Mathematical modelling with Bayesian inference to quantitatively characterize therapeutic cell behaviour in nerve tissue engineering.

Cellular engineered neural tissues have significant potential to improve peripheral nerve repair strategies. Traditional approaches depend on quantifying tissue behaviours using experiments in isolation, presenting a challenge for an overarching framework for tissue design. By comparison, mathematical cell-solute models benchmarked against experimental data enable computational experiments to be performed to test the role of biological/biophysical mechanisms, as well as to explore the impact of different design scenarios and thus accelerate the development of new treatment strategies. Such models generally consist of a set of continuous, coupled, partial differential equations relying on a number of parameters and functional forms. They necessitate dedicated in vitro experiments to be informed, which are seldom available and often involve small datasets with limited spatio-temporal resolution, generating uncertainties. We address this issue and propose a pipeline based on Bayesian inference enabling the derivation of experimentally informed cell-solute models describing therapeutic cell behaviour in nerve tissue engineering. We apply our pipeline to three relevant cell types and obtain models that can readily be used to simulate nerve repair scenarios and quantitatively compare therapeutic cells. Beyond parameter estimation, the proposed pipeline enables model selection as well as experiment utility quantification, aimed at improving both model formulation and experimental design.

A combined experimental and computational framework to evaluate the behavior of therapeutic cells for peripheral nerve regeneration.

Recent studies have explored the potential of tissue-mimetic scaffolds in encouraging nerve regeneration. One of the major determinants of the regenerative success of cellular nerve repair constructs (NRCs) is the local microenvironment, particularly native low oxygen conditions which can affect implanted cell survival and functional performance. In vivo, cells reside in a range of environmental conditions due to the spatial gradients of nutrient concentrations that are established. Here we evaluate in vitro the differences in cellular behavior that such conditions induce, including key biological features such as oxygen metabolism, glucose consumption, cell death, and vascular endothelial growth factor secretion. Experimental measurements are used to devise and parameterize a mathematical model that describes the behavior of the cells. The proposed model effectively describes the interactions between cells and their microenvironment and could in the future be extended, allowing researchers to compare the behavior of different therapeutic cells. Such a combinatorial approach could be used to accelerate the clinical translation of NRCs by identifying which critical design features should be optimized when fabricating engineered nerve repair conduits.

An alginate-based encapsulation system for delivery of therapeutic cells to the CNS.

Treatment options for neurodegenerative conditions such as Parkinson's disease have included the delivery of cells which release dopamine or neurotrophic factors to the brain. Here, we report the development of a novel approach for protecting cells after implantation into the central nervous system (CNS), by developing dual-layer alginate beads that encapsulate therapeutic cells and release an immunomodulatory compound in a sustained manner. An optimal alginate formulation was selected with a view to providing a sustained physical barrier between engrafted cells and host tissue, enabling exchange of small molecules while blocking components of the host immune response. In addition, a potent immunosuppressant, FK506, was incorporated into the outer layer of alginate beads using electrosprayed poly-ε-caprolactone core-shell nanoparticles with prolonged release profiles. The stiffness, porosity, stability and ability of the alginate beads to support and protect encapsulated SH-SY5Y cells was demonstrated, and the release profile of FK506 and its effect on T-cell proliferation in vitro was characterized. Collectively, our results indicate this multi-layer encapsulation technology has the potential to be suitable for use in CNS cell delivery, to protect implanted cells from host immune responses whilst providing permeability to nutrients and released therapeutic molecules.

Natural Biomaterials as Instructive Engineered Microenvironments That Direct Cellular Function in Peripheral Nerve Tissue Engineering.

Nerve tissue function and regeneration depend on precise and well-synchronised spatial and temporal control of biological, physical, and chemotactic cues, which are provided by cellular components and the surrounding extracellular matrix. Therefore, natural biomaterials currently used in peripheral nerve tissue engineering are selected on the basis that they can act as instructive extracellular microenvironments. Despite emerging knowledge regarding cell-matrix interactions, the exact mechanisms through which these biomaterials alter the behaviour of the host and implanted cells, including neurons, Schwann cells and immune cells, remain largely unclear. Here, we review some of the physical processes by which natural biomaterials mimic the function of the extracellular matrix and regulate cellular behaviour. We also highlight some representative cases of controllable cell microenvironments developed by combining cell biology and tissue engineering principles.

