CA1176932A - Wound dressing - Google Patents

Abstract

Abstract of the Disclosure The invention disclosed is a wound comprising a blend of a water-soluble resin material such as poly(ethylene oxide) and polyethylen-imine, and gelatin. Suitable blends are those which can be formed into a continuous film and are adherent to a wound.

Description

This invent:l.on re].ates lo sllrgi.cal. dreL.~illg; and In ~larti.cular to the covering of a wound, lesion or the like with an adherent fi].m to effec.t protection therefor.during the healing process.
A very large number of people are seriously burned in domestic and i.ndustrial. accidents ~very year, an~l the number Or these victims whic11 di.e in spite of intensive medical care is distressinp,ly hign. In Canada, the nurnber of burn injuries requlring hospital admission approaches 25,00() per year. In the United States, about 130,000 are hospitalized annually because of burns;
of these, 70,000 require intensive care at a cost e.~ceeding $300,000,000., 1() and l0,000 die.
The problem of burn treatment is even more acute in areas of the world in which there is armed conflict, since many of the weapons of modern warfare either directly or indirectly cause burns to both military personnel and civilians. In time of war the demands on medical facilities and supplies arc very Yevere, and cne mortality rate arnong burn vi.ctims is greatly increased.
In a third degree burn, the rull tllickness of the skin 11AS been destroyed. The complete absence of "skin" cells in the burned area means that a new coverlng of skin will not sp0ntalleously form thei'e except by the very slow proliferation of hea1.thy cells at tn(~ edgcs of the burn. One treat-nl ment i6 to rernove a thln sheet of healt11y skin from the pati.ent's own body andgrart it on to tlle burned area. Only a partial thickness of skin is removed, so that the ce~lls in tlle remaining layer of skin can regenerate a full thickness in the area irom which the graft was harvestcd. In cases of l)urns coverin~s 50% or more of the bo(ly ~urface area, this graftin~ procedure wi].]. be a lenisthy process carried out in several stages because of the time required ior regeneration of skin on tlle l1arvested c:i.tes.

In th(~ intcrvcr~lny, perio(l l~ctwccn llosl)ltnl i~,ation nnd glllEtin~ two very serious problems are caused by the absence of skin i.n the area of the burn. One of the most important functions of norrnal skin is to re~trict the 3(l loss of body water by evaporati.on. The dramatic incre.lse in water 1.oss caused by ~ie~;t~uction of the skin produces a larise rate of heat loss due to the cooling eff~e~ ~f evaporatlonA In order to maintclin a normal body tellll)erature, the metabolic rate must increase, and a rapid depletion of fat and protein reserves ensues. The other serious problem caused by the absence of skin is bacterial invasion. If this invasive infection is not restricted, the high bacteria population makes the wound unsuitable for skin grafting. The victim of a major burn who receives no treatment for this infection will ultimately die from it.
After removal of the layer of dead tissue (eschar) lying on top of the burned area, it is desirable to cover the wound with a dressing which will control water loss and as~ist the body's own defences in controlling bacterial proliferation until skin grafting can be carried out.
Two natural materials, pigskin and human skin from cadavers, are regarded as very effective burn dressings. These materials can, under favour-able circumstances, adhere to the wound very well and effectively control water loss and infection. The problem is that the body recognizes these biological materials as foreign substances, and begins a cellular response to reject them. Because of this, these biological dressings must be replaced every 2 to ~ days. The other major drawback of these materials is their high cost. Cadaver skin at $80. and up per square foot, and pig skin at about $30.
per square foot, are so expensive that physicians can be reluctant to use them except in cases in which they are essential for survival of the patient.
The disadvantages associated with these biological materials has given rise to the preparation of a large number of synthetic substitutes~ The more effective of these have consisted of a foam, velour, or fibrous mat laminated to a synthetic resin film. Adhesion to the wound occurs by growth of tissue into the interstices of the foam or fibres, and the film controls loss of body water and prevents entry of bacteria. This basic approach has some inherent drawbacks. Since the adhesion depends on ingrowth, some time must elapse before the dressing is firmly adherent to the wound. A more serious problem in many cases has been the tenacious adherence that eventualLy does take place. Removal of the dressing can then be a traumatic procedure which may produce excessive bleeding and leave fragments of the synthetic material in the woundO These fragments may delay the healing of the wound - tx when ski.n grnr~in~ ls cnrri.e'(l ou~.
l`wo laminates of this typc are on the market. One of these, a laminate.of microporous polypropylene and reticulated poLyuret11ane foam is sold under the trademark EPIGARD by Pnrke, ~avi.8 nnd Co. For a vnriety of reasons, EPIGARD has not been widely acceptcd for clinical use 1~y surgeons who treat burn patients. Thc other laminate is sold under tt1e trademark BIOBRANE by Hall-Woodroof Inc. It is a composite of a flexible nylon fabric and an ultra-thin silicone rubber membrane. The high cost of BIOBRANE is a very serious drawback which may limit its acceptance. Inspection of a ¢j commercial sample of BIOBRANE has revealed a number of holes in the ultra thin membrane which are irregularly spaced and easily visible to thè naked eye.
These ho1e; provl(1e external bacterin with ensy accc-ls to the wound.
A radically different type of burn dressing has been developed by IoV~ Yannas an(1 J.F. Burke and co-workers in the Unite(l States. Their approach has been to procluce a materia] which slowly biodegrades at ti1e wound surface and i9 assimilated by the body. During this biodegradation, the dressing not only restricts wnter loss and controls infectio~ ut also acts as a tissue culture meclium. Ult;mate]y, migration of epic1ermal cclls for111s a new skin over the wound ~ite. At the present state of develol)meilt of their film, the healing

