Carbohydrate Polymers 251 (2021) 117063

Contents lists available at ScienceDirect

Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol

Review

Chitosan-based drug delivery systems: From synthesis strategy to

osteomyelitis treatment – A review
Fenghua Tao a, b, 1, Sijia Ma a, 1, Hai Tao a, Lin Jin a, Yue Luo a, Jian Zheng a, Wei Xiang a, b, *,
Hongbing Deng b, *
a
Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China
b
Hubei International Scientific and Technological Cooperation Base of Sustainable Resource and Energy, Hubei Key Laboratory of Biomass Resource Chemistry and
Environmental Biotechnology, School of Resource and Environmental Science, Wuhan University, Wuhan 430079, China

A R T I C L E I N F O A B S T R A C T

Keywords: Osteomyelitis is a complex disease in orthopedics mainly caused by bacterial pathogens invading bone or bone
Chitosan marrow. The treatment of osteomyelitis is highly difficult and it is a major challenge in orthopedic surgery. The
Drug delivery system long-term systemic use of antibiotics may lead to antibiotic resistance and has limited effects on eradicating local
Antibiotic
biofilms. Localized antibiotic delivery after surgical debridement can overcome the problem of antibiotic
Implants-related infection
Osteomyelitis
resistance and reduce systemic toxicity. Chitosan, a special cationic polysaccharide, is a product extracted from
the deacetylation of chitin. It has numerous advantages, such as nontoxicity, biocompatibility, and biodegrad­
ability. Recently, chitosan has attracted significant attention in bacterial inhibition and drug delivery. Because
chitosan contains many functional bioactive groups conducive to chemical reaction and modification, some
chitosan-based biomaterials have been applied as the local antibiotic delivery systems in the treatment of
osteomyelitis. This review aims to introduce recent advances in the biomedical applications of chitosan-based
drug delivery systems in osteomyelitis treatment and to highlight the perspectives for further studies.

1. Introduction
Osteomyelitis is a complex inflammatory disease always caused by a
bacterial infection (Kavanagh et al., 2018). The prolonged osteomyelitis
often recrudesce and can lead to progressive bone destruction, and it has
become a major challenge in orthopedics (Roderick, Sen, & Ramanan,
2018). The pathogenesis of osteomyelitis is complex and varied,
including endogenous bacterial seedings such as hematogenous osteo­
myelitis and exogenous bacterial infection caused by open injury and
surgical implant contamination (Seebach & Kubatzky, 2019; Singh,
Bierrum, Wormald, & Eastwood, 2020; Thakolkaran & Shetty, 2019).
With the popularity of bone fracture internal fixation, joint replacement,
and bone substitute biomaterials, the surgical implants-related in­
fections have become the most important causes of osteomyelitis,
leading to considerable difficulties and challenges in clinical treatment
(Metsemakers et al., 2018). If not controlled well, a local infection can
develop into chronic osteomyelitis and exist for months or even years,
resulting in a prolonged hospital stay for patients (Urish & Cassat,
2020). Furthermore, sinus tract and skin squamous epithelium trans­
formation can be detected around the long-lasting infection lesions in
osteomyelitis, requiring multiple debridement operations and system­
atic antibiotic treatment (Jiang et al., 2020; Li et al., 2015). In severe
cases, osteomyelitis can lead to limb necrosis, dysfunction, and even
sepsis, which requires amputation or ICU rescue and eventually leads to
permanent disability (Shi et al., 2020).
The standard treatment for osteomyelitis involves the extensive
debridement of the infected bone, the obliteration of dead space, and a
long-term systemic administration of antibiotics (Masters et al., 2019;
Pincher, Fenton, Jeyapalan, Barlow, & Sharma, 2019). For
implant-related osteomyelitis, particularly the periprosthetic infection,
the treatment first requires the removal of the infected prosthesis.
Subsequently, the bone and joint repair surgery should be performed
after prolonged local and systemic antibiotic therapy (Masters et al.,
2019). The challenge of surgical treatment is to perform a thorough

* Corresponding authors at: Wei Xiang, Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China. Hongbing
Deng, Hubei International Scientific and Technological Cooperation Base of Sustainable Resource and Energy, Hubei Key Laboratory of Biomass Resource Chemistry
and Environmental Biotechnology, School of Resource and Environmental Science, Wuhan University, Wuhan 430079, China.
E-mail addresses: xiangwei_13@whu.edu.cn (W. Xiang), hbdeng@whu.edu.cn (H. Deng).
1
Contributed equally to this work.

