Ex Parte Kladakis et al

Patent Trial and Appeal Board

Aug 18, 2017

10775034 (P.T.A.B. Aug. 18, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/775,034 02/09/2004 Stephanie M. Kladakis 47062-019F01US
(MIT5032US
6915
30623 7590 08/22/2017
Mint7 T evin/Rns;tnn Office
EXAMINER
One Financial Center
Boston, MA 02111
PELLEGRINO, BRIAN E
ART UNIT PAPER NUMBER
3738
NOTIFICATION DATE DELIVERY MODE
08/22/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEPHANIE M. KLADAKIS, SRIDEVI DHANARAJ, and
ROBERT BOOCK
Appeal 2015-0025681
Application 10/775,034
Technology Center 3700
Before RICHARD M. LEBOVITZ, JOHN G. NEW, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to composite implants for
repairing a tissue defect in a patient and methods of making them. The
Examiner rejected the claims as anticipated under 35 U.S.C. § 102 and under
35 U.S.C. § 103 as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
1 The Appeal Brief (“Appeal Br.”) lists Depuy Mitek, Inc. as the real-party-
in-interest.
Appeal 2015-002568
Application 10/775,034
The rejections are reversed. New grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b) are entered.
STATEMENT OF THE CASE
The Examiner rejected the claims as follows:
Claims 1, 3-6, 9, 10, 13-18, 20, 21, 2A-28, 30, 31, 34—39, 42, 43, 46-
49, 52, and 53 under 35 U.S.C. § 102(b) as anticipated by WO 03/007784
A2, publ. Jan. 30, 2003 (“Malaviya”); and
Claims 44, 45, 50, and 51 under 35 U.S.C. § 103(a) as obvious in
view of Malaviya.
Claim 1, which is representative of the appealed subject matter, is
reproduced below (indentations added for clarity):
1. A composite implant for repairing a tissue defect in a
patient, comprising
a wedge-shaped porous tissue scaffold formed from a
bioresorbable, synthetic polymeric material and including at
least one pocket containing finely minced fragments of viable
tissue,
the viable tissue comprising naturally occurring cells and
their extracellular matrix, and
the naturally occurring cells and their extracellular matrix
being native to the viable tissue.
CLAIM INTERPRETATION
Native
The meaning of the term “native” as recited in the phrase
“extracellular matrix being native to the viable tissue” is at issue in this
appeal. The Examiner interpreted the term to require only that the matrix be
“natural.” Final Act. 3. As explained below, we do not agree that this
construction is the broadest reasonable interpretation of “native” as this term
is recited in the claims.
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Claim 1 requires a composite implant “including at least one pocket
containing finely minced fragments of viable tissue.” The viable tissue
“comprising naturally occurring cells and their extracellular matrix.”
Because the claim requires the tissue to be minced and to comprise “cells”
and “their” extracellular matrix (“ECM”), the most reasonable meaning is
that the extracellular matrix is present in the finely minced fragments of
viable tissue and belongs to the cells (“their”), e.g., the matrix is produced
by the cells.
The claim further recites that “their extracellular matrix being native
to the viable tissue.” This language was added in an amendment filed June
11, 2010 in response to the Examiner’s statement in an interview that the
claim was a product-by-process claim. Amendment 10-11 (June 11, 2010).
In response, Appellants deleted “wherein the viable tissue is minced to form
finely minced tissue fragments” and replaced it with “the naturally occurring
cells and their extracellular matrix being native to the viable tissue” to
clarify that the tissue is not defined how it is made. In other words,
Appellants amended the claim to clarify it is not a product-by-process claim,
but rather the tissue is defined by its structure, i.e., the matrix is “native” to
the cells and from the same source as the cells. Id. Because the claim
already requires that the extracellular matrix belongs to the cells, the
broadest reasonable interpretation of “native”, and the interpretation that is
consistent with the claim, is that the term “native” indicates that the cells and
matrix are from the same source, namely, the viable tissue. Thus, we do not
adopt the interpretation of “native” advanced by the Examiner.
Independent claims 13, 24, and 34 use the term “native” in the same
way as in claim 1.
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Application 10/775,034
Viable
The claims require the tissue comprising the cells and matrix to be
“viable.” The Specification discloses that the viable tissue “should be
effective to migrate into the scaffold to integrate with native tissue
surrounding the scaffold.” Spec. 17. The viable tissue is also described as
being capable of “cell growth.” Id. at || 7, 8. The Specification further
describes examples in which “Cellular migration and new matrix formation
of bovine minced meniscal tissue (BMT) into a small intestine submucosa
(SIS) tissue scaffold” is observed. Id. at | 83. The “cells” migrated into the
implant. Id. at | 85. Thus, we interpret “viable tissue” to mean tissue that
comprises cells capable of migration and growth.
Extracellular matrix
The Specification discloses that ‘“naturally occurring extracellular
matrix’ . . . can refer to extracellular matrix material that has been cleaned,
disinfected, sterilized, and optionally cross-linked.” Id. at 144. The
Specification also teaches that “ECM is preferably small intestine
submucosa (‘SIS’)” which can be derived from mammals, such as pigs. Id.
at 143.
NEW GROUNDS OF REJECTION
We reverse the rejection of the claims as anticipated by Malaviya
because it was based on an improper interpretation of the claims. The
obviousness rejection of the dependent claims is also reversed for the same
reason.
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Application 10/775,034
The following new grounds of rejection are made pursuant to 37
C.F.R. 141.50(b).
Claims 1, 13, 24, and 34 under pre-AIA 35 U.S.C. § 103(a) as obvious
in view of Malaviya.
Claims 1, 13, 24, and 34 under pre-AIA 35 U.S.C. § 103(a) as obvious
in view of Malaviya andU.S. Pat. No. 5,837,235, iss. Nov. 17, 1996
(“Mueller”).
We leave it to the Examiner to determine whether the dependent
claims are patentable.
FINDINGS OF FACT (“FF”)
Malaviya
Malaviya contains the following pertinent teachings:
FF1.
In some embodiments, the device for regenerating a
meniscus or a portion thereof comprises a wedge-shaped
biological scaffold material body having an apex portion and a
base portion spaced radially outwardly from the apex portion.
Malaviya 7:15—17; see also id. at 8:8—15 (“For example, a device for
regenerating a meniscus or a portion thereof may comprise a wedge-shaped
body having radially extending or circumferentially extending compartments
or channels into which the comminuted ECM is placed.”)
