Minocycline microspheres did not significantly improve outcomes after collagenase injection of tendon.
ABSTRACT: Background:Tetracycline antibiotics inhibit matrix metalloproteinases and pro-inflammatory cytokines implicated in the pathogenesis of tendinopathy, while microsphere formulations allow sustained release of drug contents. The purpose of this study was to evaluate the ability of a local minocycline microsphere injection to restore normal tendon properties in a rat model of collagenase-induced patellar tendinopathy. Methods:A total of 22 rats were randomly assigned to the control (n?=?11) or minocycline (n?=?11) group and received bilateral patellar tendon injections of collagenase. After 7 days, the minocycline group received the minocycline microsphere treatment and the control group received phosphate buffered solution. Pain was assessed via activity monitors and Von Frey filament testing. At 4 weeks post-collagenase injections, animals were euthanized. Results:Cage crossings significantly decreased among all rats 2-3 days following each injection period, however, tactile allodynia measures did not reflect this injury response. Biomechanical properties, interleukin-1 beta levels, and glycosaminoglycan content did not differ between groups. While not statistically significant, levels of leukotriene B4 were lower in the minocycline group compared to controls (p?=?0.061), suggesting a trend. Conclusions:Our study further characterizes the collagenase model of tendinopathy by demonstrating no evidence of central sensitization with collagenase-induced injury. We found no adverse effect of intratendinous injections of minocycline-loaded poly-lactic-co-glycolic acid microspheres, although no therapeutic effect was observed. Future studies involving a more substantial tendon injury with a greater inflammatory component may be necessary to more thoroughly evaluate the effects of minocycline on tendon pathology.
Project description:Patellar tendinopathy is a common condition. There are a wide variety of treatment options available, the majority of which are nonoperative. No consensus exists on the optimal method of treatment.PubMed spanning 1962-2014.Clinical review.Level 4.The majority of cases resolve with nonoperative therapy: rest, physical therapy with eccentric exercises, cryotherapy, anti-inflammatories, corticosteroid injections, extracorporeal shockwave therapy, glyceryl trinitrate, platelet-rich plasma injections, and ultrasound-guided sclerosis. Refractory cases may require either open or arthroscopic debridement of the patellar tendon. Corticosteroid injections provide short-term pain relief but increase risk of tendon rupture. Anti-inflammatories and injectable agents have shown mixed results. Surgical treatment is effective in many refractory cases unresponsive to nonoperative modalities.Physical therapy with an eccentric exercise program is the mainstay of treatment for patellar tendinopathy. Platelet-rich plasma has demonstrated mixed results; evidence-based recommendations on its efficacy cannot be made. In the event that nonoperative treatment fails, surgical intervention has produced good to excellent outcomes in the majority of patients.
Project description:Our goal was to develop a novel technique for inducing Achilles tendinopathy in animal models which more accurately represents the progressive histological and biomechanical characteristic of chronic Achilles tendinopathy in humans. In this animal research study, forty-five rabbits were randomly assigned to three groups and given bilateral Achilles injections. Low dose (LD group) (n = 18) underwent a novel technique with three low-dose (0.1mg) injections of collagenase that were separated by two weeks, the high dose group (HD) (n = 18) underwent traditional single high-dose (0.3mg) injections, and the third group were controls (n = 9). Six rabbits were sacrificed from each experimental group (LD and HD) at 10, 12 and 16 weeks. Control animals were sacrificed after 16 weeks. Histological and biomechanical properties were then compared in all three groups. At 10 weeks, Bonar score and tendon cross sectional area was highest in HD group, with impaired biomechanical properties compared to LD group. At 12 weeks, Bonar score was higher in LD group, with similar biomechanical findings when compared to HD group. After 16 weeks, Bonar score was significantly increased for both LD group (11,8±2,28) and HD group (5,6±2,51), when compared to controls (2±0,76). LD group showed more pronounced histological and biomechanical findings, including cross sectional area of the tendon, Young's modulus, yield stress and ultimate tensile strength. In conclusion, Achilles tendinopathy in animal models that were induced by serial injections of low-dose collagenase showed more pronounced histological and biomechanical findings after 16 weeks than traditional techniques, mimicking better the progressive and chronic characteristic of the tendinopathy in humans.
