Neuronanotechnology for brain regeneration

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Abstract

Identifying and harnessing regenerative pathways while suppressing the growth-inhibiting processes of the biological response to injury is the central goal of stimulating neurogenesis after central nervous system (CNS) injury. However, due to the complexity of the mature CNS involving a plethora of cellular pathways and extracellular cues, as well as difficulties in accessibility without highly invasive procedures, clinical successes of regenerative medicine for CNS injuries have been extremely limited. Current interventions primarily focus on stabilization and mitigation of further neuronal death rather than direct stimulation of neurogenesis. In the past few decades, nanotechnology has offered substantial innovations to the field of regenerative medicine. Their nanoscale features allow for the fine tuning of biological interactions for enhancing drug delivery and stimulating cellular processes. This review gives an overview of nanotechnology applications in CNS regeneration organized according to cellular and extracellular targets and discuss future directions for the field.

Introduction

Regenerative medicine, the translational discipline of stimulating human cells to regenerate in order to restore healthy biological function in damaged tissues, has advanced rapidly in the few decades since its inception. The field has produced several FDA-approved regenerative therapies currently on the market to address issues such as epidermal and bone injuries via delivery of biologics, pharmaceuticals, scaffolds, and cells [1]. Despite these promising advances, regenerative medicines for treating neurodegenerative disorders and other central nervous system (CNS) injuries have made little progress in clinical translation. The challenges in developing regenerative strategies for nervous system injuries arise from its highly complex nature, as well as the difficulty in accessing damaged nervous system tissues while limiting collateral damage [2]. Regeneration in the brain comprises of not only cellular replacement but also synaptic and functional repair and plasticity. Normal regenerative response following an injury is dictated by the neural and glial cells, the extracellular matrix, the immune system, and interactions between all these components. Manipulation of these systems in conjunction and sequence will be crucial for enhancing normal recovery and promoting repair. Nanotechnology has the potential to provide novel devices and materials to support and stimulate nervous system regeneration and can be leveraged to help manipulate each of these systems (Fig. 1). This review will outline the status of neuroregenerative strategies in the brain, discuss the various nanotechnology platforms being developed in the field, and attempt to provide an outline for potential areas of future growth and research in this field.

Section snippets

Current clinical pipeline for neuroregeneration

Currently, clinical strategies for addressing neurological diseases and injuries requiring neuroregeneration have largely focused on ameliorating secondary effects and limiting further cell death rather than directly stimulating cellular regeneration. Examples include traumatic brain injury (TBI), where supportive care and physical therapy are current interventions [3], and Parkinson's disease (PD), where dopamine replacement therapy and symptomatic treatment are mainstays of intervention [4,5

Nanoparticle delivery of growth factors to promote neurogenesis

Biological factors secreted by neurons and by cells such as microglia, astrocytes, and endothelial cells can regulate neuronal proliferation, migration, survival, and differentiation. The most commonly explored growth factors for these applications are brain-derived neurotrophic factor (BDNF) [[13], [14], [15], [16]], erythropoietin (EPO) [17,18], and nerve growth factor (NGF) [[19], [20], [21], [22]]. Other trophic factors such as glial-derived neurotrophic factor, platelet-derived growth

Nanotechnology strategies for promoting neuroregeneration by modulating the extracellular environment

The extracellular matrix (ECM) plays a critical role in mediating neuroregeneration and can likewise be harnessed for therapeutic effects (Fig. 1). Foundational studies have shown the ECM's role in neurogenesis and its pathological changes under CNS injury, revealing a promising target for nanotechnology to precisely manipulate the physical and chemical cues that promote regeneration (Table 4) [120].

Multifunctional nanosystems

Due to the highly complex nature of neural regeneration discussed above, strategies integrating multiple therapeutic targets in both cells and the ECM constitute a more holistic approach that may yield greater therapeutic efficacy. Nanotechnology approaches can be combined and designed to address multiple disease pathologies in a single nanosystem.

Conclusions and future directions

Since the inception of the field of regenerative medicine, great strides have been made to stimulate tissue regeneration for improving patient outcomes. Given the incredibly challenging nature of the CNS, successes in neural regeneration have been more limited. Few regenerative strategies for CNS injuries have achieved FDA approval for use in patients, and there is a lack of promising technologies upcoming in the clinical pipelines. Nanotechnology can provide the precise and robust stimulation

Acknowledgements

This work was supported in part by NIBIB (R01EB018306), NIH, United States, and NINDS (R01NS093416; U01NS103882), NIH, United States. We also like to thank Dr. Bindu Balakrishnan for acquiring the images in Fig. 5.

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    Current affiliation: Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, MI 48128, United States of America.

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