Tag Archive | cytokine

Residual Pain after Joint Replacement

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

In the absence of infection and aseptic loosening, significant postoperative pain persists in up to 20% of joint-replacement patients. In one study related to this predicament, investigators studied 3 groups of individuals: 1) those without a total joint replacement (TJR) and no self-reported pain, 2) patients with a well-functioning TJR and no self-reported pain (mean implant time of 1.5 years), and 3) patients with a painful TJR (self-reported pain of >8 on a 0 to10 VAS scale; mean implant time of 1.76 years)1.

Peripheral blood mononuclear cells were collected for use in a lymphocyte reactivity assay to detect anti-inflammatory (IL-1ra, IL-10, IL-13 and IL-11) and inflammatory cytokines or receptors (IL-1rII and TNFR1). In general, anti-inflammatory cytokine markers in patients with post-TJR pain were decreased compared to controls and to individuals with no pain following TJR, with IL-10 and IL-13 significantly decreased among painful TJR patients. TNFR1 was significantly elevated in those with painful TJRs, and IL-1rII was modestly elevated. The authors note that treating this “1-2 punch” of elevated proinflammatory cytokines and decreased anti-inflammatory cytokines may require “a complex pattern” of both inhibition of proinflammatory mechanisms as well as anti-inflammatory medications.

In a separate study, investigators used scanning electron microscopy (SEM) to try to determine whether implant corrosion was secondary to inflammatory cellular reactions or to the effects of electrocautery used in near proximity to metallic surfaces2. Twelve knee prostheses taken at necropsy were compared to an off-the-shelf cobalt-chromium knee implant intentionally exposed to Bovie and Aquamantys electrocautery sources. SEM data was collected using an identical method to that of the retrieved implants. Five of the 12 necropsy retrievals showed signs of inflammatory cell-induced corrosion. Compared to the necropsy-retrieved implants, the iron/carbon ratio of the Bovie electrocautery-damaged implant was significantly higher, suggesting that the mechanism by which immune cells corrode implants is different than the mechanism of electrocautery damage.

In a third study, which compared results of lymphocyte transformation testing (LTT) for metal sensitivity with histological and clinical findings in 27 cases of primary total knee arthroplasty (TKA), researchers found that LTT results alone were insufficient for the diagnosis of TKA pain-relief failure due to an immune reaction3. A positive LTT might not indicate that an immune reaction is the cause of pain and stiffness post-TKA.

It will take more research to determine whether there is a connection between surface pitting and chronic knee pain in metal-sensitive persons, whether the elevated macrophage response is an associated risk factor, and whether that is associated with metallic material response.

References

  1. Lauryn S, Caicedo M, Jacobs J, Hallab NJ. Do TJR Patients with High Self-Reported Pain Levels Exhibit Decreased Serum Anti-inflammatory Cytokine Markers? Abstract 0135 Orthopaedic Research Society 2019
  2. Sorrels JA, Heise G, Morrow B, Arnholt C, Kurtz S, Mihalko WM. Inflammatory Cell- Induced Corrosion and Electrocautery Damaged TKA Implants. Abstract 0131 Orthopaedic Research Society 2019
  3. Yang S, Dipane M, Lu CH, Schmalzried TP, McPherson EJ. Lymphocyte Transformation Testing (LTT) in Cases of Pain Following Total Knee Arthroplasty: Little Relationship to Histopathologic Findings and Revision Outcomes. J Bone Joint Surg Am. 2019 Feb 6;101(3):257-264. doi: 10.2106/JBJS.18.00134. PMID: 30730485

Preparing PRP: More Questions than Answers

This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson. 

The use of platelet-rich plasma (PRP) in the treatment of tendinitis, some sports injuries, and osteoarthritis has been popularized over the past decade. Because there is “minimal” manipulation of biologic products such as PRP, their preparation is not subject to the rigid standards used for the development of pharmacologic products.

