Unsere Publikationen

The first workshop on the “latest advances in biomedical applications of octacalcium phosphate (OCP)” was or­ganized as a satellite symposium to the Bioceramics33 conference in Solothurn, Switzerland, in October 2023. The event brought together leading researchers and industry representatives to present and discuss their latest ground­breaking research aimed at developing and com­mer­cial­izing advanced OCP-based bio­materials for bone regen­er­a­tion. The topics presented by the six invited speakers ranged from a fundamental understanding of the OCP crystal chemistry to advanced processing and characterization methods, functionalization, bio­mineralization, and com­mer­cial­ization. With this summary report, we are laying the foundation for a continuation of a series of work­shops on the subject of OCP bio­materials in order to promote the exchange between researchers and industry re­pre­sen­tatives and to drive forward the development and com­mer­cial­ization of new improved synthetic bone substitute materials.

Aims
Highly cross-linked polyethylene (HXLPE) greatly reduces wear in total hip arthroplasty, compared to conventional polyethylene (CPE). Cross-linking is commonly achieved by irradiation. This study aimed to compare the degree of cross-linking and in vitro wear rates across a cohort of retrieved and unused polyethylene cups/liners from various brands.

Methods
Polyethylene acetabular cups/liners were collected at one centre from 1 April 2021 to 30 April 2022. The trans-vinylene index (TVI) and oxidation index (OI) were determined by Fourier-transform infrared spectrometry. Wear was measured using a pin-on-disk test.

Results
A total of 47 specimens from ten brands were included. The TVI was independent of time in vivo. A linear correlation (R² = 0.995) was observed between the old and current TVI standards, except for vitamin E-containing polyethylene. The absorbed irradiation dose calculated from the TVI corresponded to product specifications for all but two products. For one electron beam-irradiated HXLPE, a mean dose of 241% (SD 18%) of specifications was determined. For another, gamma-irradiated HXLPE, a mean 41% (SD 13%) of specifications was determined. Lower wear was observed for higher TVI.

Conclusion
The TVI is a reliable measure of the absorbed irradiation dose and does not alter over time in vivo. The products of various brands differ by manufacturing details and consequently cross-linking characteristics. Absorption and penetration of electron radiation and gamma radiation differ, potentially leading to higher degrees of cross-linking for electron radiation. There is a non-linear, inverse correlation between TVI and in vitro wear. The wear resistance of the HXLPE with low TVI was reduced and more comparable to CPE.

α-tricalcium phosphate (α-TCP) is the most widespread raw material for hydraulic calcium phosphate cements (CPCs). CPCs are widely used in bone repair due to their injectability, setting ability, and osteoconductivity. This study investigated the reactivity of α-TCP powders, focusing on the impact of minor phase impurities, β-calcium pyrophosphate and hydroxyapatite, and the synthesis temperature. The α-TCP powders were synthesized via a solid-state reaction of calcium carbonate and anhydrous dicalcium phosphate, with varying Ca/P molar ratios (1.4850–1.5075) and synthesis temperatures (1175°C–1350 °C). Powders produced with a Ca/P molar ratio below 1.50 and synthesized at a temperature above the melting point of β-CPP (1296 °C) had a broader size distribution and a two to fourfold lower hydraulic reactivity. Conversely, a higher Ca/P molar ratio improved reactivity. The study underscores the importance of precise control over synthesis parameters to enhance the performance of α-TCP-based CPCs, offering insights for optimizing material design in biomedical applications.

Silicon isotope fractionation during silicification is poorly understood and impedes our ability to decipher paleoenvironmental conditions from Si isotopes in ancient cherts. To investigate isotope fractionation during silica-for‑carbonate replacement we analyzed the microscale Si and O isotope composition in different silica phases in a silicified zebra dolostone as well as their bulk δ¹⁸O and Δ’¹⁷O compositions. The subsequent replacement of carbonate layers is mimicked by decreasing δ¹⁸O and δ³⁰Si. The textural relationship and magnitude of Si and O isotope fractionation is best explained by near-quantitative silica precipitation in an open system with finite Si. A Rayleigh model for silicification suggests positive Ɛ^30/28Si during silicification, conforming with predictions for isotope distribution at chemical equilibrium from ab-initio models. Application of the modelled Ɛ³⁰Si-T relationship yields silicification temperatures of approx. 50 ^◦C. To reconcile the δ¹⁸O_chert composition with these temperatures, the δ¹⁸O of the fluid must have been between − 2.5 and − 4 ‰, compositions for which the quartz phases fall close to the oxygen equilibrium fractionation line in three-isotope space. Diagenetic silica replacement appears to occur in O and Si isotopic equilibrium allowing reconstructions of temperatures of silicification from Si isotopes and derive the δ¹⁸O composition of the fluid – a highly desired value needed for accurate reconstructions of the temperature- and δ¹⁸O histories of the oceans.

Biophotonic nanostructures rarely withstand fossilization processes occurring after burial over geologic time. Even more distinctive is a change introduced to the optical properties during diagenetic processes resulting in a different optical appearance. Here, we report and explain the optical appearance of centric diatom frustules obtained from ash-bearing carbonatecemented concretions on the Greifswalder Oie island (Pomeranian Bay, Germany, southern Baltic Sea). The ultrastructural and mineralogical analysis of the fossil frustules were carried out using electron microscopy techniques and were correlated to the macroscopic and microscopic optical appearance of the frustules before and after acid etching. The unique optical properties of the fossil diatoms were associated with diagenetic nanocrystalline calcite filling the frustules’ areolae. This fill created the macroscopic pale-yellow colour of many frustules, a microscopic iridescence probably associated with diffraction grating behaviour, and microscopic colour rings. The results highlight the unique permineralization process of diatom frustules and might be an addition to the emerging studies on frustule optics and photonics.

Calcium phosphate (CaP) biomaterials are amongst the most widely used synthetic bone graft substitutes, owing to their chemical similarities to the mineral part of bone matrix and off-the-shelf availability. However, their ability to regenerate bone in critical-sized bone defects has remained inferior to the gold standard autologous bone. Hence, there is a need for methods that can be employed to efficiently produce CaPs with different properties, enabling the screening and consequent fine-tuning of the properties of CaPs towards effective bone regeneration. To this end, we propose the use of droplet microfluidics for rapid production of a variety of CaP microparticles. Particularly, this study aims to optimize the steps of a droplet microfluidic-based production process, including droplet generation, in-droplet CaP synthesis, purification and sintering, in order to obtain a library of CaP microparticles with fine-tuned properties. The results showed that size-controlled, monodisperse water-in-oil microdroplets containing calcium- and phosphate-rich solutions can be produced using a flow-focusing droplet-generator microfluidic chip. We optimized synthesis protocols based on in-droplet mineralization to obtain a range of CaP microparticles without and with inorganic additives. This was achieved by adjusting synthesis parameters, such as precursor concentration, pH value, and aging time, and applying heat treatment. In addition, our results indicated that the synthesis and fabrication parameters of CaPs in this method can alter the microstructure and the degradation behavior of CaPs. Overall, the results highlight the potential of the droplet microfluidic platform for engineering CaP microparticle biomaterials with fine-tuned properties.

Dense and polished samples are sometimes used to test the in vitro biological response of biomaterials. However, their production can be challenging, for example for α-tricalcium phosphate (α-TCP), a commonly-used bone graft substitute. In this particular case, the ideal sintering conditions are in a temperature range close to the β-α-TCP phase transition (1125 °C). This phase transition is characterized by a 7 % volume increase which typically leads to the formation of cracks. Additionally, the production of a powder suitable for ceramic processing is difficult because α-TCP can only be produced via a thermal process. The initial aim of this study was to produce dense and polished α-TCP samples using an innovative method to produce nano-crystalline α-TCP. However, after observing the formation of β-TCP phase above the β-α-TCP phase transition (1125 °C), the focus of this study was shifted towards this unexpected phenomenon. Specifically, uniaxially compressed bulk samples were sintered at between 1160 and 1240 °C for different durations up to one week. The resulting density reached up to 95 % and was positively associated with green body density and sintering time, while being initially highest when sintered at the lowest temperature. A transient appearance of up to 6 wt% β-TCP was observed during sintering. The higher the sintering temperature was, the shorter and the smaller this transient appearance was. This behavior was attributed to the intrinsic pressure occurring within the material during sintering and which favoured the denser β-TCP phase.

Introduction: β-TCP ceramics are bone replacement materials that have recently been tested as a drug delivery system that can potentially be applied to endogenous substances like growth factors found in blood platelets to facilitate positive attributes.

Methods: In this work, we used flow chamber loading to load β-TCP dowels with blood suspensions of platelet-rich plasma (PRP), platelet-poor plasma (PPP), or buffy coat (BC) character. PRP and BC platelet counts were adjusted to the same level by dilution. Concentrations of TGF-β1, PDGF-AB, and IGF-1 from dowel-surrounding culture medium were subsequently determined using ELISA over 5 days. The influence of alginate was additionally tested to modify the release.

Results: Concentrations of TGF-β1 and PDGF-AB increased and conclusively showed a release from platelets in PRP and BC compared to PPP. The alginate coating reduced the PDGF-AB release but did not reduce TGF-β1 and instead even increased TGF-β1 in the BC samples. IGF-1 concentrations were highest in PPP, suggesting circulating levels rather than platelet release as the driving factor. Alginate samples tended to have lower IGF-1 concentrations, but the difference was not shown to be significant.

Discussion: The release of growth factors from different blood suspensions was successfully demonstrated for β-TCP as a drug delivery system with release patterns that correspond to PRP activation after Ca²⁺-triggered activation. The release pattern was partially modified by alginate coating.

