Mid-term clinical and sonographic outcomes of minimally invasive acromioclavicular joint reconstruction: mini-open versus arthroscopically assisted.

INTRODUCTION: The current literature describes various operative stabilization strategies which achieve good clinical outcomes after acute acromioclavicular joint (ACJ) dislocation. The aim of this study was to compare the mid-term clinical and sonographic treatment outcomes after minimally invasive mini-open and arthroscopic reconstruction. MATERIALS AND METHODS: We conducted a retrospective two-center study of patients with acute ACJ dislocation. Surgical treatment was performed using either a mini-open approach (MIOP) or an arthroscopic technique (AR). The primary outcome parameters of this study were the sonographically measured acromioclavicular (ACD) and coracoclavicular distances (CCD). Secondary outcome parameters included the Constant-Murley score (CS), range of motion (ROM), postoperative pain scale (VAS), return to daily routine, return to sports, complications, as well as operative revisions. RESULTS: After a mean follow-up of 29 months, 30 patients were included in this study with an average age of 41.3 ± 14.8 years (MIOP) and 41.2 ± 15.4 years (AR). The sonographic ACD (MIOP 9.11 mm vs. AR 8.93 mm, p = 0.41) and CCD (MIOP 25.08 mm vs. AR 24.36 mm, p = 0.29) distances showed no statistically significant differences. Furthermore, there was no statistically significant difference when compared to the contralateral side (p = 0.42). With both techniques, patients achieved excellent clinical outcome parameters without statistically significant differences in CS (MIOP 95 vs. AR 97, p = 0.11) and VAS (MIOP 1.76 vs. AR 1.14, p = 0.18). The return to daily activity and return to sport rates did not differ. There were neither complications nor revisions in both groups. CONCLUSION: Both minimally invasive techniques for acute ACJ stabilization achieved excellent clinical and sonographic outcomes without one technique being statistically superior to the other.

Acromioclavicular joint suture button repair leads to coracoclavicular tunnel widening.

PURPOSE: Biomechanical evaluation of three different suture button devices used in acromioclavicular joint repair and analysis of their effect on post-testing tunnel widening. METHODS: Eighteen human shoulder girdles were assigned into three groups with a similar mean bone mineral density. Three different single-tunnel acromioclavicular repair devices were tested: (1) AC TightRope® with FiberWire; (2) AC Dog Bone™ Button with FiberTape; (3) Low Profile AC Repair System. Biomechanical testing was performed simulating the complex movement of the distal clavicle as follows. A vertical load of 80 N was applied continuously. The rotation of the clavicle about its long axis was set at 10° anterior and 30° posterior for 2500 cycles at 0.25 Hz. The horizontal translation of the clavicle was set at 6 mm medial and 6 mm lateral for 10,000 cycles at 1 Hz. The coracoclavicular distance was measured before and after testing. After testing, each sample underwent micro-CT analysis. Following 3D reconstruction, the area of the bone tunnels was measured at five defined cross sections. RESULTS: In TightRope® and Dog Bone™ groups, all samples completed testing, whereas in the Low Profile group, three out of six samples showed system failure. The mean absolute difference of coracoclavicular distance after testing was significantly greater in the Low Profile group compared to TightRope® and Dog Bone™ groups (4.3 ± 1.3 mm vs 1.9 ± 0.7 mm vs 1.9 ± 0.8 mm; p = 0.001). Micro-CT analysis of the specimens demonstrated significant tunnel widening in the inferior clavicular and superior coracoid regions in all three groups (p < 0.05). CONCLUSION: Significant tunnel widening can be observed for all devices and is primarily found in the inferior parts of the clavicle and superior parts of the coracoid. The Low Profile AC Repair System showed inferior biomechanical properties compared to the AC TightRope® and AC Dog Bone™ devices. Therefore, clinicians should carefully select the type of acromioclavicular repair device used and need to consider tunnel widening as a complication.

[Combined PCL ligament bracing and ACL reconstruction in acute knee dislocation (Schenck IV) - The Hamburg Approach : Video article]. / Hamburger Konzept der operativen Versorgungsstrategie einer akuten Kniegelenkluxation (Schenck IV) : Videobeitrag.

