Recent advances in polymer-based drug delivery systems for local anesthetics

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 Department of Pharmacy, PLA Rocket Force Characteristic Medical Center, Beijing 100088, China 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 b c

a r t i c l e

i n f o

Article history: Received 8 December 2018 Received in revised form 16 May 2019 Accepted 19 May 2019 Available online 29 May 2019 Keywords: Polymer Drug delivery system Local anesthetics

a b s t r a c t Local anesthetics, which cause temporary loss of pain by inhibiting the transmission of nerve impulses, have been widely used in clinical practice. However, neurotoxicity and short half-lives have significantly limited their clinical applications. To overcome those barriers, numerous drug delivery systems (DDS) have been designed to encapsulate local anesthetic agents, so that large doses can be released slowly 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 platforms are the most extensively explored, especially in the form of polymeric nanoparticle carriers. This review gives a specific focus on the most commonly used natural and synthetic polymers for local anesthetics delivery, owing to their excellent biocompatibility, biodegradability and versatility. State-of-theart 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 compliance 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 polymer 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: [email protected] (X. Kuang), [email protected] (S. Sheng), [email protected] (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.

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B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

Contents 1. 2. 3.

4.

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

1. Introduction Pain is a common symptom in clinical practice. Patients suffering 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 significantly 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 preventing and managing undesired pain from post-operative complications. Currently, the main pharmacotherapeutic strategy that aims to manage these complications involves the optimization of anesthesia delivery systems for patients undergoing surgical procedures [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 anesthetics 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 plasmadrug concentration. Consequently, it may cause patients to experience 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 dermatologic and laser procedures. However, a number of case reports indicated 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 developed 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

56 56 57 57 57 57 57 58 59 59 59 59 59 60 60 61 62 63 63 65 65

value of plasma-drug concentration [15]. Till 2011, liposomal bupivacaine (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 delivery 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 discussed 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 toxicity. External delivery devices are inaccurate and limit the clinical use of new delivery systems. Hence, the development of a nanoparticle 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., polylactic acid (PLA) [27–30], poly (lactic-co-glycolic acid) (PLGA) [31,32] or chitosan (CS) [33–35]), inorganic material based delivery 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

A

3. Polymer-based delivery system for anesthetics

Preanesthetic medications Antacids

Antiemetics

Benzodiazepines

Anticholinergics

Antihistamines

Opioids

B F

Halothane

F

F

F F

O

Cl

F

F

F

Isofl urane

Cl

F

F

F F

Br

O

F

F

Sevoflurane F3C

O

Nitrous oxide

F

C

N N O

N N O

CF3

General anesthetics: intravenous Barbiturates

Ketamine

HN

Opioids

Etomidate

HO

O

Cl

O

NH

O

O

O

H

O H

NH

O

N

N CH 3

N

HO

Dexmedetomidine

Propofol

Benzodiazepines R1 N

OH

NH N

R 2

N

R7

R2'

