Patent Application: US-8258508-A

Abstract:
this invention relates to a method of delivering light energy to biological tissues for the acceleration of healing of damaged or diseased tissues or regeneration of such tissues . more particularly , the present invention relates to applying various wavelengths of light to articular and non - articular joints , alone , or in conjunction with techniques for restoring or regenerating cartilage , ligament and / or tendons whether in - vitro , in - situ or in - vivo . the present invention also extends to application of photo - irradiation to stimulate enhanced proliferation and site - dependent differentiation of stem cells into mature cells and to stimulate full functioning of mature cells involved in tissue repairs for regeneration of tendons , ligaments , cartilage , bone or muscle , depending on the type of tissue with which the stem cells come into contact .

Description:
the present invention is based on the finding that tissue regeneration or repair is largely dependent on immature pluripotent cells such as satellite cells in muscle , bone marrow stromal cells , mesenchymal stem cells and other peripheral and tissue specific stem cells . these cells site dependently differentiate into local tissue types , growing into mature functional tissues . it is further based on the observation that photo - irradiation of cells can have a number of stimulatory effects leading to improved proliferation in in - vitro experiments . the findings have applications in treating a wide variety of cells and tissues in - vitro prior to tissue transplantation and in - vivo . the stimulative effects of photo - irradiation can help overcome age , disease and other factors which may retard tissue repair mechanisms in the body . the application of photo - irradiation can stimulate pluripotent cells from any number of origins . in cartilage , a limited number of stem cells dwell in the surface zone along side mature chondrocytes which function to maintain the cartilage matrix . the mature chondrocytes do not function to fill in or regenerate cartilage lesions . the stem cells provide the basis of tissue regeneration . photo - irradiation stimulates mature chondrocytes to function more efficiently at maintenance of cartilage matrix while also stimulating surface dwelling stem cells to differentiate and proliferate into mature cartilage tissue . this forms the basis of a treatment to maintain joint and cartilage integrity and to stimulate repair of arthritic lesions . such therapy would function alone in this respect . additionally , stem cells dwelling peripherally throughout the body , representing the fullest variety of tissue types , serve a critical substrate function for tissue repair and regeneration . this includes satellite cells in muscle , fibroblasts in connective tissue , and osteoblasts in bone . in fact , researchers believe most every tissue in the adult body contains tissue specific stem cells . these may be the basis for repair and regeneration . application of photo - irradiation , based on in - vitro experiments , may enhance growth and differentiation of these cells , thereby enhancing tissue repair and regeneration . another aspect of this invention is to apply photo - irradiation to down - regulate pro - inflammatory cascades , at the transcriptional level , of the cycloxygenase 2 pathway to suppress prostaglandin e2 production and intervene the inflammatory degradation cycle of cartilage . cycles of inflammation , leading to degeneration of cartilage components through pro - inflammatory activation of destructive enzymes such as matrix metalloproteinases result in degradation of cartilage . by down regulating inflammation , photo - irradiation may reduce the destructive factors in cartilage , allowing reparative factors to build up cartilage integrity and health . another aspect of this invention is to apply photo - irradiation to transplanted cells . such transplant techniques are commonly used to provide an abundance of source tissue material to repair cartilaginous lesions or to replace ligaments . such transplanted tissues may consist of cells cultures , discrete pieces or segments of tissues , or may consist of entire tissue parts s in the case of ligament transplants . furthermore , such transplanted tissues may be of autologous or allogeneic sources . allogeneic transplants may originate from cadaveric tissue or from live donors . the transplanted cells or tissues may also be manipulated prior to transplant in order to prepare or enhance the tissues for more effective engraftment and growth . chondrocytes or stem cells are often grown and expanded in - vitro . they are then transplanted to a cartilage lesion and sewn into place with a covering flap of periosteum , a membrane that lines the outer surface of bones . this technique presents two applications for photo - irradiation . first is to treat the in - vitro culture to enhance cell function and growth and cell culture expansion , providing both a maximal population of cells for implantation and to enhance cell functionality and quality to maximize potential for successful engraftment . second is to photo - irradiate the cell culture in - situ , post - transplant . the transplanted cells are now in proximal contact with local recipient tissue . photo - irradiation