Impaired Tendon Healing Research Articles

Biomechanical Analysis of Knotless Flexor Tendon Repair Using Large-Diameter Unidirection Barbed Suture

In traditional flexor tendon repairs, suture knots can be sites of weakness, impair tendon healing, stimulate an inflammatory response, and increase the bulk of the tendon repair. Because of this, there has been an increased interest in knotless flexor tendon repair using barbed suture. Since knots are not required, it may be possible to increase the strength of the tendon repair by using a large-diameter barbed suture. The purpose of this study was to biomechanically compare a traditional four-strand tendon repair using 3-0 braided polyester with a similar knotless four-strand tendon repair using 0 unidirectional barbed suture. Twenty-two matched cadaveric flexor digitorum profundus tendons were lacerated and assigned to repair by a four-strand modified Kirchmayr-Kessler technique using 3-0 braided polyester (n = 11) or knotless four-strand modified Kirchmayr-Kessler repair using 0 unidirectional barbed suture (n = 11). Repaired tendons were linearly distracted to failure at 20mm/min after 1N preload. Maximum load and load at 2-mm gap formation were recorded. Maximum load and load at 2-mm gap formation were compared with the Student's t test, and p values ≤ 0.05 were considered significant. The mean maximum load of the barbed, knotless suture repair was higher than that of the traditional repair (52 vs. 42N). There was no difference between the two groups in the mean load required to produce a 2-mm gap. The four-strand knotless tendon repairs using a large-diameter unidirectional barbed suture were stronger than the traditional four-strand repairs using 3-0 braided polyester, and had similar 2-mm gap resistance.

Biomechanical analysis of regenerated rotator cuff tendon-to-bone junction by acellular matrix bioscaffold combined with a local controlled release of FGF-2

Triamcinolone acetonide (TA) injections are widely used for the treatment of rotator cuff injury with the possible side effects of tendon rupture and impaired tendon healing. Platelet rich plasma (PRP) has recently been reported to participate in the tissue repair processes. Based on these scientific backgrounds, the objective of this study was to determine whether TA has deleterious effects on the cells, and whether PRP has protective effects upon the deleterious effect caused by TA. After exposure to TA for 7 days, cell morphology became flattened and polygonal, and the cell number decreased, while cell morphology in the TA+PRP and PRP groups showed no change. The cell viability in the TA group significantly decreased at day 7. However, cell viability in the TA+PRP group was significantly progressed at days 7 and 14 when compared with the TA group. Flow cytometry showed that the percentage of apoptotic cells in the TA group significantly increased compared with control group. On the other hand, in the TA+PRP group, the percentages of apoptotic cells significantly decreased compared with TA group. Our results indicated that TA significantly decreased the viability of human rotator cuff-derived cells and caused cell apoptosis. However, these deleterious effects were prevented by the simultaneous administration of PRP. Therefore, PRP can be useful in clinical situations as a protective agent for patients receiving local TA injections.

Effects of steroids and platelet rich plasma on rotator cuff derived cells

Triamcinolone acetonide (TA) injections are widely used for the treatment of rotator cuff injury with the possible side effects of tendon rupture and impaired tendon healing. Platelet rich plasma (PRP) has recently been reported to participate in the tissue repair processes. Based on these scientific backgrounds, the objective of this study was to determine whether TA has deleterious effects on the cells, and whether PRP has protective effects upon the deleterious effect caused by TA. After exposure to TA for 7 days, cell morphology became flattened and polygonal, and the cell number decreased, while cell morphology in the TA+PRP and PRP groups showed no change.