OBJECTIVE: Stepwise reconstruction of knee stability and physiological kinematics in acute knee dislocation. INDICATIONS: The operative technique is demonstrated in a case of multiligamentous injury of the knee with involvement of both cruciate ligaments and additional medial and lateral peripheral injuries (type IV according to Schenck classification). CONTRAINDICATIONS: Critical soft tissue conditions, infections, old age, obesity, lack of compliance. SURGICAL TECHNIQUE: Time-limited arthroscopy in order to primarily identify and treat posterior horn/root injuries of the meniscus and concomitant intra-articular injuries. Anatomical placement of anterior cruciate ligament (ACL) drill wires for later ACL tunnel drilling is arthroscopically guided. Subsequent conversion to an anteromedial arthrotomy and ligament bracing of the posterior cruciate ligament. The ACL is reconstructed using the ipsilateral semitendinosus tendon. Medial and lateral peripheral injures are anatomically reconstructed followed by a posterolateral augmentation in a technique described by Arciero. FOLLOW-UP: Limited weight bearing for 6 weeks and stepwise increase of flexion using a standard knee brace and close clinical monitoring. EVIDENCE: Ligament bracing of both cruciate ligaments is an established treatment technique in acute knee dislocations and has been proven to achieve good to excellent clinical results. In an ongoing clinical study primary ACL reconstruction as a modified treatment approach indicated superior stability in a 12-month follow-up in patients with acute knee dislocations.

Early changes in the extracellular matrix of the degenerating intervertebral disc, assessed by Fourier transform infrared imaging.

OBJECTIVE: Mechanical overloading induces a degenerative cell response in the intervertebral disc. However, early changes in the extracellular matrix (ECM) are challenging to assess with conventional techniques. Fourier Transform Infrared (FTIR) imaging allows visualization and quantification of the ECM. We aim to identify markers for disc degeneration and apply these to investigate early degenerative changes due to overloading and katabolic cell activity. DESIGN: Three experiments were conducted; Exp 1.: In vivo, lumbar spines of seven goats were operated: one disc was injected with chondroitinase ABC [cABC (mild degeneration)] and compared to the adjacent disc (control) after 24 weeks. Exp 2a: Ex vivo, caprine discs received physiological loading (n = 10) or overloading (n = 10) in a bioreactor. Exp 2b: Cell activity was diminished prior to testing by freeze-thaw cycles, 18 discs were then tested as in Exp 2a. In all experiments, FTIR images (spectral region: 1000-1300 cm-1) of mid-sagittal slices were analyzed using multivariate curve resolution. RESULTS: In vivo, FTIR was more sensitive than biochemical and histological analysis in identifying reduced proteoglycan content (P = 0.046) and increased collagen content in degenerated discs (P < 0.01). Notably, FTIR analysis additionally showed disorganization of the ECM, indicated by increased collagen entropy (P = 0.011). Ex vivo, the proteoglycan/collagen ratio decreased due to overloading (P = 0.047) and collagen entropy increased (P = 0.047). Cell activity affected collagen content only (P = 0.044). CONCLUSION: FTIR imaging allows a more detailed investigation of early disc degeneration than traditional measures. Changes due to mild overloading could be assessed and quantified. Matrix remodeling is the first detectable step towards intervertebral disc degeneration.

In-vivo monitoring of acute DSS-Colitis using Colonoscopy, high resolution Ultrasound and bench-top Magnetic Resonance Imaging in Mice.