Fluorescence analysis of β-TCP ceramics is often used to describe cells found on said ceramics. However, we found, to our knowledge, so far undescribed artifacts which might sometimes be hard to differentiate from cells due to shape and fluorescence behavior. We tried prolonged ultrasound washing as well as Technovit 9100 fixation to reduce these artifacts. While untreated dowels showed no reduction in artifacts no matter the further treatment, Technovit fixation reduced the artifacts with even further reduction achieved by mechanical cleaning. As a consequence, scientists working with these dowels and likely even other types should try to avoid creating false positive results by considering the existence of these artifacts, checking additional filters for unusual fluorescence and by reducing them by using Technovit fixation when possible.

β-TCP ceramics are versatile bone substitute materials and show many interactions with cells of the monocyte-macrophage-lineage. The possibility of monocytes entering microporous β-TCP ceramics has however not yet been researched. In this study, we used a model approach to investigate whether monocytes might enter β-TCP, providing a possible explanation for the origin of CD68-positive osteoclast-like giant cells found in earlier works.
We used flow chambers to unidirectionally load BC, PRP, or PPP into slice models of either 2 mm or 6 mm β-TCP. Immunofluorescence for CD68 and live/dead staining was performed after the loading process.
Our results show that monocytes were present in a relevant number of PRP and BC slices representing the inside of our 2 mm slice model and also present on the actual inside of our 6 mm model. For PPP, monocytes were not found beyond the surface in either model.
Our results indicate the possibility of a new and so far neglected constituent in β-TCP degradation, perhaps causing the process of ceramic degradation also starting from inside the ceramics as opposed to the current understanding. We also demonstrated flow chambers as a possible new in vitro model for interactions between blood and β-TCP.

The biocompatibility and resorption characteristics of β-tricalcium phosphate (β-TCP, Ca₃(PO₄)₂) have made it a coveted alternative for bone grafts. However, the underlying mechanisms governing the biological interactions between β-tricalcium phosphate and osteoclasts remain elusive. It has been speculated that the composition at grain boundaries might vary and affect β-TCP resorption properties. Atom probe tomography (APT) offers a quantitative approach to assess the composition of the grain boundaries, and thus advance our comprehension of the biological responses within the microstructure and chemical composition at the nanoscale. The precise quantitative analysis of chemical composition remains a notable challenge in atom probe tomography, primarily due to the influence of measurement conditions on compositional accuracy. In this study, we investigated the impact of laser pulse energy on the composition of β-TCP using atom probe tomography, aiming for the most precise Ca:P ratio and consistent results across multiple analyses performed with different sets of analysis conditions and on two different instruments.

Ein dauerhafter Verbleib von Implantaten im Körper kann zu Komplikationen führen. So werden Implantate zur Behandlung von Knochenbrüchen nach erfolgter Heilung oftmals wieder entnommen. Diese Entnahme bedingt eine Zweitoperation, die wiederum Risiken mit sich bringt. Im Gegen­satz zu inerten Implantaten aus Titan oder rost­freiem Stahl degradiert metallisches Magnesium im Körper. Idealerweise stützt das biodegradierbare Magnesium-implantat das betroffene Gewebe bis zur Heilung und baut sich anschliessend ohne Nebenwirkungen ab.
Beim Kontakt mit Körperflüssigkeit setzt eine unbeschichtete, nicht passivierte Magnesium­ober­fläche Wasser­stoffgas frei. Durch eine geeignete Beschichtung lässt sich die anfängliche Gasfrei­setzung und Degradation verzögern.

Objectives
Administration of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging results in the long-term retention of gadolinium (Gd) in tissues and organs, including the bone, and may affect their function and metabolism. This study aims to investigate the effects of Gd and GBCA on the proliferation/survival, differentiation, and function of bone cell lineages.

Materials and Methods
Primary murine osteoblasts (OB) and osteoclast progenitor cells (OPC) isolated from C57BL/6J mice were used to test the effects of Gd³⁺ (12.5–100 μM) and GBCA (100–2000 μM). Cultures were supplemented with the nonionic linear Gd-DTPA-BMA (gadodiamide), ionic linear Gd-DTPA (gadopentetic acid), and macrocyclic Gd-DOTA (gadoteric acid). Cell viability and differentiation were analyzed on days 4–6 of the culture. To assess the resorptive activity of osteoclasts, the cells were grown in OPC cultures and were seeded onto layers of amorphous calcium phosphate with incorporated Gd.

Results
Gd³⁺ did not affect OB viability, but differentiation was reduced dose-dependently up to 72.4% ± 6.2%–73.0% ± 13.2% (average ± SD) at 100 μM Gd³⁺ on days 4–6 of culture as compared with unexposed controls (P < 0.001). Exposure to GBCA had minor effects on OB viability with a dose-dependent reduction up to 23.3% ± 10.2% for Gd-DTPA-BMA at 2000 μM on day 5 (P < 0.001). In contrast, all 3 GBCA caused a dose-dependent reduction of differentiation up to 88.3% ± 5.2% for Gd-DTPA-BMA, 49.8% ± 16.0% for Gd-DTPA, and 23.1% ± 8.7% for Gd-DOTA at 2000 μM on day 5 (P < 0.001). In cultures of OPC, cell viability was not affected by Gd³⁺, whereas differentiation was decreased by 45.3% ± 9.8%–48.5% ± 15.8% at 100 μM Gd³⁺ on days 4–6 (P < 0.05). Exposure of OPC to GBCA resulted in a dose-dependent increase in cell viability of up to 34.1% ± 11.4% at 2000 μM on day 5 of culture (P < 0.001). However, differentiation of OPC cultures was reduced on day 5 by 24.2% ± 9.4% for Gd-DTPA-BMA, 47.1% ± 14.0% for Gd-DTPA, and 38.2% ± 10.0% for Gd-DOTA (P < 0.001). The dissolution of amorphous calcium phosphate by mature osteoclasts was reduced by 36.3% ± 5.3% upon incorporation of 4.3% Gd/Ca wt/wt (P < 0.001).

Conclusions
Gadolinium and GBCA inhibit differentiation and activity of bone cell lineages in vitro. Thus, Gd retention in bone tissue could potentially impair the physiological regulation of bone turnover on a cellular level, leading to pathological changes in bone metabolism.

Human joint prostheses experience wear failure due to the complex interactions between Ultra-High-Molecular-Weight Polyethylene (UHMWPE) and Cobalt-Chromium-Molybdenum (CoCrMo). This study uses the wear classification to investigate the gradual and progressive abrasive wear mechanisms in UHMWPE. Pin-on-disc tests were conducted under simulated in vivo conditions, monitoring wear using Acoustic Emission (AE). Two Machine Learning (ML) frameworks were employed for wear classification: manual feature extraction with ML classifiers and a contrastive learning-based Convolutional Neural Network (CNN) with ML classifiers. The CNN-based feature extraction approach achieved superior classification performance (94% to 96%) compared to manual feature extraction (81% to 89%). The ML techniques enable accurate wear classification, aiding in understanding surface states and early failure detection. Real-time monitoring using AE sensors shows promise for interventions and improving prosthetic joint design.

Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in bone formation through a process called coupling, it is hypothesized that extended treatment protocols may impair bone healing. In this study, β-tri‑calcium-phosphate (βTCP) ceramics were inserted into critical-size long bone defects in estrogen-deficient mice under BP therapy. The study assessed the benefits of coating the ceramics with Bone Morphogenetic Protein-2 (BMP2) and an engineered BMP2 analogue (L51P) that inactivates BMP antagonists on the healing process, implant resorption, and bone formation.
Female NMRI mice (11–12 weeks of age) were ovariectomized (OVX) or sham operated. Eight weeks later, after the manifestation of ovariectomy-induced osteoporotic bone changes, BP therapy with Alendronate (ALN) was commenced. After another five weeks, a femoral critical-size defect was generated, rigidly fixed, and βTCP-cylinders loaded with 0.25 μg or 2.5 μg BMP2, 2.5 μg L51P, and 0.25 μg BMP2/2.5 μg L51P, respectively, were inserted. Unloaded βTCP-cylinders were used as controls. Femora were collected six and twelve weeks post-implantation.
Histological and micro-computer tomography (MicroCT) evaluation revealed that insertion of cylinders coated with 2.5 μg BMP2 accelerated fracture repair and induced significant bone formation compared to controls (unloaded cylinders or coated with 2.5 μg L51P, 0.25 μg BMP2) already six weeks post-implantation, independent of estrogen-deficiency and BP therapy. The simultaneous administration of BMP2 and L51P (0.25 μg BMP2/2.5 μg L51P) did not promote fracture healing six and twelve weeks post-implantation. Moreover, new bone formation within the critical-size defect was directly linked to the removal of the βTCP-implant in all experimental groups. No evidence was found that long-term therapy with ALN impaired the resorption of the implanted graft. However, osteoclast transcriptom signature was elevated in sham and OVX animals upon treatment with BP, with transcript levels being higher at six weeks than at twelve weeks post-surgery. Furthermore, the transcriptome profile of the developing repair tissue confirmed an accelerated repair process in animals treated with 2.5 μg BMP2 implants. L51P did not increase the bioefficacy of BMP2 in the applied defect model.
The present study provides evidence that continuous administration of BP does not inhibit implant resorption and does not alter the kinetics of the healing process of critical-size long bone defects. Furthermore, the BMP2 variant L51P did not enhance the bioefficacy of BMP2 when applied simultaneously to the femoral critical-size defect in sham and OVX mice.

