Note: Descriptions are shown in the official language in which they were submitted.
WO 95/25.1132 2 1 8 3 9 ~ 2 Pcrlusssl034ss
THREE-DlMENsIoNAL BIOREMODELABLE COLLAGEN FABRICS
Field of the Invention
The invention is in the field of tissue rn~in~Prin~ implantable medical
S devices and is directed to three-~imrnci~nAl bioremodelable fabrics made
from collagen threads which are used to replace or repair tissue or organs.
BACKGROUND OF THE INVENTION
One of the most important attributes of living organisms is their
capacity for self-repair. Several mf~rh~nicm~ have evolved to achieve this,
including wound healing, compensatory growth and epimorphic
regeneration. Although all tissues and organs (with the possible exception of
teeth) are capable of some degree of repair, mammals have unfortunately lost
the ability to faithfully regenerate severely damaged body parts. In an attempt
to overcome this deficiency, numerous synthetic devices have been
developed, with the intention that the implants be biological~y inert, and yet
function for the lifetime of the recipient. Experience with synthetic devices,
however, has shown that not only is biological inertness apparently
impossible, but the interaction between a 1~--"~ 1 and the surrounding
2 0 living tissue can actually contribute to the long-term success of the implant.
The concept of a resorbable scaffold for tissue repair and regeneration
has received considerable attention in recent years and has been attempted
using both synthetic and natural resorbable polymers. Yannas et al., in U.S.
Patent No. 4,060,081, fabricated implants from lyophilized sponges of collagen
and ~Iy~:u~A~ oglycans. Nyiles et al, Trans Am. Soc. Artif. Interi:. Orga7ls,
29:307-312 (1983), used resorbable polyesters for peripheral nerve regeneration.Li used a porous semipermeable collagen conduit for nerve regeneration as
described in U.S. Patent No. 4,963,146 and he used fibers of collagen to form a
resorbable prosthetic ligament as described in U.S. 5,263,984.
3 0 Collagen has long been used as a 1~ 1 (Chvapil, et al., "Medical
and Surgical Applications of Collagen," Interna~ional Review of Conl~ec~i~e
Tissue Research, volume 6, pp. 1-60 (1973); Stenzel et al, "Collagen as a
Biomaterial," Annual Review of Biopl~ysics and Bioengineering, pp. 231-253
(1974); E.E. Sabelman, "Biology, Biotechnology and Biocompatibility of
.3 5 Collagen," volume 1, pp. 27-65 (19 )). In these structures, the collagen has
been formed into fibers, threads, membranes, gels and sponges. Despite
21 8~962
W0 95/25~82 F~ 4~
extensive research over the last fifty years, these reconstituted collagen
structures do not possess the same m~t-hAnir~l properfies of the connective
tissue that they are attempting to mimic and, therefore, have often needed to
e reinforced with synthetic materials. Thus, Chvapil and co-workers
reinforced a collagen cylinder with Dacron to function as a vascular graft.
(Chvapil M. and Krajicek M., J. Surg.. Res., 3:358 (1963); Chvapil et al., J.
Biome~. Mat. Res., 3:315 (1969)). Dacron was also used to reinforce a collagen
based wound dressing. (Song et al. Surgery, 59:576 (1966)). Collagen has also
been mixed with glycol methacrylate to form a material for possible use in
orthopedic surgery. (Chvapil et al., J. Biomed. Mat. Res., 3:315 (1969))
Recon$tituted collagen fibers were first produced in the 1940s and this
technology was exploited to produce an extruded collagen suture. These
collagen fibers were woven or knitted into a mesh for use in surgery. An
open (leno) collagen weave formed from 4-0 suture materials was used by
I S Adler et al. (Adler et al., "A Collagen Mesh Prosthesis for Wound Repair and
Hernia R~i..ru~ Surgical Forum, 13:29-30 (1962)). A similar material
was also used by Friedman and Meltzer to repair endopelvic fascial defects.
(Friedman and Meltzer, "Collagen mesh prosthesis for repair of endopelvic
fascial defects," Gynecology, 106:430~33 (1970)).
Green and Patterson demonstrated in 1968 that an open weave of
formalin tanned collagen fibers IAminAf~ between layers of fibrillar collagen
dispersion could be used for pelvic floor reconstruction. (Green and
Patterson, "Collagen Film Pelvic Floor Reconstruction Following Total Pelvic
Exenteration," Surgery, Gynecology & Obstetrics, pp. 309-314 (February 1968)).
A similar device was used by Jannetta and Whayne (1965) as a dural
replacement in dogs.
