Nerve Cuff With Pocket For Leadless Stimulator

  *US08886339B2*
  US008886339B2                                 
(12)United States Patent(10)Patent No.: US 8,886,339 B2
 Faltys et al. (45) Date of Patent:Nov.  11, 2014

(54)Nerve cuff with pocket for leadless stimulator 
    
(75)Inventors: Michael A. Faltys,  Valencia, CA (US); 
  Roy C. Martin,  Maple Grove, MN (US); 
  Steven E. Scott,  Excelsior, MN (US); 
  Gerald E. Loeb,  South Pasadena, CA (US) 
(73)Assignee:SetPoint Medical Corporation,  Valencia, CA (US), Type: US Company 
(*)Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 712 days. 
(21)Appl. No.: 12/797,452 
(22)Filed: Jun.  9, 2010 
(65)Prior Publication Data 
 US 2010/0312320 A1 Dec.  9, 2010 
 Related U.S. Patent Documents 
(60)Provisional application No. 61/185,494, filed on Jun.  9, 2009.
 
Jan.  1, 2013 A 61 N 1 375 F I Nov.  11, 2014 US B H C Jan.  1, 2013 A 61 N 1 36114 L I Nov.  11, 2014 US B H C Jan.  1, 2013 A 61 N 1 3756 L A Nov.  11, 2014 US B H C Jan.  1, 2013 A 61 N 1 37205 L A Nov.  11, 2014 US B H C Jan.  1, 2013 A 61 N 1 0556 L I Nov.  11, 2014 US B H C Jan.  1, 2013 A 61 N 1 0558 L I Nov.  11, 2014 US B H C
(51)Int. Cl. A61N 001/05 (20060101); A61N 001/36 (20060101); A61N 001/375 (20060101); A61N 001/372 (20060101)
(52)U.S. Cl. 607/118; 607/36; 607/37; 607/115; 607/116; 607/149
(58)Field of Search  607/1-2, 36-37, 115-116, 118, 149

