Entnehmen Sie die neusten Publikationen von Mitarbeitenden der RMS Foundation der folgenden Liste


A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix

H. J. Seeherman, S. P. Berasi, C. T. Brown, R. X. Martinez, S. Z. Juo, S. Jelinsky, M. Cain, J. Grode, K. E. Tumelty, M. Bohner, O. Ginsberg, N. Orr, O. Shoseyov, J. Eyckmans, C. Chen, P. R. Morales, C. G. Wilson, E. Vanderploeg, J. M. Wozney

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.

Sci Transl Med. 2019 Apr 24;11(489). pii: eaar4953;

Effect of grain orientation and magnesium doping on β-tricalcium phosphate resorption behavior

M. Gallo, B. Le Gars Santoni, Th. Douillard, F. Zhang, L. Gremillard, S. Dolder, W. Hofstetter, S. Meille, M. Bohner, J. Chevalier, S. Tadier

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.

Acta Biomaterialia 2019;89:391-402;

A proposed mechanism for material-induced heterotopic ossification

M. Bohner, R. J. Miron

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.

Materials Today: Volume 22, January - February 2019, Pages 132-141; DOI: 10.1016/j.mattod.2018.10.036


Influence of UV Irradiation and Cold Atmospheric Pressure Plasma on Zirconia Surfaces: An In Vitro Study

R. Smeets, A. Henningsen, R. Heuberger, O. Hanisch, F. Schwarz, C. Precht

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.

 The International journal of oral & maxillofacial implants 34(2) · January 2018;

In vitro methods for the evaluation of antimicrobial surface designs

J. Sjollema, S. A. J. Zaat, V. Fontaine, M. Ramstedt, R. Luginbuehl, K. Thevissen, J.Li, H. C. van der Mei, H. J. Busscher

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.

Acta Biomaterialia Volume 70, 1. April 2018, Pages 12-24;

Fracture Healing and Bone Remodeling With Human Standard-Sized Magnesium Versus Polylactide-Co-Glycolide Plate and Screw Systems Using a Mini-Swine Craniomaxillofacial Osteotomy Fixation Model.

B. Schaller, J. P. M. Burkhard, M. Chagnon, S. Beck, T. Imwinkelried, M. Assad

PURPOSE: This study compared the degradation profile, safety, and efficacy of bioresorbable magnesium alloy and polylactide-co-glycolide (PLGA) polymer osteosynthesis systems for the treatment of fractures in a load-sharing maxillofacial environment using a new mini-swine fracture fixation model. MATERIALS AND METHODS: Two types of clinically relevant situations were evaluated in 5 Yucatan miniature pigs. Defined porcine midface osteotomies of the supraorbital rim and zygoma were created and fixed with either a coated magnesium (test animals) or PLGA plate and screw osteosynthesis system (control animals). After surgery, the mini-pigs were able to recover for either 1 or 9 months with continuous in vivo post-implantation monitoring. Standardized computed tomography (CT) imaging was taken immediately postoperatively and at termination for all animals. The 9-month cohort also underwent CT at 2, 4, and 6 months after surgery. At necropsy, osteotomy sites and bone-implant units were harvested, and healing was evaluated by micro-CT, histopathology, and histomorphometry. RESULTS: After clinical and radiologic follow-up examination, all fracture sites healed well for both the magnesium and polymer groups regardless of time point. Complete bone union and gradually disappearing osteotomy lines were observed across all implantation sites, with no major consistency change in periprosthetic soft tissue or in soft tissue calcification. Macroscopic and microscopic examination showed no negative influence of gas formation observed with magnesium during the healing process. Histopathologic analysis showed similar fracture healing outcomes for both plating systems with good biocompatibility as evidenced by a minimal or mild tissue reaction. CONCLUSIONS: This study confirms that WE43 magnesium alloy exhibited excellent fracture healing properties before its full degradation without causing any substantial inflammatory reactions in a long-term porcine model. Compared with PLGA implants, magnesium represents a promising new biomaterial with reduced implant sizes and improved mechanical properties to support fracture healing in a load-sharing environment.

J Oral Maxillofac Surg. 2018 Oct;76(10):2138-2150;

In vitro response of mesenchymal stem cells to biomimetic hydroxyapatite substrates: A new strategy to assess the effect of ion exchange

