Advanced Materials - 2023 - Zhang - Mimosa Inspired Stimuli Responsive Curling Bioadhesive Tape Promotes Peripheral Nerve

RESEARCH ARTICLE
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Mimosa-Inspired Stimuli-Responsive Curling Bioadhesive

Tape Promotes Peripheral Nerve Regeneration
Meng Zhang, Heng An, Zhen Gu, Zhe Huang, Fengshi Zhang, Bao-Guo Jiang,
Yongqiang Wen,* and Peixun Zhang*
1. Introduction
Trauma often results in peripheral nerve injuries (PNIs). These injuries are
particularly challenging therapeutically because of variable nerve diameters, Peripheral nerve injury (PNI) is a common
clinical condition usually caused by trauma,
slow axonal regeneration, infection of severed ends, fragility of the nerve
surgical complications, or neurological tu-
tissue, and the intricacy of surgical intervention. Surgical suturing is likely to mors. It affects more than one million peo-
cause additional damage to peripheral nerves. Therefore, an ideal nerve ple worldwide each year.[1,2] The process
scaffold should possess good biocompatibility, diameter adaptability, and a of nerve regeneration after PNI is com-
stable biological interface for seamless biointegration with tissues. Inspired by plex; repaired peripheral nerves often man-
ifest functional limitations or insufficiency,
the curl of Mimosa pudica, this study aimed to design and develop a
representing a major public health prob-
diameter-adaptable, suture-free, stimulated curling bioadhesive tape (SCT) lem. Even in the medically advanced United
hydrogel for repairing PNI. The hydrogel is fabricated from chitosan and States, as many as 20 million people are
acrylic acid-N-hydroxysuccinimide lipid via gradient crosslinking using affected by post-traumatic limb deficits, re-
glutaraldehyde. It closely matches the nerves of different individuals and sulting in significant socioeconomic losses.
regions, thereby providing a bionic scaffold for axonal regeneration. In Thus, it is imperative to develop effective
medical treatments for PNIs.
addition, this hydrogel rapidly absorbs tissue fluid from the nerve surface
Clinical treatment of small-gap PNIs is
achieving durable wet-interface adhesion. Furthermore, the chitosan-based often performed using end-to-end sutur-
SCT hydrogel loaded with insulin-like growth factor-I effectively promotes ing; however, with this technique, axonal
peripheral nerve regeneration with excellent bioactivity. This procedure for misconnection and nerve coiling are un-
peripheral nerve injury repair using the SCT hydrogel is simple and reduces avoidable, which greatly reduces the ef-
fectiveness of peripheral nerve repair.[3]
the difficulty and duration of surgery, thereby advancing adaptive
Therefore, polymer-based functional nerve
biointerfaces and reliable materials for nerve repair. guide conduits have been designed to pro-
vide biomechanical support and a specific
surface area to connect different pro-axonal
M. Zhang, F. Zhang, B.-G. Jiang, P. Zhang regeneration factors.[4] For PNIs with less tension, our team has
Department of Orthopedics and Trauma developed chitosan nerve scaffolds that bridge the repair of sev-
Peking University People’s Hospital ered nerve ends as an alternative to nerve suturing.[5] Researchers
Key Laboratory of Trauma and Neural Regeneration (Peking University)
have attempted a variety of techniques to improve hollow stents
Ministry of Education
National Center for Trauma Medicine for better rehabilitation, such as electrostatic spinning and 3D
Beijing 100044, China printing, to increase their electrical conductivity.[6–10] However,
E-mail: zhangpeixun@bjmu.edu.cn the regenerative effect of the nerve remains limited and is highly
H. An, Z. Gu, Z. Huang, Y. Wen dependent on the surgeon’s suturing technique, the size of the
Beijing Key Laboratory for Bioengineering and Sensing Technology gap between the severed ends of the nerve, and the duration of
Daxing Research Institute
School of Chemistry & Biological Engineering sustained release of loaded nerve growth factors. Existing nerve
University of Science and Technology Beijing scaffolds are often composed of natural materials such as chi-
Beijing 100083, China tosan, collagen, and alginate keratin silk fibroin protein or syn-
E-mail: wyq_wen@ustb.edu.cn thetic materials such as poly(lactic-co-glycolic acid), polyhexanoic
The ORCID identification number(s) for the author(s) of this article acid lactone, and their composites.[11–15] Among these, chitosan
can be found under https://doi.org/10.1002/adma.202212015 has many advantageous physical and chemical properties. For
© 2023 The Authors. Advanced Materials published by Wiley-VCH example, its degradation product is chitooligosaccharide, which
GmbH. This is an open access article under the terms of the Creative is naturally nontoxic and has good biocompatibility. This allows
Commons Attribution-NonCommercial-NoDerivs License, which permits for the gradual degradation of chitosan as nerve axons regen-
use and distribution in any medium, provided the original work is
properly cited, the use is non-commercial and no modifications or erate, eliminating the need for a second surgical removal to
adaptations are made. avoid foreign body reactions. In addition, the positive charge
carried by high-molecular-weight chitosan provides it with good
DOI: 10.1002/adma.202212015
Adv. Mater. 2023, 35, 2212015 2212015 (1 of 14) © 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH
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Figure 1. Stimuli-responsive curling bioadhesive tape (SCT) hydrogel allows for bionic curling, diameter adaptation, and wet adhesion to effectively
repairPNIs. a) Diagram illustrating the unique advantages of the SCT hydrogel: I) the ability of the SCT hydrogel to mimic the mimosa curl is due to
the difference in crosslinking density and the movement of water; II) SCT hydrogels can be adapted to be diameter specific for conformal contact with
neural epithelium; III) the internal interpenetrating network structure gives it greater stability and better bioadhesion in wet environments. b) Schematic
illustration of the process by which SCT can repair peripheral nerve injury quickly and effectively.
