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![A co-delivery system
with a sequential release
was introduced it was
manipulated the
concentrations and
sequences of
one polymer-[poly(D,L-
lactide)] (PDLLA), as a
sequential drug delivery
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Cont.](https://image.slidesharecdn.com/antimicrobial-osteoinductivematerials2-10-2016-161010130849/75/Antimicrobial-Osteoinductive-Biomaterials-68-2048.jpg)
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Antimicrobial Osteoinductive Biomaterials
This document discusses biomaterials with both antimicrobial and osteoinductive properties that can be applied to spinal surgery. It summarizes various biomaterials and drugs that have these properties, including nanosilver, quaternized chitosan, copper ions, and bone morphogenetic proteins (BMPs). It also discusses different methods for delivering both antimicrobial and osteoinductive drugs from biomaterials, including surface adsorption, co-encapsulation, and surface coatings. The goal is to develop materials that can simultaneously deliver these drugs to repair infected bone defects.
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Antimicrobial Osteoinductive Biomaterials
- 1. Biomaterials with Antimicrobial and Osteoinductive Propertiesapplied to Spinal Surgery GEORGE SAPKAS PROFESSOR OF ORTHOPAEDICS Metropolitan Hospital Athens Spinal Disorders and Musculo-sceletal Unit
- 2. In the pastdecade, novel biomaterials, bearing both antibacterial and osteoinductive properties, have been developed in order to provide a viable treatment option for infected bone defects. Li, X., et al, Clin. Orthop. Relat. Res., 2013 Zheng, Z., et al, Biomaterials 2010
- 3. Many novel antibacterial drugs,such as: nanosilver/silver nanoparticles (AgNPs), quanternized chitosan, Copper show a very promising clinical application potential due to their good biocompatibility and a broad bactericidal spectrum Franci, G., et al Molecules 2015 Tan, H., et al Int. J. Mol. Sci., 2013 Copper
- 4.
- 5.
- 6. AgNPs are clustersof silver atoms with diameters ranging from 1 to 100 nm. AgNPs have become highly interesting for medical applications because of their: antimicrobial, anti-inflammatory, biocompatible and wound-healing-favoring properties Chaloupka, K., et al, Trends Biotechnol. 2010
- 7. The powerful antimicrobial activitiesof AgNPs can be attributed to the following orchestrated mechanisms: the damage of bacterial membranes; the inhibition of DNA replications, protein synthesis and enzymatic activity the alteration of cell respiration Franci, G. et al, Molecules 2015
- 8. AgNPs have also anotheradvantageous property over antibiotics: an antiviral effect
- 9.
- 10. Chitosan, a naturally- derivedpolycationic polymer, has been made into various biomedical devices due to its proper biodegradability, good biocompatibility and antimicrobial activity Rabea, E.I., et al, Biomacromolecules 2003
- 11. Quanternized chitosan could also effectivelykill antibiotic-resistant bacteria, such as Methicillin-resistant Staphylococcus aureus
- 12. The mechanisms ofthe antibacterial activities of quanternized chitosan are still not totally clear. One of the major mechanisms is the clectrostatic interaction between the polycationic groups of quanternized chitosan and the anionic components of microorganisms.
- 13.
- 14. The first reportsof copper were recorded in texts of the Assyrians and Egyptians in 4000 BC . In one of the oldest books of Edwin Smith papyrus mentions the use of copper for sterilizing not only chest wounds but also drinking water (2600-2200p.Ch.) Hippocrates (460-480 BC) in his reports makes observations about the beneficial capabilities of copper in the treatment of wounds
- 15. Copper ions, upon contactwith microbes, generates electric deregulation and disorder the pump of K – Na which is located in the cell membrane . This action creates osmotic problems in the cell, thereby killing the microbes .
- 16. Mechanism of copperions Action SYTO-9 PI Cu+/Cu2 + Cu2+ Metallic Copper as an Antimicrobial Surface .Marc Solioz et al,*Appl Environ Microbiol. 2011 77(5): 1541–1547 Deregulation and disorder the pump of K – Na
- 17.
