Periprosthetic UHMWPE Wear Debris Induces Inflammation, Vascularization, and Innervation After Total Disc Replacement in the Lumbar Spine

  • Sai Y. Veruva
  • Todd H. Lanman
  • Jorge E. Isaza
  • Theresa A. Freeman
  • Steven M. Kurtz
  • Marla J. Steinbeck
Symposium: Advances in Polyethylene Biomaterials

DOI: 10.1007/s11999-016-4996-8

Cite this article as:
Veruva, S.Y., Lanman, T.H., Isaza, J.E. et al. Clin Orthop Relat Res (2016). doi:10.1007/s11999-016-4996-8



The pathophysiology and mechanisms driving the generation of unintended pain after total disc replacement (TDR) remain unexplored. Ultrahigh-molecular-weight polyethylene (UHMWPE) wear debris from TDRs is known to induce inflammation, which may result in pain.


The purpose of this study was to determine whether (1) periprosthetic UHMWPE wear debris induces immune responses that lead to the production of tumor necrosis factor-α (TNFα) and interleukin (IL)-1ß, the vascularization factors, vascular endothelial growth factor (VEGF) and platelet-derived growth factor-bb (PDGFbb), and the innervation/pain factors, nerve growth factor (NGF) and substance P; (2) the number of macrophages is associated with the production of the aforementioned factors; (3) the wear debris-induced inflammatory pathogenesis involves an increase in vascularization and associated innervation.


Periprosthetic tissues from our collection of 11 patients with contemporary TDRs were evaluated using polarized light microscopy to quantify UHMWPE wear particles. The major reason for revision (mean implantation time of 3 years [range, 1–6 years]) was pain. For control subjects, biopsy samples from four patients with degenerative disc disease with severe pain and autopsy samples from three normal patients with no history of back pain were also investigated. Immunohistochemistry and histology were used to identify secretory factors, macrophages, and blood vessels. Immunostained serial sections were imaged at ×200 magnification and using MATLAB and NIH ImageJ, a threshold was determined for each factor and used to quantify positive staining normalized to tissue sectional area. The Mann-Whitney U test was used to compare results from different patient groups, whereas the Spearman Rho test was used to determine correlations. Significance was based on p < 0.05.


The mean percent area of all six inflammatory, vascularization, and innervation factors was higher in TDR tissues when compared with normal disc tissues. Based on nonparametric data analysis, those factors showing the most significant increase included TNFα (5.17 ± 1.76 versus 0.05 ± 0.03, p = 0.02), VEGF (3.02 ± 1.01 versus 0.02 ± 0.002, p = 0.02), and substance P (4.15 ± 1.01 versus 0.08 ± 0.04, p = 0.02). The mean percent area for IL-1ß (2.41 ± 0.66 versus 0.13 ± 0.13, p = 0.01), VEGF (3.02 ± 1.01 versus 0.34 ± 0.29, p = 0.04), and substance P (4.15 ± 1.01 versus 1.05 ± 0.46, p = 0.01) was also higher in TDR tissues when compared with disc tissues from patients with painful degenerative disc disease. Five of the factors, TNFα, IL-1ß, VEGF, NGF, and substance P, strongly correlated with the number of wear particles, macrophages, and blood vessels. The most notable correlations included TNFα with wear particles (p < 0.001, ρ = 0.63), VEGF with macrophages (p = 0.001, ρ = 0.71), and NGF with blood vessels (p < 0.001, ρ = 0.70). Of particular significance, the expression of PDGFbb, NGF, and substance P was predominantly localized to blood vessels/nerve fibers.


These findings indicate wear debris-induced inflammatory reactions can be linked to enhanced vascularization and associated innervation/pain factor production at periprosthetic sites around TDRs. Elucidating the pathogenesis of inflammatory particle disease will provide information needed to identify potential therapeutic targets and treatment strategies to mitigate pain and potentially avoid revision surgery.

Level of Evidence

Level III, therapeutic study.

Supplementary material

11999_2016_4996_MOESM1_ESM.tiff (8.4 mb)
Supplemental Fig. 1A-E Representative images of immunostained TDR tissues showed the cellular production of (A) TNFα, (B) IL-1β, (C) VEGF, (D) NGF, and (E) substance P. The red arrows indicate fibroblasts. Sections were immunostained using DAB as the chromogenic substrate and counterstained with 50% hematoxylin; the scale bar is 50 μm. Supplementary material 1 (TIFF 8579 kb)

Copyright information

© The Association of Bone and Joint Surgeons® 2016

Authors and Affiliations

  • Sai Y. Veruva
    • 1
  • Todd H. Lanman
    • 2
  • Jorge E. Isaza
    • 3
  • Theresa A. Freeman
    • 4
  • Steven M. Kurtz
    • 1
    • 5
  • Marla J. Steinbeck
    • 1
    • 6
  1. 1.Implant Research CenterDrexel UniversityPhiladelphiaUSA
  2. 2.Department of NeurosurgeryUCLA David Geffen School of MedicineLos AngelesUSA
  3. 3.Tulane UniversityBaton RougeUSA
  4. 4.Department of Orthopaedic SurgeryThomas Jefferson UniversityPhiladelphiaUSA
  5. 5.Exponent, IncPhiladelphiaUSA
  6. 6.Department of Orthopaedic SurgeryDrexel University College of MedicinePhiladelphiaUSA