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Adhesions: pathogenesis and prevention-panel discussion and summary.

This article summarizes the discussions of the faculty and chairpersons on four major topics on postsurgical adhesions examined at the symposium, "Adhesions: Pathogenesis and Prevention". These topics are: 1) clinical significance; 2) pathogenesis; 3) research status and directions; and 4) recommendations for reduction or prevention. Abdominal postsurgical adhesions develop following trauma to the mesothelium, which is damaged often by surgical handling and instrument contact, foreign materials such as sutures and glove dusting powder, desiccation, and overheating. Postoperative adhesions occur after most surgical procedures and can result in serious complications, including intestinal obstruction, infertility, and pain. A long-term and unpredictable problem, postoperative adhesions impact the surgical workload and hospital resources, resulting in considerable health care expenditures. Although understanding of the pathogenesis of adhesions has improved recently, the molecular mechanisms involved continue to be delineated. Adhesions result from the normal peritoneal wound healing response and develop in the first five to seven days after injury. Adhesion formation and adhesion-free re-epithelialization are alternative pathways, both of which begin with coagulation which initiates a cascade of events resulting in the buildup of fibrin gel matrix. If not removed, the fibrin gel matrix serves as the progenitor to adhesions by forming a band or bridge when two peritoneal surfaces coated with it are apposed. The band or bridge becomes the basis for the organization of an adhesion. Protective fibrinolytic enzyme systems of the peritoneum, such as the plasmin system, can remove the fibrin gel matrix. However, surgery dramatically diminishes fibrinolytic activity. The pivotal events determining whether the pathway taken is adhesion formation or re-epithelialization are therefore the apposition of two damaged surfaces and the extent of fibrinolysis. Research in postsurgical adhesion formation and prevention abounds in a variety of avenues of investigation, including: 1) identification on a molecular level of the components involved in adhesiogenesis and their interactions; 2) clarification of the role of fibrin and fibrinolysis in adhesion formation; 3) standardization of design in preclinical and clinical studies of adhesion formation and prevention; 4) delineation of the relationship between adhesion formation and adhesive complications; and 5) elucidation of efficient, site-specific methods of prophylactic drug delivery. Currently, it seems logical to focus preventive research on development of barriers, fibrinolytic drugs, and selected agents such as phospholipids. The major strategies for adhesion prevention or reduction are adjusting surgical practice and applying adjuvants. Surgeons should adjust their major practices by: 1) becoming aware of the potential adhesive complications of a procedure; 2) minimizing the invasiveness of surgery; and 3) minimizing surgical trauma, ischemia, exposure to intestinal contents, introduction of foreign material into the body, and the use of talc- or starch-containing gloves. Available adjuvants include a newly developed by hyaluronic acid-phosphate-buffered saline solution applied intraoperatively to protect peritoneal surfaces from indirect surgical trauma and three mechanical barriers. One of these, a bioresorbable membrane consisting of hyaluronic acid and carboxymethylcellulose, has demonstrated efficacy and safety in both general and gynecological surgery. The other two barriers, one made of expanded polytetrafluoroethylene and one developed from oxidized regenerated cellulose, are indicated only for use in gynecological surgery.

Humans↗

Membrane protein glycosylation and CD44 content in the adhesion of human ovarian cancer cells to hyaluronan.

The adhesion of tumour cells to the hyaluronan (HA) pericellular coat of mesothelial cells is an important step in the peritoneal spread of ovarian cancer. Previously, we have shown that the cell surface molecule CD44 is involved in this process. Paradoxically, the degree of adhesion does not appear to be related to the amount of CD44 expressed. In order to explain this observation we have examined the in vitro adhesion to HA of four high CD44-expressing ovarian cancer lines in relation to their CD44 spliced variant content and the CD44 glycosylation. Adhesion was measured in multiwell plates coated with different concentrations of HA in order to determine both the avidity and the maximum adhesion. Two lines had high adhesion and two lines had low adhesion. The avidity for HA was different for each line, but in all cases this could be totally blocked by treatment with an anti-CD44 antibody. The standard form of CD44 was the major species detected by RT/PCR in all lines and spliced variants were present in low amounts. Neuraminidase treatment increased the adhesion of the 'low-adhesion' lines at all HA coating concentrations; but only substantially increased the adhesion of the 'high-adhesion' lines at the lower HA coating concentrations. Tunicamycin treatment decreased the adhesion of the 'high-adhesion lines' at all HA coating concentrations and only substantially decreased the adhesion of one of the 'low-adhesion' lines when the plates were coated with a low concentration of HA. The adhesion of the remaining 'low-adhesion' line was slightly increased after tunicamycin treatment. It is concluded that glycosylation and not spliced variant content of CD44 affects the adhesive properties of ovarian tumour cells. This conclusion may have important consequences for developing new therapies in ovarian cancer.

