Note: Descriptions are shown in the official language in which they were submitted.
WO93/16711 ~1 3 ~ J PCT/US93/01391
USE OF INJECTABLE_BIOMATERIALS IN TEIE
TREATMENT QF HEMORRHOIDS
Technical_Field
This invention is in the field of medical implants
and prostheses. Specifically, it concerns a nonsurgical
technique for treating hemorrhoids and pruritis ani, a related
condition, by injecting biomaterials into the soft tissue of
the anal verge.
BACKGROUND OF THE INVENTION
The anatomy of the region known as the anal canal is
l~ complex and the etiology of the condition known as hemorrhoids
has long been the subject of research and reexamination. The
anal columns (folds of epithelia and musc~e tissue) and anal
sinuses (furrows separating the anal columns from each other)
are found at the upper end of the anal canal. The anal ~inuses
en~ in valve-l~ke folds, called the anal valves, and the anal
canal is vascularized by veins derived from the superior and
inferior rectal (hemorrhoidal) veins. The vascular tissues of
the anal canal, known as the anal cushions, are found in the
left lateral, right posterior, and right anterior positions of -
the anal canal, at or above the level of th~ anal valves. ~he
anal cushi~ns are submucosal and comprise blood vessels (mainly
veins) supported by smooth muscle ~Treitz's muscle~ and
connective tissue. The anal verge refers to the external or
distal boundary of the anal canal; that is, the line where the
anal walls contact during the normal state of apposition.
Hemorrhoids are believed to be caused by ~reakdown in
the connecti~e tissue and smooth muscle that support the anal
cushions, causing displacement of the cushions into the lumen
of the distal canal. This is especially likely to occur when
there is a history of constipation or prolonged straining at
stool, leading to stretching or disruption of Treitz's muscle
together with venous engorgement. Once the cushions are
displaced, the venous engorgement may be perpetuated by a tight
internal anal sphincter.
~l ~ 3~ PCT/US93/01391 ~
Each hemorrhoid consists of an internal and external
component. The internal component lies above the line of the
anal valves, known as the dentate or pectinate line. The
external component lies below this line. The internal and
external component are clearly distinguished by a groove and by
a differential epithelial covering. The internal component is
usually covered with columnar epithelium, while the external is
covered with skin and stratif~ed squamous epithelium.
A number of predisposing factors for the development
of hemorrhoids are known, such as heredity, pregnancy, and
pelvic tumors. However, in the majority of patients, no -~
explanation for the onset of hemorrhoids can be found.
Hemorrhoids, rarely present before the third decade of life,
are commonly associated with the aging process. In fact, aging
weakens the connective tissue support of the anal cushions,
resulting in increased venous dilatation. Although hemorrhoids
occur in both sexes, they predominate in men, despite the
predisposing factor of pregnancy.
Although not a life-threatening condition, the~ ;
symptoms of hemorrhoids can cause the sufferer a great deal of
discomfort and concern. Symptoms of hemorrhoids include
anorectal bleeding during defecation; disco~fort, pain, and/or
itching in the perianal area (pruritis ani); prolapse of
submucosal tissue into the anus during defecation; swelling at
the anal margin due to the external component of the hemorr~oid
becoming engorged with blood; and excessive mucus production
and discharge due to inflammation.
Traditional classification of hemorr~oids is ~a ed
only on the symptoms of bleeding and prolapse. First degree
hemorrhoids are characterized by bleeding only. Second degree
hemorrhoids involve prolapse of submucosal tissue at defecation
(with or without bleeding) with spontaneous return of thé
tissue to the anal canal; whereas third degree hemorrhoids are
defined by prolapse (with or without bleeding) requirinq manual
3~ replacement of tissue into the anal canal. Fourth deqree
hemorrhoids protrude permanently and cannot ~e reduced or
replaced manually.
J ~ ' ?
W093tl6711 PCT~US93tO1391
Hemorrhoids are treated in response to a patient's
complaints of symptoms. Dietary modification, specifically
increasing the consumption of dietary fiber, has been shown to
have moderate success in the treatment of minor ~leeding.