The recognition and importance of immune cells during bone regeneration, including around bone biomaterials, has led to the development of an entire field termed “osteoimmunology,” which focuses on the connection and interplay between the skeletal system and immune cells. Most studies have focused on the “osteogenic” capacity of various types of bone biomaterials, and much less focus has been placed on immune cells despite being the first cell type in contact with implantable devices. Thus, the amount of literature generated to date on this topic makes it challenging to extract needed information. This review article serves as a guide highlighting advancements made in the field of osteo­immunology emphasizing the role of the osteoimmunomodulatory properties of biomaterials and their impact on osteoinduction. First, the various immune cell types involved in bone biomaterial integration are discussed, including the prominent role of osteal macrophages (OsteoMacs) during bone regeneration. Thereafter, key biomaterial properties, including topography, wettability, surface charge, and adsorption of cytokines, growth factors, ions, and other bioactive molecules, are discussed in terms of their impact on immune responses. These findings highlight and recognize the importance of the immune system and osteo­immunology, leading to a shift in the traditional models used to understand and evaluate biomaterials for bone regeneration.

One of the most widely used materials for bone graft substitution is β‐Tricalcium phosphate (β‐TCP; β-Ca₃(PO₄)₂). β-TCP is typically produced by sintering in air or vacuum. During this process, evaporation of phosphorus (P) species occurs, leading to the formation of a calcium-rich alkaline layer. It was recently shown that the evaporation of P species could be prevented by co-sintering β-TCP with dicalcium phosphate (DCPA; CaHPO₄; mineral name: monetite). The aim of this study was to see how a change of sintering atmosphere could affect the physico-chemical and biological properties of β-TCP. For this purpose, three experimental groups were considered: β‐TCP cylinders sintered in air and subsequently polished to remove the surface layer (control group); the same polished cylinders after subsequent annealing at 500 °C in air to generate a calcium-rich alkaline layer (annealed group); and finally, β‐TCP cylinders sintered in a monetite-rich atmosphere and subsequently polished (monetite group). XPS analysis confirmed that cylinders from the annealed group had a significantly higher Ca/P molar ratio at their surface than that of the control group while this ratio was significantly lower for the cylinders from the monetite group. Sintering β‐TCP in the monetite-rich atmosphere significantly reduced the grain size and increased the density. Changes of surface composition affected the activity of osteoclasts seeded onto the surfaces, since annealed β-TCP cylinders were significantly less resorbed than β-TCP cylinders sintered in the monetite-rich atmosphere. This suggests that an increase of the surface Ca/P molar ratio leads to a decrease of osteoclastic resorption.

Statement of Significance
Minimal changes of surface and bulk (< 1%) composition have major effects on the ability of osteoclasts to resorb β-tricalcium phosphate (β-TCP), one of the most widely used ceramics for bone substitution. The results presented in this study are thus important for the calcium phosphate community because (i) β-TCP may have up to 5% impurities according to ISO and ASTM standards and still be considered to be “pure β-TCP”, (ii) β-TCP surface properties are generally not considered during biocompatibility assessment and (iii) a rationale can be proposed to explain the various inconsistencies reported in the literature on the biological properties of β-TCP.

• Since the middle of the 20th century, total hip arthroplasty has become a very successful treatment for all end-stage diseases of the hip joint. Charnley solved with his low frictional torque arthroplasty the problem of wear and friction with the introduction of a new bearing couple and the reduction of the head size, which set the prerequisite for the further development of stem design.
• This narrative review presents the major developments of regular straight stems in hip arthroplasty. It does not only provide an overview of the history but also assembles the generally scarce documentation available regarding the rationale of developments and illustrates often-unsuspected links.
• Charnley's success is based on successfully solving the issue of fixation of the prosthetic components to the bone, using bone cement made of polymethyl-methacrylate. In the field of cemented anchorage of the stem, two principles showing good long-term revision rates emerged over the years: the force-closed and the shape-closed principles.
• The non-cemented anchorage bases on prosthesis models ensure enough primary stability for osteointegration of the implant to occur. For bone to grow onto the surface, not only sufficient primary stability is required but also a suitable surface structure together with a biocompatible prosthetic material is also necessary.

The aim of this study was to produce a composite of microporous β-TCP filled with alginate-gelatin crosslinked hydrogel, clindamycin and bone morphogenetic protein (BMP-2) to prolong the drug-release behaviour for up to 28 days. The most promising alginate-di-aldehyde(ADA)-gelatin gel for drug release from microcapsules was used to fill microporous β-TCP ceramics under directional flow in a special loading chamber. Dual release of clindamycin and BMP-2 was measured on days 1, 2, 3, 6, 9, 14, 21 and 28 by high performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA). After release, the microbial efficacy of the clindamycin was checked and the biocompatibility of the composite was tested in cell culture. Clindamycin and the model substance FITC-protein A were released from microcapsules over 28 days. The clindamycin burst release was 43 ± 1%. For the loaded ceramics, a clindamycin release above the minimal inhibitory concentration (MIC) until day 9 and a burst release of 90.56 ± 2.96% were detected. BMP-2 was released from the loaded ceramics in low concentrations over 28 days. The release of active substances from β-TCP and hydrogel have already been extensively studied. Directional flow loading is a special procedure in which the ceramic could act as a stabilizer in the bone and, as a biodegradable system, enables a single-stage surgical procedure. Whether ADA-gelatin gel is suitable for this procedure as a more biodegradable alternative to pure alginate or whether a dual release is possible in this composite has not yet been investigated.

The large variability of biological responses to β-TCP implants reported in the literature could possibly be related to subtle differences in the β-TCP crystal structure. The structure contains one partially occupied site Ca(4). In order to better understand the ordering of this site, 12 pairs of unit cells with different Ca(4) site occupancies were combined in different checkerboard patterns with an average occupancy of 3. Atomistic simulations were conducted to identify the lowest energy configurations. The previously published low energy configuration is not the most stable one when considering a larger supercell. Plotting the 662 simulation outputs by lattice parameters a or c versus relative lattice energy revealed clusters of high density which are composed of configurations with predominant motifs of Ca(4) occupancy. The tools introduced in this study can be applied in future simulation studies to better explain the Ca(4) site occupancy in the β-TCP crystal structure.

Background: There are no generally accepted guidelines for polyethylene (PE) glenoid component cementation techniques. In particular, it is not known whether the backside of a PE glenoid should be fully or partially cemented – or not cemented at all. We hypothesized that cementing techniques would have an impact on cement mantle volume and integrity, as well as biomechanical stability, measured as micromotion under cyclic loading.

Methods: To address our hypothesis, 3 different cementation techniques using a single 2-peg PE glenoid design with polyurethane foam were compared regarding (1) the quality and quantity of the cement mantle and (2) bio­mechanical stability after cyclic loading in vitro. Eight identically cemented glenoids per group were used. Group A underwent cement application only into the peg holes, group B received additional complete cement mantle application on the backside of the glenoid, and group C received the same treatment as group B but with additional standardized drill holes in the surface of the glenoid bone for extra cement interdigitation. All glenoids underwent cyclic edge loading by 10⁵ cycles according to ASTM F2028-14. Before and after loading, cement mantle evaluation was performed by XtremeCT and biomechanical strength and loosening were evaluated by measuring the relative motion of the implants.

Results: The cement mantle at the back of the implant was incomplete in group A as compared with groups B and C, in which the complete PE backside was covered with a homogeneous cement mantle. The cement mantle was thickest in group C, followed by group B (P = .006) and group A (P <.001). We did not detect any breakage of the cement mantle in any of the 3 groups after testing.

Organ-on-chip models, developed using microengineering and microfluidic technologies, aim to recreate physiological-like microenvironments of organs or tissues as a tool to study (patho)physiological processes in vitro. On-chip models of bone are relevant for the study of bone physiology, diseases and regenerative processes. While a few bone-on-a-chip models exist, recapitulating the cellular components of bone, these models do not incorporate the chemical and structural characteristics of bone tissue. Herein, the development of a bone-on-a-chip platform is reported that comprises a 3D structural model of bone. To build the platform, first, a 3D model of bone is produced in a polymer using two-photon polymerization (2PP) from a 3D nano-computed tomography scan of trabecular bone. This 3D model is then coated with a layer of bone mineral-like calcium phosphate. Finally, the 3D bone model is integrated inside a microfluidic device suitable for cell culture. Human mesenchymal stromal cells, cultured inside the platform for up to 21 days, show high viability and extensive production of extracellular matrix, rich in collagen. This biomimetic bone-on-a-chip platform can contribute to a better understanding of the processes related to bone formation and remodeling, which in turn can be used for the development of bone regeneration strategies.

The question whether β‐tricalcium phosphate (β‐TCP) can form a solid solution with β-calcium pyrophosphate (β-CPP) and/or hydroxyapatite (HA) has still not been solved. For this reason, wet-chemically synthesized β-TCP powders with only 20 ppm Sr (among 43 tested elements) and with different HA and β-CPP contents, or in other words Ca/P molar ratios, were used. The graphical relationship between these various Ca/P molar ratios determined by X-ray diffraction and by inductively-coupled plasma mass spectrometry showed no discontinuity, indicating the absence of a solid solution between β‐TCP and β-CPP or HA. Analysis of the β‐TCP lattice parameters as a function of the Ca/P molar ratio revealed a discontinuity at a Ca/P molar ratio of 1.500 and a maximum microstrain. These results indicated that at least two β‐TCP structures co-existed, with variable mixing ratios depending on the Ca/P molar ratio, and with a distinct jump at a Ca/P molar ratio of 1.500.