2() of ~nly relatively small wounds by tl1is elegant process is p0s-1ible. The film can be used to advantage on large wounds, but skin graEting is still required at a later stage. A commercial form of the Eilm, when avai]able, will probably be quite expensive.
In United States Patent No. 3,164,560 which issuec1 5 January l965, John F. Suter teaches the use of a gelatin/polynlky]ene ox;de comyosition in Lhe form of continuous films o~ improv((1 exl:(nsibi1-ity nn(1 rle~ ility a~
compared to gelatin fi]~ms ancl which have imploved te1lsilc strcngth and tough-ness as compared to yplyalky]ene oxide films. The iilms are used, for example, in packaging and photographic supplies. There is no teaching or suggestion O of use as wound dressings.

German pllb]is11ed p~tent al)l)licatiol1 No. 2,914,822 oF ]8 October 1979 in the name o~ i~nitika Ltd., teaches a material for the hell3ng of wounds whicll colT~i-risc~s l)lood coa~ukltlon rnc~or X[I[ an-l a wlde vnrlety of polymers including gelatin arld other polymers, such as po]y~ethylene oxide) and poly-etl1yleneimine, but no~ ln combination. Any materials of which blood coagula-tion factor XIII is a significant component would be expected to be very expensive.
It is therefore an object of the invention to fill the need for an effeetive yet inexpensive wound dressing.
~() According to Lhe inv~ntion, ~ wound ~Iressin~ is provid~d, comprising a t~lend o~ a water-soluble resin material and gelatin, in the Iorm oL a con-tinuows wo~ln(l-a~ (rent film.
Il is important to the inven~ion that the polymers uaed in the prociuc~ o~ tlle rilm are wnL(~r-sol~ll)l( nl1(l tl~c resullin~ Eilm aclheres to the wound with<)ut the need of additional securill~ d(vices. Also important is the ease of release of the Lilm from the wownd. Preferably, the Lilms should be sufficiently transparent to permit observation of the wound and the posslble appearance of purulence be11eath the Film.
In particwlar, eombinations ~f ~elatin and po1y(ethylel1t oxide) (PEO);
and ~elati(T nnd polyethyleneimine (PLI) have beerl Eound to be especially eLfective.

re~S bf ~ e n~ r, ~ l r-( ( "r,~ L ~ J~lv~ (IOr"~ c pi~s, and the Eo110win~ model wowndq were created to simu~clte those encounderedin elinical practice (i) Dollor ffitl`. l'rom nr~aJ 011 th(` ba(k m(;lsul ill~' ~r x 3 crll, ;d)oul. 0.3-0.4 mm oL skin were removed with a Si]ver dermat:olne~ rtlis top layer of skin is typical of the rnaterial wse(l for sk;n ~raftin~, and the area ~176932 .. ` ~
. . .

