Abstract
Photobiomodulation (PBM) therapy (PBMT) to treat traumatic spinal cord (SC) injury (tSCI) is a growing area of research that could present a highly effective therapy for restoring function after tSCI. SC injuries (SCIs) are severe injuries that typically result in the loss of motor, sensory, and autonomic function, dramatically affecting the lives of patients and their families. SCI has two primary parts: the primary injury, which occurs immediately at the time of injury and is a result of mechanical forces on the SC, and the secondary injury, which occurs over the months following the initial incident and is primarily the result of biochemical damage. PBM is the process through which nonionizing light is absorbed by naturally occurring chromophores in the body and causes beneficial physiological changes without causing thermal damage. In the case of tSCI, PBMT seems to work through increasing energy availability enabling normalized cellular function after tSCI reducing the functional loss from the secondary injury. When applied to tSCI, PBMT has been shown to improve the functional recovery after a tSCI. These beneficial effects have been shown extensively in rodent models across multiple studies using a variety of parameters. In order to translate this promising therapy to the clinical setting, multiple steps need to be taken including understanding dosing, establishing efficacy and safety in large animal models and humans, and the development of a clinical-grade PBMT application system. This review seeks to provide a comprehensive overview of the progress that has been made in the field of PBMT for tSCI and the steps needed to translate this promising therapy to the clinical setting.
Keywords
Introduction
Photobiomodulation (PBM) therapy (PBMT) for treating traumatic spinal cord (SC) injury (tSCI) is a relatively new field and rapidly growing area of research over the past few years. This review presents a comprehensive overview of the field and a concise synthesis of these data that have been collected. The goal is to interpret these data as a whole, understand what has been done, identify gaps in the field, and inform future directions for this promising therapy.
Spinal Cord Injury
Introduction to spinal cord injury
Spinal cord injury (SCI) is a complex and variable neurological condition that presents a significant challenge for clinical therapies due to its diverse etiologies and unpredictable outcomes. While there are multiple types of SCIs, most research in this field focuses on traumatic SCI that is classified as SCI resulting from acute external forces such as motor vehicle accidents. tSCI severely impacts patients’ quality of life and results in a broad spectrum of functional deficits. These range from complete tetraplegia to minimal or no motor and sensory deficits. 1 In the United States, roughly 18,000 people suffer a tSCI each year, and there are over 300,000 people living with a tSCI.2,3 Many of these result in complete or partial loss of motor and sensory function below the level of injury, often requiring extensive long-term care and higher mortality rates. 4 As a result, the lifetime cost to patients and their families can exceed $5 million and substantially impair patients’ educational, career, and social opportunities, further reducing the quality of life. 3
The progression of tSCI is a two-phase process consisting of the primary injury and the secondary injury. The independent impacts of the primary and secondary injuries on functional outcomes are not well characterized, but it has been shown that treating the secondary injury results in improved outcomes. 1
Primary injury
The primary injury occurs at the moment of insult, typically a blunt force trauma, and is predominantly a result of mechanical forces acting on the SC. The insult may last from milliseconds to minutes, depending on the cause of injury. During the insult, mechanical forces from blunt force trauma are exerted onto the SC, causing damage through various mechanisms including acute compression, contusion, dislocation, distraction, or laceration of the SC. These mechanical forces additionally result in damage to the local vasculature, resulting in acute ischemia and edema further causing energy deprivation and neuronal death. The cell death and injury up to this stage are considered the primary injury, with the majority being a direct result of the mechanical forces exerted on the SC.1,5,6
Secondary injury
To summarize Ahuja et al. 1 and Siddiqui et al., 6 the secondary injury occurs as an indirect response to the mechanical damage sustained during the primary injury and is the result of biochemical damage to the SC that furthers injury. It is typically divided into five phases: immediate (before 2 h), acute (2–48 h), subacute (2–14 days), intermediate (14 days–6 months), and chronic (beyond 6 months). The immediate phase picks up where the primary injury leaves off and is characterized by continued cellular damage and dysregulation of blood flow, leading to ischemia, hemorrhage, and edema. These events reduce energy availability to cells, initiate an immune response, and elevate extracellular glutamate levels, leading to excitotoxicity. Collectively, these processes contribute to continued apoptotic and necrotic cell death. About 2 h after tSCI, the injury enters the acute phase. The damage to the vasculature and blood–spinal cord barrier enables peripheral immune cell infiltration, accompanied by an increase in oxidative stress and free radical production, resulting in an excessive immune response. Poorly regulated extracellular glutamate levels and residual mechanical damage contribute to additional demyelination and ongoing necrotic and apoptotic cell death. Approximately 48 h after the insult, the injury enters the subacute phase, which can last around 2 weeks. During this phase, the vasculature starts to heal with a decrease in edema, hemorrhage, and ischemia, but not before peripherally derived macrophages infiltrate the injury site. The excessive immune response persists throughout this phase, accompanied by the onset of reactive astrogliosis. Between 2 weeks to 6 months after injury, the injury is in the intermediate phase. Inflammation gradually subsides and the glial scar starts to form as the injury begins to stabilize. Beyond 6 months, the injury moves into the chronic phase, in which the injury has stabilized and the glial scar and cyst have completely formed around the injury with Wallerian degeneration of surrounding axons persisting over the next few years.1,5,6
tSCI therapeutic challenges
Developing therapies for tSCI is challenging due to the complexity, heterogeneity of injury, and variability in the time to initiate treatments. These are intrinsic elements of the injury that potential therapies must address in order to be effective.
While immediate intervention with therapy is ideal, the unpredictable nature of tSCI often results in delays, as patients may take several hours to reach a trauma center and achieve a stable clinical state. For injuries in military situations and in developing countries, this delay is even greater, making early intervention more difficult.7,8 As a result, most therapeutic interventions cannot address the primary injury and can only be implemented during the acute or subacute phases of tSCI.
Further complicating treatment, many of the biological processes contributing to damage, such as apoptosis, inflammation, and glial scarring, also play essential roles in normal, healthy tissue repair. 8 If therapies that target these mechanisms are excessively strong, these processes may be unable to perform their normal, healthy roles in healing that could exacerbate damage to the SC. Thus, to be effective, therapies must be very precise in how they affect these biological processes.
Additionally, there is a large amount of variability between each tSCI. These injuries can occur anywhere along the SC, with the majority occurring in the cervical and upper thoracic region. The severity of the injury also occurs along a spectrum, from complete dissection of the SC to a minor contusion or compression. Also, tSCIs are not typically isolated injuries; many of them being a result of violence or vehicle accidents that result in complex injuries that can play a role in the progression of a tSCI. 3 All these factors contribute to injuries that are unique and highly specific to each patient, making it difficult to create a universal treatment.
Photobiomodulation
What is PBM
As defined by Jenkins et al. in 2024, “Photobiomodulation involves nonionizing radiation in the visible to near-infrared spectrum being absorbed by the body’s natural chromophores, triggering photophysical, and photochemical reactions at various biological levels without thermal damage.”9,10 Previously, PBM was referred to by many other terms, such as low-power laser therapy, low-intensity laser therapy, red-light therapy, soft laser, cold laser, and photobiostimulation, and low-level laser/light therapy—the most commonly used term. The term PBM was introduced to provide a clear and precise definition. 9
History of PBM
PBM was discovered in the 1960s when Professor Endre Mester was investigating the use of lasers as a way to ablate tumors. When he first attempted this in a rodent model, he unintentionally used a lower-power laser, and instead of observing ablated tumors in the treated rodents, he observed improved wound healing and hair growth. 11 Since this discovery, PBM has grown as a field and has been shown to have many beneficial effects on tissue when applied properly.12–14
How PBMT works
Although PBMT can be absorbed by multiple chromophores and influence diverse molecular pathways across tissues,12,13,15 its primary therapeutic effects are thought to arise from the absorption of red to near-infrared light by mitochondrial cytochrome c oxidase (CCO), which enhances electron transport, mitochondrial membrane potential, and Adenosine Triphosphate (ATP) synthesis.13,15–17 This restoration of cellular energy capacity improves the function of metabolically compromised neurons, glia, and immune cells within injured spinal tissue.12,15,18 PBMT also induces transient increases in reactive oxygen species (ROS) that serve as physiological redox signals, activating transcription factors such as Nuclear Factor-kappa B and Nuclear Respiratory Factor 2 to upregulate genes involved in antioxidant defense, repair, and survival. 13 Concurrent photodissociation of nitric oxide (NO) from CCO relieves respiratory inhibition and increases local perfusion. 15 By simultaneously replenishing cellular energy and normalizing redox and NO signaling, PBMT enables cells to communicate and coordinate appropriately, facilitating an immune response that supports tissue repair rather than exacerbating damage. Together, these effects create a metabolically and immunologically balanced environment that promotes neuroprotection, limits secondary injury, and advances functional recovery in patients with SCI.
