Generic placeholder image

Recent Patents on Nanotechnology

Author(s): Mala Rajendran*, Gazana Iraivan, Ghayathri B.L., Preetha Mohan, Keerthana R. Chandran, Hari P. Nagaiah and Ruby C.A. Selvaraj

DOI: 10.2174/1872210514666200811103724

DownloadDownload PDF Flyer Cite As
Antibiotic Loaded Nano Rod Bone Cement for the Treatment of Osteomyelitis

Page: [70 - 89] Pages: 20

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Polymethyl Methacrylate (PMMA) bone cement is the clinical gold standard biomaterial for local antibiotic therapy in osteomyelitis. However, it releases 50% of the antibiotic within the first three days. It generates excessive heat during polymerization and is non-biodegradable. It must be removed by another operation. The best-known alternative for PMMA is hydroxyapatite.

Objectives: The present patented work is focused on synthesizing the biodegradable hydroxyapatite in nano form for slow and sustained release of antibiotics and studying the release kinetics of antibiotics.

Methods: Nano-hydroxyapatite was synthesized by co-precipitation method and characterized by particle size analyser, transmission electron microscopy, fourier transform infrared spectroscopy and energy dispersive X-Ray analysis. Antibiotic loaded nano-hydroxyapatite was prepared as 7 mm beads. The efficiency of drug-loaded nano-hydroxyapatite beads against osteomyelitic isolates was evaluated by well diffusion assay. Zero-order, first order, second order, Higuchi model, Korsmeyer-Peppas and Gompertz models were fit into the release kinetics of antibiotics from hydroxyapatite.

Results: Average size of nano-hydroxyapatite was 5 nm. The bactericidal activity exhibited by antibiotic- loaded micro-sized hydroxyapatite was therapeutic until 10 days only, whereas antibiotic-loaded nano-hydroxyapatite was therapeutic until 8 weeks. This confirms the burst release of antibiotics from micro-sized hydroxyapatite beads. In contrast, the release was slow and sustained up to 8 weeks from nano-hydroxyapatite. Korsmeyer-Peppas model fits into the release kinetics of antibiotics from nanohydroxyapatite.

Conclusion: Nano-hydroxyapatite with a Ca/P ratio of 1.78 is suitable for the slow and sustained delivery of antibiotics for 8 weeks.

Keywords: Antibiotics, bactericidal activity, bone cement, Gompertz model, Korsmeyer-Peppas model, nano-hydroxyapatite.

