Combining Therapeutic Strategies to Treat the Injured Spinal Cord: A Translational Perspective

Abstract

Spinal cord injury (SCI) results in an array of debilitating, sometimes permanent—and at times life-threatening—motor, sensory, and autonomic deficits. A broad range of therapies have been tested pre-clinically, and there has been a significant acceleration in recent years of clinical translation of potential treatments. However, it is widely appreciated among scientists and clinical professionals alike that there likely is no “silver bullet” (single treatment) that will result in complete functional restoration after SCI. The combination of more than one treatment approach, especially treatments that can have distinct beneficial effects, increases the probability of functional improvement. This review highlights the mounting interest in the pre-clinical development and application of combination strategies to treat SCI, and some of the translational efforts made to combine promising therapies for clinical evaluation. Special attention is given to barriers and limitations faced in translating treatments for people living with SCI.

Introduction

It is widely recognized that combinations of treatments will be needed to achieve effective recovery from a spinal cord injury (SCI). In the past three decades, a wide range of therapeutic strategies have been assessed in SCI clinical trials, but few of those studies have explored combined treatment approaches. In contrast, a growing number of pre-clinical studies are now testing combined treatment strategies¹ to synergistically enhance functional improvement. The present review will first discuss combinatorial strategies in the pre-clinical testing stage in both animal and in vitro models, then reflect on some initial clinical investigations and clinical trials that are exploring individual treatments, or beginning to explore a combination of treatments. Finally, we highlight some of the translational barriers between pre-clinical combinatorial studies and those with human participants.

The known pathophysiology of human SCI has been reviewed and described in detail elsewhere.² While a detailed overview is not within the scope of this review, it’s important to briefly consider how elements of SCI pathophysiology represent distinct therapeutic targets; and accordingly, how combining treatments that target distinct pathophysiological elements should increase overall therapeutic efficacy. First, SCI can occur traumatically (e.g., blunt force impact or direct laceration of the spinal cord) or non-traumatically (e.g., degenerative cervical myelopathy, multiple sclerosis, tumors, viral infections (myelitis) and vascular lesions).^3,4 Dissipation of mechanical forces into the spinal cord damages neural tissue, disrupts vasculature, and leads to progressive infiltration of peripheral cells with secondary cascades of ischemia, excitotoxicity, apoptosis, and inflammation^5–7 (Fig. 1). Treatment of events in the acute phase may be delayed by the need for medical stabilization and other interventions, as traumatic SCI is often accompanied by other systemic injuries (polytrauma;^8,9 e.g., traumatic brain injury, chest injury, long-bone fractures, and/or injury to other internal organs, etc.). Notably, these concurrent injuries are rarely¹⁰ modeled in the pre-clinical studies of SCI.

FIG. 1.

Chronological progression of spinal cord injury (SCI) through (A) acute, (B) subacute, and (C) chronic phases. During the acute phase, tissue and blood–brain barrier disruption allows for neutrophil invasion and cytokine-mediated inflammation. In the subacute phase, inflammation can still be seen along with the start of fibrosis and axonal degeneration, and in the chronic phase, a well-defined scar can be seen with chronic inflammation around a fluid-filled cyst. Components throughout these phases of injury include fibroblasts (a), erythrocytes (b), astrocytes (c), neutrophils (d), healthy axons (e), demyelination and Wallerian degradation (f), collagen fibers (g), and chondroitin sulphate proteoglycans (CSPGs) (h). Schematic modified from Reier et al. (2017).

The secondary events that begin in acute stages and occur through “sub-acute” and “chronic”¹¹ stages of injury are often characterized by liquefactive necrosis resulting in a cystic, fluid-filled cavity surrounded by a cellular and chemical border comprised of reactive fibroblasts, glia, and macrophages producing molecules that are proinflammatory and inhibitory to repair (e.g., proinflammatory cytokines, chondroitin sulfate proteoglycans; Fig. 1).^5–7,12,13 Notably, the chronic stages of injury described in pre-clinical studies have been divided into sub-chronic (immediately following subacute injury), chronic, and super-chronic (>1 year post-injury in small animal models). Given the differences in timing that may result with different injury types and across species studied, the present discussion will refer to these collectively as chronic injury. Current prospective therapies can be classified under three overarching goals to address pathophysiology at different points in this progression: 1) limit the secondary loss of neural tissue (neuroprotection), 2) facilitate repair (regeneration of injured axons, myelin repair, establishment of de novo circuits), and 3) enhance innate neuroplasticity in either spared or damaged neural pathways and neuromuscular networks. Combining individual therapies directed to specific pathophysiologies may additively or synergistically improve functional recovery beyond any one treatment alone.

Combining Treatments for SCI

This review highlights the range of approaches taken in pre-clinical SCI research to combine quite diverse treatments, then reflects on the more limited examples of translational efforts. We define a combination therapy as multiple interventions without regard to the order or arrangement of individual components, and a combinatorial therapy as multiple treatments in a specified or overlapping sequence. The following sections provide examples of combinatorial approaches that have been tested in pre-clinical and clinical research, highlighting considerations and important lessons learned at each stage.

Pre-clinical studies

There is widespread agreement that prior to clinical testing, therapeutics should be rigorously assessed in a range of small (e.g., mouse or rat) and large (e.g., feline, canine, porcine, and non-human primate) pre-clinical animal models,^14–23 with consideration for a range of injury types (e.g., partial section, contusion, or compression).^19,24–28 Permission for initiation of clinical investigation by the Food and Drug Administration (FDA) and by institutional review boards (IRBs) usually requires the provision of sufficient data from pre-clinical models to support the safety and reasonable efficacy of the proposed studies. The “burden of evidence” is highest for those therapies perceived to have the greatest risk potential, such as cellular implantation and gene therapy. Veterinary clinical trials have also been used to test the safety and efficacy of treatments.²⁹ However, detailed histology and magnetic resonance imaging are generally not available from such studies.

Pre-clinical studies provide an opportunity to assess therapeutic efficacy under carefully controlled experimental conditions, with statistically relevant sample size, and using a battery of outcome measures to evaluate changes.¹ For example, pre-clinical studies allow a higher resolution assessment of tissue repair, and molecular and cellular changes, that cannot yet be detected in humans with clinically available imaging methods. Invasive neurophysiological techniques can be used to rigorously evaluate functional outcomes in combination with detailed anatomical assessment. The results of these different outcome measures can also be correlated statistically. Furthermore, the variation in effectiveness within highly controlled conditions has implications for clinical translation. The specific mechanisms underlying treatment effects and target engagement can be studied to optimize therapeutic delivery before moving into clinical studies.

Much like clinical rehabilitation, activity-based therapies (ABTs) used in pre-clinical animal studies typically focus on interventions that engage specific behaviors to promote their recovery and/or activate targeted muscle groups for task performance (e.g., locomotor training,^30,31 upper extremity training^32,33) Pre-clinical studies in several species have shown that activation of spinal networks, in combination with body weight support, can stimulate locomotor patterns. This encouraging finding demonstrates the critical role of appropriate rehabilitation to shape the outcome from experimental therapeutics. In 2012, van den Brand et al.³⁴ showed that voluntary control of locomotion could be restored in paralyzed rats by activating spinal networks during body weight supported locomotion. Neural stimulation and neuromodulation—whether by neurochemical or electrical means—have been demonstrated to enhance plasticity in damaged neural networks. Rehabilitation therapies and neural stimulation can also be combined with other strategies (e.g., pharmacological, transplantation) for SCI treatment, and pre-clinical studies have begun exploring this potential.^34–39 As these treatments are combined, however, there will be important considerations for how and when they are applied.