Topical ointments, pharmaceuti~al preparations, ~nd -elated
application devices have long been described in the art for the
treatment of mild symptoms.
Various mechanical, electrical, and thermal (both
heat and cold) devices for treating more severe degrees of
hemorrhoids have been described in the art. U.S. Patent
3,826,242 describes a tubular member that is inserted into the
anal canal, engaging the walls of the canal and the area around
the rectal opening, which maintains pressure on the
hemorrhoidal veins of the anal canal, lower rectum, and anal
area during defecation to prevent swelling and distention of
the he~orrhoidal veins and extrusion of the internal
hemorrhoidal veins out of the anal canal during defecation. A
device that is inserted into the rectum to treat hemorrhoids by
application of gentle pressure against the dilated veins is
disclosed in U.S. Patent 4,583,542. U.S. Patent 4,906,239
describes a cone-shaped hemorrhoid treatment rod to dilate the
anus. U.S. Patent 4,932,397 discloses a therapeutic,
horseæhoe-shaped rectal device, comprising a malleable core
element surrounded by a resilient covering, for alleviating
hemorrhoids by protecting the irritated anorectal area from
pressure and friction.
U.S. Patent 4,898,169 describes an instrument for
direct current electrical therapy of hemorrhoids. U.S. Patents
4,142,529 and 4~227,535 disclose a suppQsitory appliance that
intimately contacts the anal canal wall and hemorrhoids. The
appliance contains an internal electrical resistor for
generating h~at in response to the application of electrical
energy, which maintains the temp~rature of the appliance above
body temperature and below 45 C, thereby facilitating the
opening of the vascular channels and allowing shrinkage of the
hemorrhoids. A chemical-containing device for insertion into
the anal canal that raises the temperature of the wall surface
to approximately 45 C is described in U.S. Patent 4,696,302.
wos3/i67~3~39 rcr/uss3/013s
U.s. Patent 4,331,151 describes a hemorrhoid ~andage
or cnld pack that is positioned wit~in the anal canal to
continuously supply a cool fluid to provide a controlled
temperature within the rectal area for extended periods of time
in connection with the treatment of hemorrhoids. U.S. Patent
4,563,18~ discloses the use of a cylindrical insert comprising
a water-expandable polymer which has been previously frozen
that is inserted into the rectum to treat hemorrholds. A
cryogenic proctologic insert for treating hemorrhoids by
lowering the surface temperature of the affected portion of the
rectal canal is disclosed in U.S. Patent 4,841,970.
Any electrical, mechanical, or thermal device that is
inserted into the body is unfortunately subject to
complications resulting from the malfunction, breakage, or
displacement of ~he device. Any such device is also inherently
not "natural" to the body. Therefore, other methods are used
to treat hemorrhoids. For example, traditional nonsurgic~l
therapies for hemorrnoids include sclerotherapy, rubber band
ligation, anal dilatation, ~ryotherapy, and photocoagulation.
These procedures all have comparable success rates in the
treatment of first and second degree hemorrhoids. However, all
have side effe~-ts and result in ti~sue destruction.
Complications range from flatulence to death as a result of
infection or excessive bleeding.
Sclerotherapy i~olves the injection of solutions
containing carbolic acid into the submucosa proximal-to the
hemorrhoidal mass to induce fi~rosis of the he~morrhoid. This
procedure is seldom used in the treatment of hemorrhoids due to
unpredictable results and because the procedure is very subject
to physical error. Co~plications of this therapy may include
ulc~ration, pain, abscess and oleogranuloma (if oil-containing
solutions are used), bleeding, and bacteremia.
Although less subject to physician error r ru~ber ~and
ligation is generally more uncomfortable than sclerotherapy.
3S This treatment involves applying a rubber band to the non-
innervated portion of mucosa above the hemorrhoidal mass to
induce necrosis of the hemorrhoid. Though rare, complications
may be potentially serious or life-threatening~ Delayed
WO93/16711 ~1 3~ PCT/~S93/01391
hemorrhage due to localized infection and ulceration occurs in
about one percent (%j of patients and may result in massive
bleeding requiring hospitalization.