 
(56)References Cited
 
 U.S. PATENT DOCUMENTS
 2,164,121  A  6/1939    Pescador     
 3,363,623  A  1/1968    Atwell     
 4,073,296  A  2/1978    McCall     
 4,098,277  A  7/1978    Mendell     
 4,305,402  A  12/1981    Katims     
 4,503,863  A  3/1985    Katims     
 4,573,481  A  3/1986    Bullara     
 4,590,946  A  5/1986    Loeb     
 4,632,095  A  12/1986    Libin     
 4,649,936  A  3/1987    Ungar et al.     
 4,702,254  A  10/1987    Zabara     
 4,840,793  A  6/1989    Todd, III et al.     
 4,867,164  A  9/1989    Zabara     
 4,929,734  A  5/1990    Coughenour et al.     
 4,930,516  A  6/1990    Alfano et al.     
 4,935,234  A  6/1990    Todd, III et al.     
 4,979,511  A  12/1990    Terry, Jr.     
 4,991,578  A  2/1991    Cohen     
 5,019,648  A  5/1991    Schlossman et al.     
 5,025,807  A  6/1991    Zabara     
 5,038,781  A*8/1991    Lynch 607/61
 5,049,659  A  9/1991    Cantor et al.     
 5,073,560  A  12/1991    Wu et al.     
 5,106,853  A  4/1992    Showell et al.     
 5,111,815  A  5/1992    Mower     
 5,154,172  A  10/1992    Terry, Jr. et al.     
 5,175,166  A  12/1992    Dunbar et al.     
 5,179,950  A  1/1993    Stanislaw     
 5,186,170  A  2/1993    Varrichio et al.     
 5,188,104  A  2/1993    Wernicke et al.     
 5,203,326  A  4/1993    Collins     
 5,205,285  A  4/1993    Baker, Jr.     
 5,215,086  A  6/1993    Terry, Jr. et al.     
 5,215,089  A  6/1993    Baker, Jr.     
 5,222,494  A  6/1993    Baker, Jr.     
 5,231,988  A  8/1993    Wernicke et al.     
 5,235,980  A  8/1993    Varrichio et al.     
 5,237,991  A  8/1993    Baker et al.     
 5,251,634  A  10/1993    Weinberg     
 5,263,480  A  11/1993    Wernicke et al.     
 5,269,303  A  12/1993    Wernicke et al.     
 5,299,569  A  4/1994    Wernicke et al.     
 5,304,206  A  4/1994    Baker, Jr. et al.     
 5,330,507  A  7/1994    Schwartz     
 5,330,515  A  7/1994    Rutecki et al.     
 5,335,657  A  8/1994    Terry, Jr. et al.     
 5,344,438  A  9/1994    Testerman et al.     
 5,351,394  A  10/1994    Weinberg     
 5,403,845  A  4/1995    Dunbar et al.     
 5,458,625  A  10/1995    Kendall     
 5,472,841  A  12/1995    Jayasena et al.     
 5,487,756  A  1/1996    Kallesoe et al.     
 5,496,938  A  3/1996    Gold et al.     
 5,503,978  A  4/1996    Schneider et al.     
 5,531,778  A  7/1996    Maschino et al.     
 5,540,730  A  7/1996    Terry, Jr. et al.     
 5,540,734  A  7/1996    Zabara     
 5,567,588  A  10/1996    Gold et al.     
 5,567,724  A  10/1996    Kelleher et al.     
 5,571,150  A  11/1996    Wernicke et al.     
 5,580,737  A  12/1996    Polisky et al.     
 5,582,981  A  12/1996    Toole et al.     
 5,604,231  A  2/1997    Smith et al.     
 5,611,350  A  3/1997    John     
 5,618,818  A  4/1997    Ojo et al.     
 5,629,285  A  5/1997    Black et al.     
 5,637,459  A  6/1997    Burke et al.     
 5,651,378  A  7/1997    Matheny et al.     
 5,654,151  A  8/1997    Allen et al.     
 5,683,867  A  11/1997    Biesecker et al.     
 5,690,681  A  11/1997    Geddes et al.     
 5,700,282  A  12/1997    Zabara     
 5,705,337  A  1/1998    Gold et al.     
 5,707,400  A  1/1998    Terry, Jr. et al.     
 5,709,853  A  1/1998    Lino et al.     
 5,712,375  A  1/1998    Jensen et al.     
 5,718,912  A  2/1998    Thompson et al.     
 5,726,017  A  3/1998    Lochrie et al.     
 5,726,179  A  3/1998    Messer, Jr. et al.     
 5,727,556  A  3/1998    Weth et al.     
 5,733,255  A  3/1998    Dinh et al.     
 5,741,802  A  4/1998    Kem et al.     
 5,773,598  A  6/1998    Burke et al.     
 5,786,462  A  7/1998    Schneider et al.     
 5,788,656  A  8/1998    Mino     
 5,792,210  A  8/1998    Wamubu et al.     
 5,853,005  A  12/1998    Scanlon     
 5,854,289  A  12/1998    Bianchi et al.     
 5,902,814  A  5/1999    Gordon et al.     
 5,913,876  A  6/1999    Taylor et al.     
 5,916,239  A  6/1999    Geddes et al.     
 5,919,216  A  7/1999    Houben et al.     
 5,928,272  A  7/1999    Adkins et al.     
 5,964,794  A  10/1999    Bolz et al.     
 5,977,144  A  11/1999    Meyer et al.     
 5,994,330  A  11/1999    El Khoury     
 6,002,964  A  12/1999    Feler et al.     
 6,006,134  A  12/1999    Hill et al.     
 6,017,891  A  1/2000    Eibl et al.     
 6,028,186  A  2/2000    Tasset et al.     
 6,051,017  A  4/2000    Loeb et al.     
 6,083,696  A  7/2000    Biesecker et al.     
 6,083,905  A  7/2000    Voorberg et al.     
 6,096,728  A  8/2000    Collins et al.     
 6,104,956  A  8/2000    Naritoku et al.     
 6,110,900  A  8/2000    Gold et al.     
 6,110,914  A  8/2000    Phillips et al.     
 6,117,837  A  9/2000    Tracey et al.     
 6,124,449  A  9/2000    Gold et al.     
 6,127,119  A  10/2000    Stephens et al.     
 6,140,490  A  10/2000    Biesecker et al.     
 6,141,590  A  10/2000    Renirie et al.     
 6,147,204  A  11/2000    Gold et al.     
 6,159,145  A  12/2000    Satoh     
 6,164,284  A  12/2000    Schulman et al.     
 6,166,048  A  12/2000    Bencherif     
 6,168,778  B1  1/2001    Janjic et al.     
 6,171,795  B1  1/2001    Korman et al.     
 6,205,359  B1  3/2001    Boveja     
 6,208,902  B1  3/2001    Boveja     
 6,210,321  B1  4/2001    Di Mino et al.     
 6,224,862  B1  5/2001    Turecek et al.     
 6,233,488  B1  5/2001    Hess     
 6,266,564  B1  7/2001    Hill et al.     
 6,269,270  B1  7/2001    Boveja     
 6,304,775  B1  10/2001    Iasemidis et al.     
 6,308,104  B1  10/2001    Taylor et al.     
 6,337,997  B1  1/2002    Rise     
 6,339,725  B1  1/2002    Naritoku et al.     
 6,341,236  B1  1/2002    Osorio et al.     
 6,356,787  B1  3/2002    Rezai et al.     
 6,356,788  B2  3/2002    Boveja     
 6,381,499  B1  4/2002    Taylor et al.     
 6,405,732  B1  6/2002    Edwards et al.     
 6,407,095  B1  6/2002    Lochead et al.     
 6,428,484  B1  8/2002    Battmer et al.     
 6,429,217  B1  8/2002    Puskas     
 6,447,443  B1  9/2002    Keogh et al.     
 6,449,507  B1  9/2002    Hill et al.     
 6,473,644  B1  10/2002    Terry, Jr. et al.     
 6,479,523  B1  11/2002    Puskas     
 6,487,446  B1  11/2002    Hill et al.     
 6,511,500  B1  1/2003    Rahme     
 6,528,529  B1  3/2003    Brann et al.     
 6,532,388  B1  3/2003    Hill et al.     
 6,542,774  B2  4/2003    Hill et al.     
 6,556,868  B2  4/2003    Naritoku et al.     
 6,564,102  B1  5/2003    Boveja     
 6,587,719  B1  7/2003    Barrett et al.     
 6,587,727  B2  7/2003    Osorio et al.     
 6,600,956  B2  7/2003    Maschino et al.     
 6,602,891  B2  8/2003    Messer et al.     
 6,609,025  B2  8/2003    Barrett et al.     
 6,610,713  B2  8/2003    Tracey     
 6,611,715  B1  8/2003    Boveja     
 6,615,081  B1  9/2003    Boveja     
 6,615,085  B1  9/2003    Boveja     
 6,622,038  B2  9/2003    Barrett et al.     
 6,622,041  B2  9/2003    Terry, Jr. et al.     
 6,622,047  B2  9/2003    Barrett et al.     
 6,628,987  B1  9/2003    Hill et al.     
 6,633,779  B1  10/2003    Schuler et al.     
 6,656,960  B2  12/2003    Puskas     
 6,668,191  B1  12/2003    Boveja     
 6,671,556  B2  12/2003    Osorio et al.     
 6,684,105  B2  1/2004    Cohen et al.     
 6,690,973  B2  2/2004    Hill et al.     
 6,718,208  B2  4/2004    Hill et al.     
 6,721,603  B2  4/2004    Zabara et al.     
 6,735,471  B2  5/2004    Hill et al.     
 6,735,475  B1  5/2004    Whitehurst et al.     
 6,760,626  B1  7/2004    Boveja     
 6,778,854  B2  8/2004    Puskas     
 6,804,558  B2  10/2004    Haller et al.     
 RE38,654  E  11/2004    Hill et al.     
 6,826,428  B1  11/2004    Chen et al.     
 6,832,114  B1  12/2004    Whitehurst et al.     
 6,838,471  B2  1/2005    Tracey     
 RE38,705  E  2/2005    Hill et al.     
 6,879,859  B1  4/2005    Boveja     
 6,885,888  B2  4/2005    Rezai     
 6,904,318  B2  6/2005    Hill et al.     
 6,920,357  B2  7/2005    Osorio et al.     
 6,928,320  B2  8/2005    King     
 6,934,583  B2  8/2005    Weinberg et al.     
 6,937,903  B2  8/2005    Schuler et al.     
 6,961,618  B2  11/2005    Osorio et al.     
 6,978,787  B1  12/2005    Broniatowski     
 7,011,638  B2  3/2006    Schuler et al.     
 7,054,686  B2  5/2006    MacDonald     
 7,054,692  B1  5/2006    Whitehurst et al.     
 7,058,447  B2  6/2006    Hill et al.     
 7,062,320  B2  6/2006    Ehlinger, Jr.     
 7,069,082  B2  6/2006    Lindenthaler     
 7,072,720  B2  7/2006    Puskas     
 7,076,307  B2  7/2006    Boveja et al.     
 7,142,910  B2  11/2006    Puskas     
 7,142,917  B2  11/2006    Fukui     
 7,149,574  B2  12/2006    Yun et al.     
 7,155,279  B2  12/2006    Whitehurst et al.     
 7,155,284  B1  12/2006    Whitehurst et al.     
 7,167,750  B2  1/2007    Knudson et al.     
 7,167,751  B1  1/2007    Whitehurst et al.     
 7,174,218  B1  2/2007    Kuzma     
 7,184,828  B2  2/2007    Hill et al.     
 7,184,829  B2  2/2007    Hill et al.     
 7,191,012  B2  3/2007    Boveja et al.     
 7,204,815  B2  4/2007    Connor     
 7,209,787  B2  4/2007    DiLorenzo     
 7,225,019  B2  5/2007    Jahns et al.     
 7,228,167  B2  6/2007    Kara et al.     
 7,238,715  B2  7/2007    Tracey et al.     
 7,242,984  B2  7/2007    DiLorenzo     
 7,269,457  B2  9/2007    Shafer et al.     
 7,345,178  B2  3/2008    Nunes et al.     
 7,467,016  B2  12/2008    Colborn     
 7,544,497  B2  6/2009    Sinclair et al.     
 7,561,918  B2  7/2009    Armstrong et al.     
 7,711,432  B2  5/2010    Thimineur et al.     
 7,729,760  B2  6/2010    Patel et al.     
 7,751,891  B2  7/2010    Armstrong et al.     
 7,776,326  B2  8/2010    Milbrandt et al.     
 7,797,058  B2  9/2010    Mrva et al.     
 7,819,883  B2*10/2010    Westlund et al. 606/129
 7,822,486  B2  10/2010    Foster et al.     
 7,829,556  B2  11/2010    Bemis et al.     
 7,869,885  B2  1/2011    Begnaud et al.     
 7,937,145  B2  5/2011    Dobak     
 7,962,220  B2  6/2011    Kolafa et al.     
 7,974,701  B2  7/2011    Armstrong     
 7,974,707  B2  7/2011    Inman     
 7,996,088  B2  8/2011    Marrosu et al.     
 7,996,092  B2  8/2011    Mrva et al.     
 8,019,419  B1  9/2011    Panescu et al.     
 8,103,349  B2  1/2012    Donders et al.     
 8,165,668  B2  4/2012    Dacey, Jr. et al.     
 8,180,446  B2  5/2012    Dacey, Jr. et al.     
 8,195,287  B2  6/2012    Dacey, Jr. et al.     
 8,214,056  B2  7/2012    Hoffer et al.     
 8,233,982  B2  7/2012    Libbus     
 2001//0002441  A1  5/2001    Boveja     
 2002//0026141  A1  2/2002    Houben et al.     
 2002//0040035  A1  4/2002    Myers et al.     
 2002//0077675  A1  6/2002    Greenstein     
 2002//0086871  A1  7/2002    O'Neill et al.     
 2002//0095139  A1  7/2002    Keogh et al.     
 2002//0099417  A1  7/2002    Naritoku et al.     
 2002//0138075  A1  9/2002    Edwards et al.     
 2002//0138109  A1  9/2002    Keogh et al.     
 2002//0193859  A1  12/2002    Schulman et al.     
 2002//0198570  A1  12/2002    Puskas     
 2003//0018367  A1  1/2003    DiLorenzo     
 2003//0045909  A1  3/2003    Gross et al.     
 2003//0088301  A1  5/2003    King     
 2003//0191404  A1  10/2003    Klein     
 2003//0194752  A1  10/2003    Anderson et al.     
 2003//0212440  A1  11/2003    Boveja     
 2003//0229380  A1  12/2003    Adams et al.     
 2003//0236557  A1  12/2003    Whitehurst et al.     
 2003//0236558  A1  12/2003    Whitehurst et al.     
 2004//0015202  A1  1/2004    Chandler et al.     
 2004//0015205  A1  1/2004    Whitehurst et al.     
 2004//0024422  A1  2/2004    Hill et al.     
 2004//0024428  A1  2/2004    Barrett et al.     
 2004//0024439  A1  2/2004    Riso     
 2004//0030362  A1  2/2004    Hill et al.     
 2004//0039427  A1  2/2004    Barrett et al.     
 2004//0048795  A1  3/2004    Ivanova et al.     
 2004//0049121  A1  3/2004    Yaron     
 2004//0059383  A1  3/2004    Puskas     
 2004//0111139  A1  6/2004    McCreery et al.     
 2004//0138517  A1  7/2004    Osorio et al.     
 2004//0138518  A1  7/2004    Rise et al.     
 2004//0138536  A1  7/2004    Frei et al.     
 2004//0146949  A1  7/2004    Tan et al.     
 2004//0153127  A1  8/2004    Gordon et al.     
 2004//0158119  A1  8/2004    Osorio et al.     
 2004//0162584  A1  8/2004    Hill et al.     
 2004//0172074  A1  9/2004    Yoshihito     
 2004//0172085  A1  9/2004    Knudson et al.     
 2004//0172086  A1  9/2004    Knudson et al.     
 2004//0172088  A1  9/2004    Knudson et al.     
 2004//0172094  A1  9/2004    Cohen et al.     
 2004//0176812  A1  9/2004    Knudson et al.     
 2004//0178706  A1  9/2004    D'Orso     
 2004//0193231  A1  9/2004    David et al.     
 2004//0199209  A1  10/2004    Hill et al.     
 2004//0199210  A1  10/2004    Shelchuk     
 2004//0204355  A1  10/2004    Tracey et al.     
 2004//0215287  A1  10/2004    Swoyer et al.     
 2004//0236381  A1  11/2004    Dinsmoor et al.     
 2004//0236382  A1  11/2004    Dinsmoor et al.     
 2004//0240691  A1  12/2004    Grafenberg     
 2004//0243182  A1  12/2004    Cohen et al.     
 2004//0254612  A1  12/2004    Ezra et al.     
 2004//0267152  A1  12/2004    Pineda     
 2005//0021092  A1  1/2005    Yun et al.     
 2005//0021101  A1  1/2005    Chen et al.     
 2005//0027328  A1  2/2005    Greenstein     
 2005//0043774  A1  2/2005    Devlin et al.     
 2005//0049655  A1  3/2005    Boveja et al.     
 2005//0065553  A1  3/2005    Ben Ezra et al.     
 2005//0065573  A1  3/2005    Rezai     
 2005//0065575  A1  3/2005    Dobak     
 2005//0070970  A1  3/2005    Knudson et al.     
 2005//0070974  A1  3/2005    Knudson et al.     
 2005//0075701  A1  4/2005    Shafer     
 2005//0075702  A1  4/2005    Shafer     
 2005//0095246  A1  5/2005    Shafer     
 2005//0096707  A1  5/2005    Hill et al.     
 2005//0125044  A1  6/2005    Tracey et al.     
 2005//0131467  A1  6/2005    Boveja     
 2005//0131486  A1  6/2005    Boveja et al.     
 2005//0131487  A1  6/2005    Boveja     
 2005//0131493  A1  6/2005    Boveja et al.     
 2005//0137644  A1  6/2005    Boveja et al.     
 2005//0137645  A1  6/2005    Voipio et al.     
 2005//0143781  A1  6/2005    Carbunaru et al.     
 2005//0143787  A1  6/2005    Boveja et al.     
 2005//0149126  A1  7/2005    Libbus     
 2005//0149129  A1  7/2005    Libbus et al.     
 2005//0149131  A1  7/2005    Libbus et al.     
 2005//0153885  A1  7/2005    Yun et al.     
 2005//0154425  A1  7/2005    Boveja et al.     
 2005//0154426  A1  7/2005    Boveja et al.     
 2005//0165458  A1  7/2005    Boveja et al.     
 2005//0177200  A1  8/2005    George et al.     
 2005//0182288  A1  8/2005    Zabara     
 2005//0182467  A1  8/2005    Hunter et al.     
 2005//0187584  A1  8/2005    Denker et al.     
 2005//0187586  A1  8/2005    David et al.     
 2005//0187590  A1  8/2005    Boveja et al.     
 2005//0192644  A1  9/2005    Boveja et al.     
 2005//0197600  A1  9/2005    Schuler et al.     
 2005//0197675  A1  9/2005    David et al.     
 2005//0197678  A1  9/2005    Boveja et al.     
 2005//0203501  A1  9/2005    Aldrich et al.     
 2005//0209654  A1  9/2005    Boveja et al.     
 2005//0216064  A1  9/2005    Heruth et al.     
 2005//0216070  A1  9/2005    Boveja et al.     
 2005//0216071  A1  9/2005    Devlin et al.     
 2005//0240229  A1  10/2005    Whitehurst et al.     
 2005//0240231  A1  10/2005    Aldrich et al.     
 2005//0240241  A1  10/2005    Yun et al.     
 2005//0251220  A1  11/2005    Barrett et al.     
 2005//0251222  A1  11/2005    Barrett et al.     
 2005//0267542  A1  12/2005    David et al.     
 2005//0267547  A1  12/2005    Knudson et al.     
 2005//0282906  A1  12/2005    Tracey et al.     
 2005//0283198  A1  12/2005    Haubrich et al.     
 2006//0009815  A1  1/2006    Boveja et al.     
 2006//0015151  A1  1/2006    Aldrich     
 2006//0025828  A1  2/2006    Armstrong et al.     
 2006//0036293  A1  2/2006    Whitehurst et al.     
 2006//0052657  A9  3/2006    Zabara     
 2006//0052831  A1  3/2006    Fukui     
 2006//0052836  A1  3/2006    Kim et al.     
 2006//0058851  A1  3/2006    Cigaina     
 2006//0064137  A1  3/2006    Stone     
 2006//0064139  A1  3/2006    Chung et al.     
 2006//0074450  A1  4/2006    Boveja et al.     
 2006//0074473  A1  4/2006    Gertner     
 2006//0079936  A1  4/2006    Boveja et al.     
 2006//0085046  A1  4/2006    Rezai et al.     
 2006//0095081  A1  5/2006    Zhou et al.     
 2006//0095090  A1  5/2006    De Ridder     
 2006//0100668  A1  5/2006    Ben-David et al.     
 2006//0106755  A1  5/2006    Stuhec     
 2006//0111644  A1  5/2006    Guttag et al.     
 2006//0111754  A1  5/2006    Rezai et al.     
 2006//0111755  A1  5/2006    Stone et al.     
 2006//0116739  A1  6/2006    Betser et al.     
 2006//0122675  A1  6/2006    Libbus et al.     
 2006//0129200  A1  6/2006    Kurokawa     
 2006//0129202  A1  6/2006    Armstrong     
 2006//0135998  A1  6/2006    Libbus et al.     
 2006//0142802  A1  6/2006    Armstrong     
 2006//0142822  A1  6/2006    Tulgar     
 2006//0149337  A1  7/2006    John     
 2006//0161216  A1  7/2006    John et al.     
 2006//0161217  A1  7/2006    Jaax et al.     
 2006//0167497  A1  7/2006    Armstrong et al.     
 2006//0167498  A1  7/2006    DiLorenzo     
 2006//0167501  A1  7/2006    Ben-David et al.     
 2006//0173493  A1  8/2006    Armstrong et al.     
 2006//0173508  A1  8/2006    Stone et al.     
 2006//0178691  A1  8/2006    Binmoeller     
 2006//0178703  A1  8/2006    Huston et al.     
 2006//0178706  A1  8/2006    Lisogurski et al.     
 2006//0190044  A1  8/2006    Libbus et al.     
 2006//0200208  A1  9/2006    Terry, Jr. et al.     
 2006//0200219  A1  9/2006    Thrope et al.     
 2006//0206155  A1  9/2006    Ben-David et al.     
 2006//0206158  A1  9/2006    Wu et al.     
 2006//0229677  A1  10/2006    Moffitt et al.     
 2006//0229681  A1  10/2006    Fischell     
 2006//0241699  A1  10/2006    Libbus et al.     
 2006//0247719  A1  11/2006    Maschino et al.     
 2006//0247721  A1  11/2006    Maschino et al.     
 2006//0247722  A1  11/2006    Maschino et al.     
 2006//0259077  A1  11/2006    Pardo et al.     
 2006//0259084  A1  11/2006    Zhang et al.     
 2006//0259085  A1  11/2006    Zhang et al.     
 2006//0259107  A1  11/2006    Caparso et al.     
 2006//0271115  A1  11/2006    Ben-Ezra et al.     
 2006//0282121  A1  12/2006    Payne et al.     
 2006//0282131  A1  12/2006    Caparso et al.     
 2006//0282145  A1  12/2006    Caparso et al.     
 2006//0287678  A1  12/2006    Shafer     
 2006//0287679  A1  12/2006    Stone     
 2006//0292099  A1  12/2006    Milburn et al.     
 2006//0293720  A1  12/2006    DiLorenzo     
 2006//0293721  A1  12/2006    Tarver et al.     
 2006//0293723  A1  12/2006    Whitehurst et al.     
 2007//0016262  A1  1/2007    Gross et al.     
 2007//0016263  A1  1/2007    Armstrong et al.     
 2007//0021785  A1  1/2007    Inman et al.     
 2007//0021786  A1  1/2007    Parnis et al.     
 2007//0021814  A1  1/2007    Inman et al.     
 2007//0025608  A1  2/2007    Armstrong     
 2007//0027482  A1  2/2007    Parnis et al.     
 2007//0027483  A1  2/2007    Maschino et al.     
 2007//0027484  A1  2/2007    Guzman et al.     
 2007//0027486  A1  2/2007    Armstrong     
 2007//0027492  A1  2/2007    Maschino et al.     
 2007//0027496  A1  2/2007    Parnis et al.     
 2007//0027497  A1  2/2007    Parnis     
 2007//0027498  A1  2/2007    Maschino et al.     
 2007//0027499  A1  2/2007    Maschino et al.     
 2007//0027500  A1  2/2007    Maschino et al.     
 2007//0027504  A1  2/2007    Barrett et al.     
 2007//0055324  A1  3/2007    Thompson et al.     
 2007//0067004  A1  3/2007    Boveja et al.     
 2007//0083242  A1  4/2007    Mazgalev et al.     
 2007//0093434  A1  4/2007    Rossetti et al.     
 2007//0093870  A1  4/2007    Maschino     
 2007//0093875  A1  4/2007    Chavan et al.     
 2007//0100263  A1  5/2007    Merfeld     
 2007//0100377  A1  5/2007    Armstrong et al.     
 2007//0100378  A1  5/2007    Maschino     
 2007//0100380  A1  5/2007    Fukui     
 2007//0100392  A1  5/2007    Maschino et al.     
 2007//0106339  A1  5/2007    Errico et al.     
 2007//0118177  A1  5/2007    Libbus et al.     
 2007//0118178  A1  5/2007    Fukui     
 2007//0129780  A1  6/2007    Whitehurst et al.     
 2007//0135846  A1  6/2007    Knudson et al.     
 2007//0135856  A1  6/2007    Knudson et al.     
 2007//0135857  A1  6/2007    Knudson et al.     
 2007//0135858  A1  6/2007    Knudson et al.     
 2007//0142870  A1  6/2007    Knudson et al.     
 2007//0142871  A1  6/2007    Libbus et al.     
 2007//0142874  A1  6/2007    John     
 2007//0150006  A1  6/2007    Libbus et al.     
 2007//0150011  A1  6/2007    Meyer et al.     
 2007//0150021  A1  6/2007    Chen et al.     
 2007//0150027  A1  6/2007    Rogers     
 2007//0156180  A1  7/2007    Jaax et al.     
 2007//0239243  A1  10/2007    Moffitt et al.     
 2007//0250145  A1  10/2007    Kraus et al.     
 2007//0255320  A1  11/2007    Inman et al.     
 2007//0255333  A1  11/2007    Giftakis     
 2008//0021517  A1  1/2008    Dietrich     
 2008//0021520  A1  1/2008    Dietrich     
 2008//0046055  A1  2/2008    Durand et al.     
 2008//0058871  A1  3/2008    Libbus et al.     
 2008//0103407  A1  5/2008    Bolea et al.     
 2008//0140138  A1  6/2008    Ivanova et al.     
 2008//0183226  A1  7/2008    Buras et al.     
 2008//0183246  A1  7/2008    Patel et al.     
 2008//0208266  A1  8/2008    Lesser et al.     
 2008//0234790  A1  9/2008    Bayer et al.     
 2008//0249439  A1  10/2008    Tracey et al.     
 2008//0281365  A1  11/2008    Tweden et al.     
 2009//0012590  A1  1/2009    Inman et al.     
 2009//0048194  A1  2/2009    Aerssens et al.     
 2009//0062874  A1  3/2009    Tracey et al.     
 2009//0082832  A1  3/2009    Carbunaru et al.     
 2009//0105782  A1  4/2009    Mickle et al.     
 2009//0123521  A1  5/2009    Weber et al.     
 2009//0125079  A1  5/2009    Armstrong et al.     
 2009//0143831  A1  6/2009    Huston et al.     
 2009//0171405  A1  7/2009    Craig     
 2009//0177112  A1  7/2009    Gharib et al.     
 2009//0187231  A1  7/2009    Errico et al.     
 2009//0247934  A1  10/2009    Tracey et al.     
 2009//0248097  A1  10/2009    Tracey et al.     
 2009//0254143  A1  10/2009    Tweden et al.     
 2009//0275997  A1  11/2009    Faltys et al.     
 2009//0276019  A1  11/2009    Perez et al.     
 2009//0281593  A9  11/2009    Errico et al.     
 2010//0003656  A1  1/2010    Kilgard et al.     
 2010//0010603  A1  1/2010    Ben-David et al.     
 2010//0042186  A1  2/2010    Ben-David et al.     
 2010//0063563  A1  3/2010    Craig     
 2010//0125304  A1  5/2010    Faltys     
 2010//0191304  A1  7/2010    Scott     
 2010//0215632  A1  8/2010    Boss et al.     
 2010//0241183  A1  9/2010    DiLorenzo     
 2010//0249859  A1  9/2010    DiLorenzo     
 2010//0280569  A1  11/2010    Bobillier et al.     
 2011//0004266  A1  1/2011    Sharma     
 2011//0066208  A1  3/2011    Pasricha et al.     
 2011//0092882  A1  4/2011    Firlik et al.     
 2011//0307027  A1  12/2011    Sharma et al.     
 2012//0065706  A1  3/2012    Vallapureddy et al.     

