International Journal of Polymeric Materials and

Polymeric Biomaterials

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Polymeric microgels for bone tissue engineering

applications – a review

Lalit Kumar Meena, Hilal Rather, Dhaval Kedaria & Rajesh Vasita

To cite this article: Lalit Kumar Meena, Hilal Rather, Dhaval Kedaria & Rajesh Vasita (2019):
Polymeric microgels for bone tissue engineering applications – a review, International Journal of
Polymeric Materials and Polymeric Biomaterials

To link to this article: https://doi.org/10.1080/00914037.2019.1570512

Published online: 03 Feb 2019.

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INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
https://doi.org/10.1080/00914037.2019.1570512

Polymeric microgels for bone tissue engineering applications – a review

Lalit Kumar Meena, Hilal Rather, Dhaval Kedaria, and Rajesh Vasita
Biomaterials & Biomimetics laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar, India

ABSTRACT ARTICLE HISTORY

Microgels have recently gained exposure as a potential scaffold either alone or in combination Received 15 October 2018
with other scaffold for bone tissue engineering. Microgel has been defined as a small size particle Accepted 13 January 2019
of cross linked polymer chains with the ability of swelling and holding the large amount of solv-
KEYWORDS
ent. This review summarizes the microgel based scaffolds specifically for bone tissue engineering.
Bone regeneration; cell
Microgels for growth factor delivery, cell transplantation and hybrid scaffold synthesis have been delivery; hydrogel; microgel;
discussed in details. The success in recreating potential bone regenerative scaffold have been osteogensis
explored for clinical applications, future perspectives and its concurrent view has been deliberated
in detail.

GRAPHICAL ABSTRACT

1. Introduction morbidity, dearth of grafts and nonunion complications

Bone comes second most transplanted tissue globally after
blood with over two million bone grafting surgeries per
annum[1]. Bone regeneration is the complex phenomenon in
which active signaling from different biomolecules is
required at various stages of bone development. Small size
bone fracture whether it might be pathological or accidental
can be repaired by bone’s own regeneration capability.
However, critical size bone defect compromise the active
blood supply and infection lead to delayed unions or non-
unions. To assist the complete bone regeneration, autografts
and allograft have been used clinically for bone reconstruc-
tion. Autologous bone grafts remain gold standard techni-
ques to achieve successful bone repair however donor site
restrict their utility. Allograft provides an alternative but it
also has issues like immune rejection and pathogen trans-
mission[2,3]. Clinically need of alternative bone regeneration
strategies keeps increasing with time and population ages
globally. To compensate the demand of bone regeneration,
bone tissue engineering has made the substantial growth
and remains a matter of hope in comparison to traditional
methods from last decades[4,5].
Bone substitute materials have been a subject of augmen-
tation of the natural bone repair by providing space filler
and inert support. Bone substitute materials industry claims
more than two billion revenue from worldwide market in
2013[6]. Bone tissue engineering is the cocktail of biological

CONTACT Rajesh Vasita rajesh.vasita@gmail.com Biomaterials & Biomimetics laboratory, School of Life Sciences, Central University of Gujarat, sector-30,
Gandhinagar, Gujarat, 382030 India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpom.
ß 2019 Taylor & Francis Group, LLC
2 L. K. MEENA ET AL.

