Silk-Inspired β-Peptide Materials Resist Fouling and the Foreign-Body Response

Article abstract of DOI:10.1002/anie.202000416

The functions of implants like medical devices are often compromised by the host's foreign-body response (FBR). Herein, we report the development of low-FBR materials inspired by serine-rich sericin from silk. Poly-β-homoserine (β-HS) materials consist of

Full text of DOI:10.1002/anie.202000416

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Accepted Article
Title: Silk-inspired β-peptide Materials Resist Fouling and the Foreign-
body Response
Authors: Donghui Zhang, Qi Chen, Wenjing Zhang, Hengjiang Liu,
Jianglin Wan, Yuxin Qian, Bing Li, Songchao Tang, Yu Liu,
Shengfu Chen, and Runhui Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000416
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10.1002/anie.202000416
Angewandte Chemie International Edition
RESEARCH ARTICLE
Silk-inspired β-peptide Materials Resist Fouling and the Foreign-
body Response
Donghui Zhang[a], Qi Chen[a], Wenjing Zhang[b], Hengjiang Liu[c], Jianglin Wan[a], Yuxin Qian[b], Bing Li[b],
Songchao Tang[b], Yu Liu[c], Shengfu Chen[d] and Runhui Liu*[a, b]
[a]
D. Zhang, Q. Chen, J. Wan, and Prof. R. Liu
State Key Laboratory of Bioreactor Engineering,
School of Materials Science and Engineering,
East China University of Science and Technology, Shanghai 200237, China.
E-mail: rliu@ecust.edu.cn
[b]
[c]
[d]
W. Zhang, Y. Qian, B. Li, Prof. S. Tang and Prof. R. Liu
Key Laboratory for Ultrafine Materials of Ministry of Education,
Research Center for Biomedical Materials of Ministry of Education,
East China University of Science and Technology, Shanghai 200237, China.
H. Liu, and Prof. Y. Liu
State Key Laboratory of Chemical Engineering,
School of Chemical Engineering,
East China University of Science and Technology, Shanghai 200237, China.
Prof. S. Chen
Key Laboratory of Biomass Chemical Engineering of Ministry of Education,
College of Chemical and Biological Engineering,
Zhejiang University, Hangzhou, Zhejiang 310027, China.
Supporting information for this article is given via a link at the end of the document.
Abstract: The functions of implants like medical devices are often
compromised by the host’s foreign-body response (FBR). Here, we
developed low FBR materials inspired by serine-rich sericin from
silk; our poly-β-homoserine (β-HS) materials comprise the
hydrophilic unnatural amino acid β-homoserine. Self-assembled
monolayers (SAMs) of β-HS resist adsorption by diverse proteins, as
well as adhesion by cells, platelets, and diverse microbes.
antifouling and biologically inert material,[2f, 3] and early studies
reported that PEG exerts no immunogenicity. However, more
recent studies have revealed both immunogenicity and
antigenicity for PEG and PEG-modified objects including
PEGylated proteins, PEG-modified nanoparticles, liposomes,
and micelles.[4] Moreover, PEG can decompose in the presence
of oxygen in physiological conditions.[5] Therefore, the long-term
in vivo application of PEG is limited in biomedical applications.
Other materials such as polyglycidols, poly(2-oxazoline)s,
polyzwitterions, peptides, and peptoids, have been reported to
resist non-specific protein adsorption,[2f, 3b, 6] yet few materials
demonstrate promising anti-FBR property and the development
of materials with anti-FBR properties which are suitable for
Experiments lasting up to
3 months revealed that, whereas
implantation with control PEG hydrogels induced obvious
inflammatory responses, collagen encapsulation, and macrophage
accumulation, these responses were minimal with β-HS. Strikingly,
the β-HS hydrogels demonstrate angiogenesis in implant-adjacent
tissues. Molecular simulations indicated that the low FBR
performance of β-HS results from what we term “dual hydrogen
bonding hydration”, wherein both the backbone amide groups and
the side chain hydroxyl groups of β-HS undergo hydration. We
anticipate that our low fouling and low FBR β-HS materials can
outperform PEG for many biomedical applications.
