Patent Application: US-70160310-A

Abstract:
brain stimulators are used to treat a variety of disorders , and their range of uses continues expand . however , one problem with long - term stimulation of neural tissue is the need to increase the stimulation parameters to continue to maintain the same clinical effect . this is thought to be due to local tissue reaction to the implanted foreign body . because the implanted stimulator functions by means of contact with functional cells within the tissue , prevention of tissue reaction to the stimulator would make a significant improvement to the device &# 39 ; s performance and longevity . it is proposed that coating a neural stimulator device with decorin , and / or homologous molecules of functional or structural likeness to decorin , can function to decrease gliosis and other local tissue reaction in neural tissue . the present invention provides a novel system and method of device design and utilization that can prevent and suppress known associated tissue reactions associated with neural modulation of tissue with an implanted device , thereby improving the device &# 39 ; s performance and longevity .

Description:
the present invention provides a novel system and method of device design and utilization that can prevent and suppress known associated tissue reactions associated with neural modulation of tissue with an implanted device , and which may also treat pathology related to gliosis , inflammatory neural tissue reaction , reactive astrocytosis , microglial activation , leukocyte invasion , siderophages , tissue vacuolization , multinucleated giant cell reaction , or other related diseases and processes . it is proposed that coating the implanted neural stimulator device with decorin , and / or homologous molecules of functional or structural similarity to any portion of decorin ( hereafter referred to as a “ decorin - like molecule ”) can function to decrease gliosis and other tissue reaction in neural tissue , thereby significantly improving the device &# 39 ; s performance and longevity . the molecular structure of decorin has been detailed in the literature ( krusius and ruoslahti 1986 ; vesentini et al ., 2003 ; ncbi online database gene id 1634 ). decorin is a proteoglycan that has an average molecular weight of 87 - 140 kilodaltons ( kd ) and belongs to the family of small leucine - rich proteoglycans . decorin has a core protein component which may be bound to a glycosaminoglycan chain , and it may have many alternative splice variants . functional equivalents of decorin include decorin native proteins , decorin core protein , decorin alternative splice variants , biglycan , fibromodulin , lumican , and other modifications , to or alternative homologous amino acid sequences of decorin . evidence suggests that the mechanism of decorin in neural tissues is via inhibition of the tgf - beta signaling pathway ( yamaguchi et al ., 1990 ; johns et al ., 1992 ; rabchevsky et al ., 1998 ; logan et al ., 1999 ; asher et al ., 2000 ; dobbertin et al ., 2003 ; logan and baird , u . s . pat . no . 5 , 958 , 411 , 1995 ). evidence also suggests that decorin inhibits the egfr tyrosine kinase ( santra et al ., 2002 ), and there is preliminary evidence to suggest that other signaling pathways are involved as well . other proposed mechanisms include inhibition of complement activation ( krumdiek et al ., u . s . pat . no . 5 , 650 , 389 , 1993 ), but this has not been shown to play a primary role in the central nervous system or in neural tissue reaction to foreign bodies . the detailed mechanisms remain to be fully elucidated . decorin has been shown to have several other cellular effects , including the suppression of neurocan , brevican , phosphacan , and ng2 expression , as well as reduction of astrogliosis and basal lamina formation after local traumatic injury ( davies et al ., 2004 ). davies , et al ., also showed that decorin suppressed astrogliosis and macrophage / microglia accumulation at lesion sites in the central nervous system . it is also known that decorin naturally binds to collagen type i fibrils ( vesentini et al ., 2003 ). the novel aspect of the device is an external layer or coating with a decorin - like protein , which may be integrated or manufactured by several means . this includes chemical coupling of the molecule to the device &# 39 ; s surface , such as by either the amino groups or carboxyl groups in the amino acid sequence , or by any molecular component of the proteoglycan chain . this may be done using the chemical reagents well known in the art : for example , amine - reactive crosslinkers , such as dithiobis succinimidyl propionate ( dsp ), which uses disulfide linkages to attach to a surface and links proteins by their primary amine groups , or other compounds , such as 1 - ethyl - 3 -( 3 - dimethylaminopropyl )- carbodiimide ( edc ), etc . alternatively , the decorin - like protein may be bound by polymers that cross - link or otherwise allow for adherence or attachment to the device . alternatively , the decorin - like protein may be bound by means of its glycosaminoglycan component , its peptide backbone , its r - groups , or other moieties , or it may be modified with certain amino acid sequences that allow for binding to the surface of the device . in addition , the device surface itself may be manufactured with an absorbent or adherent coating that either contains or adheres to the decorin - like protein . this adherent coating may be made of any type of material , such as plastics , polymers , glues , ceramics , metals , silicates , carbon - based compounds , or other similar materials . the surface may also be covered with a second coating