Redox-Responsive Nanobiomaterials-Based Therapeutics for Neurodegenerative Diseases.

Redox regulation has recently been proposed as a critical intracellular mechanism affecting cell survival, proliferation, and differentiation. Redox homeostasis has also been implicated in a variety of degenerative neurological disorders such as Parkinson's and Alzheimer's disease. In fact, it is hypothesized that markers of oxidative stress precede pathologic lesions in Alzheimer's disease and other neurodegenerative diseases. Several therapeutic approaches have been suggested so far to improve the endogenous defense against oxidative stress and its harmful effects. Among such approaches, the use of artificial antioxidant systems has gained increased popularity as an effective strategy. Nanoscale drug delivery systems loaded with enzymes, bioinspired catalytic nanoparticles and other nanomaterials have emerged as promising candidates. The development of degradable hydrogels scaffolds with antioxidant effects could also enable scientists to positively influence cell fate. This current review summarizes nanobiomaterial-based approaches for redox regulation and their potential applications as central nervous system neurodegenerative disease treatments.

Mechanical properties of the spinal cord and brain: Comparison with clinical-grade biomaterials for tissue engineering and regenerative medicine.

Disorders affecting the central nervous system are a leading cause of disability in the world. Regenerative medicine using biomaterial-based therapies is a growing field that has potential application in the areas of spinal cord injury, neurodegenerative disorders and stroke. The mechanical properties of biomaterials implanted into the central nervous system are critical for effective integration with host tissue, but the biomechanical properties of the host tissue remain poorly characterised and assessing the stiffness of both soft biomaterials and central nervous system tissue remains challenging. Here, we describe a bespoke mechanical characterisation method that facilitates robust measurement of fresh spinal cord and brain tissue and allows direct like-for-like mechanical benchmarking for matching clinical-grade hydrogels suitable for regenerative medicine. We report differences in the mechanical properties of spinal cord tissue dependent on anatomical origin, regional variations in brain tissue stiffness, and quantify the extent of mechanical anisotropy within the cervical spinal cord. We then demonstrate that the mechanical properties of clinical-grade collagen, fibrin and alginate hydrogels can be tuned to closely mimic the mechanical properties of different regions within the central nervous system.

Naringin nanoparticles against neurodegenerative processes: A preliminary work.

It is well established that during Alzheimer disease (AD), gradual loss of neuronal networks occurs in the brain, consequently, affecting cognition and memory tasks of the patients. Among other causative factors, oxidative stress induces changes that are eventually accompanied by an irreversible disruption of synaptic connectivity and death of neurons. Moreover, aging and oxidative stress cause alterations to the blood brain barrier, leading to increased permeability, which are thought to further aggravate the underlying pathology. Up to date, no effective treatment is available to Alzheimer's disease patients. Lately, scientific efforts are focusing on exploiting the antioxidant properties that natural polyphenol agents such as flavonoids possess and their potential beneficial effect against neurodegenerative diseases. For that reason, the current investigation, aims at developing more effective flavonoid agents by encapsulating naringin into modified PEG 3000 Silica nanoparticles before its use at cellular level. Overall, our findings suggest an enhanced protective capacity of naringin pegylated nanoparticles against Aß amyloid linked oxidative stress mediated neurodegeneration in primary rat neuronal and glial hippocampal cultures for a certain incubation period. The functional biological reactivities of the novel flavonoid nanoparticles were in line with their physicochemical features and reflect the a) differential nature of the structural assemblies of the new nanoparticles, thereby distinguishing them from other polymeric and liposomal drug carriers, and b) significance and impact of PEG chemistry in the synthetic assembly of the nanocarriers. The ability of the employed nanoparticles to entrap a relatively high dose of otherwise insoluble drugs and their biological activity highlight their potential as brain targeting therapeutics.

