{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T03:44:07Z","timestamp":1768535047815,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T00:00:00Z","timestamp":1580947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["108-2221-E-182-004"],"award-info":[{"award-number":["108-2221-E-182-004"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012553","name":"Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPD2H0032"],"award-info":[{"award-number":["CMRPD2H0032"]}],"id":[{"id":"10.13039\/100012553","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, we explored the release characteristics of analgesics, namely levobupivacaine, lidocaine, and acemetacin, from electrosprayed poly(D,L-lactide-co-glycolide) (PLGA) microparticles. The drug-loaded particles were prepared using electrospraying techniques and evaluated for their morphology, drug release kinetics, and pain relief activity. The morphology of the produced microparticles elucidated by scanning electron microscopy revealed that the optimal parameters for electrospraying were 9 kV, 1 mL\/h, and 10 cm for voltage, flow rate, and travel distance, respectively. Fourier-transform infrared spectrometry indicated that the analgesics had been successfully incorporated into the PLGA microparticles. The analgesic-loaded microparticles possessed low toxicity against human fibroblasts and were able to sustainably elute levobupivacaine, lidocaine, and acemetacin in vitro. Furthermore, electrosprayed microparticles were found to release high levels of lidocaine and acemetacin (well over the minimum therapeutic concentrations) and levobupivacaine at the fracture site of rats for more than 28 days and 12 days, respectively. Analgesic-loaded microparticles demonstrated their effectiveness and sustained performance for pain relief in fracture injuries.<\/jats:p>","DOI":"10.3390\/ijms21031093","type":"journal-article","created":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T03:13:27Z","timestamp":1581045207000},"page":"1093","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sustained Release of Levobupivacaine, Lidocaine, and Acemetacin from Electrosprayed Microparticles: In Vitro and In Vivo Studies"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4609-7333","authenticated-orcid":false,"given":"Jian-Ming","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan 33305, Taiwan"},{"name":"Department of Mechanical Engineering, Chang Gung University, Tao-Yuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuan-Chieh","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Chang Gung University, Tao-Yuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-5552","authenticated-orcid":false,"given":"Wen-Ling","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan 33305, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-5781","authenticated-orcid":false,"given":"Jin-Chung","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Science, Chang Gung University, Tao-Yuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2083-4865","authenticated-orcid":false,"given":"Shih-Jung","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan 33305, Taiwan"},{"name":"Department of Mechanical Engineering, Chang Gung University, Tao-Yuan 33302, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.bone.2016.01.026","article-title":"Fracture pain-Traveling unknown pathways","volume":"85","author":"Alves","year":"2016","journal-title":"Bone"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1007\/s11999-011-2016-6","article-title":"Analysis of operative versus nonoperative treatment of displaced scapular fractures","volume":"469","author":"Jones","year":"2011","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1136\/emj.2005.032169","article-title":"Delivery of local anaesthetic via a sternal catheter to reduce the pain caused by sternal fractures: First case series using the new technique","volume":"23","author":"Appelboam","year":"2006","journal-title":"Emerg. Med. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1001\/jamainternmed.2014.999","article-title":"Hip fracture: A trigger for palliative care in vulnerable older adults","volume":"174","author":"Ko","year":"2014","journal-title":"JAMA Int. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/BF03020485","article-title":"Intraosseous lidocaine provides effective analgesia for percutaneous vertebroplasty of osteoporotic fractures","volume":"49","author":"Sesay","year":"2002","journal-title":"Can. J. Anesth."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1177\/000313481107700419","article-title":"Lidocaine patches reduce pain in trauma patients with rib fractures","volume":"77","author":"Zink","year":"2011","journal-title":"Am. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1159\/000441002","article-title":"Lidocaine Skin Patch (Lidopat(R) 5%) Is Effective in the Treatment of Traumatic Rib Fractures: A Prospective Double-Blinded and Vehicle-Controlled Study","volume":"25","author":"Cheng","year":"2016","journal-title":"Med. Princ. Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3171\/2010.12.SPINE10286","article-title":"Randomized controlled trial of percutaneous vertebroplasty versus optimal medical management for the relief of pain and disability in acute osteoporotic vertebral compression fractures","volume":"14","author":"Farrokhi","year":"2011","journal-title":"J. Neurosurg. Spine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.jamcollsurg.2009.10.020","article-title":"Randomized, double-blind, placebo-controlled trial using lidocaine patch 5% in traumatic rib fractures","volume":"210","author":"Ingalls","year":"2010","journal-title":"J. Am. Coll. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00264-002-0404-y","article-title":"Nonoperative treatment of hip fractures","volume":"27","author":"Jain","year":"2003","journal-title":"Int. Orthop."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2106\/JBJS.K.01708","article-title":"Effectiveness of multimodal pain management after bipolar hemiarthroplasty for hip fracture: A randomized, controlled study","volume":"95","author":"Kang","year":"2013","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"49","DOI":"10.15441\/ceem.14.008","article-title":"Ultrasound-guided regional anesthesia for the pain management of elderly patients with hip fractures in the emergency department","volume":"1","author":"Lee","year":"2014","journal-title":"Clin. Exp. Emerg. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"178","DOI":"10.11622\/smedj.2016071","article-title":"Hip fractures in the elderly: Operative versus nonoperative management","volume":"57","author":"Tay","year":"2016","journal-title":"Singap. Med. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/jgs.14538","article-title":"Trends in Operative and Nonoperative Hip Fracture Management 1990\u20132014: A Longitudinal Analysis of Manitoba Administrative Data","volume":"65","author":"Cram","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.2106\/00004623-200111000-00010","article-title":"Arthroscopic Capsular Release for the Treatment of Refractory Postoperative or Post-Fracture Shoulder Stiffness","volume":"83","author":"Holloway","year":"2001","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e339","DOI":"10.1097\/BOT.0000000000001237","article-title":"Risk Factors for Knee Stiffness Surgery After Tibial Plateau Fracture Fixation","volume":"32","author":"Reahl","year":"2018","journal-title":"J. Orthop. Trauma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.nano.2016.04.015","article-title":"Sustained relief of pain from osteosynthesis surgery of rib fracture by using biodegradable lidocaine-eluting nanofibrous membranes","volume":"12","author":"Yu","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5893","DOI":"10.2147\/IJN.S140825","article-title":"Lidocaine\/ketorolac-loaded biodegradable nanofibrous anti-adhesive membranes that offer sustained pain relief for surgical wounds","volume":"12","author":"Kao","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1590\/S0102-86502014000400005","article-title":"Analgesic comparison of systemic lidocaine, morphine or lidocaine plus morphine infusion in dogs undergoing fracture repair","volume":"29","author":"Alves","year":"2014","journal-title":"Acta Cir. Bras."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.2106\/00004623-200212000-00002","article-title":"Comparison of Intra-Articular Lidocaine and Intravenous Sedation for Reduction of Shoulder Dislocations","volume":"84","author":"Miller","year":"2002","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s12245-010-0234-4","article-title":"Pain treatment in post-traumatic hip fracture in the elderly: Regional block vs. systemic non-steroidal analgesics","volume":"3","author":"Vazquez","year":"2010","journal-title":"Int. J. Emerg. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/PEC.0b013e3182447ea3","article-title":"Ultrasound-guided femoral nerve block for pain control in an infant with a femur fracture due to nonaccidental trauma","volume":"28","author":"Frenkel","year":"2012","journal-title":"Pediatr. Emerg. Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1111\/j.1524-4725.2010.01777.x","article-title":"A lidocaine-containing formulation of large-gel particle hyaluronic acid alleviates pain","volume":"36","author":"Brandt","year":"2010","journal-title":"Dermatol. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16071","DOI":"10.1038\/natrevmats.2016.71","article-title":"Designing hydrogels for controlled drug delivery","volume":"1","author":"Li","year":"2016","journal-title":"Nat. Rev. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jconrel.2017.08.006","article-title":"Injectable hydrogels for sustained release of therapeutic agents","volume":"267","author":"Thambi","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.biomaterials.2018.12.034","article-title":"Modularly engineered injectable hybrid hydrogels based on protein-polymer network as potent immunologic adjuvant in vivo","volume":"195","author":"Phan","year":"2019","journal-title":"Biomaterials"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5424","DOI":"10.1039\/C9BM01161G","article-title":"Smart injectable biogels based on hyaluronic acid bioconjugates finely substituted with poly(\u03b2-amino ester urethane) for cancer therapy","volume":"7","author":"Thambi","year":"2019","journal-title":"Biomat. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115832","DOI":"10.1016\/j.carbpol.2020.115832","article-title":"Modularly engineered alginate bioconjugate hydrogel as biocompatible injectable scaffold for in situ biomineralization","volume":"233","author":"Kim","year":"2020","journal-title":"Carbohy. Polym."