Tissue response to bioerodible, subcutaneous drug implants: a possible determinant of drug absorption kinetics

The fibrous tissue compartments that develop in response to the subcutaneous implantation of bioerodible heat-fused rods of norethindrone and cholesterol (85 and 15%, respectively) were studied by light and electron microscopy at various intervals after implantation to determine whether the biological inflammatory response may play a role in drug absorption. Thirty-five regularly menstruating, sterilized (tubal ligation), healthy females each received four Annuelle rods. The microanatomy of seven of the largest implants (135 mg norethindrone) was studied. A dense fibrous biological compartment was found to surround each rod. By light microscopy no abnormal tissue response was revealed. Scanning and transmission electron microscopy showed that the surfaces of the rods were covered by a cellular matrix of mononuclear cells. The fibrous compartment was composed of a loose cellular bed immediately surrounding the norethindrone rod, a dense fibrous connective tissue envelope containing blood and lymphatic vessels, and an outer fatty connective tissue layer. Transmission electron microscopy confirmed that the cellular tissue immediately surrounding the rods was composed mainly of lipid laden macrophages. Norethindrone levels in tissue capsules at 3 and 10.5 months were 0.05 and 8.4% by weight, respectively. These observations suggest that the local inflammatory response plays a role in the active processing of this delivery system. This picture is qualitatively different from the general view of the fibrous capsule as a simple rate limiting membrane. The effects observed in this study suggest that a more complex, functional biological system develops in response to the subcutaneous introduction of a drug delivery device.     

Tissue response to covered Wallstents

8-epi prostaglandin F2alpha(8-epi PGF2alpha) contracted rat thoracic aorta rings in a concentration-dependent manner in the presence or absence of functional endothelium [median effective concentration (EC50) values, 455+/-52 and 268+/-34 nM, respectively; Student's t test; p=0.006]. U46619 was a more potent agonist with or without functional endothelium (EC50 values, 6.8+/-1.6 and 4.5+/-1.0 nM, respectively). SQ29548 [a thromboxane (TP)-receptor antagonist] inhibited contractions to both 8-epi PGF2alpha and U46619 in a competitive manner, with mean pA2 values of 8.3 and 7.9, respectively. 8-Epi PGF2alpha had a further contractile effect in vessels that had been contracted with noradrenaline and had been shown to possess a functional endothelium. Inhibition of thromboxane synthesis with OKY-046 or blockade of endothelin receptors with bosentan had no effect on responses to 8-epi PGF2alpha or U46619. Preincubation with 8-epi PGF2alpha or noradrenaline shifted the concentration-response curves to U46619 upward at low concentrations of U46619 with no significant change in EC50 values or maximal responses. Reduction of TP-receptor number in rat aorta with dithiothreitol caused a concentration-dependent inhibition of responses to both U46619 and 8-epi PGF2alpha, with no effect on maximal responses and or on the responses to U46619 after the preincubation with 8-epi PGF2alpha. These results indicate that 8-epi PGF2alpha is a potent vasoconstrictor in the rat aorta and are suggestive of an action of 8-epi PGF2alpha at the TP receptor.     

Bone response to surface-modified titanium implants: studies on the early tissue response to machined and electropolished implants with different oxide thicknesses

The bone formation around titanium implants with varied surface properties is investigated. Machined and electropolished samples with and without thick, anodically formed surface oxides were prepared, surface characterized and inserted in the cortical bone of rabbits (1, 3 and 6 weeks). Scanning electron microscopy, scanning Auger electron spectroscopy and atomic force microscopy revealed marked differences in oxide thickness, surface topography and roughness, but no significant differences in surface chemical composition, between the different groups of implants. Light microscopic morphology and morphometry showed that all implants were in contact with bone and had a large proportion of bone within the threads at 6 weeks. The smooth, electropolished implants, irrespective of anodic oxidation, were surrounded by less bone than the machined implants after 1 week. After 6 weeks the bone volume as well as the bone-implant contact were lower for the merely electropolished implants than for the other three groups. Our study shows that a high degree of bone contact and bone formation are achieved with titanium implants which are modified with respect to oxide thickness and surface topography. However, the result with the smooth (electropolished) implants indicates that a reduction of surface roughness, in the initial phase, decreases the rate of bone formation in rabbit cortical bone.     

