Regenerative Medicine and Brain Repair (Stem Cell Biology and Regenerative Medicine, 75) 3031497430, 9783031497438

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Stem Cell Biology and Regenerative Medicine

Philip V. Peplow Bridget Martinez Thomas A. Gennarelli   Editors

Regenerative Medicine and Brain Repair

Stem Cell Biology and Regenerative Medicine Volume 75

Series Editor Kursad Turksen, Ottawa Hospital Research Institute, Ottawa, ON, Canada

Our understanding of stem cells has grown rapidly over the last decade. While the apparently tremendous therapeutic potential of stem cells has not yet been realized, their routine use in regeneration and restoration of tissue and organ function is greatly anticipated. To this end, many investigators continue to push the boundaries in areas such as the reprogramming, the stem cell niche, nanotechnology, biomimetics and 3D bioprinting, to name just a few. The objective of the volumes in the Stem Cell Biology and Regenerative Medicine series is to capture and consolidate these developments in a timely way. Each volume is thought-provoking in identifying problems, offering solutions, and providing ideas to excite further innovation in the stem cell and regenerative medicine fields. Series Editor Kursad Turksen, Ottawa Hospital Research Institute, Canada Editorial Board Pura Muñoz Canoves, Pompeu Fabra University, Spain Lutolf Matthias, Swiss Federal Institute of Technology, Switzerland Amy L Ryan, University of Southern California, USA Zhenguo Wu, Hong Kong University of Science & Technology, Hong Kong Ophir Klein, University of California SF, USA Mark Kotter, University of Cambridge, UK Anthony Atala, Wake Forest Institute for Regenerative Medicine, USA Tamer Önder, Koç University, Turkey Jacob H Hanna, Weizmann Institute of Science, Israel Elvira Mass, University of Bonn, Germany

Philip V. Peplow · Bridget Martinez · Thomas A. Gennarelli Editors

Regenerative Medicine and Brain Repair

Editors Philip V. Peplow Department of Anatomy University of Otago Dunedin, New Zealand

Bridget Martinez Department of Pharmacology and Medicine Reno School of Medicine University of Nevada Reno Reno, NV, USA

Thomas A. Gennarelli Professor Emeritus Department of Neurosurgery Medical College of Wisconsin Milwaukee, WI, USA

ISSN 2196-8985 ISSN 2196-8993 (electronic) Stem Cell Biology and Regenerative Medicine ISBN 978-3-031-49743-8 ISBN 978-3-031-49744-5 (eBook) https://doi.org/10.1007/978-3-031-49744-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Title: “Stroke of Genius” This is an acrylic on canvas piece. Aptly named as most strokes (disease stroke/blood clots in the brain) occur from damage to endothelial tissue in the cardiovascular system (heart). Hence, comparing the equal importance of both side, by side a stroke of genius. Artist, Bridget Martinez, MD PhD

Preface

Neurodegenerative diseases and brain injury are increasing in incidence in adults. Current medications only temporarily reduce some of the symptoms but do not cure or delay progression of the disease or injury. The development of effective treatments would dramatically improve the independent living and quality of life of patients. Cell transplantation strategies offer an approach to facilitating brain repair, but efficacy is often limited by low in vivo survival rates of cells that are injected in suspension. Transplanting cells that are attached to or encapsulated within a biomaterial construct has the advantage of maintaining cell-cell and cell-material interactions and improving cell survival in vivo. A variety of biomaterials have been used in preclinical studies to assist with in vivo cell transfer and incorporation into the host tissue. It is the goal of this book to provide a forum for both experimental and clinical international experts in the field of stem cell/biomaterials research to present recent data on the latest achievements of new and emerging regenerative technologies for brain repair. Theoretical backgrounds together with tested protocols that reproduce experimental and clinical laboratory methods for educational purposes are presented. It is hoped that the topics covered herein will extend knowledge on the role of neuroregenerative technologies and that this will lead to a more effective approach to clinical management and ultimately benefit patient care. We wish to express our deep appreciation and gratitude to each of the chapter authors for the time and effort spent on writing informative reviews on their respective areas of clinical and research interest. Also, we wish to thank Dr. Gonzalo Cordova, Senior Editor, Life and Biomedical Sciences Books, Springer Nature, for help and advice in putting together this book. Dunedin, New Zealand Reno, NV, USA Milwaukee, WI, USA October 2023

