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Abstract The nature of smart factories to help manufacturing firms reducing environmental emissions has attracted the widespread attention of governments and industries. However, some research also worried that if smart factories were not effectively constructed, they may increase firms’ environmental emissions. To address this concern, we use PSM-progressive DID model to analyze the relationships between the construction of smart factories and environmental emissions, based on 144 Chinese listed manufacturing firms. The main findings are as follow. First, the construction of smart factories can lead to the short-term increase of 7.55% GHG emissions (1.001 tCO2e) and 4.12% air pollutants cost (1.011 $) per $M operation cost for firms. Second, the negative impact of smart factory construction on GHG emissions can be partially explained by physical technologies. Third, mimetic institution (industrial maturity of environment management system) can reduce the negative impact of smart factory construction, but coercive institution (government regulation) and normative institution (social media attention) have no significant moderating effect. With these findings, this study provides a clear understanding of how the construction of smart factories influences firms’ environmental sustainability and accordingly offers insights for business considering environmental objectives in smart factory development.

Summary: Pesticides may help safeguard food security but endanger the local ecosystem and farmer health. The globalization of the food trade is masking such impacts by separating production from consumption, and its effects on pesticide use and their related risks remain unclear. Here, we provide a map of the environmental and health risks associated with pesticide footprints along the soybean trade across 197 countries. We find that approximately 64% of soybeans were traded globally, embodying ∼55% of environmental-health risks linked to ∼108 kt of pesticide use. Notably, trade soybean pesticide footprints and their associated environmental-health risks are concentrated in a few hotspot nations, including the USA, Brazil, and Argentina. About 30 kt of future increase in soybean pesticide use and ∼6% of their related environmental-health risks can be offset by reducing 80% of soybean traded from high-pesticide-use-intensity nations to lower ones. Our results highlight the necessity of rethinking the role of agricultural trade in global pesticide management. Science for society: The widespread use of pesticides in food production systems impacts human, animal, and ecosystem health. Food trade complicates the issue, as it can separate consumption from production, shifting pesticide-related burdens from consumers to producers across regions. However, there is a lack of clarity on pesticide footprints and their associated impacts embodied in the global food trade, impeding sustainable pesticide management. Our research develops an integrated framework to assess nation-specific environmental and health burdens linked to pesticide use along the global soybean trade. Our study identifies a concentrated pattern of embodied soybean pesticide footprints and their related risks, as well as a declining contribution of trade to overall pesticide-related risks. Our findings reveal the potential of trade in reducing environmental-health risks associated with soybean pesticides and underscore the need to rethink the role of agricultural trade in global pesticide management.

Abstract Urban floods are the most severe disaster in most Chinese cities due to rapid urbanisation and climate challenges. Recently, media data analytics has become prominent in enhancing urban flood resilience. In this study, news media data from the GKG of the GDELT project was innovatively used to examine the pattern of news media responses towards urban flooding in China's Sponge City Programme (SCP) pilot cities. We find that public sentiments toward urban flood events have been more positive in SCP pilot cities from 2015 to 2021. News media responses towards urban floods exhibit strong seasonality, which is significantly connected with rainfall patterns. Most of the media articles were posted during the urban flood event. Finally, we suggest the opportunities and challenges in applying GKG data analytics and new technologies for urban flood resilience. The results can provide beneficial references to urban flood management strategies in China's Sponge Cities for associated policymakers and stakeholders.

Reverse logistics has gained increasing attention in recent years as a channel for companies to achieve operational excellence. The process involves manipulation of returned materials, or even products, which forms a pivotal role in sustainable development throughout the whole supply chains. To make reverse logistics possible, process re-engineering may need to be carried out. However, the processes involved in reengineering are practically complicated. Objectives, benefits, and applicability of any process re-engineering require a careful and detailed strategic planning. This paper aims to propose an easy-to-follow step-by-step framework for practitioners to perform process re-engineering, to learn and identify the critical issues in each step, and to be successful in applying process re-engineering in order to enhance reverse logistics performance. A learner-centred approach is adopted based on a case study of process re-engineering, which is demonstrated in the paper for explanation.

Designing environmentally friendly products has become a tighter requirement in the marketplace because of both the increasing trend in awareness of consumers and the obligations from legislation requirements. Unfortunately, this is not a straight forward decision for designers to evaluate whether their design options are satisfactory in terms of balancing various factors (for examples, different forms of environmental assessment) or not. This is partly attributed to the fact that there is no universally accepted approach for conducting such analysis. In this connection, this research makes reference to a European Union (EU) directive as a reference model and makes use of Analytic Hierarchical Process (AHP), which is a useful tool to help designers to make decision, for evaluating eco-design options. The AHP model is developed based on two case studies on consumer electronic products. Pairwise comparisons, one of the key steps in AHP, are conducted with the expertise gained from the case studies and the help from the software package Expert Choice. The paper also reveals how design options can be evaluated, or be screened out. The proposed method does not require the designers to conduct detailed analysis (life-cycle assessment for example) for every new product options and hence can save their time. This is particularly important when they are facing shorter and shorter product life cycle nowadays. First published online: 18 Jun 2014