The technique of anal dilatation is believed to lower
intra-anal pressures and relie~e hemorrhoidal congestion
through traumatic disruption of anal fibrotic bands. However,
because many surgeons find such uncontrolled trauma to the
sphincter mechanism offensive, this procedure has not received
widespread acceptance in the United States. Also, the
complication rate is relatively high (approachin~ 10%), with
the most freguent complications being splitting of the anal
canal, mucosal prolapse, and anal incontinence.
Cryotherapy relies on the thermal destruction of
hemorrhoidal cells. Complications include discomfort, swelling
15 and edema associated with excessi~e drainage, and prolonged -
drainage and recovery time when compared with the other ~-
nons~rgical techniques. Photocoagulation involves the use of
infrared rays to coagulate the hemorrhoidal mass, resulting in
tissue necrosis. Complications include discomfort and minor
bleeding.
Surgical hemorrhoidectomy remains the standard
against which the success of alternative treatments is judged.
However, even "minor surgery" involves inherent risks.
Therefore, surgical hemorrhaidectomy is avoided by physicians
whenever possible and is used only as a "last resort" in the
most advanced cases: incarcerated hemorrhoids, necrotic
hemor~hoids, or hemorrhoids with a significant external
comp~nent.
A condition often related to hemorrhoids is pruritis
ani. The prolapsing or inflamed hemorrhoids can cause
excessive moisture and itching in the perianal region. The
appearance cf the perianal skin varies from patient to patient
depending upon the severity of the condition. In mild cases,
the skin may appear completely normal. If the condition is
acute, the skin may be erythematous and weeping, with numerous
excoriations. In chronic cases, the skin is thickened,
leathery, and white. For mild conditions, dietary
W093t16711 ~3~ PCT/USg3/01391 ~
modifications, such as incre~slng fiber, or ~opical treatments
are sufficient to alleviate the burning and itchlng.
SUMM~Y OF THE INVENTION
. As with most diseases, the least invasive and/or
destructive treatment that is effective should be offered to
the patient. As hemorrhoids are normal anatomical structures,
they preferably should not be removed or destroyed except in
very advanced disease cases. Therefore, an ideal treatment for
hemorrhoids and/or pruritis ani would comprise an effective
nonsurgical procedure that is easy to administer, with little '
likelihood of physician error, a low rate of complications, no
serious side effects, little tissue destruction, and a low risk
for infection. An ideal hemorrhoid treatment would also be
15 "natural" to the body and would not comprise any device that ~;~
could potentially malfunction, break, or be displaced from its :~
intended position.
The present invention meets all of the above
criteria. As described herein, the invention teaches a ffl~thod
for treating hamorrhoids and/or pruritis ani by perianally
administering an effective amount of an injectable
biomaterial(s) into the soft tissues of the anal verge, thereby
preventing the displacement of submucosal tissue into the anal
canal.
DETAILED DESCRIPTION OF THE INVENTION
The invention is a nonsur~i~al method f or treating
hemorrhoids and/or pruritis ani by perianally administering an
effective amount of an in~ectable biomaterial into the soft
tissues of the anal verge to prevent the displacement of the
submucosal tissue into the anal canal. The term "effective
amount" as used herein, means the quantity of biomaterial
needed to achieve significant improvement in the symptoms of
hemorrhoids or pruritis ani or the quantity of wound healing
3S agents needed to achieve improved healing. The effective
amount of biomaterial administered may vary depending on the
patient's own ability to absorb or break down t~e biomaterial,
the consistency and concentration of the material, and the site
- W O 93/16711 ~ t 3~ PC~r/US93/01391
and condition being treated. Furthermore, the biomaterial may
De administered over a num~er of treatment sessions in order t~ ;
effect the improvement of hemorrhoid and re~ated pruritis ~ni
s~ptoms.