Any significant in vitro evaluation of cartilage tissue engineering and cartilage repair strategies has to be performed under the harsh conditions encountered in vivo within synovial joints. To this end, we have developed a novel automated physiological robot reactor system (PRRS) that is capable of recapitulating complex physiological motions and load patterns within an environment similar to that found in the human knee. The PRRS consists of a mechanical stimulation unit (MSU) and an automatic sample changer (ASC) within an environment control box in which the humidity, temperature, and gas composition are tightly regulated. The MSU has three linear (orthogonal) axes and one rotational degree of freedom (around the z-axis). The ASC provides space for up to 24 samples, which can be allocated to individual stimulation patterns. Cell-seeded scaffolds and ex vivo tissue culture systems were established to demonstrate the applicability of the PRRS to the investigation of the effect of load and environmental conditions on engineering and maintenance of articular cartilage in vitro. The bioreactor is a flexible system that has the potential to be applied for culturing connective tissues other than cartilage, such as bone and intervertebral disc tissue, even though the mechanical and environmental parameters are very different.

Prediction of primary stability is a major challenge in the surgical planning of dental and orthopedic implants. Computational methods become attractive to estimate primary stability from clinical CT images, but implicit finite element analysis of implant press-fit faces convergence issues due to contact and highly distorted elements. This study aims to develop and validate an explicit finite element method to simulate the insertion and primary stability of a rigid implant in a deformable bone while accounting for damage occurring at the bone-implant interface. Accordingly, a press-fit experiment of a conical implant into predrilled bovine trabecular bone was designed and realized for six samples. A displacement-driven cyclic protocol was used to quantify the reaction force and stiffness of the bone-implant system. Homogenized finite element analyses of the experiments were performed by modeling contact with friction and converting an existing constitutive model with elasto-plasticity and damage of bone tissue to be applicable to an explicit time integration scheme where highly distorted elements get deleted. The computed reaction forces and unloading stiffnesses showed high correlations (R² = 0.95 and R² = 0.94) with the experiment. Friction between bone and implant exhibited a strong influence on both reaction force and stiffness. In conclusion, the developed explicit finite element approach with frictional contact and element deletion accounts properly for bone damage during press-fit and will help optimizing dental or orthopedic implant design towards maximal primary stability.

No abstract available.

Validating phase quantification procedures of powder X-ray diffraction (XRD) data for an implementation in an ISO/IEC 17025 accredited environment has been challenging due to a general lack of suitable certified reference materials. The preparation of highly pure and crystalline reference materials and mixtures thereof may exceed the costs for a profitable and justifiable implementation. This study presents a method for the validation of XRD phase quantifications based on semi-synthetic datasets that reduces the effort for a full method validation drastically. Datasets of nearly pure reference substances are stripped of impurity signals and rescaled to 100% crystallinity, thus eliminating the need for the preparation of ultra-pure and -crystalline materials. The processed datasets are then combined numerically while preserving all sample- and instrument-characteristic features of the peak profile, thereby creating multi-phase diffraction patterns of precisely known composition. The number of compositions and repetitions is only limited by computational power and storage capacity. These datasets can be used as input files for the phase quantification procedure, in which statistical validation parameters such as precision, accuracy, linearity, and limits of detection and quantification can be determined from a statistically sound number of datasets and compositions.

It has been reported in the literature that thermal treatment of calcium phosphate ceramics chemically alters the surface composition by phosphate evaporation. To predict the compositional changes, we have developed a thermodynamic model for the evaporation of phosphorous species from CPP, TCP, HA, and TetCP. In an open atmosphere, the model predicts the formation of a surface layer consisting of a sequence of increasingly phosphate-depleted phases. In a closed system, the atmosphere reaches equilibrium with a single-phase surface layer. To verify our model, we performed a series of experiments which confirmed the predicted formation of phosphate-depleted surface layers. These experiments further demonstrated that controlled supersaturation of the atmosphere led to formation of a phosphate-enriched surface layer as a result of phosphate condensation. In conclusion, our thermodynamic model is capable of predicting the surface modification by phosphate evaporation and condensation of calcium phosphate phases during high-temperature processing in different environments.

Polymer surface grafting is widely used in the field of bone regeneration to increase calcium phosphate (CaP) adhesion, with the intent of improving mechanical properties of CaP-polymer composite cements. Reinforcement can be achieved using multiple combined functional groups and/or complex surface geometries that, however, concurrently influence multiple effects such as wetting, roughness, and interfacial strengthening. This study focused on the influence of a chelating group, namely aspartic acid, on the adsorption of divalent ions such as Ba²⁺ or Ca²⁺ onto poly-l-lactic acid (PLA) films. The films were analyzed using contact angle measurements and X-ray photoelectron spectroscopy. The adsorption of CaP and its interfacial mechanical properties were investigated using functionalized PLA monofilaments whose surface roughness was analyzed using white light interferometry. Mechanical analysis was conducted by performing pull-out tests. The surfaces were analyzed using scanning electron microscopy and energy dispersive X-ray spectroscopy. Using aspartic acid as a chelating group resulted in a 50 % increased adsorption of barium, an almost threefold increase in calcium coverage of the fiber compared to the control group and a twofold increase in interfacial stiffness. No significant increase in interfacial strength was determined, most likely due to the weakness of the CaP matrix, which was partially visible as residues on the monofilaments in the postfracture imaging. This study shows the potential of surfaces functionalized with aspartic acid as a simple alternative to complex polypeptide based functional groups for the adsorption of divalent ions such as calcium on poly-lactic acid in bone regenerating applications.

Bone morphogenetic protein (BMP)/carriers approved for orthopedic procedures achieve efficacy superior or equivalent to autograft bone. However, required supraphysiological BMP concentrations have been associated with potential local and systemic adverse events. Suboptimal BMP/receptor binding and rapid BMP release from approved carriers may contribute to these outcomes. To address these issues and improve efficacy, we engineered chimeras with increased receptor binding by substituting BMP-6 and activin A receptor binding domains into BMP-2 and optimized a carrier for chimera retention and tissue ingrowth. BV-265, a BMP-2/BMP-6/activin A chimera, demonstrated increased binding affinity to BMP receptors, including activin-like kinase-2 (ALK2) critical for bone formation in people. BV-265 increased BMP intracellular signaling, osteogenic activity, and expression of bone-related genes in murine and human cells to a greater extent than BMP-2 and was not inhibited by BMP antagonist noggin or gremlin. BV-265 induced larger ectopic bone nodules in rats compared to BMP-2 and was superior to BMP-2, BMP-2/6, and other chimeras in nonhuman primate bone repair models. A composite matrix (CM) containing calcium-deficient hydroxyapatite granules suspended in a macroporous, fenestrated, polymer mesh-reinforced recombinant human type I collagen matrix demonstrated improved BV-265 retention, minimal inflammation, and enhanced handling. BV-265/CM was efficacious in nonhuman primate bone repair models at concentrations ranging from ¹/₁₀ to ¹/₃₀ of the BMP-2/absorbable collagen sponge (ACS) concentration approved for clinical use. Initial toxicology studies were negative. These results support evaluations of BV-265/CM as an alternative to BMP-2/ACS in clinical trials for orthopedic conditions requiring augmented healing.

The efficiency of calcium phosphate (CaP) bone substitutes can be improved by tuning their resorption rate. The influence of both crystal orientation and ion doping on resorption is here investigated for beta-tricalcium phosphate (β-TCP). Non-doped and Mg-doped (1 and 6 mol%) sintered β-TCP samples were immersed in acidic solution (pH 4.4) to mimic the environmental conditions found underneath active osteoclasts. The surfaces of β-TCP samples were observed after acid-etching and compared to surfaces after osteoclastic resorption assays. β-TCP grains exhibited similar patterns with characteristic intra-crystalline pillars after acid-etching and after cell-mediated resorption. Electron BackScatter Diffraction analyses, coupled with Scanning Electron Microscopy, Inductively Coupled Plasma–Mass Spectrometry and X-Ray Diffraction, demonstrated the influence of both grain orientation and doping on the process and kinetics of resorption. Grains with c-axis nearly perpendicular to the surface were preferentially etched in non-doped β-TCP samples, whereas all grains with simple axis (a, b or c) nearly normal to the surface were etched in 6  mol% Mg-doped samples. In addition, both the dissolution rate and the percentage of etched surface were lower in Mg-doped specimens. Finally, the alignment direction of the intra-crystalline pillars was correlated with the preferential direction for dissolution.

Repairing large bone defects caused by severe trauma or tumor resection remains one of the major challenges in orthopedics and maxillofacial surgery. A promising therapeutic approach is the use of osteoinductive materials, i.e. materials able to drive mesenchymal stem cells into the osteogenic lineage. Even though the mechanism of this so-called intrinsic osteoinduction or material-induced heterotopic ossification has been studied for decades, the process behind it remains unknown, thus preventing any design of highly potent osteoinductive materials. We propose and demonstrate for the first time that intrinsic osteoinduction is the result of calcium and/or phosphate depletion, thus explaining why not only the material (surface) composition but also the material volume and architecture (e.g. porosity, pore size) play a decisive role in this process.

