Abbreviations used throughout text.
\r\n\tTSC involves mutations in chromosomes 9 and 16 encoding for the proteins hamartin and tuberin, respectively. Mutations in these genes cause upregulation of the mTOR pathway and inhibitors of this pathway, such as rapamycin and everolimus, have been shown to be effective in controlling the growth of unresectable tumors. Due to involvement of multiple organ systems, a multidisciplinary treatment plan is necessary and genetic counseling is often part of the management of TSC. Treatment options are quite variable and depended upon symptoms and organ involvement.
\r\n\r\n\tThe aim of this book is to provide the reader with an overview of the tuberous sclerosis complex including its genetic causes, clinical manifestations, and management of its most serious signs and symptoms.
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There are distinct forms of mechanical forces, such as centrifuge force, gravitational force, electromagnetic force, hydrostatic force and acoustic force. Acoustic forces comprise a modality of mechanical load that can be represented basically by three different types of acoustic waves: ultrasound wave, shock wave and radial pressure wave. Those waves may be applied to patients suffering from orthopaedics disorders, especially those related to osteogenesis; for instance, delayed union, nonunion, osteoporosis and acute fractures.
\nThe application of mechanical devices for medical purposes is termed mechanotherapy. Accordingly, the use of acoustic devices, which is a category of mechanical devices, for medical purposes will be termed here acoustic therapy and will be further divided into three subcategories: low-intensity pulsed ultrasound stimulation (LIPUS), extracorporeal shock wave therapy (ESWT) and radial pressure wave therapy (RPWT). This chapter discusses the physical phenomena, biological events and clinical indications of acoustic therapy on bone tissue (Table 1).
\nAbbreviations | \nMeanings | \nAbbreviations | \nMeanings | \n
---|---|---|---|
ActR | \nactivin receptor | \nMCP | \nmonocyte chemoattractant protein | \n
ALP | \nalkaline phosphatase | \nMIP | \nmacrophage-inflammatory protein | \n
AT1 | \nangiotensin II type 1 receptor | \nMsx | \nMsh homeobox | \n
ATP | \nadenosine triphosphate | \nmTOR | \nmechanistic target of rapamycin | \n
Bax | \nBcl-2-associated X protein | \nNADPH | \nnicotinamide adenine dinucleotide phosphate | \n
BMP | \nbone morphogenetic protein | \nNO | \nnitric oxide | \n
BMPR | \nbone morphogenetic protein receptor | \nNOS | \nnitric oxide synthase | \n
Ca2+ | \ncalcium ion | \nOPG | \nosteoprotegerin | \n
cbfa | \ncore binding factor subunit alpha-1, also known as Runx2 | \nPGE2 | \nprostaglandin E2 | \n
CDK | \ncyclin-dependent kinase | \nPPARγ2 | \nperoxisome proliferator-activated receptor γ2 | \n
c-fos | \nFBJ murine osteosarcoma viral oncogene homolog | \nPTHr | \nparathyroid hormone receptor | \n
c-jun | \nJun proto-oncogene | \nRac | \nRas-related C3 botulinum toxin substrate | \n
c-myc | \navian myelocytomatosis viral oncogene homolog | \nRANK | \nreceptor activator of nuclear factor kappa B | \n
cox | \ncyclooxygenase | \nRANKL | \nreceptor activator of nuclear factor kappa B ligand | \n
CXCR | \nC-X-C chemokine receptor | \nRANTES | \nregulated upon activation, normal T-cell-expressed and secreted | \n
Dlx | \ndistal-less homeobox | \nRas | \nportmanteau of “rat” and “sarcoma” | \n
egr | \nearly growth response | \nrhBMP-2 | \nrecombinant human BMP-2 | \n
ERK | \nextracellular signal-regulated kinase | \nRPWT | \nradial pressure wave therapy | \n
ESWT | \nextracorporeal shock wave therapy | \nRunx | \nrunt-related transcription factor | \n
FAK | \nfocal adhesion kinase | \nSDF | \nstromal cell-derived factor | \n
FGF | \nfibroblast growth factor | \nSmad | \nportmanteau of “small body size” and “decapentaplegic” | \n
HIF | \nhypoxia-inducible factor | \nSOST | \nsclerostin gene | \n
IGF | \ninsulin-like growth factor | \nTCF/LEF | \nT-cell factor/Lymphoid enhancer binding factor | \n
IL-8 | \ninterleukin-8 | \nTGF | \ntransforming growth factor | \n
ILK | \nintegrin-linked kinase | \nTSC | \ntransforming growth factor-beta-stimulated clone | \n
IRS | \ninsulin receptor substrate | \nTyr | \ntyrosine residue | \n
LIPUS | \nlow-intensity pulsed ultrasound stimulation | \nVEGF | \nvascular endothelial growth factor | \n
LRP | \nlow-density lipoprotein receptor-related protein | \nWnt | \nwingless-related integration site | \n
MAPK | \nmitogen-activated protein kinase | \n\n | \n |
Abbreviations used throughout text.
Bone modelling refers to changes in bone structure and density in response to increased loads. Bone remodelling is defined as, the almost obligatory, bone resorption that follows bone formation irrespective of mechanical loads. The first to describe that bone deposition occurs preferably on sites of compressive loads, whereas bone resorption occurs preferably on sites of tensile loads was Julius Wolff, whose observations were the foundation of Wolff’s law (1892) [1].
\nLater, Frost realized that different ranges of intensities (magnitudes) of bone deformation elicited different biological responses. Based on that, he published the mechanostat model (1964), in which low-frequency cyclic (less than 5–10 Hz), or static, loads lower than 50–100 μstrain (desuse range) lead to bone resorption, loads from 50–100 to 1000–1500 μstrain (physiological range) do not change bone mass, loads from 1000–1500 to 3000 μstrain (overuse range) induce osteogenesis and loads greater than 3000 μstrain (pathological overuse range) may lead to fracture or stress fracture. Strain stands for relative deformation of a cell or tissue. It should be noted that the ranges of intensities proposed by Frost refer to bone tissue, not to bone cells, which normally need higher strains to elicit an osteogenic response [1–3]. For detailed information, see reference [3].
\nBased on Wolff’s law and mechanostat model concepts, mechanical devices were developed to purposely stimulate osteogenesis. LIPUS and ESWT are applied by acoustic devices approved in many countries for clinical use in the management of bone healing disorders. On the other hand, currently, RPWT lacks evidence for its use to induce osteogenesis, but it is used to address soft tissue orthopaedic disorders.
\nLow-intensity pulsed ultrasound was developed by Duarte, and its use for accelerating fracture healing was published in 1983. Most commonly used device generates 1.5 MHz ultrasound in a pulse wave mode (duty cycle of 20%, 200 μs burst width with repetitive frequency of 1 KHz) and average intensity 30 mW/cm2. Low-intensity ultrasound waves are produced from a piezoelectric crystal within an unfocused, circular transducer. Its effective radiating area is 3.88 cm2, peak rarefactional pressure at specimen (nonderated) is 0.076 MPa and focal length is ∼130 mm [4–6].
\nESWT originally was developed for lithotripsy in order to break up and disrupt stones within genitourinary tract. Its use for osteogenesis initiated after the observation that shock waves provoked osteogenic response on the pelvis of animals during lithotripsy experiments [7].
\nThere are three main techniques for generation of shock waves. Irrespective of the technique, production of shock waves requires the conversion of electrical energy into acoustic energy. All three devices (electrohydraulic, electromagnetic and piezoelectric) are used in orthopaedics, and there is no evidence that a certain device provides better results than the other [7–10].
\nThis is the first generation of orthopaedic shock wave devices. A high-voltage electrical discharge is applied across electrode tips—a spark gap—within a water-filled semi-ellipsoid reflector. The resultant spark heats and vaporizes the surrounding water, which, in turn, generates a gas bubble filled with water vapour that expands and produces a shock wave. The wave is reflected by the metallic surface of the semi-ellipsoid and is focused into the therapeutic zone [7, 9, 11].
\nElectrohydraulic shock wave devices usually are characterized by relatively large axial diameters of the focal volume and high total energy within that volume. The spark gap wears out after about 50,000 shots (impulses) and needs to be replaced [7, 11].
\nTechnical specifications vary according to manufacturer (not all manufacturers provide complete data): energy flux density varies from 0.01 to 1.80 mJ/mm2, focal zones vary from 0 to 95 mm (fx[-6dB]) and from 4.8 to 25 mm (fz[-6dB]), frequency varies from 0.5 to 360 Hz, and penetration depth is up to 84 mm [12–15].
\nWithin this device, there is an electromagnetic coil and a metal membrane besides the coil both embedded in a water medium. A high current pulse is released through the coil, generating a strong magnetic field, which repels the membrane rapidly away from the coil, therefore pushing the surrounding water to produce a shock wave. The shock wave is focused with an acoustic lens to the therapeutic zone. The lens can be used for several hundred thousand impulses with no need to replace the elements [7, 9, 11].
\nA variation of the electromagnetic device uses a repelling membrane formed as a cylinder and the sound waves are reflected by a surrounding parabolic reflector [11].
\nTechnical specifications vary according to the manufacturer (not all manufacturers provide complete data): energy density flux varies from 0.01 to 0.55 mJ/mm2, frequency varies from 1 to 8 Hz shock waves, penetration depth is up to 80 mm and focal zone varies from 0 to 65 mm [16, 17].
\nWithin this device, a few hundred to some thousand piezoelectric crystals—usually more than a thousand—are arranged in a spherical surface filled with water. A high pulse discharge is applied to the crystals, which immediately contract and expand (piezoelectric effect) generating a shock wave in the surrounding fluid. The emitted energy of each crystal is fairly weak, but reaches higher energy at the focus where all shock waves gather together. The focal zone is relatively small and cigar shaped. Because of the spherical shape of the device’s surface, this device has an extremely precise focus and a high energy density within a well-confined focal volume. In addition, the large aperture of the source allows for almost pain-free treatment because of the low-pressure at the skin entry zone [7, 9, 11].
\nTechnical specifications vary according to the manufacturer (not all manufacturers provide complete data): energy flux density ranges from 0.03 to 0.4 mJ/mm2, frequency ranges from 1 to 8 Hz, pressure ranges from 11.5 to 82.2 MPa, focal size ranges from 1.2 to 4.8 mm (fx[-6dB] = fy[-6dB]) and from 1.2 to 14.1 mm (fz[-6dB]) and penetration depth ranges from 5 to 40 mm [18–20].
