Klaus-Peter Schmitz

In vitro and in vivo degradation studies for development of a biodegradable patch based on poly(3-hydroxybutyrate).

For the development of a resorbable gastrointestinal patch, the in vitro degradation of solution-cast films of poly(3-hydroxybutyrate) (PHB), modifications of PHB expected to influence its degradation time, as well a poly(L-lactide) (PLLA) was examined. The molecular weight of pure PHB decreased by one-half after 1 year in buffer solution (pH 7.4, 37 degrees C). Acceleration in molecular weight decrease was observed by blending with atactic PHB, whereas no influence was found with low-molecular weight PHB. Leaching of a water-soluble additive led to a slight acceleration of PHB degradability. In contrast, a deceleration in degradation rate was observed with the addition of a hydrophobic plasticizer. In vitro tests indicated an accelerating effect of pancreatin on PHB degradation, whereas PLLA degradation remained essentially uninfluenced. In comparison to simple hydrolysis, the degradation rate of PHB was accelerated about threefold. From the in vitro results, a PHB/atactic PHB blend was selected for repair of a bowel defect in Wistar rats. A patch film was fabricated by a dipping/leaching method. Twenty-six weeks post-implantation, material remnants were found in only one of four animals. The bowel defects were closed in all cases. It could be assessed that the patch material resists the intestinal secretions for a sufficiently long time but that it finally degrades completely.

Mechanical properties of laser cut poly(L-lactide) micro-specimens: implications for stent design, manufacture, and sterilization.

BACKGROUND The development of endoluminal stents from polymeric materials requires an understanding of the basic mechanical properties of the polymer and the effects of manufacturing and sterilization on those properties. METHODS Pure poly(L-lactide) (PLLA) and PLLA containing varying amounts of triethylcitrate (TEC) as a plasticizer (5-10-15%) were studied. The specimens were solution-cast and CO2 laser-cut. Specimen dimensions were adapted to the strut size of polymeric vascular stents. The properties of the PLLA micro-specimens were assessed before and after sterilization (EtO cold gas, H2O2-plasma, beta- and gamma-irradiation). Tensile tests, and creep and recovery tests were carried out at 37 degrees C. Additionally the thermal and thermo-mechanical characteristics were investigated using dynamic-mechanical analysis (DMA) and differential scanning calorimetry (DSC). RESULTS The results showed the dramatic influence of the plasticizer content and sterilization procedure on the mechanical properties of the material. Laser cutting had a lesser effect. Hence the effects of processing and sterilization must not be overlooked in the material selection and design phases of the development process leading to clinical use. Altogether, the results of these studies provide a clearer understanding of the complex interaction between the laser machining process and terminal sterilization on the primary mechanical properties of PLLA and PLLA plasticized with TEC.

Structural alterations of adhesion mediating components in cells cultured on poly-β-hydroxy butyric acid

Polymers may serve as a biodegradable material in tissue engineering. To assess the biocompatibility of poly-beta-hydroxy butyric acid (PHB), we studied the structural organization of cellular molecules involved in adhesion using osteoblastic and epithelial cell lines. On PHB, both cell lines revealed a rounded cell shape due to reduced spreading. The filamentous organization of the actin cytoskeleton was impaired. In double immunofluorescence analyses we demostrated that the colocalization of the fibronectin fibrils with the actin filaments was lost in cultures on PHB. Similarly, collagen II distribution was altered, whereas the organization of collagen I was not obviously affected. Further evidence for impaired structural organization was obtained for the beta1-integrin receptor and vinculin which mediate the interaction of the cytoskeleton with the extracellular matrix. In confluent epithelial cells, the tight junction protein ZO-1 showed a larger lateral extension in the cell-cell contacts when cells were grown on PHB. Because structural organization of components which mediate cell-matrix and cell-cell adhesion controls cell physiology these parameters could be a sensitive indicator for the biocompatibility of implant materials.

A convenient approach for finite-element-analyses of orthopaedic implants in bone contact: Modeling and experimental validation

With regard to the growing potential of finite-element-analysis (FEA) in the field of orthopaedic biomechanics, we present an approach helping in the development of appropriate models of the implant-bone compound. The algorithm is based on computed-tomography data of the bone and accordant computer-aided-design (CAD) data of the implant and aims at predicting the bone strains and interface mechanics of the included parts. The developed algorithm was validated exemplary using an acetabular cup in combination with a left and a right fresh-frozen human hemipelvis. The strains under maximum loads during the gait cycle as well as the micromotion in the bone-implant interface were measured and compared to results from equivalent finite-element-analyses. Thereby, we found strong correlation between the calculated and measured principal strains with correlation coefficients of r(2)=0.94 (left side) and r(2)=0.86 (right side). A validation of micromotion was not possible due to limited accuracy of the motion tracking system.

