Biodegradable device

There is provided a device to promote healing of cut tissue members, such as nerves, tendon or muscles, within a body. The device is of hollow construction and comprises apertures into which the cut ends of the tissue members are placed and fixed, usually by a fibrin-based tissue glue. Located between the apertures is a substance to promote healing of the tissue member such as, for example, nerve growth factor. Optionally the device may be used in conjunction with the external reservoir of the substance and/or with a time-operated pump to deliver the substance to the device. The device is biodegradable and is preferably composed of watersoluble glass.

FIELD OF THE INVENTION 
The present invention relates to a biodegradable device to aid healing. 
DESCRIPTION OF THE RELATED ART 
Advances in surgical techniques, particularly micro-surgical techniques, 
have enabled operations for re-joining or aligning severed nerves and 
blood vessels to be undertaken. However, to be successful such operations 
still rely upon the natural healing and regeneration processes of the 
body. Thus, even where the surgeon has exerted considerable skill in 
aligning nerve ends, there will be cases where the parts of nerves fail to 
re-join, or where the healing process is so slow that the effector muscle 
has atrophied by the time that the motor nerve connection becomes 
effective. 
Healing, for example nerve regeneration, remains an essentially biological 
process. Even the most advanced micro-surgical techniques for repairing 
damaged tissue members merely optimise the environment for the natural 
process. It is now believed that micro-surgery has maximised the 
mechanical processes for body repair, but a need still exists for 
enhancing the healing process still further. 
Tubes have been used to repair severed nerves, but have enjoyed little 
success because the non-biodegradable tubes remained after the 
regenerating nerve had been established and impeded subsequent maturation 
of the nerve. 
GB-A-2,099,702 describes a structural support member for skeletal and 
tissue members comprised of a biodegradable glass. However, for the 
healing process to be successful it is essential that the correct chemical 
environment is created to optimise the regeneration of the damaged body 
part, whilst protecting that part from the body's own defence system which 
can be activated against implanted foreign bodies. 
In one aspect, the present invention provides a biodegradable device of 
hollow construction having first and second apertures, each aperture being 
adapted to receive a cut end of a tissue member which is secured therein 
by means of a fixant, and wherein at least part of the portion of said 
device between said apertures contains a substance to facilitate healing 
of said tissue member. 
Generally the device will be tubular. For example the device may be an 
open-ended tube, the two open ends forming the apertures for receiving the 
ends of the cut tissue member. 
For convenience of manufacture the device may be essentially an open-ended 
cylinder of uniform internal cross-section. Alternatively, the device may 
incorporate a reservoir portion, in which reserves of the substance are 
located. In this embodiment the device may be tubular, but have an 
internal cross-section of varying diameter, for example of increased 
diameter in the portion between said apertures. To optimise the healing 
together of the two cut ends secured in the device, the apertures may be 
arranged to face each other. However, in certain instances this 
arrangement may not be essential, and the aperatures need not be aligned. 
The device of the present invention may be formed from a biodegradable 
glass. Such glasses are known to those skilled in the art and the 
composition of the glass may be adjusted to produce a glass composition 
that biodegrades over the period required, for example 1 to 6 months, or 1 
to 3 months. Desirably the products resulting from degradation of the 
glass are physiologically compatible. 
Additionally, the glass composition may itself be used as a vehicle to 
deliver biologically active agents in a controlled release manner over the 
period during which healing occurs. Controlled Release Glasses (CRG) are 
inorganic polymers, normally based on phosphates of sodium and calcium, 
which have been converted into a glassy form by melting the constituents 
at about 1000.degree. C. CRGs dissolve in water completely leaving no 
solid residue. 
The rate of dissolution can be selected by adjustment of the composition 
and physical form of the CRG and is constant for as long as any of the 
material remains. The product can be produced in many physical forms; as a 
powder or granules, fibre or cloth, tubes, or as cast blocks of various 
shapes. 
As stated above, suitable biodegradable glasses are known in the art, but 
particular mention may be made of the glasses disclosed in WO-A-90/08470 
of Giltech Limited. Typically, the glass compositions may comprise: 
______________________________________ 
Na.sub.2 O 7-33 mole % 
K.sub.2 O 0-22 mole % 
CaO 0-21 mole % 
MgO 0-22 mole % 
P.sub.2 O.sub.5 46-49 mole % 
______________________________________ 
Such glass compositions may achieve solution rates of from 0.03 to 3.0 
mgcm.sup.-2 hr.sup.-1 in de-ionised water at 37.degree. C. 