Graphical Abstract

[1]
Ribeiro M, Monteiro FJ, Ferraz MP. Infection of orthopedic implants with emphasis on bacterial adhesion process and techniques used in studying bacterial-material interactions. Biomatter 2012; 2(4): 176-94.
[http://dx.doi.org/10.4161/biom.22905] [PMID: 23507884]
[2]
Kavanagh N, Ryan EJ, Widaa A, et al. Staphylococcal osteomyelitis: Disease progression, treatment challenges, and future directions. Clin Microbiol Rev 2018; 31(2): e00084-17.
[http://dx.doi.org/10.1128/CMR.00084-17] [PMID: 29444953]
[3]
Ciampolini J, Harding KG. Pathophysiology of chronic bacterial osteomyelitis. Why do antibiotics fail so often? Postgrad Med J 2000; 76(898): 479-83.
[http://dx.doi.org/10.1136/pmj.76.898.479] [PMID: 10908375]
[4]
Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999; 104(4): 439-46.
[http://dx.doi.org/10.1172/JCI6610] [PMID: 10449436]
[5]
Moralle MR, Stekas NR. Salvage of a below knee amputation utilizing rotationplasty principles in a patient with chronic tibial osteomyelitis. J Orthop Case Rep 2016; 6: 57-62.
[6]
Gogia JS, Meehan JP, Di Cesare PE, Jamali AA. Local antibiotic therapy in osteomyelitis. Semin Plast Surg 2009; 23(2): 100-7.
[http://dx.doi.org/10.1055/s-0029-1214162] [PMID: 20567732]
[7]
Nelson CL. The current status of material used for depot delivery of drugs. Clin Orthop Relat Res 2004; (427): 72-8.
[http://dx.doi.org/10.1097/01.blo.0000143741.92384.18 PMID: 15552140]
[8]
Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res 2005; (437): 91-6.
[http://dx.doi.org/10.1097/01.blo.0000175713.30506.77 PMID: 16056032]
[9]
van Vugt TAG, Arts JJ, Geurts JAP. Antibiotic-loaded polymethylmethacrylate beads and spacers in treatment of orthopedic infections and the role of biofilm formation. Front Microbiol 2019; 10: 1626.
[http://dx.doi.org/10.3389/fmicb.2019.01626] [PMID: 31402901]
[10]
Swearingen MC, Granger JF, Sullivan A, Stoodley P. Elution of antibiotics from poly(methyl methacrylate) bone cement after extended implantation does not necessarily clear the infection despite susceptibility of the clinical isolates. Pathog Dis 2016; 74(1)ftv103
[http://dx.doi.org/10.1093/femspd/ftv103] [PMID: 26527622]
[11]
Kevin K. Current insights on antibiotic-loaded cement and the use of bioceramics in diabetic limb salvage. Diabetes Watch 2018; 31(10): 12-8.
[12]
Aquino-Martínez R, Angelo AP, Pujol FV. Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration. Stem Cell Res Ther 2017; 8(1): 265.
[http://dx.doi.org/10.1186/s13287-017-0713-0] [PMID: 29145866]
[13]
Huang X, Li L, Liu T, et al. The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in vivo. ACS Nano 2011; 5(7): 5390-9.
[http://dx.doi.org/10.1021/nn200365a] [PMID: 21634407]
[14]
Webster TJ, Ergun C, Doremus RH, Siegel RW, Bizios R. Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials 2000; 21(17): 1803-10.
[http://dx.doi.org/10.1016/S0142-9612(00)00075-2 PMID: 10905463]
[15]
Liou SC, Chen SY, Liu DM. Synthesis and characterization of needlelike apatitic nanocomposite with controlled aspect ratios. Biomaterials 2003; 24(22): 3981-8.
[http://dx.doi.org/10.1016/S0142-9612(03)00303-X PMID: 12834593]
[16]
Konsolakis M, Lykaki M, Stefa S, et al. CO2 Hydrogenation over nanoceria-supported transition metal catalysts: Role of ceria morphology (Nanorods versus Nanocubes) and active phase nature (Co versus Cu). Nanomaterials (Basel) 2019; 9(12)E1739
[http://dx.doi.org/10.3390/nano9121739] [PMID: 31817667]
[17]
Selvakumar M, Senthil KP, Bodhisatwa D, Santanu D, Chattopadhyay S. Structurally tuned antimicrobial mesoporous hydroxyapatite nanorods by cyclic oligosaccharides regulation to release a drug for osteomyelitis. Cryst Growth Des 2017; 17: 433-45.
