scholarly journals Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model

2021 ◽  
pp. 036354652098520
Author(s):  
Mikhail Golman ◽  
Xiaoning Li ◽  
Dimitrios Skouteris ◽  
Adam A. Abraham ◽  
Lee Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Failure Load ◽  
Early Period ◽  
Chemokine Production ◽  
Cuff Repair ◽  
Inhibitor Treatment

Background: More than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway. Purpose: To evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair. Study Design: Controlled laboratory study. Methods: After validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology. Results: Inhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control. Conclusion: Pharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model. Clinical Relevance: The NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.

Hyaluronic Acid Accelerates Tendon-to-Bone Healing After Rotator Cuff Repair

2017 ◽  
Vol 45 (14) ◽  
pp. 3322-3330 ◽  
Author(s):  
Hirokazu Honda ◽  
Masafumi Gotoh ◽  
Tomonoshin Kanazawa ◽  
Hiroki Ohzono ◽  
Hidehiro Nakamura ◽  
...  
Keyword(s):  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Control Group ◽  
Related Gene ◽  
Pellet Production ◽  
Cuff Repair ◽  
And Cartilage ◽  
Gene Expression Levels

Background: There is growing evidence that the subacromial injection of hyaluronic acid (HA) is effective for pain relief in rotator cuff tears; however, its effect on tendon-to-bone healing remains unknown. Purpose: To examine the effect of HA on the chondrogenesis of mesenchymal stem cells (MSCs) in vitro and on tendon-to-bone healing in a rotator cuff repair model. Study Design: Controlled laboratory study. Methods: Bilateral complete tears of the infraspinatus tendon were made in rabbits and subsequently repaired. Before closure, 1 mL HA was applied to the repaired site, and phosphate-buffered saline was used in the opposite side as a control. Biomechanical, histological, and immunohistochemical analyses were performed at 4, 8, and 12 weeks after surgery. After euthanizing each animal, the bone marrow was isolated from the femoral bone in the same rabbits. Then, MSCs were cultured in media for chondrogenic differentiation, and the chondral pellet production and cartilage-related gene expression levels in the cells were examined at various concentrations of HA. Results: At 4 and 8 weeks after surgery, ultimate load-to-failure was significantly greater in the HA group than in the control group (45.61 ± 9.0 N vs 32.42 ± 9.4 N at 4 weeks, 90.7 ± 16.0 N vs 66.97 ± 10.0 N at 8 weeks; both P < .05) but not at 12 weeks after surgery (109.6 ± 40.2 N vs 108.1 ± 42.6 N, P > .05). Linear stiffness was not significant throughout the time point evaluation. The chondroid formation area at the tendon-bone interface stained by safranin O (control vs HA group) was 0.33% ± 0.7% versus 13.5% ± 12.3% at 4 weeks after surgery ( P < .05) and 3.0% ± 5.9% versus 12.9% ± 12.9% at 8 weeks after surgery ( P < .05), but there was no significant difference at 12 weeks after surgery. Maturity of collagen at the repaired site stained by PicroSirius Red (control vs HA group) was 16.2 ± 10.6 versus 43.5 ± 21.3 at 4 weeks after surgery ( P < .05), but there were no significant differences at 8 and 12 weeks after surgery. MSCs were cultured in media for chondrogenic differentiation, and the chondral pellet production and cartilage-related gene expression levels in the cells were examined at various concentrations of HA. The number of CD44-positive cells (control vs HA group) was 8.3% ± 1.4% versus 26.2% ± 5.2% at 3 days after surgery ( P < .05), 1.8% ± 1.1% versus 26.6% ± 11.6% at 4 weeks after surgery ( P < .05), 0.6% ± 0.9% versus 0.5% ± 0.6% at 8 weeks after surgery ( P > .05), and 1.8% ± 4.0% versus 5.4% ± 4.2% at 12 weeks after surgery ( P > .05). Compared with the control group, HA significantly increased the volume of cartilaginous pellet produced by MSCs (0.0016 ± 0.0015 mm3 at 0 mg/mL of HA, 0.0041 ± 0.0023 mm3 at 1.0 mg/mL, and 0.0041 ± 0.0018 mm3 at 4.0 mg/mL), with increased mRNA expression (relative ratio to control) of type 2 collagen (1.34 ± 0.38), SOX9 (1.58 ± 0.31), and aggrecan (1.30 ± 0.22) genes in the pellet ( P < .01). Conclusion: HA accelerated tendon-to-bone healing in the rotator cuff repair model, enhancing the biomechanical strength and increasing chondroid formation and tendon maturity at the tendon-bone interface. Based on the data of in vitro experiments, HA-activated MSCs may play a crucial role in the acceleration of tendon-to-bone healing. Clinical Relevance: The data suggest the relevance of clinical application of HA to accelerate tendon-to-bone healing. It may decrease the number of retears after surgery.