Carcinoma, Endometrioid↗

The effect of autologous fibrin tissue adhesive on postoperative cerebrospinal fluid leak in spinal cord surgery: a randomized controlled trial.

STUDY DESIGN: A prospective randomized study evaluating the efficacy of autologous fibrin tissue adhesive for decreasing postoperative cerebrospinal fluid (CSF) leak in spinal cord surgery. OBJECTIVE: To compare postoperative CSF leak in 3 groups (i.e., autologous fibrin tissue adhesive used, commercial fibrin glue used, and no fibrin tissue adhesive used) of patients undergoing spinal surgery who needed dural incision. SUMMARY OF BACKGROUND DATA: Spinal cord operations, particularly when dural incision is inevitable, sometimes involve postoperative CSF leak. Because CSF leak is a serious complication, countermeasure is necessary to prevent it after dural suture. Commercial fibrin tissue adhesive was formerly used. Because the possibility of prion infection was widely noticed, commercial fibrin tissue adhesive containing animal components has been used less often. METHODS: In 13 of 39 cases in which dural incision would be made, 400 mL whole blood was drawn, and autologous fibrin tissue adhesive was made of plasma. Cases were divided into 3 groups: (1) dural closure alone, (2) use of autologous fibrin tissue adhesive after dural closure, and (3) use of commercial fibrin tissue adhesive after dural closure. The primary outcome measure was determined as postoperative (3 days) volume of drainage fluid, and results were analyzed using the analysis of variance. The secondary outcome measure was general blood test, coagulation assay, and plasma fibrinogen, and these were analyzed also using the analysis of variance. RESULTS: There was a significant difference in the primary outcome between the autologous and control groups. No complications such as infection or continuous CSF leak were observed in any case. The mean volume of drainage fluid was 586.2 mL in the group with autologous fibrin tissue adhesive and 1026.1 mL in the group without fibrin tissue adhesive. The volume of drainage fluid was significantly lower in the former group than that in the latter group. There was no statistical difference between the volumes of the group with autologous adhesive and with commercial adhesive (639.2 mL). CONCLUSIONS: We used autologous fibrin tissue adhesive as a new sealant after dural closure instead of commercial fibrin tissue adhesive. No definitive CSF leak was observed, and the volume of drainage fluid was significantly lower in the group with autologous fibrin tissue adhesive than that in the group without fibrin tissue adhesive. The use of autologous fibrin tissue adhesive was superior to that of commercial fibrin tissue adhesive in cost.

Adult↗

Incidence of postoperative adhesion formation after transperitoneal genitourinary laparoscopic surgery.

OBJECTIVES: To evaluate adhesion formation after urologic laparoscopy, a multi-institutional review was conducted among adult patients who underwent a second procedure after an initial transperitoneal laparoscopic procedure. Adhesion formation after abdominal surgery remains a major cause of postoperative morbidity. Peritoneal adhesions result in hospitalizations and interventions that result in healthcare costs of more than 1 billion dollars annually. The risk of adhesion formation from transperitoneal genitourinary laparoscopy in adults has not been previously studied. METHODS: Twenty-seven patients (mean age 45.5 years, range 24 to 71) were identified who underwent a second laparoscopic procedure after their initial urologic laparoscopic procedure was performed. The mean time between the procedures was 11.4 months (range 8 days to 38 months). At the time of the repeated laparoscopy or open surgery, the peritoneal cavity was examined and mapped for type (grade), extent (length), and location of any adhesions at the operative and trocar sites. The adhesions were graded as 0, no adhesions; 1, flimsy; 2, dense; and 3, cohesive. The extent was graded as 0, no adhesions; 1, less than 2 cm; 2, 2.1 to 10 cm; 3, greater than 10.1 cm. RESULTS: Overall, adhesions occurred in 6 (22.2%) of 27 patients. Operative site adhesions occurred in only 3 (8.2%) of 34 possible operative sites (gastric augmentation cystoplasty, renal cyst ablation, nephropexy). Trocar site adhesions occurred in 4 (3.5%) of 114 possible sites (two nephrectomies, one cyst decortication, and one orchiectomy). All adhesions were classified as grade 1 and extent 1, except for a single grade 2, extent 2 adhesion. In most patients, retroperitonealization occurred with minimal or no scarring noted. None of the patients developed symptoms as a result of the adhesion formation. CONCLUSIONS: Although intraperitoneal adhesions do occur with adult urologic laparoscopy, the incidence is low. Also, in the few patients who do form adhesions, they are flimsy and short. This evidence, when contrasted with the available data on adhesion formation after open surgery, suggests that transperitoneal laparoscopic approaches to genitourinary surgery may have advantages over traditional open transperitoneal approaches by lowering the incidence and severity of adhesion formation.