and engineering principles which provide the basis for rapid

bone regeneration. The “diamond concept” of bone tissue
engineering proposes functional bone substitute mater-
ial[7–11]. Tissue engineering approach utilizes varieties of
synthetic and natural bone substitute materials for bone
regeneration. The synthetic bone substitutes like calcium
sulfate[12], calcium phosphate (CaP)[13,14], ceramics[15–17],
bioactive glass[18,19], calcium phosphate cement (CPC)[20–23]
provide osteoconductivity supports for space filling and
mechanical stability to the fractured bone. However, the lack
of osteoinductivity remains a challenge to prove as an alter-
native of natural bone substitute materials. The use of bio-
logical growth factors as osteoinductive molecules with these
synthetic bone substitutes would be desirable to augment
the bone regeneration. The bone substitute materials based
on natural polymers also considered next generation bone
Figure 1. Light microscopic images of core-shell (collagen 0.5% for core and
grafts. Natural polymers like collagen, alginate, and chitosan chitosan 3% for shell) microgels with intact shell structure and spherical shape.
are extensively explored for bioresorption and homing envir- Core-shell structures were indicated by arrows. Images were captured with 5X
onment to the bone progenitor cells[24–29]. The composites objective lens (scale ¼ 500 mm).
of synthetic bone substitute and natural polymers are also
reported for bone regeneration. The use of b-tricalcium
phosphate (b-TCP), hydroxyapatite with biopolymers like
collagen, alginate were investigated extensively[30–40]. The
use of osteoinductive growth factors and drug molecules
with these bone substitute materials are also clinically viable
approach. The list of growth factors explored for bone tissue
engineering includes bone morphogenetic proteins (BMPs),
vascular endothelial growth factors (VEGF), fibroblast
growth factors (FGF), parathyroid hormone (PTH) and
platelet-rich plasma (PRP); however, BMP-2 and BMP-7
were only approved by US Food and Drug Administration
(FDA) for bone regeneration in 2002[41,42]. Figure 2. Schematic representation of internal structure of cross-linked micro-
The development of ideal scaffold with biocompatibility gel and swelling (size) behavior in response to external stimuli.
(support the normal cellular activity without cytotox-
icity)[43], biodegradability (providing the space for new bone ability of swelling and holding the large amount of good
growth)[44], osteoconductivity, osteoinductivity, scaffold solvent (e.g. water) (Figure 1)[50]. Because of these proper-
architecture (porosity) and mechanical properties[45–47] is ties, they have gained tremendous attention. The responsive
challenging and complex process. However scientists are try- swelling and de-swelling in response to surrounding
ing to develop scaffolds with most of these properties to medium pH, temperature and solvent makes it promising
augment the bone regeneration. As a bone substitute grafts deliver device for bioactive molecules (Figure 2). The cross
and local delivery of osteoinductive molecules by various linking of polymeric chains or cross linking density controls
types of osteoconductive scaffolds have been explored. These swelling and shape of microgel. The change in size of micro-
are the hydrogels, cryogels, microspheres, microgels and gel upon swelling is inversely proportional to cross linking
nanoparticles. Among all these, microgels recently have been density[51]. The nature of solvents also influences swelling
explored for bone tissue engineering either alone or in com- and size of microgel, for example, poly(N-isopropylacryla-
bination with other scaffold. Microgels small size, injectabil- mide) (PNIPAAm) based microgels demonstrated deswelling
ity, and live cell encapsulation efficiently, makes it and reduction in size in higher volume fraction of alcohol
promising scaffold for bone regeneration. Hence this review whereas, in low volume fraction of alcohol microgels re-
will be focused on microgel technology for bone tissue swells[52]. Therefore microgels are termed as “smart materi-
engineering and their commercial perspective. als” because of their tunable size, shape, stiffness and par-
ticular interactions under the influence of external stimuli.
Microgels are cross-linked soft particles which provide a
2. Microgel
three-dimensional (3D) network structure[53]. The porous
In 1935 Staudinger and Husemann first time fabricated network allows the cells to penetrate inside the microgel and
microgel through suspension polymerization process[48]. provides an advantage of nutrient and gaseous exchange,
However the term microgel was remained unused till which directly affects the cellular growth and proliferation.
1949[49]. Microgel has been defined as a small size particle Microgels are also called as ‘hydrogels’ because of water sol-
(0.1–1000 mm) of cross linked polymer chains with the uble nature. Microgels and hydrogels both belong to gel
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Table 1. Comparative profile of microgels and hydrogels features for bone tissue engineering.
Feature Microgels
Shape and size Spherical shape and size in micron range, hige surface to
volume ratio is helpful in higher loading of osteoinduc-
tive molecules and controlled release[54,55]
Swelling and porosity Due to confined shape and less porosity, swelling occurs in
controlled manner hence lead to controlled and sus-
tained release of osteoinductive molecules[57]
family and have capacity to hold the large amount of water.
However some features such as size, shape, swelling and
porosity make certain difference for bone tissue engineering.
These features are tabulated in following Table 1.
On the basis of charge, microgels may be neutral or
charged that mainly depends on materials composition. A
wide range of polymers and monomer/co-monomers have
been used to fabricate the microgels such as alginate[58], gel-
atin[59], collagen[60], heparin, polyethylene glycol (PEG)[61],
chitosan[62], hyaluronan[57] PNIPAAm, methylmethacrylate,
methacrylic acid (MAA), styrene, divinylbenzene, acrylic
acid (AA), N,N’-methylene bisacrylamide (MBA) and ethyl-
ene glycol dimethacrylate etc.[63] among them PNIPAAm is
extensively used[64]. The methylenebisacrylamide is com-
monly used cross-linker to impart mechanical strength and
prevents the complete dissolution of PNIPAAm
microgels[63].
Diverse methods from conventional in situ polymerization
to microfludics have been employed for the fabrication of dif-
ferent types of microgels. The chitosan based genipin cross-
linked microgels prepared by in situ emulsion crosslinking
method. This method produces homogenously crosslinked
microgels. These microgels have been employed for the post
fabrication loading of vascular endothelial growth factor iso-
forms and in vitro release[65]. Arginine–glycine–aspartic acid
(RGD) grafted alginate microgel has been fabricated by elec-
trospraying method. Electrospraying at 10 kV reported cyto-
compatible for encapsulation of human outgrowth
endothelial cells (OECs) in microgels[66]. Precipitation poly-
merization technique has been used for poly(N-isopropyla-
crylamide-co-acrylic acid) based vancomycin loaded
microgels fabrication[67]. Collagen based cell encapsulated
microgels has been prepared by aqueous two-phase system,
in which soluble polymer phase thermodynamically drive
aqueous phase to form two separated phases[60]. Gelatin and
poly(ethylene glycol)-maleimide (PEG-4MAL) microgels has
been synthesized with uniform size and reproducibility by
microfludics technique[59,68]. While solvent/water inverse
microemulsion cross-linking method has been used for the
loading of labile growth factors such as BMP-2 in heparin-
conjugated hyaluronan microgels[57].
The control over size, composition and functionality of
microgels enhances its applications in biomedical areas like
tissue engineering[69], controlled drug delivery[70,71], spinal
column implants[72] and cells delivery[73]. The aqueous
internal environment of microgel mimics extracellular
matrix that is desirable to deliver the physical and chemical
stress labile growth factors and progenitor’s cells. A high
surface area maximizes its interactions with cells and host
tissue that is prime requirement for biomedical device
3
Hydrogels
Shape not defined and size range above mm, helpful for
providing bone microenvironment[56]
Due to the higher porosity swelling occurs vary rapid that
may lead to burst release of osteoinductive molecules
integration with host tissue. The regulated swelling and deg-
radation of microgels imparts controlled release of growth
factors and cells, hence enhanced the regeneration of local
tissues such as bone, and cartilage could be achieved. These
properties of microgels could be used for bone regeneration.
In following sections the focus will be on how microgels can
assist the bone regeneration.
3. Requirements for bone tissue
engineering scaffold
Bone regeneration using biomimetic approach involves the
use of several scaffolds which mimics certain features of the
bone anatomy or physiology. It includes the use of 3D con-
structs, scaffolds or matrices for example, 3D printed scaf-
folds, hydrogels, cryogels, microspheres and nanofibers.
These constructs regulate cell migration, proliferation, and
differentiation[74–76]. Before considered for bone tissue
engineering, these scaffolds should fulfill certain criteria.
1. ECM mimicking: To imitate the fibrillary architecture
of natural ECM components.
2. Biodegradability: To support the replacement of scaffold
by the newly secreted ECM
3. Surface chemistry: To support cell attachment, prolifer-
ation, migration and differentiation
4. Osteoconductivity: To act as substrate for cells to grow
and differentiate.
5. Osteoinductivity: Release of Osteoinductive molecules,
which could promote the osteogenic differentiation of
progenitor cells.
6. Mineral deposition: Biomimetic scaffolds should provide
a microenvironment to facilitate the ossification process.
7. Mechanical properties: To provide mechanical stability
for constructs in load-bearing sites prior to synthesis of
new ECM by cells.
8. Porosity: For exchange of nutrients and gases in vitro
and infiltration of blood supply in vivo.
9. Ease of fabrication: the fabrication process should be
less sophisticated, less time consuming and least toxic
reagents should be used.
Microgels are also used to fulfill the criteria as reported
in the literature. The core-shell microgels mimic the hirer-
chial structure of the bone ECM and acts as osteoconductive
scaffolds. They can be easily fabricated from natural poly-
mers, which enhances their biodegradability. Furthermore,
the polymeric microgels are functionalized to change the
surface chemistry and alter the functionality of the micro-
gel[67]. The osteoinductivity of the microgels could be
4 L. K. MEENA ET AL.

