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Functional Ceramics in Biomedical Applications: On the Use of Ceramics for Controlled Drug Release and Targeted Cell Stimulation
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ceramics are distinguished from metals and polymers by their inorganic nature and lack of metallic properties. They can be highly crystalline to amorphous, and their physical and chemical properties can vary widely. Ceramics can, for instance, be made to resemble the mineral phase in bone and are therefore an excellent substitute for damaged hard tissue. They can also be made porous, surface active, chemically inert, mechanically strong, optically transparent or biologically resorbable, and all these properties are of interest in the development of new materials intended for a wide variety of applications. In this thesis, the focus was on the development of different ceramics for use in the controlled release of drugs and ions. These concepts were developed to obtain improved therapeutic effects from orally administered opioid drugs, and to reduce the number of implant-related infections as well as to improve the stabilization of prosthetic implants in bone.

Geopolymers were used to produce mechanically strong and chemically inert formulations intended for oral administration of opioids. The carriers were developed to allow controlled release of the drugs over several hours, in order to improve the therapeutic effect of the substances in patients with severe chronic pain. The requirement for a stable carrier is a key feature for these drugs, as the rapid release of the entire dose, due to mechanical or chemical damage to the carrier, could have lethal effects on the patient because of the narrow therapeutic window of opioids. It was found that it was possible to profoundly retard drug release and to achieve almost linear release profiles from mesoporous geopolymers when the aluminum/silicon ratio of the precursor particles and the curing temperature were tuned.

Ceramic implant coatings were produced via a biomimetic mineralization process and used as carriers for various drugs or as an ion reservoir for local release at the site of the implant. The formation and characteristics of these coatings were examined before they were evaluated as potential drug carriers. It was demonstrated that these coatings were able to carry antibiotics, bisphosphonates and bone morphogenetic proteins to obtain a sustained local effect, as they were slowly released from the coatings.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 99
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 780
Keywords [en]
Controlled release, geopolymer, sol-gel, opioid, oral administration, oral dosage form, implant, titanium, hydroxyapatite, infection, strontium carbonate, strontium
National Category
Other Materials Engineering Materials Engineering Other Engineering and Technologies not elsewhere specified
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-132377ISBN: 978-91-554-7930-5 (print)OAI: oai:DiVA.org:uu-132377DiVA, id: diva2:359515
Public defence
2010-12-10, Polhelmsalen, Ångströmslaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Note

Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 710

Available from: 2010-11-18 Created: 2010-10-19 Last updated: 2014-01-21Bibliographically approved
List of papers
1. A ceramic drug delivery vehicle for oral administration of highly potent opioids
Open this publication in new window or tab >>A ceramic drug delivery vehicle for oral administration of highly potent opioids
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2010 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, no 1, p. 219-226Article in journal (Refereed) Published
Abstract [en]

Pellets composed of the ceramic material Halloysite and microcrystalline cellulose were synthesized with the aim of producing a drug delivery vehicle for sustained release of the opioid Fentanyl with low risk for dose dumping at oral intake of the highly potent drug. Drug release profiles of intact and crushed pellets, to simulate swallowing without or with chewing, in pH 6.8, pH 1, and in 48% ethanol were recorded in order to replicate the conditions in the small intestines, in the stomach, as well as cointake of the drug with alcohol. The drug release was analyzed by employing the Weibull equation, which showed that the release profiles were either governed by fickian diffusion (intact pellets in pH 6.8 and in ethanol) or by diffusion in a fractal or disordered pore network (intact pellets in pH 1 and crushed pellets in all solutions). A sustained release for approximately 3-4 h was obtained in all studied solutions from intact pellets, whereas crushed pellets released the drug content during approximately 2-3 h. The finding that a sustained release profile could be obtained both in alcohol and after crushing of the pellets, shows that the ceramic carrier under investigation, at least to some extent, hampers dose dumping, and may thus be a promising material in future developments of new opioid containing oral dosage forms.