broad-spectrum antimicrobial properties, which are particularly this process, which facilitates the local maintenance of IGF-1 con-
important in surgical repair operations using implants, where centration. The SCT hydrogel’s internal interpenetrating network
slight localized infections and inflammatory activation can lead to structure provides greater stability and adhesion in wet environ-
failure of the surgical intervention. Recently, insulin-like growth ments (Figure 1a). This reduces the difficulty of the surgical pro-
factor-I (IGF-1), a type of growth hormone, was first studied in cedure and shortens the regeneration time while eliminating sec-
the field of diabetes; however, an increasing number of studies ondary puncture site damage and suture-related inflammation
have indicated that it can increase the heterogeneity of cell groups (Figure 1b). We report a bionic hydrogel with superior flexibility,
to promote tissue regeneration.[16–18] In addition, nerve regener- adaptability, stability of adhesion, ease of use, and capability to re-
ation has been shown to be influenced by the shape and fit of the duce trauma. We show that this bionic hydrogel promotes nerve
scaffold.[19] regeneration and reduces infection. Thus, it has great potential
This study was inspired by the stimulated curling behavior for use in clinical applications.
of Mimosa pudica. We designed a stimuli-responsive self-curling
bioadhesive tape hydrogel (SCT hydrogel) for repairing PNI. The 2. Results and Discussion
biomimicry of mimosa self-curling led to the development of a
biofunctional hydrogel patch using acrylic acid as the binder and 2.1. Design and Characterization of SCT Hydrogels
a glutaraldehyde gradient across chitosan. Imitating a mimosa
leaf, the SCT hydrogel curls, conforming to the perineural mem- We prepared a SCT hydrogel by UV photopolymerization. Acrylic
brane of the nerve. Due to the simulated physical movement, acid and acrylic acid-N-hydroxysuccinimide (AAc-NHS) lipids
water can flow from the highly crosslinked region to the low- were polymerized under UV irradiation to P(AAc-co-AAc-NHS),
crosslinked region. Conformal contact can be achieved during forming an interpenetrating network. The chitosan crosslinks
Figure 2. Mechanical properties of the SCT hydrogel. a) Standard electron microscope image and water molecule movement pattern diagram of the
SCT hydrogel. b) Dipping curl angle versus time of the SCT hydrogel. c) The SCT hydrogel can be adapted to fit neural models with a wide range of
diameters and shapes. d) Self-curling repair nerve pattern and physical diagram. e) Photograph of the elongation of the SCT hydrogel during a tensile
test. f) Stress–strain curves of SCT hydrogels. g) Toughness of three types of SCT hydrogels. h) Rheological model for measuring SCT hydrogels and
frequency scan and strain scan i) of different hydrogels (n = 5, *p < 0.05, and **p < 0.01).
© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH

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Adv. Mater. 2023, 35, 2212015

this network when adding glutaraldehyde row gradients, creat- the maximum tensile strength of the SCT4 hydrogel decreased to
ing a hydrogel (Figure S1, Supporting Information). This hydro- 1.3 MPa due to decreased crosslinking, however the tensile strain
gel is highly absorbent and removes water from the interface increased by 30% (Figure 2f). Thus the toughness of SCT4 hydro-
at the moment of contact with wet tissue. We observed the mi- gel was not significantly different from that of SCT2 hydrogel and
crostructure of the lyophilized SCT hydrogel, and as previously was much higher than that of SCT1 hydrogel (Figure 2g). There-
stated, the lyophilized SCT hydrogel exhibited a clear layered void fore, we identified SCT4 as the superior SCT hydrogel and thus
structure. As the glutaraldehyde was added, a hierarchically dis- refer SCT4 throughout this publication.
