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PubMed2004

Biological and biophysical principles in extracorporal bone tissue engineering. Part II.

The aim of this review is to characterise the biological and biophysical background of in vitro bone tissue engineering. The paper focuses on basic principles in extracorporal engineering of bone-like tissues, considering parameters such as scaffold design, tissue construction, bioreactors, and cell stimulation in vivo and in vitro. Scaffolds have a key function concerning cellular invasion and bone formation. The intra-architectural scaffold geometry, as well as the scaffold material, play an important role in the process of bone regeneration. Various types of bioreactors have been tested for their utility in bone substitute fabrication that is clinically effective and reproducible. Sophisticated bioreactor systems are those that mimic the three-dimensional morphology and the mechanical situation of bones. Mechanical stimulation as well as other biophysical stimuli appear to be critical factors for proliferation and differentiation of bone cells and for bone mineral and structure formation. Furthermore an enhancement of bone regeneration by application of chemical stimulation factors is discussed.

Animals↗
PubMed2006

Biophysical determinants of toluene diisocyanate antigenicity associated with exposure and asthma.

BACKGROUND: Toluene diisocyanate (TDI), a widely used aromatic diisocyanate with the potential to cause asthma, reacts with albumin in the airway fluid, which acts as a carrier protein for chemical presentation to the immune system. Structural elucidation of TDI-albumin conjugates is crucial to understanding the human immune response to TDI exposure. OBJECTIVE: Investigate the dependence of TDI's antigenicity on the biophysics of exposure and its association with TDI asthma. METHODS: Toluene diisocyanate-albumin conjugates were generated by exposing albumin to TDI in liquid or vapor phase (liquid or vapor TDI-albumin, respectively). Conjugates were characterized by native gel electrophoresis and matrix-assisted laser desorption/ionization-mass spectrometry, and used as antigens in ELISA assays for serum specific-IgE and IgG. RESULTS: The physical phase of TDI (vapor vs liquid) affects the formation of TDI-albumin conjugates, with measurable differences in the amount of TDI per albumin molecule, migration in native gels, matrix-assisted laser desorption/ionization-mass spectrometry mass/charge spectra, and antigenicity. Vapor TDI-albumin conjugates were recognized by IgE from 44% of subjects with TDI asthma, whereas liquid TDI-albumin conjugates are recognized by IgE from only 17% of these patients. A significant (P < .05) association between TDI exposure and vapor TDI-albumin specific serum IgG was also observed. CONCLUSION: Biophysics of TDI exposure substantially affects formation of TDI-albumin conjugates recognized by the immune system in association with exposure and asthma. CLINICAL IMPLICATIONS: The data suggest that serology may help identify TDI asthmatics and exposed workers if the appropriate form of TDI is used as the antigenic basis for analysis.

Adult↗
PubMed2004

Protein biophysical properties that correlate with crystallization success in Thermotoga maritima: maximum clustering strategy for structural genomics.

Cost and time reduction are two of the driving forces in the development of new strategies for protein crystallization and subsequent structure determination. Here, we report the analysis of the Thermotoga maritima proteome, in which we compare the proteins that were successfully expressed, purified and crystallized versus the rest of the proteome. This set of almost 500 proteins represents one of the largest, internally consistent, protein expression and crystallization datasets available. The analysis shows that individual parameters, such as isoelectric point, sequence length, average hydropathy, low complexity regions (SEG), and combinations of these biophysical properties for crystallized proteins define a distinct subset of the T. maritima proteome. The distribution profiles of the various biophysical properties in the expression/crystallization set are then used to extract rules to improve target selection and improve the efficiency and output of structural genomics, as well as general structural biology efforts.

Amino Acid Sequence↗
PubMed1999

Antioxidant properties of calcium antagonists related to membrane biophysical interactions.

The antioxidant activities of representative calcium antagonists, including amlodipine, verapamil, and diltiazem, were measured in hepatic microsomal membranes by the Fe-catalyzed, hydroxyl radical-producing system (dihydroxyfumarate + Fe3+) and assessed by malondialdehyde (MDA) formation. Despite the absence of L-type calcium channels in this membrane preparation, the calcium antagonists showed dose-dependent antioxidant activity. The biophysical mechanism for calcium-antagonist antioxidant activity was evaluated using radioligand binding assays, high-resolution differential scanning calorimetry, and small-angle x-ray diffraction approaches. These analyses demonstrated that calcium-antagonist antioxidant potency correlated directly with the compounds' relative affinity for the membrane lipid bilayer and ability to modulate membrane thermodynamic properties (amlodipine >> verapamil > diltiazem). The charged 1,4-dihydropyridine calcium antagonist, amlodipine, had the highest affinity for the membrane lipid bilayer (Kp>10(4)) and produced the largest changes in membrane thermodynamic properties, including a reduction in thermal phase transition temperature (-11%), enthalpy (-14%), and cooperative unit size (-59%), relative to control phosphatidylcholine liposomes. Electron density profiles generated from x-ray diffraction data demonstrated that amlodipine effected a broad and dose-dependent increase in molecular volume associated with the membrane hydrocarbon core. These data indicate that lipophilic calcium antagonists inhibit lipid peroxidation in cellular membranes as a result of modulating physicochemical properties of the membrane lipid bilayer, independently of calcium channel inhibition. Amlodipine had the most potent antioxidant activity as a result of distinct biophysical interactions with the membrane lipid bilayer. The nonreceptor-mediated antioxidant activity of calcium antagonists may contribute to cytoprotective mechanisms of action in cardiovascular diseases.

Amlodipine↗
PubMed1992

Effects of sustained hypoxemia on the sheep fetus at midgestation: endocrine, cardiovascular, and biophysical responses.

OBJECTIVE: The purpose of our study was to examine the effects of induced hypoxia on endocrine, cardiovascular, and biophysical measurements of the ovine fetus at 0.6 (83 to 93 days) of gestation and to compare the fetal responses at this earlier gestation with those reported near term. STUDY DESIGN: Fourteen fetal sheep were studied (9 in the hypoxia group and 5 in the control group) at 0.6 of gestation during a 24-hour control period, 8 hours of either sustained hypoxemia or room air, and a 40-hour recovery period. RESULTS: Induced fetal hypoxemia resulted in a progressive lactic metabolic acidosis; however, all fetuses had recovered within 24 hours. The fetal endocrine response was variable with norepinephrine, the only measured hormone showing a significant hypoxia-related increase (p less than 0.05). Fetal heart rate and mean arterial blood pressure showed little hypoxia-induced change, although fetal heart rate was significantly increased over the first 2 hours (p less than 0.05). The percent time fetal breathing movements, electroocular activity, and nuchal muscle activity likewise showed little hypoxia-induced change. CONCLUSION: The cardiovascular and biophysical response of the preterm fetus to induced hypoxemia is thus much less pronounced than that of the older gestational-aged fetus; this difference may impact on survival and the success of antenatal assessment protocols.

Animals↗
PubMed2003

Screening methods to determine biophysical properties of proteins in structural genomics.

We have developed and tested a simple and efficient protein purification method for biophysical screening of proteins and protein fragments by nuclear magnetic resonance (NMR) and optical methods, such as circular dichroism spectroscopy. The method constitutes an extension of previously described protocols for gene expression and protein solubility screening [M. Hammarström et al., (2002), Protein Science 11, 313]. Using the present purification scheme it is possible to take several target proteins, produced as fusion proteins, from cell pellet to NMR spectrum and obtain a judgment on the suitability for further structural or biophysical studies in less than 1 day. The method is independent of individual protein properties as long as the target protein can be produced in soluble form with a fusion partner. Identical procedures for cell culturing, lysis, affinity chromatography, protease cleavage, and NMR sample preparation then initially require only optimization for different fusion partner and protease combinations. The purification method can be automated, scaled up or down, and extended to a traditional purification scheme. We have tested the method on several small human proteins produced in Escherichia coli and find that the method allows for detection of structured proteins and unfolded or molten globule-like proteins.

Circular Dichroism↗
PubMed2000

Biophysical and lipofection studies of DOTAP analogs.

In order to investigate the relationship between lipid structure and liposome-mediated gene transfer, we have studied biophysical parameters and transfection properties of monocationic DOTAP analogs, systematically modified in their non-polar hydrocarbon chains. Stability, size and (by means of anisotropy profiles) membrane fluidity of liposomes and lipoplexes were determined, and lipofection efficiency was tested in a luciferase reporter gene assay. DOTAP analogs were used as single components or combined with a helper lipid, either DOPE or cholesterol. Stability of liposomes was a precondition for formation of temporarily stable lipoplexes. Addition of DOPE or cholesterol improved liposome and lipoplex stability. Transfection efficiencies of lipoplexes based on pure DOTAP analogs could be correlated with stability data and membrane fluidity at transfection temperature. Inclusion of DOPE led to rather uniform transfection and anisotropy profiles, corresponding to lipoplex stability. Cholesterol-containing lipoplexes were generally stable, showing high transfection efficiency at low relative fluidity. Our results demonstrate that the efficiency of gene transfer mediated by monocationic lipids is greatly influenced by lipoplex biophysics due to lipid composition. The measurement of fluorescence anisotropy is an appropriate method to characterize membrane fluidity within a defined system of liposomes or lipoplexes and may be helpful to elucidate structure-activity relationships.

Anisotropy↗
PubMed1997

Biophysical characterization of cationic lipid: DNA complexes.

To better understand the structures formed by the interaction of cationic lipids with DNA, we undertook a systematic analysis to determine the biophysical characteristics of cationic lipid:DNA complexes. Four model cationic lipids with different net cationic charge were found to interact in similar ways with DNA when that interaction was compared in terms of the apparent molar charge ratio of lipid to DNA. When DNA was present in charge excess over the cationic lipid, the complex carried a net negative charge as determined by zeta potential measurements. Under these conditions, some DNA was accessible to ethidium bromide, and free DNA was observed in agarose gels and in dextran density gradients. Between a lipid:DNA charge ratio of 1.25 and 1.5:1, all the DNA became complexed to cationic lipid, as evidenced by its inaccessibility to EtBr and its complete association with lipid upon agarose gel electrophoresis and density gradient separations. These complexes carried a net positive charge. The transition between negatively and positively charged complexes a occurred over a very small range of lipid to DNA ratios. Employing a fluorescent lipid probe, the addition of DNA was shown to induce lipid mixing between cationic lipid-containing vesicles. The extent of DNA-induced lipid mixing reached a maximum at a charge ratio of about 1.5:1, the point at which all the DNA was involved in a complex and the complex became positively charged. Together with freeze-fracture electron micrographs of the complexes, these biophysical data have been interpreted in light of the existing models of cationic lipid:DNA complexes.

Cations↗
PubMed1997

ESB Research Award 1996. Biophysical stimuli on cells during tissue differentiation at implant interfaces.

If musculoskeletal tissues are indeed efficient for their mechanical function, it is most reasonable to assume that this is achieved because the mechanical environment in the tissue influences cell differentiation and expression. Although mechanical stimuli can influence the transport of bioactive factors, cell deformation and cytoskeletal strain, the question of whether or not they have the potential to regulate tissue differentiation sequences (for example, during fracture healing or embryogenesis) has not been answered. To assess the feasibility of biophysical stimuli as mediators of tissue differentiation, we analysed interfacial tissue formation adjacent to a micromotion device implanted into the condyles of dogs. A biphasic finite element model was used and the mechanical environment in the tissue was characterised in terms of (i) forces opposing implant motion, (ii) relative velocity between constituents, (iii) fluid pressure, (iv) deformation of the tissue and (v) strain in the tissue. It was predicted that, as tissue differentiation progressed, subtle but systematic mechanical changes occur on cells in the interfacial tissue. Specifically, as the forces opposing motion increase, the implant changes from being controlled by the maximum-allowable displacement (motion-control) to being controlled by the maximum-available load (force-control). This causes a decrease in the velocity of the fluid phase relative to the solid phase and a drop in interstitial fluid pressure accompanied by a reduction in peri-prosthetic tissue strains. The variation of biophysical stimuli within the tissue can be plotted as 'mechano-regulatory pathway', which identifies the transition from motion-control to force-control as a branching event in the tissue differentiation sequence.

Animals↗
PubMed1991

Biophysical models of protein denaturation. II. Effects of denaturants and of pH.

In order to broaden the scope and increase the utility of differential scanning calorimetry, a theoretical model of calorimetric thermograms is presently proposed which facilitates their biophysical interpretation and accounts explicitly for their modifications induced by denaturing agents and/or pH. The model rests mainly on statistical-physical considerations, the denaturation-linked increase of the number of binding sites for denaturants (including H+) serving as the conceptual basis for thermogram modelling. Denaturants were envisioned as contributing indirectly to thermal denaturation by forming complexes preferentially with unfolded protein molecules, shifting thus the equilibrium towards the denatured phase. After postulating the probability of complex formation, mean numbers of the relevant molecular species were computed by ensemble averaging. Finally, an eight-parameter expression has been derived defining protein heat capacity as a function of both temperature and denaturant concentration (or pH), each of the eight parameters having a distinct biophysical meaning. The model has been tested by applying it to the prediction of the pH-dependence of thermograms. Four proteins have been considered (lysozyme, myoglobin, apomyoglobin, and ribonuclease A), each represented by a series of three to four published thermograms recorded under different pH conditions. Model equations, fitted simultaneously to all thermograms in a pH series, reproduced correctly experimental tracings. Parameter values obtained as best-fit requirements (particularly those representing the number of binding sites unmasked by denaturation and the free energy of ion binding) were in close agreement with empirical, mainly potentiometric, data from literature. The empirically established pH-independence of the total enthalpy of denaturation, the phenomenon of cold denaturation, the pH-dependence of the Gibbs free energy of denaturation, of the melting temperature and of the temperature of cold denaturation, were all correctly predicted by the model. Combined effects of multiple denaturants, including the effects of pH in the presence of denaturants other than protons, are also predictable by the model.

Calorimetry↗
PubMed2000

Biophysical profile in predicting acute ascending infection in preterm rupture of membranes before 32 weeks.

OBJECTIVE: To assess the performance of the biophysical profile (BPP) and its components within 24 hours of delivery in predicting histopathologic evidence of severe acute placental inflammation in women with premature rupture of membranes (PROM) before 32 weeks' gestation. METHODS: We examined placentas from a series of consecutive, nonanomalous, live-born, singleton infants delivered before 32 weeks' gestation after PROM. In 166 cases, biophysical profiles (BPP) were done within 24 hours of birth. Histologic evidence of acute inflammation was assessed in the maternal (amnion) and fetal (chorionic and umbilical cord vessels) compartments, and scored on a severity scale of 0-4 by a single pathologist masked to clinical data. The presence and severity of acute inflammation was related to BPP results and its individual components. RESULTS: The overall prevalence of severe acute inflammation, ie, a score of 3 or 4, was 59% (98 of 166). In 30 (18%) cases it was present in the amnion, in 49 (30%) cases in chorionic or umbilical cord vessels, and in 19 (11%) cases in maternal and fetal compartments. There was no association between abnormal BPP score and presence or absence of severe acute placental inflammation (48% versus 46%, P =.7). Our study had a 90% power to detect a 0.26 difference between them. When rates of abnormal BPP scores were compared in cases with different degrees of acute inflammation in the maternal, fetal, or both compartments, no association was found. When the individual components of the BPP were analyzed in relation to site and severity of acute inflammation, no association was detected. CONCLUSION: We did not find evidence of a dose-response relationship between acute placental inflammation and BPP score or its individual components in cases of PROM with infants delivered before 32 weeks. Mediators other than infection might affect BPP in preterm PROM.

Acute Disease↗
PubMed2003

Is the intrapartum biophysical profile useful?

OBJECTIVE: To assess the role of biophysical profile (BPP) during normal labor. The secondary goal was to assess the effect of oxytocics, regional anesthesia, and ruptured membranes on fetal behavior during labor. METHODS: The BPP (according to the Manning criteria) was performed prospectively in 100 normal, singleton pregnancies in active labor. To evaluate its role in the prediction of cesarean delivery and admission to the neonatal intensive care unit (NICU), statistical analysis included chi2 and Fisher exact tests for frequency analyses and t tests for comparisons of continuous data. RESULTS: At the mean cervical dilatation of 5.2+/-1.4 cm, 73 women had a BPP score of at least 8/10, 16 had 6/10, six had 4/10, and five had 2/10. The BPP was not influenced by use of oxytocics, prostaglandins, or epidural anesthesia. Fetal breathing (95% versus 71%; P=.002) and gross fetal movements (98% versus 84%; P=.04) decreased with rupture of amniotic membranes. A BPP score of 6/10 or less in labor was associated with a relative risk (RR) for cesarean delivery of 8.00 (95% confidence interval [CI] 2.4, 26.5). Cessation of any ultrasound component of BPP significantly increased the risk of cesarean delivery and admission to the (NICU) (RR=29; 95% CI 2.73, 308.66). In the multivariable analysis, however, fetal movements and amniotic fluid volume were most important in predicting the need for cesarean delivery. CONCLUSION: Fetal heart rate monitoring alone did not predict the need for cesarean delivery or neonatal outcome, whereas the BPP did. Biophysical profile could prove to be a clinically useful adjunctive tool in the assessment of fetal well-being in labor.

Adult↗
PubMed1999

Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy.

PURPOSE: The irradiation system and biophysical characteristics of carbon beams are examined regarding radiation therapy. METHODS AND MATERIALS: An irradiation system was developed for heavy-ion radiotherapy. Wobbler magnets and a scatterer were used for flattening the radiation field. A patient-positioning system using X ray and image intensifiers was also installed in the irradiation system. The depth-dose distributions of the carbon beams were modified to make a spread-out Bragg peak, which was designed based on the biophysical characteristics of monoenergetic beams. A dosimetry system for heavy-ion radiotherapy was established to deliver heavy-ion doses safely to the patients according to the treatment planning. A carbon beam of 80 keV/microm in the spread-out Bragg peak was found to be equivalent in biological responses to the neutron beam that is produced at cyclotron facility in National Institute Radiological Sciences (NIRS) by bombarding 30-MeV deuteron beam on beryllium target. The fractionation schedule of the NIRS neutron therapy was adapted for the first clinical trials using carbon beams. RESULTS: Carbon beams, 290, 350, and 400 MeV/u, were used for a clinical trial from June of 1994. Over 300 patients have already been treated by this irradiation system by the end of 1997.

Calibration↗
PubMed1999

Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin.

The effect of the solvent systems ethanol (EtOH), propylene glycol (PG) and combinations thereof was examined on the in vitro percutaneous absorption of the antithrombotic, aspirin, through porcine epidermis. Biophysical changes in the stratum corneum lipids were studied through the use of Fourier transform infrared (FTIR) spectroscopy. Macroscopic barrier properties of the epidermis were examined through the use of in vitro transepidermal water loss (TEWL). The flux of aspirin increased with increasing concentrations of EtOH in the solvent systems. The maximum flux of aspirin was achieved by 80% EtOH in combination with 20% PG beyond which (i.e. 100% EtOH) there was no increase in the flux. FTIR spectroscopic study was enacted in order to determine the biophysical properties of the stratum corneum when the solvents were applied. The FTIR spectra of the stratum corneum treated with 80% EtOH/20% PG showed a maximum decrease in absorbance for the asymmetric and symmetric C&z. sbnd;H peaks, which suggests a greater loss of the lipids in the stratum corneum layers. In vitro TEWL studies allowed an investigation into the macroscopic barrier integrity properties of the stratum corneum. The TEWL results indicated that each of the solvent systems significantly enhanced (P<0.05) in vitro TEWL in comparison to the control. In conclusion, 80% EtOH/20% PG enhanced the percutaneous absorption of aspirin by perturbing the macroscopic barrier integrity of the stratum corneum and through a loss of stratum corneum lipids.

Animals↗
PubMed1999

Fetal biophysical profile.

This article begins with an outline of the theoretic basis of the fetal biophysical profile, the method for the biophysical profile score (BPS), and the timing and frequency of testing. The article further discusses the clinical management based on test scores; modified methods of the BPS; and clinical application, predictive accuracy, and impact on outcome of BPS. The authors specifically examine the relationship between BPS and cerebral palsy. They conclude with a discussion of adult sequelae and fetal adaptation to asphyxia.

Adult↗
PubMed2004

Biological and biophysical principles in extracorporal bone tissue engineering. Part I.

Advances in the field of bone tissue engineering have encouraged physicians to introduce these techniques into clinical practice. Bone tissue engineering is the construction, repair or replacement of damaged or missing bone in humans or animals. Engineering of bone can take place within the animal body or extracorporal in a bioreactor for later grafting into the body. Appropriate cell types and non-living substrata are minimal requirements for an extracorporal tissue engineering approach. This review discusses the biological and biophysical background of in vitro bone tissue engineering. Biochemical and biophysical stimuli of cell growth and differentiation are regarded as potent tools to improve bone formation in vitro. The paper focuses on basic principles in extracorporal engineering of bone-like tissues, intended to be implanted in animal experiments and clinical studies. Particular attention is given in this part to the contributions of cell and material science to the development of bone-like tissues. Several approaches are at the level of clinical applicability and it can be expected that widespread use of engineered bone constructs will change the surgeon's work in the near future.

Animals↗
PubMed2000

Dentinogenic ghost cell tumor: histologic aspects, immunohistochemistry, lectin binding profiles, and biophysical studies.

Dentinogenic ghost cell tumor accompanied with calcifying odontogenic cyst (COC) was described in terms of its clinical, histological, immunohistochemical, lectin binding and biophysical properties. The case was a 38-year-old Japanese female, in whom the tumor had arisen in the right mandibular premolar and molar region. Material obtained by partial mandibulectomy was used. Decalcified paraffin sections were used to detect keratins, involucrin, and lectin binding; and non-decalcified thin sections were used for biophysical analysis. The lesion comprising dentinogenic ghost cell tumor and COC contained odontogenic epithelium with ghost cells, eosinophilic amorphous materials and osteodentin. Some of the eosinophilic material had undergone transformation into osteodentin. Keratins in odontogenic epithelia showed positive PKK1 staining in peripheral tumor cells, and stainings with KL1 and involucrin were positive in centrally located cells. Lectin binding in the amorphous materials was comparatively strong for PNA, and SBA, moderate for WGA, RCA-1, and UEA-1, and slight for DBA and ConA. Lectin binding affinities were higher in the amorphous materials than in the osteodentin. Elemental analysis with an electron probe X-ray microanalysis of the amorphous materials and osteodentin showed a pattern similar to that found in the normal dentin. The biologic properties of the eosinophilic amorphous materials suggested the material to be poorly calcified osteodentin, which gradually transformed into the well-calcified type.

Adult↗
PubMed2000

Gap junctions and biophysical regulation of bone cell differentiation.

Physical signals, in particular mechanical loading, are clearly important regulators of bone turnover. Indeed, the structural success of the skeleton is due in large part to the bone's capacity to recognize some aspect of its functional environment as a stimulus for achievement and retention of a structurally adequate morphology. However, while the skeleton's ability to respond to its mechanical environment is widely accepted, identification of a reasonable mechanism through which a mechanical "load" could be transformed to a signal relevant to the bone cell population has been elusive. In addition, the downstream response of bone cells to load-induced signals is unclear. In this work, we review evidence suggesting that gap junctional intercellular communication (GJIC) contributes to mechanotransduction in bone and, in so doing, contributes to the regulation of bone cell differentiation by biophysical signals. In this context, mechanotransduction is defined as transduction of a load-induced biophysical signal, such as fluid flow, substrate deformation, or electrokinetic effects, to a cell and ultimately throughout a cellular network. Thus, mechanotransduction would include interactions of extracellular signals with cellular membranes, generation of intracellular second messengers, and the propagation of these messengers, or signals they induce, through a cellular network. We propose that gap junctions contribute largely to the propagation of intracellular signals.

Animals↗