Acta Biomaterialia 96 (2019) 55–67

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Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat

Review article

Recent advances in polymer-based drug delivery systems for local

anesthetics
Bo Wang a,1, Shuo Wang b,1, Qi Zhang c, Yixuan Deng a, Xiang Li a, Liangyu Peng a, Xianghao Zuo d,
Meihua Piao e, Xin Kuang a,⇑, Shihou Sheng f,⇑, Yingjie Yu g,h,⇑
a
Department of Anesthesiology, The First Affiliated Hospital of the University of South China, Hengyang, Hunan 421001, China
b
Department of Pharmacy, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
c
Department of Chemical and Biomolecular Engineering, New York University, Brooklyn, NY 11201, United States
d
Department of Materials Science and Chemical Engineering, Stony Brook University, Stony Brook, NY 11794, United States
e
Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130021, China
f
Department of Gastrointestinal Surgery, China–Japan Union Hospital of Jilin University, Changchun 130033, China
g
Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen 518039, China
h
Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA

a r t i c l e i n f o a b s t r a c t

Article history: Local anesthetics, which cause temporary loss of pain by inhibiting the transmission of nerve impulses,
Received 8 December 2018 have been widely used in clinical practice. However, neurotoxicity and short half-lives have significantly
Received in revised form 16 May 2019 limited their clinical applications. To overcome those barriers, numerous drug delivery systems (DDS)
Accepted 19 May 2019
have been designed to encapsulate local anesthetic agents, so that large doses can be released slowly
Available online 29 May 2019
and provide analgesia over a prolonged period. So far, multiple classes of local anesthetic carriers have
been investigated, with some of them already on the market. Among those, polymer-based delivery plat-
Keywords:
forms are the most extensively explored, especially in the form of polymeric nanoparticle carriers. This
Polymer
Drug delivery system
review gives a specific focus on the most commonly used natural and synthetic polymers for local anes-
Local anesthetics thetics delivery, owing to their excellent biocompatibility, biodegradability and versatility. State-of-the-
art studies concerning such polymer delivery systems have been discussed in depth. We also highlight
the impact of those delivery platforms as well as some key challenges that need to be overcome for their
broader clinical applications.

Statement of significance

Currently, local anesthetics have been widely used in clinically practices to prevent transmission of nerve
impulses. However, the applications of anesthetics are greatly limited due to their neurotoxicity and
short half-lives. Moreover, it is difficult to maintain frequent administrations which can cause poor com-
pliance and serious consequences. Numerous drug delivery systems have been developed to solve those
issues. In this review, we highlight the recent advances in polymer-based drug delivery systems for local
anesthetics. The advantages as well as shortcomings for different types of polymer-based drug delivery
systems are summarized in this paper. In the end, we also give prospects for future development of poly-
mer drug delivery systems for anesthetics.
Ó 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Abbreviations: LID, lidocaine; BUP, bupivacaine; BZC, benzocaine; LBP, levobupivacaine; ATC, articaine; HA, hyaluronic acid; CARR, carrageenan; CS, chitosan; AG, alginate;
GEL, gelatin; CEL, cellulose; CD, cyclodextrin; HPMC, hydroxypropyl methyl cellulose; PLA, polylactic acid; PEG, polyethylene glycol; PLGA, poly (lactic-co-glycolic acid); PCL,
polycaprolactone; PVA, poly (vinyl alcohol); LPSPs, lipid-protein-sugar particles; BVC LPNs, BUP-loaded lipid-polymer nanoparticles; AgNPs, silver nanoparticles; CHG, CS
glutamate; icLD, LID/multivalent ion complex; THB, tetrahydroxyborate; TAT, transcriptional transactivator peptide; LBL-LA/NLCs, Layer-by-layer-coated LID-loaded
nanostructured lipid nanoparticles; OQLCS, octadecyl-quaternized lysine modified CS.
⇑ Corresponding authors at: Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen 518039,
China (Y. Yu).
E-mail addresses: kxnhfy@126.com (X. Kuang), sheng89723711@163.com (S. Sheng), yuyingjie312@outlook.com (Y. Yu).
1
Authors contributed to the paper equally.

https://doi.org/10.1016/j.actbio.2019.05.044
1742-7061/Ó 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
56 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
2. Delivery systems developed for local anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3. Polymer-based delivery system for anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.1. Natural polymer-based delivery systems for anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.1.1. Hyaluronic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.1.2. Chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.1.3. Alginate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.1.4. Gelatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.1.5. Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.1.6. Cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.2. Synthetic polymer-based delivery systems for anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.2.1. Polylactic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.2.2. Poly (lactic-co-glycolic acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
3.2.3. Polycaprolactone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.2.4. Polypeptide and peptide-drug conjugates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.2.5. Poly (vinyl alcohol). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.3. Lipid and polymer complex delivery systems for anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.4. Inorganic materials and polymer complex delivery systems for anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
4. Conclusion and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