Purpose: To compare the influence of ultraviolet (UV) irradiation and cold atmospheric pressure plasma (CAP) treatment on surface structure, surface chemistry, cytocompatibility, and cell behavior on zirconia in vitro. Materials and methods: Zirconia samples (TZ-3YSBE) were treated by UV irradiation, oxygen plasma, or argon plasma for 12 minutes each and compared with the nontreated samples. Surface analysis was conducted using scanning electron microscopy, roughness analysis, and x-ray photoelectron spectroscopy. Cell proliferation, viability, and cell attachment as well as cytotoxicity were evaluated using MC3T3-E1 murine osteoblasts cultivated directly on the zirconia samples. Results: Surface structure and roughness were not affected by the surface treatments. CAP and UV irradiation significantly reduced organic material and increased the surface oxidation on the zirconia samples. Furthermore, CAP and UV treatment significantly decreased the contact angle on the zirconia samples, indicating superhydrophilicity. Cell attachment was significantly increased on oxygen plasma-treated zirconia samples compared with the nontreated samples at all times (P < .001). After 24 and 48 hours, cell proliferation and viability (P < .001) were significantly increased on oxygen plasma-treated samples in comparison with the nontreated, UV-treated, and argon plasma-treated samples. Neither UV nor CAP treatment led to cytotoxicity. Conclusion: In vitro, surface treatment by UV irradiation or CAP causes a significant reduction of organic material, increases the hydrophilicity of zirconia, and improves the conditions for osteoblasts. Results stipulate that treatment of zirconia surfaces with oxygen plasma may favor cell proliferation.

Bacterial adhesion and subsequent biofilm formation on biomedical implants and devices are a major cause of their failure. As systemic antibiotic treatment is often ineffective, there is an urgent need for antimicrobial biomaterials and coatings. The term “antimicrobial” can encompass different mechanisms of action (here termed “antimicrobial surface designs”), such as antimicrobial-releasing, contact-killing or non-adhesivity. Biomaterials equipped with antimicrobial surface designs based on different mechanisms of action require different in vitro evaluation methods. Available industrial standard evaluation tests do not address the specific mechanisms of different antimicrobial surface designs and have therefore been modified over the past years, adding to the myriad of methods available in the literature to evaluate antimicrobial surface designs. The aim of this review is to categorize fourteen presently available methods including industrial standard tests for the in vitro evaluation of antimicrobial surface designs according to their suitability with respect to their antimicrobial mechanism of action. There is no single method or industrial test that allows to distinguish antimicrobial designs according to all three mechanisms identified here. However, critical consideration of each method clearly relates the different methods to a specific mechanism of antimicrobial action. It is anticipated that use of the provided table with the fourteen methods will avoid the use of wrong methods for evaluating new antimicrobial designs and therewith facilitate translation of novel antimicrobial biomaterials and coatings to clinical use. The need for more and better updated industrial standard tests is emphasized.

We have developed magnetically separable and reasonably stable visible light active photocatalysts containing CoFe₂O₄ and mixture of Ag₂O/Ag₂CO₃ nanoheterostructures. Obtained ternary nanoheterostructures outperform previously reported magnetically separable visible light photocatalysts, showing one of the highest visible light photocatalytic dye degradation activities in water by a magnetically separable photocatalyst. Photocatalytically active part is Ag₂O/Ag₂CO₃ whereas the CoFe₂O₄ mainly has stabilizing and magnetic separation functions. The Ag₂CO₃ phase junction on Ag₂O nanoparticle surface were obtained by straightforward phase transformation from silver oxide to silver carbonate in air due to ambient CO₂. The phase transformation was followed using X-ray diffraction (XRD), and hard X-ray photoelectron spectroscopy (HAXPES) measurements.

The accurate and detailed characterization of wear particles and ions released from total hip joint prostheses is essential to understand the cause and development of osteolysis, aseptic loosening and hypersensitivity. In this in vitro research, the wear particles and ion release of 22 different test liquids from hip simulator studies were investigated. Wear particles generated from acetabular components made of ultra-high-molecular-weight polyethylene (UHMWPE) or cross-linked polyethylene containing vitamin E (XLPE) were compared using scanning electron microscopy (SEM) and laser diffraction. Additionally, the effect of running-in versus steady-state, accelerated ageing, head materials and calcium sulphate third-body particles on the morphology and size of the created debris was investigated. The Fe, Ni, Mn, Nb, Co, Mo and Al ions released from femoral heads made of stainless steel, CoCrMo and alumina ceramic were analysed using inductively coupled plasma mass spectrometry. The combination of SEM and laser diffraction to analyse both the morphology and the particle-size distributions of the polyethylene wear particles was very powerful. The wear particles were predominantly in the submicron range and globular, with occasional fibrils. The size distributions of the UHMWPE and XLPE particles were similar; however, more fibrils were observed among the UHMWPE particles. The average particle size decreased for most samples in the steady-state phase compared to the running-in. The accelerated ageing and the presence of third-body particles generally caused larger UHMWPE wear particles only. Increasing the size of the stainless steel femoral heads led to an increase in the ion level too.

Although bone formation around and within implants has been intensively studied, the role of pores and pore geometry is still debated. Notwithstanding studies reporting the formation of bone and bone components within pores as small as a few micrometers (‘micropores’), bone ingrowth is believed to only occur in pores larger than 100 μm (‘macropores’). A thorough analysis of 10 different porous β-tricalcium phosphate cylinders (Ø: 8 mm; L: 13 mm) implanted for 2–24 weeks in an ovine model demonstrates ingrowth of mineralized tissue (MT) in pores as small as 1 μm. This tissue contained calcium phosphate, collagen, and interconnected cells. It formed within the first 3–4 weeks of implantation, extended over several hundred micrometers within the ceramic, and contributed to the majority of the early MT formation (including bone) in the defect. The indentation stiffness of the MT-ceramic composite was significantly higher than that of bone and MT-free ceramic. The presented results substantiate the importance of micropores for optimal bone healing, particularly at early implantation times.

Micro-computed tomography (microCT) is commonly used to characterize the three-dimensional structure of bone graft scaffolds before and after implantation in order to assess changes occurring during implantation. The accurate processing of the microCT datasets of explanted β-tricalcium phosphate (β-TCP) scaffolds poses significant challenges because of (a) the overlap in the grey values distribution of ceramic remnants, bone, and soft tissue, and of (b) the resorption of the bone substitute during the implantation. To address those challenges, this article introduces and rigorously validates a new processing technique to accurately distinguish these three phases found in the explanted β-TCP scaffolds. Specifically, the microCT datasets obtained before and after implantation of β-TCP scaffolds were aligned in 3D, and the characteristic grey value distributions of the three phases were extracted, thus allowing for (i) the accurate differentiation between these three phases (ceramic remnants, bone, soft tissue), and additionally for (ii) the localization of the defect site in the post-implantation microCT dataset. Using the similarity matrix, a 94±1% agreement was found between algorithmic results and the visual assessment of 556,800 pixels. Moreover, the comparison of the segmentation results of the same microCT and histology section further confirmed the validity of the present segmentation algorithm. This new technique could lead to a more common use of microCT in analyzing the complex 3D processes and to a better understanding of the biological processes occurring after the implantation of ceramic bone graft substitutes.

STATEMENT OF SIGNIFICANCE:

Calcium-phosphate scaffolds are being increasingly used to repair critical bone defects. Methods for the accurate characterization of the repair process are still lacking. The present study introduced and validated a novel image-processing technique, using micro-computed tomography (mCT) datasets, to investigate material phases present in biopsies. Specifically, the new method combined mCT datasets from the scaffold before and after implantation to access the characteristic data of the ceramic for more accurate analysis of bone biopsies, and as such to better understand the interactions of the scaffold design and the bone repair process.

Little is known regarding the associations between sex-hormone levels, sex, body mass index (BMI), age, other host factors and biomaterial stimulated bone regeneration in the human craniofacial skeleton. The aim of this study was to elucidate the associations between these factors and bone formation after sinus floor augmentation procedures (SFA) utilizing a bioactive tricalcium phosphate (TCP) bone grafting material. We conducted a prospective study in a human population in which 60 male and 60 female participants underwent SFA and dental implant placement using a staged approach. BMI as well as levels of serum estradiol (E2), total testosterone (TT), and the free androgen index (FAI) were measured by radioimmunoassay and electrochemoluminescent-immunoassay. At implant placement, 6 months after SFA, bone biopsy specimens were harvested for hard tissue histology, the amount of bone formation was evaluated by histomorphometry and immunohistochemical analysis of osteogenic marker expression. The Wilcoxon rank-sum U test, Spearman correlations and linear regression analysis were used to explore the association between bone formation and BMI, hormonal and other host factors. BMI and log E2 were significantly positively associated with bone formation in male individuals (p < 0.05). Histomorphometry revealed trends toward greater bone formation and osteogenic marker expression with non-smokers compared to smokers. In male patients, higher E2 levels and higher BMI enhanced TCP stimulated craniofacial i.e. intramembranous bone repair.

Objective

The aim of this study was to produce a novel composite of microporous β-TCP filled with alginate and Vancomycin (VAN) to prolong the release behavior of the antibiotic for up to 28 days.

Abstract Dynamic Intraligamentary Stabilization (DIS) represents a treatment option for acute anterior cruciate ligament ruptures. The device used for DIS consists of a polyethylene braid and a metallic spring system, allowing the remnants of the ligament to recombine in a stabilized position over the self-healing period. This work addresses the metallic wear generated thereby. A cadaveric study was carried out with n=8 knees over 50'000 cycles, along with a control group to validate the cleaning and assembly process. Gravimetric analysis yielded a total wear of (0.28±0.35)mg for the entire implant. 50% of the wear originated from the bush and 46% from the clamping element. In a worst case scenario, a total wear of 1.7 mg would result during the functional lifetime.