PBMT applications and evolution
PBMT is currently being researched and implemented as a therapy in the fields of wound healing, neurodegeneration, selective nerve block, pain mitigation (e.g., in dentistry applications), and many others. 12 Wound healing and inflammation are among the primary therapeutic targets of PBMT, both of which it can modulate effectively. It has been shown to reduce the effects of oxidative stress and increase cell survival, proliferation, and growth when the correct amount of light is applied. 18 However, the efficacy of PBMT has been observed to follow a biphasic dose-response; while not enough irradiance fails to trigger a therapeutic effect, excessive levels can lead to inhibition or deleterious effect, necessitating careful dosing within a therapeutic window, described further in PBMT design and future direction section. 19 While the field of PBMT has largely promoted PBMT as a noninvasive form of therapy, it is becoming apparent that to achieve sufficient dosing, invasive PBMT may be the most effective application method in many situations. This can be seen with the progression of invasive PBMT for the treatment of Parkinson’s disease and chronic pain.20–23 Invasive approaches have become necessary, especially in situations where the therapeutic target is deep within tissue, due to the large amount of scattering and absorption that takes place within the skin and other intervening tissue, which decreases the accuracy of PBMT dosing and the amount of emitted light that reaches the target. Depending on the parameters of the laser being used and the qualities of the skin being irradiated, the attenuation of infrared light through 2 mm of human skin can result in 83–91% attenuation. 24 This significant attenuation increases the emitter power requirements and, in some cases, can make it difficult or impossible to get adequate and accurate dosing to the target from outside the body.
PBMT applied to tSCI
With PBMT showing strong evidence for improving wound healing, including in other neural injury applications,14,25 it was naturally considered a potential therapy for improving recovery following tSCI. The functional deficits that result from secondary injury after tSCI are largely a result of the aforementioned inflammatory response, energy deprivation, and blood flow dysregulation and seem to be particularly good targets for PBMT.12,15,26
PBMT for tSCI was first explored in 2002 as a cotherapy with transplanted embryonic SC nerve cells in a rat tSCI model. 27 In 2005, PBMT began to be investigated as an independent therapy in a rat hemisection tSCI model. 28 With the promising results demonstrated in these first studies, research continued in this field, and multiple studies were published over the next 12 years, providing additional supporting evidence of the effectiveness of PBMT for tSCI. PBMT for tSCI started to build momentum starting in 2017, with multiple studies being published every year since then. Transcutaneous PBMT was first attempted in humans in 2018, 29 and in 2020, the first implantable PBM study in a large animal (pig) model was performed with a focus on translational safety. 30 When considering the field as a whole, there have been 53 research studies published with most of the work conducted in rodent models (38 rat studies and 10 mouse studies), 2 in swine, and 3 in humans (see Fig. 1). The majority of the rodent studies were performed using transcutaneous PBMT, with 28 being transcutaneous and 10 using percutaneous PBMT (Table 1).
Pie charts depicting the number of PBMT for tSCI studies that
An overview of the rodent studies that have evaluated photobiomodulation therapy as a treatment for traumatic spinal cord injury. Each row is a rodent study that was found and met the search criteria described in Transparency, Rigor, and Reproducibility Statement. Each row provides an overview of each study’s model, parameters, and tests used in that study. For Histology, an X means the study evaluated that marker. For the Change in BBB/BMS column, shown are [highest mean injury control group score—highest mean PBMT group score] (top) and difference between injury control and PBMT group score (bottom)
iNOS, Inducible Nitric Oxide Synthase; LED, Light-Emitting Diode; TNF-α, Tumor Necrosis Factor alpha.
While the field of PBMT for tSCI is still relatively small, the evidence is building to support its promise to promote healing following injury. The effectiveness of PBMT for tSCI has been demonstrated in several dimensions, including improved function, structural tissue preservation, and favorable modulation of molecular signaling. Research has also examined the safety of PBMT, the sensitivity of light delivery parameters, potential use in combination therapies, and early steps toward clinical implementation. In this review, we will provide an overview of PBMT as a treatment for tSCI, addressing its effects on functional outcomes, structure, molecular outcomes, dosing, combination therapies, and translation.
PBMT for tSCI implementation
The method of delivering light to the SC after tSCI significantly impacts the accuracy, precision, and uniformity of the therapeutic dose. Given that PBMT operates within a therapeutic window, implementing delivery techniques that ensure predictable and repeatable dosing is important. Current research in rodent models primarily utilizes three hardware configurations: (1) fiber optic cables with open termination coupled to laser diodes, (2) fiber optics with diffuser tips coupled to laser diodes, and (3) Light-Emitting Diode (LED) arrays.
The most prevalent configuration involves a fiber optic cable with open termination coupled to a laser diode. These systems typically utilize wavelengths ranging from 630 to 905 nm, with reported continuous wave power between 0.01 W and 1 W, although most studies utilize a range of 0.1–0.25 W (see “PBM Dosing—Irradiance” for the expected irradiances achieved).39,42,45,46,65,77 This setup is implemented through several distinct methods. The simplest approach involves positioning the fiber optic tip with micromanipulators at a fixed distance above the skin directly over the injury site for a defined duration. Some researchers repeat this application in a surrounding grid pattern (e.g., 3 × 3).44,48 Alternatively, in more invasive applications, the SC is surgically exposed, and the fiber tip is positioned directly above the neural tissue. 57 The inherent simplicity of the single-diode fiber optic setup contributes to it being commonly chosen for application in rodent models.
A second configuration utilizes fiber optic variants with modified terminations designed specifically for invasive delivery. Rather than an open fiber termination, these designs incorporate diffusers to expand the irradiated spot size and facilitate a wider light distribution for percutaneous applications near the SC. One method involves implanting a cylindrical diffuser beneath the muscle layer directly above the injury site, which is then anchored with sutures to the vertebrae flanking the lesion.58,64,66 Another specialized approach utilizes a 200 µm fiber with a diffuser tip (Thor Labs CFDSB10) positioned near the SC via an implant guide (Thor Labs OGL-5) sutured into the skin above the injury. 65
The final configuration employs LED arrays to provide irradiation across the rodent’s entire body. In this setup, commercially available 670 nm LED arrays are affixed to transparent rodent cages, typically positioned approximately 7 mm from the dorsal surface of the animal.34,43 Activating the arrays provides approximately uniform irradiation across the full dorsal surface, which reduces delivery variability compared with single-fiber approaches. However, the diffuse nature of this light can make it difficult to achieve sufficiently high peak irradiance at the depth of the SC. It is also important to note that while the direct dose to the SC may be lower in this configuration, it may induce systemic “off-target” effects that contribute to the animal’s overall functional recovery.
