Ghent University Academic Bibliography

Advanced

Development of titanium bone scaffolds with drug delivery system

Matthieu Ravelingien UGent (2010)
abstract
The regeneration of large segmental bone defects due to trauma, inflammation, and tumor surgery remains a clinical problem. The implant material has to fulfil several requirements, such as mechanical properties, biocompatibility, and corrosion resistance. Furthermore, bacterial infection related to orthopaedic implants still represents a major complication. Conventional systemic delivery of antibiotics implies poor penetration into ischemic and necrotic tissue and can cause systemic toxicity. Alternatively, local delivery of antibiotics from a carrier system may enable the maintenance of a high local antibiotic concentration for an extended duration of release without exceeding systemic toxicity. The current situation and the objectives of this research project are addressed in chapter 1. The principle purpose was to develop a local antibiotic delivery system within titanium bone scaffolds for the management of implant-associated bacterial infections. Therefore, by means of the biomimetic precipitation technique, calcium phosphate (CaP) coatings had to be deposited on titanium substrates to provide a drug carrier. Furthermore, to obtain a sustained release of antibiotics from CaP carriers, the effect of a biodegradable polymer coating had to be investigated. Chapter 2 presents an overview of the main topics of this research project. After a brief description of the structure, composition, mechanical properties and histology of bone, the evolution of bone substitute materials is discussed. The properties, fabrication methods, and surface modifications of titanium scaffolds are highlighted, since these substrates were used for CaP deposition. The final part of the introduction deals with the pathogenesis and treatment of infection related to orthopaedic implants. Chapter 3 describes the possibilities of the biomimetic precipitation technique to deposit CaP coatings on alkali-treated titanium substrates from a simulated body fluid (SBF) by studying the influence of SBF composition. The use of a more concentrated SBF solution led to a faster CaP precipitation, but a decreased surface coverage, due to the simultaneous nucleation in the solution. Depending on the presence of Mg2+ and HCO3- ions, hydroxyapatite (HA) globules or octacalcium phosphate (OCP) flake-like crystals were deposited. The precipitated OCP was thermally converted into HA at 300 °C and into beta-tricalcium phosphate (beta-TCP) at 900 °C. By altering the CaP phases, variable rates of degradation can be achieved in order to optimize the process of bone repair. The high surface-to-volume ratio of the flake-like OCP crystals was applied for loading with riboflavin phosphate (RP). A poly(D,L-lactic acid) (PDLLA) spray coating sustained the release, which was completed after 14 days. In chapter 4, the thermal decomposition of bioactive sodium titanate surfaces is characterized and discussed. Alkali-treated orthopaedic titanium surfaces have earlier shown to induce CaP deposition. A subsequent heat treatment under air improved the adhesion of the sodium titanate layer but decreased the rate of CaP deposition. Furthermore, insufficient attention was paid to the sensitivity of titanium substrates to oxidation and nitriding during heat treatment under air. Therefore, in this chapter, alkali-treated titanium samples were heat-treated under air, argon flow or vacuum. The microstructure and composition of their surfaces were characterized to clarify what mechanism is responsible for inhibiting CaP deposition after heat treatment. All heat treatments under various atmospheres turned out to be detrimental for CaP deposition. They led to the thermal decomposition of the dense sodium titanate basis near the interface with the titanium substrate. Depending on the atmosphere, several forms of TiyOz were formed and Na2O was sublimated. Consequently, less exchangeable sodium ions remained available. This pointed to the importance of the ion exchange capacity of the sodium titanate layer for CaP deposition. Chapter 5 discusses the effect of surface topography of two-dimensional and pore architecture of three-dimensional alkali-treated titanium substrates on the CaP deposition. Titanium plates with a surface roughness of Ra = 0.13 µm, 0.56 µm, 0.83 µm, and 3.63 µm were prepared by Al2O3 grit-blasting. Simple tetragonal and face-centered Ti6Al4V scaffolds with spatial gaps of 450-1100 µm and 200-700 µm, respectively, were fabricated by a three-dimensional fiber deposition (3DFD) technique. After alkali treatment, the titanium plates with a surface roughness of Ra = 0.56 µm were completely covered with HA globules after 7 days in SBF, while the coverage of the samples with other surface roughness values remained incomplete. The higher CaP deposition rate was attributed to the locally higher concentration of negative surface charges, the restricted ion mobility, and the higher amount of concave parts on the surface. Similarly, face-centered Ti6Al4V scaffolds with spatial gaps of 200­700 µm exhibited a full surface coverage after 21 days in SBF, while simple tetragonal scaffolds with spatial gaps of 450-1100 µm were only covered for 45-65%. This pointed to the importance of spatial gap size for CaP deposition by a local change in ionic concentration and/or surface charge. In chapter 6, the influence of PDLLA coating thickness on the in vitro release of vancomycin hydrochloride (VH) from a HA carrier is studied. Microporous HA fibers with a porosity of 51 v% and an average pore diameter of 1.0 µm were fabricated by a diffusion-induced phase separation technique. They were loaded with 38 mg VH / g HA and their cylindrical shape enabled the application of the spray coating technique for the deposition of uniform PDLLA coating thicknesses, varying from 6.5 µm to 28 µm. The resulting in vitro VH release varied from a complete release within 14 days for 6.5 µm coatings to a release of 23% after 28 days for 28 µm coatings. It was clear that the VH release rate from a HA fiber can be adjusted by varying the PDLLA coating thickness. Microbiological tests of these fibers against a methicillin-resistant Staphylococcus aureus (MRSA) isolate pointed to the importance of the initial burst release and confirmed that the released antibiotics had the potential to interfere with S. aureus biofilm formation.