\nRadial pressure waves are produced pneumatically (ballistically). A projectile is accelerated with compressed air, or an electromagnetic field, within a guiding tube (cylindrical piston) and strikes a metal applicator placed on the patient’s skin. The projectile produces stress waves in the applicator that transforms their kinetic energy into a radially expanding pressure—or pulse—wave towards tissue [21, 22].
\nTechnical specifications vary according to model and manufacturer (not all manufacturers provide complete data): energy density flux is up to 0.55 mJ/mm2, frequency ranges from 1 to 22 Hz, pressure ranges from 1.0 to 5.0 bar and penetration depth is up to 60 mm [23–26].
\nLow-intensity pulsed ultrasound, shock waves and radial pressure waves are different forms of acoustic waves. Their distinct physical parameters are expected to produce different physical phenomena when transmitted into biological tissues.
\nSound is the vibration (rapid motion) of molecules within a compressible medium such as air or water. It can only propagate in compressible media. When sound waves (acoustic waves) reach molecules, molecules may get closer—compression—or farther—rarefaction. By alternating compression and rarefaction, sound travels in waves transporting energy from one location (transmitter) to another (receiver). Because sound waves produce mechanical motion of molecules, they are mechanical waves. When the frequency of a sound wave is above the typical human audible range (greater than 20 kHz), this sound wave is called ultrasound. Ultrasound is an acoustic radiation that can be transmitted as high-frequency pressure waves (1–12 MHz) [4, 6, 7, 27, 28].
\nSpatial average temporal average (ISATA) lower than 150 mW/cm2 is generally regarded as the intensity spectrum of LIPUS. ISATA refers to the spatial average intensity over both the on time and the off time of the pulse. Nevertheless, there is no clear-cut upper intensity boundary to define an ultrasound wave as low-intensity ultrasound. LIPUS studies have been conducted with intensity level between 5 and 1000 mW/cm2, with frequency between 45 kHz and 3 MHz, in continuous or burst mode and with daily exposure times between 1 and 20 min. In spite of that, most used parameters for LIPUS are as originally described by its creator: intensity of 30 mW/cm2, frequency of 1.5 MHz, pulse (burst mode) of 1 KHz with duty cycle of 20% and daily exposure times of 20 min [4, 29, 30].
\nThey are also acoustic pressure waves, or sonic pulses. In general, a shock wave can be described as a single pulse with a wide frequency range up to 20 MHz (typically in the range from 16 Hz to 20 MHz), high positive pressure amplitude up to 120 MPa (often 50–80 MPa), low tensile wave up to 10 MPa with short duration (about 1 μs), small pulse width at -6dB, short life cycle of approximately 10 μs and a short rise time of the positive pressure amplitude (lower than 10 ns). The reader may find studies with measured rise times of shock wave devices in the range of 30 ns as a result of the limited time resolution of piezoelectric hydrophones. However, optical hydrophones, which are more sensitive measure devices, displayed measure rise times below 10 ns for electrohydraulic devices [7, 9, 22].
\nThe energy density (maximum amount of acoustical energy transmitted through an area per pulse) of ESWT is up to 1.5 mJ/mm2 and the pulse energy (sum of all energy densities across the beam profile multiplied by the area of the beam profile) is up to 100 mJ. Arbitrarily, energy levels up to 0.08–0.12 mJ/mm2 in the focal zone are defined as low-energy ESWT, energy levels between 0.08 and 0.28 mJ/mm2 are defined as medium-energy ESWT and energy levels greater than 0.28 mJ/mm2 are defined as high-energy ESWT (some authors consider 0.12 mJ/mm2 the cut-off from low- to high-energy ESWT) [7–9, 22, 31, 32].
\nShock waves differ from regular sound waves in that the wave front, where compression takes place, is a region of sudden change in stress and density. Shock waves travel faster than sound, and their speed increases as the amplitude (pressure) is raised. On the other hand, the intensity of a shock wave decreases faster than does of a sound wave. As a consequence, wavelets at high pressure lead to deformation of the wave so that the wave crest assumes a sawtooth appearance, which is different from the sinusoidal appearance of a regular sound wave. Furthermore, shock waves differ from ultrasound waves since the former is uniphasic with high peak pressure (in the order of a hundred MPa), and the latter is biphasic with very low peak pressure (in the order of a hundredth of MPa) [7, 22].
\nConsidering the physical definition of shock waves, radial pressure waves are wrongly termed unfocused shock waves in the literature. The rise time of the positive pressure waves produced by currently available devices are much greater than 10 ns, varying from 600 to 800 ns. Also, the maximum peak positive pressure of a radial pressure wave device varies from 0.1 to 7 Mpa, and the pulse duration varies from 1 to 5 ms. Since the time taken for the radial wave to rise is too long, the curve of the concave surface of the ray is too wide for it to be possible to focus the energy; therefore, radial waves cannot be focused, unlike ESWT. Moreover, the air pressure-accelerated projectile has a speed from 2 to 20 m/s, which is 2 orders of magnitude slower than sound speed in water or tissue. Shock waves are produced when the projectile speed is comparable or higher than sound speed (i.e. supersonic). In addition, the distinction between RPWT as “low-energy therapy” and ESWT as “high-energy therapy” is not correct. Most protocols of RPWT use energy density lower than 0.20 mJ/mm2, but the device can reach up to 0.55 mJ/mm2. Accordingly, ESWT has a wide range of energy density protocols varying from 0.02 mJ/mm2 to more than 0.60 mJ/mm2 [8, 21, 22, 26, 33].
\nWhen an acoustic wave is transmitted into a biological tissue, a portion of the acoustic energy is reflected, another portion is attenuated (lost) and the other portion is refracted and continues propagating. Much from the attenuated portion is absorbed by irreversible conversion of acoustical energy into heat mainly via viscous friction, and less is scattered by inhomogeneities within tissue that redirect some sonic energy to regions outside the original wave-propagation path. If the density of the inhomogeneity is high, multiple scattering may occur. Therefore, acoustic energy may scatter several times until it is completely absorbed by tissue and converted to heat [27, 34, 35].
\nBone has one of the highest attenuation coefficients among biologic tissues. Besides, as frequency increases, penetration decreases and attenuation increases. Therefore, acoustic waves tend to produce heat preferentially in bones and joints. Accordingly, tissue damage and pain may be produced if the intensity of acoustic energy is high enough. For instance, continuous unfocused ultrasound waves in the range of 4000–5000 mW/cm2 at 1 MHz for 5 min increase temperature by 1.8–4.3°C at different areas of bone within 1–3 cm of distance. On the other hand, ultrasound at intensities of 20–50 mW/cm2, which is LIPUS, produces negligible variation of tissue temperature (0.01 ± 0.005°C). Moreover, reports using very high ultrasound intensities (5000–25,000 mW/cm2) showed delayed bone healing and necrosis, whereas ultrasound at intensities of 200–3000 mW/cm2 has been shown to increase callus formation and accelerate fracture healing [4, 27, 35–38].
\nExtracorporeal shock waves and radial pressure waves also increase temperature of tissues either by absorption or by cavitation (see Section 3.3). However, no reports were found about temperature raise within biological tissues subjected to ESWT and RPWT. In spite of that, thermal effects may be responsible for decreased cell viability immediately after ESWT with some energy densities and number of impulses [39–44].
\nWhen near gas or vapour bubbles, a portion of the refracted acoustic wave may generate cavitation bubbles at locations termed “nucleation sites”. Cavitation refers to a range of complex phenomena that involve the creation, oscillation, growth and collapse of bubbles within a liquid or liquid-like medium. Cavitation bubbles have never been confirmed in living tissues; therefore, the following information is based on mathematical simulations and in vitro studies [3, 27, 37].
\nThe occurrence and behaviour of cavitation depend on the acoustic pressure; the existence of microheterogeneities in liquids such as free gas, solid particles or a combination of both; whether the acoustic field is focused or unfocused, or pulsed or continuous; and the nature and state of the material and its boundaries. Cavitation does not occur with ultrasound intensities below 500 mW/cm2. Consequently, LIPUS does not produce the phenomenon of cavitation. On the other hand, the biological effects of ESWT and RPWT are triggered mainly by the phenomenon of cavitation [4, 27, 30, 38, 45].
\nBubbles are gas-filled spheres in a liquid under constant hydrostatic pressure when there are no acoustic waves. In response to a sound field in which the acoustic pressure varies sinusoidally in time with a given frequency, the bubble radius oscillates (expands and contracts) with radial displacement and velocity, which vary sinusoidally in time with the same frequency of the wave. When there is lower level pressure amplitude in synchrony with bubble motion, the immediately surrounding liquid moves in and out creating a small steady flow of fluid called microstreaming. This is called stable cavitation and may occur with low-energy ESWT and some RPWT. Stable cavitation occurs near a solid boundary (e.g. bone) and creates shear stress near the bubble surface that can also mechanically stimulate cells [7, 45].
\nShock waves and radial pressure waves generate cavitation bubbles during the tensile phase of the acoustic wave due to its tensile forces that exceed the dynamic tensile strength of water. During the growth phase of the bubble, a huge amount of energy is delivered to the bubble. Following a number of shock, or radial pressure, wave pulses (sometimes after the first impulse), the bubble collapses (i.e. experiences an extremely rapid contraction), which is called inertial cavitation. As the bubble collapses, four phenomena can be observed [7, 27, 35, 45, 46]:\n
Release of energy in the form of high temperature, which can produce free radicals that may damage cells. However, the production of free radicals has not been confirmed in living tissue.
Secondary shock wave emission into the fluid that produces a direct mechanical effect on tissue.
The bubble may aggregate with surrounding bubbles, may fragment or may repeat the growth/collapse cycle several times.
When bubble collapse is not perfectly symmetric, a liquid jet can form. The liquid jet traverses the bubble and impacts on the surface of tissue perpendicularly at considerable speed.