A device made from an open collagen mesh through which three long
collagen tapes were interwoven was used by Girgis and Veenema (1965).
SrhnnhAI1.or and Eanta (1958) implanted a mesh made from chromic tanned
3 0 catgut sutures into the abdominal and dorsal fascia of dogs. All these
materials were single layers of collagen weave as can be seen in Figure 2 of
Girgis and Veenema (1965) and Abb. 1 of Srhnnh~llPr and Fanta (1958).
Weslowski et al., Surgery, 50:91 (1963) investigated production of a
compound vascular graft in which some of the monnfilAmPnt yarns were
replaced with catgut or r~nncfif11t~cl collagen suture. These researchers,
however, found that this graft did not function correctly due to the fact that
wo ss/2s~82 2 1 8 3 9 ~ 2 ~ 455
.
the collagen material was not completely absorbed by the time of healing of
the fibrous capsule.
Connective tissue derive their mechanical strength and physical
character mainly from the three~ m~ncif)nAl assembly of long, intertwined
' 5 crosslinked collagen fibrils and fibers formed from one or more of the 18
known distinct types of collagen; each of which has its own structure and
properties. The same type of collagens synthesized by different tissues
organizes itself into different organizational structures. Thus, in skin
collagen Type I, collagen fibers form a structure whereby Type I collagen fibersl 0 are laid down at various acute angles in relation to the skin surface. In
tendons and lig~m~nts, however, most of the Type I collagen fibers are
arranged with their long axis parallel to the long axis of the tissue. In cornea,
the Type I collagen fibers are oriented in orthogonal layers. In cylindrical
organs such as blood vessels and intestine, the collagen fibers are laid down ina cross-ply arrangement with the two arrays of fibers running diagonally in a
dockwise and anti-clockwise direction. In bone, the large collagen fibers are
arranged such that they best counter the loads imposed on the tissue. By
utilizing collagen fibers and the technology of forming three-~im~ncil-n~l
fabrics, this o~ " can be mimicked to some degree in the formation of
2 0 imr!~nt~hl~ bi~ ,sLl~ s which are designed to act as rl~mo~ hle scaffolds
to promote the Pct~hlichm~nt of new tissues that maintain, restore, or
improve normal biological function.
It is easier to achieve a variety of fiber ori~nt~tir)nc in three--limentiif)nc
if one is not constrained by the need to interlace fibers. (See Figure 4 of
2 5 M~hAmf~ ) This fabric lacks structural integrity as the individual fibers are
not interacting and the material needs to be impregnated with a matrix in
order to produce an integrated structure. This technique has been used with
synthetic materials to form structures with wall thirknP~c~c of up to 8 inches.
(M~h~m~rl, Americnn Scientist, 78:530-541 (1990)).
3 0 Machines which can form three-.li~ l, cylindrical, weft knits in
which the two layers can be bound together have also been developed.
(Williams, Ad~anced Composi~e Engineering, volume 2 (1987)). Warp
knitting with multiple re-reinforcing yarns can be used to produce a fabric
that is multi-layered. (Mnh~m~l, suprQ.) Braiding can also be used to
,3 5 produce highly complex, three-~im~nc;~ shapes. (Florentine, U.S. Patent
No. 4,312,261). Three-~1iml~n~iif)n~ weaves have also been formed. The
.
woss/2s~s2 21P~39k~ r~ c
fabrics can be woven with a space between the layers Icore fabrics) or woven as
thick dense structures as seen in Figure 8 of Mohamed, suprr.
SUMMARY OF THE INVENTION
S The inventors have combined collagen's fibrillogenic capacity with
textile technologies in order to bioengineer three-dimensional
bioremodelable fabrics tailor-made to suit a wide variety of applications with
varied porosity, elongation, and strength requirements based on the
knowledge gained from hiomimP~ir studies. The bioremodelability of the
collagen fabrics of this invention permits them to undergo biodegradation in
a controlled fashion so that the production of endogenous structural collagen,
v~cr~ ri7Atir,n, and epi~hPli~li7:~irln of the fabric by the ingrowth of host
cells occurs at a rate faster than the loss of bi~mPrh~nir~1 strength of the
implanted fabric due to biodegradation by host en_ymes. By the time the
imp~anted collagen fabric of this invention is resorbed by the body,
endogenous host tissue is in place and capable of m~inf~inin~ the integrity
and normal function of the tissue.
This invention provides for the production of three-~limPnsinn~l
bior~modP1~hle collagen fabrics of various configurations. These fabrics are
2 0 thus bioengineered implants and devices which serve the required physical
function while f~rili~fin~ remodeling of the replaced or repaired tissue or
organ implant.
