Novel Sol-Gel Synthesis Route for Ce- and V-Doped Ba0.85Ca0.15Ti0.9Zr0.1O3 Piezoceramics.

To meet the current demand for lead-free piezoelectric ceramics, a novel sol-gel synthesis route is presented for the preparation of Ba0.85Ca0.15Ti0.9Zr0.1O3 doped with cerium (Ce = 0, 0.01, and 0.02 mol%) and vanadium (V = 0, 0.3, and 0.4 mol%). X-ray diffraction patterns reveal the formation of a perovskite phase (space group P4mm) for all samples after calcination at 800 °C and sintering at 1250, 1350, and 1450 °C, where it is proposed that both dopants occupy the B site. Sintering studies show that V doping allows the sintering temperature to be reduced to at least 1250 °C. Undoped BCZT samples sintered at the same temperature show reduced functional properties compared to V-doped samples, i.e., d33 values increase by an order of magnitude with doping. The dissipation factor tan δ decreases with increasing sintering temperature for all doping concentrations, while the Curie temperature TC increases for all V-doped samples, reaching 120 °C for high-concentration co-doped samples. All results indicate that vanadium doping can facilitate the processing of BCZT at lower sintering temperatures without compromising performance while promoting thermal property stability.

Schwann Cells Do Not Promote Myogenic Differentiation in the EPI Loop Model.

In skeletal muscle tissue engineering, innervation and vascularization play an essential role in the establishment of functional skeletal muscle. For adequate three-dimensional assembly, biocompatible aligned nanofibers are beneficial as matrices for cell seeding. The aim of this study was to analyze the impact of Schwann cells (SC) on myoblast (Mb) and adipogenic mesenchymal stromal cell (ADSC) cocultures on poly-ɛ-caprolactone (PCL)-collagen I-nanofibers in vivo. Human Mb/ADSC cocultures, as well as Mb/ADSC/SC cocultures, were seeded onto PCL-collagen I-nanofiber scaffolds and implanted into the innervated arteriovenous loop model (EPI loop model) of immunodeficient rats for 4 weeks. Histological staining and gene expression were used to compare their capacity for vascularization, immunological response, myogenic differentiation, and innervation. After 4 weeks, both Mb/ADSC and Mb/ADSC/SC coculture systems showed similar amounts and distribution of vascularization, as well as immunological activity. Myogenic differentiation could be observed in both groups through histological staining (desmin, myosin heavy chain) and gene expression (MYOD, MYH3, ACTA1) without significant difference between groups. Expression of CHRNB and LAMB2 also implied neuromuscular junction formation. Our study suggests that the addition of SC did not significantly impact myogenesis and innervation in this model. The implanted motor nerve branch may have played a more significant role than the presence of SC.

Energy-Reduced Fabrication of Light-Frame Ceramic Honeycombs by Replication of Additive Manufactured Templates.

Ceramic components require very high energy consumption due to synthesis, shaping, and thermal treatment. However, this study suggests that combining the sol-gel process, replica technology, and stereolithography has the potential to produce highly complex geometries with energy savings in each process step. We fabricated light-frame honeycombs of Al2O3, Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT), and BaTiO3 (BT) using 3D-printed templates with varying structural angles between -30° and 30° and investigated their mechanical and piezoelectric properties. The Al2O3 honeycombs showed a maximum strength of approximately 6 MPa, while the BCZT and BaTiO3 honeycombs achieved a d33 above 180 pC/N. Additionally, the BCZT powder was prepared via a sol-gel process, and the impact of the calcination temperature on phase purity was analyzed. The results suggest that there is a large energy-saving potential for the synthesis of BCZT powder. Overall, this study provides valuable insights into the fabrication of complex ceramic structures with improved energy efficiency and enhancement of performance.

Improved Mechanical Amplification of Monolithic PZT and PZT Composite via Optimized Honeycomb Macrostructures.

Honeycomb-based, modular composites with a relative density of 0.3948 and a slenderness ratio Lges/t of 6.48 were fabricated on PZT building blocks connected with a PZT-filled phenyl silicone resin. The macro- and micro-structure, phase composition, and the interface between the two materials were analyzed by SEM and image analysis techniques. The mechanical in-plane strain response was determined with uniaxial compression tests and the transversal piezoelectric strain response was determined by applying an electric field. These deformations were analyzed by a 2D digital image correlation analysis to calculate the mechanical strain amplification of monolithic and composite PZT lattice structures. Compared to bulk PZT, the piezoelectric strain amplification in the Y-direction |aypiezo| was higher by a factor of 69 for the composite and by a factor of 12 for the monolithic cellular PZT lattice, when it was assumed that the ratio of the deformation of the bulk material to bulk material was 1. The mechanical amplification of the composite lattices increased up to 73 and that of the cellular PZT lattices decreased to 12. Special focus was given to the fracture behavior and the interface of the PZT/PZT-filled phenyl silicone resin interface.