D

Neuromuscular blockers Vecuroni um

Rocuroni um

Pancuronium

O

O O H

N

O

N

H

N

H

H O

O

N

O

H

HO

N H

H

O

H

O

Succinylcholine

Cisatracurium CH3 O H3C

H

N

H

H

Br-

H O

O

CH3 O N

O

CH3

O O

O CH3 O

E

H 3C

O -

O O S O

OO S O

O N

O

CH3

O

N

O

O

N

2Cl-

O

CH3

H 3C

O CH3

O

Local anesthetics: amides Bupivacaine H N

Lidocaine H N

N

Mepivacaine H N

N

O

O

N O

Etidocaine

Ropivacaine

Articaine O

S H N

H N

N O

OCH3

N NH

O

H N

O

F

Local anesthetics: esters Chloroprocaine

Bezocaine

Procaine

O

O

O

N

O H 2N

O

O H 2N

Cl

N

NH2

Cocaine O H 3C N

3.1. Natural polymer-based delivery systems for anesthetics 3.1.1. Hyaluronic acid Hyaluronic acid (HA) mainly exists in synovial fluid, heart valves, vitreous of the eye, and extracellular matrix. It is a nonimmunogenic naturally occurring mucopolysaccharide. Owing to its excellent biocompatibility, biodegradability and viscoelastic properties, HA has been widely used in various therapeutic applications, including drug delivery, wound healing, tissue regeneration [39,40]. Furthermore, even if problems were to arise with HA, it can be easily removed by digestion with hyaluronidase [41]. Particular attention has been focused on HA as a potential delivery for BUP. Diego et al. successfully conjugated BUP to HA derivative Hylan B particles. In vitro drug release study showed the duration of BUP prolonged to more than 16 h for HA-BUP particle, which is significantly longer than that of free BUP (0.4 h). For in vivo study, compared with free BUP, HA-BUP exhibited fivefold longer block time in impairing motor function, thus proving this HA drug delivery system effectively prolonged the duration of local anesthesia [42]. HA was also combined with other components to make composite for biomedical application due to its excellent compatibility. Ovidio et al. fabricated a multi-targeted composite carrageenan (CARR)/HA based wafers loaded with LID and silver nanoparticles (AgNPs). The AgNP loaded wafers effectively killed all the bacteria tested after 6 h incubation. Furthermore, the mechanical hardness could be easily tuned by varying the content of HA, providing good handling property for chronic leg ulcer. This composite system exhibited multiple properties such as fast drug release and the effective antimicrobial activity, indicating its potential application for chronic leg ulcer dressing (Fig. 2) [43].

General anesthetics: inhaled Desfl urane

57

O

Tetracaine

CH3

O N

O O

3.1.2. Chitosan Chitosan (CS) is a natural polysaccharide used in biological applications for decades. It can be fabricated into the form of powders, films, fiber meshes, membranes, beads, and hydrogels, depending on their future application [44,45]. CS-based materials have been widely applied in oral mucosal delivery systems due to its versatile property [46]. Several studies related to CS loaded with LID have been carried out in buccal area. Varshosaz et al. prepared films of LID with three different molecular weight of CS in various conditions. The result demonstrated that high concentration and molecular weight of CS significantly increased the flux of LID through the films. However, this system has not been tested in vivo. Further clinical studies are necessary to evaluate its clinical potential [47]. Pignatello et al. fabricated a hydrogel for the buccal application of LID using CS glutamate (CHG). To evaluate its performance, CHG hydrogel were compared with two commercial products. A much slower drug release rate has been achieved with CHG hydrogel. In vivo pharmacological activity study proved that CHG hydrogel has similar anesthetic activity as commercial products, but with less tissue inflammation [48].

O N H

Fig. 1. Classification of anesthetics. (A) Preanesthetic can be divided into six categories. (B) and (C) represent general anesthetics delivered via inhalation and intravenous injection. (D) Neuromuscular blockers facilitate tracheal intubation and surgery. (E) and (F) represent two most common chemical structures of local anesthetics.

3.1.3. Alginate Alginates (AG) are water-soluble linear polysaccharides obtained from brown algae. It has been widely used in tissue engineering for pharmaceutical and biomedical applications as drug delivery systems due to its excellent biocompatibility and biodegradability [49].

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B. Wang et al. / Acta Biomaterialia 96 (2019) 55–67

LID release LID release (% )

100 80 60 CARR CARR/HA CARR/HA CARR/HA

40 20

10 30 50

0 0

1

2 3 4 Time (hours)

5

6

Antimicrobial activity Control Wafer CARR/AgNPs CARR/AgNPs CARR/AgNPs CARR/AgNPs

Leg ulcer

Carrageenan

Silver Nanoparticle

HA

Lidocaine

Absorbance

5.0 4.0 3.0 2.0 1.0 0.0

*

**

**

** **

* ** ** **

** **

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 procedural 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, Najafabadi 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 product 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 candidate 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 efficiency to 86%. Then, the nanoparticles were further applied to a sciatic nerve blockade model. It has been demonstrated that a prolonged 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 mineral salts and proteins. It has been widely used in pharmaceutical and food industries [53]. Structurally, a typical GEL film incorporates 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 excellent analgesic effect against pain associated with needle insertion [55]. While GEL initially appeared an initial bursts issue. Specifically, 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 polylactic 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 living species, such as plants, animals, and bacteria. It has repeating units of ringed glucose molecules and a flat ribbon-like conformation. Furthermore, its abundant –OH side groups greatly facilitate the grafting of chemical species to achieve different surface properties, making it become an attractive materials for biomedical engineering [59,60]. Medhi et al. first utilized CEL to fabricate biopolymer for transdermal drug delivery. LID-loaded biopolymer composite microneedles 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 mepivacaine gels contained vasoconstrictor and penetration enhancer mixed with hydroxypropyl methyl CEL (HPMC) showed a prolonged 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 nervous system [63]. In most cases, CEL is not the single component in delivery systems; researchers combined CEL with other polymers like CS or AG. For example, a mucoadhesive bilayer device made of CS and ethylcellulose showed promising potential in controlled 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 cCD, 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 neither be too small, nor be too large [70]. At the same time, while the inside of CD is hydrophobic, the outside is hydrophilic. Drugin 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 liposomes release system. In addition, it further improved drug availability 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 dissolution 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 BUPpolyester 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 different 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 developed 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 efficient 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 several 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 anesthetic 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 concentration 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.