https://doi.org/10.1016/j.carbpol.2020.117063
Received 8 July 2020; Received in revised form 22 August 2020; Accepted 3 September 2020
Available online 12 September 2020
0144-8617/© 2020 Elsevier Ltd. All rights reserved.
F. Tao et al.
Fig. 1. Schematic diagram illustrating the process of local drug delivery system for the treatment of osteomyelitis.
debridement and preserve the normal bone tissue in order to avoid bone
nonunion and limb dysfunction. Meanwhile, the systemic antibiotic
administration requires a long-term and a large dose because the
localized bacterial plaque can inhibit the antibiotic diffusion from blood
to the infection site (Nandi et al., 2016). The limited availability of
antibiotics at the target site is often insufficient to eradicate the local
bacteria (Mahmoudian & Ganji, 2017). Additionally, the use of
long-term and high-dose systemic antibiotics may lead to antibiotic
resistance and cause side effects affecting organs (Bhattacharya, Kundu,
Nandi, & Basu, 2013; Nandi et al., 2016). Recently, to overcome these
restrictions, local antibiotic delivery system (Fig. 1) has been established
as an effective approach to cure osteomyelitis (Nandi et al., 2016). Local
drug delivery systems are superior to systemic administration because
they can control the long-term and high-dose release of antibiotics
directly to the target tissue with few hazards of toxicity to organs (Boles
et al., 2018). Filling polymethyl methacrylate (PMMA) bone cement and
beads loaded with antibiotics in the local infection sites has been
considered as the standard practice in osteomyelitis treatment for de­
cades. The usage of antibiotics-loaded PMMA in osteomyelitis is ad­
vantageous for delivering a high concentration of drugs to local infection
sites and reducing the organic toxicity (Masters et al., 2019). However,
many problems have been found in the application of PMMA-based drug
delivery systems. For example, the rapid thermal diffusivity, the
non-biodegradability and the poor drug release kinetics can affect the
therapeutic effects of antibiotic-loaded PMMA bone cement on osteo­
myelitis (Inzana, Schwarz, Kates, & Awad, 2016). Therefore, it is
necessary to develop more satisfactory drug delivery systems that should
be biocompatible and biodegradable and also have a desired loading
efficiency and an appropriate release rate to eradicate osteomyelitis
(Zeng, Hoque, & Varghese, 2019). Natural biomaterial-based drug de­
livery systems can provide reliable solutions to these problems.
Chitosan (CS) is a kind of polysaccharide polymer extracted from the
deacetylation of chitin, which is the second most abundant biological
resources in nature next to cellulose. It mainly exists in the shells of
crustaceans, insects, and fungal cells walls (Bakshi, Selvakumar, Kadir­
velu, & Kumar, 2020). CS is a cationic biopolymer with active functional
groups, which is advantageous for modification and chemical reactions
2
Carbohydrate Polymers 251 (2021) 117063
(Negm, Hefni, Abd-Elaal, Badr, & Abou Kana, 2020). In recent years,
multiple special properties of CS, such as biodegradability, biocompat­
ibility, low immunogenicity, non-toxicity, and intrinsic antibacterial
activity, have been reported (Tao et al., 2020). These special charac­
teristics have attracted increasing attention in tissue engineering.
CS-based biomaterials have been widely used in biomedical applications
such as biological substitute materials, wound dressing, drug carriers,
and antibacterials (Ding, Deng, Du, Shi, & Wang, 2014; Ding, Zhao et al.,
2014). Owing to the advantageous bioactivities, significant progresses
have been made in the field of CS-based drug delivery systems. The
application of CS-assisted antibacterial delivery has attracted immense
attention in curing bone infections (Kimna, Deger, Tamburaci, & Tih­
minlioglu, 2019). This review aims to summarize and discuss recent
developments and applications of CS-based drug loading and delivery
systems in the treatment of osteomyelitis.
2. Biological properties of CS
As a naturally derived amino polysaccharide, CS has abundant
bioactive hydroxyl and amino groups, which determine the changeable
solubility, chemical reactivity, and bioactivity of CS (Qin & Li, 2020).
The molecular structure of CS is similar to collagen and can be applied to
mimic the extracellular matrix (ECM). Due to the excellent biological
properties, it has been widely used in tissue engineering (Chen et al.,
2018). CS has been proven to be biodegradable, biocompatible,
nontoxic, nonallergenic and bioadhesive (Tao et al., 2020). Further­
more, it can be degraded into small molecular by enzymes and readily
absorbed in vivo (Fang, Lin, Sun, & Lin, 2019). Consequently, CS is a
promising biomaterial with broad application prospects in the field of
biomedicine.
CS-based biomaterials consistently demonstrate excellent biocom­
patibility to cell and bioactive substances (Li, Koenig, Sloan, & Leipzig,
2014). The molecular structure of CS determines high thermal and
chemical stability (Karakecili, Topuz, Korpayev, & Erdek, 2019). CS can
be fabricated into various scaffolds for tissue engineering by modifying
its structure and functions (Abinaya, Prasith, Ashwin, Viji Chandran, &
Selvamurugan, 2019). Biomaterials with CS as the main component are
F. Tao et al.
conducive to enhancing cell bioactivities, such as adhesion, prolifera­
tion, and differentiation, which are essential for tissue regeneration and
repair (Riaz Rajoka, Zhao, Mehwish, Wu, & Mahmood, 2019). In bone
tissue engineering, CS-based biomaterial scaffolds exhibit excellent
biocompatibility to seed cells, such as osteoblasts, osteocytes, and stem
cells (Tao et al., 2020). For example, a bioprintable CS-hydroxyapatite
(HAp) hydrogel shows good affinity to osteoblast and can maintain
cell viability and proliferation, as well as promote biomineralization and
osteogenic differentiation in an early stage (Demirtas, Irmak, &
Gumusderelioglu, 2017). CS-based membranes are good candidates for
guiding bone regeneration. The glycerylphytate crosslinked CS mem­
branes are beneficial for mesenchymal stem cells (MSC) growth, and can
promote calcium deposition and alkaline phosphatase (ALP) activity to
facilitate bone regeneration (Mora-Boza et al., 2020). The CS bioactive
glass nanoparticles hybrid scaffolds exhibit adequate degradation
properties and are conducive to the deposition of HAp to promote
osseointegration (Oudadesse et al., 2020). CS scaffolds incorporated
with HAp and pyrophosphatase can significantly promote osteoblast
proliferation and calcium phosphate deposition. These hybrid CS scaf­
folds can enhance the callus formation to facilitate bone fracture healing
(Jahan, Manickam, Tabrizian, & Murshed, 2020). CS nanoparticles can
be used to deliver BMP-2 plasmid to MSC and facilitate endogenous
BMP-2 protein secretion, which significantly enhances MSC-mediated
osteogenesis and accelerates bone formation in critical-sized defects
(Raftery et al., 2018). The CS derivatives can also improve bone bio­
materials physicochemical properties and bioactivity. Lin et al. reported
that the quaternary ammonium chitosan (QTS) can improve the anti­
bacterial efficacy, washout performance and osteogenic activity of cal­
cium silicate-based hybrid cements. These CS derivative-based hybrid
cements can be promising candidates for promoting bone defects repair
(Lin, Chen, Wu, & Ding, 2020). The carboxymethyl chitosan (CMCS)
doped synchronous self-assembly/mineralization collagen scaffolds
exhibit good antibacterial effects and can synergistically promote bone
marrow mesenchymal stromal cells (BMSCs) proliferation and osteo­
genic differentiation (Liu et al., 2020). The CS derivatives involved
multifunctional scaffolds can meet the clinical challenges of promoting
bone regeneration. These properties significantly expand the applica­
tions of CS-based biomaterials in bone tissue engineering.
As a polycation polymer, CS exhibits good affinity for negatively
charged bioactive molecules, such as antigen (Weber et al., 2010),
antibody (Polexe & Delair, 2013), enzyme (Marquardt et al., 2016),
cytokines (Anouz, Repanas, Schwarz, & Groth, 2018; Jimi, Jaguparov,
Nurkesh, Sultankulov, & Saparov, 2020), DNA (Ahmadi, De Llano, &
Barisic, 2018), and polyanion polymers (Francesko et al., 2018). A
colloidal vaccine delivery system loaded with an antigenic protein is
synthesized by the combination of CS and dextran sulfate. This delivery
system can activate the humoral and cellular immune response to
facilitate a high production of antibodies (Weber et al., 2010). The
antibody functionalized colloids can be prepared by charge neutraliza­
tion between polycation CS and polyanion hyaluronic acid. These
nano-structured particles can immobilize the antibodies on the surface
and show a broad application prospect in target drug delivery (Polexe &
Delair, 2013). CS-based scaffolds can retain a biological function and
control the release of loaded growth factors. The BMP-2 and TGF-β1
loaded visible light-cured glycol CS hydrogels can increase the bone
volume and mineral density in the bone defect sites via prolonged
releasing the bioactive molecules, and demonstrate the potential for
clinical applications in orthopedic practice (Yoon et al., 2018). An
antibacterial freestanding nano-biocomposite film is synthesized by the
layer-by-layer (LBL) assembling method. The polycationic CS-silver
nanoparticles and the polyanion hyaluronic acid are sequentially
deposited to form a stable 3D scaffold, which can inhibit bacteria growth
and prevent biofilms formation (Francesko et al., 2018). These specific
biological properties determine that CS can be widely used in the
biomedical field.
3
Carbohydrate Polymers 251 (2021) 117063
3. CS-based drug delivery systems
The presence of free amine groups in the backbone chain confers to
CS the unique polycationic character that ensures the encapsulation of
negatively charged proteins and peptides (Sultankulov, Berillo, Sultan­
kulova, Tokay, & Saparov, 2019). Simultaneously, the inherent biode­
gradability, bioadhesion, plasticity, and modifiability of CS allow its use
as a material component to prepare drug delivery systems. These
CS-based scaffolds can be designed and fabricated into various struc­
tures, shapes, and functions to meet different requirements of disease
treatments (Li et al., 2018). For example, novel CS polymeric micelles
fabricated by combining the benefits of PEGylation with acylation can
efficiently encapsulate and protect hydrophobic drugs. The new
amphiphilic CS drug carriers can act as efficient delivery systems to load
hydrophobic drugs in tissue engineering (Almeida et al., 2020). A kind
of α-helical antimicrobial peptide (AMP) can be covalently immobilized
on the CS coating. This composite scaffold exhibits good bactericidal,
hemostatic and osteoconductive properties, and can be used in several
infection scenarios, such as wound infection and bone implants- related
infection (Monteiro et al., 2020). The kartogenin-loaded CS hydrogels
modified by N-(β-maleimidopropyloxy) succinimide ester demonstrate
the enhanced shear modulus. This kind of CS-based drug delivery system
is injectable and thermosensitive. Moreover, it can control a sustained
release of kartogenin to enhanced chondrogenic differentiation (Deh­
ghan-Baniani et al., 2020). To introduce more beneficial insulin delivery
system for diabetes treatment, the quaternized CS-based thermosensi­
tive hydrogel is prepared for insulin delivery through the nasal cavity.
This drug delivery system demonstrates a uniform porous structure,
desirable swelling rate, and adequate encapsulation. These properties
contribute to the prolonged release of insulin to improve the therapeutic
effects on diabetes (Bahmanpour, Ghaffari, Milan, Moztarzadeh, &
Mozafari, 2020). In cancer treatment, the CS-based pH-sensitive
anti-tumor drug delivery system can enhance the biological activity of
the drug and selectivity against target tumor cells. The pH-sensitive
polymer can improve encapsulation efficiency and release profile of
doxorubicin by atomic interaction (J. Li et al., 2020). CS-based drug
delivery systems are widely utilized in the target disease therapy of
biomedicine.
In bone tissue engineering, CS-based drug carriers often possess good
mechanical properties and controlled drug release efficiency. These
scaffolds demonstrate great potential for promoting bone regeneration
and treating bone diseases (Venkatesan, Anil, Kim, & Shim, 2017). An
injectable biological scaffold with good mechanical properties is pre­
pared by introducing electrospun SiO2 nanofibers into CS hydrogels,
followed by homogenous dispersion and lyophilization. The composite
nanofibrous scaffolds can mimic ECM without toxic chemical cross­
linking. These composite scaffolds are found beneficial for BMSCs
adhesion and stretching. Further, the bioactive BMP-2 can be efficiently
immobilized on the scaffolds to exert the promotive function of osteo­
genesis (Wang et al., 2020). Suitable mechanical properties of bio­
materials are essential to support osteogenesis and osteointegration in
bone tissue engineering. Because CS lacks mechanical strength, con­
structing composite materials or undergoing chemical modification is
required to enhance mechanical property to facilitate biomineralization
(Deepthi, Venkatesan, Kim, Bumgardner, & Jayakumar, 2016; Sar­
avanan, Leena, & Selvamurugan, 2016). Mechanical properties of
CS-based scaffolds are always enhanced by adding HAp, bioglasses, ce­
ramics, and some inorganic salts. The novel ultralong HAp microtube-CS
composite scaffolds can demonstrate high drug loading efficiency, sus­
tained drug release capacity and high antibacterial activity. The addi­
tion of HAp provides the composite drug delivery system with excellent
mechanical properties for bone regeneration (Zhang, Zhu, Chen, & Sun,
2017). The poly(vinyl alcohol)-bioglass/CS-collagen porous scaffolds
exhibit significantly improved mechanical properties, calcium deposi­
tion, biological function and controlled drug release. These essential
characteristics make the composite scaffolds promising candidates in
F. Tao et al.
bone tissue engineering (Pon-On et al., 2014). Porous CS scaffolds
combined with ceramics show significantly improved osteoinductive
capacity by enhancing the mechanical properties and biocompatibility.
Moreover, they can control the release of a bioactive platelet-derived
growth factor to improve tissue regeneration efficacy (Lee et al.,
2002). A biodegradable bone graft dual-delivery system, fabricated by
embedding CS microspheres in calcium sulfate, can efficiently load and
release antibiotic and growth factors at the same time. This
dual-delivery system is an efficient alternative in bone tissue engineer­
ing due to the prevention of bone infection and the facilitation of bone
regeneration simultaneously (Doty, Leedy, Courtney, Haggard, &
Bumgardner, 2014). These CS-based composite drug delivery systems
can meet the requirements of mechanical and biological properties of
bone substitution biomaterials. Increasing attention has been paid to the
application value of CS-based drug delivery systems in treating osteo­
myelitis and bone defect repair.
In recent years, three-dimensional (3D) printing technique has
gained popularity in bone tissue engineering. Biomaterial scaffolds
prepared by 3D printing always have unique inherent characteristics
and enormous advantages (Pandey, Singh, Singh, Jha, & Prakash, 2020).
The antibiotic delivery systems fabricated by 3D printing method have
been widely used and are promising options for osteomyelitis treatment
(Mills, Jammalamadaka, Tappa, & Weisman, 2018; Shnol & LaPorta,
2018). A kind of rifampicin-loaded PCL drug delivery system can be
fabricated by 3D printing under low temperatures. This computer-aided
design and manufacturing porous scaffold can maintain the antibacterial
activity and control the release of rifampicin (Lee et al., 2020). The
rifampin and sitafloxacin loaded 3D-printed calcium phosphate scaf­