α-Fe 2 O 3 (hematite) thin films have been shown to be a robust sensor substrate for photoelectrochemical imaging with good stability and high spatial resolution. Herein, one-dimensional (1D) hematite nanorods (NRs) synthesized via a simple hydrothermal method are proposed as a substrate which provides nanostructured surfaces with enhanced photocurrent responses compared to previously described hematite films, good stability, and excellent spatial resolution for potential imaging applications. The photoelectrochemical sensing capability of hematite NRs was demonstrated by a high pH sensitivity without modification. The modification of the hematite NRs with a thin poly(vinyl chloride) (PVC)-based ion-selective film allowed highly reversible amperometric detection of calcium ions with sensor materials traditionally employed in potentiometric devices., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Photoelectrochemical imaging has great potential in the label-free investigation of cellular processes. Herein, we report a new fast photoelectrochemical imaging system (PEIS) for DC photocurrent imaging of live cells, which combines high speed with excellent lateral resolution and high photocurrent stability, which are all crucial for studying dynamic cellular processes. An analog micromirror was adopted to raster the sensor substrate, enabling high-speed imaging. α-Fe 2 O 3 (hematite) thin films synthesized via electrodeposition were used as a robust substrate with high photocurrent and good spatial resolution. The capabilities of this system were demonstrated by monitoring cell responses to permeabilization with Triton X-100. The ability to carry out dynamic functional imaging of multiple cells simultaneously provides improved confidence in the data than could be achieved with the slower electrochemical single-cell imaging techniques described previously. When monitoring pH changes, the PEIS can achieve frame rates of 8 frames per second., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To evaluate graft healing of decellularized porcine superflexor tendon (pSFT) xenograft in an ovine anterior cruciate ligament (ACL) reconstruction model using two femoral fixation devices. Also, to determine if pSFT allows functional recovery of gait as compared with the preoperative measurements., Methods: A total of 12 sheep underwent unilateral single-bundle ACL reconstruction using pSFT. Two femoral fixation devices were investigated: Group 1 (n = 6) used cortical suspensory fixation (Endobutton CL) and Group 2 (n = 6) used cross-pin fixation (Stratis ST). A soft screw was used for tibial fixation. Functional recovery was quantified using force plate analysis at weeks 5, 8, and 11. The sheep were euthanized after 12 weeks and comprehensive histological analysis characterized graft healing at the graft-bone interface and the intra-articular graft (ligamentization)., Results: The pSFT remodelled into a ligament-like structure and no adverse inflammatory reaction was seen. The ground reaction force in the operated leg of the Endobutton group was higher at 11 weeks (p < 0.05). An indirect insertion was seen at the graft-bone interface characterized by Sharpey-like fibres. Qualitative differences in tendon remodelling were seen between the two groups, with greater crimp-like organization and more aligned collagen fibres seen with Endobutton fixation. One graft rupture occurred in the cross-pin group, which histologically showed low collagen organization., Conclusion: Decellularized pSFT xenograft remodels into a ligament-like structure after 12 weeks and regenerates an indirect-type insertion with Sharpey-like fibres. No adverse inflammatory reaction was observed. Cortical suspensory femoral fixation was associated with more enhanced graft remodelling and earlier functional recovery when compared with the stiffer cross-pin fixation., (© 2020 Author(s) et al.)

A comparative investigation was undertaken on 1-2mm sized granules of two forms of synthetic bone graft substitute (SBG) with identical pore structure but varied bulk chemistry, stoichiometric hydroxyapatite (HA) and silicate substituted (0.8wt% Si) hydroxyapatite (SA), to assess the influence of SBG chemistry on the relative affinity of an osteogenic growth factor (GF), recombinant human bone morphogenetic protein-2 (rhBMP-2). A previously described novel fluorescent probe, fluoresceinthioureidoaminocaproic acid (FTCA), was covalently attached to rhBMP-2 to give FTCA-rhBMP-2 and facilitate the quantitative monitoring of GF uptake and release from the two chemistries of SBG. The relative affinity of rhBMP-2 for the HA and SA granules was assessed at a physiologically relevant concentration of 300ngmL -1 from three (increasingly complex) environments; phosphate buffered saline (PBS), minimum Eagles' medium (MEM) and serum supplemented MEM (SCEM) in order to closely mimic clinical bone repair procedures. The results demonstrated that rhBMP-2 affinity to SBGs was highly sensitive to both SBG chemistry and the composition of the local environment. Under the most physiologically relevant competitive conditions of SCEM, rhBMP-2 showed greater affinity to SA (P<0.05) such that 50% of the rhBMP-2 in solution was adsorbed to the SA granules after only 15min, as compared to 30% adsorbed to the HA granules. Subsequent investigation of the desorption of adsorbed GF from the SBGs demonstrated that a significantly higher percentage of the adsorbed rhBMP-2 was desorbed from HA as compared to SA granules. Together, these observations suggested that at physiologically relevant concentrations and conditions, rhBMP-2 has a greater affinity to silicate-substituted hydroxyapatite as compared to stoichiometric hydroxyapatite, which may in part explain the enhanced osteoconductivity and reported osteoinductivity for silicate-substituted hydroxyapatite based SBGs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study compared the bone forming capacity of the same formulation of silicate-substituted bone graft substitute materials with different microporosity in an instrumented posterolateral spinal fusion ovine model. Materials with a strut porosity of (i) 22.5% (SiCaP) or (ii) 36.0% (SiCaP(+)) were packed along either side of the spine. Bone apposition rates, % new bone formation, % bone-implant contact, and % graft resorption were quantified at 8, 12, and 24 weeks post surgery. Computed Tomography (CT) was used to grade the formation of fusion bridges between vertebrae. Results showed no significant difference in bone apposition rates, % new bone formation, and % bone-implant contact when the two materials were compared. However, at 8 weeks, a significantly higher CT score was obtained in the SiCaP(+) group (0.83 ± 0.17) when compared with the SiCaP group (0.17 ± 0.17; p = 0.027). Significantly less scaffold remained in the SiCaP(+) group at 12 weeks (p = 0.018). Both SiCaP and SiCaP(+) formulations augmented bone formation. Increasing the strut porosity did not significantly increase bone formation however, at 8 weeks it promoted the formation of more highly mineralized bone resulting in a significantly higher CT score, suggesting the bone tissue formed was more mature. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 805-814, 2017., (© 2016 Wiley Periodicals, Inc.)