implanted biomaterial applications remains
challenge.[2j-l, 7]
a
formidable
Inspired by nature, the silk fibers of Bombyx mori have
been studied as candidate of biocompatible and low
a
immunogenic biomaterial.[8] Silk sericin, which extends around
the exterior of silk fibers (Figure 1a, b), has been reported to
have low immunological response,[9] and has inspired detailed
analysis of its chemical composition. These efforts have
revealed that sericin is highly enriched for hydrophilic amino
acids such as serine, its most abundant amino acid (accounting
for 34% of total)[10] (Figure 1c). This led us to hypothesize that
this high serine content may contribute to sericin's low
immunogenicity.
Introduction
Implanted biomaterials and biomedical devices are extensively
used in clinical applications, including tissue engineering
scaffolds, prostheses, catheters, and glucose detectors.[1]
Nevertheless, failures of implanted biomaterials and biomedical
devices are encountered frequently due to the host’s foreign-
body response (FBR), which involves initial non-specific protein
adsorption on the implants and bacterial adhesion to the
implants in infection-related cases, followed by inflammatory and
wound-healing processes which can cause encapsulation of the
implant by a dense layer of collagen, leading to painful tissue
distortion, cutting-off nutrient transportation and increasing the
risk of reoperation.[2] To overcome FBR, passive anti-biofouling
materials have been explored, among which poly(ethylene
glycol) (PEG) is presently considered as the gold standard
Here, leveraging peptides comprising unnatural β-amino
acids which are naturally resistant to proteolysis,[11] we designed
and synthesized heterochiral poly-β-homoserine (β-HS) from a
racemic β-lactam aiming to achieve a low fouling and low FBR
materials with enhanced in vivo stability (Figure 1d, e). Surface
plasmon resonance (SPR) examination on the self-assembled
monolayers of β-HS showed that they can strongly resist
adsorption from a single protein or serum. Moreover, β-HS can
resist adhesion of cells, platelets, bacteria, and fungi, all of
which are widely encountered in implanted biomaterials and
1
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10.1002/anie.202000416
Angewandte Chemie International Edition
RESEARCH ARTICLE
devices, and may lead to FBR. Implanted hydrogels of β-HS into
mice displayed low FBR, including low inflammatory response
and macrophage density, and substantially reduced collagen
wrapping compared to PEG controls after the hydrogels were
implanted for 1 week. We also observed angiogenesis and
negligible collagen capsulation near β-HS hydrogels, compared
to dense avascular collagen around PEG hydrogels upon
implantation for 4 weeks. The β-HS hydrogels resisted both FBR
and collagen encapsulation for at least
3
months.
Mechanistically, molecular simulations indicated that the low
fouling and FBR of β-HS result from strong “dual hydrogen
bonding hydration”; i.e., strong hydrogen bonding hydration of
both the amide groups of the peptide backbone and the hydroxyl
groups of the side chain. β-HS thus has great potential for use
as an anti-FBR material for implants and other biomedical
applications.
Figure 1. Design of silk sericin inspired β-HS with low fouling and low foreign-body response. (a) Silkworm cocoons of Bombyx mori. (b) SEM image of natural silk
that contains sericin outside and fibroin inside (Image adapted with permission by Professor Norihisa Kato, Hiroshima University). (c) Amino acid component of
sericin contains 45% hydroxylic amino acid including 34% serine, which is the most abundant amino acid in sericin. (d) The design of low fouling and low FBR β-
HS composed of racemic β-homoserine that is inspired by the abundant serine within sericin. (e) β-HS materials effectively resist biofouling and foreign-body
response.
element content increase in X-ray photoelectron spectroscopy
(XPS) confirmed successful gold surface modification by β-HS
(Figure S3 and Table S1). The film thickness of the β-HS SAM
increased incrementally from 3.19 to 5.22 nm for β-HS
Results and Discussion
comprising 25 to 145 repeating units (Figure S4). Whereas the
surfaces modified with C12-SH and OEG6 had water contact
angles of 111.2° and 26.6°, respectively, all of the β-HS-modified
surfaces had water contact angles below 9°, reaching as low as
6° for the β-HS40 and β-HS60 (Figure S5 and Table S2).