Survival of cylindrical implants in composite grafted maxillary sinuses

PURPOSE: This retrospective study investigated the survival of dental implants placed in the maxilla after composite grafting of the sinus and an average of 55 months of loading. PATIENTS AND METHODS: Maxillary sinuses of 88 patients were grafted with autogenous cancellous bone combined with dense hydroxyapatite particles. After an average healing period of 3.4 months, hydroxyapatite-coated titanium endosseous implants were placed. A total of 388 implants were placed in grafted sinus floors, and 82 were placed in onlay grafted nonsinus position in the canine region. The implants were loaded with overdentures and fixed bridges 4 months (mean) after implantation, with a follow-up for a mean of 55 months. RESULTS: The cumulative implant survival was calculated according to the Kaplan-Meier method. Implant survival from the time of loading was 89% in full reconstructed cases and 90% in partially edentulous cases. The overall cumulative implant survival rate, including the loss in the surgical stage, was 82%. CONCLUSION: Implant loss in composite grafted maxillae after 70 months of follow-up was similar to loss in nongrafted maxillae.     

Tissue response to suture materials implanted subcutaneously in a rabbit model

We compared the tissue response to a nonabsorbable monofilamented suture made of expanded polytetrafluoroethylene (ePTFE), which has recently been introduced for use in plastic surgery, with the response to 10 other commercially available absorbable sutures and nonabsorbable monofilamented and multifilamented sutures. The sutures were used to secure a patch of ePTFE implanted in the dorsum of adult New Zealand White rabbits. At 30, 60, and 120 days after implantation, the tissue response to the sutures was assessed with respect to the number of foreign-body giant cells present, the thickness of the fibrous capsule that developed, and the general inflammatory response (n = 4 for each suture for each time period). Analysis of variance revealed that specific suture type was significantly associated with foreign-body giant cell count and fibrous capsule thickness. Tevdek had a significantly higher value for mean number of foreign-body giant cells. Silk and Tevdek had significantly thicker fibrous capsules, and ePTFE suture had a significantly thinner capsule. Absorbable sutures and nonabsorbable multifilamented sutures evoked a more extensive tissue response than monofilamented sutures; the differences between nonabsorbable monofilamented and nonabsorbable multifilamented sutures were significant for capsule thickness. In general, suture made of ePTFE produced a minimal tissue response. It should be a good choice for use in facial plastic surgery, in which excellent functional and aesthetic results are critical.     

Alveolar bone growth in response to endosteal implants in two patients with ectodermal dysplasia

Osteitis condensans of the clavicle is a rare condition characterized by pain in the shoulder and often limitation of motion of the shoulder. The medical history and results of the physical examination, laboratory data, and radiographic studies (including computed tomography and magnetic resonance imaging), often establish the diagnosis. Patients who have slight or no pain usually require no treatment. Varying results have been reported for many different methods of treatment, including surgical excision, chemotherapy, antibiotics, nonsteroidal anti-inflammatory medications, radiation, local corticosteroid injection, and physical therapy. A typical case report and the differential diagnosis for condensing osteitis of the clavicle are presented.     

