OBJECTIVES: This study aims to fabricate graded composite structures with different ceramic materials and explore the effect of the various ceramic materials on the microstructure, surface topography, crystal characterization, bioactivity, and mechanical properties of the ceramic scaffold. MATERIALS AND METHODS: Ceramic matrix specimens were prepared with a slip casting technique. After sintering, specimens were examined for their physical, chemical, and mechanical properties including microstructure, surface roughness, elemental composition, crystal characterization and biaxial flexural strength. Specimens from each group were immersed in a calcification solution and were evaluated for the deposition of calcium phosphate through microscopy, elemental analysis, and crystal characterization. RESULTS: Graded ceramic matrix materials were successfully fabricated using a slip-casting technique. Scanning electron microscopy revealed different surface topography as well as the deposition of calcium phosphate crystals on the specimen surface after immersion in calcification solution. Elemental composition and X-Ray Diffraction (XRD) spectra confirmed phase transformation in the composite specimen after sintering. Particle grain size significantly affected surface topography in terms of surface area roughness and topographical patterns. Moreover, the combination of alumina and bioactive glass improved mechanical properties compared to bioactive glass alone. CONCLUSIONS: 1. The ceramic matrix containing bioactive glass presented greater surface roughness compared to other ceramic matrix without bioactive glass. 2. Two crystal phases: tricalcium silicate (Ca3Si3O9) and calcium metasilicate (CaSiO3) were found in high temperature sintered bioactive glass. The combination of bioactive glass with alumina or hydroxyapatite presented another tricalcium silicate phase such as Ca3(SiO4)O. 3. The XRD analysis of the combination of alumina and hydroxyapatite detected two new phases including grossite (CaAl4O7) and calcium aluminophosphate (Ca9Al(PO4)7). 4. Ceramic matrix containing bioactive glass or hydroxyapatite presented greater deposition of calcium phosphate crystals while the combination of bioactive glass and hydroxyapatite showed the greatest amount of the precipitated crystals. 5. Alumina ceramic matrix showed the highest biaxial flexural strength while hydroxyapatite and bioactive glass presented low biaxial flexural strength. 6. The combination of alumina with hydroxyapatite or bioactive glass improved biaxial flexural strength. 7. The combination of hydroxyapatite with bioactive glass had lower biaxial flexural strength compared to a single-phase ceramic matrix.

Polymeric bone scaffolds are a promising tissue engineering approach for the repair of critical-size bone defects. Porous three-dimensional (3D) scaffolds play an essential role as templates to guide new tissue formation. However, there are critical challenges arising from the poor mechanical properties and low bioactivity of bioresorbable polymers, such as poly(epsilon-caprolactone) (PCL) in bone tissue engineering applications. This research investigates the potential use of cellulose nanocrystals (CNCs) as multi-functional additives that enhance the mechanical properties and increase the biomineralization rate of PCL. To this end, an in vitro biomineralization study of both sulfuric acid hydrolyzed-CNCs (SH-CNCs) and surface oxidized-CNCs (SO-CNCs) has been performed in simulated body fluid in order to evaluate the bioactivity of the surface functional groups, sulfate and carboxyl groups, respectively. PCL nanocomposites were prepared with different SO-CNC contents and the chemical/physical properties of the nanocomposites were analyzed. 3D porous scaffolds with fully interconnected pores and well-controlled pore sizes were fabricated from the PCL nanocomposites with a 3D printer. The mechanical stability of the scaffolds were studied using creep test under dry and submersion conditions. Lastly, the biocompatibility of CNCs and 3D printed porous scaffolds were assessed in vitro. The carboxyl groups on the surface of SO-CNCs provided a significantly improved calcium ion binding ability which could play an important role in the biomineralization (bioactivity) by induction of mineral formation for bone tissue engineering applications. In addition, the mechanical properties of porous PCL nanocomposite scaffolds were pronouncedly reinforced by incorporation of SO-CNCs. Both the compressive modulus and creep resistance of the PCL scaffolds were enhanced either in dry or in submersion conditions at 37 degrees Celsius. Lastly, the biocompatibility study demonstrated that both the CNCs and material fabrication processes (e.g., PCL nanocomposites and 3D printing) were not toxic to the preosteoblasts (MC3T3 cells). Also, the SO-CNCs showed a positive effect on biomineralization of PCL scaffolds (i.e., accelerated calcium or mineral deposits on the surface of the scaffolds) during in vitro study. Overall, the SO-CNCs could play a critical role in the development of scaffold materials as a potential candidate for reinforcing nanofillers in bone tissue engineering applications. / Ph. D.