Elements other than sodium and calcium, including most metals as their 
oxides and a limited number of inorganic anions, can be included in the 
composition of the glass. These elements, which may be biologically 
active, can then be delivered at a constant rate into an ambient aqueous 
medium (for example a physiological fluid) as the CRG dissolves. This has 
found application in veterinary medicine as a means of delivering such 
diverse substances as trace elements, anthelmintics and vaccines. 
Incorporation of a silver source (for example silver orthophosphate) into 
the Na.sub.2 O--CaO--P.sub.2 O.sub.5 systems offers the possibility of 
producing a CRG capable of releasing silver ions over a highly defined 
time, into biological systems with safety. 
In the course of developments of this type the biocompatibility and absence 
of toxicity of CRG based on Na.sub.2 O--(Ca,Mg)O--P.sub.2 O.sub.5 with and 
without other constituents have been investigated. In applications 
differing as widely as use in orthodontics devices [see Savage, Brit. J. 
of Orthodontics 9:190-193 (1982)], and in controlled supply of Cu, Co and 
Zn in cattle [see Drake et al, Biochem. Soc. Trans. 13:516-520 (1985)], no 
ill effects were observed. When CRG pellets were implanted subcutaneously, 
intramuscularly and intraperitoneally in rats, sheep and cattle, reaction 
at the implant site was limited to a sterile fibrous encapsulation less 
well developed than that expected from biocompatible surgical materials 
[see Allen et al, Vet. Soc. Commun 2:78-75 (1978)]. Other application of 
CRG in the Na.sub.2 O--CaO--P.sub.2 O.sub.5 system have been found as 
potential bone graft adjuncts/substitutes. No sign of cytotoxicity was 
observed after soft tissue implantation in sheep [see Burnie et al, 
Biomaterials 2:244-246 (1981)]. In further experiments with bone no ill 
effects nor bioincompatibility could be detected [see Burnie et al, 
"Ceramics in Surgery" Ed Vincenzini, Elseveier Scientific, 1983, pages 
169-176; Burnie et al, J. Bone & Joint Surgery 65B(3):364-365 (1983); Duff 
et al, Strathclyde Bioengineering Seminars, Biomaterials in Artificial 
Organs, and Paul et al, Macmillan Press, 1984, pages 312-317]. 
The glass composition may include one or more metal ions which are slowly 
released from the composition to facilitate healing. Mention may be made 
of K, Mg, Zn, Al, Se, Si, Fe, Ag, Cu, Mn, Ce and/or Au. 
In particular the glass composition may be manufactured to provide a 
potassium-rich environment, which may be useful in aiding healing of the 
tissue member, especially nerves. 
The substance located in the device will be selected to facilitate healing 
of the cut tissue member. The viscosity, osmolality and pH of the 
substance should therefore be chosen to be physiologically compatible with 
the type of tissue to be healed. The substance may optionally contain one 
or more physiologically active agents and mention may be made of growth 
factors (especially growth factors specific for the type of tissue 
concerned, such as nerve growths factors for nerve re-generation), 
anti-coagulants, agents to combat infections (for example antibiotics, 
silver ions etc) and the like. Mention may be made of platelet released 
and PDGF, Nerve growth factor, Keratinocyte stimulation factors, 
Insulin-like growth factor, Interleukins, peptides, enzymes and other 
topical agents, oxygenators and free radical scavengers, enzymes and 
nutritional agents such as proteins and vitamins. Optionally the surfaces 
of the glass device may be coated with silicone to reduce thrombogenesis. 
Over a number of years a great deal of evidence has emerged from in vitro 
experiments to suggest that the group of substance known as `nerve growth 
factors` or `nerve cell rescue factors` may enhance the regeneration 
process which takes place after a nerve is injured and repaired. There are 
now many such substances awaiting evaluation. Some are thought to act 
preferentially on either motor or sensory nerves and the potential for 
their use in chemically manipulating and improving the results of surgical 
nerve repair is enormous. Despite at least 20 years of study in the 
laboratory little or no success has been achieved in the method of 
delivery to this site of injury and also because the tests which are used 
to quantify nerve repair are insufficiently sensitive to resolve the small 
(but most useful) benefits which growth factors may bring. For a substance 
to have maximal effect is must be delivered at the site of regeneration, 
at an appropriate and maintained concentration and at the time at which 
its effect on the growing nerve axons will be most effective. To achieve 
this, delivery must be constant at the site of injury over the growing 
period and diffusion away from this site must be insufficient for the 
local concentration to fall below effective values. Lundborg [see G. 
