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Fig. 13.6 Modied cell
membrane with GAGs
R. Guizzardi et al.
A different lipid-based strategy was proposed
by Woods et al. [91]: a glyco-engineered lipid
anchor based on cholesterylamine was synthesized, in order to display synthetic glycans on
plasma membrane with improved residence
times, emulating natural mucins, to shed light on
the role of mucins overexpression within cancer.
Glyco-engineered cholesterylamine was durably
displayed on cell surface after internalization,
exposing linked glycopolymers for up to 10days.
The presence of the engineered glycans on cell
surface mimicked the effect of mucins in focal
adhesion and cell survival, both in vitro and
in vivo. More strikingly, the engineered glycolipid was expressed also in daughter cells
derived from a labeled mother cell. The same
group proposed an additional strategy to expose
mucin mimetics on cell surfaces. Synthetically
challenging mucin-like domains were chemically
synthesized and conjugated through a site-specic
bioorthogonal strategy to a genetically engineered
membrane protein on live mammalian cells [92].
These strategies could be adapted to replace
native glycodomains in mucin proteins with synthetic analogs, systematically varying their chem-
ical and biological properties potentially
delivering great benets to tissue engineering.
One of the greatest challenges in cell therapy
for tissue engineering is the efcient delivery of
viable cells to the tissue to be restored. Inefcient
homing of systemically delivered mesenchymal
stem cells (MSCs) is probably the major limitation of existing MSC-based cell therapies, probably caused by poor expression of adhesion
molecules on cell surfaces. In order to improve
MSCs homing, their surface was modied with
a nanopolymeric structure bearing the tetrasaccharide sialyl LeX (sLe
X
). This trisaccharide is
usually overexpressed on leukocytes and is
responsible for cell rolling during inammation
processes. sLeX glyco-engineered MSCs exhibited a robust rolling response on inamed
endothelium invivo and homed to inamed tissue with higher efciency than native MSCs.
This approach highlights an effective glycoengineering strategy for cell homing through circulation [93].
Following a similar line of research, homing
of human mesenchymal stem cells (hMSCs) to
bone was obtained by glycan engineering of
Blood group 0
Blood group A Blood group B
HO
13 Carbohydrates inRegenerative Medicine: FromScaolds toCell Fate Modulators
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145
Fig. 13.7 Blood group
antigenic determinants
HO
OH
AcHN
OH
HO
HO
O
O
HO
HO
OH
OH
O
O
O
OH
OH
OH
O
HO
O
O
OH
O
O
HO
HO
OH
OH
O
O
O
OH
glycoside hydrolase
HO
HO
HO
CD44 [94]. The native CD44 glycans of MSCs
bear α-2,3-sialylosides, but cellular recruitment
to bone occurs via E-selectin, a lectin recognizing sialofucosylated determinants. As native
CD44 lacks the key α-1,3-fucosyl hematopoietic
cell E-selectin/L-selectin ligand, an enzymatic
α-1,3-fucosylation of MSCs CD44 was performed under physiological conditions specically designed for treating live cells. This
modication conferred potent E-selectin binding
and tropism to bone, without detrimental effects
on cell viability or multipotency. This study
unveiled a great potential to program cellular
trafcking on through membrane glycoprotein
engineering for directing cellular migration, a
key issue for cell therapies.
An example of cell surface glyco-engineering
is related to blood group antigenic determinants.
The antigenicity of the ABO blood groups is
dened by the structure of carbohydrates units
(Fig.13.7) expressed on red blood cells surfaces
(RBCs). Conversion of type A, B, and AB RBCs
to universal 0 type by enzymatic removal of
galactose or N-acetylgalactosamine antigenic
carbohydrate residues by specic glycosidases
has emerged as a useful strategy to convert all
blood donations of different types into the 0 universal one. Although cell surface modication
may be accomplished by suitable enzymes, in
many practical applications, their poor association with cell surfaces due to the repulsion of two
hydrophilic entities hamper this technology,
because of the need of high concentrations of
reagent that may be toxic for cells and making
the process costly. Thus, the development of a
general process improving enzymatic reactions
on cell surfaces are particularly attractive. In this
example, the enzymatic reaction on blood group
determinants was performed with good efciency
by a strategy based on macromolecular crowding
with biocompatible and cheap neutral polymers,
such as dextran and coll [95], granting over
440-fold increase of enzymatic glycoengineering
activity on cells surface. This research empha-
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R. Guizzardi et al.
sized the relevance of discovering new and efcient methods for glycan-specic cell surface
engineering that hold promise for clinical
applications.
