Prolongation of sciatic nerve blockade by in situ cross-linked hyaluronic acid

Prolonged duration local anesthesia with minimal toxicity

“…Conventional local anesthetics are intrinsically myotoxic (3,4). They are also myotoxic when released from a wide range of delivery systems (3,5), even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure (3), suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds.…”

Does hyaluronic acid decrease the apoptotic effect of bupivacaine?

“…[15] The cross-linked hyaluronic acid formulation increased the duration of block across a range of clinically relevant concentrations of bupivacaine. [11] Viscous hyaluronic acid formulations prolonged the effect bupivacaine as observed in rabbits. [16] Hyaluronic acid is an unsulfated glycosaminoglycan polysaccharide composed of glucuronic acid and N-acetylglucosamine.…”

“…[10] Cross-linkable hyaluronic acid appears to be a safe and effective means of prolonging the duration of block of local anesthetics that merits further investigation for clinical applicability. [11] Also, the prolongation of epidural bupivacaine by hyaluronic acid viscous formulations has been demonstrated. [9] In this study, we aimed to investigate the antiapoptotic effect of hyaluronic acid on the apoptotic effects of bupivacaine in cultured rat chondrocytes in a time and dose-dependent manner.…”

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe. That tissue injury can be a crucial issue with sustained release formulations is seen in the example of a sustained-release bupivacaine-dexamethasone formulation; 3 nerve and muscle injury in preclinical animal studies and clinical human trials led to withdrawal of its Investigational New Drug application (IND#53,441).…”

“…A very broad range of controlled release formulations have been developed to provide prolonged duration local anesthesia, including polymeric microspheres, [1][2][3][4][5][6][7] surgically implantable pellets, 8 microcrystals, 9 liposomes, [10][11][12][13][14][15] (including a formulation undergoing human clinical trials 16,17 ) lipospheres, 18 cross-linkable hyaluronic acid matrices, 19 lipidprotein-sugar particles, 20,21 cyclodextrin complexes, 22,23 liposomes loaded with cyclodextrin complexes 24 and implantable membrane matrices. 25,26 Such systems have extended the duration of nerve block to varying degrees ranging from hours to weeks, but have not been widely adopted clinically.…”