Note: Descriptions are shown in the official language in which they were submitted.
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LUNG DEVICE WITH SEALING FEATURES
BACKGROUND OF THE INVENTION
Field of the Invention. This invention relates generally to a design of lung
devices for safely performing a
transthoracic procedure. In particular, the invention provides devices and
methods of using these devices to
access the thoracic cavity with minimal risk of causing pneumothorax or
hemothorax. More specifically, the
invention enables diagnostic and therapeutic access to a thoracic cavity using
large bore instruments. This
invention also provides a method for diagnostic and therapeutic procedures
using a device capable of sealing the
wound upon withdrawal of the device.
Description of related art. Pulmonary disorders affect millions of Americans,
and many more individuals
worldwide, each year. While some pulmonary disorders are chronic (e.g.,
chronic obstructive pulmonary
disease (COPD)), many are acute and deadly. For example, lung cancer is the
leading cause of death
attributable to cancer for both men and women. More people die of lung cancer,
than die of breast, prostate and
colon cancer combined. It is estimated that in the United States alone, over
170,000 new cases of lung cancer
are diagnosed each year. Of those people diagnosed with lung cancer, the
prognosis is grim: 6 of 10 will die
within one year of being diagnosed and between 7 and 8 will die within two
years of diagnosis.
Most lung cancers start in the lining of the bronchi (plural for bronchus),
although lung cancer can start in other
parts of the lung as well. Since it generally takes many years for lung cancer
to develop, there can be areas of
pre-cancerous changes in the lung long before the formation of lung cancer.
With currently available
technology, the pre-cancerous changes are often not detected because the
changes cannot be seen on an x-ray
and do not cause symptoms early on that would cause a patient to seek medical
attention. It is for this reason
that most people with lung cancer are not diagnosed during the critical early
stages of the disease.
Taking chest x-rays and checking sputum under a microscope for the appearance
of cancer cells had been
performed for screening but was found to be unreliable, and thus is not even
recommended screening for
persons of high risk (e.g., those people who smoke). Recently, spiral CT
scanning has shown promise as a
potential screening tool for finding lung cancer at an early stage. However,
at this juncture it is not known
whether the use of spiral CT scans improve the prognosis for long-term
survival by increasing the early
detection of the disease. Even with a scan indicating the possible presence of
pre-cancerous tissue, the ability to
take a biopsy for testing is difficult without causing the lungs to collapse,
which can result in a required hospital
stay.
Thus, with the current state of the art, any time a procedure requires an
instrument to be inserted through an
incision in the chest wall, the pleural layers surrounding the lung are
pierced or compromised. As a result of the
propensity for transthoracic procedures to cause, for example, pneumothorax,
there is a limitation on the outer
diameter of the instruments that are used for these procedures. This is a
significant drawback for procedures
such as percutnaeous transthoracic lung tissue biopsy, where the
interventionalist introduces a biopsy needle
through the chest wall. Other procedures which are limited when applied to
transthoracic procedures include
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percutaneous transthoracic needle aspiration (PTNA), mediastinoscopy,
thorascopy and drainage of pleural
effusions. Air leaks and bleeding frequently occur either during insertion or
removal of the device through the
opening in the pleural lining of the chest cavity. Even when using small
needles of 19-23 gauge, the incidence
of pneumothorax is relatively high, being in the range of 30-40% and the
incidence of hemothorax is 25%. For
this reason, larger bore instruments (e.g., having a gauge of less than 19 and
therefore a larger diameter) are not
typically used to access the lung through the chest cavity, and practitioners
are substantially limited in the
amount of tissue accessible or treatable using a percutaneous procedure. More
importantly, practitioners do not
fully benefit from minimally invasive techniques commonly used for diagnostic
and therapeutic procedures that
are easily performed in other areas of the body (e.g., the breast), when
treating the lung.
Treatment options for pneumothorax or hemothorax include intubation, wherein a
tube is inserted through the
chest wall into the pleural space to withdraw the air or fluid. In that
instance, the tube is typically left in place
and attached to a drainage system for several days, which requires the patient
to be hospitalized. In some
circumstances, such as where bleeding occurs, surgical intervention may be
required.
Even during the biopsy process currently practiced, multiple samples or cores
of tissue are taken through the
smallest gauge needle possible in an effort to increase biopsy efficacy while
decreasing the likelihood of, for
example, pneumothorax. However, each time the needle is reinserted, the
chances for pneumothorax or
bleeding increase. Additionally, due to the small size of the multiple
samples, the pathologist does not have the
benefit of a larger sample size that would improve the accuracy of diagnosis.
Thus, there exists a considerable need for devices and methods that provide
minimally invasive access to the
lung for diagnostics and treatment but which do not risk causing the lung to
collapse, or air or blood entering the
pleural space. Additionally, what is needed is a tool that enables potentially
cancerous tissue to be removed
(e.g., for a biopsy) but which prevents cells from migrating along the tract
used by the tool to access the tissue.
The present invention satisfies these need and provides related advantages as
well.
SUMMARY OF THE INVENTION
The present invention provides devices and methods for performing a diagnostic
or therapeutic transthoracic
procedure with minimal risk of a complications, such as a pneumothorax or
hemothorax. The present invention
also includes pre-treating and/or sealing a site of therapeutic or diagnostic
intervention. Compositions are used
in combination with the methods and devices disclosed. Other methods and
compositions are also provided in
U.S. patent applications entitled "Pleural Effusion Treatment Device, Method
and Material" application no.
_____________________________________________________________________ 11/
filed July 8, 2005 (Attorney Docket 30689-709.201); "Intra-Bronchial Lung
Volume Reduction
System," application no 11/153,235 filed June 14, 2005; "Targeting Damaged
Lung Tissue Using
Compositions," application no. 11/008,577, filed December 8, 2004; "Targeting
Damaged Lung Tissue,"
application no. 11/008,092, filed December 8, 2004; "Targeting Sites of
Damaged Lung Tissue Using
Composition," application no. 11/008,094 filed December 8, 2004; "Targeting
Sites of Damaged Lung Tissue,"
application no. 11/008,578, filed December 8, 2004; "Imaging Damaged Lung
Tissue Using Compositions,"
application no. 11/008,649, filed December 8, 2004; "Imaging Damaged Lung
Tissue," application no.
11/008,777, filed December 8, 2004; "Lung Volume Reduction Using Glue
Compositions," filed December 8,
2004; "Glue Composition for Lung Volume Reduction," application no. 11/008,087
filed December 8, 2004;
and "Lung Volume Reduction Using Glue Composition," application no. 11/008,782
filed December 8, 2004.
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An embodiment of the invention disclosed herein includes a system comprising
an elongated body adapted to
provide access to target tissue of a subject through an access hole, a cross-
linked tissue sealant, and a sealant
delivery element adapted to deliver the cross-linked tissue sealant through
the access hole. In some
embodiments of the system, it is adapted to deliver therapy or diagnostics to
the subject. Further, the sealant
delivery element can be adapted to deliver sealant to the target tissue prior
to performing a therapy on the target
tissue, at one or more locations. Further, the sealant delivery element can be
adapted to deliver a sealant to the
access hole upon removal of the system and/or adapted to deliver a sealant to
target tissue prior to performing
diagnostics on the target tissue. More than one sealant delivery element can
be provided where more than one
sealant (i.e., having more than one viscosity) is desired. The distal end of
the elongated body of the system can
be configured on its distal end to comprise a cutting element, an imaging
element, or a pharmaceutical delivery
element. The system can also be disposed within an elongated sleeve. A variety
of sealants are suitable for use
with the system, including sealants that accelerate the clotting cascade. In
some embodiments, sealant can
comprise materials selected from the group consisting of hydrogels, proteins,
polymers and cross-linking agents.