from which it i.5 removed is known a9 1 dorlor Hlte. Donor sites in human paticnts ~houLd be proLecl:ed from water 108s and infactlon rmtil thsy heal.
(ii) Exposed fascia. Small areas of healthy skin and the layer of fat beneath were surgically removed, thus c~posing the tl~in, dense tissue covering the muscle. Tllis thin covering is called Eascia.
(iii) Full thickness burn~ ~urns were administered under anaesthetic using a . .
custom made, electrically heated template measurlng 5x5 cm. The burns destroyed the full thickness of the skin. The site of the burn was ]() treated in one of two ways: -a) ufter 5-7 clays the (Jcacl tlssuc~ (cscllar) in tbe burlled area was removed surgically, thus eXpOSi11g a surfacc of subcutaneous fat.
bj after 14 days, the eschar was removed, exposing granulation tissue which had formed beneath it.
Those familiar with scientific studies of the problem of temporary closurè o ]arge, open wounds caused by the loss of skin know that the single mo~t important property of a prosthetic skirl material is adherence to the wound base. The gelatin-PE0 and c~elatin-PEI films of the present invention showecl very ral)id initial ad}lcrencc to the moist suriacc of cach of the modcl 'Jj) WOllnCIS descrLhed abovc. Firm adhcsioll scl(k)rn rccluirc~d morc thnn 1-2 minutes, and in some cascs excellent adhesion was obtained on contact. In contrast to many other dressing materials, there Wa8 no necd to secure thc films on the wounds with sutures, staples, tape, ctc., ulltil significant aclhcsion took place.
The rapld inltial adhesion of gelatin-PE0 and ~e'latin-PRI films reguires that the ~urface of the wound bc moist. The natura] moi~t-lre suppliecl by the wound is often quite satisfactory. If the wollnd is too clry, it can be moistened with water, physiological saline, or other suitable fluid; if the wound is too wet, rapid'adhesion may not occur, but thc! excess fluid can be removed by use of absorbent fabric such as surgical gau~e. In practice, prepar-

3() ation of the wound ahd adjustment of tlle moistu~e level to olle suitable forrapici àcltlésion ~f the films is an easily acquired art.

- ` ~176932 ~ he l.engt11 of time t1~;~t ~1~e ge1.nti.n-PEO and gelntin-1'EI ri.1rnr remained adherent to model wounds depended on several factors. Generally, over a peri.ocl c~L several days the7e was fl gradual loss of aclhes:ion at the edges. This loss of edge adhesion i.s due in part to the upward force exerted by a growing ].ayer of cr~1sty exudate which forms ia~ the small nrea between the edge of film and the edge of the wo~1nd. Gc~od acdhesion 3.n the central.
part of the wound persisted in some cases for as long as 14 days. Even after periods as long as this, the areas to which the films had maintained good adhesion appeared healthy and rree of frank i.nfeetion, even though no bacteria-, eidal agent of any kind was applied to the wound at any time. In the case ofburn model (iiia), small areas of dead tissue are sometimes left on top of the wound after removal of the eschar, and the deeay of this tissue may result in t]le formatioT1 o'c small pockets o.~ p~1ru1cnce beneath the film.
Adhcsion to donor sites ror periods of 6 to lO days has been observed.
Periods of thi.s cluration, depending on tl1e thlckness of the layer of skin nriginall.y removed, t1)e woun(1 i.s heal.(cl almost complet(ly, wi.thout any obvious com~licatic)rls.
TllUS, flll aclvantal!~c of fi.lms Or tl1c preslnt :inventi.on ~vcr drcsslngs wllic11 depcnd on i.ngrowtll ror adl1es;or1 i~s t:heir ~ase Or -removcll~ lly merely soaking the rilms adhering to the wounds in tap water or physio].o~ical saline ror lS minuteri at thc temperflture Or Lhe wonnd surface, the fl~ esi.c~n is greatly diminished and the fi.lms become s0fL. They can then be removed by ~entle scrapi11g or in sornc cases by simply peeling tllt`m of r.
~ nother distinct asset of the gelaLin-PEI material and in most cases o~ the gelati11/PEO material is that 111cy are su:l[icicl1t1y transpfltent wl1en adherincn to the wound to permit vi.sufll cletection o:f areas of ser:;c~us infection without removal of the film.
Rererrir1~ s~ irical1.y to po:l.yct11yl(ne oxidc ns Lh(~ watcr-soluble polyJner, it was foùnd t11at good adhesion to model wo11nds on (1omestic pigs occurred in t-1le case oE films comE)osed oE about 7 parts by weig1~t gelatin and abo~t g pàrts By weight PEO which were prepared using the following combina-ti~ns ~f t~es oi gèlatln ancl PEO:

gelatin ol Bloom 250 anrl PEO of MW l7,500 geiatin of Bloom 250 and PEO of MW 30(),000 ~elatin oI ~loom 150 and PEO Or MW loo,ooo ge]atin of Bloom 150 ancl PEO of MW 400,000 The desirable property of adhesion to a wound surface will doubtless not be restricted to these combinations, ~nd gelatins with Bk)om numbers in the range 80-290 are expected to be suitable, as are grades of PEO witll mole-cular weigllts in the range 14,000 to 10,000,000. Solutions of PEO with mole-cular weights above about 400,000 must, because of their high viscosity, be 1) very dilute to permit easy mixing with other components. E`ormation ~f films irom higllly dilute solutions i8 possible, but re(~uir~r, ev~poration of rela-tively l~rge amolmts of water.
It is expected tllat a wide range of ge]atin to PR0 ratios will pl-ocillce userul woun(l ~IresYirlgs, altllollKII tlle moLC s~ al)le mnterialff contain between 2 and 0.2 parts by weight PEO per part of weight of gelatin. Gelatin-PEO film~ having the F)referred ratio or 7:5, an(l comp()std of the preferred gelatin of Bloom ~250 and the preferrr-rl PEO of MW 17,500,are prepared from solutions containing the gelatin and PEO in 115-211 parts distil]ed water.
The solution is acidiIied until tl-e pll is 3 and thell poured onto a flat surface !) to dry in air at room temperature. The resulting dry film gcnerally has a thickness oL 0.08-0.20 mm, depending on ~he amount of water used. The propor-tion of water given above is inten(led only as a guide. Increase(l amounts of water can produce films thinner thall O.Oo mm, ancl decrease(] amolmts can pro-cluce films thicker than 0.20 mm. ~ range of tllicknesr;es of fi]ms r;uitable as wound dressings is envisaged, from about 0.06 to 0.30 rNn. Iilm6 that arr too thin may disolve in the liquid emanating from the wound. Films that are too thick will have insufficient flexibility and gre.ltLy reduced permeability to oxygen. The preferred thickness or gelatin-PEO films for donor sites is 0.15 mm, and for wounds of types (ii), (iiia) and (iiib) is 0.l0.
The preferred acid used to lower the pH of the gelatin-PEO solution is phcsphoric acid, but other mineral and organic acids may be substituted.

1~76932 'r~ r/`r(`rr(`(~ ifi 3~ r~ f;(~r~l] nf~ rll ~Ir(f~ ; c(~ lf;o I)c j,iv(`n by pll values from about 4 to 2. pH values that are higher t11an about 4 wi.llnoL pro(l~ice ~ansparer1L films.