[http://dx.doi.org/10.1021/acs.cgd.6b01190]
[18]
Marković S, Veselinović L, Lukić MJ, et al. Synthetical bone-like and biological hydroxyapatites: a comparative study of crystal structure and morphology. Biomed Mater 2011; 6(4)045005
[http://dx.doi.org/10.1088/1748-6041/6/4/045005] [PMID: 21659698]
[19]
Dalmônico GML, Franczak PF, Levandowski N Jr, et al. An in vivo study on bone formation behavior of microporous granular calcium phosphate. Biomater Sci 2017; 5(7): 1315-25.
[http://dx.doi.org/10.1039/C7BM00162B] [PMID: 28597890]
[20]
Kasir R, Vernekar VN, Laurencin CT. Inductive biomaterials for bone regeneration. Mater Res 2017; 32: 1047-60.
[http://dx.doi.org/10.1557/jmr.2017.39]
[21]
Dai CF, Li SP, Li XD. Synthesis of nanostructured methotrexate/hydroxyapatite: Morphology control, growth mechanism, and bioassay explore. Colloids Surf B Biointerfaces 2015; 136: 262-71.
[http://dx.doi.org/10.1016/j.colsurfb.2015.09.015] [PMID: 26409253]
[22]
Liu X, Wei J, Wei S. Biological effects of osteoblast-like cells on nanohydroxyapatite particles at a low concentration range. J Nanomater 2011; 2011: 6.
[http://dx.doi.org/10.1155/2011/104747]
[23]
Vukomanovic M. Skapin, Sreco Davor, Suvorov, Danilo, Inventorfunotion Alized Hydroxyapatite/Gold Composites As “Green” materials with antibacterial activity and the process for preparing and use 2013. THEREOF 2013; p. 19. [Accessed 19 December 2013.
[24]
Wang XXH, Zhao Y. Poly(lactide-co-glycolide) encapsulated hydroxyapatite microspheres for sustained release of doxycycline. Mater Sci Eng B 2012; 177: 367-72.
[http://dx.doi.org/10.1016/j.mseb.2011.12.030]
[25]
Hamanishi C, Kitamoto K, Tanaka S, Otsuka M, Doi Y, Kitahashi T. A self-setting TTCP-DCPD apatite cement for release of vancomycin. J Biomed Mater Res 1996; 33(3): 139-43.
[http://dx.doi.org/10.1002/(SICI)1097-4636(199623)33:3<139:AID-JBM3>3.0.CO;2-R] [PMID: 8864885]
[26]
Prasanna APS, Venkatasubbu GD. Sustained release of amoxicillin from hydroxyapatite nanocomposite for bone infections. Prog Biomater 2018; 7(4): 289-96.
[http://dx.doi.org/10.1007/s40204-018-0103-4] [PMID: 30478795]
[27]
Nandi SKMP, Roy S, Kundu B, Kumar De D, Basu D. Local antibiotic delivery systems for the treatment of osteomyelitis – A review. Mater Sci Eng 2009; 29: 2478-85.
[http://dx.doi.org/10.1016/j.msec.2009.07.014]
[28]
Bhattacharya R, Kundu B, Nandi SK, Basu D. Systematic approach to treat chronic osteomyelitis through localized drug delivery system: Bench to bed side. Mater Sci Eng C 2013; 33(7): 3986-93.
[http://dx.doi.org/10.1016/j.msec.2013.05.036] [PMID: 23910305]
[29]
Guo YP, Long T, Tang S, Guo YJ, Zhu ZA. Hydrothermal fabrication of magnetic mesoporous carbonated hydroxyapatite microspheres: biocompatibility, osteoinductivity, drug delivery property and bactericidal property. J Mater Chem B Mater Biol Med 2014; 2(19): 2899-909.
[http://dx.doi.org/10.1039/c3tb21829e] [PMID: 32261485]
[30]
Rauschmann MA, Wichelhaus TA, Stirnal V, et al. Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections. Biomaterials 2005; 26(15): 2677-84.
[http://dx.doi.org/10.1016/j.biomaterials.2004.06.045 PMID: 15585271]
[31]
Uskoković V. Mechanism of formation governs the mechanism of release of antibiotics from calcium phosphate nanopowders and cements in a drug-dependent manner. J Mater Chem B Mater Biol Med 2019; 7(25): 3982-92.
[http://dx.doi.org/10.1039/C9TB00444K] [PMID: 31681475]
[32]
