Treatment of scar tissue using lipoic acid

Scar tissue is reduced or inhibited by application of a composition containing lipoic acid and/or a lipoic acid derivative such as dihydrolipoic acid, a lipoic or dihydrolipoic acid ester, a lipoic or dihydrolipoic acid amide, a lipoic or dihydrolipoic acid salt, and mixtures of any of these. Some compositions further comprise .alpha.-hydroxy acids or acid derivatives such as glycolic and/or lactic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate, and/or tocotrienol. In some embodiments, a silicone gel sheet with added lipoic acid and/or a lipoic acid derivative and optional other ingredients is topically applied to scar tissue to diminish them.

TECHNICAL FIELD 
This invention relates primarily to methods and compositions for the 
treatment of scar tissue, particularly hypertrophic and keloid scars and 
straie distensae (stretch marks). Scars typically result from repair of 
damaged tissue, and this damage may be following trauma, burns, or 
disease. Because scars are cosmetically distracting and sometimes 
symptomatic, producing bothersome itching, burning, stinging or painful 
sensations, there is considerable interest in their treatment. 
BACKGROUND OF THE INVENTION 
Scars result from wound healing, which occurs in three separate phases: 
inflammation, formation of granulation tissue, and matrix formation. (For 
a review, see Sahl, W. J., and Clever, H., Internat. J. Derm., 1994, 33: 
681-691 (part I) and 763-769 (part II)). During the first phase, damage to 
endothelial cells, complement, and platelets at the wound site release 
chemotactic factors that result in the infusion of neutrophils, 
lymphocytes and macrophages, which aids in the removal of infection and 
foreign debris. As in all inflammatory processes, there is generation of 
free radicals, which damages cell membranes and results in formation of 
oxidized proteins and fats, and cross-linked new collagen, laying a 
scaffold for the next phase. 
At the end of the inflammatory phase, the granulation phase begins with an 
influx of fibroblasts and endothelial cells to the wound. Other key cells 
in this phase are macrophages and platelets. Macrophages induce the 
beginning of granulation by releasing platelet-derived growth factor 
(PDGF), tumor necrosis growth factor (TGF)-.alpha., and an epidermal 
growth factor-like substance. Activated platelets release epidermal growth 
factor (EGF), PDGF, TGF-.alpha., and TGF-.beta.. Together these play roles 
in the re-epithelialization process wherein keratinocytes cells migrate in 
sheaths over a provisional matrix consisting primarily of fibrin, 
fibronectin, type V collagen, and tenascin, and produce their own 
fibronectin receptors. 
Once re-epithelilization has occurred, keratinocytes resume their normal 
differentiated form, and matrix formation begins. Matrix formation 
consists primarily of the construction of derma matrix, which is regulated 
by fibroblasts. Chemotaxis of fibroblasts results in the production of 
abundant quantities of hyaluronate, fibronectin, and types I and III 
collagen. These components comprise the bulk of the provisional 
extracellular matrix in the early part of this wound repair phase. 
Hyaluronic acid (HA) creates an open-weave pattern in the 
collagen/fibronectin scaffold, facilitating fibroblast movement. HA 
production falls after about the fifth day of wound healing, and levels of 
chronroitin sulfate in dermatan sulfate increase. Fibronectin deposits in 
the collagen, and wound contraction begins. Biochemically during the 
contraction stage, hyaluronidase and proteinase are present, type I 
collagen synthesis is stimulated, and increased levels of chronroitin 
sulfate, dermatin sulfate and proteoglycans are observed; together these 
restructure the matrix. At the end of the healing process, the final scar 
shows collagen fibers mostly parallel to the epidermis. 
Hypertrophic and keloid-type scars result in extension of scar tissue so 
that a bulky lesion results. A keloid is an exuberant scar that 
proliferates beyond the original wound. It should be noted that keloids 
only occur in humans, often causing burning, stinging and itching 
sensations as well as cosmetic embarrassment. The etiology of unsightly 
keloid formation is not known. However, in keloids, fibronectin formation 
continues for years, while fibronectin formation in normal scars 
disappears within a few days after wound closure. Keloid scars exhibit a 
high rate of collage synthesis in comparison to normal scars, and a low 
proportion of cross-linked collagen. 
