Genetic Determinants and Personalised Healing Potential of Rotator Cuff Tears: A Systematic Review of Intra-operative Muscle and Tendon Transcriptomics

Abstract Background: Degenerative rotator cuff (RC) tears have poor healing potential. The molecular determinants and milieu underpinning RC failure remain indeterminate across small, methodologically heterogeneous human studies. Hypothesis: Rotator cuff tears demonstrate a stage-dependent transcriptional profile, with patient comorbidities amplifying adverse pathways and poor healing. Study design: Systematic review Methods: Following PRISMA guidelines, Medline, Embase and Cochrane were systematically searched to September 2025 and included studies reporting gene-expression profiles from RC tissue. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools. Results: Sixty human intra-operative studies met inclusion. Despite heterogeneity, convergent degenerative processes emerged with increasing tear severity: (i) amplification of innate inflammatory mediators and matrix-remodelling; (ii) activation of adipogenic and profibrotic pathways; and (iii) progressive loss of growth-factor and tendon/muscle structural transcripts. Partial-thickness tears showed modest perturbation, whereas large/massive tears demonstrated suppression of TGF-β/BMP signalling alongside extracellular matrix (ECM) disarray and fatty degeneration signatures. Clinical modifiers - including diabetes, smoking and vitamin D deficiency - consistently magnified pro-inflammatory, proteolytic and adipogenic responses. Conclusion: Human intra-operative transcriptomics of RC disease converge with chronic inflammation, ECM remodelling and adipogenesis, which intensify dependent upon tear size and patient factors. These signals nominate modifiable targets - macrophage polarisation, cellular senescence and metabolic optimisation - and support a translational pathway of molecular stratification and RC debridement/repair augmented with M2-skewing biologics. Clinical relevance: These data support molecular stratification of tears at the time of surgery and rational development of biologic adjuncts targeting macrophage polarisation, senescence and metabolic optimisation to enhance personalised healing.