BIORESORBABLE MATERIAL AND METHOD FOR PRODUCING THE SAME

Abstract: A synthetic material is disclosed, which is constituted by a copolymer of D, L-lactide and epsilon -caprolactone (which itself is characterised by lower degradation times than those obtainable with copolymers of L-lactic acid and epsilon -caprolactone), obtained by using as reaction control agent a sugar dianhydride with non-toxic characteristics. The use of sugar dianhydride in the reaction has a considerable control effect on the molecular weight of the copolymer and, thanks to its low molecular weight, this copolymer is characterised by extremely short resorption times, in the order for example of one or two months. The copolymer is used as covering element to be placed around tendon sutures and/or nerve tracts with the aim of preventing formation of scarry adherences between the suture lines and the soft surrounding tissues.

Description: "BIORESORBABLE MATERIAL AND METHOD FOR PRODUCING THE SAME." ******* TECHNICAL FIELD The invention relates to a method for obtaining an absorbable or bioresorbable material for use as a covering element in preventing scar adherences. More in detail, the present invention relates to a method for obtaining a material, provided with relatively εhort absorption times for the human body, for use as a covering element in a zone where scar adherences might develop, for example in the area around a suture performed on a tendon and/or a nerve tract, as well as internally of the spinal foramen after spinal surgery. The invention further relates both to the material obtained by the method and to a cladding element for prevention of adherences realised with said material. The invention finds its principal application in the medical-surgical field. BACKGROUND ART The most frequent complication consequent to surgical reconstruction of a tendon and/or a trau atically severed nervous tract is constituted by the formation of scar tissue adherences of the tendon suture line (or of the suture lines of the single nerves belonging to a bundle) , with the surrounding soft tissues cr the bone surface adjacent to the sutured lesion. These adherences, which can occur independently of the surgical technique employed in repairing the lesion, can to a considerable degree limit the tendon sliding function, so much so that it is common practice to follow a first surgical operation with a second remedial operation, once the tendon has re-established its biological continuity, to improve tendon excursion: this is particularly common in the field of hand surgery with regard to the flexor apparatus of the hand. Further, following spinal surgery operations, once the spinal foramen has been opened to afford access to the discs or nervous structures of the rachis, scar tissue forms almost constantly between the osteo-articular surfaces, the muscles around the vertebrae, the endocranial sac and the nerve roots, which limit the small movement that the nerve roots make inside the connecting foramen in order to adapt to the various positions assumed by the spinal column. This movement limitation can lead to painful clinical symptomε which might even be worse than those presented pre-operation and at the origin of the whole intervention. To obviate the above-mentioned problem, apart from rendering interventions as non-invasive as possible, a practice often employed is that of isolating the nervous structureε with free εtrandε of fatty tiεεue removed from the εottocutaneous area; absorption of the fatty tissue is not, however, controllable, and manipulation of same presents some difficulties. In the field of regeneration of single lacerated nerves, use iε made of generally tubular elementε acting as guides for the two extremities of a nerve during the regeneration period thereof. In this context, use iε made of nerve guides constituted by non-biodegradable and bioresorbable materials, such as for example silicone rubber (G. Lundborg et al., Exp Neurol. 76 (1982) 361, G. Lundborg et al . , Scand. J. Plaεtic Reconstructive Hand-Surgery 25(1991) 79, G. Lundborg et al . J Neuropathol Exp. Neurol. 41 (1982) 412, M. Merle et al. , Microsurg. 10 (1989) 130, B.R. Seckel et al. Plastic Reconstructive Surg. 78 (1986) 793), Acrylic Polymers (B.G. Uzman and G.M. Villegas, J. Neurosci. Res. 9(1993)157), polyethylene (P.G. Cordeiro et al . , Plastic Reconstructive Surg. 83 (1989) 1013) elastomer hydrogel (R.D. Keeley et al . , J. Reconstructive Microsurg. 