of mate­
Minimally invasive applications. Interfacing within rials for hydrogel interfaces necessitate the systematic
body cavities, such as abdominal and thoracic cav­ consideration of various functional modes and the cor­
ities, and tubular organs, such as the intestines, blood responding desired properties to enable multifunctional
vessels and the urinary tract, provides minimally inva­ applications. In this section, we discuss the six major
sive yet close interactions with the human body. Orally functional modes of hydrogel interfaces and the desired
administered ingestible devices have been developed properties for each functional mode.
for diverse diagnostic and therapeutic gastrointesti­
nal applications59. Recent advances in endoscopic and Mechanical mode. The mechanical mode of hydrogel
robot-​assisted surgical platforms have enabled a rapid interfaces is essential because it guarantees their integ­
growth in minimally invasive and robotic surgeries148. rity and robustness as well as their stable adhesion and
Despite the minimally invasive nature of these applica­ matching rigidity with the target tissues and organs.
tions, close interactions and communication with the Hydrogel interfaces in the mechanical mode are required
internal tissues and organs require biocompatible and to possess a set of bulk and interfacial properties
benign interfacing. Various hydrogel interfaces have (Fig. 2a and Table 3).
been incorporated in a wide range of ingestible and Many machines and devices require prolonged con­
minimally invasive devices to offer more favourable tact with the human body. For example, wearable devices
tissue–device interactions and communication (Fig. 1c). for health monitoring form close contact with the epi­
Taking advantage of the soft, biocompatible and dermis for days to weeks. Long-​term implantable devices
highly swellable characteristics of hydrogels, several can stay within the body contacting internal tissues
hydrogel-​based gastrointestinal-​retentive ingestible and organs over months to years. The various tissues and
devices have been developed for health monitoring58,149, organs in the human body possess substantially different
drug delivery57 and weight control150, including several mechanical stiffness. Mechanical interactions between
clinically approved products such as weight control the target tissues or organs and hydrogel interfaces
devices based on cellulose hydrogels (Table 2). Swollen with dissimilar mechanical stiffness can cause impaired
hydrogels have similar mechanical properties to food, functional efficacy, for example, through non-​conformal
providing favourable mechanical interactions with the contact, as well as long-​term adverse tissue responses
gastrointestinal organs during their administration, such as foreign-​body response, tissue damage or scar
retention and digestive passage from the body. formation2,33,88,114. Therefore, a desired bulk property of
Endoluminal insertion and navigation of catheters, a hydrogel interface is a mechanical stiffness, or Young’s
guidewires and stents are a routine part of minimally inva­ modulus, matching that of the target tissue or organ.
sive surgeries and daily patient care. However, mechanical The human body is a dynamic system mechan­
interactions of the inserted devices with narrow tubular ically interacting with external environments and
organs can cause complications such as frictional tissue within itself. Hence, hydrogel interfaces also face highly
damage and infection. To alleviate these issues, various dynamic mechanical interactions with the human body.
hydrogels have been introduced in clinically approved Preventing bulk failures caused by mechanical loads
catheters (in particular, polyvinylpyrrolidone hydrogels), and deformation is a key design criterion to ensure the

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Table 3 | Desired properties of hydrogel interfaces for various functional modes

Property Design criteria Target tissues Relevant clinical Examples
applications
Mechanical mode
Young’s modulus Young’s modulus Skin, muscle, nerve, Wound dressings, tissue GelMA hydrogels189,190; alginate
matching that of the internal organs adhesives, skin or nerve grafts hydrogels191–193; chitosan hydrogels194–196
target tissue
Tendon, ligament Tendon replacement Aligned-​nanofiber composite hydrogels197–201
Bone Bone grafts Hydroxyapatite-​mineralized hydrogels203,204
Fracture toughness High fracture toughness All tissues Tendon or cartilage Double-​network hydrogels158,159;
replacement nanocomposite hydrogels160,161
Interfacial High interfacial All tissues Wound dressings, tissue Tough adhesive hydrogels116,117,162–164;
toughness toughness adhesives, wearable/ hydrogel microneedles165
implantable electrodes
Friction coefficient Low friction coefficient Cartilage, meniscus Cartilage replacement Hydrogels with repulsive dangling
chains61; polymer-​filled hydrogels62,213;
lipid-​incorporating hydrogels65
Acoustic mode
Acoustic Acoustic impedance Skin Ultrasound couplants Hydrogel ultrasonic couplants93,169,170
impedance matching that of the
target tissue
Electrical mode
Electrical High electrical Brain, spinal cord, Wearable/implantable Conducting polymer hydrogels77,221,223;
conductivity conductivity peripheral nerve, electrodes CNT-​composite hydrogels219;
heart, muscle graphene-​composite hydrogels220;
Capacitance High capacitance metal nanowire-​composite hydrogels217,218
Optical mode
Transmittance High transmittance Eye Contact lenses Silicone hydrogel contact lenses108
Refractive index Tunable refractive index All tissues Implantable waveguides Step-​index hydrogel fibres141,142,174
Chemical mode
Diffusivity Tunable diffusivity All tissues Drug delivery Porous hydrogels234,235
Biodegradability Tunable biodegradability All tissues Implantable medical devices Oxidized alginate hydrogels239,240
Binding affinity High binding affinity All tissues Wearable/implantable Glucose-​sensing hydrogels178,247
to target chemical sensors
Biological mode
Cell adhesiveness High cell adhesiveness All tissues Tissue scaffolds RGD peptide-​modified hydrogels252,253
Foreign-​body Low foreign-​body All tissues Implantable medical devices Zwitterionic hydrogels66,70,73; anti-​FBR
response response drug-​eluting hydrogels258
CNT, carbon nanotube; FBR, foreign-​body response; GelMA, gelatin methacrylate; RGD, arginyl-​glycyl-​aspartic acid.