Porous bioactive glasses are attractive for use as bone scaffolds. There is increasing interest in strontium containing bone grafts, since strontium ions are known to up-regulate osteoblasts and down regulate osteoclasts. This paper investigates the influence of partial to full substitution of strontium for calcium on the dissolution and phase formation of a multicomponent high phosphate content bioactive glass. The glasses were synthesised by a high temperature melt quench route and ground to a powder of <38 microns. The dissolution of this powder and its ability to form apatite like phases after immersion in Tris buffer (pH 7.4) and simulated body fluid (SBF) was followed by inductively coupled plasma optical emission spectroscopy (ICP), Fourier transform infra red spectroscopy (FTIR), X-ray powder diffraction (XRD) and (31)P solid state nuclear magnetic resonance spectroscopy up to 42 days of immersion. ICP indicated that all three glasses dissolved at approximately the same rate. The all calcium (SP-0Sr-35Ca) glass showed evidence of apatite like phase formation in both Tris buffer and SBF, as demonstrated after 3 days by FTIR and XRD analysis of the precipitate that formed during the acellular dissolution bioactivity studies. The strontium substituted SP-17Sr-17Ca glass showed no clear evidence of apatite like phase formation in Tris, but evidence of an apatite like phase was observed after 7 days incubation in SBF. The SP-35Sr-0Ca glass formed a new crystalline phase termed "X Phase" in Tris buffer which FTIR indicated was a form of crystalline orthophosphate. The SP-35Sr-0Ca glass appeared to support apatite like phase formation in SBF by 28 days incubation. The results indicate that strontium substitution for calcium in high phosphate content bioactive glasses can retard apatite like phase formation. It is proposed that apatite formation with high phosphate bioactive glasses occurs via an octacalcium phosphate (OCP) precursor phase that subsequently transforms to apatite. The equivalent octa-strontium phosphate does not exist and consequently in the absence of calcium, apatite formation does not occur. The amount of strontium that can be substituted for calcium in OCP probably determines the amount of strontium in the final apatite phase and the speed with which it forms.

A synthetic bone graft substitute consisting of silicate-substituted calcium phosphate with increased strut porosity (SiCaP EP) was evaluated in an ovine distal femoral critical sized metaphyseal defect as a standalone bone graft, as an autologous iliac crest bone graft (ICBG) extender (SiCaP EP/ICBG), and when mixed with bone marrow aspirate (SiCaP EP/BMA). Defects were evaluated after 4, 8, and 12 weeks with radiography, decalcified paraffin-embedded histopathology, non-decalcified resin-embedded histomorphometry, and mechanical indentation testing. All test groups exhibited excellent biocompatibility and osseous healing as evidenced by an initial mild inflammatory response followed by neovascularization, bone growth, and marrow infiltration throughout all SiCaP EP-treated defects. SiCaP EP/ICBG produced more bone at early time points, while all groups produced similar amounts of bone at later time points. SiCaP EP/ICBG likewise showed more favorable mechanical properties at early time points, but was equivalent to SiCaP EP and SiCaP EP/BMA at later time points. This study demonstrates that SiCaP EP is efficacious as a standalone bone graft substitute, mixed with BMA, and as an autograft extender.

Bioactive glasses are used clinically for bone regeneration, and their bioactivity and cell compatibility are often characterized in vitro, using physiologically relevant test solutions. The aim of this study was to show the influence of varying medium characteristics (pH, composition, presence of proteins) on glass dissolution and apatite formation. The dissolution behavior of a fluoride-containing bioactive glass (BG) was investigated over a period of one week in Eagle's Minimal Essential Medium with Earle's Salts (MEM), supplemented with either, (a) acetate buffer, (b) 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer, (c) HEPES + carbonate, or (d) HEPES + carbonate + fetal bovine serum. Results show pronounced differences in pH, ion release, and apatite formation over 1 week: Despite its acidic pH (pH 5.8 after BG immersion, as compared to pH 7.4-8.3 for HEPES-containing media), apatite formation was fastest in acetate buffered (HEPES-free) MEM. Presence of carbonate resulted in formation of calcite (calcium carbonate). Presence of serum proteins, on the other hand, delayed apatite formation significantly. These results confirm that the composition and properties of a tissue culture medium are important factors during in vitro experiments and need to be taken into consideration when interpreting results from dissolution or cell culture studies., (Copyright © 2013 Wiley Periodicals, Inc.)

The bioactivity of calcium phosphate bone grafts of varying chemistry and strut-porosity was compared by determining the rate of formation of hydroxycarbonate apatite crystals on the material surface after being soaked in simulated body fluid for up to 30 days. Three groups of silicate-substituted hydroxyapatite material were tested, with each group comprising a different quantity of strut-porosity (23, 32, and 46 % volume). A commercially available porous β-tricalcium phosphate bone graft substitute was tested for comparison. Results indicate that strut-porosity of a material affects the potential for formation of a precursor to bone-like apatite and further confirms previous findings that β-tricalcium phosphate is less bioactive than hydroxyapatite.