folds can control the antibiotics release in osteomyelitis animal model.
The antibiotic loaded scaffolds can significantly reduce local bacterial
colonization for a long time and show good osteoconductive property in
osteomyelitis treatment (Trombetta et al., 2019). A kind of 3D-printed
calcium phosphate bioceramics can also be fabricated as dual antibi­
otics delivery systems for the treatment of implant-associated bone
infection (Inzana, Trombetta, Schwarz, Kates, & Awad, 2015). These
novel 3D printing scaffolds are promising patient-customized treatment
options for osteomyelitis because of their good antibacterial activity and
osteoinductivity. Recently, the CS-based biomaterials prepared by 3D
printing technology have been widely applied in bone tissue engineering
(Li et al., 2019). The fused filament fabricated CS reinforced
poly-lactic-acid (PLA) biomaterials are prepared by 3D printing. These
scaffolds have shape memory effects and good wettability for cell
adhesion and proliferation. The shape recovery characteristics and
biological activities endow the scaffolds excellent self-healing properties
for bone defects repair (Pandey et al., 2020). The CS-based biomaterial
scaffolds can be fabricated as good drug delivery systems by 3D printing
method. The 3D-printed lactoferrin-loaded carboxymethyl
cellulose-glycol CS scaffolds have stable hydrogel network. This kind of
injectable gels show sustained drug release and good biocompatibility
for osteoblasts and BMSCs growth (Janarthanan et al., 2020). The
3D-printed BMP-2 loaded poly(L-lactic-co-glycolic acid) (PLGA)/­
HAp/CS scaffolds show sustained growth factor release and can control
the early burst release of BMP-2. This kind of composite scaffolds can
significantly facilitate new bone formation in bone defect site (Deng
et al., 2019). The crosslinker modified CS scaffolds can improve the
osteoinductivity and osteointegration abilities in bone tissue engineer­
ing (Mora-Boza et al., 2020). These CS-based biomaterials are promising
implants for promoting bone regeneration and defects repair. Besides,
the 3D-printed CS scaffolds with multifunctional-therapeutic properties
exhibit many advantages in challenging the infected bone defects. The
3D-printed quaternized CS/PLGA/HA scaffolds exhibit enhanced anti­
bacterial and osteoconductive properties. The dual-functional
3D-printed CS biomaterials are promising implants in orthopedic sur­
gery (Yang et al., 2018). Thus, the preparation of patient-customized CS
drug delivery systems via 3D printing method has tremendous applica­
tion value in the treatment of osteomyelitis.
4
Carbohydrate Polymers 251 (2021) 117063
4. Local drug delivery systems for osteomyelitis treatment
The treatment of osteomyelitis is a long and complex process. The
standard treatment includes extensive surgical removal of the infected
bone and adjacent soft tissue, removal of dead bone, elimination of dead
space and long-term systemic use of antibiotics (Masters et al., 2019).
However, local recurrence of osteomyelitis may still occur. After thor­
ough debridement, local filling of a drug delivery system is capable of
maintaining the sustained release of antibiotics for a long time. It is
beneficial for keeping high concentrations of antibiotics locally to
remove the residual bacteria and prevent the recurrence of osteomyelitis
(Ford & Cassat, 2017). The development of the local drug delivery
systems can significantly improve the therapeutic effects of osteomye­
litis (Nandi et al., 2016). High concentrations of antibiotics can be
achieved at the infection sites with reduced systemic toxicity via local
antibiotic delivery systems. For a long time, PMMA bone cements beads
or coated rods antibiotic delivery systems are treated as the standard
practice for preventing periprosthetic joint infections and treating local
infection in osteomyelitis (Tan et al., 2012). PMMA bone cements do not
show significant tissue toxicity in vivo, and some broad-spectrum anti­
biotics such as gentamicin and vancomycin exhibit good biocompati­
bility with the PMMA drug delivery systems (Wentao et al., 2017).
However, some disadvantages have been found in the treatment of
osteomyelitis with PMMA bone cements-based drug delivery systems.
More precisely, 1) the temperature of drug-loaded PMMA implants will
increase during the preparing process and therefore, the loaded drugs
are required to have thermal stability; 2) PMMA implants are
non-biodegradable and often require the second surgery to remove them
from the local sites; 3) PMMA scaffolds demonstrate poor drug release
kinetics because of the low drug release efficiency and the rapid burst
release in the early stage; 4) The surface of PMMA scaffolds may become
the seeding place for bacteria colonization and biofilms formation after
antibiotics complete elution; 5) PMMA bone cements beads are prone to
breakage because of a lack of stability, and certain complications may
occur with PMMA coated rods or nails, such as cements delamination or
debonding (Cho et al., 2018; Masters et al., 2019). To overcome these
limitations, the development of novel carriers for drug delivery is critical
for the treatment of osteomyelitis.
The desired local drug delivery systems should have certain essential
properties, such as biocompatibility, biodegradability, suitable drug
elution kinetics, biomineralization capacity and osteoinductivity (Sar­
igol-Calamak & Hascicek, 2018). Currently, synthetic biodegradable
polymers, natural polymers, ceramics, bioglasses, and their blending
composites are widely used in preparing novel antibiotic delivery sys­
tems for osteomyelitis treatment. The structure, shape, and composition
are designed based on the requirements of eliminating bacteria and
promoting bone regeneration (Inzana et al., 2016). For example, poly
(ε-caprolactone) (PCL) and poly (D,l-lactic acid) (PLA) are used to pre­
pare antibiotics-loaded emulsion microspheres. The scaffolds exhibit
appropriate antibiotic release profiles and show enhanced bone affinity
when functionalized by bisphosphonate drugs (Rotman et al., 2020).
Novel silica-polymer local antibiotic delivery systems can preserve the
sustained ciprofloxacin release for a few weeks without significant toxic
effects toward osteoblasts (Skwira et al., 2019). The mesoporous
bioactive glass and PLGA composite scaffolds demonstrate controlled
degradability, improved hydrophilicity, sustained antibiotics release
efficiency, and reliable osteoinductivity. These novel inorganic-organic
composites have good application prospects in the treatment of bone
infections (Cheng, Qu, Zhang, & Zhang, 2018). Ceramic beads with high
antibiotic loading capacities can be incorporated into the porous HAp
matrix scaffolds via freeze gelation. This kind of scaffolds has large open
pores and high surface area to enhance the maximum loadable amount
and prolong the tunable release of antibiotics. It is feasible to increase
the drug loading capacity and improve the therapeutic effects of oste­
omyelitis (Hess et al., 2016). Because of high antibiotic adsorbability,
HAp/collagen composite scaffolds can be used as antibiotics delivery
F. Tao et al.
systems to improve the therapeutic effects of osteomyelitis (Egawa et al.,
2020). The silk fibroin coated Titania nanotubes can control the anti­
biotics freely release, inhibit the biofilms formation, and further facili­
tate osteoblast adhesion and development. It is a promising alternative
for osteomyelitis treatment (Fathi, Akbari, & Taheriazam, 2019). These
novel drug delivery systems show more advantages than PMMA-based
scaffolds, including controlled drug loading and release rate, suitable
biodegradability, excellent biocompatibility, excellent mechanical
properties, plasticity, modifiability, osteoinductivity, and osseointegra­
tion characteristics. Because of these special physicochemical and bio­
logical properties, CS-based biomaterials are not only used to mimic the
natural ECM, but also considered as excellent drug carriers in biomed­
icine. The inherent antibacterial and osteoinductive properties of CS
have attracted immense attention in bone tissue engineering. CS has
become one of the most appealing biopolymers in preparing local drug
delivery systems for osteomyelitis treatment.
5. CS biomaterials in osteomyelitis treatment
As a natural derived polycation polymer, CS is considered as an
important ingredient for fabricating biomaterials in tissue engineering.
The biodegradability and biocompatibility of CS enable the diverse
bioactive functions, especially as promising drug carriers for disease
therapy (Wei, Ching, & Chuah, 2020). CS-based drug delivery systems
have large drug loading capacity, a controlled drug release profile, and
improved drug bioavailability due to their polycation properties,
abundant functional groups, and special behaviors for water absorption
and swelling (Kundu et al., 2010). At present, CS-based local drug de­
livery systems have gained immense attentions in the treatment of
osteomyelitis. Here, a systematic overview of alternative CS-based bio­
materials in the management of osteomyelitis is provided.
5.1. CS-based drug carriers in treating osteomyelitis
CS-based biomaterials have a high encapsulation efficiency for an­
tibiotics, and the local implantations are proven as more effective than
systemic administration (Cevher et al., 2006; Orhan et al., 2006). Novel
three-dimensional fibrous scaffolds combined the vancomycin loaded
CS with ZIF8 nanocrystals are fabricated by the wet-spinning method.
They are metal-organic frameworks with superior properties, such as
high porosity, high thermal/chemical stability, and acceptable toxicity.
In the composite scaffolds, CS fibers provide a large surface area for
osteoblast adhesion and growth. Furthermore, the antibacterial activity
of the composite can be enhanced by the controlled release of vanco­
mycin to improve the therapeutic effects of osteomyelitis in a
pH-responsive manner (Karakecili et al., 2019). The CS sponges with
customizable sizes and porous structure can be fabricated by lyophili­
zation. The controllable pore sizes and thicknesses of the sponges are
conducive to loading high concentrations of antibiotics by passive ab­
sorption and delivering to the infected tissues by local diffusion.
CS-based drug delivery systems show great potential for managing
infected traumatic injuries (Boles et al., 2018; Wells et al., 2018). The
CS-polycaprolactone blend sponges can also be prepared as drug de­
livery systems in osteomyelitis treatment. The composite sponges can
carry and control the release of ciprofloxacin hydrochloride and
ibuprofen simultaneously. This dual delivery system demonstrates
antibacterial and anti-inflammatory activities concurrently to support
managing chronic osteomyelitis after surgical debridement (Pawar &
Srivastava, 2019).In addition, CS can also be used as an adhesive ma­
terial to immobilize antibiotics in the scaffolds. The CS-based antibac­
terial implants can provide optimum drug elution kinetics in managing
osteomyelitis (Wei et al., 2019).
Silver (Ag) is a traditional antibacterial drug that has been widely
applied in the clinics for a long time. Ag nanoparticle-loaded CS scaf­
folds show good mechanical strength and swelling properties, making
the scaffolds with sufficient protein adsorption and mineralization
5
Carbohydrate Polymers 251 (2021) 117063
capacity. The CS-based nanocomposites can be fabricated into highly
efficient antibacterial scaffolds for the treatment of osteomyelitis
(Hasan, Waibhaw, Saxena, & Pandey, 2018). A new type of vancomycin
delivery system is fabricated by embedding hydroxy propyl methyl
cellulose (HPMC)microparticles into CS thermosensitive hydrogels to
treat local bone infection. The CS-based injectable hydrogels achieve
sol-gel transition under the physiological temperature and play an
important role in extending drug release. The first burst release is mainly
caused by the diffusion of the absorbed antibiotics on the scaffold sur­
face, while the longer-term release is affected by the drug diffusion from
pores within the scaffolds and penetration through the barriers of HPMC
microparticles and hydrogel matrix (Mahmoudian & Ganji, 2017).
Injectable CS wrapped vancomycin liposomes nanosuspension can be
prepared by electrostatic deposition. This antibiotic delivery system
possesses a sustained drug release in vitro and a long retention time in
vivo. The coating of polycationic CS can improve the stability and tar­
geting of liposomes. Meanwhile, CS can make the liposomes positively
charged to interact with the polyanionic cellular membrane to promote
the absorption and transportation of hydrophilic macromolecules. The
positively charged properties and nanoparticle size are conducive to
reducing the immune response and prolonging the circulation time in
vivo, which can enhance the therapeutic effects of antibiotics in osteo­
myelitis treatment (Yang, Liu, Gao, Chen, & Huang, 2015). The prom­
ising therapeutic effects of the ciprofloxacin-loaded CS/bioactive glass
scaffolds on osteomyelitis treatment have been found. In this composite
scaffold, CS plays an important role in supporting cell adhesion and
proliferation, while the bioactive glass upregulates the ALP activity to
facilitate cell osteogenic differentiation. The CS/bioactive glass com­
posite scaffolds exhibit suitable burst release of antibiotic followed by a
sustained release profile, because CS can provide the exceptional hy­
drophilic nature and fast biodegradation rate. Furthermore, the addition
of bioactive glass can fill up the micropores of the scaffolds to reduce the
hydration of the polymer matrix to delay the antibiotic release (Mostafa,
El-Sayed, Mahmoud, & Gamal-Eldeen, 2017). CS coating can also
enhance the chronic osteomyelitis treatment effects of calcium
sulfate-based drug delivery systems. The deacetylation degree of CS has
an impact on cellular affinity and the elution rate of antibiotics. Thus,
the CS/calcium sulfate composite beads can achieve a high local con­
centration of antibiotics and promote osteogenic cell adhesion, prolif­
eration, and bone mineralization (Beenken et al., 2014). In an animal
experiment, ciprofloxacin embedded CS films show high local concen­
tration of drug and low side effects. Accordingly, they can be used as
local antibiotic delivery systems for the prophylaxis of osteomyelitis in
open fractures (Paiva Costa et al., 2016). A novel injectable CS/borate
bioactive glass cements can be prepared as local vancomycin carriers for
treating osteomyelitis. Because CS possesses high viscosity, excellent
biocompatibility, suitable degradation rate, and complexation property,
the composite drug carriers exhibit optimal elution characteristics of
antibiotics and enhance compressive strength to eradicate osteomyelitis
and support bone regeneration in the weight-bearing sites (Ding, Zhao
et al., 2014). Similarly, the gentamicin or teicoplanin-loaded CS/borate
bioactive glass drug delivery systems also demonstrate a good thera­
peutic effect on bacteria-induced osteomyelitis and support the
ingrowth of new bone in vivo (Jia, Zhang, Luo et al., 2010; Jia, Zhang,
Zhang et al., 2010; Xie et al., 2013; Zhang et al., 2010). Furthermore, the
local release profile of the antibiotics in CS/bioactive glass composite
scaffold is correlated with the sizes of scaffolds and the concentration of
the loaded drug (Soundrapandian, Datta, Kundu, Basu, & Sa, 2010).
Recently, a novel CS-calcium phosphate composite scaffolds loaded with
moxifloxacin hydrochloride are fabricated by in situ precipitation
method. These composite scaffolds are highly porous and display a
complete antibiotic release over three days. The CS-calcium phosphate
scaffolds not only show promotive effects on osteoblast proliferation and
differentiation, but also exhibit inhibitory effects on bacterial growth,
inflammation and intra-medullary fibrosis in osteomyelitis models
(Radwan, Nasr, Ishak, Abdeltawab, & Awad, 2020). These results
F. Tao et al. Carbohydrate Polymers 251 (2021) 117063

