Biomedical Engineering - Research Publications

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    The moment arms and lines of action of subscapularis after the Latarjet procedure
    Fox, A ; Ernstbrunner, L ; Henze, J ; Page, RS ; Ackland, DC (WILEY, 2023-12-30)
    The Latarjet procedure is an established surgical treatment for recurrent glenohumeral joint instability with glenoid bone loss. Intraoperatively, the conjoint tendon and its attachement on the coracoid bone graft is routed through a split in subscapularis where the graft is fixed to and augments the anteroinferior glenoid. The objective of this in vitro study was to quantify the influence of glenohumeral joint position and conjoint tendon force on the lines of action and moment arms of subscapularis muscle sub-regions after Latarjet surgery. Eight fresh-frozen, entire upper extremities were mounted onto a testing apparatus, and a cable-pulley system was used to apply physiological muscle loading to the major shoulder muscles. The lines of action and moment arms of four subregions of subscapularis (superior, mid-superior, mid-inferior, and inferior) were quantified radiographically with the conjoint tendon unloaded and loaded while the shoulder was in (i) 0° abduction (ii) 90° abduction (iii) 90° abduction and full external rotation (ABER), and (iv) the apprehension position, defined as ABER with 30° horizontal extension. Conjoint tendon loading after Latarjet surgery significantly increased the inferior inclination of the lines of action of the mid-inferior and inferior subregions of subscapularis in the scapular plane in ABER and apprehension positions (p < 0.001), as well as decreased the horizontal flexion moment arm of the inferior subscapularis (p = 0.040). Increased subscapularis inferior inclination may ultimately increase inferior joint shear potential, while smaller horizontal flexion leverage may reduce joint flexion capacity. The findings have implications for Latarjet surgical planning and postoperative rehabilitation prescription.
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    Micro-Acoustic Holograms for Detachable Microfluidic Devices
    Xu, M ; Vidler, C ; Wang, J ; Chen, X ; Pan, Z ; Harley, WS ; Lee, PVS ; Collins, DJ (WILEY-V C H VERLAG GMBH, 2024-01-04)
    Acoustic microfluidic devices have advantages for diagnostic applications, therapeutic solutions, and fundamental research due to their contactless operation, simple design, and biocompatibility. However, most acoustofluidic approaches are limited to forming simple and fixed acoustic patterns, or have limited resolution. In this study,a detachable microfluidic device is demonstrated employing miniature acoustic holograms to create reconfigurable, flexible, and high-resolution acoustic fields in microfluidic channels, where the introduction of a solid coupling layer makes these holograms easy to fabricate and integrate. The application of this method to generate flexible acoustic fields, including shapes, characters, and arbitrarily rotated patterns, within microfluidic channels, is demonstrated.
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    Seizure occurrence is linked to multiday cycles in diverse physiological signals
    Gregg, NM ; Attia, TP ; Nasseri, M ; Joseph, B ; Karoly, P ; Cui, J ; Stirling, RE ; Viana, PF ; Richner, TJ ; Nurse, ES ; Schulze-Bonhage, A ; Cook, MJ ; Worrell, GA ; Richardson, MP ; Freestone, DR ; Brinkmann, BH (WILEY, 2023-06)
    OBJECTIVE: The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing. METHODS: In this cohort study, 14 subjects underwent chronic ambulatory monitoring with a multimodal wrist-worn sensor (recording heart rate, accelerometry, electrodermal activity, and temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities and electrographic seizures). Wavelet and filter-Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology. RESULTS: Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable electroencephalographic seizure detections (mean = 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal. SIGNIFICANCE: Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time-varying approaches to epilepsy care.
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    Learning the Vector Coding of Egocentric Boundary Cells from Visual Data
    Lian, Y ; Williams, S ; Alexander, AS ; Hasselmo, ME ; Burkitt, AN (SOC NEUROSCIENCE, 2023-07-12)
    The use of spatial maps to navigate through the world requires a complex ongoing transformation of egocentric views of the environment into position within the allocentric map. Recent research has discovered neurons in retrosplenial cortex and other structures that could mediate the transformation from egocentric views to allocentric views. These egocentric boundary cells respond to the egocentric direction and distance of barriers relative to an animal's point of view. This egocentric coding based on the visual features of barriers would seem to require complex dynamics of cortical interactions. However, computational models presented here show that egocentric boundary cells can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Simulation of this simple sparse synaptic modification generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. Furthermore, some egocentric boundary cells learnt by the model can still function in new environments without retraining. This provides a framework for understanding the properties of neuronal populations in the retrosplenial cortex that may be essential for interfacing egocentric sensory information with allocentric spatial maps of the world formed by neurons in downstream areas, including the grid cells in entorhinal cortex and place cells in the hippocampus.SIGNIFICANCE STATEMENT The computational model presented here demonstrates that the recently discovered egocentric boundary cells in retrosplenial cortex can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Additionally, our model generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. This transformation between sensory input and egocentric representation in the navigational system could have implications for the way in which egocentric and allocentric representations interface in other brain areas.
