Bioactive Glasses as Angiogenic Agents for Tissue Engineering

Katharina Schuhladen and Aldo R Boccaccini, University of Erlangen-Nuremberg, Erlangen, Germany

© 2019 Elsevier Inc. All rights reserved.

Introduction 1
Key Mediators for the Regulation of Angiogenesis 1
Bioactive Glasses for Enhancing Angiogenesis and Vascularization 2
BGs as Potential Hemostatic Agents 5
Potential Risks of Using BGs to Enhance Angiogenesis and Vascularization 6
Conclusions 6
Further Reading 6

Introduction

Angiogenesis is the formation of new blood vessels from existing ones, in contrast to vasculogenesis, where new primitive blood
vessels are formed from angioblasts. During angiogenesis, new capillaries can be formed by sprouting or splitting of existing vessels.
In both cases, endothelial cells play a key role as they degrade the basement of the existing vessel and migrate into the surrounding
tissue. There, they clot and form a hollow structure, where cell splitting and rearrangement occur (Fig. 1). During evolution, blood
vessels growth to transport oxygen as well as nutrients to distant organs and to remove catabolic waste products, which makes them
crucial for organ growth. Adult endothelial cells have in general low proliferation rates, physiological exceptions can be found
during the female reproductive system as well as during specific repair processes, for example healing of wounds and fractures.
Therefore, angiogenesis plays a crucial role during healing and regeneration of various tissues (e.g., stomach, skin, heart, nerve,
bone, etc.). Moreover it is known that repairing processes in the human body without sufficient angiogenesis cannot be successful
since, besides nutrients and oxygen, inflammatory cells are needed to be transported through blood vessels. Therefore, angiogenesis
and endothelial cells are needed to organize and regulate healing.
In order to better enable and stimulate efficient blood vessel formation in healing processes, various therapeutic strategies are
being investigated by regulating key angiogenesis mediators. In the first section of this article, these key mediators will be discussed.
Further, the second section will focus on bioactive glasses (BGs) and their possible function to induce angiogenesis in different
tissue engineering approaches. BGs were originally developed 50 years ago as bioreactive inorganic materials able to bond to bone
tissue. Moreover, recent research results indicate that BGs can also be used in soft tissue applications, being able to induce
angiogenesis when they are made of specific chemical compositions. This article focuses on research done recently on the use of
BGs to promote angiogenesis (Fig. 1). A special consideration will be given to BGs doped with different therapeutic ions, which is a
potent strategy to enhance the biological activity of BGs. Furthermore, mesoporous BGs will be presented as potential drug delivery
systems, and a brief overview will be given about the use of BGs as hemostats. In the last section, challenges and possible risks of
using BGs will be summarized and discussed. This article thus give a concise overview about the possibility to use BGs to enhance
angiogenesis and vascularization in bone tissue engineering and wound healing applications.

Key Mediators for the Regulation of Angiogenesis

Angiogenesis is controlled by the body through different regulators: for upregulation, the main agents are angiogenic growth factors
(cytokines), whereas the main regulators for downregulation are endogenous angiogenic inhibitors. Angiogenesis starts due to
diverse physiological and pathological conditions. Angiogenic mediators can be for instance activated by hypoxia, inflammation,
activation of cyclooxygenase as well as by cell stretch and mechanical forces.
Angiogenic mediators can be divided into different groups according to their action. The first group includes endothelial cell
mitogens, which are believed to stimulate endothelial cells directly in a capillary to migrate and proliferate. Well-known examples
for this group are the vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet-derived
endothelial cell growth factor (PD-ECGF). VEGF derives from arteries, veins and lymphatics and is known to regulate, besides
migration and proliferation of endothelial cells, the permeability by increasing the fenestration and hydraulic conductivity.
Additionally, VEGF regulates several endothelial integrin receptors during the formation of new blood vessels and furthermore
acts as survival factor for endothelial cells. The most interesting property of VEGF is its specificity only to capillary and human
umbilical vein endothelial cells, whereas it is not mitogenic to other cells like smooth muscle cells or fibroblasts. Hypoxia greatly
controls the expression of VEGF by reversible and rapid transcription and stabilization of the mRNA. During normoxia on the other
side, VEGF production is down-regulated and can even cause regression of just newly formed blood vessels. Through this process,
the body meets precisely the demands of the particular tissue. VEGF plays also a crucial role in human cancer and affects the
development of various diseases such as diabetic retinopathy. Therefore, VEGF needs to be used and manipulated carefully.
The second group of angiogenic stimulators includes transforming growth factor beta (TGF-beta) and tumor necrosis factor
alpha (TNF-alpha), which act by stimulating secondary cells (e.g., monocytes/macrophages) to release growth factors (which then