Advanced Estimation of Compressive Strength and Fracture Behavior in Ceramic Honeycombs by Polarimetry Measurements of Similar Epoxy Resin Honeycombs.

Finding a non-destructive characterization method for cellular ceramics' compressive strength and fracture behavior has been a challenge for material scientists for years. However, for transparent materials, internal stresses can be determined by the non-destructive photoelastic measurements. We propose a novel approach to correlate the photoelastic stresses of polymer (epoxy resin) prototypes with the mechanical properties of ceramics (alumina). Regular and inverse epoxy honeycombs were 3D-printed via stereolithography with varying structure angles from -35° to 35°, with negative angles forming an auxetic and positive hexagonal lattice. Photoelastic measurements under mechanical loading revealed regions of excess stress, which directly corresponded to the initial fracture points of the ceramic honeycombs. These honeycombs were made by a combination of 3D printing and transfer molding from alumina. The photoelastic stress distribution was much more homogeneous for angles of a smaller magnitude, which led to highly increased compressive strengths of up to 446 ± 156 MPa at 0°. By adapting the geometric structural model from Gibson and Ashby, we showed that we could use a non-destructive technique to determine the compressive strength of alumina honeycombs from the median photoelastic stress measured on similar epoxy honeycomb structures.

Microsurgical Transplantation of Pedicled Muscles in an Isolation Chamber-A Novel Approach to Engineering Muscle Constructs via Perfusion-Decellularization.

Decellularized whole muscle constructs represent an ideal scaffold for muscle tissue engineering means as they retain the network and proteins of the extracellular matrix of skeletal muscle tissue. The presence of a vascular pedicle enables a more efficient perfusion-based decellularization protocol and allows for subsequent recellularization and transplantation of the muscle construct in vivo. The goal of this study was to create a baseline for transplantation of decellularized whole muscle constructs by establishing an animal model for investigating a complete native muscle isolated on its pedicle in terms of vascularization and functionality. The left medial gastrocnemius muscles of 5 male Lewis rats were prepared and raised from their beds for in situ muscle stimulation. The stimulation protocol included twitches, tetanic stimulation, fatigue testing, and stretching of the muscles. Peak force, maximum rate of contraction and relaxation, time to maximum contraction and relaxation, and maximum contraction and relaxation rate were determined. Afterwards, muscles were explanted and transplanted heterotopically in syngeneic rats in an isolation chamber by microvascular anastomosis. After 2 weeks, transplanted gastrocnemius muscles were exposed and stimulated again followed by intravascular perfusion with a contrast agent for µCT analysis. Muscle constructs were then paraffin embedded for immunohistological staining. Peak twitch and tetanic force values all decreased significantly after muscle transplantation while fatigue index and passive stretch properties did not differ between the two groups. Vascular analysis revealed retained perfused vessels most of which were in a smaller radius range of up to 20 µm and 45 µm. In this study, a novel rat model of heterotopic microvascular muscle transplantation in an isolation chamber was established. With the assessment of in situ muscle contraction properties as well as vessel distribution after 2 weeks of transplantation, this model serves as a base for future studies including the transplantation of perfusion-decellularized muscle constructs.

Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.

Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2.

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.

Enhanced vascularization andde novotissue formation in hydrogels made of engineered RGD-tagged spider silk proteins in the arteriovenous loop model.

Due to its low immunogenic potential and the possibility to fine-tune their properties, materials made of recombinant engineered spider silks are promising candidates for tissue engineering applications. However, vascularization of silk-based scaffolds is one critical step for the generation of bioartificial tissues and consequently for clinical application. To circumvent insufficient vascularization, the surgically induced angiogenesis by means of arteriovenous loops (AVL) represents a highly effective methodology. Here, previously established hydrogels consisting of nano-fibrillary recombinant eADF4(C16) were transferred into Teflon isolation chambers and vascularized in the rat AVL model over 4 weeks. To improve vascularization, also RGD-tagged eADF4(C16) hydrogels were implanted in the AVL model over 2 and 4 weeks. Thereafter, the specimen were explanted and analyzed using histology and microcomputed tomography. We were able to confirm biocompatibility and tissue formation over time. Functionalizing eADF4(C16) with RGD-motifs improved hydrogel stability and enhanced vascularization even outperforming other hydrogels, such as fibrin. This study demonstrates that the scaffold ultrastructure as well as biofunctionalization with RGD-motifs are powerful tools to optimize silk-based biomaterials for tissue engineering applications.