National Category
Other Materials Engineering
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-111786 (URN)10.1002/jps.21814 (DOI)000273151500016 ()19492338 (PubMedID)
Available from: 2009-12-21 Created: 2009-12-21 Last updated: 2018-11-05Bibliographically approved
2. Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
Open this publication in new window or tab >>Mechanically strong geopolymers offer new possibilities in treatment of chronic pain
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2010 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 146, no 3, p. 370-377Article in journal (Refereed) Published
Abstract [en]

We propose that a clay derived class of materials, known as geopolymers, may solve the problem of finding materials for controlled release with the right combination of properties necessary for a safe and sustained oral delivery of highly potent opioids. We show that the opioid Fentanyl, and its structurally similar sedative Zolpidem, can be embedded into metakaolin based geopolymer pellets to provide prolonged release dosage forms with mechanical strengths of the same order of magnitude as that of human teeth. The results presented in the current work may open up new opportunities for future development of drug delivery for high potency drugs employing high-strength and variable-pore-structure geopolymers and materials alike.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-131243 (URN)10.1016/j.jconrel.2010.05.029 (DOI)000282398100014 ()20685295 (PubMedID)
Available from: 2010-09-28 Created: 2010-09-28 Last updated: 2018-11-05Bibliographically approved
3. Adjustable nanostructure of synthetic geopolymers enables tunable and sustained release of oxycodone
Open this publication in new window or tab >>Adjustable nanostructure of synthetic geopolymers enables tunable and sustained release of oxycodone
(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-132372 (URN)
Available from: 2010-10-19 Created: 2010-10-19 Last updated: 2011-01-13Bibliographically approved
4. Formation and adhesion of biomimetic hydroxyapatite deposited on titanium substrates
Open this publication in new window or tab >>Formation and adhesion of biomimetic hydroxyapatite deposited on titanium substrates
2007 (English)In: Acta Biomaterialia, ISSN 1742-7061, Vol. 3, no 6, p. 980-984Article in journal (Refereed) Published
Abstract [en]

This study has been carried out to investigate the bioactivity of rutile and to deposit hydroxyapatite (HA) on heat-treated titanium through a biomimetic method. Biomimetic deposition of HA has gained large interest because of its low deposition temperature and good step coverage; however, it demands a substrate with bioactive properties. Commercially pure titanium is not bioactive but it can acquire bioactive properties through various surface treatments. In the present study, titanium plates were heat-treated at 800 °C to achieve rutile TiO2 surfaces. These samples were immersed in a phosphate-buffered saline solution for seven days in order to deposit a HA layer on the surface. The rutile TiO2 surfaces were found to be highly bioactive: after seven days of immersion, a layer of HA several micrometers thick covered the plates. The HA surfaces were confirmed by electron microscopy and X-ray diffraction. A scratch test was used to assess the adhesion of the HA coatings. This is a standard method to provide a measure of the coating-to-substrate adhesion and was found to be a useful method to test the thin HA coatings deposited on the bioactive surfaces. The critical pressure of the layer was estimated to be 2.4 ± 0.1 GPa.

Keywords
Hydroxyapatite, Bioactivity, Biomimetic deposition, Rutile, Adhesion
National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-13067 (URN)10.1016/j.actbio.2007.03.006 (DOI)000250394000017 ()17512265 (PubMedID)
Available from: 2008-06-09 Created: 2008-06-09 Last updated: 2018-02-08Bibliographically approved
5. Structural change of biomimetic hydroxyapatite coatings due to heat treatment
Open this publication in new window or tab >>Structural change of biomimetic hydroxyapatite coatings due to heat treatment
2007 (English)In: Journal of Applied Biomaterials & Biomechanics, ISSN 1722-6899, Vol. 5, no 1, p. 23-27Article in journal (Refereed) Published
Abstract [en]