Distinct Gene Expression Profile in Patients With Poor Postoperative Outcomes After Rotator Cuff Repair: A Case-Control Study

2021 ◽  
pp. 036354652110232
Author(s):  
Jessica M. Eager ◽  
William J. Warrender ◽  
Carly B. Deusenbery ◽  
Grant Jamgochian ◽  
Arjun Singh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rotator Cuff ◽  
Surgical Outcomes ◽  
Rotator Cuff Repair ◽  
Case Control Study ◽  
Case Control ◽  
Gene Sets ◽  
Poor Outcomes ◽  
Cuff Repair ◽  
Control Study

Background: Impaired healing after rotator cuff repair is a major concern, with retear rates as high as 94%. A method to predict whether patients are likely to experience poor surgical outcomes would change clinical practice. While various patient factors, such as age and tear size, have been linked to poor functional outcomes, it is currently very challenging to predict outcomes before surgery. Purpose: To evaluate gene expression differences in tissue collected during surgery between patients who ultimately went on to have good outcomes and those who experienced a retear, in an effort to determine if surgical outcomes can be predicted. Study Design: Case-control study; Level of evidence, 3. Methods: Rotator cuff tissue was collected at the time of surgery from 140 patients. Patients were tracked for a minimum of 6 months to identify those with good or poor outcomes, using clinical functional scores and follow-up magnetic resonance imaging to confirm failure to heal or retear. Gene expression differences between 8 patients with poor outcomes and 28 patients with good outcomes were assessed using a multiplex gene expression analysis via NanoString and a custom-curated panel of 145 genes related to various stages of rotator cuff healing. Results: Although significant differences in the expression of individual genes were not observed, gene set enrichment analysis highlighted major differences in gene sets. Patients who had poor healing outcomes showed greater expression of gene sets related to extracellular matrix production ( P < .0001) and cellular biosynthetic pathways ( P < .001), while patients who had good healing outcomes showed greater expression of genes associated with the proinflammatory (M1) macrophage phenotype ( P < .05). Conclusion: These results suggest that a more proinflammatory, fibrotic environment before repair may play a role in poor healing outcome. With validation in a larger cohort, these results may ultimately lead to diagnostic methods to preoperatively predict those at risk for poor surgical outcomes.

Evaluation of BioCorkscrew and Bioknotless RC suture anchor rotator cuff repair fixation: an in vitro biomechanical study

2007 ◽  
Vol 15 (11) ◽  
pp. 1375-1381 ◽  
Author(s):  
Jennifer Tucker Ammon ◽  
John Nyland ◽  
Haw Chong Chang ◽  
Robert Burden ◽  
David N. M. Caborn
Keyword(s):  
Rotator Cuff ◽  
Rotator Cuff Repair ◽  
Suture Anchor ◽  
Biomechanical Study ◽  
Cuff Repair

scholarly journals TOB1 Deficiency Enhances the Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Tendon-Bone Healing in a Rat Rotator Cuff Repair Model

2016 ◽  
Vol 38 (1) ◽  
pp. 319-329 ◽  
Author(s):  
Yulei Gao ◽  
Yinquan Zhang ◽  
Yanghu Lu ◽  
Yi Wang ◽  
Xingrui Kou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Cuff Repair

Background/Aims: This study investigated the effect of silencing TOB1 (Transducer of ERBB2, 1) expression in bone marrow-derived mesenchymal stem cells (MSCs) on MSC-facilitated tendon-bone healing in a rat supraspinatus repair model. Methods: Rat MSCs were transduced with a recombinant lentivirus encoding short hairpin RNA (shRNA) against TOB1. MSC cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The effect of MSCs with TOB1 deficiency on tendon-bone healing in a rat rotator cuff repair model was evaluated by biomechanical testing, histological analysis and collagen type I and II gene expression. An upstream regulator (miR-218) of TOB1 was determined in MSCs. Results: We found that knockdown of TOB1 significantly increased the proliferative activity of rat MSCs in vitro. When MSCs with TOB1 deficiency were injected into injured rat supraspinatus tendon-bone junctions, the effect on tendon-bone healing was enhanced compared to treatment with control MSCs with normal TOB1 expression, as evidenced by elevated levels of ultimate load to failure and stiffness, increased amount of fibrocartilage and augmented expression of collagen type I and type II genes. In addition, we found that the TOB1 3′ untranslated region is a direct target of miR-218. Similar to the effect of TOB1 deficiency, overexpression of miR-218 effectively promoted tendon-bone healing in rat. Conclusion: These results suggest that TOB1 may play a negative role in the effect of MSCs on tendon-bone healing, and imply that expression of TOB1 may be regulated by miR-218.