FF2
Figure 33 shows a device with a “plurality of triangular recesses”
(element 288) which are wedged-shaped. 24:28—29; 37:3—15.
The recess “may be filled with a mass of biological material such
as ECM, or with combinations of ECM and bioactive agents,
biologically derived agents or cells.” 37:13—15
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FF3
This body, which may be fabricated from sheets or strips of
naturally occurring ECM, is formed to provide a plurality of
channels or compartments disposed between the upper and
lower surfaces.
Id. at 7:20-22.
FF4. “It is also known to use naturally occurring extracellular
matrices (ECMs) to provide a scaffold for tissue repair and regeneration.
One such ECM is small intestine submucosa (SIS).” 2:4—6. “Thus, while
reference is made to SIS, it is understood that other naturally occurring
ECMs are within the scope of this invention.” 3:23—25.
FF5
These channels or compartments may be filled with comminuted
naturally occurring ECMs to provide a framework for meniscus
regeneration. In some embodiments, the comminuted ECM will
be mixed with or replaced by bioactive agents, biologically
derived agents, cells, biological lubricants, biocompatible
inorganic materials, biocompatible polymers and/or
combinations thereof.
Id. at 7:32-8:4.
FF6
A mass comprising comminuted naturally occurring ECM is
disposed in the space. In various embodiments, the mass may
also comprise bioactive agents, biologically derived agents,
cells, biological lubricants, biocompatible inorganic materials,
biocompatible polymers and/or some combination thereof mixed
with the comminuted ECM.
Id. at 4:27-31.
FF7
In this specification and claims, unless otherwise expressly
limited, “mass of biological material” is intended to include
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naturally occurring extracellular matrix, bioactive agents, and/or
biologically derived agents and cells. “Mass of biological
material” is also intended to include biological materials formed
in whole or in part from such matrices, agents and cells.
Id. at 11:15-19.
FF8
In the specification and claims, “comminuted” is intended to
mean reduced to pieces. “Piece” and “pieces” are intended to
mean any fiber, strip, ribbon, sliver, filament, shred, bit,
fragment, part, flake, slice, cut, chunk, or other portion of solid
or solid-like material. “Comminuted” is not intended to imply
any particular means of producing the pieces. No particular shape
is intended to be implied by the use of the word “comminuted”
unless otherwise expressly limited; the pieces can comprise a
variety of two and three dimensional shapes of material.
Moreover, unless a specific size of material is specified, the use
of the term “comminuted” is not intended to imply any particular
size of pieces.
Id. at 12:19-27.
FF9
“Biologically derived agents” include one or more of the
following: bone (autograft, allograft, and xenograft) and
derivates [sic, derivatives?] of bone; cartilage (autograft,
allograft, and xenograft), including, for example, meniscal
tissue, and derivatives; ligament (autograft, allograft, and
xenograft) and derivatives; derivatives of intestinal tissue
(autograft, allograft, and xenograft), including for example
submucosa; derivatives of stomach tissue (autograft, allograft,
and xenograft), including for example submucosa; derivatives of
bladder tissue (autograft, allograft, and xenograft), including for
example submucosa; derivatives of alimentary tissue (autograft,
allograft, and xenograft), including for example submucosa;
derivatives of respiratory tissue (autograft, allograft, and
xenograft), including for example submucosa; derivatives of
genital tissue (autograft, allograft, and xenograft), including for
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example submucosa; derivatives of liver tissue (autograft,
allograft, and xenograft), including for example liver basement
membrane; derivatives of skin (autograft, allograft, and
xenograft);
Id. at 13: 13-26.
FF10
“Cells” include one or more of the following: chondrocytes;
fibrochondrocytes; osteocytes; osteoblasts; osteoclasts;
synoviocytes; bone marrow cells; mesenchymal cells; stromal
cells; stem cells; embryonic stem cells; precursor cells derived
from adipose tissue; peripheral blood progenitor cells; stem cells
isolated from adult tissue; genetically transformed cells; a
combination of chondrocytes and other cells; a combination of
osteocytes and other cells; a combination of synoviocytes and
other cells; a combination of bone marrow cells and other cells;
a combination of mesenchymal cells and other cells; a
combination of stromal cells and other cells; a combination of
stem cells and other cells; a combination of embryonic stem cells
and other cells; a combination of precursor cells isolated from
adult tissue and other cells; a combination of peripheral blood
progenitor cells and other cells; a combination of stem cells
isolated from adult tissue and other cells
Id. at 14:13-24.
FF11. Malaviya teaches that scaffold can comprise a biocompatible
polymers (44:3—17; 4:32—33) which includes bioresorbable materials
(15:22-31).
Mueller
Mueller contains the following pertinent teachings:
FF12. Mueller teaches a material for regenerating bone and cartilage.
Mueller, Abstract.
FF13. The material can comprise comminuted fatty tissue which is
implanted with a carrier. Id.
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FF14.
According to the invention the omentum, or other fatty tissue
taken from the patient, is comminuted to small particles, said
tissue particles are suspended in a carrier to form a suspension,
the tissue particles from the suspension are applied, e.g. by
filtering, to a carrier material suitable for treating the damage and
the remaining suspension is separated.
Id. at col. 2:45—51.
FF15.
The tissue particles are produced by mechanical comminution of
the tissue material removed and, if necessary, by a following
enzymatic digestion. Through a corresponding mechanical
comminution it is ensured that the resulting tissue particles have
a close size distribution. The action in the case of enzymatic
decomposition produces a more regular and more homogeneous
product.
Id. at col. 4,11. 1—8.
FF16
The size of the tissue fractions to be mechanically comminuted
is limited by the size of the comminuting apparatus to be used
and typical entry sizes are 3x3x2 cm, 5x5x2 cm, or, expressed by
weight, 20 to approximately 50 g pieces. These pieces are to be
comminuted to small rods, disks or cubes with sizes of a few
millimeters, preferably 1 to 3 mm. If subsequent digestion is not
implemented, comminution is preferably to 0.5 to 1 mm
particles.
Id. at col. 5,11. 34^41.
FF17. Mueller teaches that smaller particle sizes can be obtained by
subsequent enzymatic digestion and separation by screens with a desired
mesh sizes and spacing. Id. at col. 5,1. 42 to col. 7,1. 3.
