Computational simulation of the early stage of bone healing under different configurations of locking compression plates

Flexible fixation or the so-called ‘biological fixation’ has been shown to encourage the formation of fracture callus, leading to better healing outcomes. However, the nature of the relationship between the degree of mechanical stability provided by a flexible fixation and the optimal healing outcomes has not been fully understood. In this study, we have developed a validated quantitative model to predict how cells in fracture callus might respond to change in their mechanical microenvironment due to different configurations of locking compression plate (LCP) in clinical practice, particularly in the early stage of healing. The model predicts that increasing flexibility of the LCP by changing the bone–plate distance (BPD) or the plate working length (WL) could enhance interfragmentary strain in the presence of a relatively large gap size (.3 mm). Furthermore, conventional LCP normally results in asymmetric tissue development during early stage of callus formation, and the increase of BPD or WL is insufficient to alleviate this problem.

Biobanking of blood and bone marrow : emerging challenges for custodians of public resources

The Australian Bone Marrow Donor Registry (ABMDR) is a publicly funded company that is part of an international network that facilitates unrelated bone marrow transplantation. This role means that the ABMDR has access to a large biospecimen repository, therefore making it a highly valuable research resource. Recognising the potential value of these biospecimens for research purposes, the ABMDR is in the process of determining whether, and how, to share its biospecimens with other biobanks. While this would undoubtedly be of value to the scientific community, and ultimately to the wider community, it would also inevitably transform the role of an institution whose primary role is therapeutic, and would compromise the degree of control that a custodian has over donated material. This article describe the challenges confronting the ABMDR, and organisations like it, in balancing their duties to donors, patients, researchers and the general public. These problems have led inevitably to the use of "property" rights language in the discussion of these issues but notions of gift, ownership, trusteeship and transfer might also be considered.

Delineating breast cancer cell interactions with engineered bone microenvironments

The mechanisms leading to colonization of metastatic breast cancer cells (BCa) in the skeleton are still not fully understood. Here, we demonstrate that mineralized extracellular matrices secreted by primary human osteoblasts (hOBM) modulate cellular processes associated with BCa colonization of bone. A panel of four BCa cell lines of different bone-metastatic potential (T47D, SUM1315, MDA-MB-231, and the bone-seeking subline MDA-MB-231BO) was cultured on hOBM. After 3 days, the metastatic BCa cells had undergone morphological changes on hOBM and were aligned along the hOBM's collagen type I fibrils that were decorated with bone-specific proteins. In contrast, nonmetastatic BCa cells showed a random orientation on hOBM. Atomic force microscopy-based single-cell force spectroscopy revealed that the metastatic cell lines adhered more strongly to hOBM compared with nonmetastatic cells. Function-blocking experiments indicated that β1-integrins mediated cell adhesion to hOBM. In addition, metastatic BCa cells migrated directionally and invaded hOBM, which was accompanied by enhanced MMP-2 and -9 secretion. Furthermore, we observed gene expression changes associated with osteomimickry in BCa cultured on hOBM. As such, osteopontin mRNA levels were significantly increased in SUM1315 and MDA-MB-231BO cells in a β1-integrin-dependent manner after growing for 3 days on hOBM compared with tissue culture plastic. In conclusion, our results show that extracellular matrices derived from human osteoblasts represent a powerful experimental platform to dissect mechanisms underlying critical steps in the development of bone metastases.

Breast cancer cells induce osteolytic bone lesions in vivo through a reduction in osteoblast activity in mice

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Results using Trabecular Metal™ augments in combination with acetabular impaction bone grafting in deficient acetabula

We examined whether the use of trabecular metal wedges to fill segmental defects is an effective method of socket reconstruction when used in combination with impaction grafting and implantation of a cemented socket. Fifteen hips in 14 patients underwent impaction grafting in combination with a TM wedge with a minimum of 2 years follow-up. All patients had their defects assessed using the Paprosky classification. Patients were reviewed with x-rays and migration of the implant was measured. Outcome scores were also collected. Mean follow-up was 39 months (25-83). The mean age at surgery was 67.8 (49-85) years. Seven of the patients had previously undergone impaction grafting with the use of a stainless steel rim mesh to constrain the graft. None of the patients had failed either clinically or radiologically.