Encyclopedia of Tissue Engineering and Regenerative Medicine https://doi.org/10.1016/B978-0-12-801238-3.11115-8 1

2 Bioactive Glasses as Angiogenic Agents for Tissue Engineering

Fig. 1 Schematic representation of the stimulatory effects of bulk and mesoporous bioactive glasses on angiogenesis. EC, endothelial cells.

act directly). TGF-beta for example stimulates, by acting as a chemoattractant for fibroblasts, neutrophils and macrophages, the
formation of granulation tissue, which is especially important for angiogenesis during wound healing. The third group of
angiogenic mediators includes growth factors, which stimulate the migration of endothelial cells in vitro as well as the capillary
migration in vivo. However, the proliferation of endothelial cells is not stimulated by these growth factors. Angiotropin and
platelet-derived growth factor (PDGF-BB) are representatives of this group. Angiotropin, for instance, is a copper-containing
polypeptide that stimulates in a dose-dependent and reversible manner specifically capillary endothelial cells. The angiogenic
stimulators of all three groups can be downregulated by angiogenic inhibitors, which will not be discussed here.
Beside angiogenic stimulators, the extracellular matrix (ECM) of endothelial cells is a very important component in regulating
angiogenesis. Since ECM molecules bind to cells, they act locally in accordance to external factors to modulate the cell response. The
ECM also acts as a barrier to angiogenesis and needs to be degraded during angiogenesis. Overall angiogenesis is controlled by
several factors and the process of new blood vessel formation is still not fully understood. However, increasing research efforts are
focusing on possibilities to manipulate angiogenesis and on novel biomaterials which can be used to stimulate angiogenesis,
specially in the context of tissue regeneration, with bioactive glasses representing an important group of materials in this context.

Bioactive Glasses for Enhancing Angiogenesis and Vascularization

BGs are known to act as stimulators for fibroblasts to release angiogenic growth factors (see section Key Mediators for the Regulation
of Angiogenesis and Fig. 1), which was proven in several direct and indirect in vitro and in vivo tests. The first BG composition,
discovered by Hench et al. and reported in 1971 (known as 45S5 BG) belongs to the Na2O-CaO-P2O5-SiO2 system. It was originally
proposed to be used in contact with hard tissue due to its excellent osteoconductivity and osteostimulation activity. The 45S5 BG
composition (see Table 1) has found applications as bone substituting material, small bone implants and in the dental field. The
mechanism underlying the favorable biological action of BGs is based on their ability to release ions during dissolution in an

Table 1 Overview of different BG compositions developed over the years

Composition SiO2 Na2O CaO P2O5 K2O MgO B2O3

45S5 45 wt% 24.5 wt% 24.5 wt% 6 wt%

S53P4 53 wt% 23 wt% 20 wt% 4 wt%
1393 53 wt% 6 wt% 20 wt% 4 wt% 12 wt% 5 wt%
58S 60 mol% 36 mol% 4 mol%
80S 80 mol% 15 mol% 5 mol%
18S36B 18 wt% 6 wt% 22 wt% 2 wt% 8 wt% 8 wt% 36 wt%
51.6B 6 wt% 20 wt% 4 wt% 12 wt% 5 wt% 51.6 wt%
 Bioactive Glasses as Angiogenic Agents for Tissue Engineering 3

