Bioadditive manufacturing of hybrid tissue scaffolds for controlled release kinetics

Development of engineered tissue scaffolds with superior control over cell-protein interactions is still very much infancy. Advancing through heterogeneous multifold scaffolds with controlled release fashion enables synchronization of regenerating tissue with the release kinetics of loaded biomolecules. This might be an engineering challenge and promising approach for improved and efficient tissue regeneration. The most critical limitations: the selection of proper protein(s) incorporation, and precise control over concentration gradient and timing should be overcome. Hence, tissue scaffolds need to be fabricated in a way that proteins or growth factors should be incorporated and released in a specific spatial and temporal orientation to mimic the natural tissue regeneration process. Spatial and temporal control over heterogeneous porous tissue scaffolds can be achieved by controlling two important parameters: (i) internal architecture with enhanced fluid transport, and (ii) distribution of scaffold base material and loaded modifiers. In this research, heterogeneous tissue scaffolds are designed considering both the parameters. Firstly, the three-dimensional porous structures of the scaffold are geometrically partition into functionally uniform porosity regions and controlled spatial micro-architecture has been achieved using a functionally gradient porosity function. The bio-fabrication of the designed internal porous architecture has been performed using a single nozzle bioadditive manufacturing system. The internal architecture scheme is developed to enhance fluid transport with continuous base material deposition Next, the hybrid tissue scaffolds are modeled with varying material characteristics to mediate the release of base material and enclosed biological modifiers are proposed based on tissue engineering requirements. The hybrid scaffolds are fabricated for spatial control of biomolecules and base material to synchronize the release kinetics with tissue regeneration. A pressure-assisted multi-chamber single nozzle bioadditive manufacturing system is used to fabricate hybrid scaffolds

Functionally gradient tissue scaffold design and deposition path planning for bio-additive processes

A layer-based tissue scaffold is designed with heterogeneous internal architecture. The proposed layer-based design uses a bi-layer pattern of radial and spiral layer consecutively to generate functionally gradient porosity following the geometry of the scaffold. Medial region is constructed from medial axis and used as an internal geometric feature for each layer. The radial layers are generated with sub-region channels by connecting the boundaries of the medial region and the layer’s outer contour. Proper connections with allowable geometric properties are ensured by applying optimization algorithms. Iso-porosity regions are determined by dividing the sub-regions into pore cells. The combination of consecutive layers generates the pore cells with desired pore sizes. To ensure the fabrication of the designed scaffolds, both contours have been optimized for a continuous, interconnected, and smooth deposition path-planning. The proposed methodologies can generate the structure with gradient (linear or non-linear), variational or constant porosity that can provide localized control of variational porosity along the scaffold architecture. The designed porous structures can be fabricated using bio-additive fabrication processes

The debate on the transition to flexible production: A case study on manufacturing industry in Turkey and its provinces

Thesis (Master)--Izmir Institute of Technology, City and Regional Planning, Izmir, 2003Includes bibliographical references (leaves: 195-202)Text in English; Abstract: Turkish and Englishix, 202 leavesThis thesis is mainly about the .flexible production. debates, which were introduced by the 1970s and are still concerned in various scientific disciplines. The debate has been considered not only as concerns of the transformations within the production, but also in parallel to the holistic transformation of the capitalist system. The fundamental emphasis has been on the fact that capitalism is a historical system and on its relations with .industrial production. and 'industrialization' processes.From this perspective, the three widely known approaches to flexible production, namely the 'neo-Schumpeterian approach', the 'flexible specialization approach', and the 'regulation school approach', have been evaluated in detail. It has been firmly emphasized that each of these approaches provided considerable statements within the debates on flexibility. The thesis in general has favoured the regulation school approach with its methodological means, and highlighted that it has developed the most appropriate approach in comprehensively explaining the ongoing processes.The thesis has focused on the spatial relations of flexible production debates at the city and regional levels, and highlighted the transformation on/of space throughout the transition processes. By means of a comprehensive case study on the changes in the spatial organizations of Turkey and on locational distribution of industry in relation to flexible production processes, it has been emphasized that space has a major role in current economic and social changes, and furthermore, that the experienced transformations are quite related with the successes in the urban and spatial organizations. Within the study, the urban and regional level changes have been analyzed quantitatively, and the subjects such as growth rates, comparative priorities, and the development of spatial advantages have been tested by the use of shift-share analysis