13.6 Conclusions
We showed several examples highlighting the
involvement of carbohydrates in the modulation
of cell adhesion, function, homing, and differentiation. The ability to exploit and mimic glycan
roles in a tissue-specic manner will afford new
opportunities in regenerative medicine, which in
the next future will rely on the development of
innovative and efcient glycoengineering technologies. However, research is still needed,
requiring continued crossing of disciplines, heavily including chemistry, along with complementary contributions of medicine, biotechnology,
biology, engineering, and material science. In
addition, a better understanding of glycobiology
of stem cells and signaling within complex extracellular matrix interactions is still needed in order
to fully exploit the potentialities given by the
glycocode.
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Biomimetics: ANew Abstraction
https://t.me/medicina_free
forBone Implant Design
ElizabethA.Brett, MatthiasA.Sauter,
andDominikDuscher
14
14.1 Introduction
Biomimetics and biomimicry are thought processes applied to biomaterial design, where biological implants have properties which mirror
closely those of natural material. Designing
implants with this mindset may elegantly circumvent some of the roadblocks in synthetic biomaterial design and function [1]. Bone regeneration
is a particularly attractive frame for this work,
given the tissue heterogeneity and mechanical
role of bone. However, in recent years, problems
with physical shape, surface chemistry, and
mechanical properties have been identied in
implants. Implant failure through peri- implantitis,
peri-mucositis, peri-implant disease, or infection
can lead to pain, mechanical loosening, and eventual need for extraction [2]. Similarly, some literature has outlined concerns with implants,
specically showing unfavorable physical
remodeling over time [3]. Eliminating the variability associated with implants would mean a
E. A. Brett · M. A. Sauter
Division for Experimental Plastic Surgery,
Department of Plastic and Hand Surgery,
Klinikum rechts der Isar, Technical University of
Munich, Munich, Germany
e-mail: Eliza.Brett@tum.de; matthias.sauter@tum.de
D. Duscher (*)
Department for Plastic Surgery and Hand Surgery,
Division of Experimental Plastic Surgery,
Technical University of Munich, Munich, Germany
huge decrease in patient morbidity and cost burden. These concerns have ushered biomimetics
and new material design techniques to the
forefront.
14.2 The Recipient Site
Types of bony reconstruction range from structural nonload-bearing bone (e.g., calvarium) to
larger compact load-bearing bone (e.g., femur).
Host bone can be challenging, for instance if it is
osteoporotic [4] or osteomyelotic [5, 6]. To
ensure a t of the implant in the host bone, underreaming is performed; a drilling process designed
to facilitate the implant, sometimes known to
fracture the host bone further [7]. It is especially
problematic in the context of osteoporotic bone,
which can exhibit low “pull out strength” of an
implant once in situ [8]. Another quite common
issue is poor nutrient diffusion, borne of compromised blood supply. Diffusion distance of oxygen invivo is 150–200 μm [9]. As such, certain
materials may stimulate vascular ingrowth into
the host bone. Inactivators of prolyl hydroxylase
(e.g., cobalt ions) have been shown to stabilize
HIF-1α, a potent proangiogenic factor, resulting
in upregulated expression of genes such as
GLUT1, erythropoietin, VEGF, and PDGF [10,
11]. Bone that has undergone irradiation falls in
the same category of hostile recipient sites.
Macroscopically, a threaded implant (akin to a
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8%
Compact bone composition
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screw) gives immediate stability and provides
close, xed contact between the graft and host
bone.
14.3 Mechanical Stability
ofImplant
Issues with bone implants chiey lie in materials destined for load-bearing bone healing. The
Young’s modulus of trabecular bone is 10.4–
14.8 GPa, and cortical bone measures 18.4–
20.7 GPa [12]. Naturally, stainless steel has a
much higher modulus of 180 GPa, cobalt chromium (Co-Cr) at 210 GPa, and titanium at
110 GPa [13]. “Stress shielding” is the physiological response resulting from implanting a
harder material into a softer host tissue. The
result is brous encapsulation of implant, allowing for micro-movement of the implant unit.
Mobility of an implant creates a specic wear,
called fretting [14]. Fretting implants can gradually loosen and eventually fail within the host
bone [15]. Moreover, fragments of the implant
are frequently known to break off the body of
the implant, causing local abrasion of the surrounding, softer bone tissue [16]. Debris of
implants can sometimes be found in alternate
locations in the body, such as the spleen, liver,
and abdominal lymph nodes of arthroplasty
patients [17].