Please use this url to cite or link to this publication:
author
promoter
UGent and UGent
organization
year
type
dissertation (monograph)
subject
pages
VI, 109 pages
publisher
Ghent University. Faculty of Pharmaceutical Sciences
place of publication
Ghent, Belgium
defense location
Gent : Farmaceutisch Instituut (auditorium I)
defense date
2010-09-16 18:00
language
English
UGent publication?
yes
classification
D1
additional info
dissertation in parts contains copyrighted material
copyright statement
I have transferred the copyright for this publication to the publisher
id
1057921
handle
http://hdl.handle.net/1854/LU-1057921
date created
2010-10-12 11:47:02
date last changed
2010-10-12 12:36:49
@phdthesis{1057921,
  abstract     = {The regeneration of large segmental bone defects due to trauma, inflammation, and tumor surgery remains a clinical problem. The implant material has to fulfil several requirements, such as mechanical properties, biocompatibility, and corrosion resistance. Furthermore, bacterial infection related to orthopaedic implants still represents a major complication. Conventional systemic delivery of antibiotics implies poor penetration into ischemic and necrotic tissue and can cause systemic toxicity. Alternatively, local delivery of antibiotics from a carrier system may enable the maintenance of a high local antibiotic concentration for an extended duration of release without exceeding systemic toxicity. 
The current situation and the objectives of this research project are addressed in chapter 1. The principle purpose was to develop a local antibiotic delivery system within titanium bone scaffolds for the management of implant-associated bacterial infections. Therefore, by means of the biomimetic precipitation technique, calcium phosphate (CaP) coatings had to be deposited on titanium substrates to provide a drug carrier. Furthermore, to obtain a sustained release of antibiotics from CaP carriers, the effect of a biodegradable polymer coating had to be investigated.
Chapter 2 presents an overview of the main topics of this research project. After a brief description of the structure, composition, mechanical properties and histology of bone, the evolution of bone substitute materials is discussed. The properties, fabrication methods, and surface modifications of titanium scaffolds are highlighted, since these substrates were used for CaP deposition. The final part of the introduction deals with the pathogenesis and treatment of infection related to orthopaedic implants.
Chapter 3 describes the possibilities of the biomimetic precipitation technique to deposit CaP coatings on alkali-treated titanium substrates from a simulated body fluid (SBF) by studying the influence of SBF composition. The use of a more concentrated SBF solution led to a faster CaP precipitation, but a decreased surface coverage, due to the simultaneous nucleation in the solution. Depending on the presence of Mg2+ and HCO3- ions, hydroxyapatite (HA) globules or octacalcium phosphate (OCP) flake-like crystals were deposited. The precipitated OCP was thermally converted into HA at 300 {\textdegree}C and into beta-tricalcium phosphate (beta-TCP) at 900 {\textdegree}C. By altering the CaP phases, variable rates of degradation can be achieved in order to optimize the process of bone repair. The high surface-to-volume ratio of the flake-like OCP crystals was applied for loading with riboflavin phosphate (RP). A poly(D,L-lactic acid) (PDLLA) spray coating sustained the release, which was completed after 14 days.
