| Topic | Key data/claim | Evidence type (human/animal/in vitro/trial protocol) | Source (first author, year) | PMID if known | URL | Citation context ID |
|---|---|---|---|---|---|---|
| Definition | VML is the traumatic or surgical loss of skeletal muscle resulting in functional impairment. | Human/clinical review | Grogan, 2011 |  | https://doi.org/10.5435/00124635-201102001-00007 | (pqac-00000002) |
| Quantitative threshold | Loss of skeletal muscle exceeding 20% is cited as a threshold beyond which innate repair/regeneration is permanently compromised. | Review/synthesized clinical-preclinical | Gahlawat, 2024 |  | https://doi.org/10.1007/s10439-024-03541-w | (pqac-00000022) |
| Alternative threshold | VML has also been described as loss of over ~10% of muscle mass causing functional impairment. | In vitro/review context | Patel, 2019 |  | https://doi.org/10.1088/1748-605x/ab0b06 | (pqac-00000023) |
| Trial enrollment definition | Human VML trial protocol required both a structural deficit ≥20% of the muscle group mass and a functional deficit ≥25% versus the contralateral limb. | Trial protocol | Rubin/NCT04051242, 2020 |  | https://clinicaltrials.gov/study/NCT04051242 | (pqac-00000006, pqac-00000017) |
| Epidemiology/burden | VML is disproportionately common in military populations, comprising ~50% of combat-related injuries. | Review | Gahlawat, 2024 |  | https://doi.org/10.1007/s10439-024-03541-w | (pqac-00000022) |
| Extremity trauma burden | Extremity wounds are the majority of soldier injuries in OEF/OIF, and >75% are due to explosions. | Human clinical review | Grogan, 2011 |  | https://doi.org/10.5435/00124635-201102001-00007 | (pqac-00000024) |
| Disability burden | Severe extremity injuries such as type-III open tibia fractures with major soft-tissue loss are associated with a 65% incidence of permanent disability/medical retirement. | Review | Gahlawat, 2024 |  | https://doi.org/10.1007/s10439-024-03541-w | (pqac-00000022) |
| Human cohort outcomes | In a 13-patient ECM bioscaffold cohort, mean improvement at 6 months was 37.3% in strength and 27.1% in range-of-motion versus pre-op. | Human cohort | Dziki, 2016 |  | https://doi.org/10.1038/npjregenmed.2016.8 | (pqac-00000016) |
| Human cohort baseline severity | In the same 13-patient cohort, mean estimated tissue deficit was ~66.2% (individual deficits ~25% to 90%). | Human cohort | Dziki, 2016 |  | https://doi.org/10.1038/npjregenmed.2016.8 | (pqac-00000016) |
| Human evidence caveat | Case reports of quadriceps acellular biomaterial repair showed minimal net recovery: 72%→~68% deficit at 4 months in one patient and 89%→~87% deficit at ~6 months in another. | Human case reports/review | Greising, 2019 |  | https://doi.org/10.1089/ten.teb.2019.0207 | (pqac-00000019) |
| Meta-analysis efficacy | Across 44 animal studies, pooled functional benefit of VML treatments was Hedges’ g 0.75 (95% CI 0.53–0.96; p<0.0000001), corresponding to ~16% average beneficial effect. | Animal systematic review/meta-analysis | Greising, 2019 |  | https://doi.org/10.1089/ten.teb.2019.0207 | (pqac-00000003) |
| Best-performing treatment class | Network meta-analysis suggested acellular biomaterial combined with stem/progenitor cells was the most effective experimental strategy. | Animal systematic review/meta-analysis | Greising, 2019 |  | https://doi.org/10.1089/ten.teb.2019.0207 | (pqac-00000003) |
| Critical vs subcritical injury | In murine quadriceps, 2 mm defects regenerated while 3 mm defects produced persistent fibrotic scarring and chronic inflammation through 4 weeks. | Animal primary study | Hymel, 2023 |  | https://doi.org/10.1038/s42003-023-04790-6 | (pqac-00000009) |
| Mechanism: immune dysregulation | Critical VML showed sustained M2-like and CD206hiLy6Chi hybrid macrophages co-localized with FAPs in collagen-rich regions, implicating macrophage–FAP crosstalk in fibrosis. | Animal primary study | Hymel, 2023 |  | https://doi.org/10.1038/s42003-023-04790-6 | (pqac-00000009) |
| Mechanism: spatial fibrosis program | Spatial transcriptomics/scRNA-seq showed macrophages concentrated in the defect zone, MDCs/FAPs in defect/transition zones, and MuSCs largely restricted to transition zones; TGFBR2 inhibition improved MuSC infiltration and reduced fibrosis. | Animal primary study/omics | Larouche, 2023 |  | https://doi.org/10.1101/2022.06.03.494707 | (pqac-00000008) |
| Mechanism: lipid mediators | Degenerative VML showed increased pro-inflammatory eicosanoids (e.g., LTB4, PGE2, PGF2α) with insufficient rise in pro-resolving mediators (e.g., MaR1, PD1, RvD6). | Animal primary study/metabolipidomics | Castor-Macias, 2023 |  | https://doi.org/10.7554/elife.86437 | (pqac-00000011, pqac-00000014) |
| Immunotherapy result | Delayed local IL-10 delivery after minced-muscle repair improved contractile torque to 82% of uninjured values and 170% of PBS controls at 56 days. | Animal primary study | Huynh, 2023 |  | https://doi.org/10.1038/s41598-023-27981-x | (pqac-00000012) |
| Pro-resolving mediator result | Maresin 1 repletion reduced neutrophils/macrophages, attenuated fibrosis, increased MuSC activation, and partially restored force after degenerative VML. | Animal primary study | Castor-Macias, 2023 |  | https://doi.org/10.7554/elife.86437 | (pqac-00000011, pqac-00000015) |
| Standard of care | Current clinical management includes physical therapy/orthotics and soft-tissue reconstruction such as functional free muscle transfer; these approaches have donor-site morbidity and limited restoration of function. | Human clinical review | Grogan, 2011 |  | https://doi.org/10.5435/00124635-201102001-00007 | (pqac-00000021) |


*Table: This table summarizes the most actionable quantitative definitions, burden statistics, human clinical results, and recent mechanistic findings for volumetric muscle loss. It is useful as a compact evidence map spanning disease characterization, translational thresholds, and therapeutic implications.*