Biomimetic deposition of hydroxyapatite (HA) coatings on implants could be done for two reasons, one is to study their possible bioactivity, and one is to generate bioactive coatings on implants before implantation surgery to improve the osseointegration. Heat treatment of coated implants can be performed for several reasons, for example, to ensure coating sterility and to increase the adhesion. This paper describes the morphology and crystalline structure changes occurring due to the heat treatment of biomimetic HA coatings on rutile TiO2. Rutile TiO2 surfaces were produced on titanium (Ti) plates by heating at 800 C. Afterwards, these samples were immersed in a phosphate buffer saline solution for 7 days at 37 C in order to deposit HA coatings on their surfaces. These HA coatings were then either untreated or heat treated at 600 or 800 C for 1 hr. The coatings microstructural changes were studied using X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Cross-sectional TEM samples were produced using a sample preparation method based on focused ion beam microscopy (FIB). Rutile was found to be bioactive due to HA formation on the surface. The 600 C heat treatment of the HA coating changed its morphology, increased its grain size and also increased the porosity. At 800 C the coating was completely transformed to beta-TCP according to XRD. Sample preparation using FIB and TEM analysis proved to be a useful method for high-resolution analysis of biomimetic coatings in cross-section.

Keywords
microstructure, titanium, biomimetic coating, stability
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-16172 (URN)000255726200003 ()
Available from: 2008-06-09 Created: 2009-02-26 Last updated: 2018-02-08Bibliographically approved
6. Assessing Surface Area Evolution during Biomimetic Growth of Hydroxyapatite Coatings
Open this publication in new window or tab >>Assessing Surface Area Evolution during Biomimetic Growth of Hydroxyapatite Coatings
2009 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 25, no 3, p. 1292-1295Article in journal (Refereed) Published
Abstract [en]

The surface area of biomimetically deposited hydroxyapatite (HA) coatings on metallic implants is important for the biological performance of the implant. Thus, a nondestructive method of assessing this quantity directly on the solid substrate would be highly valuable. The objective of this study was to develop such a method and for the first time assess the evolution of surface area of HA during biomimetic growth. The surface area of a TiO2-covered titanium substrate was measured prior to and following the biomimetic coating deposition using Ar gas adsorption at 77 K. The presence of HA on the surface was verified with scanning electron microscopy and X-ray diffraction. The specific surface area of the coating was found to increase linearly during 1 week of deposition at a rate of ∼100 cm2 day−1 (g substrate)−1. The presented method may be used as a tool for studying the evolution in surface area of coatings on solid substrates during biomimetic deposition or other growth processes.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-88439 (URN)10.1021/la803520k (DOI)000262827400007 ()19115807 (PubMedID)
Available from: 2009-02-02 Created: 2009-02-02 Last updated: 2018-02-08Bibliographically approved
7. Multifunctional implant coatings providing possibilities for fast antibiotics loading with subsequent slow release
Open this publication in new window or tab >>Multifunctional implant coatings providing possibilities for fast antibiotics loading with subsequent slow release
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2009 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 20, no 9, p. 1859-1867Article in journal (Refereed) Published
Abstract [en]

The possibility to fast-load biomimetic hydroxyapatite coatings on surgical implant with the antibiotics Amoxicillin, Gentamicin sulfate, Tobramycin and Cephalothin has been investigated in order to develop a multifunctional implant device offering sustained local anti-bacterial treatment and giving the surgeon the possibility to choose which antibiotics to incorporate in the implant at the site of surgery. Physical vapor deposition was used to coat titanium surfaces with an adhesion enhancing gradient layer of titanium oxide having an amorphous oxygen poor composition at the interface and a crystalline bioactive anatase TiO2 composition at the surface. Hydroxyapatite (HA) was biomimetically grown on the bioactive TiO2 to serve as a combined bone in-growth promoter and drug delivery vehicle. The coating was characterized using scanning and transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The antibiotics were loaded into the HA coatings via soaking and the subsequent release and antibacterial effect were analyzed using UV spectroscopy and examination of inhibition zones in a Staphylococcus aureus containing agar. It was found that a short drug loading time of 15 min ensured antibacterial effects after 24 h for all antibiotics under study. It was further found that the release processes of Cephalothin and Amoxicillin consisted of an initial rapid drug release that varied unpredictably in amount followed by a reproducible and sustained release process with a release rate independent of the drug loading times under study. Thus, implants that have been fast-loaded with drugs could be stored for ~10 min in a simulated body fluid after loading to ensure reproducibility in the subsequent release process. Calculated release rates and measurements of drug amounts remaining in the samples after 22 h of release indicated that a therapeutically relevant dose could be achieved close to the implant surface for about 2 days. Concluding, the present study provides an outline for the development of a fast-loading slow-release surgical implant kit where the implant and the drug are separated when delivered to the surgeon, thus constituting a flexible solution for the surgeon by offering the choice of quick addition of antibiotics to the implant coating based on the patient need.

