CA2123798A1 - The use of biomaterials for tissue repair - Google Patents
The use of biomaterials for tissue repairInfo
- Publication number
- CA2123798A1 CA2123798A1 CA002123798A CA2123798A CA2123798A1 CA 2123798 A1 CA2123798 A1 CA 2123798A1 CA 002123798 A CA002123798 A CA 002123798A CA 2123798 A CA2123798 A CA 2123798A CA 2123798 A1 CA2123798 A1 CA 2123798A1
- Authority
- CA
- Canada
- Prior art keywords
- polymer
- use according
- monomer
- curable composition
- repair
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F265/00—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
- C08F265/04—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of esters
- C08F265/06—Polymerisation of acrylate or methacrylate esters on to polymers thereof
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Materials Engineering (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
- Paints Or Removers (AREA)
- Graft Or Block Polymers (AREA)
Abstract
A curable composition of a monomeric heterocyclic acrylic or methacrylic ester and an acrylate or methacrylate polymer is used to promote tissue repair, especially cartilage repair.
Description
WO 93/09Bl9 ` , P~/GB92/02128 ,..~, 212~7~J8 THE USE OF BIOMATERIALS FOR TI~SUE REPAIR
This invention relates to the use of biomaterials for tiSSUQ
repair and is particularly concerned with the use of physiologically acceptable polymeric materials in such tissue repalr, especlally cartilage repair.
The use of physiologically acceptable polymeric mater~als in the preparation of biomedical appliances sueh as hearing aids, artificial eyes and dentures is well known, as is the use of polymeric mater~als as bone cements in the fleld of orthopaedics.
Such polymeric mater1als are often used in the form of a curable composition which is initially in a fluid9 semi-liquid, dough-like or other mouldable form, but which cures or hardens at the temperature of use to form a strong solid of physical properties . .
dependent on the use to wh1ch it is being put. Examples of such curable compositions are to ~be found in International Patent Application No. W089/03695 ànd GB Patent 2 107 341 which disclose ~ i the use of curable~compositions comprising a powdered methacrylate polymer mixed with a~methacrylate monomer. For such app7ications 20 ; as the preparation of~hearing~ aids, artific1al eyes and dentures which require; dimens~onal ~accuracy, it is important to prov~de composit~ons of low linear curing shrinkage and GB Patent 2 107 341 is directed to such an ~aim. For~use as bone cement it is important to~ prevent subsequent ~failure at the bone-cement ~1nterface and,~ to~ thl~s~ end~,~ W089/036~5 discloses the inclusion of a cell~ growth~stimalant~such ~as~human ~rowth hormone so as to increase~the rate~of~healing~ of, for~example, a bone fracture and give a~Joi~nt~of ~ncrease~strength. The emphasis in the previous use~of the~se curable composi~tions has therefore been directed to ;~ 30 attaining bonding strength and/or material strength and dimensional stability dependen~ on the intended use.
~, ~: :
:
:
/6~9 2/ 02l28 ; ` .111 ~ MAR~H l994 212379~
Surprlsingly, it has been found that certain curable I: compositions comprising a methacrylate polymer mixed with a suitable unsaturated monomer can be employed to promote ti;sue repair, with or wlthout the addition of cell growth stimulants : S such as human growth hormone. Even more surprisingly, it has been found that sUch compositlons can be employed to promote cartilage repair.
Cartilage, whi:ch dlffers from bone in construction, has previously been considered substantially non-repairable. Attempts lO to repair cartilage currently include the introduction of carbon bres behind ~the~ eartilage; however such carbon fibres are brittle and, while a fibrous tissue forms in the implanted area, the resulting growth is not that of true cartilage composed of chondrocytes expressing their normal phenotype and producing their 15 ~ own matrix componen:ts. Implantation of cartilage components and hydrogel compos~tions have also been tried with limited success.
There ~s therefore~a~ great need for a breakthrough in the treatment of~cartil~age~defects.~
The~present invention~comprlsQs the use of a monomer/polymer 20 m1xture~ ~n ~ the~ preparat~on of a~ curable composi~on for :introduction t o~a~ s;ite~ requiring tiss~e repair in a human or animàl body ;;:in order~ to promote: said t7ssue repair, the mono~er component~being~sele~ct-d~from monomerlc ~sters of general formula I
CH2~C-C0O'cH2'mx (I) wherein~R~ is~a~hyd~rogen~atom or a methyl group, m is 0, l 30 or 2, and X is a 3 to 6 membered heterocyclic ring and the ; polymer component is selected from acrylate and methacrylate Ipolymers and copolymers~thereof. Pre~erably X is an oxygen containing heterocycle.~
According~;to a~further~aspect of the invention there is ; 35 provided a process for: the promotion of tissue repair . ~
. , ~:: ' :~
¦ PCT 1~ : J.c~ti3,l ¦
WO 93/()9819 P~/GB92/02128 .` ., 21~3798 comprising introducing to a site requiring tissue repair in a human or animal body, a curable co~posltion comprising a monomer component selected from monomeric esters of general formula I above and a polymer component selected from acrylate and methacrylate polymers and copolymers thereof and causing or allowing the compos~tion to cure in contact wlth the s1te.