In this article, a method to analyze protein adsorption on porous, clinically relevant samples under physiologically relevant conditions is described. The use of fluorescent probes was identified as a methodology that would facilitate analysis under a range of conditions including fully competitive conditions where a protein of interest may be labeled in isolation and then allowed to compete with unlabeled proteins on samples that require no specialized surface pretreatment. As a first step, this article describes the covalent labeling of isolated bovine serum albumin (BSA) with fluorescent fluoresceinthioureidoaminocaproic acid, FTCA, giving FTCA-BSA. The fluorescence intensity of FTCA-BSA was then used to monitor the adsorption and desorption of the protein under noncompetitive conditions with two forms of hydroxyapatite discs (silicate-substituted, SA and stoichiometric, HA) in phosphate-buffered saline (PBS) and minimum essential Eagles' medium (MEM). Noncompetitive conditions were used to facilitate the validation of the technique in which data obtained from these experiments were corroborated against data obtained using an established total protein assay method (Quant-IT kit, Invitrogen). These experiments demonstrated that the FTCA-BSA probe had several advantages including a greater sensitivity at lower concentrations and a considerably longer lifetime. The results also demonstrated that the interaction of BSA with SA and HA was also highly temperature- and media-dependent. Under the most physiologically relevant conditions of MEM at 37 °C, BSA was more readily adsorbed to SA with significant differences between biomaterials, but no differences were observed during the desorption process. The use of this method to analyze adsorption under competitive conditions will be the subject of further investigations.

The effect of increasing strut porosity on the osteoinductive ability of silicate substituted calcium phosphate (SiCaP) biomaterials was investigated in an ectopic ovine model. Implants with strut porosities of 22.5%, 32.0% and 46.0% were inserted into the parapsinalis muscle. At 8, 12 and 24 weeks histological sections were prepared. Sections were examined using backscattered scanning electron microscopy and un-decalcified histology. Bone area, implant area and bone-implant contact were quantified. At 8 weeks there was no significant difference between the groups in terms of bone area and implant area. However at 12 weeks, the amount of bone formation observed was significantly greater in SiCaP-46 (6.17 ± 1.51%) when compared with SiCaP-22.5 (1.33 ± 0.84%) p=0.035. Results also showed significantly increased amounts of bone-implant contact to the SiCaP-46 scaffold (3.30 ± 1.17%) compared with SiCaP-22.5 (0.67 ± 0.52%, p=0.043) at 8 weeks and 12 weeks; (SiCaP-46 (21.82 ± 5.59%) vs SiCaP-22.5 (3.06 ± 1.89%), p=0.012). At 24 weeks, bone formation and graft resorption had significantly increased in all groups so that the level of bone formation in the SiCaP-46 group had increased 75-fold to 30.05 ± 8.38%. Bone formation was observed in pores <10 μm. Results suggest that bone graft substitute materials with greater strut porosity are more osteoinductive., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The effect of increasing strut porosity on the osteoinductivity of porous calcium phosphate (CaP) and silicate-substituted calcium phosphate (SiCaP) bone substitute materials was investigated in an ovine ectopic model. One to two millimeter-sized granules or block implants with strut porosities of 10, 20, or 30% were inserted into the left and right paraspinalis muscle. At 12 weeks, histological sections were prepared through the center of each implant and bone contact, bone area and implant area quantified. Backscattered scanning electron microscopy (bSEM) was used to visualize bone within small pores in the struts of the scaffolds. Increased bone formation was measured in the SiCaP with 30% strut porosity (5.482% ± 1.546%) when compared with the nonsilicate CaP with the same morphology (1.160% ± 0.502%, p = 0.02), indicating that silicate substitution may increase osteoinduction. Greater bone formation was seen in scaffolds with increased strut porosity. No bone growth was found in any of the SiCaP scaffold with 10% porosity. There was no significant difference between block and granule specimens. Scanning electron microscopy and EDX in combination with histology demonstrated bone formation within pores <5 μm in size. The use of silicate-substituted CaP material with increased strut porosity may further augment repair and regeneration in bony sites., (Copyright © 2012 Wiley Periodicals, Inc.)

We hypothesized that the electrochemical deposition of hydroxyapatite (EHA) can be used to incorporate silver (Ag), providing a controlled and sustained release of Ag ions at a bactericidal concentration. Six groups were investigated: electrochemical co-precipitation of HA and Ag (EHA/Ag); EHA pre-coated discs treated in AgN0(3) (EHA/AgN0(3)); plasma sprayed HA (PHA) pre-coated discs treated in AgN0(3) (PHA/AgN0(3)); EHA with 2 "layers" of Ag (EHA/Ag/2 layers); EHA coating only; and PHA coating only. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) and X-ray diffraction (XRD) analyses quantified coating thickness, calcium/phosphorous ratio, and % atomic silver content, respectively. Inductively coupled plasma-mass spectrometry quantified the amount of Ag released in phosphate-buffered saline, and zone of inhibition tests on agar plates using a lawn of Staph aureus were quantified in each group. XRD and EDX analysis confirmed the presence of Ag in all coatings. EHA coated discs with two layers of Ag and the EHA discs soaked in AgN0(3) showed significantly higher zones of inhibition at all time points when compared with all other groups (except PHA/AgN0(3) on day 0). This study demonstrated that Ag ions can be incorporated into a HA coating using an electrochemical technique., (Copyright © 2011 Orthopaedic Research Society.)

Background: The osteoinductivity of silicate-substituted calcium phosphate and stoichiometric calcium phosphate was investigated with use of ectopic implantation. Implants with a macroporosity of 80% and a strut porosity of 30% were inserted into sites located in the left and right paraspinal muscles of six female sheep., Methods: After twelve weeks in vivo, a longitudinal thin section was prepared through the center of each implant. Bone formation within the implant, bone formation in contact with the implant surface, and implant resorption were quantified with use of a line intersection method. The specimens were also analyzed with use of backscattered scanning electron microscopy and energy-dispersive x-ray analysis., Results: Silicate substitution had a significant effect on the formation of bone both within the implant and on the implant surface during the twelve-week period. Bone area within the implant was greater in the silicate-substituted calcium phosphate group (mean, 7.65% ± 3.2%) than in the stoichiometric calcium phosphate group (0.99% ± 0.9%, p = 0.01). The amount of bone formed at the surface of the implant was also significantly greater in the silicate-substituted calcium phosphate group (mean, 26.00% ± 7.8%) than in the stoichiometric calcium phosphate group (2.2% ± 2.0%, p = 0.01). Scanning electron microscopy demonstrated bone formation within pores that were <5 μm in size, and energy-dispersive x-ray analysis confirmed the presence of silicon within the new bone in the silicate-substituted calcium phosphate group., Conclusions: The formation of bone within muscle during the twelve-week period showed both silicate-substituted calcium phosphate and stoichiometric calcium phosphate to be osteoinductive in an ovine model. Silicate substitution significantly increased the amount of bone that formed and the amount of bone attached to the implant surface. New bone formation occurred through an intramembranous process within the implant structure.