The biomaterial used in the invention may be selected
from a number of sources; however, it must be injectable,
biocompatible, essentially non-immunogenic, and persist at the
site of placement for at least three months. Alternatively,
t~e biomaterial may be an aqueous suspension of a biopolymer
with a biocompatible fluid lubricant to improve the intrusion
of the biopolymer into the tissue. See U.S. Patent 4,803,075,
which is incorporated herein by reference. Commercially ~
available suspensions of a biopolymer and fluid lubricant may `;
be obtained from Bioplasty, Inc. (Minneapolis, Minnesota) under ~-
the tradename 8ioplastique Micro-Implants. Fluid lu~ricants
may include: hyaluronic acid, dextran sulfate, dextran,
succinylated non-crosslinked collagen, methylated non- ~
crosslinked collagen, qlycogen, glycerol, dextrose, maltose, `
triglycerides of fatty acids, egg yolk phospholipids, heparin,
and the like. Biopolymeræ may include: atelopeptide
fibrillar, crosslinked or non-crosslinked collagen, gelatin
beads, polytetrafluoroethylene beads, silicone rubber beads,
hydrogel beads, silicon carbide beads, glass beads, and the
like.
A preferred biomaterial comprises a collagen
formulation. Most preferred are those collagen formulations
wherein the collagen is atelopeptide fibrillar, crosslinked, or
non-crosslinked collagen, or collagen mixed with a mineral
material. Collagen is a major protein component of bQne,
cartilage, s~in, and connective tissue in animals. Collagen in
its native form is typically a rigid, rod-shap~-d molecule-
approximately 300 nanometers (nm) lonq and 1.5 nm in diameter.
It is co~po~ed of three collagen polypeptides whîch form a
tight triple helix. The collagen polypeptides are
characterized by a long midsection having the repeating
sequence -Gly-X-Y-, where X and Y are often proline or
hydroxyproline, bounded at each end by the "telopeptide"
regions, which constitute less than about 5% of the molecule.
W093tl6711 ~3~ PCT/US93/01391
The telopeptide -egion of the collagen chains are typically
responsible for the crosslinking between chains and for the
immunogenicity of the protein. Collagen occurs in types, of
varying physical properties; the most abundant are Types I-III.
The _ol'~gen used in the invention may ~e collected
from any number of mammalian sources, such as bovine or porcine
corium and human placenta. The preparation of purified
substantially nonantigenic collagen in solution from the skin
is basically a three-step process involving solubilization,
10 enzyme treatment, and purification. See U.S. Patents -
4,140,537; and 4,488,9ll; which are incorporated herein by
reference. The term "collagen" or "collagen material" as used
herein refers to all forms of collagen, including those which
have been processed or otherwise modified.
Preferred collagens are treated to remove the
immunogenic telopeptide regions ("atelopeptide collagen"), are
soluble, and will have been reconstituted into the fibrillar
form ("atelopeptide fibrillar"). The reconstituted fibrillar
collagen may optionally be crosslinked using methods generally
known in the art, such as by heat, radiation, or chemical
crosslinking agents. Commercially reconstituted collagens are
available under the tradenames Zyderm Collagen Implant and
Zyplast Collagen Implant (Collagen Corporation, Palo Alto,
California). See U.S. Patents 4,582,~40 and 3,94g,073; which
are incorporated herein by reference.
U.S. Patent 4,424,20~; incorporated herein-by
reference, discloses an improved collagen formulation suitable
for use in soft tissue augmentation. The for2ulation comprises
reconstituted fibrillar atelopeptide collagen in combination
with particulate, crosslinked atelopeptide collagen dispersed
in an aqueous medium~ The addition of particulate crosslinked
collagen improves the biomaterial's persistence, or ability to
resist shrinkage following injection.
U.S. Patent 4,557,764; incorporated herein by
reference, discloses a "second nucleation" collagen precipitate
which exhibits a desirable malleability and putty-like
consistency. Collagen is provided in solution [e.g~, at 2-4
- milligrams per milliliter (mg/ml)~, and a "first nucleation
WO93/16711 /~,l 3 ~ 9 .~ c PCT/US93/01391
product" is precipitated by rapid ti~ration and centrifugation.