FF18. Mueller discloses that the tissues comprise extracellular
matrix. Id. at col. 4,11. 30-39.
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OBVIOUSNESS
Malaviya
As found by the Examiner, Malaviya describes “a wedge-shaped
biological scaffold material body,” meeting the claimed limitation of the
“wedge-shaped porous tissue scaffold.” FF1. The scaffold has “at least one
pocket,” as claimed, which is filled with a mass of biological materials.
FF1-FF5.
Appellants attempt to distinguish the claimed scaffold from Malaviya
by arguing that the Malaviya material is not “formed from the bioresorbable,
synthetic polymeric material,” as recited in the claims. Reply Br. 5. This
argument is not persuasive since Malaviya discloses that the scaffold, in
addition to ECM (FF3) can comprise biocompatible polymers, including
polymers which are bioresorbable (FF11).
Malaviya describes filling the compartments in the device with
comminuted ECM. FF5, FF6. Appellants contend that such disclosure does
not meet the limitation of “finely minced” as recited in the claims. Appeal
Br. 5—6. However, as discussed by the Examiner, there is no size range
indicated by the term “comminuted” in the independent claims and Malaviya
has a broad disclosure on various forms of comminuted pieces (FF8) (e.g.,
“sliver”, “bit”, “flake”, and “chunk”). Appellants did not provide adequate
reason as to why such sizes do not meet the limitation of finely minced.
Malaviya discloses that the comminuted ECM can be combined with
other biological agents, such as cells and tissues, to form a mass of
biological material. FF5—FF7, FF9. While there is no explicit disclosure
that the biological agents are comminuted, Malaviya discloses that the
biological agents include tissues that comprise submucosa tissue (FF9), the
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Application 10/775,034
latter which contains ECM (FF4). Consequently, one of ordinary skill in the
art would have had reason to comminute the tissue because it contains ECM,
and Malaviya describes the advantages of comminuted ECM. The
comminuted tissue (FF9) would contain cells and their associated ECM, and
therefore meet the recited limitation of the “extracellular matrix being native
to the viable tissue.”
For the foregoing reason, we conclude that claim 1 is obvious in view
of Malaviya. Claims 13, 24, and 24 contain the same limitations and are
obvious in view of Malaviya for the same reasons.
Rejection based on Malaviya and Mueller
Mueller teaches a tissue regeneration material that comprises
comminuted tissue that is formed of tissue particles. FF12—FF15. Mueller
discloses preferred sizes. FF16. The preferred sizes range from 0.5 to 3
mm. FF16. The particle sizes are not specified in the independent claims.
The Specification does not define the range of sizes for the “finely minced
tissue.” Consequently, we find the range of sizes disclosed in Mueller either
meet the limitation of “finely minced tissue” or render it obvious since
Mueller teaches the a desired size can be selected utilizing a different
comminuting apparatus, enzymatic digestion, and separation with mesh
screens of desired size and spacing. FF17.
It would have been obvious to one of ordinary skill in the art to have
comminuted the tissue described in Malaviya (FF9, FF10) to form tissue
particles because Mueller teaches that such tissue particles are useful in
forming tissue regeneration materials (FF14) and Malaviya is a tissue
regeneration material (FF1). Such comminuted tissue would comprise
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Application 10/775,034
extracellular matrix because several of the tissues disclosed in Malaviya
comprise it (FF9, e.g., submucosa (see FF4 teaching that submucosa
comprises ECM)).
For the foregoing reasons, we conclude that claim 1 is obvious in
view of Malaviya and Mueller. Claims 13, 24, and 24 contain the same
limitations and are obvious in view of Malaviya and Mueller for the same
reasons.
TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review.”
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating to
the claims so rejected, or both, and have the matter reconsidered
by the examiner, in which event the prosecution will be
remanded to the examiner. The new ground of rejection is
binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the opinion
of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the claims,
appellant may again appeal to the Board pursuant to this subpart.
(2) Request rehearing. Request that the proceeding be
reheard under §41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
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Application 10/775,034
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the MPEP § 1214.01.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv). See
37 C.F.R. §§ 41.50(f), 41.52(b).
REVERSED; 37 C.F.R, $ 41.50(b)
13
Application/Control No. Applicant(s)/Patent Under Patent
Notice of References Cited 10/775,034
Appeal No.
2015-002568
Examiner Art Unit
3738 Page 1 of 1
U.S. PATENT DOCUMENTS
7C Document Number
Country Code-Number-Kind Code
Date
MM-YYYY Name Classification
A US- 5,837,235 11-1998 Mueller et al.
B US-
C US-
D US-
E c GO
F US-
G US-
H US-
i US-
J US-
K US-
L US-
M c GO
FOREIGN PATENT DOCUMENTS
* Document Number
Country Code-Number-Kind Code
Dste
MM-YYYY Country Name Classiti cation
N
O
P
Q
R
S
T
NON- PATE NT DOC U M ENTS
* include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages)
U
V
w
X
*.A copy of this reference is not being furnished with this Office action. (See [ViPEP § 707.05(a).)
Dates in MM-YYYY forma! are publication dates. Classifications may be US or foreign.
tJ.S. Patent and Trademark Office
PTO-892 (Rev. 01-2001) Nolice o? References Cited Part of Paper No.
US005837235A
United States Patent [w]
Mueller et al.
[ii] Patent Number: 5,837,235
[45] Date of Patent: Nov. 17, 1998
[54] PROCESS FOR REGENERATING BONE AND 4,609,551 9/1986 Coplan et al................................ 424/95
CARTILAGE 5,041,138 8/1991 Vacanti et al............................... 623/16
[75] Inventors: Werner Mueller, Wiesendangen;
Thomas Thaler, Zurich, both of
Switzerland
[73] Assignee: Sulzer Medizinaltechnik AG,
Winterthur, Switzerland
[21]
[22]
[86]
[87]
Appl. No.: 602,833
PCT Filed: Jul. 6, 1995
PCT No.: PCT/CH95/00158
§ 371 Date: May 9, 1996
§ 102(e) Date: May 9, 1996
PCT Pub. No.: WO96/01641
PCT Pub. Date: Jan. 25, 1996
[30] Foreign Application Priority Data
Jul. 8, 1994 [CH] Switzerland ............................ 2190/94
[51] Int. Cl.6 ........................... C12N 5/06; C12N 5/08;
C12N 11/02; C12N 11/08
[52] U.S. Cl......................... 424/93.7; 424/422; 424/520;
435/176; 435/177; 435/180; 435/395; 435/396;
435/402
[58] Field of Search ............................... 424/93.7, 520;
435/174, 176, 177, 180, 182, 240.2, 240.23,
395, 396, 402
[56] References Cited
U.S. PATENT DOCUMENTS
FOREIGN PATENT DOCUMENTS
0 570 331 Al 11/1993 European Pat. Off. .