Magnetic chrysin silica nanomaterials behavior in an amyloidogenic environment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with brain damage induced by ß-amyloid and tau accumulation. One of the hallmarks of amyloidogenesis, is the aggregation of amyloid proteins into a specific cross-ß sheet structure, which alters their biological activity thereby affecting neuronal connectivity and function. Despite significant progress in the management of AD over the recent years, the early diagnostic and treatment options still remain limited. Recently, great attention has been focused on the advancement of therapeutic strategies exploiting the antioxidant properties of naturally occurring compounds. Flavonoids, a major class of phytochemicals, have been found to possess a multiple range of health promoting effects, including neuroprotection. Chrysin (ChR) is a flavonoid of the flavone class with potent neuroprotective and anti-inflammatory activity. In addition, ChR improves cognitive decline by exerting anti-amyloidogenic and neurotrophic effects. Magnetic nanoparticles allow binding of drugs by entrapment on the particles, adsorption, or covalent attachment. In our study, well characterized ChR-loaded magnetic PEGylated silica nanospheres (MChRPNPs) were employed with potential enhanced protective characteristics against amyloid induced oxidative stress. The interactions of MChRPNPs with ß-amyloid were demonstrated in rat hippocampal cell cultures. Overall, the findings regarding the biological activity profile of MChRPNPs in a cellular amyloidogenic environment suggest an improved specificity of antioxidant properties counteracting amyloid mediated oxidative stress reactivity.

Shared pathological pathways of Alzheimer's disease with specific comorbidities: current perspectives and interventions.

Alzheimer's disease (AD) belongs to one of the most multifactorial, complex and heterogeneous morbidity-leading disorders. Despite the extensive research in the field, AD pathogenesis is still at some extend obscure. Mechanisms linking AD with certain comorbidities, namely diabetes mellitus, obesity and dyslipidemia, are increasingly gaining importance, mainly because of their potential role in promoting AD development and exacerbation. Their exact cognitive impairment trajectories, however, remain to be fully elucidated. The current review aims to offer a clear and comprehensive description of the state-of-the-art approaches focused on generating in-depth knowledge regarding the overlapping pathology of AD and its concomitant ailments. Thorough understanding of associated alterations on a number of molecular, metabolic and hormonal pathways, will contribute to the further development of novel and integrated theranostics, as well as targeted interventions that may be beneficial for individuals with age-related cognitive decline.

Chitosan encapsulation of essential oil "cocktails" with well-defined binary Zn(II)-Schiff base species targeting antibacterial medicinal nanotechnology.

The advent of biodegradable nanomaterials with enhanced antibacterial activity stands as a challenge to the global research community. In an attempt to pursue the development of novel antibacterial medicinal nanotechnology, we herein a) synthesized ionic-gelated chitosan nanoparticles, b) compared and evaluated the antibacterial activity of essential oils extracted from nine different herbs (Greek origin) and their combinations with a well-defined antibacterial Zn(II)-Schiff base compound, and c) encapsulated the most effective hybrid combination of Zn(II)-essential oils inside the chitosan matrix, thereby targeting well-formulated nanoparticles of distinct biological impact. The empty and loaded chitosan nanoparticles were physicochemically characterized by FT-IR, Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), with the entrapment and drug release studies being conducted through UV-Visible and atomic absorption techniques. The antimicrobial properties of the novel hybrid materials were demonstrated against Gram positive (S. aureus, B. subtilis, and B. cereus) and Gram negative (E. coli and X. campestris) bacteria using modified agar diffusion methods. The collective physicochemical profile of the hybrid Zn(II)-essential oil cocktails, formulated so as to achieve optimal activity when loaded to chitosan nanoparticles, signifies the importance of design in the development of efficient nanomedicinal pharmaceuticals a) based on both natural products and biogenic metal ionic cofactors, and b) targeting bacterial infections and drug resistance.