7(1991) (2) 93) or porous stainless steel (W.E. Kuhn and J.L. Hall in "Modern Developments in Powder Metallurgy", edited by H.H. Hausener and P.W. Taubenblat, American Powder Metallurgy Institute, Princeton NJ p. 279) . The nerve guides, which are synthesised in a non¬ biodegradable material that remains in si tu as a foreign body, can limit the regenerative function of the nerve and give rise to irritation, sometimes years after implantation, in some cases so εerious as to necesεitate a further operation to remove them. Alεo known, in the field of εpecific application aε nerve guideε, is the use of biodegradable and bioresorbable material in a predetermined time period, in general comprised between six months and two years. For example, the prior art teaches use of a copolymer derived from L-lactide combined with poly-ε-caprolactone (W.F.A. Den Dunnen et al. in "A new PLLA/PCL copolymer for nerve regeneration", Journal of Materials Science Materials in Medicine 4 (1993) 521-525) , G. Perego et al . in "Preparation of a new nerve guide from a poly (L-lactide- co-6-caprolactone) ", Biomaterials 1994, Vol 15 no. 3, 189- 193); with like aims an ester of hyaluronic acid (Favaro et al . in "Peripheral Nerve Regeneration Through a Novel Bioresorbable Nerve Guide", ASAIO Transactions 1990 36 (3), M291-M294) . All of the above-mentioned materials have good non¬ toxic characteristics and low rejection reactions; reabsorption times are relatively long, generally over six months, for which reason these materials are not suitable for other applications requiring much shorter reabεorption timeε, for example one month. "An Experimental Study on an Adhesionε-Blocking Membrane in the Flexor Tendon of Chicken-Part", Clinical materials 6(1) 1-12 (1990) proposed the use of a membrane realised with a copolymer of leucine-polyeurethane blocks, derived from poly (tetra glycol methylene) , toluene diisocyanate and hydrazine. Copolymers containing 70% leucine were biodegradable in vi vo (rat) in about six monthε, differently to those containing leucine 50%, which were non-biodegradable. From the published data it may be derived that an increase in leucine concentration leads to lower material elaεticity and permeability. For research -into adherence inhibition in tendon regeneration it would seem that the 70% leucine composition was chosen as it offered a reaεonable compromiεe between the needs for elasticity, permeability and biodegradability. It muεt be remembered however that thiε material can generate, during degradation, an aromatic amine (toluene diamine) , whose toxicity cannot be ignored. Document US-A-5350573 describes a method and composition for preventing adheεionε during εurgical operations . The surface of the tissues and the surgical instruments involved in the operation are covered with a solution of a water-wettable polymer before contacting tissue during the operation. The composition comprises a solution of polymer material having a molecular weight of 500000 or above with a weight concentration comprised between 0.01 and about 15%. Finally, document US-A-5358973 describes a composition which can be used in surgical operations with the aim of preventing adhesions between tissue surfaces, said composition being an aqueous solution containing dextran and hyaluronic acid. DESCRIPTION OF THE INVENTION The present invention provides a method for obtaining a new resorbable material, characterised by extremely brief resorption times, in the order of one or two monthε, and thuε indicated for use aε a covering for prevention of adherenceε, for example tendon sutures and/or nerve tracts, with healing timeε aε indicated above. Thiε iε obtained by carrying out a method having the featureε deεcribed in claim 1. Claims from 2 to 5 relate to especially advantageous forms of embodiment of the method according to the invention. The invention alεo relates to a material obtained uεing the method of the invention. The material has the features diεclosed in claim 6. Claimε from 7 to 9 describe especially advantageous forms of embodiment of the material according to the invention. Finally, the invention provides an element made of resorbable material which can be used as a covering for prevention of adherences, for example in tendon sutures and/or nerve tracts. This element is described in claims from 10 to 12. The synthetic material according to the invention is constituted by a copolymer of D,L-lactide and ε- caprolactone (which itself is characterised by lower degradation times than those obtainable with copolymers of L-lactic acid and ε-caprolactone) , obtained by using as reaction control agent a sugar dianhydride with non-toxic characteristics, and thus suitable for the purposes of the invention. Experiments carried out by the applicant have surprisingly revealed that the use of sugar dianhydride as a control agent resulted in a copolymer with very low inherent viscosity (thus having a low molecular weight) , in the example much lower than viscoεities of similar copolymers obtained without the use of sugar dianhydride. Therefore the use of sugar dianhydride in the reaction has a considerable control effect on the molecular weight of the copolymer and, thanks to its low molecular weight, this copolymer is characterised by extremely short resorption timeε, in the order for example of one or two monthε. Such resorption timeε are decidedly lower than those obtained using known-type similar materials, and can be compared to those obtained by means of other biomaterials, such as hyaluronic acid, modified or not, which does not have the often-advantageous chemical-physical and mechanical properties of aliphatic polyesters, such as lactic acid copolymers. Therefore the material according to the invention is advantageous