Philip V. Peplow Bridget Martinez Thomas A. Gennarelli

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Contents

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Initiating and Facilitating Brain Repair: Factors, Principles, and Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laura N. Zamproni and Marimelia A. Porcionatto Strategies to Upgrade the Stem Cell Application for Brain Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniel Henriques, Johannes Boltze, Luís Pereira de Almeida, and Liliana Mendonça

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Neural Stem Cell Intervention in Traumatic Brain Injury . . . . . . . . . Andrew R. Morris, Heather L. Morris, Genevieve Z. Barquet, Stuti R. Patel, Nayef A. Amhaz, Olivia C. Kenyon, Zaynab Shakkour, Jiepei Zhu, Fatima Dakroub, and Firas H. Kobeissy

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Neurotrophic Factors in Parkinson’s Disease: Clinical Trials . . . . . . 109 Arun Kumar Mahato and Mart Saarma

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Emerging Nanotechnology for the Treatment and Diagnosis of Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) . . . . . . . . 139 Sumasri Kotha, Manjari Sriparna, Joel Tyson, Amanda Li, Weiwei He, and Xiaobo Mao

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Poly(Butyl Cyanoacrylate) Nanoparticles Deliver β-Nerve Growth Factor to the Brain After Traumatic Brain Injury . . . . . . . . 175 Yong Lin

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The Significance of Biomaterials in Stem Cell-Based Regenerative Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 Meina Liu, Kai Pan, Zhikun Guo, and Zongjin Li

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Endogenous In Situ Tissue Regeneration Using Inductive Bioscaffolds After Acute Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Nadine Didwischus, Alena Kisel, and Michel Modo

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Alginate Nanofiber Scaffolds for Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Davis M. Maulding, Julia Bielanin, Parker Cole, Yang Tian, Mahsa Saeeidi, Hari S. Sharma, Aruna Sharma, and Ryan Tian

10 Developing High-Fidelity In Vitro Models of Traumatic Brain Injury to Test Therapeutic Biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . 271 Christopher Adams, Bushra Kabiri, Raja Haseeb Basit, Jessica Wiseman, and Divya Maitreyi Chari 11 Challenges and Future Perspectives of Using Bioactive Scaffolds in Brain Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Rodrigo Ramos-Zúñiga, Carlos Isaac Ramírez-Bañales, and María Fernanda Guerrero-Islas Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Contributors

Christopher Adams Neural Tissue Engineering Group, School of Life Sciences, Keele University, Staffordshire, UK Nayef A. Amhaz University of Florida, Gainesville, FL, USA Genevieve Z. Barquet University of Florida, Gainesville, FL, USA Raja Haseeb Basit Bradford Royal Infirmary, Bradford, West Yorkshire, UK Julia Bielanin (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Johannes Boltze School of Life Sciences, University of Warwick, Coventry, UK Divya Maitreyi Chari Neural Tissue Engineering Group, School of Medicine, Keele University, Staffordshire, UK Parker Cole (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Fatima Dakroub American University of Beirut, Beirut, Lebanon Luís Pereira de Almeida Institute of Interdisciplinary Research, Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal Nadine Didwischus McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA María Fernanda Guerrero-Islas Institute of Translational Neurosciences, Department of Neurosciences, CUCS Universidad de Guadalajara, Guadalajara, Mexico Zhikun Guo Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China; Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People’s Hospital, Zhengzhou, China

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Contributors

Weiwei He Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, College of Chemical and Materials Engineering, Xuchang University, Xuchang, Henan, P. R. China Daniel Henriques Institute of Interdisciplinary Research, Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal Bushra Kabiri Neural Tissue Engineering Group, School of Medicine, Keele University, Staffordshire, UK Olivia C. Kenyon University of Florida, Gainesville, FL, USA Alena Kisel Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA Firas H. Kobeissy Morehouse School of Medicine, Atlanta, GA, USA Sumasri Kotha Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA Amanda Li Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, USA Zongjin Li Nankai University School of Medicine, Nankai University, Tianjin, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, Tianjin, China Yong Lin Brain Injury Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Head Trauma, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Meina Liu Puyang People’s Hospital, Puyang, China; Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China; Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People’s Hospital, Zhengzhou, China Arun Kumar Mahato Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland Xiaobo Mao Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;