An interesting example of this was described by Petrosyan et al.,⁴⁰ who combined spinal-electromagnetic stimulation, exercise therapy, and gene therapy for growth factor delivery to enhance neuroplasticity in rats following thoracic contusion injury. Each treatment was delivered at different time points post-injury in an effort to assess the value of sequential treatment delivery, and the group receiving all three treatments showed the greatest improvement in anatomical and functional outcomes.⁴⁰ While this is an example of positive synergistic effects, combinatorial therapies are not always more efficacious than single therapies. Several studies have shown no benefit to combining various therapies with rehabilitation or no functional improvement despite apparent increased anatomical plasticity (reviewed in^1,41,42). These experiments highlight that dosing, sequence, and treatment windows are critical considerations for combinatorial strategies.

In addition to therapies designed to enhance neuroplasticity, there are a number of approaches that have been shown pre-clinically to promote axonal regeneration and tissue repair, including scaffolds and biomaterials,^43,44 peripheral nerve grafts (PNGs),⁴⁵ pharmacological approaches (e.g., trophic factors,⁴⁶ chondroitinase ABC [chABC]),^47,48 anti-myelin based strategies,^49–51 and cell transplantation⁵² (Schwann cells,^53,54 olfactory ensheathing cells,^55–58 or neural stem/progenitor cells^59–63) (Fig. 2). Cell therapies have been used to promote neuroprotection, tissue reconstruction, support regrowth, migration and regeneration, and remyelination.⁵² While some of these have been translated to clinical trial, pre-clinical use of cell therapies have also been tested in combination with a vast range of additional treatments (reviewed in Jagrit et al.⁶⁴) including biomaterials, pharmacological approaches, and even combinations of distinct cell therapies. Delivery of pharmacological agents into the injured spinal cord has also been shown to have significant pro-reparative potential in pre-clinical studies. For example, administering the bacterially-derived enzyme chABC, which removes sugar sidechains from proteoglycans that accumulate in the injury milieu and inhibit axon elongation,⁶⁵ has consistently shown efficacy in acute and subacute post-injury stages in rat models (Fig. 1).^1,66–68 Amongst reported successful combinations with chABC are fibroblast growth factor (FGF), autologous PNGs, Schwann cells, and scaffolds with astrocytes placed into the site of acute and chronic injury.^69–73 DePaul et al. showed that combining a PNG with chABC administration improved catecholaminergic axon growth more than either treatment alone.⁶⁹ ChABC has been tested in a primate model of cervical injury, and has shown efficacy without notable detriment to subjects.^74,75 Given this robust pre-clinical evidence, a strong argument exists to initiate clinical studies of chABC. Considering the current clinical testing of Schwann cells and of bioresorbable scaffolds, a potential next step in translating these interventions with greater efficacy may be the conjunctive administration of chABC and/or FGF.^69,76–79 With advances in the compounds being developed to target the CSPGs (e.g., ChASE37^80,81 intracellular sigma peptide⁸²), there may be some benefit to harnessing cells or biomaterials to ensure optimal delivery.⁸¹

FIG. 2.

Strategies that can be combined for treating spinal cord injury, can include cellular transplantation for anatomical repair (A), pharmacological interventions (B), biomimetic scaffolds (C), ABTs (D), and electrical stimulation (E). The example scaffold (C) represents a biomaterial with growth promoting/directing channels that can be implanted into the injured spinal cord. While there are continuing advances in 3D-printing capabilities for producing such scaffolds, liquid-based scaffolds and biomaterials can also be injected directly into the injured tissue. The example of ABT shown (D) also reveals how assistive devices—in this case an exoskeleton—can be used to facilitate the ABT. ABT, activity-based therapy.

Notably, while many of the compounds mentioned above have been tested through systemic delivery or direct injection into the central nervous system, an alternative translationally promising approach is the use of gene therapy. Pre-clinical studies have used gene therapy to suppress maladaptive genes that hinder repair or to enhance the expression of downregulated or therapeutic genes that promote regeneration—such as trophic factors or other pro-regenerative compounds.⁸³ This approach has been extensively reviewed elsewhere.^84–86 One recent study showed that combining i) intraspinal adeno-associated virus injections rostral to SCI in adult mice to enhance axon growth, with ii) trophic-factor releasing biomaterial (hydrogel) injections into the lesion site and caudally to attract growing axons.⁸⁷ This combination greatly increased axonal growth across the injury site, offers insight into how both enhancing axonal growth and providing chemoattraction across the injury site can improve repair potential. Notably there are several examples of cell therapy using genetically modified cells to treat the injured spinal cord,⁸⁸ but these—like assistive device-mediated ABTs—represent a single therapy (enhanced cell therapy).

By no means do the examples discussed here provide a comprehensive list of all combination therapies that have been tested, and there are many actively being investigated in pre-clinical experiments. Notably, translating the findings into clinical trials raises additional challenges, such as scale-up and timing, compared with what is done pre-clinically.

Clinical Investigations and Clinical Trials

In February 2019, the National Institutes of Health held a meeting titled SCI 2020: A Decade of Disruption. The meeting brought together scientists, clinical professionals, people living with SCI, and advocates to discuss the state of research and translation in the field of SCI, with hopes of improving the path toward translation of treatments into clinical trials. This platform for improving dialogue between all stakeholders also encouraged and fostered ongoing communication beyond the meeting, with several efforts established to improve translation. One observation that emerged from the meeting was the need for a distinction between “clinical investigations” and “clinical trials,” and the importance of both, which has perhaps been under-appreciated by those not working in these areas.

Large-scale definitive clinical trials are very resource-intensive, take many years to complete, and there is a limit to how many can co-occur in the SCI field. Therefore, it is important to establish initial safety and potential efficacy signals in smaller-scale clinical investigations. Clinical investigations play a crucial role in the early-stage evaluation of treatments. Indeed, it can be worthwhile to report single subjects when a therapy is especially high-risk. For example, Theodore et al.⁷⁸ studied a bioresorbable scaffold (e.g., Fig. 2) in the INSPIRE trial, and reported results from the first subject. Similarly, Harkema and Angeli et al.⁸⁹ reported the combination of epidural stimulation with locomotor training, initially in one individual and then in small cohorts.

A notable example of combination therapy that has advanced from pre-clinical studies to small-scale clinical investigation is the combination of weight-supported treadmill walking with epidural stimulation following SCI.^90,91 Angeli et al. showed that this regimen promotes neuroplasticity and recovery in subjects with motor and sensory complete AIS A (American Spinal Injury Association [ASIA] impairment scale; Grade A) thoracic injury, as well as motor complete cervical injury (AIS-B).⁸⁹ In that study, two of four participants achieved limited independent overground walking, while the other participants achieved unilateral independent stepping and leg swing on a treadmill.⁸⁹

A combination of transcutaneous electrical stimulation with locomotor training has shown feasibility in a large-scale study.⁹² The study reported no adverse effects as well as preliminary efficacy in functional mobility when assessed by metrics of gait speed, endurance, balance, and transitional movements.⁹² The growing number of clinical investigations that have tested the efficacy of electrical stimulation in treating non-locomotor functions (cardiovascular,⁹³ bladder function,⁹⁴ respiratory⁹⁵) offer hope for novel combination approaches in the future.

The greater investment in translation that has been discussed across multiple stakeholders in this “decade of disruption” has also led to some reflection on the number and type of formal clinical trials that were being pursued in 2020, and what changes have occurred since then. In 2020, there were 1208 clinical trials for “spinal cord injury” (not yet recruiting, enrolling/recruiting, completed, terminated, suspended, or active) listed on clinicaltrials.gov, of which 326 were recruiting/enrolling subjects. An additional 207 were listed as withdrawn or unknown status. Of these 1,415 trials, 54 (3.8%) had reached Phase IV, 78 (5.5%) progressed to Phase III, 216 (15%) were in Phase II, 127 (9.0%) were in Phase I, and 13 (<1%) were in Early Phase I stage (Fig. 3). The remaining 786 trials (55%) were described as “Phase not applicable,” which describes trials without FDA-defined phases, including some studies involving humans in which devices or behavioral interventions are tested. By May 2025, another 747 trials are listed (1,955 total), with 60 in Phase IV, 6 more in Phase III (84), 27 more in Phase II (243), 21 more in Phase I (148), and 11 more in Early Phase I (24).

