Photobiomodulation with the Proactive MR5 Platform in Regenerative Medicine: An Umbrella Study of Mechanisms, Orthobiologic Modulation, and Musculoskeletal Clinical Effects

Márcio Hiroaki Kume¹^*, Bianca Furlan², Camila Gobatto Boaventura², Mônica Andréa Probst², Edson Peracchi² and Carmen Austrália Paredes Marcondes Ribas³

Abstract

Background: Photobiomodulation (PBM) — the therapeutic use of red and near-infrared light — is one of the most widely studied non-pharmacological modalities in musculoskeletal and regenerative medicine, yet clinical adoption remains uneven because of protocol heterogeneity, imprecise dosimetry, and limited head-to-head comparison of devices. The Proactive MR5 family (ASA Laser, Vicenza, Italy) applies the proprietary Multiwave Locked System (MLS®) technology that synchronises an 808 nm continuous emission with a 905 nm super-pulsed emission and, in the LaserShower configuration, delivers this dual beam over a wider projected area with preset regimens including Tissue Repair. A structured, device-aware evidence synthesis has not been previously published.

Objectives: To (i) synthesise mechanistic, translational, and clinical evidence for PBM in regenerative medicine across mitochondrial signalling, orthobiologic priming (platelet-rich plasma [PRP], bone-marrow aspirate concentrate [BMAC], mesenchymal stem/stromal cells [MSCs], extracellular vesicles [EVs] / exosomes), and musculoskeletal indications; (ii) benchmark commonly reported dosimetric parameters against WALT 2010 recommendations; and (iii) position the Proactive MR5 / MLS platform inside this evidence landscape, distinguishing what is device-specific from what is generic to PBM.

Methods: Overview of systematic reviews (SRs) and meta-analyses (MAs) using an adapted PRISMA 2020 / PRIOR workflow. PubMed, PMC, Cochrane, ScienceDirect, Springer, MDPI, Frontiers and WALT institutional sources were searched to August 2026. Eligible records were SRs / MAs of PBM in musculoskeletal or regenerative applications, mechanistic reviews on the mitochondrial and redox pathways, in-vitro/in-vivo studies of PBM combined with orthobiologics, and primary clinical evidence using the MLS platform. Data on wavelength, power, irradiance, fluence, energy per point, sessions, comparator, effect sizes with 95% confidence intervals (CIs), certainty of evidence (Cochrane RoB, GRADE, AMSTAR-2 when reported) and authors' conclusions were extracted in duplicate. A device-explicit narrative synthesis with structured tables complemented random-effects effect-size mapping (no re-pooling was performed).

Results:  Across the ten thematic domains, PBM shows consistent, biologically coherent mechanistic evidence (photoactivation of cytochrome-c-oxidase in the 600–700 nm and 760–940 nm windows, nitric-oxide photodissociation, transient reactive-oxygen-species signalling, biphasic Arndt–Schulz dose response, and light-sensitive TRP/opsin channels). Clinical benefit is most robust when WALT-compliant dosing is used: in knee osteoarthritis, LLLT reduced pain by 14.23 mm VAS (95% CI 7.31–21.14) and with recommended doses by 18.71 mm VAS (95% CI 9.42–27.99); disability improved with SMD 0.59 (95% CI 0.33–0.86). Wavelength-specific pain effects were larger at 904–905 nm (SMD 1.42, 95% CI 0.31–2.53) than at 785–850 nm (SMD 0.82, 95% CI 0.11–1.50). Similar signal was seen for lateral elbow tendinopathy (short-term pain WMD 10.2 mm, 95% CI 3.0–17.5; 904 nm on the tendon WMD 17.2 mm, 8.5–25.9), plantar fasciitis, shoulder impingement, and temporomandibular disorders (VAS SMD −0.55, 95% CI −0.82 to −0.27). Signal was weaker for chronic non-specific low back pain and Achilles tendinopathy when PBM was added to eccentric exercise. Orthobiologic priming evidence is preclinical/translational: PBM 808 nm + PRP outperformed either alone in reducing intra-articular inflammation in Wistar rats; PBM 650/810 nm enhanced human ADSC viability (p = 0.007–0.008) and increased exosome protein yield with mean vesicle size ~86 nm; PBM at 3 J/cm² partially reversed senescence and restored proliferation in aged bone-marrow MSCs (SA-β-Gal-positive area 13.5% → 4.2%, p<0.001); 825 nm PBM promoted tenogenic differentiation of adipose-derived MSCs (Scleraxis 2.3-fold, Tenomodulin 2.3-fold). MLS-specific clinical evidence is small but positive across chronic low back pain, chronic neck pain, tendinopathy and osteoarthritis, with pain reductions from ~6.7 to ~1.9 on VAS in 12-session protocols. Certainty of evidence at meta-analytic level is generally low to very low (Cochrane RoB2, GRADE); no included SR reported AMSTAR-2 formally.