Introduction of porosity to calcium phosphate scaffolds for bone repair has created a new challenge when measuring bioresorption in vitro, rendering traditional outcome measures redundant. The aim of this study is to identify a surrogate endpoint for use with 3D scaffolds. Murine RAW 264.7 cells are cultured on dense discs of β-tricalcium phosphate in conditions to stimulate osteoclast (OC) formation. Multinucleated OCs are visible from day 6 with increases at days 8 and 10. Resorption pits are first observed at day 6 with much larger pits visible at days 8, 10, and 12. The concentration of calcium ions in the presence of cells is significantly higher than cell-free cultures at days 3 and 9. Using linear regression analysis, Ca ion release could account for 35.9% of any subsequent change in resorption area. The results suggest that Ca ion release is suitable to measure resorption of a beta-tricalcium phosphate ceramic substrate in vitro. This model could replace the more accepted resorption pit assay in circumstances where quantification of pits is not possible, e.g., when characterizing 3D tissue engineered bone scaffolds.

β-Tricalcium phosphate (β-TCP) platelets synthesized in ethylene glycol offer interesting geometries for nano-structured composite bone substitutes but were never crystallographically analyzed. In this study, powder X-ray diffraction and Rietveld refinement revealed a discrepancy between the platelet structure and the known β-TCP crystal model. In contrast, a model featuring partial H for Ca substitution and the inversion of P1O₄ tetrahedra, adopted from the whitlockite structure, allowed for a refinement with minimal misfits and was corroborated by HPO₄²⁻ absorptions in Fourier-transform IR spectra. The Ca/P ratio converged to 1.443 ± 0.003 (n = 36), independently of synthesis conditions. As a quantitative verification, the platelets were thermally decomposed into hydrogen-free β-TCP and β-calcium pyrophosphate which resulted in a global Ca/P ratio in close agreement with the initial β-TCP Ca/P ratio (ΔCa/P = 0.003) and with the chemical composition measured by inductively coupled plasma (ΔCa/P = 0.003). These findings thus describe for the first time a hydrogen-substituted β-TCP structure, i.e. a Mg-free whitlockite, represented by the formula Ca_21 − x(HPO₄)_2x(PO₄)_{14 − 2x}, where x = 0.80 ± 0.04, and may have implications for resorption properties of bone regenerative materials.

n this work, we investigate the influence of doping on the mechanical properties of ZnO nanowires (NWs) by comparing the mechanical properties of pure and Co-doped ZnO NWs grown in similar conditions and having the same crystallographic orientation [0001]. The mechanical characterization included three-point bending tests made with atomic force microscopy and cantilever beam bending tests performed inside scanning electron microscopy. It was found that the Young's modulus of ZnO NWs containing 5% of Co was approximately a third lower than that of the pure ZnO NWs. Bending strength values were comparable for both materials and in both cases were close to theoretical strength indicating high quality of NWs. Dependence of mechanical properties on NW diameter was found for both doped and undoped ZnO NWs.

This investigation addresses a need for higher quality surfaces and wear resistance of coatings used on load bearing medical implants. Multilayered cathodic arc deposited coatings are candidates for such applications and were the subject of this study. Nb–Ti–N coatings were deposited by cathodic arc using TiNb compound cathodes. The microstructure and properties of the coatings were characterized using XRD, TEM/STEM, EDS, nanoindentation, scratch tests and pin-on-disc testing. Throughout the coating, macroparticles consisting of a Nb rich core and a nitrided titanium porous shell were evidenced by STEM and EDS. It was shown that inhomogeneities related with the soft and malleable metallic Nb inclusions alter the tribological behavior of the coatings. The underlying mechanism of wear in hip-simulator test liquid against UHMWPE was investigated. During pin-on-disc tests, the top layers of the coatings were removed and the embedded niobium droplets became visible. The wear of UHMWPE during pin-on-disks tests was increased on Nb–Ti–N counter surfaces compared to the wear of UHMWPE on TiN itself. It is inferred that the wear of the coatings is initiated by the growth discontinuities and pores around the Nb droplets. The debris released from the coating acts as third body wear particles, grinds the remaining coating and causes the wear of UHMWPE pins.

The European Society for Biomaterials 2015 Translational Research Symposium focused on 'Innovating in the Medical Device Industry - Challenges & Opportunities' from different perspectives, i.e., from a non-profit research organisation to a syndicate of small and medium-sized companies and large companies. Lecturers from regulatory consultants, industry and research institutions described the innovation process and regulatory processes (e.g., 510K, PMA, combination product) towards market approval. The aim of the present article is to summarise and explain the main statements made during the symposium, in terms of challenges and opportunities for medical device industries, in a constantly changing customer and regulatory environment.

NEL-like molecule-1 (NELL-1) is a novel osteogenic protein that showing high specificity to osteochondral cells. It was widely used in bone regeneration research by loading onto carriers such as tricalcium phosphate (TCP) particles. However, there has been little research on protein controlled release from this material and its potential application. In this study, TCP was first modified with a hydroxyapatite coating followed by a chitosan coating to prepare chitosan/hydroxyapatite-coated TCP particles (Chi/HA-TCP). The preparation was characterized by SEM, EDX, FTIR, XRD, FM and Zeta potential measurements. The NELL-1 loaded Chi/HA-TCP particles and the release kinetics were investigated in vitro. It was observed that the Chi/HA-TCP particles prepared with the 0.3% (wt/wt) chitosan solution were able to successfully control the release of NELL-1 and maintain a slow, steady release for up to 28 days. Furthermore, more than 78% of the loaded protein's bioactivity was preserved in Chi/HA-TCP particles over the period of the investigation, which was significantly higher than that of the protein released from hydroxyapatite coated TCP (HA-TCP) particles. Collectively, this study suggests that the osteogenic protein NELL-1 showed a sustained release pattern after being encapsulated into the modified Chi/HA-TCP particles, and the NELL-1 integrated composite of Chi/HA-TCP showed a potential to function as a protein delivery carrier and as an improved bone matrix for use in bone regeneration research.

Self-tapping of magnesium screws in hard bone may be a challenge due to the limited torsional strength of magnesium alloys in comparison with titanium. To avoid screw failure upon implantation, the new concept of a rivet-screw was applied to a WE43 magnesium alloy. Hollow cylinders with threads on the outside were expanded inside drill holes of minipig mandibles. During the expansion with a hexagonal mandrel, the threads engaged the surrounding bone and the inside of the screw transformed into a hexagonal screw drive to allow further screwing in or out of the implant. The in vivo degradation of the magnesium implants and the performance of the used coating were studied in a human standard-sized animal model. Four magnesium alloy rivet-screws were implanted in each mandible of 12 minipigs. Six animals received the plasmaelectrolytically coated magnesium alloy implants; another six received the uncoated magnesium alloy rivet-screws. Two further animals received one titanium rivet-screw each as control. In vivo radiologic examination was performed at one, four, and eight weeks. Euthanasia was performed for one group of seven animals (three animals with coated, three with uncoated magnesium alloy implants and one with titanium implant) at 12 weeks and for the remaining seven animals at 24 weeks. After euthanasia, micro-computed tomography and histological examination with histomorphometry were performed. Significantly less void formation as well as higher bone volume density (BV/TV) and bone-implant contact area (BIC) were measured around the coated implants compared to the uncoated ones. The surface coating was effective in delaying degradation despite plastic deformation. The results showed potential for further development of magnesium hollow coated screws for bone fixation.

Calcium phosphate (CaP) ceramics are extensively used for bone regeneration; however, their clinical performance is still considered inferior to that of patient's own bone. To improve the performance of CaP bone graft substitutes, it is important to understand the effects of their individual properties on a biological response. The aim of this study is to investigate the effects of the crystal phase and particle morphology on the behavior of human mesenchymal stromal cells (hMSCs). To study the effect of the crystal phase, brushite, monetite, and octacalcium phosphate (OCP) are produced by controlling the precipitation conditions. Brushite and monetite are produced as plate-shaped and as needle-shaped particles, to further investigate the effect of particle morphology. Proliferation of hMSCs is inhibited on OCP as compared to brushite and monetite in either morphology. Brushite needles consistently show the lowest expression of most osteogenic markers, whereas the expression on OCP is in general high. There is a trend toward a higher expression of the osteogenic markers on plate-shaped than on needle-shaped particles for both brushite and monetite. Within the limits of CaP precipitation, these data indicate the effect of both crystal phase and particle morphology of CaPs on the behavior of hMSCs.

Here, we show results on X-ray absorption near edge structure spectroscopy in both transmission and X-ray fluorescence full-field mode (FF-XANES) at the calcium K-edge on human bone tissue in healthy and diseased conditions and for different tissue maturation stages. We observe that the dominating spectral differences originating from different tissue regions, which are well pronounced in the white line and postedge structures are associated with polarization effects. These polarization effects dominate the spectral variance and must be well understood and modeled before analyzing the very subtle spectral variations related to the bone tissue variations itself. However, these modulations in the fine structure of the spectra can potentially be of high interest to quantify orientations of the apatite crystals in highly structured tissue matrices such as bone. Due to the extremely short wavelengths of X-rays, FF-XANES overcomes the limited spatial resolution of other optical and spectroscopic techniques exploiting visible light. Since the field of view in FF-XANES is rather large the acquisition times for analyzing the same region are short compared to, for example, X-ray diffraction techniques. Our results on the angular absorption dependence were verified by both site-matched polarized Raman spectroscopy, which has been shown to be sensitive to the orientation of bone building blocks and by mathematical simulations of the angular absorbance dependence. As an outlook we further demonstrate the polarization based assessment of calcium-containing crystal orientation and specification of calcium in a beta-tricalcium phosphate (β-Ca3(PO4)2 scaffold implanted into ovine bone. Regarding the use of XANES to assess chemical properties of Ca in human bone tissue our data suggest that neither the anatomical site (tibia vs jaw) nor pathology (healthy vs necrotic jaw bone tissue) affected the averaged spectral shape of the XANES spectra.