 
 FOREIGN PATENT DOCUMENTS 
 
       CN       201230913                         5/2009      
       DE       2628045       A1                1/1977      
       DE       3736664       A1                5/1989      
       DE       20316509       U1                4/2004      
       EP       0438510       B1                8/1996      
       EP       0726791       B1                6/2000      
       EP       1001827       B1                1/2004      
       EP       2213330       A2                8/2010      
       EP       2073896       B1                10/2011      
       GB       04133                         2/1910      
       WO       WO93/01862       A1                2/1993      
       WO       WO97/30998       A1                8/1997      
       WO       WO98/20868       A1                5/1998      
       WO       WO00/27381       A2                5/2000      
       WO       WO00/47104       A2                8/2000      
       WO       WO01/00273       A1                1/2001      
       WO       WO01/08617       A1                2/2001      
       WO       WO01/89526       A1                11/2001      
       WO       WO02/44176       A1                6/2002      
       WO       WO02/057275       A1                7/2002      
       WO       WO03/072135       A2                9/2003      
       WO       WO20/04/000413       A2                12/2003      
       WO       WO20/04/064918       A1                8/2004      
       WO       WO20/06/073484       A1                7/2006      
       WO       WO20/06/076681       A2                7/2006      
       WO       WO20/07/133718       A2                11/2007      