DETAILED DESCRIPTION OF THE INVENTION
2 5 L Tissue F.~.. ' ~.
This invention is directed to three-rlimPncir,n~l bioremodelable fabrics
formed from collagen threads. This invention is directed to implantable
medical devices which can be used to replace or repair tissue or organs. More
particularly, this invention is directed to devices that can serve as in vivo
3 0 scaffolds for the l~g~ iOll of new tissue. In the textile industry, three-
~1imPnci~n~1 fabrics achieve their greatest strength when the threads are
intertwined, interlaced or intermeshed in the crosswise, lengthwise and
thickness directions. These directions are also termed the X-, Y-, and Z-axes.
The three-dimensional bioremodelable fabrics of this invention are
3 5 applications of textile ~Prhnirll1Pc with knowledge of collagen's fibrillogenic
capacity and ability to bioremodel. The three~ 1 bioremodelable
wo s~/2s~82 2 1 8 3 q ~ 2 p ~ I, ., ~ t~;li
o
fabrics are made from collagen threads and, using textile techniques, are
woven and/or knitted into the desired configurations to replace or repair
organs and tissues.
The three~ mpncinn~l fabrics of this invention are meant to include
~ S collagen threads in mlllfi~ l directions, as compared with two-(limPncinn~lfabrics, which only have width and length directions. A two-dimPncinn~l
fabric does, of course, have some depth based on the diameter of the threads
used in the construction, but it is not a true m~ l, three-flimPncinn~l
fabric.
As used herein "fabric" means a structure used as the three-
~iimPncinn~l framework or scaffold for biorPmo~lPlin~ which can be formed
into a number of patterns or shapes, as dictated by the hiomimp~i~ s approach
to tissue Pn~inPPrin~ Thus, for example, as explained in more detail below, a
three-dimensional bioremodelable fabric can be shaped into a structure
rPcPmhlin~ a bone, with a hollow core. ~ inn~lly, the collagen threads can
be formed into a solid configuration, such as a structure resembling a sling forhernia repair. The term "fabric" is used because it describes a construct made
from collagen threads using textile techniques. Thus, for example, the term is
meant to include braids that can be made into a wide range of geometric
2 0 shapes in which the braiding threads interlock the entire structure.
Several types of structures are described in detail in co-pending
application, U.S. serial number 08/216,527, filed concurrently herewith as
"Biocompatible Devices," the contents of which are incorporated herein by
reference in its entirety.
2 5 The biorpmnfipl~hlp collagen fabric is designed not only to perform an
immPfli~P physical function, but equally importantly, to guide and encourage
appropriate host tissue forn~tinn, dissolve, and gradually transfer the load to
the newly formed collagen. "Bioremodelable" means the ability of the
implanted collagen fabric to function as a scaffold for new host tissue
3 0 ingrowth by facilitating the production of endogenous structural collagen,
vascularization, and epifhPli~li7R~inn by the ingrowth of host cells at a rate
faster than the loss of binmPl h~nil ~l strength of the i~lL~lal,L~d fabric due to
biode~,.adaLi~ . As the biorpmnrlpl~hl fabric biodegrades, new tissue forms,
thus creating a permanent functional analog of the original tissue or organ.
,3 5 A three~ mpn~inn~l fabric is a woven and/or knitted product which is
m~ yi:~l, with X-, Y-, and Z-axes. Typically, the three--limPn~:on~l fabrics
wo 9sl2s~82 2 1 8 3 9 ~ 2 PCT~Sg5103455
are continuously formed by intertwining a plurality of strands together, some
of which are at an angle from the traditional flat fabric weaving pian. An
inherent disadvantage of fiber constructs made into two-dimensional fabric
sheets is their limited strength. Two (~inn~ncinn~l fabrics are anistropic,
exhibiting unequal strength properties when measured along the X- and Y-
axis. To extend the use and value of textile technology into bioremodelable
collagen constructs, strength in more than two directions is required. The
three-flimf~n~: -n~1 fabrics of this invention can be con3tructed from collagen
threads using textile trrhniq l~c
Three-~1im~nciorl~l fabric formation in the textile industry has been
used to produce a number of different articles. These techniques are described
in detail in the following patents, which is not intended to be limiting: U.S.
Patent Nos. 5,019,435; 4917,756; 4,863,660; 4,848,414; 4,834,144; 4,805,422;
4,805,421; 4,779,429; 4,346,741; 5,067,525; 4,936,186; 4,881,444; 4,800,796; 4,719,837;
4,615,256; 4,312,261, all of which are incorporated herein by reference.
