REPAIR OF INTERVERTEBRAL DISKS
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to the use of tissue engineering to repair a
herniated disk, and more particularly, to the use of disaggregated chondrocytes
with various matrix/delivery systems to perform such a repair.
Review of Related Art
An intervertebral disk is composed of an outer fibrous part (annulus
fibrosus) that surrounds a central gelatinous mass (nucleus pulposus). Both
tissues in the disk are chondrocytic in cell type. When a spinal disk injury
occurs (herniated disk, see Figure 1), the disk reacts much like a tire with a
bulge or blister. Over time the blister can become larger, leading to increased
interior space for the nucleus pulposus. This in turn, decreases the ability of
the disk to "cushion" the adjacent vertebrae. Depending on the location of the
herniation, the bulge may put pressure on the spinal cord which results in pain,
reduced mobility and other complications.
Current treatment modalities include two major surgical interventions:
the removal of the disk and fusion. Both of these procedures lead to limitation
in spinal motion. In some cases, a prosthetic disk is placed in the intervertebral space. However, problems with these devices include poor
biocompatibility of the device material, improper placement, or surgical complications of the procedure. Thus, there is a need for an improved method
for treating herniation of intervertebral disks. SUMMARY OF THE INVENTION
It is an object of this invention to provide a minimally invasive technique to repair a herniated disk rather than remove it altogether. This and
other objects of this invention are provided in one or more of the following
embodiments.
In one embodiment, this invention provides a method for treating a
ruptured intervertebral disk by aspirating all or part of a cell-containing
gel from the disk, thereby reducing the nucleus pulposus volume;
excising damaged tissue from the annulus fibrosus of the ruptured disk
leaving a hole therein; covering the hole with a layer containing cells,
said cells being attached to a porous matrix comprising a crosslinked
biocompatible polymer; and injecting a cell-containing suspension into
the disk through the annulus fibrosus to restore the nucleus pulposus
volume. In a preferred embodiment, the cell-containing suspension is
obtained by collecting a population of chondrocytic cells from the annulus fibrosus or the nucleus pulposus, and expanding the population
of chondrocytic cells.
In another embodiment, this invention provides a method for
treating a herniated intervertebral disk by applying over the damaged
area of the disk, a layer containing cells and a biocompatible polymer
which is crosslinked to form a porous matrix.
In yet another embodiment, this invention provides a method for
preparation of a suspension of chondrocytes suitable for injection into a
vertebral disk by expanding a population of chondrocytes obtained by
aspirating a portion of an intervertebral disk; and mixing the expanded
population of chondrocytes with a biocompatible polymer to form a
suspension of chondrocytes suitable for in vivo application onto the
exterior wall of an intervertebral disk where the suspension forms a cell-
containing hydrogel when implanted into the body of a patient.
In still another embodiment, this invention provides a method for
applying a suspension of chondrocytes to the surface of a herniated disk
for repair of the disk by mixing a population of chondrocytes with a
biocompatible polymer to form a suspension of chondrocytes that will
form a cell-containing hydrogel when implanted into the body of a patient; and applying the suspension to the surface of a herniated disk to
form one or more layers of cell-containing hydrogel adherent to the
exterior wall of the disk.
In yet another embodiment, this invention provides a method for
injecting a suspension of chondrocytes into a herniated disk for repair of
the disk, the method comprising the steps of mixing a population of
chondrocytes with a biocompatible polymer to form a suspension of
chondrocytes; and injecting the suspension into a herniated disk where
the suspension forms a cell-containing hydrogel in the disk.
In still another embodiment, this invention provides a method of
using a cell-containing hydrogel suspension for treating a herniated
intervertebral disk by implanting a cell suspension into a patient having
a herniated disk, thereby forming a cell-containing hydrogel adherent to
at least one surface of the annulus fibrosus of the herniated disk.
Preferably the cells are chondrocytes, fibroblasts or osteoblasts.
In the method of this invention, disaggregated chondrocytes,
fibroblasts or osteoblasts are suspended in a hydrogel or other
liquid/semiliquid carrier and painted, brushed, sprayed, or applied by other
means in a layer or layers to the exterior wall of the intervertebral disk to strengthen the wall construct or create replacement wall, and optionally
similarly suspended cells may be introduced into the interior of the disk as
well. A primary difference between the method of this invention and the
methods in use prior to this invention is that this method of repair allows for
the original tissue to remain in place rather than replacing it with a synthetic
material. Potential advantages of the present invention include better spinal
motion, less degeneration of surrounding area, shorter recovery time, and
overall improved results when compared to diskectomy, fusion or implantation
of a prosthetic disk.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows an portion of the spinal column having a herniated disk
between two vertebrae.
