Method of producing a microstructure in a bioresorbable element

Method of producing a microstructure in a bioresorbable element comprising a material consisting of a major portion of at least one polymer selected from the group including aliphatic polyesters and aliphatic polycarbonates and copolymers thereof. The microstructure is accomplished by using an excimer laser which is operated at a maximum wavelength of 248 nm.

The present invention relates to a method of producing microstructures in a 
bioresorbable element to be used for medical applications in a living 
organism. The element could be used e.g. to selectively influence the 
healing process by separating and guiding the tissues surrounding the 
element in such a way that regeneration is achieved, as described in WO 
90/07308. Typically, the bioresorbable materials used for the elements are 
made from homopolymers or copolymers that have been formed by 
polymerization of monomers such as hydroxy acids, hydroxy ether acids, 
lactones and cyclic dimers thereof, or cyclic carbonates. Examples of such 
monomers are glycolic acid, lactic acid, .epsilon.-caprolactone, 
trimetylene carbonate, paradioxanone, 1,5-dioxepan-2-one, valerolactone 
and .beta.-butyrolactone. The element may also be made from the naturally 
occurring polymer known as hydroxy butyrate or any copolymer of hydroxy 
butyrate and hydroxy valerate. The use of such materials in said element 
is preferred because these materials degrade in contact with water and 
thereby disintegrate into smaller molecules that are metabolized or 
excreted from the body. The tissue an then heal without disturbances, and 
no foreign material is left in the body after complete healing, which 
eliminates the long term risks for e.g. infections and other 
complications. 
An element that is to be used in the process of regeneration of living 
tissues, also should have certain properties which are not related to the 
material. Such properties may include: 
1) the element should be anchored at the implant site; 
2) the element should partly or totally separate different kinds of tissue 
and thereby allow for an early integration or a pre-programmed initial 
period of total separation before integration of two different tissues; 
3) the element should block tissue growth into or through the element for a 
longer period of time. 
Said properties can be achieved by incorporation of a microstructure into 
the element or the surface thereof. Typically, this microstructure could 
have dimensions as large as several square millimeters and as small as a 
few square micron and could cover the surface from 0 to 80%, preferably in 
the range of 2 to 50%. The microstructure may form a continuous pattern or 
a discontinuous pattern including microstructure areas positioned close to 
each other or further away from each other. The microstructure could take 
different shapes such as apertures e.g. in the form of circles or 
rectangles, grooves, and indentations, e.g. blind holes. 
Prior art technique that can be used for the purpose of obtaining related 
or comparable microstructures includes mechanical punching, freeze drying, 
extraction or sublimation of pre-placed crystals, and infrared laser 
technology. 
Mechanical punching is difficult to perform if the transverse dimension of 
the aperture to be punched is smaller than 70 .mu.m, and will be difficult 
also in case of larger dimension is many apertures are to be made within a 
small area. The success of mechanical punching is depending extensively on 
the mechanical properties of the material in which the apertures shall be 
made, and the three-dimensional design of the element. An obvious 
limitation of this technique is the fact that only through apertures can 
be made in the element. 
By the freeze drying technique only random patterns of pores or textures 
can be produced within or on the surface of the element. The same is true 
also for the extraction and sublimation technique where it is difficult to 
position crystals in a structured, planned fashion. The sublimation method 
may result in difficulties during the sublimation procedure to remove all 
of the preplaced crystals, and the extraction method may result in 
retention of water or organic solvent in the element after the extraction 
procedure that could be delicate to remove. Moreover, it is difficult to 
remove the crystals completely by extraction or sublimation without at the 
same time damaging or destroying the element. 
Infrared laser technology has been used for many years in the form of 
CO.sub.2 and Nd:YAG lasers. Typical use of these lasers, operating at a 
wave-length of 10.6 and 1.06 .mu.m, respectively, is for cutting or 
drilling purposes, the materials hit by the beam being melted and 
combusted or vaporized. The beam, the wave-length of which is in the 
infrared portion of the electromagnetic spectrum, creates an intense heat 
in the material due to lattice vibration. This principle of creating 
microstructures cannot be used in combination with thermally sensitive 
polymers such as poly-lactides or poly-glycolides, because either the 
microstructure made will be destroyed by the intense heat, or the material 
in the neighbourhood of the microstructures made will be heavily degraded, 
which will impart to the element low dimensional stability after 
implantation, due to large water uptake followed by swelling. All the 
above mentioned techniques have such limitations or disadvantages that 
they cannot be used for the purpose of producing micro-structures of 
desired shape and dimensions. 