This study reports on the synthesis and characterisation of two- and three-component visible light active photocatalytic nanoparticle heterostructures, based on TiO2 and NiFe204 and sensitized with Ag. We observe that a Ag content as small as 1 at% in the TiO2/NiFe204 heterostructure increases by more than an order of magnitude the rate constant for the visible light photocatalytic process. We rationalise this in terms of the measured structure and electronic structure data of the binary and ternary combinations of the component materials and focus on details, which show that an optimised deposition sequence is vital for attaining high values of photocatalytic efficiency, because the charge transfer across the interfaces appears to be sensitive to where the Ag is loaded in the heterostructure. The overall higher visible light photocatalytic activity of the TiO2/Ag/NiFe204 heterostructure was observed and is attributed to enhanced charge carrier separation efficiency and migration via vectorial electron transfer.

Biodegradable magnesium plate/screw osteosynthesis systems were implanted on the frontal bone of adult miniature pigs. The chosen implant geometries were based on existing titanium systems used for the treatment of facial fractures. The aim of this study was to evaluate the in vivo degradation and tissue response of the magnesium alloy WE43 with and without a plasma electrolytic surface coating. Of 14 animals, 6 received magnesium implants with surface modification (coated), 6 without surface modification (uncoated), and 2 titanium implants. Radiological examination of the skull was performed at 1, 4, and 8 weeks post-implantation. After euthanasia at 12 and 24 weeks, X-ray, computed tomography, and microfocus computed tomography analyses and histological and histomorphological examinations of the bone/implant blocks were performed. The results showed a good tolerance of the plate/screw system without wound healing disturbance. In the radiological examination, gas pocket formation was found mainly around the uncoated plates 4 weeks after surgery. The micro-CT and histological analyses showed significantly lower corrosion rates and increased bone density and bone implant contact area around the coated screws compared to the uncoated screws at both endpoints. This study shows promising results for the further development of coated magnesium implants for the osteosynthesis of the facial skeleton.

Our populations are aging. Some experts predict that 30% of hospital beds will soon be occupied by osteoporosis patients. Statistics show that 20% of patients suffering from an osteoporotic hip fracture do not survive the first year after surgery, all this showing that there is a tremendous need for better therapies for diseased and damaged bone. Human bone consists for about 70% of calcium phosphate (CaP) mineral, therefore CaPs are the materials of choice to repair damaged bone. To do this successfully, the process of CaP biomineralization and the interaction of CaPs and biological environment in the body need to be fully understood. First commercial CaP bone graft substitutes were launched 40 years ago, and they are currently often regarded as ‘old biomaterials’ or even as an ‘obsolete’ research topic. Some even talk about ‘stones’. The aim of this manuscript is to highlight the tremendous improvements achieved in CaP materials research in the past 15 years, in particular in the field of biomineralization, as carrier for gene or ion delivery, as biologically active agent, and as bone graft substitute. Besides an outstanding biological performance, CaPs are easily and inexpensively produced, are safe, and can be relatively easily certified for clinical use. As such, CaP materials have won their spurs, but they also offer a great promise for the future.

Alpha and beta-tricalcium phosphates are allotropic phases which play a very important role as bone graft substitutes, namely in calcium phosphate cements. Despite extensive research efforts, contradictory reports exist on the importance of quenching for maintaining α-TCP purity. The role of calcium pyrophosphate impurities derived from a certain calcium-deficiency, hydroxyapatite impurities derived from calcium excess, and various ionic substitutions on thermal stability of these phases was not yet fully disclosed. The present work reports on the kinetics of α ↔ β-TCP phase transformations of calcium-deficient TCP powders with different Mg-doping extents (0–5 mol%) prepared by precipitation. Mg clearly enhanced the thermal stability of β-TCP. The effect of cooling rate was more complex and interdependent on the Mg content and the heat treatment schedule. High α-TCP contents were retained upon cooling at 5 °C min−1 for Mg ≤ 1 mol% or upon quenching from 1550 °C for Mg contents ≤2 mol%.

Synthetic calcium phosphate bone graft substitutes are widely recognized for their biocompatibility and
resorption characteristics in the treatment of large bone defects. However, due to their inherent brittleness,
applications in load-bearing situations always require reinforcement by additional metallic
implants. Improved mechanical stability would eliminate the need for non-resorbable metallic implants.
In this context a new approach to obtain calcium phosphate scaffolds with improved mechanical stability
by texturing the material in specific crystal orientations was evaluated. Texture and reduction of crystal
size was achieved by recrystallizing a-TCP blocks into calcium deficient hydroxyapatite (CDHA) under
hydrothermal conditions. SEM and XRD analysis revealed the formation of fine CDHA needles
(diameter z 0.1e0.5 mm), aligned over several hundreds of micrometers. The obtained microstructures
were remarkably similar to the microstructures of the prismatic layer of mollusk shells or enamel, also
showing organization at 5 hierarchical structure levels. Brazilian disc tests were used to determine the
diametral tensile strength, sdts, and the work-of-fracture, WOF, of the textured materials. Hydrothermal
incubation significantly increased sdts and WOF of the ceramic blocks as compared to sintered blocks.
These improvements were attributed to the fine and entangled crystal structure obtained after incubation,
which reduces the size of strength-determining critical defects and also leads to tortuous crack
propagation. Rupture surfaces revealed intergranular tortuous crack paths, which dissipate much more
energy than transgranular cracks as observed in the sintered samples. Hence, the refined and textured
microstructure achieved through the proposed processing route is an effective way to improve the
strength and particularly the toughness of calcium phosphate-based ceramics.

Glass beads a few hundred micrometers in size were added to aqueous b-tricalcium phosphate pastes to
simulate the effect of porogens and drug-loaded microspheres on the injectability of calcium phosphate
cements and putties. The composition of the pastes was monitored during the injection process to assess
the effect of glass bead content, glass bead size and paste composition on the paste injectability. The
results revealed that the injection process led to both liquid and glass bead segregations: the liquid
flowed faster than the glass beads, which themselves flowed faster than the b-tricalcium phosphate
microparticles. In fact, even the particle size distribution of the glass beads was modified during injection.
These results reveal that a good design of multiphasic injectable pastes is essential to prevent phase
separation.

Recently, uniform, non-agglomerated, hexagonal b-tricalcium phosphate (b-TCP) platelets (diameter
 400–1700 nm, h  100–200 nm) were obtained at fairly moderate temperatures (90–170 C) by
precipitation in ethylene glycol. Unfortunately, the platelet aspect ratios (diameter/thickness) obtained
in the latter study were too small to optimize the strength of polymer–b-TCP composites. Therefore,
the aim of the present study was to investigate b-TCP platelet crystallization kinetics, and based on this,
to find ways to better control the b-TCP aspect ratio. For that purpose, precipitations were performed at
different temperatures (90–170 C) and precursor concentrations (4, 16 and 32 mM). Solution aliquots
were retrieved at regular intervals (10 s–24 h), and the size of the particles was measured on scanning
electron microscopy images, hence allowing the determination of the particle growth rates. The b-TCP
platelets were observed to nucleate and grow very rapidly. For example, the first crystals were observed
after 30 s at 150 C, and crystallization was complete within 2 min. The crystal growth curves could be
well-fitted with both diffusion- and reaction-controlled equations, but the high activation energies
(100 kJ mol1) pointed towards a reaction-controlled mechanism. The results revealed that the best
way to increase the diameter and aspect ratio of the platelets was to increase the precursor concentration.
Aspect ratios as high as 14 were obtained, but the synthesis of such particles was always associated
with the presence of large fractions of monetite impurities.

Powder based three-dimensional printing (3DP) allows great versatility in material and geometry. These
characteristics make 3DP an interesting method for the production of tissue engineering scaffolds. However,
3DP has major limitations, such as limited resolution and accuracy, hence preventing the widespread
application of this metho engineering. In order to reduce these limitations deeper
understanding of the complex interactions between powder, binder and roller during 3DP is needed.
In the past a lot of effort has been invested to optimize the powder properties for 3DP for a certain layer
thickness. Using a powder optimized for an 88 lm layer thickness, this study systematically quantifies
the surface roughness and geometrical accuracy in printed specimens and assesses their variation upon
changes of different critical parameters such as the moisture application time (0, 5, 10 and 20 s), layer
thickness (44 and 88 lm) and the number of specimens printed per batch (6 and 12). A best surface
roughness value of 25 lm was measured with a moisture application time (using a custom made moisture
application device mounted on a linear stage carrying the print head) of 5 s and a layer thickness of
44 lm. Geometrical accuracy was generally higher for the 88 lm thick layer, due to a less critical powder
bed stability. Moisture application enabled 3DP of a 44 lm thick layer and improved the accuracy even
for a powder initially optimized for 88 lm. Moreover, recycling of the humidified powder was not only
possible but, in terms of reactivity, even beneficial. In conclusion, moisture-based 3DP is a promising
approach for high resolution 3DP of scaffolds

Powder-based three-dimensional printing (3DP) is a versatile method that allows creating synthetic calcium
phosphate (CaP) scaffolds of complex shapes and structures. However, one major drawback is the
difficulty of removing all remnants of loose powder from the printed scaffolds, the so-called depowdering
step. In this study, a new design approach was proposed to solve this problem. Specifically, the design of
the printed scaffolds consisted of a cage with windows large enough to enable depowdering while still
trapping loose fillers placed inside the cage. To demonstrate the potential of this new approach, two filler
geometries were used: sandglass and cheese segment. The distance between the fillers was varied and
they were either glued to the cage or free to move after successful depowdering. Depowdering efficiency
was quantified by microstructural morphometry. The results showed that the use of mobile fillers significantly
improved depowdering. Based on this study, large 3DP scaffolds can be realized, which might be a
step towards a broader clinical use of 3D printed CaP scaffolds.