 OTHER PUBLICATIONS
  
  Faltys et al.; U.S. Appl. No. 12/917,197 entitled “Modulation of the cholinergic anti-inflammatory pathway to treat pain or addiction,” filed Nov. 1, 2010.
  Faltys et al.; U.S. Appl. No. 12/978,250 entitled “Neural stimulation devices and systems for treatment of chronic inflammation,” filed Dec. 23, 2010.
  Ben-Noun et al.; Neck circumference as a simple screening measure for identifying overweight and obese patients; Obesity Research; vol. 9; No. 8; pp. 470-477; Aug. 8, 2001.
  Biggio et al.; Chronic vagus nerve stimulation induces neuronal plasticity in the rat hippocampus; Int. J. Neurpsychopharmacol.; vol. 12; No. 9; pp. 1209-1221; Oct. 2009.
  Bushby et al; Centiles for adult head circumference; Archives of Disease in Childhood; vol. 67; pp. 1286-1287; 1992.
  Fields; New culprits in chronic pain; Scientific American; pp. 50-57; Nov. 2009.
  Hansson, E.; Could chronic pain and spread of pain sensation be induced and maintained by glial activation?. Acta Physiologica, vol. 187: pp. 321R327, 2006.
  Hutchinson et al.; Proinflammatory cytokines oppose opioid induced acute and chronic analgesia; Brain Behav Immun.; vol. 22; No. 8; pp. 1178-1189; Nov. 2008.
  Miguel-Hidalgo, J.J.; The role of glial cells in drug abuse; Current Drug Abuse Reviews; vol. 2; No. 1; pp. 76-82; 2009.
  Milligan et al.; Pathological and protective roles of glia in chronic pain; Nat Rev Neurosci.; vol. 10; No. 1; pp. 23-26; Jan. 2009.
  Pulvirenti et al; Drug dependence as a disorder of neural plasticity:focus on dopamine and glutamate; Rev Neurosci.; vol. 12; No. 2; pp. 141-158; 2001.
  Suter et al.; Do glial cells control pain?; Neuron Glia Biol.; vol. 3; No. 3; pp. 255-268; Aug. 2007.
  Vijayaraghavan, S.; Glial-neuronal interactions—implications for plasticity anddrug addictionl AAPS J.; vol. 11; No. 1; pp. 123-132; 2009.
  Tracey, K. J.; Reflex control of immunity; Nat Rev Immunol; 9(6); pp. 418-428; Jun. 2009.
  Levine et al.; U.S. Appl. No. 13/851,013 entitled “Devices and methods for modulation of bone erosion,” filed Mar. 26, 2013.
  Levine, Jacob A.; U.S. Appl. No. 13/338,185 entitled “Modulation of sirtuins by vagus nerve stimulation” , filed Dec. 27, 2011.
  Kawahara et al.; SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.; Cell. ; vol. 136; No. 1; pp. 62-74; Jan. 2009.
  Nadol et al., “Surgery of the Ear and Temporal Bone,” Lippinkott Williams & Wilkins, 2nd Ed., 2005, (Publication date: Sep. 21, 2004), p. 580.
  Tracey, K. J. et al., Physiology and immunology of the cholinergic antiinflammatory pathway; J Clin Invest.; vol. 117: No. 2; pp. 289-296; Feb. 2007.
  Van Der Horst et al.; Stressing the role of FoxO proteins in lifespan and disease; Nat Rev Mol Cell Biol.; vol. 8; No. 6; pp. 440-450; Jun. 2007.
  Westerheide et al.; Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1.; Science; Vo. 323; No. 5717; pp. 1063-1066; Feb. 2009.
  Payne, J. B. et al., Nicotine effects on PGE2 and IL-1 beta release by LPS-treated human monocytes, J. Perio. Res., vol. 31, No. 2, pp. 99-104, 1996.
  Pullan, R. D., et al., Transdermal nicotine for active ulceratiive colitis, N. Engl. J. Med., vol. 330, No. 12, pp. 811-815, 1994.
  Takeuchi et al., A comparision between chinese blended medicine “Shoseiryuto” tranilast and ketotifen on the anit-allergic action in the guinea pigs, Allergy, vol. 34, No. 6, pp. 387-393, 1985 (eng. abstract).
  Levine et al.; U.S. Appl. No. 13/467,928 entitled “Single-Pulse Activation of the Cholinergic Anti-Inflammatory Pathway to Treat Chronic Inflammation,” filed May 9, 2012.
  US 6,184,239, 2/2001, Puskas (withdrawn).
  Abraham, Coagulation abnormalities in acute lung injury and sepsis, Am. J. Respir. Cell Mol. Biol., vol. 22, pp. 401-404, 2000.
  Aekerlund et al., Anti-inflammatory effects of a new tumour necrosis factor-alpha (TNF-Alpha) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats, Clinical & Experimental Immunology, vol. 115, No. 1, pp. 32-41, Jan. 1, 1999.
  Antonica, A., et al., Vagal control of lymphocyte release from rat thymus, J. Auton. Nerv. Syst., vol. 48, pp. 187-197, 1994.
  Asakura et al., Non-surgical therapy for ulcerative colitis, Nippon Geka Gakkai Zasshi, vol. 98, No. 4, pp. 431-437, Apr. 1997 (abstract only).
  Benthem et al.; Parasympathetic inhibition of sympathetic neural activity to the pancreas; Am.J.Physiol Endocrinol.Metab; 280; pp. E378-E381; 2001.
  Bernik et al., Vagus nerve stimulation attenuates cardiac TNF production in endotoxic shock, (supplemental to SHOCK, vol. 15, 2001, Injury, inflammation and sepsis: laboratory and clinical approaches, SHOCK, Abstracts, 24th Annual Conference on Shock, Marco Island, FL, Jun. 9-12, 2001), Abstract No. 81.
  Bernik et al., Vagus nerve stimulation attenuates endotoxic shock and cardiac TNF production, 87th Clinical Congress of the American College of Surgeons, New Orleans, LA, Oct. 9, 2001.
  Bernik et al., Vagus nerve stimulation attenuates LPS-induced cardiac TNF production and myocardial depression in shock, New York Surgical Society, New York, NY, Apr. 11, 2001.
  Bernik, et al., Pharmacological stimulation of the cholinergic anti-inflammatory pathway, The Journal of Experimental Medicine, vol. 195, No. 6, pp. 781-788, Mar. 18, 2002.
  Besedovsky, H., et al., Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones, Science, vol. 233, pp. 652-654, 1986.
  Bhattacharya, S.K. et al., Central muscarinic receptor subtypes and carrageenin-induced paw oedema in rats, Res. Esp. Med. vol. 191, pp. 65-76, 1991.
  Bianchi et al., Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone, Journal of Experimental Medicine, vol. 183, pp. 927-936, Mar. 1996.
  Blackwell, T. S. et al., Sepsis and cytokines: current status, Br. J. Anaesth., vol. 77, pp. 110-117, 1996.
  Blum, A. et al., Role of cytokines in heart failure, Am. Heart J., vol. 135, pp. 181-186, 1998.
  Boldyreff, Gastric and intestinal mucus, its properties and physiological importance, Acta Medica Scandinavica (journal), vol. 89, pp. 1-14, 1936.
  Borovikova et al., Acetylcholine inhibition of immune response to bacterial endotoxin in human macrophages, Abstracts, Society for Neuroscience, 29th Annual Meeting, Miami Beach, FL, Oct. 23-28, 1999, Abstract No. 624.6.
  Borovikova et al., Efferent vagus nerve activity attenuates cytokine-mediated inflammation, Society for Neuroscience Abstracts, vol. 26, No. 102, 2000 (abstract only).
  Borovikova et al., Intracerebroventricular CNI-1493 prevents LPS-induced hypotension and peak serum TNF at a four-log lower dose than systemic treatment, 21st Annual Conference on Shock, San Antonio, TX, Jun. 14-17, 1998, Abstract No. 86.
  Borovikova et al., Role of the efferent vagus nerve signaling in the regulation of the innate immune response to LPS, (supplemental to SHOCK, vol.13, 2000, Molecular, cellular and systemic pathobiological aspects and therapeutic approaches, absracts, 5th World Congress on Trauma, Shock inflammation and sepsis-pathophysiology, immune consequences and therapy, Feb. 29, 2000-Mar. 4, 2000, Munich, DE), Abstract No. 166.
  Borovikova et al., Role of the vagus nerve in the anti-inflammatory effects of CNI-1493, the FASEB journal, vol. 14, No. 4, 2000 (Experimental Biology 2000, San Diego, CA, Apr. 15-18, 2000, Abstract No. 97.9).
  Borovikova et al., Vagotomy blocks the protective effects of I.C.V. CNI-1493 against LPS-induced shock, (Supplemental to SHOCK, vol. 11, 1999, Molecular, cellular, and systemic pathobioloigal aspects and therapeutic approaches, abstacts and program, Fourth International Shock Congress and 22nd Annual Conference on Shock, Philadelphia, PA, Jun. 12-16, 1999), Abstract No. 277.
  Borovikova, L. V., et al., Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation, Autonomic Neuroscience, vol. 85, No. 1-3, pp. 141-147, Dec. 20, 2000.
  Borovikova, L. V., et al., Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin, Nature, vol. 405, No. 6785: pp. 458-462, May 25, 2000.
  Bulloch et al.; Characterization of choline O-acetyltransferase (ChAT) in the BALB/C mouse spleen; Int.J.Neurosci.; 76; pp. 141-149; 1994.
  Bumgardner, G. L. et al., Transplantation and cytokines, Seminars in Liver Disease, vol. 19, No. 2, pp. 189-204, 1999.
  Burke et al., Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HIV-1) reverse transcriptase, J. Mol. Biol., vol. 264; pp. 650-666, 1996.
  Cano et al.; Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing; J.Comp Neurol.; 439; pp. 1-18; 2001.
  Carteron, N. L., Cytokines in rheumatoid arthritis: trials and tribulations, Mol. Med. Today, vol. 6, pp. 315-323, 2000.
  Corcoran, et al., The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in humans: a preliminary report, NeuroImmunoModulation, vol. 12, pp. 307-309, 2005.
  Das, Critical advances in spticemia and septic shock, Critical Care, vol. 4, pp. 290-296, Sep. 7, 2000.
  Del Signore et al; Nicotinic acetylcholine receptor subtypes in the rat sympathetic ganglion: pharmacological characterization, subcellular distribution and effect of pre- and postganglionic nerve crush; J.Neuropathol.Exp.Neurol.; 63(2); pp. 138-150; Feb. 2004.
  Dibbs, Z., et al., Cytokines in heart failure: pathogenetic mechanisms and potential treatment, Proc. Assoc. Am. Physicians, vol. 111, No. 5, pp. 423-428, 1999.
  Dinarello, C. A., The interleukin-1 family: 10 years of discovery, FASEB J., vol. 8, No. 15, pp. 1314-1325, 1994.
  Doshi et al., Evolving role of tissue factor and its pathway inhibitor, Crit. Care Med., vol. 30, suppl. 5, pp. S241-S250, 2002.
  Ellington et al., In vitro selection of RNA molecules that bind specific ligands, Nature, vol. 346, pp. 818-822, Aug. 30, 1990.
  Esmon, The protein C pathway, Crit. Care Med., vol. 28, suppl. 9, pp. S44-S48, 2000.
  Fleshner, M., et al., Thermogenic and corticosterone responses to intravenous cytokines (IL-1? and TNF-?) are attenuated by subdiaphragmatic vagotomy, J. Neuroimmunol., vol. 86, pp. 134-141, 1998.
  Fox, D. A., Cytokine blockade as a new strategy to treat rheumatoid arthritis, Arch. Intern. Med., vol. 160, pp. 437-444, Feb. 28, 2000.
  Fox, et al., Use of muscarinic agonists in the treatment of Sjorgren' syndrome, Clin. Immunol., vol. 101, No. 3; pp. 249-263, 2001.
  Fujii et al.; Simvastatin regulates non-neuronal cholinergic activity in T lymphocytes via CD11a-mediated pathways; J. Neuroimmunol.; 179(1-2); pp. 101-107; Oct. 2006.
  Gattorno, M., et al., Tumor necrosis factor induced adhesion molecule serum concentrations in henoch-schoenlein purpura and pediatric systemic lupus erythematosus, J. Rheumatol., vol. 27, No. 9, pp. 2251-2255, 2000.
  Gaykema, R. P., et al., Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion, Endocrinology, vol. 136, No. 10, pp. 4717-4720, 1995.
  Ghelardini et al., S-(-)-ET 126: A potent and selective M1 antagonist in vitro and in vivo, Life Sciences, vol. 58, No. 12, pp. 991-1000, 1996.
  Ghia, et al., The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model, Gastroenterology, vol. 131, pp. 1122-1130, 2006.
  Giebelen, et al., Stimulation of ?7 cholinergic receptors inhibits lipopolysaccharide-induced neutrophil recruitment by a tumor necrosis factor ?-independent mechanism, SHOCK, vol. 27, No. 4, pp. 443-447, 2007.
  Goyal et al., Nature of the vagal inhibitory innervation to the lower esophageal sphincter, Journal of Clinical Investigation, vol. 55, pp. 1119-1126, May 1975.
  Gracie, J. A., et al., A proinflammatory role for IL-18 in rheumatoid arthritis, J. Clin. Invest., vol. 104, No. 10, pp. 1393-1401, 1999.
  Granert et al., Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic haemophilus influenzae infection, Infection and Immunity, vol. 68, No. 9, pp. 5329-5334, Sep. 2000.
  Green et al., Feedback technique for deep relaxation, Psycophysiology, vol. 6, No. 3, pp. 371-377, Nov. 1969.
  Gregory et al., Neutrophil-kupffer-cell interaction in host defenses to systemic infections, Immunology Today, vol. 19, No. 11, pp. 507-510, Nov. 1998.
  Guslandi, M., Nicotine treatment for ulcerative colitis, Br. J. Clin. Pharmacol., vol. 48, pp. 481-484, 1999.
  Harrison's Principles of Internal Medicine, vol. 13, pp. 511-515 and 1433-1435, 1994.
  Hatton et al.; Vagal nerve stimulation: overview and implications for anesthesiologists; Int'l Anesthesia Research Society; vol. 103; No. 5; pp. 1241-1249; Nov. 2006.
  Hirano, T., Cytokine suppresive agent improves survival rate in rats with acute pancreatitis of closed duodenal loop, J. Surg. Res., vol. 81, No. 2, pp. 224-229, 1999.
  Hirao et al., the limits of specificity: an experimental analysis with RNA aptamers to MS2 coat protein variants, Mol. Divers., vol. 4, pp. 75-89, 1999.
  Hoffer et al.; Implantable electrical and mechanical interfaces with nerve and muscle; Annals of Biomedical Engineering; vol. 8; pp. 351-360; 1980.
  Holladay et al., Neuronal nicotinic acetylcholine receptors as targets for drug discovery, Journal of Medicinal Chemistry, 40, pp. 4169-4194, 1997.
  Hommes, D. W. et al., Anti- and Pro-inflammatory cytokines in the pathogenesis of tissue damage in Crohn's disease, Current Opinion in Clinical Nutrition and Metabolic Care, vol. 3., pp. 191-195, 2000.
  Hsu, et al., Analysis of efficiency of magnetic stimulation, IEEE Trans. Biomed. Eng., vol. 50(11), pp. 1276-1285, Nov. 2003.
  Hsu, H. Y., et al., Cytokine release of peripheral blood monoculear cells in children with chronic hepatitis B virus infection, J. Pediatr. Gastroenterol., vol. 29, No. 5, pp. 540-545, 1999.
  Hu, et al., The effect of norepinephrine on endotoxin-mediated macrophage activation, J. Neuroimmunol., vol. 31, pp. 35-42, 1991.
  Huston et al.; Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis; J. Exp. Med. 2006; vol. 203; pp. 1623-1628; 2006.
  Ilton et al., “Differential expression of neutrophil adhesion molecules during coronary artery surgery with cardiopulmonary bypass” Journal of Thoracic and Cardiovascular Surgery, Mosby-Year Book, inc., St. Louis, Mo, US, pp. 930-937, Nov. 1, 1999.
  Jaeger et al., The structure of HIV-1 reverse transcriptase complexed with an RNA pseudoknot inhibitor, the EMBO Journal, 17(15), pp. 4535-4542, 1998.
  Jander, S. et al., Interleukin-18 is induced in acute inflammatory demyelinating polymeuropathy, J. Neuroimmunol., vol. 114, pp. 253-258, 2001.
  Joshi et al., Potent inhibition of human immunodeficiency virus type 1 replection by template analog reverse transcriptase , J. Virol., 76(13), pp. 6545-6557, Jul. 2002.
  Kanai, T. et al., Interleukin-18 and Crohn's disease, Digestion, vol. 63, suppl. 1, pp. 37-42, 2001.
  Katagiri, M., et al., Increased cytokine production by gastric mucosa in patients with helicobacter pylori infection, J. Clin, Gastroenterol., vol. 25, Suppl. 1, pp. S211-S214, 1997.
  Kawashima, et al., Extraneuronal cholinergic system in lymphocytes, Pharmacology & Therapeutics, vol. 86, pp. 29-48, 2000.