The construction of three-dimensional bioremodelable fabrics can be
accomplished using the textile techniques of weaving and knitting. Using
these techniques, the three-dimensional bioremodelable fabrics of this
invention can be made into any of a variety of shapes: (1) a solid weave; (2)
2 0 an open weave; (3) a solid knit; and (4) an open knit. All of these fabrics can
be made with the same size threads or with different size threads in the same
construct. Further, the threads may first be plied, braided, or otherwise
manipulated to increase the diameter or strength of the threads, such as by
crnCclinkin~ prior to using them in the construction of the bioremodelable
2 5 fabrics. Additionally, a combination of knit construction and weave
cons~ruction can be used in the same fabric construct. These collagen fabrics
m~y be used for a wide variety of applications with varied porosity,
elongation, and strength re4ui~
3 0 IL Cu~ llu~livl~ of Three-D- ' Fabric~3
A. Weaving.
A woven fabric is defined in textile terms as a cloth made by interlacing
or iLl~ iwilli~g warp strands with filling strands, the woof. A warp is a seriesof strands extended lengthwise in a loom and crossed by the woof, the filling
3 5 strands.
-
wo ss~2s~82 2 1 8 ~ 9 6 ~ r~ 455
Multilayer woven fabrics are composed of several series of warp and
filling strands that form distinct layers, one above the other. The fabrics can
be woven with a space between layers (core fabrics) or woven as thick, dense
structures. The layers can be bound together by intrrl:lrin~ ~arp ends in the
structure with the filling of adjacent layers (angle interlock) or by having theends interlace between the face and back layers (warp interlock). The binding
yarns may also interlace Yertically between layers, producing an orthogonal
weave.
Multilayer woven fabrics do not need not be interlaced throughout the
fabric: the addition of vertical yarns interlaced with the top and bottom
horizontal yarns provides the same kind of reinforcement in a three-
r~imrncir,n~l structure that is provided by the over and under interlacing of
yarns in flat weaving.
Multilayer skuctures can be given ~ lition~l strength by inserting in
each layer stuffing yarns, which remain straight and contribute their full
strength in the direction in which they are oriented. Yarns that interlace
between layers as binding yarns contribute partially to the strength of their
direction; in orthogonal woven fabrics, they contribute immensely to the
strength in the kLickness direction. There are trade-offs that must be made,
2 0 however, since only one yarn can occupy any position within the structure.
An increase in the fiber volume fraction (the fraction of the total volume
occupied by fiber) in one direction can be achieved only at the expense of one
or both of the other directions.
Most commonly, shuttle looms are used and the warp yarns are taken
2 5 from a creel; since the warp is coming from many individual bobbins, it canbe taken from different sources, an arrangement which allows yarns to be
mixed and allows flexibility in the rates at which they are fed.
Traditional weaYing machines adapt well to making multilayer panels
in this way, but the complexities of creating other three-~imf~ncirln~l textile
3 0 structures require special considerations, including m~int~inin~ consistency
in yarn tension.
A key step in assuring the strength of the finished structure occurs each
time the needles cross the warp. A vertical needle, threaded with the yarn
that will secure the selvage loops on the vertical edge, is inserted from below
. 3 5 the weaving area, coming up to catch the filling yarn that has just been
brought across the warp. This selvage needle holds a loop of each filling yarn
wo ss/~s~s2 2 1 8 3 q ~ 2 PCT/I~S95/03~J55
at the edge of the warp as the filling needles return to their original positions.
Thus a double length of filling is inserted with each cycle. The selvage
needles retract for the next step, but the selvage yarn - which now holds the
filling loops - is clasped and held in its vertical position by a knitting needle.
To form a finished corner edge, the loops of selvage yarns are knitted together
as the process . ontinllec
The step that is called "beat-up" in traditional weaving is used in three-
,lirnencicln~l weaving to position the vertical (z) yarns. These yarns are
threaded through needles suspended from harness frames (similar to those
used in the traditional loom) and are passed through the vertical openings in
a reed at angles, crossing on the opposite side of the filling needles. Once
every cycle, as the z yarns are suspended in diagonal position, the reed moves
hori70nt~11y to push the filling against the already-woven length of textile.
This action pushes the crossed z yarns into a vertical arrangement. The
harnesses holding the z yarns then move up and down to reverse the
positions of the yarns before the process begins again. In this way the verticalyarn that has just been stretched from the bottom to the top of the textile is
passed over the topmost filling yarn and held in position to be placed in the
opposite direction at the next stage of the weaving.
With ~ litinn~l harness frames and devices for dobby or Jacquard
weaving, it is possible to weave many structures.