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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 ecaprolactone [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 formation of eugenol-loaded PCL nanocapsules [88]. Ligatureinduced periodontitis model in rats was selected to evaluate

in vivo performance of eugenol-loaded nanocapsule. The result indicated that eugenol-loaded nanocapsule could effectively prevent 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 generate various structure, endowing the polypeptide with various special 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 excellent ability to enhance the skin delivery of drugs. Wang et al. prepared 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 location of fluorescent of calcein encapsulated in different vehicles. TAT-conjugated polymeric liposomes group achieved the best skin penetration ability, indicating its potential for transdermal formulation (Fig. 6) [93]. In addition to the conventional used peptide, peptide with special 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-

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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) LENKSQ were assembled to form nanoparticle. An animal model of inflammatory hyperalgesia that mimics human clinical pain conditions 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 fluorescence 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 nanoparticles 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 biocompatible 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

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be removed in one piece. Most of hydrogels cannot meet such standard. However PVA-tetrahydroxyborate (THB) hydrogel exhibits this unique property due to its reversible nature of the crosslinking mechanism. Loughlin et al. successfully applied this PVATHB 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 anesthesia. When LID was loaded in PVA, the burst effect disappeared without the need to change the dosage of LID released [96]. McCarron et al. conducted a preliminary clinical trial to evaluate the performance of PVA and THB hydrogel as a means to anesthetize acute lacerations prior to suturing [97]. Through a series of optimizations, the PVA-THB system could resolve the problems of poor produce 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. Tremendous efforts have been devoted to reducing the drug toxicity and improving the targeting effect for lipid. In the field of topical anesthesia, DDS based on lipids are utilized for skin delivery, drug protection, 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-proteinsugar particles (LPSPs) as BUP carriers [23,24,104]. LPSPs provided sensory blockade durations comparable to those from PLGA microspheres. 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 properties, they suffer lack of reliability and reproducibility during manufacture. In addition, the low weight-volume ratio decrease the payload that can be attached [105]. Hence, a strategy of lipidpolymer hybrid nanoparticles (LPNs) combines the advantages of biodegradable polymeric nanoparticles and biomimetic phospholipids [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, demonstrating 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]. Ferreira 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 ropivacaine 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 nanostructured 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 natural polymeric nanoparticles and liposomes, exhibiting better anesthetic effect than their LID-liposomes counterparts and free drugs [26,109]. In addition to natural polymers, lipids can also be combined 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.

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[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 sciatic nerve blockade in the icLD 100-mg group was up to 14 h, which is dramatically longer than free LID group (Fig. 9B). An electrophysiological evaluation was also applied to evaluate whether the nerve signal would be blocked after application of drug solutions. The result clearly indicated that the rats in icLD 100-mg showed nerve blockade up to 20 h (Fig. 9C). In the end, neurotoxicity 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 neurotoxicity, 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].

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 hydroxyapatite structure. The porous hydroxyapatite/Ag scaffolds which was coated with AG could control silver ion release by a wet precipitation 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

4. Conclusion and future perspective This review sketches the essential role of polymer-based delivery systems for local anesthetics by highlighting state-of-the-art studies in the field. The specific features and applications of each

B

A 100 80 60 40

LD icLD

20 0

C

Paw Withdrawal Latency (sec)

Cumulative Release (%)

120

14 Normal LD 10-mg icLD 50-mg icLD 100-mg

12 10 8 6 4 2 0

0

5

0 hr

10 15 Time (hr)

20

0

25

1 hr 5 hrs 10 hrs 20 hrs 30 hrs

D

Hoechst

5

10 15 Time (hr)

ATF3

NeuN

20

25

Merge

Normal

Normal 5mV 10ms

LD 10-mg

LD 10-mg

icLD 50-mg

icLD 50-mg

icLD 100-mg

icLD 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.

