Preview
More Than Just a
Barrier—Challenges in the
Development of Guided Bone
Regeneration Membranes
Xian Cheng1 and Fang Yang1,*
A membrane combined with superior mechanical properties, an adequate degra-
dation rate, effective bacteriostasis, and biocompatibility are essential for the
application of guided bone regeneration. A multifunctional bilayer nanocompo-
site membrane mimicking nacre gives an inspirational message on membrane
development.
Bone regeneration, at large defects
resulting from trauma, tumor, and
abnormal development, in the clinic is
challenging. Guided bone regenera-
tion (GBR) was therefore developed,
by which an occlusive membrane is
applied to cover the defect area to
encourage new bone ingrowth while
preventing the faster-growing connec-
tive tissue from migrating into the
defect.1 GBR has been a maturing
technique in clinical dental practice
nowadays, especially in the implant
and periodontal surgery. After decades
of development, the GBR membrane
is no longer just a simple barrier.
Compared with the original mem-
branes used decades ago, present
GBR membranes provide more conve-
nience on clinical handling and various
functions for different clinical demands.
Nevertheless, there are still three major
challenges in the development of GBR
membranes (Figure 1).
The first challenge is the trade-off
between degradability and mechanical
performance. An ideal GBR membrane
provides sufficient mechanical support
against the compressive forces ex-
erted by the overlying soft tissue
during the bone regeneration process.
The non-degradable polymer mem-
558 Matter 1, 550–564, September 4, 2019 ª 2019 Elsevier Inc.
branes made of polytetrafluoroethy-
lene (PTFE) were first introduced into
the medical market because of their
excellent mechanical property for
space maintenance. Sequent develop-
ment further revealed that titanium
reinforcement of high-density PTFE
membranes could lead to superior
regenerative capacity when compared
with conventional PTFE membranes.2
Even today, metallic meshes (e.g., tita-
nium and magnesium) are still the
preferred choice to be used as GBR
membranes for large bone defects
and with autogenous bone graft, which
often need extra mechanical support,
fixation, and deformability.3 Unfortu-
nately, non-degradable membranes
suffer from the disadvantage of the
necessity of additional surgery for their
removal, which results in not only extra
pain but also an economic burden for
patients. For this reason, diverse
degradable GBR membranes have
been developed over the years. The
majority of degradable membranes on
the medical market are based on either
synthetic polyesters (e.g., polylactide)
or tissue-derived collagens.4 Never-
theless, the critical disadvantages of
these degradable membranes include
(1) insufficient mechanical properties
to support the space for large bone de-
fects, (2) unpredictable degradation
profiles to match the speed of new
bone formation, and (3) quick loss in
structural and mechanical properties
during degradation.
The next challenge is the surface func-
tionalization of GBR membranes. GBR
membranes interface with connective
tissue and bone tissue. On the soft tis-
sue interface, the primary function of
GBR membranes is a barrier to prevent
the soft tissue down-growth without
eliciting any inflammatory responses,
whereas on the bone side to enhance
hard tissue growth. Given that most of
the membrane materials are polymers,
which lack osteoconductivity, the incor-
poration of osteoconductive calcium
phosphate-related materials has been
vastly investigated in the past decade.
This sort of chemical modifications
on GBR membranes has been demon-
strated to enhance osteogenic dif-
ferentiation of pre-osteoblasts from
mesenchymal stem cells (MSCs) or peri-
odontal ligament cells (PDLs).5 Other
studies have found that engineering
the physical cues of the membranes
can also orchestrate the osteogenic be-
haviors of these cells on the bone inter-
face, including alignment of nanofibers,
size of pores, superhydrophilicity of
surfaces, mechanobiological microen-
vironments, and surface electric fields.6
However, when these works are looked
at from a clinical perspective, we begin
to introspect if enhancing osteogenic
differentiation of pre-osteoblasts on
the bone interfaces is the right direc-
tion for the functionalization of GBR
membranes. Immediately after implant
placement, blood first comes into con-
tact with the GBR membranes. Various
1Department of Biomaterials, School of Dentistry,
Radboud University Medical Center, PO Box
9101, 6500HB Nijmegen, the Netherlands
*Correspondence: fang.yang@radboudumc.nl
https://doi.org/10.1016/j.matt.2019.08.009

Figure 1. The Challenges in the Development of GBR Membranes
serum proteins are absorbed onto the
membranes, and then immunocytes
(e.g., macrophages) and osteoclasts
recruited by platelets migrate to the
surface of the materials. The osteo-
blasts appear and adhere to the mem-
branes only after several days later,
and at that moment, the osteoblast-
GBR membrane interface is not the
original membrane surface anymore.