Limited range of motion of hip resurfacing arthroplasty due to unfavorable ratio of prosthetic head size and femoral neck diameter

Background and purpose Hip resurfacing arthroplasty is being used more and more frequently. The small ratio in size between the resurfaced femoral head and the relatively thick femoral neck raises the question of whether the range of motion is sufficient, particularly with regard to the high mobility required by younger patients. We analyzed motion in a CAD model. Methods Three-dimensional CAD models of the natural hip were created from CT scans and 8 designs of hip resurfacing prostheses (head diameter between 42 mm and 54 mm combined with a hemispherical cup) were implanted in a virtual sense. We simulated 3 different leg positions and the range of motion was evaluated, considering five different implant positions. Results The range of motion of the hip resurfacing designs analyzed was far below the range of motion of stemmed total hip prostheses. None of the resurfacing prostheses provided flexion movements of 90° without impingement. The average range of motion of hip resurfacing arthroplasty was 31–48° below the range of motion of a stemmed total hip replacement with 32-mm head diameter. Interpretation The range of motion of the hip resurfacing designs examined was substantially less than that of a conventional total hip prosthesis. Since impingement of the femoral neck on the acetabular component increases the risk of neck fractures, of dislocation and of subsequent implant loosening, the design and position of the implant should be considered before using hip resurfacing arthroplasty as a standard treatment for younger patients.

Scanning electron microscopic analysis of different drug eluting stents after failed implantation: From nearly undamaged to major damaged polymers†

Background: Implantation of drug eluting stents (DES) in tortuous and/or calcified vessels is much more demanding compared with implantation of bare metal stents (BMS) due to their larger diameters. It is unknown whether drug eluting stent coatings get damaged while crossing these lesions. Methods: In 42 patients (34 male, 68.1 ± 10 years) with 45 calcified lesions (15.9 mm ± 7.9 mm), DES could not be implanted, even after predilatation. Diabetes was present in 19 patients (45 %). Sixty‐one stents were used; 19 Cypher select™, 18 Taxus Liberté™, 10 CoStar™, 5 Endeavor RX™, 4 Xience V™. 3 Janus Carbostent™, 1 Yukon Choice S™, and 1 Axxion™ DES. The entire accessible surface area of these stents, in either the unexpanded and expanded state, were examined with an environmental scanning electron microscope (XL30 ESEM, Philips) to evaluate polymer or surface damage. Results: The polymers of Taxus Liberte, Cypher Select, Xience V, CoStar, and Janus DES were only slightly damaged (less than 3% of surface area), whereas the Endeavor RX Stents showed up to 20% damaged surface area. In DES without a polymer (Yukon and Axxion), it could be shown that most of the stent surface (up to 40%) were without any layer of drug. Conclusion: Placement of drug eluting stents in tortuous vessels and/or calcified lesions could cause major surface damage by scratching and scraping of the polymer or drug by the arterial wall, even before implantation. There were remarkable differences among the stents examined, only minor damage with the Cypher, Taxus Costar, Janus, and Xience V, whereas the Endeavor, the Yukon, and the Janus DES showed large areas of surface injury.

Biodegradable Sirolimus-loaded Poly(lactide) Nanoparticles as Drug Delivery System for the Prevention of In-Stent Restenosis in Coronary Stent Application

The administration of drugs using biodegradable polymer nanoparticles as carriers has generated immense interest due to their excellent biocompatibility and the prolonged drug release. The scope of this work was to determine the applicability of sirolimus-loaded biodegradable poly(D,L-lactide) (PDLLA) nanoparticles as drug carriers to prevent restenotic processes after stent implantation. The average 250 nm sized 20%(w/w) sirolimus-loaded nanoparticles were extensively characterized with regard to in vitro degradation, biocompatibility and in vitro drug release. The particles show biphasic release kinetics consisting of a short burst release of 50%(w/w) sirolimus payload, followed by a longer, slower release phase, which are desirable for the application as a drug delivery carrier. All presented results exhibit the potential of sirolimus-loaded PDLLA nanoparticles as promising local and sustained drug delivery systems administered intraluminally to reduce in-stent restenosis after stent implantation.

A biodegradable stent based on poly(L-lactide) and poly(4-hydroxybutyrate) for peripheral vascular application: preliminary experience in the pig.