Open-Cellular Alumina Foams with Hierarchical Strut Porosity by Ice Templating: A Thickening Agent Study.

Alumina replica foams were manufactured by the Schwartzwalder sponge replication technique and were provided with an additional strut porosity by a freeze-drying/ice-templating step prior to thermal processing. A variety of thickeners in combination with different alumina solid loads in the dispersion used for polyurethane foam template coating were studied. An additional strut porosity as generated by freeze-drying was found to be in the order of ~20%, and the spacings between the strut pores generated by ice-templating were in the range between 20 µm and 32 µm. In spite of the lamellar strut pore structure and a total porosity exceeding 90%, the compressive strength was found to be up to 1.3 MPa. Combining the replica process with freeze-drying proves to be a suitable method to enhance foams with respect to their surface area accessible for active coatings while preserving the advantageous flow properties of the cellular structure. A two-to-threefold object surface-to-object volume ratio of 55 to 77 mm-1 was achieved for samples with 30 vol% solid load compared to 26 mm-1 for non-freeze-dried samples. The freeze-drying technique allows the control of the proportion and properties of the introduced pores in an uncomplicated and predictable way by adjusting the process parameters. Nevertheless, the present article demonstrates that a suitable thickener in the dispersion used for the Schwartzwalder process is inevitable to obtain ceramic foams with sufficient mechanical strength due to the necessarily increased water content of the ceramic dispersion used for foam manufacturing.

Human Umbilical Vein Endothelial Cell Support Bone Formation of Adipose-Derived Stem Cell-Loaded and 3D-Printed Osteogenic Matrices in the Arteriovenous Loop Model.

Introduction: For the regeneration of large volume tissue defects, the interaction between angiogenesis and osteogenesis is a crucial prerequisite. The surgically induced angiogenesis by means of an arteriovenous loop (AVL), is a powerful methodology to enhance vascularization of osteogenic matrices. Moreover, the AVL increases oxygen and nutrition supply, thereby supporting cell survival as well as tissue formation. Adipose-derived stem cells (ADSCs) are interesting cell sources because of their simple isolation, expansion, and their osteogenic potential. This study targets to investigate the coimplantation of human ADSCs after osteogenic differentiation and human umbilical vein endothelial cells (HUVECs), embedded in a vascularized osteogenic matrix of hydroxyapatite (HAp) ceramic for bone tissue engineering. Materials and Methods: An osteogenic matrix consisting of HAp granules and fibrin has been vascularized by means of an AVL. Trials in experimental groups of four settings were performed. Control experiments without any cells (A) and three cell-loaded groups using HUVECs (B), ADSCs (C), as well as the combination of ADSCs and HUVECs (D) were performed. The scaffolds were implanted in a porous titanium chamber, fixed subcutaneously in the hind leg of immunodeficient Rowett Nude rats and explanted after 6 weeks. Results: In all groups, the osteogenic matrix was strongly vascularized. Moreover, remodeling processes and bone formation in the cell-containing groups with more bone in the coimplantation group were proved successful. Conclusion: Vascularization and bone formation of osteogenic matrices consisting of ADSCs and HUVECs in the rat AVL model could be demonstrated successfully for the first time. Hence, the coimplantation of differentiated ADSCs with HUVECs may therefore be considered as a promising approach for bone tissue engineering.

Hierarchical Surface Texturing of Hydroxyapatite Ceramics: Influence on the Adhesive Bonding Strength of Polymeric Polycaprolactone.

The tailored manipulation of ceramic surfaces gained recent interest to optimize the performance and lifetime of composite materials used as implants. In this work, a hierarchical surface texturing of hydroxyapatite (HAp) ceramics was developed to improve the poor adhesive bonding strength in hydroxyapatite and polycaprolactone (HAp/PCL) composites. Four different types of periodic surface morphologies (grooves, cylindric pits, linear waves and Gaussian hills) were realized by a ceramic micro-transfer molding technique in the submillimeter range. A subsequent surface roughening and functionalization on a micron to nanometer scale was obtained by two different etchings with hydrochloric and tartaric acid. An ensuing silane coupling with 3-aminopropyltriethoxysilane (APTES) enhanced the chemical adhesion between the HAp surface and PCL on the nanometer scale by the formation of dipole-dipole interactions and covalent bonds. The adhesive bonding strengths of the individual and combined surface texturings were investigated by performing single-lap compressive shear tests. All individual texturing types (macro, micro and nano) showed significantly improved HAp/PCL interface strengths compared to the non-textured HAp reference, based on an enhanced mechanical, physical and chemical adhesion. The independent effect mechanisms allow the deliberately hierarchical combination of all texturing types without negative influences. The hierarchical surface-textured HAp showed a 6.5 times higher adhesive bonding strength (7.7 ± 1.5 MPa) than the non-textured reference, proving that surface texturing is an attractive method to optimize the component adhesion in composites for potential medical implants.