IgG response to pneumococcal polysaccharide-protein conjugate appears similar to IgG response to polysaccharide in bone marrow transplant recipients and healthy adults

OBJECTIVE: This study was done to determine if the detection of pericolic lymph nodes on CT scans could be used to differentiate cancer of the colon from diverticulitis. MATERIALS AND METHODS: We retrospectively evaluated 58 CT scans from 57 patients with proven diverticulitis or cancer of the colon. The CT scans were evaluated by five board-certified radiologists who were unaware of the proven diagnosis. Consensus opinions regarding the presence and size of pericolic lymph nodes were recorded. These data were correlated with the proven diagnoses to determine the correlation between the observed findings and the type of colonic abnormality. Fisher's exact test was used to determine statistical significance. RESULTS: Lymph nodes were seen in 22 (71%) of 31 cases of colonic cancer and in four (15%) of 27 cases of diverticulitis. The lymph nodes were 0.5-2.5 cm in short-axis diameter. We saw no difference in node size for patients with colonic cancer versus patients with diverticulitis. The nodes were most commonly located along the blood vessels in the mesenteric fat. Statistical analysis showed a significant difference (p < .001) in the frequency but not in the size of nodes between the two groups of patients. The detection of nodes resulted in a diagnostic sensitivity and specificity for colonic cancer of 71% and 85%, respectively. CONCLUSION: Pericolic lymph nodes are seen much more frequently in patients with colonic cancer than in patients with diverticulitis. The detection of pericolic lymph nodes in patients suspected of having diverticulitis should raise the suspicion of underlying colonic cancer that should, in turn, prompt additional evaluation.     

Structural response to shape variations in the AI-AI3Ni eutectic composite

Structural irregularities that arise due to shape variations in Al-Al₃Ni directionally solidified eutectic composites have been analyzed. The shape variations studied are axisymmetric increases in the cross-sectional area of cylindrical rods, and divergence. The results show that larger angles of divergence cause more fiber misorientation, increase the curvature of the solid-liquid interface, and result in more pronounced changes of the local growth rate in the divergence area. The disturbances were shown to be accompanied by changes in the number of fibers in a growing composite. Extra fibers should be generated when the cross sectional area increases, the solid-liquid interface curvature increases, or the growth rate is accelerated. The extra fibers were found to be mostly supplied by fiber branching mechanism rather than by individual fiber nucleation which was not observed frequently. In cases of new areas of growth, fiber branching is too slow to supply the required extra fibers. Under these conditions Al₃Ni phase nucleates in the lamellar morphology and then changes to fibers by repeated branching. In the present work Al₃Ni lamellae were nucleated at the beginning of directional solidification, areas above oxide inclusions and secondary arms of aluminum dendrites, and at the shoulders of large angles of divergence.     

Capsular synovial metaplasia as a common response to both textured and smooth implants

Recent reports suggested that the presence of synovial metaplasia in the capsular tissues of breast implants is greater with textured-shelled implants compared with smooth. Textured implants, however, have become popular only in the last few years. Therefore, the studies do not address the possibility that synovial metaplasia may be a dynamic process related to time (e.g., implant age) rather than implant shell surface. In the current study, 159 implant capsules (85 patients) removed between February of 1992 and July of 1993 at UCLA Medical Center were evaluated histologically and correlated with clinical data, including the age of implants. Synovial metaplasia was identified in 40 percent (64 of 159) of the capsule specimens. A logistic regression analysis that removed the effect of implant age demonstrated no correlation of implant shell type (textured versus smooth) with the presence of synovial metaplasia. Gel bleed, implant location, pericapsular fluid, implant rupture, and capsular contracture also did not have any significant association with synovial metaplasia in the current study. The incidence of synovial metaplasia appears to decrease with age (77 percent at < 5 years; 22 percent at > 15 years). Our findings suggest that synovial metaplasia is not rare and in fact may be a fairly common transitional histologic finding. It may be part of the common progression that occurs at the implant-capsule interface. The clinical significance remains unknown.     