It is also possible to vary the fiber volume fraction to give the
composite the ability to withstand extra stresses in a particular direction.
Since in this system the filling yarn is inserted in the form of a doubled loop,2 5 a balanced structure is achieved when the filling yarns are half the size of the
warp and z yarns. One can keep the structure balanced in this way but vary
the sizes of the yarns used in each of the three directions. In addition, the
fiber volume fraction can be varied in the vertical direction by using more
than one warp yarn for every z yarn. This proportion may not be required for
3 0 every application.
B. Knitting.
A knitted fabric is formed by int.orl~cin~ yarn or thread in a series of
connected loops. The knit stitch is a basic knitting stitch usually made with
3 5 yarn at the back of the work by inserting the right needle into the front part of
the loop on the left needle from the left side, catching the yarn with the point
WO gS/ZS-182 ~ PCTIUS9SJ03455
of the right needle, and bringing it through the first loop to form a new loop.
The purl stitch a knitting stitch usually made with the yarn at the front of thework by inserting the right needle into the front of a loop on the left needle
from the right, catching the yarn with the right needle, and bringing it
through to form a new loop.
Knitting is a versatile technique for producing strong, porous
structures and is the preferred method of making the three-dimensional
bioremodelable collagen fabrics. The main advantage of knitting over
weaving is that knitting introduces closed loops at the yarn crossover points,
allowing the product to hold sutures with very little bite, and without
needing to fold the material at the suture line. In contrast, weaving
il,L~l~oses parallel yarns, resulting in a fabric more subject to fraying when
cut. In addition, knitting offers more options for varying the physical
character of the final material than weaving does.
There are two basic types of knitting m~hinPc Weft knitting
machines use only a single end of yarn and individual needles cast off stitches
sequentially. Warp knitting machines use many ends of yarn parallel-wound
on a cylinder (the warp) and man needles (a "needle bar") cast off stitches
ciml~ltAn~nusly to produce the fabric.
2 0 Warp knitting, however, offers distinct advantages. Since weft knitted
fabrics are formed from a single end, they can unravel if that end is pulled, orif the fabric is cut in the middle and the free end is pulled. Most warp knittedfabrics do not unravel when cut. Moreover, by simultaneously using
additional warps and ~ 1itinn~1 needle bars, complex fabrics can be designed
2 5 in which a heavier weight, and more complex fabric with new mP(~h~nit ~l
properties results.
There are two main categories of warp knitting machines. The Raschel
type has a latched needle to hold the yarn. The Tricot type holds the yarn
with flexible bent tip, termed a "beard." Raschel machines offer a more
3 0 versatile array of knitting patterns, but Tricot machines exert less stress on the
fibers. Both flat and tubular structures can be made on Raschel machines;
Tricot machines are mainly used to produce flat structures. Collagen fabrics
can be made by both flat and tubular weft knitting, and both Raschel and
Tricot warp knitting. The variety of knitting designs runs the gamut from
3 5 open elastic mesh~s, to dense stable fabrics, to tubular structures, using
-
wo 9sl2s~8~ ~ 1 8 3 9 6 2 PCT/IJS95/03'155
starting materials from individual or multiple monofilament threads to
twisted or braided yarns.
Variations of knitting techniques can be used to manufacture three-
dimensional constructs in cylindrical or conical shapes. In this approach,
axial rods are placed to form the shape of the struc~ure; after radial yarns areadded, knitting needles catch the radial yarns and c~eate chain stitches to loopthese yarns around the axial rods, which are replaced with axial reinforcing
fibers when the preform is pulled off the machine.
C Braiding.
Braiding tpehniqllpc have been developed to produce complex shapes
(Florentine 1982). In essence, these are multilayered structures in which
some braiding yarns traverse the inner layers to bind the two exterior layers
together. Complex shapes can be formed by braiding over a removable
mandrel whereby the contours of the final braid match those of the mandre~
as can be seen in Figure 7 of Mohamed, supra.
IIL Collagen Threads
The collagen that can be used in this inver~tion can be formed from
2 0 collagen parts derived from animals, or from collagen produced by cells in
tissue culture. Collagen can be extracted in a number of ways from animal
parts. Suitable sources of collagen include, but are not limited to, skin,
tendons, bone, cartilage, li~AmPnts~ fascia, intestinal submucosa, placenta.