It was Albrektsson etal. in 1981 [18] who
rst showed the complete “osseointegration” of
titanium. During a fracture xation experiment
in a rabbit femur, Branemark discovered the
removal of the titanium implant from bone was
completely impossible. Further studies using
transmission electron microscopy showed a new
phenomenon of direct contact between bone and
implant, without the surrounding brous capsule
responsible for implant looseness and micromovement [19]. Filamentous collagen type 1
was found to form brils at the implant–bone
interface (resembling the strong Sharpey’s bers
of the scalp), giving the tight coupling of metal
and bone [18]. The phenomenon of the absence
of brous encapsulation around titanium
implants has inspired implant design for more
than just bone. Tissue expanders used for breast
reconstruction can include a titanium-coated
mesh to reduce the brotic content of the breast
[20]. In the context of bone, titanium is now
being tested in advanced models of craniofacial
bone healing, using titanium granules to stimulate maxillary sinuses [21]. However, in terms of
biomimetics, titanium presents some mechanical
challenges, specically in terms of difference in
stiffness between it and the host tissue, for example, femur. This hurdle is called modular mismatch [22] and can be dodged by using material
whose bulk mechanical properties more closely
resemble bone.
14.4 Grafts Based onBone
Mineral Components
The unique nature of bone is that it is largely
mineralized. In its dry mass, bone is 60–70%
mineral, which is non-immunogenic and ubiquitously found (Fig.14.1) [23]. As such, the use of
natural material already in existence presents an
option for creating biomimetic implant matter.
Nacre, or mother-of-pearl, is pure calcium carbonate produced by mollusks. Mixing pulverized
20%
80%
Compact Spongey
MINERAL
(Hydroxyapatite)
PROTEIN
(Collagen,
cells,
hyaluronic acid)
WATER
Fig. 14.1 Bone composition
70%
22%
14 Biomimetics: ANew Abstraction forBone Implant Design
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nacre with patient blood and implanting the
mixture into a human mandibular defect site was
largely effective in closing the defect and stimulating regenerative cellular activity in the location [24]. Many successful bone biomaterials
incorporate calcium or hydroxyapatite to help
facilitate bone formation and graft “take.” A
study comparing biologic bovine-derived bone
grafts (BioOss® Bone Substitute; Ed. Geistlich
Soehne, Wolhusen, Switzerland), with a highly
porous synthetic hydroxyapatite scaffold
(IngeniOs™ HA Synthetic Bone Particles;
Zimmer Dental, Inc., Carlsbad, CA), showed
highly similar chemistry, morphology, and structure [21]. FT-IR spectra revealed high crystallinity (thus low resorption) of the synthetic IngeniOs
Hydroxyapatite Synthetic Bone Particles, owing
to the purity of its manufacturing processes versus natural variation [25]. The difference in purity
between synthetic and biologic material by proxy
of uniform industrial manufacture is seen
throughout most implant forms.
Beta tricalcium phosphate (β-TCP) is a calcium salt abundant in bone, and has been shown
to be highly and quickly reactive as part of a
bone graft. This is because in an aqueous environment, TCP reacts to form hydroxyapatite
[26]. Effects of TCP can be exaggerated with
strategic addition of growth factors invivo, as
was seen throughout a series of randomized control trials using platelet-derived growth factor
and β-TCP as agents to heal periodontal intraosseous defects [27]. In fact, β-TCP has been
shown to contribute to bone healing faster than
hydroxyapatite alone, secondary to its rapid rate
of resorption [28]. Meanwhile, HAPEX is an
amalgamation of the biologic mineral hydroxyapatite and synthetic high-weight polyethylene.
This mixture makes for a bioactive polymer,
which has been used in the reconstruction of
orbital oor and middle ear defects [29].
Cerasorb is pure β-TCP, designed to be mixed
with the patient’s own blood or platelet- rich
plasma and added to the defect site, primarily for
periodontic healing. As a different oceanic
source of bone mineral, coral holds properties
which mimic bone. Coral forms hydroxyapatite
on its surface due to its calcium carbonate core
and also retains its native trabecular structure,
having inherent biomedical value as a spongy
bone substitute [30, 31].
14.5 Grafts Based onStructural
Protein
An important component of bone structure is
protein, both structural and supportive.
Hyaluronic acid (HA) is a high-molecular-weight
nonsulfated glycosaminoglycan, which is formed
in the plasma membrane of cells [32]. It is a
highly negative molecule capable of attracting
proteoglycans, which in turn harbor water.
Logically, ECM scaffolds containing HA have
reached the market for dermal applications, given
that hyaluronate is an antibrotic, hydrating
agent in a healing wound [33]. However, in the
context of bone grafts, rabbit tibias which
received HA showed increased healing 20days
after injury, exhibiting brocartilage formation,
which later ossied, in comparison to the nonHA- treated bones, which formed purely brous
unions [34]. More sophisticated, combinatorial
approaches have been designed around HA, e.g.,
use of HA in a hydrogel with calcium sulfate
hemihydrate, a bioresorbable, osteoconductive
compound [35].