FIG. 3.

Combination trials for spinal cord injury that have been listed on ClinicaTrials.gov have incorporated a range of therapeutic approaches. These can be divided into those using ABTs (and conventional rehabilitation), assistive device mediated activity, devices for stimulation, cell/tissue transplantation, material implantation, pharmacological intervention, surgical intervention, and other approaches (e.g., diet, visual imagery, acupuncture). The proportion of combination therapies that are using one of these listed treatments in the proposed combination is represented in (A). The geographical location of these trials is reflected in (B). Notably, the majority of combination trials reported on ClinicalTrials.gov are being conducted in the United States of America 54%, followed by Canada and Switzerland (7.5% each). Percentages less than 1 are not listed.

Combination studies

While 143 “combination” strategies were registered on ClinicalTrials.gov in 2020 (which can include a combination of similar interventions), this number increased to 186 in 2025. Of these 186 trials, 79 were listed as active (not recruiting), not yet recruiting, currently recruiting, or enrolling by invitation. The remaining 107 trials had been suspended, terminated, completed, withdrawn, or have an unknown status. Of the total 186 listed, only 42 had a designated clinical trial phase on ClinicalTrial.gov, with 24% in Early Phase I, 10% in Phase I, 14% in Phase I-II, 21% in Phase II, 10% in Phase II-III, 10% in Phase III, and 10% in Phase IV.

The combination strategies listed include use of pharmacological, cell strategies, material implantation, surgical interventions, neural stimulation via devices, and ABTs with or without use of assistive devices (to facilitate activity). Notably, the proportion of studies that incorporate the use of devices has increased in the last 4 years. Table 1 highlights these trials as listed on ClinicalTrials.gov, with some description of the treatments being used. In reviewing database results, the trials identified were screened to confirm that they involved actual combinations of treatments, as some listed trials referenced combinations but did not implement them.

Table 1.

A Summary of the Combination Trials for Spinal Cord Injury That Have Been Listed on ClinicaTrials.gov, Indicating the ClinicaTrials.gov ID (e.g., NCT###), the Type of Therapeutic Intervention, a Brief Summary of the Interventions Being Combined, the Country the Study is Listed in, and the Status of the Trial