J. M. Sadowska, J. Guillem-Marti, M. Espanol, C. Stähli, N. Döbelin, M. -P. Ginebra

Biomaterials can interact with cells directly, that is, by direct contact of the cells with the material surface, or indirectly, through soluble species that can be released to or uptaken from the surrounding fluids. However, it is difficult to characterise the relevance of this fluid-mediated interaction separately from the topography and composition of the substrate, because they are coupled variables. These fluid-mediated interactions are amplified in the case of highly reactive calcium phosphates (CaPs) such as biomimetic calcium deficient hydroxyapatite (CDHA), particularly in static in vitro cultures. The present work proposes a strategy to decouple the effect of ion exchange from topographical features by adjusting the volume ratio between the cell culture medium and biomaterial (VCM/VB). Increasing this ratio allowed mitigating the drastic ionic exchanges associated to the compositional changes experienced by the material exposed to the cell culture medium. This strategy was validated using rat mesenchymal stem cells (rMSCs) cultured on CDHA and beta-tricalcium phosphate (β-TCP) discs using different VCM/VB ratios. Whereas in the case of β-TCP the cell response was not affected by this ratio, a significant effect on cell adhesion and proliferation was found for the more reactive CDHA. The ionic exchange, produced by CDHA at low VCM/VB, altered cell adhesion due to the reduced number of focal adhesions, caused cell shrinkage and further rMCSs apoptosis. This was mitigated when using a high VCM/VB, which attenuated the changes of calcium and phosphate concentrations in the cell culture medium, resulting in rMSCs spreading and a viability over time. Moreover, rMSCs showed an earlier expression of osteogenic genes on CDHA compared to sintered β-TCP when extracellular calcium fluctuations were reduced.

Statement of Significance

Fluid mediated interactions play a significant role in the bioactivity of calcium phosphates. Ionic exchange is amplified in the case of biomimetic hydroxyapatite, which makes the in vitro characterisation of cell-material interactions especially challenging. The present work proposes a novel and simple strategy to explore the mechanisms of interaction of biomimetic and sintered calcium phosphates with mesenchymal stem cells. The effects of topography and ion exchange are analysed separately by modifying the volume ratio between cell culture medium and biomaterial. High ionic fluctuations interfered in the maturation of focal adhesions, hampering cell adhesion and leading to increased apoptosis and reduced proliferation rate.

Acta BiomaterialiaVolume 76, August 2018, Pages 319-332;

Extracellular matrix content and WNT/β-catenin levels of cartilage determine the chondrocyte response to compressive load

H. Praxenthaler, E. Krämer, M. Weisser, N. Hecht, J. Fischer, T. Grossner, W. Richter

During osteoarthritis (OA)-development extracellular matrix (ECM) molecules are lost from cartilage, thus changing gene-expression, matrix synthesis and biomechanical competence of the tissue. Mechanical loading is important for the maintenance of articular cartilage; however, the influence of an altered ECM content on the response of chondrocytes to loading is not well understood, but may provide important insights into underlying mechanisms as well as supplying new therapies for OA. Objective here was to explore whether a changing ECM-content of engineered cartilage affects major signaling pathways and how this alters the chondrocyte response to compressive loading.

Activity of canonical WNT-, BMP-, TGF-β- and p38-signaling was determined during maturation of human engineered cartilage and followed after exposure to a single dynamic compression-episode. WNT/β-catenin- and pSmad1/5/9-levels declined with increasing ECM-content of cartilage. While loading significantly suppressed proteoglycan-synthesis and ACAN-expression at low ECM-content this catabolic response then shifted to an anabolic reaction at high ECM-content. A positive correlation was observed between GAG-content and load-induced alteration of proteoglycan-synthesis. Induction of high β-catenin levels by the WNT-agonist CHIR suppressed load-induced SOX9- and GAG-stimulation in mature constructs. In contrast, the WNT-antagonist IWP-2 was capable of attenuating load-induced GAG-suppression in immature constructs.

In conclusion, either ECM accumulation-associated or pharmacologically induced silencing of WNT-levels allowed for a more anabolic reaction of chondrocytes to physiological loading. This is consistent with the role of proteoglycans in sequestering WNT-ligands in the ECM, thus reducing WNT-activity and also provides a novel explanation of why low WNT-activity in cartilage protects from OA-development in mechanically overstressed cartilage.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseVolume 1864, Issue 3, March 2018, Pages 851-859;

A nonlinear homogenized finite element analysis of the primary stability of the bone–implant interface

M. Ovesy, B. Voumard, P. Zysset

Stability of an implant is defined by its ability to undergo physiological loading–unloading cycles without showing excessive tissue damage and micromotions at the interface. Distinction is usually made between the immediate primary stability and the long-term, secondary stability resulting from the biological healing process. The aim of this research is to numerically investigate the effect of initial implantation press-fit, bone yielding, densification and friction at the interface on the primary stability of a simple bone–implant system subjected to loading–unloading cycles. In order to achieve this goal, human trabecular bone was modeled as a continuous, elasto-plastic tissue with damage and densification, which material constants depend on bone volume fraction and fabric. Implantation press-fit related damage in the bone was simulated by expanding the drilled hole to the outer contour of the implant. The bone–implant interface was then modeled with unilateral contact with friction. The implant was modeled as a rigid body and was subjected to increasing off-axis loading cycles. This modeling approach is able to capture the experimentally observed primary stability in terms of initial stiffness, ultimate force and progression of damage. In addition, it is able to quantify the micromotions around the implant relevant for bone healing and osseointegration. In conclusion, the computationally efficient modeling approach used in this study provides a realistic structural response of the bone–implant interface and represents a powerful tool to explore implant design, implantation press-fit and the resulting risk of implant failure under physiological loading.

