Elsevier

Acta Biomaterialia

Volume 102, 15 January 2020, Pages 1-12
Acta Biomaterialia

Review article
The use of bioactive matrices in regenerative therapies for traumatic brain injury

https://doi.org/10.1016/j.actbio.2019.11.032Get rights and content

Abstract

Functional deficits due to neuronal loss are a common theme across multiple neuropathologies, including traumatic brain injury (TBI). Apart from mitigating cell death, another approach to treating brain injuries involves re-establishing the neural circuitry at the lesion site by utilizing exogeneous and/or endogenous stem cells to achieve functional recovery. While there has been limited success, the emergence of new bioactive matrices that promote neural repair introduces new perspectives on the development of regenerative therapies for TBI. This review briefly discusses current development on cell-based therapies and the use of bioactive matrices, hydrogels in particular, when incorporated in regenerative therapies. Desirable characteristics of bioactive matrices that have been shown to augment neural repair in TBI models were identified and further discussed. Understanding the relative outcomes of newly developed biomaterials implanted in vivo can better guide the development of biomaterials as a therapeutic strategy, for biomaterial-based cellular therapies are still in their nascent stages. Nonetheless, the value of bioactive matrices as a treatment for acute brain injuries should be appreciated and further developed.

Statement of significance

Cell-based therapies have received attention as an alternative therapeutic strategy to improve clinical outcome post-traumatic brain injury but have achieved limited success. Whilst the incorporation of newly developed biomaterials in regenerative therapies has shown promise in augmenting neural repair, studies have revealed new hurdles which must be overcome to improve their therapeutic efficacy. This review discusses the recent development of cell-based therapies with a specific focus on the use of bioactive matrices in the form of hydrogels, to complement cell transplantation within the injured brain. Moreover, this review consolidates in vivo animal studies that demonstrate relative functional outcome upon the implantation of different biomaterials to highlight their desirable traits to guide their development for regenerative therapies in traumatic brain injury.

Introduction

Traumatic brain injury (TBI) is one of the leading causes of death and disability in industrialized countries, occurring predominantly in young adults. Survivors of severe TBI have a shorter life expectancy, in addition to permanent functional impairments that can altogether, impose significant socioeconomic consequences on the individual [1]. The prognosis for TBI remains poor due to the lack of viable treatments, which are predominantly aimed at supporting vital functions of the patient and minimizing neural tissue loss. Clinical trials for neuroprotective compounds, hypothermia treatment and decompressive craniectomy have not only failed to show efficacy in improving functional outcome, but have also exacerbated the neuronal loss in some cases [2], [3], [4], [5], [6]. While these findings highlight the need for therapeutics that can rescue neurological functions post-TBI, they also suggest that treatment strategies focused on providing neuroprotection are not sufficient to attenuate the debilitating effects of severe intracerebral injuries. Reconstructing functional neural circuitry via cell-based therapies therefore represents a viable, alternative therapeutic strategy to improve clinical outcome.

Section snippets

Pathophysiology

TBI occurs via an external mechanical force, leading to tissue strain or deformation. The primary brain tissue damage can cause contusions, haematoma and diffuse axonal injuries [7]. This results in immediate cell death and the initiation of secondary cascades involving physiological changes that can develop over an extended period of time after the injury. It induces secondary brain tissue damage that involves processes such as necrosis, excitotoxicity, oxidative stress, vascular disruption

Cell-based therapies

Stem cell-based restorative strategies are directed at facilitating cell replacement and regeneration at the injury site by providing a source of specific cell types and trophic support, and shaping a permissive microenvironment at the injury site for neural repair to occur [9]. Neural transplantation has been explored using different cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs) and their derivatives to treat CNS injuries

Neurogenesis

The potential for neural regeneration after an insult via endogenous recovery mechanisms in the adult brain has been extensively studied with neurogenesis in the adult mammalian brain first observed in the 1960s [55,56]. Adult neurogenesis is confined to stem-cell niches within the brain, namely the subgranular zone in the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) in the lateral ventricles (Refer to Fig. 1). These neurogenic regions contain multipotent NPSCs that are

Bioactive matrices for neural repair in TBI

Neural tissue engineering has been a prominent area of research as a viable strategy to treat CNS injuries and diseases [87,88]. Recent advances in the field have demonstrated the potential for bioactive matrices to augment neural repair and regeneration by providing physical and biochemical support for cellular migration and survival, and an alternative drug administration route. Bioactive matrices can be synthesized via the use of natural and/or synthetic polymers, which are aimed at

Conclusion

Advances in biomaterial science have been applied to neural tissue engineering by complementing cell-based therapies in regenerative medicine. While stem cell transplantation has been explored extensively, the capacity for endogenous reparative mechanisms within the brain to facilitate functional recovery following a neural injury remains elusive. This review has examined desirable traits in hydrogels used for the enhancement of reparative processes involving endogenous NPSCs in the brain, in

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

All authors contributed equally to this work.

References (154)

  • A. Nichol et al.

    Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

    Lancet

    (2015)
  • K.A. Sailor et al.

    Persistent structural plasticity optimizes sensory information processing in the olfactory bulb

    Neuron

    (2016)
  • O. Bergmann et al.

    The age of olfactory bulb neurons in humans

    Neuron

    (2012)
  • K.L. Spalding et al.

