Porous flexible sheet for tissue separation

A material for tissue separation at healing processes in injured soft tissue in mammals including man is described. The material consists of a porous flexible sheet of a protein-free bioresorbable polymer. Processes for preparation of the material and use thereof are also described.

TECHNICAL FIELD 
The present invention is related to a material for separation of injured 
tissue at healing processes. It is further related to a process for 
preparation of such material, and to use of the material in healing 
processes. 
BACKGROUND OF THE INVENTION 
In healing of injuries in soft tissue, scar tissue develops, which in many 
cases disturbs the function of the damaged organ and adjacent organs. This 
problem primarily occurs in healing of internal organs, while the problems 
in healing of skin and external mucosae may also be of cosmetic nature. 
Reference to injury and injured soft tissue herein primarily relates to 
incisions and other injuries caused by surgical operations in the organ 
subject to surgical correction, as well as in covering and adjacent 
organs. Among injuries caused by surgical operations is included injuries 
caused by surgical correction of congenital defects e.g. fistulas. The 
material according to the invention may also advantageously be employed in 
healing of injuries caused by external violence e.g. in accidents. A 
purpose with the invention is to facilitate and improve the healing by 
locking out undesired cells, other tissue and/or foreign particles. For 
this purpose, porous cloth of polytetrafluoroethylene such as 
Gore-Tex.RTM. is currently in use. The disadvantage with this is that 
foreign material will remain in the body, which may cause problems. Bowald 
et al. in The Lancet No. 8056, Jan. 21, 1978, page 153 describes the use 
of a knitted mesh of polyglactin 910 (Vicryl.RTM.) as an arterial 
substitute. A preclotted mesh was sutured as a patch graft or as an end to 
end tube in the thoratic aorta in pigs. This coarse-mesh material is only 
useful by deposition of fibrin intermingled with platelets and red blood 
cells in the mesh spaces. Further studies on coarse-mesh polyglactin 
material were reported in Surgery vol. 86, no 5, pp. 722-729, 1979, in 
Scand J Thor Cardiovasc Surg 15:91-94, 1981, in Muscle & Nerve 5:54-57, 
1982 and in Acta Chir Scand 146:391-395, 1980. SE 8604571-3 describes the 
use of resorbable and non resorbable membranes for accelerating bone 
formation and bone healing. However, cellular processes of resorptive type 
are indicated as undesirable, as they may delay bone formation and damage 
the newly formed bone. 
DESCRIPTION OF THE INVENTION 
According to the invention it has now been made possible to avoid such 
problems as mentioned above in healing of soft tissue. The invention 
provides a material for tissue separation at healing processes in injured 
soft tissue in mammals including man, characterized in that it consists of 
a porous flexible sheet of a protein-free bioresorbable polymer having a 
pore size which permits passage of water and salts through the sheet but 
which locks out cells and other tissue particles. The material of the 
invention has been found to cause a specific stimulating effect on 
formation of macrophages in soft tissue. The macrophages release a growth 
factor which stimulates tissue healing. The material of the invention does 
not require preclotting or the presence of blood for functioning. 
According to a preferred embodiment of the invention the material has a 
pore size up to 30 .mu.m, preferentially 0.1-10 .mu.m. The sheet thickness 
may be between 1 .mu.m and 5 mm, but is preferably 10 .mu.m to about 1 mm. 
The material may according to the invention be prepared according to the 
following processes, of which non-woven technique, precipitation and laser 
technique are preferred: 
Non-woven 
Non-woven fibrous material is prepared as described in U.S. Pat. No. 
4,603,070. Fibres are produced from a melt or solution of the polymer by 
pressing the material through a perforated outlet. The fibres are spread 
randomly, or with a main orientation, on a support (a still glass plate--a 
mobile net ribbon--other mould). In this manner a porous "cloth" is 
obtained which may be given varying porosity by modification of fibre 
dimension, spreading method, material thickness and/or by working up with 
heat/compression. The thickness of the cloth is preferably 300-500 .mu.m. 
Perforation 
A homogenous film/cloth of the material may be perforated by e.g. laser 
technique to achieve porosity. In particular, a weak so called excimer 
laser may be employed together with a template of perforated stainless 
steel. 
Precipitation (not applicable to PGA) 
The polymer is dissolved in a solvent which may be selected from a first 
group comprising dimethyl formamide (DMF), dimethylacetamide (DMA), 
dimethyl sulphoxide (DMSO), and tetrahydrofuran (THF), or from a second 
group comprising chlorinated hydrocarbons such as chloroform and methylene 
chloride. Precipitation of the polymer may be achieved with a 
precipitation agent, which with the first group of solvents suitably is 
water, possibly with an addition of up to 20% solvent. With the second 
group of solvents ethanol and other lower alcohols may be used as a 
precipitation agent, possibly with an addition of up to 20% solvent. Both 
the solvent and the precipitation agent may be a mixture. Temperature and 
time at the precipitation may be selected to achieve any desired pore 
size. 
Effervescence 
By admixture of an effervescing agent which releases gas e.g. in contact 
with water (at precipitation) or on heating (in a melt). 
Leaching 
Soluble particles, for example salt, are suspended in a solution of the 
polymer/admixed into a melt thereof. After evaporation/solidification the 
particles are washed out of the material by leaching in a suitable solvent 
for the particles (but not for the polymer). This washing can be done 
completely, or partially provided that a non-toxic salt such as NaCl is 
employed, whereby the residual amount of salt may be allowed to leach out 
after implanting the material into the body. 
The material is used according to the invention in healing of soft tissue, 
i.e. tissue that does not consist of cartilage, bone or teeth. Preferably 
the material is used for healing of injuries in the: 
Circulatory system (heart, blood vessels such as the pulmonary artery) 
Digestive organs (stomach, intestines, oral cavity, liver, pancreas) 
Reproductive organs (uterus e.g. in a Caesarean section, ovaries, testes 
e.g. at undescended testis in boys, the Fallopian tubes, testicular ducts) 
Urinary system (kidney, bladder, urethra) 
Respiratory system (lungs, trachea, bronchi) 
Other muscles (abdominal wall etc.) 
Suitable bioresorbable materials for the purposes of the present invention 
may readily be chosen by one skilled in the art, e.g. among those that are 
either commercially available or have been described in literature or will 
be available in the future. As examples of such bioresorbable materials 
may be mentioned polymers based on polyglycolic acid (PGA), copolymers of 
glycolic acid and lactic acid, copolymers of lactic acid and 
.epsilon.-aminocapronic acid, and various lactide polymers. PGA esters 
are, e.g. described in U.S. Pat. No. 3 463 658, while copolymers of 
glycolic acid and lactic acid are described e.g. in U.S. Pat. No. 3 982 
543. Homo and copolymers of lactic acid are described in e.g. U.S. Pat. 
No. 3 636 956. Examples of commercially available materials are 
Vicryl.RTM. (a copolymer of 90% glycolic acid sold by Ethicon, 
Sommerville, N.Y., U.S.A.--also known as Polyglactin) and Dexon.RTM. 
(Davies & Geck, Pearl River, N.Y., U.S.A.). Further examples are 
polydesoxazon (PDS) (Ethicon, U.S.A.), polyhydroxybutyric acid (PHB), 
copolymers of hydroxybutyric acid and hydroxyvaleric acid (PHBV), 
polyesters of succinic acid, and crosslinked hyaluronic acid. As suggested 
above, mixtures of the above-mentioned materials may equally well be 
employed. One skilled in the art would have no difficulty to modify such 
bioresorbable materials depending on current needs, e.g. with regard to 
resorption time, strength etc. 
Possibly, growth factors may be included in the porous structure, either 
deposited in the pores or included in the bioresorbable material for slow 
release of growth factor. 
The sheet-formed material according to the invention may suitably, in 
particular in application for strong muscles and in other locations where 
the material is subject to strong load, be combined with a resorbable 
armament e.g. a woven or knitted cloth. 
The invention is further described with reference to the following examples 
.

