Porous Alumina Ceramics with Multimodal Pore Size Distributions.

Pore networks with multimodal pore size distributions combining advantages from isotropic and anisotropic shaped pores of different sizes are highly attractive to optimize the physical properties of porous ceramics. Multimodal porous Al2O3 ceramics were manufactured using pyrolyzed cellulose fibers (l = 150 µm, d = 8 µm) and two types of isotropic phenolic resin spheres (d = 30 and 300 µm) as sacrificial templates. The sacrificial templates were homogeneously distributed in the Al2O3 matrix, compacted by uniaxial pressing and extracted by a burnout and sintering process up to 1700 °C in air. The amount of sacrificial templates was varied up to a volume content of 67 Vol% to form pore networks with porosities of 0-60 Vol%. The mechanical and thermal properties were measured by 4-point-bending and laser flash analysis (LFA) resulting in bending strengths of 173 MPa to 14 MPa and heat conductivities of 22.5 Wm-1K-1 to 4.6 Wm-1K-1. Based on µCT-measurements, the representative volume-of-interest (VOI) of the samples digital twin was determined for further analysis. The interconnectivity, tortuosity, permeability, the local and global stress distribution as well as strut and cell size distribution were evaluated on the digital twin's VOI. Based on the experimental and simulation results, the samples pore network can be tailored by changing the fiber to sphere ratio and the overall sacrificial template volume. The presence pore formers significantly influenced the mechanical and thermal properties, resulting in higher strengths for samples containing fibrous templates and lower heat conductivities for samples containing spherical templates.

Modular Lattice Constructs for Biological Joint Resurfacing.

IMPACT STATEMENT: The repair of large articular cartilage lesions is still a major challenge. In particular, the fixation of the grafts to the subchondral bone plate represents an unresolved problem. In this work, we present a completely novel concept based on a modular lattice, combining building blocks of different ceramic materials, anchoring pins and space for cell-loaded hydrogels or other scaffold materials. This concept targets not only circumscribed cartilage defects but also large osteoarthritic lesions. It spans the bridge between cell therapy and artificial joint arthroplasty, and thus is of significant medical and socioeconomic impact.

Modular ceramic scaffolds for individual implants.

Ideal artificial bone grafts aim for multiscale porosity, high mechanical strength and ensure rapid vascularization for bone ingrowth. In this work modular ceramic arteriovenous loops (AV-loops) with a hierarchical porosity approach were designed and manufactured to meet these criteria and to exceed the poor mechanical strength of monolithic scaffolds. Bioactive building blocks (ß-TCP, HAp, BCP) with dimensions of 1.5-3.0 mm were prepared by injection molding and assembled to complex AV-loop scaffolds using a customized automated assembly technology (pick and place). The building blocks were bonded with a biocompatible adhesive. Single building blocks are characterized by a compressive strength of 112.4-134.5 MPa with a residual sintering porosity of 32.2-41.5%, matching the strength of cortical bone of 100-230 MPa. The compressive strength of the modular assemblies varied between 22.3 and 47.6 MPa primary depending on the building block arrangement. The achieved compressive strengths are superior to current monolithic AV-scaffolds and sufficient for the implantation as non-load-bearing AV-loop scaffolds in isolation chambers. The modular AV-loop scaffolds provide a hierarchical interconnected pore network (P = 58.8%) combining small macropores of 4.1-4.3 µm size for possible enhanced protein absorption and large gradient macropores of 200-1700 µm size for optimum vascularization and complete bone ingrowth. The modular building block approach allows to design patient individualized scaffolds with complex hierarchical pore networks. The pore volume, size and geometry as well as the biological response can effectively be tuned by changing the dimensions, shape and placing gap of the bioactive building blocks. STATEMENT OF SIGNIFICANCE: Gold standard of bone replacement in case of surgery or cancer is still own bone material usually taken from the hip/arm or leg in second surgery with poor mechanical properties and limited amount. To avoid a second surgery and provide mechanical strong scaffold structures for fast patient regeneration a novel modular building block approach is used. This allows complex scaffold geometry with a hierarchical interconnection porosity for blood vessel ingrowth. The pore volume, size and geometry as well as the biological response can effectively be tuned by changing the dimensions, shape and placing gap of the bioactive building blocks.

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy.

Purpose: Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). Methods: Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2-/-) mice were used in the OIR model, exposed to 75% O2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR. Results: tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor α (VEGFα), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2-/- displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFα and angiopoietin expression. Conclusions: Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies.