Fig. 2. (A) Scheme of the fabrication of the oppositely charged microspheres (chitosan microspheres CSM, O-carboxymethyl chitosan microspheres CMCSM,
berberine Bbr). The SEM images of the morphology (B-C) and particle size distribution (D-E) of the CSM and CMCSM. (F) SEM image and (G) fluorescence image of
the composite scaffold. (H) LSCM fluorescence image of the assembled scaffold containing CSM (red) and CMCSM (green) and the 3D reconstruction images (I). (J)
SEM observations of cell adhesion; (K) Fluorescence staining of cell morphology (red: F-actin, green: mitochondria, blue: nucleus); (L) Fluorescence images of living
cells growing in CSM and CMCSM after culturing for 1 day and 4 days. Reprinted with permission from ref. (Cai et al., 2018). Copyright 2018 American Chemical
Society (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

indicate that the CS-based bioactive scaffolds can be used as antibiotic
carrier materials to eradicate osteomyelitis and facilitate local bone
regeneration.
A disadvantage of the CS-based drug delivery system is the uncon­
trollable initial burst of antibiotics, especially in porous scaffolds. To
overcome the drawback of fast initial burst in porous CS/β-tricalcium
phosphate (β-TCP) composites, synthetic polymer PCL is utilized as a
coating to retard the release of vancomycin. This composite drug de­
livery system contributes to the enhancement of mechanical strength
and the improvement of the drug release profile. It can be progressively
substituted by the newly formed bone (Fang, Wen, Zhou, Shao, & Dong,
2012). CS crosslinked bioactive ceramics are fabricated as biocompat­
ible antibiotic carriers. More than 75 % of the entrapped vancomycin
can be sustained and steadily released for 12 days to maintain a high
local concentration of vancomycin for inhibiting biofilms formation
(Thanyaphoo & Kaewsrichan, 2012). In some cases, high concentrations
of some antibiotics at the bone infection sites can delay bone regener­
ation by disturbing the osteoblast proliferation and differentiation.
Novel complex antibiotic carriers are composed of porous
nano-HAp/CS/konjac glucomannan and loaded with cationic liposomal
vancomycin. The biodegradable scaffolds can control the release rate of
vancomycin by adjusting the composition ratio of CS and konjac
glucomannan to avoid the side effects for osteoblast growth and devel­
opment (Ma et al., 2011). BMP-2 and berberine can be loaded in the
oppositely charged CS microspheres (CSM) and O-carboxymethyl chi­
tosan microspheres (CMCSM), respectively (Fig. 2A). These scaffolds are
scattered and compact microspheres with different diameters and a few
attached small flakes on the surface of CMS and CMCSM (Fig. 2B–E).
There are many nanopores and micropores formed in their assembled
structure (Fig. 2F–I) and can provide suitable microenvironment for
osteoblast-like cell adhesion, spreading and proliferation (Fig. 2J–L).
These drug-loaded composite scaffolds possess dual effects of high
antibacterial activity due to berberine/CMCS and significantly enhance
osteoinductivity with the assistance of BMP-2/CSM (Cai et al., 2018). CS
coatings have good affinity for water absorption and can swell to form a
diffusional barrier to retard drug release into the dissolution medium.
β-TCP scaffolds bilayer coating of CS with antibiotics by the foaming
method exhibit a highly interconnected porous microstructure. The
swelling properties of CS contribute to the prolonged drug release pro­
file for combating osteomyelitis (Kundu et al., 2010). CS has been found
of good antibacterial activity because the positively charged CS can
react with polyanion molecules on the cell surface to change the
permeability of bacteria. Additionally, the active amino groups of CS can
interfere with DNA to disrupt the synthesis of downstream RNA and