Example 1 5 parts by weight o:f "Polyethylene Glycol Compound 20 M" o:E ~nion Carbide (PEO of average MW 17,500) were dissolved in 66 parts of distilled water by stirring at room ternperature. 7 parts of gelatin of Bloom 250 (Knox brand, from Thomas j. Lipton Co.) were dissolved in 145 parts of dis-tillcd water at about 50 C. The two solutions were mixed whi]c the latter was still warm, and the ph was adjusted to 3 with 85% aqueous phosphoric acid.
This acidified solution, which, in order to prevent ge]ation, was not allowed to cool below 30 C or remain in a quiescent statc for an extended period of time, Wc1S poured onto a rlat, smooth ~sh(-et of polystyrene and left to dry i~l air .IL 1O(JIII l.eml)c1lltur(. r~hcn dry, tllC tll:ic1c11c-,s Or Lll(` ril.,n WRf7 al)Ollt 0.10 mm, T1lrning now to polyethylenimine as the water~soluble polymer, films composcd of ~clatin of B].oom lS0 and a gra(tc Or P~l called ~Po]ymin P" from I~SF, and havi.ng we:Lght ratios of gelati.n to PEI of 7:3, l:]., 45:55, 40:60, and 35:65, werc prepared and foul1d to have similar properties in the dry st/~te. Botll thc l:l and 35:65 rnateria].s were test-(1 0-1 mo(1e1. burn wounds and found to give satisf-actory adhes:ion. The preferred rati.o Ls l.:l, but ratiof; fal].ing in the range 9:1 t.o 3:7 s11olll(l b(~ fil~i.tR!)1C. Af; :i.n tllc car;c of the gelatin-PE0 film, the~ invcntior1 is n0t restricted Lo onc grade of gc].atin or to a specific gradc of PEI. Tll(~ prcr(rr((i cmbodi.m(n~ oL the gclatin-PEI filnn is prcpared by dissolvi.ng ]. pa1L of gelat:lT1 O~r n1O(Im 1.50 and 2 parts Or a 50% a~iueous solution o:f PEJ ca].].((l ~PolyTni.n P" i.n 2l-29 pl1rts disti.lled ~ater, pouring the sol~tion onto a flat surface, and a].lowing the film to dry in air at~rooln temperature. This gives a film of thickn(ss 0.15 - 0.25 mm, depending on the amo1m~ of water used. The thickner.~q of the preferred gelatin-YEI ;~l~i iised on model ~aunds has rangcd from 0.15 to 0.35 ~n. l`lle preferred hickness i.s ~)~20 m1n f(1r do1-1or ~ite~, ant1 0.15 mm ror wo1.1nc1-; o~ typc3 (il), (iiia) and (iiib). In general, the range of useful thicknesses for felatin-PEI films should be about 0.05 to 0.35 mm~
Example 2 l part gelatin of Bloom 150 :from the Davis Gelatin Co. was dissolved in 20 parts distilled water at abouL 50C snc1 this solution wa~ mi.xed with a solution of 2 parts of a commcrcial 50% aqueous solutiol1 of "Polymin P" (PEI) made by bASF in 9 parts of distilled water. The resultinp soluti.on was coo].ed to 25 to 30C and pourcd ontc1 a ilat, L;nnoot11 shect o polystyrcrle and (; left ~o ary in air at room temperain1re. Wilen dry, t1~e thickness of the fi.lm was about 0.l5 mm.
In biocompatibili-y tests, subcut1neous implanati.on of gelatin-PE0 and gelatin/PEI spesimens in B rabbit caused no haemorrhage, hyperaemia, forma-tion of exudate, or formation of capsule after 72 ho~1rs. In further tests on Kelatin/PE0 specimens no Sigll.'i of toxicity were detected over a 3 day period after intravenous injection i.nto mice of an extract of the fi.lm in physiologi-cal saline and nv si~,ns o toxicity were observcd ovcr a period of 3 days when a solution oi the il.m in p11ysi.o10gicaL sa]i.nc was injectecd intrape-rltoneally in rr1ice. The rate and naturc o~ the hcal.ing in the prcsencc of a palatin/PE0 ~) rilm wa.s cssc1ltialLy s:i1nilar Lo thnt of a ccn1tral wou11(1.
It is expcc~ed that thcse matcrials would bc usc~c1 as (i) temporary dressinps on thi.rd depree burn wounds after removal of the dead tissue and up to the timc at which skin grafting could br. car-ricd out wlth changing of the c1rcssinps as required, (ii) (1ressinps on donor sitcs until hcaling was complete or virtually complete. In addition, it is antici1)ated that these mater;.als would be ufie~-1l as d-ressings on c1ebri(Jcd sccon(1 dcgre( burn-: until l1ealing was complete or nearly complete. The sterili~ed dressings could be made avail-able in sealed po~Jc1~es ~hic1~ coulcl be stolc(J a- ambic1lt Lcmp(rctturc and rela-ti.ve humic11ty, Ahd they could bc ucied as s00n ns thi~y hac1 bccn rcmoved from fi the pouches; The packaged dressings could be used in any medical facility c'd~abi~ o~ treatin~ iiidividuali who hnvc s-1~fcred mcljor b~1r1li.

~76932 Any person skilled in the art wil1 reali~e that the advantages oE
the materials oi this invention will be enh~1nced by th! incorporation of various ~acteriacides or other suitable medicaments which can diffuse out of the films into the wounds. It is appreciated that a strengthening of the films by any of the polymer cross-linking procedures known to tho~e skilled in the art, such as gamma irradiation, is within the scope of the invention. It will also be appreciated that although this description emphasi~es the utility of the m~terials according to thc invcntion AS bUrll drCSSillg8, they (:an AlSO
be employed in thc treatmcnt of mnjor ski1l discontinuities not (IU(! to tllcrmal i injury.

- lO -~76932 .

Supplementary Disclosure It has now been found by applicant that the flexibility of pre-formed films described in the principal disclosure can be increased.
A common method of improving the flexibility of filrns o~ water-soluble polymers is to add a compatible plasticizer such as glycerol. It is believed that in many cases such additives cause plasticization of polymeric films by increasing the amount of water that they contain at equilibrium rather than by acting as plasticizers themselves. Part A of Table I below shows the effect on flexibility of the addition of various plasticizers to gelatin/PEI and gelatin/PEO films.
'~ The pH of the standard solution~~ is cast to form gelatin/PEI
films is about 10.5. Part B of Table I below shows the effect of adding various acids to change the p}~ of the standard solution used to prepare the ~elatin/PEI film.

Table I. Flexibility properties of modified gelatin/PEI and gelatin/PE0 Eilms.