- 18. Many growth factors, suchas: basic fibroblast growth factor, insulin-like growth factors (IGFs), vascular endothelial growth factor, are also capable of significantly promoting osteogenesis and angiogenesis Wang, J., et al Int. J. Mol. Sci. 2014
- 19. However, only bone morphogenetic proteins(BMPs) can uniquely induce de novo bone formation in a pro-fibrotic microenvironment, such as critical-size bone defects Guo, J., et al, Cytokine Growth Factor Rev. 2012
- 20. Thanks to therapid progress of bone tissue engineering techniques, a large variety of novel BMPs-based bone-filling materials have been developed to significantly accelerate and promote new bone regeneration. Guo, J., et al, Cytokine Growth Factor Rev. 2012
- 21. BMPs, a groupof proteinaceous growth factors, were discovered in the pioneering work by Urist in 1965 BMP family consists of more than 30 members among which 19 BMPs are found in human. Urist, M.R. et al, Science 1965 Ducy, P. et al, Kidney Int. 2000
- 22. The classical role forBMPs was the induction of de novo cartilage and bone formation in non-osseous sites Urist, M.R., et al, Science 1965 Wang, E.A., et al, Proc. Natl. Acad. Sci. USA 1988
- 23. BMPs are currently recognizedas a group of metabologens that can orchestrate tissue architecture throughout the body Reddi, A.H., et al, Cytokine Growth Factor Rev. 2009
- 24. BMPs can significantly promote thedifferentiation of multipotent mesenchymal stem cells (MSCs) along different lineages: osteogenesis adipogenesis chondrogenesis Levi, B., et al, Stem Cells 2011 Tseng, Y.H, et al, Nature 2008 Kim, H.J., et al, Tissue Eng. A 2009
- 25. The final differentiation is symbolizedby mineralization of extracellular matrix Zheng, Y., et al, Tissue Eng. A 2010 • Schematic graphs depicting the signaling pathways of bone morphogenetic proteins (BMPs) and its-induced osteogenic activities. • BMPR-I: BMP type I receptors; BMPR-II: BMP type II receptors; Runx2: runt-related transcription factor 2; • ALP: alkaline phosphatase; OCN: osteocalcin; Dlx5: distal- less homeobox 5; • JNK: c-Jun N-terminal kinase; : clarified mechanisms; : unclarified mechanisms.
- 26.
- 27. In USA, Europeand Australia, BMP2 and BMP7 have already been approved for a clinical application in nonunion bone fractures and spinal fusions. Bessa, P.C., et al, Tissue Eng. Regen. Med. 2008
- 28. In current clinicpractice, BMP2 is typically used through its superficial adsorption onto collagen sponges (e.g., INFUSE®). Deproteinized bovine bone was also rendered osteoinductive using the same. Schwarz, F, et al, Clin. Oral Implants Res. 2008
- 29. However, this out-of-date carryingmode of BMP2, that was developed decades ago, shows a series of potential side effects, such as an over-stimulated osteoclastic bone resorption and an excessive ossification at unintended sites Shields, L.B. et al, Spine 2006 Toth, J.M, et al, Spine 2009
- 30. Co-Delivery Systems for Antibacterial and Osteoinductive Drugs to RepairInfected Bone Defects
- 31. This co-delivery system shouldfirst fulfil the general requirements for a proper bone substitute: good biocompatibility sufficient mechanical strength high osteoconductivity proper degradability
- 32. The system must alsobe capable of locally and slowly delivering both antibacterial osteoinductive drugs
- 33. The drugs canbe combined with biomaterials either by: superficial adsorption binding with a chemical bond by an internal encapsulation by a coating layer
- 34. For a co-delivery system,both antibacterial and osteoinductive drugs can be released either: in a simultaneous mode in a sequential mode
- 35. Schematic graph depicting thefour different carrying modes of both antibacterial and osteoinductive drugs in biomaterials aiming to treat infected bone defects. (A) Superficial adsorption with or without physicochemical bonds; (B) A co-encapsulation; (C) A mixed carrying mode with encapsulated antibacterial drugs and superficially adsorbed BMPs; (D) surface coatings: (D1) both drugs are immobilized by chemical bonds; (D2) both drugs are encapsulated in coating layers with separation layers for a controlled release.
- 36. Superficial adsorption onto clinicallyused materials is the most common way to apply bioactive agents (A) Superficial adsorption with or without physicochemical bonds;
- 37. For example, although BMPs werefound in 1965, BMPs can be applied in clinic only through their adsorption onto collagen membrane.