Journal Biomechanics and Modelling in Mechanobiology, 17(5), pp. 1471-1480, 2018;

Reversible photodoping of TiO2 nanoparticles for photochromic applications

U. Joost, A. Sutka, M. Oja, K. Smits, N. Döbelin, A. Loot, M. Järvekülg, M. Hirsimäki, M. Valden, E. Nõmmiste

Observations on the strong photochromic effect of crystalline TiO2 quantum dots (mean size ≈ 4 nm) are presented. The synthesized quantum dots consist of irregularly shaped anatase TiO2 nanoparticles (NPs) and are dispersed in butanol (8% by mass). Obtained NPs exhibit a dramatic photoresponse to UV light, enabling effective transmittance modulation in a broad wavelength range extending from the visible to near-infrared region, and even the thermal black body radiation regime beyond 10 μm. The exceptional photoresponse is attributed to hole-scavenging by butanol, TiO2 self-reduction, injection of electrons to the conduction band, and consequent localized surface plasmon resonances in NPs. The observed optical effect is reversible, and the initial high transmittance state can be restored simply by exposing the NPs to air. The applied NP synthesis route is economic and can be easily scaled for applications such as smart window technologies.

Chem. Mater. 30, pp. 8968-74, 2018;

Changes in surface characteristics of titanium and zirconia after surface treatment with ultraviolet light or non‐thermal plasma

A. Henningsen, R. Smeets, R. Heuberger, O. T. Jung, H. Hanken, M. Heiland, C. Cacaci, C. Precht

Positive effects of irradiation with ultraviolet (UV) light or treatment with non‐thermal plasma on titanium and zirconia surfaces have been described in various studies. The aim of this study was to assess and compare the changes in the physicochemical surface conditions of titanium and zirconia surfaces after a short treatment with UV light or with non‐thermal plasmas of argon or oxygen. Titanium and zirconia samples with moderately rough surfaces were treated for 12 min either in a UV‐light oven or in a non‐thermal plasma reactor that generates non‐thermal plasmas of oxygen or argon. Changes in surface conditions were assessed by confocal microscopy, dynamic contact angle measurement, and X‐ray photoelectron spectroscopy (XPS). No changes in roughness occurred. Ultraviolet irradiation and non‐thermal plasma significantly increased the wettability of the titanium and zirconia surfaces. X‐ray photoelectron spectroscopy showed an increase of oxygen and a significant decrease of carbon after treatment with either method. Thus, ultraviolet light and non‐thermal plasma were found to be able to improve the chemical surface conditions of titanium and zirconia following a short exposure time. However, further in vitro and in vivo studies are needed to determine the relevance of the results.

European Journal of Oral sciences, 126(2), pp. 126-134;

Mechanical Testing of Maximal Shift Scarf Osteotomy with Inside-Out Plating Compared to Classic Scarf Osteotomy With Double Screw Fixation

L. Bohnert, A. Radeideh, G. Bigolin, E. Gautier, M. Lottenbach

The purpose of the present study was to biomechanically compare the primary stability of our formerly described inside-out plate fixation to the classic double screw fixation for scarf osteotomy in the treatment of hallux valgus. We performed 20 scarf osteotomies on first metatarsal composite bone models. One half were fixed using a double screw technique and the other half using a locking plate inside-out technique. Using a testing device to simulate the physiologic load, the specimen was loaded until failure, and the load at failure, displacement at failure, and work at failure were recorded. The results were compared between the 2 groups and against the findings from intact sawbones. Compared with the intact bone models, the energy absorption was low for both types of osteotomy fixation. Between the 2 fixation groups, the load at failure was greater for plate fixation, although the difference was not statistically significant (p = .051). However, a statistically significant difference was found between both groups comparing work and displacement at failure (p < .001). In conclusion, the formerly described inside-out plating technique is a biomechanically reasonable alternative to screw fixation because of its primary stability after scarf osteotomy for hallux valgus.

Journal of Foot and Ankle Surgery, Volume 57, Issue 6, November–December 2018, Pages 1056-1058;

A proposed mechanism for material-induced heterotopic ossification

Marc Bohner, R. J. Miron

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.