1. Introduction value of plasma-drug concentration [15]. Till 2011, liposomal bupi-

Pain is a common symptom in clinical practice. Patients suffer-
ing from pain reveal dysfunctional behaviors in both life and work
[1,2]. Various factors, such as physical trauma, emotional trauma,
societal and cultural pressures, can cause pain [3–6]. Although
the overall rate of perioperative mortality has declined signifi-
cantly in the past few decades, the anesthetic-related mortality
rate in developing countries is still two times higher than that in
developed countries [7]. Hence, there is a growing demand in pre-
venting and managing undesired pain from post-operative compli-
cations. Currently, the main pharmacotherapeutic strategy that
aims to manage these complications involves the optimization of
anesthesia delivery systems for patients undergoing surgical pro-
cedures [1].
Anesthetics provide several benefits including skeletal muscle
relaxation, lack of awareness, reduced anxiety, and suppression
of undesirable reflexes [8]. They are mainly categorized into four
classes: preanesthetics, neuromuscular blockers, general anesthet-
ics and local anesthetics (Fig. 1) [9]. Clinically, local anesthetics can
be classified according to potency, speed of onset and duration of
anesthesia [10]. The chemical structure of clinically used local
anesthetics contains three parts: a hydrophilic nitrogenous group,
a lipophilic phenyl group, and an intermediate chain which can be
either an amide group or an ester group (Fig. 1) [11]. Despite all the
benefits in acute and chronic pain management, applying local
anesthetics typically lead to sharp fluctuating levels of plasma-
drug concentration. Consequently, it may cause patients to experi-
ence severe side effects [12]. In addition, frequent administrations
are difficult to maintain, which may result in poor compliance [13].
Several topical anesthetics have been developed as commercial
products to decrease the pain associated with superficial dermato-
logic and laser procedures. However, a number of case reports indi-
cated that the non-FDA products were associated with adverse
outcomes, due to inappropriately high anesthetic concentrations
[14]. In order to address those challenges, researchers have devel-
oped versatile DDS that enable prolonged local anesthesia by
incorporating anesthetics into biodegradable polymeric matrices,
from which drug diffusion is prolonged to maintain at an ideal
vacaine (BUP) (ExparelÒ, Pacira Pharmaceuticals Inc., Parsippany,
NJ, USA) was originally approved by food and Drug Administration
(FDA) for use as a local anesthetic. Studies have shown that
ExparelÒ almost doubled the duration of action of sciatic never
blockade as compare to bupicacaine alone [16]. It has been proved
that nanoparticles are an effective tool for postoperative pain relief
with fewer side effects, suggesting a promising future of the DDS
for local anesthetics [17].
To date, a number of different types of controlled released deliv-
ery systems have emerged. Among them, polymers are the most
extensively explored materials for DDS owing to its excellent
applicability [18–20]. In this review, the recent advances in
polymer-based drug delivery systems for local anesthetics are dis-
cussed in detail. The impact of them as well as some key challenges
that need to be overcome for clinical application have been
highlighted.
2. Delivery systems developed for local anesthetics
Current research on injectable or implantable local anesthetic
delivery systems aim to prolong anesthetic effects and reduce tox-
icity. External delivery devices are inaccurate and limit the clinical
use of new delivery systems. Hence, the development of a nanopar-
ticle delivery system provides a safe and effective alternative in
perioperative anesthesia treatment [11].
The anesthetics most commonly studied are lidocaine (LID)
and BUP [1,18,21]. Several local anesthetic delivery systems have
been developed using a variety of materials including lipid
nanoparticles [22–26]), polymer-based nanoparticles (e.g., poly-
lactic acid (PLA) [27–30], poly (lactic-co-glycolic acid) (PLGA)
[31,32] or chitosan (CS) [33–35]), inorganic material based deliv-
ery system (e.g., calcium [36,37] or silver [38]). In this review,
specific focus is given to polymer-based local anesthetic delivery
systems classified into four categories: natural polymer-based
delivery systems, synthetic polymer-based delivery systems,
lipid/polymer complex delivery systems, and inorganic/polymer
complex delivery systems.
 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67 57

3. Polymer-based delivery system for anesthetics

A Preanesthetic medications
Antacids Antiemetics Benzodiazepines
3.1. Natural polymer-based delivery systems for anesthetics
Anticholinergics Antihistamines Opioids
3.1.1. Hyaluronic acid
B General anesthetics: inhaled
Hyaluronic acid (HA) mainly exists in synovial fluid, heart
Desfl urane Halothane Isofl urane valves, vitreous of the eye, and extracellular matrix. It is a non-
F F F Cl Cl F
F
immunogenic naturally occurring mucopolysaccharide. Owing to
F F
F O
F F O F its excellent biocompatibility, biodegradability and viscoelastic
F Br
F F properties, HA has been widely used in various therapeutic appli-
Sevoflurane Nitrous oxide cations, including drug delivery, wound healing, tissue regenera-
F3C O F tion [39,40]. Furthermore, even if problems were to arise with
N N O N N O HA, it can be easily removed by digestion with hyaluronidase [41].
CF3 Particular attention has been focused on HA as a potential deliv-
ery for BUP. Diego et al. successfully conjugated BUP to HA deriva-
C General anesthetics: intravenous
tive Hylan B particles. In vitro drug release study showed the
Barbiturates Ketamine Opioids Etomidate duration of BUP prolonged to more than 16 h for HA-BUP particle,
HO
O
Cl O
which is significantly longer than that of free BUP (0.4 h). For
O
HN NH
O H in vivo study, compared with free BUP, HA-BUP exhibited five-
NH
O O H
N CH
3
N
fold longer block time in impairing motor function, thus proving
N
O HO this HA drug delivery system effectively prolonged the duration
Dexmedetomidine Propofol Benzodiazepines of local anesthesia [42]. HA was also combined with other compo-
R1
N
R
2
nents to make composite for biomedical application due to its
OH
NH
N
excellent compatibility. Ovidio et al. fabricated a multi-targeted
R7
N
R2' composite carrageenan (CARR)/HA based wafers loaded with LID
and silver nanoparticles (AgNPs). The AgNP loaded wafers effec-
tively killed all the bacteria tested after 6 h incubation. Further-
D Neuromuscular blockers
more, the mechanical hardness could be easily tuned by varying
Vecuroni um Pancuronium Rocuroni um the content of HA, providing good handling property for chronic
leg ulcer. This composite system exhibited multiple properties
O O
O O O O