Aiken SS, Cooper JJ, Florance H, Robinson MT, Michell S. Local release of antibiotics for surgical site infection management using high-purity calcium sulfate: An in vitro elution study. Surg Infect (Larchmt) 2015; 16(1): 54-61.
[http://dx.doi.org/10.1089/sur.2013.162] [PMID: 25148101]
[33]
Karr JC, Lauretta J, Keriazes G. In vitro antimicrobial activity of calcium sulfate and hydroxyapatite (Cerament Bone Void Filler) discs using heat-sensitive and non-heat-sensitive antibiotics against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. J Am Podiatr Med Assoc 2011; 101(2): 146-52.
[http://dx.doi.org/10.7547/1010146] [PMID: 21406698]
[34]
Lian XMK, Liu X, Vang X, Cui F. In vivo osteogenesis of vancomycin loaded nanohydroxyapatite/collagen/calcium sulphate composite for treating infectious bone defect induced by chronic osteomyelitis. J Nanomater 2015; 2015 : Article ID 261492
[http://dx.doi.org/10.1155/2015/261492]
[35]
Yang CC, Lin CC, Liao JW, Yen SK. Vancomycin-chitosan composite deposited on post porous hydroxyapatite coated Ti6Al4V implant for drug controlled release. Mater Sci Eng C 2013; 33(4): 2203-12.
[http://dx.doi.org/10.1016/j.msec.2013.01.038] [PMID: 23498249]
[36]
Ghosh S, Wu V, Pernal S, Uskoković V. Self-Setting calcium phosphate cements with tunable antibiotic release rates for advanced antimicrobial applications. ACS Appl Mater Interfaces 2016; 8(12): 7691-708.
[http://dx.doi.org/10.1021/acsami.6b01160] [PMID: 26958867]
[37]
Sasikumar S. Effect of particle size of calcium phosphate based bioceramic drug delivery carrier on the release kinetics of ciprofloxacin hydrochloride: An in vitro study. Front Mater Sci 2013; 7: 261-8.
[http://dx.doi.org/10.1007/s11706-013-0216-6]
[38]
Garner S, Barbour ME. Nanoparticles for controlled delivery and sustained release of chlorhexidine in the oral environment. Oral Dis 2015; 21(5): 641-4.
[http://dx.doi.org/10.1111/odi.12328] [PMID: 25703954]
[39]
Ferraz MP, Mateus AY, Sousa JC, Monteiro FJ. Nanohydroxyapatite microspheres as delivery system for antibiotics: Release kinetics, antimicrobial activity, and interaction with osteoblasts. J Biomed Mater Res A 2007; 81(4): 994-1004.
[http://dx.doi.org/10.1002/jbm.a.31151] [PMID: 17252559]
[40]
Zhang W, Zhu B, Cao W, Li R, Wang S, Gao R. Research on the mechanism of drug-drug interaction between salvianolate injection and aspirin based on the metabolic enzyme and PK-PD model: Study protocol for a PK-PD trial. Trials 2018; 19(1): 491.
[http://dx.doi.org/10.1186/s13063-018-2861-7] [PMID: 30217228]
[41]
Le HR, Chen KY, Wang CA. Effect of pH and temperature on the morphology and phasesof co-precipitated hydroxyapatite. J Sol-Gel Sci Technol 2012; 61: 592-9.
[http://dx.doi.org/10.1007/s10971-011-2665-7]
[42]
Engin A, Girgin İ. Synthesis of hydroxyapatite by using calcium carbonate and phosphoric acid in various water-ethanol solvent systems. Cent J Chem 2009; 7: 745-51.
[43]
Narashimhan B. MSK, Peppas NA Encyclopedia of controlled drug delivery. New york: John Wiley and Sons 1999.
[44]
Grassi M, Grassi G. Mathematical modelling and controlled drug delivery: matrix systems. Curr Drug Deliv 2005; 2(1): 97-116.
[http://dx.doi.org/10.2174/1567201052772906] [PMID: 16305412]
[45]
Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963; 52: 1145-9.
[http://dx.doi.org/10.1002/jps.2600521210] [PMID: 14088963]
[46]
Korsmeyer RW, Gurnya R, Eric D, Doelkera E, Buria P, Peppas AN. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 1983; 15(1): 25-35.
[http://dx.doi.org/10.1016/0378-5173(83)90064-9]
[47]
Baker RW, Sanders LM. Controlled release delivery systems synthetic membranes: Science, engineering and applications 181. Dordrecht: Springer 1986; pp. 581-624.