6
 F. Tao et al.
Table 1
CS-based drug delivery systems for osteomyelitis treatment (MIC: minimum inhibitory concentration; DD: degree of deacetylation).
Composite Method Mw/ DD Crosslinking Morphology Drugs Burst release Cumulative release Application Reference

Chitosan-calcium phosphate In situ 100− 300 kDa / Glutaraldehyde CaP crystals homogenous Moxifloxacin 77.3 % and 90.7 Almost complete Promising platforms in (Radwan et al.,
composite scaffolds precipitation 85 % distribute within hydrochloride % on the first release by the third prevention of post- 2020)
method chitosan matrix. day day operative osteomyelitis
CS-ZIF8 nanocrystals Wet-spinning -/85 % Glyoxal 3-D fiber mesh with high Vancomycin 25 % at pH 7.4 30 % at pH 7.4 and Reduce infection and (Karakecili et al.,
and interconnected and 42 % at pH 45 % at pH 5.4 for promote osteoblast 2019)
porosity 5.4 in the first 144 h proliferation
24 h
CS-PCL sponges Lyophilization 190− 310 – Highly porous Ciprofloxacin 30 % for the first 78 % for 12 d Anti-inflammatory and (Pawar &
kDa/>75 % interconnected surface hydrochloride 3h against infection Srivastava, 2019)
CS crosslinked mesoporous In situ foaming -/- Vanillin Micropores on walls and Levofloxacin – Sustained release Candidate for (Wei et al., 2019)
silica microspheres modified method and soaking microspheres on surface hydrochloride for 42 d osteomyelitis treatment
nano-HAp/polyurethane
CS, carboxymethyl cellulose and Lyophilization 50− 190 – Highly crystalline and Silver – – Overcome bone related (Hasan et al.,
silver nanoparticle modified kDa/ porous structure nanoparticles infections like 2018)
cellulose nanowhiskers 75− 85% osteomyelitis.
HPMC microparticles and CS/ Spray drying method -/95 % – Spherical structure with Vancomycin 42 % for the first 94 % for 72 h Treat osteomyelitis (Mahmoudian &
glycerophosphate different particle size 8h Ganji, 2017)
thermosensitive hydrogel
CS with bioactive glass Lyophilization 190− 480 – Interconnected porous Ciprofloxacin 50 % for the first About 70 % for 14 As a localized (Mostafa et al.,
kDa/ structure with glass 9h d osteomyelitis treatment 2017)
65− 82% particles dispersed
CS coated vancomycin Modified reverse 50 kDa/- – Spherical shapes with Vancomycin 40 % for the first About 70 % for 70 Treat osteomyelitis, (Yang et al., 2015)
hydrochloride liposomes phase evaporation different particle size 4h h endocarditis and
and electrostatic pneumonia
7

deposition
CS-coated calcium sulfate Mixture and drying 210 kDa/78 – Pellets Daptomycin 1000 times MIC 100 times MIC Treat chronic (Beenken et al.,
implants in a desiccator % after 1 d after 10 d osteomyelitis after 2014)
surgical debridement
CS-bonded borate bioactive Mixture -/- – Heterogeneous Vancomycin 44 % for the first 86 % for 36 d Eradicate osteomyelitis (Ding, Zhao et al.,
glass particles microstructure with 2d and promote new bone 2014)
some pores regeneration
HAp and CS nanoparticles Ultrasound-assisted 190− 310 – Round particles with Clindamycin 15 % in the first About 90 % for 21 Treat osteomyelitis and (Uskokovic &
sequential kDa/- sharp edges 24 h d promote bone Desai, 2014)
precipitation regeneration
PCL coated CS/β-tricalcium Soaking 200 kDa/91 Highly porous structure Vancomycin 7.12 % in the About 72 % for 42 Treat MRSA-related (Fang et al., 2012)
phosphate % with a coating layer first 1 d d osteomyelitis
CS crosslinked Si-HAp porous Wet chemical -/- CS Bone-like apatite Vancomycin 12 %-15 % in 20 %-30 % for over Aid long-term healing of (Thanyaphoo &
scaffold method deposited on the surface the first 4 h 12 d osteomyelitis Kaewsrichan,
2012)
Nano-HAp/CS/konjac Mixture -/- – Scaffold with small Cationic – About 50 % for 72 Treat biofilms infection (Ma et al., 2011)
glucomannan scaffolds cracks and pores liposomal h caused osteomyelitis