The effects of dexamethasone on human patellar tendon stem cells: Implications for dexamethasone treatment of tendon injury

Injection of Dexamethasone (Dex) is commonly used in clinics to treat tendon injury such as tendinopathy because of its anti-inflammatory capabilities. However, serious adverse effects have been reported as a result of Dex treatment, such as impaired tendon healing and tendon rupture. Using both in vitro and in vivo approaches, this study was to determine the effects of Dex treatment on the proliferation and differentiation of human tendon stem cells (hTSCs), which can directly impact tendon healing. We found that Dex treatment stimulated cell proliferation at lower concentrations (<1,000 nM), whereas a high concentration (1,000 nM) decreased cell proliferation. Moreover, at all concentrations used (5, 10, 100, and 1,000 nM), Dex treatment induced non-tenocyte differentiation of hTSCs, as evidenced by a change in cell shape, a nearly complete suppression of collagen type I expression, and an upregulation of non-tenocyte related genes (PPARγ and Sox-9), which was especially evident when higher concentrations (>10 nM) of Dex were used. Implantation of Dex-treated hTSCs for a short time (3 weeks) resulted in the extensive formation of fatty tissues, cartilage-like tissues, and bony tissues. These findings suggest that Dex treatment in clinics may cause a paradoxical effect on the injured tendons it is supposed to treat: by inducing non-tenocyte differentiation of hTSCs, Dex treatment depletes the stem cell pool and leads to the formation of non-tendinous tissues (e.g., fatty and cartilage-like tissues), which make tendon susceptible to rupture.

Tendon‐derived stem/progenitor cell aging: defective self‐renewal and altered fate

Aging is a major risk factor for tendon injury and impaired tendon healing, but the basis for these relationships remains poorly understood. Here we show that rat tendon- derived stem ⁄ progenitor cells (TSPCs) differ in both self-renewal and differentiation capability with age. The frequency of TSPCs in tendon tissues of aged animals is markedly reduced based on colony formation assays. Proliferation rate is decreased, cell cycle progression is delayed and cell fate patterns are also altered in aged TSPCs. In particular, expression of tendon lineage marker genes is reduced while adipocytic differentiation increased. Cited2, a multi-stimuli responsive transactivator involved in cell growth and senescence, is also downregulated in aged TSPCs while CD44, a matrix assembling and organizing protein implicated in tendon healing, is upregulated, suggesting that these genes participate in the control of TSPC function.

Negative effects of parecoxib and indomethacin on tendon healing: an experimental study in rats

Conventional non-steroidal anti-inflammatory drugs (NSAIDs) and newer specific cyclooxygenase-2 (cox-2) inhibitors are commonly used in muscular skeletal trauma and in relation to orthopedic surgery to reduce the inflammatory response and pain. Studies have indicated that these drugs can have a negative effect on tendon healing in the early proliferative phase, but might be beneficial in the remodeling phase when inflammation might impede healing. Our study was designed to investigate if short-term administration of cox inhibitors after injury or postoperatively might have negative effects on the tendon healing. The right Achilles tendon of 60 rats was cut transversely, a 3 mm long segment of the tendon was removed and left unrepaired. The animals were then given parecoxib, indomethacin or saline intraperitoneally twice daily for 7 days. After 14 days, the animals were euthanized. The transverse and sagittal diameters in the healing area were measured and mechanical testing of the tensile strength of the tendons was performed. We found a significantly lower tensile strength in rats given both parecoxib and indomethacin compared to the control group. Stiffness in the healing tendons was significantly lower in the parecoxib group compared to both the placebo and the indomethacin groups. The transverse and sagittal diameters of the tendons were reduced in both the parecoxib and indomethacin groups. Both parecoxib and indomethacin impaired tendon healing; the negative effect was most pronounced with parecoxib.

Dexamethasone induces apoptosis in proliferative canine tendon cells and chondrocytes