In a recent study of autologous PRP, investigators hypothesized that “lower levels of inflammatory cytokines (ICs) within PRP stimulate positive chondrocyte and macrophage responses irrespective of the age and OA disease state of the PRP donor”1. To test this hypothesis, investigators made PRP preparations from young healthy individuals and older patients with end-stage OA using a modified double-spin protocol. The level of inflammatory cytokines (ICs) was identified in all PRP preparations. Chondrocytes were isolated from normal-appearing cartilage harvested from an arthritic knee during total joint arthroplasty. Alginate beads were created for culture and were treated with 10% PRP on days 0 and 2 of a 4-day culture period.

The results contradicted the hypothesis. There were a number of adverse results in the cultures treated with PRP donated by the OA group. Macrophage activation increased with OA disease status/age of the PRP donor. PRP from OA subjects significantly upregulated TNF-α (p <0.001) and MMP-9 (p<0.0001) in macrophage cultures irrespective of whether the PRP had “high” or “low” IC levels. Additionally, PRP from donors with OA decreased Col2a1 (p<0.05) and SOX9 (p<0.05) expression more than PRP from healthy donors, irrespective of IC grouping.

According to these findings, the functional effects of PRP appear to be dependent on the age and disease status of the plasma donor, as opposed to the IC concentration. This suggests that a more complex interaction with age or OA-related molecular factors might dictate the effect of PRP.

In a separate study, the issue of variation of PRP preparations in research was evaluated by Delphi consensus and other methodologies.2 One key consensus of the PRP experts was the importance of detailing the cellular composition of whole blood and the delivered PRP. The experts also noted marked individual variation in PRP and the need for a clear understanding of the factors influencing such variation.

References

  1. O’Donnell C, Migliore E, Grandi FC, Lingampalli N, Raghu H, Giori N N, J, Indelli PF, Robinson WH, Bhutani N, Chu CR. Donor Specific Effects of Platelet-Rich Plasma for the Treatment of Osteoarthritis Trans Orthop Res Sco. 2018. Paper 0063
  2. Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF. Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): Platelet-Rich Plasma and Mesenchymal Stem Cells. J Bone Joint Surg Am. 2017 May 17;99(10):809-819. doi: 10.2106/JBJS.16.00793

New Hope for New Bone After Osteomyelitis Debridement

Osteomyelitis Tibia for OBuzzThis basic science tip comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.

One clinical frustration following osteomyelitis debridement is poor bone healing. Impaired bone homeostasis provokes serious variations in bone remodeling that involve multiple inflammatory cytokines.

The chemokines CCL2, CCL3, and CXCL2 are known to be strong chemoattractants for neutrophils during inflammatory states, and they play a role during osteoclastogenesis. B cells are also activators of osteoclastognesis and are regulated, in part, by tissue inhibitor of metalloprotease 1 (TIMP-1).

Researchers drilled a 1 mm hole into the proximal tibia of 126 mice. In half of the mice (63), a dose of S. aureus was injected into the canal, while the controls had no bacteria injected. At two weeks, all proximal tibiae were debrided; cultures were taken 3 and 7 days after debridement to assure no residual infection. Cytokine assays and Western blots for CCL2, CCL3, CXCL2, TIMP-1, RANKL, and TNF-α were performed in selected mice in each group. Flow cytometry and histology were also done in selected mice in each group.

In the osteomyelitis group, Western blot analysis identified increased levels of CCL2, CCL3, and CXCL2. Histology revealed increased osteoclastogenesis after osteomyelitis debridement, with calcitonin-receptor and RANKL detection via immunohistochemical and fluorescence staining. There was diminished osteogenesis and proliferation in the osteomyelitis group, but TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Flow cytometry revealed elevated B cell activity in the osteomyelitis group, with subsequent increased osteoclast activity and accelerated bone resorption.

The researchers propose a RANKL-dependent osteoclastogenesis after debridement for osteomyelitis that is associated with elevated B cells and decreased osteogenesis. These findings could lead to new interventions to improve bone healing during the course of osteomyelitis treatment, particularly following debridement.

Reference
Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, Behr B. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity. J Orthop Res. 2017 Mar 6. doi: 10.1002/jor.23555. [Epub ahead of print] PMID: 28263017