controlled by loading several osteoconductive molecules[77]. for larger scaffold implant. Hence injectable properties of
Moreover, microgels could be used with hydrogels to microgels enhances its applicability in bone regeneration[73].
improve the mechanical stability, release profile and immo- Further, microgels could be used as a micro carrier for
bilization at site of implanting[78]. Furthurmore, injectable growth factor and drug delivery in bone regeneration
form of microgel is considered to be advantageous over (Figure 5). Since microgels are confined structure of poly-
other bone substitutes. Hence, microgels fulfill the basic cri- mers as compared to bulk gel, the controlled release of bio-
teria related with the bone tissue engineering scaffolds. macromoleculs could be achieved[80]. The progenitor cell
transplantation is the most effective therapeutic strategy to
augment the bone regeneration. Stem cells such as mesen-
4. Microgel for bone regeneration chymal stem cells (MSCs) have been encapsulated in micro-
The extensive research is going on the use of microgel for gels during fabrication and these microgels can be injectable
various tissue regeneration applications because of its soft at fracture site by syringe[81,82]. Alternatively, solvent access-
internal structure, elastic nature and injectable properties. ible surface of microgel also provides an adhesive site for
Bone structure is composed of two types of bony parts such cells which can be used as scaffolding. On the other hand
as cortical or compact bone and cancellous or spongy bone the therapeutic biomolecules loaded microgel can be loaded
(Figure 3a). The compact bone envelops spongy bone and in bulk gel system during hybrid scaffold fabrication[78,83].
These hybrid scaffolds could be used for progenitor cell cul-
forms a border with lower porosity and surface area. The
ture. The release of biomolecules from loaded microgels in
higher density and lower porosity of compact bone enhances
bulk gel could be mimicking the bone (ECM) microenviron-
its resistance against mechanical forces. The spongy bone is
ment[77]. A detailed discussion on aforementioned microgel
encircled by compact bone and has higher porosity and
based scaffolding (Figure 5) is provided in subsequent sec-
large surface area. The spongy bone is the network of tra-
tion of this review.
becular struts with space between them ranges from 300 to
1500 mm[79]. The bones structural organization mimicking
remains prime aim for scaffolds designing. A core-shell
microgel with different microstructure and composition can
be considered as next generation scaffolding. In Figure 3b a
core-shell microgel showed the core is mimicking spongy
bone organization while shell shows structural similarity
with compact bone. This structural similarity between bone
and microgels could be helpful to mimic cellular behavior
and transportation of signaling molecules. Bone regeneration
is the research area where the microgel providing an alterna-
tive of existing hard and soft scaffolds.
The production of homogeneous size microgels with soft
and elastic nature increases the applicability of the microgel
for injection at fracture site. Most of the studies have
explored microgels because of the some salient features as
mentioned in (Figure 4). The injectability of monodisperse
microgels at fracture site minimizes handling effort and Figure 4. Highlights the salient features of microgel which have been explored
avoids any open surgical complications, which are essential to enhance the osteogenesis.