Part A. Effect of plasticizers on gelatin/PEI and gelatin/PEO films. (see note 1) Film Film Flexibility at 20C and 46% relative humidity (see labelcomposition note 2) (batch ~ est Fractures Number of Weight (g) film when cut successive required to force thickness with creases 15 mm wide sample (mm) scissors causing through 6.5 mm fracture gap (see note 3) (see note 3) _ DGM-F-78-Agel./PEI 0.131-0.001 yes l 40.4 (a) 1.1 DGM-F-87-Agel./PEI/ 0.130-0.002 yes l 23.2 (a) sorbitol (see note 8) 5:5:2 DGM-F-78-Bgel./PEI/ 0.130-0.001 no >6 13.0 (a) glycerol 5:5:2 DGM-F 81-A gel./PÉI 0.130~0.00l yes 1 33.8 (b) 1:1 _ _ DGM-F-81-Bgel./PEI/ 0.133-0.002 yes 2 37.8 (b) PEG-1500 (slight) (see note 6) 5:5:2 DGM-F-82-A gel./PEI/ 0.162-0.001 no 3 31.2 (b) PEG-300 (see note 7) 5:5:2 (see note 4) DGM-F-85-Agel./PE0 0.091-0.001 no >6 37.8 _ _(c) 7:5 _ _ DGM-F-88-Cgel./PEO/ 0.091-0.001 no >6 24.6 (c) sorbitol 7:5:2.5 DGM-F-88-Agel./PEO/ 0.092-0.001 no >6 18.0 (c) PEG-300 _7 5 2 5 DGM-F-88-Bgel./PFO/ 0.091-0.001 no >6 ~3.8 (c) glycerol _ 7 5:2.5 .
, c~

~17693Z

Part B. Effect of lowering pH of gelatin/PEI solutions (Note 1) with various acids before casting.
Film Acid added; Flexibility at 20C and 46% relative hu~idity (see label pH of solu- note 2) (batch~) tion before Test Fractures Number of Weight (g) casting film when cut successive required to force thickness with creases 15mm wide sample (mm) scissors causing through 6.5 mm fracture gap (see note 3) (see note 3) . . .. . . _ .
DGM-G-12-A none; 10.5 0.128-0.002 yes 2 21.6 (d) _ _ DGM-G-13-A H2S04; 7 0.130-0.002 no 4 27.2 (d) DGM-G-12-B citric; 8.5 0.130-0.001 yes 1 24.6 (d) (see note 5) DGM-F-86-A none; 10.5 0.129-0.001 yes 1 33.8 (e) DGM-F-86-C H P0 ; 7 0.130-0.001 yes 6 36.4 (e) (see 3 4 note 9) _ _ DGM-F-86-B HCl; 7 0,130-0.001 no >6 6.2 (e) DGM-G-3-A none; 10.5 0.130-0.001 yes 1 28.2 (f) DGM-G-3-B HCl; 9.5 0.128-0.001 no ~6 14.0 _ (f) DGM-G-3-C HCl; 8,5 0.130 no >6 7.4 (f) DGM-G-3-D HCl; 3.5 0.147-0.001 no 1 21.6 (f) (see note 4) Footnotes to Table I
1. For gelatin/PEI films, gelatin was Bloom -~150 (retail grade) from Davis Gelatine Co. For gelatin/PE0 films, gelatin was ~nox Brand, Bloom ~250 from Thomas J. Lipton Ltd. PEI was Polymin P~ from BASF and PEO was Polyethylene Glycol Compo~md 20M (MW 15,000 - 20,000) from Union Carbide. For Part B, gelatin /PEI film used is in a weight ratio of 1:1.
2. Films were equilibrated at 20 - 2 C and 46 - 2% relative humidity for 10 hours prior to the tests.

3. See text.

4. Note that the thickness of these films differs considerably from the others within their batch.
v ~

~17693Z

5. Citric acid was added until the solution became milky, at which point the pH was 8.5. The composition of the mixture was gelatin/PEI/citric acid = 2.1:2.1:1.