Adult↗

Beta1-integrin-mediated dynamic adhesion of colon carcinoma cells to extracellular matrix under laminar flow.

To resist substantial wall shear stress exerted by blood flow metastasizing colon carcinoma cells have to form adhesive contacts with endothelial cells and subendothelial extracellular matrix (ECM). At secondary sites tumor cells have to stabilize these initial adhesive interactions to prevent detachment and recirculation. Previously we found that adhesion of colon carcinoma cells to ECM components under static conditions is mediated, in part, by various beta1-integrins. Since other malignant cells possess adhesive properties that are different under static and dynamic conditions, we analyzed human colon carcinoma cell adhesion under flow by decreasing the flow (wall shear stress, WSS) of cell suspensions and allowing cells to interact with collagen-coated surfaces in a laminar flow chamber. HT-29 colon carcinoma cells were used to study wall shear adhesion threshold (WSAT), dynamic adhesion rate (DAR) and adhesion stabilization rate (ASR). DAR was determined after a low flow period using a WSS set at 50% of WSAT. ASR was calculated 60 sec after reestablishment of high WSS. Glass slides were coated with collagen I (C I) or bovine serum albumin (BSA, negative control). In some experiments cells were pretreated with function-blocking anti-beta1 or nonspecific IgG. Rolling of cells occurred on C I- and BSA-coated surfaces at high WSS. By decreasing WSS cell sticking without definite adhesion was found, and cells stuck to BSA at WSS lower than that found for C I. Further decreasing WSS below WSAT enabled stable cell adhesion to C I, but only a few cells adhered to BSA. ASR was found to be 73% of primarily adherent cells (to C I). Pretreatment with anti-beta1 did not affect cell rolling but did inhibit cell sticking and adhesion completely, whereas nonspecific IgG was without effect. Activation of PKC using phorbol ester resulted in an increase of adhesive interactions under dynamic and static conditions, whereas its inhibition reduced adhesion. Adhesive interactions of HT-29 colon carcinoma cells with ECM-coated surfaces under laminar flow conditions occurred in various steps: (1) rolling, (2) sticking or initial adhesion, and (3) stabilization of adhesion. Under shear flow rolling of tumor cells on ECM-coated surfaces appeared to be mediated mainly by physical/mechanical and nonspecific surface-cell membrane interactions, whereas stabilized adhesion to ECM was specifically mediated by beta1-integrin binding to ECM components. PKC seems to be involved in the regulation of adhesion stabilization under static and flow conditions.

Animals↗

Organization of pp60src and selected cytoskeletal proteins within adhesion plaques and junctions of Rous sarcoma virus-transformed rat cells.

The localization of pp60src within adhesion structures of epithelioid rat kidney cells transformed by the Schmidt-Ruppin strain of Rous sarcoma virus was compared to the organization of actin, alpha-actinin, vinculin (a 130,000-dalton protein), tubulin, and the 58,000-dalton intermediate filament protein. The adhesion structures included both adhesion plaques and previously uncharacterized adhesive regions formed at cell-cell junctions. We have termed these latter structures "adhesion junctions." Both adhesion plaques and adhesion junctions were identified by interference-reflection microscopy and compared to the location of pp60src and the various cytoskeletal proteins by double fluorescence. The results demonstrated that the src gene product was found within both adhesion plaques and the adhesion junctions. In addition, actin, alpha-actinin, and vinculin were also localized within the same pp60src-containing adhesion structures. In contrast, tubulin and the 58,000-dalton intermediate filament protein were not associated with either adhesion plaques or adhesion junctions. Both adhesion plaques and adhesion junctions were isolated as substratum-bound structures and characterized by scanning electron microscopy. Immunofluorescence revealed that pp60src, actin, alpha-actinin, and vinculin were organized within specific regions of the adhesion junctions. Heavy accumulations of actin and alpha-actinin were found on both sides of the junctions with a narrow gap of unstained material at the midline, whereas pp60src stain was more intense in this central region. Antibody to vinculin stained double narrow lines defining the periphery of the junctional complexes but was excluded from the intervening region. In addition, the distribution of vinculin relative to pp60src within adhesion plaques suggested an inverse relationship between the presence of these two proteins. Overall, these results establish a close link between the src gene product and components of the cytoskeleton and implicate the adhesion plaques and adhesion junctions in the mechanism of Rous sarcoma virus-induced transformation.