Prescreening evaluation of protein adsorption on β-HS
modified surfaces using a horseradish peroxidase-conjugated
anti-IgG antibody as the test protein, indicated that all five of the
tested β-HS SAMs efficiently resisted fouling, exhibiting less
than 7% protein adsorption, with the best-performing β-HS40
and β-HS60 having only 2.2% protein adsorption, levels
comparable to the excellent antifouling material OEG6 (2.2%
Antifouling performance. Considering that FBR can be
triggered by protein adsorption on material surfaces, we
modified a gold surface by applying β-HS, which self-assembled
into monolayers (β-HS SAMs) via the terminal thiol group. In our
initial analyses, we used OEG6, with a terminal thiol group, as
the negative control which have strong repulsive force and are
considered one of the best material to resist biofouling,[12] and
the known fouling dodecanethiol (C12-SH) as the positive
control[13] (Figure S1). We synthesized heterochiral homo-
polymer β-HS with variable lengths (25, 40, 60, 95, and 145
repeating units) and with narrow dispersity (Ð = 1.03-1.18)
(Figure S2 and Table S1). The O1s and N1s peaks and the
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10.1002/anie.202000416
Angewandte Chemie International Edition
RESEARCH ARTICLE
protein adsorption) (Figure S6). We continued to evaluate the
antifouling properties of β-HS using SPR, a highly sensitive
method for measuring surface protein adsorption.[2f] Specifically,
we used β-HS40 modified sensor chips and three proteins:
fibrinogen (Fg), lysozyme (Lyz), and bovine serum albumin
(BSA) (Figure 2a-e and Table S3). We found Fg adsorption of
~487.6, ~0.8, and ~0.3 ng/cm2 on control, OEG6, and β-HS
surfaces respectively; Lyz adsorption of ~112.4, ~0.2, and ~0.2
ng/cm2 on control, OEG6, and β-HS surfaces respectively; and
BSA adsorption of ~78.4, ~0.5, and ~0.7 ng/cm2 on control,
OEG6, and β-HS surfaces respectively (Figure 2a-c). These
results show that β-HS is a low protein fouling material offering
comparable performance over OEG6 for the tested proteins.
Figure 2. β-HS SAMs resist protein adsorption as well as cell, platelet, and microbe adhesion. SPR sensorgrams of protein solutions and serum flowing over the
SAMs: (a) Fibrinogen (Fg, 340 kDa, pI 5.5) is a large, blood plasma protein that strongly adsorbs to hydrophobic surfaces that is commonly used as a model for
sticky serum proteins. (b) Lysozyme (Lyz, 14 kDa, pI 11.0) is a small, positively charged protein often used as a model for electrostatic interactions of proteins
with surfaces. (c) Bovine serum albumin (BSA, 66.4 kDa, pI 4.7) is the negatively charged and most abundant protein in the bovine plasma (∼65%). (d) 10%
serum. (e) 100% serum, which comprises a large diversity of proteins and other biomolecules. (f) Challenge of the antifouling surfaces with Fg, Lyz, BSA, 10%
serum, and serum sequentially. Fluorescence micrographs and SEM images of surface biofouling from cell and microbes: (g) Fibroblast cell. (h) Platelet. (i) C.
albicans. (j) S. aureus. (k) P. aeruginosa. Quantitative analysis on surface attachment of: (l) Fibroblast cell. (m) Platelet, n.d. represents not detected. (n) C.
albicans. (o) S. aureus. (p) P. aeruginosa.