Materials Today, Volume 22, January–February 2019, Pages 132-141;

Bisphosphonates reduce biomaterial turnover in healing of critical-size rat femoral defects

M. Hauser, M. Siegrist, A. Denzer, N. Saulacic, J. Grosjean, M. Bohner, W. Hofstetter

Treatment of osteoporotic patients with bisphosphonates (BPs) preserves bone mass and microarchitecture. The high prescription rate of the drugs brings about increases in the numbers of fractures and bone defects requiring surgical interventions in these patients. Currently, critical-size defects are filled with biomaterials and healing is supported with bone morphogenetic proteins (BMP). It is hypothesized that BPs interfere with biomaterial turnover during BMP-supported repair of defects filled with β-tricalcium phosphate (βTCP) ceramics. To test this hypothesis, retired breeder rats were ovariectomized (OVX). After 8 weeks, treatment with alendronate (ALN) commenced. Five weeks later, 6 mm diaphyseal femoral defects were applied and stabilized with locking plates. βTCP cylinders loaded with 1 μg and 10 μg BMP2, 10 μg L51P, an inhibitor of BMP antagonists and 1 μg BMP2/10 μg L51P were fitted into the defects. Femora were collected 16 weeks post-implantation. In groups receiving calcium phosphate implants loaded with 10 μg BMP2 and 1 μg BMP2/10 μg L51P, the volume of bone was increased and βTCP was decreased compared to groups receiving implants with 1 μg BMP2 and 10 μg L51P. Treatment of animals with ALN caused a decrease in βTCP turnover. The results corroborate the synergistic effects of BMP2 and L51P on bone augmentation. Administration of ALN caused a reduction in implant turnover, demonstrating the dependence of βTCP removal on osteoclast activity, rather than on chemical solubility. Based on these data, it is suggested that in patients treated with BPs, healing of biomaterial-filled bone defects may be impaired because of the failure to remove the implant and its replacement by authentic bone.

J Orthop Surg 2018;26(3):1-10;

In vitro study of new combinations for local antibiotic therapy with calcium sulphate – Near constant release of ceftriaxone offers new treatment options

P. Wahl, K. Rönn, M. Bohner, L. Decosterd, Ch. Meier, M. Schläppi, S. Festa, E. Gautier

Introduction: Local application of antibiotics provides high concentrations at the site of interest, with minimal systemic toxicity. Carrier materials might help manage dead space. Calcium sulphate (CaSO4) has a dissolution time that only slightly exceeds the usually recommended duration of systemic antibiotic treatments. This in vitro study evaluates compatibility, release kinetics and antibacterial activity of new combinations of antibiotics with CaSO4 as carrier material.

Methods: CaSO4 pellets added with 8% w/w antibiotic powder were exposed once in phosphate-buffered saline (PBS) solution and once in bovine plasma, in an elution experiment run over 6 weeks at 37 °C. Antibiotic elution was examined at various time points. Concentration was measured by liquid chromatography with tandem mass spectrometry. Antimicrobial activity was checked with an agar diffusion test.

Results: Piperacillin-tazobactam, ceftazidime, cefepime, and meropenem showed fast reduction of concentration and activity. Flucloxacillin and cefuroxime remained present in relevant concentrations for 4 weeks. Ciprofloxacin, levofloxacin and clindamycin lasted for 6 weeks, but also at cell toxic concentrations. Ceftriaxone showed a near-constant release with only a small reduction of concentration from 130 to 75 mg/l. Elution profiles from PBS and plasma were comparable.

Conclusion: CaSO4 provides new possibilities in the local treatment of bone and joint infections. Ceftriaxone appears to be of particular interest in combination with CaSO4. Release persists at clinically promising concentrations, and appears to have a depot-like slow release from CaSO4, with only a small reduction in activity and concentration over 6 weeks. To the best of our knowledge, such a particular persistent release never was described before, for any antibiotic in combination with a carrier material for local application.

J Bone Jt Infect 2018; 3(4):212-221;

Joint academic and industrial efforts towards innovative and efficient solutions for clinical needs

A. De Pieri, S. Ribeiro, D. Tsiapalis, D. Eglin, M. Bohner, P. Dubruel, Ph. Procter, D. I. Zeugolis, Y. Bayon

The 4th Translational Research Symposium (TRS) was organised at the annual meeting of the European Society for Biomaterials (ESB) 2017, Athens, Greece, with a focus on ‘Academia—Industry Clusters of Research for Innovation Catalysis’. Collaborations between research institutes and industry can be sustained in several ways such as: European Union (EU) funded consortiums; syndicates of academic institutes, clinicians and industries; funding from national governments; and private collaborations between universities and companies. Invited speakers from industry and research institutions presented examples of these collaborations in the translation of research ideas or concepts into marketable products. The aim of the present article is to summarize the key messages conveyed during these lectures. In particular, emphasis is put on the challenges to appropriately identify and select unmet clinical needs and their translation by ultimately implementing innovative and efficient solutions achieved through joint academic and industrial efforts.