Actinin↗

Penile adhesions after neonatal circumcision.

PURPOSE: The appropriate management of penile adhesions in circumcised boys is unclear. An important consideration is whether adhesions resolve spontaneously. We studied the incidence of penile adhesions as a function of patient age to assess the natural history. MATERIALS AND METHODS: We evaluated all circumcised boys presenting to our pediatric urology clinic. A standard form was used to classify adhesions as grade 0-no adhesions, 1-fine adhesions to the corona, 2-adhesions covering less than 50% of the glans and 3-adhesions covering greater than 50% of the glans. All boys were evaluated by 1 of 2 pediatric urologists. Previous treatment of adhesions was assessed and skin bridges were also noted. RESULTS: We enrolled in our study 254 boys 1 month to 19 years 8 months old. Only 7 patients had a history of treatment of adhesion, of whom 3 had recurrent adhesions at evaluation. Patients were divided into groups based on age, including younger than 12 months (61), 13 to 60 (78), 61 to 108 (51) and 109 months old or older (64). In these groups we noted an adhesion rate of 71%, 28%, 8% and 2%, respectively. The rate of adhesions more severe than grade 1 was 30%, 10% and 0% in boys 12 months old or younger, 13 to 60 and 61 months old or older, respectively. The oldest patient with grade 3 adhesions was 31 months old. Skin bridges in 6 cases involved the circumcision line in 4. CONCLUSIONS: Penile adhesions develop after circumcision and the incidence decreases with patient age. Although there is debate on whether to lyse these adhesions manually, our findings suggest that adhesions resolve without treatment. Based on our results we do not recommend lysing penile adhesions, except perhaps those involving the circumcision line.

Adolescent↗

[Preparation of buspirone hydrochloride buccal adhesive tablet and study on its drug release mechanism].

AIM: To prepare buspirone hydrochloride buccal adhesive tablet and investigate factors that influence drug release behavior and the drug release mechanism. METHODS: Buspirone hydrochloride buccal adhesive tablet was prepared with double layers structure composed of drug core and adhesive layer. The materials of the drug core were carbopol 974 and lactose, the adhesive layers were carbopol 974 and HPMC K4M. The influence of drug release factors such as adhesive layer component, adhesive layer weight and adhesive tablet hardness was investigated. The relationship between adhesive layer weight and drug release mechanism in vitro was studied. RESULTS: The results showed that the weight of the adhesive layer and the hardness of adhesive tablet showed significant effects on drug release, but the adhesive layer component showed no significant effect. The optimum prescription of buspirone hydrochloride buccal adhesive tablet was carbopol: HPMC = 1:1, adhesive layer weight = 50%, and adhesive tablet hardness = 4 kg. The study of drug release mechanism from adhesive tablet showed that it was double directions when adhesive layer weight was 20%, and single direction first then double directions when 33.33%, and single direction all along when 50%. CONCLUSION: The speed and direction of drug release from adhesive tablet can be controlled by regulating adhesive layer weight.

Acrylic Resins↗

Adhesion of multiple myeloma peripheral blood B cells to bone marrow fibroblasts: a requirement for CD44 and alpha4beta7.