The monomeric ester component is preferably selected from methacrylates where X is a heterocycllc group of formula O
~: 1 0 -CH--(CH2)n where n is l, 2, ~ or 4. Tetrahydrofurfuryl methacrylate (R~CH3, m=l, n=3) is particularly preferred.
p These mono~ers may ~be admixed with other monomers to control hydrophilicity, for example hydroxyethyl methacrylate to increase hydrophillcity or isobornyl methaerylate to decrease ;; ~ hydrophilicity. The polymer component is preferably a methacrylate polymer, preferably poly(ethyl methacrylate), but ~;; other polymers such ~as~ poly(methyl methacrylate~, poly-(hydroxyethyl methacrylate), ~ or poly(tetrahydrofurfuryl ~methacrylate~ may~be employed as well as copolymers thereof.
The copolymer component~ ~may be selected to control hydrophilicity.~
The composition is ~suitably in the form of a mixture of inely divided solid ~polymer, su~tably prepared by suspeasion 25 ~polymerisation, i~n~l1quid monomer.~ The composition may i1nclude ni~tially, or have~addsd to it at the point of use, s~itable activators~for the~;~curing s~uch as free radical catalysts, e.g.
peroxide/amine ~ i;nitiator ~ systems. Alternatively, photoinitiatQrs could be used, e.g. camphor quinone/tertiary ~i 3Q amine systems well known in the art. Additional additives such as~stabilisers and fillers ~and x-ray opacifying agents may be present. These~inc!~ude, ~ for example, quinone type inhibitors in the monomer,~ and/;or inorganic fillers to increase hardness and ~reduce ~ polymeri~sation shri~kage. In particular, hydroxyapati~e may be~used for thîs purpose and to improve : ~:~ `:
`~ ~
.
~: : :
WO 93/09819 PCI`/GB92/02128 2123~98 4_ biocompatibility. In addition, antibiotic components such as gentam1cin may be added in order to avoid 1nfection. Other poss~ble therapeutic additives lnclude anti infl~mmatory drugs, hydrocortisones, dexamethasone and drugs for the treatment of osteoarthritis when promoting tissue repair in a diseased joint. Other examples are antifungal agents and antimicrobial agents. Other possible additives include porosogens such as collagen or dextran to increase the porosity of the material or materials which function as protein carriers.
A particularly preferred additive ~s a cell growth stimulant such as those described in W089/03695, and in particular, human growth hormone. Other growth factors such as TGF-t, IGF I, IGF-t, FDGF and FGF may be used.
The ratio of monomer to polymer component can vary dependent on the reaction time required and the consistency of composition required initially. Sultably the ratio of polymer to monomer is ~from 1:1 to 2:1 by weight, preferably 1.25:1 to 1.75:1. Th~ curing should desirably occur at body temperature and curing ~s desirably effected over a period of 5 to 20 minutes, preferably ~10 to 15 minutes. The use of such co~positions as bio~aterials in dental, aural and opthalmic fields is descri~b~ed ~n GB 2 107 341.
It is ~postulated that the ability of such cured compos~itions ~to~ promote tissue repair results from ~heir abili b ~0 absor~ water to an extent which allows absorption of tissue flu~d from the ~area requirlng repair, while swelling in the ~tiss~e to provide good bonding cond~t~ons. It is postulated that,~ ~in order to be well sui ted for use i n accordance w~th the present invention, the biopolymer ~'30 composition when cured should have a water uptake in the region of 5 to 30% w~w over~ a period of six months to 2 years. It is also recognised that the low shrinkage properties of such ~;biopolymers combined with the slight swelling occurring with water uptake give materials which bond firmly in use, for example in cartilage, and are not readily dislodged.
WO 93/09819 PCI/GB92/0~128 s The monomer/polymer mixture of the invention is preferably used to manufacture a composition intended for ~ntroduction at, or ad~acent to damaged cartilage to promote cartilage repair.
It has been found advantageous to apply the composition below, preferably slightly below the surface of the subchondral bone in or~er to opti~ize the formation of a new cartilage layer.
However, the repair of other damaged ti~sue such as bone, ep~thelial and endothelial t~ssue is also contemplated within the scope of the invention, as a result of enhanced cell proliferation and differentiation in a biolog1cally advantageous matrix.
;~ The invention will now be f~rther described by way of example.
Example l A curable monomer/polymer composition was prepared by mixing poly(ethyl methacrylate) in powdered form (obtained from Bonar Polymers Ltd., Ref. T/S 1249/4, Newton Aycliffe, Co.
Durham, U.K. and of molecular ;weight about 250,000) (lOg) with tetrahydro- furfuryl methacrylate monomer (obtalned from Rohm Chemie, Darmsta~t, Germany) (S ml) containing 2.5% v/v of N,N -d1methyl- p-toluidene as act~vator. The polymer component contained 8X;w/w;BaS04~incorporated during the polymerisation process to confe~r radioopacity.
Human gro~th hormone~(obta~ned from Novo Nordisk, Denmark) 25 ~was ~ncorporated~;into~ the~water~al by mixing 12 IU with lOg powder~component prior~to adding the~m~nomer.
The composition~was cast in discs of d~ameter 2mm at a temperature ~of ~37~-C.~ Fl~ution~ of the growth hormone was ~onitored by immersion of the discs in O.lM phosphate buffered saiine at 37C at suitable time intervals using a specific ELISA. Figure l~ shows ;the in vitro release of human growth hormone.
