Mathematical modelling of tissue-engineering angiogenesis

We present a mathematical model for the vascularisation of a porous scaffold following implantation in vivo. The model is given as a set of coupled non-linear ordinary differential equations (ODEs) which describe the evolution in time of the amounts of the different tissue constituents inside the scaffold. Bifurcation analyses reveal how the extent of scaffold vascularisation changes as a function of the parameter values. For example, it is shown how the loss of seeded cells arising from slow infiltration of vascular tissue can be overcome using a prevascularisation strategy consisting of seeding the scaffold with vascular cells. Using certain assumptions it is shown how the system can be simplified to one which is partially tractable and for which some analysis is given. Limited comparison is also given of the model solutions with experimental data from the chick chorioallantoic membrane (CAM) assay

Review of emerging nanotechnology in bone regeneration: progress, challenges, and perspectives

The application of nanotechnology to regenerative medicine has increased over recent decades. The development of materials that can influence biology at the nanoscale has gained interest as our understanding of the interactions between cells and biomaterials at the nanoscale has grown. Materials that are either nanostructured or influence the nanostructure of the cellular microenvironment have been developed and shown to have advantages over their microscale counterparts. There are several reviews which have been published that discuss how nanomaterials have been used in regenerative medicine, particularly in bone regeneration. Most of these studies have explored this concept in specific areas, such as the application of glass-based nanocomposites, nanotechnology for targeted drug delivery to stimulate bone repair, and the progress in nanotechnology for the treatment of osteoporosis. In this review paper, the impact of nanotechnology in biomaterials development for bone regeneration will be discussed highlighting specifically, nanostructured materials that influence mechanical properties, biocompatibility, and osteoinductivity

The visualisation of vitreous using surface modified poly(lactic-co-glycolic acid) microparticles

This paper is freely available online under the BMJ Journals unlocked scheme, see http:// bjo.bmj.com/site/about/unlocked.xhtmAims To demonstrate the potential use of in vitro poly (lactic-co-glycolic acid) (PLGA) microparticles in comparison with triamcinolone suspension to aid visualisation of vitreous during anterior and posterior vitrectomy. Methods PLGA microparticles (diameter 10-60 mu m) were fabricated using single and/or double emulsion technique(s) and used untreated or following the surface adsorption of a protein (transglutaminase). Particle size, shape, morphology and surface topography were assessed using scanning electron microscopy (SEM) and compared with a standard triamcinolone suspension. The efficacy of these microparticles to enhance visualisation of vitreous against the triamcinolone suspension was assessed using an in vitro set-up exploiting porcine vitreous. Results Unmodified PLGA microparticles failed to adequately adhere to porcine vitreous and were readily washed out by irrigation. In contrast, modified transglutaminase-coated PLGA microparticles demonstrated a significant improvement in adhesiveness and were comparable to a triamcinolone suspension in their ability to enhance the visualisation of vitreous. This adhesive behaviour also demonstrated selectivity by not binding to the corneal endothelium. Conclusion The use of transglutaminase-modified biodegradable PLGA microparticles represents a novel method of visualising vitreous and aiding vitrectomy. This method may provide a distinct alternative for the visualisation of vitreous whilst eliminating the pharmacological effects of triamcinolone acetonide suspension.Peer reviewedFinal Published versio

Spatially-offset Raman spectroscopy for monitoring mineralization of bone tissue engineering scaffolds: feasibility study based on phantom samples

Using phantom samples, we investigated the feasibility of spatially-offset Raman spectroscopy (SORS) as a tool for monitoring non-invasively the mineralization of bone tissue engineering scaffold in-vivo. The phantom samples consisted of 3D-printed scaffolds of poly-caprolactone (PCL) and hydroxyapatite (HA) blends, with varying concentrations of HA, to mimic the mineralisation process. The scaffolds were covered by a 4 mm layer of skin to simulate the real in-vivo measurement conditions. At a concentration of HA approximately 1/3 that of bone (~0.6 g/cm 3), the characteristic Raman band of HA (960 cm-1) was detectable when the PCL:HA layer was located at 4 mm depth within the scaffold (i.e. 8 mm below the skin surface). For the layers of the PCL:HA immediately under the skin (i.e. top of the scaffold), the detection limit of HA was 0.18 g/cm 3 , which is approximately one order of magnitude lower than that of bone. Similar results were also found for the phantoms simulating uniform and inward gradual mineralisation of the scaffold, indicating the suitability of SORS to detect early stages of mineralisation. Nevertheless, the results also show that the contribution of the materials surrounding the scaffold can be significant and methods for subtraction need to be investigated in the future. In conclusion, these results indicate that spatially-offset Raman spectroscopy is a promising technique for in-vivo longitudinal monitor scaffold mineralization and bone re-growth

A Reactive Prodrug Ink Formulation Strategy for Inkjet 3D Printing of Controlled Release Dosage Forms and Implants

We propose a strategy for creating tuneable 3D printed drug delivery devices. 3D printing offers the opportunity for improved compliance and patient treatment outcomes through personalisation, but bottlenecks include finding formulations that provide a choice of drug loading and release rate, are tuneable and avoid the need for surgical removal. Our solution is to exploit 3D inkjet printing freedoms. We use a reactive prodrug that can polymerize into drug-attached macromolecules during 3D printing, and by tuning the hydrophilicity we can facilitate or hinder hydrolysis, which in turn controls the drug release. To demonstrate this approach, we attach ibuprofen to 2-hydroxyethyl acrylate through a cleavable ester bond, formulate it for inkjet 3D printing, and then print to produce a solid dosage form. This allows a much higher loading than is usually achievable-in our case up to 58 wt%. Of equal importance, the 3D inkjet printing freedoms mean that our drug delivery device is highly tuneable: by selection of spacer monomers to adjust the hydrophilicity; through geometry; by spatially varying the components. Consequently, we create bespoke, hierarchical release systems, from the molecular to macro. This approach represents a new paradigm for the formulation of printable inks for drug-loaded medical devices

