Is the Superficial Peritendinous Tissue an Additional Pain Driver in Patellar Tendinopathy?-Studies on Morphology and Innervation in a Case Series.

Background and Objectives: Ultrasound (US) and Doppler (DP) guided arthroscopic shaving targeting the area with neovessels and nerves on the dorsal side of the tendon has shown good clinical results. Recently, we observed that in a sub-group of patients there is also local tenderness on the superficial side of the proximal patellar tendon; Material and Methods: The aim was to examine morphology and innervation patterns of the superficial peritendinous tissue from patients (four men and two women; mean age 23 years, range 17-31 years) that on US+DP examination showed a locally thickened paratenon including high blood flow. Tissue sections were stained for morphology (hematoxylin and eosin, H&E) and immunohistochemically for nerve markers (ß-tubulin; tyrosine hydroxylase, TH; calcitonin related gene peptide, CRGP); Results: All tissue specimens contained high levels of blood vessels and nerves (fascicles, sprouting nerve fibers, perivascular innervation) as evidenced by evaluation for H&E and ß-tubulin reactions. Nerve fascicles mainly contained sensory but also sympathetic axons. Nerves related to blood vessels were sympathetic fibers; Conclusions: There was a marked innervation in the superficial peritendinous tissue in a sub-group of patients with patellar tendinopathy and severe tenderness in the proximal patellar tendon. The results indicate that this tissue might be an additional pain driver in some patients and should be considered in further studies.

Autonomic responses to ultrasound-guided percutaneous needle electrolysis of the patellar tendon in healthy male footballers.

BACKGROUND: Ultrasound (US)-guided percutaneous needle electrolysis (PNE) is a novel minimally invasive approach, which involves the application of a galvanic current via an acupuncture needle. As in any procedure involving needling, vagal reactions have been reported during PNE. OBJECTIVE: To examine for changes in autonomic activity during the US-guided PNE technique on healthy patellar tendons by measurement and analysis of heart rate variability (HRV). METHODS: Twenty-two male footballers were randomly allocated to: a control group (11 players), for whom HRV was recorded for 10 min, both at rest and during an exhaustive US examination of the patellar tendon and adjacent structures; and an experimental group (11 players), for whom HRV was recorded for 10 min, both at rest and during application of US-guided PNE on the patellar tendon. The following HRV parameters were assessed: mean NN interval, mean heart rate, time domain parameters (SDNN, rMSSD, pNN50), diameters of the Poincaré plot (SD1, SD2), stress score, and sympathetic/parasympathetic ratio. RESULTS: There were no differences between groups in any baseline measurements, nor were there any significant differences between control group measurements (baseline vs intervention). The experimental group exhibited statistically significant increases in SDNN/SD1 (p=0.02/p=0.03) and SD2 (p=0.03), indicating increased parasympathetic and decreased sympathetic activity, respectively. CONCLUSIONS: US-guided PNE was associated with an autonomic imbalance characterised by greater parasympathetic activity, which could potentially result in a vasovagal reaction. Care should be taken to monitor for adverse reactions during US-guided PNE and simple HRV indicators may have a role in early detection.

Coexistence of up-regulated NMDA receptor 1 and glutamate on nerves, vessels and transformed tenocytes in tendinopathy.

Elevated levels of the neurotransmitter glutamate and the presence of its receptor, N-methyl-d-aspartate receptor type 1 (NMDAR1), have been established in patients with tendinopathy, i.e. chronic tendon pain and degeneration. However, whether NMDAR1 is up- or down-regulated in tendinopathy and co-localized with glutamate is still unexplored. We hypothesize that an alteration in tissue expression and in the coexistence of NMDAR1 and glutamate occurs in tendinopathy and might play a role in nociception and possibly also progression of tendon degeneration (tendinosis). We therefore examined the tissue distribution and levels of NMDAR1 and glutamate in biopsies from patients with patellar tendinopathy (n=10) and from controls (n=8). The biopsies were single- and double-stained immunohistochemically for glutamate and NMDAR1 and assessed subjectively and semi-quantitatively. The chronic painful tendons exhibited a significant elevation of NMDAR1 (ninefold), which was independent of the observed increase in glutamate (10-fold). This up-regulation of NMDAR1 and glutamate was found to be co-localized on nerve fibers as well as on morphologically altered tenocytes and blood vessels. None of the controls exhibited neuronal coexistence of glutamate and NMDAR1. The neuronal coexistence of glutamate and NMDAR1, observed in painful tendinosis but not in controls, suggests a regulatory role in intensified pain signalling.