Carbohydrate Polymers 251 (2021) 117063

vancomycin
CS-bonded borate bioactive Mixture -/98 % – Smooth surface with Teicoplanin 47 % in the first 83 % for 30 d Treat MRSA induced (Zhang et al.,
glass pellets drying cracks and air day chronic osteomyelitis 2010)
bubbles remnants
CS/nano-HAp/ethyl cellulose Mixture and freeze- 40 kDa/95 – Round granules with Gentamicin 38 % at the first Sustained 49 days Treat chronic (Shi et al., 2010)
microspheres granules drying % coarse surface day in vitro and 45 days osteomyelitis
in vivo
CS microspheres Spray drying method 190− 310 – Spherical with porous Vancomycin – 58.68 % for 170 h Eradicate implant- (Cevher et al.,
kDa/ surface and roughness hydrochloride related osteomyelitis 2006)
75− 85%
F. Tao et al. Carbohydrate Polymers 251 (2021) 117063

Table 2
CS modified implants for osteomyelitis treatment.
Composite Method Morphology Drug Application Reference

CS covered nanaotubular TiZr Dip-coating Nanoporous surface Gentamicin Anti-inflammatory and reduce (Stoian et al.,
infection 2020)
CS coated porous Ti Direct metal printing and Coating with Ag Ag Against infection in vitro, but (Croes et al.,
electrophoretic deposition nanoparticles not reduce infection in vivo 2018)
TiO2-SiO2 and CS-Lysine coated Ti alloy Electrophoretic deposition Hierarchically porous Gentamicin Inhibit infection and against (Mohan Raj
structures corrosion et al., 2018)
CS deposit on HAp coated Ti6Al4V implant Electrolytic deposition Dense and smooth film Vancomycin Prophylaxis and therapy of (Yang et al.,
osteomyelitis 2013)
Ti coated with TiO2-SrHAP and CS/Gelatin Co-precipitation and A smooth uniform well- Vancomycin Control osteomyelitis and favor (Nancy &
electrophoretic deposition oriented morphology bone mineralization Rajendran,
2018)
CS/alginate multilayer films coated TiO2 LBL self-assembly A uniform smooth surface Gentamicin Improve osteoblast growth and (Liu et al., 2017)
nanotube arrays on Ti enhance antibacterial
properties
Hyaluronic acid/CS (Mw: 261 kDa, DD: 79.4 LBL deposition A smooth surface Triclosan Enhance the antibacterial (Valverde et al.,
%) polyelectrolyte multilayers coated properties of implant 2019)
Ti6Al4V alloys
GHK-Cu loaded mesoporous silica Electrophoretic deposition Particles homogeneously Cu2+ Show excellent antibacterial (Ning et al.,
nanoparticles -CS (DD: ≥75 %) coated Ti distributed properties 2019)

(DD: Degree of deacetylation).

protein (Adhikari & Yadav, 2018; Shi et al., 2010). The
gentamicin-impregnated CS/nano-HAp/ethyl cellulose microspheres
granules show a controllable drug release profile with a prolonged
elution time for 49 days in vitro and 45 days in vivo, meeting the
requirement of four to six weeks curative duration for chronic osteo­
myelitis treatment (Shi et al., 2010).
These results indicate that CS-based drug delivery systems can be
prepared via chemical conjugation and physical interaction. They are
assembled to achieve diverse shapes and structures, such as sponges,
hydrogels, microparticles, fibrous scaffolds, coating films, porous ma­
terials, and composites (Table 1). These drug delivery systems possess
thermal and chemical stability to maintain normal antibacterial effi­
ciency. Furthermore, the CS-based antibiotic carriers demonstrate
optimized release kinetics in osteomyelitis treatment by maintaining
and continuously releasing high concentrations of antibiotics locally.
5.2. CS-modified implants against osteomyelitis
Implants-related infection is an important cause of osteomyelitis.
The risk of implants-related infection is 2–5 % in orthopedic surgeries
(Chouirfa, Bouloussa, Migonney, & Falentin-Daudre, 2019). The colo­
nization of bacteria on implants can induce tissue inflammation, pro­
mote biofilms formation, disrupt the osseointegration process, and
accelerate metal corrosion, eventually leading to implants failure
(Arciola, Campoccia, & Montanaro, 2018). The treatment of
implants-related infection represents an orthopedic surgical challenge.
The dual functions of anti-bacteria and osseointegration are required for
the design of ideal orthopedic implants (Zhao et al., 2020). Surface
modifications and coatings of implants can reduce bacteria adhesion,
inhibit biofilms formation and improve the affinity of osteogenic cells to
facilitate osseointegration (Chouirfa et al., 2019). Titanium (Ti) and its
alloys are the most commonly used orthopedic implant materials, which
have excellent mechanical properties and biocompatibility (Jing et al.,
2020). However, implants-related infections remain the main cause
leading to Ti implants failure. Owing to the special biological properties
of CS, the CS-based biomaterials can be applied to modify and func­
tionalize the orthopedic implants to prevent the implants-related in­
fections (Pawar, Topkar, & Srivastava, 2018). Recently, the CS modified
implants are widely used in the treatment of osteomyelitis (Table 2).
TiZr alloys with a nanostructured surface can be modified by the
gentamicin-loaded CS delivery system. This composite implant exhibits
more hydrophilic and higher molecular polarity than the simple TiZr.
The thickness of CS film controls the drug release with predictable ki­
netics, which enables the implants to have desired and targeted
treatment effects for osteomyelitis. The CS-modified implants can sup­
press inflammation in the short-term, demonstrate a better antibacterial
effect in the middle-term, and promote fracture repair in the longer-term
(Stoian, Demetrescu, & Ionita, 2020). The CS modification can also
improve biocompatibility and antibacterial properties of Ti implants.
The CS/alginate multilayer films modified TiO2 nanotube arrays can be
coated on the surface of the Ti substrate. The surface modification can
accelerate osteoblast growth, enhance osseointegration, and reduce
bone infection by inhibiting bacteria adhesion and controlling antibac­
terial drug release from TiO2 nanotube arrays (Liu et al., 2017). TiO2-­
SiO2/CS-Lysine modified Ti alloys can be good carriers for the local
delivery of gentamicin in osteomyelitis treatment. The composite im­
plants show high gentamicin loading efficiencies because of the abun­
dant nano pores and active OH- and NH2 groups, which provide the
implants excellent affinity to gentamicin molecules. Furthermore, these
ceramic/biopolymer coated implants demonstrate not only the first
burst release and sustained release of gentamicin, but also appreciable
corrosion resistance in vitro (Mohan Raj, Priya, & Raj, 2018).
Vancomycin-loaded CS/gelatin coatings can be immobilized on Ti im­
plants by electrophoretic deposition without the cytotoxic chemical
crosslinking. The addition of CS and gelatin can facilitate the ingrowth
of biomineralization and vascularization. These composites demonstrate
dual functions of inhibiting biofilms formation and enhancing cellular
interaction at the bio-interface, making them promising candidates for
eradicating osteomyelitis and promoting bone regeneration (Nancy &
Rajendran, 2018; David & Nallaiyan, 2018). Vancomycin loaded
CS/HAp composites can be immobilized on the surface of Ti6Al4V im­
plants by the electrochemical method. Vancomycin and CS are tightly
conjugated by the hydrogen bonds and filled in the pores of HAp coat­
ings to form a dense and smooth film (Fig. 3A–B). The first burst release
of vancomycin is reduced to 55 % and sustained for more than 30 days
after modification due to the polar water molecular mediated destruc­
tion of hydrogen bonding (Fig. 3C). The enhanced antibiotic elution
kinetics contributes to maintaining the stable antibacterial function for
chronic osteomyelitis treatment in animal models (Fig. 3D). Addition­
ally, the vancomycin loaded CS/HAp composite coating can also pro­
mote osteointegration on the Ti6Al4V implants by facilitating
osteoblast-like cell proliferation, differentiation, and mineralization
(Fig. 3E–H) (Yang, Lin, Liao, & Yen, 2013). The Ti6Al4V alloys
surface-modified by LBL deposition of hyaluronic acid/CS poly­
electrolyte multilayers demonstrate excellent antibacterial properties.
The CS-based coating can significantly reduce the contact angle of the
implant surface and improve hydrophilic behavior similar to the smooth
surface. It is beneficial for inhibiting bacteria adhesion and proliferation