N
H
H

H
N
N
H
H

H
N O
N
H N such as fast drug release and the effective antimicrobial activity,
Br-

indicating its potential application for chronic leg ulcer dressing

O H H
H O
H HO
O O H

(Fig. 2) [43].
Cisatracurium Succinylcholine
CH3 CH3
O O
CH3 H 3C O
2Cl-
H3C
O
N

O
O O

O
N
O
CH3
N
O
O
N
3.1.2. Chitosan
O
-
O-

O
O
O S O O S O
O
Chitosan (CS) is a natural polysaccharide used in biological
CH3 O
CH3 H 3C
O CH3
applications for decades. It can be fabricated into the form of pow-
ders, films, fiber meshes, membranes, beads, and hydrogels,
depending on their future application [44,45].
E Local anesthetics: amides
CS-based materials have been widely applied in oral mucosal
Bupivacaine Lidocaine Mepivacaine delivery systems due to its versatile property [46]. Several studies
H
N
N
H
N H related to CS loaded with LID have been carried out in buccal area.
N N
O
O
N Varshosaz et al. prepared films of LID with three different molecu-
O
lar weight of CS in various conditions. The result demonstrated
Ropivacaine Etidocaine Articaine
O that high concentration and molecular weight of CS significantly
S
H
N
H
N OCH3 increased the flux of LID through the films. However, this system
N N
O O NH has not been tested in vivo. Further clinical studies are necessary
O H
N to evaluate its clinical potential [47]. Pignatello et al. fabricated a
hydrogel for the buccal application of LID using CS glutamate
F Local anesthetics: esters (CHG). To evaluate its performance, CHG hydrogel were compared
Chloroprocaine Procaine Bezocaine with two commercial products. A much slower drug release rate
O O
O has been achieved with CHG hydrogel. In vivo pharmacological
N
O O
N
O activity study proved that CHG hydrogel has similar anesthetic
H 2N
H 2N Cl NH2 activity as commercial products, but with less tissue inflammation
Cocaine Tetracaine [48].
O
CH3 O
H 3C N O
N
O O

O N
H
3.1.3. Alginate
Alginates (AG) are water-soluble linear polysaccharides
Fig. 1. Classification of anesthetics. (A) Preanesthetic can be divided into six obtained from brown algae. It has been widely used in tissue engi-
categories. (B) and (C) represent general anesthetics delivered via inhalation and
intravenous injection. (D) Neuromuscular blockers facilitate tracheal intubation and
neering for pharmaceutical and biomedical applications as drug
surgery. (E) and (F) represent two most common chemical structures of local delivery systems due to its excellent biocompatibility and
anesthetics. biodegradability [49].
58 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

LID release
100

LID release (% )
80

60
CARR
40 CARR/HA 10
CARR/HA 30
20 CARR/HA 50

0
0 1 2 3 4 5 6
Time (hours)

Antimicrobial activity

5.0 Control Wafer

CARR/AgNPs
4.0 CARR/AgNPs

Absorbance
CARR/AgNPs
CARR/AgNPs
3.0
Leg ulcer
2.0

1.0 * *
** **
Silver Nanoparticle ** ** ** ** ** **
Carrageenan 0.0 **

HA Lidocaine

Fig. 2. Scheme of composite CARR and HA dressings loaded with LID and AgNPs. Reprinted with permission from [43], copyrightÓ 2017 Polymer.

Propofol is a short-acting intravenously administered hypnotic
agent which is used for induction of general anesthesia and proce-
dural sedation. Commercial lipid emulsion of propofol (DiprivanÒ)
has certain drawbacks such as pain on injection and emulsion
instability. In order to improve its stability and solubility, Najafa-
badi et al. developed a facile method for preparation of (C8)-
grafted alginate. The propofol encapsulated nanoparticles with
the size of less than 80 nm have been successfully prepared. This
nanoparticles exhibited great stability for more than 6 months.
The release profile of nanoparticle was similar to commercial pro-
duct DiprivanÒ. Then sleep recovery test was applied on rats, the
AG nanoparticle has similar anesthesia effect as DiprivanÒ. This
study proved that AG nanoparticles served as a promising candi-
date to replace DiprivanÒ. However, safety evaluation for AG
nanoparticles should be the next step for its clinical application
[50].
Similar to CS, AGs are also incorporated with other materials,
such as hydroxyapatite, to make multifunctional scaffold. Dubnika
et al. combined the hydroxyapatite with CS and AG to ensure LID
delivery up to 60 h [51]. The polymers are formed into gel by ionic
gelation method when mixed with cationic polymers (such as CS)
or divalent cations (such as Ca2+) [52]. Grillo et al. developed BUP
encapsulated AG/CS nanoparticles [34]. Compared with single
component system, AG/GS nanoparticles improved loading effi-
ciency to 86%. Then, the nanoparticles were further applied to a
sciatic nerve blockade model. It has been demonstrated that a pro-
longed duration of motor and sensory blockades was achieved with
AG/GS nanoparticles in a sciatic nerve blockade model.
3.1.4. Gelatin
Gelatin (GEL) is derived from animal tissue consisting of min-
eral salts and proteins. It has been widely used in pharmaceutical
and food industries [53]. Structurally, a typical GEL film incorpo-
rates a coil structure and triple-helixes (Fig. 3) [54].
The topical LID solution formulations prepared by using GEL,
agar, and a food thickener as the delivery base, showed an excel-
lent analgesic effect against pain associated with needle insertion
[55]. While GEL initially appeared an initial bursts issue. Specifi-
cally, a film system composed of sunflower oil and GEL could
release benzocaine (BZC) in a controlled manner, but with an initial
burst [56]. Then, Huang et al. rectified this issue by dipping poly-
lactic acid/polyethylene glycol (PLA/PEG) microspheres into a
dilute GEL solution [57]. Consequently, a two-stage release system