The remaining supernatant (containing the bulk of the original
collagen) i5 then decanted and allowed to stand overnight. The
precipitated second nucleation product is collected by
S centrifugation.
Copending U.S. Patent Application Serial No.
07/433,441, incorporated herein by reference, discloses an
improved injectable collagen formulation which is conjugated to
a chemically activated polymer, such as polyethylene glycol.
The conjugated collagen has improved persistence at the
implantation site. Also disclosed in the pending application
is a method for crosslinking the collagen material with a
bifunctional activated polymer in situ, such as polyethylene
glycol. This improved process method allows the collagen
implant to be crosslinked to the h~st tissue by the activated
polymer.
Another embodiment of the biomaterial to be used in
the invention includes a high collagen concentration
formulation, which is disclosed in copending U~S. Patent
Application Serial No. ~7/a~ - 3 ~ _ , filed aa ~ y~q~.
(Attorney Number 05921-13~ incorporated herein by reference.
Brie~ly, collagen in solution ~Vitrogen 100 Collagen, Celtrix
Laboratories, Palo Alto, California) is reconstituted to fibril
$orm by neutralizing the solution with the addition of a
phosphate ~uffer at am~ient temperatures. The resultant
fibrillar collagen may be optionally cro~slinked using standard
tachniques known in the art prior to concentration. The high
concentration collagen materials disclosed herein are passed
through a homogenizer (~C5000, Microfluidics Corporation,
Newton, Massachusetts) to improve the ex~rudability of the
material through a fine gauge needle. High concentrations of
non-crosslinked and crosslinked fibrillar collagen are expected
to have improved persistence compared to commercially available
forms.
Another particularly useful biomaterial to be used in
the disclosed invention is described in copending U.S. Patent
Application Serial No. ~7/~43,b4~ , filed 1~ R~
(Attorney Number 05921-11) incorpora~ed hexein by reference,
W O 93/16711~ ~ 3~ PC~r/US93/01391
which descri~es an injecta~le collaqen/ceramic formulation.
Briefly, porous and/or non-porous ceramic particles are
prepared to have a uniform particle size distribution ln the
range of about 50-2s0 microns. The preferred ceramic particles
_ are admixed with fibrillar collagen to produce an injectable
ceramic/collagen formulation. The addition of the ceramic
particles improves the persistence of the injectable collagen
formulation.
Other commercially available biomaterials useful in
the described invention are a polytetrafluoride (Teflon) paste,
~nown as Polytef Paste, and a porcine collagen particulate
suspended in saline, known as Fibrel Gelatin Matrix Implant
tboth available from Mentor Corporation, Santa Barbara,
California). Further biomaterials include fluid suspensions
containing: gelatin beads, glass beads, hydrogel beads,
silicone r~bber or carbide beads, polytetrafluoride beads, and
the like.
An effective amount of wound healing agents may be
added to the biomaterial used in the invention. These a~ents
include protein growth factors such as fibroblast growth
factors (FGFs), platelet derived growth factors (PDGFs),
epider~al growth factors (EGFs), connective tissue activated
peptides (CTAPs), txansforming growth factors (TFGs), and the
like. These biolo~ically active agents are known to facilitata
regrowth of connective tissue cells and accumulation of
fibroblasts, endothelial cells; and wound healing regulatory
cslls to speed wound healing. One or more of these agents in
co~bination can be used in the invention. The a~ount of wo~nd
healing agent(s) to be included with the biomaterial may vary,
depending upon the biomaterial used, the patient (age, sex,
medical history) and the site being treated. Typically the
weight ratio of wound healing agent(s) to t~e biomaterial would
be in the range of about 1:5,000 to 1:50,000.
The wound healing agents may be isolated from native
or natural sources, such as from mammalian cells, or ~ay be
pre~ared synthetically, such as by recombinant DNA or by
chemical processes. In addition, analogs, fragments, or
derivatives of these aqents may be used provided they exhibit
WO93/16711 ,J t 3 0 ~ t~ CT/US93/01391
some of ~he ~iological activity or wound healing properties of
the native molecule. For example, analogs can be prepared by
expression of genes altered by site-specific mutagenesis or
other genetic engineering techniques.