Functional Outcomes
The loss of motor function following tSCI affects many patients and results in functional deficits that can dramatically impact their lives. Retaining and/or recovering even small margins of motor function after tSCI can significantly affect patients’ independence, opportunities, and quality of life. For instance, patients who would have needed a respirator may be able to breathe on their own or for those who would have had a diagnostically complete injury may now have an incomplete injury. PBMT has enabled major improvements in motor and sensory function across many rodent studies, demonstrating its potential to significantly improve tSCI patients’ lives after tSCI. This section outlines data on the effects of PBMT on motor, sensory, and urinary function after tSCI.
Motor recovery
The primary metric for evaluating hind limb motor function in rodent tSCI models is the Basso, Beattie, and Bresnahan (BBB) 78 scale for rats or the Basso mouse scale (BMS) 79 for mice. The BBB uses a 21-point scale, while the BMS uses a 9-point scale. A score of 0 on either scale indicates complete paralysis of the hind limbs, while a score of 21 (BBB) or 9 (BMS) signifies normal motor function.78,79 After a tSCI, the BBB/BMS score typically decreases to near zero immediately and then increases for roughly 4–6 weeks as spinal shock resolves and the SC heals. After 4–6 weeks, as the secondary injury subsides and the injury stabilizes, the BBB/BMS score will typically plateau and not improve or decline further.
Twenty-six PBMT-for-tSCI studies have evaluated motor function using the BBB scale, all of which saw significant BBB score improvement in the PBMT group when compared with the tSCI control. The effects of PBMT were rapid and durable with significant improvements typically seen within 1 week and persisting until the end of the experiments, which lasted from 1 to 9 weeks after tSCI. Since the injury and motor function were stable after 4 weeks, the significant improvements observed are expected to persist, even though studies were not conducted beyond 9 weeks. The difference in BBB scores between the PBMT treatment group and the tSCI control group was mean 5 (n = 26), median 4.3 (n = 26), standard deviation 2.96 (n = 26), and a range of 14.6, and these are depicted in Figure 2. When the percent difference was determined at 4 weeks after tSCI, all studies had >25% mean improvement (Fig. 2).35–38,39–42,32,44–52,57–60,62,63,66 These are meaningful improvements with a 5-point BBB score improvement potentially representing the difference between a rat that can only move its hind limb joints to a rat that is taking frequent weight-bearing steps, albeit uncoordinated and inconsistent. If these findings translate to humans, PBMT would go a long way to decrease functional deficits and improve the quality of life after tSCI.
Eight studies have used the BMS to evaluate the effect of PBMT on hind limb motor function in mouse models of tSCI. These studies found similar improvements with PBMT, with a mean ending BMS score increase of 1.75, median 1.45, standard deviation 1.03, and a range of 3. Significant improvements in BMS score were observed as early as 3 days after injury and persisted until the studies concluded, which was 28 days after injury.67,70–76 None of these studies ran for longer than 28 days, but, based on the rat data, it would be expected that the improvement from PBMT would persist. These improvements in BMS score further demonstrate the potential of PBMT to improve motor function following tSCI.
Other tests have been used to evaluate motor function, including the Louisville Swim Scale (LSS), beam walk test, rotarod, ladder test, combined behavioral score (CBS), and gait analysis. Two studies used the LSS to evaluate motor function (Fig. 3), and both studies showed improvements of at least 2.5 (65%) at 4 weeks, with significant increases in LSS seen as early as 1 week after injury.59,60 Two studies also showed significant improvements when motor function was evaluated with the beam walk test. At 8 weeks after injury, they found there was a significant decrease in beam-crossing time (35%) and an increase in mean beam walk scores of 75% and 255%, indicating that PBMT-treated animals had improved motor function and coordination, allowing them to cross the beam faster.42,46 One study evaluated motor function using a rotarod and found that there was a significant 19-sec increase in time to fall (50% improvement). 46 Two studies used the ladder crossing test and mixed results were reported. One study did not find any difference between control and PBMT groups when looking at cross times and foot falls. 28 The other study found a significant decrease of 55% in slips per total steps. 65 One study used the CBS and found that the PBMT group had a decrease of 18 (67%) when compared with the tSCI control. 36 There have been nine studies that have performed gait analysis to evaluate motor function after tSCI. While gait analysis has been performed through various methods, the general trend is that PBMT causes an improvement toward normal gait. More specifically, these studies found that there was a significant decrease in stride width (e.g., 28%, 2.4 cm) and increase in stride length (e.g., 68%, 5 cm).59,61,62,64 One study did not see a significant difference in stride length but did see an improvement in foot rotation with less rotation correlating with improved recovery. 31 Another study also saw a return to normal foot rotation as soon as 1 week after injury. 28 In summary, PBMT has been shown to improve motor function after tSCI with multiple evaluation methods supporting the efficacy of PBMT for tSCI.
Bar plots showing the difference in outcomes between the tSCI injury control group and best-performing PBMT group for
Sensory recovery
Sensory function is severely affected by tSCI and significantly affects patients’ independence and well-being. Evaluating sensory function in animal models often depends heavily on motor responses to variable sensory inputs, and this is particularly difficult in tSCI models because motor function is heavily impaired. Despite these difficulties, multiple studies found effective ways to evaluate the efficacy of PBMT on various aspects of sensory recovery, including mechanical allodynia, cold allodynia, thermal hyperalgesia, mechanical hyperalgesia, and cumulative sensitivity scores (CSSs).
Mechanical Allodynia
Mechanical allodynia refers to a condition in which normally nonpainful mechanical stimuli are perceived as painful. There have been nine studies that have evaluated the effect of PBMT on mechanical allodynia after tSCI, all of which used Von Frey testing. PBMT consistently led to a significant decrease in hypersensitivity, with three studies reporting improvements as early as 1 week after injury. These beneficial effects persisted for at least 4 weeks, when data collection concluded (Fig. 3).41,44,63 Two studies found that their tSCI model did not produce significant mechanical allodynia, which resulted in no significant differences between the injury control and therapy group.39,52 Two studies found that, while their tSCI model produced mechanical allodynia, they observed sporadic significant and nonsignificant improvements when comparing the therapy with the injury control.49,51 The lack of consistent improvement may be a result of the experimental design not producing a statistically significant measurable effect. Two other studies observed a decrease in hypersensitivity in the injury control group compared with healthy control, and the injury + PBMT groups showed an increase in hypersensitivity toward the values observed in the healthy control.37,48 This effect is opposite to what was seen in the other studies, and the reason for this difference is not clear. Overall, these studies provide evidence that PBMT has the potential to reduce mechanical allodynia after tSCI in some cases, but the inconsistency highlights the need for further research in this area.
Cold Allodynia
Cold allodynia is a condition in which innocuous cold stimuli are perceived as painful. There have been eight studies that have evaluated the effect of PBMT on cold allodynia after tSCI, all of which used the acetone test. Six of these studies reported a significant reduction in hypersensitivity to acetone in the PBMT groups compared with injury controls,41,44,49,51,63 while two studies found no significant difference at 5 and 8 weeks after injury.48,52 One group’s tSCI model did not produce an effective cold allodynia model, which also resulted in no significant difference. 39 These studies have shown that PBMT is able to decrease the effects of cold allodynia after tSCI, but there is some variability in results. More work needs to be done to better understand discrepancies between studies.
Thermal Hyperalgesia
Thermal hyperalgesia is a condition in which normally nonpainful thermal stimuli are perceived as painful. There have been eight studies that have evaluated the effect of PBMT on thermal hyperalgesia after a tSCI, all of which used either the Hargreaves test or the hotplate test. 80 Seven of these studies found that there was a significant increase in the paw withdrawal threshold in PBMT-treated groups when compared with SCI control groups (Fig. 3).41,42,44,48,49,51,63 The other group was able to establish the heat hyperalgesia model and saw a small improvement that was statistically significant in some cases, but the data were inconsistent and fluctuated between showing significant improvements and showing no improvement. 39 Overall, these studies show that PBMT is able to increase paw withdrawal thresholds to a noxious thermal stimulus and support the idea that PBMT may improve sensory state following tSCI.