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    Remote Control in Formation of 3D Multicellular Assemblies Using Magnetic Forces
    Jafari, J ; Han, X-L ; Palmer, J ; Tran, PA ; O'Connor, AJ (AMER CHEMICAL SOC, 2019-05)
    Cell constructs have been utilized as building blocks in tissue engineering to closely mimic the natural tissue and also overcome some of the limitations caused by two-dimensional cultures or using scaffolds. External forces can be used to enhance the cells' adhesion and interaction and thus provide better control over production of these structures compared to methods like cell seeding and migration. In this paper, we demonstrate an efficient method to generate uniform, three-dimensional cell constructs using magnetic forces. This method produced spheroids with higher densities and more symmetrical structures than the commonly used centrifugation method for production of cell spheroids. It was also shown that shape of the cell constructs could be changed readily by using different patterns of magnetic field. The application of magnetic fields to impart forces on the cells enhanced the fusion of these spheroids, which could be used to produce larger and more complicated structures for future tissue engineering applications.
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    Engineering highly effective antimicrobial selenium nanoparticles through control of particle size
    Huang, T ; Holden, JA ; Heath, DE ; O'Brien-Simpson, NM ; O'Connor, AJ (Royal Society of Chemistry, 2019-08-21)
    The overuse of antibiotics has induced the rapid development of antibiotic resistance in bacteria. As a result, antibiotic efficacy has become limited, and infection with multidrug-resistant bacteria is considered to be one of the largest global human health threats. Consequently, new, effective and safe antimicrobial agents need to be developed urgently. One promising candidate to address this requirement is selenium nanoparticles (Se NPs), which are made from the essential dietary trace element Se and have antimicrobial activity against Gram-positive bacteria. The size of nanomaterials can strongly affect their biophysical properties and functions; however, the effects of the size of Se NPs on their antibacterial efficacy has not been systematically investigated. Therefore, in this work, spherical Se NPs ranging from 43 to 205 nm in diameter were fabricated, and their mammalian cytotoxicity and antibacterial activity as a function of their size were systematically studied. The antibacterial activity of the Se NPs was shown to be strongly size dependent, with 81 nm Se NPs showing the maximal growth inhibition and killing effect of methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA). The Se NPs were shown to have multi-modal mechanisms of action that depended on their size, including depleting internal ATP, inducing ROS production, and disrupting membrane potential. All the Se NPs were non-toxic towards mammalian cells up to 25 μg mL−1. Furthermore, the MIC value for the 81 nm particles produced in this research is 16 ± 7 μg mL−1, significantly lower than previously reported MIC values for Se NPs. This data illustrates that Se NP size is a facile yet critical and previously underappreciated parameter that can be tailored for maximal antimicrobial efficacy. We have identified that using Se NPs with a size of 81 nm and concentration of 10 μg mL−1 shows promise as a safe and efficient way to kill S. aureus without damaging mammalian cells.
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    Development of Macroporous Chitosan Scaffolds for Eyelid Tarsus Tissue Engineering
    Sun, MT ; O’Connor, AJ ; Milne, I ; Biswas, D ; Casson, R ; Wood, J ; Selva, D (Springer Science and Business Media LLC, 2019-12-01)
    Background: Reconstruction of large eyelid defects remains challenging due to the lack of suitable eyelid tarsus tissue substitutes. We aimed to evaluate a novel bioengineered chitosan scaffold for use as an eyelid tarsus substitute. Methods: Three-dimensional macroporous chitosan hydrogel scaffold were produced via cryogelation with specific biomechanical properties designed to directly match characteristics of native eyelid tarsus tissue. Scaffolds were characterized by confocal microscopy and tensile mechanical testing. To optimise biocompatibility, human eyelid skin fibroblasts were cultured from biopsy-sized samples of fresh eyelid skin. Immunological and gene expression analysis including specific fibroblast-specific markers were used to determine the rate of fibroblast de-differentiation in vitro and characterize cells cultured. Eyelid skin fibroblasts were then cultured over the chitosan scaffolds and the resultant adhesion and growth of cells were characterized using immunocytochemical staining. Results: The chitosan scaffolds were shown to support the attachment and proliferation of NIH 3T3 mouse fibroblasts and human orbital skin fibroblasts in vitro. Our novel bioengineered chitosan scaffold has demonstrated biomechanical compatibility and has the ability to support human eyelid skin fibroblast growth and proliferation. Conclusions: This bioengineered tissue has the potential to be used as a tarsus substitute during eyelid reconstruction, offering the opportunity to pre-seed the patient’s own cells and represents a truly personalised approach to tissue engineering.