reliable functionality of hydrogel interfaces. Thus, a high mechanical interactions between hydrogel interfaces
fracture toughness is another desirable bulk property for and the target tissues and organs can cause frictional
Fracture toughness
hydrogel interfaces158–161. wear. Sustained frictional wear can cause the interfacial
Γ = Gc,bulk = −dUbulk /dA, where
Gc,bulk is the critical energy Various applications of hydrogel interfaces, such erosion of poorly lubricated hydrogel interfaces and/or
release rate that drives bulk as epidermal electrodes, tissue adhesives and sealants, tissue damage. Hence, a low friction coefficient is desir­
crack propagation in require interfacial integration with the target tissues to able to minimize frictional wear in applications such as
the material, Ubulk is the total provide the desired functionality (Table 1). Interfacial minimally invasive medical devices64,154 and artificial
potential energy of the mate-
rial and A is the crack area
integration of hydrogel interfaces with the human body cartilage65,166.
measured in the undeformed requires establishing and maintaining robust adhesion
state33,159. Unit: Jm-2. to biological tissues. Adhered hydrogel interfaces can Acoustic mode. Owing to its non-​destructive and non-​
undergo interfacial failures, which can result in func­ invasive nature, the sound wave-​based diagnosis of dis­
Interfacial toughness
tional loss, for example, through the detachment of eases and health conditions has become standard clinical
Γinter = Gc,inter = −dUinter /dA,
where Gc,inter is the critical devices, or detrimental clinical complications such as practice94. Furthermore, the capability of ultrasound to
energy release rate that drives leakage from failed tissue sealants. To achieve robust deliver energy into deep tissues in a non-​destructive
interfacial crack propagation, interfacial integration, hydrogel interfaces require high manner has been utilized in various therapeutic appli­
Uinter is the total potential interfacial toughness116,117,162–165. cations, including thermal treatments and non-​thermal
energy of the adhered materi-
als and A is the crack area
Another important function of hydrogel interfaces therapies exploiting mechanical effects, such as ultra­
measured in the undeformed in the mechanical mode is the reduction of friction sonic lithotripsy96, as well as in drug delivery167,168.
state33,162. Unit: Jm-2. and wear with the target tissues and organs. Interfacial Hence, the acoustic mode of hydrogel interfaces can be

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a Mechanical mode Mechanical failures

Desired properties (bulk)
Hydrogel interface • Tissue-matching Young’s modulus
• High fracture toughness
Bulk Desired property (interfacial integration)
• High interfacial toughness
Interface
Bulk Interfacial Frictional Desired property (interfacial lubrication)
Target tissue failure failure wear • Low friction coefficient

b Acoustic mode
Acoustic imaging Acoustic stimulation
Ultrasound transducer and receiver Ultrasound transducer

Desired property
Zhydrogel ≈ Ztissue Zhydrogel ≈ Ztissue • Tissue-matching acoustic impedance
Transmitted Transmitted
and reflected and delivered
sound waves Target Ztissue sound waves Target Ztissue

c Electrical mode
Electrophysiological recording Electrophysiological stimulation
AP AP

Injected charge Desired properties

σ, C Recorded signal σtissue σ, C and stimulation σtissue • High electrical conductivity
• High capacitance
Ric r Ric
Ce Ce
Vrecording Vstimulation
IAP Iinjection
Electrode Re Tissue Electrode Re Tissue

d Optical mode
Light transmission Light delivery
Transmitted light Desired property (transmission)
• High transmittance
nout nin > nout Desired property (delivery)
• High transmittance
• Tunable refractive index (application
dependent)

Delivered light

e Chemical mode
Chemical delivery Chemical sensing
Delivery by Delivery by Desired properties (delivery)
diffusion degradation • Tunable diffusivity (application
dependent)
• Tunable biodegradability (application
dependent)
Desired property (sensing)
• High binding affinity to target chemical
Selective binding and sensing

f Biological mode
Tissue remodelling Reduced FBR
Anti-FBR Desired properties (tissue remodelling)
• High cell adhesiveness
Fibrosis • Tunable biodegradability (application
dependent)
Desired property (FBR)
• Low FBR
Degradation and
Cell adhesion cell infiltration High FBR Low FBR

Fig. 2 | Functional modes of hydrogel interfaces. Various functional modes interface; FBR, foreign-​body response; IAP, target cell’s transmembrane cur-
of communication and interactions between humans and machines via rent amplitude of action potential; Iinjection, current injected to the target tissue
hydrogel interfaces, including mechanical (part a), acoustic (part b), electrical by electrophysiological stimulation; r, distance between the electrode and
(part c), optical (part d), chemical (part e) and biological (part f) modes and the target cell; Re, resistance of the hydrogel interface; Ric, interconnect resist-
the desired properties of hydrogel interfaces for each mode. σtissue, conduc- ance; Vrecording, electric potential of the electrophysiological recording;
tivity of the tissue media; AP, action potential; Ce, capacitance of the hydrogel Vstimulation, applied electric potential for electrophysiological stimulation.