scholarly journals Postoperative Tendon Loading With Treadmill Running Delays Tendon‐to‐Bone Healing: Immunohistochemical Evaluation in a Murine Rotator Cuff Repair Model

2019 ◽  
Vol 37 (7) ◽  
pp. 1628-1637 ◽  
Author(s):  
Susumu Wada ◽  
Amir H. Lebaschi ◽  
Yusuke Nakagawa ◽  
Camila B. Carballo ◽  
Tyler J. Uppstrom ◽  
...  
Keyword(s):  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Treadmill Running ◽  
Cuff Repair

scholarly journals Is a Local Administration of Parathyroid Hormone Effective to Tendon‐to‐Bone Healing in a Rat Rotator Cuff Repair Model?

2019 ◽  
Vol 38 (1) ◽  
pp. 82-91 ◽  
Author(s):  
Jong Pil Yoon ◽  
Seok Won Chung ◽  
Jae Wook Jung ◽  
Yong‐Soo Lee ◽  
Kwang‐Il Kim ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Local Administration ◽  
Cuff Repair

scholarly journals Biomechanical evaluation of a novel double rip-stop technique with medial row knots for rotator cuff repair

2020 ◽  
Vol 9 (6) ◽  
pp. 285-292
Author(s):  
Zhanwen Wang ◽  
Hong Li ◽  
Zeling Long ◽  
Subin Lin ◽  
Andrew R. Thoreson ◽  
...  
Keyword(s):  
Rotator Cuff ◽  
Rotator Cuff Repair ◽  
Failure Modes ◽  
Failure Load ◽  
Biomechanical Properties ◽  
Gap Formation ◽  
Ultimate Failure Load ◽  
Fresh Frozen ◽  
Ultimate Failure ◽  
Cuff Repair

Aims Many biomechanical studies have shown that the weakest biomechanical point of a rotator cuff repair is the suture-tendon interface at the medial row. We developed a novel double rip-stop (DRS) technique to enhance the strength at the medial row for rotator cuff repair. The objective of this study was to evaluate the biomechanical properties of the DRS technique with the conventional suture-bridge (SB) technique and to evaluate the biomechanical performance of the DRS technique with medial row knots. Methods A total of 24 fresh-frozen porcine shoulders were used. The infraspinatus tendons were sharply dissected and randomly repaired by one of three techniques: SB repair (SB group), DRS repair (DRS group), and DRS with medial row knots repair (DRSK group). Specimens were tested to failure. In addition, 3 mm gap formation was measured and ultimate failure load, stiffness, and failure modes were recorded. Results The mean load to create a 3 mm gap formation in the DRSK and DRS groups was significantly higher than in the SB group. The DRSK group had the highest load to failure with a mean ultimate failure load of 395.0 N (SD 56.8) compared to the SB and DRS groups, which recorded 147.1 N (SD 34.3) and 285.9 N (SD 89.8), respectively (p < 0.001 for both). The DRS group showed a significantly higher mean failure load than the SB group (p = 0.006). Both the DRS and DRSK groups showed significantly higher mean stiffness than the SB group. Conclusion The biomechanical properties of the DRS technique were significantly improved compared to the SB technique. The DRS technique with medial row knots showed superior biomechanical performance than the DRS technique alone.

scholarly journals Pulsed electromagnetic field therapy improves tendon-to-bone healing in a rat rotator cuff repair model

2016 ◽  
Vol 35 (4) ◽  
pp. 902-909 ◽  
Author(s):  
Jennica J. Tucker ◽  
James M. Cirone ◽  
Tyler R. Morris ◽  
Courtney A. Nuss ◽  
Julianne Huegel ◽  
...  
Keyword(s):  
Electromagnetic Field ◽  
Rotator Cuff ◽  
Bone Healing ◽  
Rotator Cuff Repair ◽  
Pulsed Electromagnetic Field ◽  
Field Therapy ◽  
Pulsed Electromagnetic ◽  
Pulsed Electromagnetic Field Therapy ◽  
Cuff Repair
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