During the 80s, excimer laser technology has been developed. These lasers 
operate with a pulsed beam having a distinct wave-length in the UV-light 
range such as, but not limited to, 308, 248 and 193 nm. The high photon 
energy of such light is of the same order as that required for breaking up 
chemical bonds in most organic molecules. If the molecules of the 
material, wherein the microstructures shall be made, have such a chemical 
structure for which the absorption coefficient of the specific wave-length 
used is high, most of the output energy of these lasers, that reaches the 
material, will be consumed by the photo chemical bond-breaking process 
that will take place in the material, and a very small portion of the 
energy will be converted into thermal energy which can heat up the 
material. As a consequence of such heating portions or areas of the 
element being processed which should be left unaffected, may be degraded 
or melted. It is therefore very important to keep the proportion of 
energy, that is converted into thermal energy at a low level. This is 
especially true for such thermal sensitive materials as the group of 
aliphatic polyesters or polycarbonates mentioned above. The initiation of 
the photo ablation process, e.g. removal of material from the surface by 
means of light, is also dependent of the energy density of the laser beam 
at the surface of the material. A certain barrier called the threshold 
energy, must be overcome in order to start the ablation process. The 
threshold energy is the energy density per pulse required to break a 
sufficient number of bonds in the surface layer of the material so that 
the pressure due to the large number of small molecules formed builds up 
to a sufficiently high level for the degraded material to be expelled. The 
technique has been used for some years on polymers containing aromatic 
groups in their repeating unit such as aromatic polyesters e.g. 
poly-ethyleneterephtalate, aromatic polycarbonates and poly-imides, these 
types of materials having a high absorption coefficient at the typical 
excimer laser wave length and also known as polymers having a high thermal 
stability. Such polymers are mentioned in WO 87/03021 which describes a 
method using, among others, excimer lasers for producing microstructures 
in shape of elevations and depressions in fibres and similar elements. The 
typical depth or height in that case ranges from 0.1 to 2 .mu.m but also 
10 .mu.m is mentioned. The spacing between the elevations or depressions 
ranges from 1 to 5 .mu.m. The laser energy density ranges from 5 to 500 
mJ/cm.sup.2 and preferably between 20-50 mJ/cm.sup.2. The increased 
specific surface area of the fibres, accomplished by the microstructure, 
yields structures with excellent filtration properties and also great dye 
absorption capacity. Said structures are also claimed to provide 
advantages in the field of medicine, surgical sewing materials, prosthetic 
articles and artificial veins being mentioned. 
Bioresorbable elements, that is elements made of polymers which are 
hydrolysed in contact with water in the living body, the hydrolysis 
products being absorbed by the surrounding tissue and metabolized or 
excreted, which are used for implantation are commonly made of a material 
consisting of a major portion (usually at least 70% by weight) of at least 
one polymer selected from the group including aliphatic polyesters and 
aliphatic polycarbonates or copolymers thereof. Examples of such polymers 
are poly-lactide, poly-glycolide, poly-.epsilon.-caprolactone, 
poly-valerolactone, poly-hydroxybutyrate, poly-1,4-dioxan-2-one, 
poly-1,5-dioxepan-2-one, polytrimethylene carbonate or any copolymers or 
blends thereof. These materials, being aliphatic polyesters, possess a 
very weak UV-light absorbing ester bond in the UV region above 200 nm. 
They are also known to be very unstable when exposed to heat. This is even 
more so if the material is plasticized in order to obtain a softer 
material. Usually the plasticizer chosen for the above mentioned polymers 
is ethyl, butyl and hexyl esters of acetylated or non-acetylated citric 
acid ester, triacetin or an oligomer, 1 to 10 repeating units, made from 
one of the monomers mentioned above although the choice is not limited to 
these materials. 
The present invention provides a method of producing a microstructure in a 
bioresorbable element comprising a material consisting of a major portion 
of at least one polymer selected from the group including aliphatic 
polyesters or aliphatic polycarbonates or copolymers thereof, by the use 
of an excimer laser operated at a maximum wave-length of 248 nm and an 
energy density at the surface of the material of at least 200 mJ/cm.sup.2. 