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Friction coefficient
exploited for two types of applications: acoustic imag­ conductivity (low Re) and high capacitance (high Ce)
μ = f /N, where f is the ing by facilitating the delivery of sound waves to and are advantageous. Notably, physiological environments
measured friction force and reflection from the target, such as in ultrasonography, exhibit native ionic conductivity (0.3–0.7 Sm-1)19,171
N is the applied normal force and acoustic stimulation by facilitating the delivery because of the high water content of biological tissues
to the material. Unitless.
of sound waves to the target such as in ultrasonic (Box 1) and their rich ionic compositions comprised of
Acoustic impedance ­lithotripsy (Fig. 2b). salts and charged proteins. Hence, the electrical con­
For a homogeneous material, Ultrasonic transducers and probes used for these ductivity of hydrogel interfaces should be substantially
the acoustic impedance is applications are made of conventional materials with higher than that of the surrounding tissue to ensure the
Z = ρeff K eff , where ρeff is the an acoustic impedance substantially different from that quality of recorded signals5,172,173.
effective density and Keff is
the effective bulk modulus
of skin33. Furthermore, the high mechanical rigid­ In electrophysiological stimulation, a high Iinjection, often
of the material. Unit: Pa∙sm−3. ity of the ultrasonic transducers and probes prevents measured as charge injection capacity, is desirable. Hence,
their conformal interfacial contact with skin, result­ for a given stimulation device (Ric) and input (Vstimulation), high
Transmittance ing in air-​filled gaps that also have disparate acoustic electrical conductivity (low Re) and high capacitance
T=I/I0, where I0 is the intensity of
incident light and I is the inten-
impedance compared to skin. The resultant mismatch (high Ce) are advantageous. Therefore, high electrical
sity of transmitted light through in acoustic impedance at the skin–probe interface can conductivity and high capacitance are desirable proper­
the material. Unitless and often severely hinder the transmission of acoustic waves owing ties of hydrogel interfaces in the electrical mode for both
denoted in percentage. to interfacial reflections and scattering169, deteriorating ­recording and stimulation applications.
functional efficacy (for example, decreasing the quality
of sonographic images). Hence, tissue-​matching acoustic Optical mode. The optical mode of hydrogel interfaces
impedance and conformal interfacial contact with skin relies on the transmission and delivery of light to the
are advantageous for hydrogel interfaces that work in the human body (Fig. 2d and Table 3). Unblocked transmis­
acoustic mode93,169,170 (Fig. 2b and Table 3). sion of incident light to the eye is a critical requirement
for visual functionality and eyesight. Hence, hydrogel
Electrical mode. Machines can communicate and inter­ interfaces for ophthalmic applications require high
act with electrically active tissues and organs in the transmittance to minimize the attenuation of transmitted
human body, such as the brain, nerves, muscles and light to the eye108,110. Beyond ophthalmic interfacing, the
heart, through hydrogel interfaces functioning in the delivery of a broad spectrum of light to diverse tissues
electrical mode5. The electrical mode of hydrogel inter­ and organs is enabling the use of hydrogel interfaces
faces can be used in two types of applications based on for photonic diagnosis and treatment110. Light delivery
the direction of electrical communication: from the requires an optical pathway typically in the form of a
human body to hydrogel interfaces for electrophysio­ waveguide that provides directional guidance for the
logical recording, and from hydrogel interfaces to the transmitted light, where the transmittance and refrac­
human body for electrophysiological stimulation (Fig. 2c tive index respectively modulate the transmission and
and Table 3). internal reflection of light143,144. Therefore, hydrogel
Based on a simplified equivalent circuit model5 interfaces for light delivery require high transmittance
(Fig. 2c), the electrical potential in electrophysiological and a tunable refractive index141,142,174.
recording and the injected current in electrophysiological
stimulation can be quantitatively expressed as: Chemical mode. Physiological activities involve diverse
chemical processes and reactions and, therefore, chemi­
 1   cal interactions with the human body are one of the key
1  + sCe R icIAP functional modes of hydrogel interfaces. The high water
Vrecording =    (1)

4πσtissuer  Re   content of biological tissues and hydrogel interfaces
inherently allows the exchange of waterborne chemicals.
Based on the direction of the chemical communication,
−1
 −1  the chemical mode of hydrogel interfaces can be further
1
Iinjection =  + sCe  + R ic Vstimulation (2) divided into two types: from hydrogel interfaces to the
 Re   human body for chemical delivery, and from the human
body to hydrogel interfaces for chemical sensing (Fig. 2e
where σtissue is the conductivity of the tissue, r is the dis­ and Table 3).
tance between the electrode and the target cell, Re is the Chemical delivery is commonly utilized for the
resistance of the hydrogel interface, s is the complex administration of pharmacological substances, such
frequency of the action potential (for recording) or the as drugs and other biologics, for therapeutic interven­
stimulation waveforms (for stimulation), Ce is the capac­ tions and treatments84,86,87,145. The therapeutic efficacy
itance of the hydrogel interface, Ric is the interconnect and toxicity of drugs are highly sensitive to their dosage and
resistance, IAP is the target cell’s transmembrane cur­ release profile; therefore, the capability to engineer
rent amplitude of action potential, Iinjection is the current controlled release from hydrogel interfaces is a critical
injected to the target tissue by the electrophysiological requirement145. Chemicals within hydrogel interfaces
stimulation, and Vstimulation is the applied electric potential can be released to the surrounding tissue by diffusion
for electrophysiological stimulation5. or by degrading the hydrogel. The rate and profile of
In electrophysiological recording, a high Vrecording chemical delivery by diffusion are determined by the
is desirable. Hence, for given physiological (σtissue, r, specific diffusivity of the chemicals in the hydrogel84,
s, IAP) and recording (Ric) conditions, high electrical whereas the rate and profile of chemical delivery by