OBJECTIVE: The aim of this study was to establish and evaluate (colour Doppler-) high-resolution-ultrasound (hrUS) and bench-top magnetic resonance imaging (btMRI) as new methods to monitor experimental colitis. MATERIALS AND METHODS: hrUS, btMRI and endoscopy were performed in mice without colitis (n = 15), in mice with acute colitis (n = 14) and in mice with acute colitis and simultaneous treatment with infliximab (n = 19). RESULTS: Determination of colon wall thickness using hrUS (32 MHz) and measurement of the cross-sectional colonic areas by btMRI allowed discrimination between the treatment groups (mean a vs. b vs. c - btMRI: 922 vs. 2051 vs. 1472 pixel, hrUS: 0.26 vs. 0.45 vs. 0.31 mm). btMRI, endoscopy, hrUS and colour Doppler-hrUS correlated to histological scoring (p < 0.05), while endoscopy and btMRI correlated to post-mortem colon length (p < 0.05). CONCLUSIONS: The innovative in vivo techniques btMRI and hrUS are safe and technically feasible. They differentiate between distinct grades of colitis in an experimental setting, and correlate with established post-mortem parameters. In addition to endoscopic procedures, these techniques provide information regarding colon wall thickness and perfusion. Depending on the availability of these techniques, their application increases the value of in vivo monitoring in experimental acute colitis in small rodents. KEY POINTS: • Improved in vivo monitoring might balance interindividual differences in murine colitis. • In monitoring murine colitis, btMRI and hrUS are safe and technically feasible. • Very short examination times underline the usefulness especially of hrUS. • Results of btMRI and hrUS correlate with endoscopic and post-mortem findings.

Surgical accuracy in identifying the elbow rotation axis on fluoroscopic images.

PURPOSE: To assess the accuracy of surgeons in identifying elbow rotation axis (RA) on fluoroscopic images and to measure the interobserver variability. METHODS: Five healthy subjects underwent 3-dimensional computed tomography (CT) analysis of their nondominant elbow. Real-time rotation software enabled surgeons to approximate the elbow RA on CT-reconstructed fluoroscopy, which was repeated twice with different starting positions to increase the number of observations. The surgeons used anatomical landmarks of choice. Analysis of variance (ANOVA) was used to determine structural error differences between surgeons, and intraclass correlation coefficients (ICCs) were used to determine the corresponding interobserver variability. RESULTS: Eight subspecialty-trained trauma surgeons (P.K., N.W.L.S., V.M.d.J., P.J., G.M.K., R.W.P., T.S., B.A.v.D.) participated and attempted to identify the RA on reconstructed fluoroscopy. A total of 15 RA definitions on 5 elbows were recorded per surgeon. The surgeons had a mean rotational error of 5° (range, < 1°-13°) and mean translational error of 1 mm (range, < 1-8 mm), compared with the true elbow RA as measured by the 3-dimensional CT analysis. The ANOVA showed structural differences between surgeons in rotational and translational errors, indicating that some surgeons consistently had more accurately identified the elbow RA than others. The ICC was 0.12 for rotational error and 0.10 for translational error, indicating a large interobserver variability. CONCLUSIONS: We show in this in vivo study that identification of the elbow RA on fluoroscopy is associated with substantial rotational errors and large inconsistencies among surgeons. Implementation of standardized anatomical landmarks is required to improve surgeons' accuracy. These landmarks should preferably take into account both the coronal and the sagittal planes, using the orientation of the capitellum and trochlea as well as the posterior distal humeral cortex. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Towards the optimization of drug delivery to the cochlear apex: Influence of polymer and drug selection in biodegradable intracochlear implants.

There is growing need for new drug delivery systems for intracochlear application of drugs to effectively treat inner ear disorders. In this study, we describe the development and characterization of biodegradable, triamcinolone-loaded implants based on poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) respectively, prepared by hot-melt extrusion. PEG 1500 was used as a plasticizer to improve flexibility and accelerate drug release. The sterilization process was performed by electron beam irradiation, resulting in minimal but acceptable polymer degradation for PEG-PLGA implants. The implants have been characterized by texture analysis, differential scanning calorimetry and X-ray powder diffraction. Compared to PLGA implants, PEG-PLGA implants offer similar flexibility but with improved mechanical stability, which will ease the handling and intracochlear application. A controlled release over three months was observed for dexamethasone and triamcinolone extrudates (drug load of 10%) with similar release profiles for both drugs. PEG-PLGA implants showed an initial slow release rate over several days regardless of the amount of PEG added. Mathematical simulations of the pharmacokinetics of the inner ear based on the in vitro release kinetics indicate a complete distribution of triamcinolone in the whole human scala tympani, which underlines the high potential of the developed formulation.