Fig. 3. Scheme of GEL film structure. Left: amorphous coils; middle: triple helixes and coils; right: bundles of triple helixes and coils. Reprinted with permission from [54],
copyrightÓ 2012 Polymer.
 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67
has been successfully developed to inhibit the initial burst release
in drug release tests.
GEL as a composition of denatured collagens, frequently
changes its own structure during gelation, which substantially
affects the concentration, temperature and energy of GEL. Besides,
there are numerous hydrogen bonds on the side chains of amino
acids, which not only contribute to the formation of gelation, but
also increase the complexity of hydrophobic interactions between
GEL and the carried drugs [58]. Therefore, more efforts should be
made to produce a standardized DDS with GEL on a large scale.
3.1.5. Cellulose
Cellulose (CEL) is an extensively used biopolymer existed in liv-
ing species, such as plants, animals, and bacteria. It has repeating
units of ringed glucose molecules and a flat ribbon-like conforma-
tion. Furthermore, its abundant –OH side groups greatly facilitate
the grafting of chemical species to achieve different surface prop-
erties, making it become an attractive materials for biomedical
engineering [59,60].
Medhi et al. first utilized CEL to fabricate biopolymer for trans-
dermal drug delivery. LID-loaded biopolymer composite micronee-
dles from fish scale-nanocellulose were fabricated. This
microneedles could pierce the stratum corneum and get dissolved
in skin to release the loaded LID. A desirable drug loading capacity
has been achieved for LID [61]. In order to develop gel formulations
with suitable bioadhesion for transdermal drug delivery, the mepi-
vacaine gels contained vasoconstrictor and penetration enhancer
mixed with hydroxypropyl methyl CEL (HPMC) showed a pro-
longed local anesthetic action compared with control group [62].
Another possible application is based on the nasal administration.
A LID nasal gel was developed using HPMC as the base material to
transport LID directly from the nasal cavity into the central ner-
vous system [63]. In most cases, CEL is not the single component
in delivery systems; researchers combined CEL with other poly-
mers like CS or AG. For example, a mucoadhesive bilayer device
made of CS and ethylcellulose showed promising potential in con-
trolled delivery of anesthetics to the oral cavity [64].
3.1.6. Cyclodextrin
Cyclodextrins (CD) are cyclic oligosaccharides made of several
repeating dextrose units (a-, b, and c-CDs, respectively) joined
through one to four bonds [65]. They have found applications in
food and pharmaceutical products for decades.
A plethora of research proved sustained-release of various kinds
of local anesthetic encapsulated with CD. Although methyl and
ethyl thioether groups could be in the positions of a-, b-, and c-
CD, only the b-CD derivatives exhibit high affinity to anesthetic
drugs, like halothane and sevoflurane [66]. The complexing of
levobupivacaine (LBP) with maltosyl-b-CD was effective to use in
intrathecal block and was able to extend the duration of anesthesia
effects in a sciatic nerve block [67]. Moreover, other anesthetics
like LID or BUP can also be complexed with CD, both of which
revealed to prolong local nerve block [68,69].
The size of inner hydrophobic cavity depends on the number of
glucopyranose units in CD. Hence, the loaded molecules can nei-
ther be too small, nor be too large [70]. At the same time, while
the inside of CD is hydrophobic, the outside is hydrophilic. Drug-
in CD-in liposome system can be used as an excellent platform to
improve solubility and stability of drug. It effectively resolved
the rapid release issue inherited from conventional single-use lipo-
somes release system. In addition, it further improved drug avail-
ability through skin rout by increasing drug solubility and
permeation across the skin [71]. One example of this application
is conducted by Maestrelli et al. who combined both BZC and
butamben with hydroxypropyl-b-CD. The best solubility and disso-
lution properties were achieved. When loaded in liposomes, the
59
complexation revealed a significant enhancement of intensity
and duration of anesthetic effect [71].
3.2. Synthetic polymer-based delivery systems for anesthetics
3.2.1. Polylactic acid
PLA is a versatile material polymerized from lactic acid, it is
mainly used for biodegradable products such as plastic bags and
planting cups [72].
Firstly, PLA was used as the delivery system to develop BUP-
polyester microspheres to prolong percutaneous blockade of
peripheral nerves [27]. Then, the key formulation variables that
affected the release of BUP or BZC from different biodegradable
drug delivery devices in the PLA solutions were investigated
[28,29]. As a result, these nanocapsules exhibited completely dif-
ferent behaviors than those of the pure anesthetic in solution.
Recently, LID-coated poly (L-lactide) (PLLA) microneedle arrays
were fabricated based on micro-molding technique. A newly devel-
oped dip-coating device enable LID to be coated only at the needle
tips and significantly reduced drug loss. LID coated on the arrays
was released rapidly into PBS within 2 min. Surprisingly, more effi-
cient skin penetration was achieved with PLLA microneedle arrays
compared to the commercial product EMLAÒ cream. This PLLA
microneedle arrays could rapidly release LID in a painless manner,
which is beneficial for transdermal delivery (Fig. 4) [30]. In most
cases, instead of being used as a single formulation, PLA is often
copolymerized with PEG to form tunable micelles by changing
the ratio of PLA and PEG, thereby significantly enhancing the drug
incorporation efficiency [73,74].
3.2.2. Poly (lactic-co-glycolic acid)
PLGA has been among the most attractive polymers applied in
biomedical engineering for decades. It is approved by FDA for sev-
eral therapeutic applications due to its excellent biocompatibility,
biodegradability and mechanical properties [75]. Hence, countless
studies concerning application of PLGA in tissue engineering and
drug delivery have been carried out.
Initially, Moraes et al. [76] prepared ropivacaine-loaded PLGA
nanospheres and found PLGA drug delivery system effectively
reduced the toxicity of ropivacaine formulation. Then, they further
applied this PLGA delivery system to encapsulate other anesthetics
such as BUP and BZC, offering the possibility of prolonged anes-
thetic effect and reduced toxicity [31,77,78]. LID was also loaded
in PLGA microparticles and displayed sustainable delivery into
the cochlea, suggesting LID-PLGA microparticles could be used
for the attenuation of peripheral tinnitus [79]. When using PLGA
microparticles as a delivery system, the ‘‘microparticle mass/ bulk
fluid volume” ratio should be taken into account during in vitro
drug release measurements [80].
Combinational therapy has drawn tremendous attention owing
to its synergistic effect. Zhang et al. developed an injectable PLGA
hydrogel/microsphere (GEL/MS) composite co-delivery system to
simultaneously encapsulate BUP and dexmedetomidine (DEX) for
synergistic analgesia. DEX served as a local anesthetic additive
drugs in this combinational therapy, which exhibited long-term
vasoconstriction effect and improved the local anesthetic concen-
tration at injection site. Neurobehavioral analyses showed that
the duration of sensory blockade in the GEL/(DEX-MS/BUP) group
was 37 h, which is significantly longer than that of control groups.
Pharmacokinetics and biodistribution study have been carried out
to evaluate the toxicity and the safety of this co-delivery system.
Furthermore, the mechanism of DEX have been comprehensively
studied. The result indicated that the addition of DEX could greatly
reduce the amount of drug entering the bloodstream, therefore
reducing the safety of the GEL/MS co-delivery system (Fig. 5). This
comprehensive study laid a solid foundation for its application.
60 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