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hydrogel degradation rely on the biodegradability of the between hydrogels and machines, hydrogel–machine
hydrogel84. Because different drugs have different sizes interfaces require robust integration with high inter­facial
and interactions with hydrogel matrices, tunable mesh toughness162,163. For the acoustic, electrical and optical
sizes, interactions with chemicals (such as binding and modes of hydrogel interfaces, the robust integration
release) and/or biodegradability are highly desirable for between hydrogels and machines should also provide
chemical delivery87. high acoustic transmittance, high optical transparency162
The sensing of a certain chemical species requires and high electrical conductivity139, respectively. In addi­
selectivity in interactions between the target chemical tion, chemical delivery and sensing can be performed by
and hydrogel interfaces146,175–179. This selectivity can be a machine, such as a drug reservoir or a sensor coated
controlled by tuning the binding affinity to the target in the hydrogel, instead of by the hydrogel itself. In this
chemical as a higher binding affinity provides a higher case, a high permeability or diffusivity of the chemicals
selectivity177. Hence, a high binding affinity to target at the hydrogel–machine interface is required to allow
chemicals is desirable for selective chemical sensing. unhindered transportation of chemicals between the
target tissue and the machine87. This Review focuses
Biological mode. Interfaces between machines and bio­ primarily on hydrogel–tissue interfaces but several
logical tissues inherently involve a broad range of reviews are available that discuss hydrogel–machine
biological interactions that substantially influence the interfaces33,34,88.
machines’ efficacy, reliability and biosafety. As a result,
the biological mode of hydrogel interfaces is of essential Design principles for hydrogel interfaces
importance, especially in applications that require higher Enabling the functional modes of hydrogel interfaces
invasiveness and long-​term interactions with the human requires the implementation of various desired hydro­
body such as implantable devices. The biological mode gel properties (Table 3). Although hydrogels can offer
of hydrogel interfaces can be divided into various types diverse properties, achieving optimal properties for
depending on the application requirements: promotion a desired functional mode is complex33,37. As a result,
of biological activities (such as cell adhesion, prolifer­ Edisonian approaches based on trial and error have
ation, infiltration and differentiation) and suppres­ limited success5,33, particularly for the development of
sion of biological activities (such as anti-​foreign-​body multifunctional hydrogel interfaces.
responses)180 (Fig. 2f and Table 3). In this section, we summarize rational design princi­
Cell adhesion and infiltration to hydrogel interfaces ples to achieve desired properties for hydrogel interfaces,
and subsequent partial or full remodelling of the hydro­ providing some examples from the literature (Table 3
gel interfaces by native tissues are favourable for vari­ and Fig. 3).
ous implantable applications. For example, implanted
devices for drug delivery and tissue repair (such as tis­ Mechanical properties. Mechanical interactions between
sue adhesives and sealants) require the gradual infiltra­ hydrogel interfaces and the human body are affected by
tion of cells from the surrounding tissue with ultimate the hydrogel bulk and interfacial mechanical properties,
resorption and tissue remodelling to avoid the need for including Young’s modulus, fracture toughness, inter­
surgical removal of the devices and potential long-​term facial toughness and friction coefficient (Fig. 2a). Because
adverse effects such as chronic inflammation87,114,181. the mechanical properties of tissues are determined by
Cellular interactions and tissue remodelling processes their compositional and structural features, the design
rely on the initial attachment of cells to the hydrogel, principles for the mechanical properties of hydrogel
which is followed by the progressive degradation of the interfaces are largely based on mimicking the target
hydrogel and infiltration of cells31,35,81,182,183. Hence, high tissue compositional and/or structural characteristics.
cell adhesiveness and biodegradability are important in Soft tissues (which include skin, muscle, nerve and
applications where tissue remodelling is desired. internal organs) have relatively low Young’s moduli
Regulating unfavourable biological interactions (1 kPa to 10 MPa) owing to their crosslinked extracellu­
between the implanted device and the surrounding tis­ lar matrices (Box 1). Conventional hydrogels consisting
sue is also an important function of hydrogel interfaces. of crosslinked polymer networks show compositional
Biofouling and foreign-​body response in physiological and structural similarities with soft tissues, including
environments and the resultant fibrosis can be detrimen­ low Young’s moduli33. The Young’s moduli of conven­
tal to the long-​term efficacy of hydrogel interfaces4,23. tional hydrogels can be tuned by controlling the density
Because fibrotic encapsulation and scar tissues possess of polymer chains per unit volume, n, as follows:
much lower electrical conductivity and chemical diffu­
sivity than native tissues, they substantially reduce the E hydrogel ~ nkT (3)
efficacy of electrical sensing and stimulation2–5,173,184
as well as of chemical delivery and sensing9,23,185–188. where k is the Boltzmann constant and T is the abso­
Therefore, a low foreign-​body response is highly desir­ lute temperature 33; n can be engineered by vary­
able for efficient long-​term communication in the ing the polymer concentration and the crosslink
electrical, chemical and optical modes28,185,188. density of the hydrogel33. Hence, diverse conventional
hydrogels with varying compositions (for example,
Hydrogel–machine interfaces. In addition to hydro­ GelMA hydrogels 189,190, alginate hydrogels 191–193 or
gel–tissue interfaces, interfaces between hydrogels and chitosan hydrogels194–196) have been adopted in hydrogel
machines are also important. To avoid interfacial failure interfaces to provide tissue-​matching Young’s moduli.