  Kees et al; Via beta-adrenoceptors, stimulation of extrasplenic sympathetic nerve fibers inhibits lipopolysaccharide-induced TNF secretion in perfused rat spleen; J.Neuroimmunol.; 145; pp. 77-85; 2003.
  Kensch et al., HIV-1 reverse transcriptase-pseudoknot RNA aptamer interaction has a binding affinity in the low picomolar range coupled with high specificity, J. Biol. Chem., 275(24), pp. 18271-18278, Jun. 16, 2000.
  Kimball, et al., Levamisole causes differential cytokine expression by elicited mouse peritoneal macrophases, Journal of Leukocyte Biology, vo. 52, No. 3, pp. 349-356, 1992 (abstract only).
  Kimmings, A. N., et al., Systemic inflammatory response in acute cholangitis and after subsequent treatment, Eur. J. Surg., vol. 166, pp. 700-705, 2000.
  Kirchner et al.; Left vagus nerve stimulation suppresses experimentally induced pain; Neurology; vol. 55; pp. 1167-1171; 2000.
  Kokkula, R. et al., Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity, Arthritis Rheum., 48(7), pp. 2052-2058, Jul. 2003.
  Krarup et al; Conduction studies in peripheral cat nerve using implanted electrodes: I. methods and findings in controls; Muscle & Nerve; vol. 11; pp. 922-932; Sep. 1988.
  Kumins, N. H., et al., Partial hepatectomy reduces the endotoxin-induced peak circulating level of tumor necrosis factor in rats, SHOCK, vol. 5, No. 5, pp. 385-388, 1996.
  Lee, H. G., et al., Peritoneal lavage fluids stimulate NIH3T3 fibroblast proliferation and contain increased tumour necrosis factor and IL6 in experimental silica-induced rat peritonitis, Clin. Exp. Immunol., vol. 100, pp. 139-144, 1995.
  LeNovere, N. et al., Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells, J. Mol. Evol., 40, pp. 155-172, 1995.
  Leonard, S. et al., Neuronal nicotinic receptors: from structure to function, Nicotine & Tobacco Res. 3:203-223 (2001).
  Lips et al.; Coexpression and spatial association of nicotinic acetylcholine receptor subunits alpha7 and alpha10 in rat sympathetic neurons; J.Mol.Neurosci.; 30; pp. 15-16; 2006.
  Lipton, J. M. et al.; Anti-inflammatory actions of the neuroimmunomodulator ?-MSH, Immunol. Today, vol. 18, pp. 140-145, 1997.
  Loeb et al.; Cuff electrodes for chronic stimulation and recording of peripheral nerve activity; Journal of Neuroscience Methods; vol. 64; pp. 95-103; 1996.
  Madretsma, G. S., et al., Nicotine inhibits the in vitro production of interleukin 2 and tumour necrosis factor-alpha by human monocuclear cells, Immunopharmacology, vol. 35, No. 1, pp. 47-51, 1996.
  Martindale: The extrapharcopoeia; 28th Ed. London; The pharmaceutical press; pp. 446-485; 1982.
  Martiney et al., Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent, Journal of Immunology, vol. 160, No. 11, pp. 5588-5595, Jun. 1, 1998.
  McGuinness, P. H., et al., Increases in intrahepatic CD68 positive cells, MAC387 positive cells, and proinflammatory cytokines (particulary interleukin 18) in chronic hepatitis C infection, Gut, vol. 46, pp. 260-269, 2000.
  Minnich et al.; Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls; Proceedings of the Nutrition Society; vol. 63; pp. 437-441; 2004.
  Molina et al., CNI-1493 attenuates hemodynamic and pro-inflammatory responses to LPS, Shock, vol. 10, No. 5, pp. 329-334, Nov. 1998.
  Nagashima et al., Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life, J. Clin. Invest., 109, pp. 101-110, 2002.
  Nathan, C. F., Secretory products of macrophages, J. Clin. Invest., vol. 79, pp. 319-326, 1987.
  Navalkar et al.; Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis; Journal of the American College of Cardiology; vol. 37; No. 2; pp. 440-444; 2001.
  Noguchi et al., Increases in Gastric acidity in response to electroacupuncture stimulation of hindlimb of anesthetized rats, Jpn. J. Physiol., 46(1), pp. 53-58, 1996.
  Norton, Can ultrasound be used to stimulate nerve tissue, BioMedical Engineering, 2(1), pp. 6, 2003.
  Palmblad et al., Dynamics of early synovial cytokine expression in rodent collagen-induced arthritis: a thereapeutic study unding a macrophage-deactivation compound, American Journal of Pathology, vol. 158, No. 2, pp. 491-500, Feb. 2, 2001.
  Prystowsky, J. B. et al., Interleukin-1 mediates guinea pig gallbladder inflammation in vivo, J. Surg. Res., vol. 71, No. 2, pp. 123-126, 1997.
  Pulkki, K. J., Cytokines and cardiomyocyte death, Ann. Med., vol. 29, pp. 339-343, 1997.
  Rayner, S. A. et al., Local bioactive tumour necrosis factor (TNF) in corneal allotransplantation, Clin. Exp. Immunol., vol. 122, pp. 109-116, 2000.
  Rinner et al.; Rat lymphocytes produce and secrete acetylcholine in dependence of differentiation and activation; J.Neuroimmunol.; 81; pp. 31-37; 1998.
  Romanovsky, A. A., et al.,The vagus nerve in the thermoregulatory response to systemic inflammation, Am. J. Physiol., vol. 273, No. 1 (part 2), pp. R407-R413, 1997.
  Saghizadeh et al.; The expression of TNF? by human muscle; J. Clin. Invest.; vol. 97; No. 4; pp. 1111-1116; 1996.
  Saindon et al.; Effect of cervical vagotomy on sympathetic nerve responses to peripheral interleukin-1beta; Auton.Neuroscience Basic and Clinical; 87; pp. 243-248; 2001.
  Saito, Involvement of muscarinic M1 receptor in the central pathway of the serotonin-induced bezold-jarisch reflex in rats, J. Autonomic Nervous System, vol. 49, pp. 61-68, 1994.
  Sandborn, W. J., et al., Transdermal nicotine for mildly to moderately active ulcerative colitis, Ann. Intern. Med, vol. 126, No. 5, pp. 364-371, 1997.
  Sato, E., et al., Acetylcholine stimulates alveolar macrophages to release inflammatory cell chemotactic activity, Am. J. Physiol., vol. 274, pp. L970-L979, 1998.
  Sato, K.Z., et al., Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukosytes and leukemic cell lines, Neuroscience Letters, vol. 266, pp. 17-20, 1999.
  Scheinman, R. I., et al., Role of transcriptional activation of I?B? in mediation of immunosuppression by glucocorticoids, Science, vol. 270, pp. 283-286, 1995.
  Schneider et al., High-affinity ssDNA inhibitors of the review transcriptase of type 1 human immunodeficiency virus, Biochemistry, 34(29), pp. 9599-9610, 1995.
  Shafer, Genotypic testing for human immunodeficiency virus type 1 drug resistance, Clinical Microbiology Reviews, vol. 15, pp. 247-277, 2002.
  Shapiro et al.; Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery; Thromb Haemost; vol. 80; pp. 773-778; 1998.
  Sher, M. E., et al., The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease, Inflamm. Bowel Dis., vol. 5, No. 2, pp. 73-78, 1999.
  Shi et al.; Effects of efferent vagus nerve excitation on inflammatory response in heart tissue in rats with endotoxemia; vol. 15, No. 1; pp. 26-28; 2003 (Eng. Abstract).
  Snyder et al., Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors; Nature Medicine, 5(1), pp. 64-70, Jan. 1999.
  Stalcup et al., Endothelial cell functions in the hemodynamic responses to stress, Annals of the New York Academy of Sciences, vol. 401, pp. 117-131, 1982.
  Steinlein, New functions for nicotine acetylcholine receptors?, Behavioural Brain Res., vol. 95, pp. 31-35, 1998.
  Sternberg, E. M., Perspectives series: cytokines and the brain ‘neural-immune interactions in health and disease,’ J. Clin. Invest., vol. 100, No. 22, pp. 2641-2647, Dec. 1997.
  Strojnik et al.; Treatment of drop foot using and implantable peroneal underknee stimulator; Scand. J. Rehab. Med.; vol. 19; pp. 37R43; 1987.
  Sugano et al., Nicotine inhibits the production of inflammatory mediators in U937 cells through modulation of nuclear factor-kappaβ activation, Biochemical and Biophysical Research Communications, vol. 252, No. 1, pp. 25-28, Nov. 9, 1998.
  Sykes, et al., An investigation into the effect and mechanisms of action of nicotine in inflammatory bowel disease, Inflamm. Res., vol. 49, pp. 311-319, 2000.
  Toyabe, et al., Identification of nicotinic acetylcholine receptors on lymphocytes in the periphery as well as thymus in mice, Immunology, vol. 92, pp. 201-205, 1997.
  Tracey et al., Mind over immunity, Faseb Journal, vol. 15, No. 9, pp. 1575-1576, Jul. 2001.
  Tracey, K. J. et al., Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia; Nature, 330: pp. 662-664, 1987.
  Tracey, K. J. et al., Shock and tissue injury induced by recombinant human cachectin, Science, vol. 234, pp. 470-474, 1986.
  Tracey, K.J., The inflammatory reflex, Nature, vol. 420, pp. 853-859, 2002.
  Tsutsui, H., et al., Pathophysiolocical roles of interleukin-18 in inflammatory liver diseases; Immunol. Rev., 174:192-209, 2000.
  Tuerk et al., RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase; Proc. Natl. Acad. Sci. USA, 89, pp. 6988-6992, Aug. 1992.
  Tuerk et al., Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase; Science, 249(4968), pp. 505-510, Aug. 3, 1990.
  Van Dijk, A. P., et al., Transdermal nictotine inhibits interleukin 2 synthesis by mononuclear cells derived from healthy volunteers, Eur. J. Clin. Invest, vol. 28, pp. 664-671, 1998.
  Vanhoutte, et al., Muscarinic and beta-adrenergic prejunctional modulation of adrenergic neurotransmission in the blood vessel wall, Gen Pharmac., vol. 14, pp. 35-37, 1983.
  vanWesterloo, et al., The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis, The Journal of Infectious Diseases, vol. 191, pp. 2138-2148, Jun. 15, 2005.
  Ventureyra, Transcutaneous vagus nerve stimulation for partial onset seizure therapy, Child's Nery Syst, vol. 16, pp. 101-102, 2000.
  Villa et al., Protection against lethal polymicrobial sepsis by CNI-1493, an inhibitor of pro-inflammatory cytokine synthesis, Journal of Endotoxin Research, vol. 4, No. 3, pp. 197-204, 1997.
  Von Känal, et al., Effects of non-specific ?-adrenergic stimulation and blockade on blood coagulation in hypertension, J. Appl. Physiol., vol. 94, pp. 1455-1459, 2003.
  Walland et al., Compensation of muscarinic brochial effects of talsaclidine by concomitant sympathetic activation in guinea pigs; European Journal of Pharmacology, vol. 330, pp. 213-219, 1997.
  Wang et al; Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation; Nature; 421; 384-388; Jan. 23, 2003.
  Wang, H., et al., HMG-1 as a late mediator of endotoxin lethality in mice, Science, vol. 285, pp. 248-251, Jul. 9, 1999.
  Waserman, S. et al., TNF-? dysregulation in asthma: relationship to ongoing corticosteroid therapy, Can. Respir. J., vol. 7, No. 3, pp. 229-237, 2000.
  Watanabe, H. et al., The significance of tumor necrosis factor (TNF) levels for rejection of joint allograft, J. Reconstr. Microsurg., vol. 13, No. 3, pp. 193-197, 1997.
  Wathey, J.C. et al., Numerical reconstruction of the quantal event at nicotinic synapses; Biophys. J., vol. 27: pp. 145-164, Jul. 1979.
  Watkins, L.R. et al., Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication, Neurosci. Lett., vol. 183, pp. 27-31, 1995.
  Watkins, L.R. et al., Implications of immune-to-brain communication for sickness and pain, Proc. Natl. Acad. Sci. U.S.A., vol. 96, pp. 7710-7713, 1999.
  Webster's Dictionary, definition of “intrathecal”, online version accessed Apr. 21, 2009.
  Whaley, K. et al., C2 synthesis by human monocytes is modulated by a nicotinic cholinergic receptor, Nature, vol. 293, pp. 580-582, Oct. 15, 1981.
  Woiciechowsky, C. et al., Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury, Nature Med., vol. 4, No. 7, pp. 808-813, 1998.
  Yeh, S.S. et al., Geriatric cachexia: the role of cytokines, Am. J. Clin. Nutr., vol. 70, pp. 183-197, 1999.
  Zhang et al., Tumor necrosis factor, The Cytokine Handbook, 3rd ed., Ed. Thompson, Academic Press, pp. 517-548, 1998.
  Beliavskaia et al.,“On the effects of prolonged stimulation of the peripheral segment of the vagus nerve on blood clotting time under different bodily conditions,” Fiziologicheskii Zhurnal SSSR Imeni I.M. Sechenova., vol. 52(11); p. 1315-1321, Nov 1966.
  Cicala et al., “Linkage between inflammation and coagulation: An update on the molecular basis of the crosstalk,” Life Sciences, vol. 62(20); pp. 1817-1824, 1998.
  Kalishevskaya et al. “The character of vagotomy-and atropin-induced hypercoagulation,” Sechenov Physiological Journal of the USSR, 65(3): pp. 398-404, 1979.
  Kalishevskaya et al.; Neural regulation of the fluid state of the blood; Usp. Fiziol. Nauk;,vol. 13; No. 2; pp. 93-122; 1982.
  Khatun, S., et al., “Induction of hypercoagulability condition by chronic localized cold stress in rabbits,” Thromb. and Haemost., 81: pp. 449-455, 1999.
  Kudrjashov, et al. “Reflex nature of the physiological anticoagulating system,” Nature, vol. 196(4855): pp. 647-649; 1962.
  Kuznik, et al., “Secretion of blood coagulation factors into saliva under conditions of hypo-and hypercoagulation,” Voprosy Meditsinskoi Khimii, vol. 19(1): pp. 54-57; 1973.
  Kuznik, et al., “Heart as an efferent regulator of the process of blood coagulation and fibrinolysis,” Kardiologiia, vol. 13(3): pp. 10-17, 1973.
  Kuznik, et al., “Role of the heart and vessels in regulating blood coagulation and fibrinolysis,” Kagdiologiia, vol. 13(4): pp. 145-154, 1973.
  Kuznik, “Role of the vascular wall in the process of hemostatis,” Usp Sovrem Biol., vol. 75(1): pp. 61-85, 1973.
  Kuznik, et al., “Blood Coagulation in stimulation of the vagus nerve in cats,” Biull. Eskp. Biol. Med., vol. 78(7): pp. 7-9, 1974.
  Kuznik, et al., “The role of the vascular wall in the mechanism of control of blood coagulation and fibrinolysis on stimulation of the vagus nerve,” Cor Vasa, vol. 17(2): pp. 151-158, 1975.
  Kuznik, et al., “The dynamics of procoagulatible and fibrinolytic activities during electrical stimulation of peripheral nerves,” Sechenov Physiological Journal of the USSR, vol. 65; No. 3: pp. 414-420, 1979.
  Lang, et al., “Neurogienic control of cerebral blood flow,” Experimental Neurology, 43: pp. 143-161, 1974.
  Mishchenko, “The role of specific adreno-and choline-receptors of the vascular wall in the regulation of blood coagulation in the stimulation of the vagus nerve,” Biull. Eskp. Biol. Med., vol. 78(8): pp. 19-22, 1974.
  Mishchenko, et al., “Coagulation of the blood and fibrinolysos in dogs during vagal stimulation,” Sechenov Physiological Journal of the USSR, vol. 61(1): pp. 101-107, 1975.
  Pateyuk, et al.,“Treatment of Botkin's disease with heparin,” Klin. Med., vol. 51(3): pp. 113-117, 1973.
  Sokratov, et al. “The role of choline and adrenegic structures in regulation of renal excretion of hemocoagulating compounds into the urine,” Sechenov Physiological Journal of the USSR, vol. 63(12): pp. 1728-1732, 1977.
  Von Känal, et al., Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo, Eur. J. Haematol., vol. 65: pp. 357-369, 2000.
  Cohen, “The immunopathogenesis of sepsis,” Nature., vol. 420(19): pp. 885-891, 2002.
  Weiner, et al., “Inflammation and therapeutic vaccination in CNS diseases,” Nature., vol. 420(19): pp. 879-884, 2002.
  Benoist, et al., “Mast cells in autoimmune disease” Nature., vol. 420(19): pp. 875-878, Dec. 2002.
  Zitnik et al.; U.S. Appl. No. 12/874,171 entitled “Prescription pad for treatment of inflammatory disorders,” filed Sep. 1, 2010.
 