The question arises as to whether or
not the osteogenic differentiation of
pre-osteoblasts will indeed be influ-
enced by the functionalized membrane
surfaces directly. The underlying mech-
anism mediating the interactions be-
tween cells and material in vivo is left
for us to explore, which, in reverse,
can guide us toward the design of novel
and efficient GBR membranes in the
future.
The last, but not least, challenge arises
when using the membrane to act as a
reservoir to release therapeutic drugs.
One of the major reasons for the failure
of GBR is bacterial infections caused by
pathogen colonization at wound sites in
the process of bone healing. Many re-
searchers have incorporated different
antibacterial agents into the GBR mem-
branes to release these drugs locally to
replace their systemic usage.7 How-
ever, the commercial products of these
drug-loaded GBR membranes are few
due to the fact that the fine control of
the release of these drugs and their
long-term effects on bacterial resis-
tance remains a challenge. Therefore,
the use of the intrinsic antibacterial ac-
tivity of certain (nano)materials is prob-
ably more promising.
In a recent study by Zhang et al., all the
challenges as mentioned above were
addressed by a novel material
approach, ‘‘biomimetic assembly of
nanoscale building blocks and polymer
matrices.’’8 Inspired by natural nacre’s
‘‘brick-and-mortar’’ structure, the au-
thors fabricated a chitosan (CS) gra-
phene oxide (GO) calcium silicate
(CaSi) bilayer nanocomposite mem-
brane by the evaporation-induced
self-assembly and ice-templating tech-
niques, where GO nanosheets and
CaSi nanowires were embedded in the
CS matrix. The highlight of this study
is to appropriately utilize the excellent
mechanical property of GO and CaSi
and the adjustable biodegradation
property of CS to face the first chal-
lenge of GBR membranes we have dis-
cussed above. Meanwhile, thanks to
the intrinsic antibacterial properties of
GO and CS, the membranes inhibited
the growth of Staphylococcus aureus,
Escherichia coli, and Streptococcus mu-
tans. These multifunctional membranes
were also shown good cytocompatibil-
ity with enhanced cell attachment at
the porous surface.
Although graphene and its derivatives-
related materials are heralded as 21st
century miracle materials with diverse
applications in various sectors from
energy to environmental science to
electronics, the successful commercial
products are limited due to the high
cost of manufacture. This study ex-
plores a very promising application for
graphene-related materials in medi-
cine, given the fact that the cost con-
cerns are largely relieved considering
the simple and straightforward manu-
facture method used in this study and
the relatively high selling price of the
GBR membranes.
However, there are still some limita-
tions in this study. Although the mem-
branes are probably strong enough to
maintain the space at bone defects,
the deformability of these membranes
during the surgical operation and the
dynamic change of mechanical proper-
ties during the degradation are still
unclear. On the other hand, the con-
cerns exist because CS has the poten-
tial to induce inflammatory responses9
and GO might bring safety issues.10 In
addition, in vivo data of these nano-
composite membranes are expected
to be revealed in the authors’ future
work in order to further confirm the
application potential of the mem-
branes. Every year, piles of articles on
novel biomaterials are published,
but only a tiny minority of them can
finally reach commercialization. With
no doubt, this work introduces an
exciting biomaterial development in
terms of GBR applications, but for our
biomaterial scientists there is still a
long way to go to translate the funda-
mental biomaterial research into clin-
ical applications.
1. Yang, F., Both, S.K., Yang, X., Walboomers,
X.F., and Jansen, J.A. (2009). Development of
an electrospun nano-apatite/PCL composite
membrane for GTR/GBR application. Acta
Biomater. 5, 3295–3304.
2. Bottino, M.C., Thomas, V., Schmidt, G.,
Vohra, Y.K., Chu, T.-M.G., Kowolik, M.J., and
Janowski, G.M. (2012). Recent advances in
the development of GTR/GBR membranes
Matter 1, 550–564, September 4, 2019 559
 for periodontal regeneration–a materials
perspective. Dent. Mater. 28, 703–721.
3. Rakhmatia, Y.D., Ayukawa, Y., Furuhashi, A.,
and Koyano, K. (2013). Current barrier
membranes: titanium mesh and other
membranes for guided bone regeneration in
dental applications. J. Prosthodont. Res. 57,
3–14.
4. Elgali, I., Omar, O., Dahlin, C., and
Thomsen, P. (2017). Guided bone
regeneration: materials and biological
mechanisms revisited. Eur. J. Oral Sci. 125,
315–337.
5. Ji, W., Yang, F., Seyednejad, H., Chen, Z.,
Hennink, W.E., Anderson, J.M., van den
Beucken, J.J.J.P., and Jansen, J.A. (2012).