Multi-function based modeling of 3D heterogeneous wound scaffolds for improved wound healing

This paper presents a new multi-function based modeling of 3D heterogeneous porous wound scaffolds to improve wound healing process for complex deep acute or chronic wounds. An imaging-based approach is developed to extract 3D wound geometry and recognize wound features. Linear healing fashion of the wound margin towards the wound center is mimicked. Blending process is thus applied to the extracted geometry to partition the scaffold into a number of uniformly gradient healing regions. Computer models of 3D engineered porous wound scaffolds are then developed for solid freeform modeling and fabrication. Spatial variation over biomaterial and loaded bio-molecule concentration is developed based on wound healing requirements. Release of bio-molecules over the uniform healing regions is controlled by varying their amount and entrapping biomaterial concentration. Thus, localized controlled release is developed to improve wound healing. A prototype multi-syringe single nozzle deposition system is used to fabricate a sample scaffold. Proposed methodology is implemented and illustrative examples are presented in this paper

3D hybrid wound devices for spatiotemporally controlled release kinetics

This paper presents localized and temporal control of releasekinetics over 3-dimensional (3D) hybridwounddevices to improve wound-healing process. Imaging study is performed to extract wound bed geometry in 3D. Non-Uniform Rational B-Splines (NURBS) based surface lofting is applied to generate functionally graded regions. Diffusion-based releasekinetics model is developed to predict time-based release of loaded modifiers for functionally graded regions. Multi-chamber single nozzle solid freeform dispensing system is used to fabricate wounddevices with controlled dispensing concentration. Spatiotemporal control of biological modifiers thus enables a way to achieve target delivery to improve wound healing

Effects of Curcumin on Iron Overload in Rats

Background: Iron overload, common in patients with hematological disorders, is a key target in drug development. This study investigated the effects of curcumin on iron overload in rats. Methods: Forty male Wistar rats weighing 139.78 ± 11.95 gm (Mean ± SD) were divided into three equal groups: (i) controls; (ii) iron overload group that received six doses of iron dextran 1000 mg/kg–1 by intraperitoneal injections (i.p.); and (iii) iron overload curcumin group that received six doses of curcumin (1000 mg/kg BW by i.p.).  In addition to six doses of iron dextran 1000 mg/kg–1 by i.p., we studied the effects of curcumin on liver function enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]); antioxidant enzymes (malondialdehyde [MDA], total oxidant status [TOS], total antioxidant status [TAS]); hematological parameters (hemoglobin [Hb], hematocrit [Hct], red blood cells [RBC], white blood cells [WBC], mean corpus volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC]); and iron parameters (serum iron profile, transferrin, total iron-binding capacity [TIBC], ferritin, and transferrin saturation [TS%]). Results: Curcumin caused a significant decrease in the Hct and Hb concentrations in Group III (P < 0.05). It also significantly reduced the serum levels of ALT (52.45 ± 4.51 vs 89.58 ± 4.65 U/L) and AST (148.03 ± 6.47 vs 265.27 ± 13.02 U/L) at the end of the study (P < 0.05). The TIBC, transferrin levels, and TS significantly decreased when the rats were administered curcumin serum iron (P < 0.05). The TAS level significantly increased in Group III in comparison to Group I (the control group) (P < 0.05). At the end of the study, curcumin significantly reduced the serum levels of TOS (12.03 ± 2.8 vs 16.95 ± 5.05 mmol H2O2/L) while the TAS (1.98 ± 0.42 vs 1.06 ± 0.33 mmol Trolox equiv./L) was increased. Conclusion: The findings of the present study suggest the therapeutic potential of curcumin against iron overload

Addressing the innovation gap: Lessons from the Stairway to Excellence (S2E) project