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a High fracture toughness b High interfacial toughness c Low friction coefficient

Lubricating Interface view
Process zone
Loading Strong interface
Counter-surface
interfacial linkages

Stress
Crack Repulsive Repulsion
Energy chains
dissipation
or fillers
Process zone Unloading
Detachment Hydrogel
Stretch Tissue

Design principle Design principle Design principle

Introducing dissipation in stretchy networks Integrating toughness and strong interfacial linkages Introducing repulsive surfaces

d High electrical conductivity Examples of electrically conductive phases e High capacitance

Conductive hydrogel O O
Percolated electrically Injected charge
conductive phases
Device interface S N
Electrical n H n

communication PEDOT PPy Graphene CNT

H
N N
Tissue Device interface
Design principle N N Design principle
H n
Percolating electrically conductive phases Incorporating volumetric capacitance
PAni

f Tunable diffusivity g Tunable biodegradability Examples of biodegradation chemistry

Polymer network Biodegradation Biodegradable hydrogel
Diffused chemicals Biodegradable Hydrolysis of ester groups
polymers and
ξ O O
crosslinkers H2O
O OH + HO

rs
Enzymolysis of amide groups
O O
Enzyme
Design principle Design principle
N OH + H2N
Controlling the mesh size of hydrogels Incorporating biodegradable networks H

h Low FBR Examples of anti-FBR surfaces

Drug Cationic group
Foulants (cells, proteins) Resisting adhesion Anionic group
OH OH OH OH OH
of foulants
H-bond O H
Hydrogel Hydrophilic surface Drug-releasing surface Zwitterionic surface
Implant
Representative zwitterionic moieties
O
Anti-FBR surface O- O
O O
P N+ N+ S O- N+ O-
Design principle Biomolecule O O
Introducing anti-FBR surfaces Phosphatidylcholine Sulfobetaine Carboxybetaine
Biomolecule-functionalized surface

Fig. 3 | Design principles for hydrogel interfaces with desired properties. Rational design principles to achieve desired
properties for hydrogel interfaces, including mechanical properties such as high fracture toughness36,158,159 (part a), high
interfacial toughness162,163,209 (part b) and low friction coefficient212 (part c); electrical properties such as high electrical
conductivity5,217–219,223 (part d) and high capacitance5,77,221 (part e); chemical properties such as tunable diffusivity230–232 (part f)
and tunable biodegradability181,269 (part g); and biological properties such as a low foreign-​body response (FBR)28,70,73,75,188,258
(part h). The grey dotted boxes provide an enlarged view of selected areas. ξ, mesh size of the hydrogel polymer
network; CNT, carbon nanotube; H-​bond, hydrogen bond; PAni, polyaniline; PEDOT, poly(3,4-​ethylenedioxythiophene);
PPy, polypyrrole; rs, radius of the chemical.

Stiff connective tissues, such as tendons and liga­ Young’s moduli (1–30 GPa) owing to the rich mineral
ments, exhibit significantly higher (10 MPa to 1 GPa) and contents of their main component, hydroxyapatite202.
anisotropic (stiffer in the longitudinal direction) Young’s Hence, several bone-​matching hydrogel interfaces have
moduli than soft tissues. These properties largely origi­ been developed by incorporating a high concentration of
nate from their highly aligned fibrous microstructures197. hydroxyapatite within the hydrogel matrix203,204.
Several strategies using synthetic polymers such as poly­ Notably, additional considerations can arise for
vinyl alcohol and biopolymers such as alginate, silk specific applications. For instance, hydrogel interfaces
and cellulose197–201 have achieved aligned fibrous hydro­ with a Young’s modulus higher or lower than that of
gels that are tendon-​like. Bone tissues show very high the target tissue can influence cellular responses via

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mechanotransduction, a mechanism that modulates acid) hydrogels synthesized on Teflon substrates),