We have earlier described the presence of phenotypically unusual monoclonal B cells within the peripheral blood of multiple myeloma (MM) patients. To determine the biological properties of these B cells as compared to B cells from normal donors, we investigated the potential of CD19+ MM blood B cells to adhere to endothelial cell and bone marrow (BM)-fibroblast monolayers. We find that 30-60% of freshly isolated CD19+ MM blood B cells adhere to endothelial cell monolayers, and 50-80% adhere to BM fibroblast monolayers. The adhesion of MM blood B cells to either monolayer was not increased by in vitro activation, suggesting that these cells were activated in vivo. In contrast, fewer than 10% of CD19+ B cells from peripheral blood of normal donors adhered. Function-blocking monoclonal antibodies (mAbs) were used to determine which adhesion receptors were involved in CD19+ MM blood B cell interaction with BM fibroblasts. mAbs against very late antigen 4, the beta7-integrin subunit, and CD44, but not mAbs against very late antigen 5 and beta1, inhibited adhesion 61, 50, and 30%, respectively. The lack of inhibition with mAbs against beta1 implicates alpha4beta7 but not alpha4beta1 in adhesion of CD19+ MM blood B cells. To determine the alpha4beta7 ligand that mediated MM blood B cell adhesion, mAbs against vascular cellular adhesion molecule 1 and fibronectin, as well as CS1 and RGD peptides, were used as inhibitors. These were unable to reduce the adhesion of CD19+ MM blood B cells to BM fibroblasts, suggesting that fibronectin and vascular cellular adhesion molecule 1 are not involved in adhesion. Also, adhesion of MM blood B cells to mucosal addressin cell adhesion molecule 1-transfected Chinese hamster ovary cells was not enhanced compared to control-transfected Chinese hamster ovary cells, suggesting that mucosal addressin cell adhesion molecule 1 was not promoting adhesion of these cells. These data implicate CD44:HA interactions, as well as alpha4beta7 and an as yet unidentified ligand in the adhesion of in vivo activated MM blood B cell adhesion to BM fibroblasts. The adhesion properties of MM CD19+ B cells distinguishes them from normal B cells. Although the malignant status of these cells is as yet undefined, their adhesion properties implicate MM blood B cells in migratory spread of the disease.

Amino Acid Sequence↗

Single-step adhesives are permeable membranes.

OBJECTIVES: This study tested the hypotheses that micro-tensile bond strengths of all currently available single-step adhesives to dentine are adversely affected by delayed activation of a light-cured composite, and that such a phenomenon only occurs in the presence of water from the substrate side of the bonded interface. METHODS: In experiment I, a control three-step adhesive (All-Bond 2, Bisco) and six single-step adhesives (One-Up Bond F, Tokuyama; Etch&Prime 3.0, Degussa; Xeno CF Bond, Sankin; AQ Bond, Sun Medical; Reactmer Bond, Shofu and Prompt L-Pop, 3M ESPE) were bonded to sound, hydrated dentine. A microfilled composite was placed over the cured adhesive and was either light-activated immediately, or after leaving the composite in the dark for 20 min. In experiment II, three single-step adhesives (Etch&Prime 3.0, Xeno CF Bond and AQ Bond) were similarly bonded to completely dehydrated dentine using the same delayed light-activation protocol. In experiment III, a piece of processed composite was used as the bonding substrate for the same three single-step adhesives. The microfilled composite was applied to the cured adhesives using the same immediate and delayed light-activation protocols. Bonded specimens were sectioned for micro-tensile bond strength evaluation. Fractographic analysis of the specimens was performed using SEM. Stained, undemineralised sections of unstressed, bonded specimens were also examined by TEM. RESULTS: When bonded to hydrated dentine, delayed light-activation had no effect on the control three-step adhesive, but significantly lowered the bond strengths of all the single-step adhesives (p < 0.05). This adverse effect of delayed light-activation was not observed in the three single-step adhesives that were bonded to either dehydrated dentine or processed composite. Morphological manifestations of delayed light-activation of composite in the hydrated dentine bonding substrate were exclusively located along the composite-adhesive interface, and were present as large voids, resin globules and honeycomb structures that formed partitions around a myriad of small blisters along the fractured interfaces. CONCLUSION: These features resembled the 'overwet phenomenon' that was previously reported along the dentine-adhesive interfaces of some acetone-based three-step adhesives. The cured adhesive layer in single-step adhesives may act as semi-permeable membranes that allow water diffusion from the bonded hydrated dentine to the intermixed zone between the adhesive and the uncured composite. Osmotic blistering of water droplets along the surface of the cured adhesive layer and emulsion polymerisation of immiscible resin components probably account for the compromised bond strength in single-step adhesives after delayed activation of light-cured composites.

Biocompatible Materials↗

Echinoderm adhesive secretions: from experimental characterization to biotechnological applications.