 
     * cited by examiner
 
     Primary Examiner —Deborah Malamud
     Art Unit — 3766
     Exemplary claim number — 1
 
(74)Attorney, Agent, or Firm — Shay Glenn LLP

(57)

Abstract

An extravascular nerve cuff that is configured to hold a leadless, integral, implantable microstimulator. The nerve cuff may include a cuff body having a pocket or pouch for removably receiving the implantable device within. The nerve cuff can be secured around the nerve such that the electrodes of the device are stably positioned relative to the nerve. Furthermore, the nerve cuff drives the majority of the current from the stimulation device into the nerve, while shielding surrounding tissues from unwanted stimulation.
15 Claims, 18 Drawing Sheets, and 48 Figures


CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. §119 of U.S. Provisional Patent Application No. 61/185,494, filed on Jun. 9, 2009, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR”.

INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

FIELD OF THE INVENTION

[0003] The present invention relates generally to implantable neural stimulators, and more specifically to a nerve cuff with a pocket for removably receiving an active leadless stimulation device, and methods of stimulating a nerve using such nerve cuff.

BACKGROUND OF THE INVENTION

[0004] Implantable electrical stimulation devices have been developed for therapeutic treatment of a wide variety of diseases and disorders. For example, implantable cardioverter defibrillators (ICDs) have been used in the treatment of various cardiac conditions. Spinal cord stimulators (SCS), or dorsal column stimulators (DCS), have been used in the treatment of chronic pain disorders including failed back syndrome, complex regional pain syndrome, and peripheral neuropathy. Peripheral nerve stimulation (PNS) systems have been used in the treatment of chronic pain syndromes and other diseases and disorders. Functional electrical stimulation (FES) systems have been used to restore some functionality to otherwise paralyzed extremities in spinal cord injury patients.
[0005] Typical implantable electrical stimulation systems can include a system with one or more programmable electrodes on a lead that are connected to an implantable pulse generator (IPG) that contains a power source and stimulation circuitry. However, these systems can be difficult and/or time consuming to implant, as the electrodes and the IPG are usually implanted in separate areas and therefore the lead must be tunneled through body tissue to connect the IPG to the electrodes. Also, leads are susceptible to mechanical damage over time as they are typically thin and long.
[0006] Recently, small implantable neural stimulator technology, i.e. microstimulators, having integral electrodes attached to the body of a stimulator has been developed to address the disadvantages described above. This technology allows the typical IPG, lead and electrodes described above to be replaced with a single device. Elimination of the lead has several advantages including reduction of surgery time by eliminating, for example, the need for implanting the electrodes and IPG in separate places, the need for a device pocket, tunneling to the electrode site, and strain relief ties on the lead itself. Reliability is therefore increased significantly, especially in soft tissue and across joints because active components, such as lead wires, are now part of the rigid structure and are not subject to the mechanical damage due to repeated bending or flexing over time.
[0007] However, the leadless integral devices tend to be larger and more massive than the electrode/lead assemblies, making it difficult to stably position the device in the proper position in respect to a nerve. Without device stability, the nerve and/or surrounding muscle or tissue can be damaged due to movement of the assembly.
[0008] There remains a need for a leadless integral device that is stably positioned on the nerve, and can provide for removal and/or replacement of the stimulation device with relative ease.

SUMMARY OF THE INVENTION

[0009] Described herein are extravascular nerve cuffs for securing a leadless, integral, implantable device to a nerve. The nerve cuff typically includes a pouch or pocket. The cuff electrode configuration of the stimulation device allows the device to be stably positioned proximate a nerve, such as the vagus nerve. Furthermore, the cuff electrode configuration also has the characteristics of driving most of the current into the nerve, while shielding surrounding tissues from unwanted stimulation. Methods of securing a leadless microstimulator using such nerve cuffs are also described herein, as well as methods of stimulating a nerve using microstimulators secured using such cuffs.
[0010] There are numerous advantages to using leadless cuffs with a microstimulator, including a decrease in encapsulation (e.g., to about 100 microns) compared to systems without leadless cuffs, since there is less “tugging” on the leadless cuff. Furthermore, leadless cuffs, which may securely attach to a nerve and hold a microstimulator in position, may allow a microstimulator to be modified or replaced while maintaining the same positioning relative to the nerve.
[0011] In one embodiment of the invention, the nerve cuff generally includes a cuff body or carrier, made of a flexible material such as a medical-grade soft polymeric material (e.g., Silastic™ or Tecothane™) forming a cuff or sleeve, having a pocket or pouch defined therein for removably receiving a leadless stimulation device. The leadless stimulation device is positioned within the pocket or sleeve such that the electrodes of the device are positioned proximate the nerve to be stimulated. The pocket can be defined by the space between the stimulation device and an inner surface of the cuff body or can comprise a pouch-like structure attached to the cuff body for containing the stimulation device. The nerve cuff can be coupled to the nerve, a surrounding sheath that contains the nerve, or both depending on the desired level of stability.
[0012] The nerve cuff can be implanted by first dissecting the nerve, such as the vagus nerve, from its surrounding sheath, wrapping the nerve cuff around the nerve, coupling or suturing the nerve cuff to one of either the nerve or the sheath and inserting the stimulation device within the pocket or pouch of the cuff body such that the stimulation device is proximate the nerve.
[0013] For example, described herein are nerve cuffs for securing a leadless microstimulator in stable communication with a nerve. A nerve cuff may include: a cuff body having a channel extending within the length of the cuff body for passage of a nerve; a pocket within the cuff body, configured to removably hold the leadless microstimulator; and an elongate opening slit extending the length of the cuff body configured to be opened to provide access to the pocket.
[0014] The nerve cuff may also include an internal electrical contact within the cuff body. For example, the internal electrical contact may be configured to electrically couple the microstimulator and the nerve. In some variations, the nerve further includes an external electrical contact on the outer surface of the cuff body configured to couple with the microstimulator.
[0015] In some variations, the cuff body comprises shielding configured to electrically isolate the microstimulator within the nerve cuff. The cuff body may be of uniform thickness, or it may have a non-uniform thickness. For example, the cuff body may have a thickness between about 5 and about 20 mils.
[0016] In some variations, the outer surface of the nerve cuff is substantially smooth and atraumatic. The nerve outer surface of the nerve cuff may be rounded and/or conforming. For example, the body may conform to the region of the body into which the cuff and/or microstimulator are implanted.
[0017] In some variations, the channel comprises a support channel configured to support the nerve within therein, to prevent pinching of the nerve.
[0018] The elongate opening slit may extend the length of the cuff body in an interlocking pattern. In some variations, the slit extends along the side of the cuff body, adjacent to the channel. In other variations, the slit extends along the top of the cuff body, opposite to the channel.
[0019] The nerve cuff may also include one or more attachment sites in the elongate opening slit configured to help secure the slit closed. For example, the attachment sites may be holes or passages for a suture.
[0020] In some variations, the cuff body is formed of a flexible and biocompatible polymer (e.g., a polymeric biocompatible material such as a silicone polymer.
[0021] Also described herein are nerve cuffs for securing a leadless microstimulator in stable communication with a nerve, comprising: an insulating cuff body having a nerve channel extending within the length of the cuff body for passage of a nerve, wherein the cuff body electrically isolates the microstimulator within the cuff body; a conductive surface within the nerve channel configured to engage one or more electrical contacts on the microstimulator; a pocket within the cuff body, configured to removably hold the leadless microstimulator; and an elongate opening slit extending the length of the cuff body configured to be opened to provide access to the pocket.
[0022] As mentioned above, the nerve cuff may include one or more external electrical contact on the outer surface of the cuff body configured to couple with the microstimulator.
[0023] In some variations, the nerve cuff body has a uniform thickness; in other variations, the nerve cuff body has a non-uniform thickness. The cuff body may have a thickness between about 5 and about 20 mils.
[0024] The outer surface of the nerve cuff may be substantially smooth and atraumatic. For example, the outer surface of the nerve cuff may be contoured.
[0025] In some variations, channel through the nerve cuff comprises a support channel configured to support the nerve within therein, to prevent pinching of the nerve.
[0026] In some variations, the elongate opening slit extends the length of the cuff body in an interlocking pattern. For example, the interlocking pattern may be a zig-zag pattern, or a sinusoidal pattern.
[0027] Also described herein are methods of implanting a leadless microstimulator in communication with a vagus nerve, the method comprising: exposing a vagus nerve; opening a slit of a nerve cuff having a nerve cuff body, wherein the slit opens along the length of the nerve cuff body; placing the nerve cuff around the vagus nerve so that the nerve is within a channel extending the length of nerve cuff; inserting a leadless microstimulator within a pocket in the nerve cuff; and securing the slit of the nerve cuff closed so that the leadless microstimulator is in electrical communication with the nerve and electrically isolated within the nerve cuff body.
[0028] In some variations, the step of securing the opening slit of the nerve cuff closed comprises securing the slit so that the leadless microstimulator engages an internal electrical contact within the nerve cuff body. The leadless microstimulator may engage an internal electrical contact configured to provide circumferential stimulation around the nerve within the channel.
[0029] The step of securing may comprise suturing the slit closed. In some variations, the slit may be self-closing. For example, there may be enough tension in the cuff to keep it closed by itself. In some variations, dissolvable sutures may be used to keep it closed until the body encapsulates it.
[0030] The method may also include the step of testing the microstimulator to confirm electrical communication with the nerve.
[0031] In some variations, the step of placing the nerve cuff comprises placing an oversized nerve cuff around the vagus nerve.
[0032] Also described herein are methods of implanting a leadless microstimulator in communication with a vagus nerve including the steps of: exposing a vagus nerve; opening a slit of a nerve cuff having a nerve cuff body, wherein the slit opens along the length of the nerve cuff body; placing the nerve cuff around the vagus nerve so that the nerve is within a channel extending the length of nerve cuff; inserting a leadless microstimulator within a pocket in the nerve cuff so that the microstimulator communicates with one or more internal electrical contacts within the nerve cuff; and closing the slit of the nerve cuff so that the nerve is in electrical communication with the one or more internal electrical contact.
[0033] In some variations, the leadless microstimulator and the internal electrical contact is configured to provide circumferential stimulation around the nerve within the channel. The step of closing may include the step of securing the slit of the nerve cuff closed. For example, the step of closing may comprise suturing the slit closed. The step of placing the nerve cuff may comprise placing an oversized nerve cuff around the vagus nerve.
[0034] The above summary of the invention is not intended to describe each illustrated embodiment or every implementation of the present invention. The figures and the detailed description that follow more particularly exemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 is a perspective view depicting a nerve cuff with stimulation device implanted proximate a nerve, according to an embodiment of the invention.
[0036] FIG. 1A is a top view depicting the implanted nerve cuff with stimulation device of FIG. 1;
[0037] FIG. 1B is a top view depicting the implanted nerve cuff with stimulation device according to an alternative embodiment of the invention;
[0038] FIG. 2 is a front view depicting an implanted nerve cuff with strain relief according to an embodiment of the invention;
[0039] FIG. 3 is a front view depicting an implanted nerve cuff with suture holes according to an embodiment of the invention;
[0040] FIG. 4 is an open view depicting the nerve cuff with suture holes of FIG. 3;
[0041] FIG. 5 is a top view depicting a closing device for the implanted nerve cuff of FIG. 1;
[0042] FIG. 6 is a perspective view depicting marsupializaton of the stimulation device within a pocket of the nerve cuff of FIG. 1;
[0043] FIG. 7A is a top view depicting a nerve cuff having a conforming shield according to an embodiment of the invention.
[0044] FIG. 7B is a front view of the nerve cuff of FIG. 7a.
[0045] FIG. 8A is a top view depicting an open nerve cuff according to an embodiment of the invention;
[0046] FIG. 8B is a front view of the nerve cuff of FIG. 8a; and
[0047] FIG. 8C is a top view depicting the nerve cuff of FIG. 8 in a closed configuration.
[0048] FIGS. 9A and 9B show side views through a section of the cuff body wall, indicating uniform and varying thicknesses, respectively.
[0049] FIGS. 10A-10D illustrate one variation of a nerve cuff as described herein. FIG. 10A shows an end view, FIG. 10B is a side perspective view, FIG. 10C is a side view, and FIG. 10D is a longitudinal section through the device attached to a nerve, showing internal features including a microstimulator.
[0050] FIGS. 11A-11D illustrate another variation of a nerve cuff. FIG. 11A shows an end view, FIG. 11B is a side perspective view, FIG. 11C is a side view, and FIG. 11D is a longitudinal section through the device attached to a nerve, showing internal features including a microstimulator.
[0051] FIG. 12 shows one variation of a microstimulator that may be used in the nerve cuffs described herein.
[0052] FIG. 13A shows a perspective view of another variation of a microstimulator that may be used as described herein. FIGS. 13B and 13C are end and bottom views, respectively, of the microstimulator shown in FIG. 13A.
[0053] FIGS. 14 A and 14B illustrate side and end views, respectively of another variation of a nerve cuff.
[0054] FIGS. 15A-15C show top, side and sectional views, respectively of a nerve cuff such as the one shown in FIG. 14A, attached to a nerve. FIG. 15D is a section though the middle of a nerve cuff with a microstimulator secured there.
[0055] FIG. 16 is an internal end view of a microstimulator similar to the ones shown in FIGS. 14A-15D.
[0056] FIG. 17 is a sectional view showing the inside of another variation of a nerve cuff.
[0057] FIG. 18 is a side perspective view of the top-opening nerve cuff shown in FIG. 17.
[0058] FIG. 19 is a side perspective view of a side-opening nerve cuff.
[0059] FIG. 20 is a transparent view of the bottom of a nerve cuff, showing the nerve channel.
[0060] FIG. 21 is a side view of another variation of a nerve cuff.
[0061] FIGS. 22A-22H illustrate steps for inserting a nerve cuff such as the nerve cuffs described herein.
[0062] FIG. 23 shows an equivalent circuit modeling current loss when the nerve cuff is only loosely arranged over the nerve.
[0063] While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