Hypertrophic scars sometimes are difficult to distinguish from keloid scars 
histologically and biochemically, but unlike keloids, hypertropic scars 
remain confined to the injury site and often mature and flatten out over 
time. Both types secrete larger amounts of collagen than normal scars, but 
typically the hypertrophic type exhibits declining collagen synthesis 
after about six months. However, hypertrophic scars contain nearly twice 
as much glycosaminoglycan as normal scars, and this and enhanced synthetic 
and enzymatic activity result in significant alterations in the matrix 
which affects the mechanical properties of the scars, including decreased 
extensibility that makes them feel firm. 
Atrophic scars are characterized by a thinning and diminished elasticity of 
the skin due to a loss of normal skin architecture. An example of an 
atrophic scar is striae distensae, also known as stretch marks. Striae 
commonly occur in postpartum women after childbirth and also during times 
of larger-than-average weight gain and also in association with steroids. 
Atrophic scars are sometimes also observed after trauma, infection and 
disease, and may show loss of surface markings and smoothness or dry, fine 
wrinkles over time. 
Formation of scars, especially hypertrophoic and keloid scars, is dependent 
on systemic growth factors such as interleukins and other cytokines, and 
their influence on fibronectin and collagen biosynthesis. Cytokines are 
released and are present in the wound healing process and sometimes are 
released in the inflammatory stage. Growth factors and other cytokines 
vary in the inflammatory stage and are released based, among other complex 
interactions, upon the redox state of the cells. The presence of free 
radicals in the inflammatory stage plays an important factor in wound 
healing. Factors that increase the presence of free radicals, such as 
infection, radiation, and continued trauma, may instigate hypertrophic and 
keloid scar formation. It is important to note that cytokines have been 
suggested to regulate nitric oxide synthetase, which controls the 
formation of nitric oxide, which plays an important role in signal 
transduction in the cells. It has also been suggested that nitric oxide 
synthetase activity is aberrant in keloid scars when compared to normal 
scar tissue (Lim, T. C., et al., Plastic and Reconst. Surgery, 1996, 
98:911-912). Hypertrophic and keloid scars also show inflammatory activity 
that is not seen in mature scars. 
Many scar treatments have been suggested, but few are satisfactory. 
Treatment of keloid or hypertrophic scars have consisted of surgical 
excision followed in many cases by graft application. Pressure has also 
been used to cause scar thinning after injury or scarring. For example, 
pressure bandages placed over scars have resulted in some scar thinning, 
but a pressure of at least about 25 mm Hg must be maintained constantly 
for approximately six months in usual situations for any visually 
observable effect. Ionizing radiation therapy has also been employed. 
Other treatments include application of silicone pads to the scar tissue 
surface, sometimes under pressure provided by an elastomeric bandage, 
application of silicone gel sheets, with or without added vitamin E 
(Palmieri, B., et al., J. Derm., 1995, 34: 506-509), and topical or 
intralesional treatment with corticosteroids. 
Scars are one of the strongest forces driving the cosmetic industry. It 
would be desirable to have alternative, preferably new and improved, 
treatments for scar reduction and remodeling. 
SUMMARY OF THE INVENTION 
It is an objective of this invention to provide compositions and methods 
for the treatment and inhibition of scar tissue, including hypertrophic, 
keloid, and atrophic scars. 
It is another and more specific objective of the invention to provide 
topical compositions and methods for scar reduction and inhibition based 
upon topical application of compositions containing lipoic acid and/or 
lipoic acid derivatives, typically in association with a dermatologically 
acceptable carrier or vehicle and/or a silicone gel sheet, to scars and to 
injured skin sites susceptible to scarring. 
These and other objectives are accomplished by the present invention, which 
provides compositions and methods for the treatment and/or inhibition of 
cutaneous scars, which comprises topical application to the scars or 
injured skin areas of an effective amount of lipoic acid, lipoic acid 
derivatives or mixtures thereof. Some embodiments employ compositions 
containing lipoic acid and/or a lipoic acid derivative in a 
dermatologically acceptable carrier which is applied to diminish or 
inhibit scar tissue. Others utilize a silicone gel sheet having added 
lipoic acid and/or a lipoic acid derivative which is applied to scar 
tissue. 