Dexamethasone (Dexa) has been commonly used in humans and domestic animals, particularly in the treatment of tendon injuries and cartilage degeneration. However, it is often associated with tendon rupture and impaired tendon and cartilage healing. In the present study, we investigated Dexa's in vitro effects on the growth of cell proliferation and the induction of apoptosis in canine Achilles tendon cells and chondrocytes. Cell proliferation after treatment with Dexa for two to six days was quantified by a 2,3-bis{2-methoxy-4-nitro-5-sulfophenyl}-2H-tetrazolium-5-carboxyanilide inner salt assay (XTT). The results showed that Dexa could inhibit the proliferation of tendon cells and chondrocytes at increasing concentrations (0.1-50 microg/ml) compared with untreated cells. Cell apoptosis was induced by Dexa, as evidenced by the typical nuclear apoptosis using Hoechst 33258 staining. Dexa increased the apoptosis of canine tendon cells and chondrocytes in a time-dependent manner. In canine tendon cells and chondrocytes that were treated with 25 and 50 microg/ml concentration of Dexa, the number of condensed apoptotic nuclei was significantly increased. In addition, culturing with Dexa and the glucocorticoid receptor blocker, mifepristone, significantly arrested apoptosis of tendon cells and chondrocytes. Based on our in vitro data, we hypothesized that in vivo treatment with glucocorticoids may diminish the proliferation of tendon and cartilage cells by increasing apoptosis and suppressing the proliferation. Our findings suggest that Dexa could be used with caution in dogs with articular or tendon problems.

Low molecular weight heparin impairs tendon repair

Thrombin has many biological properties similar to those of growth factors. In a previous study, we showed that thrombin improves healing of the rat tendo Achillis. Low molecular weight heparin (LMWH) inhibits the activity and the generation of thrombin. We therefore considered that LMWH at a thromboprophylactic dose might inhibit tendon repair. Transection of the tendo Achillis was carried out in 86 rats and the healing tested mechanically. Low molecular weight heparin (dalateparin) was either injected a few minutes before the operation and then given continuously with an osmotic mini pump for seven days, or given as one injection before the operation. In another experiment ,we gave LMWH or a placebo by injection twice daily. The anti-factor Xa activity was analysed. Continuous treatment with LMWH impaired tendon healing. After seven days, this treatment caused a 33% reduction in force at failure, a 20% reduction in stiffness and a 67% reduction in energy uptake. However, if injected twice daily, LMWH had no effect on tendon healing. Anti-factor Xa activity was increased by LMWH treatment, but was normal between intermittent injections. Low molecular weight heparin delays tendon repair if given continuously, but not if injected intermittently, probably because the anti-factor Xa activity between injections returns to normal, allowing sufficient thrombin stimulation for repair. These findings indicate the need for caution in the assessment of long-acting thrombin and factor Xa inhibitors.

Glucocorticoids inhibit tenocyte proliferation and Tendon progenitor cell recruitment

Corticosteroid injection is commonly used to treat tendon injuries but is often associated with tendon rupture and impaired tendon healing. The effects of dexamethasone on tenocytes have been studied in vitro but only using high concentrations of dexamethasone in monolayer cultures of tenocytes over short periods of time. We have therefore investigated the effects of physiological and pharmacological concentrations of dexamethasone on monolayer cultures of tenocytes over extended time periods. We have also used fibroblastic-colony forming unit cultures to examine the effects of dexamethasone on a progenitor cell population located in tendons. Culturing tenocytes in the presence of dexamethasone for a period of 24 days resulted in a concentration-related decrease in cell number and collagen synthesis as compared to control cultures. This effect was time dependent with cell number in both dexamethasone-treated and control cultures leveling off after 14 days with the control cultures reaching higher cell densities. In contrast in control cultures, collagen accumulation continued to increase until week 4, whereas in the presence of dexamethasone, this tended to level off after 14 days. To study the role of progenitor cell recruitment, the effects of dexamethasone were investigated using the fibroblastic-colony forming unit assay. Treatment with dexamethasone at concentrations of 0.1 nM to 10 microM leads to a progressive reduction in mean colony size as compared to control cultures. Colony number remained constant at concentrations below 10 nM but fell progressively at concentrations above this. In conclusion, dexamethasone reduces both cell number and collagen synthesis in tenocyte cultures in a concentration-dependent manner by both direct effects on tenocyte proliferation and collagen accumulation, and also by modulating the recruitment of tendon progenitor cells.

Microarray Analysis of Mechanical Shear Effects on Flexor Tendon Cells

Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon strength. The authors hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing. To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis. Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, the authors also found up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with the authors' microarray data. The authors demonstrate an overall antifibrotic expression pattern in response to shear stress in tendon cells that may provide insight into the mechanisms by which early mobilization decreases adhesion formation without impaired tendon healing.