	NCT Number	Conv Rehab	ABT	Assist. Device	Stim. Device	Drugs	Cells	Material Implant	Surgery	Other	Interventions	Country	Status
1	NCT03643770		✓	✓							1. Upper extremity training with Armeo Spring (Robotic assistive device) and 2. intermittent hypoxia	USA	ACTIVE_NOT_RECRUITING
2	NCT03998527		✓		✓						1. Transcutaneous Electrical Spinal Cord Stimulation (TcESCS) with 2. task specific trianing	USA	ACTIVE_NOT_RECRUITING
3	NCT02936453			✓	✓						1. closed-loop Epidural Electrical Stimulation (EES) and 2. overground robot assisted rehabilitation	Switzerland	ACTIVE_NOT_RECRUITING
4	NCT03975634		✓		✓						1: Transcutaneous Spinal Stimulation with 2: locomotor training	USA	ACTIVE_NOT_RECRUITING
5	NCT04241250			✓	✓						1. exoskelton with 2. either spinal cord epidural or transspinal stimulation	USA	ACTIVE_NOT_RECRUITING
6	NCT05008484				✓					✓	1: Neuromuscular Electrical Stimulation NMES and 2: DRUG: Vitamin D	USA	ACTIVE_NOT_RECRUITING
7	NCT03702842		✓		✓						1: Soterix Medical tsDCS stimulator 2: Locomotor training	USA	ACTIVE_NOT_RECRUITING
8	NCT06188130			✓	✓						1: active rTMS or tDCS with 2: robotic therapy	Turkiye	ACTIVE_NOT_RECRUITING
9	NCT04809987		✓							✓	OTHER: Virtual Gait|OTHER: Physical Exercise|OTHER: Documental projection	Spain	ACTIVE_NOT_RECRUITING
10	NCT02313194				✓	✓					1. Epidural Stimulation 2. drug Buspirone	USA	ACTIVE_NOT_RECRUITING
11	NCT06351995				✓	✓					1. DRUG: Combination of Neostigmine and Glycopyrrolate 2. DEVICE: I-Box by Dynatronics	USA	ACTIVE_NOT_RECRUITING
12	NCT05976087			✓	✓✓						1. DEVICE: SensoExo. 2. rehabilitation with exoskeleton	Switzer.	ACTIVE_NOT_RECRUITING
13	NCT04027972				✓	✓					1. DRUG: Combination of Neostigmine and Glycopyrrolate. 2.DEVICE: I-Box by Dynatronics	USA	ACTIVE_NOT_RECRUITING
14	NCT03184792		✓		✓						1. DEVICE: Transcutaneous spinal stimulation. 2.OTHER: Physical therapy	USA	ACTIVE_NOT_RECRUITING
15	NCT04232657					✓✓					1. DRUG: Romosozumab; 2. DRUG: Denosumab	USA	ACTIVE_NOT_RECRUITING
16	NCT02713269					✓			✓	✓	1. radiation; 2. thermal ablation therapy; 3. Stereotactic Radiosurgery	USA	ACTIVE_NOT_RECRUITING
17	NCT04077346		2713		✓						1. Biostim-5 Transcutaneous Spinal Stimulator + 2. Activity Based Locomotor Training	USA	ENROLLING_BY_INVITATION
18	NCT05994846		✓		✓✓						1. RISES-T System using electrical and magnetic stim with 2. task specific training	USA	ENROLLING_BY_INVITATION
19	NCT05091463		✓		✓						1: Biostim-5/Neostim transcutaneous spinal stimulator and 2: Activity-based locomotor training	USA	ENROLLING_BY_INVITATION
20	NCT05191121		✓		✓						1: Task specific training with 2: conventional or wide-pulse high-frequency FES.	USA	ENROLLING_BY_INVITATION
21	NCT06104735		✓		✓						1. Paired brain and SC stim. 2. Exercise	USA	NOT_YET_RECRUITING
22	NCT04910204		✓		✓						1. FES Therapy combined with 2. task-specific training	Canada	NOT_YET_RECRUITING
23	NCT06296771		✓							✓	1. Dietary energy restriction group (D) 2. and exercise (E)	UK	NOT_YET_RECRUITING
24	NCT06698224		✓		✓✓						1: Spinal cord transcutaneous stimulation, 2: peripheral nerve stimulation and 3: physical therapy	USA	NOT_YET_RECRUITING
25	NCT05465486			✓						✓	1: Brain-Computer Interface control of robotic arms with 2: augmented reality	Greece	NOT_YET_RECRUITING
26	NCT06743607		✓		✓						1: upper extremity functional task-specific training with 2: non-invasive transcutaneous spinal stimulation	USA	NOT_YET_RECRUITING
27	NCT05940636		✓		✓✓						1: Visual feedbak training combined with either 2: FES alone or FES+ transcutaneous spinal cord stimulation (TSCS)	Canada	NOT_YET_RECRUITING
28	NCT06650202			✓	✓						1. The Tethered Pelvic Assist Device (TPAD), 2. physical stimulation (not quite rehab)	USA	NOT_YET_RECRUITING
29	NCT06541041				✓✓				✓		1. DEVICE: Brief intraoperative electrical stimulation|DEVICE: Temporary Postoperative Peripheral Nerve Stimulation. 2. surgical intervention	USA	NOT_YET_RECRUITING
30	NCT06154122		✓							✓	1. DEVICE: Virtual Reality Upper Limb Rehabilitation Games. 2. OTHER: Upper Limb Rehabilitation	UK	NOT_YET_RECRUITING
31	NCT06733025					✓			✓		1. PROCEDURE: Tendon lengthening surgery; 2.DRUG: BoNT Injections	Sweden	NOT_YET_RECRUITING
32	NCT05563103		✓✓		✓						1. Daily acute intermittent hypoxia 2. Walking 3. transcutaneous spinal stimulation	USA	RECRUITING
33	NCT06313515			✓	✓						1. Transcutaneous Spinal Cord Stimulation 2. Arm-crank bike exercise	USA	RECRUITING
34	NCT06248476			✓	✓						1: Transcranial Magnetic Stimulation with 2: Robotic rehab	Turkiye	RECRUITING
35	NCT04520178					✓✓					1: 5-Hydroxytryptophan combined with 2: Carbidopa	Canada	RECRUITING
36	NCT06274021				✓	✓					1. Transcutaneous spinal stimulation at 100 Hz or 50 Hz and 2. single dose of baclofen or tizanidine	USA	RECRUITING
37	NCT06541197			✓	✓						1. Robotic rehabilitation with 2. Functional Electrical Stimulation (FES) bicycle ergometry	Turkiye	RECRUITING
38	NCT06260735		✓		✓						1. Trans-spinal electrical stimulation 2. Electrical muscle activation 3. Treadmill walking	Canada	RECRUITING
39	NCT05700942		✓		✓						1: High and low Dose Intervention-tsDCS with 2. LT	USA	RECRUITING
40	NCT05708274		✓			✓					1: 3 approved FDA drugs (cyproheptadine (CPH), carbidopa-levodopa (CD-LD), or atomoxetine (ATX) + 2:hand training	USA	RECRUITING
41	NCT05887752		✓	✓							1: Standard rehabilitation alone or with 2: Hunova® assited rehabilitation	Italy	RECRUITING
42	NCT05982171			✓	✓						1: Exoskeleton training + 2: TSCS	USA	RECRUITING
43	NCT05926843		✓		✓						1: Spinal cord stimulation surgery (device) and 2:motor rehabilitation	Italy	RECRUITING
44	NCT03509558		✓		✓						1: Transcutaneous Spinal Stimulation with 2: locomotor training	USA	RECRUITING
45	NCT04032990		✓		✓						1: Biostim-5 transcutaneous spinal stimulator and 2: task specific UE training	USA	RECRUITING
46	NCT05447676		✓		✓	✓					1. DRUG: Dalfampridine (4-AP), 2: STDP stimulation and 3: Exercise training	USA	RECRUITING
47	NCT06243952		✓		✓						1: DEVICE: ARC-BSI Lumbar system and 2: neurorehabilitation.	Switzer.	RECRUITING
48	NCT06101199		✓		✓						1: Acute Intermittent Hypercapnic Hypoxia and 2: Transcutaneous spinal cord stimulation	USA	RECRUITING
49	NCT06472986		✓		✓						1: Activity-based therapy and 2: transcutaneous spinal cord stimulation	Canada	RECRUITING
50	NCT06494020		✓		✓						1: Task Practice combined with 2: Transcutaneous Spinal Cord Stimulation( (TSCS)	USA	RECRUITING
51	NCT06596369		✓		✓						1: Transcutaneous spinal cord stimulation with 2: Upper extremity rehabilitation	USA	RECRUITING
52	NCT06596174			✓	✓						1: Transcutaneous spinal cord stimulation (tSCS) paired with 2:: Short-term Machine-Assisted Ankle Movement Training	Taiwan	RECRUITING
53	NCT06440538		✓		✓						1: paired neurostimulation (PCMS) with 2: contralateral motor training	USA	RECRUITING
54	NCT05178056		✓		✓						1: Spinal Cord Epidural Stimulation with 2: Respiratory Training	USA	RECRUITING
55	NCT06019949		✓		✓						1: Transcutaneous spinal cord stim with 2: Respiratory Training	USA	RECRUITING
56	NCT05744271		✓		✓						1 closed-loop FES system with 2: visual feedback balance training (VFBT)	Canada	RECRUITING
57	NCT06010251		✓		✓						1: tDCS and 2. bodily illusions	USA	RECRUITING
58	NCT05187650			✓	✓						1: Powered exoskeleton therapy (EksoNR, Ekso Bionics)| combined with 2: FES (RehaMove2, Hasomed)	Switzer.	RECRUITING
59	NCT05386537			✓						✓	1. assistive device, 2. virtual reality	USA	RECRUITING