Figure 2 is a schematic representation of the steps in the method for
repair of a herniated disk.
Figure 3 is a schematic representation of the steps in the method for
strengthening the annulus fibrosus.
DETAILED DESCRIPTION OF THE EMBODIMENTS
This invention utilizes a minimally invasive technique to repair a herniated disk rather than remove it altogether as is the current standard of
care. Disaggregated chondrocytes, fibroblasts or osteoblasts are suspended in
a hydrogel or other liquid/semiliquid carrier and painted, brushed, sprayed, or
applied by other means in a layer or layers to the exterior wall of the
intervertebral disk. This method can reinforce the annulus fibrosus in the case
of a minor herniation or can be used as a "patch" when the herniated tissue is
removed. Either application should prevent further damage and/or rupture and
may lead to the restoration of full disk function.
Cell/Matrix Compositions
According to this invention, herniated disks are repaired using
materials made up of cells dispersed in a matrix. The cell-containing matrix
adheres to the disk. The cells may be suspended in a liquid/semiliquid carrier
which is applied to the disk and then hardens into a cell-containing matrix.
Alternatively, material which forms the matrix may be applied to the disk, and
the matrix subsequently seeded with cells. The matrix material may be
applied in the fluid state to conform to the shape of the disk surface and then
cure, crosslink or harden to form the matrix, or the matrix may be formed first
and then applied to the surface of the disk.
The matrix material is biocompatible and forms a porous matrix under physiological conditions, typically by cross-linking of biocompatible
polymers. The polymers may be natural or synthetic, biodegradable or non-
biodegradable, and the polymer(s) may be further modified for enhanced
properties. Typical materials for the matrix are described in European Patent
No. 0 299 010 or in International Patent Publication No. WO 94/25080, both
of which are incorporated herein by reference. In one preferred mode, the
matrix is a hydrogel, but use of other materials which form a porous, fibrous
network that can contain cells is also within the contemplation of this
invention. Suitable raw materials which may be used to produce the hydrogel
in which the cells are suspended include sodium alginate, which has been
tested with chondrocytes, as well as PLURONICS™ and TETRONICS™.
Procedures for preparing the matrices and seeding them with cells are
described in these publications, and the skilled worker will readily adapt those
procedures to this invention in view of the guidance provided herein. The
hydrogel-cell suspension may be prepared as described for products used in
treatment for vesicoureteral reflux using autologous auricular chondrocytes in
sodium alginate. Alternatively, the hydrogel-cell suspension may be prepared
as described in International Patent Publication No. WO 97/17038, by Vacanti,
et al., entitled "Hydrogel-cell composition - for generating new tissue on
surface of structure or organ," incorporated herein by reference. Other cell- containing suspensions which can be "painted" on physiological surfaces in an
equivalent manner to the hydrogel-cell suspension described herein may also
be used to repair intervertebral disks according to this invention.
The cells in the matrix may be any suitable cell type, but preferably the
cells will be derived from the structure to be repaired (i.e., cells from the
herniated disk, or cells of the same cell type, will be used). Typically the cells
are chondrocytes, although osteoblasts or fibroblasts may be used.
Chondrocytes may be obtained from any cartilaginous tissue in the patient, or
may be allogeneic chondrocytes, so long as care is taken to mitigate any
adverse reactions to the allogeneic cells. Alternatively, other cell types known
in the field of tissue engineering to proliferate on the matrix of this invention
may be used in this method.
Cells obtained for use in the matrix may be used directly or expanded
by culture under suitable conditions. Standard cell culture conditions may be
used, taking into account that results of this cell expansion process must be
suitable for re-introduction into the patient. The cell suspension may contain
additives, such as growth factors, colony stimulating factors, cytokines,
adhesion peptides, antibiotics, cell nutrients, physiologically compatible
buffers and salts, and the like. The components of the cell suspension may be
combined using any procedure which preserves viability of a substantial portion of the cells (typically 35% of the cells, preferably at least 50%). Such
procedures are known to those skilled in the art of tissue engineering, and
suitable procedures are described in the patent publications incorporated herein
by reference.
Treatment Modalities
This invention is directed to the repair of intervertebral disks.
Defect(s) which may be overcome by the method of this invention include
damage of, abnormal development of, weakness of, or missing sections of
exterior or outer intervertebral disk wall. This method may be used for repair
of spinal/skeletal injuries by augmenting existing tissue which would result in
increased strength, improved or restored function, or providing a bridge for
missing sections. In a preferred embodiment, the method of this invention is
used as a first step/additional treatment in combination with spinal cord pain
management/reconstruction by removing fluid from inside the disk thus
reducing pressure on the outer wall of the disk. The cells in the fluid may then
be expanded in vitro and re-implanted once the disk wall has been
strengthened by application of the cell-matrix structure according to this
invention.