6. PEG-1500 is polyethylene g]ycol of molecular weight 1500. The film was very hazy.

7. PEG-300 is polyethylene glycol of molecular weight 300. The film was slightly hazy.

8. Sorbitol is HOCH2-(CHOH)4-CH2OH, molecular weight 182.

9. The H3PO4 produced a cloudiness at about pH 8 which increased as the pH was lowered further to 7. The dry film from the cloudy solution was clear.
A method was devised which permits rapid flexibility measurements to be made. The numbers obtained are dependent on film thickness, and consequently measurements were carried out as far as possible on samples of the same thick-ness. A simple device (not shown) having two sets of wheels of diameter 9 mm were placed on parallel axles so that the gap between the wheels, when pushed away from each other against their respective axles, was 6.5 mm. The test film was placed on top of the two sets of wheels and a rod 5.0 mm in diameter was placed on the film perpendicular to its length and parallel to and between the two axlesO Weights were placed at both ends of the rod. The combined weight of the rod and the weights which caused the film to bend enough to drop between the rotating wheels was taken as an indication of the flexibility. In practice, the rod was placed gently on the film and observed for a period of 10 seconds.
If the film did not bend enough to allow the rod to pass through the gap, the rod was removed, weights were added at the ends in dumbell fashion, and it was gently placed on the film again. This was repeated until the rod fell through.
In three cases, after the measurement had been completed on a sample, the same specimen was turned over and the measurement was repeated by bending the film in the opposite direction~ The same results were obtained.
The value given by this method is a function of the width of the film as well as the thickness, and a standard width of 15 mm was used. The length of the test specimen was about 30 mm. A rotating wheel system was chosen because there would be a subs~antial friction force if the film had to pass between a gap defined by immovable surfaces. The results are tabulated in - . , ~i7693Z

~able I above.
In addition to a flexibility test, it was desirable to have a simple procedure for measuring the relative brittleness of the film materials. Two tests were used. One was an examination of the edges of the film for fracture lines after cutting with high quality scissors. The other was a crease test in which one end of a specimen was folded to meet the opposite end and the loop between the joined ends was pinched tightly between thumb and forefinger. The same ends of the film were then moved to fold the film in the opposite direction, and the loop was pinched along the same crease line as before. This was repeated until the film had broken completely at the crease line. The test was stopped if the film had not broken by the sixth creasingO Most of the films which have a value of " 6" in Table I showed no sign of fracture after the sixth creasing.
Results given by all three of the above tests depend on the moisture-level in the film. All of the films in Table I were exposed to an atmosphere of 20 + 2C and 46 + 2V/o relative humidity for 10 hours immediately prior to, and dùring, the tests.
Results For both the gelatin/PEI and gelatin/PEO films, glycerol was the most effective plasticizer. Polyethylene glycol-300 and particularly polyethylene glycol-1500 (numbers referring to molecular weights) were poorly compatible with the 1:1 mixture of gelatin and PEI.
The great improvement in flexibility caused by the adjustment of the gelatin/PEI solution of pH 7 was unexpectedO The use of the polybasic acids H2SO4 and H3PO~ appeared to decrease flexibility as measured by the weight reqllired to force film specimens through a 6.5 mm gap, but slightly increased the brittleness as assessed by the crease test. Citric acid was added until the solution become cloudy; the pH at that point was 8.5. Citric acid also caused, if anything, a decrease in flexibility.
Many of the modified films were subjected to short term adhesion tests on experimental wounds. In general, the modified films were as good as the standard films in terms of initial adhesion, but were not as good after a period li7693Z
of two hours because of a reduction in either adhesion or physical properties.
The gelatin/PEI film obtained from a solution adjusted to pH 7 with HCl al)peared to be the best of the modified films tested. This, combined with its superior flexibility, makes it a preferred material.
It has also been found that the preformed films according to tne invention have bacteriostatic activity. For example, the bacteriostatic activity of a 0.16 mm thick sample of the preferred gelatin/PEI film described in the principal disclosure at page 8, line 24 to page 9, line 3 was demon-strated as follows. Agar plates were flooded with a broth culture of a test organism. Excess broth was sucked off a disc 5 mm in diameter of the gelatin/
PEI film was placed on top of the thin layer of organisms. The plates were then incubated at 37 overnight ~about 18 hours) and examined for zones of inhibition of microbial growth. Two gram-positive bacteria, two gram-negative bacteria, and two fungi were tested. The film exhibited substantial inhibition of the growth of all six organisms. They were: Micrococcus luteus, Staphylo-COCCU8 aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Paecillomyces variotii. P. aeruginosa, S. aureus, and C. albicans are three oE
the most common burn wound pathogens.
It has now been found that satisfactory gelatin/PEI films can be made using gelatin of higher Bloom ~t than 80 - 290 as recited in the principal dis-closure .Example 3 1 part of de-ionized gelatin of Bloom ~ 300 from KIND and KNOX was dissolved in 9 parts of distilled water at about 50C and this solution was mixed with a solution of 2 parts of a commercial 50% aqueous solution of Polymin P~ (PEI) made by BASF in 10 parts of distilled water. The resulting solution was cooled to 25 - 30C and poured onto a flat, smooth sheet of poly-styrene and left to dry in air at room temperature. When dry, the thickness of the film was about 0.18mrn.
It is now contemplated that useful gelatin/PEI and gelatin/PEO films can be made using gelatin with Bloom ~ 's extending up to 350.