60	NCT05665998		✓		✓						1. epidural stimulation drive by cortical signals ARC-BSI Cervical system; 2. upper limb rehabilitation	Switzer.	RECRUITING
61	NCT04057456					✓				✓	1. drug: Nabilone Capsules. 2. Anti-inflammatory diet	Canada	RECRUITING
62	NCT06087445		✓		✓						1. NeuroLife EMG-FES Sleeve System for electrical EMG stimulation. 2. task-oriented rehabilitation protocol	USA	RECRUITING
63	NCT03048331				✓				✓		1. Functional Electrical Stimulation	Switzer.	RECRUITING
64	NCT06710808				✓					✓	1. transcranial direct current stimulation. 2. Virtual walking	Switzer.	RECRUITING
65	NCT04894734				✓				✓		1. DEVICE: EES on. 2. surgery (conventional medical treatment)	USA	RECRUITING
66	NCT06351852				✓	✓					1. DRUG: Combination of Neostigmine and Glycopyrrolate. 2. DEVICE: I-Box by Dynatronics	USA	RECRUITING
67	NCT05023772								✓	✓	1. surgery; 2. radiation PROCEDURE: Stereotactic Laser Ablation|RADIATION: Stereotactic Radiosurgery|DIAGNOSTIC_TEST: MRI guided laser ablation	USA	RECRUITING
68	NCT06533969				✓✓						PROCEDURE: Epidural Spinal Cord Stimulation|DEVICE: Electrocorticographic|DEVICE: Electroencephalographic	USA	RECRUITING
69	NCT05163639				✓				✓		1. surgery. 2. cortical and spinal stimulation	USA	RECRUITING
70	NCT04736849		✓		✓✓						1. DEVICE: Percutaneous epidural stimulation; 2. dorsal root stimulation; 3. rehabilitation	USA	RECRUITING
71	NCT05429736		✓		✓						1. BEHAVIORAL: Motor Skill Training (MST). 2. DEVICE: Transcutaneous Spinal Stimulation (TSS)	USA	RECRUITING
72	NCT06069999		✓		✓						1. DEVICE: HandyMotion Treatment Program; 2. rehabilitation	USA	RECRUITING
73	NCT06515223		✓	✓	✓						1. DEVICE: Epidural Spinal Cord Stimulation; 2. device assisted tasks; 3. bladder and pelvic floor muscle training (PFMT) in combination with eSCS.	UK	RECRUITING
74	NCT04276181								✓✓		1. combined nerve and tendon transfer (CNaTT)	Sweden	RECRUITING
75	NCT03780829		✓✓			✓					1. hypoxia ABT? 2.DRUG: D-cycloserine; 3. exercise training	USA	RECRUITING
76	NCT05967325						✓	✓			1. Material implant: Stromal Vascular Fraction (SVF) combined with Functional self-assembling peptide nanofiber hydrogels	Hong Kong	RECRUITING
77	NCT05726591			✓	✓						1. robotic assisting device; 2. walking	USA	RECRUITING
78	NCT04798378				✓						1. DEVICE: Neurosleeve	USA	RECRUITING
79	NCT04623593								✓✓		1. PROCEDURE: Anterior cervical discectomy with fusion (ACDF); 2.PROCEDURE: Anterior cervical discectomy with arthroplasty (ACDA)	Nether.	RECRUITING
80	NCT03229031					✓			✓		1: ES135 (a recombinant human acid fibroblast growth factor (rhFGF1) with 135 amino acids) with 2. spinal cord surgical repair	Taiwan	SUSPENDED
81	NCT04000919					✓✓					1: either 5HTP or L-DOPA in combiantion with 2: Carbidopa	USA	SUSPENDED
82	NCT05210166			✓	✓						1. Transcutaneous spinal stim. 2. Lokomat	Spain	COMPLETED
83	NCT06079138		✓		✓						1. Transcranial direct current stimulation (Active) 2. Telerehabilitation exercise	Thailand	COMPLETED
84	NCT04034108		✓						✓		1. Surgical intervention 2. weight-supported ambulation training	Hong Kong	COMPLETED
85	NCT04132596		✓		✓						1. Transcutaneous spinal cord stimulation 2. Activity Based Therapy	UK	COMPLETED
86	NCT04790149		✓		✓						1. Conventional Rehabilitation or NEUROM 2. Transcranial direct current stimulation (tDCM)	Lebanon	COMPLETED
87	NCT02554058		✓		✓						1. Cycling and 2. Mechanical stimulation	Canada	COMPLETED
88	NCT01621113		✓			✓					1. Dalfampridine and 2. locomotor training	USA	COMPLETED
89	NCT05504200		✓		✓						1. Transcut. SC stim and 2. Bladder and Pelvic Floor Muscle Training	UK	COMPLETED
90	NCT01471613					✓	✓				1. DRUG: Lithium Carbonate Table and 2. BIOLOGICAL: Cord Blood Cell	China	COMPLETED
91	NCT02537899		✓			✓					1. NeuroAiD and 2. Rehab	Singapore	COMPLETED
92	NCT04211311		✓	✓							1. functional electrical legcycling with 2. voluntary armwork (hybrid training) as either skiergometer or armcycling	Denmark	COMPLETED
93	NCT03834324		✓		✓						1. repetitive exercise with 2. FES	UK	COMPLETED
94	NCT02562001			✓	✓						1. transcranial direct-current stimulation (tDCS) with 2. Lokomat assisted gait training	Brazil	COMPLETED
95	NCT03810963				✓					✓	1: High intensity interval training (HIIT)-FES Cycling with 2: Nutritional Counseling	USA	COMPLETED
96	NCT03112941								✓	✓	1: surgical decompression with 2: hyperbaric oxygen	China	COMPLETED
97	NCT02495545								✓	✓	1: Cerebrospinal Fluid Drainage (CSFD) and 2: elevation of mean arterial pressure (MAP)	USA	COMPLETED
98	NCT05801536		✓		✓						1. Transcutaneous Electrical Stimulation with 2. Upper Limb Tas-specific training	UK	COMPLETED
99	NCT00060983		✓		✓						1: Body weight supported locomotor training and 2: Functional electrical stimulation	USA	COMPLETED
100	NCT05249985				✓					✓	1: quadriceps neuromuscular electrical stimulation (NMES) r and 2: DIETARY_SUPPLEMENT: Protein	UK	COMPLETED
101	NCT02701777		✓		✓						1: Spike timing dependent plasticity (STDP) stim with 2: Motor Training	USA	COMPLETED
102	NCT03752749		✓							✓	1: Prednisolone + 2: Acute Intermittent Hypoxia	USA	COMPLETED
103	NCT04309448		✓		✓						1: Perturbation-based balance training with 2: functional electrical stimulation	Canada	COMPLETED
104	NCT01143597		✓		✓						1: somatosensory stimulation with 2: either massed practive or conventional resistence training	USA	COMPLETED
105	NCT05411692		✓		✓						1: Functional electrical stimulations and 2: Conventional physical therapy	Pakistan	COMPLETED
106	NCT03036527		✓	✓	✓						1: spinal epidural stimulation with 2: Activity-based locomotor training, stand training or upper arm ergometry	USA	COMPLETED
107	NCT06624566		✓✓								Combined 1: aerobic rehabiliation with 2 strength neurorehabilitation	Spain	COMPLETED
108	NCT04670406									✓✓	BEHAVIORAL: acceptance and commitment therapy (ACT) combined with psychoeducation	USA	COMPLETED
109	NCT02862080			✓	✓						1: transcutaneous spinal direct current stimulation (tsDCS) cathode or anode with 2: Ekso gait training	USA	COMPLETED
110	NCT03517787		✓		✓						1: FES + 2: exercise	Estonia	COMPLETED
111	NCT03414424		✓		✓						1: Cervical Electrical Stimulation with 2: active hand or wrist movements	USA	COMPLETED
112	NCT02441179		✓	✓							1: Acute Intermittent Hypoxia with 2: Body weight-assisted treadmill training	Chile	COMPLETED
113	NCT04697472		✓		✓						1: LIFT System - electrical spinal cord stimulation (ARC Therapy) and 2: Task-specific training	Switzer.	COMPLETED
114	NCT00856440					✓✓					DRUG: Fleets Oral Sodium Phosphate Solution (OSPS)|DRUG: Colyte|DRUG: Dual (OSPS & Colyte)	USA	COMPLETED
115	NCT01484184					✓✓✓					Conbined DRUG: SPINALON (buspirone + levodopa + cardidopa)	Sweden	COMPLETED
116	NCT04500223		✓✓								1: Cervical stretch exercise plus 2; cardiopulmonary rehabilitation	Taiwan	COMPLETED
117	NCT04910412		✓		✓						1: transcranial direct current stimulation with 2; Gait training	Thailand	COMPLETED
118	NCT00291317	✓		✓							1: RT 300-P (physician-prescribed, FDA Class II medical device) FES hand Cycle and 2: Standard of care rehab	USA	COMPLETED
119	NCT06509841	✓								✓	1: conventional rehabilitation treatment and 2: Acupuncture treatment rehabilitation	China	COMPLETED
120	NCT04624607			✓	✓✓						1: Transspinal-transcortical paired-associative stimiulation combined with 2: robotic gait training	USA	COMPLETED
121	NCT03237234		✓		✓						1: Motor Skill Training paired with 2: Transcranial direct current stimulation (tDCS)	USA	COMPLETED