EXAMPLE 1 
Preparation of a sheet material for replacement of a part of the 
pericardium. 
5 ml of a solution of 10 g Biopol (PHBV, 20% hydroxyvaleric acid) in 100 ml 
dimethylacetamide (about 50.degree. C.) was spread on a glass plate. The 
glass plate was thereafter placed in water of ambient temperature for 12 
hours. In this manner a porous patch (8.times.8 cm) was formed having 
about 1 mm thickness. The patch was washed in water, dried, packed and 
sterilized (ethylene oxide). 
Example 2 
Use for healing of pericardiac defects. 
In connection with cardiac surgery, difficulties occur almost always in 
closing the pericardium. This results in the pericardium often being left 
open. The result is adhesion which causes severe difficulties on 
re-operations and also an decreased motility of the heart, the function of 
which is impaired. 
In connection with cardiac operations on sheep the defect caused was 
replaced with a patch of tissue-compatible resorbable polymer prepared 
according to Example 1. The patch was stitched into the defect by a 
continuous suture. When the animal after four months of healing was 
sacrificed and autopsy was performed, virtually normal pericardiac tissue 
was found to be formed without growing together with the heart surface, 
and the heart had been freely motile in the pericardium. 
Example 3 
Producing a nonwoven patch for reconstruction of pericardium. 
The nonwoven material was made from solution spun PHB-fibres pressed 
together to a patch (produced in accordance with U.S. Pat. No. 4,603,070). 
Patch thickness was about 0.4 mm with about 70 per cent pore volume, patch 
size 15.times.15 cm. The patch was sterilized in ethylene oxide. 
Example 4 
Nonwoven PHB patches, produced according to Example 3, was used to replace 
a part of the pericardium in 10 sheep. The animals have been followed up 
for more than one year after the operation and have been sacrificed at 
different times. After two months regeneration of the pericardium had 
started, a very loose adhesion could be found. In the tissue a very active 
phagocytosis, with macrophages as the dominating type of cells, could be 
seen. No other kind of inflammation was present. 
Later there were no signs of adhesion and already after four months a 
healing, very much like normal pericardium could be seen. The inner side 
was very smooth and glossy and mesothelial cells were present, which means 
that real pericardium had regenerated. 
Up to ten months a slight darkness of the patch area could be observed due 
to partly remaining polymer. The darkness disappeared when all polymer was 
resorbed. 
Example 5 
Producing a tube for urethra reconstruction. 
Vicryl.RTM.-fibre was knitted to form a thin tube. The tube mesh, 10 cm 
long, was mounted on a glass stick, diameter 4 mm. The tube was dipped in 
a solution of 10 g PHB:HV (80:20) in 100 ml DMAc and then dipped in water 
for 12 hours to get a porous structure. After washing, drying and 
packaging the urethra tube was sterilized in ethylene oxide. 
Example 6 
The urethra in 4 dogs was replaced by a urethra tube, produced according to 
Example 5. Six to nine months later the prosthesis had been resorbed and a 
fully functional urethra tissue was reconstructed in all animals.