The focus of this dissertation is on the development of an additive manufacturing system and methodology for fabricating structures with functionally graded porous internal properties and complex three-dimensional external characteristics. For this purpose, a multi-scale three-dimensional printing system was developed, with capabilities and fabrication methodologies refined in the context of, but not limited to, manufacturing of porous bone substitutes. Porous bone implants are functionally graded structures, where internally, the design requires a gradient in porosity and mechanical properties matching the functional transition between cortical and cancellous bone regions. Geometrically, the three-dimensional shape of the design must adhere to the anatomical shape of the bone tissue being replaced. In this work, control over functionally graded porous properties was achieved by integrating specialized modules in a custom-made additive manufacturing system and studying their effect on fabricated constructs. Heterogeneous porous properties were controlled by: (i) using a micro-syringe deposition module capable of embedding sacrificial elements with a controlled feature size within the structure, (ii) controlling the amount of binder dispersed onto the powder substrate using a piezoelectric printhead, (iii) controlling the powder type or size in real-time, and/or (iv) selecting the print layer stacking orientation within the part. Characterization methods included differential scanning calorimetry (DSC)-thermo gravimetric analysis (TGA) to establish the thermal decomposition of sacrificial elements, X-ray diffraction (XRD) and dispersive X-ray spectroscopy (EDAX) to investigate the chemical composition and crystallinity, scanning electron microscopy (SEM) and optical microscopy to investigate the physical and structural properties, uniaxial mechanical loading to establish compressive strength characteristics, and porosity measurements to determine the bulk properties of the material. These studies showed that the developed system was successful in manufacturing embedded interconnected features in the range of 100-500 $ \mu m $, with a significant impact on structural properties resulting in bulk porosities in the range of 30-55% and compressive strength between 2-50 MPa. In this work, control over the the three-dimensional shape of the construct was established iteratively, by using a silhouette extraction image processing technique to determine the appropriate anisotropic compensation factors necessary to offset the effects of shrinkage in complex-shaped parts during thermal annealing. Overall shape deviations in the range of +/- 5-7 % were achieved in the second iteration for a femoral condyle implant in a sheep model. The newly developed multi-scale 3DP system and associated fabrication methodology was concluded to have great potential in manufacturing structures with functionally graded properties and complex shape characteristics.

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Knorpeldefekte des Kniegelenks zeichnen sich durch eine sehr begrenzte spontane Heilungstendenz aus und führen im Verlauf häufig zur Arthrose. Trotz intensiver Forschungsbemühungen konnte bisher keine neue Therapieoption eine zufrieden-stellende Alternative zu den bisherigen Therapien hervorbringen. Eine ACI in Kombination mit einem künstlich hergestellten Knorpel-Knochen-Ersatzmaterial scheint jedoch großes Potential für die Therapie von Knorpel-Knochen-Schäden zu besitzen. Im vorliegenden Langzeittierversuch mit Kaninchen wurde eine einzeitige ACI mit einem biphasischen Ersatzmaterial (TruFit®) und platelet-rich-plasma (PRP) kombiniert. Zu diesem Zweck wurde in der medialen Femurkondyle ein critical-size-Defekt mit einem Durchmesser von 4,5 mm gesetzt. In der ersten Versuchsgruppe blieb der Defekt unbehandelt (Leer). Bei der zweiten Gruppe wurde die Defekthöhle mit einem TruFit®-Zylinder aufgefüllt (TFP). Gruppe drei erhielt zusätzlich PRP (TFP+PRP) und Gruppe vier wurde darüber hinaus mit einer einzeitigen ACI kombiniert (TFP+PRP+C), bei der Chondrozyten mit Hilfe eines speziellen Kollagenase-Schnellverdaus isoliert werden konnten. Die Auswertung der Knorpel-Knochen-Regeneration erfolgte nach 12 Monaten durch eine Mikroradiographie, eine intravitale Fluoreszenzmarkierung des Knochens und durch Toluidinblau-O- und Safranin-O-Färbungen. Verwendet wurden die Scores nach Wakitani und O’Driscoll. Dabei konnte gezeigt werden, dass eine TruFit®-Therapie die Knochenregeneration positiv beeinflussen kann. Die Zugabe von PRP bewirkte die Bildung von zahlreichen dünnen Trabekeln mit einer erhöhten Anzahl trabekulärer Verbindungen, allerdings auch eine schlechtere Rekonvaleszenz der subchondralen Knochenschicht. Bezüglich der Knorpelheilung schnitt die Gruppe TFP+PRP+C am besten ab, wobei die Unterschiede nicht signifikant waren. Insgesamt zeigten alle Versuchsgruppen eine unzureichende osteochondrale Regeneration, so dass für die Therapie am Menschen zunächst weitere Studien nötig sind, die sowohl ossär als auch chondral eine verbesserte Heilungspotenz demonstrieren können. Bisher fehlen groß angelegte Studien um Therapieempfehlungen bezüglich des Ersatzmaterials, der genauen Durchführung der einzeitigen ACI und Zusätzen wie Wachstumsfaktoren zu machen.