Fig. 4. Pristine PLA microneedle array (a) was observed by stereo microscopy. LID-coated PLA microneedle array was fabricated and observed by stereo microscopy (b) and
FE-SEM of 290.6 ± 45.9 mg LID was coated on the array (c). Reprinted with permission from [30], copyrightÓ 2017 Biomed. Microdevices.

Fig. 5. Schematic illustration of the preparation and in vivo nerve blockade effect of the Gel-microsphere system with BUP. Reprinted with permission from [82], copyrightÓ
2018 Biomaterials.

This system was then further applied for sustained released BUP. It
proves that this GEL/MS system is able to offer a precisely guided
drug release and retention system, exhibiting great potential to
be used as an alternative for clinical pain management [81,82].
Therefore, the aforementioned studies proves that PLGA, as an
appealing biocompatible polymer, has broad application prospect
for anesthetic delivery.
3.2.3. Polycaprolactone
Polycaprolactone (PCL) has been approved by the FDA as a
suture material, a drug delivery device and an adhesion barrier
[83]. It is an aliphatic polyester composed of repeating hexanoate
units, which is produced by ring opening polymerization of e-
caprolactone [84].
Silva de Melo et al. encapsulated articaine (ATC) with PEG-PCL
nanocapsules. This system was stable for up to 120 days of storage
at ambient temperature. Satisfactory encapsulation efficiency was
achieved with values of around 60%. At the same time, the toxicity
of this PEG-PCL nanocapsules was much less than that of free drug
group, indicating its clinical application for the carrier of ATC [85].
In another study, PEG-PCL-PEG hydrogel has been applied to
encapsulate LID or LBP. It could produce longer anesthesia effects
than that of the pure solution at the same dose [86,87]. Parmod
et al. applied eugenol loaded PCL in the treatment of periodontal
infections. Solvent displacement method was applied for the for-
mation of eugenol-loaded PCL nanocapsules [88]. Ligature-
induced periodontitis model in rats was selected to evaluate
in vivo performance of eugenol-loaded nanocapsule. The result
indicated that eugenol-loaded nanocapsule could effectively pre-
vent septal bone resorption.
3.2.4. Polypeptide and peptide-drug conjugates
Polypeptides are recombinant proteins genetically engineered
from cells. They are biodegradable and are made up of simple
amino acid residues [18,89]. Different amino acid sequences gener-
ate various structure, endowing the polypeptide with various spe-
cial properties [90,91].
Peptide-drug conjugates are prodrugs formed by covalent
attachment of the peptide and drug via a cleavable linker [92].
Among them, transcriptional transactivator peptide (TAT), as one
of the most frequently used cell-penetrating peptides, has excel-
lent ability to enhance the skin delivery of drugs. Wang et al. pre-
pared a LID loaded TAT-peptide-conjugated nanoparticle for
transdermal delivery. In vivo skin permeation studies were applied
to evaluate the penetration depth in skin by monitoring the loca-
tion of fluorescent of calcein encapsulated in different vehicles.
TAT-conjugated polymeric liposomes group achieved the best skin
penetration ability, indicating its potential for transdermal formu-
lation (Fig. 6) [93].
In addition to the conventional used peptide, peptide with spe-
cial property has been well explored recently. Leu-enkephalin
(LENK) has been regarded as a promising painkiller due to its high
affinity toward d-opioid. Nevertheless, due to its pharmacokinetic
issues, including plasma stability and blood-brain barrier perme-
 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67 61

Fig. 6. Polypeptide or peptide-drug conjugates based local anesthetics delivery system. (A) Synthesis process of TAT-peptide-conjugated OQLCS and Schematic illustration of
the preparation of drug loaded TAT-liposomes. (B) In vivo mouse skin permeation of calcein encapsulated liposomes and calcein encapsulated TAT-conjugated liposomes.
Reprinted with permission from [93], copyrightÓ 2013 Int. J. Pharm.