can enhance growth , proliferation , functionality and ( in the case of stem cells transplant vs mature chondrocyte transplant ) site - dependent differentiation into the appropriate local tissue type . in the case of discrete tissue segment transplantation , photo - irradiation may enhance engraftment and functionality . another popular cartilage transplant technique is mosaicplasty , which involves boring out cylinders of cartilage from healthy areas of a joint ( either autologous or from an allogeneic donor ) and transplanting to the site of a cartilage lesion . treatment of the cartilage cylinders prior to transplant may prepare the cells in the tissue to function optimally upon transplantation . post transplantation , application of photo - irradiation may enhance engraftment and functionality of the plugs . furthermore , in the cases of both cell culture transplant and mosaicplasty , the long term duration and survival of the transplant may be enhanced by photo - irradiation . in addition , the present invention has application for enhancing transplantation of ligament tissue , improving engraftment and mechanical integrity through stimulation of fibroblasts and other ligament cells . another aspect of the present invention is to enhance tissue regeneration techniques that utilize mesenchymal progenitor or stem cells drawn from inside the bone via techniques such as “ microfracture ” to proliferate and site - dependently differentiate into the normal local cartilaginous tissue type at the site of a cartilage lesion , and to fully function upon reaching cell maturity . the microfracture technique involves puncturing holes into the underlying bone to allow bone marrow stem cells to leak out , forming “ super clots ” which can in - fill debrided cartilage lesions , leading to new cartilage formation , or to anchor ligament implants . in the case of ligaments ( for example , anterior cruciate [ acl ], posterior cruciate [ mu .] and others ), a separated ligament is reattached , or a transplanted ligament ( either autologous or allogeneic in origin ) is attached . in either case the superclot acts as a rich substrate material which site - dependently differentiates into ligament cells and forms a stronger attachment and does so faster than in absence of such stem cells . two limitations on this technique have been observed . first , in the case of cartilage lesions , often fibrocartilage form in articular lesions rather than hyaline . this provides a less functional repair than if hyaline cartilage formed . second , in patients over 40 years old , it has been observed that microfracture technique is less effective , whether in ligament repair or cartilage repair . photo - irradiation can be applied post surgically to enhance proliferation , differentiation and function . again , age related retardation of tissue repair and regeneration is a common issue . photo - irradiation can enhance cell function to partially or wholly overcome this issue . another aspect of the present invention is employment of a variety of electromagnetic radiation wavelengths . studies of photo - biostimulation generally have ranged from 445 nanometers ( indigo / blue ) to 700 nanometers ( red ). the most effective wavelengths for stimulating cell proliferation seem to center around red wavelengths ( around 630 nanometers ) and in the near infrared range ( 800 to 920 nanometers ). there are some additional indications that wavelengths longer than these , ranging up to 50 , 000 nanometers may have beneficial effects . different wavelengths may be more effective for one type of tissue over another . this suggests that not only monochromatic wavelengths are indicated for treatments , but also mixtures of light wavelengths ( polychromatic ) may be useful . the photo - irradiation may be delivered from any number of sources , including incandescent , light emitting diodes , super luminous diodes , and laser . experts in photo - biology conclude that lasers are just convenient machines that produce radiation . it is the radiation that produces the photobiological and / or photophysical effects and therapeutic gains , not the machines , and that radiation must be absorbed to produce a chemical or physical change , which results in a biological response . photo - irradiation produces local biostimulatory responses so the light source must be delivered in close proximity to the treated tissue so as to deliver adequate energy — at least 1 joule / cm 2 , optimally 1 - 20 joules / cm 2 . some doses may be delivered as high as 2 , 700 joules / cm 2 . in the case of incandescent photo - irradiation sources , the light emitting bulb should be held or fixed within 10 cm of the treated body part so as to ensure adequate transmission of energy without burning tissue with associated heat generation . in the case of light emitting diodes or super luminous diodes , the light sources may be held or fixed directly against the skin covering the treated body part , or against a translucent material held or fixed in direct contact with the skin . in the case of low intensity ( or cold ) laser apparatuses , the device should be held or fixed within 2 to 5 cm of the treated body part to ensure adequate and consistent transmission of energy . application of photo - 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