Superficially hydrolyzed biocompatible polyamide material

Polyamide materials for the construction of protheses and surgical sundries are made biocompatible by inducing a superficial hydrolysis by treating such materials, either raw or in the form of shaped articles, with a normal multiple solution of hydrogen chloride. Thrice normal or fourfold normal solutions are preferred and the treatment time being a function of the temperature. At human body temperature (37.degree. C.) a treatment time from 30 to 60 minutes will do.

This invention relates to a process for the preparation of biocompatible 
materials of a polyamide type; it relates, in addition, to the products 
thus obtained. 
The use of polymeric materials in the biomedical art has become more and 
more widespread in the last years. 
One of the major hindrances against an ever wider use of such materials is 
their usually poor compatibility with blood. For this reason, materials 
which have now attained appreciable mechanical properties and which would 
be extremely useful in artificial protheses, do not find, in the actual 
practice, an application on account of their high tendency towards the 
formation of thrombi. Nylon is an example, which, on account of its 
mechanical properties, would find a wide application in the field referred 
to above, should it not be extremely prone to the formation of thrombi. 
The problem of the thrombogenic nature of the polymeric materials has 
invited many searchers to try and find out the origins. More particularly, 
the properties of the surfaces have been studied in order to find out a 
possible correlation between them and the materials in question when 
placed in contact with blood. 
A few authors have tried to correlate the thrombogenic nature of the 
polymeric materials with the surface tension or the Z potential. See, for 
example, the articles by S. D. Bruck in Biomat., Med. Dev. Art. Org. 1, 
191, 1973 and in J. Biomed. Mat. Res. Symposium No. 8 page 1 (1977), from 
which it would appear that the biocompability of a few materials such as 
polyurethans may be correlated with a negative Z-potential measured in 
vitro using the Krebs solution, and with a critical surface tension below 
30 dynes/cm. 
It is generally believed that a material having a negative surface charge 
has good chances of being biocompatible, on account of the fact the blood 
platelets have a negative surface charge. 
Another parameter which is generally accepted in evaluating the materials 
is the capacity of selectively adsorbing a few proteins on the surface 
when placed in contact with blood. 
In this connection, see the article by D. J. Simon, in Trans. Amer. Soc. 
Art. Int. Organs, XXI, 49, 1975 wherein the lack of adhesion of the 
platelets to several materials such as polyurethans, silastic resins and 
Teflon (Reg. Trade Mark) is correlated with the preferential adsorption of 
albumin as compared with globulins and fibrinogen. 
It is likewise known that polyamide substrates can be hydrolized in order 
to set free completely the amine and carboxyl groups, but it has proven 
extremely difficult to carry out such a hydrolysis in such a way as to 
obtain a final product which is only partially modified. 
It is thus extremely surprising that the present applicants have succeeded 
in carrying out a unique superficial hydrolysis of the starting materials 
and concurrently obtaining biocompatible materials which can be employed 
for the purposes indicated above without suffering of any of the 
shortcomings aforementioned. 
As a matter of fact, the object of the present invention is to provide a 
process for the superficial hydrolysis of polyamide materials, which 
permits to obtain materials which are only partially modified and exhibit 
a high degree of biocompability. 
Such a reaction is carried out by carefully checking the hydrolizing agent 
and the reaction conditions. More particularly, hydrochloric acid is used 
as a concentration of from 3 to 4-normal and the temperature is maintained 
in the interval from 20.degree. C. to 40.degree. C. Substantially all 
unreacted hydrochloric acid is removed by first washing with a base, such 
as sodium hydroxide, followed by washing with water. 
The reaction time, in its turn, is selected as a function of the working 
temperature: thus one passes from 10 to 30 hours at a temperature of 
25.degree. C. to 30 to 60 minutes at a temperature of 37.degree. C. There 
is, in practice, an inverse relationship between the temperature within 
the range considered above and the reaction time; these two parameters 
must be accurately coordinated in order that the desired values may be 
obtained, inasmuch as lower values of the temperature require longer 
reaction times. 
As regards the starting materials, it is possible to start from any kind of 
material of a polyamide nature: poly-caprolactam and the various types of 
aliphatic or aromatic nylons are especially advisable. The treatment 
consists, in practice, in introducing on the surface of such materials, an 
infinity of dipoles the overall charge of which is zero. 
Inasmuch as the procedure which renders the articles made with these 
materials biocompatible is a bland superficial hydrolysis, it can be 
surmised that any chemical modification undergone by biocompatible 
articles of this kind (provided that it is a nondestructive modification, 
of course) will not impair the characteristics of biocompatibility of the 
material concerned. 
It is possible to select, from among the wide host of existing polyamides, 
materials which lend themselves to different uses. It becomes thus 
possible to exploit articles which range from those adapted from 
long-lasting protheses to thin membranes which are gas-pervious and can be 
used for heart-lung machines and for artificial kidneys. 
The articles can be made starting from an already modified polyamide, or 
the modification can be carried out on an already shaped article. In 
addition, the polyamide can be admixed with one or more conventional 
ingredients.