8
F. Tao et al. Carbohydrate Polymers 251 (2021) 117063

Fig. 3. SEM observation of the vancomycin-CS/HA composite coated specimen for cross section (A) and surface morphology (B). (C) The curve of drug release from
the vancomycin-CS/HA composite coated specimen. (D) The X-ray image for Ti6Al4V alloy pin implanted in the tibia of rabbit. (E-H) SEM images of osteoblast-like
cells on the vancomycin-CS/HA composite coated specimen. Reprinted with permission from ref.(C. C. Yang et al., 2013). Copyright 2013 Elsevier.

9
F. Tao et al. Carbohydrate Polymers 251 (2021) 117063

Table 3
CS derivates drug delivery systems for osteomyelitis treatment.
Composite Method Mw / DD Crosslinking Morphology Drug Application Reference

Quaternised CS-loaded PMMA Mixture 200 kDa / – Well-connected highly Gentamicin Combat implant (Tan et al.,
91.83 % porous structures infections and 2012)
osteomyelitis
N-trimethyl CS nanoparticles- Mixture and -/- – Spherical nanoparticle Vancomycin Treat chronic (Zhang,
poly(trimethylene carbonate) drying in on surface osteomyelitis and Liang et al.,
vacuum promote bone 2017)
healing
Hydroxypropyltrimethyl Mixture 150 kDa / – Granules embedded in BMP-2 Treat infected bone (Wang
ammonium chloride CS 95–98 % CS network defects et al.,
2019)
Copper-containing CMCS/ Freeze-drying – 2% CaCl2 An interconnected Cu2+ Promote new bone (Lu et al.,
alginate scaffolds porous structure formation and avoid 2018)
bacterial infection
CMCS decorated Polydopamine 9.5− 20.9 – Homogeneous Bone-forming Have high (Xu et al.,
polyetheretherketone ternary tag strategy kDa / ≥86 dispersion of carbon peptide disinfection efficacy 2016)
biocomposite % fibers and nano-HA and better
particles on the surface osteointegration
CMCS-modified Ti Anchoring by -/ ≥75 % – – BMP-2 Inhibit bacterial (Zheng
dopamine colonization and et al.,
enhance osteoblast 2013)
functions
CMCS/oxidized alginate Freeze-drying -/- Chemical cross- Interconnecting Tetracycline Show effective (Ren et al.,
hydrogel blended with calcium linking via Schiff- porous three- hydrochloride antibiotic activity 2018)
carbonate microspheres/ HAp base reaction dimensional structure
nanoparticles
Hydroxypropyltrimethyl Mixture 200 kDa / – Particles distributed – Inhibit biofilms (Tan et al.,
ammonium chloride CS loaded 91.83 % and well-connected formation 2012)
PMMA pore structure
Quaternary ammonium CS Mixture -/ 84 % Tripolyphosphate Nanoparticles – Combat bacterial (Shi et al.,
derivative nanoparticles in distributed on the infections in joint 2006)
PMMA surface replacements

to prevent implants-related infection (Valverde et al., 2019). The
physical and chemical properties of CS can be changed by functional
groups substitution, and the derivates of CS can also exert promotive
effects on the improvement of antibacterial and osteogenic properties of
implants. The hydroxypropyltrimethyl ammonium chloride chitosan
(HACC) based multilayer coating on the porous Ti is fabricated by the
LBL covalent-immobilized method. The CS derivative mediated surface
modification can inhibit bacteria colonization and biofilms formation,
and prevent bone destruction in vivo. The slow release of HACC after
degradation by collagenase can eliminate the planktonic bacteria, while
the remaining HACC contributes to the suppression of the colonized
bacteria. The CS derivative HACC assisted surface modification is a
novel potential strategy to prevent implants-related infections in or­
thopedics (Ao et al., 2019).
Therefore, the antibacterial activities of implants can be significantly
improved by modifying or coating with CS-based antibiotic delivery
systems. This therapeutic strategy is conducive to maintaining pro­
longed antibiotic release to inhibit bacteria colonization on implants
surfaces and providing an affiliative interface for osteogenic cell growth
and osseointegration. Thereby, CS-based implants modification is a
promising strategy to prevent the occurrence of implants-related oste­
omyelitis and promote the peri-implant osseointegration.
5.3. CS derivatives in osteomyelitis treatment
CS, a kind of polysaccharide polymers, also has some characteristics
that limit its application in tissue engineering. For example, CS always
needs to be dissolved in acidic solvents for preparing biomaterial scaf­
folds. The residual solvents can disrupt the homeostasis of the micro­
environment in vivo and have a negative impact on cell growth and
development (Tao et al., 2020). The unmodified CS molecules are easily
hydrolytically cleaved and metabolized by lysozyme and N-ace­
tyl-β-D-glucosaminidase in vitro and in vivo (Lim et al., 2008). These
characteristics will restrict the application prospects of CS in tissue en­
gineering. Therefore, the chemical modification and functionalization of
the CS molecular chain enable the scaffolds with special biological
properties to improve the therapeutic effects of osteomyelitis and pro­
mote bone regeneration. The chemical modification and functionaliza­
tion of CS can be realized by substituting and reacting with the active
hydroxyl and amino groups in the molecular chain. These structural and
functional changes can expand the application of CS in different fields
(Ma, Zhong, Peng, Xu, & Sun, 2020). Recently, various studies have
found that CS derivatives demonstrate excellent drug delivery efficiency
for the treatment of osteomyelitis (Table 3).
Carboxymethyl chitosan (CMCS), as a water-soluble derivative of CS,
possesses better hydrophilicity than CS and accordingly, it has attracted
increasing attention in osteomyelitis treatment. CMCS-based scaffolds
exhibit excellent antibacterial properties and promotive effects on bone
regeneration (Shi, Neoh, Kang, Poh, & Wang, 2009). A
polysaccharide-based hydrogel is fabricated by introducing tetracycline
hydrochloride (TH) loaded calcium carbonate microspheres (CM) and
HAp into CMCS and oxidized alginate (OAlg). The composite scaffold is
crosslinked by the Schiff-base reaction between CMCS and OAlg to
enhance bioactivity and mechanical strength (Fig. 4A). This drug de­
livery vehicle is injectable (Fig. 4B) and the drug-loaded CMs show a
coarse surface to delay the burst release for TH (Fig. 4C-D). The
freeze-dried composite hydrogels exhibit porous structures and the
porous walls can uniformly disperse in PBS (Fig. 4E-J). These special
structural features can contribute to maintaining the good mechanical
property and the high antibacterial activity in bone tissue engineering
(Ren et al., 2018). Owing to the hydrolyzation and ionization of the
acidic carboxyl groups and basic amino groups, CMCS can be treated as
an amphoteric polysaccharide at different pH conditions. For example, it
can be positively charged in an acidic condition and negatively charged
in a neutral or alkaline environment (Tu et al., 2019). The active amino
groups and carboxyl groups of CMCS can bind to the charged surface of
bacteria to destroy the membranes homeostasis and disrupt the sub­
stances transmission of an intra- or extra-cellular environment. This
characteristic contributes to the improvement of the inherent antibac­
terial properties of the polysaccharide polymer derivative (Maya et al.,

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F. Tao et al. Carbohydrate Polymers 251 (2021) 117063

Fig. 4. (A) Schematic summary of the TH loaded CMCS-OAlg-HAp-CMs hydrogel scaffolds (carboxymethyl chitosan CMCS, and oxidized alginate OAlg, hydroxy­
apatite HAp, calcium carbonate microspheres CMs, tetracycline hydrochloride TH). (B) An image shows the gel scaffold injected from a syringe needle. (C-D) SEM
images of the TH loaded CMs under different magnification. (E-H) SEM images of 6% HAp/gel scaffolds combined with different concentration of CMs after immersed
in PBS for 1 h. (I-J) High magnification images of (G). Reprinted with permission from ref. (Ren et al., 2018). Copyright 2018 Elsevier.