Ascorbic acid, particularly fat-soluble fatty acid esters of ascorbic acid 
such as ascorbyl palmitate, can, optionally, also be utilized for further 
enhancing the efficacy of the therapeutic or prophylactic treatment. In 
other embodiments, tocotrienols or derivatives thereof or vitamin E 
compositions enriched with tocotrienols or tocotrienol derivatives such as 
tocotrienol-enriched fractions of natural oils are included in the lipoic 
acid composition with or without an ascorbic acid ingredient. Still other 
embodiments include .alpha.-hydroxy acids or their derivatives and the 
like in the lipoic acid composition with or without other optional 
ingredients. 
In a preferred practice of the invention, the lipoic acid (or derivative) 
is applied in admixture with a dermatologically acceptable carrier or 
vehicle (e.g., as a lotion, cream, ointment, soap, or the like) so as to 
facilitate topical application and, in some cases, provide additional 
therapeutic effects as might be brought about, e.g., by moisturizing of 
the affected skin areas. As noted, other ingredients, particularly 
ascorbyl palmitate and/or tocotrienol and/or an .alpha.-hydroxy acid, can 
be advantageously included in the compositions. In one preferred 
embodiment, a silicone gel sheet having added lipoic acid and/or 
dihydrolipoic acid and/or other optional ingredients is applied to scar 
tissue or injured cutaneous sites susceptible to scarring. 
The amount of lipoic acid or derivative thereof (hereinafter referred to 
collectively as lipoic acid or LA for ease of reference) necessary to 
bring about enhanced reduction and/or inhibition of scar tissue is not 
fixed per se, and necessarily is dependent upon the identity and form of 
lipoic acid employed, the amount and type of any additional ingredients 
(such as ascorbyl esters, tocotrienol, and/or .alpha.-hydroxy acids) used, 
the user's skin type, and the severity and extent of the patient's 
scarring. In some typical embodiments, the composition contains from about 
0.1% to about 7 weight %, lipoic acid or dihydrolipoic acid. In one 
embodiment, about 2% to 3% lipoic acid is employed. 
DETAILED DESCRIPTION OF THE INVENTION 
This invention is based upon the finding that lipoic acid and/or its 
derivatives are useful for the reduction and inhibition of epidermal and 
subepidermal cutaneous scar tissue, including underlying membrane and 
connective tissue typically damaged in various types of skin trauma. 
As used herein, the term "lipoic acid" encompasses thioctic acid 
(1,2-dithiolane-3-pentanoic acid; 1,2-dithiolane-3-valeric acid), C.sub.8 
H.sub.14 O.sub.2 S.sub.2, formula weight 206.32. Lipoic acid was 
originally identified as a bacterial growth factor present in the 
water-soluble fraction of liver and yeast. It was found to be necessary 
for the oxidative decarboxylation of pyruvic acid by Streptococcus fecalis 
and for the growth of Tetrahymena gelii, and replaced acetate for the 
growth of Lactobacillus casei. It has been variously known as acetate 
replacing factor, protogen A, and pyruvate oxidation factor. 
Subsequent research showed that lipoic acid (LA) was a growth factor for 
many bacteria and protozoa, and it served as a prosthetic group, coenzyme, 
or substrate in plants, microorganisms, and animal tissues. Elucidation of 
its structure and function determined that it is a co-factor for 
.alpha.-keto-dehydrogenase complexes, typically bound as lipoamide, that 
participates in acyl transfer reactions. Its reduced form, dihydrolipoic 
acid, is a potent sulfhydryl reductant. In aqueous systems, both exhibit 
antioxidant actions. Some experiments have shown that lipoic acid may 
maintain microsomal protein thiols, protect against hemolysis, and protect 
against neurological disorders (mentioned in the introduction of Maitra, 
et al., Free Rad. Biol. Med. 1995, 18:823-829). The protective effect of 
dietary supplementation of LA against ischemia/reperfusion injury in the 
Langendorff isolated heart model has also been suggested (ibid.). LA has 
been used in treating liver cirrhosis, atheroschlerosis, and polyneuritis 
of diabetes mellitus (ibid.). Results of ex vivo rat experiments using 
butathione sulfoximine suggested LA might be useful in preventing 
cataracts (ibid.), and the compound was disclosed as an ingredient with 
others for tyrosinase inhibition in a cosmetic composition for skin 
whitening (Abstract, Jap. Ap. Pub. 63008315). It has also been used as an 
antidote to poisonous mushrooms (particularly Amanita species, Merck 
Index, 11th ed., 1989, entry 9255). 