various biological processes205 such as cell migration uncrosslinked polymers62,213 (such as for porous poly­
(for example, fibroblast migration towards a substrate acrylamide hydrogels filled with uncrosslinked alginate)
with higher Young’s modulus), proliferation or differen­ and lipids65 (such as for poly(hydroxyethylmethacrylate)
tiation (for example, promoted osteoblast differentiation hydrogels with incorporated phosphatidylcholine lipids).
on a substrate with higher Young’s modulus). Moreover, In these hydrogels, the lubricating components provide
beyond Young’s modulus, rate-​dependent mechanical non-​adhesive surfaces against the counter surfaces,
properties, such as viscoelasticity and poroelasticity, resulting in highly lubricated interfaces with low friction
can be beneficial for certain applications, including tis­ coefficients.
sue engineering83,206 and bioelectronics78,207, to match the
mechanical properties of the target tissue. Acoustic properties. Tissue-​matching acoustic imped­
To achieve high fracture toughness, mechanical ance is critical to minimize interfacial reflection or
dissipation and stretchability must be synergistically scattering of acoustic waves in the acoustic mode214.
combined33,36,208 (Fig. 3a). The resultant fracture toughness The acoustic impedance of a homogenous material is
can be expressed as follows: determined by the effective density and bulk modulus
of the material. Hence, to match the acoustic imped­
Γ = Γ0 + ΓD (4) ance of biological tissues, the effective density and bulk
modulus of the hydrogel interfaces must correspond to
where Γ0 is the intrinsic fracture toughness and ΓD is the those of the target tissue94. Notably, because the effective
contribution of the mechanical dissipation in the process density and bulk modulus of hydrogels with high water
zone (the region ahead of the crack tip that dissipates content are almost the same as those of water215, the
mechanical energy) to the total fracture toughness36,159. acoustic impedance is approximately the same as that of
Because the intrinsic fracture toughness of conven­ water-​rich biological tissues93,169,170. For example, hydro­
tional hydrogels is commonly limited to 10–100 Jm-2, gels with a high water content based on polyacrylamide,
high mechanical dissipation is needed for high fracture polyvinyl alcohol, polyacrylic acid and poly(hydroxyethyl­
toughness36. The mechanical dissipation of a hydrogel methacrylate) have been adopted as acoustic couplants
within the process zone is proportional to the area of in both academic and clinical settings93,95,216 (Table 2).
the hysteresis loop in its stress–stretch curve during a
loading–unloading cycle (Fig. 3a). Various strategies to Electrical properties. Electrical conductivity is commonly
provide high mechanical dissipation have been developed, introduced to hydrogels by incorporating electrically
such as using double-​network hydrogels158,159 (hydrogels conductive phases5. However, if these phases are non-​
consisting of two interpenetrating networks) and nano­ continuous, they cannot effectively transport electrical
composite hydrogels160,161 (hydrogels containing nano­ currents. Hence, the percolation of electrically conductive
scale crosslinkers), to introduce sacrificial networks and phases within hydrogel interfaces is needed for high electri­
bonds into hydrogels. cal conductivity (Fig. 3d). Various conductive fillers, includ­
To achieve high interfacial toughness for hydrogels ing metal nanowires217,218 (such as Ag and Au), carbon
adhered to tissues, high fracture toughness and strong nanotubes219, graphene19,220 and conducting polymers137
interfacial linkages between the hydrogel and tissue need (such as poly(3,4-​ethylenedioxythiophene):poly(sty­
to be synergistically integrated33,162 (Fig. 3b). The resultant rene sulfonate), polypyrrole and polyaniline), have been
interfacial toughness can be expressed as follows: used to form percolated electrically conductive phases
in hydrogel interfaces (Fig. 3d). Notably, hydrogel inter­
Γ inter = Γ inter
0 + Γ inter
D (5) faces purely consisting of percolated conducting poly­
mers have been developed and show very high electrical
where Γ0inter is the intrinsic interfacial toughness from conductivity77,138,221–223.
the interfacial linkages and ΓDinter is the contribution The capacitance of metallic electrodes is typically
of the mechanical dissipation in the process zone162,209. low because it originates from the surface-​b ound
High intrinsic interfacial toughness can be achieved by electrical double layer5. Low capacitance at the electrode–
strong interfacial linkages between the hydrogel and tissue interface can result in high electrical impedance
the tissue. Mechanisms that provide strong interfacial and inefficient charge injection, which are highly
linkages between tough dissipative hydrogels and bio­ undesirable for electrophysiological recording and
logical tissues or machines include covalent bonds19,117,210 stimulation, respectively 5,172. Incorporating volu­
(such as amide bonds), high-​density hydrogen bonds211 metric capacitance into the hydrogels to overcome
(such as in dry-​annealed polyvinyl alcohol hydrogels) the limitation of the surface-​bound electrical double
and topological interpenetration of polymers116,164 (such layer can help in achieving high capacitance5 (Fig. 3e).
as in topologically interpenetrating chitosan solutions). To incorporate volumetric capacitance, conducting
By making the hydrogel surface non-​adhesive, low polymer-​based hydrogel interfaces have been devel­
friction coefficients between hydrogels and tissue surfaces oped that can form electrical double layers in the nano­
can be achieved63,212 (Fig. 3c). Non-​adhesive hydrogel sur­ porous structure of the conducting polymers 224,225.
Electrical double layer faces with low friction coefficients have been developed For example, conducting polymer hydrogels based
Accumulation of charged ions
around the electrode within
based on the incorporation of various lubricating compo­ on poly(3,4-​ethylenedioxythiophene):poly(styrene
electrolytic medium under nents, including non-​adhesive dangling chains61 (such as sulfonate) have high volumetric capacitance, low
the applied electric potential. for poly(2-​acrylamido-2-​methyl-1-​propanesulfonic impedance and high charge injection capacity in wet