Contributors

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Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA Davis M. Maulding (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Liliana Mendonça Institute of Interdisciplinary Research, Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal Michel Modo Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA Andrew R. Morris University of Florida, Gainesville, FL, USA Heather L. Morris Target RWE, Durham, NC, USA Kai Pan Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China; Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People’s Hospital, Zhengzhou, China Stuti R. Patel University of Florida, Gainesville, FL, USA Marimelia A. Porcionatto Department of Biochemistry, Neurobiology Laboratory, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil Rodrigo Ramos-Zúñiga Institute of Translational Neurosciences, Department of Neurosciences, CUCS Universidad de Guadalajara, Guadalajara, Mexico Carlos Isaac Ramírez-Bañales Institute of Translational Neurosciences, Department of Neurosciences, CUCS Universidad de Guadalajara, Guadalajara, Mexico Mart Saarma Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland Mahsa Saeeidi (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Zaynab Shakkour American University of Beirut, Beirut, Lebanon Aruna Sharma (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA

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Contributors

Hari S. Sharma (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Manjari Sriparna Virginia Commonwealth University School of Medicine, Richmond, VA, USA Ryan Tian (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Yang Tian (ARSC)-Arts & Sciences. (CHBC)-Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA Joel Tyson Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, Baltimore, MD, USA Jessica Wiseman Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK Laura N. Zamproni Department of Biochemistry, Neurobiology Laboratory, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil Jiepei Zhu Morehouse School of Medicine, Atlanta, GA, USA

Chapter 1

Initiating and Facilitating Brain Repair: Factors, Principles, and Mechanisms Laura N. Zamproni and Marimelia A. Porcionatto

Abstract Introduction: Acute injuries to the brain result in a wide range of sequelae, and several factors contribute to the severity of a brain lesion, including age, overall health, and extension and site of the injury. Complete brain repair after a massive traumatic brain injury or stroke remains challenging. During the acute phase of the injury, the inflammatory microenvironment can induce further neuronal death. The lack of structural support for cellular repopulation, anchoring, and synapse formation reduces the repair chances. After the acute phase, the glial scar formed by reactive astrocytes and oligodendrocytes dramatically decreases the possibility for the surviving neurons to restore damaged synapses. Methods: We reviewed studies describing the development of bioengineering techniques, with the production of biocompatible new biomaterials that can become the next step in neurorepair. Results: Various natural and synthetic materials have been used to replace damaged tissue, and using induced pluripotent stem cells to originate neurons from the patient dramatically reduces the chances of rejection of biomaterial populated with cells, creating innovative biopatches. Besides using biomaterial constructs to deliver cells, bioscaffolds can deliver genes, nanoparticles, soluble factors, and exosomes to induce neurorepair in a more controllable and permanent manner. Conclusions: Understanding the cellular and molecular mechanisms activated in response to brain injury is critical to designing and developing successful brain repair strategies. Keywords Bioscaffolds · Biomaterials · Brain repair · Tissue engineering · Stem cells

L. N. Zamproni · M. A. Porcionatto (B) Department of Biochemistry, Neurobiology Laboratory, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 P. V. Peplow et al. (eds.), Regenerative Medicine and Brain Repair, Stem Cell Biology and Regenerative Medicine 75, https://doi.org/10.1007/978-3-031-49744-5_1

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Abbreviations 3D BBB BDNF BMPs CCL11 CCL2 CNS CSPG CXCL1 CXCL12 DAMPs DRG ECM EPO ESCs FGF FOXA2 GAL1 GAL3 GFAP IGFs IL10 IL1β IL6 iPSCs LMX1B MAG Micro-TENNs MMPs MSCs NGF NSCs NT3 NURR1 O4 OMGp PAX6 PROK2 PRRs RMS SGZ SPMs