Mechanical Hyperalgesia
Mechanical hyperalgesia is an increased sensation of pain from a mechanical stimulus, which is typically perceived as painful. Five studies have evaluated the effect of PBMT on mechanical hyperalgesia after tSCI, all of which have used the Analgesy-Meter. Four of these studies found an increase in the paw withdrawal threshold that began as early as 1 week after injury and lasted at least 5 weeks (Fig. 3), when data collection concluded.39,41,44,47 The other study was able to induce a state of mechanical hyperalgesia in their tSCI model but did not see any significant differences between PBMT and control groups. 48 This same group saw significance of PBMT in this test in their 2020 publication 44 with almost identical parameters, which suggests that some elements of the methods may have changed, resulting in a discrepancy. Overall, these studies indicate that PBMT may lead to a decrease in mechanical hyperalgesia after tSCI in a rat model.
Cumulative Sensitivity Score
The CSS is the sum of the measures of sensitivity to increased sensation at six points on the back of a rat. Three studies evaluated the effect of PBMT on the CSS after tSCI. All three studies saw a significant decrease in hypersensitivity in the PBMT groups when compared with the SCI control groups.34,43,63
Sensory Recovery Summary
Following tSCI, there can be severe impacts on sensory function resulting in chronic pain, loss of sensation, and hypersensitivity. Multiple studies have shown in rat models that PBMT after tSCI is able to decrease hyperalgesia and allodynias, indicating that PBMT has the ability to increase the amount of retained normal sensory function after tSCI and potentially decrease chronic pain. While not all of the studies saw improvements, most of the results that did not show improvement came from one study, which suggests that the study may have been an anomaly. 39 Variability in the magnitude of improvement was observed (Fig. 3), which may be the result of variability in PBMT application parameters, indicating that there is an opportunity to optimize PBMT application. Overall, the data from these studies suggest that PBMT can ameliorate some of the sensory sequelae associated with the injury.
Urinary control
Bladder control is commonly affected after a tSCI, resulting in increased risk of urinary tract infection and related complications, making it one of the top recovery priorities for tSCI patients.81–83 In rat models, after inducing a tSCI at the cervical and thoracic levels, the animal will lose its ability to volitionally void for days to weeks after injury, depending on the severity of injury. Until voluntary bladder function is restored, manual expression is performed through bladder massage. Two studies assessed PBMT for its effect on the time required to regain urinary control after tSCI. One study recorded how many days after the injury manual bladder expression was required. That study found that PBMT-treated rats required bladder massages for significantly fewer days after tSCI than injury controls, with longer applications of PBMT showing better improvements. 47 Another study evaluated the rats’ bladder sphincter independence at 2 and 21 days. They found, at 2 and 21 days, only 10% of injury-control animals regained independent bladder control compared with 100% of PBMT-treated animals. 32 These findings suggest that PBMT may enhance retention of function of complex systems such as urinary control following tSCI.
Structural
Tissue preservation
tSCIs cause large amounts of structural damage to the SC that lead to the death of cells in both the gray and white matter of the SC. The damage begins at the center of the injury and spreads outward, creating a lesion that can span 0.5–2 cm longitudinally in rats, depending on the injury’s severity. 42 As the tSCI progresses, the activated astrocytes attempt to contain the damage and encapsulate the injury. As the tissue degrades within the encapsulation, a cavity is generated in the center of the injured portion of the SC. The size of this cavity and amount of preserved healthy gray and white matter surrounding the cavity are commonly used as a histological metric. The cavity size is used to determine the severity of injury, and more preserved tissue correlates with improved functional outcomes.78,84
Five studies have evaluated the effect of PBMT on the size of the injury site and the amount of preserved tissue. One study applied three different daily durations of PBMT and found that the shorter duration (140 sec) yielded a nonsignificant trend in the direction of reduced injury volume. The longer durations (212 and 282 sec) resulted in injury volumes that were significantly smaller (45%) than those of the control group. This study shows that PBMT is able to decrease the injury volume. It also highlights the importance of dosing, showing that longer durations can have a greater effect, with marginal gains observed once a sufficient duration is reached. 37 Another paper also reported that PBMT decreased injury/cavity size by over 50% when compared with controls. 57 This second group applied light at the surface of the SC, enabling accurate spatial dosing of PBMT. A third study evaluated the percentage of the SC that the cavity occupied and, while they did see a trend toward a decrease in cavity size, the data were not significant. 35 This study calculated the cavity size as a percentage of the total SC area, and this is a difficult measurement to control because the presence of the cavity can result in deformation during the histological processing of the tissue, altering the shape and size of the cavity. Depending on the variability in where the rostrocaudal center of the injury is determined to be and subsequent sampling intervals surrounding that point, additional inconsistencies can occur. This may be one reason these data were not as consistently statistically significant. The fourth study evaluated the area of retained white and gray matter at and surrounding (±7 mm) the injury center after tSCI, and the data showed trends toward improved gray and white matter area at ±2 mm from the injury’s center, but these were not statistically significant. However, a significant increase in both gray and white matter area was found between 3 and 7 mm rostrocaudally on either side of the injury’s center. These data suggest that while there may not be a significant improvement in spared tissue at the longitudinal center of the injury, PBMT may be able to double the amount of spared tissue in the surrounding area. 42 Another study measured injury volume at 4 and 8 weeks after injury. At 4 weeks, injury volume did not differ between control and PBMT groups. By 8 weeks, injury volume had increased in controls but remained stable with PBMT, resulting in a significantly smaller injury volume in the PBMT group. 52 This suggests that PBMT is able to decrease tissue loss at later stages of the injury progression. In summary, this group of studies shows that PBMT is able to increase the amount of spared tissue and decrease the cavity size following tSCI.
Axon regrowth
After tSCI, the number of axons that extend rostrocaudally across the injury site is significantly reduced. This limits the transmission of information across the lesion and contributes to the functional deficits observed after injury. There have been four studies that have shown that PBMT is able to increase the amount of axon regeneration after tSCI.27,28,31,65 The first indication of PBMT promoting axon regrowth was seen in the initial tSCI study. This research observed increased axon sprouting in PBMT-treated rats that had been implanted with embryonic nerve cells. 27 Axon regrowth was more clearly demonstrated by Byrnes et al., who used a dorsal hemisection tSCI model and found that PBMT led to an over 60% increase in axons that crossed the lesion site. 28 The same group published another study that showed similar results in both hemisection and contusion tSCI models, with significant increases in both the number and length of axons surrounding the injury. 31 Another group also saw a significant increase in total axon counts between 2 and 6 mm caudal to the injury when using a contusion model. 65 Improving axon regrowth is crucial because it could increase the number of axonal connections across the injury site. This would allow more neural information to cross the injury, thereby improving natural motor and sensory function after tSCI.
Molecular Outcomes
Inflammatory signaling
After a tSCI, extreme cellular energy deprivation disrupts communication among neurons, glia, and infiltrating immune cells. This breakdown initiates a complex and overactive immune response that fails to resolve, driving inflammation and secondary tissue injury. In normal wound healing, inflammation supports tissue repair and resolution; in contrast, after tSCI, the same process becomes self-perpetuating, with disrupted signaling amplifying further dysregulation in a feed-forward manner.5,85
ATP
ATP depletion is one of the earliest and most critical consequences of tSCI, as mitochondrial dysfunction severely limits the energy available for maintaining ionic gradients, signaling, and cellular homeostasis. 85 Three studies have shown marked decreases in ATP concentration at the injury site in rodent models.57,61,64 In two of these, PBMT treatment significantly increased ATP by 76% (51 nmol/mg protein) and 124% (74 nmol/mg protein) relative to injury controls.61,64 One study reported a similar upward trend, though not statistically significant, with PBMT-treated animals exhibiting higher ATP than injury controls. 57 Moreover, PBMT combined with mitochondrial transplantation produced even greater ATP restoration than either therapy alone. 64 These findings are consistent with PBMT’s known mechanism of stimulating mitochondrial CCO activity, enhancing ATP generation, and re-establishing the energy balance necessary for normal cellular signaling.
