La pérdida de legitimidad de las instituciones electorales

The use of therapeutic ultrasound for wound repair has been extensively studied over the years, and these effects are reported usually as been due to non-thermal effects.

Ultrasound effects in the inflammatory phase of repair

Therapeutic ultrasound can interact with several cell types present in this phase of repair. Acoustic microstreaming forces have been shown to produce changes in platelet membrane permeability leading to the release of serotonin (Williams, 1974). If microstreaming can stimulate the release of serotonin it may also influence the release of the other factors produced by platelets.

A single treatment with therapeutic ultrasound if given immediately after injury can stimulate mast cells to degranulate releasing histamine into the surrounding tissues (Fyfe and Chahl, 1982). It is possible that ultrasound is stimulating the mast cell to degranulate by increasing its permeability to calcium, since these cells usually degranulate in response to increased levels of intracellular calcium.

There is much evidence that ultrasound can produce membrane changes in a number of cells. Reversible membrane permeability changes to calcium have been demonstrated using therapeutic levels of ultrasound

(Mortimer and Dyson, 1988; Dinno et ai, 1989). This effect can be suppressed

by insonation under pressure, suggesting that cavitation is the physical- mechanism responsible. Other ion permeability changes such as potassium'

have also been demonstrated (Chapman et ai, 1979). Ultrasound» can also

modify the electrophysiological properties of a tissue, by reducing the sodium-

potassium ATPase pump activity (Dinno et ai, 1989). This could be used as a

Chapter 2 - Literature Review - Section III - Ultrasound

ultrasound, if it occurs in neuronal plasma membranes, reducing neural transmission.

Altering the calcium transport through cell membranes with therapeutic ultrasound is very important, since calcium can act as an intracellular or second messenger activator, altering cellular activity. Macrophages stimulated with ultrasound showed increased synthesis and secretion of wound factors, explained by this mechanism (Young and Dyson, 1990b). This study showed that ultrasound at 0.75 MHz appeared to be most effective in encouraging immediate release of factors already present in cell cytoplasm, whereas the higher frequency of 3.0 MHz was most effective in stimulating the production of new factors, released later. This was evaluated by stimulating fibroblast growth with the media of these insonated macrophages, and was also noted by Hart (1993). Heating is more likely to occur at 3.0 MHz, and cavitation is more likely at lower frequencies, which can probably explain the difference in results.

The rapid resolution of oedema observed clinically in oral surgery as compared to dexamethasone suggested that ultrasound had anti-inflammatory

activities (El-Hag et al, 1985). However several papers have shown that

ultrasound is not anti-inflammatory in its action, and encourages oedema

formation to occur more rapidly (Goddard at al, 1983; Fyfe and Chahl, 1985;

Hustler at al, 1978). ', it accelerates the whole inflammatory phase,

leading the wound to the proliferative phase. This has been confirmed in vivo

in rat excised full thickness skin lesions, where the ultrasound treated rats had significantly less inflammatory cells and more granulation tissue in the wound bed at 5 days post-injury (Young and Dyson, 1990a). These results suggest that there was an acceleration of the healing through the inflammatory phase of repair.

Ultrasound affects in the proliferative phase of repair

The main events occurring during this phase are cell infiltration (e.g. fibroblasts) and proliferation, angiogenesis and re-epithelisation. Mummery (1978) showed

that ultrasound can increase fibroblast motility in vitro. In this thesis we show

osteoblasts (Reher et al, 1997c) and endothelial cells in vitro. This is supported by in vivo studies which show a marked increase in wound bed cell number (Young and Dyson, 1990a; Dyson and Pond, 1970). Much debate exists if this is a direct effect of ultrasound or an indirect effect through the stimulation of the macrophage, which then secrete?stimulatory factors (Young and Dyson, 1990b,, Hart 1993). As shown in this thesis, we believe that both mechanisms are involved.

Fibroblasts stimulated with ultrasound have increased production of

collagen (Harvey at al, 1975). This effect is intensity dependent, when exposed

to continuous ultrasound (0.5W/cm^ (^^)), 20% increase was noted, and when

pulsed (0.5 W/cm^ (sapa)j^ 30 % increase was observed. Webster at al (1978)

also observed increase of 29% in protein synthesis by fibroblasts, and suggests a role for cavitation in this process. In this thesis we also noted increased

collagen production in mice calvaria (Reher at al, 1997a and b), fibroblasts and

osteoblasts (Reher ef a/, 1997c; 1998a).

Another main event of this phase of repair is angiogenesis (see previous section). When chronically ischaemic muscle is exposed to ultrasound,

capillaries develop more rapidly (Hogan at al, 1982). Ultrasound therapy is the

simplest way of delivering therapeutic angiogenesis. Young and Dyson (1990a) reported the induction of angiogenesis by ultrasound, observed in rat skin lesions. Osteoradionecrosis is specifically an area that benefits from therapeutic angiogenesis. After radiotherapy, the irradiated area becomes hypoxic, hypocellular and hypovascular (Marx, 1983a). The tissues have a complex metabolic/homeostatic deficiency, bordering an ischaemic necrosis, and are

prone to breakdown, leading to a chronic non-healing wound, i.e.

osteoradionecrosis. Therefore, the treatment or prevention of this complication aims to restore the normal soft tissue and bone vascularity. Therapeutic angiogenesis induced by ultrasound has proved to be clinically successful in osteoradionecrosis (Harris, 1992). Furthermore this thesis gives more objective evidence of the induction of angiogenesis induced by therapeutic ultrasound. This can be due to a direct effect on proliferation of endothelial cells, or

Chapter 2 - Literature Review - Section III - Ultrasound

indirectly by the stimulation of angiogenic factors produced by other cells (R eh erefa /, 1998c).

Ultrasound effects in the remodelling phase of repair

In this phase the wound becomes relatively acellular and avascular, collagen content increases, leading to more tensile strength of the wound.

Ultrasound can stimulate wound contraction, as demonstrated by the contraction of cryosurgical lesions (Dyson and Smalley, 1983). Further evidence was shown by Hart (1993) which showed stimulation of wound contraction, leading to smaller scars in rat excised skin lesions treated with 3 MHz pulsed ultrasound. This effect could be observed at 0.1 and at 0.5 W/cm^ (SAPA)^ and he recommends the lowest intensity. Similar observations were also made in humans. Ultrasound significantly accelerated the reduction in varicose

ulcer area (Dyson et al, 1976). Chronic leg ulcers showed a 20% increase in

the healing rate when treated with weekly ultrasound at 1 MHz, pulsed, 0.5

W/cm^(^^^^) (Callam et al, 1987). However there are papers which did not show

statistically significant improvements for the treatment of chronic venous ulcers

(Lundeberg et al, 1990). Another use of ultrasound in this context is in the

treatment of chronic wounds such as pressure sores (Paul et al, 1960;

McDiarmid et al, 1985). This effect was more evident in microbially infected

sores which may be explained by the greater number of inflammatory and

repair cells that may be stimulated as well (McDiarmid et al, 1985).

The effect of ultrasound on this phase depends upon the time when therapy is used. Usually the best results in relation to tensile strength and elasticity of the scar are obtained when ultrasound is applied during the

inflammatory phase of repair (Webster et al, 1980; Byl et al, 1993). Treatment

with ultrasound during the inflammatory phase of repair not only increases the amount of collagen deposited in the wound, but also encourages its deposition in an 3D architecture similar to normal uninjured skin (Dyson, 1981). Increased, tensile strength and elasticity in injured tendons can also be achieved with