Composite biomimetic grafts over simple
hydrogel injection are required for healing of
large load-bearing bones. For instance, addition
of protein to a hydrogel or impregnated into an
implant introduces necessary cellular osteogenic mechanisms. In a canine femoral defect
model, bone morphogenetic protein (BMP) in
tandem with collagen type-1/TCP showed
increased healing of the femur in the presence
of bone marrow aspirate [36]. These studies
suggest collagen type 1 as a logical and functional agent to match the modulus of the femur.
Similarly, there is utility of bone marrowderived cells stimulated by pro-osteogenic
growth factors in bone healing.
A highly osteogenic component of bone is
the periosteum, a stratied structure of an inner
cell layer (cambium layer), and tough, brous
outer layer [37]. Damaged bone which under-
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goes delayed reconstruction may show heterotopic ossication, disorganized bony formations
at the injury site due to disrupted periosteum
[38]. As such, strategically placed periosteal
grafts present a highly biomimetic solution of
autografting onto damaged bone [39]. Due to
the sheet-like structure of the periosteum, periosteal grafts have found their primary utility in
dental and alveolar grafting, as opposed to long,
load-bearing bone reconstruction [40].
14.6 Grafts Based onCellular
Implants
Despite orthopedic management of fractures
becoming better and better, some healed injuries will persist with brous nonunions [41]. To
address this, “The Diamond Concept” has been
developed, which encompasses four different
aspects of invivo bone regeneration: an osteoconductive scaffold, a suitable mechanical
environment, osteoinductive signals, and a proosteogenic cell population [42].
The ability to direct stem cells to an osteogenic pathway represents a huge regenerative
role. Addition of cells to bone grafts is a concept
based on isolating cell types, which will either
immediately and directly add bone (osteoblasts/
osteoclasts), or have the potential to differentiate,
providing angiogenic and osteogenic factors
(mesenchymal stem cells (MSCs) and adiposederived stem cells (ASCs) [43].
Cell surface markers indicative of osteogenic behavior can vary from poorly dened
CD markers to more well-known pro-osteogenic growth factor receptors. BMP receptor
type-1b (BMPR-1b) binds BMP and has an
important role in directing bone formation [44].
As such, using FACS to select for BMPR-1bpositive cells from ASCs results in a population
with increased osteogenic gene expression and
in vitro osteogenic potential [45]. Moreover,
when coupled with a porous, osteoconductive
scaffold coated in osteoinductive hydroxyapatite, rapid bone formation is observed invivo
[46]. Similarly, ASCs positive for CD90 (Thy-
1) have been shown to signicantly increase
healing of bone defects when compared with
their negative and unsorted control groups [
48]. Importantly, CD90 expression has been
shown to vary dramatically between invivo and
in vitro settings, making use of this marker
unpredictable [49]. Similarly, other markers
also have difcult expression proles to track
and analyze, such as CD105 (endoglin), a bone
marrow mesenchymal cell marker. However, it
was discovered that isolating CD105- negative
cells and waiting 36 h in culture yielded a subpopulation with enhanced osteogenic potential
in vivo [
although in that it acts as a co-receptor for
TGF- β1, which is a known antagonist of osteo-
genic differentiation [51], thus explaining a
parallel decrease in bone formation with
increased expression. These ndings simultaneously highlight the promise and problems of
using surface marker selection criteria in isolating heterogeneous stem cell populations for
bone regenerative purposes.
being researched under an autologous cell
transfer lens. For instance, the efcacy of bone
regeneration by autologous bone marrow harvested from the anterior iliac crest has been
shown in atrophic diaphyseal nonunion. Here, a
biomaterial was created by concentrating marrow via centrifugation, which could be loaded
into a syringe and injected into the recipient
site. Analysis of diseased tibias postmarrow
transplant showed increased bone callus mineralization [52]. Similarly, osteogenesis imperfecta (OI) is a genetic disease of the
mesenchymal cells, whereby a defective collagen type 1 is produced, giving rise to bone
weakness and malformation. Unmanipulated
bone marrow donations from healthy matched
siblings or family members have been shown to
increase trabecular bone formation in the recipient OI patient [53]. On the cellular level, the
harvest, culture, and transplant of bone marrow-derived stromal cells have been found to be
effective in repairing large bone defects in
human [54]. However, these cells are most efcient when placed in situ seeded on a macroporous scaffold [55].
50]. CD105 is especially nuanced,
There are multiple different bone diseases
47,
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