Injection Molding of 3-3 Hydroxyapatite Composites.

The manufacturing of ideal implants requires fabrication processes enabling an adjustment of the shape, porosity and pore sizes to the patient-specific defect. To meet these criteria novel porous hydroxyapatite (HAp) implants were manufactured by combining ceramic injection molding (CIM) with sacrificial templating. Varied amounts (Φ = 0-40 Vol%) of spherical pore formers with a size of 20 µm were added to a HAp-feedstock to generate well-defined porosities of 11.2-45.2 Vol% after thermal debinding and sintering. At pore former contents Φ ≥ 30 Vol% interconnected pore networks were formed. The investigated Young's modulus and flexural strength decreased with increasing pore former content from 97.3 to 29.1 GPa and 69.0 to 13.0 MPa, agreeing well with a fitted power-law approach. Additionally, interpenetrating HAp/polymer composites were manufactured by infiltrating and afterwards curing of an urethane dimethacrylate-based (UDMA) monomer solution into the porous HAp ceramic preforms. The obtained stiffness (32-46 GPa) and Vickers hardness (1.2-2.1 GPa) of the HAp/UDMA composites were comparable to natural dentin, enamel and other polymer infiltrated ceramic network (PICN) materials. The combination of CIM and sacrificial templating facilitates a near-net shape manufacturing of complex shaped bone and dental implants, whose properties can be directly tailored by the amount, shape and size of the pore formers.

Phase Evolution, Filler-Matrix Interactions, and Piezoelectric Properties in Lead Zirconate Titanate (PZT)-Filled Polymer-Derived Ceramics (PDCs).

PZT-silsesquioxane-based 0-3 hybrid materials are prepared by mixing lead zirconate titanate (Pb(Zr,Ti)O3; PZT) powder with a [R-SiO3/2]n (R = H, CH3, CH=CH2, C6H5) silsequioxane preceramic polymer. A PZT load up to 55 vol.% can be reached in the final composite. The piezoelectric and mechanical properties are investigated as a function of the filler content and are compared with theoretical models and reference samples made of the pure preceramic polymer or PZT filler. The piezoelectric response of the composites, as expressed by the relative permittivity and the piezoelectric coefficients d33 and g33, increases with an increasing PZT content. The bending strength of the composites ranges between 15 MPa and 31 MPa without a clear correlation to the filler content. The thermal conductivity increases significantly from 0.14 W∙m-1∙K-1 for the pure polymer-derived ceramic (PDC) matrix to 0.30 W∙m-1∙K-1 for a sample containing 55 vol.% PZT filler. From X-ray diffraction experiments (XRD), specific interactions between the filler and matrix are observed; the crystallization of the PDC matrix in the presence of the PZT filler is inhibited; conversely, the PDC matrix results in a pronounced decomposition of the filler compared to the pure PZT material.

Vegetable hierarchical structures as template for bone regeneration: New bio-ceramization process for the development of a bone scaffold applied to an experimental sheep model.

Long bone defects still represent a major clinical challenge in orthopedics, with the inherent loss of function considerably impairing the quality of life of the affected patients. Thus, the purpose of this study was to assess the safety and potential of bone regeneration offered by a load-bearing scaffold characterized by unique hierarchical architecture and high strength, with active surface facilitating new bone penetration and osseointegration in critical size bone defects. The results of this study showed the potential of bio-ceramization processes applied to vegetable hierarchical structures for the production of new wood-derived bone scaffolds, further improved by surface functionalization, with good biological and mechanical properties leading to successful treatment of critical size bone defects in the sheep model. Future studies are needed to evaluate if these scaffolds prototypes, as either biomaterial alone or in combination with augmentation strategies, may represent an optimal solution to enhance bone regeneration in humans.

Intrinsic Vascularization of Recombinant eADF4(C16) Spider Silk Matrices in the Arteriovenous Loop Model.