There is a considerable territorial disparity in terms of research and innovation (R&I) performance within Europe between EU15 and EU13 Member States (MSs) . The two biggest European funds, European Structural and Investment Funds (ESIF) and Horizon 2020 (H2020), aim at supporting the development of European competitiveness, growth, knowledge generation and as well as closing the innovation gap and promoting research excellence across Europe. Smart Specialisation Strategies (S3) play a key role in fostering an efficient and inclusive Research and Innovation (R&I) ecosystem by creating the right framework for focused investments based on selected high value added priorities and a shared vision of territorial development. Also, the European Commission's project Stairway to Excellence (S2E) is focussed on the provision of assistance to EU MSs and Regions with emphasis on promoting R&I excellence and maximising the specific value added of S3 investments such as the capacity building to support for R&I activities and exploitation of research results for raising the overall social/economic impact. This report summarises the main outcomes of the activities undertaken by the S2E team during the initial phase of the project from June 2014 to January 2017). It focuses on the S2E Country Reports – produced by the national independent experts and provided analysis on the optimal use of key European R&I funds – and the Joint Statements of S2E National Events – an outcome of national events covering the issues and main conclusions - as well as the other analytical work of the project. By picking those issues and actions common to more than one country and frequently mentioned, the main bottlenecks and possible policy actions to address these issues are summarised within three dimensions; namely, quality of R&I governance, capacity building, and innovation and commercialisation. This analysis and particularly the policy recommendations offer solutions for these issues that can also contribute to closing the innovation gap in Europe, which is demonstrated by the annual European Innovation Scoreboard comparing the performance of the EU MSs.JRC.B.3-Territorial Developmen

Designing heterogeneous porous tissue scaffolds for additive manufacturing processes

A novel tissue scaffold design technique has been proposed with controllable heterogeneous architecture design suitable for additive manufacturing processes. The proposed layer-based design uses a bi-layer pattern of radial and spiral layers consecutively to generate functionally gradient porosity, which follows the geometry of the scaffold. The proposed approach constructs the medial region from the medial axis of each corresponding layer, which represents the geometric internal feature or the spine. The radial layers of the scaffold are then generated by connecting the boundaries of the medial region and the layer's outer contour. To avoid the twisting of the internal channels, reorientation and relaxation techniques are introduced to establish the point matching of ruling lines. An optimization algorithm is developed to construct sub-regions from these ruling lines. Gradient porosity is changed between the medial region and the layer's outer contour. Iso-porosity regions are determined by dividing the subregions peripherally into pore cells and consecutive iso-porosity curves are generated using the isopoints from those pore cells. The combination of consecutive layers generates the pore cells with desired pore sizes. To ensure the fabrication of the designed scaffolds, the generated contours are optimized for a continuous, interconnected, and smooth deposition path-planning. A continuous zig-zag pattern deposition path crossing through the medial region is used for the initial layer and a biarc fitted isoporosity curve is generated for the consecutive layer with C-1 continuity. The proposed methodologies can generate the structure with gradient (linear or non-linear), variational or constant porosity that can provide localized control of variational porosity along the scaffold architecture. The designed porous structures can be fabricated using additive manufacturing processes

Optimized normal and distance matching for heterogeneous object modeling

This paper presents a new optimization methodology of material blending for heterogeneous object modeling by matching the material governing features for designing a heterogeneous object. The proposed method establishes point-to-point correspondence represented by a set of connecting lines between two material directrices. To blend the material features between the directrices, a heuristic optimization method developed with the objective is to maximize the sum of the inner products of the unit normals at the end points of the connecting lines and minimize the sum of the lengths of connecting lines. The geometric features with material information are matched to generate non-self-intersecting and non-twisted connecting surfaces. By subdividing the connecting lines into equal number of segments, a series of intermediate piecewise curves are generated to represent the material metamorphosis between the governing material features. Alternatively, a dynamic programming approach developed in our earlier work is presented for comparison purposes. Result and computational efficiency of the proposed heuristic method is also compared with earlier techniques in the literature. Computer interface implementation and illustrative examples are also presented in this paper

Modeling of multifunctional porous tissue scaffolds with continuous deposition path plan

A novel modeling technique for porous tissue scaffolds with targeting the functionally gradient variational porosity with continuous material deposition planning has been proposed. To vary the porosity of the designed scaffold functionally, medial axis transformation is used. The medial axis of each layers of the scaffold is calculated and used as an internal feature. The medial axis is then used connected to the outer contour using an optimum matching. The desired pore size and hence the porosity have been achieved by discretizing the sub-regions along its peripheral direction based on the pore size while meeting the tissue scaffold design constraints. This would ensure the truly porous nature of the structure in every direction as well as controllable porosity with interconnected pores. Thus the desired controlled variational porosity along the scaffold architecture has been achieved with the combination of two geometrically oriented consecutive layers. A continuous, interconnected and optimized tool-path has been generated for successive layers for additive-manufacturing or solid free form fabrication process. The proposed methodology has been computationally implemented with illustrative examples. Furthermore, the designed example scaffolds with the desired pore size and porosity has been fabricated with an extrusion based bio-fabrication process