tinct crosslinked structure was formed. This type of pore space The hydrodynamic properties of SCT hydrogels were further
facilitated water absorption and shape changes, thus mimick- investigated. Rotational rheology is a common method for char-
ing the curl of M. pudica (Figure 2a; Movie S1, Supporting In- acterizing the effect of additives on the flow behavior of poly-
formation). Figure 2b and Figure S2 (Supporting Information) meric materials. We determined the energy storage modulus (G′)
show that the SCT hydrogel rapidly curls into a scaffold shape on and loss modulus (G″) of hydrogels at 1.0% strain using a small-
contact with saline. Thus, the SCT hydrogel can adapt to differ- amplitude oscillation frequency scanning method. The results
ent diameters and shapes of the nerve models (Figure 2c). This showed that the rheological curves of all hydrogels were solid
was also demonstrated in isolated sciatic nerves in a rat model rheological curves G′ > G″ at a frequency of 0.1 rad−1 . Stor-
(Figure 2d). Theoretically, this is due to the different porosities age modulus (G′) is reported to be directly related to crosslink-
of the upper, middle, and lower layers of the hydrogel caused by ing density and hardness.[23] The rheological results, shown in
the settling of the glutaraldehyde. The difference in the swelling Figure 2h, indicated that as the glutaraldehyde content decreased,
rate between the different layers results in water-absorbing reac- the crosslinking density of the network decreased, and the hy-
tive curling of the hydrogels. When glutaraldehyde was added, drogel became less rigid. Although the modulus of the hydrogels
chitosan began to crosslink with P(AAc-co-AAc-NHS). To distin- decreased with decreasing glutaraldehyde content, there was no
guish the differences in self-crimping and mechanical proper- significant decrease in the G′ of SCT1 and SCT4. The increase
ties, as well as the histocompatibility of the SCT hydrogels, we in the loss factor G″ indicated higher viscous dissipation and re-
prepared several hydrogel mixtures using different ratios of chi- versible bonding in the hydrogel network (Figure S4, Support-
tosan and glutaraldehyde. As shown in Table S1 (Supporting In- ing Information). As the percentage of glutaraldehyde increased,
formation), 200 (SCT1), 100 (SCT2), and 50 mg (SCT4) of glu- the crosslinking point of the hydrogel increased; therefore, the
taraldehyde were added to the surface of the hydrogel formed dissipation increased and the reversible bonding of the hydrogel
by crosslinking with 200 mg of chitosan. The structures of the increased, as the hydrogel was composed of Schiff base bonds.
AAc, chitosan, glutaraldehyde, and SCT hydrogels were char- The correlation between hydrogel deformation and glutaralde-
acterized using Fourier-transform infrared spectroscopy (Figure hyde was further confirmed by a deformation scan of the hydro-
S3, Supporting Information). The carboxyl group in acrylic acid gels.
and glutaraldehyde shows characteristic peaks at 1730 cm−1 . As With an increase in the glutaraldehyde content, the crosslink-
expected, the amino group in chitosan exhibited a peak at 1600 ing point of the SCT hydrogel increased, and the deformation of
cm−1 . However, when chitosan and glutaraldehyde reacted, the the hydrogel increased as the hydrogel was composed of Schiff
characteristic peak of Schiff base appeared at 1745 cm−1 , prov- base. The relationship between glutaraldehyde content and de-
ing that crosslinking occurred. During the repair of peripheral formation of the hydrogel was further confirmed by scanning the
nerves, a faster repair rate results in reduced tissue exposure. deformation of the SCT hydrogel. As shown in Figure 2i, the hy-
When the isolated rat sciatic nerve came in contact with the SCT drogel began to change as the deformation rate increased, and the
hydrogel soaked in saline, it curled quickly, wrapping around and SCT1 hydrogel was damaged when the deformation rate reached
adhering to the nerve surface (Movie S2, Supporting Informa- 300%. Damage to the SCT4 hydrogel occurred when deformation
tion). Compared with bridging with surgical sutures, the new hy- reached 100%. The deformation of the hydrogel increased with
drogel significantly reduced the difficulty and time of the pro- a decrease in GA content, and its maximum deformation also
cedure, avoided secondary damage caused by needles, and pre- increased with an increase in GA content, which was consistent
vented inflammatory suture pain. [20–22] with the stress–strain image of the hydrogel (Figure 2f).
The SCT hydrogel exhibited good mechanical and tensile prop-
erties. It has a length of 19 mm and could be stretched to 29 mm,
exceeding 150% of its initial deformation (Figure 2e). During 2.2. Adhesive Capacity of SCT Hydrogel
nerve repair, the nerves should be handled as gently as possible
to avoid excessive tissue stretching. The SCT hydrogel exhibits Tissue adherence plays an important role in tissue repair.[24]
good deformability and meets the requirements of the procedure. The interface between conventional bioengineered scaffolds and
Typical stress–strain curves showed that the tensile strength and tissue is weakly physically bonded, which results in unstable
maximum tensile strain of the SCT1 hydrogel were 2.4 MPa and connections over time and poor reliability.[25] The ability to create
27%, respectively. With a decrease in the glutaraldehyde content, tissue adhesions is the basis for suturing without stitches in
Figure 3. Adhesion of hydrogel bioadhesives and mechanism. a) Adhesion to visceral tissue; weights and rulers using SCT hydrogel as an adhesive.
b) Photographs of SCT hydrogel bonded to porcine muscle tissue. No cracks or detachment occurred between the SCT hydrogel and tissue during
distortion, long-term immersion, or bending. c,d) The 180° peel test showing the adhesion between the SCT hydrogel and pork skin. e) Interfacial
toughness of different SCT hydrogels. f) The 100 cycles test pattern diagram. g) The 100 cycles test on nerve-attached SCT hydrogel. h) The 100 cycles
test on nerve-sutured chitosan conduit. i) Mechanism of adhesion of the SCT hydrogel to wet nerves (n = 5, *p < 0.05, and **p < 0.01).
peripheral nerve repair surgery.[26] Hydrogels with good tissue teractions, at the instant of contact with the tissue surface.[29] Af-
adhesion can closely bridge the broken ends of nerves to form ter 5 min, the SCT hydrogel cleaved the NHS ester and then co-
dense gaps, prolong the duration of factor loading, and facilitate valently crosslinked with the primary amino group on the tissue
nerve tissue regeneration.[27] The SCT hydrogels exhibited good surface, further improving the stability and strength of long-term
wet tissue adhesion. When this hydrogel was used to adhere adhesion. Thus, this bionic hydrogel effectively binds to tissues
to fresh tissue, the adhesion was greater than that of the aged under moist conditions and promotes tissue anchoring and inte-
tissue. The SCT hydrogel provides a versatile adhesive interface gration.