National Category
Engineering and Technology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-122095 (URN)10.1007/s10856-009-3749-6 (DOI)000268786400010 ()19399593 (PubMedID)
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2018-02-08Bibliographically approved
8. Co-loading of bisphosphonates and antibiotics to a biomimetic hydroxyapatite coating
Open this publication in new window or tab >>Co-loading of bisphosphonates and antibiotics to a biomimetic hydroxyapatite coating
2011 (English)In: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 33, no 6, p. 1265-1268Article in journal (Refereed) Published
Abstract [en]

We have incorporated bisphosphonates and antibiotics simultaneously into a biomimetic hydroxyapatite implant coating aiming to use the interaction between drug-molecules and hydroxyapatite to enable local release of the two different substances to obtain a dual biological effect. A sustained release over for 43 h of antibiotics (cephalothin) was achieved without negative interference from the presence of the bisphosphonate (clodronate) which, in turn, successfully bonded to the coating surface. To our knowledge, this is the first study that indicates the possibility to simultaneously incorporate both antibiotics and bisphosphonates to an implant coating, a strategy that is believed to improve implant stability and reduce implant-related infections.

National Category
Nano Technology Medical Biotechnology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-145824 (URN)10.1007/s10529-011-0542-7 (DOI)000291655200027 ()21287232 (PubMedID)
Available from: 2011-02-11 Created: 2011-02-11 Last updated: 2018-02-08Bibliographically approved
9. In vitro characterization of bioactive titanium dioxide/hydroxyapatite surfaces functionalized with BMP-2
Open this publication in new window or tab >>In vitro characterization of bioactive titanium dioxide/hydroxyapatite surfaces functionalized with BMP-2
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2009 (English)In: Journal of biomedical materials research. Part B, Applied biomaterials, ISSN 1552-4981, Vol. 91B, no 2, p. 780-787Article in journal (Refereed) Published
Abstract [en]

Poor implant fixation and bone resorption are two of the major challenges in modern orthopedics and are caused by poor bone/implant integration. In this work, bioactive crystalline titanium dioxide (TiO(2))/hydroxyapatite (HA) surfaces, functionalized with bone morphogenetic protein 2 (BMP-2), were evaluated as potential implant coatings for improved osseointegration. The outer layer consisted of HA, which is known to be osteoconductive, and may promote improved initial bone attachment when functionalized with active molecules such as BMP-2 in a soaking process. The inner layer of crystalline TiO(2) is bioactive and ensures long-term fixation of the implant, once the hydroxyapatite has been resorbed. The in vitro response of mesenchymal stem cells on bioactive crystalline TiO(2)/HA surfaces functionalized with BMP-2 was examined and compared with the cell behavior on nonfunctionalized HA layers, crystalline TiO(2) surfaces, and native titanium oxide surfaces. The crystalline TiO(2) and the HA surfaces showed to be more favorable than the native titanium oxide surface in terms of cell viability and cell morphology as well as initial cell differentiation. Furthermore, cell differentiation on BMP-2-functionalized HA surfaces was found to be significantly higher than on the other surfaces indicating that the simple soaking process can be used for incorporating active molecules, promoting fast bone osseointegration to HA layers.