Lipoic acid derivatives include thioctic acid esters, particularly alkyl 
esters such as fatty acid esters, amides, particularly those isolated from 
or mimicking naturally occurring lipoamides, salts, particularly alkali 
metal salts, anhydrides and specifically includes the reduced form, 
dihydrolipoic acid and its esters, amides and salts. Since lipoic acid is 
both fat- and water-soluble, it is an advantage of the invention that it 
can be used in either lipid- or aqueous-based compositions, and it readily 
crosses cellular membranes and disperses in extracellular and 
intracellular tissue components. Derivatives may also include those 
involving other reactive groups known to those skilled in the art. As used 
herein, the term "derivatives" includes metabolic precursors of lipoic 
acid. Where lipoic acid derivatives are employed, they must be 
functionally equivalent to lipoic acid. 
As mentioned above, lipoic acid is fat-soluble. Therefore, lipoic acid 
preparations can be applied neat to scar tissue. It is an advantage of the 
invention that the active compound is fatty so that it physically 
contributes to the lubrication of affected skin areas to which it is 
applied. 
However, only effective amounts of lipoic acid are needed to reduce or 
inhibit scar tissue, so generally topical application to exposed or 
affected skin sites is accomplished in association with a carrier, and 
particularly one in which the active ingredient is soluble per se or is 
effectively solubilized (e.g., as an emulsion or microemulsion) or 
available when applied in a silicone gel sheet or other linament. Where 
employed, the carrier is inert in the sense of not bringing about a 
deactivation of the lipoic acid or derivative, and in the sense of not 
bringing about any adverse effect on the skin areas to which it is 
applied. 
Suitable carriers include water, alcohols, oils and the like, chosen for 
their ability to dissolve or disperse lipoic acid and any other 
ingredients used in the treatment. Generally, even low concentrations of 
active ingredients in a carrier are suitable, depending upon the 
application regimen and adjunct ingredients employed. Many embodiments 
contain from about 0.1% to about 7% by weight LA or LA derivative. Many 
embodiments contain more than 1 weight % lipoic acid and/or lipoic acid 
derivative, e.g., from about 1.1% to about 3 to 5 weight % LA. One 
efficacious embodiment contains from about 2% to about 3% by weight. 
Examples are illustrated hereafter. 
While the carrier for lipoic acid can consist of a relatively simple 
solvent or dispersant, it is generally preferred that the carrier comprise 
a composition more conducive to topical application, and particularly one 
which will form a film or layer on the skin to which it is applied so as 
to localize the application and provide some resistance to perspiration 
and/or one which aids in percutaneous delivery and penetration of the 
active ingredients into lipid layers of the scarred area. Many such 
compositions are known in the art, and can take the form of lotions, 
creams, gels or even solid compositions (e.g., stick-form preparations). 
Typical compositions include lotions containing water and/or alcohols and 
emollients such as hydrocarbon oils and waxes, silicone oils, hyaluronic 
acid, vegetable, animal or marine fats or oils, glyceride derivatives, 
fatty acids or fatty acid esters or alcohols or alcohol ethers, lanolin 
and derivatives, polyhydric alcohols or esters, wax esters, sterols, 
phospholipids and the like, and generally also emulsifiers (nonionic, 
cationic or anionic), although some of the emollients inherently possess 
emulsifying properties. These same general ingredients can be formulated 
into a cream rather than a lotion, or into gels, or into solid sticks by 
utilization of different proportions of the ingredients and/or by 
inclusion of thickening agents such as gums or other forms of hydrophilic 
colloids. Such compositions are referred to herein as dermatologically 
acceptable carriers. Most preferred for skin are those carriers which are 
fat-soluble, i.e., those which can effectively penetrate skin layers and 
deliver LA to all skin layers. 
Alternative embodiments employ a silicone gel sheet or other linament to 
which LA and/or an LA derivative has been added. These may be pressure or 
adhesive bandages. Silicone gel sheets useful in the practice of the 
invention are typically cross-linked polydimethylsiloxane containing or 
impregnated with LA and/or an LA derivative. It is an advantage of the 
invention that LA augments the effectiveness of previously disclosed 
methods of using silicone pads or gel sheets for diminishing scars (see 
Palmieri, et al., cited above). 