WO86/01111 2/1986 WIPO .
WO 87/03812 7/1987 WIPO .
Primary Examiner—David M. Naff
Attorney, Agent, or Firm—Lowe Hauptman Gopstein
Gilman & Berner
[57] ABSTRACT
Bone and cartilage are regenerated in a patient by a process
of removing fatty tissue such as omentum tissue from a
patient, comminuting the tissue to form small tissue
particles, suspending the particles in a liquid to form a
suspension, depositing the suspension on a solid carrier to
prepare a solid implanting material, implanting the implant­
ing material in a patient in an environment favoring bone or
cartilage formation, and regenerating bone or cartilage in the
patient. The carrier can be demineralized bone, collagen,
mineral material or synthetic polymer material in
pulverulent, textile, porous particle or monolith form. A cell
adhesion agent may be applied to the carrier or added to the
suspension, and a growth factor may be deposited on the
carrier. Comminuting is performed by digesting with an
enzyme and/by mechanically comminuting. Liquid used to
form the suspension may contain a gel precursor which is
gelled after the suspension is deposited to the carrier.
Preferably, the implanting material is implanted within
about 1 hour of removing the fatty tissue from the patient.
26 Claims, 1 Drawing Sheet4,458,678 7/1984 Yannas et al. 128/155
U.S. Patent Nov. 17, 1998 5,837,235
5,837,235
1
PROCESS FOR REGENERATING BONE AND
CARTILAGE
This application is a 371 of PCT/CH95/00158, filed Jul.
6, 1995.
The invention relates to a process for producing implant
materials with bone-regenerating and/or cartilage­
regenerating characteristics.
BACKGROUND OF THE INVENTION
The healing of bone regression, such as can e.g. occur in
connection with artificial prostheses, or the healing or treat­
ment of serious bone damage caused by accidents can,
according to the prior art, be brought about or improved/
accelerated at the damaged points by inplantation of
endogenic material, e.g. in the form of a mixture of ground
bone material and blood. As a result of the vital osteoblasts
present in the implanted bone material a regeneration of
bone material is initiated or assisted at the damaged point.
Such bone material autotransplantations are admittedly very
complicated, but offer the best prospects to bring about
healing and cure in very difficult cases.
The difficulties encountered in the autotransplantation of
bone material are in particular that the removal of the
material, e.g. from the iliac crest, represents a relatively
serious operation and that the removable quantity, particu­
larly in children is very small. As a result of these
difficulties, autotransplantation of bone material as the
method with the highest healing chances is only used in the
most serious cases.
In order to overcome the problem of the quantitative
availability of endogenic bone material, it has therefore been
proposed to remove it from the patient and subsequently
reproduce or propagate the osteoblasts contained therein in
vitro (A. I. Caplan, J. Orthop, Res. 9, 641-650, 1991). M. J.
Doherty et al. (Bone and Mineral 25, Suppl. 1, p 9, 1994)
have shown on rats that in bone damage areas implanted,
demineralized bone material, which was coated beforehand
with in vitro propagated osteoblasts of rats, improved the
healing of bone damage and in fact did so more than
implanted, demineralized bone material without such a
coating, which although assisting bone regeneration, can
clearly not initiate the latter. The difference in the results of
the two healing attempts was that when using demineralized
bone material alone, there was only a bone growth from the
edges of the damage, i.e. from the living, damaged bone,
whereas when using coated bone material it started directly
on the latter, i.e. from the centre of the damage. In many
cases of treatment with only demineralized bone material
radioulnar coalescence was observed, but this did not occur
in the case of treatment with coated material.
Similar healing improvements were obtained by
Shigeyukui Wakitani et al. (The Journal of Bone and Joint
Surgery, vol. 76-A, No. 4, April 1994, pp 579 to 592), who
used a collagen gel for the treatment of defects in stressed
knee joint surfaces of rabbits and into said gel was incor­
porating endogenic cells extracted from the bone marrow or
periosteum and which was cultured in vitro. It was found
that the implant material in particular assisted and improved
the regeneration of the joint cartilage, and also assisted in the
regeneration of the underlying bone. It can be gathered from
the tests described, that cells obtained from bone material
(mesenchymal cells) are able to form bone or cartilage, as a
function of the particular environment.
TTie advantage of a method in which bone material is
taken from the patient, propagated in vitro and then
2
implanted at the damaged point of a bone, compared with
the direct autotransplantation method, is that there is a much
larger quantity of vital material available for implantation
purposes. The disadvantage is that for the removal or
extraction of the material, the same difficult operation is
needed, which must be separated in time from the implant
operation by e.g. six weeks for in vitro culturing purposes.
SUMMARY OF THE INVENTION
The problem being addressed by this invention is to
provide a process for producing an implant material with
characteristics for regenerating bone and/or cartilage, with
which the aforementioned disadvantages of the known
methods are avoided and in particular to provide means to
make it possible to obviate the seriousness of the removal
operation, the low available quantity of vital material, or the
time separation between the bone matter removal operation
and the implant operation.
Thus, using the process according to the invention it is to
be possible to produce, from endogenic material taken from
the patient in an easily performable removal operation
immediately preceding the implant operation, an implant
material and to use it at the damaged point in an implant
operation directly following the removal operation. When
using the implant material produced according to the process
of the invention the healing chances are significantly better
than when implanting purely artificial (not-vital) materials.
The technical problem is to process a suitable endogenic
material in the short time between the removal operation and
the implant operation, i.e. in approximately one hour, so as
to give a suitable implant material. The advantages resulting
from the process according to the invention and the implant
materials produced by it relate to the removal operation and
the healing chances, i.e. the activity of the surgeon and the
situation of the patient.
BRIEF DESCRIPTION OF THE DRAWING
The FIGURE shows an apparatus for producing implant
material.