Tissue regeneration in bony defects adjacent to immediately loaded titanium implants placed into extraction sockets: a study in dogs

In this study of six greyhound mandibles, 24 implants were placed into extraction sockets. Eighteen of the implants were connected with abutments and immediately placed into normal function, and the remaining six submerged implants served as controls. At placement, dehiscence areas were created adjacent to 12 of the implants to study bone regeneration in extended membrane-protected defects. Six of the defects were covered with expanded polytetrafluoroethylene membranes, and six of the defects were augmented with autologous bone grafts and covered with expanded polytetrafluoroethylene material. The clinical and radiographic evaluations demonstrated that all implants achieved functional osseointegration and no implants were lost. Implant sites where membranes were used to regenerate bone over dehiscence defects demonstrated a high rate of membrane exposure and variable response to treatment. On completion of the study at 16 weeks, histomorphometric analysis demonstrated osseointegration with direct bone-to-implant contact for all implants, although the percentage of contact varied considerably. Histomorphometry indicates that the quality of osseointegration may be less favorable than the clinical and radiographic result would suggest.     

Biochemical analysis of the response in rat bone marrow cell cultures to mechanical stimulation

Bone marrow cells obtained from rat femora were subjected to primary culture with 15% fetal bovine serum in the presence of 10(-8) M dexamethasone, and following trypsin treatment 5 days later were seeded on Petriperm dishes which have a flexible bottom. After a 2-day subculture, a cyclic stress consisting of a 1 s stretch (0.3% strain. 0.5 Hz) and a 1 s relaxation for 30 min every day was started. Culture tissue was removed on day 2 of the subculture (immediately prior to start of stimulation), and then on days 5 and 8 (3 and 6 days after the start of stimulation, respectively), at which times dry weight, DNA, alkaline phosphatase (ALP) activity, and bone Gla protein (BGP, osteocalcin) were measured. Both the dry weight and DNA showed a significant increase in the stimulated group by day 8, while the ALP activity showed a significant increase by day 5. The BGP began to increase in the stimulated group on day 5 in contrast to the control group in which it only increased on day 8. These results support the contention that mechanical stimulation promotes the differentiation of osteogenic cells and enhances bone formation. Since in this experimental model the acceleration of bone formation by mechanical stimulation can be reproduced in vitro, it is extremely useful for investigating the mechanisms underlying mechanical stimulation.     

Characterization of the response of human bone marrow endothelial cells to in vitro irradiation

Endothelial cell dysfunction is a classic consequence of radiation damage. Bone marrow endothelial cells (BMEC) are a critical component of the stroma in the regulation of haemopoiesis. In animal models, radiation-induced injury of BMEC has been described and a role for BMEC in haemopoietic regeneration after irradiation has been suggested. However, functions of BMEC involved in the haemopoietic regeneration have not been assessed. Therefore we studied the functional response of human BMEC to irradiation using the transformed human BMEC line (TrHBMEC) irradiated with 2. 5 or 10Gy. Our results showed a time- and a dose-dependent increase in damage to irradiated TrHBMEC measured by a decreased number of adherent cells which correlated with increased apoptosis and augmented release of soluble ICAM-1 and von Willebrand factor. 2 Gy irradiated TrHBMEC expressed more ICAM-1 on their surface than non-irradiated cells, whereas no change in VCAM-1, E-selectin and PECAM-1 expression was observed. An increased production of G-CSF, GM-CSF, IL-8, IL-6, IL-1alpha, IL-11, MIP-1alpha and SCF and no production of LIF, TNF-alpha, TPO and IL-3 by 2 Gy irradiated TrHBMEC was observed. The haemopoietic supportive function of TrHBMEC was not altered after a 2 Gy exposure. These results suggest that although radiation induces endothelial cell damage, irradiated cells still support the proliferation and the differentiation of CD34+ haemopoietic cells.     