    Dynamics of hippocampal neurogenesis in adult humans

    Cell

    (2013)
  • G.M. Thomsen et al.

    Traumatic brain injury reveals novel cell lineage relationships within the subventricular zone

    Stem Cell Res.

    (2014)
  • B. Saha et al.

    Cortical lesion stimulates adult subventricular zone neural progenitor cell proliferation and migration to the site of injury

    Stem Cell Res.

    (2013)
  • F. Mirshahi et al.

    SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models

    Thromb. Res.

    (2000)
  • B. Li et al.

    Brain self-protection: the role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia

    Brain Res.

    (2010)
  • F.M. Chen et al.

    Advancing biomaterials of human origin for tissue engineering

    Prog. Polym. Sci.

    (2016)
  • J. Guan et al.

    Transplantation of human mesenchymal stem cells loaded on collagen scaffolds for the treatment of traumatic brain injury in rats

    Biomaterials

    (2013)
  • J.D. Kretlow et al.

    Injectable matrices and scaffolds for drug delivery in tissue engineering

    Adv. Drug. Deliv. Rev.

    (2007)
  • E.M. Ahmed

    Hydrogel: Preparation, characterization, and applications: a review

    J. Adv. Res.

    (2015)
  • T.Y. Cheng et al.

    Neural stem cells encapsulated in a functionalized self-assembling peptide hydrogel for brain tissue engineering

    Biomaterials

    (2013)
  • L.Y. Sang et al.

    A self-assembling nanomaterial reduces acute brain injury and enhances functional recovery in a rat model of intracerebral hemorrhage

    Nanomedicine

    (2015)
  • X. Li et al.

    Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair

    Biomaterials

    (2017)
  • D.W. Simon et al.

    The far-reaching scope of neuroinflammation after traumatic brain injury

    Nat. Rev. Neurol.

    (2017)
  • G.L. Clifton et al.

    Lack of effect of induction of hypothermia after acute brain injury

    N. Engl. J. Med.

    (2001)
  • D.W. Wright et al.

    Very early administration of progesterone for acute traumatic brain injury

    N. Engl. J. Med.

    (2014)
  • D.J. Cooper et al.

    Decompressive craniectomy in diffuse traumatic brain injury

    N. Engl. J. Med.

    (2011)
  • D. Lozano et al.

    Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities

    Neuropsychiatr. Dis. Treat.

    (2015)
  • O. Lindvall et al.

    Stem cell therapy for human neurodegenerative disorders-how to make it work

    Nat. Med.

    (2004)
  • P. Riess et al.

    Embryonic stem cell transplantation after experimental traumatic brain injury dramatically improves neurological outcome, but may cause tumors

    J. Neurotrauma

    (2007)
  • D.J. Chang et al.

    Therapeutic potential of human induced pluripotent stem cells in experimental stroke

    Cell Transplant.

    (2013)
  • R.A. Fricker et al.

    Site-specific migration and neuronal differentiation of human neural progenitor cells after transplantation in the adult rat brain

    J. Neurosci.

    (1999)
  • F.H. Gage

    Mammalian neural stem cells

    Science

    (2000)
  • A. Swistowski et al.

    Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions

    Stem Cells

    (2010)
  • T. Vierbuchen et al.

    Direct conversion of fibroblasts to functional neurons by defined factors

    Nature

    (2010)
  • S.C. Zhang et al.

    In vitro differentiation of transplantable neural precursors from human embryonic stem cells

    Nat. Biotechnol.

    (2001)
  • J. Kim et al.

    Direct reprogramming of mouse fibroblasts to neural progenitors

    Proc. Natl. Acad. Sci. USA

    (2011)
  • W.F. Alsanie et al.

    Specification of murine ground state pluripotent stem cells to regional neuronal populations

    Sci. Rep.

    (2017)
  • A.L. Perrier et al.

    Derivation of midbrain dopamine neurons from human embryonic stem cells

    Proc. Natl. Acad. Sci. USA

    (2004)
  • H. Ma et al.

    Transplantation of neural stem cells enhances expression of synaptic protein and promotes functional recovery in a rat model of traumatic brain injury

    Mol. Med. Rep.

    (2011)
  • M. Skardelly et al.

    Long-term benefit of human fetal neuronal progenitor cell transplantation in a clinically adapted model after traumatic brain injury

    J. Neurotrauma

    (2011)
  • E.W. Baker et al.

    Induced Pluripotent Stem Cell-Derived Neural Stem Cell Therapy Enhances Recovery in an Ischemic Stroke Pig Model

    Sci. Rep.

    (2017)
  • D. Kondziolka et al.

    Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial

    J. Neurosurg.

    (2005)
  • T. Yamashita et al.

    Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain

    Cell Transplant.

    (2011)
  • H. Kawai et al.

    Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain

    J. Cereb. Blood Flow Metab.

    (2010)
  • X. Wei et al.

    Mesenchymal stem cells: a new trend for cell therapy

    Acta Pharmacol. Sin.

    (2013)
  • D. Sarmah et al.

    Mesenchymal Stem Cell Therapy in Ischemic Stroke: A Meta-analysis of Preclinical Studies

    Clin. Pharmacol. Ther.

    (2018)
  • R. Zhang et al.

    Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury

    J. Neuroinflammation

    (2013)
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