Project description:BACKGROUND: Ectopic expression of BMP-2, BMP-4 and BMP-7 was observed in clinical samples of tendinopathy and collagenase-induced (CI) tendon injury rat model. TDSCs isolated from the CI model showed increased non-tenogenic differentiation potential and hence altered fate compared to the TDSCs isolated from the healthy animals (HT) but the mechanism is unclear. We hypothesized that sensitization of the BMP/Smad pathway in TDSCs (CI) might account for this difference. This study aimed to compare the activation state of the BMP/Smad pathway at basal level and upon BMP-2 stimulation in TDSCs (CI) and TDSCs (HT). METHODS: Collagenase or saline was injected into the patellar tendon of rats for 2 weeks. TDSCs (CI) and TDSCs (HT) were then isolated from the patellar tendon. The mRNA and protein expression of BMPs and BMP receptors in TDSCs (CI) and TDSCs (HT) were analysed. TDSCs from both sources were treated with rhBMP-2 and the expression of phosphorylated and total Smad1/5/8 was examined. RESULTS: Except for the mRNA levels of Bmp7 and Bmpr2, there were significant higher mRNA and protein expression of BMPs and BMP receptors in TDSCs (CI) compared to TDSCs (HT). TDSCs (CI) showed higher basal expression of total Smad1/5/8 but similar basal level of phosphorylated Smad1/5/8 compared to TDSCs (HT). TDSCs (CI) exhibited higher total and phosphorylated Smad1/5/8 upon BMP-2 stimulation. CONCLUSIONS: The sensitization of the BMP/Smad pathway in TDSCs (CI) might account for their higher non-tenogenic differentiation potential and hence altered fate. It also provided further support of BMPs and the BMP/Smad signaling pathway in the pathogenesis of tendinopathy.
Project description:Introduction:The effect of chronic patellar tendinopathy on tissue function and integrity is currently unclear and underinvestigated. The aim of this cohort comparison was to examine morphological, material, and mechanical properties of the patellar tendon and to extend earlier findings by measuring the ability to store and return elastic energy in symptomatic tendons. Methods:Seventeen patients with chronic (>3 months, VISA-P < 80), inferior pole patellar tendinopathy (24 ± 4 years; male = 12, female = 5) were carefully matched to controls (25 ± 3 years) for training status, pattern, and history of loading of the patellar tendon. Individual knee extension force, patellar tendon stiffness, stress, strain, Young's modulus, hysteresis, and energy storage capacity, were obtained with combined dynamometry, ultrasonography, magnetic resonance imaging, and electromyography. Results:Anthropometric parameters did not differ between groups. VISA-P scores ranged from 28 to 78 points, and symptoms had lasted from 10 to 120 months before testing. Tendon proximal cross-sectional area was 61% larger in the patellar tendinopathy group than in the control group. There were no differences between groups in maximal voluntary isometric knee extension torque (p = 0.216; d < -0.31) nor in tensile tendon force produced during isometric ramp contractions (p = 0.185; d < -0.34). Similarly, tendon strain (p = 0.634; d < 0.12), hysteresis (p = 0.461; d < 0.18), and strain energy storage (p = 0.656; d < 0.36) did not differ between groups. However, patellar tendon stiffness (-19%; p = 0.007; d < -0.74), stress (-27%; p< 0.002; d < -0.90) and Young's modulus (-32%; p = 0.001; d < -0.94) were significantly lower in tendinopathic patients compared to healthy controls. Discussion:In this study, we observed lower stiffness in affected tendons. However, despite the substantial structural and histological changes occurring with tendinopathy, the tendon capacity to store and dissipate energy did not differ significantly.