for both planar (gastrocnemius and liver) and curved (heart and
spleen) tissues. The tissues were first pressed by a force for 5
s and then inverted at 180°; the SCT hydrogel-bonded visceral 2.3. Biocompatibility of SCT Hydrogel
tissues remained unseparated from the different tissues. The
SCT hydrogel stably and seamlessly bonded 100 g weights to the The biocompatibility of the hydrogel is strongly related to its ca-
glass slides, except for the tissues. Interestingly, the tissue that pacity for tissue repair. We conducted in vitro hemolysis experi-
bonded to the hydrogel did not diminish during movement of ments using rabbit blood samples. The experimental values were
the ruler (Figure 3a). To further verify whether the SCT hydrogel normalized to those obtained from Phosphate buffered saline
maintained adhesion to tissues despite the dynamic process, we (PBS, 0% hemolysis) and Triton X-100 (100%) solutions. Hemo-
performed distortion and soaking experiments using porcine compatibility was evaluated, and the results showed no statistical
muscle tissue (Figure 3b). The SCT hydrogel remained intact differences in the hemolysis percentage data for all SCT groups
after deformation, prolonged immersion in water, or distortion, (Figure S5, Supporting Information). We further determined the
indicating that SCT hydrogels have considerable potential for in percentage of hemolysis for the SCT hydrogels at concentrations
vivo applications. We tested the interfacial toughness between of 5–25 mg mL−1 ; the differences were negligible. Thus, the SCT
the SCT and wet nerve tissue using a 180° peeling test, as hydrogel interacted weakly with mammalian erythrocytes and ex-
shown in Figure 3c.[28] The SCT hydrogel was attached to the hibited high hemocompatibility (Figure 4a).
wet nerve tissue and loaded onto the tensile testing machine at No compatibility was observed between the cells in the absence
both ends, followed by slow movement at 13 mm s−1 . The hy- of cell viability.[30] In order to detect cell survival, live/dead stain-
drogel effectively adhered to wet nerves. As shown in Figure 3d, ing and CCK-8 assay are commonly used (Figure 4b). Different
when the SCT hydrogel was in contact with the wet nerve, the masses of the SCT hydrogel were soaked in Dulbecco’s Modified
maximum adhesion force was 0.6 N after 5 s (1 kPa) of gentle Eagle Medium (DMEM) total nutrient medium for 24 h. The un-
pressure, showing an instantaneous adhesion ability, and this soaked medium was used as the control (Figure S6, Supporting
viscosity allows the hydrogel to adhere well to the nerve. We Information). As shown in Figure 4c, the CCK-8 kit was used
also measured the adhesion forces of hydrogels with different to measure the viability of RSC96 cells. The effect of a hydro-
glutaraldehyde contents and found that the adhesion force of the gel concentration of less than 5 mg mL−1 on RSC96 cells was
hydrogel increased with decreasing glutaraldehyde content. This minimal, and the survival rate was >85% in all cases. In addi-
is because the degree of crosslinking increases with the increase tion, we examined RSC96 cells cultured in the same leachate us-
in glutaraldehyde. The molecular chain at the hydrogel interface ing live/dead staining. The cell density gradually increased as the
is difficult to move, and the interfacial adhesion decreases. The time of cell culture increased, and there was no statistical differ-
interfacial toughness of the SCT hydrogel is about 100 J m−2 on ence in cell growth between the experimental and control groups
the wet nerve surface (Figure 3e). Additionally, we performed (Figure 4d). The SCT hydrogel exhibited good biocompatibility.
pulling experiments with the SCT hydrogel adhering to isolated We evaluated the hemostatic performance of the SCT hydrogel
porcine skin under brief and prolonged immersion in saline by tail amputation in rats and selected medical cotton as the con-
(Movie S3, Supporting Information). We found that the SCT trol group (Figure 4e). From the photographs, we can clearly ob-
hydrogel adhered to both wet and dry nerves. serve that the hydrogel has good hemostatic properties, which
Nerves need to be protected from movement after conven- promotes the regeneration of perineural blood vessels to some
tional surgical repair because the scaffold repair with stitches can- extent.