Effects of static and dynamic training on the stiffness and blood volume of tendon in vivo.

The purpose of this study was to investigate the effects of static and dynamic training on the stiffness and blood volume of the human tendon in vivo. Ten subjects completed 12 wk (4 days/wk) of a unilateral training program for knee extensors. They performed static training on one side [ST; 70% of maximum voluntary contraction (MVC)] and dynamic training on the other side (DT; 80% of one repetition maximum). Before and after training, MVC, neural activation level (by interpolated twitch), muscle volume (by magnetic resonance imaging), stiffness of tendon-aponeurosis complex and patella tendon (by ultrasonography), and blood volume of patella tendon (by red laser lights) were measured. Both protocols significantly increased MVC (49% for ST, 32% for DT; both P < 0.001), neural activation level (9.5% for ST, 7.6% for DT; both P < 0.01), and muscle volume (4.5% for ST, 5.6% for DT; both P < 0.01). The stiffness of tendon-aponeurosis complex increased significantly after ST (55%; P = 0.003) and DT (30%; P = 0.033), while the stiffness of patella tendon increased significantly after ST (83%; P < 0.001), but not for DT (P = 0.110). The blood volume of patella tendon increased significantly after DT (47%; P = 0.016), but not for ST (P = 0.205). These results implied that the changes in the blood volume of tendon would be related to differences in the effects of resistance training on the tendon properties.

[Patellar tendinopathy ('jumper's knee'); a common and difficult-to-treat sports injury]. / Patellatendinopathie ('jumper's knee'); een veelvoorkomende en lastig te behandelen sportblessure.

Patellar tendinopathy is a common and difficult-to-treat overuse injury of the patellar tendon with a very negative impact on the careers of many athletes. It appears to involve a failed healing process in the tendon--not inflammation--and has consequences for the treatment strategy. Rehabilitation programs are based on the principles of load reduction and an eccentric exercise program to improve muscle-tendon function and optimize the kinetic chain. Prolonged rehabilitation is necessary because of slow tendon recovery. Anti-inflammatory treatment is often unsuccessful. Surgery does not guarantee a quick symptom-free return to sport at the original level either. Extracorporeal shock wave therapy, ultrasound-guided sclerosing of new vessels and tendinous and peritendinous injections of aprotinin and autologous growth factors seem to be promising new treatment options.

Marked sympathetic component in the perivascular innervation of the dorsal paratendinous tissue of the patellar tendon in arthroscopically treated tendinosis patients.

During the recent years, a few studies have shed new light on the innervation patterns of the human patellar tendon, but the area of the loose paratendinous connective tissue dorsal to the proximal tendon proper has yet not been investigated. That is a drawback, since this is the area targeted in promising treatment regimens of chronic painful patellar tendinosis, namely sclerosing Polidocanol injection therapy, and a new surgical method conforming to ultrasound and color Doppler guided arthroscopic shaving, directed at neovessels found in the region. The present study thus aimed at investigating the paratendinous area dorsal to the proximal patellar tendon proper in seven patients being operated for tendinosis. Biopsies were collected through the new arthroscopic technique, approaching the tendon from the dorsal side. Samples were investigated using immunohistochemistry with antibodies delineating general (PGP 9.5), sensory (SP/CGRP), and sympathetic (TH/NPY) nerve patterns, and also antibodies against alpha1- and alpha2A-adrenoreceptors. Both small and large blood vessels had a marked perivascular innervation (PGP 9.5). Surprisingly, this perivascular innervation was found only to a very limited extent to correspond to sensory nerves, while there were marked immunoreactions for sympathetic markers. Adrenoreceptor immunoreactions frequently occurred in blood vessel walls. In conclusion, this study demonstrates, for the first time, the innervation patterns of the area dorsal to the patellar tendon in man. It shows that the area investigated is under marked influence by the sympathetic nervous system. Thus, sympathetic effects are likely to occur for blood vessels of the area, which is interesting since color Doppler has revealed that vessels of this area ("neovessels") display a pathologically high blood flow in tendinosis. The findings are discussed in relation to aspects of vascular regulation, and to pain symptoms of tendinosis.

Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man.

Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha1-, alpha2A-, and beta1-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha1-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves

Treatment of Jumper's knee: promising short-term results in a pilot study using a new arthroscopic approach based on imaging findings.

Sclerosing injections targeting the area with neovessels and nerves on the dorsal side of the patellar tendon has been demonstrated as giving promising clinical results in patients with chronic painful Jumper's knee-patellar tendinosis (PT). However, a mean number of three treatments with 6-8 weeks in between were needed for a good clinical result. This study aimed to evaluate a more radical removal of the area with neovessels and nerves by using arthroscopic shaving. Fifteen patients (12 men and three women) with the diagnose Jumper's knee-PT in altogether 15 patellar tendons were included. All patients had a long duration of pain-symptoms (mean 27 months) from the patellar tendon, and ultrasonography (US) + colour Doppler (CD) examination showed structural tendon changes with hypo-echoic areas and a neovascularisation inside and on the dorsal side of the tendon, corresponding to the painful area. All patients were treated with arthroscopic shaving of the dorsal side of the proximal tendon. At follow-up (mean 6 months) after treatment, there was a good clinical result in 13/15 tendons (6/8 elite athletes). The satisfied patients were back to previous (before injury) sport activity level, and the amount of pain recorded on a visual analogue scale (VAS)-scale had decreased significantly (VAS from 79 to 12, P < 0.05). A telephone follow-up 13 months (mean) postoperatively showed that the same 13/15 were still satisfied and active in their sports, and that the 2/15 poor cases were still not satisfied with the treatment. Our short-term results indicate that arthroscopic shaving targeting the area with neovessels and nerves on the dorsal side of the patellar tendon has a potential to reduce the tendon pain and allow for the majority of patients to go back to full tendon loading activity within 2 months after surgery. Further studies evaluating this new technique for treating Jumper's knee-PT are in progress.

The role of osteopontin in tendon tissue remodeling after denervation-induced mechanical stress deprivation.

It has been shown that musculoskeletal tissues undergo dynamic tissue remodeling by a process that is quite sensitive to the mechanical environment. However, the detailed molecular mechanism underlying this process remains unclear. We demonstrate here that after denervation-induced mechanical stress deprivation, tendons undergo dynamic tissue remodeling as evidenced by a significant reduction of the collagen fibril diameter. Importantly, the transient up-regulation of osteopontin (OPN) expression was characteristic during the early phase of tendon tissue remodeling. Following this dynamic change of OPN expression, matrix metalloproteinase (MMP)-13 expression was induced, which presumably accounts for the morphological changes of tendon by degrading tendon collagen fibrils. The modulation of MMP-13 expression by OPN was specific, since the expression of MMP-2, which is also known to be involved in tissue remodeling, did not alter in the tendons under the absence or presence of OPN. We also demonstrate that the modulation of MMP-13 expression by OPN is due to the signaling through cell surface receptors for OPN. Thus, we conclude that OPN plays a crucial role in conveying the effect of denervation-induced mechanical stress deprivation to the tendon fibroblasts to degrade the extracellular matrices by regulating MMP-13 expression in tendon fibroblasts.

Adductor T and H reflexes in humans.