aqueous environment leading to the precipitation of a hydroxyapatite layer on their surface. Hench described the proposed stages of
hydroxyapatite formation on the 45S5 BG composition during immersion in simulated body fluid: a rapid ion exchange reaction
occurs first between the hydrogen ions from the media and the glass network modifiers Ca2þ and Naþ. Afterwards, soluble silica is
released to the solution, which then condensates on the glass surface. This process leads to the formation of a silica-rich surface layer.
On top of this silica rich layer an amorphous calcium phosphate structure forms by the reaction between the calcium and phosphate
groups in the medium. This layer can further crystallize to hydroxyapatite. The formation of this hydroxyapatite surface layer is the
reason why BGs are especially interesting for bone tissue engineering. However, the release of ions, as calcium, silicon and
phosphorus in the case of 45S5 BG and other biologically active ions in special BG compositions, in biological relevant
concentrations makes BGs also interesting for applications in contact with soft tissue. For both fields, soft and hard tissue
engineering, angiogenesis is a crucial process and therefore the influence of BGs on angiogenesis becomes highly relevant for
their applications in these fields.
One of the first studies carried out to investigate the effect of silicate BGs on the secretion of angiogenic growth factors by
fibroblasts and therefore on angiogenesis was conducted by Day et al. (2004). In this study, different concentrations of 45S5 BG
powder were coated on a cell culture well plate and then fibroblasts were seeded on top. Fibroblasts grown in contact with low
concentrations (0.01%–0.2% wt/vol) of 45S5 BG showed increased proliferation and normal morphology, whereas fibroblasts in
contact with higher concentrations of BGs showed less cell proliferation. Moreover, the secretion of VEGF was significantly increased
by bringing the cells in contact with low concentrations of BGs, proven by analyzing the conditioned media collected from
fibroblasts with an enzyme-linked immunosorbent assay. Additionally, 45S5 BG coated polyglcolic acid meshes were implanted
in inbred adult male Lewis rats and increased neovascularization of the tissue was found postoperatively after 28 and 42 days.
Therefore, that study indicated for the first time that BGs (in particular 45S5 BG) are able to stimulate neovascularization. These
results were further confirmed by later studies, a selection of the most interesting results will be presented here.
There are several options to investigate both in vitro and in vivo the influence of BGs on angiogenesis. For instance, an
arteriovenous loop (AVL) in vivo model in the medial thigh of rats has been used to evaluate the angiogenic effect of 45S5 BG
granules. By analyzing this model after 3 weeks postoperatively through microcomputed tomography and histology examinations,
it is possible to evaluate the newly formed vessels originating from the AVL in the presence of the BG. Results from previous studies
using this model showed that highly vascularized, cell-rich connective tissue grew around the vascular axis. Another way to study the
ability of BGs to stimulate angiogenesis it to examine the effect of BGs on gap junction related behavior of endothelial cells.
By cultivating human umbilical vein endothelial cells (HUVECs) in cell culture media containing ion dissolution products (IDPs) of
45S5 BG, a stimulatory effect was found on gap junction communication between cells by upregulating the expression of an
important protein (connexin43). Additionally, higher expression of VEGF and bFGF could be measured. All these effects were found
to be dependent on the amount of IDPs from 45S5 BG in the medium.
Since the invention of 45S5 BG, several other silicate BG compositions have been developed, with SiO2 content in the range of
40–50 mol%. One popular composition, the S53P4 BG (see Table 1), is known to have antibacterial properties and it is applied
commercially to combat bone infection. The ability of this BG composition to increase VEGF secretion from human fibroblasts has
been also examined. The cells were cultivated in contact with S53P4 granules of different sizes (between 0.5 and 3.2 mm). The VEGF
release was enhanced in the presence of BG granules smaller than 2 mm, whereas in the presence of larger particles VEGF release was
inhibited. The biological effect of 45S5 BG particles was compared to another silicate BG, the 1393 BG (composition see Table 1) in
a setup of indirect and direct experiments. The 1393 BG composition showed overall a higher biological effect on cells than 45S5
BG. Such comparative studies are relevant as they confirm that cells could be less tolerant to some BG compositions, showing a
different release of biologically active ions, thus enabling the selection of the proper BG composition for a particular application.
Traditionally, BGs are produced by the melt-quenching technique. However, in 1991 it was shown that BG can be also
synthesized by sol-gel processing. The advantages of sol-gel derived BGs are that they tend to be more bioactive and degrade
more rapidly than melt-derived glasses of similar compositions. For instance, the 58S nanosized BG (composition see Table 1)
produced via the sol-gel route was reported to enhance wound healing to a higher extent than the melt-derived 45S5 BG. Moreover,
by using the sol-gel process, compositions with higher amount of SiO2 can be produced which remain bioactive by varying either
the environmental or thermal processing history of the glass. The effect of nanosized 58S as well as 80S BGs (composition see
Table 1) on cultures of endothelial cells has been examined and the results showed that in the presence of the two sol-gel BGs, the
expression of VEGF and bFGF was stimulated. Furthermore, by using an ECM gel tube formation assay, enhanced blood vessel
formation could be found. These results indicate that sol-gel glasses, and especially the 58S and 80S compositions, possess
significant angiogenic ability.
In order to be suitable for specific applications, BGs are often combined with polymers to overcome the intrinsic brittleness of
BGs. For instance collagen and polycaprolactone were combined with 58S nanoparticles to create nanofibrous scaffolds for wound
healing applications. The composite scaffolds were tested in vitro by using endothelial cells and showed an upregulation of
angiogenesis marker (CD31). Moreover, BG-composite scaffolds were examined in an in vivo model. The results showed a
stimulation of mRNA and expression of VEGF. Furthermore, the same composite scaffolds can be used to deliver endothelial
progenitor cells (EPCs). In vitro, the composite scaffold led to increased angiogenic ability of EPCs by activation of VEGF and other
relevant growth factors. Moreover, the scaffolds containing EPCs were able to enhance blood vessel formation and showed rapid
re-epithelialization and regeneration in an in vivo wound model.
One potential drawback of silicate glasses is the low solubility of silica, which could lead to unconverted glass remaining in the
human body. Therefore, besides using silica, also phosphorus pentoxide and boron trioxide can be used as main glass forming
4 Bioactive Glasses as Angiogenic Agents for Tissue Engineering

