A chitosan thermogel for delivery of ropivacaine in regional musculoskeletal anesthesia

Abstract

Postoperative pain within the first days following musculoskeletal surgeries is a significant problem for which appropriate management correlates to positive clinical outcomes. While a variety of pain management modalities are currently used for postoperative pain, an optimal strategy has yet to be identified. Utilizing local anesthetics to convey analgesia through neural blockade represents a promising approach to alleviate postoperative pain. Unfortunately, local anesthetics are often associated with short half-lives, local tissue site reactions, and systemic toxicity. Drug delivery systems such as liposomes, microparticles, and nanoparticles have been previously utilized to extend analgesia, but these systems can easily diffuse from the injection site. In order to overcome this limitation a combination of drug delivery technologies were utilized. Ropivacaine base nanoparticles were fabricated and entrapped with dexamethasone using a chitosan thermogel delivery system in order to enhance neural blockade. Using a rat sciatic neural blockade model, this system was able to limit sensory function and motor function for up to 48 h. This approach utilized a low solubility drug, a drug action enhancer, nanoparticles, and a thermogel matrix together to yield a multi-faceted delivery system capable of providing moderate-term pain management.

Introduction

A variety of musculoskeletal procedures including fracture fixation, total knee replacement, total hip replacement, and rotator cuff repair result in considerable postoperative pain for up to 48 h following surgery [1]. A variety of medications are available to patients dealing with postoperative pain such as acetaminophen, non-steroidal anti-inflammatory drugs, corticosteroids, anesthetics, and opioids. Recently, the use of local anesthetics to provide postoperative analgesia has received considerable scientific and clinical interest [2], [3]. While promising, local anesthetics possess short durations of action so neural blockade enhancers like dexamethasone are often utilized in combination with these drugs [4], [5]. A variety of local anesthetics are available on the market with the amino-amide drugs lidocaine, bupivacaine, and ropivacaine being three of the most commonly used. Bupivacaine and ropivacaine have been shown to cause longer peripheral neural blockade (4.5–12 h) than lidocaine (1–2 h) [6], [7], [8]. In order to extend the activity of these fast acting local anesthetic drugs, a neural blockade enhancer like dexamethasone is often included. Bupivacaine is a widely used long-acting anesthetic, but is associated with significant cardiotoxicity and neurotoxicity [9], [10]. Ropivacaine, the propyl analog of bupivacaine, has been shown to be less cardiotoxic and neurotoxic than bupivacaine [11], [12] while maintaining a similar duration of action [13]. Additionally, ropivacaine possesses lower lipid solubility [14] and vasodilation [15] than bupivacaine allowing for better retention in the local environment it is delivered. While promising, local anesthetics require continuous infusion to maintain desirable postoperative pain management [16] which can lead to significant issues such as adverse local tissue reactions [17] and systemic toxicity [18], [19].

The use of biomaterials to achieve controlled release of local anesthetics has the potential to yield a safe, localized, long-acting postoperative pain management system. A number of biomaterial-based carriers have been previously explored including liposomes [5], microparticles [20], and nanoparticles [21]. These materials are capable of extending the release of encapsulated drugs, but can freely diffuse from the injection site. Thermogels are a class of biomaterials capable of existing as injectable solutions at room temperature that transition to colloidal gels in situ as they warm to body temperature. These materials are ideal for sustained, localized anesthetic delivery since the drug can be easily dispersed and then injected into the patient where upon gelation, the thermogel will maintain drug delivery at the injection site. Thermogels can be composed of a variety of different synthetic [22], [23] or natural polymers [24], [25]. Chitosan is a linear polysaccharide that is synthesized by deacetylating chitin, a structural element found in the exoskeleton of crustaceans. It can be crosslinked by inorganic phosphate salts to become a thermogelling solution which has shown promise as an injectable drug delivery vehicle for over ten years [26], [27]. Chitosan thermogels are non-cytotoxic [28], can be tailored to gelate quickly [29] while capable of maintaining sustained payload delivery [28], [30], and degrade slowly over time into bioresorbable products [31], making them promising local anesthetic delivery vehicles.

In the present study, chitosan thermogels were utilized to deliver ropivacaine base nanoparticles with and without dexamethasone. Our hypothesis was that a gel system composed of chitosan, ropivacaine and dexamethasone would result in controlled anesthetic drug delivery and sustained anesthetic effects in vivo.