In the belief that changes in the adductor reflex (AR) may be helpful in evaluating lumbar root and plexus lesions, expression of the AR was studied in 43 healthy human subjects. ARs elicited with an electronic reflex hammer were recorded from the inner side of the proximal thigh using needle and surface electrodes, and patellar reflexes (PRs) were recorded simultaneously. These reflexes were obtained by tapping the ipsilateral medial aspect of the knee, the contralateral patellar tendon, the ipsilateral and contralateral anterior superior iliac spines, and the Achilles tendon. The H reflex of the obturator nerve was also evaluated in 17 cases. ARs were evoked consistently by tapping the ipsilateral medial aspect of the knee and by contralateral patellar tap, and by tapping ipsilateral and contralateral anterior superior iliac spines when a needle recording electrode was used. Sometimes an Achilles tendon tap also elicited the AR ipsilaterally. By contrast, the PR could only be elicited by a tap to the ipsilateral patellar tendon. ARs have somewhat different features than other well-known tendon reflexes such as the PR and are recorded consistently when a needle electrode is used, being elicited from both distal and proximal areas of the legs by tapping the Achilles tendon or anterior superior iliac spines unilaterally or bilaterally. Their role in evaluating lumbar root disease and monitoring adductor spasticity merits investigation.

Pronociceptive and antinociceptive neuromediators in patellar tendinopathy.

BACKGROUND: The occurrence of nerve ingrowth and its relation to chronic tendon pain (tendinopathy) are still largely unknown. In healthy tendons, the innervation is confined to the paratenon, whereas the tendon proper is devoid of nerve fibers. In this study on the pathogenesis of tendinopathy, the authors examined sensory and sympathetic nerve fiber occurrence in the patellar tendon. HYPOTHESIS: Nerve ingrowth and altered expression of sensory and sympathetic neuromediators play a major role in the pathophysiology of pain in patellar tendinopathy. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Biopsies from the patellar tendon in patients with patellar tendinopathy (n = 10) were compared with biopsies from a control group (n = 10) without any previous or current knee symptoms compatible with patellar tendinopathy. The biopsies were stained immunohistochemically for sensory and autonomic nerve markers. The biopsies from the 2 groups were compared using subjective and semiquantitative methods. RESULTS: Chronic painful patellar tendons exhibited increased occurrence of sprouting nonvascular sensory, substance P-positive nerve fibers and a decreased occurrence of vascular sympathetic nerve fibers, positive to tyroxin hydroxylase, a marker for noradrenaline. CONCLUSION: The altered sensory-sympathetic innervation suggests a role in the pathophysiology of tendinopathy. Ingrowth of sprouting substance P fibers presumably reflects a nociceptive and maybe a proliferative role, possibly as reactions to repeated microtraumata, whereas the decreased occurrence of tyroxin hydroxylase may represent a reduced antinociceptive role. These findings could be used to develop targeted pharmacotherapy for the specific treatment of tendinopathy.

The medial patellofemoral ligament: a dissection study.

This study examined the anatomy including the innervation of the medial patellofemoral ligament (MPFL) and its relation to neighboring structures to help interpretation of magnetic resonance images and to improve the surgical approach to MPFL repair. The medial aspect of 39 unpreserved human knees were dissected and the MPFL and its relations to neighboring anatomical structures were measured exactly. The morphology and the attachments are described. The MPFL was present in all knees although varying in quality between individuals but not from side to side. The width of the MPFL was 1.9 cm (1.0-3.0) and length 5.3 cm (4.5-6.4). The superior edge of the MPFL medial to the vastus medialis muscle was always easily identified. Failure to identify the superior edge during MPFL surgery is therefore highly suggestive of a MPFL tear. The variation in the ratios of patella height to MPFL length and of patella width to MPFL length ratios was to high too be used to calculate the MPFL length in MPFL reconstruction surgery. The medial patellomeniscal ligament had a wide insertion at the anterior horn of the medial meniscus and a narrow insertion (0.3-0.5 cm) at the inferomedial corner of the patella in layer 3. Histological examination was made of 14 ligaments documenting the presence of free nerve endings but no mechanoreceptors.