- 38. Consequently, an unphysiologically high amount (e.g.,milligrams) of BMPs has to be applied to elicit the osteoinductive effects Park, D.K., et al, Spine 2013
- 39. However, the transiently highamount is associated with a series of potential possible side effects, such as an over-stimulation of local bone resorption Toth, J.M., et al, Spine 2009
- 40. The introduction of newmaterials that bear physicochemical binding sites for drugs may render the release of adsorbed drugs much slower.
- 41. A silica calcium phosphate nanocompositeas a co-delivery system for vancomycin and BMP2, was used. Pacheco, H., et al, J. Biomed. Mater. Res. A 2014
- 42. It was shownthat interactions between PO4 -3 and negatively charged moieties of vancomycin as well as between the Si–O–Si functional groups and BMP2 do happen Pacheco, H., et al, J. Biomed. Mater. Res. A 2014 Si – O – Si
- 43.
- 44. The release kineticsof encapsulated drugs is mostly simultaneous and is largely dependent on the permeability the degradability of the carrying materials.
- 45. A collagen wasused as a co-delivery system for AgNPs and BMP2 Sun,C.Y, et al, Biotechnol. Lett. 2015 Kong, Y., et al, Nanoscale 2013 AgNPs
- 46. The BMP2/AgNP/collagen scaffold composites showed astrong antibacterial activity without adversely affecting the adherence or proliferation of bone marrow-derived MSCs (BMSCs). Bone marrow-derived MSCs (BMSCs).
- 47. Calcium sulfate, aquick self-setting material, is widely used as a bone- defect-filling material.
- 48. It is alsofrequently adopted as an antibiotic carrier for the treatment of infected bone defects It has many advantages such as low price full biodegradability, good biocompatibility and high osteoconductivity Kanellakopoulou, K., et al, Int. J. Antimicrob. Agents 2009 Sanicola, S.M., et al, J. Foot Ankle Surg. 2005
- 49. Calcium was used sulfateto carry BMP2 and vancomycin through an internal co-encapsulation Wang, Y., et al, Arch. Orthop. Trauma Surg. 2011
- 50. However, this kindof materials usually forms a solid block and lacks of porous structure, which may hinder the ingrowth of bone tissues BMP2 was first adsorbed onto chitosan/calcium phosphate microspheres, which was thereafter embedded into calcium sulfate Doty, H.A., et al, J. Mater. Sci. Mater. Med. 2014
- 51. Polymers are another groupof materials that were introduced biodegradable polyurethane (PUR) scaffolds to deliver BMP2 and vancomycin Guelcher,S.A., et al, J. Orthop. Trauma 2011
- 52. The vancomycin release kineticsconsisted of two phases: The first burst release for a week to protect the graft from contamination A subsequent sustained release with over the minimum inhibitory concentrations for Staphylococcus aureus for 2 months
- 53. A Mixed CarryingMode for a Sequential Release
- 54. Antibacterial and osteoinductive drugs canalso be delivered by a carrying material through different carrying modes
- 55. For example, an antibacterialdrug is encapsulated into a carrying material with an osteoinductive drug superficially adsorbed onto its surface, or vice versa AgNP’S
- 56. The two carryingmodes can realize different aims: the former mode is mainly aimed for promoting bone regeneration with a prevention of potential infection, while the latter mode is mainly aimed for suppressing an existing bacterial activity and thereafter promoting bone regeneration
- 57. Zein was usedas a major starch storage protein found in corn, as a carrying material for antibacterial HACC (hydroxypropyl- trimethyl ammonium chloride chitosan) (a quanternized chitosan) BMP2 Strobel, C., et al, J. Control. Release 2011 Zein
- 58. 10 wt %HACC was encapsulated into zein, which showed a strong antibacterial effect without significantly compromising cell proliferation HACC Chitosan
- 59. The release ofthe superficially adsorbed BMP2 was significantly slowed down with the higher ratio of mesoporous silica SBA-15 nanoparticles In addition, the mesoporous silica SBA-15 nanoparticles also enhanced the cell viability of human MSCs SBA-15
- 60. It was concludedthat Silica/HACC/zein scaffolds with both antibacterial and osteoinductive activities had an immense potential in orthopedics and other biomedical applications Zhou, P., et al, Biomaterials 2014 Silica/HACC/zein scaffolds
- 61.