By this method minimal degradation in the element is achieved, which 
reduces the problem of high water absorption. High water absorption leads 
to swelling which causes deformation of the element and is especially 
pronounced in copolymers of glycolide and lactide but also in pure 
poly-lactide. Incorporation of a microstucture into a medical device 
always have one or more specific purposes, some of these having been 
mentioned above. It is important to maintain the shape of these structures 
over a certain period of time. It is commonly known that resorbable 
polymers starts to deform when the molecular weight have been reduced by 
hydrolysis to such a point that the mechanical strength of the polymeric 
material is lower than the force or pressure acting on the material from 
the inside by the hydrolysis products and the absorbed water. The first 
step in this process of resorption is the water uptake which cause stress 
release and volume changes, swelling, in the element which therefore 
starts to deform and at a later stage breaks up into fragments due to the 
on-going hydrolysis. This problem of dimensional stability of a preshaped 
element used for implantation is more pronounced in elements made of 
polymeric materials containing polymers with low molecular weights, and 
therefore it is of special interest to minimize thermal or any kind of 
degradation in the element while exposing the element to the laser beam 
for incorporation of the microstucture. If too much degradation occurs in 
areas which should not be processed by the laser beam, the dimensional 
stability of the element will be greatly reduced. 
The microstructures created must, in order to function successfully in 
guiding the tissue growth, have dimensional stability over a certain 
period of time after implantation. In many applications the element should 
be made of a soft malleable material rather than the stiff homo- or 
copolymers of poly-glycolide and poly-lactide. Poly-glycolide, 
poly-lactide and copolymers or blends thereof can be plasticized to 
possess softness and malleability. However, a drawback of using 
plasticizers is swelling of the material due to water uptake. The degree 
of water uptake can be controlled by the choice of plasticizer and polymer 
used. In all cases the swelling also depend on the molecular weight of the 
polymer used as the main matrix component. It is thus very important that 
the laser treatment in order to create the microstructures does not cause 
(extensive chain scission at other places than just where the 
microstructure is to be created, i.e. the thermal degradation of the 
material due to heat build-up must be kept at a minimum.

examples will be described, which have been performed and wherein holes 
with a typical diameter of 200 .mu.m and a centre distance between the 
holes of typically 400 .mu.m have been made. The holes were arranged in a 
hexagonal pattern over the surface of a 100 .mu.m thick film of 
plasticized poly-lactic acid. Two compositions were used: 
1) 75% by weight poly-d,1-lactic acid and 10% by weight poly-1-lactic acid 
plasticized with 15% by weight acetyltri-n-butyl citrate, and 
2) 80% by weight poly-d,1-lactic acid plasticized with 20% by weight ethyl 
terminated oligomer of lactic acid. 
The wave-lengths used in these experiments were 308, 248 and 193 nm, and 
the pulse rate was kept low, typically less than 5 Hz. At 308 nm the 
ablation process did not start, no holes were created in the surface. 
Photo ablation occurred in both of the two different types of film 
described above when the wave-length of the laser light was 248 or 193 nm. 
It was, however, a marked difference in the result when the two different 
wave-lengths were used; 248 nm produced holes of good quality at low pulse 
rate. However, as can be seen in FIG. 1, an increase of the pulse rate 
created holes which had pronounced rounded edges because the material had 
melted. Also small bubbles could be found, which are believed to be gas 
pockets, around the holes. These gas pockets, most pronounced for material 
composition 2, are certainly due to thermal degradation of the polymer but 
may also be due to a residue of water, usually found in these kinds of 
material, that vaporises at heating of the material. The vapour or gas 
formed due to thermal degradation, will expand in the material to form 
bubbles. 
In order to achieve good results as judged by visual inspection of the 
holes made, the polymer film had to rest against a backing material, e.g. 
steel, glass or any inert material, that can take up and transfer the heat 
built up in the polymer film. To test the "in vitro" dimensional stability 
of the films containing the microstructures structures that were made at 
low pulse rate and the proper choice of backing, the films were placed in 
a phosphate buffered saline solution of pH 7.4 and incubated at 37.degree. 
C. A result of such a test is shown in FIG. 2. After 1 day an opaque ring 
could easily be seen around each hole. This opaque colour seen in the 
material close to and at the wall zone of the holes is typically formed in 
aliphatic polyesters due to water uptake and indicates a rather fast and 
large water uptake in the area that has been affected by the laser beam. 
The explanation for this goes back to the thermal breakdown that occurs 
due to heat build-up in the material not hit by the laser beam, which will 
create a large number of free chain ends in the poly-lactic acid polymer. 