Fungaemia caused by Candida pulcherrima.

Although neonatal bloodstream infections may be caused by a variety of fungi, invasive fungaemia due to Candida pulcherrima in a premature neonate has not been previously reported. We describe such a case in which antifungal susceptibility test data led to successful therapy. A colonized catheter used for parenteral nutrition is presumed to have been the main source of this persistent infection.

[Distraction arthroplasty for treatment of posttraumatic elbow stiffness]. / Distraktionsarthroplastik zur Behandlung der posttraumatischen Ellenbogensteife.

A stiff elbow is usually defined as having less than 30° in extension or less than 130° in flexion. Most activities of daily living are possible if the elbow has a range of motion of 100° (30-130° of flexion, Morrey's arc of motion). Loss of mobility of the elbow is not uncommon after trauma, burns or coma and severely impairs upper limb function. Loss of mobility may be difficult to avoid and is challenging to treat. Detailed analysis of the etiology and diagnostic evaluation is of utmost importance for planning any surgical intervention for elbow stiffness. Current operative techniques, such as closed distraction with external fixation (arthroplasty), are presented and evaluated. Elbow arthrolysis is a technically demanding procedure but if the indications and techniques are used correctly and the surgeon, physiotherapist and even the patient are familiar with the procedure, good long-term results may be achieved. Contraindications are poor compliance, poorly controlled diabetes mellitus, active hepatitis B and C infections, HIV infection and acute articular infections.

[External fixation with motion capacity in complex dislocation of the knee joint and associated injuries]. / Der Bewegungsfixateur bei komplexer Kniegelenkluxation mit Begleitverletzung.

Closed and open dislocations of the knee joint with vascular and nerve injuries are treated immediately and may present an indication for external fixation. In acute trauma definitive treatment and reconstruction of the complex capsule and ligamentous injuries are often impossible. The application of a medial transarticular external fixator with motion capacity combines the treatment of remaining joint instability with the benefit of early joint movement. Disadvantages of prolonged joint immobilisation until definitive stabilisation of the knee are reduced.

Novel biodegradable Round Window Disks for inner ear delivery of dexamethasone.

Drug delivery to the inner ear is an important and very challenging field. The cochlea is protected by several barriers that need to be overcome in the drug delivery process. Local drug delivery can avoid undesirable side effects arising from systemic drug delivery. We developed a biodegradable dexamethasone-loaded Round Window (RW) Disk based on poly(D,L-lactic-co-glycolic acid) (PLGA) for local drug therapy to the inner ear by RW membrane administration by a film-casting method. The optimal drying time was characterized by thermogravimetric analysis and differential scanning calorimetry. In addition, the mass and polymer degradation over time of drug release was measured in vitro showing a total mass loss of 70% after 3 weeks. Dexamethasone release was determined by a RW model setup using a polyethylene terephthalate membrane. We achieved a controlled release over 52 days. Ex vivo implantation of a RW Disk onto a guinea pig RW membrane indicated well-fitting properties of the drug delivery device leading to a close surface contact with the membrane and the successful proof of concept. The developed RW Disks could be new and promising drug delivery device to achieve effective local drug delivery to the inner ear for an extended time.

Engineering osteogenic microenvironments by combination of multilayers from collagen type I and chondroitin sulfate with novel cationic liposomes.

