Biomedical Engineering - Research Publications

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    Tissue Programmed Hydrogels Functionalized with GDNF Improve Human Neural Grafts in Parkinson's Disease (Adv. Funct. Mater. 47/2021)
    Hunt, CPJ ; Penna, V ; Gantner, CW ; Moriarty, N ; Wang, Y ; Franks, S ; Ermine, CM ; de Luzy, IR ; Pavan, C ; Long, BM ; Williams, RJ ; Thompson, LH ; Nisbet, DR ; Parish, CL (Wiley, 2021-11)
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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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    The Challenge of Cartilage Integration: Understanding a Major Barrier to Chondral Repair
    Trengove, A ; Di Bella, C ; O'Connor, AJ (MARY ANN LIEBERT, INC, 2022-02-01)
    Articular cartilage defects caused by injury frequently lead to osteoarthritis, a painful and costly disease. Despite widely used surgical methods to treat articular cartilage defects and a plethora of research into regenerative strategies as treatments, long-term clinical outcomes are not satisfactory. Failure to integrate repair tissue with native cartilage is a recurring issue in surgical and tissue-engineered strategies, seeing eventual degradation of the regenerated or surrounding tissue. This review delves into the current understanding of why continuous and robust integration with native cartilage is so difficult to achieve. Both the intrinsic limitations of chondrocytes to remodel injured cartilage, and the significant challenges posed by a compromised biomechanical environment are described. Recent scaffold and cell-based techniques to repair cartilage are also discussed, and limitations of existing methods to evaluate integrative repair. In particular, the importance of evaluating the mechanical integrity of the interface between native and repair tissue is highlighted as a meaningful assessment of any strategy to repair this load-bearing tissue. Impact statement The failure to integrate grafts or biomaterials with native cartilage is a major barrier to cartilage repair. An in-depth understanding of the reasons cartilage integration remains a challenge is required to inform cartilage repair strategies. In particular, this review highlights that integration of cartilage repair strategies is frequently assessed in terms of the continuity of tissue, but not the mechanical integrity. Given the load-bearing nature of cartilage, evaluating integration in terms of interfacial strength is essential to assessing the potential success of cartilage repair methods.
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    Superior Hemostatic and Wound-Healing Properties of Gel and Sponge Forms of Nonoxidized Cellulose Nanofibers: In Vitro and In Vivo Studies
    Mohamed, E ; Wang, Y ; Crispin, PJ ; Fitzgerald, A ; Dahlstrom, JE ; Fowler, S ; Nisbet, DR ; Tsuzuki, T ; Coupland, LA (WILEY-V C H VERLAG GMBH, 2022-10)
    Many materials have been engineered and commercialized as hemostatic agents. However, there is still a gap in the availability of hemostats that offer biocompatibility and biodegradability in combination with effective hemostatic properties. Cellulose nanofibers are investigated as hemostatic materials with most studies focusing on oxidized cellulose-derived hemostats. The recent studies demonstrate that by optimizing the morphological properties of nonoxidized cellulose nanofibers (CNFs) enhanced hemostasis is achieved. Herein, the hemostatic and wound-healing properties of CNFs with optimized morphology using two forms, gel, and sponge is investigated. In vitro thromboelastometry studies demonstrate that CNFs reduce clotting time by 68% (±SE 2%) and 88% (±SE 5%) in gel and sponge forms, respectively. In an in vivo murine liver injury model, CNFs significantly reduce blood loss by 38% (±SE 10%). The pH-neutral CNFs do not damage red blood cells, nor do they impede the proliferation of fibroblast or endothelial cells. Subcutaneously-implanted CNFs show a foreign body reaction resolving with the degradation of CNFs on histological examination and there is no scarring in the skin after 8 weeks. Demonstrating superior hemostatic performance in a variety of forms, as well as biocompatibility and biodegradability, CNFs hold significant potential for use in surgical and first-aid environments.
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    The "Spin-3/2 Bloch Equation": System matrix formalism of excitation, relaxation, and off-resonance effects in biological tissue
    Wu, C ; Blunck, Y ; Johnston, LA (WILEY, 2022-09)
    PURPOSE: This work proposes "Spin-3/2 Bloch Equation" (SBE), a consolidated formalism for spin-3/2 dynamics in biological environments. The formalism encapsulates excitation, relaxation, and off-resonance with accessible matrix representation for a straightforward implementation with high computational efficiency. THEORY: The SBE is derived using spherical tensor operators to encapsulate the spin-3/2 dynamics in biological systems in a single system matrix, a formalism akin to the well-known Bloch Equations (BE). METHODS: Using the proposed SBE, simulations of three classical 23 Na pulse sequences were performed to demonstrate the versatility and applicability of the model, returning the evolution of the 23 Na spin system during these experiments: soft rectangular and adiabatic inversion recovery (IR) and triple-quantum filtering. IR simulations were compared with two existing spin-3/2 simulators and the adaptive BE as a first-order approximation. RESULTS: The proposed SBE is straightforward to implement and facilitates accurate and fast simulations of the underlying higher order coherence in sodium experiments of biological tissues. SBE simulations and comparison spin-3/2 simulators outperform the BE simulations as expected, with the SBE offering superior computational efficiency achieved by the single system matrix formalism. CONCLUSION: The proposed SBE enables comprehensive and accurate simulations for spin-3/2 systems in biological tissue. With a one-line call to an ordinary differential equation solver, it offers a computationally efficient and accessible method for use in 23 Na pulse sequence design.
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    Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy: an in silico study.
    Ghosh, S ; Guglielmi, G ; Orfanidis, I ; Spill, F ; Hickey, A ; Hanssen, E ; Rajagopal, V (The Royal Society, 2022-11-21)
    Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy (EM) and computational modelling to understand the impact of diabetes-induced ultrastructural changes on cardiac bioenergetics. We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using EM. Micrographs were converted to finite-element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation (OXPHOS) and creatine kinase (CK) reactions to simulate diabetes-induced mitochondrial dysfunction. Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with the depressed activity of mitochondrial CK enzymes, leads to large spatial variation in adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% owing to lower mitochondrial area fraction and dysfunction in OXPHOS. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.
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    CardioVinci: building blocks for virtual cardiac cells using deep learning
    Khadangi, A ; Boudier, T ; Hanssen, E ; Rajagopal, V (ROYAL SOC, 2022-11-21)
    Advances in electron microscopy (EM) such as electron tomography and focused ion-beam scanning electron microscopy provide unprecedented, three-dimensional views of cardiac ultrastructures within sample volumes ranging from hundreds of nanometres to hundreds of micrometres. The datasets from these samples are typically large, with file sizes ranging from gigabytes to terabytes and the number of image slices within the three-dimensional stack in the hundreds. A significant bottleneck with these large datasets is the time taken to extract and statistically analyse three-dimensional changes in cardiac ultrastructures. This is because of the inherently low contrast and the significant amount of structural detail that is present in EM images. These datasets often require manual annotation, which needs substantial person-hours and may result in only partial segmentation that makes quantitative analysis of the three-dimensional volumes infeasible. We present CardioVinci, a deep learning workflow to automatically segment and statistically quantify the morphologies and spatial assembly of mitochondria, myofibrils and Z-discs with minimal manual annotation. The workflow encodes a probabilistic model of the three-dimensional cardiomyocyte using a generative adversarial network. This generative model can be used to create new models of cardiomyocyte architecture that reflect variations in morphologies and cell architecture found in EM datasets. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.
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    Electrodetection of Small Molecules by Conformation-Mediated Signal Enhancement
    Murugappan, K ; Sundaramoorthy, U ; Damry, AM ; Nisbet, DR ; Jackson, CJ ; Tricoli, A (AMER CHEMICAL SOC, 2022-11-28)
    Electrochemical biosensors allow the rapid, selective, and sensitive transduction of critical biological parameters into measurable signals. However, current electrochemical biosensors often fail to selectively and sensitively detect small molecules because of their small size and low molecular complexity. We have developed an electrochemical biosensing platform that harnesses the analyte-dependent conformational change of highly selective solute-binding proteins to amplify the redox signal generated by analyte binding. Using this platform, we constructed and characterized two biosensors that can sense leucine and glycine, respectively. We show that these biosensors can selectively and sensitively detect their targets over a wide range of concentrations-up to 7 orders of magnitude-and that the selectivity of these sensors can be readily altered by switching the bioreceptor's binding domain. Our work represents a new paradigm for the design of a family of modular electrochemical biosensors, where access to electrode surfaces can be controlled by protein conformational changes.