Biogenic implant for drug delivery and method

A medicament-dispensing medical implant is described which is fabricated from relatively non-inflammatory biogenic tissue or biopolymers for implantation in or adjacent to a target issue in the human body. The implant, whic is non-thrombogenic, optically transluscent and relatively non-inflammatory, delivers relatively high doses of one or a combination of medicaments locally in a sustained fashion while systemically delivering a relatively low dose of said medicament(s). In one embodiment, a biogenic tissue such as endothelium from the interior of an artery of a donor animal is first stabilized by appropriate chemical treatment, then burdened with a medicament. The implant, which is preferably in the form of a stent, plug or a patch, releases the medicament over a period of time. Desirable sequellae to the implantation of the device includes the relative absence of an inflammatory response when compared to synthetic implants and reendotheliazation of the implant with autologous endothelium which encapsulates and anatomically stabilizes the implant.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates generally to an implantable device for the sustained 
delivery of a medicament and, more particularly, to a device and method 
for preventing restenosis following atherectomy. 
2. Reference to a Related Patent Application 
Reference is made to a copending patent application Ser. No. 08/002,209 
filed Jan. 8, 1983, entitled: "Medicament Dispensing Stent for Prevention 
of Restenosis of a Blood Vessel" by the present inventor. 
3. Prior Art 
Cardiovascular disease (CVD) is the leading cause of death in the U.S. One 
commonly used method of treating CVD is angioplasty/atherectomy 
(mechanical or laser). While angioplasty/atherectomy is acutely successful 
in relieving the symptoms of CVD, the procedure is limited by a high rate 
of arterial reclosure or restenosis. Various methods of preventing 
restenosis have been tested with little success reported to date. 
One possible treatment for the prevention of restenosis is Photodynamic 
Therapy (PDT), also known as Photoatherolytic () Therapy when referring 
to vascular applications of PDT. Therapy requires the delivery of a 
photosensitizing drug to the stenosing atheroma which is selectively 
retained by the proliferating component of atheromatous plaques which is 
believed to be the cell type responsible for restenosis. Once sequestered 
in the problematic proliferating cells, the drug is converted from its 
ground or dormant state to an excited, highly toxic state by the 
absorption of light energy at a very specific wavelength. A currently 
preferred therapeutic modality consists of administering the 
photosensitizer (PS) drug systemically in a single-dose bolus. Since the 
drug is initially delivered to all cells of the body, a delay time is 
required to allow the PS drug to clear from normal cells while it is 
retained by the proliferating cells prior to activation with light. 
Since restenosis is a complex process which can begin immediately after 
therapeutic intervention (angioplasty/atherectomy) and continue for months 
post intervention, it is desirable to provide a device and method capable 
of providing the sustained delivery of a PS drug to inhibit the 
proliferation of smooth muscle cells and ultimately to lyse the PS ladened 
cells with therapeutic light energy. 
One approach to the problem of sustained long term drug delivery employs 
implantable biodegradable polymer/drug combinations in a variety of ways 
to achieve a controlled regular or continuous administration of the drug. 
Biodegradable polymers are useful as carriers for many different types of 
drugs because they serve as a temporary matrix to hold the drug, but do 
not chemically interact with the drug. As the matrix erodes, the drugs are 
released and can diffuse into the tissues. 
In one prior art embodiment, a synthetic (non-biogenic) biodegradable 
polymer matrix is homogeneously impregnated with a medicament so that the 
medicament is released more or less continuously and uniformly as the 
supporting polymer matrix erodes. In another variation of this basic idea, 
a single reservoir of the drug or medicament in solution is encapsulated 
by a semi-porous polymer matrix. The drug diffuses continuously out of the 
reservoir, through the polymer, and finally to the intended delivery area. 
Metal stents coated with bioabsorbable synthetic polymer have also been 
used to deliver medicament but such metal stents are optically opaque and 
thrombogenic. In still a further variation, tiny discrete "pockets" of the 
drug are encapsulated throughout the synthetic polymer. If the polymer is 
biodegradable then it will completely dissolve thereby releasing all of 
the impregnated or encapsulated drug. The above prior an devices are known 
in the art and are made from synthetic polymers. The problems with 
implants fabricated using non-biogenic material are that such prior art 
implants are thrombogenic and being a "foreign body" stimulate the host's 
inflammatory response. 