Cationic liposomes composed of a novel lipid (N-{6-amino-1-[N-(9Z) -octadec9-enylamino] -1-oxohexan-(2S) -2-yl} -N'- {2- [N, N-bis(2-aminoethyl) amino] ethyl} -2-hexadecylpropandiamide) (OO4) and dioleoylphosphatidylethanolamine (DOPE) possess high amounts of amino groups and are promising systems for lipofection. Moreover, these cationic liposomes can also be used as a polycationic entity in multilayer formation using layer-by-layer technique (LbL), which is a method to fabricate surface coatings by alternating adsorption of polyanions and polycations. Since liposomes are suitable for endocytosis by or fusion with cells, controlled release of their cargo on site is possible. Here, a polyelectrolyte multilayer (PEM) system was designed of chondroitin sulfate (CS) and collagen type I (Col I) by LbL technique with OO4/DOPE liposomes embedded in the terminal layers to create an osteogenic microenvironment. Both, the composition of PEM and cargo of the liposomes were used to promote osteogenic differentiation of C2C12 myoblasts as in vitro model. The internalization of cargo-loaded liposomes from the PEM into C2C12 cells was studied using lipophilic (Rhodamine-DOPE conjugate) and hydrophilic (Texas Red-labeled dextran) model compounds. Besides, the use of Col I and CS should mimic the extracellular matrix of bone for future applications such as bone replacement therapies. Physicochemical studies of PEM were done to characterize the layer growth, thickness, and topography. The adhesion of myoblast cells was also evaluated whereby the benefit of a cover layer of CS and finally Col I above the liposome layer was demonstrated. As proof of concept, OO4/DOPE liposomes were loaded with dexamethasone, a compound that can induce osteogenic differentiation. A successful induction of osteogenic differentiation of C2C12 cells with the novel designed liposome-loaded PEM system was shown. These findings indicate that designed OH4/DOPE loaded PEMs have a high potential to be used as drug delivery or transfection system for implant coating in the field of bone regeneration and other applications.

Intracochlear PLGA based implants for dexamethasone release: Challenges and solutions.

The effective treatment of diseases of the inner ear is currently an unmet medical need. Local controlled drug delivery to the cochlea is challenging due to the hidden location, small volume and high sensitivity of this organ. A local intracochlear delivery of drugs would avoid the problems of intratympanic (extracochlear) drug application, but is more invasive. The requirements for such a delivery system include a small size and appropriate flexibility. The delivery device must be rigid enough for surgical handling but also flexible to avoid traumatizing cochlear structures. We developed biodegradable dexamethasone loaded PLGA extrudates for the controlled intracochlear release. In order to achieve the desired flexibility, Polyethylene glycol (PEG) was used as a plasticizer. In addition to the drug release, the extrudates were characterized in vitro by differential scanning calorimetry (DSC) and texture analysis. Simulation of the pharmacokinetics of the inner ear support the expectation that a constant perilymph drug level is obtained after few hours and retained over several weeks. Ex vivo implantation of the extrudates into a guinea pig cochlea indicate that PEG containing extrudates have the desired balance between mechanical strength and flexibility for direct implantation into the cochlea. The location of the implant was visualized by computer tomography. In summary, we postulate that intracochlear administration of drug releasing biodegradable implants is a new and promising approach to achieve local drug delivery to the cochlea for an extended time.

Indomethacin functionalised poly(glycerol adipate) nanospheres as promising candidates for modified drug release.

The linear polyester poly(glycerol adipate) (PGA) with its free pendant hydroxyl groups was covalently grafted with indomethacin which yields polymeric prodrugs. It was possible to produce nanospheres with narrow particle size distribution of these polymer-drug conjugates with an optimized interfacial deposition method. Nanospheres were characterized by zeta potential measurements, dynamic light scattering, electron microscopy and nanoparticle tracking analysis. Moreover, cell viability studies and cytotoxicity tests in three different cell lines were carried out showing low toxicity for three different degrees of grafting. In addition, the nanospheres had (in contrast to the free drug) low hemolytic activity in vitro. Release studies of nanodispersions are challenging. The use of a specially developed setup with highly porous aluminum oxide membranes enabled us to overcome problems associated with other setups (e.g. dialysis membranes). A slow and controlled release profile without any burst was observed over 15 days. The results indicate that indomethacin-PGA conjugates can be formulated successfully as nanospheres with the desired characteristics of small size with narrow distribution, controlled drug release and low toxicity. The newly developed particles have the potential to improve the therapy of inflammation and associated diseases.

Reconstruction of a Mason type-III fracture of the radial head using four different fixation techniques. An experimental study.