Additionally, during the positive pressure phase of a second shock, or radial pressure, wave pulse, may also push the liquid of the surrounding medium towards one of the walls of a preformed bubble. That wall goes under deformation and reaches the opposite wall of the same bubble to originate a water jet in the same direction of the propagation of the shock wave. The formation of a water jet usually occurs in the vicinity of boundary areas between materials of differing density, such as bone and cartilage, in the direction of the boundary area. The generated water jet is faster with increasing softness of the interface and more damaging than jets from inertial cavitation. In addition, the presence of a hard biomaterial (e.g. bone and cartilage) causes the bubble to collapse towards it. Besides, as the bubble expands, the interface between the medium and the biomaterial is pushed away from the bubble; however, when the bubble collapses, the interface moves slightly towards the bubble. It should be noted that inertial cavitation bubbles near softer material, such as fat, skin and muscle, tend to collapse by splitting into two or three smaller bubbles without the formation of water jets [7, 21, 38, 46, 47].
\nThis is the proposed mechanism by which LIPUS stimulates living tissues. The authors also believe this is the main mechanism by which ESWT and RPWT stimulate living tissues. Acoustic radiation pressure tends to increase in proportion to intensity, is generally relatively small in magnitude and produces forces and motions at much lower frequencies than those of the incident acoustic wave. While the tensile phase of the shock and radial pressure waves generates cavitations, the positive pressure phase of those waves produces acoustic radiation pressure [9, 35, 37, 45].
\nRadiation pressure is a universal phenomenon in any wave motion involving sound. It is exerted on surface or media interfaces and acts in the direction of propagation of the wave thereby producing direct and indirect mechanical stress. Direct mechanical stress is produced by strain. Following mechanical deformation, bone exhibits electrical activity and cellular activation. It is unclear, however, whether the main responsible for bone electrical activity is piezoelectricity, streaming potentials, or ion channels and ATP receptor activities (see 3.4.1) [4, 28, 34, 45].
\nIndirect mechanical stress is produced by acoustic streaming and modal conversion. When acoustic waves are refracted from water to soft tissues, waves propagate longitudinally (in the same direction of the beam source) due to impedance similarity. Differently, when acoustic waves are refracted to materials with impedance mismatch, such as bones, modal conversion occurs, that is, shear waves (waves at right angles to the direction of the beam source) are produced along with longitudinal waves. Shear waves may produce direct mechanical deformation to tissue, called shear stress [7, 27, 36, 45].
\nAcoustic radiation pressure decreases with the distance of the wave from its source; hence, radiation pressure gradients are formed within the fluid. As a result, fluid flow originates, which is called acoustic streaming. The flow is directed away from the transducer with gradual build up of the axial streaming speed with distance from the transducer and a peak of velocity in the focal region. The fluid flow continues beyond the focal region and returns to the transducer as recirculation vortices. Fluid flow can also build up again in the acoustic beam after a membrane. Acoustic streaming and microstreaming are often used as synonyms in the literature. Although both produce fluid flow which can modulate osteogenesis, they are distinct phenomena. As described above, acoustic streaming results from radiation pressure gradients, whereas microsteaming is generated by stable cavitation bubbles. Furthermore, not only mechanical deformation but also acoustic streaming increases cell membrane permeability and generates streaming potentials. It has not been shown, however, whether acoustic streaming directly affects cell membrane permeability, or triggers cellular reactions that increase membrane permeability [30, 37, 45, 48]. For a detailed explanation of streaming potentials, see reference [3].
\nBone exhibits electrical activity when subjected to mechanical forces. The opposite is also true: bone undergoes deformation when exposed to electric potentials. For instance, ESWT induces transient cell membrane hyperpolarization. There are three possible contributors to electric potentials on bone. First, mechanically induced activity of ion channels and ATP receptors promotes ion transport between the intra and extracellular environments resulting in membrane action potentials; second, piezoelectricity, which is the generation of electricity when asymmetric crystalline materials—as those that form the extracellular matrix of bone—are subjected to strain; and finally, streaming potentials that result from mechanically induced flow of fluid containing high conductivity ions [3, 4, 44, 49].
\nThe various cell types that populate bone—osteoblasts, osteocytes, osteoclasts, periosteal cells (fibroblasts and progenitor cells) and bone marrow cells (include mesenchymal stem cells)—are responsive to mechanical stimulation. Bone is a hard material that can handle up to 2% of strain (i.e. 20,000 μstrain) without failure (fracture). However, based on in vitro studies, bone cells need strains up to 10% in order to direct their response to osteogenesis. In addition, a large amount of energy is lost during wave propagation within bone by means of attenuation and reflection; as such, bone cells may be exposed to low pressure waves. A possible explanation would be that strains are amplified at tissue level, so that cells are exposed to higher strain intensities. At the moment, that hypothesis could not be proved. Nevertheless, the following mathematic-based model supports that explanation [1–3, 41, 43, 44, 50–57].
\nThe model for strain amplification was based on the microanatomy of osteocytes, which are the main mechanosensors of bone. Cytoplasmic processes of osteocytes are separated from their canalicular wall by a pericellular space filled with albumin-rich fluid. Moreover, cytoplasmic processes are anchored to their canalicular wall by transverse fibrils. When mechanically induced fluid flow collides with fibrils, hoop strains are generated on the membrane-cytoskeleton system of cytoplasmic processes. Hoop strains produce forces which are 20–100 times higher than at bone’s surface. The magnitude of hoop strains depends on the relationship between fluid and transverse fibrils within pericellular space, and between cell membrane and cytoskeleton constituents (i.e. actin filaments and fimbrins) [3, 57–61].
\nSeveral structures at cell membrane act as “mechanoreceptors.” Mechanically-induced structural deformation of mechanoreceptors triggers their activation. Sequentially, a cascade of biological reactions initiates and results in osteogenesis. Known mechanoreceptors of bone cells include integrins, ATP receptors, ion channels, growth factors (includes hormones) receptors, low-density lipoprotein receptors, frizzled proteins, G proteins and connexins. Among those mechanoreceptors, only integrins were proved to have a role in mechanosensation of ESWT. Regarding mechanosensation of LIPUS, integrins, ATP receptors, growth factors receptors, low-density lipoprotein receptors and frizzled proteins have established participation. In the following sections, the molecular events triggered by LIPUS and ESWT are described. To date, RPWT effects on bone cells have not been investigated properly. It should be noted that acoustic loading refers only to LIPUS, ESWT or RPWT, and mechanical loading refers to any type of mechanical forces that may, or not, be acoustic loads. Tables 2 and 3 enlist molecular events related to LIPUS and ESWT [1, 10, 50, 55, 62–66].
\nMechanoreceptors convert mechanical deformations into biological reactions, a process called mechanotransduction. Among mechanoreceptors, it is believed that integrins are vital for mechanotransduction. Evidence suggests the activation of all others mechanoreceptors and a multitude of signalling pathways are integrin-dependent. Therefore, osteogenic response of bone cells (adhesion, migration, differentiation and proliferation) depends on integrins. The expression of α2, α5, β1, β3 integrins subunits are increased by mechanical loading. Furthermore, clusters of α5β1 and αvβ3 integrins formed at the deformation site—also known as focal adhesions—attract a number of cytoplasmic proteins and trigger a cascade of reactions [3, 10, 37, 43, 50, 53, 55, 60, 67–71].
\nSignalling pathways | \nLIPUS | \nESWT | \n
---|---|---|
α5β1 and αvβ3 integrins/FAK/Scr/Grb2/Sos/Ras/Raf-1/MEK/ERK/IKKα,β/IκBα/NFκB/cox-2/PGE2 | \nX | \n\n |
α5β1 and αvβ3 integrins/FAK/Scr/Grb2/Sos/Ras/Raf-1/MEK/ERK/IKKα,β/IκBα/NFκB/iNOS/NO | \nX | \n\n |
α5β1 integrin/FAK/Scr/Grb2/Sos/Ras/Raf/MEK/ERK | \n\n | X | \n
α5β1 and αvβ3 integrins/FAK/PI3K/Akt/NFκB/cox-2/PGE2 | \nX | \n\n |
α5β1 integrin/β-catenin | \nX | \nX | \n
AT1/ERK-1,2 | \nX | \n\n |
Ras/Rac1/NADPH/superoxide/ERK/cbfa1 | \n\n | X | \n
Ras/Rac1/NADPH/superoxide/HIF-1α/VEGF | \n\n | X | \n
α5β1 and αvβ3 integrins/FAK/PI3K/Akt/Bcl-2 | \nX | \n\n |
Signalling pathways triggered by acoustic stimulation.
Biological effects | \nLIPUS | \nESWT | \n
---|---|---|
Increased expression of α5 and β1 integrins | \nX | \nX | \n
Increased expression of α2 and β3 integrins | \nX | \n\n |
β1 and β3 integrins clustering | \nX | \n\n |
α5β1-mediated FAK activation | \nX | \nX | \n
αvβ3-mediated FAK activation | \nX | \n\n |
Increased IRS-1 activity | \nX | \n\n |
Increased P2X7receptor activation and activation, and ATP release | \nX | \n\n |
P2Y1 receptor activation | \n\n | \n |
mTOR activation | \nX | \n\n |
Bax expression | \nX | \nX | \n
ILK phosphorylation | \nX | \n\n |
IκBα degradation | \nX | \n\n |
Increased parathyroid hormone receptor-1 expression | \nX | \n\n |
Increased iNOS, NO, cox-2 and PGE2 production | \nX | \nX | \n
Increased HIF-1α and VEGF expression | \nX | \nX | \n
RANKL production | \nX | \n\n |
Increased IGF-1 production | \nX | \n\n |
Increased TGF-β1 production | \n\n | X | \n
Increased cyclin E2/CDK2 activation | \n\n | X | \n
Increased bone sialoprotein expression | \nX | \nX | \n
Increased osterix expression | \nX | \n\n |
Increased osteopontin expression | \nX | \nX | \n
Increased osteocalcin expression | \nX | \nX | \n
Increased ALP activity | \nX | \nX | \n
Increased type I collagen expression | \nX | \nX | \n
Increased bone nodule formation | \nX | \nX | \n
Increased CBFA1 expression (core binding factor alfa-1) | \nX | \nX | \n
Increased SDF-1 (serum and bone) and CXCR4 expression | \nX | \n\n |
Increased c-fos, c-jun, c-myc, TSC-22 (transforming growth factor-beta stimulated clone), SOST, FGF-23, Msx2, Dlx | \nX | \n\n |
Increased BMP-2 | \nX | \nX | \n
Increased BMP-4, BMP-7, BMPR-IA, BMPR-IB, ActR-I, BMPR-II, ActR-IIA, ActR-IIB, Smad1 | \nX | \n\n |
Increased FGF-2 | \n\n | X | \n
Increased egr-1 (early growth response) | \nX | \n\n |
Decreased PPARγ activity | \nX | \n\n |
Increased superoxide production | \n\n | X | \n
Osteoblast differentiation | \nX | \n\n |
Osteoblast proliferation | \nX | \nX | \n
Osteoblast adhesion | \n\n | X | \n
Osteoblast migration | \n\n | X | \n
Bone marrow cells proliferation | \nX | \nX | \n
Bone marrow cells osteogenic differentiation | \n\n | X | \n
Mesenchymal stem cell migration and differentiation | \nX | \n\n |
Biological effects of LIPUS and ESWT.