Keywords
biomimetic hydroxyapatite, growth factors, BMP-2, anatase titanium dioxide, mesenchymal stem cells, differentiation, viability, morphology
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-108680 (URN)10.1002/jbm.b.31456 (DOI)000270868600034 ()19582842 (PubMedID)
Available from: 2009-09-26 Created: 2009-09-26 Last updated: 2018-02-08Bibliographically approved
10. In Vivo Evaluation of Functionalized Biomimetic Hydroxyapatite for Local Delivery of Active Agents
Open this publication in new window or tab >>In Vivo Evaluation of Functionalized Biomimetic Hydroxyapatite for Local Delivery of Active Agents
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2011 (English)In: Journal of Biomaterials and Nanobiotechnology, ISSN 2158-7027, 2158-7043, Vol. 2, no 2, p. 149-154Article in journal (Refereed) Published
Abstract [en]

This study was carried out to investigate the biological response in vivo to biomimetic hydroxyapatite implant coatings functionalized with bisphosphonates and bone morphogenetic proteins. The functionalization was carried out by a simple soaking procedure in the operating room immediately prior to surgery. Cylindrical titanium samples with and without coatings were implanted in the distal femoral epiphysis of sheep and retrieved after 6 weeks. The histological analysis proved that all samples were integrated well in the tissue with no signs of intolerance. Fewer osteoclasts were observed in the vicinity of bisphosphonate-functionalized samples and the bone was denser around these samples compared to the other samples. Samples functionalized with bone morphogenetic protein induced more bone/implant contact but showed a more inconsistent outcome with reduced bone density around the samples. This study demonstrates a simple method to functionalize implant coatings, which provides surgeons with an option of patient-specific functionalization of implants. The observed biological impact due to the delivery of active molecules from the coatings suggests that this strategy may also be employed to deliver antibiotics from similar coatings.

National Category
Engineering and Technology Polymer Chemistry
Research subject
Engineering Science with specialization in Materials Science; Engineering Science with specialization in Nanotechnology and Functional Materials; Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-156129 (URN)10.4236/jbnb.2011.22019 (DOI)
Funder
Swedish Research Council
Available from: 2011-07-11 Created: 2011-07-11 Last updated: 2018-02-08Bibliographically approved
11. A novel method for local administration of strontium from implant surfaces
Open this publication in new window or tab >>A novel method for local administration of strontium from implant surfaces
2010 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 21, no 5, p. 1605-1609Article in journal (Refereed) Published
Abstract [en]

This study proves that a film of Strontianite (SrCO(3)) successfully can be formed on a bioactive surface of sodium titanate when exposed to a strontium acetate solution. This Strontianite film is believed to enable local release of strontium ions from implant surfaces and thus stimulate bone formation in vivo. Depending on the method, different types of films were achieved with different release rates of strontium ions, and the results points at the possibility to tailor the rate and amount of strontium that is to be released from the surface. Strontium has earlier been shown to be highly involved in the formation of new bone as it stimulates the replication of osteoblasts and decreases the activity of osteoclasts. The benefit of strontium has for example been proved in studies where the number of vertebral compression fractures in osteoporotic persons was drastically reduced in patients receiving therapeutical doses of strontium. Therefore, it is here suggested that the bone healing process around an implant may be improved if strontium is administered locally at the site of the implant. The films described in this paper were produced by a simple immersion process where alkali treated titanium was exposed to an aqueous solution containing strontium acetate. By heating the samples at different times during the process, different release rates of strontium ions were achieved when the samples were exposed to simulated body fluid. The strontium containing films also promoted precipitation of bone like apatite when exposed to a simulated body fluid.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-125407 (URN)10.1007/s10856-010-4022-8 (DOI)000277603000023 ()20162327 (PubMedID)
Available from: 2010-05-18 Created: 2010-05-18 Last updated: 2018-02-08Bibliographically approved

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