not be maintained when exposed to repeated pulling for a pro- The antimicrobial effect of a material is crucial for the suc-
longed time. However, the hydrogel bonded to the repair site was cessful surgical repair of peripheral nerve injuries.[31] The poly-
better at maintaining the docking of the severed end of the nerve. cationic structure of chitosan confers natural antimicrobial prop-
We tested the SCT hydrogel with 100 tension cycles on nerve tis- erties. Additionally chitosan has been shown to promote neurite
sue connections. At the 100th cycle, the maximum tension was growth and enhance neuronal function.[32–34] Therefore, we de-
60% of the initial tension. When the same cycling test was carried signed the SCT hydrogel with the addition of chitosan molecules
out on a conventionally sutured chitosan scaffold for nerve repair to use the high density of positive charges for antimicrobial pur-
the maximum tension at the 100th cycle was less than 5% of the poses. The inhibition diameter of SCT hydrogel was measured
initial tension (Figure 3f–h). We analyzed the adhesion mecha- by the inhibition ring method, and a 0.5 cm diameter prototype
nism of the SCT hydrogel, as shown in Figure 3i. The SCT hy- SCT hydrogel was placed on a solid nutrient medium uniformly
drogel consists of chitosan and P(AAc-co-AAc-NHS), forming an coated with bacterial suspension and incubated at 37 °C for 12
interpenetrating network in the dry state. Its immediate adhesion h. Statistical results showed that the inhibition rate of Staphylo-
relies on the removal of interfacial water from the wetted neu- coccus aureus was more than 53.1%, and the inhibition rate of
ral tissue surface by a highly hygroscopic network, which forms Escherichia coli was a remarkable 72.2% (Figure 4f,g). Therefore,
physical crosslinks, such as hydrogen bonds and electrostatic in- the hydrogel is an effective bactericide, preventing postoperative
Figure 4. The SCT hydrogel is biocompatible, hemostatic, and antibacterial. a) Hemocompatibility of different quality SCT hydrogels. b) Live/dead
staining was performed after culturing RSC96 cells with the SCT hydrogel leachate and normal medium (control) for 24, 48, and 72 h, respectively,
bar: 100 μm. c) Cell viability of RSC96 cells treated with different hydrogel concentrations for 24 h. d) The optical density (450 nm) value of RSC96
cells. e) Hemostatic performance of hydrogels in severed tail Sprague–Dawley rats (n = 3). f) PBS and SCT hydrogel (5 mm) on bacterial clones using
the inhibition loop method. g) Inhibition rates of bacterial clones (E. coli and S. aureus) on culture plates after contact with PBS and SCT hydrogel,
respectively. h) The degradation process of the SCT hydrogel in PBS. i) Degradation model of SCT hydrogel implanted subcutaneously in rats. j) In vivo
degradation of the SCT hydrogel (n = 5, *p < 0.05, and **p < 0.01).
Figure 5. Histomorphology evaluation of regenerating nerve fibers and blood vessels. a) Schematic of setting up different restoration options for PNI.
b) Representative pictures of PNI with different treatments, bar: 5 mm. c) Immunofluorescent staining of the neural fiber maker NF200 (green) in
each group, bar: 100 μm. d) Quantitative expression of NF200. e) Immunofluorescent staining of the neural myelin sheath maker S100 (red) in each
group, bar: 100 μm. f) Quantitative expression of S100. g) Toluidine blue stained transverse sections of regenerated nerves, bar: 60 μm. h) Quantitative
expression of nerve fibers density. i) Transmission electron microscopy images of the cross section of regenerated nerves, bar: 5 μm. j) Statistical analysis
of myelin sheath thickness. k) CD31 (green) immunofluorescence staining of regenerating perineural vessels, bar: 300 μm (n = 5, *p < 0.05, and **p
< 0.01).
implant-induced infections. To verify the safety of the SCT hydro- whereas the SCT and SCT@IGF groups employed the innate
gel, we performed in vitro and in vivo degradation experiments self-curling to wrap the nerve (Figure 5b). Owing to its bionic
with PBS and subcutaneous implantation, which showed that the design, the inner surface can absorb water and curl quickly af-
hydrogel could be completely degraded at week 18, fully satis- ter affixing the nerve, quickly removing water from the surface
fying the requirements for nerve regeneration (Figure 4h–j). In of the nerve tissue and laying the foundation for tight adhesion.
addition, we performed subacute chronic reaction experiments, Simultaneously, the SCT hydrogel formed physical crosslinking
and the results confirmed that the SCT hydrogel was nontoxic to (hydrogen bonding) and covalent crosslinking (amide bonding)
the rat organism (Figure S7, Supporting Information). with the tissue surface, successively allowing the curled hydrogel
to form a broken-end bridge around the nerve. This can signifi-
cantly reduce the time and difficulty required for surgery (Movie
2.4. Evaluation of Nerve Repair Effect S4, Supporting Information). The regenerated sciatic nerve was
again visualized at 12 weeks postoperatively and evaluated.
Female, 4-week-old Sprague–Dawley (SD) rats were used as stan- In this study, we used various methods, such as immunoflu-
dard animal models for clinical research. The rats were divided orescence, toluidine blue staining, and transmission electron
into six groups according to the restorative material: IGF group, microscopy (TEM), to evaluate the rate and effect of peripheral
chitosan group, chitosan-loaded IGF-1 group (chitosan@IGF), nerve regeneration. The results showed good anastomosis of
SCT group, SCT-loaded IGF-1 group (SCT@IGF), and sham the severed nerve ends in all groups. However, the regenerated
group (Figure 5a; Figure S8, Supporting Information). The sci- nerves showed different extent of healing. As shown in Figure 5c–
atic nerve was then carefully dissected and severed. For the chi- f, the density of regenerated axonal fibers was higher in the SCT
tosan group a prefabricated scaffold for suture repair was used, group than in the chitosan group, and the density of SCT@IGF
was also higher than that of the chitosan@IGF group. Similar To further verify the repair effect of the SCT hydrogel, we sup-
trends were observed for regenerated myelin sheaths. This may plemented the critical-size defect model in a 20 mm gap and an-
be because the adhesive repair method avoids local inflammatory alyzed the footprints of rats from different groups (Figure 6g;
reactions caused by the direct action of sutures on the peripheral Figure S11, Supporting Information). The results indicated that
nerve trauma. A relative state of noninflammatory tissue creates both the SCT@IGF and SCT groups presented similar trends.