The sealants of the invention can have an adhesion force up to 3Ø In other
embodiments, it may be desirable to
include a detectable label, an enzyme, a radioactive isotope, or a luminescent
substance in the sealant. Typically,
the sealant will have a viscosity greater than 1.1 centipose.
In another embodiment of the invention, a lung device system is provided
comprising an elongated body
adapted to make contact with an inner part of the lung or surrounding tissue
of the lung through an access hole,
a glutaraldehyde based sealant, and a hole closing element for closing the
access hole adapted to deliver the
glutaraldehyde based sealant through the access hole. The glutaraldehyde based
sealant can be heat-treated.
Further, the hole closing element can be adapted to mitigate air leakage into
a space between the lung and
pleural membrane. Mitigating leakage in the embodiments of the device
mitigates pneumothorax and
hemothorax. The device can, in some embodiments, be adapted for excising
tissue, imaging tissue, and
delivering pharmaceutical compositions. The sealants used in the embodiments
of the invention can initiate or
accelerate the clotting cascade. In some embodiments of the invention, the
elongated body has a distal end and a
proximal end, with the distal end comprising a cutting element. Further, a
sleeve can be disposed about the
elongated body. Sealants used in the embodiments of the invention are
typically glutaraldehyde based sealants
that are a tissue-bonding material. The glutaraldehyde based sealants suitable
for the embodiments of the
invention can comprise hydrogel, protein, polymer, and cross-linking agents.
The adhesive force of the sealant is
from 0.2 psi to 3.0 psi. It may be desirable to include a detectable label in
some embodiments of the sealant.
Typically, the sealant has a viscosity greater than 1.1 centipoise.
Embodiments of the invention also include a method of performing tissue
treatment or diagnosis in a subject,
comprising: delivering a device through an incision to a target site within
the subject, the device comprising a
sealant delivery element adapted to deliver a cross-linked sealant; performing
treatment or diagnosis at the site;
and delivering the cross-linked tissue sealant to the incision. In some
embodiments, the method includes the step
of delivering a cross-linked tissue sealant through the incision prior to
delivering the device through the incision
to the target site. Further, the target site can be a subject's lung. During
the process of removing the device,
cross-linked tissue sealant can be applied prior to beginning withdrawal,
during withdrawal, or following
withdrawal. It is anticipated that for some embodiments the sealant delivery
element will be adapted to mitigate
air leakage into a space between the lung and pleural membrane, including
pneumothorax and hemothorax.
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Some embodiments of the method can employ a device that comprises an imaging
element, an element adapted
to deliver a pharmaceutical compound, or a cutting element. Additionally,
embodiments of the method can use a
device with a sealant delivery element that is a syringe or a plunger. The
sealants used can be biologically
compatible cross-linked tissue sealant that are tissue-bonding material.
Typically the biological compatible
cross-linked sealant can include hydrogels, collagen, polysalactic acid, cyano
acrylates, and glutaraldehyde.
INCORPORATION BY REFERENCE
All publications and patent applications mentioned in this specification are
herein incorporated by reference to
the same extent as if each individual publication or patent application was
specifically and individually indicated
to be incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the
appended claims. A better
understanding of the features and advantages of the present invention will be
obtained by reference to the
following detailed description that sets forth illustrative embodiments, in
which the principles of the invention
are utilized, and the accompanying drawings of which:
FIGS. 1A-D illustrates the anatomy of the respiratory system, along with an
example of hemothorax caused from
blood entering the pleural space.
FIGS. 2A-B illustrate a lung during a procedure wherein the device breaches
the pleura.
FIGS. 3A-B illustrate an image of a small pneumothorax which has progressed
into a large pneumothorax during
a transthoracic procedure.
FIGS. 4A-B illustrate a device penetrating a pleura to access the interior of
the lung; with the device sealing the
entry tract as the device is removed.
FIG. 5 illustrates a device used to pre-treat the access site at various
locations for a target tissue location, such as
pleura.
FIG. 6 illustrates a device having a wire stylet penetrating a pleura that has
been pre-treated with sealant.
FIG. 7 illustrates a device adapted to communicate with a suction syringe
penetrating a pleura that has been pre-
treated with sealant to access lung tissue.
FIGS. 8A-B illustrate a therapeutic device removing lung tissue through a
cannula that penetrates a pre-treated
pleura; FIG. 8B illustrates the removal of the device which is sealing its
entry tract during removal.
FIGS. 0A-B illustrate a device adapted to connected to a cryosurgical probe.
FIG. 10 illustrates a device adapted to connect to cutter for removal of
tissue and a vacuum trap.
FIG. 11 illustrates a tool suitable for diagnostic and therapeutic uses with a
sealant delivery element.
FIGS. 12A-B illustrate a delivery device with a dual chamber for holding
sealant components prior to delivery,
and a delivery cannula; FIG. 12B illustrates the mixing chamber and delivery
trocar of the device.
FIG. 13 is a flow chart illustrating the steps of a method practiced under the
invention.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, a principal aspect of the present invention is the design of
lung devices that can safely perform
a transthoracic procedure without impacting the negative pressure required to
maintain lung function. In
particular, the present devices allow accessing the interior of the lung or
the surrounding tissue to perform
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therapeutic or diagnostic functions while reducing the risk of complications
associated with the accessing
procedure. The devices and methods are used with adhesive compositions that
have cross-linkable moiety and
adhering moiety that enable the glue to adhere to lung tissue with low
toxicity. Suitable adhesives, such as glue,
act as a sealant to prevent the passage of liquid or gas.
The invention provides methods, materials and devices for providing diagnostic
and therapeutic treatment to a
target tissue, such as lung, using a suitable adhesive, such as glue, as a
sealant to prevent the passage of liquid or
gas. The materials used in the method include a fast-acting adhesive that
cures in less than three days, more
preferably less than two days, even more preferably less than one day, and
most preferably less than one hour.
A specific cure time may be tunable to allow for glue distribution within the
target site before curing fully.
Some glue formulations may require ancillary light sources, primers,
catalysts, radiofrequency energy, electrical
energy or radiation to cause the glue to cure.
Glue formulations for use with this invention may include solids, semi-solids,
hydrogels, foams, agars or sol-
gels. Some glue formulations work in wet or dry tissue surface conditions.
Some glue formulations may also
stop active bleeding (i.e., provide hemostasis). The glues are preferably
biocompatible and can successfully
fuse tissue in wet conditions. The glues are flexible and conformable to
tissue geometry, and they possess high
tensile strength. Solvents can be used to deliver the glue in order to drive
the glue into the tissue.
One preferred embodiment is a glue formulation that crosslinks (chemically
bonds) to the biological tissue it is
applied to. More specifically, the adhesive either crosslinks to collagen or
promotes the crosslinlcing of collagen
at two adjoining tissue surfaces to be fused and allow for high adhesion.
Another preferred embodiment is a glue formulation that has a radiopaque
component so that the glued
boundary can be identified using x-ray-based imaging techniques during or
after the procedure. Additives may
include tantalum, platinum, bismuth, radiopaque metals and polymers. Polymers
can include, for example,
poly(lactic acid) and poly(glycolide). Agents and drugs can also be added as
primers.