to slow the diffusion of the decorin - like molecule into surrounding tissue . with reference to the implantable electrical stimulation device used in concert with the decorin - like molecule , it may be of any design that incorporates a conductive surface that contacts the tissue , whether made of metal ( e . g ., platinum - iridium , cobalt - chrome , or other alloys ) or other conductive material ( e . g ., conductive polymers or ceramics ) ( geddes and roeder , 2003 ; gimsa et al ., 2005 ). the device may also have an insulative material to shield from conduction of current at non - targeted tissue sites . both the conductive surfaces and insulative surfaces may integrate the decorin - like molecular surface . the device may utilize monopolar , bipolar , or multipolar stimulation , and may have any number of electrical leads , and may incorporate electrical feedback systems . the device may be internally or externally powered , and may be temporarily or permanently placed in the tissue . the device may be of any length , width , and curvature . the device may also be used for extraction or sampling of tissue or fluids , and may also be used for delivery of pharmaceutical agents or solutions , for example , through a cannula system . many variations of the device may be constructed which are bound within the scope of the invention . the advantages and features of the invention are further described in the following drawings . fig1 a is an example of a brain stimulator . this drawing shows only one of many possible examples of neural stimulation devices . fig1 b is an expanded view of the surface of the device that illustrates multiple examples of possible embodiments of the invention , wherein the decorin - like molecule is attached or adhered to the surface of the stimulator device . fig1 a is one of many possible examples of a neural stimulator device . the following is a reference for the numbered labels . 1 ) a neural stimulator device ; in this case , a type of deep brain stimulator . 2 ) the conductive connection between the electrodes and a microprocessor system . 3 ) the substantive core of the device , which may be solid or hollow . 4 ) the insulative outer surface of the device . 5 ) the conductive surface electrode , which contacts the targeted tissue for electrical modulation . fig1 b is an enlarged view of the surface of the device , wherein four possible examples of embodiments of the invention are illustrated . 6 ) the decorin - like molecule , coupled directly to the surface of the device . it should be noted that the decorin - like coating is only illustrated on one edge of the device , but that the entire device may be coated with the molecule . 7 ) the decorin - like molecule , coupled to the surface of the device by means of 8 ) an intermediary molecular structure . 9 ) the decorin - like molecule , coupled to the surface of the device by means of 10 ) an adhesive or adsorbant layer , which may be composed of plastics , polymers , glues , ceramics , metals , silicates , carbon - based compounds , or any other similar materials that can adhere the molecule to the device &# 39 ; s surface . 11 ) the decorin - like molecule , coupled to the surface of the device with 12 ) a separate outer coating consisting of any plastics , polymers , glues , ceramics , metals , silicates , carbon - based compounds , or other similar materials , which may slow the diffusion of the decorin - like molecule into surrounding tissue . mcmurtrey , richard j . “ decorin and gliosis and related system and method .” u . s . provisional patent no . 61 / 151 , 334 . filed feb . 10 , 2009 . krumdiek r , hook m , volanakis j . university of alabama at birmingham research foundation . “ methods for the inhibition of complement activation .” u . s . pat . no . 5 , 650 , 389 . filed mar . 1 , 1993 . logan a , baird a . the whittier institute for diabetes and endocrinology . “ methods of inhibiting ecm accumulation in the cns by inhibition of tgf - beta .” u . s . pat . no . 5 , 958 , 411 . filed mar . 24 , 1995 asher r a , morgenstern d a , moon l d , fawcett j w . “ chondroitin sulphate proteoglycans : inhibitory components of the glial scar .” prog . brain res . 132 : 611 - 619 , 2001 . davies j e , tang x , denning j , archibald s j , davies s . “ decorin suppresses neurocan , brevican , phosphacan and ng2 expression and promotes axon growth across adult rat spinal cord injuries ” eur j of neuroscience 19 : 1226 - 1242 , 2004 . dobbertin a , rhodes k e , garwood j , properzi f , heck n , rogers j h , fawcett j w , faissner a . “ regulation of rptpbeta / phosphacan expression and glycosaminoglycan epitopes in injured brain and cytokine - treated glia .” mol . cell . neurosci . 24 : 951 - 971 , 2003 . geddes l a , roeder r . “ criteria for the selection of materials for implanted electrodes .” ann . biomed . eng ., 31 ( 7 ): 879 - 890 , 2003 . gimsa j , habel b . schreiber u , van rienen u , strauss u , gimsa u . “ choosing electrodes for deep brain stimulation experiments — electrochemical considerations .” j neurosci methods , 142 ( 2 ): 251 - 265 , 2005 . johns l d , babcock g , green d , freedman m , sriram s , ransohoff r m . “ transforming growth factor - beta 1 differentially regulates proliferation and mhc class - ii antigen expression in forebrain and brainstem astrocyte primary cultures .” brain res . 585 : 229 - 236 , 1992 . krack p , batir a , van blercom n , chabardes s , fraix v , ardouin c , koudsie a , limousin p d , benazzouz a , lebas j f , benabid a l , pollak p . “ five - year follow - up of bilateral stimulation of the subthalamic nucleus in advanced parkinson &# 39 ; 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