Conclusions: PBM has a coherent mechanistic base and reproducible short-term clinical benefit in several musculoskeletal indications when WALT-compliant, wavelength- and dose-transparent protocols are used. The Proactive MR5 / MLS platform is well positioned within this window (808 nm continuous + 905 nm super-pulsed), and its dual-emission architecture is biologically rational for orthobiologic priming, but device-specific randomised, sham-controlled trials — including ex-vivo photoactivation of PRP, BMAC, MSCs and EVs — are needed before adjuvant use can be considered evidence-based. Future work must standardise TIDieR-compliant dosimetry, adopt AMSTAR-2 appraisal, and separate PBM effects from orthobiologic effects using factorial designs.

Keywords

Photobiomodulation; low-level laser therapy; MLS Multiwave Locked System; Proactive MR5; platelet-rich plasma; mesenchymal stem cells; exosomes; osteoarthritis; tendinopathy; regenerative medicine; umbrella review.

Introduction

Photobiomodulation (PBM) therapy — historically referred to as low-level laser therapy (LLLT) — is defined by the World Association for Photobiomodulation Therapy (WALT) as the therapeutic application of non-ionising light in the visible red and near-infrared (NIR) ranges to elicit non-thermal biological effects. Contemporary mechanistic evidence converges on cytochrome-c-oxidase (unit IV of the mitochondrial respiratory chain) as the principal photoacceptor, whose photonic activation displaces inhibitory nitric oxide, restores mitochondrial membrane potential, increases oxygen consumption and ATP production, and triggers a brief burst of reactive oxygen species (ROS) that acts as a redox signal for anti-apoptotic, anti-inflammatory, and pro-regenerative transcriptional programs [9,10,11].

This mechanistic base has produced more than a thousand controlled experimental and clinical studies across musculoskeletal, dermatological, neurological, and stomatognathic indications. However, translation into routine care is impeded by three persistent problems: (i) dosimetric opacity — many trials report wavelength or nominal 'preset' but omit irradiance, fluence, energy per point, and total delivered dose; (ii) the biphasic Arndt–Schulz dose-response, which means that both underdosing and overdosing can abolish or reverse effect; and (iii) device heterogeneity — reviews pool RCTs using devices whose optical, spectral, and pulsing behaviour differ substantially, obscuring real between-device differences [12,13,14].

The Proactive MR5 family (ASA Laser, Vicenza, Italy) is one of the more distinctive devices in current musculoskeletal practice because it applies the proprietary Multiwave Locked System (MLS®) technology, which synchronises within a single impulse a 808 nm continuous-wave emission (typically associated with anti-inflammatory and anti-oedema effects) and a 905 nm super-pulsed emission (typically associated with analgesic effect and deeper penetration). The MR5 ACTIV PRO and MR5 LaserShower configurations further extend this dual-wavelength delivery over a larger projected area and offer clinician-facing presets such as Tissue Repair. This architecture is biologically rational both for direct tissue treatment and — an emerging line of investigation — for ex-vivo priming of orthobiologics (platelet-rich plasma [PRP], bone-marrow aspirate concentrate [BMAC], adipose-derived stem cells [ADSCs], extracellular vesicles [EVs] / exosomes) prior to intra-articular administration.

Despite this rationale, no structured evidence synthesis has previously (i) mapped the mechanistic, translational, and clinical PBM literature onto the same evidence grid, (ii) benchmarked reported doses against WALT recommendations, and (iii) positioned the Proactive MR5 / MLS platform explicitly inside this landscape. The present umbrella study addresses that gap. Its intended readership is clinicians and researchers in orthopaedics, sports and regenerative medicine planning device-aware clinical programmes and translational trials.

Objectives

• Primary. To synthesise the highest available level of evidence on PBM in regenerative medicine across three integrated domains — (i) mechanisms and photobiology, (ii) orthobiologic priming (PRP, BMAC, MSCs, EVs/exosomes), and (iii) musculoskeletal clinical indications — and to explicitly locate the Proactive MR5 / MLS platform in that landscape.
• Secondary. (a) To benchmark reported PBM parameters against WALT 2010 dose recommendations; (b) to identify indications where PBM is supported by ≥1 systematic review with meta-analysis showing a clinically relevant effect; (c) to map preclinical evidence on ex-vivo PBM priming of orthobiologics; and (d) to derive practical, device-explicit recommendations and a research agenda for the MR5 platform.