ability, its clinical application has been restrained. Recently, Feng
et al. designed a facile method to conjugate neuropeptide LENK
to squalene, and then the corresponding (LENK-squalene) LENK-
SQ were assembled to form nanoparticle. An animal model of
inflammatory hyperalgesia that mimics human clinical pain condi-
tions was applied to evaluate the antihyperalgesic properties of
LENK-SQ nanoparticles [94]. The LENK-SQ nanoparticles exhibited
an impressive antihyperalgesic effect that last twice as long as
morphine. Furthermore, biodistribution studies using in vivo fluo-
rescence imaging were applied to investigate the target delivery
ability of LENK-SQ nanoparticles. When compared to a single
LENK-SQ molecular form, very low accumulation of fluorescence
signal in the non-inflamed paw and brain area was obtained for
LENK-SQ nanoparticles group, suggesting that LENK-SQ nanoparti-
cles group can be easily delivered to inflamed area.
3.2.5. Poly (vinyl alcohol)
Poly (vinyl alcohol) (PVA) is one of the most widely used bio-
compatible and water soluble polymers with rather low cost
[95]. It has been widely used in drug delivery and tissue
engineering.
Effective topical anesthesia demand a special delivery formula
which has sufficient viscous flow to enable it to exactly flow into
the wound, meanwhile exhibiting sufficient cohesive integrity to
62 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

be removed in one piece. Most of hydrogels cannot meet such stan-
dard. However PVA-tetrahydroxyborate (THB) hydrogel exhibits
this unique property due to its reversible nature of the cross-
linking mechanism. Loughlin et al. successfully applied this PVA-
THB hydrogel system to load LID for drug delivery to exposed
epithelial surfaces [95]. Petrisor et al. demonstrated that PVA can
effectively eliminate burst release effects and restrain rapid anes-
thesia. When LID was loaded in PVA, the burst effect disappeared
without the need to change the dosage of LID released [96]. McCar-
ron et al. conducted a preliminary clinical trial to evaluate the per-
formance of PVA and THB hydrogel as a means to anesthetize acute
lacerations prior to suturing [97]. Through a series of optimiza-
tions, the PVA-THB system could resolve the problems of poor pro-
duce flow with wound area and problematic removal due to
hydrogel fracturing, indicating its promising clinical applicability
(Fig. 7) [98].
3.3. Lipid and polymer complex delivery systems for anesthetics
Lipids are of significant interest for drug delivery field thanks to
its aptitude to trap both hydrophilic and lipophilic drugs. Tremen-
dous efforts have been devoted to reducing the drug toxicity and
improving the targeting effect for lipid. In the field of topical anes-
thesia, DDS based on lipids are utilized for skin delivery, drug pro-
tection, and controlled release [99–101]. Various strategies have
been explored to increase drug release controllability, solubility,
and stability using multicomponent systems, such as CS-lipid and
CD-liposome [26,102,103]. Kohane et al. prepared lipid-protein-
sugar particles (LPSPs) as BUP carriers [23,24,104]. LPSPs provided
sensory blockade durations comparable to those from PLGA micro-
spheres. Histological sections were applied to study tissue reaction
to both particles. They found out that tissue reaction to PLGA
microspheres lasted considerably longer than that to LPSPs,
demonstrating that LPSPs are more biocompatible since they are
composed of natural ingredients.
Although lipid-based carriers have attracted biological proper-
ties, they suffer lack of reliability and reproducibility during man-
ufacture. In addition, the low weight-volume ratio decrease the
payload that can be attached [105]. Hence, a strategy of lipid-
polymer hybrid nanoparticles (LPNs) combines the advantages of
biodegradable polymeric nanoparticles and biomimetic phospho-
lipids [106]. Researchers compared BUP-loaded LPNs (BVC LPNs)
with BUP PLGA nanoparticles (BVC NPs) (Fig. 8). In vitro and
in vivo studies illustrated that BVC LPNs had better anesthesia
effect and lower toxicity than free BUP nanoparticles, demonstrat-
ing that the combination of both delivery systems was superior
than single delivery system [107].
Typically, anesthetics were first conjugated with polymers, then
the mixture was coated with liposomes. CD complexes are rapidly
metabolized into urine and induce toxicity. Therefore, a ternary
system consisting of proparacaine, CD, and liposome is used to
overcome these complications. Firstly, BZC and butamben were
combined with CD. Then, they were loaded in liposomes [102]. Fer-
reira et al. found that drug released from this delivery system was
sustained for a longer period of time without causing toxic effect
[108]. They further employed this delivery system with ropiva-
caine and observed that it caused less inflammatory response than
that of a plain liposomal delivery system.
However, in other studies, anesthetics were first covered by
lipid. Then the hybrids were coated by polymers. For example, a
layer-by-layer technique was used in order to achieve a prolonged
anesthetic effect and better bioavailability through transdermal
administration. The LID was first loaded in core-shell nanostruc-
tured lipid nanoparticles. Afterwards, they were coated with CS
and HA to achieve topical anesthesia. This polymer/lipid hybrid
nanoparticles combined the beneficial characteristics of both natu-
ral polymeric nanoparticles and liposomes, exhibiting better anes-
thetic effect than their LID-liposomes counterparts and free drugs
[26,109]. In addition to natural polymers, lipids can also be com-
bined with synthetic polymers. The BUP-loaded lipid-polymer

Fig. 7. Representative images of formulation F3 (10.0% PVA, 2.5% w/w THB) that displayed the most appropriate characteristics for clinical use by scoring highest in
qualitative assessments. (A) Wound prior to hydrogel application, (B) formulation F3 applied to the wound, and (C) removal of the formulation from the wound in one piece.
Reprinted with permission from [98], copyrightÓ 2011 Acad. Emerg. Med.