Although many alternative glue formulations may be suitable to achieve these
goals, one preferred glue
formulation consists of a combination of a cross-linking agent, such as
glutaraldehyde or stable polyaldehyde
and a protein, such as albumin, porcine albumin and collagen, with or without
additional additives. One such
material suitable for use as a sealant during therapeutic and diagnostic
procedures is described in US Patent
Application Publ. No. 2004/0081676. The glue's intrinsic viscosity can be
tuned to allow for fast or slow
spreading across target regions. The glue may be used for other purposes as
well, such as anastomosis of blood
vessels. Another adhesive that may be suitable is a cyanoacrylate adhesive.
Alternative glue formulations may be suitable to achieve these goals such as a
combination of any one of the
previously described components in combination with other additives that may
include elastin, fibrin,
glycoprotein, liposomes, thrombin, calcium, neuroleptics, vitamins, growth
factors, glucocorticosteroids,
steroids, antibiotics, antibacterial compounds, bacteriocidal and
bacteriostatic compounds, antiviral compounds,
antifungal compounds, antiparasitic compounds, tumoricidal compounds,
tumoristatic compounds, toxins,
enzymes, enzyme inhibitors, proteins, peptides, minerals, neurotransmitters,
lipoproteins, glycoproteins,
immunomodulators, immunoglobulins and fragments thereof, dyes, radiolabels,
radiopaque compounds,
fluorescent compounds, fatty acids, polysaccharides, cell receptor binding
molecules, anti-inflammatories,
antiglaucomic compounds, mydriatic compounds, anesthetics, nucleic acids, and
polynucleotides.
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The glue can be packaged sterile, in a single part or in two liquid parts in
an applicator. Upon delivery of a two-
part formulation, liquid components can be mixed as they are delivered, by an
applicator or stirring or mixing
nozzle device. After application, the formulation may quickly or slowly
solidify into a flexible solid glue. The
glue can also be premixed and then applied. The glue may be formulated as a
two part solution that can be
applied independently. In doing so, the first part may be applied and allowed
for spread time before the second
is applied.
FIG. lA illustrates the respiratory system 10 located primarily within a
thoracic cavity 11. The respiratory
system 10 includes the trachea 12, which brings air from the nose 8 or mouth 9
into the right primary bronchus
14 and the left primary bronchus 16. From the right primary bronchus 14 the
air enters the right lung 18; from
the left primary bronchus 16 the air enters the left lung 20. The right lung
18 and the left lung 19, together
comprise the lungs 19. The left lung 20 is comprised of only two lobes while
the right lung 18 is comprised of
three lobes, in part to provide space for the heart typically located in the
left side of the thoracic cavity 11, also
referred to as the chest cavity.
As shown in more detail in FIG. 1B, the primary bronchus, e.g. left primary
bronchus 16, that leads into the
lung, e.g. left lung 20, branches into secondary bronchus 22, and then further
into tertiary bronchus 24, and still
further into bronchioles 26, the terminal bronchiole 28 and finally the
alveoli 30. The pleural cavity 38 is the
space between the lungs and the chest wall. The pleural cavity 38 protects the
lungs 18, 20 and allows the lungs
to move during breathing. As shown in FIG. 1C, the pleura 40 defmes the
pleural cavity 38 and consists of two
layers, the visceral pleurae 42 and the parietal pleurae 44, with a thin layer
of pleural fluid therebetween. The
space occupied by the pleural fluid is referred to as the pleural space 46.
Each of the two pleurae layers 42, 44,
are comprised of very porous mesenchymal serous membranes through which small
amounts of interstitial fluid
transude continually into the pleural space 46. The total amount of fluid in
the pleural space 46 is typically
slight. Under normal conditions, excess fluid is typically pumped out of the
pleural space 46 by the lymphatic
vessels.
The lungs 19 are an elastic structure that float within the thoracic cavity
11. The thin layer of pleural fluid that
surrounds the lungs 19 lubricates the movement of the lungs within the
thoracic cavity 11. Suction of excess
fluid from the pleural space 46 into the lymphatic channels maintains a slight
suction between the visceral
pleural surface of the lung pleura 42 and the parietal pleural surface of the
thoracic cavity 44. This slight suction
creates a negative pressure that keeps the lungs 19 inflated and floating
within the thoracic cavity 11. Without
the negative pressure, the lungs 19 collapse like a balloon and expel air
through the trachea 12. Thus, the
natural process of breathing out is almost entirely passive because of the
elastic recoil of the lungs 19 and chest
cage structures. As a result of this physiological arrangement, when the
pleura 42, 44 is breached, the negative
pressure that keeps the lungs 19 in a suspended condition disappears and the
lungs 19 collapse from the elastic
recoil effect.
When fully expanded, the lungs 19 completely fill the pleural cavity 38 and
the parietal pleurae 44 and visceral
pleurae 42 come into contact. During the process of expansion and contraction
with the inhaling and exhaling of
air, the lungs 19 slide back and forth within the pleural cavity 38. The
movement within the pleural cavity 38 is
facilitated by the thin layer of mucoid fluid that lies in the pleural space
46 between the parietal pleurae 44 and
visceral pleurae 42.
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For purposes of illustration, FIG. 1D illustrates a lung 20 with blood in the
pleural space 50 (also referred to as
hemothorax). As evidenced from the drawing, the presence of blood 50 in the
pleural space 46 results in a
contraction of the lung 20 to a much smaller size. Clinically, the patient
would have a difficult time breathing air
into the collapsed lung because the act of breathing relies on the lungs being
suspended in a state of negative
pressure. As will be appreciated by those of skill in the art, fluid or air
within the pleural space 46 will achieve a
similar clinical impact on the size of the lung relative to the thoracic
cavity as the hemothorax illustrated in
FIG. 1D.
A variety of events can cause the pleural space to be violated and fill with
gas (such as air) or fluid. For
example, rupture of subpleural apical emphysematous blebs, smoking, and
physical height resulting in great
distending pressure on the alveoli over time can result in a spontaneous
pneumothorax; while transthoracic
needle aspiration procedures, subclavian and supraclavicular needle sticks,
thoracentesis, mechanical
ventilation, pleural biopsy, transbronchial lung biopsy, cardiopulmonary
resuscitation and tracheostomy can
result in iatrogenic pneumothorax. Pleural space can also be filled with
fluid, such as blood, as a result of, for
example, blunt trauma, penetrating trauma (including iatrogenic), nontraumatic
or spontaneous neoplasia
(primary or metastatic), blood dyscrasias, including complications of
anticoagulation, pulmonary embolism with
infarction, torn pleural adhesions in association with spontaneous
pneumothorax, bullous emphysema,
necrotizing infections, tuberculosis, pulmonary arteriovenous fistulae,
hereditary hemorrhagic telangiectasia,
nonpulmonary intrathoracic vascular pathology (e.g., thoracic aortic aneurysm,
aneurysm of the internal
mammary artery), intralobar and extralobar sequestration, abdominal pathology
(e.g., pancreatic pseudocyst,
splenic artery aneurysm, hemoperitoneum), and/or catamenial. For purposes of
illustration of the effect a
pneumothorax or hemothorax can have on the lung structure, FIGS. 2A-B depicts
the lungs 19 during a procedure
wherein a biopsy device 80 is deployed to obtain a tissue sample 82 and
breaches the pleura. As a result of the
breach, air inside the affected lung 18 exits the lung (indicated by arrows)
around the opening 84 in the lining
made by the device 80. As illustrated in FIG. 20 a device 86 is inserted into
the trachea 12 and fed down the
right primary bronchus 14 where the device 86 thereafter inadvertently
punctures the wall of the bronchus 14.