Lundborg, Nerve Injury and Repair, 1988, Edinburgh Churchill-Livingston] 
has to a small extent achieved this by wrapping the site in silicon tubes 
containing growth factors. However there is still an inadequate 
concentration over time and the permanent tube constricts the growing 
nerve in its maturation phase. The end result is worse rather than better 
and no surgeon in human practice would contemplate a second operation to 
remove a silicon tube. 
The biodegradable device of the present invention offers two features which 
address these issues. First the device can be made to dissolve over a 
timecourse which would include the period of growth in length when growth 
factors could be delivered to an isolated environment but dissolution 
would occur before the non-growth-factor-dependant phase of maturation 
(growth in diameter). Secondly, growth factors could be delivered into the 
device through a side hole by means of an osmotic pump. If the outlet 
silicon rubber tube is glued into the device a watertight system is 
effected. Using proprietary osmotic pumps, growth factors can be delivered 
in appropriate constant concentration for four weeks after repair. This 
encompasses the time for growth factor-dependant regeneration. At the end 
of this time the device will biodegrade and the pump and its tubing can be 
removed from its remote subcutaneous site under local anaesthetic in a 
very small and simple operation. The nerve is thus left unimpeded to 
mature. 
The substance may be any means to facilitate healing, including cellular 
matrices which encourage and mechanically guide regeneration e.g. of nerve 
or muscle, and/or humeral substances such as chemical growth factors. By 
increasing the concentration of the supplied substance at the site of 
injury and regeneration the latter may be enhanced and its specificity 
improved. 
The fixant may be any means of securing the cut end of the tissue member 
into an aperture of the device. Desirably the fixant substantially seals 
the tissue member end into the aperture. Mention may be made of sutures, 
clips and other mechanical means, but desirably the fixant should be 
biodegradable. Thus physiologically compatible "glues" may be preferred. 
One particular example is a fibrin-based tissue glue. 
The device itself nay comprise means to secure a tissue member end in an 
aperture of the device. For example, the internal diameter of the device 
may decrease in the proximity of the aperture. In one preferred embodiment 
the device includes internal barbs which grip the tissue member once 
inserted. Desirably however a physiologically acceptable "glue" is used to 
seal the aperture after insertion of the tissue member. Thus the glue can 
be used to protect the damaged ends of the tissue member from the body's 
defence mechanisms. 
The device of the present invention is particularly useful for enhancing 
the healing of severed nerves, including individual nerve fibres as well 
as nerve bundles. The device may also be of utility for aiding the healing 
of tissue members such as tendons, blood vessels (especially capillary 
blood vessels), muscle fibres and ducts. 
The ends of the tissue member may be inserted into the aperture of the 
device by any suitable means. For example, the aperture may be large 
enough for the tissue member end to be simply placed therein; the end then 
being secured by any suitable means, preferably a physiologically 
acceptable glue. However in certain circumstances it may be desirable for 
the aperture to be of similar internal diameter to the external diameter 
of the tissue member. In this instance a suture, threaded through the 
device is drawn through the tissue member end which can then be pulled 
through the aperture as required. 
In one embodiment the device has a semi-porous or porous region, preferably 
located between said aperatures. Prior to implantation the device is 
exposed to physiologically useful agents which may be taken up into the 
porous or semi-porous region of the device for release after implantation. 
The agents may facilitate the healing of the tissue member. Thus, the same 
device could be used to facilitate healing for different types of tissue 
members, but will be adapted specifically for each depending on the 
physiologically useful agents taken up into the porous or semi-porous 
region. Following implantation, said physiologically useful agent(s) can 
be injected adjacent to the implant, pass through the porous region and 
onto the tissue member under repair. 
In a further embodiment, the device may include an opening to enable 
introduction of a substance into the device before implantation and/or 
after implantation. The opening may optionally also be used for exit of 
the suture pulling the end of the tissue member through the aperature. In 
one particular embodiment the device of the present invention may be 
replenished with the substance after implantation. Thus, for example, the 
device could be connected to a reservoir external to the patient and/or a 
time-operated pump to automatically replenish the substance in said 
device. 
In a further aspect, the present invention provides a method to facilitate 
healing of a cut tissue member, said method comprising inserting each end 
of said tissue member into a separate aperture therefor in the device of 
the present invention and securing the tissue member ends into said 
apertures by means of a fixant. 
The technique of inserting the tissue member ends, for example nerve ends, 
into a tube and securing them there with fibrin-based tissue glue is very 
simple. This technique dispenses with the need for an operating 
microscope, expensive microsurgical sutures and instruments and the need 
for a trained microsurgeon. It may thus have considerable implications for 
current surgical practice and could further extend the repair of nerves to 
underdeveloped countries where at present nerve injuries may be 
untreatable. 