Extraction methods that have been commercialized for the production of
2 5 collagen preparations can be divided into the categories of dispersion,
digestion, and ~liccollltl~n
Dispersion tPf~hniql1Pc generally involve swelling and eomminlltic)n of
connective tissue. This results in heterogeneous material with a high solids
content formed from portions of collagen fibrils. Digestion utilizes
3 0 proteolytic enzymes which cleave the telopeptides downstream of the
crosslinks. This method produces a monomeric solution of partially
degraded collagen which, although still contain intact triple helical regions,
has now lost most or all of the telopeptide region. The ~liccnllltinn of collagen
relies on the acid labile nature of the newly formed covalent cross linkages.
3 5 This tP~ hniqllP, which employs low pH solutions, results in extraction of the
intact, collagen molecule. Although yields are relatively low compared to the
Wo9~2s~8z 2 ~ 2 PCTlUS9sJ03455
enzymatic digestion methods, there are major benefits to this technique due
to the fact that the complete, native structure is m~int:linP(l
Various types of collagen threads can be used in this invention.
Different types of collagen threads are described in a number of patents, for
example, Silver, U.S. Patent No. 5,171,273; Shu Tun Li, U.S. Patent No.
5,263,984; PCT application W093/06791 and co-pending patent application,
U.S. serial n~. 08/216,527, "Biocompatible Devices," all of which are
incorporated herein by reference. Collagen sutures are also included in the
definition of collagen threads and can be used in this invention. Collagen
l O sutures are described in U.S. Patent Nos. 3,114,593 and 3,114,591, incorporated
herein by reference.
Thread size can be measured two ways. The diameter can be measured
microscopically (IOX) using a measuring eyepiece, averaging the readings
taken on at least five thread samples in at least five random locations.
Another way to measure diameter, which is more characteristic of textile
fibers, is to measure thread mass per length, or denier (mass in grams per
9000 meters of length). For use in this invention, the denier can range from
about 15 to about 300, typically about 80.
Thread strength can be determined by mounting a 50 mm sample
2 0 lengths in a force gauge (Chatillon Corp., Agawam, Massachusetts) and
pulling at 50% strain per minute until failure. Ultimate Pll-n~ti~n and load
at break can then be ( h~r~ftPri7Pd
Thread knitability may be evaluated by knitting a 5 mm diameter
tubular fabric on a circular (weft) knitting machine (Lamb, Chicopee, MA).
Shrinkage ~ p~laLu ~, a measure of the stability of the collagen triple
helix, can be measured by immersing a 5 to 7 loop of thread loaded with 2.5 g
in 1.0 mM pOl. ssiul.l phosphate monobasic, 11 mM sodium phosphate
dibasic, and 150 rnM NaCl at pH 7.30, and heating at 1C per minute until
shrinkage occurs. The temperature at which the sample shrinks by at least
3 0 10% is the shrinkage temperature.
IV. Uses of Three-D; . ~
Bi.,.l -' ' hleFabrics
The three-dimensional bioremodelable collagen fabrics of this
3 5 invention have many uses as organ implants or in tissue repair or
rPpl~rPmPnt I 1
wo9~ 82 21~396~ ~"~
BiorPmrr~Pl:~hlP collagen constructs can be braided or bundled for use as
load bearing orthopedic ~los~ ses such as bone, cartilage, tendon or ligament
repl~rPmPn~c. When used as a bone prosth~sis, the collagen constructs can be
shaped into a structure with a hollow core. Alternatively, the bone prosthesis
can be formed of (1) an outer, hollow tubular structure with the desired
strength and binmPrh~nir~l properties required to bear the load exerted on
the particular bone being replaced and the necessary diameter required to
achieve a suitdble match at the site of implantation and (2) an inner matrix of
collagen fabric of the desired porosity to permit it to be seeded with
hematopoietic stem cells.
Collagen fabric knitted or woven into tubular form may also be used as
a support for a vascular prosthesis, providing that a luminal smooth flow
surface is also provided. Similarly, tubes of larger diameter could be woven
for use as implants in the reconstructive~ LulaLive surgery of tubular organs
such as the larynx, trachea, bronchi, esophagus, urethra, intestine, colon or
bile ducts.
Collagen fabric constructs may also be formed in the shape of a wedge
for illl~ld-lldliull in synovial joints to replace a damaged articular miniscus or
in the shape of a disk to replace damaged illL~lv~ blrl disks. The implants
2 0 will be bioremodeled with ~lldog~lluu~ fibrocartilage to create a new miniscus
or disk.
The collagen fabric constructs of this invention can also be sprayed or
coated with antibiotics, antiviral agents, growth factors, thrombosis-resistant
agents or the like before implantation to enhance rPmrlclPlin~ or to prevent
2 5 infection.