As in the previous example, air inside the affected lung 18 exits the lung
(indicated by arrows) around the
opening 88 created when the device 86 punctured the wall of the bronchus 14.
As will be appreciated by persons skilled in the art, the invention and its
embodiments have been described for
purposes of illustration with respect to diagnostic and treatment of lung
tissue. However, certain aspects of the
devices and methods, for example, the sealing component, are applicable to
diagnostic and therapeutic
procedures, including treatment modalities, and devices suitable for use
elsewhere in a subject. Other areas of
the body suitable for treatment or diagnostics include, but is not limited to,
liver, connective tissue, pancreas,
breast, kidney, gastrointestinal tract, brain, mediastinum, joints, bladder,
and prostate. Treatment modalities
include, but is not limited to, filling voids, repairing tissue lacerations,
and repairing dissections.
FIG. 3A illustrates an image of a cross-section of the thoracic cavity 11
taken during a fine needle aspiration
procedure where a needle 90 has been inserted into the left lung 20 and
breached the parietal pleura 44 and
visceral pleura 42. Although care has been exercised during the procedure, a
pneumothorax has resulted as
illustrated in FIG. 30. As shown, in a cross-section of the same thoracic
cavity 11 taken shortly thereafter, the
pneumothorax has progressed and the pleural space 46 has filled with air and
the size of the left lung 20 has
collapsed away from the parietal plurea 44.
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FIGS. 4A-B illustrate a device 100 configured according to an embodiment of
the invention positioned between
adjacent ribs 99, 99' in the rib cage before penetrating parietal pleura 44,
the pleural space 46 and the visceral
pleura 42 to access the interior of the lung. As illustrated in FIG. 4B, the
device 100 is adapted to seal its entry
path 110 with, for example, a biocompatible heat-treated glutaraldehyde glue
120 as the device 100 is removed.
Sealing the entry path 110 provides several advantages, including preventing
the pleural space 46 from being
filled with gas (such as air) or fluid (such as blood) as a result of the
procedure. Additionally, sealing the entry
tract or wound 110 prevents migration of cells along the entry path 110 after
the procedure. Thus, if a device
100 is inserted to obtain, for example, a tissue sample for biopsy and the
tissue in or near the sample site has
cancerous cells, sealing the entry tract prevents the migration of cells,
including potentially dangerous cancer
cells, into other areas.
FIG. 5 illustrates a device 200 configured according to an embodiment of the
invention adapted to pre-treat an
intended entry path 110 with sealant 220, 222, 224 as described herein. For
purposes of illustration, the device
200 has delivered a first sealant 220 on the proximal (exterior surface) of
the parietal pleura 44, a second sealant
222 within the pleural space 46 and a third sealant 224 on the distal
(interior surface) of the visceral pleura 42.
As will be appreciated by those skilled in the art, a single one of the three
sealants illustrated can be delivered
without departing from the scope of the invention. Further, a combination of
two of the three sealants illustrated
can also be delivered without departing from the scope of the invention.
Finally, as described above, this
technique can be used with respect to other areas of the body and other
treatment modalities without departing
from the scope of the invention.
As illustrated in FIG. 6 a device 100 is inserted through the sealant 220,
222, 224 to enable a wire stylet 102 to
access target tissue 104 within the lung space. Accessing the lesion through
the pre-delivered sealant further
prevents the procedure from resulting in a pneumothorax or hemothorax.
Further, pre-delivering sealant to an
access site can enable the use of large bore instruments as discussed below,
previously not practical to employ,
to access the lung. Where, as illustrated in FIG. 6, the device deployed is a
smaller bore device the device can be
inserted and removed through the pre-delivered sealant, without the additional
step of delivering sealant through
the entry tract upon withdrawal of the device. However, those skilled in the
art will appreciate that the
additional step of delivering sealant to the entry tract upon removal of the
device can be practiced even for small
bore devices. Further, where sealant is pre-delivered to an access site, the
viscosity of the pre-treatment adhesive
can be different than the viscosity of the adhesive used to close the entry
path. Where adhesives of more than
one viscosity are desired to be delivered during the process, the device can
be adapted to provide multiple
adhesive delivery mechanisms within the device.
FIG. 7 illustrates a device 300 adapted to communicate with a suction syringe
302 penetrating adjacent ribs 99,
99' to penetrate a parietal pleurae 44, a pleural space 46, and a visceral
pleurae 42 that has been pre-treated with
sealant to access target tissue 104. In the illustrated embodiment, sealant
220, 222, 224 has been pre-delivered to
the injection tract site to facilitate the use of a cannulated instrument
having a larger bore to interface with the
target tissue 104.
Turning to yet another embodiment, FIGS. 8A-B illustrate a therapeutic device
400 adapted to remove target
tissue 104 through a cannula 108 that penetrates a pre-treated pleura having
sealant 220, 222, 224. As discussed
above, the use of a large bore device (such as a cutting device with a
diameter of 0-1 inch or a gauge size of 1-
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22), can be more advantageously employed where the delivery tract 110 has been
pre-treated with sealant and
the device 400 is adapted to deliver sealant 120 into the delivery tract 110
during removal, as shown in FIG. 8B.
FIG. 9A illustrates another embodiment of the invention wherein device 500 is
a cryosurgical probe. The
cryosurgical probe 500 is connected to a switch 502 a regulator 504 and a CO2
or liquid nitrogen source.
Additional information about cryosurgical probes is available in U.S. Patent
5,452,582. The cryosurgical probe
is inserted penetrating between adjacent ribs 99, 99' to penetrate a parietal
pleurae 44, a pleural space 46, and a
visceral pleurae 42 that have been pretreated with sealant 220, 222, 224 to
access target tissue 104. As persons
skilled in the art know, the cryosurgical probe is suitable for performing
cryosurgery, such as killing tissue in
surgical procedures. FIG. 9B illustrates another embodiment of the invention
wherein the device 500 has a
sealant delivery device 501 adapted to deliver sealant into the delivery tract
prior to or concurrent with removal
of the device 500.
FIG. 10 illustrates a tumor excising device 600 adapted to connect to vacuum
pump 602. The vacuum pump 602
is used to suction, for example to remove fluid.
FIG. 11 illustrates a generic device 700 of the present invention. Device 700
has a tool 710 at the distal end of
an elongated body 702 adapted to make contact with, and perform some function
on, an inner part of the lung or
the surrounding tissue through an access hole or other hole. Lung device 700
also has a hole closing element
720 for closing the access hole. As shown in FIG. 11, body 702 is disposed
within a sleeve 704 or other dilating
device, with tool 710 extending from the distal end of the sleeve. Tool 710
and body 702 may be inserted
through sleeve 704 after the sleeve is in place within the body.
Alternatively, tool 710 and body 702 may be
partially or completely disposed within sleeve 704 during insertion of sleeve
704 into the patient through an
access hole. Sleeve 704 may also have a sharp distal end 706 to form the
access hole.
In one embodiment, hole closing element 720 is adapted to deliver biologically
compatible sealant to close the
access hole. A syringe 722 may be operated by the user to deliver sealant to
the area of the hole or incision
through perforations 708 at the distal end of sleeve 704. Preferably, the tool
is withdrawn from the sleeve 704
before delivering sealant to the site. Alternatively, the sealant may be
delivered through sleeve 704 around the
tool body 703.