ATP receptors promote the exchange of calcium from intracellular deposits to extracellular environment, or from extracellular environment to intracellular environment. ATP receptors complex with integrins and G proteins, and some (P2X7 and P2Y1) are activated by mechanical loading. By means that need to be explored, mechanically induced activation of P2X7 and P2Y1 induce osteogenic differentiation—represented by increased expression of cbfa-1, osterix, type I collagen, bone sialoprotein, osteopontin and osteocalcin—and osteoblasts proliferation [3, 64, 72].
\nActivation of Wnt canonical pathways involves the formation of complexes between Wnt1, or Wnt3a, Frizzled proteins and LRP-5/6, which may be integrin dependent. Those complexes prevent cytoplasmic β-catenin degradation, which, in turn, translocates to nucleus, where it activates members of the TCF/LEF family to promote osteogenesis. Acoustic stimulation increases expression of Wnt1, Wnt3a, β-catenin and Frizzled proteins 2/4. It also activates β-catenin in an integrin-dependent manner. Wnt5a, which plays a role in Wnt non-canonical pathway, is responsive to mechanical stimulation, but its responsiveness to acoustic stimulation is yet to be evaluated [3, 10, 73].
\nDifferent growth factors and hormones induce osteogenesis that includes bone cells proliferation, migration and adhesion to stimulation sites, angiogenesis and osteogenic differentiation. Mechanical stimulation possesses the same effect and affects growth factors and hormones signalling. Acoustic stimulation increases the expression of BMP-2/4/7 and related receptors (BMPR-IA, BMPR-IB, ActR-I, BMPR-II, ActR-IIA, ActR-IIB), FGF-2, IGF-1, PTHr-1, TGF-β1 and VEGF. Nevertheless, the exact signaling pathways of those factors are still not fully understood [37, 44, 54, 66, 74–80].
\nBMP-2, BMP-4 and BMP-7 play important roles in osteogenesis following fracture. They stimulate mesenchymal cell proliferation and osteogenic differentiation, induce osteoprogenitor cell migration, modulate osteoclast activity and promote angiogenesis. Their mechanism of action involves Smad-1, which is activated by BMP receptors; then Smad-1 translocates to nucleus where it upregulates transcription of osteogenic factors as cbfa1. Acoustic stimulation activates Smad-1, but it has not been proved whether BMP receptors activity is responsible to Smad-1 acoustically induced activation [66, 75].
\nSimilar to BMPs, TGF-β1 induces cellular proliferation, osteogenic differentiation, mineralization and angiogenesis. Acoustic force-induced TGF-β1 production depends on superoxide production which is possibly promoted by Ras/Rac-1/NADPH oxidase pathway. Superoxide is a free radical that, in contrary to common knowledge, is harmless to bone cells when produced by a certain range of acoustic pressure (that is yet to be determined). Moreover, superoxide promotes ERK activation, which induces osteogenic differentiation through cbfa-1 transcription [79, 81].
\nAngiogenesis is vital for fracture healing. BMPs, TGF-β1 and VEGF induce angiogenesis. Among those factors, VEGF seems to be the most important for angiogenesis. HIF-1α is a transcription factor that regulates VEGF expression and is activated by acoustic stimulation. In addition, superoxide and Ras mediate HIF-1α activation and VEGF expression. However, VEGF expression is not dependent on BMP-2, TGF-β1, IGF-1, cox-2, PGE2 and Ca2+ influx. Interestingly, LIPUS-induced VEGF expression depends on NO production, whereas ESWT-induced VEGF expression does not [81–83].
\nA variety of differentiation markers are modulated by acoustic stimulation, such as cbfa-1, osterix, bone sialoprotein, osteopontin, osteocalcin, type I collagen and ALP. Contrarily, the unique report investigating RPWT effects in osteoblasts showed decreased expression of cbfa-1, osterix, type I collagen, bone sialoprotein and osteocalcin. RPWT is commonly used for orthopaedic pathologies of soft tissues with satisfactory results, but no reports were found for bone-related orthopaedic disorders. Therefore, further investigations are required to determine the biological effects of RPWT on bone [33, 43, 44, 75, 76].
\nRegarding cellular proliferation, there are some transcriptional factors that are affected by acoustic forces, such as c-fos, c-jun, c-myc, egr-1, TSC-22, SOST, FGF-23, Dlx, Msx2 and cyclin E2/CDK2 [37, 39, 43, 55, 68, 69, 84–86].
\nCells must migrate to the healing site so that new bone can be generated. SDF-1 is an important chemotactic factor mostly produced by immature osteoblasts in the endosteal region near stem cells population. SDF-1 normally is released from the fracture site to attract mesenchymal stem cells which will differentiate into osteoblasts. SDF-1 binds to CXCR4, a seven transmembrane G-protein coupled receptor, and triggers a cascade of reactions leading to cellular migration and survival. Reports have shown that acoustic loading increases expression of SDF-1 and CXCR4, thereby resulting in mesenchymal stem cells migration to the fracture site. In spite of that, more investigation is needed to clarify the exact cascade of reactions triggered by SFD-1/CXCR4 [56, 87–89].
\nBone remodelling is an important step of bone healing. This important stage follows bone formation and is governed by osteoclasts—bone cells of the granulocyte/monocyte lineage—that resorb extracellular matrix. In order to attract osteoclast progenitor cells to the healing site, osteoblasts express MCP-1, MIP-1, RANTES and IL-8. Osteoblasts also express, or secrete, RANKL, which induces osteoclasts differentiation through their native RANK; and secrete OPG, a decoy receptor of RANKL, which antagonizes RANKL-mediated osteoclastogenesis. Acoustic loading in the form of LIPUS affects osteoclastogenesis by increasing the expression of MCP-1, MIP-1b, RANKL and OPG in osteoblasts through AT1. Increased RANKL expression is also dependent on integrins activity. Moreover, acoustic forces increase the expression of MIP-2, which may also be involved in osteoclastogenesis. On the other hand, it has been shown that low-energy ESWT decreases OPG and RANKL expression in osteoblasts; RPWT does not change OPG expression, but decreases RANKL; and LIPUS does not change the expression of OPG (contradictory results) and RANTES in osteoblasts. Those data show that acoustic deformation affects osteoclastogenesis; however, the exact influence on osteoclastogenesis needs to be better elucidated [33, 43, 50, 55].
\nThere is another list of proteins whose activation has been shown to be influenced by acoustic waves, but there is poor information about their role in mechanotransduction and osteogenesis:\n
AT1 is classically involved in arterial pressure control. This receptor was identified in bone cells, but its role is yet to be determined. AT1 is required for mechanically induced ERK-1/2 activation [50].
Bax is a key component for apoptosis induced through interactions with pore proteins on the mitochondrial membrane. Bax mechanism of activation is complex and not fully understood, but may be modulated by acoustic deformation in favour of cell survival. Bax activation is also integrin dependent [43, 70].
IRS-1 activity increased in intact and healthy bones of rats subjected to acoustic stimulation. IRS-1 is involved in insulin-mediated and IGF-1-mediated bone formation, but its mechanism of activation following acoustic loading is yet to be determined [90].
p38 is a MAPK that regulates cell proliferation and differentiation. Because conflicting results were found for p38 activation following LIPUS and ESWT, more investigation is required. Some studies report increased activity, while others report unchanged activity [68, 81, 91, 92].
PPARγ2 is expressed in mesenchymal stem cells. Upon acoustic stimulation, PPARγ2 drives those cells to differentiate into osteogenic lineage [68].
As previously described, acoustic loads can be exerted by different types of waves, such as LIPUS, ESWT and RPWT. Changing some physical properties (e.g. magnitude and frequency) and mode of application (e.g. axial distance, incidence angle and number of cycles) of acoustic waves can elicit different cellular responses. No studies explored the subject with RPWT.
\nAccording to mechanostat model, for strains within the overuse range, bone formation increases as a proportion of the load magnitude. Loads within the pathological overuse range stimulate osteogenesis, but also damage tissue until bone breaks (about 15,000–20,000 μstrain). Furthermore, cellular response also increases as a proportion of the number of cycles [3].
\nLIPUS at intensities between 2 and 150 mW/cm2 were compared. Higher intensities produced greater bone formation, faster healing rate, and better torsional stiffness and failure torque. The best results were found for 30 mW/cm2. Average temperature at the soft tissue was 1.74°C higher for 150 mW/cm2 in comparison with 30 mW/cm2. Temperature elevation may affect some enzymes like collagenase I and cause tissue damage, resulting in worse biological response. LIPUS commonly is applied as a daily 20-min treatment; therefore, the number of cycles are not changed [29, 93, 94].
\nOn the contrary, there is no exact protocol for ESWT that determines the best response to stimulation. ESWT at magnitudes ranging from 0.05 to 0.62 mJ/mm2 positively affects osteogenesis. The number of impulses of shock waves corresponds to the number of cycles of ESWT. In studies, number of impulses varies from 250 to more than 4000. Moreover, biological response is different when treatment is performed in vitro, or in vivo with small animals (e.g. rodents), or in vivo with large animals (e.g. goats) and humans. For most in vitro studies, 500 impulses promote the best cellular response; above this threshold, cellular damage surpasses bone formation. On the other hand, the best intensity (mJ/mm2) could not be found, suggesting that, for cells directly exposed to ESWT, the number of cycles affects cellular response more than the intensity of energy density itself. On the other hand, most in vivo studies in animals show that better responses are elicited by higher energy densities up to 0.47 mJ/mm2 in comparative studies, while number of cycles (impulses) was not proved to have the same influence [54, 95–98].