We subsequently increase the complexity of the challenge
by exposing the surfaces to serum, which comprises a large
diversity of proteins and other biomolecules. For 10% serum and
100% serum fluid treatments, the β-HS SAMs had protein
adsorption of only ~1.4 and ~1.6 ng/cm2, respectively,
comparable to OEG6 (~0.5 and ~2.5 ng/cm2) (Figure 2d, e and
Table S2). Even upon sequentially challenge with Fg, Lyz, BSA,
10% serum, and 100% serum, the β-HS SAM had a total protein
adsorption of only ~3.3 ng/cm2 comparable to OEG6 (~2.5
ng/cm2) (Figure 2f and Table S2). These protein adsorption
results highlight the low fouling performance of the β-HS
materials.
3
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Cell, platelet, and microbe adhesion are also major types
of biofouling known to trigger inflammation and FBR,[2h, 4e, 6e, 6g, 14]
so we continued to examine the performance of β-HS to resist
these challenges. The β-HS SAM efficiently resisted adhesion of
fibroblast cells and platelets (Figure 2g-h, m), and also
effectively resisted adhesion of fungi (C. albicans), Gram
positive bacteria (S. aureus), and Gram negative bacteria (P.
showing no collagen encapsulation and open collagen structure,
which facilitates the exchange of oxygen, nutrients and
metabolites between the implant and the body (Figure 3g).
Antifouling and anti-FBR mechanism. We hypothesized that
the low fouling and low FBR performance of β-HS results from
strong hydration, so we performed molecular simulations to
calculate the hydration free energy, radial distribution functions
(RDFs), the number of hydrogen bonds, and the distance
between proteins and the β-HS SAM surface; we also performed
simulations for OEG6. Our study showed that the chirality has
little effect on the simulation result and therefore we chose β-HS
with the same chirality in each repeating unit for the simulation.
The hydration free energies were −192 and −777 KJ/mol,
respectively, for OEG6 and β-HS, indicating much stronger
hydration of β-HS than OEG6 (Figure 4a). The RDFs result
indicated that the OH-Owater, C=O-Owater, and N-Owater RDF
profiles of β-HS all had peaks at r < 0.3 (Figure 4b), indicating
the existence of hydrogen bonding interactions with water for
both the hydroxyl groups of the β-HS side chains as well as for
the amide groups of the backbone along the β-HS polymer
chains. We termed the combination of these distinct hydrogen
bonding interactions as “dual hydrogen bonding hydration”. The
sharp RDF peaks for OH-Owater and C=O-Owater indicate that the
O atoms from both the multi-amide bondsin the backbone and
from the hydroxyl groups in the side chain contribute significantly
to the hydration. A snapshot of β-HS in aqueous solution
indicates that the β-HS is surrounded by a hydration shell, and
the hydrogen-bonding waters are located near both the
backbone amide groups and the hydroxyl groups in the side
chain (Figure 4c).
We also examined interfacial hydration by assessing the number
of hydrogen bonds between the SAMs (β-HS or OEG6) and the
water molecules (Figure 4d). Only the top layer OH groups of
the OEG6 SAM form hydrogen bonds with water, and each of
these has an average of only 0.56 hydrogen bonds. For β-HS
SAM, we simulated the five closest units to the interface
between SAM and water, and found that both the carbonyl and
hydroxyl groups could form hydrogen bonds with water; the
average number of the hydrogen bonds for the carbonyl and
hydroxyl groups was 1.88 and 3.04, respectively. The total
average hydrogen bond number of β-HS is 8.8 times higher than
that of OEG6, supporting our proposed “dual hydrogen bonding
hydration” as the likely source of β-HS's low fouling and low FBR.