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    Antimicrobial nanoparticle coatings for medical implants: Design challenges and prospects
    Li, X ; Huang, T ; Heath, DE ; O'Brien-Simpson, NM ; O'Connor, AJ (AMER INST PHYSICS, 2020-11)
    Microbial colonization, infection, and biofilm formation are major complications in the use of implants and are the predominant risk factors in implant failure. Although aseptic surgery and the administration of antimicrobial drugs may reduce the risk of infection, the systemic use of antibiotics can lead to a lack of efficacy, an increase in the risk of tissue toxicity, and the development of drug-resistant infections. To reduce implant-related infections, antimicrobial materials are increasingly being investigated and applied to implant surfaces using various methods depending on the agents and their microbicidal mechanisms. Through the development of biomaterials and nanotechnology, antimicrobial nanoparticles are becoming promising candidates for implant coatings, as their multifactorial antimicrobial mechanisms combat microbial adherence, viability, and biofilm formation. Despite their antimicrobial promise, the application of nanoparticles onto implant surfaces while retaining their antimicrobial potency faces many challenges. Herein, we review the potential and challenges associated with the design and implementation of antimicrobial nanoparticle coatings for the medical implant industry, particularly focusing on manufacturing considerations, sterilization, long-term stability, protein fouling, regulation, and safety, with a view to providing researchers the necessary tools to aid the translation of materials from the bench to the clinic.
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    Multifunctional Antimicrobial Polypeptide-Selenium Nanoparticles Combat Drug-Resistant Bacteria
    Huang, T ; Holden, JA ; Reynolds, EC ; Heath, DE ; O'Brien-Simpson, NM ; O'Connor, AJ (AMER CHEMICAL SOC, 2020-12-16)
    Antibiotic-resistant bacteria are a severe threat to human health. The World Health Organization's Global Antimicrobial Surveillance System has revealed widespread occurrence of antibiotic resistance among half a million patients across 22 countries, with Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae being the most common resistant species. Antimicrobial nanoparticles are emerging as a promising alternative to antibiotics in the fight against antimicrobial resistance. In this work, selenium nanoparticles coated with the antimicrobial polypeptide, ε-poly-l-lysine, (Se NP-ε-PL) were synthesized and their antibacterial activity and cytotoxicity were investigated. Se NP-ε-PL exhibited significantly greater antibacterial activity against all eight bacterial species tested, including Gram-positive, Gram-negative, and drug-resistant strains, than their individual components, Se NP and ε-PL. The nanoparticles showed no toxicity toward human dermal fibroblasts at the minimum inhibitory concentrations, demonstrating a therapeutic window. Furthermore, unlike the conventional antibiotic kanamycin, Se NP-ε-PL did not readily induce resistance in E. coli or S. aureus. Specifically, S. aureus began to develop resistance to kanamycin from ∼44 generations, whereas it took ∼132 generations for resistance to develop to Se NP-ε-PL. Startlingly, E. coli was not able to develop resistance to the nanoparticles over ∼300 generations. These results indicate that the multifunctional approach of combining Se NP with ε-PL to form Se NP-ε-PL is a highly efficacious new strategy with wide-spectrum antibacterial activity, low cytotoxicity, and significant delays in development of resistance.
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    Simultaneous Interpenetrating Polymer Networks Based on Poly(2-Oxazoline)s
    Shah, SZO ; Trengove, A ; O'Connor, AJ ; Quinn, JF ; Kempe, K (Wiley Open Access, 2024-01-01)
    Interpenetrating polymer networks (IPNs), comprised of two or more independent crosslinked networks in which the individual networks are interlaced, can be used to enhance material properties and increase functionality for applications such as tissue engineering, drug delivery, and biofabrication. IPNs can be formed by either simultaneous or sequential crosslinking, with sequential crosslinking being complicated by the need to infiltrate the constituents of the second network into the first network. Herein, the study reports the first simultaneous IPN based on the cationic ring-opening polymerization (CROP) of 2-methyl-2-oxazoline (MeOx) with bis(butyl-2-oxazoline) (BBOx) crosslinker and the reversible addition-fragmentation chain-transfer (RAFT) polymerization of N,N-dimethylacrylamide (DMAAm) with N,N`-methylene bis(acrylamide) (BAM) crosslinker. Specifically, the compatibility of the synthesis techniques is demonstrated for the preparation of simultaneous IPNs, and it is shown that, by varying the amounts of the two crosslinkers and comparing to single-component networks, the equilibrium degree of swelling (EDS) in water and compressive modulus can be tuned. The results reported demonstrate the utility of CROP and RAFT for preparing IPNs and suggest that with appropriate optimization the technique can be expanded to other monomer pairs which are polymerizable via CROP and RAFT.