Arthroscopic soft tissue tenodesis versus bony fixation anchor tenodesis of the long head of the biceps tendon.

BACKGROUND: Currently there are no prospective data available that compare the different tenodesis techniques of the long head of the biceps tendon with regard to their clinical and structural results. HYPOTHESIS: Soft tissue tenodesis provides clinical and structural results equivalent to those of bony fixation anchor tenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fifty-seven patients with arthroscopically proven lesions of the long head of the biceps tendon (LHB) were prospectively included in this study. Thirty patients (7 women, 23 men; mean age, 57.9 years) were treated with an arthroscopic soft tissue tenodesis (STT) and 27 patients (8 women, 19 men; mean age, 61 years) with an arthroscopic bony fixation anchor tenodesis (BFAT). The clinical evaluation included the Constant score as well as a newly developed LHB score (maximum 100 points) that includes evaluation of pain and cramps (maximum 50 points), the patient- and examiner-dependent grading of the cosmetic result (maximum 30 points), and the measurement of elbow flexion strength (maximum 20 points). The integrity of the tenodesis construct was evaluated indirectly by detecting the position of the LHB using magnetic resonance imaging. A proximal intertubercular location of the tendon was judged as an intact tenodesis construct (3 points), a distal intertubercular location as a failure of tenodesis followed by autotenodesis in the sulcus (2 points), and an extratubercular location as a complete failure (1 point). RESULTS: Twenty-four patients (5 women, 19 men; mean age, 58.6 years; mean follow-up, 19.6 months) in the STT group and 20 patients (5 women, 15 men; mean age, 59.1 years; mean follow-up, 22.4 months) in the BFAT group could be evaluated. The overall Constant score did not reveal any significant difference in the STT group (mean, 75.0 points) compared with the BFAT group (mean, 78.3 points) (P > .05). However, the BFAT group showed significantly better results in the LHB score (BFAT mean, 91.8 points vs STT mean, 80.9 points), the examiner-dependent evaluation of the cosmetic result (BFAT mean, 11.3 points vs STT mean, 8.0 points), as well as in the evaluation of the structural integrity of the tenodesis construct (BFAT mean, 2.7 points vs STT mean, 2.2 points) (P < .05). CONCLUSION: When arthroscopic tenodesis of the LHB is indicated, the authors recommend a bony fixation over soft tissue fixation because anchor fixation provides significant advantages concerning the clinical and structural outcome.

Diagnostic values of clinical tests for subscapularis lesions.

Subscapularis (SSC) lesions are often underdiagnosed in the clinical routine. This study establishes and compares the diagnostic values of various clinical signs and diagnostic tests for lesions of the SSC tendon. Fifty consecutive patients who were scheduled for an arthroscopic subacromial or rotator cuff procedure were clinically evaluated using the lift-off test (LOT), the internal rotation lag sign (IRLS), the modified belly-press test (BPT) and the belly-off sign (BOS) preoperatively. A modified classification system according to Fox et al. (Type I-IV) was used to classify the SSC lesion during diagnostic arthroscopy. SSC tendon tears occurred with a prevalence of 30% (15 of 50). Five type I, six type II, three type IIIa and one type IIIb tears according to the modified classification system were found. Fifteen percent of the SSC tears were not predicted preoperatively by using all of the tests. In six cases (12%), the LOT and the IRLS could not be performed due to a painful restricted range of motion. The modified BPT and the BOS showed the greatest sensitivity (88 and 87%) followed by the IRLS (71%) and the LOT (40%). The BOS had the greatest specificity (91%) followed by the LOT (79%), mod. BPT (68%) and IRLS (45%). The BOS had the highest overall accuracy (90%). With the BOS and the modified BPT in particular, upper SSC lesions (type I and II) could be diagnosed preoperatively. A detailed physical exam using the currently available SSC tests allows diagnosing SSC lesions in the majority of cases preoperatively. However, some tears could not be predicted by preoperative assessment using all the tests.

Targeting of stabilized plasmid lipid particles to hepatocytes in vivo by means of coupled lactoferrin.

For non-viral gene delivery we prepared stabilized plasmid lipid particles (SPLPs), to which lactoferrin (LF) was coupled as a hepatocyte specific targeting ligand. LF-SPLPs and untargeted SPLPs labeled with [3H]cholesteryloleyl-ether were injected into rats. About 87% of the LF-SPLPs were eliminated from the blood within 5 min, while 80% of untargeted SPLPs were still circulating after 2 h. Fifty-two percent of the LF-SPLPs were taken up by hepatocytes, while non-parenchymal liver cells accounted for 16% of the uptake. Despite the efficient targeting of LF-SPLPs to hepatocytes and their capacity to transfect HepG2 and COS-7 cells in vitro, expression of a reporter gene was not detected in vivo. Overall, covalent coupling of LF to SPLPs leads to massive delivery in hepatocytes after systemic administration. However, these LF-SPLPs are not able to transfect these cells in vivo.

Cell-specific targeting of lipid-based carriers for ODN and DNA.

It is well recognized that there is an urgent need for non-toxic systemically applicable vectors for biologically active nucleotides to fully exploit the current potential of molecular medicine in gene therapy. Cell-specific targeting of non-viral lipid-based carriers for ODN and DNA is a prerequisite to attain the concentration of nucleic acids required for therapeutic efficacy in the target tissue. In this review we will address the most promising approaches to selective targeting of liposomal nucleic acid carriers in vivo. In addition, the routes of entry and intracellular processing of these carrier systems are discussed as well as physiological factors potentially interfering with the biological and/or therapeutic activity of their nucleotide pay-load.