Immune cell activation
Energy depletion, cellular damage, and disrupted signaling cause resident microglia and infiltrating macrophages to shift from their resting or reparative M2 phenotype toward a sustained pro-inflammatory M1 state. While M1 and M2 macrophages both play roles in wound healing, prolonged M1 dominance exacerbates tissue damage and scarring. Multiple studies have demonstrated that PBMT reverses this imbalance: The proportion of M1 cells decreases significantly, while M2 populations increase, indicating a shift toward a more neuroprotective and regenerative environment significantly.34,58,67,74 Although the precise molecular mechanisms remain unclear, these results suggest that PBMT helps restore metabolic and signaling conditions that favor repair rather than degeneration.34,58,60,67,74
Inflammatory mediators
A downstream hallmark of the secondary injury dysregulation is the altered expression of key inflammatory mediators, including interleukin (IL)-6, IL-10, IL-1β, Inducible Nitric Oxide Synthase (iNOS), and Tumor Necrosis Factor alpha (TNF-α). Many studies have shown that PBMT modulates their expression extensively (Table 1).
IL-6
IL-6 can function as both a pro- and anti-inflammatory cytokine depending on many variables and is known to increase its expression after tSCI. Nine studies have investigated the effect of PBMT on IL-6 expression in and around the injury site. These studies found that PBMT significantly decreases the expression of IL-6 by 57–99% when compared with injury controls.28,39,41,44,63,70,71,74,76 These data indicate that PBMT results in less IL-6 expression after tSCI.
IL-10
IL-10 is typically considered an anti-inflammatory cytokine but can play a pro-inflammatory role in some contexts. Three studies investigated the effect of PBMT on IL-10 expression after tSCI. Two of the studies found significant increases of 67% 46 and 20% 63 in the expression of IL-10 when compared with SCI controls. One study found a nonsignificant decrease of 76% in IL-10 expression when compared with injury controls. 48 One possible explanation for this discrepancy in effects could be the wavelengths used to generate the PBM effect. Both studies that saw increases in IL-10 used 810 nm light, while the study that saw a decrease used 660 nm light. More work needs to be done to better understand the effect of PBMT and wavelength on IL-10 expression following tSCI.
IL-1β
IL-1β is commonly considered a pro-inflammatory cytokine, which is involved in immune cell recruitment to an injury area. There have been five studies that have investigated the effect of PBMT on IL-1β expression after tSCI. Four of these studies found that there was a significant decrease in the expression of IL-1β,46,63,74,76 while one study did not see any significant changes in IL-1β expression after PBMT when compared with tSCI controls. 43 The Hu et al. 2020 study used 670 nm for PBMT, 43 while the others used 810 nm, indicating that the change in IL-1β expression may depend on wavelength, but more work needs to be done to better understand these discrepancies. Overall, these studies suggest that PBMT at 810 nm can suppress the expression of IL-1β after tSCI.
iNOS
iNOS is an enzyme that acts as an inflammatory marker and is involved in the production of NO, which can be either neuroprotective at normal concentrations or neurotoxic at higher concentrations. Eight studies have investigated the effect of PBMT on the concentration of iNOS after tSCI. These studies found that PBMT can significantly decrease the concentration of iNOS within the injured tissue after tSCI, which may infer a decrease in NO production. 86 While these groups showed significant suppression, they were collected at different time points (ranging from 6 h to 28 days after tSCI).28,36,58,60,67,70,71,74 Thus, the data all suggest that PBMT reduces iNOS levels, but the exact timing of this effect after tSCI remains unclear.
TNF-ɑ
TNF-ɑ is a commonly measured pro-inflammatory marker but, in specific situations, can perform anti-inflammatory functions. There have been five studies that have investigated the effect of PBMT on TNF-ɑ expression and concentration after tSCI. These studies all found that PBMT significantly decreased the concentration and expression of TNF-ɑ in injured tissue after tSCI compared with the untreated control groups.36,46,63,74,76
Integrative summary
Together, these findings illustrate a coherent cascade: ATP loss triggers disrupted communication, which skews immune cell activation and drives aberrant cytokine release. As this dysregulation feeds forward, inflammation becomes self-sustaining and destructive. PBMT interrupts this cycle by restoring mitochondrial energy production, normalizing signaling between cells, shifting macrophage polarization toward repair, and rebalancing inflammatory mediator expression. Across multiple studies, this multifaceted modulation corresponds with improved motor, sensory, and structural outcomes, underscoring PBMT’s neuroprotective potential after tSCI.
PBMT Dosing
The effectiveness of PBMT depends on multiple interrelated parameters, such as wavelength, irradiance, initiation time, application duration, total therapy duration, beam size, beam profile, and other optical or biological factors. The studies reported here have used very different parameters and seen beneficial effects, which suggests that the phenomenon is robust. Despite the importance of these parameters, only a limited number of studies have examined their impact on PBMT efficacy, leaving dosing strategies largely unoptimized and without consensus. To better understand the dosing of PBMT for tSCI, this section will examine many of the most important parameters and summarize what has been previously explored.
Wavelength
The wavelength used in PBMT is a critical parameter that dictates several key aspects of its biological effect. The wavelength determines which chromophores absorb light and modulates the interplay between scattering and absorption, ultimately governing the depth and distribution of light within tissue. Optimizing this parameter is crucial for effective treatment. While studies have used several different wavelengths (Fig. 1C), the most common wavelength is 808–810 nm, which has been used in 29 studies. This is most likely because CCO is known to absorb 808–810 nm. 87 This is followed by 660–670 nm, which has been used in 12 studies and is also well known to be absorbed by CCO. 88 Further work needs to be done to compare wavelengths within the same studies to better understand the optimal wavelength or set of wavelengths.
Irradiance
It is difficult to compare irradiance at the SC surface (let alone the irradiance inside the SC) across studies because researchers typically do not report the irradiance at the level of the SC itself. In studies using transcutaneous PBMT, irradiance is primarily reported as mW/cm2 at the emitter or at the surface of the skin, with only a few studies estimating it at the SC. These studies reported irradiances at the emitter between 10045,47 and 1070 mW/cm2, 52 at the skin to be between 35.4 43 and 819 mW/cm2, 35 and at the SC surface to be ∼3.2 43 and 24.4 mW/cm2. 55 With the information provided in these studies, it is difficult to confidently estimate the irradiance at the SC. In studies that applied PBMT at the surface of the SC invasively (e.g., surgically or percutaneously), reported irradiances at the SC were 8 57 and 24.42 mW/cm2, 65 and one group did multiple studies and reported delivering 500 mW/cm2 from a radial emitter at 150mW.58–64,66 The spot size of PBMT varied greatly across studies, including 0.3 58 and 3.14 cm2, 57 reported in percutaneous studies, 0.197 47 and 0.3 cm2, 56 (skin) reported for transcutaneous studies, and even full-body light application. 43 The data suggest that a wide range of irradiances can be used for effective PBMT. Still, greater improvements were seen at some irradiances compared with others, and optimization should be pursued.
Initiation time
Identifying when PBMT must begin after a tSCI to achieve therapeutic benefit is a key consideration in clinical application. tSCI is unpredictable, which can result in it taking hours to days before patients can reach a trauma facility and be stable enough for therapeutic interventions to be implemented. This means that we need to understand the sensitivity of the effectiveness of PBMT to the initiation time of the therapy. Most existing studies applied light within minutes of causing the tSCI in their rodent models. There is one study that evaluated the effect of initiation time with start times of 6 and 48 h after injury. This study found that applying light at both 6 and 48 h after injury resulted in significant improvement of function, with an 11-point improvement in BBB score. 32 While this preliminary evidence suggests that delayed PBMT can yield significant benefits, further studies are needed to better define the therapeutic window.