Relative effects of wound healing and mechanical stimulus on early bone response to porous-coated implants

We hypothesized that early bone adaptation to well fixed porous-coated implants is influenced more by wound healing than by mechanical loading. To test this hypothesis, two groups of dogs with identical, hydraulically controlled porous-coated implants interference fit within distal femoral trabecular bone were used. One group had no load: the other had 35 N of load applied to the implants. At 5 weeks after surgery, the resulting adaptation of bone around the implants was quantified on a cellular basis by cytochemical analysis of type-I procollagen synthesis and on a structural basis using three-dimensional micro-computed tomography imaging. The percentage of trabecular surfaces covered by osteoblasts expressing type-I procollagen was significantly increased in bone surrounding the implant in both groups compared with contralateral control bone tissue. There was no difference between the groups with no load or 35 N of load. In addition, measures of trabecular bone structure did not differ significantly between the load and no-load groups. Taken together, these results suggest that wound healing plays a much greater role in the early response of bone to well fixed porous-coated implants than does mechanical stimulus.     

Stress in bone adjacent to dental implants

Finite element analysis (FEA) was employed to assess patterns of stress in bone adjacent to an implant after application of loads through an attached distal extension cantilever. Under all loading conditions, the highest stresses occurred at the distal cervical bone margin adjacent to the cantilever. In clinical studies, this is not consistently the site of the greatest bone changes seen radiographically. This suggests that extrapolation of FEA studies to clinical implantology should be approached with caution until further data become available on both mechanical properties of bone and patterns of bone remodelling induced by defined functional stresses in mandible and maxillae.     

Is the implantation of a second intraocular lens prior to the removal of the first implants remaining in the vitreous cavity incorrect medical treatment?

BACKGROUND: The implantation of an intraocular lens into the capsular bag is a common procedure in modern cataract surgery. In case of a break of the posterior capsule it is possible to implant the intraocular lens by rhexis-, ciliary sulcus- or pars-plana-fixation. The following case is in so far remarkable, as a second intraocular lens has been implanted while a dislocated intraocular lens was still in the vitreous cavity. PATIENT: We report on a 70-year-old patient who underwent cataract surgery. After a break in the posterior capsule the intraocular lens dislocated into the vitreous cavity. A second intraocular lens has been implanted in the ciliary sulcus. 41 days after cataract surgery the dislocated intraocular lens has been removed by pars-plana-vitrectomy without any problems. CONCLUSION: Intraocular lens implantation in the ciliary sulcus is not proved to be a hindrance with regard to the transcleral removal of a posteriorly dislocated intraocular lens, following the principles of intraocular foreign body surgery.     

Autoimmunity to collagen in human lung cancer

The pressure dependence of the flexibility of the 8-anilino-1-naphthalene sulfonate (ANS)-apomyoglobin complex was investigated in the range between atmospheric pressure and 2.4 kbar by frequency domain fluorometry. We examined two structural states: native and acidic compact. The conformational dynamics of the ANS-apomyoglobin complex were deduced by studying the emission decay of ANS, which can form a noncovalent complex with the apoprotein in both the native and the acidic compact forms. Because the free fluorophore has a very short lifetime (less than 75 ps), its contribution can be separated from the long-lived emission. The latter arises from ANS molecules bound to the protein and provides information on the structural and dynamic characteristics of the macromolecule. The fluorescence emission decay of the ANS-apomyoglobin complex at neutral pH has a broad fluorescence lifetime distribution (width at half-maximum = 4.1 ns). The small changes in the fluorescence distribution parameters that occur with changes in pressure indicate that the ANS-apomyoglobin complex at neutral pH holds its compactness even at 2.4 kbar. A small contraction of molecular volume has been detected at low pressure, followed by a slight swelling with an increase in flexibility at higher pressures. The heterogeneity of ANS fluorescence in the acidic compact state of apomyoglobin is even greater than that in the native form (distribution width = 10 ns); moreover, the acidic compact state appears more expanded and accessible to solvent molecules than the native state, as suggested by the distribution center, which is 11 ns for the former and 19 ns for the latter. The lifetime distribution center remains constant with increasing pressure, which suggests that no other binding site is formed at high pressure.