Figure 3. Bone structural organization, (a) schematic representation of internal structure of bone with clear demarcation between compact bone and spongy bone,
(b) SEM image of core-shell microgel internal structure with highly porous core and less porous and compact shell.
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
4.1. Microgel as delivery device
4.1.1. Microgel based growth factor delivery
Growth factors are the bioactive polypeptides that transduce
the signal by cell surface receptors and guide the cells fate
process in vitro as well as in vivo[84,85]. The bone ECM
provides homing environment and spatio-temporal
Figure 5. Schematic demonstration of different applications of microgel in
bone regeneration.
Figure 6. Involvement of growth factors in different bone regeneration stages.
5
presentation of growth factors to guide the bone regener-
ation in vivo[86]. Growth factors are the key to augment the
bone regeneration (Figure 6) and maintain the
bone metabolism.
During natural fracture healing mechanism, an array of
bioactive signaling molecules become operational to guide
the bone cells to repair the fractured bone. In critical
defects, the disruption of blood vessels could imbalance the
signaling of growth factors. This interrupted signaling many
times causes the delayed union or nonunion. Therefore
recreation of local microenvironment became essential for
complete bone fracture repair. To simulate the natural heal-
ing mechanism, therapeutically relevant growth factors are
administered by various means. Conventionally practiced
systemic delivery of growth factors is least preferred due to
lack of targeted delivery and bioavailability[87]. The longer
circulation time of growth factors in body fluid leads to
decrease in bioactivity and half life which increase the
requirement of higher dose size for effective signaling initi-
ation. The increase in dose size or supara-physiological dose
causes the systemic side effects like ectopic bone formation,
neoplasia and inflammatory reactions[88,89]. Alternatively
delivery vehicles such as collagen sponges, hydrogels, mem-
branes, microparticles, implant coating, nanoparticles,
fibrous scaffolds, microgels and nanogels were explored for
localized delivery. Since present review is focused on micro-
gels applications in bone regeneration the remaining scaf-
folds will not be discussed further. The water holding
capacity, large solvent accessible area and ECM mimicking
environment inside the microgel[90] facilitates encapsulation
and release of therapeutic biomolecules and growth
6 L. K. MEENA ET AL.
factors[91,92]. Loading of therapeutic biomolecules in micro-
gels is the critical step and mainly achieved by two ways. In
one way the therapeutic biomolecules can be loaded during
microgel fabrication, called prefabrication. Pre-fabrication
loading can be used to achieve higher loading and sustained
release of therapeutic biomolecules. The exposure of fabrica-
tion environment to the labile therapeutic biomolecules may
reduce its bioactivity. In another way loading can be
achieved after microgel fabrication by immersing the micro-
gels into therapeutic biomolecules solution is called as post-
fabrication loading. Due to the small size and higher surface
area of microgels post-fabrication loading is the rapid and
mild process[55]. The lower amount adsorption and uncon-
trolled release of therapeutic biomolecules limits this process
applicability. Since the interactions of functional groups of
polymeric microgels with therapeutic biomolecules also plays
important role in determining the release profile and loading
capacity of microgels. A range of natural and synthetic poly-
mers including collagen[60], heparin, PEG[61], chitosan[62],
hyaluronan[57], poly(N-isopropylacrylamide) have been
explored for fabrication of growth factor loaded microgel.
The growth factor BMP-2 is extensively studied growth fac-
tor and participates in all phases of bone regeneration.
BMP-2 also reported for its role in MSCs recruitment and
proliferation during inflammatory phase and MSCs differen-
tiation in soft callus formation and mineralization (Figure
6). To modulate the release profile of BMP-2 functionally
active polymers such as heparin has been used. In one study,
Zhao et al. synthesized heparin-conjugated hyaluronan (HA-
Hp) microgels through inverse emulsion polymerization
technique. Three different concentration of heparin was
evaluated for its effect on loading efficiency and release of
BMP-2. With increasing heparin concentration the loading
efficiency of BMP-2 increased from 53% to 90%[57]. BMP-2
possesses basic heparin binding domain that might electro-
statically interact with acidic sulfate groups on heparin[93].
The availability of BMP-2 throughout the bone healing is
desirable to achieve the complete bone regeneration. The
sustain release profile maintains a continuous supply of
BMP-2. In aforementioned study, the in vitro release pattern
of BMP-2 from HA-Hp microgels also showed sustained
release with 7% at day 1 in compared to 26% at day 1 from
HA microgels. The remaining BMP-2 showed sustained
release for 15 days from HA-Hp microgels. Results showed
that the increased content of heparin in HA microgels
imparts sustained release pattern for BMP-2[57]. It might be
due to increased electrostatic interactions between heparins
N- and O-sulfated residues and BMP-2 lysine and arginine
residues[94]. In conclusion, biological material based micro-
gels showed more controlled release of BMP-2 and high
loading efficiency that would be helpful in bone
regeneration[57].
Although microgels have been used for growth factor
delivery alone but its use with hydrogel may improve the
mechanical stability, release profile and immobilization at
site of implanting. In a different study, Yuan et al. used gly-
cidyl methacrylate to surface modification of heparin-conju-
gated hyaluronan microgel. These microgels were used to
reinforce the glycidyl-methacrylated hydrogel for sustained
delivery of BMP-2[78]. The in vitro release of BMP-2 showed
20% at day one from heparin-conjugated hyaluronan micro-
gel reinforced hydrogel in comparison to bulk gel (glycidyl-
methacrylated hyaluronan gel) with 60% burst release at day
one. The controlled release achieved in this study is desir-
able for osteogenic cells differentiation. Further this study
also demonstrated the relationship between swelling ratio
and BMP-2 loading. The higher swelling ratio of bulk gel
claims highest BMP-2 loading 43.4 ± 0.9 ng/mg, in compari-
son to microgels reinforced glycidyl-methacrylated hydrogel
(without heparin) with 21.9 ± 3.3 ng/mg loading. But as hep-
arin content increasing from 1 to 10%, BMP-2 loading also
increased from 28.2 ± 1.6 ng/mg to 42.4 ± 2.2 ng/mg in
microgels reinforced glycidyl-methacrylated hydrogel. In
spite of low swelling of microgels, reinforced glycidyl-metha-
crylated hydrogel with 10% heparin showed comparable
BMP-2 loading as bulk gel[78]. In conclusion swelling ratio
was not the only factor for higher BMP-2 loading but nega-
tively charged heparin content in microgels also play a part.
Study demonstrated that microgel reinforced hydrogel could
be desirable way to deliver the BMP-2 in more sustained
manner for bone regeneration application.
4.1.2. Microgel based drug delivery
The delivery of bioactive drug molecules is the first step
which decides the fate of elicited responses. The systemic
delivery of drug associated without any vehicle raises sys-
temic toxicity and associated side effects. The reduced bio-
activity, bioavailability and repeated dosage further
complicated the patients complains. An answer to following
limitations could be vehicle based drug delivery. Polymeric
microgel systems have been developed for extended drug
delivery. Polymers such as poly(N-isopropylacrylamide-co-
acrylic acid)[67], polyvinyl alcohol (PVA)[95], collagen[77] and
locust bean gum (LBG)[96] have been explored in the form
of microgel for osteoinductive drug, antibiotics deliv-
ery[77,97]. Infection is the major barrier in bone recovery and
may lead to loss of limb[98,99]. During the open fracture sur-
gery antibiotics such as cefazolin, pipercacillin, tazobactam,