[0064] Embodiments of the invention are directed to a retaining device, such as a carrier or cuff, which positions active contacts, i.e. electrodes, of a stimulation device against the targeted nerve directing the current from the electrodes into the nerve. The retaining device also inhibits or prevents the current from flowing out to the surrounding tissue.
[0065] Referring to FIG. 1, one example of a nerve cuff 100 adapted for holding a stimulation device is coupled to a nerve 102. Nerve 102 can comprise any nerve in the human body targeted for therapeutic treatment, such as, for example, the vagus nerve. Nerve cuff adapter 100 generally comprises an outer carrier or cuff 104 body that can comprise any of a variety of medical grade materials, such as, for example, Silastic™ brand silicone elastomers, or Tecothane™ polymer.
[0066] In general, a nerve cuff including a cuff 104 body having (or forming) a pouch or pocket 106 for removably receiving an active, implantable stimulation device 108 having one or more integrated, leadless electrodes 110 on a surface of stimulation device 108 proximate nerve 102. As illustrated in FIGS. 1 and 1A, nerve cuff 100 wraps around nerve 102 such that electrodes 110 are positioned proximate nerve 102.
[0067] Contacts or electrodes 110 can be positioned directly against nerve 102, as illustrated in FIG. 1A, or in close proximity to nerve 102, as illustrated in FIG. 1B. Referring specifically to FIG. 1B, close proximity of electrodes 110 and nerve 102 will leave a gap or space 112 that may naturally be filled with fluid or connective tissue. In one embodiment of the invention, electrodes 110 and/or the inner surface of cuff body 104 can include optional steroid coatings to aid in reducing the local inflammatory response and high impedance tissue formation.
[0068] In one embodiment, the pocket 106 for containing the stimulation device 108 is defined by the open space between the nerve 102 and the inner surface of the cuff body 104. Stimulation device 108 can be passively retained within pocket 106 by the cuff body 104, or can be actively retained on cuff body with fastening means, such as, for example, sutures. In other embodiments, pocket 106 can comprise a pouch-like structure attached to cuff body 104 into which stimulation device 108 can be inserted. Stimulation device 108 can be passively retained within a pouch-like pocket by simply inserting the device 108 into the pocket or can be actively retained with fastening means. A pouch-like pocket can be positioned either in the interior or on the exterior of cuff body 104. Pouch-like pocket 106 and/or cuff body 104 can include access openings to allow electrodes to be positioned directly proximate or adjacent to nerve 102.
[0069] Cuff body 104 can have a constant thickness or a varying thickness as depicted in FIGS. 9A and 9B. The thickness of cuff body 104 can be determined to reduce the palpable profile of the device once the stimulation device is inserted. In one embodiment, the thickness of cuff body can range from about 1 to about 30 mils, or from about 5 to about 20 mils. In one embodiment shown in FIG. 9B, cuff 104 can have a greater thickness at a top and bottom portion of the cuff and a smaller thickness in a middle portion where the stimulation device is contained.
[0070] A key obstacle to overcome with implanting stimulation devices proximate nerves or nerve bundles is attaching a rigid structure that makes up the stimulation device along a fragile nerve in soft tissue. In one embodiment of the invention, this issue is resolved by encasing nerve 102 and device 108 in a cuff body 104 that comprises a low durometer material (e.g., Silastic™ or Tecothane™) as described above, that conforms around nerve 102. Further, as illustrated in FIG. 2, cuff body 104 can comprise strain reliefs 114 on its ends that reduce or prevent extreme torsional rotation and keep nerve 102 from kinking Strain reliefs 114 can coil around nerve 102, and are trimmable to a desired size, such as the size of nerve 102. Further, strain relief 114 can be tapered. In some variations, the lateral ends of the nerve cuff, forming the channel into which the nerve may be place, are tapered and have a tapering thickness, providing some amount of support for the nerve. In some variations, the channel through the nerve cuff in which the nerve may sit, is reinforced to prevent or limit axial loading (e.g., crushing) of the nerve or associated vascular structures when the nerve is within the cuff.
[0071] Given the design or architecture of cuff body 104, any vertical movement of cuff body 104 on nerve 102 is not critical to electrical performance, but can result in friction between device 108 and nerve 102 that could potentially damage nerve 102. For that reason, device 108 should readily move up and down nerve 102 without significant friction while being sufficiently fixated to nerve 102 so that eventually connective tissue can form and aid in holding device 108 in place. The challenge is stabilizing device 108 so that it can be further biologically stabilized by connective tissue within several weeks.
[0072] Nerve cuff 100 should not be stabilized to surrounding muscle or fascia that will shift relative to the nerve. Therefore, referring to FIGS. 3 and 4, nerve cuff 100 can further comprise connection devices, such as suture holes or suture tabs, for coupling and stabilizing cuff body 104 with device 108 to at least one of the nerve bundle or nerve 102, and the surrounding sheath that contains nerve 102. In one embodiment of the invention, for example, as shown in FIG. 3, cuff body 104 can comprise suture holes 116 that can be used with sutures to couple cuff 104 body with device 108 to the surrounding nerve sheath. In an alternative embodiment of the invention, shown in FIG. 4, suture tabs 118 with suture holes 116 extend from one or both sides of cuff body 104.
[0073] Several stabilizing mechanisms can be used, including suture tabs and holes, staples, ties, surgical adhesives, bands, hook and loop fasteners, and any of a variety of coupling mechanisms. FIGS. 3 and 4, for example, illustrates suture tabs and holes that can be fixed to the surrounding sheath with either absorbable sutures for soft tissue or sutures demanding rigid fixation.
[0074] FIG. 5 illustrates sutures 120 that clamp or secure cuff body 104 with device 108 to a surgeon-elected tension. Sutures 120 can be tightened or loosened depending on the level of desired stability and anatomical concerns. As shown in FIG. 5, a gap 122 can be present so long as cuff adapter 100 is sufficiently secured to nerve 102, with a limit set to a nerve diameter to prevent compression of the vasculature within nerve 102. Surgical adhesives (not shown) can be used in combination with sutures 120 on surrounding tissues that move in unison with the neural tissue.
[0075] Muscle movement against cuff adapter 100 can also transfer undesired stresses on nerve 102. Therefore, in an embodiment of the invention, low friction surfaces and/or hydrophilic coatings can be incorporated on one or more surfaces of cuff body 104 to provide further mechanisms reducing or preventing adjacent tissues from upsetting the stability of nerve cuff 100.
[0076] FIG. 6 illustrates a nerve cuff 100 with a stimulator device removably or marsupially secured within pocket or pouch 106 of cuff body 104. By the use of reclosable pouch 106, active stimulator device 108 can be removed or replaced from cuff body 104 without threatening or endangering the surrounding anatomical structures and tissues. Device 108 can be secured within cuff body 104 by any of a variety of securing devices 124, such as, for example, sutures, staples, ties, zippers, hook and loop fasteners, snaps, buttons, and combinations thereof. Sutures 124 are shown in FIG. 6. Releasing sutures 124 allows access to pouch 106 for removal or replacement of device 108. Not unlike typical cuff style leads, a capsule of connective tissue can naturally encapsulate nerve cuff 100 over time. Therefore, it will most likely be necessary to palpate device 108 to locate device 108 and cut through the connective tissue capsule to access sutures 124 and device. The removable/replaceable feature of nerve cuff 100 is advantageous over other cuff style leads because such leads cannot be removed due to entanglement with the target nerve and critical vasculature.
[0077] As discussed supra, compression of nerve 102 must be carefully controlled. Excess compression on nerve 102 can lead to devascularization and resulting death of the neural tissue. Compression can be controlled by over-sizing or rightsizing nerve cuff 100, so that when pocket sutures 124 are maximally tightened, the nerve diameter is not reduced less that the measured diameter. Cuffs formed from Silastic™ or Tecothane™ materials are relatively low cost, and therefore several sizes can be provided to the surgeon performing the implantation of nerve cuff 100 to better avoid nerve compression.
[0078] Miniature stimulators, such as device, are still large enough to be felt and palpated by patients as are state-of-the-art commercial cuff systems. Referring to FIG. 7, to avoid such palpation, nerve cuff 100 can further comprise a protecting shield 126 conforming to the shape of the anatomical structures, such as in the carotid sheath. In this embodiment, nerve cuff 100 is secured around the vagus nerve, while isolating device 108 from contact with both the internal jugular vein (IJV) 132, and common carotid artery 134. Shield 126 then further isolates device 108 from other surrounding tissues. It is critical to minimize the profile of the entire cuff adapter 100 while maintaining the compliance of such materials as Silastic™ or Tecothane™. In one embodiment of the invention, protective shield 126 is formed from a PET material, such as Dacron®, optionally coated with Silastic™ or Tecothane™ forming a thin and compliant structure that will allow for tissue separation when required.
[0079] When a nerve does not provide sufficient structural strength to support nerve cuff adapter 100, collateral structures can be included in or on cuff body 104. Because of a high degree of anatomical variance such a scheme must demand the skill of the surgeon to utilize a highly customizable solution. FIG. 8a illustrates a variable size nerve cuff 100 with a wrappable retainer portion 128 extending from cuff body 104. As shown in FIG. 8c, cuff body 104 is secured around nerve 102, while retainer portion 128 is secured around the sheath or other surrounding anatomical structures, such as the IJV 132 and/or carotid artery 134. As shown in FIG. 8b, wrappable retainer portion 128 can include securing devices 130, such as suture holes, for securing the entire nerve cuff 100 around the desired anatomical structures. This configuration allows for access to device 108 through pocket 106 as in previous embodiments, while adapting to a multitude of anatomical variations to obtain the desired stability of nerve cuff 100 on nerve 102.
[0080] FIGS. 10A-10D illustrate a variation of a nerve cuff that includes a cuff body forming a channel (into which a nerve may be fitted) and an slit formed along the length of the nerve cuff body. In this example, the nerve cuff body also includes a pocket region within the cuff body positioned above the nerve channel. The top of the body (opposite from the nerve channel) includes a long slit 1003 along its length forming on opening. The cuff body may be along the slit by pulling apart the edges, which may form one or more flaps. In the example shown in FIG. 10A, the slit may be split open to expose the inside of the nerve cuff and allow the nerve to be positioned within the internal channel, so that the cuff is positioned around the nerve. The same split may be used to insert the microcontroller as well. In some variations a separate opening (slit or flap) may be used to access the pocket or pouch for the microcontroller.
[0081] FIG. 10B shows a perspective view of the nerve cuff holding a microcontroller after it has been inserted onto a nerve (e.g., the vagus nerve). FIG. 10C shows a side view of the same. FIG. 10D shows a section though the view of FIG. 10C, illustrating then nerve within the channel formed through the nerve cuff, and a microstimulator held snugly within the nerve cuff so that the microstimulator is in electrical communication with the nerve via a shared surface between the two. In some variations, as discussed below, the microstimulator is held in a separate, possibly isolated, compartment and electrical contact with the nerve is made by one or more internal leads that couple the microstimulator with the nerve through an internal contact.
[0082] The exemplary cuff shown in FIGS. 10A-10D has a conformal configuration, in which the wall thickness is relatively constant, as can be seen from the sectional view in FIG. 10D. In contrast, FIGS. 11A-11D illustrate a variation of a nerve cuff in which the wall thickness varies along the perimeter. This non-uniform thickness may effectively cushion the device relative to the surrounding tissue, even as the patient moves or palpitates the region. This may have the added benefit of preventing impingement of the nerve. Similarly, the variable thickness may enable smooth transitions and help conform the cuff to the surrounding anatomy.
[0083] For Example, FIG. 11A shows an end view (with exemplary dimensions illustrated). It should be noted that in any of the figures or examples provided herein, the dimensions shown or described are for illustration only. In practice the dimensions may be +/− some percentage of the values shown (e.g., +/−5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, etc.). The section through the device shown in FIG. 11D illustrates the non-uniform thickness of the walls.
[0084] Both nerve cuff variations shown in FIGS. 10A-10D and FIGS. 11A-11D are substantially rounded or conforming, and have non-traumatic (or atraumatic) outer surfaces. As mentioned, this relatively smooth outer surface may enhance comfort and limit encapsulation of the nerve cuff within the tissue.
[0085] As can be seen from FIGS. 10D and 11D, the microstimulator typically rests above (in the reference plane of the figure) the length of the nerve when inserted into the nerve cuff. In some variations, the microstimulator includes a contoured outer surface onto which one or more contacts (for contacting the nerve or an internal conductor within the nerve cuff) are positioned. For example, FIG. 12 illustrates one variation of a microstimulator 1201. In this example, the microstimulator includes one or more contacts on its outer surface with which to provide stimulation to a nerve. FIG. 13A shows another variation of a microstimulator 1301 in which the outer surface (the bottom in FIG. 13A) is curved to help form a channel surrounding the nerve when the microstimulator is inserted into the nerve cuff. FIG. 13B shows an end view, illustrating the channel concavity 1303 extending along the length of the microstimulator, and FIG. 13C shows a bottom view, looking down onto the channel region. In practice, the microstimulator shown may be placed within the nerve cuff and be held in position at least partially around the nerve. Thus, the microstimulator may help protect the nerve, which may lie within this channel. As mentioned above, and described in greater detail below, it is not necessary that the nerve lie against the contacts, as current may be conducted to the nerve from within the nerve cuff, which may be insulated sufficiently to prevent excessive leak or spillover of the current even when the cuff is oversized and only loosely surrounds the nerve. Furthermore, the nerve cuff may include one or more internal contacts allowing the current from the microstimulator to be distributed to the nerve via one or more internal contacts or leads, including circumferentially around the nerve.
[0086] FIGS. 14A and 14B show another variation of a nerve cuff. In this example, the slit forming the opening is positioned on the upper surface (opposite to the nerve channel) along the length of the device. The slit is formed in an interlocking pattern. In FIG. 14a, the slit forms a zig-zag pattern, although other interlocking patterns may be used. For example, a sinusoidal or square-wave pattern may be used. The interlocking pattern may distribute the strain of closing the cuff around the nerve and microstimulator, and may make it easier to close the cuff once it has been positioned and the microstimulator has been inserted. FIG. 14B shows an end view of the same cuff shown in FIG. 14A.
[0087] FIGS. 15A-15C show a similar cuff to the one shown in FIG. 14A from top and side views, connected to a nerve. In these example, the nerve extends through the internal channel and out the openings (which may be oval shaped, as shown in FIG. 14B) at either end. In FIG. 15C, a section through the length of the device shows that the microstimulator is positioned in the pouch (cavity) above the nerve. The microstimulator maybe held in place by the walls of the cuff. A conforming microstimulator (such as the one shown in FIG. 13A-13C) may be used, as illustrated in the cross-sectional view shown in FIG. 15D. The contacts 1503 of the conforming microstimulator are positioned on the bottom of the device.
[0088] As mentioned briefly above, in some variations of the nerve cuff, the inner surface of the cuff body includes one or more internal contacts configured to couple with the microstimulator held within the pouch, and transmit any applied energy to the nerve (or receive energy from the nerve) positioned within the channel through the nerve cuff. The internal lead may be positioned so that it applies current to the underside (along the bottom region of the channel), or around the sides of the nerve as it sits within the channel. In some variations the internal conductor or lead is configured around the channel so that the nerve may be circumferentially stimulated, optimizing the applied stimulation. FIG. 17 is a long section though a nerve cuff, showing the inside of the cuff, and illustrates a variation of a nerve cuff having an internal lead 1703 that may apply stimulation to the underside of the nerve. This internal lead may be formed of any biocompatible conductive material, including medals, conductive plastics, or the likes. The internal lead may include exposed electrode surfaces 1703 for making contact with the nerve. Electrodes may be active contacts, also formed of any appropriate conductive material (e.g., metals, conductive polymers, braided materials, etc.). In some variations, the internal lead is coated or treated to help enhance the transfer of energy between the microstimulator and the nerve. Circumferential stimulation or conduction around the lead may reduce the impedances and assure uniform cross-sectional stimulation of the nerve bundle.
[0089] FIG. 19 shows another variation of a nerve cuff as described herein. In this example, the nerve cuff includes slit 1903 along one side of the device, adjacent to the nerve channel, which can be opened (e.g., by pulling apart the flaps or sides of the cuff) to expose nerve channel and the pocket for the microstimulator.
[0090] Many of the nerve cuff variations described herein may be opened and positioned around the nerve, for example, by splitting them open along a slit or hinge region. The device may be configured so that they have sufficient resiliency to close themselves, or remain closed if the edges of the slit region are brought together. Thus, the device may have a shape memory property that encourages them to close. In some variations, as already mentioned, it may be useful to hold them closed, at least temporarily, once they have been positioned over a nerve and the microstimulator has been positioned within the pocket. Thus, the device may include one or more closure elements. For example, the device may include a suture hole or passage for suturing the device closed. In some variations the nerve cuff includes a button or other fastener element. In some variations, as illustrated in FIGS. 6 and 18, the device may be sutured close with a dissolvable suture. A few weeks or months after insertion, the nerve cuff may be encapsulated or engulfed by the surrounding tissue, and will be held closed by this encapsulation. Thus, the dissolvable sutures merely keep the cuff closed for initial anchoring before biointegration and encapsulation occurs.
[0091] Any of the nerve cuffs described herein may also include one or more external leads or contacts facing the outside of the nerve cuff body, which may be used to stimulate tissues outside of the nerve cuff, and not just the nerve within the channel through the cuff. FIG. 21 illustrates one variation of a nerve cuff having external leads. In this example, the nerve cuff includes two external contacts 2103 that are connected (through the wall of the nerve cuff body) to the microstimulator held within the nerve cuff pocket. Such external leads may be used for sensing in addition to (or instead of) stimulation. For example, these electrical contacts may be used to sense other physiological events such as muscle stimulation and/or cardiac function. These signals can be applied to aid synchronization of target nerve stimulation to minimize artifacts of target stimulation. Such signals may be too faint for reliable remote sensing, however the position of the microstimulator (insulated within the housing of the nerve cuff) may allow accurate and reliable sensing.
[0092] A nerve may sit within a supported channel through the nerve cuff. As illustrated in FIG. 20, the channel 2003 may be formed having generally smooth sides, so as to prevent damage to the nerve and associated tissues. In some variations the nerve channel though the cuff is reinforced to prevent the cuff from pinching the device or from over-tightening the device when closed over the nerve. Supports may be formed of a different material forming the nerve cuff body, or from thickened regions of the same material. Although multiple sizes of nerve cuff may be used (e.g., small, medium, large), in some variations, an oversized nerve cuff may be used, because the insulated cuff body will prevent leak of current from the microstimulator to surrounding tissues.
[0093] In general, the nerve cuff body may be electrically insulating, preventing leakage of charge from the microstimulator during operation. In some variations the nerve cuff includes shielding or insulation sufficient to electrically insulate the microstimulator within the nerve cuff body. Shielding material may particularly include electrically insulative materials, including polymeric insulators.
[0094] It may be shown mathematically using an equivalent circuit of the microstimulator, as shown in FIG. 23, that the current from a microstimulator is not appreciably passed out of even a loosely applied nerve cuff. This allows for the use of oversized nerve cuffs, rather than requiring rigorous sizing, or risking constricting the nerve.
[0095] For example, assuming a nerve with a cross section of Narea is surrounded by a column of fluid Farea enclosed by the nerve cuff, where contacts on the inside the microstimulator are spaced Espacing apart (center to center) and have a width Ewidth and circle around the column of fluid and nerve Edegrees, it can be shown that the current will leak out the ends through a distance between the center of the electrode and the end of the nerve cuff that is defined by a distance Dguard.
[0096] The electrical model (illustrated in FIG. 23) consists of a current source that drives through DC isolation capacitors (Ciso2 optional), through the capacitance of each electrode (Cdl1 and Cdl2). From the electrodes, the current passes through either path RS or Rlp1+Rb+Rlp2. Where as a portion of the current passing through Rs provides useful work and the current passing through Rlp1+Rb+Rlp2 passes outside of the device and may cause undesirable effects.
[0097] If the nerve has a tight fit, then all the current passing through Rs would contribute towards stimulation, but only a portion of the current can activate the nerve in the case of a loose fit. Based on this model, it can be shown that (assuming that the nerve and fluid columns form an ellipse defined by the major and minor axis a and b, and the pulse width is short and capacitances are large) just the real impedance and efficiency can be estimated.
[0098] The electrode surface area is determined to estimate the complex portion of the impedance: Farea=π*aF*bF and Narea=π*aN*bN.
[0099] Assuming the impedance of the cuff contained fluid and nerve has a similar conductance p and electrodes are spaced at Espacing then the real resistance of the conduction volume is: Rworking=Espacing*ρ/Farea, where the wasted resistance that should be maximized is calculated by: Rwasted=2*Dguard*ρ/Farea+Rbulk, where Rbulk is defined as the free field resistance between the two ends of the cuff.
[0100] So the efficiency (η) of the real current delivered in the POD is Rwasted/(Rworking+Rwasted), and for the case of an undersized nerve assuming the conductivity of tissue and the fluid column is about equivalent then the stimulation efficiency is defined as ηT=η*Narea/Farea.