a good microenvironment for the regeneration of Schwann cells Both had better toe extension and sciatic nerve function index
and promotes peripheral extension into regeneration.[35,36] We (SFI) (Figure 6h,i). Similar findings were observed in the mus-
implanted SCT hydrogel without suture and chitosan suture cle Masson staining and electrical conductivity tests (Figures S12
subcutaneously in rats and obtained the surrounding tissues and S13, Supporting Information).
for hematoxylin an eosin immunohistochemical staining after We found that the SCT hydrogel loaded with IGF-1 exhibited
1 week, which demonstrated a lower inflammatory response a combination of diameter adaptation, stable adhesion to wet tis-
present in the SCT hydrogel group (Figure S9, Supporting sue, hemostasis, antibacterial activity, and promotion of axonal
Information). Toluidine blue staining was also performed on the regeneration. This is an ideal combination that has long been
myelin sheaths of the regenerated nerves in the different groups sought but is difficult to achieve in synthetic hydrogel neuroscaf-
(Figure 5g).[37] The result show that the SCT@IGF group had folds. Here, we summarize the common methods and novel ma-
considerably greater regeneration than the chitosan@IGF and terials used to repair PNIs. Some studies have shown reduced
IGF groups (Figure 5h). Well-rounded, thick myelin sheaths tend tissue trauma, improved nerve regeneration, reduced postoper-
to predict better nerve function. Therefore, we performed TEM ative pain, and faster surgical procedures compared with tradi-
on the regenerated nerve tissue. The surgically repaired regen- tional suturing methods (Figure 7a).[39–57] However, our hydrogel
erated myelin sheaths were fewer in number, irregular in shape, not only has all these features but also has some special advan-
thinner in myelin thickness, and less developed than those in tages (Figure 7b). For example, the bionic curl simplifies opera-
the sham group. Furthermore, we analyzed the thickness and di- tions and increases flexibility. The hydrogel’s internal interpene-
ameter of the regenerated myelin sheaths (Figure 5i). We found trating network structure provides greater stability and adhesion
that nerves repaired using SCT@IGF exhibited results similar to in wet environments. Conformal contact with the neuroepithe-
those of the sham group, although they were moderately worse lium could also be achieved by automatically adapting it to dif-
in terms of myelin thickness. Compared to the chitosan group, ferent diameters (Figure 7c). We have developed an ideal hydro-
the SCT group showed significantly greater myelin sheath gel for peripheral nerve repair. It absorbs tissue fluid around the
diameter and thickness (p < 0.01) (Figure 5j). These results nerve and produces shape changes, stabilizing the apposition to
suggested that the SCT hydrogel with IGF promoted Schwann the nerve and providing a regenerative scaffold (Figure S14, Sup-
cell proliferation and directed axonal regeneration.[38] Interest- porting Information).[58–90] This hydrogel platform is expected to
ingly, as visualized by CD31 immunofluorescence staining, we replace microsuturing techniques, reduce surgical difficulty, and
found that the SCT and SCT@IGF groups effectively promoted facilitate patient recovery.
perineural vascularization, although they were unable to match
the level of the sham group (Figure 5k). 3. Conclusions
In summary, we developed an SCT hydrogel with stimuli-
responsive curling and transient adhesion on moist tissue.
2.5. Functional Assessment In Vivo Loading the SCT hydrogel with IGF-1 factor can be used for
the repair of PNI. This SCT hydrogel can absorb water from
In rats with PNI, histological regeneration of the nerve was the surface of the nerve tissue on contact. Like the M. pudica,
insufficient. Therefore, we examined functional recovery after it actively changes its shape from a flat membrane to a tube
surgery. The gastrocnemius and soleus muscles were dissected instantly, tightly bonding and bridging both sides of the nerve
(Figure 6a), and different degrees of muscle atrophy were ob- dissection. Compared with the existing chitosan biological
served in these groups. The wet muscle weight in the SCT@IGF scaffold, it can effectively repair the nerve without relying on
group was higher than that in the chitosan@IGF group and that stitches, avoiding secondary damage to the severed ends of the
in the SCT group was higher than that in the chitosan group, in- nerve, while shortening the surgery duration and reducing the
dicating that the SCT hydrogel could effectively maintain the tar- difficulty of surgery. In addition, this bionic fit actively adapts to
get muscle (Figure 6b). Masson staining showed that the mus- the curvature of different nerve diameters to achieve conformal
cle fiber density in the SCT@IGF and SCT groups was greater contact, thereby eliminating the need to prepare scaffolds of
than that in the chitosan group (p < 0.01) (Figure 6c,d). Electri- different diameters during the procedure. At the same time,
cal signal conduction of the sciatic nerve was also examined in because of the presence of NHS groups in the SCT hydrogel,
each group (Figure 6e). The compound muscle action potential covalent crosslinking allows the hydrogel to adhere to the severed
(CAMP) amplitude was higher in the SCT group than in the chi- ends of the nerve, forming a dense gap, which facilitates better
tosan group (p <0.05) (Figure 6f). CAMP latency was lower in local release and prolonged maintenance of its loaded IGF-1.