Adhesion is a way of life in echinoderms. Indeed, all the species belonging to this phylum use adhesive secretions extensively for various vital functions. According to the species or to the developmental stage considered, different adhesive systems may be recognized. (1) The tube feet or podia are organs involved in attachment to the substratum, locomotion, feeding or burrowing. Their temporary adhesion relies on a duo-gland adhesive system resorting to both adhesive and de-adhesive secretions. (2) The larval adhesive organs allow temporary attachment of larvae during settlement and strong fixation during metamorphosis. (3) The Cuvierian tubules are sticky defence organs occurring in some holothuroid species. Their efficacy is based on the instantaneous release of a quick-setting adhesive. All these systems rely on different types of adhesion and therefore differ in the way they operate, in their structure and in the composition of their adhesive. In addition to fundamental interests in echinoderm bioadhesives, a substantial impetus behind understanding these adhesives are the potential technological applications that can be derived from their knowledge. These applications cover two broad fields of applied research: design of water-resistant adhesives and development of new antifouling strategies. In this context, echinoderm adhesives could offer novel features or performance characteristics for biotechnological applications. For example, the rapidly attaching adhesive of Cuvierian tubules, the releasable adhesive of tube feet or the powerful adhesive of asteroid larvae could each be useful to address particular bioadhesion problems.

Adhesiveness↗

Adhesion molecules and their role in cancer metastasis.

This article describes various adhesion molecules and reviews evidence to support a mechanistic role for adhesion molecules in the process of cancer metastasis. A variety of evidence supports the involvement of specific adhesion molecules in metastasis. 1. For example, some cancer cells metastasize to specific organs, irrespective of the first organ encountered by the circulating cancer cells. This ability to colonize a specific organ has been correlated with the preferential adhesion of the cancer cells to endothelial cells derived from the target organ. This suggests that cancer cell/endothelial cell adhesion is involved in cancer cell metastasis and that adhesion molecules are expressed on the endothelium in an organ-specific manner. 2. Further, inclusion of peptides that inhibit cell adhesion, such as the YIGSR- or RGD-containing peptides, is capable of inhibiting experimental metastasis. 3. Metastasis can be enhanced by acute or chronic inflammation of target vessels, or by treatment of animals with inflammatory cytokines, such as interleukin-1. In vitro, cancer cell/endothelial cell adhesion can be enhanced by pretreating the endothelial cell monolayer with cytokines, such as interleukin-1 or tumor necrosis factor-alpha. This suggests that, in addition to organ-specific adhesion molecules, a population of inducible endothelial adhesion molecules is involved and is relevant to metastasis. 4. Further support for this model is found in the comparison to leukocyte/endothelial adhesion during leukocyte trafficking. Convincing evidence exists, both in vivo and in vitro, to demonstrate an absolute requirement for leukocyte/endothelial adhesion before leukocyte extravasation can occur. The relevance of this comparison to metastasis is reinforced by the observation that some of the adhesion molecules involved in leukocyte/endothelial adhesion are also implicated in cancer cell/endothelial adhesion. The involvement of adhesion molecules suggests a potential therapy for metastasis based on interrupting adhesive interactions that would augment other treatments for primary tumors.

Animals↗

Tyrosine phosphorylation and cytoskeletal tension regulate the release of fibroblast adhesions.