oxides to produce BGs. Phosphate glasses are known for their easily controlled degradation rate, whereas borate glasses are
characterized by their relatively high mechanical properties and high reactivity. Borosilicate and borate BGs are of special interest
for angiogenesis related applications, since the release of boron ions from these glasses has been reported to induce neovascular-
ization. Moreover, it has been shown that endothelial cells cultivated in contact with borate glasses exhibit the ability to form
tubules and secrete proangiogenic cytokines. For example, different borosilicate and borate glasses were tested in an in vitro study
using bone marrow stromal cells (ST2) to evaluate the angiogenic potential of these glasses. After cultivating the cells with the IDPs
of the boron-containing glasses for 48 h, the cell viability and the cell morphology as well as the amount of VEGF secreted from the
cells were evaluated. The cell viability was found to be strongly dependent on the amount of boron ions released from the glasses.
Moreover, it was confirmed that the BGs, especially in the case of borosilicate glasses, were able to promote the secretion of VEGF.
In general, studies have shown that the bioactive behavior of BGs is strongly dependent on the composition of the glass and on
the time-dependent concentration of ions released from the BGs. Both, the kind as well as the concentration of the released ion play
a crucial role. For instance, Si and Mg are known to be essential for the formation and calcification of bone, Si additionally for the
stimulation of the formation of collagen. Ca favors for example the extracellular matrix mineralization, which is important for the
angiogenic process, as described above. Boron is known to stimulate fibroblast cells and to enhance angiogenesis by upregulating
the release of VEGF. One approach to further increase the biological function of BGs is to introduce several biologically active ions.
Here, especially copper is interesting, since it is known to promote angiogenesis by mimicking hypoxia (which upregulates the
expression of VEGF, as discussed in section Key Mediators for the Regulation of Angiogenesis) and is a well-studied antibacterial
agent. 18S36B BGs (composition see Table 1) doped with up to 3 wt% Cu were tested in form of scaffolds in vivo. The results
showed that the scaffolds significantly improved blood vessel formation at 8 weeks postimplantation (Fig. 2). The same Cu-doped
borosilicate glass was previously combined with poly (lactic-co-glycolic acid) (PLGA) to fabricate a composite dressing for wound
healing applications. Additionally, the dressing was loaded with vitamin E to further enhance the biological function of the scaffold
by introducing anti-inflammatory properties. The in vitro study demonstrated that the combination of Cu containing BG, PLGA and
vitamin E was effective in inducing VEGF secretion as well as migration and tubule formation in HUVECs. Moreover, in vivo, the
dressing showed enhanced vessel sprouting and collagen remodeling. These results showed that BGs doped with copper can be
combined with other materials to create a tunable composite suitable for specific applications. Besides using copper, also other ions
are interesting to provide additional functionality to BGs. For example, the borate 156B glass (composition see Table 1) incorpo-
rating additionally to copper also zinc has been developed, since zinc is known for its bactericidal behavior and its antiinflamma-
tory effects. The produced melt-derived glass was tested in vivo and it was found that the co-doped glass led to improved angiogenic