the SCT@IGF group than in the chitosan@IGF and IGF groups Therefore, a biomimetically curled active-adhesive tape was used
(p < 0.05) (Figure S10, Supporting Information). This suggests to replace the preformed tubular scaffold, allowing a seamless fit
that the SCT hydrogel can effectively improve the conduction of between the material and the tissue. The geometric deformation
nerve electrical signals after peripheral nerve injury and promote and interfacial adhesion of the SCT hydrogel can be coordinated,
functional recovery. thus promising a new tissue-engineering solution for wet tissue
Figure 6. Regenerative sciatic nerve motor function and target muscle reconstruction. a) Pictures of the restored gastrocnemius and soleus muscles, bar:
5 mm. b) Quantitative analysis of the wet weight rate. c) Masson trichrome staining of the gastrocnemius on the treated side, bar: 200 μm; magnification
bar: 50 μm. d) Quantitative analysis of muscle fiber density. e) Regenerated sciatic nerve electrical conduction examination, bar: 5 ms. f) Statistical analysis
of compound muscle action potentials amplitude and latency. g) Schematic of the rat sciatic nerve critical size defect model in a 20 mm gap. h) Walking
footprint and pressure in Sprague–Dawley rats at the 8th week after surgery. i) Quantitative analysis of sciatic nerve index (n = 5, *p < 0.05, and **p
< 0.01).
repair. The SCT hydrogel has excellent biocompatibility, superior ameter glass plate. The polymerization was catalyzed under UV light (365
mechanical properties, and antimicrobial properties, all of which nm, 10 W power) for 30 min, followed by the slow dropwise addition of
are extremely important for peripheral nerve repair following 0.5% glutaraldehyde on the surface until the hydrogel was completely sat-
urated, and finally dried in an oven at 35 °C for 6 h. After complete drying,
injury. This bionic tissue engineering material will certainly be-
SCT was encapsulated in plastic bags and stored in a −20 °C refrigerator.
come a hot topic for research, and its self-adaptive properties will Tensile Test: Tensile tests, which evaluated the tensile strength and
inspire researchers to develop new materials. With additional elongation of the samples, were performed using a universal tensile tester
refinement and clinical research, SCT hydrogels can be loaded (MARK-10, New York, USA). The SCT was individually cut into rectangular
with a variety of novel pro-peripheral nerve regeneration drugs sheets, 10 mm wide and 1 mm thick, at a rate of 13 mm s−1 . The test was
or factors, bringing new hope for clinical applications. terminated by repeating it at least three times for each set of samples until
the hydrogel broke.
Rheological Experiments: The rheological properties of SCT were tested
with a rheometer (Anton Paar MCR302, Anton Paar Ltd., UK) at 25 °C.
4. Experimental Section The gel was placed on a circular plate with a diameter of 6 mm and a
separation distance of 1 mm to test the energy storage modulus (G′) and
Fabrication of SCT: SCT was prepared by glutaraldehyde gradient loss modulus (G″). Scanning tests were performed at a constant frequency
crosslinking. First, 20% (w/w) acrylic acid and 1% (w/w) AAc-NHS were of 1 Hz, with strain values ranging from 0.01 to 100%. Each sample was
dissolved in deionized water, and then 2% (w/w) chitosan and 0.2% (w/w) tested in triplicate.
𝛼-ketoglutarate were added. The mixture was then filtered through a 0.4 Adhesion Properties: The adhesion of the hydrogel was measured us-
μm pore size filter, and the filtered solution was spread on a 75 mm di- ing a universal tensile machine (MARK-10), which was attached to pig skin.
Figure 7. Characteristics of the mimosa-inspired stimuli-responsive curling bioadhesive tape. a) Schematic illustrating research related to repairing PNI.
b) The unique advantages of this work compared to other publications (responsive curling, wet adhesive, conformal contact, simple operation, trauma
reduction, axonal regeneration). The orange color represents the material with this characteristic. c) SCT Hydrogel can be adapted to different parts of
the nerve.
The frozen pig skin was first thawed in a 37 °C water bath; the pig skin and suspensions was measured at 540 nm using an enzyme marker (Imark,
SCT were cut into rectangular slices with dimensions of 20 mm × 10 mm USA). Each sample was tested in triplicate.
× 1 mm, respectively. The adhesion between the attached tissue and the Cytocompatibility (CCK-8): A Cell counting kit (Dojindo, JPN) was
sample was measured using a 180° peel test, with the peel speed set at 13 used to quantify the effect of the SCT leachate on the cellular activity of
mm s−1 . The test was repeated in triplicate for each set of samples. the RSC96 cell line. RSC96 cell suspensions (100 μL per well) were inoc-
Hemolytic Activity Assay: The hemocompatibility of SCT was studied ulated in 96-well plates with DMEM medium as the control group and
by measuring the absorbance of hemoglobin released after erythrocyte different concentrations of SCT4 leachate (5, 2.5, 1.2, and 0.6 mg mL−1 )
lysis.[73] Adult rabbit blood was collected in a centrifuge tube containing as the experimental group. The plates were then preincubated in an in-
10 mL EDTA. The blood was then gently shaken and centrifuged at 1500 cubator (37 °C, 5% CO2 ). Ten microliters of CCK-8 working solution was
RPM for 5 min. Subsequently, the serum was removed, and an equal vol- added to each well and incubation was continued for 2 h. The absorbance
ume of freshly prepared PBS solution was added. This step was repeated was measured at 540 nm using an enzyme marker tester (Imark, USA).