We have investigated the mechanisms by which fibroblasts release their adhesions to the extracellular matrix substrata using a permeabilized cell system in which the adhesions remain relatively stable. A large number of different molecules were assayed for their effect on focal adhesion stability using immunofluorescence with antibodies against different focal adhesion constituents. ATP uniquely stimulates a rapid breakdown of focal adhesions, and at high ATP concentrations (> 5 mM), many cells are released from the dish. The remaining cells appear contracted with talin, alpha-actinin, and vinculin localized diffusely throughout the cell. Integrin containing tracks of variable intensity outline the regions where cells had resided before they detached from the substratum. At lower ATP concentrations (0.5-5 mM) the cells remain spread; however the focal adhesion components, including integrin, show an array of phenotypes ranging from diffusely localized throughout the cell to a localization in small, thin focal adhesions. Okadaic acid, a serine, threonine phosphatase inhibitor, enhances the contracted phenotype, even at low concentrations (0.5 mM) of ATP. The localization of focal adhesion components is different in okadaic acid-treated cells. In highly contracted cells, integrin is present in tracks where the cells resided before the contraction; however focal adhesions are no longer apparent. Talin, vinculin, and alpha-actinin localize in trabecular networks toward the periphery of the cell. Interestingly, phosphotyrosine staining as well as nascent, intracellular integrin precedes the recruitment of focal adhesion constituents into the trabecular network. The ATP-stimulated focal adhesion breakdown appears to operate through two mechanisms. First, ATP stimulates the tyrosine phosphorylation of several cytoskeletally associated proteins. These tyrosine phosphorylations correlated well with focal adhesion breakdown. Furthermore, addition of a recombinant, constitutively active tyrosine phosphatase inhibits both the tyrosine phosphorylations and the breakdown of the focal adhesions. None of the major tyrosine phosphoproteins are FAK, integrin, tensin, paxillin, or other phosphoproteins implicated in focal adhesion assembly. The second mechanism is cell contraction. High ATP concentrations, or lower ATP concentrations in the presence of okadaic acid induce cell contraction. Inhibiting the contraction by addition of a heptapeptide IRICRKG, which blocks the actin-myosin interaction, also inhibits focal adhesion breakdown. Neither the peptide nor the phosphatase inhibits focal adhesion breakdown under all conditions suggesting that both tension and tyrosine phosphorylations mediate the release of adhesions.

Adenosine Triphosphate↗

Physical and biological properties of a novel siloxane adhesive for soft tissue applications.

The aim of this study was to investigate the adhesive properties of an in-house aminopropyltrimethoxysilane-methylenebisacrylamide (APTMS-MBA) siloxane system and compare them with a commercially available adhesive, n-butyl cyanoacrylate (nBCA). The ability of the material to perform as a soft tissue adhesive was established by measuring the physical (bond strength, curing time) and biological (cytotoxicity) properties of the adhesives on cartilage. Complementary physical techniques, X-ray photoelectron spectroscopy, Raman and infrared imaging, enabled the mode of action of the adhesive to the cartilage surface to be determined. Adhesion strength to cartilage was measured using a simple butt joint test after storage in phosphate-buffered saline solution at 37 degrees C for periods up to 1 month. The adhesives were also characterised using two in vitro biological techniques. A live/dead stain assay enabled a measure of the viability of chondrocytes attached to the two adhesives to be made. A water-soluble tetrazolium assay was carried out using two different cell types, human dermal fibroblasts and ovine meniscal chondrocytes, in order to measure material cytotoxicity as a function of both supernatant concentration and time. IR imaging of the surface of cartilage treated with APTMS-MBA siloxane adhesive indicated that the adhesive penetrated the tissue surface marginally compared to nBCA which showed a greater depth of penetration. The curing time and adhesion strength values for APTMS-MBA siloxane and nBCA adhesives were measured to be 60 s/0.23 MPa and 38 min/0.62 MPa, respectively. These materials were found to be significantly stronger than either commercially available fibrin (0.02 MPa) or gelatin resorcinol formaldehyde (GRF) adhesives (0.1 MPa) (P < 0.01). Cell culture experiments revealed that APTMS-MBA siloxane adhesive induced 2% cell death compared to 95% for the nBCA adhesive, which extended to a depth of approximately 100-150 microm into the cartilage surface. The WST-1 assay demonstrated that APTMS-MBA siloxane was significantly less cytotoxic than nBCA adhesive as an undiluted conditioned supernatant (P < 0.001). These results suggest that the APTMS-MBA siloxane may be a useful adhesive for medical applications.

Acrylamides↗

Prevention of postoperative pericardial adhesions. An animal study.

Following heart operations, adhesions uniformly form between the epicardium and surrounding structures such as the pericardium, mediastinal fat, pleura, and sternum. These adhesions make reoperations both difficult and hazardous. Three groups of 15 dogs each were studied to assess the effectiveness of pharmacologic manipulation in reducing the adhesions. In the control group, adhesions were created by allowing epicardial/pericardial surfaces to dry, and then adding cotton fibers and blood before closing the pericardium. In the methylprednisolone group, 500 mg of methylprednisolone was given intravenously at the time of operation, followed by 0.3 mg/kg orally three times a day for one week. In the ibuprofen group, 12.5 mg/kg of ibuprofen was given intravenously at operation and then orally three times in one day, followed by 5 mg/kg orally three times a day for six days. Dogs were killed at three to four weeks and the adhesions between pericardium and epicardium were graded. In the control group, none were adhesion-free and none had filmy adhesions; three dogs had dense patchy adhesions and 12 had dense diffuse adhesions. In the methylprednisolone group, 14 dogs had no adhesions; one had filmy adhesions; and none had dense patchy or dense diffuse adhesions. In the ibuprofen group, none were adhesion-free; one dog had filmy adhesions; four had dense patchy adhesions; and ten had dense diffuse adhesions. The near-total elimination of pericardial/epicardial adhesions utilizing methylprednisolone, if also achievable in humans, would markedly reduce the difficulty and increase the safety of cardiac reoperations.