It has been proposed that one of the underlying mechanisms contributing to the bioactivity of osteoinductive or osteoconductive calcium phosphates involves the rapid dissolution and net release of calcium and phosphate ions from the matrix as alternatively a precursor to subsequent re-precipitation of a bone-like apatite at the surface and/or to facilitate ion exchange in biochemical processes. In order to confirm and evaluate ion release from sintered hydroxyapatite (HA) and to examine the effect of silicate substitution into the HA lattice on ion exchange under physiological conditions we monitored Ca(2+), PO(4)(3-) and SiO(4)(4-) levels in Earl's minimum essential medium (E-MEM) in the absence (serum-free medium, SFM) or presence (complete medium, C-MEM) of foetal calf serum (FCM), with both microporous HA or 2.6 wt% silicate-substituted HA (SA) sintered discs under both static and semi-dynamic (SD) conditions for up to 28 days. In SFM, variation in Ca(2+) ion concentration was not observed with either disc chemistry or culture conditions. In C-MEM, Ca(2+) ions were released from SA under static and SD conditions whereas with HA Ca(2+) was depleted under SD conditions. PO(4)(3-) depletion occurred in all cases, although it was greater in C-MEM, particularly under SD conditions. SiO(4)(4-) release occurred from SA irrespective of medium or culture conditions but a sustained release only occurred in C-MEM under SD conditions. In conclusion we showed that under physiological conditions the reservoir of exchangeable ions in both HA and SA in the absence of serum proteins is limited, but that the presence of serum proteins facilitated greater ionic exchange, particularly with SA. These observations support the hypothesis that silicate substitution into the HA lattice facilitates a number of ionic interactions between the material and the surrounding physiological environment, including but not limited to silicate ion release, which may play a key role in determining the overall bioactivity and osteoconductivity of the material. However, significant net release of Ca(2+) and PO(4)(3-) was not observed, thus rapid or significant net dissolution of the material is not necessarily a prerequisite for bioactivity in these materials.

Background Context: A number of different synthetic calcium-based bone graft substitutes (BGS) are currently available for clinical use. There is, however, a lack of comparative performance data regarding the relative efficacy of these materials when placed in an osseous defect site., Purpose: To compare the rate, quality, and extent of osseous healing in a standard rabbit defect model for three commercially available BGS materials by measuring early bone formation and completion of defect healing and to identify whether rapid scaffold resorption stimulated or impaired bone healing., Study Design: Osteochondral defects, 4.8 mm in diameter and 6 to 7 mm deep, were made through the articular surface into the subchondral bone of the femoral condyle of New Zealand White rabbits and filled with cylindrical pellets of one of three commercially available BGS materials: dense calcium sulfate (DCaS), ultraporous tricalcium phosphate (beta-TCP), and porous silicated calcium phosphate (Si-CaP). The repair response was examined at 1, 3, 6, and 12 weeks after surgery (n=4 per BGS per time point)., Method: Qualitative histological and quantitative histomorphometric (% new bone, % bone graft substitute, capillary index, and mineral apposition rates) analysis., Results: Rapid resorption of D-CaS, primarily through dissolution, elicited a mild inflammatory response that left the defect site empty before significant quantities of new bone were formed. Both beta-TCP and Si-CaP scaffolds supported early bone apposition (<1 week). However, beta-TCP degradation products subsequently provoked an inflammatory response that impaired and reversed bone apposition within the defect site. The Si-CaP scaffolds appeared to be more stable and supported further bone apposition, with the development of an adaptive bone-scaffold composite; cell-mediated resorption of scaffold and new bone were observed in response to local load and contributed to the production of a functional repair within the defect site., Conclusions: Rapid BGS resorption impaired the regenerative ability of local bone via three pathways: 1) insufficient persistence of an osteoconductive scaffold to encourage bone apposition, 2) destabilization of early bony apposition through scaffold disintegration, and 3) stimulation of an inflammatory response by elevated levels of particulate degradation products. This had a significant impact on the ultimate rate of healing. D-CaS did not stimulate early bone apposition, but bone repair was more advanced in D-CaS-treated defects at 12 weeks as compared with those treated with beta-TCP, despite the beta-TCP supporting direct bone apposition at 1 week. Si-CaP appeared to provide a more stable osteoconductive scaffold, which supported faster angiogenesis and bone apposition throughout the defect site, with the development of a functionally adaptive trabecular structure through resorption/remodelling of both scaffold and new bone. There was rapid formation of mineralized tissue at week 1 within the center of the defect and complete infiltration with dense, predominantly mature bone by weeks 3 to 6. The progressive remodeling of bone ingrowth and scaffold to reflect the distribution of local host tissue, combined with histological evidence of targeted osteoclastic resorption of both scaffold and bone, suggest that bone adaptation within the scaffold could be in response to Wolff's law. Although this model may not directly translate to a spinal fusion model and the products may vary according to the environment, these results suggest that, in patients in whom bone regeneration may be compromised, the degradation observed with some resorbable bone grafts may contribute to the decoupling of bone regeneration and resorbtion within the graft site, which may ultimately lead to incomplete bone repair.