122	NCT04052776				✓	✓					1: Epidural Stim with 2: DRUGs Buspirone +/− Levodopa-Carbidopa	Switzer.	COMPLETED
123	NCT04221373	✓		✓							1: exoskeletal-assisted walking (EAW) training with 2: regular acute inpatient rehabilitation (AIR)	USA	COMPLETED
124	NCT03833674		✓✓		✓						1: Daily Acute Intermittent Hypoxia (AIH) with 2: Respiratory Strength Training	USA	COMPLETED
125	NCT04102826			✓	✓						1: Functional electrical stimulation (FES) with 2: mobile arm support	UK	COMPLETED
126	NCT05558657		✓							✓	1. Home-based, acupressure combined with nursing education|OTHER: Home-based, manual light touch of the abdomen combined with nursing education	Hong Kong	COMPLETED
127	NCT00745095					✓				✓	1: Standard Oral Colonoscopic Preparations with either 2: DRUG - Neostigmine or colonic irrigation	USA	COMPLETED
128	NCT04777149		✓		✓						1. Transcranial Random Noise Stimulation (tRNS). 2. Upper extremity training	USA	COMPLETED
129	NCT03240601		✓		✓						1.Transcutaneous spinal stimulation. 2. locomotor training	USA	COMPLETED
130	NCT02098135			✓	✓						1. device; 2. task-specific training	Switzer.	COMPLETED
131	NCT01740128		✓	✓							1. Robotic body weight supported treadmill training. 2. Harness-supported multimodal balance training	USA	COMPLETED
132	NCT02218203					✓✓					1. DRUG: Dextromethorphan; 2. DRUG: Lidocaine	USA	COMPLETED
133	NCT01225055				✓	✓					1. DRUG: Teriparatide. 2.DEVICE: vibration	USA	COMPLETED
134	NCT04727866				✓✓						1. DEVICE: transcutaneous spinal direct current stimulation (tsDCS) - coronal. 2. DEVICE: transcutaneous spinal direct current stimulation (tsDCS)	USA	COMPLETED
135	NCT00826228		✓			✓					1. DRUG: teriparatide 2. weight-bearing activity	USA	COMPLETED
136	NCT01467817		✓							✓	1: Lifestyle Intervention 2: Exercise Control	USA	COMPLETED
137	NCT04171375		✓		✓						1.DEVICE: trans-spinal Electrical Stimulation (tsES). 2. rehabilitation	Hong Kong	COMPLETED
138	NCT01891110				✓✓						1: ES of the abdominal muscles 2: ES of the limb muscles 3. ES of limbs & abdomen	Switzer.	COMPLETED
139	NCT03179475					✓✓					DRUG combo 1: Oxycodone 2: Naloxone	Canada	COMPLETED
140	NCT04671030					✓✓					DRUG combo 1. Neostigmine; 2. Glycopyrrolate	USA	COMPLETED
141	NCT03851302		✓							✓	1: Active Remote Ischemic Conditioning 2: Isometric hand exercise	USA	COMPLETED
142	NCT02370862					✓✓					DRUG combo 1. Neostigmine and 2. Glycopyrrolate	USA	COMPLETED
143	NCT04566809		✓		✓						1. FES; 2. Criteria Based Assessment rehabilitation	Italy	COMPLETED
144	NCT00634426					✓			✓		1. Surgical excision of the metastatic process; 2. Radiotherapy of the metastatic spine process	USA	COMPLETED
145	NCT04972773		✓							✓	1. Mindfulness meditation (MM); 2. rehabilitation	Canada	COMPLETED
146	NCT03690726		✓		✓						1. repetitive transcranial magnetic stimulation. 2. rehabilitation	Denmark	COMPLETED
147	NCT00987155		✓		✓						1. FES; 2. maximal strength training;	Norway	COMPLETED
148	NCT05615402		✓							✓	1. Bone-specific strength training 2. DIETARY_SUPPLEMENT: Nutrition optimalisation	Norway	COMPLETED
149	NCT02406859			✓	✓						1. device: Bowel Biofeedback.2. device assisted Anorectal Manometry	USA	COMPLETED
150	NCT03302793				✓✓						1. breathing-controlled electrical stimulation (BreEStim); 2. transcranial direct current stimulation (tDCS)	USA	COMPLETED
151	NCT04578574				✓					✓	1. Bodily Illusion (BI); 2. Transcranial direct electrical stimulation (tDCS) on neuropathic pain.	USA	COMPLETED
152	NCT02236065					✓✓					1. allogeneic umbilical cord blood (UCB); 2.granulocyte-colony stimulating factor (G-CSF)	USA	COMPLETED
153	NCT03458169			✓	✓						1. robotic device 2. device assisted rehabilitaion	Switzer.	COMPLETED
154	NCT04854057		✓		✓						1. Intermittent Hypoxia - hypoxia air mixture and 2. TESS - Transcutaneous Electrical Spinal Cord Stimulation and 3. Functional Task Practice	USA	TERMINATED
155	NCT03536338		✓		✓						1: Spinal Stimulation and 2: Sit-to-stand Training	UK	TERMINATED
156	NCT05354206		✓		✓						1: Transcutaneous spinal cord stimulation (SCS) with 2: motor training	USA	TERMINATED
157	NCT01962675		✓		✓						1: Transcranial direct current stimulation + 2: step training	USA	TERMINATED
158	NCT01404065				✓					✓	1. device Transcranial Direct Current Stimulation (tDCS). 2. visual illusion	USA	TERMINATED
159	NCT03669302			✓	✓						1. OTHER: Robotic gait training. 2. low-frequency transspinal stimulation	USA	TERMINATED
160	NCT03655080					✓✓					1. RADIATION: Radiation therapy; 2. DRUG: nab-Paclitaxel	USA	TERMINATED
161	NCT00004415				✓✓						1. DEVICE: Medlink spinal cord electrode sitmulation of intercostal and diaphragm	USA	TERMINATED
162	NCT05196204										1. Trunk-oriented task training combined 2. functional electrical stimulation	Canada	UNKNOWN
163	NCT02663310		✓						✓		1. Surgery and 2. Rehabilitation	Hong Kong	UNKNOWN
164	NCT05200091		✓✓								1. explosive strength training and 2. and specific balance training group	Canada	UNKNOWN
165	NCT05522920	✓			✓						1 Conventional Therapy 2. with and without spinal cord stimulation	UK	UNKNOWN
166	NCT03922802		✓✓		✓						1.: Acute Intermittent Hypoxia + 2. Non Invasive Spinal Cord Stimulation + 3. Gait Training	USA	UNKNOWN
167	NCT03394560		✓		✓						1. High frequency repetitive transcranial magnetic stimulation and 2. body weight-support treadmill training	Brazil	UNKNOWN
168	NCT04921592		✓		✓						1. Transcut. SC Stim and 2. ATB	USA	UNKNOWN
169	NCT03966794				✓			✓			1. Epidural Electrical Stimulation and 2. collagen scaffold transplantation	China	UNKNOWN
170	NCT02688049						✓	✓			1. NeuroRegen scaffold/ and 2. either mesenchymal stem cells transplantation OR neural stem cells transplantation	China	UNKNOWN
171	NCT04194099				✓✓						1. Repetitive Transcranial magnetic stimulation (rTMS) (Brain) and 2. tsDCS (Spinal) stim	Taiwan	UNKNOWN
172	NCT02317640		✓		✓	✓					1: Testosterone Gel applied by a pump 2: Stand Training and 3: Electrical Stimulation	USA	UNKNOWN
173	NCT04496609		✓		✓						1: lumbosacral epidural electrical stimulation with 2: locomotor training	France	UNKNOWN
174	NCT03555838			✓	✓						1. transcranial direct current stimulation and 2: robotic training	USA	UNKNOWN
175	NCT04632290		✓		✓						1: STIMO-BSI stim with 2: neurorehabilitation	Switzer.	UNKNOWN
176	NCT04568928			✓	✓						1: Robotic assisted rehab – assisted overground walking training with Powered Exoskeleton (OLTP/PE) + 2: FES	Canada	UNKNOWN
177	NCT05142943	✓								✓	1: Visual illusion with 2: Conventional Physical exercise	USA	UNKNOWN
178	NCT03262766		✓	✓							1: Acute Intermittent Hypoxia (AIH) and 2: Upper extremity training	USA	UNKNOWN
179	NCT03052244				✓					✓	1: Transcranial direct current stimulation over motor cortex with 2: Visual illusion (footage of walking)	Israel	UNKNOWN
180	NCT01753882		✓			✓					1: Lexapro (selective serotonin reuptake inhibitor; SSRI) and 2: walking training	USA	UNKNOWN
181	NCT04052009		✓✓								1: Conventional gait training with/without 2: End-effector based gait training	Switzer.	UNKNOWN
182	NCT01800409				✓						1. Electrical stimulation of the abdominal muscles. 2.mechanical insufflation-exsufflation	UK	UNKNOWN
183	NCT04641793			✓	✓						DEVICE: Motion and electromyogram (EMG) Control	USA	UNKNOWN
184	NCT02227407				✓						1. DEVICE Combo: RGOs(reciprocating gait orthoses)	Taiwan	UNKNOWN
185	NCT03874988									✓✓✓	1. Portion-Controlled Meals 2. Enhanced Self-Monitoring 3. GLB-SCI	USA	UNKNOWN
186	NCT01867268					✓				✓	1. Acetazolamide 2. prone positioning	Iran	UNKNOWN