2012; Tu et al., 2019). A kind of multifunctional scaffolds with the
porous structure is fabricated by the addition of copper (Cu) nano­
particles into anionic CMCS and alginate. These composite scaffolds are
gradually crosslinked by the sustainable release of the antibacterial Cu2+
ions and show multiple functions of inhibiting bacteria and promoting
osteoblast adhesion and osteogenic differentiation (Lu et al., 2018).
CMCS can also be applied to modify and functionalize the surface of
implants to facilitate antibacterial activity and bone regeneration
simultaneously. The CMCS-functionalized Ti substrates exhibit excellent
antibacterial properties and enhance osteoblast mineralization by
conjugating vascular endothelial growth factor (VEGF) on the CMCS
surface (Hu et al., 2010). The CMCS modified Ti substrates show an
inhibitory effect on bacterial colonization and contribute to the pro­
motion of osteoblast growth and mineralization after being functional­
ized by BMP-2 (Zheng, Neoh, Shi, & Kang, 2013). A kind of newly
developed CMCS and bone-forming peptide-conjugated biocomposites
demonstrate dual functions of significantly bacterial adhesion inhibition
and osteointegration acceleration (Xu et al., 2016). Additionally,
CMCS-Zn2+ coated implants show antibacterial properties in vivo and
are effectively used in preventing pin tract infection (Martin et al.,
2018). Thus, CMCS-based biomaterials possess good antibacterial ac­
tivity, excellent biocompatibility, and osteoinductivity, and can be

11
F. Tao et al.
treated as potential transplantable scaffolds for osteomyelitis treatment.
The antibacterial activity of CS is always restricted by its poor sol­
ubility in water. To solve this problem, a new quaternary ammonium CS
derivative has been prepared. The antibacterial activity and water sol­
ubility can be improved by increasing the chain length of the alkyl
substituent (Shi, Neoh, Kang, & Wang, 2006). PMMA bone cements
modified by adding quaternary ammonium CS derivative nanoparticles
show high antibacterial effectiveness and have no significant negative
effects on the mechanical properties of bone cements. These composite
bone cements have potential applications in combating joint
implants-related infection (Shi et al., 2006). CS derivative HACC ex­
hibits excellent biocompatibility in biomedical applications and can be
fabricated as desirable drug delivery systems. A kind of BMP-2-loaded
HACC scaffold exhibits good antibacterial efficiency and controlled
release of a growth factor. This HACC-based biomaterial can be a
multifunctional scaffold with sequential antibacterial and osteoinduc­
tive properties for treating osteomyelitis (Wang et al., 2019). Further­
more, HACC-loaded PMMA scaffolds demonstrate strong antibacterial
activity and good biocompatibility with osteogenic cell simultaneously.
This composite scaffold can effectively inhibit biofilms formation on the
implant surface and suppress virulence-associated gene expression of
antibiotic-resistant staphylococcus. Thus, it is utilized in combating
implants-related infections and osteomyelitis (Tan et al., 2012). Addi­
tionally, another water-soluble CS derivate N-trimethyl chitosan (TMC)
can be fabricated into a high-efficiency antibiotic delivery system. The
vancomycin-loaded TMC nanoparticles exhibit great biodegradable,
cytocompatible, and antibacterial properties. In this drug delivery sys­
tem, the positively charged feature and the large surface area contribute
to the high protein adsorption and promoting vancomycin transport
across the cytomembrane. The cumulation of active regulatory proteins
on the scaffolds can facilitate osteoblast adhesion, infiltration and pro­
liferation. These vancomycin-loaded TMC nanoparticles show great
potential for promoting bone healing and can be promising candidates
for chronic osteomyelitis treatment (Zhang, Liang et al., 2017).
However, many factors affect the antibacterial properties of bio­
materials and the elution profile of antibiotics, such as physicochemical
properties, porosity, biodegradability, drug loading capacity, and the
differences in microenvironments. Specific capacities for inhibiting
bacteria of many CS-based biomaterials have been proven. However, not
all CS-assisted drug delivery systems show significant therapeutic effects
on combating osteomyelitis. For example, the CS-based coatings on Ti
implants incorporated with different concentrations of Ag nanoparticles
demonstrate enhanced antibacterial activity in vitro but poor antibac­
terial effects on osteomyelitis in vivo. Furthermore, this composite CS/Ag
coating shows negative regulatory effects on bone remodeling by
enhancing osteoclast activity and disturbing innate immune response,
resulting in the abnormal regeneration and the persistent infection of the
bone (Croes et al., 2018). A novel drug carrier fabricated by impreg­
nating CS films with ciprofloxacin presents a high local concentration of
antibiotic and low systemic side effects. However, this CS-based drug
delivery system is not effective in eradicating infection in vivo and does
not exhibit significant efficacy in the prophylaxis of osteomyelitis sec­
ondary to open fracture (Paiva Costa et al., 2016). The nanoparticulate
HAp/CS composite scaffolds are considered as potential drug delivery
systems. These scaffolds can mitigate the initial burst release and pro­
mote sustained release kinetics of antibiotics in the treatment of osteo­
myelitis. However, the antibacterial efficacy of the clindamycin-loaded
HAp/CS scaffolds has been reported as markedly lower than that of the
antibiotic-loaded HAp. Furthermore, the addition of CS to HAp nano­
particles shows negative effects on osteoblast proliferation, decreasing
osteoblast spreading and adhesion in biomaterials/cell interface, and
delaying osteoblast osteogenic differentiation in vitro (Uskokovic &
Desai, 2014). These results indicate that the therapeutic effects of
CS-based biomaterials as drug delivery systems for osteomyelitis is not
invariable, and various factors affecting material properties and drug
release kinetics need to be considered. The loading capacity of the drug,
12
Carbohydrate Polymers 251 (2021) 117063
the observation time of the experiment and the differences in microen­
vironments in vivo and in vitro may directly affect the release efficiency
and antibacterial activity. Therefore, more rigorous experimental
schemes and material designs are required to verify the therapeutic ef­
fects of CS-based biomaterials on the treatment of osteomyelitis in vivo.
6. Conclusion and future perspectives
Osteomyelitis represents a severe infectious disease that needs to be
treated timely and efficiently. Most CS-based local drug delivery systems
exhibit dual functions of a controlled antibiotics release profile for
eradicating osteomyelitis and promotion effects on bone regeneration.
CS, as a naturally derived polymer, possesses numerous advantages such
as biocompatibility, biodegradability, bioadhesion, nontoxicity and
antibacterial activity. These biological properties significantly
contribute to various applications in tissue engineering. The extensive
literature reveals that CS-based drug carriers can mitigate the first burst
release and facilitate the prolonged release of antibiotics in the treat­
ment of osteomyelitis. These CS-based drug delivery systems show
desired elution kinetics for antibiotics release and the versatile bioactive
characteristics for bone regeneration, attributing to the polycationic
properties, the abundant bioactive groups, and the deacetylation degree
of CS. These critical biological properties of CS are conducive to elimi­
nating bacteria in local infected sites and coating the orthopedic im­
plants to prevent infection. However, it is necessary to pay more
attention to the negative regulatory factors on biomaterial physico­
chemical properties, drug elution profile, and bone regeneration
mechanism. In conclusion, CS-based biomaterials are promising candi­
dates for eradicating osteomyelitis and favoring bone regeneration.
Declaration of Competing Interest
There are no conflicts of interest to declare.
Acknowledgements
This work was supported by the National Natural Science Foundation
of China (No. 51873157), National Key R&D Program of China (No.
2016YFB0303303), the Fundamental Research Funds for the Central
Universities (2042019kf0064), Hubei Provincial Key Research and
Development Project (No. 2020BAA029), and Natural Science Founda­
tion for Distinguished Young Scholars of Hubei Province of China (No.
2020CFA105).
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