As summarized above, many preferred embodiments of this invention contain 
at least one other ingredient in addition to lipoic acid. For example, 
fat-soluble fatty acid esters of ascorbic acid (vitamin C) may be added to 
the lipoic acid composition in some embodiments. The more 
oxidation-resistant saturated fatty acid esters of ascorbic acid are 
preferred, including, but not limited to, ascorbyl laurate, ascorbyl 
myristate, ascorbyl palmitate, ascorbyl stearate, and ascorbyl behenate. 
Ascorbyl palmitate is used in one embodiment. As denoted herein, where 
fatty acid esters are described, e.g., ascorbyl stearate, compositions 
having predominantly that ester, e.g., predominantly stearate, are 
included. The esters may be prepared using hydrogenated oils or fats, or 
fractions thereof, and contain small amounts of another ester. Ascorbyl 
stearate prepared using canola, for example, commonly contain about 4% 
ascorbyl palmitate. 
.alpha.-Hydroxy acids and/or their derivatives may also be added to lipoic 
acid compositions of the invention with or without added ascorbyl esters. 
As used herein, the terminology ".alpha.-hydroxy acid" has reference to 
and encompasses the general class of organic compounds containing at least 
one hydroxy group and at least one carboxyl group, and wherein at least 
one hydroxyl group is located on the .alpha.-carbon atom. Typically, the 
compounds are organic acids having at least one carboxylic acid group and 
at least one hydroxyl group on the .alpha.-carbon atom, and may contain 
other functional groups including additional hydroxyl and carboxylic acid 
moieties. Most typically, .alpha.-hydroxy acids will have a basic 
structure of lower aliphatic compounds having from two to six carbon 
atoms. 
The "derivatives" of these .alpha.-hydroxy acids most typically will 
involve derivatives related to the carboxyl functionality, i.e., wherein 
the hydrogen or hydroxyl portion of the carboxyl moiety is substituted by 
metallic ions (to form salts), alkoxy groupings (to form esters), ammonium 
ions (to form ammonium salts), as well as other substitution reactions and 
products leading to formation of corresponding lactones, anhydrides or 
amines. However, the derivatives may also include reactions involving the 
.alpha.-hydroxyl group, most notably ketone formation, to form 
corresponding .alpha.-keto carboxylic acids. 
Among the hydroxy acids and derivative compounds useful in the present 
invention are hydroxy monocarboxylic acids such as glycolic acid, 
hydroxymethylglycolic acid, lactic acid, glucuronic acid, galacturonic 
acid, gluconic acid, glucoheptonic acid, .alpha.-hydroxybutyric acid, 
.alpha.-hydroxyisobutyric acid, .alpha.-hydroxyvaleric acid, 
.alpha.-hydroxyisovaleric acid, .alpha.-hydroxycaproic acid, and 
.alpha.-isocaproic acid. Also included are di- and tri-carboxylic hydroxy 
acids such as tartronic acid, tartaric acid, malic acid, hydroxyglutaric 
acid, hydroxyadipic acid, hydroxypimelic acid, muric acid, citric acid, 
isocitric acid, saccharic acid, dihydroxymaleic acid, dihydroxytartaric 
acid, and dihydroxyfumaric acid. Derivatives involving keto groups include 
keto acids and keto esters such as pyruvic acid, methyl pyrivate, ethyl 
pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate, 
and ethyl benzoylformate. In some preferred embodiments, .alpha.-hydroxy 
acids having an aliphatic backbone of 2 to 3 carbons such as glycolic 
and/or lactic acid or their derivatives are employed. 
Tocotrienol may also be added to lipoic acid compositions of the invention, 
alone or in combination with an ascorbyl esters and/or .alpha.-hydroxy 
acids or their derivatives in some embodiments. The term "tocotrienol" 
encompasses natural and/or synthetic counterparts of tocopherol (vitamin 
E) that bear unsaturated tails, and include, but not limited to, .alpha.-, 
.beta.-, .gamma.-, and .delta.-tocotrienols, tocotrienol P25, 
desmethyl-tocotrienol, didesmethyl-tocotrienol, their synthetic 
counterparts, their counterparts having methylated or demethylated chroman 
rings, and mixtures thereof. The double bonds may be cis or trans or 
mixtures thereof. 