tobramycin and penicillin are extensively used via systemic
route[100]. The higher dose size and frequent administration
of antibiotics causes side effects and patient discomfort
respectively. To combat the infection at open fracture site
initial faster release followed by sustained release of anti-
biotic molecules for longer time is desirable. In one study,
vencomycin has been used in three different ways to provide
the antibiotic functionality to the BioglassV-based scaf-
R
folds[67]. In first group vancomycin was directly coated with
Poly (D,L-lactide-co-glycolide) (PLGA) solution on
BioglassV-based scaffolds. In second group the vancomycin
R
loaded poly(N-isopropylacrylamide-co-acrylic acid) micro-
gels coated with PLGA solution on BioglassV-based scaffolds.
R
In third group vancomycin loaded microgel coated with
double layer of PLGA on BioglassV-based scaffolds. The
R
drug release study of group one scaffold demonstrated initial
burst release of vancomycin at 40 min. and remaining drug
was released within 8 h. On the contrary, group two and
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
three scaffolds showed initial slower burst release of vanco-
mycin at 6 h, and further extended controlled release until
4 days. So vancomycin loaded microgel coating provides a
release profile where initial rapid release followed by long
term sustains release of vancomycin is desirable to prevent
the infection and achieve the healing[67]. The release behav-
ior of drug from microgels can be regulated further by
changing the polymer. A study by Lv et al. presents polyvi-
nyl alcohol-borax (PVA-B) based microgels that were inves-
tigated for burst release of vancomycin hydrochloride. 94%
of drug was released in 5 min and remaining 6% was
released within 4 h. The rapid burst release can be attributed
to hydrophilic nature of microgels, which measured by con-
tact angle analysis (38.2 ± 0.64 ). The hydrophilic nature
allows rapid swelling of microgels and facilitates burst
release of drug[95]. Such studies demonstrated that microgels
of different polymers could be used as delivery vehicle for
antibiotic molecules. The microgel based initial burst release
followed by sustain release of antibiotic is desirable to mini-
mizes the chances of infection and rapid healing of
bone fracture.
In addition to antibiotics, microgels also have been inves-
tigated to assist the delivery of osteoinductive drug such as
dexamethasone in bone regeneration. The collagen microgels
integrated with poly(L-Lactide) (PLLA)-Dexamethsone
(Dex)-collagen hybrid scaffold were used to induce osteo-
genic differentiation in MSCs[77]. In this study author used
PLLA-collagen scaffold without collagen microgel as control
with 2.5% dexamethasone. While collagen microgel loaded
PLLA-collagen hybrid scaffold with dexamethasone concen-
tration 0%, 2.5%, and 5% were used. The results demon-
strated the initial burst followed by sustained release of
dexamethasone from all types of scaffolds. As the dexa-
methasone concentration increased in microgel loaded
PLLA-Collagen hybrid scaffolds, the initial burst release was
also increased. The initial rapid followed by sustained release
of dexamethasone could be desirable to maintain the thera-
peutic concentration. The loaded microgels assisted in sus-
tained release of dexamethasone in therapeutic window for
up to 28 days. While scaffold without microgel showed low
initial burst and slowest sustained release, which could be
due to hydrophobic PLLA. The effect of release pattern of
dexamethasone from Dex-microgel loaded PLLA-Collagen
hybrid scaffolds showed significantly increased expression of
COL1 (approximetly 1.7 fold) in cultured MSCs as com-
pared to without microgel scaffold after 21 days[77]. The ini-
tial burst release from Dex-microgel loaded PLLA-Collagen
hybrid scaffolds maintains therapeutic (325 ± 27 nM) concen-
trations in culture medium that might have caused increased
expression of COL1. In another study, the stimuli responsive
microgels were investigated for delivery of dexamethasone
and vencomycin. Poly(N-isopropylacrylamide-co-acrylic
acid) based temperature sensitive microgels prepared by pre-
cipitation polymerization method showed higher release of
dexamethasone at 37  C in compared to at 25  C. It is due
to the release of isopropyl group bound water by thermal
induction, which increases the intra and intermolecular
hydrophobic interactions between isopropyl groups. The
7
effect of cross linker density on dexamethasone release was
also studied. Results showed higher release rate of dexa-
methasone at lower crosslinking density. It was due to the
easier diffusion of drug from less dense polymer net-
work[101]. These studies demonstrated the applicability of
microgels as a drug delivery vehicle for osteoinductive and
antibiotic molecules in bone tissue engineering. In conclu-
sion the micro sized geometry of gel provides high surface-
to-volume ratio and good diffusion properties to control the
release of cargo. The ECM mimicking nature of microgel
helps to protect growth factors bioactivity for longer time.
While the stimuli responsive microgels advances its applica-
tion as delivery vehicle.
4.1.3. Microgel for cell transplantation
In addition to growth factors and drugs, cells are another
key player in bone tissue regeneration. The disturbed pool
of osteoblasts, osteocytes and osteoclasts and imbalanced
microenvironment of cellular talk in fractured bone leads to
delayed union and non union. The cells transplantation is a
viable strategy to restore the bone cells population at frac-
ture site. Stem cells like MSCs[102], murine embryonic stem
cells (ESCs)[103,104] and primary cells like human umbilical
vein endothelial cells (HUVECs)[105–107] have the potential
to regenerate the diseased and injured bone tissue[108–110].
However, their transplantations or delivery at site of regen-
eration remains challenging due to poor viability and reten-
tion of cells at the site of injury[111]. Cytocompatible and
hydrated microgel would be desirable carrier for encapsula-
tion of cells and their localized delivery[112,113]. Microgels
further facilitates large surface area to volume ratio, cellular
microenvironment, cell-cell and cell-matrix interactions[114].
Due to these properties, microgels are more suitable for
maintaining the encapsulated cells metabolically live for lon-
ger time period.
Microgel based delivery of cells can be achieved by two
different ways. In first approach cells can be delivered via
seeding on microgel surface and in second cells can be
encapsulated within microgel matrix and delivered at target
site. Following section will discuss the recent investigation
explored by both methods.
4.1.3.1. Microgel for delivery of surface adhered cells.
Microgels as microcarrier for cells transplantation offer sev-
eral advantages including large surface area in comparison
to conventional 2D surfaces. It enhances the chances of high
number of cells culture and proliferation in small volume of
culture media before transplantation. Microgels surface give
the opportunity to customize the chemical and physical
properties relevant to true cellular microenvironment[59].
Microgel surfaces can be tailored to enhance cells adhesion,
proliferation and differentiation (Figure 7a, b). Fabrication
of specific growth factor loaded microgel with cells seeded
on the surface could be the new approach. After injection of
this type of microgels, sustained release of growth factor to
differentiate the cells population would be expected.
However no such study has been reported until but in
future this is possible for bone regeneration. In a study by
8 L. K. MEENA ET AL.
Figure 7. Microgel based cell delivery strategies, (a) SEM image of pre-osteoblast MC3T3-E1 cells cultured on surface of core-shell microgel (cells indicated by red
arrow), (b) schematic demonstration of MSCs adhered on ECM mimicking surface of microgel, (c) schematic demonstration of encapsulated MSCs in the ECM mim-
icking microgel bulk matrix.
Schmidt et al. the arginine-glycine-aspartic acid (RGD) pep-
tide were used to tailor the surface of alginate microgels.
They found increased cell growth rate and osteogenic differ-