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kind of polymer-based DDS have been systematically summarized in Table 1. In general, natural polymers are superior in biodegradability, while synthetic polymers typically have a longer degradation 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

[42]

CARR-HA

LID

Free BUP (3 mg/kg) admixed with BUP (13 mg/kg) conjugated to Hylan B particles showed a four to 5-fold longer impairment of motor function over the free BUP formulations with a total block time of 19 h. The LID release profiles for CARR and CARR/HA wafers showed controlled release over 6 h. The AgNPs/LID loaded wafers 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 LID, and relatively high bioadhesion and tensile strength. Hydrogels for a controlled local release of LID using CHG with the addition of glycerin were produced. LID-loaded mucoadhesive hydrogels can be of aid in reducing the pain symptoms that characterize aphthosis and other mouth diseases. Albumin-CS microparticles loading tetracaine was found to significantly increase the duration of action of the drug up to 4-fold.

[47]

LID tetracaine AG-CS

BUP

PLGA-CS

BUP

lipid-CS

LID

GEL

BZC LID mepivacaine

CD lipid-CD

LBP BZC

PLA

BUP BZC LID

The efficiency of association of BUP in AG/CS and AG/bis(2-ethylhexyl) sulfosuccinate nanoparticles was high, with 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. A gel-based PLGA-CS-microparticles encapsulating BUP displayed sustained, tunable release of BUP up to 7 days. This formulation showed controlled release of local anesthetics to treat acute/subacute pain while avoiding enhanced inflammation. The anesthetic activity of LID-LPNs revealed a more rapid anesthetic effect in the first few minutes and also displayed 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. A film system composed of sunflower oil and GEL could release BZC in a controlled manner, but with an initial burst A LID nasal gel was developed using HPMC as the base material to transport LID directly from the nasal cavity into the central nervous system Mepivacaine gel containing polyoxyethylene 2-oleyl ether and tetrahydrozoline produced a 2.36-fold increase in anesthetic activity compared to the control gel without any additives, suggesting that the bioadhesive mepivacaineHPMC gel containing permeation enhancer and vasoconstrictor could be developed for enhanced local anesthetic action. The complex of LBP with CD prolonged the anesthetic effect of LBP in both intrathecal and sciatic nerve blocks in rats. When loaded in liposomes, the complexation of BZC and CD revealed a significant enhancement of intensity and duration of anesthetic effect Developed an injectable local anesthetic preparation that provides 2–5 days blockade of the sciatic nerves of rat in vivo and plasma BUP levels are below the range associated with systemic toxicity. BZC-containing PLA nanocapsules have good chemical stability and colloidal over a 60-day period. the release profile of BZC in 73% PLA caused BZC water solubility to be increased six times. The microneedle arrays were released rapidly into PBS within 2 min, and its storage stability lasted 3 weeks for varying 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.

[43]

[48] [33] [34]

[35]

[109]

[56] [63] [62]

[67] [71] [27] [29] [30]

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 comparison with the effect produced by free BUP, indicating a reduced toxicity. Sensory blockade duration for 50% (w/w) LID was 255 min. LID and BUP-PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. BZC loaded PLGA nanocapsules released different amounts of drug after 1500 min in HEPES buffer, compared with free BZC

[31,32]

LID BZC

[32] [77]

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. BVC LPNs can reverse or reduce the cytotoxicity of free BVC at the same drug concentration.

[107]

PEG-PCL-PEG

LID

A LID-loaded PCEC hydrogel produced more enduring local antinociceptive effects compared with LID aqueous solution at the same dose. LBP in situ gels maintained good anesthesia effects even after 9 h of injection and rats’ stinging reaction maintained at a relatively low level Suspensions of PEG-PCL nanocapsules loaded with ATC were moderately stable over a period of 120 days. Cytotoxicity assays confirmed that the encapsulation of ATC reduced its toxicity.