Fig. 8. Lipid/polymer complex delivery systems for local anesthetics. Scheme of the fabrication of LBL-LA/NLCs. Reproduced from P. Ma, T. Li, H. Xing, S. Wang, Y. Sun, X. Sheng,
K. Wang. Local anesthetic effects of bupivacaine loaded lipid-polymer hybrid nanoparticles: in vitro and in vivo evaluation. Biomed. Pharmacother. 2017; 89: 689–695. Copyright Ó
2017 Elsevier Masson SAS. All rights reserved.
 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67 63

nanoparticles (BVC LPNs) with PLGA was fabricated as the core
[107]. In vitro and in vivo evaluation illustrated that BVC LPNs have
better anesthesia effect and lower toxicity than free BUP
nanoparticles.
3.4. Inorganic materials and polymer complex delivery systems for
anesthetics
Silver compounds have been widely used as antibacterial agents
to prevent bacterial infections and was first applied in the hydrox-
yapatite structure. The porous hydroxyapatite/Ag scaffolds which
was coated with AG could control silver ion release by a wet pre-
cipitation method. These scaffolds could be used for bone tissue
engineering, with both long-term local antibacteria (up to one
year) and short-term anesthetic effects (LID release up to two
weeks) [51]. Another AgNPs prepared by reducing silver ions with
glucose in alkaline medium showed stability over time through
adding tetraethyl orthosilicate and L-asparagine as stabilizers.
Nonetheless, AgNPs exhibited high sensitivity to the anesthetics
(procaine, dibucaine, or tetracaine) [38].
Jang et al. designed a facile method to fabricate LID/multivalent
ion complex (icLD) for sustained release via the gradual ionic
exchange between multivalent ions and monovalent ions
[110,111]. This icLD continuously released LID at a constant rate
for 24 h. In contrast, free LID showed a much faster initial burst
within the first 1 h (Fig. 9 (A)). For in vivo study, the duration of sci-
atic nerve blockade in the icLD 100-mg group was up to 14 h,
which is dramatically longer than free LID group (Fig. 9B). An elec-
trophysiological evaluation was also applied to evaluate whether
the nerve signal would be blocked after application of drug solu-
tions. The result clearly indicated that the rats in icLD 100-mg
showed nerve blockade up to 20 h (Fig. 9C). In the end, neurotox-
icity was evaluated through immunocytochemical images, and
the result showed that ATF3 expression was significantly reduced
through encapsulation (Fig. 9D). Hence, both the vitro and in vivo
study indicated that icLD offers a prolonged period of LID release,
and thus provided longer nerve blockade effect with less neurotox-
icity, proving its potential for clinical applications. More evaluation
concerning the safety of this system is desirable before pushing its
application to the next stage [110].
4. Conclusion and future perspective
This review sketches the essential role of polymer-based deliv-
ery systems for local anesthetics by highlighting state-of-the-art
studies in the field. The specific features and applications of each

A B
14
120
Paw Withdrawal Latency (sec)

Normal
12 LD 10-mg
100
Cumulative Release (%)

icLD 50-mg
10 icLD 100-mg
80
8
60 6

40 4
LD
20 icLD 2

0
0 0 5 10 15 20 25
0 5 10 15 20 25
Time (hr) Time (hr)

C 0 hr 1 hr 5 hrs 10 hrs 20 hrs 30 hrs

D Hoechst ATF3 NeuN Merge

Normal Normal
5mV
10ms

LD LD
10-mg 10-mg

icLD icLD
50-mg 50-mg

icLD icLD
100-mg 100-mg

2 mm

Fig. 9. Inorganic materials and polymer complex delivery systems for anesthetics. (A) Patterns of cumulative release of LD from the free LD and the icLD powders. (B) Changes
in the latency of paw withdrawal at different time points after application of three drug solutions, * p < 0.05. (C) Electrophysiological recordings of compound muscle action
potentials conducted through the sciatic nerves in the normal and experimental groups at different time points. (D) Immunfluorescence images at 3 days after application of
the three drug solutions. Reprinted with permission from [110], copyrightÓ 2017 Eur. J. Pharm. Biopharm.
64 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

kind of polymer-based DDS have been systematically summarized
in Table 1. In general, natural polymers are superior in biodegrad-
ability, while synthetic polymers typically have a longer degrada-
tion process in comparison, but possess more versatile
functionalities. In addition, the synthetic polymers can be easily
used in combination with other delivery systems such as lipids
and inorganic nanoparticles. Therefore, both natural and synthetic
polymers exhibit their unique properties, providing various
options for local anesthetics in need.
Clinically used local anesthetics, such as LID and BUP, are
known for their effectiveness. However, they also suffer from a
short duration of action (e.g., the effect of LID lasts only 1–2 h)

Table 1
Summary of polymer-based local anesthetic delivery systems.