entiation as RGD peptide density increased on microgel sur-
face from 6.22  107 to 6.22  108 RGD/mm2 on single
microgel. On the microgel surface, RGD peptide enhances
bone marrow-derived MSCs adhesion as compared to with-
out RGD microgel. The increased RGD density on microgel
surface also increased the secretion of osteocalcin and osteo-
pontin as osteogenic differentiation markers. It might be
due to the increased cells integrin-RGD interactions as com-
pared to without RGD modified microgels[115]. This study
provides a new approach to design the novel cell adherent
microgels for delivery of therapeutic multipotent stem cells
to enhance the bone tissue regeneration.
4.1.3.2. Microgels for delivery of encapsulated cells.
Homing of precursor cells in three dimensional (3D) micro-
environments that could direct their osteogenic differenti-
ation is a major focus of tissue engineers. Various types of
biomaterial based scaffolds have been developed to recreate
the bone tissue microenvironment; however, because of the
harsh fabrication conditions, only few techniques have
gained the success of cell encapsulation. Microgels have
gained some attention because they provide the three
dimensionality to the cells entrapped in them[116] and entrap
the live cells during the fabrication process without much
damage to the cell viability (Figure 7c). The other advan-
tages for encapsulation of cells in microgel include the pro-
tection of the cells from external stress during injection and
transplantation. Furthermore, they avoid the faceoff with
host immune system hence increases their chance for inte-
gration to the host body. The encapsulations of stem cells
are more challenging as they are intends to self-renew and
differentiate simultaneously. Guermani et al. engineered
microgel array to evaluate the differentiating potential of
encapsulated human mesenchymal stem cells (hMSCs). They
used gelatin methacrylate (GelMA) and thiolated hyaluronic
acid (HA-SH) to engineer the hMSCs laden microgel arrays
through 3D printing system. Prepolymer GelMA with
hMSCs in form of microdrops were crosslinked by UV
irradiation while hMSCs laden prepolymer HA-SH micro-
drops were crosslinked by four-arm PEG-acrylate. In case of
HA-SH microgel, two different concentrations 0.5% and 1%
of four-arm PEG-acrylate was used. In results the compres-
sive modulus was improved from 5 kPa to 10 kPa due to
high cross linking density. The 5 kPa increase in compressive
modulus of microgels with increasing concentrations of
four-arm PEG-acrylate demonstrated mechano-compatibility
of microgel that is desirable for bone regeneration applica-
tion. The cytocompatibility of GelMA and HA-SH microgel
with hMSCs were evaluated. The viability of encapsulated
hMSCs was maintained in both types of microgel from day
1 to 7[117]. This result demonstrates the feasibility of micro-
gels in oxygen and nutrient diffusion to maintain the cell
viability. In one study Hou et al. prepared hMSCs and
BMP-2 loaded degradable microgel of poly(vinyl alcohol)
(PVA) through the micro-fluidic technology to provide
osteoinductive microenvironment for encapsulated hMSCs.
The 50% release of BMP-2 in 10 days from microgel was
observed. This controlled release of BMP-2 was able to
maintained osteoinductive concentration of BMP-2 inside
the microgel for encapsulated hMSCs. In osteoinductive
environment the ALP activity was significantly increased
2.0  103 nmol/ng, in compared to microgel without BMP-
2 with approximately 1.0  103 nmol/ng. The calcium con-
tent also increased approximately 30 fold in treatment group
compared to the control group at 28 days. The osteogenesis
related genes expression of Runx2 (approximately 1 fold)
and OPN (approximately 2 fold) was also increased signifi-
cantly after 3 week with treatment compared to the control
group. The results of study indicate that the long-term sus-
tained release of BMP-2 enhanced hMSCs osteogenic differ-
entiation. Therefore, osteoinductive microgel approach is a
promising strategy for controlled cell delivery in bone
regeneration[82].
Bone tissue engineering is a complex process, which
requires regulating three- dimensionality of cellular interac-
tions. Because during osteogenic differentiation cells
undergo cellular condensation, which amplifies the number
of osteogenic cells[118]. It is found that the early spheroid
formation resulted from cellular condensation, leads to upre-
gulation of several bone related genes[119]. Furthermore, cell
spheroid formation enhances bone formation both in vitro
and in vivo[120]. Alginate- -RGD microgels were used to
encapsulate human MSCs spheroids to retain their structure.
The morphology of the spheroid was retained within micro-
gel, since the solid gel formed by cross linking of alginate
molecules around the spheroid. RGD mimics the extracellu-
lar component of the matrix; hence exhibit the cell-matrix
interactions. The encapsulation of human MSC spheroids in
the microgel demonstrate enhanced osteogenic
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
differentiation[121]. In summary, the microgel is the most
desirable delivery device for therapeutic cells delivery in
bone regeneration. It is because of good diffusion properties
and ECM mimicking 3 D microenvironment that helps to
maintain cells viability. In future, there is ample opportunity
to develop the microgel based delivery system for multiple
cells with signaling molecules delivery to enhance the bone
regeneration.
4.2. Microgel as scaffolds
It is proven that microgels are desirable vehicle for deliver-
ing the growth factors, drugs or even cells. However, their
immobilization at site of implant, integration at target tissue
and poor sustained release remains open challenges for their
use as implantable devices. Integration of microgels with
existing scaffolding technology would be an interesting and
innovative approach for bone tissue engineering. In prin-
ciple, microgels can be used in combination with the other
osteoinductive or osteoconductive scaffolds, however only
few studies have been performed so far and the field has a
potential to be explored more. Nanda et al used osteoinduc-
tive microgels in combination with the osteoconductive
hybrid scaffold[77]. The collagen microgels were used to
mimic the osteoid microenvironment and assisted the
release of dexamethasone which is osteoinductive in action.
The incorporation of the collagen microgel was observed to
control the interconnected pore structure, which allowed
MSCs to infiltrate and distribute in the scaffold. The porous
structure of the hybrid scaffold resulted in the increased cell
growth. Furthermore, the microgel facilitated spatio-tem-
poral control of dexamethasone release to induced the dif-
ferentiation of human bone marrow derived MSCs towards
osteogenic lineage. The collagen-dexamethasone microgel
loaded PLLA-Collagen hybrid scaffold showed increased
expression of alkaline phosphatase, osteopontin, integrin-
binding sialoprotein, and runt-related transcription factor 2
after 21 days. Where, the expression of collagen type 1 was
highest in Dexamethasone-microgel loaded hybrid scaf-
fold[77]. Another study performed by Olalde et al. has also
shown the potential of microgel hybrid scaffold in bone
regeneration/osteogenic differentiation. The microgel was
used as a hybrid scaffold in a different manner. They devel-
oped a new family of scaffolds, incorporating biopolymer
coatings on BioglassV derived foams. The biopolymer coat-
R
ing was used as an antibiotic drug carrier. They found that
the coating with PLGA with vancomycin imparts antibiotic
functions to the scaffold. The primary object of the study
was to develop the multifunctional scaffold. They found that
coating of BioglassV with vancomycin loaded poly(N-isopro-
R
pylacrylamide-co-acrylic acid) microgel dispersed in PLGA
provides a rapid delivery of drug. They showed the antibac-
terial effect of the drug loaded hybrid microgel scaffold at
the wound site. Although, no direct assay for bone regener-
ation was performed; however, the microgel was found to
increase the bioactivity of scaffold by acting as nucleation
center for hydroxyapatite crystal formation in simulated