The surface~ properties of the discs as cast were examined by ~scanning electron microscopy. This revealed that the cured ~:: :
:~ :
WO 93/09819 PCI'/GB92/02128 r 212379~3 ~ 6 -polymer had a smooth surface, as compared to the rough surfaces-obtained with more conventionally employed polymethyl methacrylate.
Portions of 2ml of the curable composition prepared as above, immediately after mlxing, were inserted by syringe into drilled holes in the knees of three rabb~ts (adult Sandy Lop, weight of least 3.5kg) which were then kept unrestrained for eight months. Rapid healing and wound closure were noted and the rabbits quickly re~ained mobility and appetite. The tissue response at the bone-polymer interface and cartilage-polymer interface were examined. At the macroscopic level it was apparent that the cartilage defect had healed.
.
Example 2 A curable composition as described in Example 1 was lS employed. The somposition was in the form of a liquid monomer containing the dispersed polymer.
A single 3 mm diameter defect was drilled into the intercondylar ~notch ~of~the artlcular cartilage of 18 mature Sandy Lop rabb~ts. Into each defect was inserted 0.15 ml of the c~urable~ compos~tion containing human growth hormone (12 international units ~per Sg polymer powder) into the subchondral bone ~below the ~area of ~removed cart~lage. Plain curable composition~without~ any growth hormone was inserted into a sim~lar cartllage ~efect ln ~the ~contralateral limb. R~bbits ~ were~sacrlficed at 3,6,9` and~lZ weeks and 8 months.
;; HistoloqY.~`At~each tlme lnterval, excess bone was removed from the~ emoral~ condyles before fixation in 2%
paraformaldehyde~ and~ 0.5% glutaraldehyde, ~t 4C, for 48 hours. Each spec~men was decalcified in neutral EDTA at 4C
~' 30 prior to either low ~temperature (4C) dehydration and wax embedding, or frozen~section preparation.
Crvosection~ina.~ At ~each time interval decalcified specimens were; frozen ln~ cryomountant using liquid nitrogen.
These were cryostat~sectioned at -20C, whilst the polymer was held in place with double-sided sellotape, sections were then mounted on glass slides and stained.
~, ~
WO 93/09819 PCl`~GB92/02128 212379~
Immunolocalisation of ~olla~en type II. chQndroitin 4 sulph~t!~ ~nd ~hondroitin 6 sulphate. Dewaxed sections were chondroitinase digested (0.25 iulml) for one hour at 38C to reYeal the epitopes before immunolocalisation. Selected pr~mary monoclonal antibodies were used indlv~dually and a rhodamine con~ugated anti-murine serum was applied to each section, after appropriate wash steps between stages.
Non-immune mouse serum was applied as control to all immunolocalisations and pre-absorbed anti-collagen type II
monoclonal was used as an extra control for the localisation of ;~ collagen type II which is specific to cartilage.
Electron Mi~ro$copv. At each time interval, excess bone was removed from the femoral condyles before fine trimming to the area of defect repair, before fixation with 2.5%
glutaraldehyde in sodium cacodylate buffer at 4C, for a mini~um 48 hours. Specimens were post fixed in 1% osmium tetroxide for 2 ho(rs before dehydration through a methanol series into propylene oxide and embedding in Spurr's resin.
The results observed were as follows:
.
:~ 20 MacroscQpic findings. None of the rabb1ts died, nor was there any evidence o~ infection. The rabbits were housed in ~.
group pens which allowed freedom of movement i.e. running, ump~ng, standing on hind l~gs. The ani~als showed no sign of discomfort and~all enjoyed ~ull mob~l~ty~ , ~In most rabbits~ the~ knee joints showed a white gl~stening cartilage-like tissue resembling the normal surrounding articular cartilag~.~ There appeared to be a g~od overgrowth of cartilage over the polymer within the de~ect. In three rabbit knees the tissue covering was incomplete; hlstological ~, 30 observations revealed that the polymer had been set above the level of the subchondral bone in the cartilage defect. Since cartil~ge cannot grow through the polymer, it is therefore ;impor$ant that the polymer is set at the right level to allow good resurfacing WO 93/09819 PCI`/GB92/02128 ` 21~3~9~ 8 -Two rabbits were kept for a longer study ~eight months).
The joints remained functional throughout the study period.
The histology revealed that the new cartilage remained intact but the density of the matrix had still not achieved that of the original cartilage. There were st~ll a mixed population of , cells and areas of f~brous and chondrogenic regions. The ~; subchondral bone had remodelled and in it the polymer became surrounded by very dense collagen.
Frozen sectiQns., Cryostat sectioning allowed visualisation of the intact polymer-tissue interface, hence the ~; ~ extracellular matrix components of the tissue growing over the polymer three~ weeks after surgery were eharacterised.
Histologically a~ variety of tissues were observed. Most ;~ pr~minant in the; early stages was the observation of a highly' cellular fibrous tissue. A thin layer of synovial appearance separated the;~n,ew~ tissue ~covering the polymer from the intracondylar space.~ Bony spicules appeared to be associated with areas of new tissue immediately adjacent to the polymer surface. Above~thls interface the fibrous layer contained ; 20 areas of rounded ~ce~lls in a~ metachromatically stained matrix believed to be~chondrog;enic~nodules.