Treatment session duration
Knowing how long the light needs to be applied for during a therapy session is important for optimizing and translating PBMT as a therapy for tSCI. How PBMT will be clinically implemented depends on whether PBMT needs to be applied for a few minutes, longer durations, or continuously. Existing studies used different durations of light application, from 8 sec to 60 min, all seeing significant improvements in recovery, but it is difficult to compare the outcomes directly due to the many other differences in parameters and injury model. There have been three studies that started to explore this issue specifically by changing the duration of each light application while holding all other parameters constant. One study applied PBMT with four different treatment session durations, including 27, 45, 90, and 117 sec. 47 They found that 27 sec of PBMT resulted in no change in BBB scores, fibroblast numbers, GPX-activity, and urinary control compared with control animals. The 45-, 90-, and 117-sec duration all yielded significantly improved outcomes over the injury control and the 27-sec duration PBMT groups, but there were no significant differences between the 45-, 90-, and 117-sec groups. 47 Another study applied two 90- and 117-sec session durations. 49 Both durations showed significant improvements in BBB score, cold allodynia, thermal hyperalgesia, and fibroblast counts, with no significant differences between different durations. The only significant differences seen between 90- and 117-sec duration groups were an increase in DNA methyltransferase 3 alpha and glutamic acid decarboxylase 65-kilodalton (GAD65) expression in the 90-sec group compared with 117-sec group. 49 A different study compared durations of 141, 212, and 282 sec. 37 They found that only the 282-sec groups resulted in significant improvements in BBB score, mechanical allodynia, and macrophage/microglia counts. Both the 212- and 282-sec groups resulted in a significant decrease in injury volume. 37 While not always statistically significant, across these three studies, longer durations of PBMT trended toward better outcomes than shorter durations. While more work needs to be done to better characterize the effect of treatment session duration, it does appear that longer durations (within the studied range—up to 282 seconds) provided more consistent and better outcomes.
Treatment regimen duration
It is important to understand the optimal duration and frequency of PBMT application to achieve beneficial effects. For instance, should it be applied one time at 24–48 h after injury, once a day for 2 weeks after injury, or continuously for 1 week after injury? Understanding this parameter will inform how PBMT should be translated into the clinical setting and provide insight into PBMT device design. As seen in Table 1, most existing studies (n = 22) have applied PBMT once per day for 14 days, starting minutes or hours after injury. There are three studies that have compared applying PBMT once a day for a different number of days. Two studies compared applying PBMT for 14 and 28 days following tSCI.47,48 Neither study found a significant difference in motor or sensory outcomes between 14 and 28 days of PBMT. The only significant changes between 14 and 28 days of PBMT were a decrease in fibroblasts at the injury site, an increase in GAD65 expression, and a decrease in P2X3 at 28 days.47,48 Another study compared applying PBMT for 7 or 14 days after tSCI. 39 In this study, the only significant differences between 1 and 2 weeks of PBMT were a significant decrease in fibroblasts and demyelination. While not statistically significant, they did observe trends in which 2 weeks of PBMT appeared to have better motor and sensory recovery than 1 week. While there is currently no established optimal duration or frequency, the current data suggest there is a broad range of durations and frequencies that can be effective (from 4 to 28 days after injury). There does seem to be a minimum duration to be effective, and longer durations do not always provide better functional outcomes, but there does not seem to be a drop-off in efficacy with longer durations. Future research should focus on understanding the relationship between treatment duration and the amount of therapeutic benefit, to enable the best clinical results. Many of these studies do not run long enough for complete maturation of the injury, so it would be important to determine the effect of applying PBMT during the later stages of the injury. Finally, species-specific differences in healing time should be considered.
Combination Therapies
While PBMT has been shown to be effective on its own, several studies have combined it with other approaches to achieve an additional improvement. The therapies studied in conjunction with PBMT are human adipose-derived stem cell (hADSC) administration, 41 human umbilical cord mesenchymal stem cell (hUCMSC) transplantation, 45 embryonic SC nerve cell transplantation, 27 chondroitinase ABC (chABC) injection,35,44 meloxicam, 40 mitochondrial transplantation, 64 and cerium oxide nanoparticle (CeONP)-loaded scaffold. 51
Human adipose-derived stem cells
Cell therapies are being actively investigated for the treatment of neural injuries and diseases, with hADSCs emerging as a promising option due to their ease of accessibility and multipotent potential. 68 In a single study, PBMT was applied with hADSCs, which were implanted into the dorsal horn of the SC at the injury site (T13-L1) 1 week after tSCI. This combination therapy led to a significant improvement in both motor and sensory recovery compared with the injury control group. 41 When compared with either PBMT alone or hADSC implantation alone, there was only a minor, nonsignificant improvement in motor and sensory recovery. Additionally, there was a significant decrease in cavity size and an increase in the number of spared axons in the combination therapy group when compared with the injury control and individual PBMT or hADSCs therapy groups. 41
Human umbilical mesenchymal stem cells
Another cell therapy is the transplantation of hUCMSCs, which are used due to their low immunogenicity and rapid proliferation. 89 Transplantation of hUCMSCs and accompanying PBMT after tSCI resulted in no significant differences in motor recovery compared with PBMT or hUCMSC transplantation alone, but all three experimental groups saw a significant improvement compared with tSCI controls. 45 There was also an increase in nerve regeneration and a decrease in the inflammatory response in the experimental arms compared with the tSCI control group. 45
Embryonic SC nerve cells
The first study to evaluate PBMT for tSCI implemented PBMT as a combination therapy that included transplanting embryonic SC nerve cells and applying light. Embryonic SC cells were chosen because it was previously shown that they can increase axon growth. 90 For this study, embryonic nerve cells were attached to gelatinous, biodegradable microcarriers and implanted in the transected area of the SC, and then PBMT was applied once a day for 14 days after injury. In the study, the authors found that the combination of cell therapy and PBMT led to greater improvements in motor recovery, SC conduction, and axonal sprouting than the cell therapy alone. 27 These data suggest that PBMT improves the effectiveness of transplanted embryonic SC cells.
Chondroitinase ABC
There were two studies that evaluated the effect of co-administration of chABC and light. In these studies, PBMT was applied once a day starting immediately after the injury, and chABC was injected intraspinally at the level of the injury on day 7 after injury. One study found that there was significant improvement in sensory and motor recovery in the PBMT group, chABC group, and combination group when compared with injury controls. There were no significant differences found between each of the therapy groups. 44 This suggests that while both individual therapies were effective by themselves, the combination therapy did not further improve recovery after tSCI. 44 The second study investigated the effect of the combination therapy on motor function, cavity size, and protein expression. 35 This study found that, when compared with the control group, there was a significant increase in motor function, a decrease in cavity size, and a decrease in symptomatic protein expression after a tSCI. Additionally, they found that there was a significant improvement in these metrics when compared with independent therapies. 35 Overall, these two studies showed that chABC delivered in conjunction with light can have beneficial improvements in motor recovery and tissue preservation, but the benefit of the combination therapy compared with the individual therapies on pain is nonconclusive.
Meloxicam
Meloxicam was also investigated as a combination therapy with PBMT to treat tSCI. 40 Meloxicam is a nonsteroidal anti-inflammatory drug that has been shown to decrease inflammation, has neuroprotective effects, and promotes axon regeneration. 91 Transcutaneous PBMT was applied once per day for the first week after injury and every other day for the second week, with 1 mg/kg meloxicam being injected subcutaneously once a day for the first week and 0.5 mg/kg being injected once a day for the second week. There was a significant improvement in BBB scores in the meloxicam, PBMT, and PBMT + meloxicam groups when compared with controls. There was no significant difference between the combination therapy and the individual therapy groups. Additionally, there were no significant differences in the amount of gray and white matter preserved between any of the therapy groups and the controls. 40 These data suggest that PBMT and meloxicam can individually improve motor recovery after tSCI, but no further improvement was obtained by combining the therapies. One possible explanation for the similar results could be that meloxicam and PBMT both have the ability to act as cyclooxygenase 2 inhibitors.92,93 This results in potential redundancy in the mechanism that is being utilized, resulting in no additional effect when the therapies are combined.