DETAILED DESCRIPTION OF THE
INVENTION
According to the invention the omentum, or other fatty
tissue taken from the patient, is comminuted to small
particles, said tissue particles are suspended in a carrier to
form a suspension, the tissue particles from the suspension
are applied, e.g. by filtering, to a carrier material suitable for
treating the damage and the remaining suspension is sepa­
rated. Depending on the specific implantation application,
the carrier material can be pulverulent or gel-like and the
finished implant material can be paste-like, so that it is
suitable for use in implants that have no mechanical strength
function requirements, e.g. for the treatment of missing
bones and/or cartillage due to regression, tumor removals,
etc. However, the carrier can also be substantially preshaped
and sponge-like or porous and can e.g. comprise a ceramic
or metallic material and, as a function of the specific chosen
carrier material, can fulfil a mechanical strength function.
The aforementioned paste-like material can also be applied
to a carrier material which provides the mechanical function.
The removal or extraction of omentum or other fatty
tissue is a very simple operation. In addition, such tissue can
be removed without harmful consequences to the patient in
much larger quantities than bone material. From 1 g of fatty
tissue it is possible to isolate between 50xl03 and 200xl03
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vital cells, which is sufficient for producing approximately 1
ml of paste-like implant material or for producing a corre­
sponding volume of a porous shaped carrier.
In addition to other cells and non-cellular tissue fractions,
omentum or other fatty tissue, also contains cells suitable to
form (or produce) ossified tissue and/or cartilage. This can
be deduced from the existence of ectopic bone formations,
which under certain circumstances can occur at body points,
at which no bone marrow and no periosteum is present, these
being known to contain bone tissue and cartilage-forming
osteoblasts or mesenchymal cells (cf. hereinbefore). Thus, if
the tissue particles applied to the carrier material are
exposed to a bone or cartilage formation-favouring medium,
they will initiate a bone or cartilage formation of the same
type as would result from implanted, endogenic bone mate­
rial with osteoblasts or mesenchymal cells cultured in vitro
on a carrier material.
Frequently the environment around the point to be treated
will be sufficient for producing a corresponding medium.
Other means for producing a bone formation-favouring
medium, such as e.g. bone matrix, hydroxyapatite,
hydroxyapatite ceramic, etc. are known per se and need not
therefore be described here.
In addition to the bone and/or cartilage formation-
initiating cells, fatty tissue also contains endothelial cells,
which, after implantation, leads to a vascularization of the
bone tissue being formed, so that there is a good blood flow
through said tissue and the healing and mineralization are
positively influenced. In certain circumstances such endot­
helial cells should be removed for the regeneration of
cartilage through which there is no blood flow.
The carrier for the implant materials for bone defects can
be most of the per se known, non-vital bone implant
materials, i.e. materials having a biological origin
(demineralized bone material, collagen sponge), degradable
or non-degradable, synthetic polymers, mineral materials
such as hydroxyapatite or hydroxyapatite ceramic or metals
and, as previously stated, part of these materials also ensure
that there is a bone formation-furthering medium. For aiding
mineralization, the carrier material can also be provided with
growth factors, such as e.g. TGF|3 (Transforming Growth
Factor Beta) or BMP (Bone Morphogenetic Protein). As has
already been stated, the carrier can be pulverulent and can
give a pasty implant material or can be preshaped and when
implanted can take over the strength function of the dam­
aged bone or part thereof. For such functions use is more
particularly made of metallic gauzes and plates, e.g. of
titanium.
As implant materials for cartilage or cartilage-covered
bone surfaces are suitable carriers in the form of a sponge,
in the form of fibrils, in the form of textiles (woven fabric,
felts, etc.) or as a gel. It is possible to use as carrier materials
known materials having a biological origin (e.g. collagen)
and degradable and non-degradable, synthetic polymers.
The detailed performance of the process according to the
invention is based on the process for the production of
endoprostheses described in European patent application
93810297.7 (publication number 570331 Al) of the same
applicant. It is essentially based on the following findings:
The cells initiating a bone formation need not be isolated
from the vital tissue used for the production of the
implant material. Other cells and non-cellular tissue
fractions do not disturb the healing process. It is merely
necessary to sufficiently finely comminute the tissue to
tissue particles and suspend the same and immediately
treat the carrier therewith.
4
The tissue particles are produced by mechanical commi­
nution of the tissue material removed and, if necessary,
by a following enzymatic digestion. Through a corre­
sponding mechanical comminution it is ensured that
the resulting tissue particles have a close size distribu­
tion. The action in the case of enzymatic decomposition
produces a more regular and more homogeneous prod­
uct.
When using tissues with a very high fat content, which
could lead to fat embolisms, it is advantageous to
separate off a large proportion of the fat fraction by
allowing the suspended particles to settle and separat­
ing the fatty phases from the suspension.
The byproducts resulting from enzymatic digestion need
not necessarily be removed, for example by filtration
from the suspension before the carrier is treated there­
with. If necessary, following the incorporation of the
tissue particles, the carrier can be rinsed with a rinsing
solution for cleaning purposes and also oily-fatty frac­
tions can be rinsed out. If the carrier is gel-like, the
tissue particles are separated from the suspension and
by counterfiltration with the gelling solution, they are
received in the latter. Alternatively, the tissue particles
may be added to the gel precursor and mixed prior to
the final solidification of the gel.
Tissue particles with a very uniform size and a high vital
cell content are obtained in that the process step of mechani­
cal comminution and the process step of enzymatic digestion
are precisely matched to one another.
Of the many known enzymes for decomposition, e.g.
pancreatin, dispase, trypsin, etc., collagenase has proved to
be particularly suitable during in vitro tests. As a result of its
specific action the collagenase contributes to dissolving out
of the tissue individual cells and also small cell
combinations, without damaging to any significant extent
the vitality of the cells. If the collagenase had a 100%
specificity for the collagen of the extracellular matrix, it
could possible bring about the decomposition of the tissue
without in the slightest damaging the cells or their surface.
This is an ideal picture, because it has been found that cells
which over a long period (e.g. two hours) are exposed to the
action of proteolytic enzymes or trypsin, suffer damage to
their surface receptors and could even lose their entire
vitality. These effects are much weaker or may not even be
detectable in the case of suitable collagenase preparations.
