Cartilage growth from cell seeded ceramic compositions

Details Cartilage growth from cell seeded ceramic compositions Cartilage growth from cell seeded ceramic compositions

1998-02-13

2001-08-21

Isabella, David J (Department: 3738)

Prosthesis (i.e., artificial body members), parts thereof, or ai

Implantable prosthesis

Bone

C623S066100

Reexamination Certificate

active

06277151

ABSTRACT:

BACKGROUND OF THE INVENTION
One of the goals of reconstructive surgery is to be able to replace damaged tissue with new tissue, perhaps grown from a patient's own cells. For example, researchers have endeavored to develop cartilage regeneration systems in which isolated chondrocytes are injected into a damaged area in the context of a polymer scaffold (see, for example, Atala et al.,
J. Urol.
150:747, 1993; Freed et al.,
J. Cell. Biochem.
51:257, 1993 and references cited therein). Similar seeded scaffold systems have been studied in the context of bone repair, where osteoblast cells are utilized in conjunction with polymeric or ceramic supports (see, for example, Elgendy et al., Biomater. 14:263, 1993; Ishaug et al.,
J. Biomed. Mater. Res.
28:1445, 1994). Seeded compositions have also been studied for their utility in bladder control and vesicoureteral applications (see, for example, Griffith-Cima et al., published PCT application no. WO 94/25080.
Researchers in the field have identified several characteristics that are desirable for scaffold materials to be used in such seeded compositions. For example, Freed et al. (Bio/Technology 12:689, 1994) list the following six factors as desirable features:
(1) the scaffold surface should permit cell adhesion and growth;
(2) neither the scaffold material nor its degradation products should provoke inflammation or toxicity when implanted in vivo;
(3) the scaffold material should be reproducibly processable into three dimensional structures;
(4) the scaffold material should have a porosity of at least 90% so that it provides high surface area for cell-scaffold interactions, sufficient space for extracellular matrix regeneration, and minimal diffusion constraints during in vitro culture;
(5) the scaffold material should resorb once it has served its purpose of providing a template for the regenerating tissue; and
(6) the scaffold degradation rate should be adjustable to match the rate of tissue regeneration by the cell type of interest.
Much effort has been spent in attempts to identify materials that can act as effective scaffolds for tissue repair. There remains a need for the development of suitable new materials for use as scaffolds in cell seeding applications.
Definitions
“Amorphous”—By “amorphous” as that term is used here, it is meant a material with significant amorphous character. Significant amorphous character contemplates greater than 75% amorphous content, preferably greater than 90% amorphous content, and is characterized by a broad, featureless X-ray diffraction pattern. It is recognized that a small degree of crystallinity may exist in the material. However, for the amorphous precursor materials of the present invention, it is preferable that the degree of crystallinity be less than that desired in the product material.
“Bioactive”——Bioactive” refers to a material that induces hard tissue formation in and about the implant. When implanted in soft tissue, the bioactivity may also require the presence of a growth or trophic factor, or the seeding of the implant with a hard tissue forming cell type.
“Biocompatible”—The term “biocompatible”, as used herein, means that the material does not elicit a substantial detrimental response in the host. There is always concern, when a foreign object is introduced into a living body, that the object will induce an immune reaction, such as an inflammatory response that will have negative effects on the host. For example, although hydroxyapatite is generally considered to be “biocompatible”, significant inflammation and tissue necrosis have been observed when crystalline hydroxyapatite microcarriers are inserted intramuscularly in animals (see, for example, IJntema et al.,
Int. J. Pharm
112:215, 1994).
“Bioresorbable”—“Bioresorbable” refers to the ability of a material to be resorbed in vivo. “Full” resorption means that no significant extracellular fragments remain. The resorption process involves elimination of the original implant materials through the action of body fluids, enzymes or cells. Resorbed calcium phosphate may, for example, be redeposited as bone mineral, or by being otherwise reutilized within the body, or excreted. “Strongly bioresorbable”, as that term is used herein, means that at least 80% of the total mass of material implanted intramuscularly or subcutaneously is resorbed within one year. In preferred embodiments of the invention, the strongly resorbing PCA calcium phosphate is characterized in that, when at least 1 g (preferably 1-5 g) of PCA material is implanted at a subcutaneous or intramuscular site, at least 80% of the material is resorbed w/in one year. In more preferred embodiments, the material will be resorbed within nine months, six months, three months, and ideally one month. Furthermore, particularly preferred materials are characterized in that they can be fully resorbed in the stated time periods. For the purpose of this disclosure, “weakly” resorbable means that less than 80% of the starting material is resorbed after one year.
“Cells”—the term “cells”, as used herein, refers to any preparation of living tissue, including primary tissue explants and preparations thereof, isolated cells, cells lines (including transformed cells), and host cells.
“Effective Amount”—An effective amount of a biologically active agent is an amount sufficient to elicit a desired biological response.
“Hardening”—“Hardening” refers to the process by which the hydrated precursor is transformed into a hardened PCA material. The PCA material is considered to be “hardened” when it is a substantially non-formable solid. Such a hardened PCA material has minimal compressibility and tends to undergo plastic as opposed to elastic deformation.
“Hydrated precursor” The term “hydrated precursor”, as used herein, refers to the paste or putty formed by hydration of the dry PCA precursors in the presence of a limited amount of aqueous solution (i.e., less than approximately 1 mL aqueous solution/1 g precursor powder). The hydrated precursor may comprise both reactants and products, in various combinations, depending on the extent to which the conversion has progressed. Both the “injectable” and “formable” PCA precursor pastes described herein are hydrated precursors. Preferred “injectable” hydrated precursors have a consistency appropriate for delivery through an 18 gauge needle.
“Poorly crystalline apatitic calcium phosphate”, “PCA calcium phosphate” and “PCA material”, as those terms are used herein, describe a synthetic poorly crystalline apatitic calcium phosphate. The PCA material is not necessarily restricted to a single calcium phosphate phase provided it has the characteristic XRD and FTIR pattern. A PCA calcium phosphate has substantially the same X-ray diffraction spectrum as bone. The spectrum is generally characterized by only two broad peaks in the region of 20-35° with one centered at 26° and the other centered at 32°. It is further characterized by FTIR peaks at 563 cm
−1
, 1034 cm
−1
, 1638 cm
−1
and 3432 cm
−1
(±2 cm
−1
). Sharp shoulders are observed at 603 cm
−1
and 875 cm
−1
, with a doublet having maxima at 1422 cm
−1
and 1457 cm
−1
.
“Promoter”—The term “promoter”, as used herein, describes a material or treatment that promotes hardening of a hydrated precursor and may enhance the ACP to PCA calcium phosphate conversion. Some promoters participate in the conversion and are incorporated into the product PCA material; others, known as “passive” promoters, do not participate.
“Reactive”—“Reactive” is used herein to refer to the ability of an amorphous calcium phosphate when mixed with liquid to form a hydrated precursor to undergo conversion to the PCA material of the present invention in the presence of a promoter in association with hardening of the precursor materials. Preferred ACPs are characterized by an ability to convert completely, an ability to convert quickly with hardening, an ability to undergo conversion with otherwise inert compounds and/or an ability to convert into a substan

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