The invention is described in detail with the aid of the following examples 
which are not to be construed as limitations. 
EXAMPLE 1 
5 Meters of Nylon-6 thread (dia. 0.25 mm, commercial polycaprolactam) have 
been twice extracted with dioxan and petroleum ether (40/60 by vol), under 
reflux conditions for two hours. The thread has been subsequently washed, 
first with acetone and then with water, whereafter it has been subjected 
to a superficial hydrolysis with HCl (3 time normal=3 N) at 37.degree. C. 
The hydrolysis last 30 minutes, whereafter the thread has been washed with 
0.1 N NaOH and then with water. 
The completion of the hydrolysis and thus the presence of amine groups on 
the surface of the thread has been confirmed by colorimetric assays. A 
sample of the thread has been immersed in a 0.1% (wt/vol) solution of 
trinitrobenzenesulfonic acid in saturated tetraborate and, after one hour, 
it took a yellow-reddish hue, whereas a reference sample which had not 
been hydrolized did not take any color. The hydrolized nylon thread thus 
obtained has been carefully and evenly wrapped around an intravenous 
Teflon (R.T.M.) catheter (Wallace, length 30 cm, I.D.. 0.69 mm, O.D. 1.14 
mm) so as to cover the surface satisfactorily. A similar comparison 
catheter has been prepared by using a non-hydrolized nylon thread. The two 
catheters have been inserted in the femoral veins of a medium-size dog 
kept under general aneasthesia (Pentothan, R.T.M.), free breathing. A 
collateral of the femoral vein has been isolated, and a probe has been 
introduced along the entire length of the collateral so that a predominant 
portion of the probe was floating in the iliac vein and in the inferior 
vena cava. The end of the probe has been tied to the collateral branch of 
the femoral vein and covered by the muscle bundles. Eventually, the wound 
has been stitched. In the same way, the second probe has been introduced 
in the other femoral vein of the test animal. Both before and after the 
operation, heparin has been administered to the animal to prevent vascular 
thrombi due to the surgical wounds. The probes have been left in situ for 
30 days without administering any further anticoagulants: on completion of 
this period, the animal has been killed and the probes withdrawn. The 
probe having the hydrolized nylon thread wrapper has been found clean and 
clot-free. Also the vascular wall was found in good conditions. The 
reference probe with the untreated nylon thread wrapper, conversely, has 
been found coated by numerous thrombi. 
EXAMPLE 2 
3 Meters of tube of Nylon-66 (O.D. 9 mm, I.D. 7 mm) have been subjected to 
superficial hydrolysis by having a 3% solution of HCl flowing therethrough 
at 37.degree. C. for about one hour. On completion of the reaction, the 
tube has been washed with decinormal (0.1 N) NaOH and then with water. The 
completion of the hydrolysis has been confirmed by the colorimetric 
procedure described in the previous Example. The test of platelet 
adhesiveness has been carried out on sections of hydrolized nylon tube and 
on sections of untreated nylon tubes. The method of A. J. Hellem 
("Platelet adhesiveness in von Willebrand's disease". A study with a new 
modification of the glass bead filter method, Scand. J. Haemat, 7, 374, 
1970) has been followed by using native blood of a healthy individual, 
drawn and caused to flow through the tubes being tested by means of a pump 
having a rate of delivery of 4 mls per minute. Platelet counts have been 
made both before and after the flow of the blood through the nylon tubes. 
The counts have been made by collecting blood samples in an aqueous 
solution containing bipotassic EDTA at the concentration of 6 milligrams 
per 10 milliliters. 
The platelet count has been made with a phase contrast microscope according 
to the method of Brecher and Cronkite (Morphology and enumeration of human 
blood platelets, J. Appl. Physiol. 3, 365, 1950). 
In the case of hydrolized Nylon tubes, no significant decrease has been 
observed of the number of platelets in solution. On the contrary, on the 
untreated Nylon tubes, the platelet adhesiveness was 56.5%. 
EXAMPLE 3 
Rings of Nylon-66 have been prepared (length 9 mm, I.D. 7 mm, O.D. 8 mm) 
and special care has been taken in machining the edges, which have been 
beveled and rounded. A certain number of such rings has been hydrolized 
with HCl (3.5 normal) at 37.degree. C., for one hour. Also in this case, 
the completeness of the hydrolysis has been confirmed by the 
trinitrobenzene sulfonate tests. The rings of superficially hydrolized 
Nylon and other comparison rings have been inserted in the inferior vena 
cava of dogs of medium size by a thoracotomy under general anaesthesia 
(Nembutal, R.T.M.). Special care has been taken when inserting the rings. 
Care has been taken that the rings did not contact the atrium wall and 
that the vein wall was not damaged too much when inserting the ring. It 
has been observed that the reference rings, after two hours, already 
exhibited numerous clots stuck to the walls and in some cases, even the 
obstruction of the prothesis has been experienced. The hydrolized nylon 
rings, conversely, have been withdrawn after two weeks, cleaned and only 
in few cases a few thrombi have been seen on the inner ring wall.