\nNormally, load frequencies within the range of 1–30 Hz at physiological and overuse ranges progressively induce osteogenesis. Higher frequencies (17–90 Hz), in the form of vibration, induce osteogenesis but at a much lower strain range (about 5 μstrain; i.e. strain in the order of 10−5). LIPUS is a low magnitude and high frequency wave, which, based on mathematical and experimental models, produces strains in the order of 10−5 at 1.5 MHz. Because of high frequency, those strains promote the same effects as strains in the order of 10−1 (i.e. 10% = 100,000 μstrain) at 1 Hz on cells, and the estimated intracellular strain on organelles is about 0.5% (i.e. 5000 μstrain). Accordingly, it was shown that LIPUS increased transcriptional factors (c-fos, c-jun and c-myc) as frequency increased, resulting in maximum response at 5 MHz (within a range from 2 to 8 Mhz). Those calculations were obtained for strains at cellular level. For strains at bone level, it is believed that the model for strain amplification (see Section 4.1) may apply firstly, followed by the estimative presented here. No investigations were found about the role of frequency on ESWT and RPWT [3, 99–101].
\nEnergy distribution varies according to the distance from the transducer and the surface (axial distance). For LIPUS, two zones were defined according to axial distance: near field (close to transducer) and far field (about 130 mm away from transducer). There is also a mid-near field, when the surface is about 60 mm away from transducer. Within near field, energy distribution of LIPUS beam is not uniform. As such, there are many peaks of acoustic pressure (maxima and minima) across the beam diameter. As the distance from transducer increases, the number of peaks of acoustic pressure across the beam diameter decreases (less maxima and minima). When surface is at far field, a regular beam is formed [5, 102].
\nAs LIPUS transducer is placed transcutaneously during treatment, superficial and deeper cells are exposed to different acoustic fields. Although LIPUS promotes osteogenesis within near, mid-near and far fields, axial distance affects the biological effects of LIPUS. Mid-near field LIPUS elicited greater callus formation in a fractured-femur rat model; on the other hand, in that same model, femurs subjected to far field LIPUS exhibited higher peak torque and torsional stiffness. Those results indicate that, mid-near field LIPUS is optimal for cellular proliferation, while far field LIPUS stands for osteogenic differentiation (bone mineralization). Reinforcing that, mid-near LIPUS incited more NO production whereas far field LIPUS promoted increased ALP activity and mineralization in preosteoblasts. Moreover, both mid-near and far field LIPUS produced increased β-catenin nuclear translocation [5, 102].
\nDuring ESWT, maximal intensity of energy density is obtained at the focus. Consequently, superficial and deeper cells are exposed to different acoustic fields. However, no studies were found on this subject for ESWT and RPWT.
\nAs previously described, acoustic waves transmitted into bone can be decomposed in longitudinal waves and shear waves. The magnitude of each wave depends on the incidence angle of the acoustic wave. Accordingly, two critical angles were determined. The first critical angle is defined as the angle of incidence after which incident acoustic waves travel along the medium surface and only shear waves are refracted to that medium. In that case, longitudinal waves do not travel into the medium. The second critical angle is defined as the angle at which acoustic waves are totally reflected and shear waves travel along the medium surface, but not into the medium. For LIPUS, the first critical angle is 22°, and the second critical angle is 48°. Between the first and second critical angles, at 35°, the amount of transmitted shear waves is maximized, and an optimal cellular response is obtained. Those critical angles were not determined for ESWT and RPWT [36].
\nAs previously described, the method for producing low-intensity pulsed ultrasound waves is unique, but there are three generation methods for extracorporeal shock waves. No clinical studies compare the effectiveness between the three methods, but one experimental research compared osteoblasts responses to electrohydraulic and electromagnetic ESWT. It was found greater cell viability and osteocalcin expression for electrohydraulic-stimulated cells, and greater expression of type I procollagen-C enzyme, and TGF-β1 production for electromagnetic-stimulated cells. These findings can be attributed to the difference in the pressure distribution at the focal zone between the electrohydraulic and electromagnetic generators [40].
\nMechanical stimulation can be combined with different types of acoustic waves or with growth factors.
\nElectromagnetic ESWT and LIPUS combined therapy applied to periosteal cells showed no difference regarding cell proliferation, cell viability and ALP activity in comparison with ESWT alone, but, in comparison with LIPUS alone, showed worse results for early response (after 6 days) and better results for late response (after 18 days) [42].
\nBMPs are known osteogenic factors. Their combined therapy (BMP-7 or rhBMP-2) with LIPUS enhances bone formation, osteogenic differentiation and biomechanical properties of bone [103, 104].
\nBisphosphonates are anti-osteoclastic agents that increase or maintain bone mineral density in osteoporotic patients. Combined therapy with LIPUS is not better than alendronate or LIPUS alone to increase bone healing. On the other hand, combined therapy with LIPUS enhances bone mineral density more than separate treatment [105].
\n1,25-Dihydroxyvitamin D3 increases the expression of VEGF in osteoblasts and modulates cellular proliferation and differentiation. Combined treatment with LIPUS, however, does not ameliorate cellular response in comparison with LIPUS or 1,25-dihydroxyvitamin D3 alone [106].
\nStatins (e.g. simvastatin, mevastatin and lovastatin) stimulate osteogenesis through Ras/Smad/ERK/BMP-2 pathway. Combined therapy with LIPUS does not increase bone formation rate more than statins or LIPUS alone [77].
\nNo studies were found on the subject for ESWT and RPWT.
\nClinical applications for acoustic therapy include nonunions and delayed unions. Debatable applications include acceleration of fracture healing, acceleration of segmental defects healing, enhancement of bone density and quality, management of stress fracture, enhancement of bone-tendon junction healing and management of avascular necrosis of the femoral head.
\nLIPUS has a unique protocol of treatment, which consists of daily 20-min sessions at 30 mW/cm2. On the contrary, ESWT has no established protocol regarding energy levels, frequency, number of sessions and number of cycles (impulses). This heterogeneity makes it difficult for the clinician to adopt the best approach for ESWT. No studies were found on the subject for RPWT.
\nNormally, patients with nonunion and delayed union are managed surgically for revision of a primary surgery or for biological stimulation. Those managed surgically for biological stimulation may be the best candidates for a non-invasive approach with acoustic therapy, since there is no problem with hardware and fracture reduction. Those experiencing technical problems related to the first procedure (gross bone instability, broken hardware, malalignment) should be subjected to revision surgery combined with acoustic therapy to provide also biological stimulation.
\nLIPUS exhibits healing rate from 67 to 92% and may challenge surgical treatment for delayed union and nonunion. Patients aged 70–79 years feature decreased healing rates (83.3 vs 86.2%), and older than 80 years feature even lower healing rates (77.8 vs 86.2%). LIPUS may also be an alternative approach to treat conservatively congenital pseudarthrosis of the tibia. Mean body mass index, open fracture, multiple prior surgical procedures, time to initiate treatment with LIPUS, type of surgical procedure, comorbidities and number of smoking years represented no risk factor for failure with LIPUS in a cohort of 767 patients. Smaller cohorts present some conflicting data: decreased healing rate was found in late treated (more than 12 months) nonunions and smokers. Moreover, atrophic nonunions may be a risk factor for decreased healing rates. Interestingly, LIPUS combined with iliac crest autograft exhibits synergistic effect to overcome spinal pseudarthrosis created by nicotine administration, although LIPUS alone cannot [94, 107–114].
\nESWT also shows healing rates that may challenge surgical treatment for nonunion and delayed union, with successful rates ranging from 63.6 to 95% using electrohydraulic or electromagnetic devices. No reports explored the effectiveness of piezoelectric devices, and RPWT. Energy density varied from 0.25 to 0.70 mJ/mm2, 1000–10000 impulses, single or multiple sessions. Technical parameters depended on bone size and authorship. Specifically for scaphoid pseudarthrosis, energy density varied from 0.05 to 0.12 mJ/mm2 depending on patient’s pain tolerance. Some studies also investigated serum level of BMP-2, NO, TGF-β1 and VEGF, which were higher in treated individuals. Again, atrophic nonunions, smoking and treatment performed at late stages (after 12 months) provided decreased healing rates [115–124].
\nThe potential benefits of LIPUS and ESWT to accelerate healing of bone defects and fractures have been shown in various animal studies, but there is not sufficient clinical evidence to support their routine use.
\nLIPUS promoted earlier callus formation, promoted larger callus width, increased biomechanical strength, reduced adverse outcomes (nonunion and delayed union), accelerated maturation of newly formed bone and healing time in distraction osteogenesis and reduced time for fracture healing. LIPUS reduced 18–36 days of healing time in conservatively treated fractures, and decreased about 30% of the healing time for surgically managed closed comminuted diaphyseal tibial and femoral fractures (irrespective of implant choice). Open fractures and patients older than 60 years had pronounced benefit from LIPUS treatment. LIPUS’ effectiveness increases as soon as treatment is initiated. In addition, fractures of the metatarsal, radius, scaphoid, ankle, fibula and ulna exhibited better healing rates. Smoking, diabetes, vascular insufficiency, osteoporosis, cancer, rheumatoid arthritis and obesity are risk factors for failure. A large cohort of 4190 patients showed 96% healing rate, which is greater than literature averages (93%). In that study, patients between 20 and 29 years old had greater healing rate than patients over 30 years old. Furthermore, LIPUS has no reported adverse effects [37, 56, 86, 125–132].
\nOnly electrohydraulic devices investigated the beneficial effects of ESWT for bone defects and fracture healing. Energy density varied from 0.16 to 0.62 mJ/mm2, 500–6000 impulses, single or multiple sessions. Increased callus formation; biomechanical properties; ALP activity; and expression of BMPs, IGF-1, eNOS, TGF-β1 and VEGF were reported. Patients subjected to ESWT exhibited better pain scores and decreased nonunion rates, but no difference of fracture-related complications rate. Reported complications include skin petechiae, scarring to the muscle at the treatment site (only for small animals) and subcutaneous swelling. No neuronal damage has been reported even for vertebral exposure (study with small animals) [54, 80, 91, 95, 98, 133–136].