The osseous response to silicon (Si) level (0, 0.2, 0.4, 0.8 and 1.5 wt% Si) within 5 batches of matched porosity silicate-substituted hydroxyapatite (SA) scaffold was assessed by implantation of 4.6 mm diameter cylinders in the femoral intercondylar notch of New Zealand White rabbits for periods of 1, 3, 6 and 12 weeks. Histological evaluation and histomorphometric quantification of bone ingrowth and mineral apposition rate (MAR) demonstrated the benefits to early (<1 week) bone ingrowth and repair through incorporation of Si, at all levels, in porous hydroxyapatite (HA) lattices as compared to stoichiometric (0 wt% Si) HA. The group containing 0.8 wt% Si supported significantly more bone ingrowth than all other groups at 3 and 6 weeks (P<0.05), initially through its elevated MAR between weeks 1 and 2, which was significantly higher than that of all other Si-containing groups (P<0.05). The level of silicate substitution also influenced the morphology and stability of the repair, with elevated levels of bone resorption and apposition apparent within other Si-containing groups at timepoints >3 weeks as compared to the 0 and 0.8 wt% Si groups. At 12 weeks, the net amount of bone ingrowth continued to rise in the 0, 0.8 and 1.5 wt% groups, apparently as a result of adaptive remodelling throughout the scaffold. Ingrowth levels remained highest in the 0.8 wt% Si group, was characterised by a dense trabecular morphology in the superficial region graduating to a more open network in the deep zone. These results highlight the sensitivity of healing response to Si level and suggest that an optimal response is obtained when SA is substituted with 0.8 wt% Si through its effect on the activity of both bone forming and bone resorbing cells.

This paper describes the use of surface titration as a more direct probe of the surface chemistry of hydroxyapatite (HA) than zeta-potential measurements. The variation in HA surface charge with pH for two different KCl electrolyte concentrations was determined titrimetrically and the point of zero charge (PZC) found to be at a pH of 7.3 +/- 0.1. The curves also demonstrated that HA accumulates positive charge more readily below the PZC than it accumulates negative charge above it. Extended titration data indicated that dissolution occurred more rapidly in increasingly acidic conditions, but was inhibited by increasing electrolyte strength. Similar experiments with 2.5 mM Ca(2+) in the electrolyte show that Ca(2+) adsorption balances loss of H(+) to give a near-neutral surface at any pH above 7 (subject to availability of calcium ions and adsorption sites). The mechanism for adsorption has been shown to be deprotonation of adjacent surface HPO(4)(2-) sites and subsequent adsorption of a calcium ion to the lattice surface site. Furthermore, inhibition of dissolution under alkaline conditions in the presence of Ca(2+) suggested that dissolution was driven by desorption of Ca(2+). Modelling of the adsorption/desorption processes demonstrated that in both pure water and under physiological conditions phosphate groups will predominate at the HA surface. Furthermore, the (200) plane was identified as the likely form of the HA surface. These methodologies and findings are particularly relevant to investigation of biological response with respect to modification of surface hydrophobicity and surface energy or charge.

Aim: Published clinical series suggest the osteoodontokeratoprosthesis (OOKP) may have a lower extrusion rate than current synthetic keratoprostheses. The OOKP is anchored in the eye wall by autologous tooth. The authors' aim was to compare adhesion, proliferation, and morphology for telomerase transformed keratocytes seeded on calcium hydroxyapatite (the principal mineral constituent of tooth) and materials used in the anchoring elements of commercially available synthetic keratoprostheses., Methods: Test materials were hydroxyapatite, polytetrafluoroethylene (PTFE), polyhydroxyethyl methacrylate (HEMA), and glass (control). Cell adhesion and viability were quantified at 4 hours, 24 hours, and 1 week using a calcein-AM/EthD-1 viability/cytotoxicity assay. Focal contact expression and cytoskeletal organisation were studied at 24 hours by confocal microscopy with immunoflourescent labelling. Further studies of cell morphology were performed using light and scanning electron microscopy., Results: Live cell counts were significantly greater on hydroxyapatite surfaces at each time point (p<0.04). Dead cell counts were significantly higher for PTFE at 7 days (p<0.002). ss(1) integrin expression was highest on hydroxyapatite. Adhesion structures were well expressed in flat, spread out keratocytes on both HA and glass. Keratocytes tended to be thinner and spindle shaped on PTFE. The relatively few keratocytes visible on HEMA test surfaces were rounded and poorly adherent., Conclusions: Keratocyte adhesion, spreading, and viability on hydroxyapatite test surfaces is superior to that seen on PTFE and HEMA. Improving the initial cell adhesion environment in the skirt element of keratoprostheses may enhance tissue integration and reduce device failure rates.

This paper describes an investigation into the influence of microporosity on early osseointegration and final bone volume within porous hydroxyapatite (HA) bone graft substitutes (BGS). Four paired grades of BGS were studied, two (HA70-1 and HA70-2) with a nominal total porosity of 70% and two (HA80-1 and HA80-2) with a total-porosity of 80%. Within each of the total-porosity paired grades the nominal volume fraction of microporosity within the HA struts was varied such that the strut porosity of HA70-1 and HA80-1 was 10% while the strut-porosity of HA70-2 and HA80-2 was 20%. Cylindrical specimens, 4.5 mm diameter x 6.5 mm length, were implanted in the femoral condyle of 6 month New Zealand White rabbits and retrieved for histological, histomorphometric, and mechanical analysis at 1, 3, 12 and 24 weeks. Histological observations demonstrated variation in the degree of capillary penetration at 1 week and bone morphology within scaffolds 3-24 weeks. Moreover, histomorphometry demonstrated a significant increase in bone volume within 20% strut-porosity scaffolds at 3 weeks and that the mineral apposition rate within these scaffolds over the 1-2 week period was significantly higher. However, an elevated level of bone volume was only maintained at 24 weeks in HA80-2 and there was no significant difference in bone volume at either 12 or 24 weeks for 70% total-porosity scaffolds. The results of mechanical testing suggested that this disparity in behaviour between 70 and 80% total-porosity scaffolds may have reflected variations in scaffold mechanics and the degree of reinforcement conferred to the bone-BGS composite once fully integrated. Together these results indicate that manipulation of the levels of microporosity within a BGS can be used to accelerate osseointegration and elevate the equilibrium volume of bone.