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physiological environments, which are required for or macroscopic porosity234,235 (such as porous algi­
in vivo electrophysiological modulation77,138,139,223. nate hydrogels), and stimuli responsiveness236 (such as
poly(N-​isopropylacrylamide)) have also been devel­
Optical properties. The transmittance of light in materi­ oped. Several reviews discuss diffusivity in hydrogel
als is determined by the degree of scattering and blockage interfaces86,87,237,238.
of the incident light within the material. When the size of The degradation of hydrogels mostly relies on
the hydrogel constituents (for example, the polymer breaking the network building blocks (for example,
aggregates or crystalline domains) is greater than one-​ polymer chains or crosslinks) and thus losing mass
tenth of the wavelength of the incident light, light scatter­ to the surrounding physiological environment. Hence,
ing becomes substantially higher, resulting in decreased the biodegradability of hydrogel interfaces depends
transmittance226. Hence, to achieve high transmittance, on the incorporation of biodegradable building blocks181
light scattering must be minimized by limiting the size of (Fig. 3g, left). The rate of biodegradation can be con­
the hydrogel constituents. This design principle has been trolled by engineering the ratio of degradable build­
implemented by minimizing the size of phase-​separated ing blocks to their non-​degradable counterparts. The
polymer-​rich and water-​rich domains141 (such as for poly­ biodegradation of hydrogel interfaces depends on two
ethylene glycol hydrogels with high molecular weight) major mechanisms: hydrolysis and enzymolysis (Fig. 3g,
and by fabricating nanoscale semi-​crystalline domains227 right). In wet physiological environments, water drives
(such as for nanocellulose-​reinforced polyvinyl alcohol the hydrolysis of ester groups. For example, introducing
hydrogels) to achieve hydrogel interfaces with high ester groups in the networks produces hydrolytically
optical transparency. biodegradable hydrogel interfaces, such as oxidized
Light delivery through optical waveguides relies on alginate239,240 and polyethylene glycol241,242. Hydrogel
total internal reflection, which requires a higher refrac­ interfaces containing biopolymers can undergo biodeg­
tive index for the internal medium than for the external radation via enzymolysis. Cells and physiological fluids
medium141. Hence, it is critical to ensure that the refrac­ in the human body are rich in enzymes that can cleave
tive index of the hydrogel is higher than that of the target and digest various chemical bonds (for example, amide
tissue141 or the cladding material141,142,174. The refractive groups) in biopolymers such as collagen31, gelatin189,190,
indices of hydrogels are inversely proportional to the hyaluronic acid243 and chitosan194–196.
hydrogel water content, ranging between the refractive To achieve a high binding affinity to target chem­
index of pure water (n = 1.331) and that of pure polymers icals, binding components such as ligands have to be
(n = 1.4–1.7)141. Hence, the refractive index can be tuned incorporated into the hydrogel interfaces146,175,177,244.
by controlling the water content of the hydrogel inter­ Hydrogel interfaces developed for the sensing of diverse
faces. For example, step-​index hydrogel optical fibres chemicals (for example, glucose or reactive oxygen spe­
have been developed based on a hydrogel core (such as cies) or chemical groups in cells (for example, B cells)
with polyethylene glycol hydrogels) and cladding (such incorporate the corresponding ligands or active func­
as with alginate hydrogels) with a varying equilibrium tional groups178,245–248 (such as glucose oxidase for glu­
water content142,174. cose and T cells for B cells) into the network. Notably,
the high binding affinity between drugs and ligands in
Chemical properties. The diffusivity of chemicals in hydrogel interfaces can also be used for the controlled
hydrogel interfaces (Dhydrogel) is determined by the inter­ release of drugs in the human body175 (for example, poly­
actions between the chemicals and the polymer net­ acrylamide hydrogels coupled with the GyrB protein
works of the hydrogel228,229. In particular, the relative size used for the triggered release of vascular endothelial
of the chemicals (their radius rs) and of the hydrogel growth factor)121. Several other reviews address the
network (the mesh size ξ) significantly affect chemical design of hydrogel interfaces for chemical sensing and
diffusivity87,145: release176,177,246.
D hydrogel  r 
~ exp− s  (6) Biological properties. Cells adhere to substrates through
D water  ξ  the binding of proteins such as of integrins to ligands
on the surface249. Hence, incorporating cell-​adhesive
where D water is the diffusivity of the chemical in ligands into hydrogel interfaces provides cell adhesive­
water230–232. ness. Because various biopolymers in the extracellular
When the size of the chemical is smaller than the matrix (such as collagen, gelatin or hyaluronic acid)
hydrogel mesh size, the chemical can diffuse freely within possess integrin-​binding ligands, cells can readily adhere
the hydrogel. Otherwise, the diffusion of the chemical is to hydrogel interfaces containing these biopolymers31.
substantially slowed by steric hindrances from the poly­ Specific cell-​adhesive proteins (such as fibronectin)250,251
mer network. Hence, choosing the mesh size based on and peptide motifs (such as arginyl-​g lycyl-​aspartic
the size of the chemical employed for delivery or sensing acid (RGD))252,253 have also been incorporated for cell
tunes the diffusivity of the chemical in hydrogel inter­ adhesiveness.
faces (Fig. 3f). The mesh size of hydrogels depends on To achieve alow foreign-​b ody response, hydro­
various parameters such as water content and crosslink­ philic, biomolecule-​functionalized, zwitterionic and
ing density31–33,87. To further increase the diffusivity of drug-​releasing surfaces have been introduced to
chemicals, hydrogel interfaces with nanostructures233 hydrogels28,67,188 (Fig. 3h). Hydrophilic surfaces form
(such as poly(amidoamine) dendrimers), microscopic a hydration layer as a result of bonding with water

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a Physiological Multimodal hydrogel interfaces should focus on addressing these

environment Anti-FBR hydrogel interface challenges using multidisciplinary investigations and
rationally guided design rules. In this section, we dis­
cuss future perspectives based on two conceptual
Implanted device
next-​generation hydrogel interfaces (Fig. 4a,b).