Although many alternative sealant formulations may be suitable for this
purpose, a preferred sealant would
consist of primarily a combination of stable polyaldehyde, albumin, including
porcine albumin and collagen
with or without additional additives. The sealant can also have agents that
initial or accelerate the clotting
cascade so the sealant can be used as a hemostatic agent. For example, a
suitable material is described in US
Patent Application Publ. No. 2004/0081676. This sealant works as a biologic
glue that cures within a few
minutes to seal pleural layers without causing inflammation or heat. The
glue's intrinsic viscosity can be tuned
to allow for fast or slow delivery through a delivery system, such as those
shown above and includes glue
viscosity more than 1.1 centipoise. This glue formulation is appropriate for
use with all lung tissue and
structures within the pulmonary system as well as pulmonary vasculature. It
can also be formulated and used
for any adhesive or anti-adhesion purpose including anastomosis of blood
vessels and bronchi/bronchioles and
to seal pulmonary structures from air leaks, bleeding or fluid leaks. Ideally,
the sealant will cure within a few
minutes, works well in a damp or wet environment, and blocks air or fluid from
entering the pleural cavity.
Typically, the glues are composed of a condensation product of glutaraldehyde
that consists of cross-linked
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albumin, including porcine albumin. Adhesion values for the glue can be up to
1.5 psi, more preferably between
0.2¨ 0.6 psi.
Alternative sealant formulations may be suitable to achieve these goals such
as a combination of any one of the
previously described components in combination with other additives that may
include elastin, fibrin,
glycoprotein, liposomes, thrombin, calcium, neuroleptics, vitamins, growth
factors, glucocorticosteroids,
steroids, antibiotics, antibacterial compounds, bacteriocidal and
bacteriostatic compounds, antiviral compounds,
antifungal compounds, antiparasitic compounds, tumoricidal compounds,
tumoristatic compounds, toxins,
enzymes, enzyme inhibitors, proteins, peptides, minerals, neurotransmitters,
lipoproteins, glycoproteins,
immunomodulators, immunoglobulins and fragments thereof, dyes, radiolabels,
radiopaque compounds,
fluorescent compounds, fatty acids, polysaccharides, cell receptor binding
molecules, anti-inflammatories,
antiglaucomic compounds, mydriatic compounds, anesthetics, nucleic acids and
polynucleotides.
The sealant may be delivered to the incision site as a sealant delivery device
according to the embodiments
herein, is withdrawn from the incision to seal, for example, the pleural
lining, blood vessels, airways, or other
holes, apertures, or channels formed during the procedure. Alternatively,
sealant may be delivered before the
device is withdrawn from the incision. The sealant and its delivery system may
be bundled together with one or
more tools in a kit to perform particular therapeutic or diagnostic
procedures.
In the embodiment shown in FIG. 11, tool 710 is a grasper. In other
embodiments, the tool may be a cutting
element (e.g. having a diameter of 0-1 inch or a gauge size of 1-22), a
needle, forceps, a scalpel, a scraper,
brushes, scissors and other ablation tools, such as RF loops, heaters, laser
ablation, probes, mechanical excision
devices, x-ray, radiation, cryosurgical probes and other devices. The sealing
function enables a wide range of
different sizes of these cutting elements to be used for purpose of the
present invention. In particular, the biopsy
devices of the present invention can include large-size cutting elements that
would otherwise be unsuitable for
lung biopsy because of their propensity to cause pneumothorax or hemothorax.
Details of designs for the tool
portion of the device would be apparent to those skilled in the art. Details
of suitable tool designs can be found
in US Patent Nos. 6,902,536; 5,599,294; 5,916,210; 6,080,113; 6,267,732;
6,540,694; 6,638,275; 6,689,072;
6,716,180; 6,730,044; 6,808,525; 6,825,091; 6,840,948; 6,902,526; 6,902,536.
Many of these agents cause tissue binding to form localized adhesions or a bio-
response that will help maintain
permanent bonding. Introduction of these materials instigates one or more
elements of a tissue remodeling
cascade process. The process includes tissue polymer decomposition and/or
necrosis that leads to recruitment of
cellular respondents that include one or more of the following: Neutrophils,
white blood cells, macrophages,
CD8+, MMP's, Interlukens, cytokins and protocylins. The tissue then remodels
to initiate tissue formation and
thickening that culminates in the formation of tissue adhesions.
Other materials that can initiate this effect are cadmium, smoke artifacts,
tars, materials that irritate tissue such
as alcohols, solvents, organic solvents, acids, materials that are basic and
materials that are acidic. These
materials include compounds or compositions that have pH levels between 1 and
6.9 with materials closest to 1
being a preferable acid material. Additionally, compounds or materials that
have pH levels between 7.5 and 14
work very well; materials closest to 14 work best.
Some adhesives can be formed as, for example, two-part compositions. FIG. 12A
illustrates the sealant delivery
portion of the device 900. The proximal end 902 of the device 900 features the
dual chamber 904 delivery
housing 901. The sealant delivery housing is separated into at least two
chambers 906, 906' in order to separate
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components of the sealant to be delivered. The two parts of a two-part
adhesive composition can be delivered
down the separate channels of the device 900. A plunger 908 is provided to
advance the glue components down
each chamber of the delivery housing. The glue components are advanced through
separate sealed tips 910, 910
in order to facilitate easily replacing the stir chamber 920 in the event of a
clog. The sealant delivery housing
901 is easily separable from the stir chamber 920 to facilitate replacement
during a procedure. The stir chamber
920 receives the glue components from the at least two ports of the sealant
delivery housing. Mixing elements or
baffles 922 are provided within to mix the glue components together as the
components advance down the stir
chamber 920. The mixing chamber can have prongs that interact with tips to
break its seals when the mixing
chamber is connected to the device. The distal end of the stir chamber 920
features a porous plug filter 924 that
enables air to escape the stir chamber 920 through an air bleed hole 926
located on the side of the stir chamber
920 at its distal end. Suitable filters include microfilters available from
GenProbe. The filter properties are such
that air can be dispersed through the filter transverse to the axis of the
glue while the glue will be forced axially
through the filter. FIG. 12B illustrates another delivery device having a
plunger 950 advancing glue 952 through
a chamber while air 953 is advanced through a porous plug filter 924 where it
can exit through the air bleed hole
926 before the glue is delivered through the cannula into the target tissue.
Embodiments of the device may also include an imaging element to aid in the
diagnosis and/or treatment of a
condition. The imaging element may be connected to the distal end of the
elongated body. The type of imaging
element to be coupled to the elongated body will vary depending on the
intended application in which the
subject device is to be employed. In general, to view a subject's lung or any
specific parts thereof, the imaging
element may comprise a camera, preferably a microcamera, even more preferably
a digital microcamera
equipped to transmit real-time images of the lung tissues. Additionally, the
imagining element may include
visualization light fiber bundles, laser light fibers, light canes, and light
tubes. Moreover, the imaging element
may include an ultrasonic probe, or preferably, a magnetic resonance imaging
(MRI) probe to provide high-
resolution images of different layers of the lung and the surrounding tissues.
A particularly suitable MRI probe
is described in U.S. Patent No. 6,549,800.
The subject device can also be coupled to a delivery element adapted to
channel a pharmaceutical composition
to the lung. The element is typically connected to the proximal end of the
elongated body. The element can be
any access structure familiar to skilled artisans, which can store and release
the pharmaceutical composition
upon reaching a desired site of the lung or the surrounding areas. Non-
limiting exemplary delivery elements
include tubes and catheters which are known in the art. For example U.S.
Patent 4,739,760.