Thus, the duration of the enzyme action must be suffi­
ciently long to split off the tissue into sufficiently small
particles and this time requirement is greatly dependent on
the size of the particles that are available. Flowever, it must
not be too long, so as not to unnecessarily reduce the vitality
of the dissolved out cells. Since, therefore, for particles of
different sizes there are no common, optimum digestion
parameters, it must be ensured by a corresponding mechani­
cal comminution of the tissue, that the tissue parts to be
digested have an optimum size for enzymatic digestion and
are therefore preferably all of roughly the same size.
According to the invention, the enzymatic digestion is
preceded by a cell-protecting, mechanical comminution, so
as to produce tissue particles which are all of about the same
size. Comminution processes are cell-protecting
(atraumatic), if the tissue is cut and not squeezed or crushed.
According to the invention this is achieved by treating the
tissue with a plurality of very sharp blades moved in a
coordinated manner.
A close, precisely defined size distribution of the tissue
particles to be digested makes it possible to determine a
clearly defined, optimized collagenase action time.
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The process according to the invention consists of the
following steps.
1. preparation of a suspension of tissue particles of
endogenic omentum or other fatty tissue,
2. (possible) separation of excessively large tissue par­
ticles and/or most of the fatty fractions,
3. (possible) intermediate storage of the suspension,
4. application of the tissue particles to the carrier by
filtering the suspension through the carrier (porous or
pulverulent carrier), by filtering with the carrier
(pulverulent carrier), filtering off and subsequent coun­
terfiltration with a gelling liquid (gel-like carrier) or
mixing with a not completely solidified gel (gel-like
carrier),
5. (possible) rinsing of the implant material consisting of
carrier material and associated tissue particles,
6. (possible) treatment of the implant material for obtain­
ing the moisture level necessary for the applied, vital
cells,
7. (possible) intermediate storage of the implant material
produced.
Steps 1 and 4 are necessary, whereas the remaining steps
may or may not be used, as a function of the implant material
to be produced.
In order to keep the traumatization of the cells as low as
possible, the removed tissue is very carefully mechanically
comminuted, in that it is treated with a large number of very
sharp blades which are moved in coordinated manner. The
aim is to obtain a very high percentage of vital cells and at
the same time a high, absolute cell yield. Despite these
conditions the comminution must take place in a relatively
short time, e.g. 1 to 3 minutes/100 g of tissue mass.
The size of the tissue fractions to be mechanically com­
minuted is limited by the size of the comminuting apparatus
to be used and typical entry sizes are 3x3x2 cm, 5x5x2 cm
or, expressed by weight, 20 to approximately 50 g pieces.
These pieces are to be comminuted to small rods, disks or
cubes with sizes of a few millimeters, preferably 1 to 3 mm.
If subsequent digestion is not implemented, comminution is
preferably to 0.5 to 1 mm particles.
Subsequently the mechanically comminuted tissue may
be enzymatically decomposed, e.g. with collagenase, in
order to at least partly free the cells from the connective
tissue and consequently further comminute the tissue par­
ticles. The collagen and elastic fractions of the connective
tissue are decomposed, so that the cells are freed, but
damaged to a minimum extent (minimum decomposition of
constituents of the cell surface). The enzymatic decompo­
sition must also take place as rapidly and carefully as
possible, which is controlled by means of the temperature
and enzyme concentration. A thorough mixing of the phases
is brought about by movement and this additionally speeds
up decomposition.
Various such procedures for the treatment of living cells
are known and can be correspondingly applied. It has
surprisingly been found that stirring with a magnetic stirrer
is more efficient than shaking the complete reaction vessel.
The magnetic stirrer rods can appropriately be members
having no sharp edges and preferably rounded rods, because
they prevent a rolling up of the tissue. The stirrer is freely
suspended or has only a minimum bottom contact, so that a
grinding of the suspended cellular material is prevented.
It is e.g. possible to use collagenase for decomposition
and a recommended concentration is approximately 400 to
20,000 Mandl-U/ml, typically 750 to 3,000 U/ml, the tem­
perature being at least 37° C., but not exceeding 40° C. and
6
preferably 37° to 38° C. and the tissue to enzyme solution
volume ratio is 1:1 to 1:2.
Following decomposition the suspension can be separated
for partial purification. This part of the process must also be
rapidly performed, because the material involved has a
relatively high metabolic activity under the processing
temperatures, as opposed to the processing of cooled tissue
materials. In addition, a rapidly performable process is
sought for medical reasons. A purification of the suspension
with a view to bringing about a quantitative separation of the
enzymes used or the separation of cells other than those
desired for bone and/or cartilage formation is, as has already
been stated, unnecessary for most applications.
Apartial separation of the suspension for removing exces­
sively large particles or part of the fat-containing fractions
can be advantageous. This can be performed either utilizing
the specific weight (allowing the suspended particles to
settle and separating the lighter phase) and/or the size of the
aggregates (filtration). Both separating methods will be
briefly discussed hereinafter.
Firstly specific weight-based separation (allowing the
suspended particles to settle and separating the layers): in
the case of fatty tissues, there is a relatively rapid upward
floating of particles of the suspension which have a suffi­
ciently large fat fraction. Contrary to the prevailing opinion
there is no need for forced sedimentation by centrifuging
and instead sedimentation in the gravitational field is suffi­
cient. This leads to the advantage that sedimentation can be
carried out in a closed, static system.
Sedimentation can be accelerated, e.g. by a suitable
choice of the depth of the sedimentation vessel, by diluting
the suspension at the end of enzymatic decomposition and/or
by other appropriate measures. For example, the suspension
to be sedimented is diluted with a buffer solution to 1.5 to
10 times, preferably 1.5 to 2 times the volume, e.g. 300 g of
tissue+300 ml of enzyme solution=suspension for digestion
(decomposition), which for sedimentation is topped up to
1000 ml (corresponding to a 1.67 times dilution). In a 15 cm
high, 10 cm diameter, cylindrical vessel, sedimentation for
such volumes lasts 1 to 15 and preferably 3 to 10 minutes.
After this time there is a clear boundary between the aqueous
and the oily phase. Sedimentation can be further assisted by
slow stirring using a magnetic stirrer, because as a result the
lighter constituents enclosed in the sediment can be released
and because, particularly in the case of dense suspensions
(collagenase:tissue=l:l), the separation of tissue particles on
the basis of their specific weight is aided by additional, weak
movement.