\nDiabetes is a systemic disease that affects bone healing. Therefore, diabetic individuals are at risk of developing delayed unions, nonunions and pseudarthrosis. Those individuals may also exhibit impaired biomechanical strength of newly formed bone. LIPUS does not increase cellular proliferation during fracture healing in diabetic animals but increases bone healing and biomechanical properties. Additionally, LIPUS increases the expression of TGF-β1 and VEGF but not the expression of IGF-1 and PDGF-β. There are no reports on ESWT and RPWT in diabetic animals or individuals [137, 138].
\nFracture healing slows and endochondral ossification is impaired with senescence. At the molecular aspect, fracture-induced cox-2 expression in aged rats is lower than youngsters. Thankfully, bone cells keep their mechanosensitivity; as such, acoustic stimulation accelerates fracture healing. It has been shown that LIPUS accelerates fracture healing in estrogen-deficient osteoporotic bone and regains biomechanical strength so that it becomes comparable to non-osteoporotic bones also subjected to LIPUS. Furthermore, LIPUS increases the activity of ALP, and the expression of aggrecan, BMP-2/4/6, cbfa-1, cox-2, FGF-2, OPG, osteocalcin, osterix, RANKL, TGF-α1, VEGF and types I, II and X collagen. The effects of ESWT and RPWT were not investigated for fractures in osteoporotic bones [139–141].
\nOsseointegration of implants is an important step for recovery of biomechanical strength of bone. Facilitation of this biological process may decrease recovery time and the risk of hardware failure. LIPUS accelerates osseointegration of titanium screws in tibias and femurs, porous hydroxyapatite ceramic and miniscrew implants. Histologically, LIPUS-induced osseointegration provides denser trabecular microstructure at implant-bone interface and thicker newly formed bone. Those findings suggest acoustic therapy may be used as adjunctive therapy to increase hardware lifetime (e.g. for arthroplasties) and decrease recovery time. No reports were found on the subject for ESWT and RPWT [142–144].
\nBone graft substitutes provide an osteoconductive scaffold for filling large osseous defects, and they are an alternative for autologous bone graft, which adds morbidity to the patient. Acoustic therapy provides osteoinductive stimulation for bone. Therefore, combination of acoustic therapy and bone graft substitutes may be a finer alternative to treat fractures associated with large defects. A report showed LIPUS increased bone formation in ulna defect filled with β-tricalcium phosphate (bone graft substitute). In addition, LIPUS did not alter resorption rate of the bone graft substitute. The influence of ESWT and RPWT on large osseous defects filled with bone graft substitutes needs to be explored [86].
\nHealing at bone-tendon junction is crucial for tendon repairs (e.g. quadriceps tendon repair, rotator cuff repair, calcaneal tendon repair) and ligament reconstruction (e.g. anterior cruciate ligament of the knee reconstruction and medial patellofemoral ligament reconstruction) to ensure early recovery and improved biomechanical strength. Acoustic therapy may be used as adjunctive therapy in those situations since LIPUS and ESWT were found to enhance healing of bone-tendon junction. Histologically, those acoustic therapies promoted better remodelling of the newly formed trabecular bone, increased bone mineral density and improved tendon-to-bone collagen fibre reconnection [145–147].
\nStress fractures are pathological overuse injuries common in athletes and military recruits. Those injuries result from repetitive loading beyond the regenerative capacity of bone, and represent failure of the adaptive mechanisms of bone to mechanical loads. Results regarding this subject are variable.
\nLIPUS at 30 mW/cm2 used to treat incomplete stress injury of the posteromedial tibia, fibula, or second to fourth metatarsals was ineffective to accelerate recovery during a 4-week treatment. On the other hand, LIPUS at 100 mW/cm2 accelerated stress fracture healing of ulnae even in the presence of non-steroidal anti-inflammatory drugs, which normally delay fracture healing. In addition, athletes with delayed or nonunions of stress fractures of tibia or fifth metatarsus experienced bone healing within 6–14 weeks of exposure to electromagnetic ESWT [148–150].
\nDespite fractures, bone is subject to other diseases that alter its biomechanical strength, such as osteoporosis; or produce disabling pain, such as avascular necrosis of the femoral head. Acoustic therapy may be used for prevention and treatment of some bone disorders.
\nIt is not known how healthy and intact bone reacts to acoustic loading. Most studies focus on pathological conditions, such as fractures and osteoporosis. The understanding of the normal response of bone to acoustic loads within the physiological range and overuse range is required to ameliorate the comprehension of tissue behaviour in pathological situations, and to prevent some disorders; for instance, stress fractures and osteoporosis.
\nIntact and healthy bones subjected to LIPUS experience increased density of trabecular spongiosa, and increased activity of FAK, ERK-1/2 and IRS-1. Electrohydraulic ESWT (from 0.15 to 0.47 mJ/mm2, 500–6000 impulses, single session), in turn, promotes angiogenesis, increased cellular population and bone formation, increased activity of ERK-1/2 and Akt, and increased TGF-β1 production, but no difference on biomechanical tests was found following ESWT exposure [54, 79, 90, 95, 151–153].
\nStudies demonstrated that LIPUS does not increase bone mineral density of osteoporotic bones and does not prevent osteoporosis as measured by dual energy X-ray absorptiometry. However, in those studies the exposure to LIPUS occurred within a short time (from 4 to 12 weeks), and the population of some investigations was heterogeneous. Additionally, histological and molecular analysis of osteoporotic bones subjected to LIPUS showed increased bone formation, normal density of trabecular spongiosa, decreased disruption of trabecular spongiosa and greater expression of cbfa-1 (although lower than controls) [37, 153–157]. Therefore, the authors believe LIPUS possesses beneficial effects for treating osteoporosis.
\nElectromagnetic ESWT exhibited more pronounced effects on osteoporotic intact bones than LIPUS since ESWT showed increased bone mineral density and decreased bone loss [158].
\nConcern exists about possible negative effects of ESWT on ephiphyseal plaque in skeletally immature individuals; therefore, ESWT is not formally indicated for children. Contrarily, LIPUS is not contraindicated for skeletally immature individuals. Two studies addressed the effects of ESWT on epiphyseal plaques of animals. It was found that electrohydraulic or electromagnetic ESWT, from 0.38 to 0.60 mJ/mm2, 1500–3000 impulses, single or multiple sessions, did not harm epiphyseal plaque cells and did not impair growth. Furthermore, histological analysis revealed increased number of chondrocytes in the proliferative zone and increased thickness of the epiphyseal plaque, suggesting a possible role for growth stimulation. No studies were found for LIPUS that could suggest a possible role for growth stimulation in skeletally immature individuals [96, 97].
\nPatients who develop avascular necrosis of the femoral head experience groin pain and disability, and further may necessitate joint replacement. A novel possible approach for initial stages of that condition, when bone collapse and osteoarthritis have not established yet, is acoustic therapy. Experimental studies with avascular necrosis of the femoral head models showed that LIPUS and electrohydraulic ESWT increase neovascularization, osteogenesis, osteogenic differentiation of bone marrow cells, decreased size of fat cells—which substitute dead bone—and biomechanical strength of bone. Increased expression of proliferative factors, such as BMP-2, FGF, IGF-1, NO and VEGF, was also found. Furthermore, a clinical and an experimental research revealed that electrohydraulic ESWT may be more effective than core decompression and non-vascularized fibular grafting in patients with early-stage disease; reverts osteonecrosis by one stage; decelerates, or stops, disease’ progression; and decreases pain and functional disability [10, 38, 149, 159, 160].
\nUndoubtedly, acoustic devices are useful tools to stimulate osteogenesis. Nevertheless, there is a wide list of topics that require further investigations: physical phenomena elicited by acoustic forces need to be proved in vivo, signalling molecules need to be assigned to specific signalling pathways, the control of cellular response to acoustic loads needs to be clarified, RPWT and piezoelectric ESWT influence on bone biology lack investigations, clinical protocols for ESWT and RPWT should be established and, finally, randomized controlled trials addressing acoustic therapy should be performed. As a conclusion, a lot of research is expected within the next years to clarify the unanswered questions about the relationship of bone tissue and acoustic forces.
\nTraditionally, intraoperative endoscopy (IOE) was the only means for the visualization of small bowel mucosal lesions not accessible to upper gastrointestinal endoscopy and colonoscopy. However, with the advances in abdominal imaging and the advent of capsule endoscopy (CE), the use of IOE diminished. A comparative study of CE and IOE found the sensitivity and specificity of CE to be 95% and 75%, respectively [1]. Hence, most guidelines recommend CE for detection of suspected small bowel lesions in patients with obscure gastrointestinal (GI) bleed. However, the main disadvantage of CE was inability to perform therapeutic procedures. Subsequently, the device assisted enteroscopy (DAE), namely, spiral endoscopy, double balloon enteroscopy (DBE) and single balloon enteroscopy (SBE) was developed which has brought paradigm shift in the treatment of small bowel mucosal diseases. DAE allows visualization, biopsy and removal of the small bowel mucosal lesions.
However, IOE is still an indispensable tool for the evaluation and treatment of small bowel diseases in special situations and institutions with lack of DAE facilities. The reported success rate of IOE to achieve complete enteroscopy ranges between 57–100% in different series [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. The advantages and disadvantages of IOE have been summarized in Table 1.
Advantages of IOE | Disadvantages of IOE |
---|---|
Complete bowel examination is possible in same sitting | Anesthesia and laparotomy related complications |
The procedure is safe as it is performed under direct vision | Enterotomy related complications |
Allows peritoneal, mesentery and omental examination and biopsy, if required | Availability of the endoscopy equipments and endoscopist at the time of surgery |
Allows definitive treatment of the disease in the same sitting | Inability to negotiate the endoscope in case of dense bowel adhesions |
Minimizes the number of procedures and enterotomies in patients with multiple lesions like PJS | Inability to visualize the mucosa in case of massive bleeding |
Advantages and disadvantages of intraoperative endoscopy.