The chain ends, being of polar nature bring about a more hydrophilic 
environment in the polymer and, thus, a faster water absorption may occur. 
FIG. 3 shows that in time, typically 5-15 days, this will lead to 
deformation of the microstructures s the material starts to swell, and 
ultimately ruin said structures. Even though it is possible to make 
microstructures that look good by visual inspection, by using a 248 nm 
excimer laser, these structures will start to deform soon after 
implantation of the element due to the chemical alteration of the polymer 
composition taking place under the influence of the thermal effects. 
FIG. 4 and FIG. 5 show the result when the laser was operated at 193 nm, 
FIG. 5 showing rectangular holes. The results turned out to be quite 
different, and no thermal damage could be detected around the holes, even 
at pulse rates up to 50 Hz. It was not necessary to use any form of 
backing material, and incubation "in vitro" showed that the water uptake 
was very much the same as for untreated films. This shows that degradation 
due to heat built up and also UV-light scattering is very low at 193 nm 
and that most of the energy is used for the ablation process. The holes 
are very exact, and no more swelling of the microstructure could be 
observed after 20 days than that to be expected normally in polymers of 
these types. 
FIG. 6 shows schematically the laser and optical set-up which could be used 
to create a certain pattern or microstructure on the surface of an 
element. The beam from a laser 10, scans by means of a mirror unit 11 over 
the surface of a mask 12 made of metal, which is used to mask off the 
laser beam. The image of the mask is projected on the surface of the 
element to be processed by a field lens 13 and an imaging lens 14. By the 
use of an x-y table 15 the element can be moved in such a way that it will 
be possible to scan large objects and at the same time to maintain the 
energy density required for the desired photo ablation process to take 
place. 
It is furthermore of great importance when processing sensitive materials 
as mentioned above to maintain focus of the projected mask over the area 
of the element to be processed. To maintain focus it is necessary to keep 
constant the distance between the mask and the lens and the distance 
between the lens and the element to be processed. This can be done either 
by holding the element rigidly in a frame or to support it on some 
structure so that the distance between the lens and the element is kept 
constant to a high degree of accuracy. Such a frame or support is 
preferably made from metal or an equivalent material. 
Instead of using a projecting system as that described above the 
microstructures can be produced in the element by having the mask in close 
contact with the element the problem of focusing the beam thereby being 
eliminated. The mask can also be lifted from the surface, typically 0 to 5 
mm, preferably 0 to 1 mm, in order to minimize the risk of contamination 
of the element by foreign particles coming from the mask when the same is 
hit by the laser beam. Such contamination can typically be metal dust if 
the mask is made of a metal. 
The following example illustrate the application of using the excimer laser 
in order to create a microstructure having the properties mentioned, in 
pure and plasticized poly-lactides of the compositions mentioned above. 
EXAMPLE 1 
The beam from an excimer laser, Questek 2440, operating at 193 nm (argon 
fluoride gas fill) giving out approximately 200 mJ of energy per laser 
pulse in an area close to 20.times.10 mm was focused by means of a 
spherical lens having a focal length of 350 mm. The beam was allowed to 
expand to a point where the size became approximately 7.times.3.5 mm. At 
this point the energy density in the beam approximate to 800 mJ/cm.sup.2. 
This reduced beam was allowed to fall on the surface of an appropriate 
mask made of beryllium copper or other metallic material, clamped in the 
proximity of the polymer supported in a backing material so that during 
the cutting operation the mask could not move with respect to the polymer 
material. The separation between the mask and the polymer was 100 to 200 
.mu.m. In order to process a large area of polymer the beam was scanned 
over the mask and the polymer by moving the latter two items forward and 
backwards in the beam in a direction parallel to the smaller dimension of 
the laser beam cross section. The cutting process was continued until the 
beam was observed to pass through the film over the entire area. Care was 
taken to keep the laser pulse rate at a sufficiently low level so that 
thermal damage to the material did not occur. For a poly-lactide film of 
130 .mu.m thickness a maximum pulse rate of 30 Hz was used. 
