Review Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies Neha Chopra 1,2 , Spiro Menounos 1 , Jaesung P. Choi 3 , Philip M. Hansbro 3 , Ashish D. Diwan 1,2 and Abhirup Das 1,2, *   Citation: Chopra, N.; Menounos, S.; Choi, J.P.; Hansbro, P.M.; Diwan, A.D.; Das, A. Blood-Spinal Cord Barrier: Its Role in Spinal Disorders and Emerging Therapeutic Strategies. NeuroSci 2022, 3, 1–27. https:// doi.org/10.3390/neurosci3010001 Academic Editor: Masato Nakafuku Received: 18 November 2021 Accepted: 14 December 2021 Published: 21 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Spine Labs, St. George & Sutherland Clinical School, University of New South Wales, Kogarah, NSW 2217, Australia; Neha@spine-service.org (N.C.); s.menounos@student.unsw.edu.au (S.M.); A.Diwan@spine-service.org (A.D.D.) 2 Spine Service, St. George Hospital, Kogarah, NSW 2217, Australia 3 Centre for Inflammation, Faculty of Science, Centenary Institute, School of Life Sciences, University of Technology Sydney, Sydney, NSW 2050, Australia; Jaesung.Choi@uts.edu.au (J.P.C.); Philip.Hansbro@uts.edu.au (P.M.H.) * Correspondence: abhirupdas@unsw.edu.au Abstract: The blood-spinal cord barrier (BSCB) has been long thought of as a functional equivalent to the blood-brain barrier (BBB), restricting blood flow into the spinal cord. The spinal cord is supported by various disc tissues that provide agility and has different local immune responses compared to the brain. Though physiologically, structural components of the BSCB and BBB share many similarities, the clinical landscape significantly differs. Thus, it is crucial to understand the composition of BSCB and also to establish the cause–effect relationship with aberrations and spinal cord dysfunctions. Here, we provide a descriptive analysis of the anatomy, current techniques to assess the impairment of BSCB, associated risk factors and impact of spinal disorders such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS), peripheral nerve injury (PNI), ischemia reperfusion injury (IRI), degenerative cervical myelopathy (DCM), multiple sclerosis (MS), spinal cavernous malformations (SCM) and cancer on BSCB dysfunction. Along with diagnostic and mechanistic analyses, we also provide an up-to-date account of available therapeutic options for BSCB repair. We emphasize the need to address BSCB as an individual entity and direct future research towards it. Keywords: blood-spinal cord barrier (BSCB); spinal cord injury (SCI); amyotrophic lateral sclerosis (ALS); degenerative cervical myelopathy (DCM); peripheral nerve injury (PNI); ischemia reperfusion injury (IRI); multiple sclerosis (MS); spinal cavernous malformations (SCM) 1. Introduction Blood vessels are essential for delivering oxygen and nutrients throughout the body. In the vascular tree, the controlled communication that occurs between blood vessels and components of central nervous system (CNS) is unique. Physiologically, there are three specialised interfaces in the human body that selectively permit entry of nutrients, ions, lipids and small molecules from the blood stream to either the brain (blood-brain barrier; BBB), cerebral spinal fluid (blood-cerebral spinal fluid barrier; BCSFB) or spinal cord (blood-spinal cord barrier; BSCB). Of these the BBB is the most studied and its dysfunction is associated with neurological disorders such as multiple sclerosis (MS), Alzheimer’s disease. and Parkinson’s disease [1]. Recent evidence suggests that BBB dysfunction is an underlying mechanism associated with age-related neuronal deterioration [2]. As a result of improved understanding of the morphology and the consequences of dysfunction of the BBB, various translational drugs and models have been realised. Drugs such as Natalizumab, a humanized monoclonal antibody acting on the VLA- 4/VCAM-1 axis, modulates BBB leakage and inhibits the entry of T cells into the CNS in relapsing MS patients [3]. In Alzheimer’s disease, “Trojan horse” strategies have been used, NeuroSci 2022, 3, 1–27. https://doi.org/10.3390/neurosci3010001 https://www.mdpi.com/journal/neurosci