Three-dimensional Blood-brain barrier Brain-derived neurotrophic factor Bone morphogenetic proteins C-C motif ligand 11 C-C motif ligand 2 Central nervous system Chondroitin sulfate proteoglycan C-X-C motif ligand 1 C-X-C motif ligand 12 Damaged-associated molecular patterns Dorsal root ganglion Extracellular matrix Erythropoietin Embryonic stem cells Fibroblast growth factor Forkhead box A2 Galectin 1 Galectin 3 Glial fibrillary acidic protein Insulin-like growth factors Interleukin 10 Interleukin 1 beta Interleukin 6 Induced pluripotent stem cells LIM homeobox transcription factor 1-beta Myelin-associated glycoprotein Microtissue-engineered neural networks Metalloproteinases Mesenchymal stem cells Nerve growth factor Neural stem cells Neurotrophin 3 Nuclear receptor-related 1 Oligodendrocyte progenitor marker Oligodendrocyte myelin glycoprotein Paired box protein 6 Prokineticin 2 Pattern recognition receptors Rostral migratory stream Subgranular zone Specialized pro-resolving mediators

1 Initiating and Facilitating Brain Repair: Factors, Principles …

SVZ TBI TH TNF α TUBBIII VEGF

3

Subventricular zone Traumatic brain injury Tyrosine hydroxylase Tumor necrosis factor alpha Class III beta-tubulin Vascular endothelial growth factor

Initiation of Neuroinflammation: The Role of Microglia Neuroinflammation is common among neurological disorders, including brain trauma and stroke [1–3]. It will vary in intensity, range, and duration depending on the context and course of the primary injury. Neuroinflammation can be transient and self-limited, facilitating tissue repair, or persistent and dysregulated, leading to a chronic inflammatory state and tissue degeneration [4]. After a brain injury, the inflammatory process is initiated by debris formed from the cells that died from the acute injury. The molecules released from damaged or dying cells are collectively known as damaged-associated molecular patterns (DAMPs) [5]. DAMPs activate microglia receptors called pattern recognition receptors (PRRs), initiating the inflammatory response. Activated microglia removes cell debris and release inflammatory proteins, such as interleukin 1 beta (IL1β), interleukin 6 (IL6), tumor necrosis factor alfa (TNF α), and several chemokines, such as C–C motif ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL1) and prokineticin 2 (PROK2) [6–8]. Astrocytes become reactive as part of the inflammatory process and undergo several changes, such as hypertrophy, increased expression of glial fibrillary acidic protein (GFAP), galectin 1 (GAL1), and galectin 3 (GAL3) [9–11]. Also, as part of astrocyte reactivation, metalloproteinases (MMPs) and chemokines such as C-X-C motif ligand 12 (CXCL12) secretion increases [12]. The consequence of increased MMP secretion is the degradation of extracellular matrix (ECM) proteins that will allow for tissue remodeling but also leads to the breakdown of the blood–brain barrier (BBB) due to basal lamina degradation [13]. Circulating immune cells enter the brain parenchyma through the disrupted BBB, thus enhancing the inflammatory process and creating a positive loop [14]. The inflammation resolution, or the end of the inflammatory response, follows the acute inflammation phase and is driven by the release of a class of molecules, the specialized pro-resolving mediators (SPMs), by endothelial cells, macrophages, and neutrophils [15]. Several SPMs have been described, resulting from the metabolism of polyunsaturated fatty acids released by lipoxygenase, cyclooxygenase, or cytochrome P450 monooxygenase. The SPMs resolvins, protectins, maresins, and lipoxins are signaling molecules that play important roles in inflammation resolution [16, 17]. During neuroinflammation resolution, anti-inflammatory cytokines such as interleukin 10 (IL10) and trophic factors are released, favoring

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tissue regeneration [18]. However, if the inflammatory process remains unresolved, it can lead to chronic central nervous system (CNS) inflammation and neurodegeneration.

