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Home , Nanomedicine, Regenerative Medicine

Advanced Reviews 148 (2019) 1–2

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Nanotechnology enabled regenerative for neurological disorders

Tao L. Lowe a,⁎, Vivek Agrahari b, Rangaramanujam M. Kannan c, Sujatha Kannan d

Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA CONRAD, Eastern Virginia , Arlington, VA 22209, USA Center for , Department of , Wilmer Eye Institute, School of Medicine, Baltimore, MD 21231, USA Department of and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Regenerative has evolved significantly in recent years with endogenous regenerative pathways in the brain. The authors discuss promising approaches to restore function of diseased, damaged and -based approaches that target cellular and extracellular aged tissues and organs. It is a highly interdisciplinary field that has components to enhance neural while suppressing cellular been made possible by the intersection of recent advances in bioengi- and extracellular inhibitory mechanisms triggered by injury that could neering, biology and nanotechnology. Incorporation of nano- impair repair and plasticity in the brain. In the perspective review by technology may allow better control over physicochemical and the Ferriero group [2], the unique challenges in considering advanced biological properties of a biomaterial compared to conventional tech- regenerative in the newborn brain are discussed. Newborn nologies. Nanotechnology applications to regenerative therapy have brains are immature and actively changing due to normal brain devel- all the potential to revolutionize tissue regeneration and repair, and ul- opment. Ferriero et al. discuss that regenerative strategies need to be timately . This theme issue of Advanced Drug De- tailored to the gestational age at injury for enabling appropriate devel- livery Review provides comprehensive and critical reviews of recent opment and growth. Although injury to the spinal cord remains devas- developments, future directions, and possible challenges in advancing tating, significant advances have been made in developing novel regenerative therapy for treating neurological disorders using nano- therapies for regeneration of the spinal cord in the last decade. Schmidt technology. This issue has covered the fabrication, characterization, im- et al. [3] provide a thorough insight on the fabrication of aging, and theranostic applications of nanotechnology-based systems in ranging from , nanofibers, nanotubes to quantum dots and central nervous system (CNS) including brain and spinal cord, eye and their therapeutic effects, especially targeting inhibitory environment, in peripheral nerve regeneration. It also reviews in detail the progress of spinal cord injury. They also highlight including nanotechnology in speeding up stem cell research and development optogenetics, immunotherapy and genome editing through CRISPR/ for regenerative neurological medicine. Furthermore, this theme issue Cas9 for spinal cord repair, where nanomaterials have synergistic roles discusses nanoneurotoxicity and hurdles in nanomedicine clinical to play. translation and strategies for pre-clinical evaluation of nanocarriers for Several preclinical studies focused on advanced regenerative thera- regeneration and repair in the nervous system. Nanomaterials as tools pies have shown promise, however, clinical translation of these still re- for understanding CNS disease , neuroplasticity as a target mains challenging. Development of these therapies is expensive and for biomaterial-based therapies for stroke, nanotheranostics as a com- complex requiring close collaboration between researchers, , bined diagnostic and therapeutic entity for personalized medicine in regulatory bodies and industry. Fatemi and group [4] provide a detailed neurological disorders, nanomaterials as gene delivery devices to repro- overview of the challenges involved in translating regenerative thera- gram cells for ocular regeneration, nanomaterials as immunomodula- pies from the lab to the clinic. Pandit et al. [5] present a comprehensive tors to restore healthy immune system for neuronal regeneration, and insight and design of histological, bio-imaging, molecular and behav- the use of zebrafish as a model for evaluating neuroregenerative thera- ioral modalities to screen brain-targeted nanosystems in pre-clinical peutics are some of the unique and promising topics featured in this models. Agrahari et al. [6] thoroughly review the effects of the composi- theme issue. tion of cell culture and biological matrices and nanoformulations’ phys- In general, regenerative therapies following injury can be considered icochemical properties on the in vivo performance of nanoformulations as either exogenous cell-based therapies to replace injured cells or en- for brain-. The authors also discuss the related an- dogenous strategies that enhance intrinsic regenerative capacities in alytical techniques under industrial settings to provide an enhanced un- the organ. The first article of this theme issue by S. Kannan and co- derstanding of the optimal design of brain-targeted nanoformulations workers [1] explores nanotechnology-based strategies to enhance for a successful clinical translation. Besides the comprehensive coverage of nanomaterials for develop- ⁎ Corresponding author. ing CNS therapies, this theme issue combines four papers by R. Kannan E-mail address: [email protected] (T.L. Lowe). et al. [7], Shoichet et al. [8], Yang et al. [9] and Song et al. [10] addressing

