Genetic Determinants and Personalized Healing Potential of Rotator Cuff Tears: A Systematic Review of Intraoperative Muscle and Tendon Transcriptomics
Andrew Kailin Zhou, Dave Osinachukwu Duru, Shirom Chabra, Salma Chaudhury, Mark Birch, Andrew McCaskieBackground:
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:
RC tears demonstrate a stage-dependent transcriptional profile, with patient comorbidities amplifying adverse pathways and poor healing.
Study Design:
Systematic review, Level 4.
Methods:
Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the Medline, Embase, and Cochrane databases were systematically searched up 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:
A total of 60 human intraoperative studies met the inclusion criteria. Despite heterogeneity, convergent degenerative processes emerged with increasing tear severity: (1) amplification of innate inflammatory mediators and matrix-remodeling; (2) activation of adipogenic and profibrotic pathways; and (3) 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 signaling alongside extracellular matrix (ECM) disarray and fatty degeneration signatures. Clinical modifiers—including diabetes, smoking, and vitamin D deficiency—consistently magnified proinflammatory, proteolytic, and adipogenic responses.
Conclusion:
Human intraoperative transcriptomics of RC disease converge with chronic inflammation, ECM remodeling, and adipogenesis, which intensify depending on tear size and patient factors. These signals nominate modifiable targets—macrophage polarization, cellular senescence, and metabolic optimization—and support a translational pathway of molecular stratification and RC debridement/repair augmented with M2-skewing biologics. These data support molecular stratification of tears at the time of surgery and rational development of biologic adjuncts targeting macrophage polarization, senescence, and metabolic optimization to enhance personalized healing.