Segmental sensory innervation of the anterior cruciate ligament and the patellar tendon of the cat's knee.

We performed a study in cats to describe and quantify the segmental sensory innervation of the anterior cruciate ligament of the knee. We also studied the patellar tendon to show that transport occurs from an extraarticular, dense connective tissue structure and to obtain comparable quantitative information. We injected a tracer (horseradish peroxidase HRP, coupled to wheat germ agglutinin WGA) in the anterior cruciate ligament and observed the reaction product in the articular nerves of the injected knee and in the cell bodies of ipsilateral dorsal root ganglia. In these experiments, we found an average of 26 (13-52) labeled neurons, mostly large, after injecting the anterior cruciate. More than half of the labeled neurons were found in the dorsal root ganglion of L7 (last lumbar segment in the cat). We counted an average of 204 (17-426) labeled neurons, mostly small, after injecting the patellar tendon. More than half of these labeled neurons were found in the L5 spinal ganglion. No product was observed in contralateral spinal ganglia. Surgical ablation of the medial and lateral articular nerves (MAN and LAN) before injecting HRP-WGA in the anterior cruciate ligament, showed that the remaining afferents in the posterior articular nerve (PAN) projected mainly to L7. After excision of PAN, the projection was maintained through MAN and LAN, mostly to L5. Our quantitative data show that the anterior cruciate ligament is poorly innervated, if compared to the patellar tendon. The anterior cruciate segmental sensory innervation is directed to L7 (corresponding to the main ventral root forming the sciatic nerve in the cat), but also to L5 and L6 (main femoral nerve ventral roots). These segmental data indicate that anterior cruciate innervation influences muscle tone regulation, not only of the hamstrings (neuromuscular system of the sciatic nerve), but also of the quadriceps muscle (neuromuscular system of the femoral nerve).

Nerve regeneration during patellar tendon autograft remodelling after anterior cruciate ligament reconstruction: an experimental and clinical study.

The innervation of the rat and human anterior cruciate ligament, patellar tendon, and patellar tendon autograft after reconstruction of the anterior cruciate ligament was investigated by immunohistochemical and histological methods. A rat model of reconstruction with patellar tendon autograft was evaluated during active graft remodelling (2-16 weeks) and compared with normal ligament and tendon. The knees of 10 patients who had undergone reconstruction with patellar tendon autograft were examined 5-37 months postoperatively (remodeling fully completed) with arthroscopy and biopsy. As a control, biopsies from normal ligament and tendon were obtained from four patients. Nerve fibers were identified using antisera for protein gene product 9.5, a general neural marker. Neuronal regeneration was assessed by the expression of growth-associated protein 43/B-50. The sensory type of innervation was characterized by assessing the distribution of nerves containing the sensory neuropeptides calcitonin gene-related peptide and substance P. Immunoreactivity for all neural markers was found in both rat and human anterior cruciate ligament and patellar tendon. Two weeks after reconstruction, the rat autograft was acellular and no innervation could be identified. After 4 weeks, the grafts were viable, and immunoreactivity for protein gene product 9.5, growth associated protein 43/B-50, and calcitonin gene-related peptide was found until the 16th week postoperatively. Immunoreactivity for substance P was found in rat autografts at 4 weeks postoperatively only. All biopsies of human patellar tendon autograft showed signs of the remodelling process being fully completed, with revascularization and a sinusoidal collagen pattern with fibroblast repopulation. Neuropeptide immunoreactivity, however, was not found. The presence of immunoreactivity to sensory neuropeptides in the anterior cruciate ligament and patellar tendon may indicate a nociceptive and neuromodulatory function of these structures. The expression of sensory neuropeptides in the rat patellar tendon autograft suggests a possible involvement of sensory innervation during healing of the graft.