J Mater Sci Mater Med 2018; 29(8):129;

Comparison of Fixation Techniques for Acetabular Fractures Involving the Anterior Column with Disruption of the Quadrilateral Plate: A Biomechanical Study

C. May, M. Egloff, A. Butscher, M. J. B. Keel, T. Aebi, K. A. Siebenrock, J. D. Bastian

Background: In elderly patients who have sustained an acetabular fracture involving disruption of the quadrilateral plate (QLP), postoperative loading of the joint beyond the level of partial weight-bearing can result in medial redisplacement of the QLP. The purpose of this biomechanical study was to compare the performances of 4 different fixation constructs intended to prevent medial redisplacement of the QLP.

Methods: Anterior column posterior hemitransverse (ACPHT) fractures with disruption of the QLP were created on synthetic hemipelves (fourth-generation Sawbones models) and subsequently stabilized with (1) a 12-hole plate bridging the QLP (Group 1), (2) the plate with added periarticular screws along the QLP (Group 2), (3) the plate combined with an infrapectineal buttress plate (Group 3), or (4) the plate with the added periarticular screws as well as the buttress plate (Group 4). The point of load application on the acetabulum was defined to be the same as the point of application of maximum vertical hip contact force during normal walking. Loads were applied to simulate either partial weight-bearing (20 cycles, from 35 to 350 N) or inadvertent supraphysiologic loads (linearly increasing loads until the onset of failure, defined as fragment displacement of >3 mm). A universal testing machine was synchronized with a digital image correlation system to optically track redisplacement at the QLP. The level of significance was set at p < 0.05.

Results: During experimental simulation of partial weight-bearing, maximum fracture step openings never exceeded 2 mm. During simulation of inadvertent supraphysiologic load, the median load to failure was higher (p < 0.05) in Group 2 (962 N; range, 798 to 1,000 N) and Group 4 (985 N; range, 887 to 1,000 N) compared with Group 1 (445 N; range, 377 to 583 N) and Group 3 (671 N; range, 447 to 720 N).

Conclusions: All 4 fixation constructs performed in an acceptable manner on testing with simulated partial weight-bearing. Only additional periarticular screws along the QLP increased the fixation strength.

Clinical Relevance: Redisplacement of the QLP resulting in an incongruency of the hip joint has been associated with poor long-term outcomes. Within the constraints of this study, periarticular long screws were superior to infrapectineal buttress plates in preventing medial redisplacement of the QLP.

JBJS: June 20, 2018 - Volume 100 - Issue 12 - p 1047–1054; DOI: 10.2106/jbjs.17.00295

Absorbable mineral nanocomposite for biomedical applications: Influence of homogenous fiber dispersity on mechanical properties

E. Mulky, K. Maniura-Weber, M. Frenz, G. Fortunato, R. Luginbuehl

Electrospun micro- and nanosized fibers are frequently used as reinforcing elements in low temperature ceramic composites for biomedical applications. Electrospinning of fibers yield, however, not individual fibers, but rather fiber-mats that are difficult to separate. Most investigations have been performed on diced mats and highly nonhomogenous composites. We examined the influence of dispersed electrospun single micro- and nanometer fibers on the mechanical properties of calcium phosphate cement composites. Absorbable poly-l-lactic-acid was electrospun yielding fibers with diameters of 244 ± 78 nm, named nanofibers (NF), and 1.0 ± 0.3 μm, named microfibers (MF). These fibers were cut using a particle assisted ultrasonication process and dispersed with hydroxyapatite nanoparticles and composites of low (5%) and high (30%) NF/MF content were engineered. The homogeneity of the fiber distribution was investigated by analyzing fracture areas regarding the number of fibers and Voronoi area size distribution. Variation of fiber distribution was significantly lower in the NF group as compared to the MF group. For composites containing 5% NF (V/V), an eightfold increase in the compressive fracture strength, and for the 30% NF (V/V) a threefold increase compared was measured. The composite containing 5% NF was identified as optimal regarding fiber distribution and strength. Our new method of engineering these composites allows for high volume fractions of NF with low variation in fiber distribution to be incorporated into composites, and shows the importance of using single filaments as reinforcing agents.

J Biomed Mater Res Part A: 106A: 850–857, 2018; DOI: 10.1002/jbm.a.36284

Global chondrocyte gene expression after a single anabolic loading period: Time evolution and re-inducibility of mechano-responses