Sex-specific compromised bone healing in female rats might be associated with a decrease in mesenchymal stem cell quantity

Introduction The clinically known importance of patient sex as a major risk factor for compromised bone healing is poorly reflected in animal models. Consequently, the underlying cellular mechanisms remain elusive. Because mesenchymal stem cells (MSCs) are postulated to regulate tissue regeneration and give rise to essential differentiated cell types, they may contribute to sex-specific differences in bone healing outcomes. Methods We investigated sex-specific variations in bone healing and associated differences in MSC populations. A 1.5 mm osteotomy gap in the femora of 8 male and 8 female 12-month-old Sprague-Dawley rats was stabilized by an external fixator. Healing was analyzed in terms of biomechanical testing, bridging and callus size over time (radiography at 2, 4, and 6 weeks after surgery), and callus volume and geometry by μCT at final follow-up. MSCs were obtained from bone marrow samples of an age-matched group of 12 animals (6 per gender) and analyzed for numbers of colony-forming units (CFUs) and their capacity to differentiate and proliferate. The proportion of senescent cells was determined by β-galactosidase staining. Results Sex-specific differences were indicated by a compromised mechanical competence of the callus in females compared with males (maximum torque at failure, p = 0.028). Throughout the follow-up, the cross-sectional area of callus relative to bone was reduced in females (p ≤ 0.01), and the bridging of callus was delayed (p 2weeks = 0.041). μCT revealed a reduced callus size (p = 0.003), mineralization (p = 0.003) and polar moment of inertia (p = 0.003) in female animals. The female bone marrow contained significantly fewer MSCs, represented by low CFU numbers in both femora and tibiae (p femur = 0.017, p tibia = 0.010). Functional characteristics of male and female MSCs were similar. Conclusion Biomechanically compromised and radiographically delayed bone formation were distinctive in female rats. These differences were concomitant with a reduced number of MSCs, which may be causative for the suboptimal bone healing.

Controlling whole blood activation and resultant clot properties by carboxyl and alkyl functional groups on material surfaces : a possible therapeutic approach for enhancing bone healing

Most research virtually ignores the important role of a blood clot in supporting bone healing. In this study, we investigated the effects of surface functional groups carboxyl and alkyl on whole blood coagulation, complement activation and blood clot formation. We synthesised and tested a series of materials with different ratios of carboxyl (–COOH) and alkyl (–CH3, –CH2CH3 and –(CH2)3CH3) groups. We found that surfaces with –COOH/–(CH2)3CH3 induced a faster coagulation activation than those with –COOH/– CH3 and –CH2CH3, regardless of the –COOH ratios. An increase in –COOH ratios on –COOH/–CH3 and –CH2CH3 surfaces decreased the rate of coagulation activation. The pattern of complement activation was entirely similar to that of surface-induced coagulation. All material coated surfaces resulted in clots with thicker fibrin in a denser network at the clot/material interface and a significantly slower initial fibrinolysis when compared to uncoated glass surfaces. The amounts of platelet-derived growth factor-AB (PDGF-AB) and transforming growth factor-b (TGF-b1) released from an intact clot were higher than a lysed clot. The release of PDGF-AB was found to be correlated with the fibrin density. This study demonstrated that surface chemistry can significantly influence the activation of blood coagulation and complement system, resultant clot structure, susceptibility to fibrinolysis as well as release of growth factors, which are important factors determining the bone healing process.

Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone

The development of effective therapeutic strategies against prostate cancer bone metastases has been impeded by the lack of adequate animal models that are able to recapitulate the biology of the disease in humans. Bioengineered approaches allow researchers to create sophisticated experimentally and physiologically relevant in vivo models to study interactions between cancer cells and their microenvironment under reproducible conditions. The aim of this study was to engineer a morphologically and functionally intact humanized organ bone which can serve as a homing site for human prostate cancer cells. Transplantation of biodegradable tubular composite scaffolds seeded with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone construct including a large number of human mesenchymal cells which were shown to be metabolically active and capable of producing extracellular matrix components. Micro-CT analysis demonstrated that the newly formed ossicle recapitulated the morphological features of a physiological organ bone with a trabecular network surrounded by a cortex-like outer structure. This microenvironment was supportive of the lodgement and maintenance of murine haematopoietic cell clusters, thus mimicking a functional organ bone. Bioluminescence imaging demonstrated that luciferase-transduced human PC3 cells reproducibly homed to the humanized tissue engineered bone constructs, proliferated, and developed macro-metastases. This model allows the analysis of interactions between human prostate cancer cells and a functional humanized bone organ within an immuno-incompetent murine host. The system can serve as a reproducible platform to study effects of therapeutics against prostate cancer bone metastases within a humanized microenvironment.

A deconvolution method for deriving the transit time spectrum for ultrasound propagation through cancellous bone replica models

The acceptance of broadband ultrasound attenuation for the assessment of osteoporosis suffers from a limited understanding of ultrasound wave propagation through cancellous bone. It has recently been proposed that the ultrasound wave propagation can be described by a concept of parallel sonic rays. This concept approximates the detected transmission signal to be the superposition of all sonic rays that travel directly from transmitting to receiving transducer. The transit time of each ray is defined by the proportion of bone and marrow propagated. An ultrasound transit time spectrum describes the proportion of sonic rays having a particular transit time, effectively describing lateral inhomogeneity of transit times over the surface of the receiving ultrasound transducer. The aim of this study was to provide a proof of concept that a transit time spectrum may be derived from digital deconvolution of input and output ultrasound signals. We have applied the active-set method deconvolution algorithm to determine the ultrasound transit time spectra in the three orthogonal directions of four cancellous bone replica samples and have compared experimental data with the prediction from the computer simulation. The agreement between experimental and predicted ultrasound transit time spectrum analyses derived from Bland–Altman analysis ranged from 92% to 99%, thereby supporting the concept of parallel sonic rays for ultrasound propagation in cancellous bone. In addition to further validation of the parallel sonic ray concept, this technique offers the opportunity to consider quantitative characterisation of the material and structural properties of cancellous bone, not previously available utilising ultrasound.