Low temperat~e~ wax embedded tissue sections. ImmunQ-local~isat~ion of~coll,ageo ~type II within the cartilaginous nodul~es confirmed~the~chondrogenic PhenotYpe of these areas of 25~ ~the ~tissue.~ lmmunoloca;l~isation studi~es also demonstrated an elaboration~ o~ chondroitin 4-sulphate and chondroitin ;",~ 6-sulphate~g~lytosami~noglycan ~side;,chains both in the fibrous tissue~ and;~ in ;~the~ regions of chondrogenic nodules. The ` varieties of cell phenotypes within the layer covering the polymer were shown histologically and by immunolocalisation of their matrix molecules during the first twelve weeks after implantation.
Transmission~ electron misroscopv of the trans-polymer tissue layer after 8~,months of implantation showed the rounded appearance of ceils wi~thin a proteoglycan rich matrix, ,.. .~
: 2~237~8 g indicating the chondrogenic nature of the tissue. The presence of chondron at the cartilage and bone interface was noted.
Growth hormone ~ncorporation. It was shown that the cured polymer system was a good veh~cle for the release of growth hormone. Morpholog~cal comparisons were made between the tissue covering the growth hormone and plain polymer.
Figures 2 to 6 illustrate the above findings as follows:
Fiaure 2 After 3 weeks of implantation a fibrous tissue layer (f) had grown over the polymer (P) surface. The polymer ~P) had been inserted into a sub-chondral de~ect in the bone (B) below the level o~ the remaining cartilage (C).
Decalcified tissue~ embedded in wax. Section is stained with Methylene blue-Azur II.
Fiqure 3 After 6 weeks of implantation two zones of repair tissue were observed. Bony~ spicules (b) and nodules containing chondrocytes ~arrowed) are seen in the zone immediately above m the polymer (P~ surface. Where the defect has been made in the cartt~lage (C) ~a tissue layer similar in appearance but less organi~sed than~normal cartilage (c) has formed above the bony zone.~ Original~bone~ is denoted B and the original cartila~e is denoted C.
Deca~lcified~tlssue ~embedded in wax. Section ls st~ined 25 ~with~Methylene blue-Azur I~I.
F~ure 4 After 9 weeks of implantation there is ~ore new bone (b) above~ the polymer ~P) ;su~rface. There are nodules containing chondrocytes (arrow) in the bony layer. The new cartilage (c) ~'~! 30 is disorganised. Original bone is denoted B and the original cartilage is denoted C.
Decaleified tissue embedded in wax. Section is stained with Methylene blue-Azur II.
' :
., .~ .~
212~798 - lo ~ . Figure 5 :~: By transmission electron microscopy clusters of chondrocytes are seen to be contained within a collagenous ~: ~ basket (co).~ These S are referred to as chondrons and are structures normally ` observed in the deep zones of mammalian cartilage. The normal ,, ~ .
extracellular:~matrix is denoted M.
The cells with:in the~ chondron (Co) appear to be actively : lO: synthesising cell~; products indicated by the enormous amount of endoplasmic reti;culum~(ER).:: The cell nucleus is denoted N and the normal extracellu1ar:matrix is denoted M.
`i ~ :: : ~ : :
This invention relates to the use of biomaterials for tiSSUQ
repair and is particularly concerned with the use of physiologically acceptable polymeric materials in such tissue repalr, especlally cartilage repair.
The use of physiologically acceptable polymeric mater~als in the preparation of biomedical appliances sueh as hearing aids, artificial eyes and dentures is well known, as is the use of polymeric mater~als as bone cements in the fleld of orthopaedics.
Such polymeric mater1als are often used in the form of a curable composition which is initially in a fluid9 semi-liquid, dough-like or other mouldable form, but which cures or hardens at the temperature of use to form a strong solid of physical properties . .
dependent on the use to wh1ch it is being put. Examples of such curable compositions are to ~be found in International Patent Application No. W089/03695 ànd GB Patent 2 107 341 which disclose ~ i the use of curable~compositions comprising a powdered methacrylate polymer mixed with a~methacrylate monomer. For such app7ications 20 ; as the preparation of~hearing~ aids, artific1al eyes and dentures which require; dimens~onal ~accuracy, it is important to prov~de composit~ons of low linear curing shrinkage and GB Patent 2 107 341 is directed to such an ~aim. For~use as bone cement it is important to~ prevent subsequent ~failure at the bone-cement ~1nterface and,~ to~ thl~s~ end~,~ W089/036~5 discloses the inclusion of a cell~ growth~stimalant~such ~as~human ~rowth hormone so as to increase~the rate~of~healing~ of, for~example, a bone fracture and give a~Joi~nt~of ~ncrease~strength. The emphasis in the previous use~of the~se curable composi~tions has therefore been directed to ;~ 30 attaining bonding strength and/or material strength and dimensional stability dependen~ on the intended use.
~, ~: :
:
:
/6~9 2/ 02l28 ; ` .111 ~ MAR~H l994 212379~
Surprlsingly, it has been found that certain curable I: compositions comprising a methacrylate polymer mixed with a suitable unsaturated monomer can be employed to promote ti;sue repair, with or wlthout the addition of cell growth stimulants : S such as human growth hormone. Even more surprisingly, it has been found that sUch compositlons can be employed to promote cartilage repair.