body fluid[67]. Hence, it could promote the bone
9
regeneration because the hydroxyapatite formation is consid-
ered as gold standard for determination of osteogenic differ-
entiation, as it is the major constituent of bone[122–124]. To
the best of our knowledge, so far only few microgel hybrid
scaffolds are being used for the osteogenic differentiation/
bone regeneration applications, which are mentioned above.
However, few studies have reported only the formulations
for developing microgel osteoconductive hybrid scaffolds.
Their applications for osteogenic differentiations are yet to
be reported. Birkholz et al. has fabricated microgel-b-TCP
composite scaffolds. The microgel was fabricated using
Poly(N-vinlycaprolactam), 2-(methacryloyloxy)ethyl acetoa-
cetate and 1-vinylimidazol. The microgel dispersions were
mixed with b-TCP and freeze dried or spray dried to yield
composite granulates. They proved that the microgel chem-
ically interacted with b-TCP particles without use of any
binder. Therefore it is possible to use these hybrid scaffolds
without any phase impurities for the manufacturing of bone
implants via powder based 3D-printing. Furthermore, the
porosity of the printed scaffolds can be increased by burning
out of microgels in a sintering process, which can give an
advantage in the process of bone resorption[125].
Cell morphological changes are correlated with the cellu-
lar differentiation. Jhala et al. has reported that change in
the cell shape has influenced their differentiation potential.
The cell shape changed from spindle to polygonal shaped
during osteogenic differentiation. The cells shapes were
influenced by growing them on different types of sub-
strates[76]. Microgels have also shown the potential to influ-
ence the change in cell morphology to induce osteogenic
differentiation. In a study by Dai et al. cell culture dishes
were coated with Poly(N-isopropylacrylamide-co-acrylic
acid) microgels to culture MSCs. Cells grown on microgel-
coated surface changed their morphology from spindle shape
to more stretched and elongated cell shape (Figure 8).
Furthermore, cell morphological changes were accompanied
with the change in expression of osteopontin, Runt-related
transcription factor 2 (RUNX2) and collagen type 1, which
are osteogenesis related genes. Microgels were also observed
to elevate the expression level of these genes without any
inducing factor[126].
For the bone defect regeneration, injectable gel systems
have many advantages over the conventionally used scaffolds
such as increased handling properties, controlled flowability
and adaptability to the defect site[127,128]. Furthermore, the
injectable gel can be incorporated with growth factors or
any bioactive molecule which could aid and increase the
bone defect reconstruction[129]. Therefore, injectable form of
microgel is considered to be advantageous over other bone
substitutes. Nanohydroxyapatite incorporated chitin-poly(e-
caprolactone) (Chitin-PCL-nHAp) based injectable microgels
has been used by Kumar, et al. for bone defect repair. Their
results depicted that Chitin-PCL-nHAp microgel elicited an
early osteogenic differentiation compared to Chitin-PCL
gel[130]. In another study, Das et al. used injectable hybrid
microgel/microspheres for the delivery of sphingolipid
growth factor FTY720 to critical size cranial defects in rats.
The microgel composed of chitosan and inorganic
10 L. K. MEENA ET AL.
Figure 8. Shows the immunostaining of F-actin in MSCs grown on normal culture plate (left) and plates coated with Poly(N-isopropylacrylamide-co-acrylic acid)
microgels (right), the pointed arrows show the increased density of actin which enhances the morphological changes in the cells. The figure is reproduced from
reference[126].
phosphate to deliver sphingolipid growth factor FTY720
loaded in poly(lactide-co-glycolic acid) microspheres. They
showed that sustained release of FTY720 from microspheres
improves vascularization and bone formation in critical size
cranial defects in Sprague Dawley rats. Furthermore, these
growth factor releasing microgel/microsphere hybrids
reduced the infiltration of inflammatory cells and promoted
recruitment of bone progenitor cells after stimulation with
BMP-2[62]. Therefore, injectable microgel has the potential
to regenerate the bone defects which are irregularly shaped,
even in deeper planes and complex in nature.
4.3. Microgel as 3D microarrays
Microenvironmental cues determine the differentiation of
stem cells into the specialized cell types. These microenvir-
onmental cues are governed by the cell-cell interactions,
cell-ECM interactions[131–133], soluble factors[131], matrix
topography and stiffness[132–135]. These cues act in a syner-
gistic manner to determine the fate of stem cells to form the
functional tissue. Particularly, the three dimentionality of
the ECM regulate the cell behavior and differentiation[136].
It is a well-known fact that the cellular functions substan-
tially deviate on 3D scaffolds compared to 2D sub-
strates[137,138]. Therefore, it is crucial to develop 3D scaffolds
with controlled presentation of the environmental cues for
studying the stem cell response. Development of the 3D
combinatorial microenvironments is an important step to
simultaneous provides various cues to the stem cells[139].
Multiwell based combinatorial microenvironments have
been well explored for screening the fate of stem
cells[140–142]. In these techniques, stem cell encapsulated
ECM rich hydrogels are directly added to the regular multi-
well plates[140]. In other approaches, polymeric solutions are
deposited into the multiwell plates to generate the scaffold
arrays[141,142]. Despite of wide applications, these multiwell
based platforms face several limitations due to high reagent
cost which leads to the less versatile technology[139].
Therefore, development of cost-efficient platforms can
address these limitations of versatility. Microarray technol-
ogy has enabled the development of versatile platforms to
address the limitations of conventional assays[143–145].
However, microarray technology utilizes 2D substrate system
to understand the cellular behavior[146–150]. They provide
valuable insight about the differentiation of stem cells but
fails to mimic the tissue architecture[146,147,150]. Current
focus of microarray based technology for bone regeneration
is the development of 3D miniaturized cellular platforms.
For instance, Microgel arrays are utilized as 3D miniaturized
cellular platforms for off-the-shelf-tissue studies. The micro-
gel environments were composed in a manner to resemble
native vascularized and bone marrow tissue architectures.
The complex heterogeneous tissue like structure lead to the
localized cell spreading and osteogenic differentiation of
hMSCs[117]. In another study, Gelatin methacrylate/nHA
photocrosslinkable microgel arrays encapsulating human
periodontal ligament stem cells were used for in vitro and in
vivo studies. The microgel arrays facilitated the in vitro cell
viability, proliferation and osteogenic differentiation of stem
cells; and promoted bone formation in vivo[151]. In another
study, combinatorial screening of hMSCs differentiation
using 3D cell-laden gel microarray platform in response to
ECM components and growth factors has been performed.
It used an automated printing technique to fabricate the
microgel units composed of hMSCs embedded in methacry-
lated gelatin (GE) along with ECM proteins and growth fac-
tors. ECM proteins including fibronectin, laminin and
osteocalcin in different compositions along with BMP-2 and
BMP-5 were used for microgel fabrication. The technique
utilizes 1000 fold less materials and cells compared to con-
ventional multiwell based assays[152]. Figure 9a shows the
schematic of the microarray fabrication process. Cell laden
GE hydrogel with different combination of ECM proteins
are robotically spotted in the form of microgels. The depos-
ited microgels are then crosslinked by ultraviolet light
exposure to develop cell-laden constructs. Figure 9b shows
the different combinations used for the microgel fabrication.
Florescent imaging Figures 9c and 9d revels the ECM
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS 11