Increases in reconstructive orthopaedic surgery, such as total hip replacement and spinal fusion, resulting from advances in surgical practice and the ageing population, have lead to a demand for bone graft that far exceeds supply. Consequently, a number of synthetic bone-graft substitutes (BGSs) have been developed with mixed success and surgical acceptance. Skeletal tissue regeneration requires the interaction of three basic elements: cells, growth factors (GFs) and a permissive scaffold. This can be achieved by pre-loading a synthetic scaffold with GFs or pre-expanded cells; however, a 'simpler' approach is to design intrinsic 'osteoinductivity' into your BGS, i.e. the capability to recruit and stimulate the patient's own GFs and stem cells. Through investigation of the mechanisms controlling bone repair in BGSs, linking interactions between the local chemical and physical environment, scientists are currently developing osteoinductive materials that can stimulate bone regeneration through control of the scaffold chemistry and structure. Moreover, this body of research is providing the foundations for future generations of BGSs and bone-repair therapies and may ultimately contribute towards improving the quality of life through maintenance of the skeleton and reversal of disease states, as opposed to the mending of broken bones that we currently practice. Will we be able to grow our own bones in a bioreactor for use as autologous graft materials in the future? Could surgery be limited to accidental trauma cases, with greater restoration of function through biochemical or gene therapies? The technology and research probes necessary to this task are currently being developed with the advent of nanotechnology, genomics and proteomics: are we about to embark on a chemical revolution in medicine? This paper aims to discuss some of the current thinking on the mechanisms behind bioactivity and biocompatibility in bone and how a fuller understanding of the interactions between cells and the materials used today could bring about completely new approaches for the treatment of bone fracture and disease tomorrow.

Hydroxyapatite has been shown to be biocompatible and bioactive. Incorporation of porosity has been shown to enhance osteointegration; however, difficulty in controlling the extent and type of porosity has limited investigation into determining the role of both macro- and microporosity. The current investigation reports on the synthesis of four types of phase-pure hydroxyapatite with varying levels of porosity (HA1-HA4), and with defined levels of macro- and microporosities. Transmission electron microscopy was used to evaluate qualitatively the effect of these two parameters on cell-material interactions following a 30-day incubation period. Biological mineralization was observed within vesicles and the needle-like minerals were confirmed as hydroxyapatite using X-ray microanalysis. This demonstrated the suitability of primary human osteoblast-like cells as a tool to assess the extent of mineralization. Furthermore, internalization of hydroxyapatite particles was observed. Our findings show that the variation in macro- and microporosity does not affect the extent of cell-material interaction, with collagen synthesis evident in all samples.

The biocompatibility of hydroxyapatite has been demonstrated by previous studies, with enhancement of osteointegration through the use of porous hydroxyapatite (pHA). Emphasis has been focused on the use of coralline hydroxyapatite or the introduction of macroporosity into synthetic hydroxyapatite. The current study investigates the role of macro- and microporosities in synthetic phase-pure porous hydroxyapatite on the morphological aspects of human osteoblast-like cells using scanning electron microscopy. Cells were seeded on four different types of porous hydroxyapatite (HA1, HA2, HA3 and HA4) and examined following 1, 2, 14 and 30 days of incubation in vitro. The results indicated that the cells had an affinity to micropores through filopodia extensions, at initial stage of attachment. Cellular proliferation and colonization was evident on all materials with cells forming cellular bridges across the macropores at day 14 with cellular canopy formation covering entire macropores observed by day 30. This study demonstrates that while the introduction of microporosity has no evident effect on cellular morphology at later time points, it seems to play a role in initial cellular anchorage and attachment.

Previous investigations have shown that both the early biological response and the mechanical properties of a porous hydroxyapatite bone graft substitute are highly sensitive to its pore structure. The objective of this study was to evaluate whether the pore structure continued to influence bone integration in the medium to long term. Two screened batches of porous hydroxyapatite (PHA) designated as batch A and batch B, with porosities of approximately 60 and 80%, respectively, were selected for this study and implanted for periods of 5, 13, and 26 weeks into the lower femur of New Zealand White rabbits. Histomorphometric analysis of the absolute volume of bone ingrowth within batch A and B implants from 5 to 26 weeks showed that the absolute volume of bone ingrowth was consistently lower in batch A (10-21%), compared to batch B implants (24-31%). However, when the volume of bone ingrowth was normalised for the available pore space, this difference was reduced (23-47% and 32-42% for batches A and B, respectively). These observations suggest that differences in the volume of bone ingrowth initially depended on pore interconnectivity rather than pore size, whereas the volume or morphology of the PHA influenced the volume and morphology of bone ingrowth at later time points. Compression testing showed that bone ingrowth had a strong reinforcing effect on PHA bone graft substitutes, and a strong correlation was identified between mechanical properties and the absolute volume of ingrowth for both batches A and B. Furthermore, at 13 and 26 weeks, there was no significant variation in the ultimate compressive strength of integrated batch A and B implants. This similarity in ultimate mechanical properties indicated that the absolute volume of ingrowth may be mediated by the PHA structure through its impact on the dynamics of the local biomechanical environment. The results of push-out testing showed that fixation of PHA bone graft substitutes was independent of density within the range studied, with no significant difference in the interfacial shear stress between batches A and B at each time point throughout the study., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 187-200, 2004)