Target Mechanical Ultrasound Bioelectronic Optical sensing Drug delivery Multimodal hydrogel interfaces. In the human body,
tissue integration stimulation communication and stimulation and sensing internal organs are integrated with one another by
connective tissue to form robust, seamless and multi­
b Physiological
environment All-hydrogel functional interfaces. The internal organs also maintain
Anti-FBR hydrogel machine anatomical boundaries without adhesion by serous
Insulating membranes (or serosa) at their outermost surfaces.
hydrogel These characteristics provide inspiration for multimodal
hydrogel interfaces for seamlessly integrated, long-​term
Target Bioadhesive Conductive Hydrogel Drug-loaded Tissue and multifunctional devices.
tissue hydrogel hydrogel waveguide hydrogel scaffold
For epidermal and wearable applications, multimodal
hydrogel interfaces can offer multifunctional interfac­
Fig. 4 | Next-generation hydrogel interfaces. a | A multimodal hydrogel interface
providing multifunctional interfacing between a machine (implanted device) and a ing between the skin and various sensors and devices.
target tissue. b | An all-​hydrogel machine providing a multifunctional interface to a target For instance, advanced wound dressings may require
tissue. FBR, foreign-​body response. hydrogel interfaces with multiple modes of interaction,
including mechanical integration to the skin, electrical,
optical, acoustic and chemical sensing for wound moni­
molecules in wet physiological environments254. The toring, and chemical delivery of therapeutic substances53.
hydration layer acts as a physical barrier against For ingestible and minimally invasive applications, mul­
the adhesion of foulants (such as proteins and cells)255. timodal hydrogel interfaces can potentially offer new
Physical barriers against foulants, based on various treatment strategies by synergistically combining vari­
surface-​functionalized biomolecules such as antimicro­ ous functionalities. For example, low-​friction, conduc­
bial peptides256,257, have also been introduced to hydro­ tive, transparent and drug-​releasing hydrogel coatings
gels. Furthermore, zwitterionic polymers have also been on catheters, guidewires or stents may provide electrical
widely utilized to form anti-​foreign-​b ody response and/or optical monitoring of the target tissues and deliv­
surfaces75. Poly(phosphatidylcholine), poly(sulfobe­ ery of drugs on top of the conventional clinical treatments
taine) and poly(carboxybetaine) are the most com­ offered by minimally invasive medical devices260,261. For
monly adopted zwitterionic polymers that can form implantable applications, anti-​foreign-​body response
hydrogels or that can be grafted to other hydrogel hydrogel interfaces around the implanted device may
networks66,70,73. Apart from various physical barriers, provide a long-​term functional interface to the human
drug-​releasing surfaces have been explored to gradually body, similar to serosa in organs (Fig. 4a). Similar to con­
elute anti-​foreign-​body response drugs from the surfaces nective tissue in organs, bio-​integrative hydrogel inter­
of hydrogels258. faces between the implanted device and the target tissue
Notably, various biologically important functional may provide seamless and multifunctional interfacial
groups can be introduced to hydrogel interfaces to facil­ integration with the human body.
itate desirable cell or tissue responses (for example, cell To achieve multimodal hydrogel interfaces, new
proliferation or differentiation) beyond cell adhesion hydrogels with improved properties will be required.
and anti-​foreign-​body response. Several reviews offer To minimize the foreign-​b ody response, hydrogels
more detailed discussions31,81,183,259. with improved efficacy and longevity in diverse tissue
environments must be developed. Bio-​integration also
Future perspectives requires tissue adhesive hydrogels capable of long-​term
Recent advances in diverse applications have shown the integration to the target tissue without inflamma­
great promise of hydrogel interfaces for the bridging of tory responses and subsequent fibrotic encapsula­
the human body and machines (Fig. 1); however, there tion. Furthermore, there is a need to address potential
are remaining challenges and opportunities for future tradeoffs between different properties and functional
developments to effectively achieve this. The importance modes of hydrogel interfaces. For example, increasing
of continued innovations is particularly highlighted by the electrical conductivity of a hydrogel interface often
the stark limitations in establishing long-​term func­ leads to less favourable mechanical (such as stretchabil­
tional interfaces between implantable devices and the ity, fracture toughness and interfacial toughness) and
human body. Despite tremendous progress in implant­ optical (such as transparency) properties5.
able devices and hydrogel interfaces for therapeutic,
diagnostic and assistive applications in recent decades, All-​hydrogel machines. Existing devices are mostly com­
the loss of function and failure of long-​term implants posed of conventional materials, such as metals, plastics
in the human body owing to suboptimal integration with and elastomers, that are dissimilar to biological tissues.
the target tissues, tissue damage, foreign-​body response By contrast, biological tissues and organs (except teeth,
and/or fibrotic isolation of the implants remain unsolved nails and bones) are essentially multifunctional struc­
problems4,188. Hence, the development of next-​generation tures fully consisting of hydrogels seamlessly integrating

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cells and extracellular matrices. Hence, biological tis­ machines in physiological environments. Hydrogels
sues and organs not only serve as applicational targets with new properties, such as electrically semiconduct­
but also provide inspiration for all-​hydrogel machines ing and insulating properties, will require novel materi­
(Fig. 4b). als to replace existing silicon-​based semiconductors and
Because of their tissue-​like composition and prop­ plastic-​based or elastomer-​based insulators, respectively.
erties, all-​hydrogel machines offer promise for the Furthermore, synergistically with material developments,
improvement of device biocompatibility. Furthermore, new and advanced fabrication strategies should be devel­
the absence of conventional materials can potentially oped to manufacture future all-​hydrogel machines.
enable functional devices that are truly transient and While various advanced fabrication methods, such as
tissue-​integrative by allowing the ultimate biodegrada­ photolithography and additive manufacturing, have
tion and tissue in-​growth of the all-​hydrogel machine been utilized for individual hydrogel materials, manu­
without leaving residual materials. Although all-​hydrogel facturing of all-​hydrogel machines consisting of a broad
machines may benefit a broad range of applications, they range of hydrogels with diverse functionalities in a highly
would be particularly advantageous for implantable integrated and precise manner would necessitate further
applications where biocompatibility, degradation and improvement of existing methods and development of
tissue integration are critical requirements207. new fabrication strategies.
The realization of all-​hydrogel machines will require Overall, hydrogel interfaces will play an essential
the development of hydrogels with new and improved role towards the futuristic vision of a seamless merger
properties. For example, conductive hydrogels with of machines and humans. Despite a promising outlook,
improved electrical properties (such as electrical con­ hydrogel interfaces will undoubtedly face numerous sci­
ductivity and capacitance) and hydrogel waveguides entific, engineering and translational challenges during
with optimized optical properties (such as transmit­ future development and implementation. However, in
tance and refractive index) must be developed to suc­ our wildest imagination, hydrogel interfaces may one
cessfully replace existing metal-​based electrodes and stiff day allow us to blur the boundary between biological and
optical waveguides, respectively. Similar to multimodal abiotic systems and may enable future human–machine
hydrogel interfaces, bio-​integration and an improved hybrids.
anti-​foreign-​body response will be critical to ensuring
the long-​term functional preservation of all-​hydrogel Published online 13 October 2022

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