Influence of Different Irradiation Protocols on Vascularization and Bone Formation Parameters in Rat Femora.

Aim of the present study was the establishment of an efficient and reproducible model for irradiation of rat femora as a model for impaired osteogenesis and angiogenesis. Four different irradiation protocols were compared: single irradiation of the left femur with 20 Gy and explantation after 4 or 8 weeks (group A, B) and three irradiation fractions at 3-4 days intervals with 10 Gy and explantation after 4 or 8 weeks (group C, D). The contralateral, unirradiated femur served as control. Evaluation included histology, microcomputertomography (µCT), and real-time polymerase chain reaction. Histology showed a pronounced increase of vacuoles in bone marrow after irradiation, especially after 4 weeks (group A and C), demonstrating bone marrow edema and fatty degeneration. Irradiation provoked a decrease of total cell numbers in cortical bone and of hypoxia-inducible factor 1 alpha (HIF1α)-positive cells in bone marrow. The expression of several markers (osteocalcin [OCN], runt-related transcription factor 2 [RUNX2], transforming growth factor beta 1 [TGFß1], tumor necrosis factor alpha [TNFα], vascular endothelial growth factor A [VEGFA], and HIF1α) was decreased in group A after irradiation. This might suggest a decreased metabolism after irradiation. A significant decrease in small-sized vessels was seen in µCT evaluation in group A and D. Single irradiation with 20 Gy had the most severe and reproducible impact on osteogenesis and angiogenesis after 4 weeks while being well tolerated by all animals, thus making it an excellent model for evaluation of bone healing and vascularization in irradiated tissue.

Compensation for spill-in and spill-out partial volume effects in cardiac PET imaging.

BACKGROUND: Partial volume effects (PVEs) in PET imaging result in incorrect regional activity estimates due to both spill-out and spill-in from activity in neighboring regions. It is important to compensate for both effects to achieve accurate quantification. In this study, an image-based partial volume compensation (PVC) method was developed and validated for cardiac PET. METHODS AND RESULTS: The method uses volume-of-interest (VOI) maps segmented from contrast-enhanced CTA images to compensate for both spill-in and spill-out in each VOI. The PVC method was validated with simulation studies and also applied to images of dog cardiac perfusion PET data. The PV effects resulting from cardiac motion and myocardial uptake defects were investigated and the efficacy of the proposed PVC method in compensating for these effects was evaluated. RESULTS: Results indicate that the magnitude and the direction of PVEs in cardiac imaging change over time. This affects the accuracy of activity distributions estimates obtained during dynamic studies. The defect regions have different PVEs as compared to the normal myocardium. Cardiac motion contributes around 10% to the PVEs. PVC effectively removed both spill-in and spill-out in cardiac imaging. CONCLUSIONS: PVC improved left ventricular wall uniformity and quantitative accuracy. The best strategy for PVC was to compensate for the PVEs in each cardiac phase independently and treat severe uptake defects as independent regions from the normal myocardium.

Application of MRI-based partial-volume correction to the analysis of PET images of mu-opioid receptors using statistical parametric mapping.

UNLABELLED: The accurate quantification of brain radioactivity concentration is limited by the spatial resolution of the PET scanner for structures smaller than 2-3 times the resolution. In the presence of enlarged cerebrospinal fluid spaces or regions of cortical neuronal loss, a significant underestimation of gray-matter radioactivity concentration due to the resulting partial-volume averaging can potentially occur. To recover the true radioactivity concentration from PET data, algorithms that use the high-resolution anatomic information provided by MRI have been developed. Their effect on PET quantification has been assessed using regions of interest and non-operator-dependent voxel-based analyses such as statistical parametric mapping (SPM), although the mechanisms that lead to an improvement in PET quantification after partial-volume correction (PVC), compared with no PVC, have not been addressed. METHODS: We studied the influence of our previously described MRI-based PVC algorithm on SPM analysis of age effects on mu-opioid receptor (mu -OR) binding using (11)C-carfentanil PET in 14 healthy subjects (age range, 29-74 y). RESULTS: Mu-OR binding increased with age at a rate of about 0.9% per year in the left temporal cortex after PVC, consistent with the results obtained from human autoradiographic studies. Without PVC, no significant relationship with age was observed. PVC decreased mainly the residual variability of voxel mu-OR binding values around the age regression line. CONCLUSION: MRI-based PVC improves the sensitivity and accuracy of voxel-based statistical analysis of PET data.