inasmuch as it is constituted by homo- and copolymers of lactic acid with controlled molecular weight, with the help of a non-toxic agent for control of the reaction. According to a form, of embodiment of the invention, the copolymer of lactic acid was obtained by εynthesising D,L-lactide and ε-caprolactone in the presence of tin octanoate as catalyst and using 1, 4 : 3 , 6-dianhydride- (D) - sorbitol at 0.44% concentration. More precisely, L-lactide was syntheεised from D,L- lactic acid at 90% (Fluka, Buchs, CH) ; 1000 ml of D,L- lactic acid were placed in a two-litre two-neck flask, and heated gradually to 200° C, contemporaneously distilling the water formed by the reaction. The viscous product thus obtained was depolymerised in the presence of a tin powder catalyst, at a temperature of 200°C and 0.1 Torr, contemporaneously distilling the D,L- lactide formed by the reaction. The raw lactide thus obtained was recryεtallised three times by methyl isobutyl ketone, obtaining thus 385g of white crystalline product, having a fusion temperature of 124-126°C. The preparation was completed with a final drying stage at 45°C and 0.1 Torr for 24 hours. Subsequently the ε-caprolactone (Fluka) was dried on CaCl 2 distilled at reduced pressure and conserved in nitrogen. The 1 , 4 : 3 , 6-dianhydride-D-sorbitol (Fluka) was recrystallised using ethyl acetate, dried at 45°C and 0.1 Torr for 24 hours, and conserved in nitrogen. The tin octanoate (Sigma) was conserved in nitrogen on activated molecular sieves and used without further purification treatment. The copolymeriεation waε carried out in a nitrogen atmosphere in a 100ml two-neck flask, in which 118.89g of D,L-lactide, 50.95g of ε-caprolactone equal to 47.4ml, 0.743g of 1.4 :3 , 6-dianhydride-D-sorbitol and O.lOOg of tin octanoate were located in dry-box conditions. The copolymerisation reaction was protracted for 7 hours at a temperature of 150°C, whereafter the flask was left to return to atmospheric temperature. The material was rubbery and transparent. The copolymer obtained in thiε way exhibitε an inherent viεcoεity of 0.59dl/g, meaεured in chloroform at 25°C, considerably lower than the viscoεity valueε (generally comprised between 2.5 and 3.5dl/g) normally obtained for the same copolymer in the absence of molecular weight control agents. A material having low resorption times, in the order of one or two months, is well adapted to use in setting up a surgical method for covering tendon sutures and/or nerve tracts with the aim of preventing formation of scarry adherences between the suture lines and the soft εurrounding tissues. To this end, the suture zone is enveloped in a covering element made of a material having a low resorption time, which isolates the sutured segment from the surrounding tiεεues for a period of time which iε limited to the completion of the healing processes. The covering element can be constituted by a sheet of resorbable material, cell-proof, or by a tubular element internally of which an extremity of the operable tendon or nerve tract iε inserted before surgical intervention, and which is arranged above the suture zone after the operation for connecting the endε of the tendon and/or the nerve tract. Experiments carried out by the applicant have demonstrated that a low-resorption time material, such as for example the copolymer of lactic acid obtained with the sugar dianhydride control agent of the invention can advantageously be used in carrying out a method such as the one described above. The covering element made from low-resorption timeε material haε in fact been εhown to be non-toxic, non- interacting with the healing proceεses, and resorbable in a conεiderably εhorter time than that needed by a like- composed material obtained without the control agent. For example, the applicant carried out an in vivo experimental study on an animal . The experiment was on chicken deep digital flexor. Chicken was chosen as best for the purpose, because: - it has a digital flexor apparatus which anatomically similar to Human, and the sizeε are εuitable for εurgical treatment; - the biological processes consequent to surgical lesion and healing are known and sufficiently close to thoεe of Human; - a valid flexion responεe can be obtained from mechanical stimulation of Chicken (by applying the palm of the claw to a cylindrical bar of εuitable dimenεionε and rotating the bar, causing a constant prehensile response with powerful digit flexion) , so that the posεible flexion range could be meaεured. The study was carried out on three groups of animalε. The first group was used to evaluate the biological aεpects of tendon repair in an isolated environment . It was conεtituted by five animalε, who were εubjected under general anaesthetic to traumatic lesion of the flexor apparatus of the second digit of each claw. The wound was palm-transverεal -throughout, intereεting the skin, subcutaneous level, flexor tendons up to the bone of the median phalanx. Subεequently the animalε were operated, with a longitudinal lateral incision of the digit and raising of the palm cutaneous flap, avulsion of the