Mesenchymal stem cell therapies for bone and tendon conditions

Bone, tendon, and cartilage are highly specialized musculoskeletal connective tissues that are subject to injury and degeneration. These tissues have relatively poor healing capabilities, and coupled with their variable response to established medical treatments, produce significant morbidity. Mesenchymal stem cells (MSCs) are capable of regenerating skeletal tissues and therefore offer great promise in the treatment of connective tissue pathologies. Adult MSCs are multipotent cells that possess the properties of proliferation and differentiation into all connective tissues. Furthermore, they can be gene modified to secrete growth factors and utilized in connective tissue engineering. Potential MSC-based therapies for bone and tendon conditions are reviewed in this chapter.

methoxy-poly(ethylene glycol) modified poly(L-lactide) enhanced cell affinity of human bone marrow stromal cells by the upregulation of 1-cadherin and delta-2-catenin

Poly(l-lactide) (PLLA), a versatile biodegradable polymer, is one of the most commonly-used materials for tissue engineering applications. To improve cell affinity for PLLA, poly(ethylene glycol) (PEG) was used to develop diblock copolymers. Human bone marrow stromal cells (hBMSCs) were cultured on MPEG-b-PLLA copolymer films to determine the effects of modification on the attachment and proliferation of hBMSC. The mRNA expression of 84 human extracellular matrix (ECM) and adhesion molecules was analyzed using RT-qPCR to understand the underlying mechanisms. It was found that MPEG-b-PLLA copolymer films significantly improved cell adhesion, extension, and proliferation.This was found to be related to the significant upregulation of two adhesion genes, CDH1 and CTNND2, which encode 1-cadherin and delta-2-catenin, respectively, two key components for the cadherin-catenin complex. In summary, MPEG-b-PLLA copolymer surfaces improved initial cell adhesion by stimulation of adhesion molecule gene expression.

Practices surrounding event photos

Sharing photos through mobile devices has a great potential for creating shared experiences of social events between co-located as well as remote participants. In order to design novel event sharing tools, we need to develop in-depth understanding of current practices surrounding these so called ‘event photos’- photos about and taken during different social events such as weddings picnics, and music concert visits among others. We studied people’s practices related to event photos through in-depth interviews, guided home visits and naturalistic observations. Our results show four major themes describing practices surrounding event photos: 1) representing events, 2) significant moments, 3) situated activities through photos, and 4) collectivism and roles of participants.

Practices surrounding children's photos in homes

New parents cherish photos of their children. In their homes one can observe a varied set of arrangements of their young ones' photos. We studied eight families with young children to learn about their practices related to photos. We provide preliminary results from the field study and elaborate on three interesting themes that came out very strongly from our data: physical platforms; family dynamics and values; and creative uses of photos. These themes provide an insight into families' perceived values for photo curating, displaying and experiencing them over a longer period. We provide future directions for supporting practices surrounding children's photos.

Quantitative fit analysis of orthopedic bone plates : methods, criteria and approach

Studies on quantitative fit analysis of precontoured fracture fixation plates emerged within the last few years and therefore, there is a wide research gap in this area. Quantitative fit assessment facilitates the measure of the gap between a fracture fixation plate and the underlying bone, and specifies the required plate fit criteria. For clinically meaningful fit assessment outcome, it is necessary to establish the appropriate criteria and parameter. The present paper studies this subject and recommends using multiple fit criteria and the maximum distance between the plate and underlying bone as fit parameter for clinically relevant outcome. We also propose the development of a software tool for automatic plate positioning and fit assessment for the purpose of implant design validation and optimization in an effort to provide better fitting implant that can assist proper fracture healing. The fundamental specifications of the software are discussed.

Preparation of mesoporous bioglass coated zirconia scaffold for bone tissue engineering

Porous yttria-stabilized zirconia (YSZ) has been regarded as a potential candidate for bone substitute due to its high mechanical strength. However, porous YSZ is biologically inert to bone tissue. It is therefore necessary to introduce bioactive coatings onto the walls of the porous structures to enhance its bioactivity. In this study, porous YSZ scaffolds were prepared using a replication technique and then coated with mesoporous bioglass due to its excellent bioactivity. The microstructures were examined using scanning electron microscopy and the mechanical strength was evaluated via compression test. The biocompatibility and bioactivity were also evaluated using bone marrow stromal cell (BMSC) proliferation test and simulated body fluid test.