In an alternative embodiment, the hole closing element may deliver a plug, a
clip or sutures to close the hole.
For example, the hole closing element may deliver expanding plugs that use a
polymer covered NiTi frame.
Solid collagen, ceramic or polymer plugs can be placed so that the plug can
clip the lung wall to the chest wall.
Expanding stents made from NiTi, Ti, stainless steel or polymer can be placed
to anchor the lung and seal the
pleura from air leaking in. The stent devices can be covered with silicone,
polyurethanes, polyethelynes, nylons,
Dacron, ePTFE, PTFE, Chronoprene, Chronoflex or other biocompatible polymers
or other folded or elastic
material that help prevent air leakage. Clip designs may be placed to secure
the pleura walls and then a plug can
be placed inside the clip to seal off potential air leakage into the pleural
space. The hole may also be sutured
closed using minimally invasive suturing tools either delivered through sleeve
704 or inserted into the incision
after sleeve 704 and/or tool 710 has been withdrawn.
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A variety of materials are suitable for fabricating the patient-contacting
elements of the present invention. In
general, the materials are inert so that they do not readily react with the
biologically compatible sealant under
physiological buffer conditions and/or body temperatures. Non-limiting
examples of such materials include
glass, semi-conductors such as silicon and germanium, metals such as platinum
and gold, and a vast number of
plastic polymers. Exemplary plastic polymers include polyamide (PA), polyimide
(PI), polyacrylonitrile (PAN),
polybutylene (PB), polybutadiene (PBD), polycaprolactam (PCL), polyethylene
(PE),
polychlorotrifluoroethylene (PCTFE), polytetrafluoroethylene (PTFE),
polydimethylsiloxane (PDMS),
polyethylene terephathalate (PET), polyisobutylene (Pm), polystyrene (PS),
polyolefme (PO), polymeric
polyisocyanate (PPI), polyvinylchloride (PVC), polyvinylidene chloride (PVDC),
polyvinyl fluoride (PVF),
acrylonitrile-acryloid-styrene (AAS), acrylonitrile-butadiene-styrene (ABS),
acrylonitrile-chlorizate ethylene-
styrene (ACS), and any other inert polymers provided by commercial vendors.
The devices of the present invention provide effective tools for a variety of
diagnostic and/or therapeutic
interventions. Accordingly, in one embodiment, the invention provides a method
of performing a lung biopsy in
a subject. The method comprises the steps of delivering a biopsy device to a
site within the subject's lung or
surrounding tissue of the lung, where a biopsy sample is to be taken;
obtaining a biopsy sample from the lung;
and using the biopsy device to apply a biologically compatible sealant to the
lung.
As described above, the devices are adapted to mitigate air and fluid leakage
into a space between the pleural
membrane. The devices are particularly suited for mitigating pneumothorax or
hemothorax while accessing
tissue from the thoracic cavity. As illustrated in FIG. 13, the procedure can
involve (a) accessing a thoracic
cavity and then, e.g., (b) obtaining a biopsy sample from any part of the lung
or the surrounding tissue, (c)
imaging a portion or the entire lung, (d) delivering a pharmaceutical
composition, (e) excising tissue, or (f) any
combination of the above. After the desired therapeutic or diagnostic
procedure, or combination thereof, has
been performed, the device is removed while sealing the access tract of the
device to prevent migration of tissue
or cells into the tract and to prevent fluid or air from entering the cavity.
Optionally, the sealant can also be pre-
applied to the access hole.
In another embodiment, the present invention provides a method of preventing,
for example, pneumothorax or
hemothorax, resulting from accessing a subject's lung or surrounding tissue of
the lung with the use of the
external device. Such method comprises delivering the external device to gain
access to the subject's lung or
the surrounding tissue; and using the device to apply a biologically
compatible sealant to the lung. Depending
on the intended application, the subject methods can be used to view, biopsy,
and treat one or more lobes of the
lung, namely, the right upper lobe, the right middle lobe, right lower lobe,
the left upper lobe, and the left lower
lobe. Sealant can be delivered before the therapeutic or diagnostic procedure,
during the procedure, or
following the procedure (e.g. as the device is removed).
Sealant components for this application may include fibrin/thrombin, activated
PEG/PEG-diamine,
albumin/PEG, and albumin/glutaraldehyde sealants. The sealant is an
implantable material that may contain
hemostatic agents such as chitin derivatives including but not limited to
carboxymethyl chitin and chitosan (1-
100% deacetylated). The sealant components may also contain additives that
affect viscosity, set time,
adhesion, and biocompatibility. The albumin component may be formulated in
weight to weight ratios of 10-
50% where the remaining mass balance is aqueous solutions of salts, buffers,
and additives or combinations
thereof. The other component of the sealant is a cross-linker containing
glutaraldehyde, heat treated
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glutaraldehyde, processed glutaraldehyde (PGA), or derivatives thereof in
weight to volume ratios of 1-25%
where the remaining balance is an aqueous solution with or without additives,
salts, or buffers or combinations
thereof. These solutions may be applied from dispensers that deliver a ratio
of 1 unit volume of protein solution
per 1 unit volume of cross-linker solution (1:1 protein:cross-linker) and may
be applied in ratios up to 10 unit
volumes of protein solution per unit volume of cross-linker solution.
Furthermore, mixing may occur by
passing the solutions through a static mixing tip with helical or other
geometrical devices that enhance the
mixing efficiency. Sealants prepared from these solutions contain 5-45%
protein and 0.5-14% crosslinker.
Other suitable sealants and other agents are described in US Publication No.
2004/0052850 Al; US Patent No. 7303757;
US Publication No. 7005/0281799 Al; US Publication No. US 2005/0281796 Al; US
Publication No. 2005/0281798
Al; US Publication No. 2005/0281800 Al; US Publication No. 2005/0281739 Al; US
Publication No. US
2005/0281740 Al; US Patent No. 7678767; US Patent No. 7608579; US Patent No.
7468350; US Patent No. 7553810
Materials that solidify such as glue compositions form a structure that is
typically stiffer than the intrinsic
stiffness of lung tissue. Specifically, pull tests of lung parenchyma
(comprised of alveolar sacks and collagen)
sections show that the composite stiffness is very low. When agents are
combined that form a stiffer structure
than the underlying biomaterial or lung tissue, the modulus mismatch causes
irritation, inflammation, tissue
thickening, fibrosis, a remodeling cascade and adhesions that will promote and
maintain lung volume reduction.
Compositions that dry out or maintain viscosity levels above 2 centipoise (a
measure of dynamic viscosity)
generate shear and cause this stiffness mismatch to promote adhesions. Agents
and hydrogel materials thicker
than 10 centipoise work better. The glutaraldehyde glue technology employed
can produce compositions that
have 15 centipoise viscosity and higher levels up to and beyond 150
centipoise. By increasing the glue cross-
linking properties, agents can be delivered that solidify to a gel or harder
substance. Materials that gel to
produce solids with a modulus greater than 10-20 centimeters of H20 will
produce this same effect. Materials
that are stiffer in a range between 20 and 100 centimeter of H20 are better.
Materials that are stiffer than 100 cm
H20 are preferable. Implantable materials with viscosity enhancing agents to
promote these effects can be
manufactured.
Many of these agents cause tissue binding to form localized adhesions or a bio-
response that will help maintain
permanent pleurae bonding. Introduction of these materials instigates one or
more elements of a tissue
remodeling cascade process. The process includes tissue polymer decomposition
and/or necrosis that leads to
recruitment of cellular respondents that include one or more of the following:
Neutrophils, white blood cells,
macrophages, CD8+, MMP 's, Interlukens, cytokins and protocylins. The tissue
then remodels to initiate tissue
formation and thickening that culminates in the formation of tissue adhesions.