Mitochondrial transplant
Transplanting mitochondria into the injury site after tSCI is a treatment that has shown promise in improving the motor response and increasing the amount of tissue preservation. 94 A single study investigated the use of PBMT combined with mitochondrial injection for tSCI in a rat model. Around 10 μL of mitochondria was injected, and PBMT was applied once a day for 14 days following injury. This study found that the individual therapies and the combined therapy all showed significant improvements in motor recovery, tissue preservation, and a decrease in inflammation when compared with the control group. Additionally, the results showed that the combined therapy led to significantly greater improvement than either of the therapies individually, consistent with the idea that the effect of light on mitochondria is a notable part of the PBMT mechanism. 64
CeONP-loaded scaffold
Biomaterial-based therapies for treating tSCI, such as scaffolds, have been explored as regenerative therapies that help create beneficial microenvironments that promote neural regeneration. 95 One study investigated the effect of using CeONPs in combination with PBMT to treat tSCI. 51 To achieve this, they performed a spinal hemisection in a rat model and promptly implanted CeONPs at the lesion site. PBMT was then applied daily for 30 min per day for 28 days after injury. This study found that PBMT and the CeONPs, alone and in combination, resulted in significant improvements over injury control in both motor and sensory tests. The only significant difference in a result found between an individual versus combined therapy was a significant increase in the Con 43 expression resulting from CeONPs compared with the combination therapy. While not significant, the combination therapy did appear to show a trend toward improved recovery. Overall, these results suggest that the combination of PBMT and CeONPs as a therapy for tSCI does not have significant improvements over PBMT alone. 51
Translation
While transcutaneous PBMT has been very effective at improving motor recovery in rodent studies, a transcutaneous approach is not expected to be effective in humans. This is due to the differences in spatial scale between the species. The tissue between the emitter and SC in rodents is typically between 0.5 and 1 cm. In humans, this distance varies between patients and for different vertebral levels and can range from 3.5 to 9.5 cm.96–98 This 3.5- to 19-fold increase in the thickness of intervening tissue dramatically increases the amount of absorption and scattering that occurs, resulting in a much greater attenuation of light before reaching the target tissue. Further, the skin in rodents is thinner and, in many species, is an albino skin that scatters much less light than the skin of most patients. Thus, traditional transcutaneous PBMT methods are not likely to deliver adequate light to the target tissue or to be able to control the dose of light. These challenges make translation of transcutaneous PBMT extremely difficult, and multiple groups are now moving to an invasive light delivery system that is positioned much closer to the SC.
Clinical studies
PBMT has been evaluated clinically in two studies: one primarily assessed the safety of an implantable percutaneous system in humans along with motor and sensory function, 99 while the other investigated transcutaneous PBMT during the later stages of tSCI. 29 The clinical safety study on the implantable device found minimal differences between the PBMT and control groups in safety measures such as infection, inflammation, light sensitivity markers, vital signs, and motor and sensory scores. The only significant changes seen in the PBMT group were a slight increase in infection markers (most likely as a result of the stress from the PBMT implant procedure) and slight improvements in American Spinal Injury Association motor and sensory scores when compared with pre-PBMT scores. This study supports the conclusion that PBMT is a safe and potentially therapeutic approach in humans. 99
In the second study, the investigators applied light transcutaneously in patients 6 months after tSCI. This study reported no significant side effects or therapeutic improvements. 29 This result might be expected for two reasons: first, the injuries had already stabilized, and it is not clear that PBMT would result in a benefit after the secondary injury has resolved. Second, the aforementioned attenuation of light that occurs in transcutaneous light delivery would have been expected to limit the therapy’s effectiveness. These studies demonstrate that more work needs to be done in translating PBMT into the clinic to achieve the significant improvements that have been seen in rodent models.
Safety of invasive and implantable PBMT
For invasive or implantable PBMT systems to advance toward clinical translation, their safety must first be rigorously established. Across all available data, including 48 rodent studies and multiple porcine and early human evaluations, there is general consensus that PBMT, when applied at therapeutic power levels, does not produce significant tissue or neurological damage.30,99,100 No adverse effects have been reported in any of the rodent studies to date, further supporting the safety of PBMT within the therapeutic range.
In a healthy piglet model, continuous 810 nm light was delivered using an implantable PBMT system at emitter powers of 200, 300, 500, and 1000 mW. 30 These levels were chosen to span and exceed the estimated therapeutic range derived from prior rodent work. No adverse effects on neurological function or gait were observed at any power tested. Analysis of inflammatory mediators and damage markers (IL-6, Caspase-3, TNF-α, and HSP70) revealed no increased expression at expected therapeutic levels (200 and 300 mW), minimal elevation at 500 mW, and a significant increase only at 1000 mW. Histological assessment showed no structural abnormalities at any power level. Thermal monitoring indicated that SC temperature rose by <3°C at 200 and 300 mW with no signs of discomfort, by <4°C at 500 mW with no discomfort, and by more than 8°C at 1000 mW, which was associated with noticeable distress. 30
A follow-up study from the same group further evaluated PBMT safety in a similar porcine model. 100 In this study, light was applied at 300 mW (60 mW/cm2) for 1 h daily over 14 days. After treatment, a 3 cm segment of the SC corresponding to the illuminated region was excised for analysis. Hematoxylin and eosin and Bielschowsky staining revealed no evidence of structural damage, scarring, or necrosis. Immunofluorescence and immunohistochemistry showed no differences in immune cell infiltration or astrocyte density between PBMT-treated and control tissue. 100
An observational human safety study has also been performed, providing further evidence that PBMT could be safe for human use. 99 This study applied implantable 810 nm light at 300 mW (23 mW/cm2 calculated, 20 mW/cm2 measured at the SC surface) for 30 min/day for 7 days starting 1 day after the injury and decompression surgery with no control groups. For each patient, the vitals, infection indicators, and neurological stability indicators were measured and recorded for up to 90 days after PBMT initiation. There were no significant changes in vital signs seen during or after PBMT for the applications on days 1, 3, 5, and 7. When evaluating infection indicators, there were significant increases in white blood cell, neutrophil, and high-sensitivity C-reactive protein counts after 3 days of PBMT compared with pre-PBMT levels. However, these levels returned to baseline after 7 days of treatment. While these changes are correlated with PBMT, the lack of control groups and other confounding factors, such as variability in injury and procedure, make it difficult to confidently determine causation. All other infection indicators showed no significant differences. 99
Together, these findings demonstrate that PBMT delivered at or below estimated therapeutic levels is well tolerated, producing neither thermal injury nor histological or behavioral deficits. Power levels above estimated therapeutic levels begin to induce mild thermal elevation and cellular stress responses, defining an important upper safety boundary. These data provide strong preclinical evidence that implantable PBMT systems can be applied safely within the therapeutic range, supporting their continued development for clinical translation.
Discussion
tSCI is a severe injury that can result in significant disabilities and health complications, dramatically affecting the lives of patients and their families. The mechanisms of injury and the healing processes following tSCI are highly complex, often resulting in permanent disabilities of varying types (e.g., motor, sensory, autonomic) and severities. PBMT presents a potential therapy to reduce the amount of disability after tSCI by promoting better healing to retain more natural function. Supporting data have primarily been demonstrated in small animal models, which have shown improvement in motor and sensory function recovery, along with increased tissue preservation and regeneration. Additionally, it has been shown that PBMT results in biochemical and cellular changes in the immune response that are consistent with a reduced secondary injury. While the mechanism through which PBMT causes all of these effects is not completely understood, current research provides insight into how PBMT could be functioning.