Droplet Microfluidic Optimisation Using Micropipette Characterisation of Bio-Instructive Polymeric Surfactants

Droplet microfluidics can produce highly tailored microparticles whilst retaining monodispersity. However, these systems often require lengthy optimisation, commonly based on a trial-and-error approach, particularly when using bio-instructive, polymeric surfactants. Here, micropipette manipulation methods were used to optimise the concentration of bespoke polymeric surfactants to produce biodegradable (poly(d,l-lactic acid) (PDLLA)) microparticles with unique, bio-instructive surface chemistries. The effect of these three-dimensional surfactants on the interfacial tension of the system was analysed. It was determined that to provide adequate stabilisation, a low level (0.1% (w/v)) of poly(vinyl acetate-co-alcohol) (PVA) was required. Optimisation of the PVA concentration was informed by micropipette manipulation. As a result, successful, monodisperse particles were produced that maintained the desired bio-instructive surface chemistry

Study protocol for the Australian autism biobank: an international resource to advance autism discovery research

BACKGROUND: The phenotypic and genetic heterogeneity of autism spectrum disorder (ASD) presents considerable challenges in understanding etiological pathways, selecting effective therapies, providing genetic counselling, and predicting clinical outcomes. With advances in genetic and biological research alongside rapid-pace technological innovations, there is an increasing imperative to access large, representative, and diverse cohorts to advance knowledge of ASD. To date, there has not been any single collective effort towards a similar resource in Australia, which has its own unique ethnic and cultural diversity. The Australian Autism Biobank was initiated by the Cooperative Research Centre for Living with Autism (Autism CRC) to establish a large-scale repository of biological samples and detailed clinical information about children diagnosed with ASD to facilitate future discovery research. METHODS: The primary group of participants were children with a confirmed diagnosis of ASD, aged between 2 and 17 years, recruited through four sites in Australia. No exclusion criteria regarding language level, cognitive ability, or comorbid conditions were applied to ensure a representative cohort was recruited. Both biological parents and siblings were invited to participate, along with children without a diagnosis of ASD, and children who had been queried for an ASD diagnosis but did not meet diagnostic criteria. All children completed cognitive assessments, with probands and parents completing additional assessments measuring ASD symptomatology. Parents completed questionnaires about their child's medical history and early development. Physical measurements and biological samples (blood, stool, urine, and hair) were collected from children, and physical measurements and blood samples were collected from parents. Samples were sent to a central processing site and placed into long-term storage. DISCUSSION: The establishment of this biobank is a valuable international resource incorporating detailed clinical and biological information that will help accelerate the pace of ASD discovery research. Recruitment into this study has also supported the feasibility of large-scale biological sample collection in children diagnosed with ASD with comprehensive phenotyping across a wide range of ages, intellectual abilities, and levels of adaptive functioning. This biological and clinical resource will be open to data access requests from national and international researchers to support future discovery research that will benefit the autistic community

Computer Vision for Substrate Detection in High‐Throughput Biomaterial Screens Using Bright‐Field Microscopy

High-throughput screening (HTS) can be used when ab initio information is unavailable for rational design of new materials, generating data on properties such as chemistry and topography that control cell behavior. Biomaterial screens are typically fabricated as microarrays or “chips,” seeded with the cell type of interest, then phenotyped using immunocytochemistry and high-content imaging, generating vast quantities of image data. Typically, analysis is only performed on fluorescent cell images as it is relatively simple to automate through intensity thresholding of cellular features. Automated analysis of bright-field images is rarely performed as it presents an automation challenge as segmentation thresholds that work in all images cannot be defined. This limits the biological insight as cell response cannot be correlated to specifics of the biomaterial feature (e.g., shape, size) as these features are not visible on fluorescence images. Computer Vision aims to digitize tasks humans do by sight, such as identify objects by their shape. Herein, two case studies demonstrate how open-source approaches, (region-based convolutional neural network and algorithmic [OpenCV]), can be integrated into cell-biomaterial HTS analysis to automate bright-field segmentation across thousands of images, allowing rapid, spatial definition of biomaterial features during cell analysis for the first time

Fungal Attachment-Resistant Polymers for the Additive Manufacture of Medical Devices

This study reports the development of the first copolymer material that (i) is resistant to fungal attachment and hence biofilm formation, (ii) operates via a nonkilling mechanism, i.e., avoids the use of antifungal actives and the emergence of fungal resistance, (iii) exhibits sufficient elasticity for use in flexible medical devices, and (iv) is suitable for 3D printing (3DP), enabling the production of safer, personalized medical devices. Candida albicans (C. albicans) can form biofilms on in-dwelling medical devices, leading to potentially fatal fungal infections in the human host. Poly(dimethylsiloxane) (PDMS) is a common material used for the manufacture of medical devices, such as voice prostheses, but it is prone to microbial attachment. Therefore, to deliver a fungal-resistant polymer with key physical properties similar to PDMS (e.g., flexibility), eight homopolymers and 30 subsequent copolymers with varying glass transition temperatures (Tg) and fungal antiattachment properties were synthesized and their materials/processing properties studied. Of the copolymers produced, triethylene glycol methyl ether methacrylate (TEGMA) copolymerized with (r)-α-acryloyloxy-β,β-dimethyl-γ-butyrolactone (AODMBA) at a 40:60 copolymer ratio was found to be the most promising candidate by meeting all of the above criteria. This included demonstrating the capability to successfully undergo 3DP by material jetting, via the printing of a voice prosthesis valve-flap using the selected copolymer