[48]
Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on Hydroxypropyl Methylcellulose (HPMC). Adv Drug Deliv Rev 2001; 48(2-3): 139-57.
[http://dx.doi.org/10.1016/S0169-409X(01)00112-0 PMID: 11369079]
[49]
Waterman P, Barber M, Weintrob AC, et al. The elution of colistimethate sodium from polymethylmethacrylate and calcium phosphate cement beads. Am J Orthop 2012; 41(6): 256-9.
[PMID: 22837988]
[50]
Sriprapha P, Rungsiyakull C, Pengpat K, Tunkasiri T, Eitssayeam S. A study of mechanical properties of bone cement containing micro- and nano- hydroxyapatite particles. Key Eng Mater 2018; 766: 117-21.
[http://dx.doi.org/10.4028/www.scientific.net/KEM.766.117]
[51]
Jevtić M, Mitrić M, Škapin S, Jančar B, Ignjatović N, Uskoković D. Crystal structure of hydroxyapatite nanorods synthesized by sonochemical homogeneous precipitation. Cryst Growth Des 2008; 8(7): 2217-22.
[http://dx.doi.org/10.1021/cg7007304]
[52]
Chen F, Wang Z-C, Lin C-J. Preparation and characterization of nano-sized hydroxyapatite particles and hydroxyapatite/chitosan nano-composite for use in biomedical materials. Mater Lett 2002; 57(4): 858-61.
[http://dx.doi.org/10.1016/S0167-577X(02)00885-6]
[53]
Hadeel AJLE, Rohanizadeh R, Coster H, Dehghani F. preparation of nanostructured hydroxyapatite in organic solvents forclinical applications. Trends Biomater Artif Organs 2011; 25(1): 12-9.
[54]
Peng XG. Mechanisms for the shape-control and shape-evolution of colloidal semiconductor nanocrystals. Adv Mater 2003; 15: 459-63.
[55]
Pu’ad NASM, Koshy P, Abdullah HZ, Idris MI, Lee TC. Review Article-syntheses of hydroxyapatite from natural sources. Heliyon 2019; 5(5)e01588
[56]
Cai Y, Liu Y, Yan W, Hu Q, Tao J, Zhang M. Role of hydroxyapatite nanoparticle size in bone cell proliferation. J Mater Chem 2007; 17: 3780-7.
[http://dx.doi.org/10.1039/b705129h]
[57]
Vlad MD, Gómez S, Barracó M, López J, Fernández E. Effect of the calcium to phosphorus ratio on the setting properties of calcium phosphate bone cements. J Mater Sci Mater Med 2012; 23(9): 2081-90.
[http://dx.doi.org/10.1007/s10856-012-4686-3] [PMID: 22639154]
[58]
Han J-K, Song H-Y, Saito F, Lee B-T. Synthesis of height purity nano-sized hydroxyapatite powder by microwave-hydrothermal method. Mater Chem Phys 2006; 99: 235-9.
[http://dx.doi.org/10.1016/j.matchemphys.2005.10.017]
[59]
Gheisari H, Karamian E, Abdellahi M. A novel hydroxyapatite –Hardystonite nanocomposite ceramic. Ceram Int 2015; 41(4): 5967-75.
[http://dx.doi.org/10.1016/j.ceramint.2015.01.033]
[60]
Adak MD, Purohit KM. Synthesis of nano-crystalline hydroxyapatite from dead snail shells for biological implantation. Trends Biomater Artif Organs 2011; 25(3): 101-6.
[61]
Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev 1997; 10(3): 505-20.
[http://dx.doi.org/10.1128/CMR.10.3.505] [PMID: 9227864]
[62]
Bilal H, Hasan F, Bilal S. Susceptibility pattern of pseudomonas aeruginosa against various antibiotics along with computational analysis. Int J Sci Basic Appl Res 2015; 24: 23-45.
[63]
Abreu AC, Paulet D, Coqueiro A, et al. Antibiotic adjuvants from Buxus sempervirens to promote effective treatment of drug-resistant Staphylococcus aureus biofilms. RSC Advances 2016; 6(97): 95000-9.
[http://dx.doi.org/10.1039/C6RA21137B]
[64]
Adedeji AB, Abdulkadir AO. Etiology and antimicrobial resistance pattern of bacterial agents of urinary tract infections in students of tertiary institutions in Yola Metropolis. Adv Biol Res 2009; 3: 67-70.
[65]
Javiya VA, Ghatak SB, Patel KR, Patel JA. Antibiotic susceptibility patterns of Pseudomonas aeruginosa at a tertiary care hospital in Gujarat, India. Indian J Pharmacol 2008; 40(5): 230-4.