The surgically induced angiogenesis by means of arteriovenous (AV) loops represents a powerful method to significantly enhance vascularization of biomaterials. Regarding tissue engineering applications, spider silk is a promising biomaterial with a good biocompatibility and slow biodegradation. This study aims at investigating vascularization as well as de novo tissue formation of fibrous matrices made of electro-spun (ES) or wet-spun (WS) engineered ADF4(C16) spider silks in the rat AV loop model. Either ES or WS spider silk fibrous matrices were filled into Teflon chambers. Intrinsic vascularization was induced by means of an AV loop. After 4 weeks of vascularization, de novo tissue formation and biocompatibility were analyzed. Regardless of their significantly differing fiber diameters, both ES and WS eADF4(C16) fiber matrices displayed a good biocompatibility and initiated de novo tissue formation as well as vessel formation. Both matrices demonstrated partial vascularization originating from the AV loop, with more vessels in spider silk matrices with lower fiber diameters. We were able to demonstrate intrinsic vascularization of spider silk fibrous matrices by means of the AV loop. Moreover, our study indicates that the adjustment of the fiber diameter of engineered spider silks enables new possibilities to optimize vascularization. Impact Statement Spider silk is a promising biomaterial demonstrating excellent biocompatibility and biodegradation. Biotechnology allows the high-volume production of recombinant spider silk proteins, such as eADF4(C16), with the required purity for biomedical applications. In this study, eADF4(C16) fibrous matrices were produced by either electro- or wet-spinning, resulting in different fiber diameters. Forming an arteriovenous fistula, surgical vascularization of the scaffolds was induced. After 4 weeks, both silks demonstrated a good biocompatibility and tissue formation. The thinner electro-spun fibers displayed a faster biodegradation and vascularization, indicating that the adjustment of the fiber diameter is a valuable tool to fine-tune vascularization and biodegradation.

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.

Encapsulation of Mesenchymal Stem Cells Improves Vascularization of Alginate-Based Scaffolds.

Vascularization of bioartificial tissues can be significantly enhanced by the generation of an arteriovenous (AV) loop. Besides the surgical vascularization, the choice of the scaffold and the applied cells are indispensable cofactors. The combination of alginate dialdehyde and gelatin (ADA-GEL) and mesenchymal stem cells (MSCs) is a promising approach with regard to biocompatibility, biodegradation, as well as de novo tissue formation. In this study, we targeted the investigation of the vascularization of ADA-GEL with and in the absence of encapsulated MSCs in the AV loop model. A Teflon chamber filled with ADA-GEL microcapsules was placed in the groin of Lewis rats and an AV loop was placed into the chamber. Group A encompassed the ADA-GEL without MSCs, whereas group B contained 2 × 106 DiI-labeled MSCs/mL ADA-GEL. Four weeks postoperatively, tissue formation and vascularization were investigated by histology and microcomputed tomography. We were able to prove vascularization originating from the AV loop in both groups with statistically significant more vessels in group B containing MSCs. Moreover, encapsulated MSCs promoted biodegradation of the ADA-GEL microcapsules. In the present study, we were able to demonstrate for the first time, the successful vascularization of ADA-GEL microcapsules by means of the AV loop. Furthermore, ADA-GEL displayed a good biocompatibility and encapsulation of MSCs into ADA-GEL microcapsule-enhanced vascularization as well as biodegradation.

Dextran-coated superparamagnetic iron oxide nanoparticles for magnetic resonance imaging: evaluation of size-dependent imaging properties, storage stability and safety.

BACKGROUND: Rising criticism of currently available contrast agents for magnetic resonance imaging, either due to their side effects or limited possibilities in terms of functional imaging, evoked the need for safer and more versatile agents. We previously demonstrated the suitability of novel dextran-coated superparamagnetic iron oxide nanoparticles (SPIONDex) for biomedical applications in terms of safety and biocompatibility. METHODS: In the present study, we investigated the size-dependent cross-linking process of these particles as well as the size dependency of their imaging properties. For the latter purpose, we adopted a simple and easy-to-perform experiment to estimate the relaxivity of the particles. Furthermore, we performed an extensive analysis of the particles' storage stability under different temperature conditions, showing their superb stability and the lack of any signs of agglomeration or sedimentation during a 12 week period. RESULTS: Independent of their size, SPIONDex displayed no irritation potential in a chick chorioallantoic membrane assay. Cell uptake studies of ultra-small (30 nm) SPIONDex confirmed their internalization by macrophages, but not by non-phagocytic cells. Additionally, complement activation-related pseudoallergy (CARPA) experiments in pigs treated with ultra-small SPIONDex indicated the absence of hypersensitivity reactions. CONCLUSION: These results emphasize the exceptional safety of SPIONDex, setting them apart from the existing SPION-based contrast agents and making them a very promising candidate for further clinical development.