Sedimentation and separation of the resulting layers is
preferably performed immediately following enzymatic
digestion, preferably in the same vessel and at 20° to 40° C.,
but preferably at 30° to 37° C. for fatty tissue.
It can be advantageous to separate excessively large
particles. To improve the cell yield and prevent clogging, in
the case of larger material quantities (as from 50 g of tissue)
multistage screens are recommended. Up to 300 g of tissue,
e.g. 3 stages, the diameter of the screens being 4 to 6 cm and
the spacing between two screens 2 to 6 cm. For the final
screen a mesh size of 0.5 to 1 mm is to be chosen for
maximum particle dimensions of 0.25 mm. This means that
the entire mass of the fraction left behind does not increas­
ingly burden a single screen layer, so that an increasing flow
resistance is formed and in particular the screening effect is
drastically modified, so that with increasing charging the
size of the particles passing through decreases, so that there
are considerable cellular material losses. Flowever, in the
case of multistage screens the total quantity, number and
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mesh size of the screens used are correspondingly distrib­
uted and the flow resistance and screening effect are much
less influenced.
The screens are preferably horizontally superimposed, in
order to be able to carry out filtration by gravity, which
permits a more uniform screen charging and therefore a
clearly defined filtration. In addition, with such an arrange­
ment less equipment is needed, which also assists in con­
nection with the strict sterility requirements.
However, filtration by pump transport or transfer is also
possible, where essentially the same criteria must be
respected. However, a pump transport has in particular the
advantage that it permits filtration counter to gravity, which
allows an air bubble-free liquid transfer in a simple manner,
which is important for the subsequent carrier material treat­
ment.
The pumps used are flow inducers, preferably those with
2-roll heads. It has surprisingly been found that this only
causes insignificant vital cell losses. In simple manner the
use of such pumps permits a controlled process, which is not
merely just subject to gravity, in a closed system, which is
not only clinically significant with respect to sterility, but is
also important for the time-controlled performance of the
process.
Dissolved components of the suspension, such as
collagenase, which are used for enzymatic decomposition,
and liquid components, such as oily fat from the tissue are,
if only a size-based separation is carried out, subsequently
removed during or after the treatment of the carrier material.
Subsequently the suspension is filtered through the pul­
verulent or porous and preshaped and, if necessary, corre­
spondingly moistened carrier material. If it is a pulverulent
carrier material, it can also be added to the suspension and
filtered together therewith through a suitable filter or can be
at least partly separated from the suspension solution by
allowing it to settle. It may also be advantageous in such a
case to add to the suspension a cell adhesion-aiding medium,
such as e.g. fibronectin.
In the case of a gel-like carrier the suspension is filtered
through a correspondingly fine filter and consequently the
tissue particles are separated from the suspension solution.
Immediately thereafter and in the opposite direction, a
gelling liquid (e.g. cold, neutralized collagen solution) is
pressed through the filter and consequently the tissue par­
ticles are taken up in the liquid, which is subsequently left
to stand for gelling.
In order to satisfy the high sterility requirements of the
process, the suspension must be kept in a closed system
throughout the entire process, preferably including applica­
tion to the carrier material and said closed system also
contains the carrier. This is made possible e.g. by providing
tube connections between the digestion vessel and the
coating module, with which the incorporation of the cellular
material in the carrier material is brought about. The liquid
transfer can take place by gravity (different heights in the
arrangement of the equipment) or by means of flow
inducers, roller pumps or other positive displacement
pumps, preferably those where the suspension only comes
into contact with disposable parts. In the following example,
for liquid delivery for the application of the cellular material
to a carrier material, use is made of a Watson pump with 2
rolls having a silicone tube with an approximate diameter of
8 mm and which has no slip. It has been found that the
number of vital cells in the suspension is not significantly
reduced even by pumping five times.
In order that the cell vitality of the implant material
produced is maintained up to the time of use, as the final
8
stage of the process the cells can be specially protected up
to wound closure. Thus, the vital cells are more particularly
protected against drying.
Now, with the aid of the drawing, a discussion will take
place of an example of a closed apparatus for performing the
process according to the invention. The individual equip­
ment components are in part those which are already com­
mercially available. The interconnection of this equipment
in accordance with the presently described, novel, com­
pressed and surprisingly biologically effective process rep­
resents the process sequence according to the invention and
consequently constitutes an apparatus for producing implant
materials. The apparatus can be such that it can also be used
in an operating theatre and permits the production of the
implant material according to the invention in situ.
In a diagrammatically simplified manner the drawing
shows a completely sealable apparatus, in which the entire
process can be performed in a continuous, closed vessel and
tube system. It can easily be placed on a movable or portable
chassis or frame and in this way is mobile for use e.g. in the
laboratory or operating theatre. The compact, closed nature
naturally does not exclude feedlines for the solution,
reagents and tissue to be processed. However, the closed
nature of the apparatus is intended to illustrate how the strict
sterility requirements can be met.
A first unit comprises the equipment for mechanical
comminution, a drive 1, a conveyor 3, which is directed
towards a knife/perforated plate pair 5, 7, and for the
decomposition of the tissue material for freeing the cells a
digestion cell 9 with a stirrer 10 for assisting decomposition
and a first sedimentation. The equipment can be interlinked
so that the comminuted tissue mass drops directly from the
perforated plate 7 into the digestion vessel. At the end of
digestion sedimentation the separation of the oily-fatty
phase can also take place in said vessel. For this purpose at
the start of sedimentation the vessel can be further topped up
with buffer solution in order to assist separation. With the
same aim, e.g. using a magnetic stirrer, it is possible to
produce a slight movement of 0.1 to 1 U/sec. The suspension
obtained in the first unit is transferred by a conveying means
13 into a second unit comprising a filter part 15 and a
collecting vessel 17. During the conveying into the vessel
17, a slight flow is also produced in the vessel 9. The filter
part 15 here is a multistage filter for extracting particles of
a specific size and collecting the remainder as a suspension
in the collecting vessel. In this form the sedimentation
tendency of the suspension is only small and is eliminated in
the vessel 17 by a second magnetic stirrer 18. A further
conveying means 19 transfers the now usable homogeneous
suspension into the third unit 25 for filter deposition on to
the carrier material. This unit comprises a container, into
which the e.g. pulverulent carrier material is introduced in
such a way that there is a uniform flow of the entering
suspension through it. Prior to the filtering of the suspension,
it may be advantageous to condition the dry carrier material
with physiological solution.