We have evaluated four different fixation techniques for the reconstruction of a standard Mason type-III fracture of the radial head in a sawbone model. The outcome measurements were the quality of the reduction, and stability. A total of 96 fractures was created. Six surgeons were involved in the study and each reconstructed 16 fractures with 1.6 mm fine-threaded wires (Fragment Fixation System (FFS)), T-miniplates, 2 mm miniscrews and 2 mm Kirschner (K-) wires; four fractures being allocated to each method using a standard reconstruction procedure. The quality of the reduction was measured after definitive fixation. Biomechanical testing was performed using a transverse plane shear load in two directions to the implants (parallel and perpendicular) with respect to ultimate failure load and displacement at 50 N. A significantly better quality of reduction was achieved using the FFS wires (Tukey's post hoc tests, p < 0.001) than with the other devices with a mean step in the articular surface and the radial neck of 1.04 mm (SD 0.96) for the FFS, 4.25 mm (SD 1.29) for the miniplates, 2.21 mm (SD 1.06) for the miniscrews and 2.54 mm (SD 0.98) for the K-wires. The quality of reduction was similar for K-wires and miniscrews, but poor for miniplates. The ultimate failure load was similar for the FFS wires (parallel, 196.8 N (SD 46.8), perpendicular, 212.5 N (SD 25.6)), miniscrews (parallel, 211.8 N (SD 47.9), perpendicular, 208.0 N (SD 65.9)) and K-wires (parallel, 200.4 N (SD 54.5), perpendicular, 165.2 N (SD 37.9)), but significantly worse (Tukey's post hoc tests, p < 0.001) for the miniplates (parallel, 101.6 N (SD 43.1), perpendicular, 122.7 N (SD 40.7)). There was a significant difference in the displacement at 50 N for the miniplate (parallel, 4.8 mm (SD 2.8), perpendicular, 4.8 mm (SD 1.7)) vs FFS (parallel, 2.1 mm (SD 0.8), perpendicular, 1.9 mm (SD 0.7)), miniscrews (parallel, 1.8 mm (SD 0.5), perpendicular, 2.3 mm (SD 0.8)) and K-wires (parallel, 2.2 mm (SD 1.8), perpendicular, 2.4 mm (SD 0.7; Tukey's post hoc tests, p < 0.001)). The fixation of a standard Mason type-III fracture in a sawbone model using the FFS system provides a better quality of reduction than that when using conventional techniques. There was a significantly better stability using FFS implants, miniscrews and K-wires than when using miniplates.

Poly(glycerol adipate) - indomethacin drug conjugates - synthesis and in vitro characterization.

The linear biodegradable polyester poly(glycerol adipate) (PGA) was synthesized via enzymatic polycondensation using lipase B from Candida antarctica (CAL-B). Every monomer unit of PGA possesses a pendant hydroxyl group which is responsible for the hydrophilic character and moisture swelling. These OH groups were esterified to different degrees with the anti-inflammatory drug indomethacin in order to create a prodrug with a pH-sensitive linker for modified drug release. The structure of the conjugates was determined via ATR FT-IR spectroscopy, NMR spectroscopy, GPC and UV/VIS spectroscopy. The physical properties of polymers with different drug load were investigated using DSC, contact angle measurements and oscillatory rheology. Drug release was monitored over one month in vitro. A very slow, but continuous release was observed in PBS. Slightly acidic conditions and lipase activity are accelerating the indomethacin release. Therefore, poly(glycerol adipate) - indomethacin conjugates are promising prodrugs for the local sustained release of indomethacin.

Mechanistic analysis of PLGA/HPMC-based in-situ forming implants for periodontitis treatment.

In-situ forming implant formulations based on poly(lactic-co-glycolic acid) (PLGA), acetyltributyl citrate (ATBC), minocycline HCl, N-methyl pyrrolidone (NMP) and optionally hydroxypropyl methylcellulose (HPMC) were prepared and thoroughly characterized in vitro. This includes electron paramagnetic resonance (EPR), nuclear magnetic resonance ((1)H NMR), mass change and drug release measurements under different conditions, optical microscopy, size exclusion chromatography (SEC) as well as antibacterial activity tests using gingival crevicular fluid samples from periodontal pockets of periodontitis patients. Based on these results, deeper insight into the physico-chemical phenomena involved in implant formation and the control of drug release could be gained. For instance, the effects of adding HPMC to the formulations, resulting in improved implant adherence and reduced swelling, could be explained. Importantly, the in-situ formed implants effectively hindered the growth of bacteria present in the patients' periodontal pockets. Interestingly, the systems were more effectively hindering the growth of pathogenic bacterial strains (e.g., Fusobacterium nucleatum) than that of strains with a lower pathogenic potential (e.g., Streptococcus salivarius). In vivo, such a preferential action against the pathogenic bacteria can be expected to give a chance to the healthy flora to re-colonize the periodontal pockets.