In a further embodiment the device of the present invention may be used to 
test the effect of different factors on tissue healing. For example the 
device may be considered as a model system in which growth factors may be 
tested to find out whether and to what extent such factors may be helpful 
in promoting and directing the natural process of regeneration. 
In a yet further embodiment the present invention provides a kit to aid 
healing of a cut tissue member, said kit comprising a device of hollow 
construction having two apertures adapted to receive the cut ends of a 
tissue member; said kit further comprising a physiologically acceptable 
fixant and a substance to aid healing of said tissue member. 
The device of the present invention may also be used in vitro to promote 
growth of a tissue member; the regenerated tissue member may subsequently 
be used for transplantation, for example to replace a damaged tissue 
member. 
In a further aspect, the present invention provides a method of treating a 
human or non-human animal body having a cut tissue member, said method 
comprising inserting the cut ends of said tissue member into separate 
aperatures of the device according to the invention. Optionally the device 
may be used in conjunction with an external reservoir of the substance 
and/or with a time operated pump to deliver the substance to the device.

DETAILED DESCRIPTION OF THE INVENTION 
FIG. 1 shows a biodegradable glass tube 1 suitable for use in the present 
invention, especially for nerve repair. Tube 1 consists of a hollow, 
essentially cylindrical, glass body having aperatures 2, 3 at the ends 
thereof. Two diametrically opposed suture holes 4,4' are located in tube 
1, close to aperature 2. Two similar diametrically opposed suture holes 
5,5' are also located in tube 1, close to aperature 3. Approximately 
mid-way down the length of tube 1 is an injection port 6, which enables 
access to the interior volume of tube 1, even when tube 1 is in place 
within a patient. 
FIG. 2 illustrates a similar tube 1 to that shown in FIG. 1, having 
flexible tubing 7 (for example silicone tubing) passed through injection 
port 6 into the interior volume of tube 1. Tubing 7 may be connected to a 
pump or reservoir (not shown) containing a substance or active agent 
capable of promoting healing of the body part in question. Once sufficient 
healing has taken place tubing 7 may be simply removed, without disturbing 
tube 1. 
In use, one of the ends of the damaged body part will be inserted into 
aperature 2 of tube 1, optionally after trimming the end of the body part. 
A suture will then be passed through a first suture hole 4, through the 
end of the body part inserted through aperature 2 and out through suture 
hole 4'. The ends of the suture will then be securely fastened. Optionally 
a tissue glue may then be used to seal the body part into the aperature 2 
of tube 1. 
The process described above will then be repeated with the other end of the 
damaged body part, aperature 3 and suture holes 5,5' of tube 1. 
Optionally tubing 7 may be passed through injection port 6 into the 
interior volume of tube 1 and an appropriate substance fed into the free 
space within tube 1 to provide an environment suitable for healing the 
body part. The two ends of the body part will gradually grow down the 
interior of tube 1 and, on meeting will knit together. Alternatively the 
substance may be simply injected into the free volume within tube 1 by any 
suitable means (e.g. syringe). 
For very small body parts (e.g. the sciatic nerve of rats, the common 
peroneal nerve of rabbits or similarly sized body parts of other animals), 
the length of the glass tube may be 20-26 mm (e.g. 22 mm) with an outer 
diameter of 4-5 mm. The tube itself may have a thickness of 1-2 mm (e.g. 
1.2 mm) and the suture holes and injection ports may each typically have a 
diameter of 0.5-1 mm (e.g. 0.7 mm). 
For slightly larger body parts, a larger dimensioned tube will be required, 
and the dimensions recited above may be adapted as required. For example 
in sheep, a tube length of 30 mm having an outer diameter of 8-9 mm and 
inter diameter of 7 mm, with suture hole and port diameter of 1.2-1.3 mm 
may be sufficient. 
The invention will be further described with reference to the following, 
non-limiting, examples. 
EXAMPLE 1 
All procedures were performed on rats and under sterile conditions. 
1. The biceps femoris muscle was retracted. Care was taken not to involve 
the medial femoral circumflex artery which supplies these muscles. 
2. The sciatic nerve was cut about 2 cm from the sciatic notch. (Midway 
down the nerve). 
3. A biodegradable glass tube (as illustrated in FIG. 1) was cut to size 
enabling 2 mm of nerve to extend into the centre of the tube. 