In the current era, despite the widespread use of DAE, IOE plays an important in the management of various GI disorders. In a 10-year study by Kopacova et al., the authors performed IOE in 41 patients with the commonest indication being obscure gastrointestinal bleeding followed by Peutz-Jeghers syndrome (PJS) [6]. The indications of IOE in the present scenario are as follows:
Obscure gastrointestinal bleeding – It is recurrent or persistent bleeding from the unknown source in the GI tract that could not be identified on conventional endoscopy, colonoscopy and barium studies or enteroclysis [11]. Small bowel lesions account for 45–75% cases of obscure gastrointestinal bleed [11, 12]. In such cases, extensive investigations including enterography using computed tomography (CT) or magnetic resonance imaging (MRI), CE, DBE and RBC scan can often help in identifying the lesion (Figure 1). However, sometimes it is not possible to identify the site and cause of GI bleed in such patients despite exhaustive work-up. IOE is very helpful in detecting the mucosal lesions within the small bowel of patients with GI bleed (Figure 2). In a recent series of 67 patients with GI bleed, CE, colonoscopy, upper gastrointestinal endoscopy and DBE was performed in 96%, 87%, 87% and 73% cases respectively [10]. Despite these preoperative investigations, IOE was performed in 40% patients with the diagnostic yield of 76% [10].
PJS – It is characterized by presence of multiple hamartomatous polyps throughout the GI tract, mucocutaneous pigmentation and an increased risk of GI cancers. These polyps are predominantly located in the small and can lead to several problems including recurrent abdominal pain, GI bleed, intussusception, bowel obstruction and perforation. As per the recommended guidelines, polyps more than 1 cm should be excised to prevent future complications [13]. Previously, these patients required surgical excision with or without IOE. But with the availability of DAE, many of these polyps can be removed endoscopically (Figure 3). Nevertheless, surgery and IOE is required in many cases for complete exploration of small bowel and resection of large or malignant polyps (Figure 4). In a recent study of 27 patients with PJS, the success rate of enteroscopy was 76% [14]. IOE was required in 4 patients which improved the complete treatment rate to 92%. IOE has also been shown to facilitate polyp resection, reduce the number of laparotomies [6] and extensive bowel resection [15].
Familial adenomatous polyposis (FAP) – It is an autosomal dominant disorder characterized by development of premalignant adenomatous polyps in the colon. Moreover, these patients are at the risk of development of duodenal polyposis, duodenal cancer, jejunal and ileal polyps [16]. Most of these can be visualized using conventional upper gastrointestinal endoscopy and colonoscopy. CE and DAE are useful for the visualization of jejunal and ileal polyps. However, in FAP patients with history of abdominal surgery such as pancreatoduodenectomy for duodenal cancer or total proctocolectomy for colorectal cancer, diagnostic and/or therapeutic DAE can be difficult. In such cases, IOE can be used to achieve complete clearance [16].
Crohn’s disease (CD) – It is an inflammatory bowel disease predominantly affecting the small intestine. The transmural inflammation leads to the development of deep ulcers causing GI bleeding and small bowel strictures causing intestinal obstruction. In presence of strictures, CE is contraindicated due to the risk of impaction. DAE also has its limitation in passing across the tight strictures making complete small bowel examination difficult. IOE helps in examining the mucosal side of the involved bowel segments to determine the disease activity. Previous studies involving CD patients have reported that IOE can identify new lesions not seen on preoperative examination [17].
Computed tomography - a 53-year-old lady presented with anemia, weight loss and recurrent abdominal pain for one year. On computed tomography, she was found to have thickening in the mid segment of the ileum (arrow) with proximal dilated bowel loops containing feculent material (A: Axial section, B – Coronal section).
Intraoperative enteroscopy via enterotomy of the patient with ileal thickening on computed tomography showing normal mucosal folds (A, B, C), a suspected vascular lesion (arrow, D), a small mucosal lesion (arrow, E) which was biopsied (F). No ileal stricture or significant mucosal disease was identified.
Peutz-Jeghers syndrome – The follow-up gastroscopy of the patient with Peutz-Jeghers syndrome one year after intraoperative enteroscopy and polyp excision showing multiple small polyps throughout the stomach (A). Few pedunculated polyps were present in the large bowel (B, C) which were excised endoscopically (D).
Peutz-Jeghers syndrome – A 29-year-man presented with recurrent abdominal pain. On evaluation, he was found to have multiple polyps throughout the small and large intestine causing intussusception. At surgery, intraoperative enteroscopy via oral and anal route was performed and small polyps amenable to endoscopic resection were excised. Two large polyps, one in the transverse colon (A) and another in the proximal jejunum (B) were marked by endoscopy and excised surgically.
Patients not responding to medical therapy or those who develop persistent GI bleeding or intestinal obstruction require surgical intervention. At surgery, multiple segments of small bowel with skip areas are often involved. The extent and type of surgery in such cases is difficult to ascertain. IOE allows complete small bowel examination and helps in surgical planning. In such cases, surgical intervention is most often performed for tight strictures (<15 mm diameter), stricture with active ulcer and bleeding ulcer [18].
IOE is also useful in CD patients undergoing emergency surgery for intestinal obstruction or perforation without prior endoscopic examination. In such cases, complete small bowel evaluation along with ileocecal junction is important to prevent postoperative complications and avoid repeated surgeries.
Bowel obstruction or perforation – Sometimes, patients presenting with small bowel obstruction or perforation without prior endoscopic evaluation may require IOE for appropriate surgical treatment. One such situation is the presence of multiple strictures on preoperative CT. Similar to CD, patients with multiple strictures due to other causes such as tuberculosis requiring emergency surgery for intestinal obstruction or perforation can undergo IOE in the same sitting if feasible to allow complete small bowel examination and avoid multiple surgeries (Figure 5). Another clinical situation is difficulty in identification of the cause of bowel obstruction. In one of our previously reported cases, a patient of moderately severe acute gallstone pancreatitis developed colonic obstruction in the follow up [19]. On CT abdomen, there was a resolving peripancreatic collection surrounding the transverse colon with grossly dilated ascending colon and small bowel loops. In order to rule out mucosal disease, IOE via enterotomy route was performed (Figure 6). As there was no mucosal disease, side-to-side ileo-transverse colonic anastomosis was performed without colonic resection [19].
Foreign body (FB) removal – Most of the cases of non-impacted FB ingestion can be managed conservatively. Sharp FB ingestion require endoscopic removal if feasible. Few cases with impacted FB in the small bowel not accessible to endoscopic removal or those who develop complications such as intestinal perforation require surgery.
Intraoperative enteroscopy via enterotomy of a patient with multiple small bowel strictures on computed tomography showing a narrow stricture in the proximal ileum (A). Rest of the small bowel showed mild mucosal edema at few places with no obvious strictures (B, C, D).
Intraoperative enteroscopy via enterotomy of a patient with resolving acute pancreatitis and colonic obstruction showing mucosal edema at the site of obstruction (A, B) with grossly dilated colon loaded with feculent material (C).
Some cases with multiple FB ingestion located at different locations may require IOE to remove all the foreign bodies with minimum enterotomies. IOE can also help in such cases to confirm complete clearance during the operation [20].
Failure of DAE to identify or treat the lesion – Often, complete small bowel examination is not possible with DAE. The reasons for failure of DAE include previous laparotomies, bowel adhesions, anatomical variations, etc. [21]. In such cases, IOE is useful in achieving complete bowel evaluation and treatment if required in the same sitting.
Abdominal surgery required for other reasons – In some situations such as CD with symptomatic gallstone disease or FAP with periampullary carcinoma, if the patient is planned for abdominal surgery, then IOE can be performed in the same sitting instead of DAE.
Identification of the site of disease during surgery – In the era of DAE, most of the small bowel lesions requiring surgical excision are marked with India ink. However, in some cases were the ink is not visible or cases were the mucosal lesions were detected on CE such as ectopic pancreatic tissue, arteriovenous fistula, and hemangioma, IOE is useful for intraoperative localization.
Lack of DAE facility – DAE is available at most centers in developed countries. However, in low income countries or in limited resource setting, IOE is a safe and effective alternative to DAE. It allows diagnosis and treatment of the small bowel diseases in the same sitting.
IOE is mainly performed via conventional laparotomy. However, it can be performed by mini-laparotomy [22, 23] or laparoscopy [24, 25, 26, 27]. IOE can be performed by gastroscope, colonoscope, pediatric scope or balloon enteroscope depending upon the probable site of the lesions, the indication for IOE and the availability of the equipments. In rare circumstances, IOE can be performed using a laparoscope [28]. IOE can be conducted through oral route, anal route and through an enterotomy site (Figure 7). The choice of the preferred route for IOE depends upon the location of the lesion.
Schematic presentation of different routes for intraoperative enteroscopy: (A) Transoral route, (B) transanal route and (C) enteroscopy via enterotomy.
The patients are admitted before the procedure. All routine investigations including cardiorespiratory work up are done to rule out any contraindication for surgery. The day before the procedure the standard bowel preparation (the same as for colonoscopy) with either polyethylene glycol or sodium phosphate is given [29]. The patients are asked to fast for 6 hours before the surgery.
All the endoscopes and the accessories are sterilized before the procedure. The endoscopist has to scrub like any other member of the operating team. The part of the endoscope to be inserted in the operating field is covered with a plastic sleeve routinely used for laparoscopic procedures. This will help in maintaining the sterility of the procedure. The procedure is performed under general anesthesia.
Transoral endoscopy can be performed with the patient in supine or left lateral position [30]. Prior to the insertion of the endoscope, a nasogastric tube is placed to decompress the stomach. Subsequently, the nasogastric tube is removed and the gastroscope is inserted.
Like the routine endoscopy, the gastroscope is passed in to the duodenum (Figure 7A). If the intraoperative endoscopy is pre-planned, then the endoscope can be passed as far as possible into the duodenum before the abdominal incision to take benefit of the tamponade effect of the abdominal wall.
During the passage of the endoscope, a loop tends to form along the greater curvature of the stomach and the ‘C’ of the duodenum. Once, the endoscope has reached the jejunum, the assistant surgeon can place the right hand along the greater curvature of the stomach and the left hand over the second part of the duodenum to straighten the endoscope. This will help in going further deep in to the small bowel via the oral route.
Deeper passage of the scope in to the jejunum is performed with the help of the operating team. Mobile small bowel and mesentery is necessary to facilitate smooth passage of the scope and avoid bowel injury. Hence, if adhesions are present then adhesiolysis should be performed by the operative team before initiating IOE.