S. Scholtes, E. Krämer, M. Weisser, W. Roth, R. Luginbühl, T. Grossner, W. Richter

Aim of this study was a genome-wide identification of mechano-regulated genes and candidate pathways in human chondrocytes subjected to a single anabolic loading episode and characterization of time evolution and re-inducibility of the response. Osteochondral constructs consisting of a chondrocyte-seeded collagen-scaffold connected to β-tricalcium-phosphate were pre-cultured for 35 days and subjected to dynamic compression (25% strain, 1 Hz, 9 × 10 min over 3 hr) before microarray-profiling was performed. Proteoglycan synthesis was determined by 35S-sulfate-incorporation over 24 hr. Cell viability and hardness of constructs were unaltered by dynamic compression while proteoglycan synthesis was significantly stimulated (1.45-fold, p = 0.016). Among 115 significantly regulated genes, 114 were up-regulated, 48 of them ≥ twofold. AP-1-relevant transcription factors FOSB and FOS strongly increased in line with elevated ERK1/2-phosphorylation and rising MAP3K4 expression. Expression of proteoglycan-synthesizing enzymes CHSY1 and GALNT4 was load-responsive as were factors associated with the MAPK-, TGF-β-, calcium-, retinoic-acid-, Wnt-, and Notch-signaling pathway which were significantly upregulated SOX9, and BMP6 levels rose significantly also after multiple loading episodes at daily intervals even at the 14th cycle with no indication for desensitation. Canonical pSmad2/3 and pSmad1/5/9-signaling showed no consistent regulation. This study associates novel genes with mechanoregulation in chondrocytes, raising SOX9 protein levels with anabolic loading and suggests that more pathways than so far anticipated apparently work together in a complex network of stimulators and feedback-regulators. Upregulation of mechanosensitive indicators extending differentially into the resting time provides crucial knowledge to maximize cartilage matrix deposition for the generation of high-level cartilage replacement tissue.

Journal of Cellular Physiology, Volume 233, Issue 1, January 2018, Pages 699–711; DOI: 10.1002/jcp.25933

Multimodal analysis of in vivo resorbable CaP bone substitutes by combining histology, SEM, and microcomputed tomography data

A. Sweedy, M. Bohner, G. Baroud

This study introduced and demonstrated a new method to investigate the repair process of bone defects using micro- and macroporous beta-tricalcium phosphate (β-TCP) substitutes. Specifically, the new method combined and aligned histology, SEM, and preimplantation microcomputed tomography (mCT) data to accurately characterize tissue phases found in biopsies, and thus better understand the bone repair process. The results included (a) the exact fraction of ceramic remnants (CR); (b) the fraction of ceramic resorbed and substituted by bone (CSB); and (c) the fraction of ceramic resorbed and not substituted by bone (CNSB). The new method allowed in particular the detection and quantification of mineralized tissues within the 1–10 µm micropores of the ceramic (“micro-bone”). The utility of the new method was demonstrated by applying it on biopsies of two β-tricalcium phosphate bone substitute groups with two differing macropore sizes implanted in an ovine model for 6 weeks. The total bone deposition and ceramic resorption of the two substitute groups, having macropore sizes of 510 and 1220 μm, were 25.1 ± 8.1% and 67.5 ± 3.2%, and 24.4 ± 4.1% and 61.4 ± 6.5% for the group having the larger pore size.

J Biomed Mater Res Part B: Appl Biomater, 106B: 1567–1577, 2018; DOI: 10.1002/jbm.b.33962

Photofunctionalization and non-thermal plasma activation of titanium surfaces

A. Henningsen, R. Smeets, P. Hartjen, O. Heinrich, R. Heuberger, M. Heiland, C. Precht, C. Cacaci


The aim of this study was to compare UV light and non-thermal plasma (NTP) treatment regarding the improvement of physical material characteristics and cell reaction on titanium surfaces in vitro after short-term functionalization.

Materials and methods

Moderately rough (Ra 1.8–2.0 μm) sandblasted and acid-etched titanium disks were treated by UV light (0.05 mW/cm2 at λ = 360 nm and 2 mW/cm2 at λ = 250 nm) or by NTP (24 W, -0.5 mbar) of argon or oxygen for 12 min each. Surface structure was investigated by scanning electron microscopy, confocal microscopy and X-ray photoelectron spectroscopy (XPS). Hydrophilicity was assessed by dynamic contact angle measurement. Cell attachment, viability, cell proliferation and cytotoxicity were assessed in vitro using murine osteoblast-like cells.


UV irradiation or NTP treatment of titanium surfaces did not alter the surface structure. XPS analysis revealed a significantly increased oxidation of the surface and a decrease of carbon after the use of either method. NTP and UV light led to a significant better cell attachment of murine osteoblasts; significantly more osteoblasts grew on the treated surfaces at each time point (p < 0.001).


UV light as well as NTP modified the surface of titanium and significantly improved the conditions for murine osteoblast cells in vitro. However, results indicate a slight advantage for NTP of argon and oxygen in a short time interval of surface functionalization compared to UV.

Clinical relevance

UV light and NTP are able to improve surface conditions of dental implants made of titanium.