[http://dx.doi.org/10.4103/0253-7613.44156] [PMID: 20040963]
[66]
Sia IG, Berbari EF. Infection and musculoskeletal conditions: Osteomyelitis. Best Pract Res Clin Rheumatol 2006; 20(6): 1065-81.
[http://dx.doi.org/10.1016/j.berh.2006.08.014] [PMID: 17127197]
[67]
Bistolfi A, Massazza G, Verné E, et al. Antibiotic-loaded cement in orthopedic surgery: A review. ISRN Orthop 2011; 2011290851
[http://dx.doi.org/10.5402/2011/290851] [PMID: 24977058]
[68]
van de Belt H, Neut D, Schenk W, van Horn JR, van der Mei HC, Busscher HJ. Gentamicin release from polymethylmethacrylate bone cements and Staphylococcus aureus biofilm formation. Acta Orthop Scand 2000; 71(6): 625-9.
[http://dx.doi.org/10.1080/000164700317362280] [PMID: 11145392]
[69]
del Real RP, Padilla S, Vallet-Regí M. Gentamicin release from hydroxyapatite/poly(ethyl methacrylate)/poly(methyl methacrylate)composites. J Biomed Mater Res 2000; 52(1): 1-7.
[http://dx.doi.org/10.1002/1097-4636(200010)52:1<1:AID-JBM1>3.0.CO;2-R] [PMID: 10906668]
[70]
Rebecca J, Hintz C, Johnson K. The effect of particle size distribution on dissolution rate and oral absorption. Int J Pharm 1989; 51(1): 9-17.
[http://dx.doi.org/10.1016/0378-5173(89)90069-0]
[71]
Dressman JB, Fleisher D. Mixing-tank model for predicting dissolution rate control or oral absorption. J Pharm Sci 1986; 75(2): 109-16.
[http://dx.doi.org/10.1002/jps.2600750202] [PMID: 3958917]
[72]
Philip L, Ritger A, Peppas N. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. J Control Release 1987; 5(1): 37-42.
[http://dx.doi.org/10.1016/0168-3659(87)90035-6]
[73]
Alt V, Bechert T, Steinrücke P, et al. In vitro testing of antimicrobial activity of bone cement. Antimicrob Agents Chemother 2004; 48(11): 4084-8.
[http://dx.doi.org/10.1128/AAC.48.11.4084-4088.2004 PMID: 15504825]
[74]
Cunha MT, Murça MA, Nigro S, Klautau GB, Salles MJC. In vitro antibacterial activity of bioactive glass S53P4 on multiresistant pathogens causing osteomyelitis and prosthetic joint infection. BMC Infect Dis 2018; 18(1): 157.
[http://dx.doi.org/10.1186/s12879-018-3069-x] [PMID: 29614973]
[75]
Neut D, de Groot EP, Kowalski RS, van Horn JR, van der Mei HC, Busscher HJ. Gentamicin-loaded bone cement with clindamycin or fusidic acid added: Biofilm formation and antibiotic release. J Biomed Mater Res A 2005; 73(2): 165-70.
[http://dx.doi.org/10.1002/jbm.a.30253] [PMID: 15761830]
[76]
Sato K, Inoue Y, Fujii T, Aoyama H, Mitsuhashi S. Antibacterial activity of ofloxacin and its mode of action. Infection 1986; 14(Suppl. 4): S226-30.
[http://dx.doi.org/10.1007/BF01661277] [PMID: 3028966]
[77]
Schindler KM, Wayne F, Smith DB. , Warsaw. Biomet Manufacturing, LLC, Warsaw, assignee. Antimicrobial methacrylate cements. US Patent 13/313,764,. 2014.
[78]
David M. Queen's University At Kingston, Assignee. Anaesthetic bone cement. US patent US 2002/0137813 A1, . 2002.
[79]
Brian R. University of South Carolina, Columbia, SC (US), assignee bocompatible cement containing reactive calcum phosphate nanoparticles and methods for making and using such cement. 2009.
[80]
Thomas JGM, Lars ET, Steen SSM, Rosengren S. Biomet SAS (FR), assignee method and apparatus for delivery of bone cement. 2016.
[81]
Lu Donghui, Shuxin Zhou S. high strength biological cement composition and using the same. 2009.
[82]
Lett JA, Sagadevan S, Prabhakar JJ, et al. Drug leaching properties of vancomycin loaded mesoporous hydroxyapatite as bone substitutes. Processes (Basel) 2019; 7(11): 826.
[http://dx.doi.org/10.3390/pr7110826]