The collagen fabric could also be produced from collagen threads that
have been formed from a mixture of collagen and one or more of the
following:
(a) l~luLeo~ly~ s or other extra-cellular matrix components such as
3 0 fibronectin, laminin, tenascin;
(b) Cytokines such as members of the transforming growth factor betas
(TGFbs), platelet derived growth factor (PDGF), insulin like growth factors
(IGFs), fibroblast growth factors (FGFs), bone morphogenic proteins (BMPs) or
interleukin (IL) families. These factors could be uniformly incorporated
3 5 within the col!agen thread or coextruded such that a gradient of factor was formed from the center to the edge of the thread.
WO 95/25~82 2 1 8 ~ q G 2 r~l",~ lCC
(c) Antiviral, ~ntih~rtrri:ll or anti-fungal agents.
The collagen fabric could also be produced from non crosslinked
collagen and implanted in this state. The collagen fabric may also be
crosslinked by any of the known crosslinking agents described in U.S. Patent
No. 5,263,984, Column 3, lines 5~62. Moreover, the individual threads could
be crosslinked prior to formation of the construct so that in order to control
the biomPrh~nir~l properties of and cell response to the construct the fabric
could be made from mixtures of crosslinked and non crosslinked threads.
The following examples are offered by way of illustration and not by
l 0 way of limit~tir,n.
EXAMPLE 1
Formation of an Abdominal Wall Repair System
This fabric was m~nl~f;~rtllred first by producing a 2-ply collagen yarn.
Collagen threads were made by the process described in copending patent
application, U.S. serial number 08/216,527, filed concurrently herewith, as
"Biocompatible Devices." Two mr~nnfil~mrnt strands of thread were each
twisted at 1.5 twists-per-inch (tpi) in the Z-direction; then, they were twistedtogether at 2.5 tpi in the S-direction. The result was a 2-ply yarn which does
not unravel or spring. This yarn was then warped using a conventional
single and warper (more convenient for trial quantities than a creel) onto an
ordinary knitting beam. The hernia repair hbric under investigation used
three such beams on a 20-gauge Tricot sample knitting machine in a pattern
designed for high bulk and low eYtrncihility The stitch design is as follows:
2 5 Front bar (#1): 0-1/1-0//
Middle bar (#2): 1-0/4-5//
Back bar (#3): 4-5/1-0//
This fabric was evaluated as an abdominal wall replacement in the rat model,
using a full muscle layer defect measuring 2 cm by 2 cm. Before imrl~nt~tir,ll,
3 0 the fabric was cleaned with acetone, crosslinked with 50 mM EDC in 90%
acetone at room temperature overnight, depyrogenated in 0.1 N NaOH at 4C
overnight, and cold chemical sterilized. The fabric could also be sterilized
(dry) by gamma irradiation or ethylene oxide.
In this study, collagen fabric was examined for its ability to close a full-
. 3 5 thickness ~h ~omin~l excision in a rat model. A 2 cm x 2 cm full-thickness
abdominal wall defect was created in each of 5 Sprague-Dawley rats. A 2.5 cm
l3
wo ss/2s~82 2 1 8 3 9 ~ 2 r.l~u~,s~o~4ss
x 2.5 cm piece of collagen fabric was sutured over the defect using six ~0
polypropylene, with a 0 25 cm overlap around the perimeter. Additional
continuous sutures were placed around the fabric perimeter, through the
fabric and muscle. At timepoints of 3 weeks and 12 weeks, the animals were
S ~y~mined for herniation and m~(~h:lnit-~l stability of the implant. The
implants, along with a margin of surrounding tissue, were then removed and
fixed for hi~tnlo~ir~l processing as described below The area of the repair was
assessed by tracing the perimeter of the wound.
All animals were healthy for the duration of the experiment. No
abdominal hf~rni~ion was observed up to 12 weeks postimplantation. On
visual inspection at 3 weeks, the fabric was a dark-pink color, s--~Pcting good
neov~ ri7~til-n Blood supply to the tissue within the fabric was provided
from a single small projection of the omen-turn (about 2 mm wide) to the
underside of the fabric. No visceral adhesions were noted. Histology at 3
weeks showed a vigorous cellular infiltrate, with numerous fibroblasts and
some macrophages. Abundant matrix deposition could be seen in the
inti~rctiC~c of the fabric.
This fabric has high bulk and thickness with low eY~ncihility, and
would be useful for space-filling applications with moderate load-bearing
2 0 requirements. Further, several layers of 3-dime~lsional fabric could be thus
joined to provide compound fabric of any thickness desired.