Project description:PURPOSE: The efficacy of platelet-rich plasma (PRP) in the treatment and healing of chronic tendinopathy through stimulation of cell proliferation and total collagen production has been demonstrated by both in vitro and in vivo studies. The aim of this study is to evaluate the effectiveness of ultrasound (US)-guided autologous PRP injections in patellar and Achilles tendinopathy. MATERIALS AND METHODS: Autologous PRP was injected under US-guidance into the Achilles and patellar tendons (30 Achilles tendons, 28 patellar tendons) in 48 prospectively selected patients (30 males, 18 females, mean age 38 ± 16 years, range 20-61 years). All patients were previously evaluated according to the Victoria Institute of Sport Assessment (VISA) scale, which assessed pain and activity level, and they all underwent US of the tendon before treatment and at follow-up after 20 days and 6 months. Statistical analysis was performed with Chi-square and Wilcoxon tests. RESULTS: 20 days after PRP injection the patients presented a non-significant improvement of clinical symptoms. At the 6-month follow-up VISA score increased from a mean value of 57-75.5 (p < .01). US evaluation revealed a reduction of hypoechoic areas in 26 tendons (p < .01) associated with a widespread improvement of fibrillar echotexture of the tendon and reduced hypervascularity at power Doppler. CONCLUSION: PRP injection in patellar and Achilles tendinopathy results in a significant and lasting improvement of clinical symptoms and leads to recovery of the tendon matrix potentially helping to prevent degenerative lesions. US-guidance allows PRP injection into the tendon with great accuracy.
Project description:Mesenchymal stromal cells attract much interest in tissue regeneration because of their capacity to differentiate into mesodermal origin cells, their paracrine properties and their possible use in autologous transplantations. The aim of this study was to investigate the safety and reparative potential of implanted human mesenchymal stromal cells (hMSCs), prepared under Good Manufacturing Practice (GMP) conditions utilizing human mixed platelet lysate as a culture supplement, in a collagenase Achilles tendon injury model in rats.Eighty-one rats with collagenase-induced injury were divided into two groups. The first group received human mesenchymal stromal cells injected into the site of injury 3 days after lesion induction, while the second group received saline. Biomechanical testing, morphometry and semiquantitative immunohistochemistry of collagens I, II and III, versican and aggrecan, neovascularization, and hMSC survival were performed 2, 4, and 6 weeks after injury.Human mesenchymal stromal cell-treated rats had a significantly better extracellular matrix structure and a larger amount of collagen I and collagen III. Neovascularization was also increased in hMSC-treated rats 2 and 4 weeks after tendon injury. MTCO2 (Cytochrome c oxidase subunit II) positivity confirmed the presence of hMSCs 2, 4 and 6 weeks after transplantation. Collagen II deposits and alizarin red staining for bone were found in 6 hMSC- and 2 saline-treated tendons 6 weeks after injury. The intensity of anti-versican and anti-aggrecan staining did not differ between the groups.hMSCs can support tendon healing through better vascularization as well as through larger deposits and better organization of the extracellular matrix. The treatment procedure was found to be safe; however, cartilage and bone formation at the implantation site should be taken into account when planning subsequent in vivo and clinical trials on tendinopathy as an expected adverse event.
Project description:UNLABELLED: Aprotinin is a broad spectrum proteinase inhibitor (including matrix metalloproteinase [MMP] inhibitor) used for treating patellar and Achilles tendinopathies. One previous randomized control trial demonstrated aprotinin injections superior to both corticosteroid and saline injections in patellar tendinopathy (Level II), whereas results reported for aprotinin treatment in Achilles tendinopathy have been mixed. We performed a case review and followup questionnaire for 430 consecutive patients with tendinopathy treated by 997 aprotinin injections (30,000 KIU). A response rate of 72% was achieved with a minimum followup of 3 months (average, 12.2 months; range, 3-54 months). Seventy-six percent of patients had improved, 22% of patients reported no change, and 2% were worse. Sixty-four percent of patients thought aprotinin injections were helpful, while 36% believed they had neither a positive nor negative effect. Mid-Achilles tendinopathy patients (84% improvement) were more successfully treated than patellar tendinopathy patients (69% improvement). Despite stronger published evidence of benefit in patellar tendinopathy, clinical outcomes appeared better with aprotinin use in Achilles tendinopathies. LEVEL OF EVIDENCE: Level IV, case series.