Cartilage, whi:ch dlffers from bone in construction, has previously been considered substantially non-repairable. Attempts lO to repair cartilage currently include the introduction of carbon bres behind ~the~ eartilage; however such carbon fibres are brittle and, while a fibrous tissue forms in the implanted area, the resulting growth is not that of true cartilage composed of chondrocytes expressing their normal phenotype and producing their 15 ~ own matrix componen:ts. Implantation of cartilage components and hydrogel compos~tions have also been tried with limited success.
There ~s therefore~a~ great need for a breakthrough in the treatment of~cartil~age~defects.~
The~present invention~comprlsQs the use of a monomer/polymer 20 m1xture~ ~n ~ the~ preparat~on of a~ curable composi~on for :introduction t o~a~ s;ite~ requiring tiss~e repair in a human or animàl body ;;:in order~ to promote: said t7ssue repair, the mono~er component~being~sele~ct-d~from monomerlc ~sters of general formula I
CH2~C-C0O'cH2'mx (I) wherein~R~ is~a~hyd~rogen~atom or a methyl group, m is 0, l 30 or 2, and X is a 3 to 6 membered heterocyclic ring and the ; polymer component is selected from acrylate and methacrylate Ipolymers and copolymers~thereof. Pre~erably X is an oxygen containing heterocycle.~
According~;to a~further~aspect of the invention there is ; 35 provided a process for: the promotion of tissue repair . ~
. , ~:: ' :~
¦ PCT 1~ : J.c~ti3,l ¦
WO 93/()9819 P~/GB92/02128 .` ., 21~3798 comprising introducing to a site requiring tissue repair in a human or animal body, a curable co~posltion comprising a monomer component selected from monomeric esters of general formula I above and a polymer component selected from acrylate and methacrylate polymers and copolymers thereof and causing or allowing the compos~tion to cure in contact wlth the s1te.
The monomeric ester component is preferably selected from methacrylates where X is a heterocycllc group of formula O
~: 1 0 -CH--(CH2)n where n is l, 2, ~ or 4. Tetrahydrofurfuryl methacrylate (R~CH3, m=l, n=3) is particularly preferred.
p These mono~ers may ~be admixed with other monomers to control hydrophilicity, for example hydroxyethyl methacrylate to increase hydrophillcity or isobornyl methaerylate to decrease ;; ~ hydrophilicity. The polymer component is preferably a methacrylate polymer, preferably poly(ethyl methacrylate), but ~;; other polymers such ~as~ poly(methyl methacrylate~, poly-(hydroxyethyl methacrylate), ~ or poly(tetrahydrofurfuryl ~methacrylate~ may~be employed as well as copolymers thereof.
The copolymer component~ ~may be selected to control hydrophilicity.~
The composition is ~suitably in the form of a mixture of inely divided solid ~polymer, su~tably prepared by suspeasion 25 ~polymerisation, i~n~l1quid monomer.~ The composition may i1nclude ni~tially, or have~addsd to it at the point of use, s~itable activators~for the~;~curing s~uch as free radical catalysts, e.g.
peroxide/amine ~ i;nitiator ~ systems. Alternatively, photoinitiatQrs could be used, e.g. camphor quinone/tertiary ~i 3Q amine systems well known in the art. Additional additives such as~stabilisers and fillers ~and x-ray opacifying agents may be present. These~inc!~ude, ~ for example, quinone type inhibitors in the monomer,~ and/;or inorganic fillers to increase hardness and ~reduce ~ polymeri~sation shri~kage. In particular, hydroxyapati~e may be~used for thîs purpose and to improve : ~:~ `:
`~ ~
.
~: : :
WO 93/09819 PCI`/GB92/02128 2123~98 4_ biocompatibility. In addition, antibiotic components such as gentam1cin may be added in order to avoid 1nfection. Other poss~ble therapeutic additives lnclude anti infl~mmatory drugs, hydrocortisones, dexamethasone and drugs for the treatment of osteoarthritis when promoting tissue repair in a diseased joint. Other examples are antifungal agents and antimicrobial agents. Other possible additives include porosogens such as collagen or dextran to increase the porosity of the material or materials which function as protein carriers.
A particularly preferred additive ~s a cell growth stimulant such as those described in W089/03695, and in particular, human growth hormone. Other growth factors such as TGF-t, IGF I, IGF-t, FDGF and FGF may be used.
The ratio of monomer to polymer component can vary dependent on the reaction time required and the consistency of composition required initially. Sultably the ratio of polymer to monomer is ~from 1:1 to 2:1 by weight, preferably 1.25:1 to 1.75:1. Th~ curing should desirably occur at body temperature and curing ~s desirably effected over a period of 5 to 20 minutes, preferably ~10 to 15 minutes. The use of such co~positions as bio~aterials in dental, aural and opthalmic fields is descri~b~ed ~n GB 2 107 341.