Glial Scar and Neural Tissue Remodeling: The Role of Astrocytes Along with the resolution of the acute inflammation, molecules derived from reactive astrocytes and oligodendrocytes produce scar tissue known as glial scar [9, 19– 21]. The glial scar is composed of neuronal outgrowth inhibitory molecules such as chondroitin sulfate proteoglycan (CSPG), NOGO, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGp). Figure 1.1 summarizes the phases from acute brain injury to tissue remodeling. Over the years, there have been many attempts to reduce glial scar as a strategy to reduce injury sequelae. Still, the strategies to inhibit or degrade the scar components resulted in enhanced inflammation and worsening of the pathology, indicating that the glial scar is necessary for the process of inflammation resolution [22–25]. Conditional

Fig. 1.1 Schematic representation of damaged tissue after traumatic brain injury (TBI) with a timeline of the overlapping phases. The inflammatory phase is characterized by the rupture of the blood–brain barrier (BBB) and infiltration of leukocytes into the brain parenchyma, causing the death of neuronal and non-neuronal cells. The tissue replacement phase begins around 48 h post-injury when proliferating and migrating cells reach the injury site and start restructuring the damaged tissue and blood vessels. The tissue remodeling phase comprises the activation of metalloproteases (MMPs), incorporation of newly synthesized extracellular matrix (ECM) proteins, myelin-associated proteins, and chondroitin sulfate proteoglycans (CSPG) by reactive astrocytes and oligodendrocytes, culminating with the production of a glial scar (Original illustration by Dr. Julia C. Benincasa)

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ablation of reactive astrocytes in mice leads to increased local tissue disruption, severe demyelination, and neuron and oligodendrocyte death [19]. Reactive astrocytes have a dual role in the resolution of brain injuries. On one side, astrocytes produce molecules that surround the primary injury site, avoiding expansion of the injury, and on the other hand, astrocytes secrete molecules that will provide survival signals for the undamaged neurons. The pro-survival molecules include glucose, nutrients, and growth factors such as insulin-like growth factors (IGFs), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT3) [25, 26]. Additionally, astrocytes stimulate local angiogenesis by recruiting endothelial cells and fibroblasts into the lesioned area [25].

Post-Injury Neurogenesis and Brain Plasticity Brain plasticity refers to any process that leads to regaining functions and restoring functional neuronal circuits after an injury. Plasticity involves short-distance axon sprouting, leading to new connections and strengthening existing connections [27]. The plasticity process allows signals to bypass damaged areas by creating new circuits and reassigning new functions to undamaged areas of the CNS. After brain injuries, such as a stroke, neurons in the perilesional area upregulate signaling pathways that promote axonal outgrowth and synapse formation [28]. The turnover of dendritic spines is enhanced, providing a substrate for new connections. Neurons in perilesional tissue can project new axons by several millimeters into nearby cortical areas where new functional synaptic connections are formed [29]. The adult mammalian brain contains two well-defined neurogenic niches: the hippocampus’s subgranular zone (SGZ) in the dentate gyrus and the subventricular zone (SVZ) in both lateral ventricles. Extensive work has been done in identifying and characterizing the cellular and molecular components of those niches and searching for new areas in the CNS that can generate new neurons in adults [30–35]. Neural stem cells (NSC) in the SVZ are pluripotent stem cells that can produce astrocytes, oligodendrocytes, and neurons. Newborn neurons, or neuroblasts, produced by NSCs in the SVZ neurogenic niche, migrate through the rostral migratory stream (RMS) to the olfactory bulbs, where they differentiate into mature interneurons [36]. The discovery of adult neurogenesis in mammalian brains shed light on new possibilities for brain repair. In rodent brain trauma and stroke models, there is increased cell proliferation in the SVZ and the recruitment of neuroblasts that migrate along blood vessels towards the injury [37, 38]. Again, the reactive astrocytes are essential players in this process and are critical regulators of adult neurogenesis. Astrocytes are one of the primary sources of molecules such as bone morphogenetic protein (BMP) and WNT, which regulate NSC proliferation and differentiation. NSCsderived neuroblasts are attracted to the injury site by chemoattractive agents like C–C motif ligand 2 (CCL2), C–C motif ligand 11 (CCL11), and CXCL12, mostly produced by astrocytes [6, 12, 39–43].