https://doi.org/10.1016/j.addr.2019.11.006 0169-409X/© 2019 Published by Elsevier B.V. 2 the opportunities and challenges in leveraging the tremendous variety Finally, Mumm et al. [14] give a comprehensive review on the advan- of nanomaterials for understanding CNS disorders. It is important to rec- tages of zebrafish model in neuroregenerative imaging and therapeu- ognize that despite the common features between many CNS disorders, tics. They describe how zebrafish allow direct visualization of dynamic each presents a unique facet, and the nanoparticles must be tailored to cellular and molecular processes governing endogenous stem cell address the specific pathophysiology of a particular disorder. R. Kannan niche activities during regeneration. They also discuss how zebrafish and group [7] highlight how intrinsic association between model can help to study the of nanocarriers and and disease pathology can be used for microglia-targeted therapies for screen -based drugs to find lead drugs that can promote en- neuroinflammation, producing promising neurobehavioral improve- hanced neuroregeneration. ments in multiple CNS models, an approach that is entering clinical tri- Together, this theme issue assembles cutting-edge articles from als for an unmet pediatric CNS disorder and beyond. Biomaterials can be leading experts in the field. We express our sincere gratitude to all au- vital tools enabling us to interact with brain cells and tissue, sensing thors who contributed to this timely and broadly informative theme their health and communicating it to a device, or using external stimuli issue of Advanced Drug Delivery Reviews. This special issue would not to manipulate brain cells to improve therapeutic outcomes. Shoichet have been possible without the critical evaluations by the reviewers et al. [8] identify factors and targets that influence post-stroke plasticity and the assistance provided by the journal editorial staff members to processes and discusses the role of biomaterials in enhancing the effi- ensure that the submissions are evaluated and published at high stan- cacy of treatment strategies for stroke. The manuscript by Yang et al. dards. Also, our sincere acknowledgement to Dr. Hamid Ghandehari, [9] provide a critical review of biodegradable materials that function Editor-in-Chief and Dr. María J. Vicent, Executive Editor of Advanced as electroactive, photoactive and magnetic materials facilitating man- Drug Delivery Reviews, for giving us the opportunity to develop this agement of neurological disorders. If biomaterials enable nerve regener- theme issue. We sincerely hope this theme issue will accelerate integra- ation in a safe manner, it would be a major advance in CNS disorders. In tive engagements in nanotechnology and to a similar vein, Song and group [10] discuss how nanomaterials can en- move this exciting new field forward for revolutionary solutions to re- able improved functionality of stem cell therapies for CNS disorders. generate compromised, lost or damaged cells and tissues to treat neuro- For example, appropriately tailored nanoparticles can be tools for supe- logical disorders and improve the quality of life of patients in the future. rior , reprogramming, post-implant imaging, and drug delivery, addressing many challenges in stem cell therapies. References They outline the need for more in vivo studies for further translation.