80
BG *
60
Vessel number

40

20

0
BG BG-3Cu

50
BG-3Cu
40
*
Vessel area (%)

30

20

10

0
BG BG-3Cu
Fig. 2 The influence of Cu-doped (3 wt%) and undoped BGs (in wt%: 8%K2O, 8% MgO, 36% B2O5, 18% SiO2, 6% Na2O, 22% CaO, 2% P2O5) on blood vessel
formation in rat calvarial defects 8 weeks postoperatively. Left: reconstructed image of micro-CT evaluation in rat calvarial defects, right: morphometric analysis of
new blood vessel number and area ( P < .05). The image is reproduced from Wang et al. (2016). Materials Science and Engineering C, 58, 194–203 with
permission from Elsevier.
 Bioactive Glasses as Angiogenic Agents for Tissue Engineering 5

properties compared to undoped borate and silicate 45S5 BG. However, since results were not compared with the same glass, just
doped with copper or just doped with zinc, it is not clear whether the effect resulted from one of the ions or from a synergistic effect
of both ions acting simultaneously.
By using the sol-gel route in combination with supramolecular chemistry of surfactants, other types of BGs can be produced,
which are known as mesoporous BGs. These glasses are especially of interest due to their ability to load the mesoporous BG structure
with drugs or growth factors and to release the payload in a controlled way. This behavior can be achieved by controlling the highly
ordered mesopore channel structure of these glasses. Mesoporous silicate glasses have been for example combined with a
decellularized matrix from porcine small intestinal submucosa (SIS) in order to design a suitable composite for bone regeneration.
The composite was in vitro tested with bone marrow stromal cells and HUVECs, resulting in angiogenic gene expression and tube
formation capacity. Moreover, the in vivo results showed enhanced neovascularization as well as bone formation for BG/SIS
composites compared to SIS without BG. Moreover, it is possible to incorporate VEGF in sol-gel derived mesoporous silicate glass.
It was shown that VEGF could be continuously released from mesoporous BG particles over three weeks. Endothelial cells in contact
with the loaded BGs were synergistically stimulated. Furthermore, studies in the chicken chorioallantoic membrane model showed
neoblood vessel sprouting (Fig. 3). Mesoporous glasses can also be successfully doped with ions. For instance, a mesoporous silicate
BGs based on the 80S composition (see Table 1) was doped with Cu which was evaluated in vitro and in vivo. The results
demonstrated that the BG was able to promote angiogenesis. Beside these examples, various strategies including the addition/
delivery of therapeutic ions, growth factors and drugs to enhance the biological activity of mesoporous glasses have been put
forward, which confirmed their great potential in applications where angiogenesis and neovascularization are needed.

BGs as Potential Hemostatic Agents

Recent research has proven that angiogenesis and blood clotting (hemostasis) are interrelated. Proteins generated by the hemostatic
system coordinate blood clotting and endothelial cell stabilization followed by endothelial cell growth and repair of damaged
blood vessels. Therefore, the mechanism of hemostasis and the possible role of BGs will be briefly discussed.
The blood clotting process can be divided in two stages: the primary and the secondary hemostasis. In the primary hemostasis,
prothrombin is converted into thrombin under the catalyzing effect of thrombokinease and calcium, whereas during the second
hemostasis step the conversion of fibrinogen to fibrin by using thrombin occurs. Despite notable advances in developing
hemostatic systems, there is still no ideal hemostatic agent for universal applications and without any side effects. Compared to
organic hemostats containing animal or human derived proteins, inorganic hemostatic agents have shown high efficiency without
the risks of allergic reactions. BGs can be used as rapid-acting hemostatic agents based on their Ca release capability. Moreover,
during dissolution BGs provide negatively charged Si species, which can act as a support for surface-dependent thrombotic
reactions.
By using mesoporous glasses and incorporating therapeutic inorganic dopants (ions), new biomaterials with improved blood
clotting activity can be designed. For example, studies have been conducted loading mesoporous glasses (composition see Table 1)
with Ga2O3 in order to additionally provide antibacterial properties. In comparison to currently used hemostatic agents, the doped
mesoporous glass showed the highest efficiency by resulting in larger platelet aggregates and higher levels of thrombin formation.
Additionally, cytotoxicity studies of gallium doped BGs indicated improved cytocompatibility compared to commercial products.
In summary, an emerging number of results is showing the great potential of BGs as hemostat, offering additionally the possibility

w/o VEGF Si Si + VEGF

Fig. 3 Synergistic effect of released Si and VEGF from mesoporous glasses on blood vessel sprouting in chicken chorioallantoic membrane. Reproduced from
Dashnyam et al. (2017). Biomaterials, 116, 145–157.
6 Bioactive Glasses as Angiogenic Agents for Tissue Engineering

of providing extra biological functions by introducing therapeutic ions which are released in a controlled manner during the wound
healing process.