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Although neuroblasts born in the SVZ migrate toward the injury site, most of them cannot penetrate the glial scar due to the presence of chondroitin sulfate proteoglycan (CSPG) that impairs cell protrusions and adhesion dynamics through Rho GTPase inhibition [21]. Neuroblasts that reach the injury site are attracted by CXCL12 secreted by astrocytes and PROK2 secreted by microglia [6] but die by apoptosis induced by partially cleaved CXCL12 [44]. These processes expose the complexity of the cellular and molecular mechanisms involved in attempts to promote brain repair and, so far, indicate that adult endogenous neurogenesis alone is insufficient for complete brain repair [45]. More recently reactive astrocytes have been suggested as a new possibility for endogenous neurogenesis to repair injured tissue due to their capacity to dedifferentiate and acquire NSC phenotype [10, 11, 46].

Strategies to Repair the Injured Brain The term “repair,” when used to describe the healing of damaged tissue, means to restore tissue architecture and function, and comprises two processes: regeneration and replacement. Regeneration occurs when the damaged tissue grows into new tissue and is restored to its normal state. Replacement occurs when a different tissue, usually connective tissue, is deposited over the damaged tissue, producing a scar [47]. The complexity of CNS anatomy, physiology, and cellular composition makes repair challenging. Rebuilding the brain means rebuilding the complex brain tissue architecture and its intricate and extensive vascular networks [48]. As presented in the previous section, although these processes are limited, the mammalian brain possesses regenerative mechanisms, including endogenous neurogenesis and neuroplasticity [27, 49]. Beyond the discovery and development of new drugs to overcome the obstacles to neuroregeneration, new therapeutic strategies include stem cell transplantation, gene therapy, and tissue engineering. More recently, various combinations of biomaterials, stem cells, and chemical and physical cues have produced bioengineered tissue-like structures to replace in vivo tissues and organs [50].

Biomaterials Biomaterials refer to biocompatible materials that can be from natural sources, such as ECM proteins, for example, collagens and fibronectin, or algae-derived polysaccharides, such as alginate; biomaterials can also derive from non-natural materials engineered to integrate with a biological system and provide beneficial effects by directing or controlling cell interaction [51–55]. In brain injuries, biomaterials are mainly used for two purposes: as scaffolds to provide mechanical support to the injured brain while providing cues for new neural circuits formation or as carriers, to

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deliver content such as stem cells, growth factors, exosomes, and gene vectors to the site of injury [53, 56–58]. By replacing the virtual cavity formed after a brain injury, bioscaffolds can provide a tissue-appropriate physical and trophic environment for new neural cells and circuitry to survive and integrate into the host tissue [56]. The biomaterial must be compatible with the tissue in which it will be implanted and interact with the tissue-specific ECM. In the brain, the ECM components regulate several neural processes, including neurite outgrowth, synaptogenesis, synaptic stabilization, and injury-related plasticity, both in development and adulthood [59]. The main components of the brain ECM are glycosaminoglycans (chondroitin sulfate, heparan sulfate, hyaluronic acid), proteoglycans (neurocan, brevican, versican, and aggrecan), glycoproteins (tenascin-R), and low levels of fibrous proteins (collagen, fibronectin, and vitronectin) [59]. Also, brain ECM varies in different compartments of the neural tissue, for example, the vascular basement membrane is composed of collagen, laminin, fibronectin, and proteoglycans; the perineuronal matrix is made primarily of CSPG, and the interstitial matrix contains mainly proteoglycans, hyaluronic acid, and small amounts of collagen, elastin, laminin, and fibronectin [60]. As mentioned, a glial scar is formed after a brain injury, and it contains a higher amount of CSPG than the surrounding healthy tissue. Unlike other tissues in the body, the glial scar is softer than the healthy neural tissue [61], impacting astrocyte response [62]. The brain ECM structure imposes the biomaterial to be used in the brain must possess specific characteristics. Besides being biocompatible, the biomaterial must possess mechanical properties similar to the brain tissue. Stiffer materials lead to increased astrogliosis, and softer materials lead to poor material stability at the implant site. The ideal biomaterial should not induce or worsen neuroinflammation. In this way, long-term implants can cause a chronic inflammatory reaction, degradability is desirable, and degradation products should be non-cytotoxic. Since the brain is confined to the skull, the biomaterial must present minimal swelling to avoid rising intracranial pressure [55, 56]. The rigid skull also imposes in the biomaterial delivery route, making injectable and shape-adaptable materials like hydrogels preferred over solid scaffolds requiring invasive surgical implantation [56]. Hydrogels are formed by physical or chemical cross-linking of hydrophilic polymers or by self-assembly systems. Their mechanical properties are usually similar to the brain tissue, and they can be injected in a liquid form, fill the irregular injury cavity, and then polymerize, forming a gel, a feature extremely relevant for the delivery method of choice [63].