In this invention, using the laser set up as described in Example 1, the 
influence of the laser energy density on the shape of the microstructure 
being produced has been investigated. The microstructure may be in the 
form of perforations, blind holes or grooves which cover the surface of 
the element in a continuous or discontinuous pattern, spaced 1 to 800 
.mu.m, preferably 10 to 400 .mu.m. Such microstructures could specifically 
be apertures going through the element or part of the element. Apertures 
necessary for nutrition across the element in the shape of a film or foil 
should have a diameter in the range of 1 to 30 .mu.m. For tissue ingrowth 
into the element for the purpose of anchoring or integrating the element 
the dimensions 30-1000 .mu.m and specifically 50 to 500 .mu.m have been 
found very useful. In order to create microstructures with dimensions of 1 
to 20000 .mu.m, preferably in the range of 5-1000 .mu.m, in bioresorbable 
materials of the types referred to it is necessary to exceed the threshold 
energy for the photo ablation process to occur. The effect of different 
energy densities on the shape of the microstructures made will be 
discussed with reference to the graph in FIGS. 7 and 8 wherein the 
material codes appearing in the graphs stand for 
CK12Z: 75% by weight poly-d, 1-lactic acid and 10% by weight poly-1-lactic 
acid plasticized with 15% by weight acetyltri-n-butyl citrate, and 
TM4D: 80% by weight poly-d, 1-lactic acid plasticized with 20% by weight 
ethyl terminated oligomer of lactic acid.graph 
Typically, the threshold energy, i.e. the energy density per pulse, is 
around 200 mJ/cm.sup.2 for pure or plasticized poly-lactides as can be 
seen in FIG. 7. There is also an upper limit, around 1200 mJ/cm.sup.2, set 
by the fact that beyond this point thermal effects commence and also the 
efficiency of removal of material is decreasing. For the purpose of 
producing the said microstructures it is necessary to have an energy at 
the surface of the element to be processed between 200 to 1200 mJ/cm2, 
preferably between 400 to 1000 mJ/cm2. All structures created by means of 
the excimer laser will be tapered, i.e. the input end of an aperture 
always will have a greater area than the output end. The taper angle 
depends on the material composition and the energy density of the beam as 
seen in FIG. 8. The taper angle can be very high for low energy densities, 
as seen in FIG. 8, but will decrease as the energy density is increased. 
Depending on the shaped of the microstructures to be made and the purpose 
of the same adjustment to the proper level of energy density is necessary. 
For example if a circular hole or perforation 100 .mu.m in diameter is to 
be made in an element 100 .mu.m thick by using an energy density of 300 
mJ/cm.sup.2, the output diameter of the hole will be about 20 .mu.m, while 
if an energy density of 800 mJ/cm.sup.2 is used, the output diameter will 
be 90 .mu.m. It is therefore necessary to choose an energy density which 
gives an acceptable etch rate in combination with the desiered dimension 
of the microstructure. Such energy densities can be found to be in he 
range between 300 to 500 mJ/cm2 for thinner elements wherein ablation 
depths of up to 50 .mu.m is required, and in the range of 500 to 1000 
mJ/cm2, preferably in the range of 700 to 900 mJ/cm2 for thicker material 
where ablation depths up to 250 .mu.m is required. For poly-lactide the 
angle of taper is within acceptable range for structures that have a depth 
of typically 250 .mu.m or less, using an energy density of 800 
mJ/cm.sup.2. 
A further example will be given in which the microstructure in the shape of 
perforations which go all the way through the element is made by utilizing 
the technique of projecting the image of the mask on the surface of the 
element to be processed, such a system being shown in FIG. 6. 
EXAMPLE 2 
The beam from an excimer laser, Lumonics Excimer 600, giving out 
approximately 200 mJ of energy at 193 nm was adjusted in size using an 
appropriate optical system so that the energy density of 100 mJ/cm.sup.2 
was obtained at the surface of an appropriate mask. An optical projection 
system consisting of a field lens and an imaging lens was set up to 
produce a reduced image of the mask at the surface of the polymer. For the 
particular example of cutting poly-lactide films of 130 .mu.m thickness a 
x3 linear reduction system was used. For this material the poly-lactide 
film was held in a silica windowed cassette so that the poly-lactide was 
always maintained in a sterile environment. To cover a large area at the 
polymer the laser beam was scanned using moving mirrors over the area of 
the mask in an appropriate raster or linear scan pattern. During this 
process the corresponding x3 reduced pattern size of the polymer was also 
scanned. The process was continued until the required structure was 
drilled completely through the polymer film. The laser pulse rate used 
depended on the area of the polymer film scanned and on the scanning rate 
in order to keep the power input below a level that would not cause 
thermal damage to the material, e.g. for an area of 20.times.10 mm to be 
scanned of the polymer, the laser pulse rate was held below 30 Hz.