The method described herein can be performed in open surgery or endoscopically. A typical procedure is illustrated in Figure 2. Figure 2-1
shows a side view of herniated disk 10 in which the wall (annulus fibrosus 20)
has a damaged section 30. Figure 2-2 shows the first step in the repair
procedure. Herniated tissue 30 is removed. Usually, a small fragment of
undamaged annulus fibrosus will be taken at the same time and sent to a cell
culture facility for isolation and expansion of the cell population. After cell
expansion, a second procedure would seed cells into the interior of the disk
and/or onto the matrix. Preferably, all or a part of the nucleus pulposus (40) of
herniated disk 10 is aspirated. Removal of part of nucleus pulposus 40
relieves the pressure on the ruptured wall and/or the patch placed over the
rupture as described in the following paragraph. The aspirated material may
be stored for later re-introduction into the interior of the disk; any method of
cell storage which maintains adequate viability for future use is within the
contemplation of this invention. Alternatively, the cell population contained
in the aspirate may be expanded.
As shown in Figure 2-3, a matrix "patch" 50 is placed over the
resulting hole 60 in the annulus fibrosus. Patch 50 may be formed from a fluid
composition containing a polymer that will harden when in contact with
biological tissue to form a porous matrix, or it may be a preformed layer of
fibrous material that can be applied to the exterior disk wall. A preformed porous patch applied during an open surgical procedure may be sutured in
place, or fibrin glue may be used to secure the patch in either endoscopic or
open surgery. The fluid composition may contain cells in suspension, or cells
may be seeded 70 onto the matrix once it has formed (See Figure 2-4).
After hole 60 in the annulus fibrosus has been closed, the volume of
the nucleus pulposus is preferably restored by injection 80 of stored aspirate or
a cell suspension, which preferably contains expanded cells described above,
and more preferably, contains material that will have fluid consistency similar
to the original nucleus pulposus, e.g., polymers that crosslink under
physiological conditions to form a hydrogel with the desired properties.
Suitable procedures for injecting material for volume restoration are analogous
to the surgical procedures for introducing and removing arterial catheters.
In a alternative embodiment (shown in Figure 3), minor herniated
tissue can be strengthened with layers of the cell suspension as needed. Disk
15 in Figure 3-1 has a minor herniation which weakens the wall (25) without
significantly changing the volume of disk 15. As shown in Figure 3-2,
annulus fibrosus 25 may be strengthened by applying a layer (55) over
damaged section 35 which is a fibrous matrix containing cells. Preferably, the
layer is applied as a cell-containing suspension which is painted, sprayed or
brushed on an area corresponding to at least damaged section 35 of the exterior disk wall. Suitable procedures for preparation of such a cell suspension as
well as procedures that may be adapted for applying the suspension to the disk
wall are described in International Patent Publication No. WO 97/17038.
Treatment according to this invention may optionally include
administration of drugs and/or other biological materials as appropriate. For
example, one or more antibiotics, one or more growth factors for maintenance
or stimulation of the cells, or nutrient medium components to support cell
viability may be included in the cell suspension. Alternatively, such
components may be administered separately, preferably by direct application
in the region of the disk. Preferably, local administration of antibiotics is
included in the method to reduce the risk of infection in the procedure. Where
the cell suspension contains allogeneic cells or other foreign immunogenic
material, immunosuppressive drugs may also be included.
Work reported by Ashton and Eisenstein in Spine, Feb 15, 1996, pages
421-426, states that the neuropeptide, Substance P had a small stimulatory
effect on disk cell proliferation in vitro. Their conclusion is that further
investigation is required to establish if Substance P has a biologic relevance to
the maintenance or repair of the intervertebral disk. Substance P may be used
according to this invention to help in the expansion and growth of cells used in
the procedure. Application of Substance P for cell expansion in vitro may use conditions analogous to those described by Ashton and Eisenstein. Suitable
conditions for use of Substance P in vivo will be readily determined by the
skilled clinician in view of the disclosures of Ashton and Eisenstein.
For purposes of clarity of understanding, the foregoing invention has
been described in some detail by way of illustration and example in
conjunction with specific embodiments, although other aspects, advantages
and modifications will be apparent to those skilled in the art to which the
invention pertains. The foregoing description and examples are intended to
illustrate, but not limit the scope of the invention. Modifications of the
above-described modes for carrying out the invention that are apparent to
persons of skill in the art of tissue engineering, medicine, and surgery, and/or
related fields are intended to be within the scope of the invention, which is
limited only by the appended claims.
All publications and patent applications mentioned in this specification
are indicative of the level of skill of those skilled in the art to which this
invention pertains. All publications and patent applications 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.