Bioscaffolds for Brain Repair The ideal bioscaffold must match the brain biochemical environment in terms of water content and pH, the brain biophysical environment such as viscoelastic properties and porosity, the ECM three-dimensional (3D) architecture on a biologically relevant length scale, and also stimulate cells to infiltrate its structure [64, 65]. Bioscaffolds’

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mechanical forces can regulate the cellular microenvironment and control cell–cell and cell-ECM interactions [66–68]. Mechanical forces can influence cell functions such as migration, proliferation, differentiation, and apoptosis [69]. For the CNS, bioscaffold electroconductive properties are usually desirable. It is well established that an electroconductive surface can increase neuronal differentiation, stimulate axon growth, and facilitate synapsis formation [70, 71]. Fibrous scaffolds, particularly those with oriented fibers, can regulate and guide axon sprouting and synapse formation [72, 73]. One of the concerns regarding biomaterials implantation in the brain is the possibility of a foreign body response that would lead to an increase in neuroinflammation [74, 75]. Although some materials have been shown to modulate inflammation, for example, high molecular weight hyaluronic acid decreases microglia and glial scarring at the injury site [76], there is a concern of adverse immune reactions resulting in exacerbated inflammation, healing impairment, fibrotic encapsulation, and isolation and rejection of medical devices [74]. One of the strategies to overcome this issue is incorporating bioactive molecules, such as cytokines and growth factors, that could modulate the inflammatory response. Combining bioscaffolds with stem cells, growth factors, and exosomes show great perspectives of positive results for the development of new strategies for brain repair [77] (Table 1.1). Table 1.1 Examples of studies focusing on bioscaffolds for brain repair Cell

Scaffold

Outcome

References

Embryonic mouse Silk fibers cortical neural cells

• Increased neurite extension • Guided axonal elongation • Guided cell migration from cellular spheroids along the fibers

[78]

Rat hippocampal neurons

Graphene

• Induced neuronal networks formation • Increased GABAergic activity

[79]

Mouse NG108-15 cells

Graphene oxide/silk fibers

• Increased cell proliferation • Increased neurite extension

[80]

(continued)

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Table 1.1 (continued) Cell

Scaffold

Outcome

References

Neuroglioma cells

Poly (3,4-ethylene dioxythiophene)/ chitosan fibers

• Increased cell proliferation • Increased axon density

[81]

Mouse NG108-15 cells

Poly • Increased cell (3,4-ethylenedioxythiophene)-polystyrene proliferation • Increased sulfonate (PEDOT: PSS)/silk fibers neurite extension

[82]

Human neuroblastoma cells

Poly-ε-caprolactone (PCL) nanofibers

• Increased neurite extension

[83]

Human neuroblastoma cells

Poly(3,4-ethylenedioxythiophene) (PEDOT)/Carbon nanotubes

• Increased neuronal markers

[84]

Rat hippocampal cells

Aragonite skeleton of the coral Trachyphyllia geoffroyi

• Promoted [85] elongation of astrocytic processes • Increased GFAP expression in astrocytes

Rat adipose tissue-derived neuron-like cells

Corning® PuraMatrix™ hydrogel

• Increased cell proliferation • Increased neuronal markers expression

[86]

Rat Porcine brain decellularized ECM pheochromocytoma cells

• Increased neuronal differentiation

[87]

Human Glioblastoma cells (U-87MG)

Carbon nanotubes

• Reduced cell growth

[88]

Rat embryonic NSCs

Collagen/heparan sulfate porous scaffolds • Improved [89] regeneration of neurons, nerve fibers, synapses, and myelin sheaths • Reduced brain edema and cell apoptosis • Recovered rat motor and cognitive functions (continued)