It is ~postulated that the ability of such cured compos~itions ~to~ promote tissue repair results from ~heir abili b ~0 absor~ water to an extent which allows absorption of tissue flu~d from the ~area requirlng repair, while swelling in the ~tiss~e to provide good bonding cond~t~ons. It is postulated that,~ ~in order to be well sui ted for use i n accordance w~th the present invention, the biopolymer ~'30 composition when cured should have a water uptake in the region of 5 to 30% w~w over~ a period of six months to 2 years. It is also recognised that the low shrinkage properties of such ~;biopolymers combined with the slight swelling occurring with water uptake give materials which bond firmly in use, for example in cartilage, and are not readily dislodged.
WO 93/09819 PCI/GB92/0~128 s The monomer/polymer mixture of the invention is preferably used to manufacture a composition intended for ~ntroduction at, or ad~acent to damaged cartilage to promote cartilage repair.
It has been found advantageous to apply the composition below, preferably slightly below the surface of the subchondral bone in or~er to opti~ize the formation of a new cartilage layer.
However, the repair of other damaged ti~sue such as bone, ep~thelial and endothelial t~ssue is also contemplated within the scope of the invention, as a result of enhanced cell proliferation and differentiation in a biolog1cally advantageous matrix.
;~ The invention will now be f~rther described by way of example.
Example l A curable monomer/polymer composition was prepared by mixing poly(ethyl methacrylate) in powdered form (obtained from Bonar Polymers Ltd., Ref. T/S 1249/4, Newton Aycliffe, Co.
Durham, U.K. and of molecular ;weight about 250,000) (lOg) with tetrahydro- furfuryl methacrylate monomer (obtalned from Rohm Chemie, Darmsta~t, Germany) (S ml) containing 2.5% v/v of N,N -d1methyl- p-toluidene as act~vator. The polymer component contained 8X;w/w;BaS04~incorporated during the polymerisation process to confe~r radioopacity.
Human gro~th hormone~(obta~ned from Novo Nordisk, Denmark) 25 ~was ~ncorporated~;into~ the~water~al by mixing 12 IU with lOg powder~component prior~to adding the~m~nomer.
The composition~was cast in discs of d~ameter 2mm at a temperature ~of ~37~-C.~ Fl~ution~ of the growth hormone was ~onitored by immersion of the discs in O.lM phosphate buffered saiine at 37C at suitable time intervals using a specific ELISA. Figure l~ shows ;the in vitro release of human growth hormone.
The surface~ properties of the discs as cast were examined by ~scanning electron microscopy. This revealed that the cured ~:: :
:~ :
WO 93/09819 PCI'/GB92/02128 r 212379~3 ~ 6 -polymer had a smooth surface, as compared to the rough surfaces-obtained with more conventionally employed polymethyl methacrylate.
Portions of 2ml of the curable composition prepared as above, immediately after mlxing, were inserted by syringe into drilled holes in the knees of three rabb~ts (adult Sandy Lop, weight of least 3.5kg) which were then kept unrestrained for eight months. Rapid healing and wound closure were noted and the rabbits quickly re~ained mobility and appetite. The tissue response at the bone-polymer interface and cartilage-polymer interface were examined. At the macroscopic level it was apparent that the cartilage defect had healed.
.
Example 2 A curable composition as described in Example 1 was lS employed. The somposition was in the form of a liquid monomer containing the dispersed polymer.
A single 3 mm diameter defect was drilled into the intercondylar ~notch ~of~the artlcular cartilage of 18 mature Sandy Lop rabb~ts. Into each defect was inserted 0.15 ml of the c~urable~ compos~tion containing human growth hormone (12 international units ~per Sg polymer powder) into the subchondral bone ~below the ~area of ~removed cart~lage. Plain curable composition~without~ any growth hormone was inserted into a sim~lar cartllage ~efect ln ~the ~contralateral limb. R~bbits ~ were~sacrlficed at 3,6,9` and~lZ weeks and 8 months.
;; HistoloqY.~`At~each tlme lnterval, excess bone was removed from the~ emoral~ condyles before fixation in 2%
paraformaldehyde~ and~ 0.5% glutaraldehyde, ~t 4C, for 48 hours. Each spec~men was decalcified in neutral EDTA at 4C
~' 30 prior to either low ~temperature (4C) dehydration and wax embedding, or frozen~section preparation.
Crvosection~ina.~ At ~each time interval decalcified specimens were; frozen ln~ cryomountant using liquid nitrogen.
These were cryostat~sectioned at -20C, whilst the polymer was held in place with double-sided sellotape, sections were then mounted on glass slides and stained.
~, ~
WO 93/09819 PCl`~GB92/02128 212379~
Immunolocalisation of ~olla~en type II. chQndroitin 4 sulph~t!~ ~nd ~hondroitin 6 sulphate. Dewaxed sections were chondroitinase digested (0.25 iulml) for one hour at 38C to reYeal the epitopes before immunolocalisation. Selected pr~mary monoclonal antibodies were used indlv~dually and a rhodamine con~ugated anti-murine serum was applied to each section, after appropriate wash steps between stages.
Non-immune mouse serum was applied as control to all immunolocalisations and pre-absorbed anti-collagen type II
monoclonal was used as an extra control for the localisation of ;~ collagen type II which is specific to cartilage.
Electron Mi~ro$copv. At each time interval, excess bone was removed from the femoral condyles before fine trimming to the area of defect repair, before fixation with 2.5%
glutaraldehyde in sodium cacodylate buffer at 4C, for a mini~um 48 hours. Specimens were post fixed in 1% osmium tetroxide for 2 ho(rs before dehydration through a methanol series into propylene oxide and embedding in Spurr's resin.
