title: Evaluation of tumor necrosis factor α blockade on early tendon-to-bone healing in a rat rotator cuff repair model.
abstract: OBJECTIVE
  The purpose was to determine whether systemic tumor necrosis factor α (TNF-α) blockade can improve rotator cuff healing in a rat model.
  
  
  METHODS
  One hundred twenty Lewis rats underwent unilateral detachment and repair of the supraspinatus. Rats were randomized into 2 groups. The experimental group received injections of pegylated soluble tumor necrosis factor receptor type I (3.0 mg/kg every other day for 3 doses). The control group received saline solution on the same dosing schedule. At 2, 4, and 8 weeks, 20 animals in each group were killed (4 for histologic assessment and 16 for biomechanical testing). Outcomes included qualitative histologic assessment to determine new fibrocartilage formation and collagen fiber organization. Immunohistochemical staining was performed to localize TNF-α, ED1 and ED2 macrophages, and tartrate-resistant acidic phosphatase. Biomechanical testing was performed to determine the ultimate load to failure, stiffness, cross-sectional area, and ultimate stress to failure.
  
  
  RESULTS
  Qualitative assessments of histology showed that the experimental group had more cartilage formation at 4 weeks but not at 2 or 8 weeks. There was less TNF-α staining in the experimental group at 4 and 8 weeks, and there were fewer ED1 macrophages at 4 weeks compared with controls. The ultimate load to failure was greater in the experimental group compared with controls at 2 weeks (13.3 ± 2.6 N v 11.2 ± 2.7 N, P = .05) and at 4 weeks (21.7 ± 4.6 N v 18.5 ± 2.1 N, P = .04). The experimental group also had a higher stiffness at 2 weeks (7.2 ± 2.3 N/mm v 5.8 ± 1.4 N/mm, P = .04) and at 4 weeks (10.5 ± 2.7 N/mm v 8.4 ± 1.7 N/mm, P = .01). There were no differences in any biomechanical variable at 8 weeks.
  
  
  CONCLUSIONS
  TNF-α blockade can improve the biomechanical strength of tendon-bone healing in a rat rotator cuff model at early time points, which corresponded with modest qualitative improvements in histology. However, these differences were not maintained at 8 weeks.
  
  
  CONCLUSIONS
  TNF-α blockade may influence rotator cuff tendon healing.
authors.affiliation: Laboratory for Soft Tissue Research, Hospital for Special Surgery, New York, New York 10021, USA. gulottal@hss.edu
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Gulotta
authors.forename: David
authors.initials: D
authors.lastname: Kovacevic
authors.forename: Frank
authors.initials: F
authors.lastname: Cordasco
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rodeo
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002921:Cicatrix / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D053331:Ectodysplasins / Q000032:analysis; D051445:Fibrocartilage / Q000502:physiology; D006811:Humerus / Q000473:pathology; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011917:Rats, Inbred Lew; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000008:administration & dosage / Q000627:therapeutic use*; D012038:Regeneration / Q000187:drug effects; D017006:Rotator Cuff / Q000473:pathology / Q000601:surgery*; D016037:Single-Blind Method; D013536:Suture Techniques; D013710:Tendons / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D053331:Ectodysplasins; C496217:PEGylated tumor necrosis factor alpha receptor 1; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols