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Lupine Publishers| Monitoring Time-Progression of Structural, Magnetic Properties of Ni Nano Ferrite During Synthesis
Lupine Publishers| Journal of Material Science
We present time-progression of structural, magnetic properties of NiFe2O4 nano ferrite during its synthesis via sol-gel auto combustion technique, monitored by x-ray diffraction XRD, and magnetic measurements. XRD patterns of the samples collected between 18-52 minutes shows the formation of the nano spinel phase (grain diameter: 15.4 nm-28.6 nm), presence of a-Fe2O3phase was also detected. Samples collected between 8-14 minutes show the amorphous nature of the samples. Time-progression studies show: a) sample taken after 20 minutes shows a sharp decrease of specific surface area (range between 39.01 m2/g to 72.73 m2/g), b) non-equilibrium cationic distribution for samples taken between 16-20 minutes with a continuous increase of Fe3+ ions population on B-site with simultaneous decrease of Ni2+ population, c) for samples taken after 22, 52 minutes, cationic distribution is close to its ideal value of (Fe3+) [Ni2+Fe3+], d) alteration of a degree of inversion (d), oxygen parameter (u), modification of A-O-B, A-O-A, B-O-B super-exchange interactions, e) ferrimagnetically aligned core, and spin disorder on the surface with a thickness between 1.9 nm to 3.6 nm, reducing the saturation magnetization (ranging between 11.7 - 25.5 Am2/kg), as compared to bulk Ni ferrite (55 Am2/kg), f) low squareness ratio values (0.15-0.22) shows the presence of multi-domain nanoparticles, with coercivity between 111-157 Oe.
Keywords: Time-evolution of properties; Sol-gel auto combustion synthesis; XRD; Nano Ni ferrite; Cationic distribution; Magnetic properties
Spinel ferrites with general formula Me2+O.Fe3+2 O3, [Me: Divalent metal ion e.g. – Ni2+, Zn2+, Mg2+ Co2+ etc.], display face-centered cubic (fcc) structure, with two inter-penetrating sub-lattices: tetrahedrally coordinated (A site), octahedrally coordinated (B site) [1]. Nickel ferrite (NiFe2O4) has inverse spinel structure expressed as: (Fe3+) [Ni2+Fe3+] [1]. Allocation of cations on A, B site is crucial in determining properties of spinel ferrites [2,3], can be effectively used to achieve desired properties. Literature gives Ni ferrite synthesis using various methods including mechanical milling [4], coprecipitation [5], hydrothermal synthesis [6], sol-gel auto combustion method [7], showing the effect of the technique on structural, magnetic properties. Literature also reports real-time monitoring (in-situ studies) of properties [8,9], require special, sophisticated equipment, may not be available in all laboratories. Ex-situ monitoring of properties [10], describing the time-evolution of structural, magnetic properties, is a rather simple, more convenient way to perform experiments by utilizing standard laboratory equipment available in many laboratories. Ni ferrite is used in magnetic resonance imaging (MRI) agents [5], photocatalysis for water purification, antimicrobial activity [11], etc.) hence tuning its properties are preferred for improved efficiency.So, in this work, we present the time-development of structural, magnetic properties of NiFe2O4 nano ferrite during its synthesis via sol-gel auto combustion technique. Prepared samples are investigated via x-ray diffraction 'XRD,' vibration sample magnetometry, to get complimentary information on structural, magnetic properties.
Experimental Details
NiFe2O4 ferrite samples were synthesized by the sol-gel auto-combustion protocol, as described in detail in [12], by utilizing AR grade -nitrate/acetate-citrate precursors: Nickel acetate - Ni(CH₃CO₂)₂·4H₂O, Ferric nitrate (Fe(NO3)3.9H2O), Citric acid - C6H8O7]. The precursors were mixed in the stoichiometric ratio, were dissolved in 10 ml de-ionized water by keeping metal salts to fuel (citric acid) ratio as 1:1. At the same time, the solution pH was maintained at 7. Now the solution was heated at ~110 ̊C. As dry gel starts to form (taken as 0 minutes) small part of the sample is taken out from the reaction vessel (in an interval of 8, 10, 12, 14, 16, 18, 22, and 52 minutes), and were immediately ice-quenched to room temperature. Powder samples were used for Cu-K- X-ray diffraction 'XRD' measurements (Bruker D8 diffractometer), hysteresis loops by vibrating sample magnetometer. Full-profile XRD analysis was done by MAUD Rietveld refinement software [13] to obtain the lattice parameter (apex.). XRD analysis gives Scherrer's crystalline size D (calculated by the integral width of 311 peak, corrected for instrumental broadening), specific surface area (S), inversion parameter (d), oxygen parameter (u). XRD data was also analysed to get cationic distribution via Bertaut method [14], This provides cationic distribution by comparing experimental and computed intensity ratio of planes I(220)/I(400) and I(400)/I(422), susceptible to cationic distribution [12]. Cationic distribution was used to calculate theoretical or Néel magnetic moment at 0K (Ms(th)), theoretical lattice parameter (ath.), bond angles (θ1, θ2, θ3, θ4, θ5) as shown in [3]. Coercivity (Hc), saturation magnetization (Ms), remanence (Mr), squareness ratio (Mr/Ms) was obtained from hysteresis loops. (Figure 1) gives the schematic of sample synthesis and characterization.
Figure 1: Schematic of sample synthesis and characterization.
(Figure 2) (a) gives XRD-patterns of the studied NiFe2O4 samples collected after 18, 20, 22, and 52 minutes, confirm the formation of the spinel phase. XRD patterns also show the presence of a-Fe2O3 phase, ascribable to sample synthesis at a reasonably lower temperature (~110̊C), as reported in [15], while its disappearance is seen after higher sintering temperature. Figure 1(a) inset shows XRD patterns of samples collected after 8, 10, 12, 14 minutes show the amorphous nature of the samples. Only in the sample collected after 14 minutes, there is the start of spinel phase formation (indicated by a dotted circle). Illustrative Rietveld refined XRD pattern (Figure 2) b) of NiFe2O4 sample taken after 20 minutes also validates the cubic spinel ferrite phase formation. (Figure 2)(c) shows a variation of D (range between 15.4 nm to 28.6 nm) and S (range between 39.01 m2/g to 72.73 m2/g) for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. A perusal of (Figure 2) (c) shows a well-known inverse relationship shown by the expression: [S = [6/(D ´rXRD)], where rXRDis x-ray density, as was also reported in[2]. (Figure 2) (c) shows that for samples taken after 22, 52 minutes, D sharply increases with concurrent reduction of S, is ascribable to significant changes in cationic distribution via migration of Ni2+ions to B site with simultaneous migration of Fe3+ ions on A site(as can be seen in Table 1). (Figure 2 )(c) inset display linear relation between d and u as was also observed earlier [3], shows that reduction of the degree of inversion (d) leads to a reduction of oxygen parameter (u), a measure of disorder in the studied system, is expected to affect the properties of the studied samples. Table 1 depicts the variation of experimental and theoretical lattice parameter (aexp., ath. ), inversion parameter (d), oxygen parameter (u), Cation distribution (for A, B site), and calculated, observed intensity ratios for I400/422, I220/400 plane for the studied samples. The observed variation of aexp. is consistent with changes in cationic distribution, and variation of the degree of inversion (d). Close agreement between observed, calculated aexp., ath. suggests that the computed cationic distribution agrees well with real distribution [16]. Close matching of calculated, observed intensity ratios for I400/422, I220/400 signifies an accurate cationic distribution among A, B site [17]. Cationic distribution illustrates that as we go from NiFe2O4 samples taken after 16, 18, and 20 minutes, the population of Fe3+ ions on B site increases from 1.2 to 1.5 with a concurrent decrease of Ni2+ ions from 0.80 to 0.50. For samples taken after 22, 52 minutes Fe3+ population on B site decreases, while Ni2+ ion population increases up to 0.98, which is close to the ideal inverse cationic distribution of (Fe3+) [Ni2+Fe3+] [1].
Figure 2: (a): XRD patterns of the studied NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes showing the formation of the spinel phase. Inset: XRD patterns of the studied samples taken after 8, 10, 12, 14 minutes. (b): Illustrative Rietveld refined XRD pattern of NiFe2O4 sample taken after 20 minutes (* - Experimental data, Solid line - theoretically analyzed data, |- Bragg peak positions, Bottom line- Difference between experimental, and fitted data). (c) variation of grain diameter (D) and specific surface area (S) for NiFe2O4samples taken after 16, 18, 20 22, 52 minutes. Line connecting points guide to the eye. Inset: variation of inversion parameter (d) with oxygen parameter (u). The straight line is a linear fit to the experimental data.
Figure 3 depicts the variation of bond angles between cations, cation-anion q1, q2,q3, q4and q5, for the studied samples taken between 16 - 52 minutes. In samples taken after 8, 10, 12, and 14 minutes, due to the absence of the spinel phase, bond angles could not be computed. Bond angles provide information on super-exchange interaction (A-O-B, A-O-A, B-O-B), mediate by oxygen. (Figure 3) shows that for samples taken after 16, 16, 20 minutes q1, q2, q5, decreases while q3, q4increases, indicates a weakening of A–O–B, A– O–A and strengthening B–O–B super-exchange interaction as is also observed earlier [16]. For samples taken after 22, 52 minutes q1, q2, q5, increases, and q3, q4decreases reveals strengthening of A-O-B, A-O-A, and weakening of B-O-B super-exchange interaction, reported in the literature with compositional changes [3]. Samples taken after different times, there is a modification of A-O-B, A-O-A, B-O-B super-exchange interactions, are attributed to changes in dand u as shown in(Table 1), observed with compositional changes [3,16]. Observed A-O-B, A-O-A, B-O-B super-exchange interactions should mirror in magnetic properties, matches well with reported literature [3,16]. Thus, collecting samples after different times during synthesis is analogous to compositional changes in spinel ferrites, affects structural, magnetic properties [3, 12, 16, 18].
Figure 3: Dependence of bond angles (q1A-O-B,q2A-O-B, q3B-O-B,q4B-O-B, q5A-O-A) for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Line connecting points guide to the eye.
Figure 4 depicts hysteresis loops, reveal changes in Ms(exp.)samples taken after 16, 18, 20 22, 52 minutes, attributable to alteration of B-O-B, A-O-B, and A-O-A interaction, depends on bond angles, as shown in (Figure 3), and cationic distribution, as shown in (Table 1). (Figure 4) inset displays hysteresis loops of the samples taken after 8, 10, 12, 14 minutes, showing very low magnetization, attributable to the fact that in these samples ferrite phase is not formed, as was also observed in XRD data shown inset of (Figure 2) (a). Observed lower values of Ms(exp.) (ranging between 11.7 - 25.5 Am2/kg) as compared to the multi-domain bulk Ni ferrite (55 Am2/kg) is attributed to the two-component nanoparticle system as described in [19]consisting of a spin-disorder on the surface layer and ferrimagnetically aligned spins within the core. Computed magnetic dead layer thickness as described in [20,21]for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes are respectively 2.3, 1.8, 1.9, 2.5 and 3.6 nm. They confirm the contribution of 'dead layer thickness' in the reduction of Ms(exp.), apart from B-O-B, A-O-B, and A-O-A super-exchange interaction and cationic distribution.
Figure 4: Hysteresis loops of the studied NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Inset: Hysteresis loops of the samples taken after 8, 10, 12, 14 minutes.
Table 1: Variation of experimental and theoretical lattice parameter (aexp., ath.), inversion parameter (), oxygen parameter (u), Cation distribution (for A, B site), and observed, calculated intensity ratios for I400/422, I220/400 plane for the studied samples.
Figure 5(a) depicts Variation of Ms(exp.), Ms(th.)for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. A perusal of figure 5(a) shows that observed behaviour is attributable to alteration of B-O-B, A-O-B, and A-O-A super-exchange interaction, depends on bond angles (see figure 3), and cationic distribution (see Table 1). Non-similar trend of Ms(exp.), Ms(th.)in (Figure 5)(a), shows that the magnetization behaviour is governed by Yafet-Kittel three sub-lattice model, described in [22], confirmed by the computed canting angle (aY-K) values for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes, which are respectively 52.7, 56.6, 46.2, 55.7, 46.9 ̊. The canting angle provides information on spin canting on the surface, is so-called 'magnetic dead layer,' leads to a reduction of Ms(exp.), which is lower than bulk saturation magnetization of Ni ferrite (55 Am2/kg). Inset of Figure 5 (a) shows the variation of Ms(exp.) with oxygen parameter 'u'(which is a measure of disorder in the samples [1]). Figure 5 (a) shows the disorder-induced enhancement of Ms(exp.),as was also reported in [3]. (Figure 5) (b) depicts the Coercivity(Hc) variation for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Obtained Hcand related Dvalues imply that studied samples lie in the region with overlap between single or multi-domain structures, as reported earlier [3]. (Figure 5) (b) Inset depicts the variation of Mr/Ms for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Mr/Ms values ranging between 0.15-0.22 reveal enhanced inter-grain interactions suggesting isotropic behavior of the material [23] reveal multi-domain particles with no preferential magnetization direction. Time-dependent tunable structural, magnetic properties during synthesis are valuable in achieving optimal properties of Ni ferrite for their usage in magnetic resonance imaging [5], hyperthermia [24] for cancer treatment, photocatalysis for water purification [11].
Figure 5: (a) Variation of Ms(exp.), Ms(th.)for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Inset: Dependence of Ms(exp.)on oxygen parameter (u), line connecting points in Inset are linear fit to the experimental data.; (b) Coercivity(Hc) variation for NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes. Inset: Variation of Mr/Msfor NiFe2O4 samples taken after 16, 18, 20 22, 52 minutes.
To summarize, the sol-gel auto combustion technique is used to observe the time-development of structural, magnetic properties of Ni ferrite. Changes in cationic distribution lead to modification of structural properties, magnetic interactions, responsible for observed magnetic properties. Time-progression of properties are of use to alter structural, magnetic properties of Ni ferrite as a material for its prospective usage in heterogeneous catalysis, water purifications, biomedical applications.
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Lupine Publishers| The Synthesis of Alginate Microparticles and Nanoparticles
Lupine Publishers| Journal of Drug Designing & Intellectual Properties
Alginate is a natural polysaccharide that is widely used as a component of pharmaceuticals and in food industry. Alginate particles can be used for encapsulation of substances with the necessity of prolonged release. They can also provide appropriate microenvironment for cells. Here the methods of the synthesis of alginate beads, micro- and nanoparticles are reviewed with special attention to the calcium alginate ones. The results from publications that did not deal with alginate particles but, to our opinion, could be applied in this field are also included in order to give an outline for possible future research. The suggested applications of the particles are mentioned as well. The two main methods for the synthesis of calcium alginate particles are internal and external gelation, but the external gelation techniques can be themselves subdivided into several subtypes. Currently, a technique being able to produce alginate nanoparticles with any desirable size does not exist. We analyze the possibilities of employing aerosolization method for this purpose. The potentials to overcome the problem of burst release of the encapsulated substances by means of cyclodextrin inclusion complexes and employing additional crosslinking agents are also discussed. The clinical application of alginate nanoparticles is still limited because of the burst release of encapsulated drugs and the poor size control of the particles formed. Further research must concentrate on overcoming these problems and on topical application of alginate particles without entering bloodstream rather than on investigation of model drug release in vitro without taking the above-mentioned problems into account.
Keywords: Calcium alginate; Alginate beads; Alginate microparticles; Alginate nanoparticles; Drug encapsulation; Particle size control; Aerosol
Alginates are polysaccharides. The commercially available ones come from brown algae. They are linear copolymers of (1→4)-linked units of β-D-mannuronic acid and α-L-guluronic acid. The molar ratio between them and their distribution along the commercial polymer depend on the algal source, its location, age, collection season and extraction technique. Guluronic acid residues can form so-called egg-box complexes with calcium ions or some other divalent metal cations leading to gel formation (Figure 1). The name 'egg-box' is used because, if depicted schematically, the cations look like eggs situated inside puckered boxes formed by four guluronic acid residues of two superimposed chains. Mannuronic acid residues have much less affinity to metal ions [1]. Barium ions have more affinity to alginate than the calcium ones. If reacted with calcium alginate at lower concentrations, they create new gelling junctions. At higher concentrations, barium ions also displace calcium ions from existing junctions [2].
Figure 1: The egg-box model.
To extract alginate, algae are usually washed with organic solvents and water, dried and milled. After acid pretreatment, alginate is solubilized with Na2CO3 . The crude extract is concentrated, dialyzed against water and then freeze-dried or precipitated with ethanol. Acidification or treatment with Ca2+ can be used instead. Brown algae are abundant in nature; however, the possibility of cultivating them exists as well [1]. The viscosity of aqueous sodium alginate solution rapidly increases with its concentration. For example, the addition of 10% of alginate to water leads to a ~100-fold increase in viscosity. But the poly electrolyte nature of alginate has little effect on its hydration, and in the above example less than 3.7% of the water molecules present in solution is involved in alginate hydration. Such a large viscosity increase is determined by the polysaccharide network, with large bulk-like water pools present between the polysaccharide chains [3].
Sodium alginate may act as a mucoadhesive polymer. A comparative study of adhesion between buccoadhesive compacts and pig buccal mucosa or sodium alginate solution revealed that the results were of similar performance [4]. Sodium alginate was proposed as a mucoadhesive component of a nasal gel [5] or in buccal patches containing salbutamol sulfate [6]. Sodium alginate conferred in situ gelling mucoadhesive properties and retarded drug release from liquid rectal suppositories. These suppositories were successfully tested on Guinea pigs to alleviate symptoms of histamine-induced bronchospasm [7]. Sodium alginate was also evaluated as an excipient in salbutamol sulfate sublingual films [8] and tablets [9]. However, drug release was found to be too slow in the films [8] or too rapid in tablets [9]. Only salbutamol sulfate tablets formulated from granules containing mastic and sodium alginate excelled commercial tablets in the terms of drug release when tested on rabbits [10]. In combination with hydroxy propyl methyl cellulose and propylene glycol sodium alginate was used in the formulation of terbutaline sulfate sublingual films [11]. Sodium alginate could be also used as a component of plugs for water-soluble parts of crosslinked gelatin capsules containing pellets with encapsulated salbutamol sulfate. The plug absorbed the surrounding fluid, and began to release the drug through the swollen matrix and was finally ejected out of the capsule by erosion of the material. The usability of the system was shown on rabbits [12].
Chitosan-alginate complex was proposed as an excipient for orodispersible tablets, and their disintegration time was so short that it was even referred to as a 'super dis-integrant' [13]. One optimized formulation containing the excipient for 5-fluorouracil tablets, suitable for trans buccal and rectal drug delivery, contained this chitosan-alginate complex along with the same components un-complexed in order to avoid burst release and to improve the mucoadhesive properties [14].
Sodium alginate itself also has a therapeutic effect. When admixed to foods for diabetic human patients, it decreased gastric emptying rate and rises glucose in blood, serum insulin and plasma C-peptide levels [15]. Orally administered, sodium alginate significantly alleviated small intestinal enteritis in rats, caused by treatment with the anti-inflammatory drug indomethacin, and this relief seemed to be independent of the sodium alginate viscosity administered [16]. Oral disposal of sodium alginate to rats with colitis led to a significant reduction of colonic damage, decreased lesion formation [17,18] and inhibited mucosal injury [17]. Orally administered alginate oligosaccharide obtained from hydrolysis of sodium alginate by Bacillus subtilis improved histopathological and biochemical parameters of mice having ovalbumin-induced asthma in a dose-dependent manner [19]. Rats fed with sodium alginate drank more water, and their urine volume and pH rose sharply. In contrast, calcium alginate caused very little changes in the same parameters [20].
Commercially available calcium alginate swabs were used for sampling nasal flora for subsequent DNA extraction [21]. The mucoid exopolysaccharide produced by the pathogenic bacterium Pseudomonas aeruginosa is alginate, but it has low immunogenicity if it is not conjugated with a carrier protein. Even in the form of conjugate it is non-toxic if administered intraperitoneally to mice or guinea pigs and non-pyrogenic if administered intravenously to rabbits [22]. When alginate beads with encapsulated tumor cells were implanted to mice, a process of angiogenesis was observed in the implants zone. The beads were prepared from commercially available alginate [23]. It may be considered as a further proof of alginate biocompatibility.
Sodium alginate was also shown to be beneficial for agriculture. Being administered as dietary supplement to the white shrimp Litopenaeus vannamei, it acted as an immunostimulant and improved its resistance against the attack of Vibrio alginolyticus bacterium [24]. Sodium alginate digested with alginate lyase promoted root elongation of rice, carrot [25], lettuce [26] and barley plants [27,28] even under hypoxic conditions [28]. It was hypothesized that digested alginate might initiate some signal transduction pathway [27,28]. Under hypoxic conditions digested alginate also caused enhancement of the activity of the enzymes regenerating NAD+ [28].
Alginate oligomers promoted the germination of unhulled rice and Komatsuna seeds as well as tobacco callus differentiation. The mixture of oligomers was assumed to contain so-called oligosaccharine, an oligosaccharide inducing unusual proliferation and/or differentiation of plant cells. There are several kinds of oligosaccharines. They act as a chemical signal for the stimulation of hormone synthesis [29]. The promoting effect of alginate oligosaccharides on root formation and growth in rice was mediated by endogenous indole-3-acetic acid [30]. But proliferation of the microalga Chlamidononas reinhardtii was repressed by the same oligomers [29]. It should be noted that only digested sodium alginate shows this effect. And the possibility of alginate degradation by the lyases of soil bacteria is assumed [28]. Therefore, it is speculated that these active substances can be formed from alginate under natural conditions. Another notable advantage of alginate is its ability to bind micronutrients. Some important Mn, Cu, Zn and Mo fertilizers are MnCl2 , CuSO4 ·5H2O, ZnCO3 and Na2 MoO4 ·2H2O, respectively [31]. Manganese can be complexed with alginate by addition of MnCl2 to the gelling solution of CaCl2 or BaCl2 , and slow release of manganese ions from the beads into physiological saline has been reported [32] because the affinity of alginate to Ca2+ is higher than to Mn2+ [33]. The beads containing Ba and Mn could be used for manganeseenhanced magnetic resonance imaging and were tested on rats [32]. The use of CuSO4 [34] or CuCl2 [35] as a gelling solution led to copper alginate hydrogel being able to release copper ions into simulated body fluid [34] or into phosphate buffer (pH 6) [35] in a prolonged manner. The use of basic zinc carbonate for zinc alginate hydrogel formation using internal gelation method has also been reported. The hydrogel was active against E. coli [36]. Molybdenum can be adsorbed by preformed calcium alginate beads preferably in the form of H2[MoO4] or [Mo(H2O)6]3+ at pH 2 and released back up to 50% into 0.1M HCl. If radioactive molybdenum is used, the method is suitable for radiotherapy [37]. Copper ions from CuCl2 may also be adsorbed onto preformed calcium alginate beads [38]. Copper alginate shows activity against Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus pyogenes and E. coli [34].
The biodegradability of unmodified alginate particles, their ability to bind micronutrients and the beneficial effect of alginate make them promising carriers of agrochemicals. This is especially important because in a recent review [39] the authors expressed great concerns regarding the use of nanoparticles in agriculture because of the negative impact of metal and oxide nanoparticles on soil microorganisms, earthworms and even on cultivated plants.
Alginate beads can also have industrial applications:
• Wastewater treatment. The beads with encapsulated horseradish peroxidase could be reused up to 3 times, although the encapsulation decreased enzyme activity in comparison with the free enzyme [40]. In another report, the efficiency of phenol removal by encapsulated horseradish peroxidase was demonstrated by reducing to half the initial phenol quantity after only 5 reaction cycles [41].
• Food industry. Xylanase immobilized in alginate beads may be used for fruit juice clarification [42]. Lactobacillus helveticus and Streptococcus thermophilus immobilized in alginate beads were intended for use as lactic starters in milk fermentation [43]. Alginate particles with encapsulated healthy nutrients can also be used as components of functional foods.
• Enzyme production by cells immobilized in alginate beads. A good example is glucoamylase [44]. In this case fungus Thermomucor indicae-seudaticae was immobilized in alginate beads, and cane molasses was used as a cheap medium [44]. In all these applications alginate is exploited because of its natural origin, i.e. it cannot be a harmful admixture if separated incompletely. Beads (and not nanoparticles) are chosen because they can be easily separated by sedimentation. As could be seen above, not only enzymes themselves but also enzyme-producing bacteria can be immobilized in alginate beads.
In contrast to metal nanoparticles, alginate particles can be modified either before or after their synthesis. In the former case, bulk alginate is modified and then used to prepare the particles. This way is usually preferable from the two options because it avoids the leak or destruction of encapsulated substance during the modification. The chemical modification of alginate is reviewed widely in [45].
Alginate microparticles and nanoparticles are usually used to encapsulate and carry various substances, and the goal of many studies is to achieve sustained release of them. It should be noted, however, that the results of experiments dealing with the release of poorly water-soluble drugs might often be misinterpreted, because the drug not found in the solution is assumed to remain encapsulated in the particles. However, it may decompose after the release or simply precipitate out. Supersaturated solutions with varying extent of supersaturation can also be formed, making the results irreproducible. Special care must be taken in the case of putting the particles into a dialysis bag, because the films act as an additional diffusion barrier. If centrifugation is used for separation of the medium with the released substance from the nanoparticles, the pressure generated during the process can disturb the equilibrium. It can also make difficult resuspending the nanoparticles in the fresh portion of medium for further incubation [46].
For consistency, throughout this review we will use the following terms (even if different names for them were used in the respective publications):
• Encapsulation efficiency: the percentage of the substance that was encapsulated (i.e. not lost).
• Loading efficiency (expressed in percent): the ratio of the weight of the successfully encapsulated substance regarding to the total weight of the particle. Some authors calculate loading efficiency using different formulae, but we will give their values without a special discussion. We have rounded encapsulation and loading efficiencies as well as zeta potentials to the nearest integer values.
• Nanoparticles are considered smaller than 1µm. Microparticles have size from 1 to 1000µm. Beads have size in a millimeter range. We have rounded bead size to the first decimal place.
Also, some authors term their particles 'microcapsules'. However, we will use this term only if they have demonstrated or at least assumed the presence of a liquid core in their particles. In other cases, we will refer them to as microparticles.
Alginate-chitosan particles
Since alginate is a polyanion and chitosan is a polycation, they can form a polyelectrolyte complex upon mixing, provided both of them are charged, i.e. at suitable pH. This mixture can spontaneously form particles. The pKa of alginate carboxyl group is close to 5, and that of the ammonium group of chitosan is about 6.2 [1].
Alginate-chitosan nanoparticles were prepared by dropwise addition of a chitosan solution containing glutathione into an alginate solution at pH 4, under stirring. If prepared at 0.75 alginate: chitosan ratio, the formed nanoparticles with encapsulated glutathione had the following characteristics: size 361nm, polydispersity index 0.33, zeta potential 27mV [47,48]. At 1.5 alginate: chitosan ratio, the values were 212nm, 0.4 and 23mV, respectively, although the storage stability decreased, making these nanoparticles less suitable for application. In the same way, the pH increase from 5.0 to 6.5 and further caused aggregation [48]. The encapsulation efficiency was 27% [47] or 80% at ratio 0.75 and fell to 1% at ratio 1.5 [48]. The respective investigations were aimed to achieve the synthesis of mucoadhesive nanoparticles with an encapsulated NO donor needed for treat important diseases because of the multifaceted role of NO in vivo. Therefore, encapsulated glutathione was nitrosated inside the nanoparticles by adding sodium nitrite to the solution. S-nitrosoglutathione decomposition at 400µM was delayed by its encapsulation in the nanoparticles. At 18µM encapsulated S-nitroso glutathione was not cytotoxic to cultured Chinese hamster lung fibroblast cells (V79), whereas free S-nitroso glutathione was slightly cytotoxic at the same concentration. This assay could enable the use of these anti microbial nanoparticles in pharmaceutical applications such as wound healing without severe side effects [47,48].
Later, the same technique was used by the same group to encapsulate mercaptosuccinic acid and nitrosate it inside the particles. In this case, the hydrodynamic size of the nanoparticles was ~750nm. The encapsulation efficiency was 89%. Burst release of NO in aqueous solution was followed for 4 hours, although the release in the normal mode continued for 6 hours more. These nanoparticles were assayed for topical application for bovine mastitis. The minimal inhibitory concentration of the nanoparticles for Staphylococcus aureus determined in vitro was 125-250µg/ml. The number of colony forming units was 10-fold and 1000-fold lower after bacteria were incubated with nitrosated nanoparticles at 500µg/ml for 4 and 7 hours, respectively, compared with bacteria growth in the presence of empty nanoparticles at the same concentration and time. The CFU drastically decreased further upon the addition of a second dose of nitrosated nanoparticles. For E. coli the minimal inhibitory concentration exceeded 2000µg/ml, i.e. these nanoparticles were inefficient against this bacterium. The 50% cytotoxicity concentration of the nanoparticles for cultured HEp-2 cells was 640µg/ml. Chitosan nanoparticles without alginate at the same concentrations of the acid released more NO at higher rates. Nevertheless, it was concluded that NO-releasing nanoparticles might be used to combat bacteria for treating and preventing bovine mastitis [49].
Spherical alginate-chitosan beads with encapsulated lemongrass oil having size of 1.8-2.1mm displayed significant antibacterial and antioxidant activity. For unencapsulated oil the same activity was observed only at higher concentration. This beneficial action was attributed to the strong interaction between chitosan and the oil. This kind of beads has potential applications as a greener agent for medical purposes [50].
The following advantages of alginate-chitosan particles can be underlined:
• Chitosan can enhance drug bioavailability by its capacity of infiltration into the mucus layer of the small intestine with subsequent opening of tight junctions of epithelial cells [51].
• Unlike calcium alginate, alginate-chitosan polyelectrolyte complex cannot be disintegrated by chelatoring agents. Their main disadvantage could be the necessity to use an acidic solution of chitosan because of its insolubility at neutral pH.
Preparation of alginate particles without employing gelation
Now we describe the techniques for preparation of particles from bulk sodium alginate or its solution as well as spontaneous formation of particles of modified alginic acid in water. The resultant particles are usually intended to be ready to use. However, dry sodium alginate particles can be later treated with CaCl2 solution in order to convert them to calcium alginate particles.
There exists a patented technique for producing alginate, cellulose, starch or collagen particles from bulk substances by ball milling with the possibility to control particle size from 100nm to 50µm. The resultant nanoparticles containing therapeutic proteins have shown efficacy in treating solid tumors, single dose vaccination, and oral delivery. For instance, tumor-bearing mice that received these nanoparticles containing Texas red and cisplatin showed significant tumor size diminishing. If the same nanoparticles were coupled to dendritic cell-binding peptide and contained encapsulated pneumococcal surface protein A, together with an adjuvant, they were effective to combat the bacterial load of the mice that was reduced (in the terms of infected tissue volume) after exposition to nanoparticles. The nanoparticles produced by the same milling technique were also used to induce passive immunity against anthrax toxin in mice by means of oral delivery of monoclonal antibodies developed versus anthrax toxin [52].
Another technique consists in dropwise addition of pure ethanol or acetone to 1% sodium alginate in water containing drug solution in dimethyl formamide. Mixing [53] and cooling down to 3-5 °C is needed during the process. At low mixing speed aggregation was observed [54]. These microparticles can be separated by filtration, washed with the same solvent and dried on air, in a heating oven [53] or in a desiccator [54]. Using nitrofurazone as an example of an encapsulated drug, the loading efficiency and yield of microparticles decreased as the particle size increased from 5 to 30μm with ethanol dripping rate increasing. The presence of 0.1% ammonia [54] (pH 8-9) and of a surfactant was needed in order to avoid particle aggregation in the case of nitrofurazone. Other drugs, viz. acridone, tetracycline, dibazole and metronidazole were encapsulated in the same way (but without ammonia), although the encapsulation conditions needed to be optimized for every drug separately. The yield varied from 31% for metronidazole to 77.5% for tetracycline, and the loading efficiency varied from 2% for metronidazole to 43% for nitrofurazone [53]. In a later publication, the same group reported that in the case of nitrofurazone the yield of microparticles was 81% with a loading efficiency of 34%. Spray drying instead of filtration was recommended to increase the yield [54]. The stability of nitrofurazone-loaded microparticles resuspended in water was reported to increase with pH [53]. At 1% and 2% of particles (nitrofurazone concentration was 0.34% and 0.68%, respectively) these solutions were more active against E. coli, P. aeruginosa, P. vulgaris, S. aureus and B. subtilis than aqueous nitrofurazone solution having drug concentration less than 0.02% because of its insolubility. In the case of Candida albicans the same solutions of microparticles excelled in antifungal activity nitrofurazone solutions in DMSO with the concentrations of 1% and 2% [54]. The ability of the particles to form stable suspensions and to enhance drug solubility in water broadens the field of drug application [53,54]. The encapsulated drugs are expected to be more stable under ambient conditions [53].
Spray drying the sodium alginate solution containing the payload (caffeine-loaded peptidic nanoparticles) yielded microparticles having size of about 4μm. The crosslinking with CaCl2 solution increased their mean size to 7.4µm but decreased their shrinkage and slowed down the release of caffeine into simulated gastric fluids. The particles are potentially bioactive because of the presence of antioxidant peptides [55]. Spray drying the solution containing sodium alginate, pectin and gentamicin sulfate at inlet temperature of 90 ºC was used for wound dressing preparation. The volume diameter at the 50th percentile (spanning from 310 to 1003nm for various samples), the width of particle size distribution, water content and drug release rate increased with nozzle spray mesh diameter and with feed solution concentration at constant ratio of the components. Flowability of the powders, the adhesive strength of the gel formed from them in contact with simulated wound fluid as well as its activity at 0.25mg/ml of gentamicin sulfate against Staphylococcus aureus and Pseudomonas aeruginosa showed the opposite tendency. Antimicrobial activity was expressed as the diameter of the zones of clearance around the two samples spotted on agar plates with the spread bacterial culture after incubation for 24 hours. For Staphylococcus aureus the activity of two samples was also tested in culture medium after 3, 6, 9 and 12 days of incubation. The particles were mainly spherical, but other shapes appeared when either feed concentration or mesh nozzle increased, and further increase led to large collapsed particles. All the particles were composed of smaller aggregated particles. The encapsulated drug was being released in simulated wound fluid in Franz-type diffusion cells for up to 5 days. Loading efficiency was around 24-27% with an encapsulation efficiency between 70 and 83%, and for all the samples initial burst release was observed. At 40 °C and 75% relative humidity drug content was preserved for 6 months with only slight increase in water content. Swelling rate in contact with simulated wound fluid depended on particle size. The yield increased with feed solution concentration but decreased with nozzle spray mesh diameter. The nanoparticulate powder may be used as a self-consistent formulation having great potential application in the treatment of both acute and chronic infected wounds [56].
Low molecular weight alginic acid prepared by acid hydrolysis of sodium alginate formed nanoparticles itself (without calcium ions) when its hydroxyl groups were functionalized with oleoyl residues. The nanoparticles were loaded with vitamin D3 by addition of its solution to the reconstituted solution of vacuumdried nanoparticles. Loading efficiency increased with the vitamin concentration from 0.3 to 0.9%, but the encapsulation efficiency also decreased from 68% to 46%. Mean nanoparticle hydrodynamic diameter also decreased from 559nm to 305nm, and particle formation rate was sped up when substitution degree increased. An unimodal particle size distribution was revealed. In simulated gastric fluid they retained spherical shape and released ~40% of the encapsulated vitamin for 3 hours. But in simulated intestinal fluid they became irregularly shaped, their hydrodynamic diameter was 757nm and burst release of 40% of the vitamin occurred, with 60% of the vitamin released after 7 hours. The nanoparticles can be used as oral carriers for liposoluble nutraceuticals [57]. The great disadvantage of sodium alginate particles is the very limited possibility of prolonged drug release because of sodium alginate solubility leading to fast disintegration of the particles. The particles of modified alginic acid offer convenient manipulation, but the need of its prior chemical functionalization limits the applicability of the technique for non-specialized, e.g. biomedical laboratories.
Production of Alginate Particles Using Other Particles as Cores
In this method, sodium alginate is physically adsorbed or covalently linked to the surface of other particles. The particles can also be formed already capped with alginate. In some cases subsequent gelation with CaCl2 is carried out. For CaCO3 particles there is a possibility of their generation simultaneously with alginate gelation.
Dropwise addition of chitosan nanoparticles with encapsulated bovine serum albumin modified with rhodamine isothiocyanate to sodium alginate solution at controlled pH yielded negatively charged nanoparticles having hydrodynamic diameter of several hundred nanometers depending on the solution composition. The highest diameters were registered in water. The nanoparticles successfully delivered the protein into cultured cells, with the localization depending on cell type. Significant increase in peroxide production by HCEC cells was observed at 300 and 600µg/ml of empty nanoparticles after exposure for 4 hours. However, there was almost no superoxide production after either 4 or 24 hours of exposure. The metabolic activity of LN229 and MCF-7 cells remained unchanged for up to 72 hours of incubation with the empty nanoparticles. But MDA-MB-231 and HCEC cells displayed significantly decreased metabolic activity at nanoparticle concentration above 180µg/ml after 72 hours of exposure, but not after 24 hours. Similar survival decrease at these concentrations of nanoparticles was observed for A549 cells. Dose dependencies acquired after 24 or 72 hours of exposure were almost the same. Survival of HT29 and CaCO2 cells was significantly increased only after exposure to 600µg/ml of the nanoparticles for 72 hours. The nanoparticles have potential applicability as nanocarriers in cancer therapy [58]. A similar technique was used for enoxaparin encapsulation. The proposal was to evaluate nanoparticles loaded with this low molecular weight heparin for its oral delivery, controlled and prolonged release in order to improve patient compliance. In this, chitosan nanoparticles were covered with sodium alginate (applied in phosphate buffer) and treated with CaCl2 . Parameters of the optimized formulation were as follows: average size 335nm, spherical, polydispersity index 0.37, zeta potential –31mV, encapsulation efficiency >70%, drug release in simulated gastric fluid for 2 hours 2%, in simulated intestinal fluid for 14 hours ~60%. Degradation and erosion of nanoparticles was identified as a possible drug release mechanism. The pharmacokinetic parameters of the drug given orally to fasted rats through cannula in a dose of 50mg/kg body weight were improved. Nevertheless, those of intravenously administered free enoxaparin at 1mg/kg were better. 75% of the encapsulated drug applied at 2mg/ml reached across the intestine to the serosal fluid for 90 minutes, as shown in vitro by means of everted intestinal sac model. 900 IU of orally administered encapsulated drug reduced thrombus formation by 59% compared with buffer. Significant uptake of the nanoparticles by the intestinal mucosa for 1 hour was shown by administration of nanoparticles loaded with fluorescein isothiocyanate instead of the drug through gastric cannula to fasted rats. Therefore, the nanoparticles proved their utility as oral delivery vehicle for enoxaparin. Such a vehicle is a foremost requirement for non-invasive and non-hospitalized treatment of vascular disorders (deep vein thrombosis, pulmonary embolism and venous thromboembolism). But subcutaneously injected free drug was even better [51].
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Lupine Publishers | Keratin
Lupine Publishers | Journal of Research and Reviews on Health Care
Eating foods high in protein gives the body the amino acids it needs to make keratin. Red meat, fish, chicken, pork, eggs, milk and yogurt all protein rich. The best plant sources of protein include beans, nut, Nat butters and quinoa. Most adults need two to three servings of protein each day to meet their daily requirements. Keratin is more of a restorative treatment borday says "Elen if you have a good hair type, it still strengthens the hair shaft and makes your hair mover salient. Sadock recommends checking with a demonologist before getting a keratin treatment if you have protasis or seborrheic dermatitis (Figure 1).
Keywords: Foods; Protein; Nut Butters; Strengthens; Keratin
"Keratin treatment" has become the term of choice for hair- smoothing processes that leave your hair frizz-free for weeks (even months) but forget about the word keratin. "It's just a make ting buzz word – it's not doing anything to smooth the hair", first, a quick chemistry lesson. Think of straight hair as a lader and curly hair as a spiral staircase. The steps on both are the hair's bonds. If you break those bonds, you can rebuild the spiral stair case as ladder so curly hair becomes straight. Ammonium thiol collate and sodium hydroxide permanently break the bonds that's how traditional relaxers and "jopynose straightening" treatments transform the texture of the hair, "these treatments last until your hair grows out, bat they can be damaging, say schaeller. (And they will subject you to a very awkward growing-out phase.) some "keratin treatment" (and the popular brozillinbleu out original solution) saturate the hair with of onal dehyde solution before its dried and flat ironed; the format dehyde (yes, it's a suspected cancer gen for human) looks the hair into that straighter positions. Its stays smooth beyond your next shampoo. Your natural texture then gradually returns over two five months.
Keratin treatments won't make your hair break, but the flatironing might. "The hair breakage has nothing to do with the treatments and everything to do with the flat irons that are used to dry and seal the hair a fleruard", some stylists may use a flat iron that is way too hot and scorches hair making it break off". Think of straight hair as a ladder and curly hair as a spiral staircase. The steps on both are the hair's bonds. If you break those bonds. You can rebuild the spiral staircase as ladder-so curly hair becomes straight. No hair treatment will technically contain formaldehyde (because a little more chemistry you it's a gas). What they are able contain are methylene glycol, formalin, methanol, and methane did – ingredients that release formaldehyde when heated or mixed with water. Several new hairs-smoothing treatments use glyoxylic acid (or a derivative of it) to lock the hair into a straighter position. Results don't usually last more than two or three months and these treatments won't dramatically soften your curl pattern the way formaldehyde solution can.
Biotin-Rich Foods
Biotin is needed to metabolize the amino acids that create keratin and is generally recommended to strengthen hair and nails. Dietary sources of biotin contain nut, beans, wholegrains, caul flower and mushrooms.
Foods with Vitamin A
Vitamin A is needed for keratin synthesis good dietary sources of vitamin A contain orange fruits and vegetables like pumpkin, sweet potatoes, butternut squash, raw carrots and cantaloupe. Kedgerees like spinach, kale and collards are also high in vitamin A. Boost your hair, nails and skin from within care for your precious hair by eating the right vitamins and foods that increase keratin production. Included is knowledge on why keratin is important and which foods and vitamins will offer the best support.
Increasing Keratin Production
a. Fruit and vegetable: It aren't a surprise that increase keratin production include fruits and veggies. Produce that orange, such as mangoes, carrots, sweet potatoes, and cantaloupe are high in carotene, which helps your body produce keratin. Carotene can also found in spinach, green peppers and squash.
b. Meat and dairy: Iron-rich protein can boost the production of keratin in the body and improve the health of skin, hair and nails, liver, fish and lean meats build keratin in your body.
c. Iron rich foods: Iron-rich animal protein includes turkey, duck, chicken, pork, shrimp, eggs, lean beef and lamb. Plant foods that contain iron-rich protein include beans, spinach, black-eyed peas, soybeans, to fuand lenticls.
d. Vitamin C: foods rich in vitamin C include brocade, frazzles sprouts, kale, peppers, guava, papaya, grape fruit, oranges, pine apples, strawberries and lemons.
e. B vitamins: Foods with folate include a meal, fortified whole grain cereal, spinach, beets, parsnips, broccoli, okra, black-eye peas and soybeans.
f. Zinc: Consume foods with zinc, such as asters, crab, pork, ronde lain, turkey, veal, chicken, peanut butter, wheatgerm and chick peas.
Result and Discussion
Keratin treatments won't make your hair break, but the flat-ironing might. No Nair treatment with technically contain formaldehyde (because - a little more chemistry you it's a gas). Results don't usually last more than two- or three-month biotin contain nut, beans, wholegrains, cauliflower and mushrooms. Vitamin A contain orange fruits and vegetables.
a. Like pumpkin, sweet potatoes.
b. Fruit vegetables
c. Spinach, green peppers and squash.
d. Meat and dour: liver, fish and lean meats build keratin in body.
e. Iron: beans, spinach, black-eyed peas, soybeans, tufa and lentils.
f. Vitamin C: include: broccoli, brussels sprouts kale, peppers, guava, papaya.
g. B vitamin: broccoli, okra, black-eye peas and soybeans.
h. Zink: turkey, veal, chicken, peanut, wheatgerm and chick peas.
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Aspergillus Niger is one of the most important microorganisms in biotechnology. It has been already used to produce extracellular enzymes such as glucose oxidase, pectinase, α-amylase and glucoamylase, organic acids, and recombinant proteins. In addition, A. Niger is used for bio transformations and waste treatment [1-3]. Among the various enzymes produced by the fungus are included proteases. The major extracellular proteolytic activities in A. Niger appear to be due to acid proteases [4]. Acid proteases [E.C.3.4.23] are endopeptidases that depend on aspartic acid residues for their catalytic activity and show maximal activity at low ph. These enzymes offer a variety of applications in the food, beverage industry, and medicine [5]. Keratin is a fibrous protein that occurs in vertebrates and exerts protective and structural functions. It is the major component of feathers, wool, scales, hair, stratum corneum, horns, scalps, and nails [6]. Keratin is insoluble and presents high mechanic resistance, as well as recalcitrance to common proteolytic enzymes like pepsin, trypsin, and papain [7]. This resistance is because of the tight folding of protein chain in α-helix (α-keratin) and β-sheets (β-keratin) in a super-coiled polypeptide chain, kept by strong association by disulfide bonds [8,9]. Keratinases [EC 3.4.21/24/99.11] are specific proteases that display the capability of keratin degradation. These enzymes are gaining importance in the last years, with many applications associated with hydrolysis of keratinous substrates, mainly byproducts of agroindustry processes [10]. Generally, keratinases have optimum pH from neutral to alkaline [11]. The utilization of agroindustry wastes may represent an added value to the industry and meets the increasing awareness for energy conserving and recycling [12]. This fact stimulates the investigation for alternatives to convert keratinous waste into valuable products [10]. One example is the poultry industry that generates huge number of byproducts, which may represent a potential environmental hazard if they are incorrectly destined or processed. The processing and/ or treatment of slaughterhouse waste have been one of the great concerns of poultry industry, mainly because of the restrictions on environmental questions [13]. In this work, the production of proteolytic enzymes by a new keratinolytic strain of A. Niger was investigated. The enzyme activity was partially characterized, and a culture medium based on keratinous substrate was selected, evaluating the influence of growth substrate concentration and medium pH on the production of proteolytic enzymes (Figure 3).
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Lupine Publishers | Endometriosis Involving Colon and Rectum: A Literature Review and Laparoscopic Management
Lupine Publishers | Journal of Surgery & Case Studies
Introduction: Endometriosis is characterized by the presence of functional endometrial tissue consisting of glands and/ or stroma located outside the uterus [1], although implanted ectopically, this tissue presents histopathological and physiological responses that are similar to the responses of the endometrium [2].
Clinical Features: Endometriosis usually becomes apparent in the reproductive years when the lesions are stimulated by ovarian hormones. Forty percent of the patient's present symptoms in a cyclic manner, which are usually related with menses Pelvic pain, infertility and dyspareunia are the characteristic symptoms of the disease, but the clinical presentation is often non-specific [1].
Diagnosis and Investigations: A precise diagnosis about the presence, location and extent of rectosigmoid endometriosis is required during the preoperative workup because this information is necessary in the discussion with both the colorectal surgeon and the patient. Furthermore, almost all patients with intestinal endometriosis have lesions in multiple pelvic locations and it is difficult to know what symptoms are caused by the intestinal disease versus the pelvic disease.
Treatment: Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. Pain symptoms may persist despite seemingly adequate medical and/ or surgical treatment of the disease. In such circumstances, a multi-disciplinary approach involving a pain clinic and counselling should be considered early in the treatment plan.
Endometriosis is characterized by the presence of functional endometrial tissue consisting of glands and/ or stroma located outside the uterus [1], although implanted ectopically, this tissue presents histopathological and physiological responses that are similar to the responses of the endometrium [2].
Prevalence and Epidemiology
The reported prevalence of endometriosis is 1%-20% in asymptomatic women, 10%-25% in infertile patients and 60%- 70% in women with chronic pelvic pain [1]. Endometriosis is a common benign disease among women of reproductive age and affects the intestinal tract in 15%-37% of all patients with pelvic endometriosis [3]. Multiple births and extended intervals of lactation decrease the risk of being diagnosed with endometriosis, whereas nulliparity, early menarche, frequent menses, and prolonged menses increase the risk [4]. Endometriosis also appears to be associated with a taller, thinner body habitus and lower body mass index [5]. The prevalence appears to be lower in blacks and Asians than in Caucasians [6]. Growth and maintenance of endometriotic implants are dependent upon the presence of ovarian steroids. As a result, endometriosis occurs during the active reproductive period: women aged 25 to 35 years [6]. Other factors that appear to play important roles in determining if a woman will develop the clinical condition include [7]:
a) Reproductive lifestyle, especially a delay in childbearing
b) Poorly understood immunological factors
c) Some environmental factors, probably including exposure to a range of environmental toxins
d) Reproductive tract occlusion, such as an imperforate hymen.
Pathogenesis
Endometriosis is a common disease of unknown etiology. Many theories have been proposed to explain this condition: retrograde menstruation theory, metaplastic, transformation, the migration of cells through the lymphatic system or via hematogenous spread, Iatrogenic during CS. However, other factors, immunological, genetic and familial, could be involved in the pathogenesis of this disease [1].
Sampson's Theory of Retrograde Menstruation
The implantation theory proposes that endometrial tissue passes through the fallopian tubes during menstruation, then attaches and proliferates at ectopic sites in the peritoneal cavity. Recent studies using laparoscopy have demonstrated that retrograde menstruation is a nearly universal phenomenon in women with patent fallopian tubes. Classic studies performed in the 1950s demonstrated viability of sloughed endometrial cells and the capacity to implant at ectopic sites. Patients with mullerian anomalies and obstructed menstrual flow through the vagina may have an increased risk of endometriosis. The anatomic distribution of endometriosis also provides evidence for Sampson's theory [8].
Coelomic Metaplasia Theory
The theory of coelomic metaplasia proposes that endometriosis may develop from metaplasia of cells lining the pelvic peritoneum. Iwanoff and Meyer are recognized as originators of this theory. A prerequisite of the coelomic metaplasia theory is that mesothelial cells lining the ovary and pelvic peritoneum contain cells capable of differentiating into endometrium. An attractive component of the coelomic metaplasia theory is that it can account for the occurrence of endometriosis anywhere mesothelium is found. This includes reports of endometriosis occurring in the pleural cavity. Pleural endometriosis could result from local metaplasia of pleural mesothelium. On the other hand, it could also result from transdiaphragmatic passage of peritoneal fragments of endometrium as well as vascular metastasis of endometrium. Coelomic metaplasia is thought to account for the rare occurrences of endometriosis reported in males. In these reports of endometriosis, the men were all undergoing estrogen therapy. Although coelomic metaplasia was a possibility, estrogen stimulation of mullerian rests could not be excluded. Likewise, the occurrence of endometrial carcinoma in males is thought to possibly arise from mullerian remnants. Still, further support for the coelomic metaplasia theory may be found in the study of benign and malignant epithelial ovarian tumors. Both are considered to be derivatives of germinal epithelium. The presence of ovarian surface endometriosis could be accounted for by this type of transformation [8].
Induction Theory
The induction theory is an extension of the coelomic metaplasia theory. This theory proposes that menstrual endometrium produces substances that induce peritoneal tissues to form endometriotic lesions [8].
Embryonic Rests Theory
Von Recklinghausen and Russell are credited with the theory that endometriosis results from embryonic cell rests. These embryonic rests, when stimulated, could differentiate into functioning endometrium. As described above, rare cases of endometriosis have been reported in men. Transformation of embryonic rests is a plausible explanation for this phenomenon [8].
Lymphatic and Vascular Metastasis Theories
The lymphatic metastasis theory of endometriosis is often referred to as Hal ban's theory. He reported that endometriosis could arise in the retroperitoneum and in sites not directly opposed to peritoneum. Sampson had also suggested that endometriosis could result from lymphatic and hematogenous dissemination of endometrial cells. An extensive communication of lymphatics has been demonstrated between the uterus, ovaries, tubes, pelvic and vaginal lymph nodes, kidney, and umbilicus. Metastasis of endometrial cells via the lymphatic system to these areas is therefore anatomically possible. These findings are consistent with a literature review showing a 6.7% incidence of lymph node endometriosis in 178 autopsy cases. Lymphatic and vascular metastasis of endometrium has been offered as an explanation for rare cases of endometriosis occurring in locations remote from the peritoneal cavity. In addition to pleural tissue, endometriosis has been reported in pulmonary parenchyma. Vascular or lymphatic metastasis may also explain cases of endometriosis that have been reported in bone, biceps muscle, peripheral nerves, and the brain [8].
Composite Theory
Javert proposed a composite theory of the histogenesis of endometriosis which combines the implantation, vascular/ lymphatic metastasis, as well as a theory of direct extension of endometrial tissue through the myometrium. Along similar lines, Nisolle and Donnez have recently argued that the histogenesis of endometriosis depends on the location and 'type' of the endometriotic implant. For example, peritoneal endometriosis can be explained by the implantation theory. Ovarian endometriomas could be the result of coelomic metaplasia of invaginated ovarian epithelial inclusions. Rectovaginal endometriosis, which often resembles adenomyosis, could result from metaplasia of Mullerian remnants located in the rectovaginal septum. These composite theories are attractive in that they recognize a multifaceted mechanism of histogenesis. It seems logical that a disease with such variable manifestations may originate via several mechanisms [8].
Altered Immunity
Alterations in immunologic response to retrograde menstruation have been implicated in the genesis and maintenance of the endometriotic lesion. This defective immunosurveillance may lead to decreased clearance of menstrual debris from the peritoneal cavity and may allow for attachment of ectopic endometrium to peritoneal surfaces. An abnormal immune response could also promote the persistence and growth of ectopic endometrial tissue [8].
The "Neurologic Hypothesis"
It is a new concept in the pathogenesis of endometriosis: There is a close histological relationship between endometriotic lesions of the large bowel and the nerves of the large bowel wall. Endometriotic lesions seem to infiltrate the large bowel wall preferentially along the nerves, even at distance from the palpated lesion, while the mucosa is rarely and only focally involved [9].
Pathology and Sites of Involvement
Endometriosis can be divided into intra- and extraperitoneal sites. In decreasing order of frequency, the intra-peritoneal locations are ovaries (30%), uterosacral and large ligaments (18%-24%), fallopian tubes (20%), pelvic peritoneum, pouch of Douglas, and gastrointestinal (GI) tract. Extra-peritoneal locations include cervical portio (0.5%), vagina and rectovaginal septum, round ligament and inguinal hernia sac (0.3%-0.6%), navel (1%), abdominal scars after gynaecological surgery (1.5%) and caesarian section (0.5%). Endometriosis rarely affects extraabdominal organs such as the lungs, urinary system, skin and the central nervous system [1]. Endometriosis affects the intestinal tract in 15% to 37% of patients with pelvic endometriosis [10], involvement have been reported from the small bowel to the anal canal, but more frequently the disease involves the rectum and the sigmoid colon (74%), followed by the rectovaginal septumn (12%), cecum (2%), and appendix (3%) . When the ileum is involved, the most common tract is the distal part. A full-thickness involvement of the colonic wall is infrequent since the mucosa is usually spared. One of the classic locations is the anterior rectal wall in the region of the pouch of Douglas. This can be single nodule or can simulate a cancer. Because of the invasive appearance, the disease can be mistaken for cancer [11].
Gross and Microscopic Pathology of Bowel Endometriosis
The appearance and size of the implants are quite variable. Areas of endometriosis appear as raised flame-like patches, whitish opacifications, yellow-brown discoloration, translucent blebs, or reddish or reddish-blue irregularly shaped islands. The peritoneal surface may be scarred or puckered.
The Microscopic Appearance
Of endometriotic tissue is similar to that of endometrium in the uterine cavity; the two major components of both are endometrial glands and stroma. Unlike endometrium, however, endometriotic implants often contain fibrous tissue, blood, and cysts (Figure 1(a) & 1(b)).
Figure 1(a): Low-power image of the colonic wall, with a few endometrial glands and stroma embedded in the muscular layer.
Figure 1(b): High-power view of the colonic wall, with endometrial glands and stroma embedded in the smooth muscle of the colon [12].
Link to Cancer
Endometriosis is considered a benign disorder; however, it shares some of the characteristics of malignancy, such as abnormal morphology, deregulated cell growth, cellular invasion, and neoangiogenesis. The glandular epithelium occasionally displays DNA aneuploidy. In vitro evidence suggests that endometriosis may have a monoclonal origin. In addition to being monoclonal, endometriotic deposits showed loss of heterozygosity in 28% of lesions. In 2002, Nezhat et al. with immunohistochemistry, found that alterations in bcl-2 and p53 may be associated with the malignant transformation of endometriotic cysts [12]. The development of a malignancy is a relatively common complication of endometriosis. In fact, several publications have reported malignant neoplasms arising from endometriosis. Most of these publications are case reports or refer to a small series of patients presenting either ovarian carcinomas with associated endometriosis or invasive endometrioid adenocarcinomas involving adjacent pelvic structures. Malignant transformation of extraovarian endometriosis, including the intestinal tract, however, has not been reported as frequently. The largest reported series of neoplastic changes in gastrointestinal endometriosis includes 17 cases [10] (Figure 2(a-d)). Some studies suggest that the development of malignancies may occur in up to 5.5 % of female patients with endometriosis. Only 21.3% of the cases arise from extragonadal pelvic sites, and endometriosis-associated intestinal tumors are even rarer. Malignant transformation of primary gastrointestinal endometriosis without pelvic involvement is uncommon, and its real incidence is unknown. It can mimic a primary gastrointestinal neoplasm. Most of these neoplasms are carcinomas, but sarcomas and müllerian adenosarcomas have also been described. Petersen et al, in a large review of the previously published endometrioid adenocarcinomas arising in colorectal endometriosis, report less than 50 cases of neoplastic transformation, 22 of which were adenocarcinomas. The others included sarcomas and mixed müllerian tumors. The progression to invasive cancer has been related with hyperestrogenism, either of endogenous or of exogenous origin. A possible genetic background favoring the onset of cancer has been reported in some patients without hyperestrogenism and with a family history of cancer. The anatomic distribution and frequency of these cancers parallel the occurrence of which benign endometriosis is found at various sites. In order to classify a malignancy as arising from endometriosis, strict histopathologic criteria need to be fulfilled. Sampson first proposed these criteria in the year 1925. He suggested that the following should be fulfilled:
Figure 2(a): Rectal endometriod adenocarcinoma with adjacent focus of endometriosis (hematoxylin-eosin, 20x).
Figure 2(b): Rectal endometriod adenocarcinoma endometriosis (hematoxylin-eosin, 100x).
Figure 2(c): Cytokeratin 20 immunostaining negative (100x).
Figure 2(d): Cytokeratin 7 immunostaining positive (100x). [10]
a) the presence of both malignant and benign endometrial tissue in the same organ.
b) the demonstration of cancer arising in the tissue and not invading it from elsewhere.
c) the finding of tissue resembling endometrial stroma surrounding characteristic glands.
Years later, Scott suggested an additional qualification to complete Sampson's criteria: the demonstration of microscopic benign endometriosis contiguous with the malignant tissue [10]. Endometriosis and its possible malignant changes should be taken into account in the differential diagnosis of intestinal masses in females. Also, clinical suspicion for malignancy should be aroused in patients with abdominal pain or rectal bleeding and a previous history of quiescent endometriosis. Recognition of these lesions is important because of the different management required by primary gastrointestinal neoplasms and by those arising from endometriosis. These differences may have significant clinical implications [10].
Endometriosis usually becomes apparent in the reproductive years when the lesions are stimulated by ovarian hormones. Forty percent of the patient's present symptoms in a cyclic manner, which are usually related with menses Pelvic pain, infertility and dyspareunia are the characteristic symptoms of the disease, but the clinical presentation is often non-specific [1]. Symptoms are initially cyclical but may become permanent when the lesions progress. It is difficult to establish a preoperative diagnosis of GI endometriosis, because GI tract symptoms can mimic a wide spectrum of diseases, including irritable bowel syndrome, infectious diseases, ischemic enteritis/colitis, inflammatory bowel disease and neoplasm. GI endometriosis patients present with relapsing bouts of abdominal pain, abdominal distention, tenesmus [1], constipation and diarrhoea. Rectal bleeding and pain during defecation may also occur. Endometriosis infiltrating the muscularis propria may lead to localized fibrosis in the bowel wall, strictures, and small or large bowel obstruction. The true incidence of endometriosis causing bowel obstruction is unknown, although complete obstruction of the bowel lumen occurs in less than 1% of cases. Endometriosis of the distal ileum is an infrequent cause of intestinal obstruction, ranging from 7% to 23% of all cases with intestinal involvement. The incidence of intestinal resection for bowel obstruction is 0.7% among patients undergone surgical treatment for abdominopelvic endometriosis [1]. Rectal bleeding may be caused by mucosal injury during the passage of stools through a stenosed colon with the intramural endometriotic tissue increased at the time of menses if it occurs. Colonic mucosa heals rapidly, and no signs are detectable at endoscopy [1] (Table 1).
Differential diagnosis [1]
a) irritable bowel syndrome,
b) infectious diseases,
c) ischemic enteritis/colitis,
d) inflammatory bowel disease
e) neoplasm
f) Other causes of intestinal obstruction (Acute/chronic, small/large bowel)
Diagnosis and Investigations
A precise diagnosis about the presence, location and extent of rectosigmoid endometriosis is required during the preoperative workup because this information is necessary in the discussion with both the colorectal surgeon and the patient. Furthermore, almost all patients with intestinal endometriosis have lesions in multiple pelvic locations and it is difficult to know what symptoms are caused by the intestinal disease versus the pelvic disease. In particular, in the case of sigmoid endometriosis, the lesion cannot be suspected at clinical examination, which is why sigmoid endometriosis is often diagnosed only during surgery. Although several radiological techniques have been proposed for the diagnosis of bowel endometriosis, data are inconclusive, and no gold standard is currently available [13].
Although endoscopic diagnosis of colonic endometriosis has been reported, the mucosa is usually normal or shows minimal mucosal abnormalities, friability, extrinsic process or fibroses stenoses [1]. Endoscopic biopsies usually yield insufficient tissue for a definitive pathologic diagnosis as endometriosis involves the deep layers of the bowel wall [14]. Endometriosis can induce mucosal changes without any specific pattern, which mimic findings of other diseases such as inflammatory bowel disease, ischemic colitis or neoplasm [1]. Colonoscopy is helpful to rule out colorectal malignancy [11].
Double Contrast Barium Enema
Radiologically, lesions of endometriosis are either of constricting and polypoid type or both. On barium studies, radiographic findings caused by implants in the ileum are similar to those in the colon. Rectosigmoid or cecal endometriosis on double contrast barium enema studies is seen as an extrinsic mass with speculation and tethering of folds [1]. Shortening or flattening of the bowel wall, crenulation of the mucosa, or a combination of these factors [15], Double-contrast barium enema may be effective in determining the precise location of the endometriotic nodules, but it cannot clearly demonstrate the depth of parietal involvement. Furthermore, the experience of the radiologist in the diagnosis of bowel endometriosis remains a critical limit of this technique [13] (Figures 3 & 4(a & b)).
Figure 3: Thirty-four years old woman with suspected intestinal implants of endometriosis. A and B, Lateral A and oblique B spot images show three endometriotic lesions exhibiting extrinsic mass effect with crenulation of contour and speculation that are direct signs of infiltration of bowel wall (arrows). Small polypoid lesion (arrowhead) is benign tubular adenoma confirmed at surgery [15].
Figure 4(a): Twenty-eight years old woman with suspected intestinal implants of endometriosis and finding of rectal localization of intestinal endometriosis. DCBE image shows extrinsic mass effect and speculation (arrow) of rectal wall that appears infiltrated [15].
Figure 4(b): Twenty-three years old woman with suspected intestinal implants of endometriosis. DCBE examination showing pathologic pelvic process involving bowel serosa at rectosigmoid junction. Finding of extrinsic mass effect and speculation (arrows) owing to poor wall distention after air insufflation suggesting wall infiltration [15].
Transvaginal Us
Transvaginal ultrasonography can be useful not only in the first-line exploration of the pelvic cavity, but also in diagnosing rectosigmoid endometriosis. However, relevant limitations of transvaginal ultrasonography consist in the impossibility of determining the exact distance of rectal lesions from the anal margin and of evaluating precisely the depth of rectal wall involvement. In addition, locations above the rectosigmoid junction might be beyond the field of view of a transvaginal approach and limited by the presence of air for a transabdominal approach [15]. Transvaginal us combines with rectal water contrast is more accurate than TVS in diagnosing rectal infiltration reaching at least the muscularis propria in women with rectovaginal endometriosis. However, this exam cannot determine whether the infiltration reaches the rectal submucosa. RWC-TVS may be more painful than TVS, therefore it could be used when TVS cannot exclude the presence of rectal infiltration in women with rectovaginal endometriosis [15] (Figure 5).
Figure 5: A large rectovaginal nodule infiltrating the bowel muscularis (indicated by the asterisk) demonstrated by Rectal Water Contrast- Transvaginal Sonography (RWC-TVS) [16].
CT & MSCT
CT is not the primary imaging modality for evaluation of bowel endometriosis, although it can occasionally demonstrate a stenosing rectosigmoid mass. Multislice CT (MSCT) has a great potential for detecting alterations in the intestinal wall, especially if it is combined with enteroclysis (MSCTe). Biscaldi et al carried out a study on 98 women with symptoms suggestive of colorectal endometriosis and MSCTe identified 94.8% of bowel endometriotic nodules [1]. Biscaldi et al reported the usefulness of multislice CT combined with distention of the colon by rectal enteroclysis for bowel endometriosis. The sensitivity was 98.7% and specificity was 100% in identifying women with intestinal endometriosis. This method is thought to be very helpful for diagnosing intestinal endometriosis, but requires bowel preparation, such as the need for a low-residue diet for 3 d, drinking of 4-6 doses of a granular powder dissolved in 500 mL of water per dose and intravenous administration of iodinated contrast medium. This technique is thus inappropriate for patients with obstructive symptoms or allergy to iodinated contrast medium [3] (Figures 6 & 7).
Figure 6: Endometriotic nodule infiltration the muscular layer, A: Axial MSCTe image of the abdomen, the arrow indicates the endometriotic nodule. The lesion is enhanced, and it infiltrates the bowel wall involving the muscular layer. B: Coronal reconstruction demonstrating the extension of the sigmoid endometriotic nodule (indicated by the arrow) C: Formaldehydefixed resected bowel segment, the endometriotic nodule of the sigmoid colon was previously demonstrated by MSCT [14].
Magnetic resonance imaging (MRI) has a high sensitivity (77%- 93%) in the diagnosis of bowel endometriosis. The depth of rectal wall infiltration by endometriosis is poorly defined by MRI. A combination of MRI and rectal endoscopic ultrasonography (EUS) has recently been proposed. When retroperitoneal infiltration is present, it is mandatory to know if the bowel wall is involved in order to identify patients requiring bowel resection. Both rectal EUS sensitivity and negative predictive value range from 92% to 100%. The specificity and positive predictive value are rather poor, which are 66% and 64%, 83% and 94%, respectively, as reported in two different studies [1]. Imaging examination is thus essential for the preoperative diagnosis of intestinal endometriosis, but some reports have described preoperative confusion between this disease and cancer according to colonoscopy and CT with barium enema, particularly in patients with lesions involving the mucosal surface. In such patients, MRI is helpful for differential diagnosis. In a typical endometrial lesion, MRI showed signal hyperintensity on T1-weighted imaging and signal hypointensity on T2-weighted imaging. However, smooth muscle components are reportedly recognized frequently in endometrial lesions. In such lesions, as seen in the present case, MRI indicates signal hypointensity on both T1- and T2-weighted imaging, and differential diagnosis from other diseases such as cancer and gastrointestinal stromal tumor is thus difficult. In fact, Chapron et al reported that MRI specificity for deeply infiltrating endometriosis was 97.9%, but sensitivity was only 76.5% [3] (Figures 8 & 9).
Figure 8: T2- weighted axial view: fecal matter attached to the rectal wall, simulating thickening of the rectal wall [17].
Figure 9: T2- weighted sagittal (a) and axial (b) views.
Nodule of the rectosigmoid junction adhering to the posterior surface of the uterus [17].
Transrectal EUS
The involvement of the colon is difficult to detect because the implants rarely invade through the intestinal mucosa. For this reason, the rectal ultrasound is of primary importance to assess the rectal involvement [11]. Also, the depth of rectal wall infiltration by endometriosis is poorly defined by MRI. A combination of MRI and rectal endoscopic ultrasonography (EUS) has recently been proposed. When retroperitoneal infiltration is present, it is mandatory to know if the bowel wall is involved in order to identify patients requiring bowel resection [1]. Endoscopic ultrasonography is also a useful and noninvasive examination for the diagnosis of intestinal endometriosis. Sensitivity and specificity are reportedly about 97% for the diagnosis of rectal involvement in patients with known pelvic endometriosis. In addition, EUS-FNAB provides accurate tissue and may be the only procedure for correct preoperative diagnosis of intestinal endometriosis, but the overall specificity, sensitivity and accuracy of EUS-FNA for neoplasms of the gastrointestinal tract are reportedly 88%, 89% and 89%, respectively [3]. Among these examinations, it is considered that MRI and EUS (and/or EUS-FNAB) are the most useful examinations for intestinal endometriosis. However, it is important to perform valuable examinations for diagnosis of intestinal endometriosis, including radiological, histological and etiological examinations, as the condition basically involves a benign lesion requiring minimally invasive treatment [3] (Figure 10).
Figure 10: Rectal endoscopic ultrasonography showing a uterosacral endometriosis nodule (2 cm x 3 cm) with bowel infiltration.
P = probe, M = mucosa, SM = submucosa, MP = muscularis propria [18].
7- Serum Markers
There is a great interest in the use of serum markers to diagnose endometriosis, but they are not sufficiently accurate for use in clinical practice. Cancer antigen CA-125 has been used to monitor the progress of endometriosis [16]. CA19-9 has a lower sensitivity than CA-125, and cytokine interleukin-6 may be more sensitive and specific than CA-125 [1]. Mol et al reported a systematic review of the diagnosis of endometriosis and concluded that serum CA125 level may be elevated in endometriosis, but this measurement had no value as a diagnostic tool compared to laparoscopy [3].
Laparoscopy is a primary diagnostic and therapeutic tool providing the opportunity to explore the abdominal cavity and obtain biopsies. The magnified vision enables the surgeon to operate with the best possible exposure. Although it was once believed that intestinal endometriosis was best managed by hormonal regimens or surgical castration, the advent of laparoscopic surgery has dramatically changed this approach [11] (Table 2).