surface flexor tendon up to bone inεertion, repairing of the deep flexor by modified Bunnell technique with εingle thread εuture Prolene 4-0, and covering of the tendon in a tube of material according to the invention, extending by 1cm proximally and diεtally of the tendon εuture line. The claws were immobilised in a plaster-of-paris cast with the operated claw arranged in a three-quarters of total flexion excursion. The animals were sacrificed reεpectively at 1, 2, 3, 4 and 6 weeks after the operation, the claws amputated and the regions operated subjected to a histological study to evaluate the extent of biological reparation in the various phases, as well as to check for presence and characteristics of any scar adherences around the tendon. The findings could then be compared with those relating to the numerous existing studieε on tendon leεion healing in the absence of interplaced material. The εecond and the third groups were respectively constituted by five animals each. The animals were subjected to trauma and surgical treatment similar to that of the firεt group, with the difference that for the animalε of the second group no interposing material was uεed. The animals of the two groups were thus healed, and the caεt removed five weekε after the operation, and the flexion capacity of the operated digit evaluated using the above-described method of the cylindrical bar immediately after removal of the cast and in the two following weeks. Digital flexion of the two groups was compared to evaluate the degree of usefulness of the material according to the invention. From the experiments it was found that there is a total absence of adherences and an almost total resorption of the material of the invention. The invention haε been described herein with reference to some preferred embodiments thereof. However, it is clear that the invention is not absolutely limited to the above-described embodiments, and that it comprises numerous variations which belong in the scope of the invention, specifically with regard to the composition of the low-resorption-times materials. Low resorption times materials, both in lactic acid copolymer form as in the above-described material, and in other types of aliphatic polyester with especially short resorption times, such as for example copolymers derived from glycol and ε-Caprolactor.^, that is, using glycolic acid in the place of lactic acid, and derivatives of hyaluronic acid. With regard to the covering element made using such a material, it is clear that it can be made both in a tubular shape and in a leaf which can be enveloped about the εuture zone.

Claims: CLAIMS 1. A method for obtaining a resorbable material having low resorption times, comprising a copolymerisation reaction of D, L-lactide and e-caprolactone, characterised in that a synthesisation is performed using as reaction control agent a sugar dianhydride. 2. A method as in claim 1, characterised in that said sugar dianhydride iε constituted by 1,4:3,6- dianhydride- (D) -εorbitol or by 1 , 4 : 3 , 6-dianhydride- (D) -mannitol. 3. A method aε in claim 2, characteriεed in that the 1 , 4 : 3 , 6-dianhydride- (D) -sorbitol is uεed at a concentration comprised between 0.30% and 0.60%, advantageously 0.44%. 4. A method as in any one of the preceding claims, characterised in that the copolymerisation reaction is carried out with a presence of a special catalyst. 5. A method as in claim 4, characterised in that said catalyεt iε constituted by tin octanoate. 6. A reεorbable material for use as a cladding element for prevention of scar adherences between surfaces of tissueε εubεequent to εurgical operationε thereon, characteriεed in that εaid material iε conεtituted by a copolymer of ■ D,L-lactide and ε-caprolactone having a molecular weight which iε lower than 1 dl/g. 7. A material aε in claim 6, characteriεed in that it haε a molecular weight which iε about 0.59 dl/g. 8. A material as in any one of claims 6 or 7, characteriεed in that it iε resorbable over a period of time compriεed between about one and two monthε. 9. A material aε in any one of claimε from 6 to 8, characteriεed in that it is obtained by using a method as deεcribed in any one of claims from 1 to 5. 10. A covering element for prevention of scar adherences between tissue surfaceε εubsequent to surgical operation, characterised in that it is constituted by a material according to any one of claims from 6 to 9 11. A covering element aε in claim 10, characterised in that it is used for prevention of scar adherences between tissue surfaces subεequent to operationε for surgical reparation on tendons and/or nerve tracts, as well aε for εpinal εurgery internally of the spinal foramen. 12. A covering element as in any one of claims 10 or 11, characterised in that it exhibits a tubular or a flat shape.

Inventors: PEREGO GABRIELE, ZUCCATO ALESSANDRO, PEREGO, GABRIELE, ZUCCATO, ALESSANDRO
Applicants: PEREGO GABRIELE, SANITARIA SCALIGERA SPA, ZUCCATO ALESSANDRO, PEREGO, GABRIELE, SANITARIA SCALIGERA S.P.A., ZUCCATO, ALESSANDRO
Application year: 1996
Main classification: C08G63
IPC codes: A61L31, C08G63