Other: alternative interventions, including dietary interventions, visual stimuli and imagery, and acupuncture.

Conv. Rehab, conventional rehabilitation; ABT, activity-based therapy; Assist. Device, assistive device; Stim. Devicem, device for stimulation; Drugs, pharmacological intervention; Cells, cell- or tissue-based therapy; Material Implant, biomaterial or scaffold-based intervention; Surgery, surgical intervention

While any trial assessing the additive effects of multiple therapies may be considered a combination trial, few are combinatorial, with one example being the completed, randomized trial by Hayes et al.⁹⁶ (NCT01272349). That study tested the effects of combining acute intermittent hypoxia followed by locomotor training after different time intervals to determine the optimal respective timing of interventions.

An overview of combination/combinatorial studies currently in trials can be easily reviewed on ClinicalTrials.gov. Given the breadth of individual treatments that have undergone testing in early clinical research or trials, we can hope that there will be novel combinations of these tested in the near future. The following sections highlight some treatment strategies that have been translated to clinical trials, with consideration for hurdles faced in the translational process, and how combining these approaches could be harnessed in the future.

Activity-based therapies

ABTs, which include standard-of-care rehabilitation, stand out among the plethora of strategies undergoing rigorous pre-clinical research as they have consistently demonstrated improved functional outcomes across a broad range of SCIs (varying in level and extent, and even across animal models tested). New developments in ABTs include modalities such as treadmill training, and may include respiratory training strategies such as intermittent hypoxia. While some clinical ABTs use assistive devices (e.g., exoskeletons for assistive mobility) or stimulation (functional electrical stimulation) to help patients perform specific activities, they are often not classified as combination therapies, since the device or stimulation serves as a tool to enable the activity rather than representing a separate therapeutic strategy. In contrast, a study combining stimulation with a specific task-oriented ABT would be considered a combination therapy if both components are intended to independently contribute to improving overall function.

Although rehabilitation is often regarded as an essential component of care given to people with SCI, the availability and scope may be contingent upon access to facilities and financial resources. Notably, clinical trials exploring other treatments (e.g., pharmacological, cell therapies) can incorporate existing rehabilitation therapies, ensuring that the trial does not disrupt established treatment protocols or interfere with standard care. Alternatively, some clinical studies have also made an effort to actively combine aspects of conventional rehabilitation with another therapy to harness the benefits of both (see Table 1).

Neural interfaces and operative neuromodulation

Open-loop electrical stimulation like dorsal column epidural stimulation (Fig. 2) is an established implanted technology to reduce chronic neuropathic pain.⁹⁷ Lumbosacral epidural and transcutaneous stimulation have been shown clinically to also enhance neuroplastic recovery in SCI patients receiving intensive rehabilitation.^98,99 The exact mechanisms by which this electrical stimulation enhances neuroplasticity are incompletely understood, but one potential mechanism is that stimulation may lower the threshold of N-methyl-D-aspartate receptor activation and encourage long-term potentiation, in accordance with the notion that “neurons that fire together wire together.”^100,101 When considering electrical stimulation for combination treatments, additional components like physical therapy (ABT) or robotic assistive devices (Fig. 2) may support beneficial neuroplasticity and reduce maladaptive changes. There are two clinical trials involving electrical stimulation as a component in a combined treatment model, one combination trial with a pro-regenerative scaffold (NCT03966794) and the other a combinatorial trial with a partial serotonin 5HT agonist, Buspar (NCT04458324). More recently, advances by the ONWARD group in Switzerland led to the initiation of several small trials, including a combination of epidural stimulation with task practice (NCT04196114). Given that several early clinical investigations have demonstrated efficacy for electrical neuromodulation, this may prove to be an effective component in more definitive clinical trials.^89,97,98 Parallel pre-clinical studies are not only further developing epidural and transcutaneous stimulation strategies, they have also begun to identify the neural substrate that is responsible for the effects seen with epidural stimulation.¹⁰²

Pharmacological agents

Pharmacological agents (drugs and biologics) remain a prevalent therapeutic strategy in the current clinical landscape for most diseases. Notably, several pharmacological agents that have been explored in clinical testing for SCI have been repurposed from other approved clinical uses, which can shorten the drug developmental timeline. Approved therapeutics can also be re-purposed for “compassionate care” of patients, which enables clinical professionals to provide these treatments for off-label uses.

One pharmacological agent that has received significant attention for neural injury is riluzole, a neuroprotective drug that attenuates excitotoxicity by inhibiting release of presynaptic glutamate.^76,103 Riluzole also blocks sodium channels in their inactivated state.¹⁰⁴ These neuroprotective properties have already been extensively studied in humans in the context of ALS, leading to the first FDA-approved treatment for the disease. The North American Clinical Trials Network (NACTN) was able to test riluzole in SCI, based on an FDA waiver, due to the extensive data from Amyotrophic Lateral Sclerosis studies.¹⁰⁵ Results published from completed trials for riluzole in SCI have shown some improvement of sensory and motor function,^106–108 with possibly greater benefits seen in people with incomplete cervical-level injuries.¹⁰⁸ Another FDA-approved drug that is being tested in SCI is minocycline, a tetracycline antibiotic with anti-inflammatory properties.^76,109 A phase II clinical trial has been reported in which minocycline was associated with efficacy signal in incompletely injured patients.^76,109 Other promising potential pharmacological agents being assessed in clinical trials include glibenclamide, granulocyte colony-stimulating factor, Cethrin, Buspar, and anti-Nogo-antibody.^76,110,111

Therapeutic combinations are the standard in SCI care (e.g., use of pharmacological and non-pharmacological interventions), but associated outcomes are often not rigorously assessed. Some pharmacological approaches are also sensible to combine with non-drug treatments and may warrant further clinical exploration and research. For example, pre-clinical studies have already offered some insights into combining drug therapy with cell transplantation, showing that while riluzole appears to negatively impact donor cells,^112,113 delivery of trophic factors aids donor cells.^114–116 Ideally, neuroprotective drugs could promote preservation of neural tissue for subsequent use of plasticity-enhancing (ABTs or stimulation) or regenerative (cell, scaffold, or other pharmacologic) therapies, increasing overall efficacy. Alternatively, regenerative drugs could act synergistically with non-pharmacologics like ABTs and/or stimulation that can further promote growth, axon guidance, and synapse formation.

Procedural interventions

Procedural interventions encompass surgical and non-surgical management strategies. For example, evidence for the benefit of early decompressive surgery is substantial.^117–119 Other validated clinical methods included the use of a spinal sealant for closing dura post-invasive surgical procedures (NCT00458354), novel approaches for airway clearance,¹²⁰ and nerve transfer surgery.¹²¹ Hypothermia continues to be investigated for its benefit in acute SCI,¹²² purportedly through inflammation reduction.¹²³ Surgical interventions also include trials of implantation of devices for stimulation, implantation of biologics for repair, and novel rehabilitative and behavioral strategies for functional improvement.^76,124 Pharmacological agents to suppress the immune response against these implants or transplants are a crucial combination for these invasive procedural interventions,¹²⁵ although which immunosuppressant is optimal for each procedure and patient, and for what duration of time, requires further study.