- 62. Titanium metallic implants are biologicallyinert cannot induce new bone regeneration inhibit bacterial activity Vlacic-Zischke,J., et al, Biomaterials 2011
- 63. Such a limitationmakes their implantation very challenging when they are used in the sites with compromised bone regeneration capacity high infection risk
- 64. In these cases,it is in great need to develop implants with both antibacterial osteoinductive functions One approach is to coat the surfaces of implants Ionic debris is additive to the influences of particulate debris and can have a significant impact on local cytotoxicity.
- 65. Attempts have been doneto prepare either polymeric coatings with incorporated antibacterial drugs inorganic coatings with incorporated BMP2 Radin, S., et al, Biomaterials 2007 Wu,G., et al, TissueEng. CMethods2010 Wu, G., et al, Biomaterials 2010
- 66. By carefully combining theprinciples of polymeric inorganic coatings a co-delivery system was developed for antibacterial and osteoinductive drugs, which contained electrochemically deposited chitosan/Ag/Haand adsorbed haperin /BMP2 Xie, C.M., et al, ACS Appl. Mater. Interfaces 2014
- 67. This coating could simultaneously releaseAg+ and BMP2
- 68. A co-delivery system witha sequential release was introduced it was manipulated the concentrations and sequences of one polymer-[poly(D,L- lactide)] (PDLLA), as a sequential drug delivery coating with three distinctly different release profiles Cont.
- 69. A burst releaseof gentamicin; A burst release of IGF- I followed by a sustained release and A slow release of BMP2 Strobel, C., et al, J. Control. Release 2011
- 70. Gentamicin, incorporated in the outerlayer, exhibited a burst release profile, which was due to the very thin 0.5 x or 1 x PDLLA layers and its direct expose to an aqueous environment
- 71. IGF-I (insulin-like growth factorI), in the middle layer, exhibited a fast release and a subsequent slow release, which was controlled by the erosion of the thicker middle layer
- 72. BMP2, in theinner layer, exhibited no significant burst release but as low and sustained release by this sandwich approach Strobel, C., et al, J. Control. Release 2011
- 73. Such a sequentialrelease profile was supposed to exert the functions of these drugs sequentially: the rapidly-released gentamicin to suppress bacterial activities; the secondly-released IGF-1 to stimulate the proliferation of osteoblasts; the slowly-released BMP2 to enhance an osteogenic differentiation. Strobel, C., et al, J. Control. Release 2011
- 74. Using a layer-by-layer (LBL) principle,a novel system was introduced that could realize a tunable staged release of dual drugs for orthopedic implants Min, J., et al, Biomaterials 2014
- 75. This multilayered coating consistsof two parts: a base osteoinductive component by dipping into a sodium acetate solutioncontainingBMP2,poly(β- aminoesters)(Mn~10kDa) and poly(acrylicacid)(MW ~ 450 kDa); an overlying antibacterial layer by dipping into a sodium acetate solution containing gentamicin, poly(β- amino esters) (Mn ~ 11 kDa) and poly(acrylic acid) (MW ~ 1.25 MDa) Min, J., et al, Biomaterials 2014
- 76. Cationic chitosan or poly (diallyldimethylammoni umchloride) (MW ~ 200–300 kDa) and anionic laponite clay were alternately sprayed onto both osteoinductive and antibacterial layers Min, J., et al, Biomaterials 2014 Cationic chitosan
- 77.
- 78. The repair ofinfected bone defects remains a formidable challenge in the fields of: oral implantology, maxillofacial surgery and orthopedics Due to the less optimal efficacy of current clinical treatments, novel biomaterials with both antibacterial osteoinductive properties have been developed in order to provide a viable treatment option
- 79. In comparison withthe clinically used antibiotics, many novel antibacterial biomaterials showed very promising application potential due to their broader bactericidal spectrum, nearly no resistance and good biocompatibility BMPs, particularly BMP2, are the most potent osteoinductive drugs to induce an in vitro osteoblastogenesis and an in vivo osteogenesis Silver
- 80. The antibacterial and osteoinductivedrugs can be incorporated into co-delivery system through the following modes: Superficial adsorption / binding with a chemical bond An internal encapsulation A mixed carrying mode with a superficial adsorption and an internal encapsulation A surface coating
- 81. By manipulating thecarrying modes, the antibacterial and osteoinductive drugs can be released in varied modes with different kinetics (burst or slow) and temporal characteristics (simultaneous or sequential). These novel biomaterials with both antibacterial and osteoinductive properties showed very a promising potential for clinical applications. BMPs Silver nanoparticles