Methods

This overview of systematic reviews was conducted following the PRIOR (Preferred Reporting Items for Overviews of Reviews) statement and the PRISMA 2020 checklist adapted for overviews. No formal PROSPERO registration was in place at the time of drafting; prospective registration is recommended before submission.

Eligibility criteria

Inclusion criteria — Population: humans (adults or children) with musculoskeletal, tendinous, cartilaginous, neural, or wound-healing conditions; or biological substrates relevant to regenerative medicine (PRP, BMAC, MSCs, chondrocytes, tenocytes, EVs/exosomes). Intervention: PBM delivered by laser or LED in the 400–1064 nm range, in vivo or ex vivo, including MLS-based devices. Comparator: sham/placebo PBM, alternative modality, or untreated control. Outcomes: pain (VAS/NRS), function (WOMAC, KOOS, PRTEE, DASH, NDI, ODI, VISA-A), range of motion, cell viability/proliferation/differentiation, growth factor/cytokine profiles, EV/exosome yield or size, and safety. Study design: systematic reviews with or without meta-analysis, umbrella reviews, mechanistic narrative reviews indexed in PubMed/PMC, and — for the MR5-specific and orthobiologic priming sections — primary controlled trials or high-quality preclinical studies. Language: English, Portuguese, or Spanish.

Exclusion criteria — Conference abstracts without full text, case reports, editorials without an evidence base, veterinary studies (unless they were the only evidence for a specific MLS parameter), and duplicate reports.

Information sources and search strategy

PubMed, PMC, Cochrane Library, ScienceDirect, SpringerLink, MDPI, Frontiers, Nature portfolio, and the World Association for Photobiomodulation Therapy (WALT) institutional site were searched to 28 August 2026. Search strings combined MeSH and free-text terms including (photobiomodulation OR PBM OR 'low-level laser therapy' OR LLLT OR 'photobiostimulation') AND (mechanisms OR cytochrome c oxidase OR 'nitric oxide' OR mitochondria OR 'biphasic dose response' OR wavelength) AND (osteoarthritis OR tendinopathy OR 'lateral epicondylitis' OR 'rotator cuff' OR 'plantar fasciitis' OR 'temporomandibular disorder' OR 'carpal tunnel' OR 'low back pain' OR 'muscle regeneration' OR 'bone healing' OR 'nerve regeneration' OR 'wound healing') AND ('systematic review' OR meta-analysis OR umbrella). Device-specific searches added ('Multiwave Locked System' OR MLS OR 'ASA Laser' OR 'MR5' OR 'LaserShower'). Orthobiologic searches combined PBM terms with ('platelet-rich plasma' OR PRP OR BMAC OR 'bone marrow aspirate' OR 'mesenchymal stem cells' OR MSC OR exosomes OR 'extracellular vesicles' OR ADSC).

Study selection, data extraction, and quality appraisal

Two reviewers screened titles and abstracts. Data on citation, design, population, PBM parameters (wavelength[s], output power, irradiance, fluence, energy per point, sessions, area, device brand), comparator, effect size with 95% CI, certainty of evidence (Cochrane RoB2, GRADE), and authors' conclusions were extracted into structured tables. Methodological quality of each included systematic review was appraised qualitatively using an AMSTAR-2 lens (PICO framing, protocol registration, comprehensive search, duplicate screening/extraction, list of included/excluded studies, risk-of-bias assessment, appropriate synthesis, publication bias, and conflicts of interest); numeric AMSTAR-2 scoring was not re-done when the SR did not report it, in line with PRIOR guidance.

Synthesis

A structured, device-aware narrative synthesis with tabular effect-size mapping was performed. No re-pooling of individual patient data was conducted. When multiple systematic reviews addressed the same indication, the largest, most recent, and lowest risk-of-bias review was retained as the primary source, and older or smaller reviews were used for triangulation. Parameters were benchmarked against WALT 2010 dose tables for 780–860 nm and 904 nm. The Proactive MR5 platform is discussed in a dedicated section synthesising the peer-reviewed evidence that explicitly identifies the MLS technology or MR5 device.

Results

Study flow and included evidence

The searches retrieved 255 unique records after deduplication across 40 exploratory queries. Following title/abstract screening against eligibility criteria and full-text assessment, 38 records were retained for structured extraction: 15 systematic reviews with meta-analysis on PBM in musculoskeletal or wound-healing indications, 7 mechanistic narrative or PRISMA-based reviews, 8 preclinical or clinical studies on PBM combined with orthobiologics (PRP, MSCs, ADSCs, exosomes, PRF), 5 primary clinical or preclinical studies using the MLS platform explicitly, 1 umbrella review (diabetic foot ulcers) providing methodological benchmarking, 1 systematic PRISMA review of PBM parameters (Zein et al. 2018), and the WALT 2010 dose tables as regulatory-style guidance.