Materials Anesthetics Comments Ref

HA BUP Free BUP (3 mg/kg) admixed with BUP (13 mg/kg) conjugated to Hylan B particles showed a four to 5-fold longer [42]
impairment of motor function over the free BUP formulations with a total block time of 19 h.
CARR-HA LID The LID release profiles for CARR and CARR/HA wafers showed controlled release over 6 h. The AgNPs/LID loaded wafers [43]
did not interfere with cell viability and growth.
CS LID A film prepared from 3% high MW CS and cross-linked by 0.1% of tripolyphosphate penta sodiu salt showed a high flux of [47]
LID, and relatively high bioadhesion and tensile strength.
LID Hydrogels for a controlled local release of LID using CHG with the addition of glycerin were produced. LID-loaded muco- [48]
adhesive hydrogels can be of aid in reducing the pain symptoms that characterize aphthosis and other mouth diseases.
tetracaine Albumin-CS microparticles loading tetracaine was found to significantly increase the duration of action of the drug up to [33]
4-fold.
AG-CS BUP The efficiency of association of BUP in AG/CS and AG/bis(2-ethylhexyl) sulfosuccinate nanoparticles was high, with [34]
values in excess of 75%. The release profile of BUP was modified when associated with the nanoparticles, being slower
and more sustained when compared with the kinetics of free BUP in both the cases.
PLGA-CS BUP A gel-based PLGA-CS-microparticles encapsulating BUP displayed sustained, tunable release of BUP up to 7 days. This [35]
formulation showed controlled release of local anesthetics to treat acute/subacute pain while avoiding enhanced
inflammation.
lipid-CS LID The anesthetic activity of LID-LPNs revealed a more rapid anesthetic effect in the first few minutes and also displayed [109]
sustained activity compared with the LID-liposomes. The sustained anesthetic effect of the LID-LPNs could bring about
better local anesthetic therapy effects than the LID-liposomes.
GEL BZC A film system composed of sunflower oil and GEL could release BZC in a controlled manner, but with an initial burst [56]
LID A LID nasal gel was developed using HPMC as the base material to transport LID directly from the nasal cavity into the [63]
central nervous system
mepivacaine Mepivacaine gel containing polyoxyethylene 2-oleyl ether and tetrahydrozoline produced a 2.36-fold increase in [62]
anesthetic activity compared to the control gel without any additives, suggesting that the bioadhesive mepivacaine-
HPMC gel containing permeation enhancer and vasoconstrictor could be developed for enhanced local anesthetic action.
CD LBP The complex of LBP with CD prolonged the anesthetic effect of LBP in both intrathecal and sciatic nerve blocks in rats. [67]
lipid-CD BZC When loaded in liposomes, the complexation of BZC and CD revealed a significant enhancement of intensity and [71]
duration of anesthetic effect
PLA BUP Developed an injectable local anesthetic preparation that provides 2–5 days blockade of the sciatic nerves of rat in vivo [27]
and plasma BUP levels are below the range associated with systemic toxicity.
BZC BZC-containing PLA nanocapsules have good chemical stability and colloidal over a 60-day period. the release profile of [29]
BZC in 73% PLA caused BZC water solubility to be increased six times.
LID The microneedle arrays were released rapidly into PBS within 2 min, and its storage stability lasted 3 weeks for varying [30]
temperatures. in vitro studies showed enhanced skin penetration and more efficient LID delivery into the skin compared
to EMLAÒ cream 1, 2, and 5 min after application.
PLA-PEG procaine PLA-PEG 30:5 nanoparticles enhance the incorporation efficiency of drug. [74]
PLGA BUP Sensory blockade duration for 50% (w/w) BUP was 840 min. BUP loaded-PLGA nanospheres increased cell viability, in [31,32]
comparison with the effect produced by free BUP, indicating a reduced toxicity.
LID Sensory blockade duration for 50% (w/w) LID was 255 min. LID and BUP-PLGA microspheres resulted in similar degrees [32]
of myotoxicity, irrespective of drug loading.
BZC BZC loaded PLGA nanocapsules released different amounts of drug after 1500 min in HEPES buffer, compared with free [77]
BZC
lipid-PLGA BUP Compared with BVC NPs, the release profile of BVC LPNs presented a low burst effect and kept sustained release for 96 h. [107]
BVC LPNs can reverse or reduce the cytotoxicity of free BVC at the same drug concentration.
PEG-PCL-PEG LID A LID-loaded PCEC hydrogel produced more enduring local antinociceptive effects compared with LID aqueous solution [86]
at the same dose.
LBP LBP in situ gels maintained good anesthesia effects even after 9 h of injection and rats’ stinging reaction maintained at a [87]
relatively low level
PEG-PCL ATC Suspensions of PEG-PCL nanocapsules loaded with ATC were moderately stable over a period of 120 days. Cytotoxicity [85]
assays confirmed that the encapsulation of ATC reduced its toxicity.
PVA-THB LID D-mannitol was effective in formulating LID into PVA-THB hydrogels. It can increase the solubility of LID and prevent the [95]
demixing effect seen in PVA-THB hydrogels brought about by LID concentrations that exceed 3.0% w/w. As temperature
increased through 37 to 50 °C, the solubility of LID was reduced progressively.
LID A formulation (10.0% PVA, 2.5% w/w THB) displayed the most appropriate characteristics in application and removal of [98]
adhesiveness. The release of LID was proportional to the concentration of LID incorporated.
LID PVA-THB hydrogels loaded with LID could be formulated without addition of a polyol modulator to a maximum [97]
concentration 1.5% w/w, and these hydrogels provided a sustained release over 24 h.
peptide-polymer LID The transdermal flux of LID-TAT-liposomes was approximately 4.17 and 1.75 times higher than that of LID solution and [93]
LID liposomes.
inorganic-polymer LID The icLD continuously released LID at a constant rate for 24 h with a mild initial burst. The duration of sciatic nerve [110]
blockade in the icLD 100-mg group was up to 14 h, which is longer than free LID group. the rats in icLD 100-mg showed
nerve blockade up to 20 h, providing longer anesthetic action.
 B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67
and safety issues, mainly in neurotoxicity and cardiotoxicity [112].
To overcome these barriers, polymeric DDS have been developed to
prolong duration time and reduce the side effects for local anes-
thetics [113]. Furthermore, synergistic analgesia could be achieved
with properly designed DDS that impart physicians with additional
clinical medication options.
PLGA, PLA, and liposome/polymer are the most commonly used
DDS in local anesthetic delivery systems, whereas other materials
are still sparsely studied. For instance, gold nanoparticles have
been utilized as DDS for decades and exhibited promising effects
in both photo-diagnostics and photothermal therapy [114–116].
Moreover, researchers managed to promote the replacement of
painful injections by patient-friendly needle-free topical formula-
tions, which is advantageous and will have promising applications
in local anesthetics [117].
In summary, the latest advances of polymer nanocarriers have
been comprehensively reviewed in this article. We detailed the
arsenal of polymer nanocarriers for local anesthetics. Despite
numerous studies on encapsulating anesthetics with polymer
nanocarriers are ongoing, few of them are projected to enter clin-
ical stages. It remains a challenge to select an appropriate nanocar-
rier since several factors can simultaneously affect delivery
efficiency and circulation of nanoparticles. Therefore, more sys-
tematic studies are desired to eventually generate clinically useful
nanocarriers for local anesthetics delivery.
Acknowledgement
This work was supported by Hunan Provincial and Municipal
Joint Funds (NO. 2017JJ4049).
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