Other materials that can initiate this effect are cadmium, smoke artifacts,
tars, materials that irritate tissue such
as alcohols, solvents, organic solvents, acids, materials that are basic and
materials that are acidic. These
materials include compounds or compositions that have pH levels between 1 and
6.9 with materials closest to 1
being a preferable acid material. Additionally, compounds or materials that
have pH levels between 7.5 and 14
work very well; materials closest to 14 work best.
When applying an implantable hydrogel comprised of a biocompatible material,
or an implantable liquid that
undergoes a physical transition from a liquid to a gel or other solid such as
solid adhesives, control of deposition
is very important. Ways of controlling deposition include localized dispensing
of the sealant through a suitable
device containing a lumen, and also through the addition of agents that
increase the viscosity of one or more
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components of the implantable material. Such agents include biocompatible
materials with viscosities that are
greater than those of water, and include glycerol, polymeric materials such as
proteins, carbohydrate-based
polymers and derivatives thereof, synthetic materials including polyethylene
glycols (PEG), polyethylene oxides
(PEO), polyvinyl pyrrolidone (PVP), polyvinyl alcohol and other components
described in the "United States
Pharmacopeia" and the "Handbook of Pharmaceutical Excipients", edited by A. H.
Kibbe. Other materials for
controlling viscosity include oils, lipids, and fatty acids, including oleic
acid, and phosphocholines. Phase
separation can be controlled with emulsifiers including poly sorbate. For
sealants prepared by mixing two or
more components, the viscosities of one or more of the components can be
modified by adding an appropriate
agent to control spreading after application. Viscosities of these components
can range from 1 to 1000
centistokes (a, measure of kinematic viscosity).
Deposition and control of spreading of sealants containing two or more
components are also affected by the gel
time, or set time, of the mixed sealant. Sealants with short set times are
preferably to those with longer set
times. Ideal set times for the present invention and method range from 1-600
seconds, and preferable from 1-60
seconds. Set time can be controlled by the addition of set time modifiers,
including agents that reduce or
increase the set time relative to the corresponding formulation lacking the
set time modifier. An example of an
agent that decreases the set time is carboxymethyl cellulose. An example of an
agent that increases the set time
is glycerol.
Glutaraldehyde, as currently processed and used in some commercial sealants,
undergoes reversible reactions
that cause reoccurring inflammation. These properties can be improved by
chemical modification of the
glutaraldehyde. One such modification includes glutaraldehyde condensation
reactions, as described in
"Bioconjugate Techniques" by G. T. Hermanson. This condensation involves the
formation of derivatives of
glutaraldehyde in aqueous solutions containing acid or base. This reaction can
be monitored by ultraviolet
spectroscopy at or near 280 and 234 nanometers. At 280 nanometers, pure
glutaraldehyde has significant
absorbance, and little or no absorbance at 234 nanometers when measured as an
aqueous solution at 0.5%
weight to volume. When glutaraldehyde is chemically modified, it has
significant absorbance at 234
nanometers. These derivatives are effective cross-linking agents when used
with nucleophilic substrates such as
proteins, including albumins. Furthermore, sealants prepared from
glutaraldehyde derivatives are adhesive in
vivo, through chemical or mechanical means, or a combination of chemical and
mechanical means.
Implantable materials for the present invention are any agents administered
into tissue, including sealants, which
may be comprised of hydrogels, proteins, or other biocompatible materials,
that can be implanted into
compromised tissue to benefit the patient. Examples of hydrogels include those
prepared from natural sources
including carbohydrate-based materials. Such materials include hyaluronans,
hyaluronic acid, alginates, chitins,
chitosans, and derivatives thereof. Proteins that enable the present invention
include albumins, including
porcine albumins, collagens, gelatins, and other proteins that can be cross-
linked or that form solutions with
viscosities greater than water. Although a wide variety of collagenous tissue
can be employed, low collagen
content collagenous tissue, such as lung parenchyma and pleura, are
particularly suitable. Other implantable
materials include those prepared by mixing two or more components so that a
viscous solution, gel, or solid is
formed. Such implantable materials are prepared from a protein substrate where
the protein is derived from
natural, synthetic, or semi-synthetic processes. The protein may also be
derived from recombinant DNA
technology and may be isolated from cell-culture processes, as well as from
transgenic plants and animals.
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Examples of proteins include albumins, including porcine albumins, collagens,
and gelatins. Cross-linkers
employed as part of the implantable material precursors include aldehydes,
polyaldehydes, esters, and other
chemical functionality suitable for cross-linking protein(s). Examples of
homobifunctional cross-linking agents
are described in "Bioconjugate Techniques" by G. T. Hermanson.
Materials of the invention, e.g., the cross-linked protein adhesives and heat-
treated glutaraldehyde glues, when
subjected to a swell test, have values in a percentile range lower than 100.
To determine the swell test value, the
material is placed in water and allowed to hydrate. The hydrated material is
then weighed. Following the step of
weighing the hydrated material, the hydrated material is then dried (e.g. by
heating) and weighed again to
determine a dry weight. The ratio of these two weights (hydrated vs. dry)
comprises the result of the swell test
and indicates how much moisture a material can take on in a percentage of its
weight. Thus, for example, most
non-glutaraldehyde glues typically have a swell test of 100-150%, which makes
the glue come apart in a moist
environment. Fibrin based glues have an even higher swell test value. Cross-
linked albumin based glues of this
invention have a lower swell test value which enables the glues to perform
well in moist environments, with a
swell test value ranging from -50% to 100%.
The implant components, including the cross-linking agent and the substrate,
can be formulated at a pH in the
range of 5-10 by adjusting the pH and/or by adding suitable buffers in the
range of 1-500 mM. Examples of
buffers include phosphate, carbonate, bicarbonate, borate, or imidazole, or
mixtures thereof. Additionally,
additives or stabilizers may be added to improve the stability of one or more
of the components. Furthermore,
imaging agents may be added to allow for detection of the material. Such
agents include iodine, iodine
compounds, metals such as gadolinium, radioisotopes, and other compounds for
gamma scintigraphy, magnetic
resonance imaging, fluoroscopy, CT, SPECT and other imaging modalities.
Additionally, the material may be
formulated such that the mechanical properties are suitable for applications
in the specific tissue to which the
implantable material is applied. Such properties include elasticity, modulus,
stiffness, brittleness, strain,
cohesion, adhesion, and stress. Agents for modifying the properties include
fillers, plasticizers, and adhesion
modifiers. Furthermore, the implant may induce a natural adhesive mechanism
with or without the addition of
chemical agents which may be added to the implant to induce a natural
response. Such agents include particles
in the range of 100 nm to 1 millimeter. Agents include chemical or biochemical
agents (proteins or nucleic
acids) that induce a natural response. Examples of such agents include
bleomycin, cytokines and chemokines,
and single stranded RNA molecules.