Biocompatibility and degradation
Preview
Nanowires Pin Neurons: a
Nano ’’Moon Landing‘‘
Xingcai Zhang1,*
Recently, Harvard University scientists initiated a nano ‘‘moon landing.’’ They
developed hairpin-like nanowires to land and pin neurons to study their inner
signals without cellular damage, decoding the communication within and be-
tween neuron networks and providing tools for future brain disease studies.
From nanowires to neurons, our under-
standing of the physical and biological
world advances with the efforts of
bold innovators. Charles Lieber, a
University Professor at Harvard Univer-
sity, is one of the most eminent nano-
scientists in the world. His pioneering
work on nanowires and nanodevices
has led us to a flourishing world of
nanoscience and nanotechnology,
bridging the fields of chemistry, mate-
rials, electronics, and biology. His
progress in neuron studies is similar
to the ambitions of the moon landing:
the exploring of a new and fantastic
(nano-)world.
Since the emergence of nanotechnol-
ogies, our understanding of the physical
world has advanced rapidly. We can
poke and probe many materials at the
560 Matter 1, 550–564, September 4, 2019 ª 2019 Elsevier Inc.
characteristics of PLGA-based electrospun
nanofibrous scaffolds with nanoapatite
incorporation. Biomaterials 33, 6604–6614.
6. Liu, W., Wei, Y., Zhang, X., Xu, M., Yang, X.,
and Deng, X. (2013). Lower extent but similar
rhythm of osteogenic behavior in hBMSCs
cultured on nanofibrous scaffolds versus
induced with osteogenic supplement. ACS
Nano 7, 6928–6938.
7. Song, J., Klymov, A., Shao, J., Zhang, Y., Ji,
W., Kolwijck, E., et al. (2017). Electrospun
nanofibrous silk fibroin membranes
containing gelatin nanospheres for
controlled delivery of biomolecules. Adv.
Healthc. Mater. 6, 1700014.
8. Zhang, K.-R., Gao, H.-L., Pan, X.-F., Zhou, P.,
Xing, X., Xu, R., Pan, Z., Wang, S., Zhu, Y., Hu,
nanoscale and measure properties and
behaviors. However, the understanding
of the biological world, especially the
brain, is still in its infant stage. It is diffi-
cult to poke and probe such ‘‘living’’ ma-
terials—they tend to change rapidly and
produce very complex signals, like radio
channels with static and distortion. The
development of hairpin-like nanowires
to cross the neuron membranes and
pin neurons to study their inner signals
is an important advancement, as
described by Zhao et al. from the Lieber
group recently in Nature Nanotech-
nology.1 We can now directly read
from neurons. Let us shuttle through
the nano-pin to explore this new
‘‘moon’’ of possibilities.
This recent study improves our ability
to physically tap into messages be-
B., et al. (2019). Multifunctional bilayer
nanocomposite guided bone regeneration
membrane. Matter 1, this issue,
770–781.
9. Shao, J., Yu, N., Kolwijck, E., Wang, B., Tan,
K.W., Jansen, J.A., Walboomers, X.F., and
Yang, F. (2017). Biological evaluation of silver
nanoparticles incorporated into chitosan-
based membranes. Nanomedicine (Lond.)
12, 2771–2785.
10. Fadeel, B., Bussy, C., Merino, S., Vázquez, E.,
Flahaut, E., Mouchet, F., Evariste, L.,
Gauthier, L., Koivisto, A.J., Vogel, U., et al.
(2018). Safety assessment of graphene-
based materials: focus on human health and
the environment. ACS Nano 12, 10582–
10620.
tween neurons and their interactions.
Neurons are nerve cells in the brain.
The human brain contains about 86
billion neurons that are wired into
complex circuits to process informa-
tion conveyed by electrical signals.
Neurons are electrically excitable and
use electrical currents to function and
signal to one another. As such, reading
electrical activities from neurons is the
basis of understanding of the brain.
Decoding the communication between
neurons helps us to understand brain
functions. Translating the brain activ-
ities into control signals for devices,
such as artificial limbs, assists people
with paralysis. Most of the tools devel-
oped today read brain activities by
picking up signals that are leaked
outside of the neurons2—like listening
to voices behind a closed door. To
achieve the most accurate functional
readings and the finest control of
neural activities, direct access to the
interior of neurons is critical3—we
want to be in the same room! The
most conventional method for intracel-
lular recording is the patch-clamp
1John A. Paulson School of Engineering and
Applied Sciences, Harvard University,
Cambridge, MA, 02138, USA
*Correspondence: xingcai@seas.harvard.edu
https://doi.org/10.1016/j.matt.2019.08.011