Figure 9. Schematic of the microgel based microarray fabrication. (a) GE hydrogel containing hMSCs with different combination of ECM proteins are spotted robot-
ically. The microgel spots are crosslimked by UV light exposure. (b) shows the various combination of ECM proteins and the media formulations used to conduct
the experiments. (c) shows the florescence images of the ECM proteins used in the fabrication of microgel array. (d) shows the florescence images to depict the via-
bility of the cells with colour-diagram of percent cell viability. The images are reproduced from reference[152].

protein combinations used for the microgel fabrication and
the viability of the encapsulated cells in the microgels
respectively.
Different applications of microgels for bone tissue engin-
eering also have been summarized in Table 2.
5. Microgel: commercial aspect
The current research on microgel is majorly focused on
novel fabrication methods and applications in bone tissue
engineering. There are very few microgel devices available
commercially for bone tissue engineering applications.
Microgels have been available as micro-carriers, which can
be used for expansion culture of cells in vitro[153]. These
micro-carriers were explored for large scale production of
bioactive compounds and bioreactor cultures of human
mesenchymal stem cells. No direct study was performed for
bone tissue engineering; however these devices were utilized
for stem cells expansion and growth for tissue engineering
applications[154,155]. For instance, Cytodex 3 is commercially
available micro-carrier from GE healthcare. These micro-
carriers are dextran matrix coated with collagen for cell
attachment. It was observed that 3000 micro-carriers per ml
suspension with 5X cell density to micro-carrier showed
optimum hMSCs expansion. The maximum yield was
obtained at 10 days of culture having 20-fold increased cell
per micro-carrier[156]. Microgel based devices have been
studied in vivo on small animal models for bone regener-
ation applications[157,158]. For growth factor/drug delivery,
none of microgel device is been available commercially or
been extended to clinical phase till date. Similarly, the
12 L. K. MEENA ET AL.
Table 2. Various applications of microgels for bone tissue engineering.
Device type Composition
Microgels Heparin, hyaluronan
Microgels reinforced hydrogels Glycidyl methacrylate, heparin, hyaluronan,
poly(N-isopropylacrylamide-co-acrylic acid), PLGA, BioglassV
Microgels coated scaffold
Microgels polyvinyl alcohol-borax
Microgels based scaffold Collagen, poly(L-Lactide)
Microgels Poly(N-isopropylacrylamide-co-acrylic acid)
Microgels Alginate, RGD peptide
Microgels Gelatin, methacrylate, thiolated hyaluronic acid
microgel loaded hybrid scaffolds also not explored clinically
to date.
The literature suggests that still there is no such device
available exclusively for bone tissue engineering applications.
However, considering the numbers of in vitro and in vivo
studies significant growth and translation of devices can be
anticipated.
6. Conclusions and future perspectives
Bone replacement is becoming the most widely transplant-
ation in the world, utilizing various types of innovative
materials and scaffolds. In recent years, microgels have been
explored as potential scaffolds for bone tissue engineering.
The soft and elastic nature of microgels imparts the inject-
ability of scaffolds eliminate the dependency of open surgical
procedures, which greatly expand its applicability in bone
tissue engineering. Its structural and physic-chemical fea-
tures provide the adhesive and encapsulation properties,
which allow them to utilize for osteoconductive molecules
or progenitor cells delivery. Moreover, small size can widen
the fabrication parameters to make hybrid scaffolds. Taken
all together these third generation devices have not merely
scaffolding the bone tissue, rather dynamically participate in
and enhance the bone regeneration. Which have signifi-
cantly advanced the bone transplantation strategies.
However, this field is continuously growing, having limited
commercially developed devices, indicates further require-
ment of research and development for clinical efficacy and
commercial scale-up.
In addition, these scaffolds have enormous potential to
explore in several ways to design and develop for specific
bone tissue engineering applications as a future perspective.
In particular, bone regeneration is a multifaceted process
comprising involvement of numerous molecules and com-
plex cell-matrix interactions orchestrated at a time.
Recapitulating this multipart process is essential for achiev-
ing accurate bone restoration. The biological prospect could
include the involvement of multiple growth factor and cells
in to elicit multi-scale signaling pathways. Furthermore, a
multilayered microgel would be designed to incorporate
more than one molecule/growth factor in a single device
having sequential release. This would be helpful to stimulate
the different stages of bone regeneration. A desired device
could also be envisioned as stimuli responsive device for
release of signaling molecules based on requirement.
Application
Controlled release of BMP-2 for bone regeneration[57]
Sustained delivery of BMP-2 for bone regeneration[78]
R
Initial rapid followed by sustained release of vancomycin for
prevent the infection in bone healing[67]
Controlled release of vancomycin for prevent the infection in
bone healing[95]
Controlled release of dexamethsone for osteoblasts differenti-
ation of MSCs[77]
Controlled release of dexamethsone and vancomycin[101]
Scaffold for MSCs culture and delivery[115]
Encapsulation and delivery of hMSCs[117]
Looking forward, recent advancement in microgel based
technologies could enrich translational bone tissue engineer-
ing field and advance the current bone rejuven-
ation strategies.
Acknowledgements
The author acknowledges the University Grant Commission (Govt of
India) for a senior research fellowship.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The RV acknowledges the GSBTM [GSBTM/MD/Projects/SSA/1431/
2014-15] for providing the financial support.
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