Such devices can also be constructed from naturally occurring biopolymers 
and derivatives thereof or biogenic tissue. Biological materials such as 
bovine and porcine tissues harvested from donor animals are commonly used 
for implantation into the human body. They are known to be 
non-thrombogenic and non-inflammatory. The porcine heart valve is one such 
example. Such biogenic tissues are well received and well tolerated by the 
host human tissues and, unlike biodegradable synthetic polymers, biogenic 
tissue implants are less likely to induce an inflammatory host response 
and are replaced over time by the host natural tissue produced in situ. 
Human tissues harvested from a human donor (autologous or heterologous) 
are also viable tissue types for this device. 
Cancer is the second leading cause of death in the U.S. A stent-type device 
for the slow sustained delivery of an appropriate medicament to cancers on 
a luminal wall such as esophageal cancer, and a patch or plug-type of 
device for implantation within bulk tumors is desired. Preferably, such a 
stent, plug or patch should be minimally inflammatory, non-thrombogenic, 
optically transluscent, biologically compatible and capable of sustained 
drug delivery to a localized area of a tubular tissue over the period of 
time required to effect a permanent therapy. 
SUMMARY 
Therapy is believed to be potentially effective for the prevention of 
restenosis. PDT has also been demonstrated to be very effective in the 
treatment of various cancers. In one embodiment, a stent-type device made 
from biogenic tissue and/or biopolymers is described which can be used to 
deliver a PS drug locally to a target tissue over a period of time. In 
another embodiment, a plug-type of implantable device is described which 
can be embedded in solid tissue thereafter to deliver medicament to a 
target. In still another embodiment the implant may take the form of a 
substantially planar patch. 
In a particular preferred embodiment a medical implant is described for the 
local delivery of medicament to an intraluminal target tissue. The device 
and method involves the use of a bio-absorbable biogenic patch or stent 
which is impregnated or otherwise burdened with a photosensitizer drug, 
with or without complimentary medicaments, to locally deliver said drug(s) 
into target tissue on the vessel wall over a prolonged period of time as 
the stent is absorbed. Although the use of bioabsorbable, non-biological, 
but biocompatible stents have been proposed for such a therapy and remain 
a viable solution, these materials are often inflammatory to the host 
tissue. 
Accordingly, it is an object of this invention to produce a medicament 
dispensing implant which is non-thrombogenic, minimally inflammatory and 
generally well received and well tolerated by the human body. 
It is another object of this invention to produce a medicament-dispensing 
implant which is absorbed by the body over time. 
It is yet another object of this invention to produce a 
medicament-dispensing implant which can deliver medicaments substantially 
only to selected target tissues. 
It is still another object of this invention to provide a biodegradable 
biogenic tissue implant which can deliver medicaments over a sustained 
period of time and be replaced by host tissue. 
It is another object of this invention to describe a method in which this 
device can be used to locally deliver medicament(s) over a prolonged 
period of time. 
It is still another object of this invention to describe a method in which 
this device can be used to locally deliver medicament(s) including a 
photosensitizer over a sustained period of time which is ultimately used 
in PDT. 
The above referenced objectives are met by the present invention which is 
best understood by referring now to the preferred embodiments of the 
invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Preparation of the Biogenic Tissue 
Biogenic tissue such as endothelium from the innermost layer of an artery 
(intima), collagen, fibrin, etc. is surgically removed from a donor animal 
such as swine or a human donor (autologous or heterologous) and maintained 
in a nutrient rich solution. These viable tissues can then be "fixed" 
using a stabilized glutaraldehyde process at pressures less than 2 mm Hg 
that is well known in the art and used for such implants as replacement 
porcine heart valves. 
