Sumito Kawamura

Indomethacin and Celecoxib Impair Rotator Cuff Tendon-to-Bone Healing

Background Nonsteroidal anti-inflammatory drugs are commonly prescribed after rotator cuff repair. These agents can impair bone formation, but no studies have evaluated their impact on tendon-to-bone healing. Hypothesis Traditional nonselective nonsteroidal anti-inflammatory drugs and cyclooxygenase-2–specific nonsteroidal antiinflammatory drugs interfere with tendon-to-bone healing. Study Design Controlled laboratory study. Methods One hundred eighty Sprague-Dawley rats underwent acute rotator cuff repairs. Postoperatively, 60 rats received 14 days of celecoxib, a cyclooxygenase-2–specific nonsteroidal anti-inflammatory drug; 60 received indomethacin, a traditional nonselective nonsteroidal anti-inflammatory drug; and 60 received standard rat chow. Animals were sacrificed at 2, 4, and 8 weeks and evaluated by gross inspection, biomechanical testing, histologic analysis, and polarized light microscopy to quantify collagen formation and maturation. Results Five tendons completely failed to heal (4 celecoxib, 1 indomethacin). There were significantly lower failure loads in the celecoxib and indomethacin groups compared with the control groups at 2, 4, and 8 weeks (P< .001), with no significant difference between nonsteroidal anti-inflammatory drug groups. There were significant differences in collagen organization and maturation between the controls and both nonsteroidal anti-inflammatory drug groups at 4 and 8 weeks (P< .001). Controls demonstrated progressively increasing collagen organization during the course of the study (P< .001), whereas the nonsteroidal anti-inflammatory drug groups did not. Conclusion Traditional and cyclooxygenase-2–specific nonsteroidal anti-inflammatory drugs significantly inhibited tendon-tobone healing. This inhibition appears linked to cyclooxygenase-2. Clinical Relevance If the results of this study are verified in a larger animal model, the common practice of administering nonsteroidal anti-inflammatory drugs after rotator cuff repair should be reconsidered.

Biologic augmentation of rotator cuff tendon-healing with use of a mixture of osteoinductive growth factors.

BACKGROUND Clinical studies have demonstrated a high rate of incomplete healing of rotator cuff tendon repair. Since healing of such a repair is dependent on bone ingrowth into the repaired tendon, we hypothesized that osteoinductive growth factors would improve rotator cuff tendon-healing. METHODS Seventy-two skeletally mature sheep underwent detachment of the infraspinatus tendon followed by immediate repair. The animals received one of three treatments at the tendon-bone interface: (1) an osteoinductive bone protein extract on a Type-I collagen sponge carrier, (2) the collagen sponge carrier alone, and (3) no implant. The animals were killed at six and twelve weeks, and the repaired rotator cuff was evaluated with use of magnetic resonance imaging, plain radiographs, histologic analysis, and biomechanical testing. RESULTS A gap consistently formed between the end of the repaired tendon and bone in this model, with reparative scar tissue and new bone spanning the gap. Magnetic resonance imaging showed that the volume of newly formed bone (p < 0.05) and soft tissue (p < 0.05) in the tendon-bone gap were greater in the growth factor-treated animals compared with the collagen sponge control group at both time-points. Histologic analysis showed a fibrovascular tissue in the interface between tendon and bone, with a more robust fibrocartilage zone between the bone and the tendon in the growth factor-treated animals. The repairs that were treated with the osteoinductive growth factors had significantly greater failure loads at six weeks and twelve weeks (p < 0.05); however, when the data were normalized by tissue volume, there were no differences between the groups, suggesting that the treatment with growth factor results in the formation of poor-quality scar tissue rather than true tissue regeneration. The repairs that were treated with the collagen sponge carrier alone had significantly greater stiffness than the growth factor-treated group at twelve weeks (p = 0.005). CONCLUSIONS This model tests the effects of growth factors on scar tissue formation in a gap between tendon and bone. The administration of osteoinductive growth factors resulted in greater formation of new bone, fibrocartilage, and soft tissue, with a concomitant increase in tendon attachment strength but less stiffness than repairs treated with the collagen sponge carrier alone.