Potential Risks of Using BGs to Enhance Angiogenesis and Vascularization

The complex processes occurring during the implantation and dissolution of BGs in the human body are not yet completely
understood. As mentioned earlier, BGs have the ability to convert to hydroxyapatite, which is favorable for applications in contact
with bone and in the dental sector. However, the interplay between the formation of hydroxyapatite during the dissolution of BGs
and soft tissue regeneration mechanisms is still not clear. Therefore, further research needs to be carried out to decode the role of
BGs during regeneration of different tissues and to identify mechanisms to prevent potential ectopic soft tissue calcification (given
the Ca release from BG), which might be also harmful for angiogenesis.
In addition, ion release from BGs needs to be carefully controlled, since at a certain release level specific ions can become
cytotoxic. For instance borate glasses, releasing a high amount of boron, have been found to be cytotoxic at the same concentration
levels as borosilicate glasses releasing lower levels of boron. Here, especially ion-doped glasses need to be carefully designed, since
for ions such as Cu or Co even low levels can lead to cytotoxicity or other undesirable effects. Moreover, the possible pH-raise during
the dissolution of BGs due to ion exchange reactions needs to be considered. Especially in vitro, several studies showed the
development of pH-dependent cytotoxicity, which makes the in vitro assessment of the biological activity of ion doped BG
impossible. Besides having a negative impact on mammal cells, the local increase of pH through dissolution of BGs can lead to
favorable antibacterial effects.
The fact that mesoporous BGs can be loaded with drugs, growth factors, and other biomolecules makes them especially
interesting as drug release systems for regenerative medicine. However, besides the more complex production process of these
loaded BGs, the type and amount of the loaded substance must be carefully chosen depending on the final application. As already
mentioned, growth factors involved in the angiogenic process can also play a crucial role in various diseases and furthermore can act
as angiogenic inhibitors. For instance, in vivo studies have shown hypotension associated with FGF and VEGF administration due to
arteriolar vasodilatation and nitric oxide release. Further concerns by using angiogenic growth factors are plaque angiogenesis,
occult malignancies and proliferative retinopathy. Moreover, the use of drug release systems is based on the assumption that the
drug (or growth factor) employed can lead to a complete angiogenic response. In fact, single substance therapies are insufficient to
coordinate the entire and complex angiogenic cascade to form a vascular network. Therefore, in the future more research should
focus on the synergistic effects of several biologically active substances in combination and the studies should systematically
evaluate their behavior in vivo. Here, BGs are potential candidates, since the composition and therefore the release of therapeutic
elements can be easily controlled and combined with several substances (e.g., drugs, growth factors) by loading them into the BGs
structure, particularly into mesoporous BGs.

Conclusions

BGs of varying compositions have been shown to be effective in promoting angiogenesis by affecting the secretion of relevant
growth factors or cytokines. It has been shown that the effect could be mainly achieved through the release of therapeutic ions from
BGs. Here, it is possible to control cellular responses by introducing several biologically active ions in specific concentrations.
Currently it is not clear which BG composition and which doped ions lead to the highest angiogenic effect. More research is
therefore necessary to identify which compositions should be used to reach a specific biological response or targeted stimuli for
several applications in wound healing and tissue engineering. Moreover, it has been shown that by using mesoporous BGs, it is
possible to combine the release of therapeutic ions with drugs or growth factors. However, the concentration of both, the ions
released as well as the used substance loaded on the BG structure, must be carefully chosen. The controlled delivery of biologically
active ions makes BG promising candidates for improving angiogenesis and vascularization. Angiogenesis and blood clotting are
interrelated, therefore BG effects on hemostatic molecules are being also investigated. By modifying BGs and combining them with
other substances, multifunctional biomaterial platforms can be created to target specific requirements and this material develop-
ment strategy around BGs opens exciting opportunities for future improvement of medical therapies.

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 Bioactive Glasses as Angiogenic Agents for Tissue Engineering 7

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