Calcium phosphates (CaPs) are widely used as bone graft substitutes but are inherently brittle, hence
restricting their use to mechanically protected environments. Combining them with a tough polymer
matrix could potentially lead to a composite with load-bearing properties. However, the highest mechanical
properties can only be achieved if the CaP particles possess very precise features: they should be
uniform in size and shape, non-agglomerated, elongated and thin. The aim of the present study therefore
was to assess a novel method to produce such particles. This involved the precipitation of CaP particles in
ethylene glycol at moderate temperatures (90e170
C) and the variation of different reaction parameters
(temperature, concentration, pH, etc) to study their influence on particle composition, size, shape and
dispersion was studied. As a result, two main CaP phases were obtained as well-dispersed and highly
uniform platelets in the form of: (i) b-tricalcium phosphate (b-TCP) hexagonal prisms and (ii) monetite
(DCP) flat parallelepipeds. The size dispersion was the narrowest for b-TCP (standard deviation/
mean < 5%) whereas the aspect ratio was the highest for DCP (up to 25). In both cases, the thickness of
the platelets was below 300 nm which should be ideal for the synthesis of strong CaP-based composites.

Three-dimensional printing (3DP) is a versatile method to produce scaffolds for tissue engineering. In 3DP
the solid is created by the reaction of a liquid selectively sprayed onto a powder bed. Despite the importance
of the powder properties, there has to date been a relatively poor understanding of the relation
between the powder properties and the printing outcome. This article aims at improving this understanding
by looking at the link between key powder parameters (particle size, flowability, roughness,
wettability) and printing accuracy. These powder parameters are determined as key factors with a predictive
value for the final 3DP outcome. Promising results can be expected for mean particle size in the
range of 20–35 lm, compaction rate in the range of 1.3–1.4, flowability in the range of 5–7 and powder
bed surface roughness of 10–25 lm. Finally, possible steps and strategies in pushing the physical limits
concerning improved quality in 3DP are addressed and discussed.

Despite 40 years of efforts, researchers have failed to provide calcium phosphate bone graft substitutes performing well enough to replace bone
grafting procedures: their osteogenesis potential is limited, and calcium phosphates are too brittle. However, there is hope to solve the two aforementioned
problems. First, it is now clear why nacre and bone are very tough despite a high ceramic load. Also, recent studies suggest that calcium
and phosphate ions can trigger osteoinduction. The present article aims: (i) to review our current knowledge in the field of synthetic bone graft
substitutes, (ii) to explain why ceramics and in particular calcium phosphates are still the most promising materials for bone graft substitution, and
(iii) finally to describe the strategy to obtain osteoinductive calcium phosphate bone graft substitutes as strong as cortical bone.

Hundreds of studies have been devoted to the search for the ideal architecture for bone scaffold. Despite
these efforts, results are often contradictory, and rules derived from these studies are accordingly vague.
In fact, there is enough evidence to postulate that ideal scaffold architecture does not exist. The aim of
this document is to explain this statement and review new approaches to decipher the existing but complex
link between scaffold architecture and in vivo response.

This article reviews the current state of knowledge concerning the use of powder-based three-dimensional
printing (3DP) for the synthesis of bone tissue engineering scaffolds. 3DP is a solid free-form fabrication
(SFF) technique building up complex open porous 3D structures layer by layer (a bottom-up
approach). In contrast to traditional fabrication techniques generally subtracting material step by step
(a top-down approach), SFF approaches allow nearly unlimited designs and a large variety of materials
to be used for scaffold engineering. Today’s state of the art materials, as well as the mechanical and structural
requirements for bone scaffolds, are summarized and discussed in relation to the technical feasibility
of their use in 3DP. Advances in the field of 3DP are presented and compared with other SFF methods.
Existing strategies on material and design control of scaffolds are reviewed. Finally, the possibilities and
limiting factors are addressed and potential strategies to improve 3DP for scaffold engineering are
proposed.

The ability of a porous bone graft substitute to be impregnated with an aqueous solution is of great
importance for tissue engineering and in vivo applications. This study presents an impregnation test
setup and assesses the effect of various synthesis parameters such as sintering temperature, composition,
macroporosity and macropore size on the impregnation properties of porous b-tricalcium phosphate
scaffolds dipped in water. Among those parameters, the macropore size had by far the largest effect; generally,
the bigger the macropore size, the lower the saturation level. The results also showed that impregnation
was less complete when the samples were fully dipped in water than when they were only
partially dipped, owing to the requirement for the system to create air bubbles under water.

A microsized a-tricalcium phosphate (a-TCP) powder was calcined at various temperatures (350 C < T < 800 C) for various durations
(1–24 h) and the resulting physico-chemical and reactivity changes were measured. Without calcination, the a-TCP powder started
reacting within minutes after contacting a 0.2 M Na2HPO4 solution as measured by isothermal calorimetry. The overall reaction was
finished within a few days. After calcination at 350 C 6 T 6 550 C for 24 h, no significant changes in the crystalline composition, crystallite
size, particle size or specific surface area were noticed. However, the powder reactivity was progressively changed. More specifically,
the hydraulic reaction of the powders calcined at 500 and 550 C only started after 2–3 h whereas the overall hydraulic reaction was
only slightly postponed, suggesting that physical or chemical changes had occurred at the particle surface. As mainly physical changes
were detected at the particle surface during calcination at 500 C, it was speculated that the appearance of this reaction delay (= induction
time) was due to the disappearance of surface defects during the calcination step, i.e. to the need to create surface defects to induce
dissolution and hence reaction.

Nowadays, the scientific community widely accepts the statement that silicon-substituted calcium
phosphates have better biological properties compared to pure calcium phosphates. For example, a review
published in this journal in 2007 started with the sentence ‘‘Silicon (Si) substitution in the crystal
structures of calcium phosphate (CaP) ceramics such as hydroxyapatite (HA) and tricalcium phosphate
(TCP) generates materials with superior biological performance to stoichiometric counterparts’’ [1]. A
critical look at published articles demonstrates that this sentence is controversial and somehow
misleading, because there is no experimental evidence that Si ions are released from Si-substituted calcium
phosphates at therapeutic concentrations, and because there is no study linking the improved biological
performance of Si-substituted calcium phosphates to Si release. The aim of this article is to explain this
statement in more details.

The goal of the present study was to assess the possibility to change the composition of a calcium
phosphate scaffold from a high-temperature phase to a phase only stable at or close to room temperature
without macrostructural changes. For that purpose, macroporous b-TCP scaffolds were converted into
a-TCP by high-temperature thermal treatment and then dipped into a phosphoric acid solution to obtain
a more acidic calcium phosphate phase called monetite or dicalcium phosphate (DCP; CaHPO4). Two
different solid-to-liquid ratios (SLR: 0.067 and 0.200 g/mL) and three different temperatures (T: 37,
60 and 80 C) were used. The reaction was followed by measuring the change of sample size and weight,
by determining the compositional changes by X-ray diffraction (Rietveld analysis), and by looking at the
micro- and macrostructural changes by scanning electron microscopy and micro-computed tomography.
The results revealed that the transformation proceeded faster at a higher temperature and a higher SLR
value but was achieved within a few days in all cases. Morphologically, the porosity decreased by 10%,
the pore size distribution became wider and the mean macro pore size was reduced from 0.28 to
0.19 mm. The fastest conversion and the highest compressive strength (9 MPa) were measured using an
incubation temperature of 80 C and an SLR value of 0.2 g/mL.

Many calcium phosphate bone substitutes are based on the use of a-tricalcium phosphate (a-TCP) powder. This compound has been
intensively studied, but some aspects of a-TCP reactivity are still controversial. The goal of this study was to determine the setting kinetics of a-TCP based on a new approach that compared particle size distribution data to isothermal calorimetry data. Results indicated that a-TCP conversion is mostly controlled by surface reactions, with at later stages a diffusion-controlled mechanism. The presence of an X-ray amorphous a-TCP fraction in the crystalline a-TCP powder increased the dissolution rate threefold, without modifying the reaction mechanism.

The goal of the present study was to assess the effect of macropore size on the in vivo behavior of ceramic scaffolds. For that purpose,
b-tricalcium phosphate (b-TCP) cylinders with four different macropore sizes (150, 260, 510, and 1220 mm) were implanted into drill hole
defects in cancellous bone of sheep and their resorption behavior was followed for 6, 12 and 24 weeks. The scaffolds were evaluated for
biocompatibility, and new bone formation was observed macroscopically, histologically and histomorphometrically. Histomorphometrical
measurements were performed for the whole defect area and for the area subdivided into three concentric rings (outer, medial, and
inner ring). All implants were tolerated very well as evidenced by the low amount of inflammatory cells and the absence of macroscopic
signs of inflammation. Resorption proceeded fast since less than 5% ceramic remained at 24-week implantation. Hardly any effect of
macropore size was observed on the in vivo response. Samples with an intermediate macropore size (510 mm) were resorbed significantly faster than samples with smaller macropore sizes (150 and 260 mm). However, this fast resorption was associated with a lower bone content and a higher soft tissue content. At 12 and 24 weeks, the latter differences had disappeared. Bone was more abundant in the outer ring than in the rest of the blocks at 6 weeks, and in the outer and medial ring compared to the inner ring at 12 weeks.