Despite being a gynecologic pathology, deep infiltrating endometriosis is not of exclusive gynecologic concern. A multidisciplinary approach involving urologists and colorectal surgeons therefore is recommended strongly for complete evaluation and correct management. A minimally invasive approach offers convenient advantages concerning the surgical management of multifocal deep infiltrating endometriosis. Traditionally, radical surgery [17] was considered the best measure to prevent disease relapse. However, because of the prevalence of endometriosis among women of reproductive age and the advances in surgical techniques, minimally invasive conservative surgery now is encouraged more [18]. Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multidisciplinary approach involving a pain clinic and counselling should be considered early in the treatment plan. It is also important to involve the woman in all decisions; to be flexible in diagnostic and therapeutic thinking; to maintain a good relationship with the woman, and to seek advice where appropriate from more experienced colleagues or refer the woman to a centre with the necessary expertise to offer all available treatments in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy [19]. The objective of the treatment in pelvic endometriosis is to cease the endometrial stimulus in order to ameliorate the symptoms. Thus, danozol, gonadotropin- releasing hormones, oral contraceptives, and prostaglandin inhibitors can be used. The conclusive treatment of endometriosis is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all endometrial foci. Because malignant transformation cannot be excluded preoperatively and medical treatment may cause fibrosis, the definitive treatment is surgical. Also, in the case of intestinal obstruction and severe rectal and abdominal pain, surgery is indicated. The main objective of surgery is the resection of the affected bowel segment, enabling the histopathological examination of the resection material. Limited surgery, such as excision or cauterization of superficial lesions, following confirmation through frozen section analysis could be performed. In conclusion, intestinal endometriosis is a disease that may imitate various gastrointestinal system diseases. The definite diagnosis could only be done by histopathologic confirmation, since there are no pathognomonic radiological or colonoscopic findings. In female patients who have unexplained digestive complaints, endometriosis should also be considered in the differential diagnosis [20].
The Treatment of Uncomplicated Intestinal
It depends on the patient's age and intention to conceive. Bowel resection is indicated if there are symptoms of obstruction or bleeding, and if malignancy cannot be excluded. In patients of childbearing age, resection of the involved colon followed by hormonal treatment may be sufficient; otherwise, hysterectomy and bilateral oophorectomy is the treatment of choice [21]. Medical suppressive therapy may be beneficial in some patients with symptomatic rectovaginal endometriosis, but often it is either ineffective or only temporarily effective, whereas surgical therapy is effective in relieving pain conditions. Other studies have shown that operative therapy of rectovaginal endometriosis does not modify reproductive prognosis but significantly reduces pain and improves quality of life. The best long-term results are obtained after complete excision of the endometriotic tissue [22]. The surgeon's judgment on bowel involvement with the consequence of bowel resection is of the utmost importance [22]. Redwing has suggested a severity scoring system for intestinal endometriosis based on the form of surgical management required: grade I, superficial seromuscular; grade II, partial thickness to mucosa; grade III, full thickness; grade IV, segmental. The surgical approaches to intestinal disease include simple excision (with cautery or laser), mucosal skinning, full thickness disc excision with primary closure, and formal bowel resection [23]. Full thickness disc resection of bowel endometriotic lesion is often incomplete, at least one-third of patients with bowel endometriosis treated by full thickness disc resection have persistent disease. The surgeons must always weigh the risk of potential complications of surgery against the benefit of the complete removal of bowel endometriotic lesions. To date, no clear guideline exists for the pre-operative assessment of patients with suspected endometriosis; therefore, bowel resections should only be performed after a careful pre-operative evaluation of patients' symptoms and a radiological examination of the bowel [23]. Bowel resection can be performed according to previously published criteria (Remorgida et al.): single lesion >3 cm in diameter, single lesion infiltrating >50% of the bowel wall, three or more lesions infiltrating the muscular layer [15].
Operative Technique
The collaboration of a laparoscopically skilled gynaecologist and colorectal surgeon has been recognised as ideal in the surgical management of colorectal endometriosis. Patients undergo bowel preparation 24 h prior to surgery with a Fleet® ACCU-PREP® Bowel Cleansing System (C.B. Fleet Co., Braeside, Vic., Australia) [24]. Prophylactic anticoagulant therapy was given the evening before the operation, and prophylactic antibiotic therapy was given at the beginning of the operation [25]. Surgery is performed with the patient in the lithotomy position. Five ports are used with placement as shown in Figure 11. Five-millimetre 0° and 5-mm 30° endoscopes are used and most dissection is undertaken using the harmonic scalpel (Ethicon Endo-Surgery, Inc., Cincinnati, OH, USA). Pneumoperitoneum is maintained at 12-14 mmHg with a flow rate of 40 L/min. For an anterior segmental bowel resection, the descending colon is mobilised up to the level of the splenic flexure. The ureter is identified crossing the pelvic brim on the left, and mobilisation continued inferiorly to open the para-rectal space medial to the uterosacral ligament. The right mesocolon is then opened and dissection extended down to the right pararectal space medial to the uterosacral ligament. The right ureter is identified during this dissection. The sigmoid colon is then elevated with bowel grasping forceps, and the space posterior to the sigmoid mesocolon is opened. During this dissection the inferior mesenteric vessels are identified and divided using an endoscopic linear cutter 45 mm (ATW45 Ethicon Endo-Surgery, Inc.) once the requirement for a bowel resection is established. Further elevation of the sigmoid colon allows the posterior dissection to continue inferiorly to the presacral plane, allowing mobilization of the rectum. Having mobilized the rectosigmoid laterally and posteriorly, the rectum is then dissected free from the posterior cervix. This is the most difficult part of the dissection and an attempt is made to free disease from the posterior cervix and posterior vaginal wall as completely as possible. If there is coexisting invasive uterosacral disease, this is excised end bloc with the affected rectal segment. The inferior dissection is complete when the normal tissue in the rectovaginal septum is encountered. Once the level of rectal transection is identified, the mesorectum is divided at that point leaving the rectal tube. An endoscopic articulating linear cutter 45 mm (ATG45 Ethicon Endo-Surgery, Inc.) is introduced and applied transversely across unaffected distal rectum. The stapler is fired to separate the affected rectal segment from the distal rectal stump. Two firings may be required. The lower right 12 mm port site is then converted to a minilaparotomy incision, approximately 3-4 cm in length. The affected rectal segment is then delivered through this wound, clamped and divided above the level of disease. The anvil from an endoscopic curved intraluminal stapler 29 mm (ECS29 Ethicon Endo-Surgery, Inc.) is secured into the proximal colon with a purse-string suture. The proximal segment is then returned to the abdominal cavity and the mini laparotomy wound closed. Pneumoperitoneum is reestablished. The ECS29 is passed transanally, and the distal rectal stump is elevated. The circular stapling device is opened, passing a metal spike through the distal rectal stump adjacent to the staple line. The anvil within the proximal segment is then docked to the spike and the circular stapling device closed. The circular stapling device is then fired to complete the anastomosis. After removing the transanal stapler, an integrity check is performed by distending the rectum with Betadine after occluding the sigmoid colon at the pelvic brim. Further check of integrity is undertaken by instilling air into the rectum after flooding the pelvis with saline. A 17-gauge drain is left in the operative site, after which all ports are removed [24]. Terminal-to-terminal anastomoses were classified according to distance from the anus as high/medium (>8 cm), low (5-8 cm) or ultralow (<5 cm). The choice to perform primary ileostomy or colostomy was based on intraoperative findings [26]. For a disc excision, a lesser degree of descending colon mobilization is required, less posterior rectosigmoid dissection may be required and there is no requirement to divide the inferior mesenteric vessels. The principles of pelvic dissection are otherwise as described. Once the rectal disease has been identified and isolated, a figure of eight suture is placed through the lesion. An ECS33 stapling device is passed transanally with the anvil intact. The device is then opened and angled towards the rectosigmoid lesion. The suture is grasped with laparoscopic forceps, and the disease drawn down into the open stapler. The stapling device is then closed, rotated slightly to ensure that the posterior rectal wall has not become entrapped, and then fired. An anterior arc of rectal wall containing the lesion is therefore removed and the rectal wall stapled in a single action. Rectosigmoid integrity checks are then undertaken as described above [24]. The extent of the lesions as well as the severity of the symptoms justifies the extensive nature of the surgery undertaken. The findings of additional areas of the bowel that are macroscopically normal but microscopically involved, as well as involvement of the lymph nodes, suggest to us that simple local excision of a disc may on occasions be inadequate to remove the whole of the involved area of the bowel [12]. There are no data to justify hormonal treatment prior to surgery to improve the success of surgery [19]. However, according to ESHRE guidelines Postoperative treatment for endometriosis in general might include danazol or a GnRH agonist for 6 months after surgery as it reduces endometriosis associated pain and delays recurrence at 12 and 24 months compared with placebo and expectant management. However, postoperative treatment with a COC is not effective [19].
Figure 11: Placement of five port sites used in Surgery.
The risk of complications depends on the clinical conditions, such as the level of bowel stenosis, opening of the vaginal wall, the extent of endometriosis infiltration, and the surgeon's experience. Moreover, the possibility of performing this kind of surgery (complete eradication with colorectal surgery) in a referral center reduces the risk of complications and improves clinical outcomes. Indeed, women who undergo intestinal surgery are at higher risk of complications mainly in the short-term, but close surveillance reduces the risk of need for reintervention and allows a good recovery within a few weeks [27]. Complications include:
a) Internal hemorrhage
b) Bowel fistula
c) Vaginal fistula
d) Retention of urine
e) Constipation
f) Abdominal wall hematoma
g) Ureteral injury and stenosis
h) Bladder perforation
i) Uterine perforation
j) Cystitis
k) Adynamic ileus
l) Mechanical bowel obstruction
m) Peritonitis
n) Peritoneal effusion
Outcome after Surgery
The indications of colorectal resection for endometriosis are controversial, and the likely risk/benefit ratio must be discussed with each patient. No menstrual pelvic pain, pain on bowel movement, cramping, and cyclic rectal bleeding improved or disappeared in all the women concerned, in keeping with previous studies of colorectal resection for endometriosis. dysmenorrhea, dyspareunia, pain on defecation, and no menstrual pelvic pain improved significantly, on the basis of visual analog scores, whereas no impact was noted on pain on bowel movement, lower back pain, or asthenia. Recent results confirm those of Redwing and Wright, showing that women with dysmenorrhea, dyspareunia, pain on defecation, or no menstrual pelvic pain associated with complete endometriotic obliteration of the sac of Douglas are the best candidates for extensive resection [28]. Bowel resection is not completely free of recurrence of endometriosis, but the incidence of recurrence is significantly lower [29]. In conclusion, laparoscopic rectosigmoid resection and end-to-end anastomosis seem safe and effective in women with deep infiltrating colorectal endometriosis, where the bowel lumen is largely restricted, and bowel function is greatly impaired. Results of long-term follow up demonstrate significant reductions in painful and dysfunctional symptoms associated with deep bowel involvement [30]. Laparoscopic segmental colorectal resection for endometriosis is associated with a significant improvement in quality of life and gynecological and digestive symptoms [25].
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