A pulverulent carrier material can also be supplied to the
vessel 17, filtered by a filter integrated into the unit 25 or
directly removed from the vessel 17.
The filter 15 can be connected, even without the vessel 17,
between the vessel 9 and the unit 25 for the treatment of the
carrier material, so that the suspension can be passed from
the filter, without intermediate storage, directly to the carrier
material. In the case of a gel-like carrier produced by gelling
a liquid, in which the tissue particles are received, into the
vessel 17 is placed at least one filter which is sufficiently fine
for the filtration removal from the suspension of the tissue
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particles desired for the implant material. The filtrate is
removed after filtration and a gelling liquid is pumped in the
opposite direction through the filter. By means of the filter
the gelling solution with the tissue particles received therein
is removed from the vessel (line 20 indicated in dot-dash
line) and passed into the vessel 25, which in this case serves
as a gelling vessel, where it is gelled e.g. under correspond­
ing heating.
As a function of the size and complication of the overall
apparatus, it can be equipped for mass production of implant
materials or for the ad hoc production of individual portions
of such materials in the operating theatre.
We claim:
1. A process for the forming and applying an implant
material with bone regenerating characteristics to form bone
in a patient, comprising:
removing fatty tissue containing no osteoblasts or mesan-
chymal cells derived from bone, bone marrow or peri­
osteum from a patient in need of bone regeneration;
comminuting said fatty tissue material to produce small
fatty tissue particles;
suspending at least some of the small fatty tissue particles
in a physiologically acceptable, liquid to form a sus­
pension comprising the particles;
depositing at least a substantial portion of the suspended
fatty tissue particles from said suspension on a physi­
ologically acceptable, solid carrier material by contact­
ing the suspension with the carrier material to form a
solid implanting material;
implanting said solid implanting material into a bone in
need of regeneration in a patient; and
allowing bone to regenerate in the patient,
wherein said removing of said fatty tissue and implanting
of said implanting material are carried out in at most
about 1 hour of elapsed time.
2. The process as claimed in claim 1 wherein said fatty
tissue is not cultured between removal thereof from said
patient and implantation thereof into said patient.
3. The process as claimed in claim 1 further wherein said
solid carrier material is pulverulent.
4. The process as claimed in claim 1 wherein said solid
carrier material has a form selected from the group consist­
ing of sponge form, textile form, porous particle form, and
monolith form.
5. The process as claimed in claim 1 further comprising
filtering said suspension through said solid carrier material
to deposit at least a substantial portion of said particles on
said carrier material.
6. The process as claimed in claim 1 further comprising
applying a cell adhesion agent to said solid carrier material
prior to completion of contact thereof with said suspension.
7. The process as claimed in claim 1 further comprising
admixing a cell adhesion agent with said suspension prior to
contacting said suspension with said carrier material.
8. The process as claimed in claim 1 wherein said
suspending liquid comprises a gel precursor, and said gel
precursor is gelled after said tissue particles are deposited on
said carrier material.
9. The process as claimed in claim 1 further comprising
mechanically comminuting said fat tissue.
10. The process as claimed in claim 1 further comprising
comminuting said tissue by digesting said fatty tissue with
at least one enzyme.
11. The process as claimed in claim 9 further comprising,
in addition to said mechanical comminution, comminuting
said fatty tissue by digesting said fatty tissue with at least
one enzyme.
12. The process as claimed in claim 1 wherein said solid
carrier material comprises at least one material selected from
10
the group consisting of demineralized bone, collagen, min­
eral material, and synthetic polymer material.
13. The process as claimed in claim 11 further comprising
depositing at least one growth factor on said carrier material
with said fatty tissue particles deposited thereon.
14. A process for forming and applying an implant mate­
rial with cartilage regenerating characteristics to form car­
tilage in a patient, comprising:
removing fatty tissue material containing no chondrocytes
or other cartilage forming cells derived from cartilage,
bone marrow or periosteum from a patient in need of
cartilage regeneration;
comminuting said fatty tissue to produce small fatty tissue
particles;
suspending at least some of said small fatty tissue par­
ticles in a physiologically acceptable, liquid to form a
suspension comprising the fatty tissue particles;
depositing at least a substantial portion of said fatty tissue
particles from said suspension on a physiologically
acceptable, solid carrier, by contacting the suspension
with the carrier material to form a solid implanting
material;
implanting said solid implanting material into a cartilage
in need of regeneration in a patient; and
allowing cartilage to regenerate in the patient;
wherein said removing of the fatty tissue and implanting
of said implanting material are carried out collectively
in at most about 1 hour.
15. The process as claimed in claim 14 wherein said fatty
tissue is not cultured between removal thereof from said
patient and implantation thereof into said patient.
16. The process as claimed in claim 14 wherein said solid
carrier material is pulverulent.
17. The process as claimed in claim 14 wherein said solid
carrier material has a form selected from the group consist­
ing of sponge form, textile form, porous particles, and
monolith form.
18. The process as claimed in claim 14 comprising
filtering said suspension through said solid carrier material
to deposit at least a substantial portion of said fatty tissue
particles on the carrier material.
19. The process as claimed in claim 14 further comprising
applying a cell adhesion agent to said solid carrier material
prior to completion of contact thereof with said suspension.
20. The process as claimed in claim 14 further comprising
admixing a cell adhesion agent with said suspension prior to
contacting said suspension with said carrier material.
21. The process as claimed in claim 14 wherein said
suspending liquid comprises a gel precursor, and said gel
precursor is gelled after the fatty tissue particles are depos­
ited on the carrier material.
22. The process as claimed in claim 14 further comprising
mechanically comminuting said fatty tissue.
23. The process as claimed in claim 14 further comprising
comminuting said tissue by digesting said fatty tissue with
at least one enzyme.
24. The process as claimed in claim 22 further
comprising, in addition to said mechanical comminution,
comminuting said tissue by digesting said fatty tissue with
at least one enzyme.
25. The process as claimed in claim 14 wherein said solid
carrier material comprises at least one material selected from
the group consisting of demineralized bone, collagen, min­
eral material, and synthetic polymer.
26. The process as claimed in claim 14 further comprising
depositing at least one growth factor on said carrier material
with said fatty tissue particles deposited thereon.
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