Alternatively, biogenic macromolecules (alternatively referred herein as 
"biopolymers"), such as a collagen, chitin, chitosan or cellulose may also 
be used to fabricate a biogenic implant. Chitin, for example, comprises 
the bulk of the organic material in arthropod exoskeletons such as crab 
shell. If the exoskeleton is demineralized using strong acid the remaining 
chitinous fraction may be extracted, deacetylated (if desired), and 
pressed in to the desired shape for implantation. Cellulose is a polymer 
comprising glucose rings derived from plants. Derivatives of cellulose 
which may be suitable for implantation include methylcellulose, 
ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and sodium 
carboxymethylcellulose. 
Preparation Of the Biogenic Implant 
After the biogenic tissue has been prepared as described above, the 
biogenic tissue is soaked in a solution containing a relatively high 
concentration of the desired medicament(s) such as, for example, a 
photosensitizer (i.e. 0.1-1.0 mg of PS/ml solution--the desired 
concentration of PS in the device implantable will depend on the thickness 
of the lesion being treated and its location) for a period of 1-5 hours 
(the time will again depend on the tissue absorption characteristics and 
the location and application of the implant). The biogenic tissue is 
maintained at 37.degree. C. during the PS drug-burdening process while 
excluding light at wavelengths which might activate the PS. Other 
medicaments may be added to the bath permeate the implant. One such drug 
which is potentially complimentary to the PS is heparin which has the 
characteristics being an anti-coagulant, anti-platelet, anti-fibrin, 
anti-collagen agent and may facilitate the prevention of restenosis. New 
molecules having Heparin--like activity may also be employed. 
Method of Using the Biogenic Implant 
An exemplary method for using the biogenic implant according to the present 
invention may taught by looking first at a stent as shown in FIG. 1. The 
stent 10 is a tubular member comprising a biogenic tissue 11 with 
medicament 12 incorporated therein. The medicament may be a 
photosensitizer which has been shown to be useful for preventing 
restenosis following atherectomy, or it may be any other medicament which 
is desirable to have released over a long period of time. The medicament 
may be encapsulated in discrete cells or evenly distributed throughout the 
body of the stent. 
Turning now to FIG. 2 we see the stent 10 with a balloon catheter 22 having 
a distal tip 23 inserted therein. The balloon catheter 22 has a balloon 
portion 21 which can be partially inflated so that the outer surface of 
the balloon portion 21 firmly and snugly engages the inner surface of the 
stent 10. A sheath (not shown) may or may not be used over the 
balloon/stent catheter to prevent the undesired deployment of the stent 
while advancing and positioning the catheter. Standard angioplasty 
procedures are used to deliver the stent through the femoral artery or 
other arterial point of entry and advancing the stent to the site of the 
target tissue. 
In FIG. 3, a longitudinal, cross-sectional view of an arterial member is 
shown having an arterial wall 32 and a lumen 31. A atheromatous patch 31 
on the wall 32 of the vessel (the "target tissue" in this example) has 
been partially removed to permit passage of the catheter 22 therethrough. 
The catheter 22 is advanced through the vessel until the balloon portion 
21 directly underlies the area of the vessel in which it is desirable to 
deploy the stent 10. Once in position, the stent can be deployed by 
inflating the balloon member 21 so that the outer surface of the stent 10 
pressed against the atheromatous lesion 31 on the wall of the vessel 32 as 
shown in FIG. 4. The expanded stent may then be "welded" to the 
atheromatous tissue 31 on the wall 32 of the vessel. This "welding" may be 
accomplished by the application of heat to the stent. Once the stent 10 
has been deployed and adhered to the target tissue 31 and the wall of the 
vessel, the balloon portion 21 of the catheter 22 is deflated and catheter 
removed as shown in FIG. 5. In FIG. 6 we see a fragmentary section of the 
vessel wall with the stent deployed therein and the balloon catheter 
removed. With the foregoing description in mind, I present an example of 
the device and method used to prevent restenosis following atherectomy. 