Animals↗

Expression of adhesion molecules in the lower uterine segment during term and preterm parturition.

Term and preterm cervical ripening and dilatation have similarities with an inflammatory reaction. Since cell adhesion molecules are involved in this process, investigations on the expression of intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and platelet endothelial cell adhesion molecule in the lower uterine segment and in vitro experiments on human umbilical vein endothelial cells were performed. In addition, current reports on expression of endothelial adhesion molecules by the uterine cervix were summarized. Cell adhesion molecule expression by lower uterine segment and uterine cervix in term and preterm parturition was measured using immunohistochemistry, enzyme immunoassay, and Northern blot analysis. Regulation of adhesion molecule expression was evaluated in vitro by indirect immunofluorescence and flow cytometry using human umbilical vein endothelial cells. Investigations in term parturition revealed that intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 expression increases during parturition. In preterm labor, the expression of endothelial leukocyte adhesion molecule-1 and intercellular adhesion molecule-1 in the lower uterine segment increased. Expression of platelet endothelial cell adhesion molecule did not change in term and preterm parturition. Expression of adhesion molecules was localized mainly on lower uterine segment vascular endothelial cells and to a smaller extent on leukocytes. In vitro experiments showed that expression of adhesion molecules by human umbilical vein endothelial cells can be stimulated by tumor necrosis factor-alpha, 17beta-estradiol, prostaglandin E(2), and the antigestagen onapristone. Progesterone exerted no stimulatory effect. Cervical ripening and dilatation during term and preterm parturition are associated with an increased expression of endothelial cell adhesion molecules by lower uterine segment and uterine cervix. The expression can be modulated by pro-inflammatory cytokines, sex hormones, and prostaglandin E(2). Mechanisms controlling the extravasation of leukocytes may play a fundamental role in term and preterm parturition.

Cell Adhesion Molecules↗

Modeling of adhesion in tablet compression. II. Compaction studies using a compaction simulator and an instrumented tablet press.

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.

Adhesiveness↗

Clinical effectiveness of contemporary adhesives: a systematic review of current clinical trials.

OBJECTIVES: The purpose of this paper was to review current literature on the clinical effectiveness of contemporary adhesives when used to restore cervical non-carious class-V lesions. Restoration retention in function of time was recorded in order to find out if adhesives with a simplified application procedure are as clinically effective as conventional three-step adhesives. DATA SOURCES: Literature published from January 1998 up to May 2004 was reviewed for university-centred clinical trials that tested the clinical effectiveness of adhesives in non-carious class-V lesions. Restoration-retention rates per adhesive reported in peer-reviewed papers as well as IADR-AADR abstracts and ConsEuro abstracts were included and depicted as a function of time in graphs for each of the five adhesive classes (three- and two-step etch-and-rinse adhesives, two- and one-step self-etch adhesives, and glass-ionomers). The guidelines for dentin and enamel adhesive materials advanced by the American Dental Association were used as a reference. Per class, the annual failure rate (%) was calculated. Kruskal-Wallis analysis and Dwass-Steel-Chritchlow-Fligner pairwise comparisons were used to determine statistical differences between the annual failure percentages of the five adhesive categories. RESULTS: Comparison of retention of class-V adhesive restorations as a measure to determine clinical bonding effectiveness of adhesives revealed that glass-ionomers most effectively and durably bond to tooth tissue. Three-step etch-and-rinse adhesives and two-step self-etch adhesives showed a clinically reliable and predictably good clinical performance. The clinical effectiveness of two-step etch-and-rinse adhesives was less favourable, while an inefficient clinical performance was noted for the one-step self-etch adhesives. SIGNIFICANCE: Although there is a tendency towards adhesives with simplified application procedures, simplification so far appears to induce loss of effectiveness. Clinical performance can be correlated with, and predicted by, appropriate types of laboratory study.

Adhesives↗