Purpose: To assess the technical feasibility and biocompatibility of a novel stent based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for peripheral vascular applications. Methods: A polytetrafluoroethylene aortobi-iliac graft was implanted in 5 pigs through a midline abdominal incision. After transverse graft limb incision, 5 PLLA/P4HB stents and 5 metal stents (316L stainless steel) were randomly deployed at both iliac anastomotic sites with 6-mm balloon catheters. Angiography was performed to determine patency prior to sacrifice at 6 weeks. Stented segments were surgically explanted and processed for quantitative histomorphometry. Vascular injury and inflammation scores were assigned to the stented iliac segments. Results: No animals were lost during follow-up. All PLLA/P4HB stents were deployed within 2 minutes by balloon inflation to 8 bars without rupture of the stent struts or anastomotic suture. All stents were patent on postprocedural angiography. Histological analysis showed no signs of excessive recoiling or collapse. PLLA/P4HB stents demonstrated decreased residual lumen area and increased neointimal area after 6 weeks (12.27±0.62 and 8.40±1.03 mm2, respectively) compared to 316L stents (13.54±0.84 and 6.90±1.11 mm2, respectively) as the result of differences in stent areas (PLLA/P4HB: 4.31±0.15 mm2; 316L: 2.73±0.29 mm2). Vascular injury scores showed only mild vascular trauma for all stents (PLLA/P4HB: 0.41±0.59; 316L: 0.32±0.47). Inflammatory reaction was slightly higher around PLLA/P4HB stent struts (1.39±0.52) compared to 316L (1.09±0.50). Conclusion: Rapid balloon expansion of PLLA/P4HB stents is feasible without risk of strut rupture. PLLA/P4HB stents provide adequate mechanical stability after iliac anastomotic stenting in pigs. Smaller residual luminal areas in the PLLA/P4HB stents might have been caused by tissue ingrowth into the larger strut interspaces due to higher strut thickness (stent area) in this group. This limitation needs to be addressed in future work on the stent design.

Iliac Anastomotic Stenting with a Sirolimus-Eluting Biodegradable Poly-L-Lactide Stent: A Preliminary Study after 6 Weeks

Purpose: To assess technical feasibility and biocompatibility of a new biodegradable sirolimus-eluting poly-L-lactide (PLLA) vascular anastomotic stent. Methods: A polytetrafluoroethylene bifurcated graft was implanted in 9 pigs through a midline abdominal incision. After transverse graft limb incision, 6 unloaded PLLAs, 6 sirolimus-loaded PLLAs, and 6 unloaded stainless steel (316L) stents were randomly implanted at both iliac anastomotic sites. Stents were deployed with a 6-mm balloon under direct vision without the use of angiography. Prior to sacrifice after 6 weeks, contrast-enhanced computed tomography (CT) was performed to determine patency of the target vessels. Stented segments were surgically explanted and processed for histology to measure the mean luminal diameter and intimal thickness and to assign vascular injury and inflammation scores. Results: No animals were lost during the study period. All stented graft limbs were patent on CT and histology. At the anastomotic sites and iliac arteries, the mean luminal diameter of SIR-PLLA stents (4.11±0.15 and 4.08±0.13 mm, respectively) were comparable to metal stents (4.23±0.35 and 4.21±0.26 mm, respectively), but significantly higher compared to unloaded PLLA stents [3.32±0.56 mm (p<0.001) and 3.29±0.39 mm (p=0.013), respectively]. At the iliac arteries, the mean intimal thickness was significantly lower with SIR-PLLA stents (0.09±0.02 mm) compared to unloaded PLLA stents (0.31±0.15 mm, p<0.001) and metal stents (0.19±0.04 mm, p=0.004). Vascular injury scores demonstrated only mild vascular trauma for all stents (SIR-PLLA: 0.42±0.63, PLLA: 0.51±0.62, metal: 0.50±0.62). Only mild inflammatory reaction was noted around SIR-PLLA stent struts (1.14±0.46), which was comparable to metal stents (1.27±0.45) but significantly lower than PLLA stents (1.79±0.56, p<0.001). Conclusion: SIR-PLLA stents showed comparable luminal diameter compared to metal stents, so incorporating sirolimus could reduce the inflammatory and neointimal response to PLLA stents. These findings need to be assessed with longer follow-up to confirm maintenance of efficacy.

Comparison of the accommodation theories of Coleman and of Helmholtz by finite element simulations.

PURPOSE The accommodation process of the human eye is still a controversial subject. Coleman assumes that the lens, together with the zonula fibers, forms a diaphragm which is held in a catenary shape due to the pressure difference between the aqueous and vitreous body of the lens. The aim of the paper is to compare the results of two simulations (according to the Helmholtz and to the Coleman theories) with ultrasonographic data. METHODS An axisymmetric static finite element model of the lens was generated using the literature data for geometry, material properties and loads. The refractive power of the lens was calculated for two different ages (29 and 45 years). RESULTS The application of a pressure to the posterior lens surface did not yield an increase in refractive power change during accommodation. Rather a decrease in accommodation related refractive power was found. CONCLUSIONS Physiologically relevant refractive power changes are obtained by a simulation in accordance with the Helmholtz theory. A simulation in accordance with the Coleman theory does not yield physiological values of refractive power change.