In chapter 4, the thermal decomposition of bioactive sodium titanate surfaces is characterized and discussed. Alkali-treated orthopaedic titanium surfaces have earlier shown to induce CaP deposition. A subsequent heat treatment under air improved the adhesion of the sodium titanate layer but decreased the rate of CaP deposition. Furthermore, insufficient attention was paid to the sensitivity of titanium substrates to oxidation and nitriding during heat treatment under air. Therefore, in this chapter, alkali-treated titanium samples were heat-treated under air, argon flow or vacuum. The microstructure and composition of their surfaces were characterized to clarify what mechanism is responsible for inhibiting CaP deposition after heat treatment. All heat treatments under various atmospheres turned out to be detrimental for CaP deposition. They led to the thermal decomposition of the dense sodium titanate basis near the interface with the titanium substrate. Depending on the atmosphere, several forms of TiyOz were formed and Na2O was sublimated. Consequently, less exchangeable sodium ions remained available. This pointed to the importance of the ion exchange capacity of the sodium titanate layer for CaP deposition.
Chapter 5 discusses the effect of surface topography of two-dimensional and pore architecture of three-dimensional alkali-treated titanium substrates on the CaP deposition. Titanium plates with a surface roughness of Ra = 0.13 {\textmu}m, 0.56 {\textmu}m, 0.83 {\textmu}m, and 3.63 {\textmu}m were prepared by Al2O3 grit-blasting. Simple tetragonal and face-centered Ti6Al4V scaffolds with spatial gaps of 450-1100 {\textmu}m and 200-700 {\textmu}m, respectively, were fabricated by a three-dimensional fiber deposition (3DFD) technique. After alkali treatment, the titanium plates with a surface roughness of Ra = 0.56 {\textmu}m were completely covered with HA globules after 7 days in SBF, while the coverage of the samples with other surface roughness values remained incomplete. The higher CaP deposition rate was attributed to the locally higher concentration of negative surface charges, the restricted ion mobility, and the higher amount of concave parts on the surface. Similarly, face-centered Ti6Al4V scaffolds with spatial gaps of 200\-700 {\textmu}m exhibited a full surface coverage after 21 days in SBF, while simple tetragonal scaffolds with spatial gaps of 450-1100 {\textmu}m were only covered for 45-65\%. This pointed to the importance of spatial gap size for CaP deposition by a local change in ionic concentration and/or surface charge.
In chapter 6, the influence of PDLLA coating thickness on the in vitro release of vancomycin hydrochloride (VH) from a HA carrier is studied. Microporous HA fibers with a porosity of 51 v\% and an average pore diameter of 1.0 {\textmu}m were fabricated by a diffusion-induced phase separation technique. They were loaded with 38 mg VH / g HA and their cylindrical shape enabled the application of the spray coating technique for the deposition of uniform PDLLA coating thicknesses, varying from 6.5 {\textmu}m to 28 {\textmu}m. The resulting in vitro VH release varied from a complete release within 14 days for 6.5 {\textmu}m coatings to a release of 23\% after 28 days for 28 {\textmu}m coatings. It was clear that the VH release rate from a HA fiber can be adjusted by varying the PDLLA coating thickness. Microbiological tests of these fibers against a methicillin-resistant Staphylococcus aureus (MRSA) isolate pointed to the importance of the initial burst release and confirmed that the released antibiotics had the potential to interfere with S. aureus biofilm formation.},
  author       = {Ravelingien, Matthieu},
  language     = {eng},
  pages        = {VI, 109},
  publisher    = {Ghent University. Faculty of Pharmaceutical Sciences},
  school       = {Ghent University},
  title        = {Development of titanium bone scaffolds with drug delivery system},
  year         = {2010},
}

Chicago
Ravelingien, Matthieu. 2010. “Development of Titanium Bone Scaffolds with Drug Delivery System”. Ghent, Belgium: Ghent University. Faculty of Pharmaceutical Sciences.
APA
Ravelingien, M. (2010). Development of titanium bone scaffolds with drug delivery system. Ghent University. Faculty of Pharmaceutical Sciences, Ghent, Belgium.
Vancouver
1.
Ravelingien M. Development of titanium bone scaffolds with drug delivery system. [Ghent, Belgium]: Ghent University. Faculty of Pharmaceutical Sciences; 2010.
MLA
Ravelingien, Matthieu. “Development of Titanium Bone Scaffolds with Drug Delivery System.” 2010 : n. pag. Print.