In-situ forming composite implants for periodontitis treatment: How the formulation determines system performance.

Periodontitis is the primary cause of tooth loss in adults and a very wide-spread disease. Recently, composite implants, based on a drug release rate controlling polymer and an adhesive polymer, have been proposed for an efficient local drug treatment. However, the processes involved in implant formation and the control of drug release in these composite systems are complex and the relationships between the systems' composition and the implants' performance are yet unclear. In this study, advanced characterization techniques (e.g., electron paramagnetic resonance, EPR) were applied to better understand the in-situ forming implants based on: (i) different types of poly(lactic-co-glycolic acid) (PLGA) as drug release rate controlling polymers; (ii) hydroxypropyl methylcellulose (HPMC) as adhesive polymer; and (iii) doxycycline or metronidazole as drugs. Interestingly, HPMC addition to shorter chain PLGA slightly slows down drug release, whereas in the case of longer chain PLGA the release rate substantially increases. This opposite impact on drug release was rather surprising, since the only difference in the formulations was the polymer molecular weight of the PLGA. Based on the physico-chemical analyses, the underlying mechanisms could be explained as follows: since longer chain PLGA is more hydrophobic than shorter chain PLGA, the addition of HPMC leads to a much more pronounced facilitation of water penetration into the system (as evidenced by EPR). This and the higher polymer lipophilicity result in more rapid PLGA precipitation and a more porous inner implant structure. Consequently, drug release is accelerated. In contrast, water penetration into formulations based on shorter chain PLGA is rather similar in the presence and absence of HPMC and the resulting implants are much less porous than those based on longer chain PLGA.

Solid lipid nanoparticles: production, characterization and applications.

Solid lipid nanoparticles (SLN) have attracted increasing attention during recent years. This paper presents an overview about the selection of the ingredients, different ways of SLN production and SLN applications. Aspects of SLN stability and possibilities of SLN stabilization by lyophilization and spray drying are discussed. Special attention is paid to the relation between drug incorporation and the complexity of SLN dispersions, which includes the presence of alternative colloidal structures (liposomes, micelles, drug nanosuspensions, mixed micelles, liquid crystals) and the physical state of the lipid (supercooled melts, different lipid modifications). Appropriate analytical methods are needed for the characterization of SLN. The use of several analytical techniques is a necessity. Alternative structures and dynamic phenomena on the molecular level have to be considered. Aspects of SLN administration and the in vivo fate of the carrier are discussed.

In vivo detection of anthralin-derived free radicals in the skin of hairless mice by low-frequency electron paramagnetic resonance spectroscopy.

Free radicals were directly detected in vivo in the skin of hairless mice by low-frequency electron paramagnetic resonance spectroscopy after topical application of anthralin under pertinent therapeutic conditions. The electron paramagnetic resonance signal intensity increased steadily, reaching a maximum after about 1 d and decreased slowly in the following days, probably because of desquamation of the skin. We conclude from the spectroscopic features (single line with a line width of 6 gauss; g = 2.0036) and from the pharmacokinetic pattern that the observed signal arises from the final products of anthralin metabolism (ether-insoluble polymeric structures--"anthralin brown"). Two potential antioxidants, vitamin E and the spin trap tert-butylphenylnitrone, decreased the amount of the anthralin-derived radical that was formed. Neither vitamin E radicals nor tert-butylphenylnitrone spin adducts were observed. We suggest that electron paramagnetic resonance is a valuable tool for the noninvasive and direct in vivo monitoring of drug-induced radical formation in the skin under therapeutic conditions.