Tendon Healing in a Bone Tunnel Differs at the Tunnel Entrance Versus the Tunnel Exit An Effect of Graft-Tunnel Motion?

Background Motion between a tendon graft and bone tunnel may impair graft incorporation and lead to tunnel widening. Hypothesis Healing of a tendon graft in a bone tunnel is inhibited by graft-tunnel motion. Study Design Controlled laboratory study. Methods Anterior cruciate ligament reconstruction was performed in 5 cadaveric rabbit limbs, and 3-dimensional graft-tunnel motion was measured using micro–computed tomography. The authors then performed bilateral anterior cruciate ligament reconstruction in 15 rabbits and used histomorphometry to compare tendon-to-bone healing between the tunnel aperture, midtunnel, and tunnel exit and between the anterior and posterior aspects of the tunnel. Results Graft-tunnel motion was greatest at the tunnel apertures and least at the tunnel exit in cadaveric testing. Healing of the graft was slowest at the tunnel apertures. Tendon-bone interface width was greater at the aperture than at the tunnel exit for the femoral tunnel (P =. 04). There was an inverse correlation between time zero graft-tunnel motion and healing in the femoral tunnel (P =. 005). There was closer apposition of new bone to the tendon graft in the posterior half of the interface (P <. 05). Osteoclasts were found at the tunnel apertures. Conclusion Although graft-tunnel motion was only measured in cadaveric animals, results suggest that healing may be affected by the local mechanical environment, as graft healing in the femoral tunnel was inversely proportional to the magnitude of grafttunnel motion. Clinical Relevance Graft-tunnel motion may impair early graft incorporation and may lead to osteoclast-mediated bone resorption, contributing to tunnel widening. Early, aggressive postoperative rehabilitation may have detrimental effects on graft-to-bone healing.

Bone Morphogenetic Proteins-Signaling Plays a Role in Tendon-to-Bone Healing A Study of rhBMP-2 and Noggin

Background Successful anterior cruciate ligament reconstruction requires secure healing between tendon and bone. Hypothesis Bone morphogenetic protein-signaling plays an important role in tendon-to-bone healing. rhBMP-2, a powerful osteoinductive agent, can improve tendon-bone interdigitation. Study Design Controlled laboratory study. Methods The study was designed in 2 phases: Phase I consisted of a dose-response study where 21 New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstructions. Rabbits received either rhBMP-2 (11.5, 50, or 115 µg) or noggin (10, 15, 30, or 100 ng) (a potent bone morphogenetic proteins inhibitor) delivered in an injectable calcium phosphate matrix. Animals were sacrificed at 2 weeks and histomorphometric analyses were performed. In phase II, 60 rabbits underwent bilateral anterior cruciate ligament reconstructions and were assigned to 3 groups rhBMP-2 (115 µg), noggin (30 ng) in a calcium phosphate carrier, and calcium phosphate carrier alone. Animals were sacrificed at 2, 4, and 8 weeks and histomorphometric and biomechanical analyses were performed. Results rhBMP-2 treatment led to a significant increase in the width of new bone formation at the tendon-bone interface in a dose-dependent fashion (0.24-0.35 mm vs 0.13-0.16 mm in controls). All dosages of noggin inhibited new bone formation (0.06-0.1 mm vs 0.15-0.16 mm in controls); however, there was no dose-dependent effect in the concentrations studied. In the phase II study, rhBMP-2 resulted in a significant increase in new bone formation (81%, 89%, and 113%) at increasing time periods compared with controls. Tunnel diameters in the rhBMP-2 group were significantly smaller (15%-45%) than in the carrier group. The negative effect of noggin was not sustained, as new bone formation increased with time. The rhBMP-2 group demonstrated significantly increased stiffness at 8 weeks, while there was no significant difference in ultimate tensile load when compared with the other 2 groups. Conclusion rhBMP-2 demonstrated a strong, positive dose-dependent effect on osteointegration at the tendon-bone junction. In contrast, noggin decreased osteointegration. No tunnel widening was detected with rhBMP-2 using the calcium phosphate carrier. Clinical Relevance Further studies are needed to investigate the potential clinical application of enhancing healing and decreasing recovery time using bone morphogenetic proteins in soft tissue ligament reconstruction.