Further, the mean distance between lysozyme and the β-HS
SAM surface was predicted at 3.57 nm, a value higher than the
2.53 nm for the OEG6 SAM, results again emphasizing the β-HS
SAM's superior resistance to protein adsorption (Figure 4e, f). In
addition to above simulation, the “dual hydrogen bonding
hydration” hypothesis was also supported by the general
conclusion from precedent studies in antifouling that antifouling
property is strongly related to the surface hydration that is
governed by the hydrogen bonding for uncharged hydrophilic
polymers.[6f] Poly(N-hydroxyethyl acrylamide), having both an
amide group and a hydroxyl group within the same subunit, also
showed strong antifouling performance;[17] however, either
oligoalanine or polyvinyl alcohol that has only the amide group
aeruginosa) for at least
7 days (Figure 2i-k, 2n-p). It’s
noteworthy that we observed no platelet adhesion on β-HS
surface, which is comparable to the performance of two types of
important antifouling materials, PEG and zwitterionic
materials.[15]
Analysis of foreign-body response. To examine the FBR of β-
HS, we prepared β-HS hydrogels for implantation into mice. We
synthesized the gelation precursor polymer, β-HSDA, via an
anionic ring-opening polymerization of trityl-protected β-lactam
monomer HSβ, using acryloyl chloride and acrylamide pendent
β-lactam (AAβ) as the co-initiator and C-terminal functional
reagent respectively, followed by treatment with trifluoroacetic
acid (TFA) in the presence of triethyl silane (Et3SiH) to remove
the trityl protection (Figure 3a). As characterized by GPC and 1H
NMR, β-HSDA has a polymer length of 11 repeating units and a
dispersity of 1.27 (Figure S7). Hydrogels of β-HS and PEG were
prepared via UV-initiated gelation of 25% (w/w) β-HSDA and
PEGDA solutions respectively, using Irgacure 2959 as the
photoinitiator. The water content of PEG and β-HS hydrogels
was 74.5 ± 0.8% and 77.4 ± 1.1%, respectively.
The β-HS and PEG hydrogels were implanted
subcutaneously in C57BL/6 mice, a genotype known to produce
a strong fibrotic response similar to the FBR observed in human
patients.[16] We evaluated the mice for inflammatory responses,
acrophage density, and collagen density in tissues around the
hydrogels at 1 week after implantation (Figure 3b). Hematoxylin
and eosin (H&E) staining showed obvious inflammation around
the PEG hydrogel, consistent with previous reports,[2j] yet
observed a surprisingly low inflammatory response around the
β-HS hydrogel. F4/80 staining revealed a mass of macrophage
cells in tissues surrounding the PEG hydrogel, while
a
substantially lower density of macrophage cells was observed in
tissues surrounding the β-HS hydrogel. Masson’s trichrome
staining showed a thick collagen layer surrounding the PEG
hydrogel but no obvious collagen encapsulation surrounding the
β-HS hydrogel.
After implantation over 4 weeks, the PEG hydrogels were
encapsulated by a high density layer of avascular collagen; the
surrounding tissue of the β-HS hydrogels had a very low density
of collagen (Figure 3c, d). It is notable that a large amount of
new blood vessels exhibiting red blood cells were found in
tissues surrounding the β-HS but not PEG hydrogels, as shown
in Masson’s trichrome stained histology sections; this
angiogenesis was also confirmed via CD31 staining of
endothelial cells (Figure 3e). Specifically, the blood vessel
densities in tissues surrounding the PEG and β-HS hydrogels
were 22 and 148 vessels/mm2, respectively (Figure 3f). The
significant appearance of the blood vessel surrounding β-HS
hydrogels is indicative of active mass transport between the host
and the implanted material. We also evaluated the implanted
hydrogels for their long-term performance at 3 months after
implantation using Masson’s trichrome stain and found that
whereas the PEG hydrogels were encapsulated by a dense
layer of collagen, the β-HS hydrogels still efficiently resisted FBR,
or the hydroxyl group showed compromised antifouling
18]
properties.[6c,
All these supported the hypothesis that “dual
hydrogen bonding hydration” is the key to the antifouling and
anti-FBR performance of β-HS polymers.