For the examination of the small bowel beyond the proximal jejunum, the operating surgeon straightens the bowel loops as the endoscopist gently pushes the endoscope in to the jejunum. Subsequently, about 40–50 cm of small bowel is telescoped on to the shaft of the endoscope by the operating surgeon.
Advancement of the endoscope through the small bowel must be smooth, slow, gentle and under direct vision to avoid mucosal trauma by the endoscope and avoid excessive tension on the mesentery.
The mucosa is thoroughly examined during the insertion and withdrawal of the endoscope. Any lesion if detected is biopsied or excised endoscopically using the standard techniques. Bleeding from the endoscopic excision site can be controlled by endoscopic techniques or transmural sutures by the operating team.
If the lesion is big and requires surgical excision, then the site of the lesion must be marked with a simple suture by the operating team.
In most cases, it is possible to examine the whole small bowel via oral route using the standard-length colonoscope. But if not possible, then the terminal ileum can be examined in a retrograde fashion via transanal route.
The distal most point up to which the scope reaches in the small bowel is marked with a simple suture by the surgical team.
Throughout the procedure, the operating room lights are dimmed so that the endoscopy team is able to clearly visualize the bowel mucosa and the location of the endoscope. The abnormal vascular lesions can be better identified by transillumination.
During withdrawal, after inspecting the mucosa, the air is aspirated by the endoscopist and the surgeon occludes the intestinal lumen with his index and middle fingers to avoid re-insufflation.
After completion of the endoscopy, the lesions at the marked sites are excised surgically by multiple enterotomies or segmental bowel resection depending upon the intraoperative findings.
This is the least preferred route for IOE due to limited maneuverability.
The procedure can be performed in lithotomy or left lateral position.
The steps are similar to that of colonoscopy (Figure 7B). In case of difficulty in negotiating the scope across the colonic flexures, the operating surgeons can guide the scope.
Small lesions can be excised or biopsied endoscopically while large lesions can be marked with simple suture for subsequent surgical excision.
After reaching the ileocecal region, the surgeon slowly pushes the ileal loops over the scope for the mucosal examination. However, evaluation of the small bowel beyond terminal ileum via anal route is difficult.
In such cases, if there is a large colonic lesion requiring surgical excision, a colotomy can be made near the site of resection and the colonoscope can be advanced through it to facilitate further small bowel examination.
After appropriate adhesiolysis, whole of the small bowel is freed.
A circular purse-string suture is taken at a suitable point (usually the mid portion) of the small intestine on the anti-mesenteric side [6]. A small enterotomy is made at the center of the purse string suture just sufficient enough to allow the passage of the endoscope.
The endoscope is inserted through the enterotomy and the circular suture is tied around the scope over the bowel to prevent air leak during insufflation (Figure 7C).
First, the proximal part of the small intestine is examined due to lower bacterial load.
Enteroscopy should be performed slowly with gradual advancement of the scope and minimum insufflation to prevent bowel injury.
Endoscopic biopsy or excision is performed for the visualized mucosa lesions as appropriate. If surgical excision is required, then the site of lesion is marked by the operating surgeon with a simple suture.
During the inspection of the proximal half of the small bowel, the distal part if clamped and vice-versa to prevent over-inflation.
The endoscopic views during IOE are different from the routine endoscopic picture due to transillumination by the operating lights in the theater. However, the operating lights can be dimmed if required as per the endoscopist’s choice.
In order to avoid contamination of the operative field, some authors have described the use of laparoscopic port.
In this technique, a 12-mm or 15-mm bladeless laparoscopic port with or without balloon is inserted from the enterotomy site in to the bowel [31, 32, 33, 34].
The laparoscopic camera sleeve is fixed to the port with tape.
The endoscope is passed through the camera sleeve and port in to the bowel for enteroscopy.
This technique allows to maintain the sterility of the operative field.
In this technique, in order to avoid the laparotomy, the endoscope is passed through one of the 12- or 15-mm laparoscopic port [24, 25, 26].
IOE can be performed via oral [25, 27, 34], anal [35] or enterotomy route [24, 26].
The procedure for IOE via oral or anal route is same as described above except that the adhesiolysis and handling of the small bowel is performed laparoscopically. Additionally, the bowel insufflation has to be minimum to allow space for laparoscopic bowel manipulation [24].
For IOE through enterotomy, a small jejunotomy is made and the endoscope is passed through it in to the bowel.
Although the mobility of the scope is restricted compared to conventional IOE through laparotomy, it is possible to visualize the whole small intestine with careful manipulation of the small bowel loops.
After the withdrawal of the endoscope, the enterotomy wound is sutured laparoscopically.
However, this procedure is technically more demanding and time consuming. Both the laparoscopist and endoscopist need to be highly skilled and experienced.
DAE is possible in most of the cases. However, in some cases, DAE may be difficult due to previous laparotomy, or inability to reduce the forming loops during DAE leading to incomplete bowel examination.
In such cases, DAE can be performed under laparoscopic guidance. Laparoscopy can be undertaken by conventional 3-ports or SILS technique [21, 27].
In SILS technique, a SILS port is inserted at the umbilicus. A 10-mm laparoscope and two 5-mm non-traumatic graspers are inserted through the SILS port. Laparoscopic adhesiolysis is performed before starting enteroscopy.
Enteroscopy is performed using conventional flexible endoscope or DBE. Surgical manipulation of the bowel loops is done during enteroscopy if required.
The visualized lesions can be excised endoscopically or laparoscopically depending upon the location and size of the lesions and the available expertise.
In a recent study of 13 patients who underwent SILS enteroscopy, target pathology could be reached in all but one patient with PJS, in whom antegrade DBE failed to reach up to the target polyp and a small enterotomy was required to complete IOE and excise the polyp [21].
A review of 16 studies involving 468 patients by Voron T, et al. reported that the site of bleeding could be successfully identified in 371 patients (79.3%) [16]. The predominant lesions responsible for obscure GI bleed were vascular lesions (n = 227, 61%), benign ulcers (n = 70, 19%), tumors (n = 36, 10%) and diverticula (n = 15, 4%) [16]. The most common route of IOE was transoral followed by trans-enterotomy. A recent study by Manatsathit W, et al. also reported vascular lesions, ulcers and tumors to be the most common lesions detected on IOE [36].
The reported rates of diagnostic and therapeutic yield of IOE are 79.3% (58–100%) and 75.7% (48–94%), respectively [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 16, 36]. The diagnostic yield for obscure GI bleeding after non-diagnostic abdominal imaging has been reported to be 91–100% and after non-diagnostic VCE/DAE varies from 14.2% to 66.7% [1, 6, 9, 36]. Traditionally, the treatment of the lesions detected during IOE were performed surgically. But, with the advancement in the endoscopic techniques, the lesions are being increasingly tackled endoscopically as far as possible and surgical treatment is performed for the rest of the lesions especially in condition like PJS.
IOE via enterotomy converts clean surgery in to clean-contaminated surgery which increases the risk of infective complications. Another problem of IOE is excessive bowel handling which increases the risk of postoperative ileus. The reported complication rates of IOE vary between 1 and 50% [16, 36, 37]. According to a combined data of 10 studies involving 309 patients, the overall morbidity rate was 16.8% which included surgical and medical morbidities [37]. The complications were mainly related to general anesthesia, laparotomy and bowel surgery required for bowel lesions and not solely related to IOE. Prolonged postoperative ileus was one of the predominant surgical morbidity. Other morbidities included bowel obstruction, wound infection, intrabdominal collections/abscess, intra-abdominal bleeding, chest infection and cardiorespiratory failure [18, 37]. The complications directly related to IOE include mucosal laceration, bowel wall hematoma, mesenteric hematoma or bleeding due to excessive handling during IOE and rarely, bowel perforation [38].
The overall mortality rate of IOE from the combined data of 14 studies including 419 patients was 5% [37]. The main causes of death were multiorgan failure, septic shock, diffuse intravascular coagulopathy and hemorrhagic shock [37].
An important issue in patients with obscure GI bleed after any investigation or treatment is the development of recurrent GI bleed. The reported incidence of recurrent GI bleed ranges from 13–52% in different series [9, 36, 37]. It is important to note that differentiation between iatrogenic mucosal trauma from mucosal vascular lesions by IOE is difficult [39]. Secondly, vascular lesions can be evanescent, hence early IOE or at time of bleeding can make the detection of these lesions possible [40]. Other reasons for rebleeding could be appearance of new lesions due to same or different disease, incomplete endoscopic treatment of the existing lesions such as angiodysplasia, etc.
IOE involves lot of small bowel handling and manipulation to allow smooth passage of the endoscopy across the bowel loops. In cases of dense adhesions with shortened mesentery, IOE can be difficult and increase the risk of bowel injury. Another situation where IOE is difficult is in the presence of massive GI bleeding as the lumen is completely filled with blood and examination of the bowel mucosa is not possible [7].
With the increasing use of DAE, the need for IOE has reduced. However, it continues to be an extremely useful tool in patients with obscure GI bleed, multiple polyposis syndromes, multiple foreign bodies or bowel obstruction where DAE cannot be performed or has failed. Moreover, IOE has been found to reduce the need for repeated surgeries by allowing complete small bowel examination and treatment in the same sitting. Although IOE via laparotomy remains the gold standard, availability of advanced minimally invasive equipments have allowed IOE to be performed via multiport or single port laparoscopy.
The authors have no conflict of interest to declare.
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\\n\\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\\n\\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\\n\\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\\n\\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\\n\\nAUTHOR'S DUTIES
\\n\\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\\n\\nThe Author agrees to:
\\n\\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\\n\\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\\n\\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\\n\\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\\n\\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\nAUTHOR'S WARRANTY
\\n\\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\\n\\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\\n\\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\\n\\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\nTERMINATION
\\n\\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\\n\\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\nIntechOpen’s DUTIES AND RIGHTS
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\\n\\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\\n\\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\\n\\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\nMISCELLANEOUS
\\n\\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\\n\\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\\n\\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\\n\\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\nSubject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\nThe Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\nThe Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\nIn the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nIntechOpen’s DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\nIntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\nIntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\nVariation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
\n\nSeverance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\nNo partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\nGoverning law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\nPolicy last updated: 2018-09-11
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}},{id:"6495",title:"Dr.",name:"Daniel",middleName:null,surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6495/images/1947_n.jpg",biography:"Daniel Eberli MD. 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