Claims (34)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A wound dressing, comprising a blend of a water-soluble resin material and gelatin, in the form of a continuous wound-adherent film.

2. A wound dressing, comprising a blend of a water-soluble synthetic resin material selected from the group consisting of poly(alkylene oxide) and polyalkylenimine, and gelatin, in the form of a continuous wound adherent film.

3. A wound dressing, according to claim l or 2, wherein the water-soluble resin material is selected from the group consisting of poly(ethylene-oxide) and polyethylenimine.

4 A wound dressing according to claim 2, wherein the water-soluble synthetic resin is poly(ethylene oxide).

5. A wound dressing to according to claim 5, wherein the gelatin has a 0.2-2 parts poly(ethylene oxide) per part of gelatin.

6. A wound dressing according to claim 5, wherein the gelatin has a Bloom number of 80-290 and the poly(ethylene oxide) has a molecular weight of 14,000 -10,000,000.

7. A wound dressing according to claim 6, comprising gelatin and poly-ethylene oxide) in a weight ratio of about 7:5.

8. A wound dressing according to claim 7, wherein the gelatin has a Bloom number of about 250 and the molecular weight of poly(ethylene oxide) is about 17,500.

9. A wound dressing according to claim 4, 6 or 7, wherein the thickness of the continuous film is 0.06 to 0.30 mm.

10. A wound dressing according to claim 4, 7 or 8, wherein the thickness of the continuous film is 0.10 to 0.15 mm.

11. A would dressing according to claim 2, wherein the water-soluble synthetic resin is polyethylenimine.

12. A wound dressing according to claim 11, wherein the blend comprises gelatin and polyethylenimine in weight ratios of 9:1 to 3:7.

13. A wound dressing according to claim 12, comprising gelatin and poly-ethylenimine in a weight ratio oi about 1:1.

14. A wound dressing according to claim 13, wherein the gelatin has a Bloom number of about 150.

15. A wound dressing according to claim 14, wherein the thickness of the continuous film is 0.05 to 0.35 mm.

16. A wound dressing according to claim 15, wherein the thickness of the continuous film is 0.15 to 0.20 mm.

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE

17. A wound dressing, comprising a blend of a water-soluble resin material, gelatin and a compatible plasticizer, in the form of a continuous wound-adherent film.

18. A wound dressing according to claim 17, wherein the water-soluble synthetic resin material is poly(ethylene oxide).

19. A wound dressing according to claim 17, wherein the water-soluble synthetic resin material is polyethylenimine.

20. A wound dressing according to claim 17, 18 or 19, wherein the plasticizer is glycerol.

21. A wound dressing according to claim 18, wherein the gelatin has a Bloom # of 250 and the poly(ethylene oxide) has a molecular weight of 15,000 to 20,000.

22. A wound dressing according to claim 21, wherein the thickness of the film is about 0.09 mm.

23. A wound dressing according to claim 17, 18 or 22, comprising gelatin, poly(ethylene oxide) and glycerol in a weight ratio of 7:5:2.5.

24. A wound dressing according to claim 19, wherein the gelatin has a Bloom # of 150 and the polyethylenimine is Polymin p?

25. A wound dressing according to claim 24, wherein the thickness of the film is about 0.13 mm.

26 A wound dressing according to claim 17, 19 or 25, comprising gelatin, polyethylenimine and glycerol in a weight ratio of 5:5:2.

27, A method for making a continuous wound-adherent film, said film comprising gelatin and polyethylenimine, the method comprising a) dissolving gelatin and an aqueous solution of polyethylenimine in distilled water;
b) adding to the aqueous solution a suitable acid to lower the pH
of the solution to 7-9.5;
c) pouring the solution onto a flat surface; and d) allowing the solution to dry in air at room temperature to form the film.

28. A method according to claim 27, wherein the acid is selected from the group consisting of H2SO4, H3PO4 and HCl.

29. A method according to claim 28, wherein the acid is HCl.

30. A method according to claim 29, wherein the pH is about 7.

31. A method according to claim 30, wherein the gelatin has a Bloom # of 150 and the polyethylenimine is Polymin P?.

32. A method according to claim 31, wherein the weight ratio of gelatin to Polymin P? is 1:1.

33. A wound dressing according to claim 19, wherein the gelatin has a Bloom # of about 80 - 350 and the polyethylenimine is Polymin P?.

34 A wound dressing according to claim 33, wherein the gelatin has a Bloom # of about 300.