In some embodiments, it may be desirable to use bioabsorbable sealants that
expand or swell in the presence of
aqueous fluids such as biological fluids. A commonly used sealant of this type
includes both natural and
synthetic hydrogels. Synthetic hydrogels can be prepared from the following
classes of polymers and these are
generally considered to be non-biodegradable: poly (hydroxyalkyl
methylacrylates) such as poly(glyceryl
methacrylate)poly(acrylamide) and poly(methacrylamide) and derivativespoly(N-
vinyl-2-pyrrolidone)anionic
and cationic hydrogelspoly(vinyl alcohol)poly(ethylene glycol) diacrylate and
derivatives from block
copolymers composed of poly(ethylene oxide)-poly(propylene oxide)-
poly(ethylene oxide) and poly(propylene
oxide)-poly(ethylene oxide)-poly(propylene oxide) blocks, respectively. All of
these materials can be cross-
linked with agents such as ethylene glycol dimethacrylate or methylene-bis-
acrylamide. Biodegradable
synthetic hydrogels can be prepared from polymers such as those listed above
by incorporating one or more of
the following monomers: Glycolide, Lactide, e-Caprolactone, p-Dioxanone and
Trimethylene Carbonateln
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addition. Exemplary hydrogels based on natural products include polypeptides
such as gelatin and
polysaccharide such as starch and dextran. These natural products can be
further processed by cross-linking
with formaldehyde, glutaraldehyde and various other dialdehydes.
The biologically compatible sealant of the present invention may also comprise
a detectable label. The
detectable labels suitable for use in the present invention include any
composition detectable by spectroscopic,
photochemical, biochemical, immunochemical, electrical, optical or chemical
means. A wide variety of
appropriate detectable labels are known in the art, which include luminescent
labels, radioactive isotope labels,
and enzymatic labels. In preferred embodiments, one will likely desire to
employ a fluorescent dye or label.
These exemplary labels may be incorporated by a number of means well known to
those of skill in the art. For
instance, the label can be mixed with the sealant. Alternatively, labels can
be chemically conjugated to the
sealant molecules.
The use of a detectable label is particularly desirable for imaging the
pleural region. The specific imaging
means will depend on the particular type of label being used. For instance,
radioactive labels can be detected by
X-ray imaging. Fluorescent labels can be detected by an array of fluoroscopic
equipment commonly employed
by artisans in the field.
Ideally the composition of the sealant enables it to perform in a wet tissue
environment. As is known in the art
and discussed above, fibrin glue alone does not operate well in a wet
environment and has been abandoned for
use in many medical applications because of its inability to perform in a wet
environment. The sealants used
herein, in combination with the devices and methods, provide high adhesion in
a wet environment. The adhesion
of the sealant is beyond a low threshold that fibrin provides in wet tissue.
In determining an appropriate sealant to use with the devices and methods, two
pieces of thin collagen based
tissue (e.g. 1 inch wide by 2 inches long) are submerged into water (H20) or
saline. The glue or sealant to be
tested is then applied to the surface of one of the pieces and the two pieces
are placed together in the water bath.
The testing environment and materials are maintained at 67-69 F. The glue or
sealant joint between the two
layers of collagen is formed within 2 minutes of removing the tissue from the
fluid without benefit of drying.
The test section is 1 square inch of overlapped tissue that is glued with the
excess tissue extending out both ends
so that the two pieces can be gripped independently. The ends are gripped and
pulled in opposite directions to
test the force to shear the 1 inch section apart. The result is measured as
shear stress or shear pressure and is
recorded as pounds force per unit area. Currently available fibrin glues
tested using this method fail at
approximately 0.0¨ 0.2 pounds force per square inch. Sealants and glues with a
composition suitable for this
invention fail at levels above 0.2 to well above 3.0 depending on the
formulation.
In determining an appropriate sealant to use in another embodiment, the
sealant is tested for biocompatibility
based on MEM Elusion tests and the Agar Overlay tests.
In the MEM Elusion test, solids with uniform surface area and thickness of
around <0.5 mm: 120 cm2, solids
with uniform surface area and thickness > 0.5 mm: 60 cm2, solids without
uniform surface area of 4 grams, or
liquids up to 10 mL are tested. The samples are extracted in a serum-
supplemented mammalian cell culture
media (MEM). Extractions may be performed in 0.9% saline or cell culture media
without serum if desired.
Samples are then extracted for 24-25 hours at 37 1 C in 5 1% CO2. The
extracts are then filtered and placed
in contact with a monolayer of L-929 cells (mouse fibroblasts). The cells are
incubated at 37 2 C in 5 1%
CO2 for 48 3 hours, 72 3 hours or whatever incubation time is desired. The
cells are then scored for
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PCT/US2005/024173
cytopathic effect. The L929 cell line is the most commonly used for the test,
however, as will be appreciated by
those skilled in the art, other cell lines may be suitable as well.
Agar Overlay tests typically are used for solids of 300 mm2 or 300 mg and
liquids of 3 mL. In the Agar Overlay
test, a layer of agarose mixed with cell culture media is placed on top of a
monolayer of L929 cells (mouse
fibroblasts). The samples are placed on top of the agar layer. The cells are
incubated for a minimum of 24 hours
at 37 1 C in 5 1% CO2. The cells are scored for cytopathic effect. The L929
cell line is most commonly
used for testing. However, as will be appreciated by those skilled in the art,
other cell lines can be used without
departing from the scope of the invention.
Using either the MEM Elusion test or the Agar Overlay test result, the sealant
should have a cytotoxicity, on a
scale from 0-4, of 0 or 1, even if the sealant has glutaraldehyde to improve
adhesion in the composition.
In practicing the subject methods, one may choose to remove the device while
concurrently applying the
biologically compatible sealant to the lung. Alternatively, the biologically
compatible sealant may be applied
shortly after the removal of the device, so long as the lapse of time does not
cause a substantial risk of
pneumothorax.
As noted above, the device of the present invention can be used for
therapeutic intervention. Accordingly, in
some embodiments, the subject methods are practiced to deliver a
pharmaceutical composition alone, or in
conjunction with diagnostic interventions including but not limited to imaging
and biopsy. Where desired, the
selected pharmaceutical composition can be delivered to one or more lobes in
the lung, namely, the right upper
lobe, the right middle lobe, right lower lobe, the left upper lobe, and/or the
left lower lobe.
In the preferred embodiments, the pharmacological composition comprises a
therapeutically effective amount of
the active ingredient to provide the desired effect. Non-limiting examples of
pharmacological composition are
anti-inflammatory drugs, chemotherapeutic drugs, immunosuppressive agents,
antihistaminics, analgesics,
tranquilizers, antianxiety drugs, narcotic antagonists, antimigraine agents,
coronary, cerebral or peripheral
vasodilators, hormonal agents, antithrombotic agents, diuretics,
antihypertensive agents, cardiovascular drugs,
opioids, and the like. Preferred pharmaceutical compositions are therapeutics
for treatment of pulmonary
diseases, including but not limited to chronic obstructive pulmonary disease
and lung cancer.
The amount of pharmacologically active ingredient administered and the dosing
regimen used will, of course, be
dependent on the particular drug selected, the age and general condition, or
the pharmacological condition of the
subject being treated, the severity of the subject's condition, and the
judgment of the prescribing physician.
The above descriptions with reference to certain illustrated embodiments and
certain exemplary practices are
provided as a guide to a practitioner of ordinary skill in the art, and are
not meant to be limiting in any way.
While preferred embodiments of the present invention have been shown and
described herein, it will be obvious
to those skilled in the art that such embodiments are provided by way of
example only. Numerous variations,
changes, and substitutions will now occur to those skilled in the art without
departing from the invention. It
should be understood that various alternatives to the embodiments of the
invention described herein may be
employed in practicing the invention. It is intended that the following claims
define the scope of the invention
and that methods and structures within the scope of these claims and their
equivalents be covered thereby.
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