4
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10.1002/anie.202000416
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 3. Hydrogel synthesis and evaluation of FBR for hydrogels implanted in mice. (a) Synthesis and gelation of β-HS precursor (β-HSDA) polymers to
generate hydrogels, which were implanted subcutaneously into the backs of C57BL/6 mice. (b) Histological analysis after 1 week of implantation: H&E,
hematoxylin & eosin, nuclei were stained blue and the cell cytoplasm was stained pink; F4/80, macrophage marker stained in brown; M&T, Masson’s trichrome,
collagen was stained in blue, nuclei was stained in black, and the cytoplasm was stained in red to evaluate collagen deposition. (c) Masson’s trichrome staining to
evaluate collagen encapsulation (red arrows) and visualized blood vessels (black arrows) after implantation for 4 weeks. (d) Collagen density within 100 µm (at
10-µm steps) of the hydrogel-tissue interface after implantation for 4 weeks. (e) Visualization of blood vessels (red fluorescence), via immune-staining with the
endothelial cells marker CD31, in tissues surrounding hydrogels after 4 weeks of implantation. (f) quantified blood vessel density in tissues surrounding hydrogels
after 4 weeks of implantation. (g) Masson’s trichrome staining to evaluate collagen encapsulation (red arrows) after implantation for 3 months. *P<0.01; **P<0.001,
using one-way ANOVA with Tukey’s post-test.
5
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Figure 4. Molecular simulations exploring the mechanisms underlying β-HS's strong antifouling and anti-FBR performance. (a) Hydration free energy of OEG6
and β-HS. (b) Radial distribution functions between water molecules and the atoms of β-HS (the oxygen atoms in the hydroxyl and carbonyl groups, respectively,
and the nitrogen atom). (c) Snapshot of β-HS in aqueous solution, the hydrogen bonding waters near both the backbone amide groups and the side chain
hydroxyl groups. (d) The average number of hydrogen bonds (HB) between the SAM and water molecules. (e) Distance between the protein (mass center) and
the SAM surface of OEG6 and β-HS. (f) Snapshot of lysozyme on the OEG6 and β-HS SAM, with explicit water molecules.
Analysis and Test of East China University of Science and
Technology for the help on the characterization.
Conclusion
Keywords: Foreign-body response • silk-inspired • poly-β-
In summary, we designed and synthesized β-HS materials,
inspired by silk sericin that has low immunogenicity. β-HS
materials can resist adsorption of diverse proteins, as well as
adhesion of cells, platelets, bacteria, and fungi, all of which are
widely encountered in implantable biomaterials and may trigger
FBR. Furthermore, the β-HS hydrogel displays low FBR as
shown with negligible inflammatory responses, substantially and
significantly reduced collagen encapsulation, and substantially
increased density of blood vessels in surrounding tissues
compared to control PEG hydrogel after the hydrogels were
implanted in the mice. Molecular simulations indicated that ‘dual
hydrogen bonding hydration’ between β-HS and water can
account for its low fouling and low FBR. The superior
performance of β-HS in antifouling and anti-FBR implies its
potential application of β-HS in implanted biomaterials and
biomedical devices.
homoserine • fouling • dual hydrogen bonding hydration
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Acknowledgements
We thank Prof. Qian Yu, Dr. Ting Wei and Yangcui Qu at
Soochow University for their help on surface characterization
with ellipsometry. This research was supported by the National
Natural Science Foundation of China for Innovative Research
Groups (No. 51621002), the National Natural Science
Foundation of China (No. 21774031, 21861162010, 21574038,
21776070), the National Key Research and Development
Program of China (2016YFC1100401), the Natural Science
Foundation of Shanghai (18ZR1410300), Research program of
State Key Laboratory of Bioreactor Engineering, the
Fundamental Research Funds for the Central Universities
(22221818014) and the Shanghai Rising Star Program
(19QA1402400). The authors also thank Research Center of
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10.1002/anie.202000416
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
The low immunogenic silk sericin has high content of serine, which inspired us to explore poly-β-homoserine (β-HS) as a new class of
low foreign-body response (FBR) material. β-HS showed excellent antifouling property and substantially lower FBR in implanted
hydrogels than did PEG, suggesting β-HS as promising materials to address the formidable and long-lasting challenge of FBR that
are associated with implants.
8
This article is protected by copyright. All rights reserved.