three times to completely remove the remaining broken red blood cells Each sample was tested at least thrice. Cell viability was calculated using
(RBCs). Finally, the RBCs were diluted with PBS to a concentration of 1 the following equation (Equation (S2) , Supporting Information)
× 108 mL−1 in the RBC suspension. Subsequently, the SCT1, SCT2, and
SCT4 hydrogels were added to the RBC suspensions, and PBS and Triton Asapmple − Ablank
Cell viability rate (%) = × 100% (2)
X-100 (1%) were used as negative and positive controls, respectively. After Acontrol − Ablank
incubation at 37 °C for 60 min, the upper suspension was collected and
centrifuged at 1500 rpm for 5 min. The supernatant was collected in drops Antibacterial Test: The bacterial inhibition rates of different hydrogels
from the 96-well plates. Absorbance of the solution was measured using were measured by colony counting and inhibition ring methods. Gram-
an enzyme marker tester (Imark, USA). The hemolysis rate was calculated positive S. aureus and Gram-negative E. coli were used as the bacterial
as follows (Equation (S1), Supporting Information) models. Each sample group was analyzed three times. The cell viability
was calculated using the following equation (Equation (S3) , Supporting
Information)
As − Ac
Hemolysis rate (%) = × 100% (1)
At Antibacterial rate (%)
cell count of control group - cell count of SCT 4 hydrogel

where As, Ac, and At represent the absorbance at 540 nm of the sample, = × 100% (3)
cell count of control
PBS, and Triton-X100 groups, respectively.
Cytocompatibility (Live/Dead Assays): The effect of SCT leachate on the Treating PNI with SCT Hydrogel: All animal protocols in this study were
proliferation of RSC96 cells was studied using a live/dead assay to as- approved by the Medical Ethics Committee of Peking University People’s
sess the cytotoxicity of the material. RSC96 cells were inoculated in 35 Hospital (approval number: 2022PHE078). To avoid the aggressive behav-
mm Corning dishes (cell density 9 × 105 per well) and incubated in con- ior of male rats, we used only female rats in the study. Thirty female SD
trol dishes in DMEM/high glucose (Hyclone, USA) medium with 10% fe- rats (6-8 weeks old, initial mass 200–220 g) were randomly divided into
tal bovine serum (Gibco, USA) at 37 °C in a CO2 incubator. The media IGF, chitosan, chitosan@IGF, SCT, SCT@IGF, and sham groups, with five
leachate of SCT4 was added to the experimental group culture dishes. At rats in each group (Beijing Vital River Laboratory Animal Technology Co.
specific incubation periods (24, 48, and 72 h), the cells were stained us- Ltd.). All rats were anesthetized with 5 L/min isoflurane (Zhong Mu Bei
ing a calcein-AM/PI kit (Solarbio, PRC) to distinguish live cells from dead Kang Pharmaceutical Co., Ltd.). Anesthesia was maintained at a flow rate
cells (live cells: green; dead cells: red). Fluorescence images of the cells at of 2 L/min. Hair over the right hind limb was shaved off using a razor. The
490 and 545 nm were obtained using an inverted fluorescence microscope right sciatic nerve was exposed, freed, and cut 5 mm above its branches to
(ZEISS, GER). The cells were then digested with trypsin-EDTA (Gibco, create a mold. Under a direct microscopic (Leica) view, the nerve stump
USA) and dropped into 96-well plates; the absorbance of the RSC96 cell was bridged to the scaffold with a 10–0 nylon suture in the chitosan group,
which was moistened with saline and bridged by an adhesive in the SCT Data Availability Statement
group. The nerve was fully freed but not severed in the sham group as a
control. A gap of 2 mm was maintained between the nerve stumps. The Research data are not shared.
muscles and skin were disinfected again and sequentially sutured into lay-
ers. Pain-relieving jelly was administered to the rats for the first 3 days after
modeling. Keywords
Peripheral Nerve Regeneration: Eight weeks after the repair surgery, we
collected nerve tissue distal to the injury. One nerve was removed from bioactivity, bioadhesion, bionic hydrogels, peripheral nerve injury, suture-
each group using OTC freeze fixation and cut into sections of 5 μm thick- free scaffolds
ness, and immunofluorescence staining was performed. The regeneration
of axons (NF200; green) and myelin sheaths (S100; red) was observed in Received: December 22, 2022
each group and recorded using fluorescence confocal microscopy. Two ad- Revised: May 14, 2023
ditional nerves were removed from each group and fixed using glutaralde- Published online: June 29, 2023
hyde (1%) in semi-thin and ultrathin sections. The semi-thin sections were
stained with 1% toluidine blue (Millipore Sigma) for axonal staining and
then observed under a light microscope (Leica), while the ultrathin sec-
tions were recorded using a TEM. All images were analyzed using ImageJ
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Advanced Materials - 2023 - Zhang - Mimosa Inspired Stimuli Responsive Curling Bioadhesive Tape Promotes Peripheral Nerve

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Advanced Materials - 2023 - Zhang - Mimosa Inspired Stimuli Responsive Curling Bioadhesive Tape Promotes Peripheral Nerve

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RESEARCH ARTICLE

Mimosa-Inspired Stimuli-Responsive Curling Bioadhesive

© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH

Adv. Mater. 2023, 35, 2212015

cell count of control group - cell count of SCT 4 hydrogel

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