Guided development and support of hydrogel-cell compositions

Details Guided development and support of hydrogel-cell compositions Guided development and support of hydrogel-cell compositions

1998-11-25

2001-01-09

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C623S017120, C623S016110

Reexamination Certificate

active

06171610

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods of generating tissue such as cartilage, bone, nervous system, skin, organs, and epithelial layers, to repair or replace tissue damaged by disease or injury, augment existing tissue, or create tissue not originally present.
BACKGROUND OF THE INVENTION
There is much interest within the medical community for methods and materials for use in reconstructive surgery of tissue. An emerging approach is tissue engineering, in which new tissue is grown from tissue-precursor cells and engineered into desired shapes and structures. The types of tissues that can be grown and engineered include, for example, bone, and cartilage.
One of the primary uses for replacement cartilage is to correct defects in the articular surface of various joints. For example, a damaged cartilage meniscus in a patient's knee can be replaced with an artificially engineered meniscus. See, for example, U.S. Pat. No. 5,041,138 (Vacanti et al.). In other examples of tissue engineering, hollow spaces or lumens within tissues can be filled with tissue-precursor cells suspended in, for example, gelatin, collagen, fibrin, or various hydrogels. See, for example, International Patent Application WO 94/25080 entitled “Injectable polysaccharide-cell compositions” (Griffith-Cima et al.).
SUMMARY OF THE INVENTION
The invention features a method of generating new tissue in a patient by delivering a liquid hydrogel-cell composition, which contains a hydrogel and tissue precursor cells, into a permeable, biocompatible support structure. The hydrogel-cell composition fills the permeable support structure and takes the shape of the support structure as the composition solidifies and new tissue is formed as the cells grow and multiply. After being saturated with the hydrogel-cell composition, the support structure can be implanted into a patient. Alternatively, the support structure can be filled with the liquid hydrogel-cell composition after it is implanted into the patient. For example, the support structure can be implanted and subsequently injected with the hydrogel-cell composition using a syringe or catheter. The support structure is shaped to corresponded to the desired tissue to be grown, e.g., a bone, a meniscus for a knee, an ear, an organ, a nose, a portion of the spinal cord, or other tissue, e.g., cartilaginous tissue or autonomic nervous system tissue.
The combination of suspending the tissue precursor cells in the hydrogel and delivering the hydrogel-cell composition into a support structure profoundly improves the quality of the new tissue growth and the range of tissue shapes and structures that can be grown. The hydrogel-cell composition forms a uniform distribution of cells with a well-defined and precisely controllable density. Moreover, the hydrogel can support very large densities of cells, e.g., 50 million cells/ml. These factors improve the quality and strength of the new tissue. In addition, the hydrogel allows diffusion of nutrients and waste products to, and away from, the cells, which promotes tissue growth.
The support structure provides support for the hydrogel-cell composition and guides the development and shape of the growing tissue, which fills the support structure. Since it is the hydrogel that sustains and suspends the tissue precursor cells, rather than the support structure, the support structure can have any shape or structure from a wide range of shapes and structures. In particular, suitable support structures are sufficiently permeable to carry the hydrogel-cell composition and allow the exchange of nutrients and waste products between the hydrogel within the support structure and bodily fluids outside the support structure. Furthermore, the support structures can be biodegradable or biocompatible. Examples of support structures include sponges, foams, corals, rigid inorganic, ceramic, or metal structures having internal pores such a honeycomb structure made from titanium, a skeleton of fine struts, such as a mesh of thin interwoven polymer fibers, and a skeleton of thick struts, such as a network of metal, inorganic, ceramic, or plastic rods.
In general, in one aspect, the invention features a method for generating new tissue, the method including: obtaining a liquid hydrogel-cell composition including a hydrogel and tissue precursor cells; delivering the liquid hydrogel-cell composition into a permeable, biocompatible support structure; and allowing the liquid hydrogel-cell composition to solidify within the support structure and the tissue precursor cells to grow and generate new tissue.
The liquid hydrogel-cell composition can be delivered to the support structure by injecting the liquid composition into the support structure.
The method can further include implanting the support structure into an animal, e.g., a mammal such as a human. After the support structure is implanted into the animal, the hydrogel-cell composition can be delivered to the support structure.
In another aspect, the invention features a tissue forming structure that includes: a permeable, biocompatible support structure having a predetermined shape that corresponds to the shape of desired tissue; and a hydrogel-cell composition at least partially filling the support structure, wherein the hydrogel-cell composition includes a hydrogel and tissue precursor cells.
For example, the cells can be bone forming cells and the support structure can include porous hydroxyapatite. Also, the hydrogel-cell composition can be a solidified suspension of hydrogel supporting dispersed tissue precursor cells.
The methods and tissue forming structure can include any of the following features.
The support structure can include any of ceramic material, metal, sponge, foam, porous hydroxyapatite, a mesh of fibers (e.g., a mesh of polyglycolic acid fibers and polylactic acid), and various polymers. For example, the support structure can be formed from polyanhydride, polyorthoester, polyglycolic acid, polylactic acid, polyglactin, or combinations thereof. Also, the support structure can be compressible or rigid, or elastic.
The support structure can be shaped in the form of desired tissue, such as in the form of articular cartilage adjacent a joint, a bone, a portion of a bone, a bone defect, or a brain or other central nervous system tissue defect. The support structure can be also shaped in the form of a cylinder having the diameter of the spinal cord of a mammal to be treated. The support structure can also be biodegradable.
The hydrogel can include any of the following: polysaccharides, proteins, polyphosphazenes, poly(oxyethylene)-poly(oxypropylene) block polymers, poly(oxyethylene)-poly(oxypropylene) block polymers of ethylene diamine, poly(acrylic acids), poly(methacrylic acids), copolymers of acrylic acid and methacrylic acid, poly(vinyl acetate), and sulfonated polymers.
The tissue precursor cells can include any of the following: epidermal cells, chondrocytes and other cells that form cartilage, macrophages, dermal cells, muscle cells, hair follicles, fibroblasts, organ cells, osteoblasts and other cells that form bone, endothelial cells, mucosal cells, pleural cells, ear canal cells, tympanic membrane cells, peritoneal cells, Schwann cells, corneal epithelial cells, gingiva cells, neural cells, neural stem cells such as central nervous system (CNS) stem cells, e.g., spinal cord or brain stem cells, as well as autonomic nervous system (ANS) stem cells, e.g., post-ganglionic stem cells from the small intestine, bladder, liver, lung, and heart, (for engineering sympathetic or parasympathetic nerves and ganglia), tracheal epithelial cells, hepatocytes, pancreatic cells, and cardiac cells. The tissue precursor cells can also be neuroendocrine stem cells.
In another aspect, the invention features isolated, mammalian adult autonomic nervous system neural stem cell. These stem cells can be isolated from any innervated tissues in the body, including the heart, bladder, intestine, lung, liver, and kidney tissue. The invention also includes isolated, mammalian neuroendocrine st

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