The results observed were as follows:
.
:~ 20 MacroscQpic findings. None of the rabb1ts died, nor was there any evidence o~ infection. The rabbits were housed in ~.
group pens which allowed freedom of movement i.e. running, ump~ng, standing on hind l~gs. The ani~als showed no sign of discomfort and~all enjoyed ~ull mob~l~ty~ , ~In most rabbits~ the~ knee joints showed a white gl~stening cartilage-like tissue resembling the normal surrounding articular cartilag~.~ There appeared to be a g~od overgrowth of cartilage over the polymer within the de~ect. In three rabbit knees the tissue covering was incomplete; hlstological ~, 30 observations revealed that the polymer had been set above the level of the subchondral bone in the cartilage defect. Since cartil~ge cannot grow through the polymer, it is therefore ;impor$ant that the polymer is set at the right level to allow good resurfacing WO 93/09819 PCI`/GB92/02128 ` 21~3~9~ 8 -Two rabbits were kept for a longer study ~eight months).
The joints remained functional throughout the study period.
The histology revealed that the new cartilage remained intact but the density of the matrix had still not achieved that of the original cartilage. There were st~ll a mixed population of , cells and areas of f~brous and chondrogenic regions. The ~; subchondral bone had remodelled and in it the polymer became surrounded by very dense collagen.
Frozen sectiQns., Cryostat sectioning allowed visualisation of the intact polymer-tissue interface, hence the ~; ~ extracellular matrix components of the tissue growing over the polymer three~ weeks after surgery were eharacterised.
Histologically a~ variety of tissues were observed. Most ;~ pr~minant in the; early stages was the observation of a highly' cellular fibrous tissue. A thin layer of synovial appearance separated the;~n,ew~ tissue ~covering the polymer from the intracondylar space.~ Bony spicules appeared to be associated with areas of new tissue immediately adjacent to the polymer surface. Above~thls interface the fibrous layer contained ; 20 areas of rounded ~ce~lls in a~ metachromatically stained matrix believed to be~chondrog;enic~nodules.
Low temperat~e~ wax embedded tissue sections. ImmunQ-local~isat~ion of~coll,ageo ~type II within the cartilaginous nodul~es confirmed~the~chondrogenic PhenotYpe of these areas of 25~ ~the ~tissue.~ lmmunoloca;l~isation studi~es also demonstrated an elaboration~ o~ chondroitin 4-sulphate and chondroitin ;",~ 6-sulphate~g~lytosami~noglycan ~side;,chains both in the fibrous tissue~ and;~ in ;~the~ regions of chondrogenic nodules. The ` varieties of cell phenotypes within the layer covering the polymer were shown histologically and by immunolocalisation of their matrix molecules during the first twelve weeks after implantation.
Transmission~ electron misroscopv of the trans-polymer tissue layer after 8~,months of implantation showed the rounded appearance of ceils wi~thin a proteoglycan rich matrix, ,.. .~
: 2~237~8 g indicating the chondrogenic nature of the tissue. The presence of chondron at the cartilage and bone interface was noted.
Growth hormone ~ncorporation. It was shown that the cured polymer system was a good veh~cle for the release of growth hormone. Morpholog~cal comparisons were made between the tissue covering the growth hormone and plain polymer.
Figures 2 to 6 illustrate the above findings as follows:
Fiaure 2 After 3 weeks of implantation a fibrous tissue layer (f) had grown over the polymer (P) surface. The polymer ~P) had been inserted into a sub-chondral de~ect in the bone (B) below the level o~ the remaining cartilage (C).
Decalcified tissue~ embedded in wax. Section is stained with Methylene blue-Azur II.
Fiqure 3 After 6 weeks of implantation two zones of repair tissue were observed. Bony~ spicules (b) and nodules containing chondrocytes ~arrowed) are seen in the zone immediately above m the polymer (P~ surface. Where the defect has been made in the cartt~lage (C) ~a tissue layer similar in appearance but less organi~sed than~normal cartilage (c) has formed above the bony zone.~ Original~bone~ is denoted B and the original cartila~e is denoted C.
Deca~lcified~tlssue ~embedded in wax. Section ls st~ined 25 ~with~Methylene blue-Azur I~I.
F~ure 4 After 9 weeks of implantation there is ~ore new bone (b) above~ the polymer ~P) ;su~rface. There are nodules containing chondrocytes (arrow) in the bony layer. The new cartilage (c) ~'~! 30 is disorganised. Original bone is denoted B and the original cartilage is denoted C.
Decaleified tissue embedded in wax. Section is stained with Methylene blue-Azur II.
' :
., .~ .~
212~798 - lo ~ . Figure 5 :~: By transmission electron microscopy clusters of chondrocytes are seen to be contained within a collagenous ~: ~ basket (co).~ These S are referred to as chondrons and are structures normally ` observed in the deep zones of mammalian cartilage. The normal ,, ~ .
extracellular:~matrix is denoted M.
The cells with:in the~ chondron (Co) appear to be actively : lO: synthesising cell~; products indicated by the enormous amount of endoplasmic reti;culum~(ER).:: The cell nucleus is denoted N and the normal extracellu1ar:matrix is denoted M.