Clinical Oral Investigations: March 2018, Volume 22, Issue 2, pp 1045–1054; DOI: 10.1007/s00784-017-2186-z


Facile synthesis of magnetically separable CoFe2O4/Ag2O/Ag2CO3 nanoheterostructures with high photocatalytic performance under visible light and enhanced stability against photodegradation

A. Sutka, N. Doebelin, U. Joost, K. Smits, V. Kisand, M. Maiorov, K. Kooser, M. Kook, R. F. Duarte, T. Käämbre

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.

Journal of Environmental Chemical Engineering, 5(4), pp 3455-3462, 2017, DOI: 10.1016/j.jece.2017.07.009

Particles and Ions Generated in Total Hip Joint Prostheses: In Vitro Wear Test Results of UHMWPE and XLPE Acetabular Components

H. Zohdi, B. Andreatta, R. Heuberger

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.

Tribol Lett  (2017) 65:92; DOI: 10.1007/s11249-017-0872-2

Characterization and distribution of mechanically competent mineralized tissue in micropores of β-tricalcium phosphate bone substitutes

M. Bohner, G. Baroud, A. Bernstein, N. Döbelin, L. Galea, B. Hesse, R. Heuberger, S. Meille, P. Michel, B. von Rechenberg, J. Sague, H. Seeherman

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.

Materals Today, Vol. 20, Issue 3, April 2017, Pages 106-115; DOI: 10.1016/j.mattod.2017.02.002

A novel method for segmentation and aligning the pre- and post-implantation scaffolds of resorbable calcium phosphate bone substitutes

A. Sweedy, M. Bohner, G. H. van Lenthe, G. Baroud

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.


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.

Acta Biomaterialia, May 2017; 54:441-453; DOI: 10.1016/j.actbio.2017.03.001

Effect of sex-hormone levels, sex, body mass index and other host factors on human craniofacial bone regeneration with bioactive tricalcium phosphate grafts

C. Knabe, A. Mele, P. H. Kann, B. Peleska, D. Adel-Khattab, H. Renz, A. Reuss, M. Bohner, M. Stiller

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.

Biomaterials, pp 123:48-62, 2017; DOI: 10.1016/j.biomaterials.2017.01.035

Composite material consisting of microporous β-TCP ceramic and alginate for delayed release of antibiotics

M. Seidenstuecker, J. Ruehe, N. P. Suedkamp, A. Serr, A. Wittmer, M. Bohner, A. Bernstein, H. O. Mayr


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.

Material and methods

Using the flow chamber developed by the group, porous ceramics in a directional flow were filled with alginates of different composition containing 50 mg/mL of antibiotics. After cross-linking the alginate with calcium ions, incubation took place in 10 mL double-distilled water for 4 weeks at 37 °C. At defined times (1, 2, 3, 6, 9, 14, 20 and 28 days), the liquid was completely exchanged and analyzed by capillary zone electrophoresis and microtiter trials. For statistical purposes, the mean and standard deviation were calculated and analyzed by ANOVA.


The release of VAN from alginate was carried out via an external calcium source over the entire period with concentrations above the minimal inhibitory concentration (MIC). The burst release measured 35.2 ± 1.5%. The release of VAN from alginate with an internal calcium source could only be observed over 14 days. The burst release here was 61.9 ± 4.3%. The native alginate’s burst release was 54.1 ± 7.8%; that of the sterile alginate 40.5 ± 6.4%. The microtiter experiments revealed efficacy over the entire study period for VAN. The MIC value was determined in the release experiments as well in a range of 0.5–2.0 μg/mL against Staphylococcus aureus.

Statement of Significance

Drug release systems based on β-TCP and hydrogels are well documented in literature. However, in all described systems the ceramic, as granule or powder, is inserted into a hydrogel. In our work, we do the opposite, a hydrogel which acts as reservoir for antibiotics is placed into a porous biodegradable ceramic. Eventually, this system should be applied as treatment of bone infections. Contrary to the “granule in hydrogel” composites it has the advantage of mechanical stability. Thus, it can take over functions of the bone during the healing process. For a quicker translation from our scientific research into clinical use, only FDA approved materials were used in this work.

Acta Biomaterialia pp 51:433-46, 2017; DOI: 10.1016/j.actbio.2017.01.045

Low metallic wear of dynamic intraligamentary stabilization

Ch. May, B. Gueorguiev, R. Heuberger, J. Sague, Ch. Gross, Ph. Henle, D. Delfosse, J. Häberli

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.

Tribology International, Volume 109, May 2017, Pages 217-221; DOI: 10.1016/j.triboint.2016.12.041

Surrogate Outcome Measures of In Vitro Osteoclast Resorption of β Tricalcium Phosphate

S. A. Clarke, J. Martin, J. Nelson, J. -C. Hornez, M. Bohner, N. Dunne, F. Buchanan

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.