The effect of osteoclastic activity on tendon-to-bone healing : An experimental study in rabbits

BACKGROUND Healing of a tendon graft in a bone tunnel depends on bone ingrowth into the interface between tendon and bone. Excessive osteoclastic activity may contribute to bone resorption, tunnel widening, and impaired healing. We hypothesized that inhibition of osteoclastic activity by osteoprotegerin (OPG) would increase bone formation around a tendon graft in anterior cruciate ligament reconstruction in a rabbit model, while increased osteoclastic activity due to the application of receptor activator of nuclear factor-kappa B ligand (RANKL) would impair bone ingrowth. METHODS Sixty skeletally mature, male New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstruction. OPG (100 microg per tunnel) or RANKL (10 microg per tunnel) was delivered to the tendon-bone interface with use of a synthetic calcium phosphate carrier vehicle. Twenty animals were killed at two, four, and eight weeks after surgery. Two rabbits from each group were prepared for histological evaluation, and the other rabbits were used for biomechanical testing. RESULTS A significantly greater amount of bone surrounded the tendon at the healing tendon-bone interface in the OPG-treated limbs compared with the controls and the RANKL-treated limbs at all time-points (p < 0.05). There were significantly fewer osteoclasts in the OPG-treated limbs compared with the controls and the RANKL-treated limbs (p < 0.05). The average tunnel area in the OPG group was significantly smaller than that in the RANKL group (p = 0.003 at two weeks and p = 0.004 at four weeks). The femur-anterior cruciate ligament-tibia complex of the OPG-treated limbs had significantly increased stiffness compared with RANKL-treated limbs at eight weeks (p = 0.04). CONCLUSIONS Osteoprotegerin significantly improves bone formation around the grafted tendon and improves the stiffness at the healing tendon-bone junction in a rabbit model.

A Case Report of Familial Mediterranean Fever Diagnosed Following the Total Knee Arthroplasty

Postoperative fever following orthopedic surgical procedures is common, but the cause of fever and its relation to infections is often unclear. Periprosthetic joint infection is a devastating complication following the total joint arthroplasty [8]. In the USA, periprosthetic joint infection is currently the most common indication for revision total knee arthroplasty and the third most common indication for revision total hip arthroplasty [2, 8]. Since no highly accurate diagnostic method exists, the diagnosis of infection is based on a combination of clinical suspicion, serological tests, culture results, histology, and basic molecular techniques. We present the case of a 62-year-old female who presented to our clinic with a fever of unknown origin following a total knee replacement. She was suspected to have a periprosthetic joint infection. Because of her recurrent febrile episodes associated with peritonitis, pleuritis, and synovitis, familial mediterranean fever (FMF) was suspected based on the Tel-Hashomer criteria, if two major or one major + two minor criteria are met (Major criteria are (1) recurrent febrile episodes associated with peritonitis, pleuritis, or synovitis; (2) amyloidosis of AA-type without a predisposing disease; and (3) favorable response to daily colchicine. Minor criteria are (1) recurrent febrile episodes, (2) erysipelas-like erythema, and (3) positive history of familial mediterranean fever in a first degree relative) [5]. As part of the workup for her fever, a genomic search for the mediterranean fever gene (MEFV) was performed, and heterozygous L110P, E148Q, and M694I mutations were found in the patient. FMF was confirmed by the mutation in the hot spot of MEFV. The patient’s symptoms were successfully controlled by administration of colchicine.