10

L. N. Zamproni and M. A. Porcionatto

Table 1.1 (continued) Cell

Scaffold

Outcome

References

Human fetal brainand spinal cord-derived NSCs

Aligned collagen sponge scaffolds

• Stem cell long-term cell survival • Stem cell neuronal differentiation • Reduced inflammation • Reduced glial scar formation • Recovered rat locomotor functions

[90]

Rat adipose tissue MSCs

Self-assembling nano-peptide scaffold RADA4GGSIKVAV (R-GSIK)

• Reduced reactive astrocytes • Reduced microglial cells • Reduced TLR4, TNF, and IL6

[91]

Human umbilical cord MSCs

Collagen hydrogels

• No differences in proteomics between treated and control group

[92]

Human umbilical cord MSCs

Collagen scaffolds

• Increased motor [93] scores • Enhanced amplitude, and shortened latency of the motor evoked potential • Reduced injury area in magnetic resonance imaging

Adipose-derived MSCs overexpressing BDNF and NT3

Silk fibroin/chitosan scaffold

• Reduced scar tissue • Decreased inflammation • Increased nerve fiber formation

[94]

Rat NSCs

Matrigel

• Decreased reactive astrogliosis • Improved functional recovery

[95]

(continued)

1 Initiating and Facilitating Brain Repair: Factors, Principles …

11

Table 1.1 (continued) Cell

Scaffold

Outcome

References

Human Hyaluronic acid hydrogel ESC-derived NSCs

• Increased [96] oligodendrocyte differentiation • Improved locomotor function

Mouse iPSCs-derived NSCs

FGF and chondroitin sulfate hydrogel

• Improved vascular remodeling • Improved cortical blood flow • Improved sensorimotor function

[97]

Embryonic rat NSCs

3D bioprinted collagen/silk fibroin scaffold

• Reduced glial scar • Increased regenerative axons • Improved functional recovery • Improved electrophysiologic tests

[98]

Mouse CGR8 ESCs Poly ε-caprolactone (PCL)/gelatin scaffolds

• Promoted neural [99] differentiation • Promoted efficient secretion of dopamine

Human iPSC- and Poly(ethylene glycol) ESC- derived NSCs diacrylate-crosslinked porous scaffolds

• Increased neural [100] cells functional maturity

Human iPSCs

Fibrin hydrogel

• Increased Olig2, [101] MBP, Sox10, and PDGFRα expression • Increased oligodendrocyte differentiation

Human olfactory MSCs

Chitosan-aniline pentamer/gelatin/ agarose scaffolds

• Promoted [102] differentiation into motor neuron-like cells (continued)

12

L. N. Zamproni and M. A. Porcionatto

Table 1.1 (continued) Cell

Scaffold

Outcome

Rat hippocampal NSCs

Poly-ε-caprolactone (PCL) fibers

• Increased cell [103] proliferation • Increased astrocyte and oligodendrocyte differentiation

References

NSCs

Poly (L-lysine) modified silk fibroin film

• Increased cell proliferation • Decreased apoptosis • Increased neuronal differentiation

[104]

Mouse MSCs

Graphene foam

• Promoted dopaminergic neuronal differentiation

[105]

Bioscaffolds Containing Stem Cells Stem cell-based therapies are largely explored for CNS repair in neurological pathologies such as TBI, stroke, Alzheimer’s and Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), among other neurodegenerative disorders [49, 95, 106– 112]. Stem cell sources include embryonic stem cells (ESC), mesenchymal stem cells (MSC), induced pluripotent stem cells (iPSC), and NSC [113]. In many stem cell transplant studies published, the expectation was that stem cells would exert therapeutic properties by differentiating into neurons at the injury site, repopulating the injured tissue. Still, the cells often function as bioreactors producing and secreting soluble factors that promote survival, neuroprotection, angiogenesis, and neurogenesis [113]. As mentioned, the ECM of the injured brain does not offer a proper microenvironment for cell anchoring, proliferating, and differentiating [114, 115], and this poses a challenge for conventional stem cell delivery. Intravenous or intracardiac administration of MSCs after a rat model of TBI showed that