`i ~ :: : ~ : :
Claims (11)
1. The use of a monomer/polymer mixture in the preparation of a curable composition for introduction to a site requiring tissue repair in a human or animal body in order to promote said tissue repair, the monomer component being selected from monomeric esters of general formula I
I
where R is a hydrogen atom or a methyl group, m i 0, 1 or 2 and X is a 3 to 6 membered heterocyclic ring and the polymer component is selected from acrylate and methacrylate polymers and copolymers thereof.
I
where R is a hydrogen atom or a methyl group, m i 0, 1 or 2 and X is a 3 to 6 membered heterocyclic ring and the polymer component is selected from acrylate and methacrylate polymers and copolymers thereof.
2. A use according to Claim 1 wherein X in the monomer component of formula I is an oxygen containing heterocycle.
3. A use according to Claim 2 wherein the monomer component is tetrahydrofurfuryl methacrylate.
4. A use according to Claim 1, 2 or 3 wherein the polymer component is polyethylmethacrylate.
5. A use according to any one of the preceding claims in the preparation of a curable composition having a polymer to monomer ratio of 1:1 to 2:1 by weight.
6. A use according to any one of the preceding claims, in the preparation of a curable composition further comprising one or more components selected from antibiotic and therapeutic agents, antifungal and antimicrobial agents, porosogens, protein carriers and cell growth stimulants.
7. A use according to Claim 6 wherein the, or one of the, additives is human growth hormone.
8. A use according to any one of the preceding claims in the preparation of a curable composition for introduction to a site requiring cartilage repair.
9. A process for the promotion of tissue repair comprising introducing to a site requiring tissue repair in a human or animal body a monomer/polymer mixture as recited in any one of Claims 1 to 7 and causing or allowing the composition to cure in contact with the site.
10. A process according to Claim 9 for the promotion of cartilage repair.
11. A process according to Claim 9 wherein the curable composition is introduced below the surface of the subchondral bone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9124487.1 | 1991-11-18 | ||
| GB9124487A GB2261672A (en) | 1991-11-18 | 1991-11-18 | The use of biomaterials for tissue repair |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2123798A1 true CA2123798A1 (en) | 1993-05-27 |
Family
ID=10704827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002123798A Abandoned CA2123798A1 (en) | 1991-11-18 | 1992-11-17 | The use of biomaterials for tissue repair |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5468787A (en) |
| EP (1) | EP0613380B1 (en) |
| JP (1) | JP3168007B2 (en) |
| AT (1) | ATE188128T1 (en) |
| AU (1) | AU662024B2 (en) |
| CA (1) | CA2123798A1 (en) |
| DE (1) | DE69230499T2 (en) |
| DK (1) | DK0613380T3 (en) |
| ES (1) | ES2144427T3 (en) |
| GB (1) | GB2261672A (en) |
| WO (1) | WO1993009819A1 (en) |
| ZA (1) | ZA928866B (en) |
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| CA1044838A (en) * | 1973-08-07 | 1978-12-19 | Henry L. Lee (Jr.) | Rapid setting high bond strength adhesive |
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-
1991
- 1991-11-18 GB GB9124487A patent/GB2261672A/en not_active Withdrawn
-
1992
- 1992-11-17 US US08/244,322 patent/US5468787A/en not_active Expired - Fee Related
- 1992-11-17 ZA ZA928866A patent/ZA928866B/en unknown
- 1992-11-17 DK DK92923088T patent/DK0613380T3/en active
- 1992-11-17 AU AU29131/92A patent/AU662024B2/en not_active Ceased
- 1992-11-17 AT AT92923088T patent/ATE188128T1/en not_active IP Right Cessation
- 1992-11-17 WO PCT/GB1992/002128 patent/WO1993009819A1/en active IP Right Grant
- 1992-11-17 DE DE69230499T patent/DE69230499T2/en not_active Expired - Fee Related
- 1992-11-17 EP EP92923088A patent/EP0613380B1/en not_active Expired - Lifetime
- 1992-11-17 JP JP50910093A patent/JP3168007B2/en not_active Expired - Fee Related
- 1992-11-17 ES ES92923088T patent/ES2144427T3/en not_active Expired - Lifetime
- 1992-11-17 CA CA002123798A patent/CA2123798A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2913192A (en) | 1993-06-15 |
| DE69230499D1 (en) | 2000-02-03 |
| WO1993009819A1 (en) | 1993-05-27 |
| EP0613380A1 (en) | 1994-09-07 |
| JPH07500990A (en) | 1995-02-02 |
| ATE188128T1 (en) | 2000-01-15 |
| DE69230499T2 (en) | 2000-07-06 |
| EP0613380B1 (en) | 1999-12-29 |
| AU662024B2 (en) | 1995-08-17 |
| DK0613380T3 (en) | 2000-04-25 |
| JP3168007B2 (en) | 2001-05-21 |
| US5468787A (en) | 1995-11-21 |
| GB9124487D0 (en) | 1992-01-08 |
| ES2144427T3 (en) | 2000-06-16 |
| GB2261672A (en) | 1993-05-26 |
| ZA928866B (en) | 1994-05-17 |
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| FZDE | Discontinued |