~hese agents may be added to the biomaterial during
preparation or just prior to treatment. It is preferred that
the wound healin~ agents be incorporated into the biomaterial
such that the agents are released through a sustained delivery~
In this way, the agents can be released over an extended period
of time into the hemorrhoid sites and surrounding areas,
promoting wound healing. It is most preferred that these
agents will be included in the treatment of patients with
hemorrhoids associated with inflammatory bowel disease, whose
wounds may heal poorly, worsening symptoms.
Optionally, antimicrobial additives and/or antibodies
may be added to these biomaterials to reduce the potential for
infection at the treatment site. In addition, local
anesthetics may be used at the injection site. Any appropriate
additive may be utilized as long as it is compatible wit~ the
biomaterial used and the patient.
A preferred method of the invention is performed in
an outpatient setting under aæeptic conditions with the patient
in the lithotomy position. A retractor is used to clearly
visualize the anal ori~ice, and the biomaterial is typically
supplied in a sterile 3.0 cubic centimeters (cc) syringe fitted
with a 25 gauge needle.
A complete anorectal examination should be conducted
prior to treatment. The exam includes inspection, palpation,
sigmoidoscopy, and proctoscopy. Inspection will provide the
physician with a great deal of information regarding the
severity and degree of a pa~ient's hemorrhoids. Palpa~ion will
help the physician to estimate the tone of the anal sphincter.
Any thrombosed area will feel indurated, but it should be
emphasized that uncomplicated hemorrhoids are not palpable~ As
the symptoms of hemorrhoids may resemble those of serious
color,ectal disease, namely cancer and inflammatory bowel
disease, sigmoidoscopy is performed to rule out other problems.
~he concurrent presence of inflammatory bowel disease will
~ j3~ ~, PCT/US93tO13')1
modify the physician's approach to treating hemorrhoids, and
tumors must be excluded. The exam concludes with proctoscopy
to give the physician a more accurate assessment of the
hemorrhoids.
Anal manometric evaluation is also sometimes
perfo~ed prior to hemorrhoid treatment, as increased sphincter
activity and anal canal pressure have been shown to be
associated with hemorrhoids. However, no correlation has been
found between sphincter activity and anal canal pressure with
respec~ to predominant symptoms, duration and severity of
symptoms, size of hemorrhoids, or length of symptom history.
It has been suggested that increased sphincter activity is an
effect of the presence of hemorrhoids, rather than their cause.
In fact, the passage of a standard proctoscope has been shown
to produce a decrease in anal canal pressure equivalent to that
measured after successful hemorrhoid treatment. Therefore,
anal manomet~y may be of little value in the treatment of the
individual patie~t.
When treating hemorrhoids, the biomaterial is ~
injected perianally into the soft tissues and/or skin of the
anal verge until the treated area is completely filled with
biomaterial. A preferred amount of biomaterial to be used is
approximat~ly l-lO cc, most preferably 5 cc. The amount of
material necessary to restore the tissue to its original
position will, of course, vary from person to person. The
exact amount of material used is ~herefore left to the
discretion of the administering physician.
As treatment is performed in r sponse to a patient's
complaints of symptoms, treatment success is defined by a
patient's report of an improvement in symptoms. Improvement is
expected to last approximately 3 to 12 months as a result of
treatmentO The injections may optionally be repeated on a
regular basis to maintain p~tient comfort level. Subsequent
injections will likely require the use of 1 ss material than
the initial treatment.
Thus, methods for treating hemorrhoids and/or
pruritis ani may be conducted by perianally administering an
injectable biomaterial, with or without wound healing agents,
12
WO 93/16711 ` r~ ~ 3 0 ~ PCT/US93/01391
into the soft tissues of the anal verge. These methods provide
nonsurgical approaches to relieve the symptoms of hemorrhoids
and related conditions. The invention has been described above
in some detail for the purposes of clarity and understanding.
It will be apparent, however, that certain changes and
modifications may be practiced within the scope of the appended
claims.
: 13