The glass of the tube was composed as follows: 
______________________________________ 
Mole % 
______________________________________ 
Na.sub.2 O 
32.0 
CaO 21.0 
P.sub.2 O.sub.5 47.0 
______________________________________ 
The glass had a solution rate when annealed of 0.4 mgcm.sup.-2 hr.sup.-1 in 
de-ionised water at 37.degree. C. The tube had a physiological life 
expectancy of approximately 40-50 days. 
4. The tube was secured by either suture, clip or glue. 
5. The animal was kept for over 60 days before undergoing 
electrophysiological studies and microscopic analysis under anaesthesia. 
6. EMG was taken to measure conduction velocity. The sciatic nerve was 
exposed as in step 1 and dissected out 2 cm above the graft and 2 cm 
below. EMG was then taken at each point to determine the speed of 
conduction: 
##EQU1## 
The Extensor digitorum longus muscle was chosen for the EMG because the 
nerve supply is the Deep Peroneal Nerve which is a direct tributary of the 
Sciatic-Common Peroneal Division. 
______________________________________ 
Results 
Conduction 
Healing 
Length (mm) Velocity time 
Type of Graft (if removed) (M/s) (days) 
______________________________________ 
Tube and Clip 
13 4.33 46 
Tube and Clip 24 25.26 67 
Tube and Clip 25 31.25 114 
Tube and Suture 12.5 8.06 47 
Tube and Suture 38 19.46 68 
Tube and Suture 27 31.76 68 
Tube and Suture 15 21.43 90 
Tube and Suture 18 21.18 90 
Tube and Suture 23 17.04 96 
Normal 18 36 -- 
______________________________________ 
EXAMPLE 2 
A further study was conducted to establish: 
a) that a biodegradable glass tube (BGT) was compatible with effective 
nerve repair; and 
b) that the BGT was not toxic to the regenerating nerve or to the 
surrounding tissue and that the BGT did not provoke a fibrotic tissue 
reaction or immune response likely to affect nerve regeneration adversely. 
The experiments were performed in rats. The sciatic nerve was divided and a 
BGT (as used in Example 1) placed over it. With the BGT pushed to one side 
the nerve stumps were repaired by epineurial suture. The BGT was then 
placed at the repair site and fixed in place with epineurial sutures and 
fibrin glue. Electrophysiological and morphometric assessment was carried 
out at 100 days. It was found that normal nerve regeneration had taken 
place and that the BGT had completely dissolved. There was no sign of any 
adverse reaction. 
EXAMPLE 3 
This experiment was conducted on New Zealand large white rabbits. In each 
rabbit the common peroneal nerve was divided and repaired in the upper 
thigh. The tibial nerve was left intact. BGTs were all as described in 
Example 1 and all of 1.5 cm in length. Each of the methods of repair 
represented by the contents of the tube are accepted clinical techniques 
for nerve repair with the exception of the gap which was a control and 
which would not be expected to be compatible with recovery of nerve 
function. 
1) BGT+1 cm gap in nerve (control) 
2) BGT+1 cm freeze-thawed muscle autograft (FTMG) 
3) BGT+1 cm nerve autograft 
4) BGT+nerve and FTMG short lengths in series to length of 1 cm 
5) FTMG without tube (control). 
There were 5 rabbits in each group. 
Each animal was reviewed 6 months after nerve repair. Under anaesthesia the 
repair site was re-exposed and the nerve was subjected to a number of 
electrophysiological tests. Some of these tests have become well 
established as a means of assessing recovery after nerve repair. Others 
are new tests which are currently being evaluated in an attempt to find 
tests which will resolve the small but important improvements in nerve 
regeneration which may be expected where nerve growth factors are used. In 
all cases the opposite limb was used as a control. 
After electrophysiological assessment, the segments of repaired and control 
nerve were excised and processed for microscopic examination. Computerized 
morphometric assessment was used to measure indices of nerve regeneration 
such as axon and fibre diameter and G-ratio. 
In group 1 above it was surprising to find that regeneration had taken 
place albeit to a limited extent. It seems likely that isolating the 
regenerating nerve within the tube may have improved its chances of 
crossing the gap. This result speaks well for the fact that the tube does 
not impede nerve regeneration. 
In groups 2, 3 and 4 all of the indices of recovery showed comparability 
with the best results obtained by conventional means. This means that as a 
supporting medium for either direct repair or repair using short neural 
and FTMG grafts the BGT system performs as well as anything else currently 
available. 
Group 2 demonstrated the best results, with all groups 1, 2 and 3 giving 
successful regeneration of the peripheral nerve. There were no signs of 
neuroma in any of the groups and the BGT was completely dissolved after 
the 6 month test period.