Microfabricated tissue as a substrate for pigment epithelium transplantation

Abstract

An ocular implant is provided with a substrate and a membranous tissue layer secured to the substrate. Cells such as IPE cells, RPE cells and stem cells are attached on the surface of the membranous tissue layer either in situ or in vivo through cells transplantation. The cells are separated into regions on the surface by creating a pattern on the surface enclosing regions for receiving the cells. The substrate is a bioabsorbable and / or polymeric substrate. Examples of membranous tissue layer are lens capsule, inner limiting membrane, corneal tissue, Bruch's membrane tissue, amniotic membrane tissue, serosal membrane tissue, mucosal membrane tissue and neurological tissue. The membranous tissue layer could have a micropattern of biomolecules. A microfluidic network could be placed onto the microfabricated membranous tissue layer.

Description

FIELD OF THE INVENTION [0001] The present invention relates generally to the field of treatment of eye disorders, in particular retinal disorders such as age-related macular degeneration, retinitis pigmentosa, and other retinal diseases. In addition, the invention relates to methods and apparatus for modifying tissues, and for the transplantation of cells and tissues. BACKGROUND OF THE INVENTION [0002] Diseases of the retina, such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and other diseases, are the leading cause of severe visual impairment or blindness in the industrialized world. One hallmark of AMD, as in RP, is the degeneration and loss of cells of the retinal pigment epithelium (RPE). Bruch's membrane is also thought to be damaged; such damage may be the initiating stimulus for RPE demise. RPE cells are vital to the survival and proper functioning of retinal photoreceptors, which are the only cells in the eye which directly sense light. RPE degenerat...

AI Technical Summary

Benefits of technology

[0014] Methods for modifying membranous tissues include bulk modification methods and surface modification methods. Surface modification methods and bulk modification methods may be applied alone, or may each be applied together to the same membranous tissue. Modification of the surface and bulk properties of the membranous tissue improves the tissue's suitability for transplantation into an animal. Such tissue modification may improve the ability of cells to attach and grow on the tissue, and may improve the permeability properties of the tissue so that nutrients, electrolytes, and other desired substances are better able to pass through the modified tissue.

[0025] The masking step may be performed by placing a grid onto the surface of the membranous tissue, or by using microcontact printing techniques to apply a pattern of protecting molecules onto the surface of the membranous tissue effective to prevent ECM denaturation in regions covered by the protecting molecules or grid.

[0029] The present invention is directed to methods and related products for treating retinal diseases such as AMD, RP, and other retinal diseases. For example, one therapy for AMD is to transplant suspensions of either retinal pigment epithelial (RPE) cells, iris pigment epithelial (IPE) cells, stem cells, or other cells, to rescue the diseased retina. The present invention provides novel tissue engineering techniques to precision engineer autologous human tissues (e.g., human lens capsule) as a substrate for transplanting cells, such as IPE cells, RPE cells, stem cells, and other cells. Transplanted pigment epithelium cells grown on the modified tissue and substrates of the invention are able to grow to high density and to exhibit features indicative of differentiation, important characteristics of these cells in normal retinas. In addition, unlike prior methods, the modified membranous tissues (including modified ocular membranous tissues, such as lens capsule, inner limiting membrane, and other substrates provided by the present invention, and such substrates with growing epithelial cells) are effective to replace many of the functions of Bruch's membrane, which may be damaged in degenerative retinal diseases. Thus the present methods and apparatus for transplantation of pigment epithelial cells provide transplanted cells which grow to high density and are able to perform needed physiological functions lacking in patients with retinal degenerative diseases.

Problems solved by technology

Bruch's membrane is also thought to be damaged; such damage may be the initiating stimulus for RPE demise.

Damage to Bruch's membrane, which may occur due to accumulation of waste products from outer segment metabolism, for example, prevents the exchange of oxygen, growth factors and waste products.

Such impaired exchange leads to hypoxia in the photoreceptors.

However, such approaches have not met with great success.

However, this approach has not succeeded in the past, due in part to the failure of the transplanted cells to function properly and in part due to rejection of the cells by the host animals.

However, challenges to both IPE and RPE transplantation methods include i) difficulty in repairing the diseased Bruch's membrane, ii) inability to secure and position newly transplanted cells, and iii) lack of control over extracellular matrix signaling molecules that are critical to the structure, function, and survival of the pigment epithelial cell.

For these and other reasons, techniques for IPE and RPE transplantation using antibiotics or immunosuppressants have not been successful.

There has been no demonstration of significant visual improvement with these approaches, and problems of tissue reintegration remain.

Thus, despite the apparent promise of the transplantation approach, AMD and other retinal diseases remain without successful therapeutic interventions.

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