Project description:The prevalence of patellar tendinopathy is elevated in elite soccer compared to less explosive sports. While the burden of training hours and load is comparably high in youth elite players (age < 23 years), little is known about the prevalence of patellar tendinopathy at this age. There is only little data available on the influence of age, the amount of training, the position on the field, as well as muscular strength, range of motion, or sonographical findings in this age group. The purpose of the present study was to examine the above-mentioned parameters in all age groups of a German youth elite soccer academy.One hundred nineteen male youth soccer players (age 15,97 ± 2,24 years, height 174, 60 ± 10,16 cm, BMI 21, 24 ± 2,65) of the U-13 to U-23 teams were part of the study. Data acquisition included sport specific parameters such as footwear, amount of training hours, leg dominance, history of tendon pathologies, and clinical examination for palpatory pain, indurations, muscular circumference, and range of motion. Subjective complaints were measured with the Victorian Institute of Sport Assessment Patellar (VISA-P) Score. Furthermore, sonographical examinations (Aplio SSA-770A/80; Toshiba, Tokyo, Japan) with 12-MHz multifrequency linear transducers (8-14 MHz) of both patellar tendons were performed with special emphasis on hyper- and hypo echogenic areas, diameter and neovascularization.The prevalence of patellar tendinopathies was 13.4%. Seventy-five percent of the players complained of pain of their dominant leg with onset of pain at training in 87.5%. The injured players showed a medium amount of 10.34 ± 3.85 training hours and a medium duration of symptoms of 11.94 ± 18.75 weeks. Two thirds of players with patellar tendinopathy were at the age of 15-17 (Odds ratio 1.89) while no differences between players of the national or regional league were observed. In case of patellar tendinopathy, VISA-P was significantly lower in comparison to healthy players (mean ± SD 76.80 ± 28.56 points vs. 95.85 ± 10.37). The clinical examination revealed local pain at the distal patella, pain at stretching, and thickening of the patellar tendon (p = 0.02). The mean tendon diameter measured 2 cm distally to the patella was 4.10 ± 0.68 mm with a significantly increased diameter of 0.15 mm in case of an underlying tendinopathy (p = 0.00). The incidence of hypo-echogenic areas and neovascularizations was significantly elevated in players with patellar tendon syndrome (PTS) (p = 0.05).The prevalence of patellar tendinopathy in youth elite soccer is relatively high in comparison to available data of adult players. Especially players at the age of 15 to 17 are at considerable risk. Tendon thickening, hypo-echogenic areas, and neovascularization are more common in tendons affected by PTS.
Project description:We partnered with Zymo Research, Inc. to detect genome-wide methylation changes associated with the initiation and progression of tendinopathy induced by TGF-β1 in a murine Achilles tendon model. All genes identified as significantly differentially methylated were present in only one experimental group showing that both the gene identified and its modified methylation status are dependent on the injury time-course and activity level. In summary, we identified five genes (Leprel2, Foxf1, Mmp25, Igfbp6 and Peg12) which demonstrate significant relevance to tendon biology with three exhibiting functions in collagen fibril organization. We postulate that a study of the molecular genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multifactorial disease. Overall design: Chronic Achilles tendinopathy was induced in WT C57/Bl6 male mice via two injections of TGF-β1 directly into the body of the tendon. Methylome analysis was conducted on the tendon DNA for the acute (3 day) response as well as the chronic response (14 and 28 days) under normal cage activity or with treadmill running and compared to un-injured mice.
Project description:INTRODUCTION:Patellar tendinopathy is a degenerative disease of the patellar tendon, which affects athletes from a variety of sports, and is especially predominant in sports involving high-impact jumping. The aim of this study is to determine the additional effect of two interventions combined with eccentric exercise and compare which one is the most effective at short-term and long-term follow-up for patients with patellar tendinopathy. METHODS AND ANALYSIS:This study is a randomised controlled trial with blinded participants. Measurements will be carried out by a specially trained blinded assessor. A sample of 57 patients with a medical diagnosis of patellar tendinopathy will participate in this study and will be divided into three treatment groups. Eligible participants will be randomly allocated to receive either: (a) treatment group with percutaneous needle electrolysis, (b) treatment group with dry needling or (c) treatment group with placebo needling. In addition, all groups will perform eccentric exercise. Functionality and muscle strength parameters, pain, ultrasound appearances and patient perceived quality of life shall be evaluated using the Victorian Institute of Sports Assessment for patellar (VISA-P), jump tests, Visual Analogue Scale, ultrasound images and Short Form-36 (SF-36), respectively. Participants will be assessed at baseline, at 10 weeks and at 22 weeks after baseline. The expected findings will allow us to advance in the treatment of this injury, as they will help determine whether a needling intervention has additional effects on an eccentric exercise programme and whether any of the needling modalities is more effective than the other. ETHICS AND DISSEMINATION:This protocol has been approved by the Ethics Committee of Aragon (N° PI15/0017). The trial will be conducted in accordance with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER:NCT02498795.