EXAMPLE 2
rl ' of a Menisci Repair Device for Knees
2 5 When the knee bends, the menisci stretch to accommodate the
movement. When the knee bends and twists, the menisci may UV~l:,Ll~
and tear. The medial meniscus is especially vulnerable to tearing because it is
anchored to the tibial collateral ligament, and so has less mobility than the
lateral m~nic~lc The lateral or medial meniscus can be repaired using the
3 0 meniSci repair device of this invention.
To form the menisci repair device, the knitted fabric described in
Example 1 above, is rolled by laying the fabric on a flat surface, and taking the
length of one side of the fabric and rolling it end over end. The fabric is rolled
to approximate the overall length and diameter of meniscus to be repaired.
3 5 The rolled menisci repair device is then curled to conform to the original
contours of the meniscus. 14
,
WO 95/25~82 2 1 8 3 9 6 2 PCTIUS95103455
The rolled menisci repair device is then crosslinked with standard
techniques using 50mM l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (EDC) for 8 hours in 90% acetone, then rinsing exhaustively
with water. Before imrl:~nt~finn, the device is depyrogenated by soaking in
0.1M NaOH overnight at 4C, and sterilized by room temperature ethylene
oxide (EtO) treatment.
The device is implanted into the lateral or medial, or both, meniscus
surrounding the kneecap.
I O EXAMPLE 3
Formation of Tubular Structures for Bone Repair
Fabric constructs with hollow structures are also produced by direct
tubular knitting. The yarn described in Example 1 above is Raschel knitted
with two needle bars into a tube using the following pattern:
. Front bar: 1-0/1-2
Back bar: 1-2/1-0
A tubular fabric has its inner and outer diameter llimPncinns, mP~h~ni~l
strength and porosity ciP~prminpd by the specific knitting design employed. If
necessary, nesting structures of ~lu~ iv~ly larger diameters may be joined
2 0 to provide a hollow tube of any wall desired wall thickness. The center of the
cylinder may be filled with collagen in any form, for example, a parallel
bundle of collagen threads formed as described above, a paste of homogenized
collagen fibers, a collagen gel. Any of the elements of the structure may be
coated with various agents such as bone morphogenic proteins to stimulate
2 5 bone repair. A knitted device may be attached over either end of non-union
fracture in order to stimulate bone repair.
EXAMPLE 4
r~ ~in- of a Braided Tubular Structure for Bone Repair
3 0 A tubular structure may be formed from more than one coaxial layer of
braided collagen such that the outer diameter of the braid matched that of the
bone to be repaired. The braid may be hollow or completely filled with
braided material. If a hollow braid was used, the center of the cylinder may be
filled with collagen in any form, for example, with a parallel bundle of
. 3 5 collagen threads formed as described above; a paste of homogenized collagen
fibers; a collagen gel; and the like Any of the elements of the structure may
WO 9512548~ 2 1 8 3 9 ~ 2 PCT/US95/03455
be coated with various agents, such as bone morphogenic proteins to
stimulate bone repair. A braided medical device formed in this fashion may
be attached over either end of a non-union fracture to stimulate bone repair.
S EXAMPLE 5
r~ - ~ of a Woven Fabric for Filling a Deep DerJnal Wound
1. Collagen threads formed from any of the threads described above
in the description may be used to weave the fabric.
2. Threads are woven by loading sets of bobbins with collagen
thread. One set supplies the warp (lengthwise) yarns. These will be stationary
during the weaving process. A hamess suspends the vertical yams at oblique
angles (some from above and some from below). Two A~lriitinnAI sets of yarns
are used: "filling yarns" which are inserted from the side by two hnri7nntAI
sets of needles and "selvage yarns" inserted from below by a pair of vertical
I S needles. Two knitting needles are also positioned so that they can knit loops
of selvage yarn together at the corners of the woven structure. To weave the
structure the filling needles move between layers of warp and vertical yarns
to inset the filling yarns in a crosswise direction. Before these needles retract,
the vertical selvage needles move up to catch the filling; a horizontal bar in
2 0 turn catches the selvage yams at the top. The filling needles then retract and
a pair of knitting needles clasps the selvage yarns to allow the cross bar to also
retract. The reed which is a comblike device positioned in front of the
harness then moves horizontally to pack the yarns into their final
configuration. While this occurs, the vertical yarns are pushed *om their
2 5 diagonal position into a vertical Ali~nmPnt At the end of each knitting cycle,
the knitting needles pass the new loop of selvage yarn through the previous
one and the harnesses switch to reverse the position of the vertical yarns for
the next cycle.
3 0 Although the foregoing invention has been described in some detail by
way of illustration and example for purposes of clarity of understanding, it
will be obvious that certain changes and modifications may be practiced
within the scope of the appended claims.
I 6