[86]

LBP PEG-PCL

ATC

PVA-THB

LID

LID LID peptide-polymer

LID

inorganic-polymer

LID

D-mannitol was effective in formulating LID into PVA-THB hydrogels. It can increase the solubility of LID and prevent the 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. A formulation (10.0% PVA, 2.5% w/w THB) displayed the most appropriate characteristics in application and removal of adhesiveness. The release of LID was proportional to the concentration of LID incorporated. PVA-THB hydrogels loaded with LID could be formulated without addition of a polyol modulator to a maximum concentration 1.5% w/w, and these hydrogels provided a sustained release over 24 h. The transdermal flux of LID-TAT-liposomes was approximately 4.17 and 1.75 times higher than that of LID solution and LID liposomes. The icLD continuously released LID at a constant rate for 24 h with a mild initial burst. The duration of sciatic nerve 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.

[87] [85] [95]

[98] [97] [93] [110]

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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 anesthetics [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 formulations, 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 clinical stages. It remains a challenge to select an appropriate nanocarrier since several factors can simultaneously affect delivery efficiency and circulation of nanoparticles. Therefore, more systematic 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). References [1] P. Bhusal, J. Harrison, M. Sharma, D.S. Jones, A.G. Hill, D. Svirskis, Controlled release drug delivery systems to improve post-operative pharmacotherapy, Drug Deliv. Transl. Res. 6 (5) (2016) 441–451. [2] R.J. Alencar de Castro, P.C. Leal, R.K. Sakata, Pain management in burn patients, Braz. J. Anesthesiol. 63 (1) (2013) 149–158. [3] Y. Olsen, J.M. Sharfstein, Chronic pain, addiction, and Zohydro, N. Engl. J. Med. 370 (22) (2014) 2061–2063. [4] D. Dowell, T.M. Haegerich, R. Chou, CDC guideline for prescribing opioids for chronic pain–United States, 2016, J. Am. Med. Assoc. 315 (15) (2016) 1624– 1645. [5] J. Gierthmühlen, R. Baron, Neuropathic pain, Semi. Neurol. 36 (5) (2016) 462– 468. [6] D.B. Gordon, O.A. de Leon-Casasola, C.L. Wu, K.A. Sluka, T.J. Brennan, R. Chou, Research gaps in practice guidelines for acute postoperative pain management in adults: findings from a review of the evidence for an american pain society clinical practice guideline, J. Pain 17 (2) (2016) 158– 166. [7] D. Bainbridge, J. Martin, M. Arango, D. Cheng, Perioperative and anaestheticrelated mortality in developed and developing countries: a systematic review and meta-analysis, Lancet 380 (9847) (2012) 1075–1081. [8] G. Kannan, S.P. Kambhampati, S.R. Kudchadkar, Effect of anesthetics on microglial activation and nanoparticle uptake: implications for drug delivery in traumatic brain injury, J. Controll. Release 263 (2017) 192–199. [9] K. Whaken, Lippincott’s Illustrated Reviews: Pharmacology, Lippincott, Williams & Wilkins, Philadelphia, 2014. [10] K. Welin-Berger, J.A. Neelissen, J. Engblom, Physicochemical interaction of local anesthetics with lipid model systems-correlation with in vitro permeation and in vivo efficacy, J. Controll. Release 81 (1–2) (2002) 33–43. [11] L. Zorzetto, P. Brambilla, E. Marcello, N. Bloise, M.D. Gregori, L. Cobianchi, A. Peloso, M. Allegri, L. Visai, P. Petrini, From micro- to nanostructured implantable device for local anesthetic delivery, Int. J. Nanomed. 11 (2016) 2695–2709. [12] A. Swain, D.S. Nag, S. Sahu, D.P. Samaddar, Adjuvants to local anesthetics: current understanding and future trends, World J. Clin. Cases 5 (8) (2017) 307–323. [13] F.F. Tu, Insights gained from a negative trial of steroid blocks for perineal pain, Br. J. Obstet. Gynaecol. 124 (2) (2016). 261-261. [14] J.F. Sobanko, C.J. Miller, T.S. Alster, Topical anesthetics for dermatologic procedures: a review, Dermatol. Surg. 38 (5) (2012) 709–721. [15] S.J. Holland, B.J. Tighe, P.L. Gould, Polymers for biodegradable medical devices. 1. The potential of polyesters as controlled macromolecular release systems, J. Control. Release 4 (3) (1986) 155–180.

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