Optimized targeting of polyethylene glycol-stabilized anti-intercellular adhesion molecule 1 oligonucleotide/lipid particles to liver sinusoidal endothelial cells.

We prepared polyethylene glycol (PEG)-stabilized antisense oligonucleotide (ODN)/lipid particles from a lipid mixture including the positively charged amphiphile 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and anti-intercellular adhesion molecule 1 (ICAM-1) antisense ODN by an extrusion method in the presence of 40% ethanol. These particles were targeted to scavenger receptors on liver endothelial cells by means of covalently coupled polyanionized albumin. Two types of such targeted particles were prepared, one with the albumin coupled to a maleimide group attached to the particle's lipid bilayer and the other with the protein coupled to a maleimide group attached at the distal end of added bilayer-anchored PEG chains. Upon intravenous injection, the ODN particles with bilayer-coupled albumin were cleared from the blood circulation at the same low rate as untargeted particles (<5% in 30 min). By contrast, the distal-end coupled particles were very rapidly cleared from the blood and preferentially taken up by the endothelial cells of the hepatic sinusoid (55% of injected dose after 30 min). Despite this substantial endothelial targeting, no consistent inhibition of ICAM-1 expression could be demonstrated in this cell type, either in vivo or in vitro. However, in J774 cells that also express scavenger receptors and ICAM-1, significant down-regulation of ICAM-1 mRNA was achieved with distal-end targeted lipid particles, as determined with real-time RT-PCR. It is concluded that massive delivery of ODN to cell types that express scavenger receptors can be achieved if lipid particles are provided with negatively charged albumin distally attached to bilayer anchored PEG chains.

Stabilized lipid coated lipoplexes for the delivery of antisense oligonucleotides to liver endothelial cells in vitro and in vivo.

We report on the preparation and in vivo/in vitro disposition of antisense ODN encapsulating coated cationic lipoplexes (CCLs), prepared by a procedure essentially developed by Stuart and Allen (Stuart, D.D. and Allen, T.M. (2000) "A new liposomal formulation for antisense oligodeoxynucleotides with small size, high incorporation efficiency and good stability", Biochim. Biophys. Acta 1463, pp. 219-229). The behavior of untargeted CCLs was compared with CCLs that were targeted to scavenger receptors on liver endothelial cells by covalent coupling of the poly-anion aconitylated human serum albumin (Aco-HSA) to the particle surface. By means of cryo transmission electron microscopy (cryo-TEM) particles of high electron density could be distinguished from electron-translucent particles, representing high and low ODN encapsulation, respectively. The two populations were separated by sucrose density gradient centrifugation. Upon injection into rats, the untargeted particles showed long circulating properties with a half-life of >10 h. These untargeted CCLs barely bound to liver endothelial cells in vitro while Aco-HSA CCLs massively and specifically interacted with scavenger receptors on these cells. With J774 cells, a macrophage cell line expressing scavenger receptors, downregulation of ICAM-1 mRNA levels was achieved when the ODN was specifically delivered by Aco-HSA targeted CCLs.

Bioactivatable, membrane-permeant analogs of cyclic nucleotides as biological tools for growth control of C6 glioma cells.

In the present study, the cAMP analogs 8-bromo-cAMP (8-Br-cAMP), N6-2'O-dibutyryl-cAMP (DBcAMP) and 8-para-chlorophenylthio-cAMP (8-CPT-cAMP), as well as the corresponding cAMP-acetoxymethyl (AM)-ester-prodrugs were tested in a HPLC study for their membrane permeability, intracellular accumulation and biotransformation. Antiproliferative activities of these compounds were studied in the rat C6 glioma cell line. Chromatographic analysis revealed that the AM-ester analogs of the cyclic nucleotides penetrate quantitatively into rat C6 glioma cells and generate high amounts of their parent cyclic nucleotides intracellularly within 60 min; however, long-term growth inhibition tested in C6 cells is only slightly enhanced with the AM-ester prodrugs of 8-Br-cAMP or DBcAMP.

Massive and selective delivery of lipid-coated cationic lipoplexes of oligonucleotides targeted in vivo to hepatic endothelial cells.

PURPOSE: Previously we reported on massive uptake of liposomes surface-modified with negatively charged aconitylated albumin (AcoHSA) by liver sinusoidal endothelial cells (EC) in vivo. In the present work we applied this principle for the in vivo delivery of antisense oligonucleotides (ODN) to these cells. METHODS: Anti ICAM-1 ODN was complexed with the cationic lipid DOTAP and the complex was coated by an excess of neutral lipids including a lipid-anchored poly(ethylene glycol). Aco-HSA was coupled to the coated cationic lipoplexes (CCLs). Plasma disappearance, organ and intrahepatic distribution of Aco-HSA modified CCLs were determined in rats, using [3H]-cholesteryl oleyl ether and 32P-labeled ODN as markers. RESULTS: The Aco-HSA coupled CCLs were <160 nm in size, contained 1.03+/-0.35 nmol ODN and 54+/-18 microg Aco-HSA per micromol total lipid. These CCLs were rapidly eliminated from plasma, about 60% the injected dose of 3H- or 32P-label being recovered in the liver after 30 min. Within the liver, the EC accounted for two thirds of total liver uptake. Control non-targeted CCLs were eliminated very slowly: after 30 min still >90% of the particles was in the blood. CONCLUSIONS: Our results demonstrate efficient targeting of antisense ODN to EC in vivo, employing plasma-stable coated cationic lipoplexes, surface modified with negatively charged albumin. 40% of the injected ODN was delivered to the target cells within 30 min.