Scaffolds and cell-based therapies

The purpose of therapeutic tissue scaffolds is to engender tissue repair. Scaffolds have been used pre-clinically¹²⁶ and clinically with the intent of preserving tissue and promoting tissue repair (e.g., INSPIRE Study [NCT02138110]¹²⁷). Initial reports from the INSPIRE Study reported some functional improvement in approximately half of the 16 individuals studied based on AIS score conversion, however the study did not meet its pre-specified primary outcome. The provision of a physical substrate for new tissue formation and axonal regeneration by these scaffolds may be enhanced in combination with targeted release of proregenerative factors or inclusion of cells with pro-regenerative properties such as Schwann cells.^128–131

Mesenchymal stem cells (MSCs) are a very popular cell-based strategy that have been used to increase neural repair, among other therapeutic effects.¹³² At the time of submission of this article, eight clinical trials are currently recruiting to test MSCs in humans, and two have been completed, one of which (NCT02481440) utilized MSCs from the human umbilical cord. There are reports of minor complications such as fever, headache, and transient muscle tension that resolved with conservative management.¹³³ Improvements were noted in pinprick sensation, muscle spasticity, and bladder and bowel function.¹³³

Pre-clinical studies have explored the use of neural precursor cell (NPC) transplantation (Fig. 2) to provide new populations of neurons and glia for spinal cord repair (reviewed in^59,134). These studies served as the foundation for several clinical trials conducted throughout the United States, Europe, and Asia, and have been reviewed in detail elsewhere.⁵⁹ These NPCs were most often derived from fetal stem cell lines.⁵⁹ Another recently explored source for these cells are induced pluripotent stem cells,¹³⁵ with the first in-human clinical trial now underway. As discussed in Fischer et al.,⁵⁹ transplantation of NPCs has long been thought to have potential for synergy with adjunct treatments such as ABTs to synergistically facilitate improved outcomes. Testing these approaches in combination is now becoming an important pre-clinical goal with strong translational relevance.^35,36

Barriers to Translation

Barriers to programs & investigators

Due to the variable nature of SCI type, extent, and severity, as well as demographic and covariate disease considerations, functional recovery will vary. For example, respiratory, cardiovascular, and upper extremity function are priorities in patients with cervical and high thoracic injuries, whereas ambulation, bowel, bladder, and sexual function are a focus for individuals with lower spinal injuries.^120,136 The range of recovery targets has revealed that available outcome measures for e.g., bladder recovery may be inadequate or impractical to serve as endpoints for clinical trials.¹³⁷ While this challenge is present even for singular interventions, it is amplified when multiple treatments are tested to distinguish between the effects of component therapies.

The use of common data elements (CDEs) outlined by the National Institute of Neurological Disorders and Stroke will aid clinical researchers in advancing therapies¹³⁷ by harmonizing the language used to report clinical values and endpoints across studies. The creation of a similar set of CDEs for pre-clinical researchers might improve translation, especially if they can be used both pre-clinically and clinically (e.g., use of evoked potentials).

The success of a particular combination or combinatorial strategy in an animal model may not predict success in people.^138,139 In addition to the uncertainty of improvement when combining individually successful therapeutics, investigators must also consider that negative interactions between treatments are possible.^139,140 With this in mind, the importance of publishing the study outcomes and sharing data is crucial to guide decisions on how to a) recombine treatments in a novel sequence or temporal fashion, or b) re-evaluate whether investments are better off made in alternative treatments. There are likely substantial data from pre-clinical and clinical data studies that have produced “negative” data (the treatments were not successful as applied), that influence whether or not they are pursued for translational studies, but these results and interpretations have historically not been well documented. Furthermore, although registration of trials on clinicaltrials.gov recommends that clinical trial results are uploaded upon trial completion, this is currently not uniformly practiced.

Randomized clinical trials investigating combinatorial therapeutic strategies often encounter challenges in maintaining adequate statistical power. The more therapies a trial includes, the more test groups that might be required. In addition, the number of eligible subjects is limited by the number and type of inclusion/exclusion criteria employed. Current thinking is that a separate group would be necessary for each therapy, and in the case of more than two therapies, different permutations might also be required. Arranging groups via permutation rather than combination increases the number of groups. However, this is a necessary step in order to consider the optimal timing of therapies relative to one another—thus meeting the standard of a combinatorial trial.¹⁴¹

Another important challenge to investigators is research funding. In the United States, industry funding for biomedical research outpaces federal funding,¹⁴² and companies with a vested interest and ownership of a therapeutic may be hesitant to engage in its combined use with other component therapies to which they do not have in-house or licensed IP. That is, two separate companies, each with a promising treatment for SCI, may not have sufficient incentive to combine their treatments for a joint clinical trial. For combination and/or combinatorial treatments to be realized in SCI, regulatory, legal and entrepreneurial challenges must be overcome so that sufficient incentives exist for sponsors/investors. These challenges may be more complex than any individual treatment might face.

Epidemiological barriers

There is no “typical” SCI patient, and there is a need for adaptable graded SCI management approaches to reflect this heterogeneity. Furthermore, the epidemiology of SCI is changing. The average age of the traumatic SCI patient population has increased from 29 years in the 1970s to 43 years since 2015,¹⁴³ and the average age of chronic SCI patients is increasing due to lower mortality rates after SCI related to better medical care,¹⁴⁴ and the growing number of new SCI cases among older individuals, especially considering SCI arising from degenerative cervical myelopathy. The average age at injury is now bimodal, with one group between 15 and 29 years, and the other 65 and older.¹⁴⁵ The younger individuals generally suffer from high-energy trauma (e.g., motor vehicle collision, assault), whereas older individuals from lower-energy trauma (e.g., fall) or non-traumatic (e.g., spinal degenerative disease) causes.¹⁴⁵ These two different age groups may also have different goals and capacity for function, based on age and their prevalence of common age-related comorbidities. There are also a large number of SCIs that arise from violence, including bullet, concussive blast, and shrapnel injuries and stabbing wounds. These have different tissue injury patterns and are rarely modeled in pre-clinical SCI research, and treatment tends to be very conservative.

Epidemiological research in SCI is essential due to rapid changes in demographics such as the average age at injury,¹⁴⁶ with consideration of optimal care in different age groups and injury cohorts. The diverse patient demographics and SCI heterogeneity necessitate inclusive approaches to research design. Ideally, multi-modal strategies would be adapted to the unique aspects of each patient’s underlying health and injury responses. However, this personalized medicine should be grounded in the universal principles that apply to most patients, such as adequate spinal cord decompression, reduction of infection, early mobilization, and transfer to rehabilitation. Late-stage translation following clinical trials needs to consider the inclusion/exclusion criteria and demographics specific to those studies when applying the findings to more diverse populations. Multi-center collaboration and data-sharing from registry-based studies may be helpful in accumulating statistical power in investigational trials with multiple sub-cohorts.

Closing Remarks

SCI is a devastating ailment affecting more than 300,000 individuals in the United States,¹⁴⁷ and several million world-wide.^148–150 Despite a well-studied underlying pathophysiology, and advancements in research on many individually promising therapies, there is no widely available approved combined therapeutic approach that confers significant functional neurological recovery. Combined approaches are likely to be key to improving functional recovery, as it is accepted that no single treatment alone can act as a “silver bullet.” Due to many recent advances targeting neurological protection, repair and recovery, there is justifiable optimism within the field of SCI translational research for combination/combinatorial therapies. However, daunting challenges in the path toward cures remain, and addressing them will require i) a better understanding of the limitations of combination/combinatorial therapies and their component strategies, ii) logistically and ethically appropriate study design, iii) reliable, and psychometrically standardized outcome assessments, iv) accessibility to treatment, and v) multi-discipline and multi-center collaborations.

To successfully drive promising treatments and combination strategies forward, pre-clinical research needs to be conducted in a highly rigorous fashion with extensive data sharing and widespread dissemination, so that it can most accurately inform translational studies. Similarly, translational research needs to build on this foundation laid by pre-clinical research, with a deep understanding of its practical applications and target populations. This depth of understanding is crucial for translating scientific and clinical results into tangible clinical practices.