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1097\/AJP.0000000000000053","article-title":"A phase 2 study of lower-dose, indomethacin submicron particle capsules demonstrates early onset of acute pain relief","volume":"30","author":"Manvelian","year":"2014","journal-title":"Clin. J. Pain"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sun, X., Xu, C., Wu, G., Ye, Q., and Wang, C. (2017). Poly(Lactic-co-Glycolic Acid): Applications and Future Prospects for Periodontal Tissue Regeneration. Polymers, 9.","DOI":"10.3390\/polym9060189"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/polym3031377","article-title":"Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier","volume":"3","author":"Makadia","year":"2011","journal-title":"Polymers"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3390\/polym3010131","article-title":"Electrospraying, a Reproducible Method for Production of Polymeric Microspheres for Biomedical Applications","volume":"3","author":"Bock","year":"2011","journal-title":"Polymers"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"33013","DOI":"10.1039\/C4RA04581E","article-title":"Electrosprayed poly(vinylidene fluoride) microparticles for tissue engineering applications","volume":"4","author":"Correia","year":"2014","journal-title":"RSC Adv."},{"key":"ref_34","first-page":"159","article-title":"Addition of lidocaine to levobupivacaine reduces intrathecal block duration: Randomized controlled trial","volume":"64","author":"Yazicioglu","year":"2014","journal-title":"Revista Brasileira de Anestesiologia"},{"key":"ref_35","first-page":"224","article-title":"Comparative study between a combination of lidocaine and levobupivacaine and that of lidocaine, levobupivacaine, and dexmedetomidine during peribulbar anesthesia for phacoemulsifi cation cataract surgery","volume":"10","author":"Botros","year":"2017","journal-title":"Ain-Shams J. Anaesthesiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.2147\/IJN.S202402","article-title":"Anesthetics and human epidermal growth factor incorporated into anti-adhesive nanofibers provide sustained pain relief and promote healing of surgical wounds","volume":"14","author":"Kao","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/jps.21496","article-title":"Characterization of four crystal polymorphs and a monohydrate of s-bupivacaine hydrochloride (levobupivacaine hydrochloride)","volume":"98","author":"Niederwanger","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0301-4622(02)00202-8","article-title":"Spectroscopic evidence for a preferential location of lidocaine inside phospholipid bilayers","volume":"99","author":"Fraceto","year":"2002","journal-title":"Biophys. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1107\/S2052252514004229","article-title":"Acemetacin cocrystals and salts: Structure solution from powder X-ray data and form selection of the piperazine salt","volume":"1","author":"Sanphui","year":"2014","journal-title":"IUCrJ"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.jcot.2015.11.002","article-title":"Plating versus conservative treatment in mid shaft fractures of clavicle: A comparative study","volume":"7","author":"Dhakad","year":"2016","journal-title":"J. Clin. Orthop. Trauma"},{"key":"ref_41","first-page":"RC01","article-title":"To operate or not to operate the Mid-Shaft Fractures of the Clavicle: A Comparative Study of Functional Outcomes of the Two Methods of Management","volume":"11","author":"Shetty","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"774","DOI":"10.2106\/00004623-200006000-00003","article-title":"Nonoperative treatment of ipsilateral fractures of the scapula and clavicle","volume":"82","author":"Edwards","year":"2000","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12178-012-9151-x","article-title":"Scapula fractures","volume":"6","author":"Cole","year":"2013","journal-title":"Curr. Rev. Musculoskelet. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hsu, M.-Y., Feng, C.-H., Liu, Y.-W., and Liu, S.-J. (2019). An Orthogonal Model to Study the Effect of Electrospraying Parameters on the Morphology of poly (d,l)-lactide-co-glycolide (PLGA) Particles. Appl. Sci., 9.","DOI":"10.3390\/app9061077"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.colsurfb.2017.07.038","article-title":"Recent applications of PLGA based nanostructures in drug delivery","volume":"159","author":"Mir","year":"2017","journal-title":"Colloids Surf. B Biointerface"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jemermed.2014.10.009","article-title":"Intravenous lipid emulsion in the emergency department: A systematic review of recent literature","volume":"48","author":"Cao","year":"2015","journal-title":"J. Emerg. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/3-540-32702-9_3","article-title":"Microparticles used as drug delivery systems","volume":"133","author":"Siepmann","year":"2006","journal-title":"Progr. Colloid Polym. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/3\/1093\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:55:28Z","timestamp":1760172928000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/3\/1093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,6]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21031093"],"URL":"https:\/\/doi.org\/10.3390\/ijms21031093","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,6]]}}}