Example of Using the Biogenic Stent for Preventing Restenoisis 
Following Atherectomy or Angioplasty 
A drug-burdened biogenic implant in the tubular form of a stent 10 is 
loaded over a light diffusing catheter such as described by Narciso, Jr. 
in U.S. Pat. No. 5,169,395. A sheath may or may not be used over the 
balloon/stent catheter to prevent the undesired deployment of the stent 
while advancing and positioning the catheter. 
To deploy the stent, standard angioplasty procedures are used to deliver 
the stent through the femoral artery or other arterial point of entry. In 
summary, following identification of the target tissue comprising 
atheromatous plaque on the wall of the vessel, the stent should be 
deployed in the area of injury and utilized according to the following 
steps: 
a. the stent-deploying balloon catheter is positioned at the lesion site 
immediately after the completion of the angioplasty/atherectomy (the 
protective sheath should be pulled back to expose the PS-laden stent at 
this point if a sheath was used); 
b. the balloon is expanded until the surface of the PS-ladened biogenic 
stent implant fully engages the arterial wall for the full 360.degree.; 
c. the tissue is irradiated through the transparent balloon wall with a 
wavelength of light (i.e. 800-1000 nm) which produces low level heating to 
cause the denaturation and "welding" of the biogenic stent to the host 
vessel. The wavelength of the light used should not be one which activates 
the PS in the stent. If the activation wavelength and the welding 
wavelength overlap, an alternative method of heating should be employed. 
As example of an alternative heating method, a radio frequency (RF) heated 
balloon or a balloon which incorporates circulating hot fluid may be 
employed to effect "welding". Alternatively, a photochemical cross-linking 
dye may be employed to facilitate the welding process. Such dyes include, 
for example, brominated 1, 8-naphthalimide compounds. These dyes are 
activated by visible light and, following activation, covalently bind to 
amino acid residues, both free and in proteins, rendering them useful as 
protein and peptide cross-linking agents. Care should be taken to choose a 
photochemical cross-linking dye with an activation wavelength which will 
not activate the PS if one is present. The absorption maximum for the 
naphthalimide compounds is around 420 nm, well removed from the activation 
wavelength of PS compounds used in PDT. 
d. the balloon is then deflated and all catheters are removed from the 
body; and 
e. (Only used for PDT applications.) A predetermined time later, the PS 
which has been absorbed by the vessel should be activated by means of a 
suitable light delivery catheter such as the catheter described by 
Narciso, Jr. in U.S. Pat. No. 5,169,395 and using standard Therapy 
techniques. The PS acts to inhibit the proliferation of cells post 
angioplasty thereby reducing restenosis. 
The foregoing procedure for preventing restenosis is exemplary and not 
limiting Similar methods can be employed to deploy a stent in non-arterial 
lumens such as the colon or esophagus for PDT treatment of cancer. Once 
deployed in the artery or other tubular tissue of the host, the stent will 
locally deliver the medicament(s) to the lesion area over a sustained 
period of time (i.e. 2 weeks to 6 months). Two weeks post stent placement, 
re-endothelialization should occur covering the stent with natural 
autologous endothelium thus encapsulating the stent in the luminal wall. 
If necessary, two weeks to six months following the deployment of the 
stent, the patient may be brought back to the catheterization laboratory. 
Using standard angioplasty techniques and an invasive intravascular light 
diffusing catheter, the lesion site can be irradiated to receive a dose of 
light sufficient to activate the PS causing cell lysis and cell necrosis. 
The medicament-dispensing biogenic implant of the present invention may be 
formed into a patch or plug for insertion into a target tissue such as a 
solid tumor. Such a plug 70 is shown in FIG. 7. The plug 70 is dimensioned 
to fit within the bore of a needle 71 having a tip 72. The needle 71 may 
be inserted into the target tissue until the tip is embedded within or 
adjacent to the target tissue. The plug 70 may then be extruded through 
the tip 72 and the needle 71 removed. 
While particular embodiments of the present invention have been illustrated 
and described, it would be obvious to those skilled in the art that 
various other changes and modifications can be made without departing from 
the scope of the invention. It is, therefore, intended to cover in the 
appended claims all such changes and modifications that are within the 
scope of the invention.