Tocotrienol useful in compositions of the invention may be 
tocotrienol-enriched vitamin E preparations obtained from natural or 
synthetic sources, such as those obtained by removal of tocopherol from 
vitamin E compositions. Many embodiments employ tocotrineol isolated from 
natural sources such as tocotrienol-enriched fractions obtained from 
sunflower seed, wheat germ, bran, palm, or other vegetable oils by high 
performance liquid chromatography or other methods, or 
tocotrienol-enriched extracts obtained from barley, brewer's grains oats, 
and other tocotrienol-containing natural products by alcohol extraction, 
molecular distillation and the like. Useful tocotrienols can be 
tocotrienol-enriched fractions or extracts, or mixtures of these with 
vitamin E fractions. As used herein, the term "tocotrienols" includes all 
of these tocotrienol-rich fractions and extracts obtained from these 
natural products as well as the pure compounds and mixtures of any of 
these. 
As with other vitamin E preparations, tocotrienol or tocotrienol-enriched 
preparations include those containing tocotrienol and, in some cases, 
tocopherol derivatives, particularly stabilized derivatives. These 
typically include derivatives related to the phenolic hydroxyl 
functionality, i.e., wherein it is acylated with an organic acid to form 
an ester. Examples of such stabilized tocotrienols include, but are not 
limited to, tocotrienol acetate, tocotrienol succinate, and mixtures 
thereof. However, the derivatives may also include those involving other 
reactive groups known to those skilled in the art. Where tocotrienol 
derivatives are employed, they must be functionally equivalent to 
tocotrienol. Preferred derivatives contain both the chromanol nucleus and 
three double bonds in the hydrocarbon tail. 
While not wishing to be bound to any theory, it is possible that lipoic 
acid is efficacious in the treatment of scar tissue because it is fat- and 
watersoluble and readily disperses in cell membranes and other cellular 
components. It acts as a free radical scavenger and neutralizer, and 
prevents the cross-linking of cell membranes that is seen in scar 
formation, particularly keloid scar formation. By the same token, LA 
modulation of free radicals and other oxidative species affects gene 
expression, including expression of nuclear factor .kappa.-B 
(NF-.kappa.B), nitric oxide synthetase and other mediators at all stages 
of proinflammation and inflammation. Lipoic acid's alteration of lipid 
peroxidation, protein cross-linking, growth factor stimulation, and 
membrane permability may explain its negative effect on scar tissue 
formation. 
The method of the present invention is particularly useful for reducing or 
inhibiting scars caused by minor lacerations, surgical wounds, vaccines, 
burns, and abrasions, as well as stretch marks observed in aging and after 
weight loss or childbirth and various types of fibroses. Generally, the 
composition is topically applied to the affected skin areas in a 
predetermined or as-needed regimen either at intervals by application of a 
lotion or the like, or continuously using a silicone gel sheet, it 
generally being the case that gradual improvement is noted with each 
successive application. Insofar as has been determined based upon clinical 
studies to date, no adverse side effects are encountered.

The following examples are presented to further illustrate and explain the 
present invention and should not be taken as limiting in any regard. 
Unless otherwise indicated, all percentages are by weight. 
EXAMPLES 
Fifteen patients between the ages of 20 and 57 years who had hypertrophic 
scars applied a composition containing 5% glycolic acid and 1% 
.alpha.-lipoic acid in a lecithin base to the scars twice daily for a 
period of three months. The scars were observed and photographed at weeks 
4, 8, and 12. Comparison of the assessment photographs with those taken of 
untreated lesions showed a greater than 50% reduction in lesions in 90% of 
the patients. 
A second study was made on five subjects aged 18 to 30 years having striae 
distensae. Compositions containing 3% lipoic acid, a 1% tocotrienol-rich 
palm oil fraction, and 1% ascorbyl palmitate were applied to the striae 
twice daily for two months. At the end of that period, two of the subjects 
exhibited an 80% reduction in striae, while the remainder showed a 50% 
reduction in striae. 
The papers and patents cited above are expressly incorporated in their 
entireties by reference. 
The above description is for the purpose of teaching the person of ordinary 
skill in the art how to practice the present invention, and it is not 
intended to detail all those obvious modifications and variations of it 
which will become apparent to the skilled worker upon reading the 
description. It is intended, however, that all such obvious modifications 
and variations be included within the scope of the present invention, 
which is defined by the following claims. The claims are intended to cover 
the claimed components and steps in any sequence which is effective to 
meet the objectives there intended, unless the context specifically 
indicates the contrary.