A well-established mechanism for PBMT is the effect light at specific wavelengths can have on ATP production within mitochondria. In PBM, red–near-infrared light is absorbed by CCO and other chromophores. When NO is bound to CCO, photons can photodissociate it, relieving inhibition and restoring oxygen reduction so electron transport and ATP production rise. Even when NO is not associated with CCO, light can still increase ATP by directly exciting CCO’s metal centers to boost turnover and mitochondrial membrane potential (ΔΨm), or via alternative chromophores and ion channels (e.g., transient receptor potential channels) that trigger Ca2+-dependent signaling to upregulate respiration. The resulting shifts in ΔΨm, ROS/NO signaling, and gene expression are wavelength- and dose-dependent and typically biphasic.13,14 Through applying PBMT with specific parameters, this mechanism could be the reason PBMT improves function in tSCI.
Consistent with the idea that this mechanism may play a role in PBMT for tSCI, multiple studies have shown that there is a decrease in ATP at the injury site following tSCI and that PBMT is able to increase the intracellular concentration of ATP.57,64 If we assume that this hypothesis (PBMT facilitates cellular respiration and increases ATP production) is a critical part of the PBMT for tSCI mechanism, we start to form a picture of how PBMT might be having such a profound effect on recovery. In particular, it is well known that ATP plays a vital role in most cellular functions, including protein synthesis, intra- and extracellular signaling, inflammation, and programmed cell death, all of which are necessary for optimal wound healing. Without sufficient ATP, there is excessive apoptosis, necrosis, and dysregulated inflammation, resulting in additional damage.101,102 After a tSCI, there is a decrease in ATP concentration at the injury site along with inflammatory dysregulation. Intra- and extracellular communication is severely affected by the injury that leads to an improperly regulated signaling at the injury site. This dysfunctional communication limits the body’s ability to carry out normal healthy function, leading to additional damage.5,6 PBMT seems to improve this state by increasing intracellular ATP levels, which in turn help correct and maintain healthy communication. In this way, PBMT appears to normalize the body’s reaction to the injury, enabling the body to carry out functions such as inflammation and apoptosis in a healthier way, leading to better healing of the injury.
Future directions
PBMT has shown great potential as an effective treatment for tSCI. While it has led to excellent improvements in functional recovery in rodent models, as previously mentioned, there are still fundamental challenges to translating it for use in humans. To overcome these challenges, multiple steps will need to be taken, including determination of the best approach, demonstrating effectiveness in large animal models and humans, dose optimization, and device design.
The delivery of PBMT for tSCI in rodent models is currently being approached using both transcutaneous and percutaneous methods. While transcutaneous PBMT is effective in rodent models, this is not a translatable approach due to substantially more intervening tissue between the skin and the SC and the corresponding attenuation of light. Skin scatters and absorbs light exceptionally well, with transmission of light through 2 mm of skin resulting in up to 90% attenuation.24,103 Muscle and other intervening tissues can result in an additional 30–40% attenuation of light. 104 This increase in intervening tissue not only limits the amount of light that can reach the target but also makes accurate dosing impractical due to variability between patients. Although technically more challenging, placing light emitters in the epidural space (such that the dura and cerebrospinal fluid are the only intervening tissues) would limit attenuation and enable accurate dosing. This approach, which we call EpiPBMT, is being explored by a few groups and includes work in rodent models and safety evaluations in both pigs and humans.30,58,65,99
The next step is to demonstrate the effectiveness of EpiPBMT in large animal models or in humans. Although there is clear efficacy data supporting PBMT for tSCI in rodent models, data in higher-order species are lacking and needed.
Clinical translation will also be heavily reliant on a deep understanding of the required dosing parameters for PBMT to treat tSCI. Currently, there has been limited work done on dosing, with few studies exploring the effects of irradiance, timing, and duration thresholds, along with the impact of wavelength, spot size, and other parameters. Understanding and optimizing these PBMT parameters will inform the translational approach and ensure that PBMT has the best chance of achieving significant effects when effectiveness is evaluated in humans.
A major step toward translation will be the development of a clinical-grade device for PBMT application. There are many considerations when developing such a device. A device that emits light in or near the epidural space could be either fully implantable or a percutaneous system that applies the light only during a relevant part of the healing period. Based on the research currently available, applying light during the weeks following tSCI seems vital, but there does not seem to be any benefit in applying light chronically following this yet to be defined critical period. A percutaneous system could potentially be designed to be removed readily without additional surgery, while fully implantable systems would require an invasive surgical procedure to remove the entire system or would remain implanted even when no longer used or needed. Further, fully implantable systems are very expensive, and this would likely limit accessibility of EpiPBMT.
These considerations favor the development of a percutaneous EpiPBMT system, such as the system depicted in Figure 4, which can deliver light accurately to the SC during the critical portion of the recovery period, and then be removed. We envision placement of the system during the standard-of-care decompression and stabilization surgery, such that no additional surgery is required. One group has sutured a percutaneous system to existing spine stabilization hardware, 99 and we imagine that specialized hardware for this purpose could be developed. The light source could be part of a fluid-resistant module inside the body or could be outside the body and deliver light through a percutaneous waveguide. Once therapy is completed, the percutaneous element(s) could be removed by pulling it (them) out of the body. Other concepts for an EpiPBMT system could be proposed.
Potential future design for an implantable EpiPBM system to treat tSCI.
The current data suggest that EpiPBMT is likely safe. Development of a clinical-grade EpiPBMT system would enable large animal evaluations of safety and efficacy, followed by clinical evaluations of the same. These have been initiated by one group,30,99 and we anticipate that others may follow, suggesting that translation of EpiPBMT may be on the horizon.
Conclusion
tSCI severely impacts patients and their families’ lives. Improvements in the recovery of motor and sensory function for these patients can mean the difference between needing a ventilator versus breathing on their own, or needing a full-time caregiver versus living independently. PBMT is a promising candidate for reducing the amount of functional loss after tSCI. Notable improvements in motor and sensory function have been shown consistently in numerous rodent studies by different laboratories, and if these translate to humans, they would dramatically improve the lives of tSCI patients. PBMT seems to operate by facilitating cellular respiration and ATP production and theoretically could readily be used in combination with many other therapeutic strategies. Several combination therapies have been successfully evaluated in rodents. Additionally, PBMT has been shown to be safe, with no recorded negative side effects associated with PBMT reported in rodent, pig, or human studies. While there are still steps that need to be taken before mainstream clinical implementation (e.g., development of a human light delivery system, better understanding of dosing, and rigorous clinical demonstration of safety and effectiveness in humans), the abundance of small animal work and the early large animal and human work is extremely encouraging.
Transparency, Rigor, and Reproducibility Statement
Studies were identified through searching the PubMed, Google Scholar, and Scopus databases. Search terms included photobiomodulation, photobiomodulation therapy, low-level laser therapy, low-intensity laser therapy, spinal cord, SCI, traumatic SCI, and acute SCI. Studies that did not include in vivo or in vitro work were excluded. Additionally, this review only looks at work that was published before August 2025. Not all values were explicitly provided in the papers, so some data points were estimated based on the provided figures. Due to variations in parameters and experimental setups, some studies were excluded from comparisons and evaluations.
Authors’ Contributions
B.R.: Conceptualization, investigation, data curation, formal analysis, writing—original draft, writing—reviewing and editing, visualization, and funding acquisition. M.J. and M.M.: Conceptualization, writing—reviewing and editing, supervision, project administration, and funding acquisition.
Footnotes
Acknowledgments
Dr Michael L. Kelly, Department of Neurosurgery Chair, MetroHealth, reviewed clinical application sections of the article for clinical accuracy. The Cleveland FES center assisted with the medical illustration in 
through the Veterans Affairs Office of Research and Development—I50RX002359-06. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS121372. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under grant number 1937968.
Author Disclosure Statement
The authors have submitted a provisional patent related to photobiomodulation technology to treat traumatic SCI.
Funding Information
This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health—R01NS121372, the National Science Foundation Graduate Research Fellowship Program (NSFGRPF)—1937968, and the Veterans Affairs Office of Research and Development—I50RX002359-06.