Furthermore, this theme issue includes extensive review by Gendelman [1] K. Liaw, Z. Zhang, S. Kannan, Neuronanotechnology for brain regeneration, Adv. et al. [11] on theranostic strategies targeting neurological disorders, that Drug Deliv. Rev. 148 (2019) 3–18. is, bringing together diagnostic and therapeutic agents to be delivered [2] O.A. Cabeza, A. Mikrogeorgiou, S. Kannan, D.M. Ferriero, Advanced therapies to pro- mote neuroregeneration in the injured newborn brain, Adv. Drug Deliv. Rev. 148 from the same platform. This work provides a comprehensive overview (2019) 19–37. of disease history, epidemiology, pathogenesis and therapeutics for a [3] Y.H. Song, N.K. Agrawal, J.M. Griffin, C.E. Schmidt, Recent advances in spectrum of neurodegenerative disorders in the CNS, and obstacles in nanotherapeutic strategies for spinal cord injury repair, Adv. Drug Deliv. Rev. 148 – diagnosis and as well as various treatment modalities for the disorders. (2019) 38 59. [4] C.L. Nemeth, A.S. Fine, A. Fatemi, Translational challenges in advancing regenerative They then discuss how neurotheranostics especially macrophage-based therapy for treating neurological disorders using nanotechnology, Adv. Drug Deliv. theranostic and nanotechnology play important roles in developing Rev. 148 (2019) 60–67. personalized medicine for neurodegenerative disorders. [5] J. Samal, A.L. Rebelo, A. Pandit, A window into the brain: tools to assess pre-clinical efficacy of biomaterials-based therapies on central nervous system disorders, Adv. Nanotechnology enables regenerative medicine for neurological dis- Drug Deliv. Rev. 148 (2019) 68–145. orders not only in the brain but also in the eye and peripheral nervous [6] V. Agrahari, P.-A. Burnouf, T. Burnouf, V. Agrahari, Nanoformulation properties, char- system. Lowe et al. [12] comprehensively review various nanoscaffolds acterization, and behavior in complex biological matrices: challenges and opportu- fi nities for brain-targeted drug delivery applications and enhanced translational including electro-spun nano bers, self-assembled peptides and potential, Adv. Drug Deliv. Rev. 148 (2019) 146–180. nanotopographies used for cornea, lens, and retina regenerations. [7] E.S. Smith, J.E. Porterfield, R.M. Kannan, Leveraging the interplay of nanotechnology They summarize nanomaterials as carriers for gene and immunomodu- and neuroscience: designing new avenues for treating central nervous system disor- ders, Adv. Drug Deliv. Rev. 148 (2019) 181–203. lators to reprogram cells and restore healthy immune system, respec- [8] J.M. Obermeyer, E. Ho, A. Gracias, M.S. Shoichet, Influencing neuroplasticity in stroke tively, for ocular tissue regeneration. They provide current treatment with advanced biomaterials-based approaches, Adv. Drug Deliv. Rev. 148 perspectives in nanotechnology for tracking cells in the eye and person- (2019) 204–218. [9] D. Shan, C. Ma, J. Yang, Enabling biodegradable functional biomaterials for the man- alized regenerative ophthalmology. Reis and group [13] provide a com- agement of neurological disorders, Adv. Drug Deliv. Rev. 148 (2019) 219–238. prehensive review of all the various nanomaterials that have been [10] C. Vissers, G.-l. Ming, H. Song, Nanoparticle technology and stem cell therapy team evaluated for peripheral nerve regeneration. They discuss how carbon up against neurodegenerative disorders, Adv. Drug Deliv. Rev. 148 (2019) 239–251. nanomaterials, carbon nanotubes, carbon nanofibers, graphene [11] B.D. Kevadiya, B.M. Ottemann, M.B. Thomas, I. Mukadam, S. Nigam, J. McMillan, S. Gorantla, T.K. Bronich, B. Edagwa, H.E. Gendelman, Neurotheranostics as personal- nanomaterials, nanodiamonds, and inorganic, metallic and polymeric ized , Adv. Drug Deliv. Rev. 148 (2019) 252–289. nanoparticles have been explored both in vivo and in vitro in various [12] F.F. Sahle, S. Kim, K.K. Niloy, F. Tahia, C.V. Fili, E. Cooper, D.J. Hamilton, T.L. Lowe, Nanotechnology in regenerative ophthalmology, Adv. Drug Deliv. Rev. 148 (2019) nerve injury models and have shown promise in regeneration of periph- – N 290 307. eral nerves, especially across large gaps ( 30 mm). [13] C.R. Carvalho, J. Silva-Correia, J.M. Oliveira, R.L. Reis, Nanotechnology in peripheral The zebrafish is a well-established and cost-effective vertebrate nerve repair and reconstruction, Adv. Drug Deliv. Rev. 148 (2019) 308–343. model for whole-organism phenotypic and compound screening. Due [14] D.T. White, M.T. Saxena, J.S. Mumm, Let's get small (and smaller): combining zebrafish and nanomedicine to advance neuroregenerative therapeutics, Adv. to its rapid regenerative capacities, this model system also allows direct Drug Deliv. Rev. 148 (2019) 344–359. correlations between observed phenomena and functional recovery.