Phase pure hydroxyapatite (HA) and a 0.8 wt % silicon substituted hydroxyapatite (SiHA) were prepared by aqueous precipitation methods. Both HA and SiHA were processed into granules 0.5-1.0 mm in diameter and sintered at 1200 degrees C for 2 h. The sintered granules underwent full structural characterization, prior to implantation into the femoral condyle of New Zealand White rabbits for a period of 23 days. The results show that both the HA and SiHA granules were well accepted by the host tissue, with no presence of any inflammatory cells. New bone formation was observed directly on the surfaces and in the spaces between both HA and SiHA granular implants. The quantitative histomorphometry results indicate that the percentage of bone ingrowth for SiHA (37.5%+/-5.9) was significantly greater than that for phase pure HA (22.0%+/-6.5), in addition the percentage of bone/implant coverage was significantly greater for SiHA (59.8%+/-7.3) compared to HA (47.1%+/-3.6). These findings indicate that the early in vivo bioactivity of hydroxyapatite was significantly improved with the incorporation of silicate ions into the HA structure, making SiHA an attractive alternative to conventional HA materials for use as bone substitute ceramics.

Hydroxyapatite has been investigated for use in the osseous environment for over 20 years and the biocompatibility of the ceramic and its osseoconductive behavior is well established. Therefore, the use of porous hydroxyapatite for the repair of osseous defects seems promising with potential for complete penetration of osseous tissue and restoration of vascularity throughout the repair site. However, there have been few systematic studies of the effects of physical properties such as macropore size and pore connectivity on the rate and quality of bone integration within porous hydroxyapatite implants. This paper quantifies the early biological response to a well-characterized series of implants with uniform microstructure and phase composition, but differing macrostructures and demonstrates the dependence of the rate of osseointegration on the apparent density of porous hydroxyapatite as a function of pore connectivity. Furthermore, compression testing established that bony ingrowth has a strong reinforcing effect on porous hydroxyapatite implants, which is more pronounced in the lower density implants, as a result of a greater relative volume of bone ingrowth., (Copyright 1999 Kluwer Academic Publishers)

Hydroxyapatite has been considered for use in the repair of osseous defects for the last 20 years. Recent developments have led to interest in the potential of porous hydroxyapatite as a synthetic bone graft. However, despite considerable activity in this field, regarding assessment of the biological response to such materials, the basic materials characterization is often inadequate. This paper documents the characterization of the chemical composition, mechanical integrity, macro- and microstructure of a porous hydroxyapatite, Endobon (E. Merck GmbH), intended for the bone-graft market. Specimens possesed a range of apparent densities from 0.35 to 1.44 g cm(-3). Chemical analysis demonstrated that the natural apatite precursor of Endobon was not converted to pure hydroxyapatite, but retained many of the ionic substituents found in bone mineral, notably carbonate, sodium and magnesium ions. Investigation of the microstructure illustrated that the struts of the material were not fully dense, but had retained some traces of the network of osteocyte lacunae. Macrostructural analysis demonstrated the complex inter-relationship between the structural features of an open pore structure. Both pore size and connectivity were found to be inversely dependent on apparent density. Furthermore, measurement of pore aspect ratio and orientation demonstrated a relationship between apparent density and the degree of macrostructural anisotropy within the specimens, while, it was also noted that pore connectivity was sensitive to anisotropy. Compression testing demonstrated the effect of apparent density and macrostructural anisotropy on the mechanical properties. An increase in apparent density from 0.38 to 1.25 g cm(-3) resulted in increases in ultimate compressive stress and compressive modulus of 1 to 11 MPa and 0.2 to 3.1 GPa, respectively. Furthermore, anisotropic high density (> 0.9 g cm(-3)) specimens were found to possess lower compressive moduli than isotropic specimens with equivalent apparent densities. These results underline the importance of full structural and mechanical characterization of porous ceramic implant materials., (Copyright 1999 Kluwer Academic Publishers)

The standardization of characterization techniques is becoming increasingly important for bone replacement materials as it becomes apparent that, for the field to advance, testing must be developed to allow the biocompatibility or bioactivity of a new material to be assessed and directly compared with existing materials. Currently there are many forms of biocompatibility test for materials destined for the osseous environment, ranging from immersion in simulated body fluid to implantation into living bone. However, the variety of ways in which the data from these tests may be acquired and interpreted, as a result of changes in parameters such as surgical technique and mechanical test conditions, means that much of the published data within the field is not comparable. This paper will introduce the concept of biocompatibility by considering calcium phosphate bioceramics, and discusses some aspects of in vivo experimental design, including simple histomorphometry techniques, in addition to considering practical methods for the assessment of the biomechanical characteristics of an osseointegrated implant.

Porous hydroxyapatite (Endobon) specimens were implanted into the femoral condyle of New Zealand White rabbits for up to 6 months. After sacrifice, specimens were sectioned for histology and mechanical testing, where the extent of reinforcement by bony ingrowth was assessed by compression testing and fixation was assessed by push-out testing. From histological observations, it was established that the majority of bone ingrowth occurred between 10 day and 5 weeks after implantation and proceeded predominantly from the deep end of the trephined defect, with some integration from the circumferential sides. At 3 months, the implants were fully integrated, exhibiting bony ingrowth, vascularization and bone marrow stroma within the internal macropores. After 5 weeks, the mean ultimate compressive strength of retrieved implants (6.9 MPa) was found to be greater than that of the original implant (2.2 MPa), and by 3 months the fully integrated implants attained a compressive strength of approximately 20 MPa. Push-out testing demonstrated that after 5 weeks in vivo, the interfacial shear strength reached 3.2 MPa, increasing to 7.3 MPa at 3 and 6 months.