Advanced Healthcare Materials Volume 6, Issue 1 January 11, 2017;1600947,  DOI: 10.1002/adhm.201600947


Hydrogen-substituted β-tricalcium phosphate synthesized in organic media

Ch. Stähli, J. Thüring, L. Galea, S. Tadier, M. Bohner, N. Döbelin

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 Ca21 − x(HPO4)2x(PO4)14 − 2x, where x = 0.80 ± 0.04, and may have implications for resorption properties of bone regenerative materials.

Acta Crystallographica Section B B72:875-884, 2016; DOI: 10.1107/S2052520616015675

Effect of cobalt doping on the mechanical properties of ZnO nanowires

M. Vahtrus, A. Šutka, B. Polyakov, S. Oras, M. Antsov, N. Döbelin, R. Lohmus, E. Nõmmiste, S. Vlassov

In 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.

Materials Characterization 121, pp. 40-47, 2016; DOI: 10.1016/j.matchar.2016.09.027

Effect of niobium onto the tribological behavior of cathodic arc deposited Nb–Ti–N coatings

D. D. La Grange, N. Goebbels, A. Santana, R. Heuberger, T. Imwinkelried, L. Eschbach, A. Karimi

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.

Wear Vol. 368-369, pp 60-69, 2016; DOI: 10.1016/j.wear.2016.09.003

Innovating in the Medical Device Industry - Challenges & Opportunities. ESB 2015 Translational Research Symposium

Y. Bayon, M. Bohner, D. Eglin, P. Procter, R. G. Richards, J. Weber, D. I. Zeugolis

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.

J Mater Sci Mater Med 27, pp. 144, 2016; DOI: 10.1007/s10856-016-5759-5

Controlled release of NELL-1 protein from chitosan-modified ATCP particles

Y. Zhang, R. Dong, Y. Park, M. Bohner, X. Zhang, K. Ting, C. Soo, B. M. Wu

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.

International Journal of Pharmaceutics 511, pp. 79-89, 2016; DOI: 10.1016/j.ijpharm.2016.06.050

In vivo degradation of a new concept of magnesium-based rivet-screws in the minipig mandibular bone

B. Schaller, N. Saulacic, S. Beck, Th. Imwinkelried, B. T. Goh, K. Nakahara, W. Hofstetter, T. Iizuka

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.

Materials Science and Engineering C 69, pp 247-254, 2016; DOI: 10.1016/j.msec.2016.06.085

The Effects of Crystal Phase and Particle Morphology of Calcium Phosphates on Proliferation and Differentiation of Human Mesenchymal Stromal Cells

Ch. Danoux, D. Pereira, N. Döbelin, Ch. Stähli, J. Barralet, C. van Blitterswijk, P. Habibovic

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.

Advanced Healthcare Materials 5(14), pp. 1775-1785, 2016; DOI: 10.1002/adhm.201600184

Full-field Calcium K-Edge X-ray Absorption Near-Edge Spectroscopy on Cortical Bone at the Micron-Scale: Polarization Effects Reveal Mineral Orientation

B. Hesse, M. Salome, H. Castillo-Michel, M. Cotte, B. Fayard, Ch. Sahle, W. De Nolf, J. Hradilova, A. Masic, B. Kanngiesser, M. Bohner, P. Varga, K. Raum, S. Schrof

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.

Analytical Chemistry 88(7), pp. 3826–3835, 2016; DOI: 10.1021/acs.analchem.5b04898

Ag sensitized TiO2 and NiFe2O4 three-component nanoheterostructures: Synthesis, electronic structure and strongly enhanced visible light photocatalytic activity

A. Šutka, T. Käämbre, R. Pärna, N. Döbelin, M. Vanags, K. Smits, V. Kisand

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.

RSC Advances 6(23):18834-18842, 2016; DOI: 10.1039/C6RA00728G

In vivo degradation of magnesium plate/screw osteosynthesis implant systems: Soft and hard tissue response in a calvarial model in miniature pigs

B. Schaller, N. Saulacic, Th. Imwinkelried, S. Beck, E. W. Y. Liu, J. Gralla, K. Nakahara, W. Hofstetter, T. Iizuka

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.

Journal of Cranio-Maxillofacial Surgery 44 (3), pp 309-317, 2016; DOI: 10.1016/j.jcms.2015.12.009

Calcium phosphates in biomedical applications: materials for the future?

W. Habraken, P. Habibovic, M. Epple, M. Bohner

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.

Materals Today 19(2): 69-87, 2016; DOI: 10.1016/j.mattod.2015.10.008

Influence of Mg-doping, calcium pyrophosphate impurities and cooling rate on the allotropic α↔β-tricalcium phosphate phase transformations

P. M. C. Torres, J. Abrantes, A. Kaushal, S. Pina, N. Döbelin, M. Bohner, J. M. F. Ferreira

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%.

Journal of the European Ceramic Society, 36:817-27, 2016; DOI: 10.1016/j.jeurceramsoc.2015.09.037

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