Methods of Insertion

[0101] In operation, any of the devices described herein may be positioned around the nerve, and the microstimulator inserted into the nerve cuff, in any appropriate manner. FIGS. 22A-22H illustrate one variation of a method for applying the nerve cuff around the nerve and inserting a microstimulator. In this example, the patient is prepared for application of the nerve cuff around the vagus nerve to hold a microstimulator device securely relative to the nerve (FIG. 22A). An incision is then made in the skin (≈3 cm) along Lange's crease between the Facial Vein and the Omohyoid muscle (FIG. 22B), and the Sternocleidomastoid is retracted away to gain access to the carotid sheath (FIG. 22C). The IJV is then reflected and ≦2 cm of the vagus is dissected from the carotid wall.
[0102] In some variations, a sizing tool may be used to measure the vagus (e.g., diameter) to select an appropriate microstimulator and cuff (e.g., small, medium, large). In some variations of the method, as described above, an oversized cuff may be used. The nerve cuff is then placed under the nerve with the opening into the nerve cuff facing the surgeon (FIG. 22D), allowing access to the nerve and the pocket for holding the microstimulator. The microstimulator can then be inserted inside cuff (FIG. 22E) while assuring that the microstimulator contacts capture the vagus, or communicate with any internal contacts/leads. The nerve cuff may then be sutured shut (FIG. 22F). In some variations, the microstimulator may then be tested (FIG. 22G) to confirm that the device is working and coupled to the nerve. For example, a surgical tester device, covered in a sterile plastic cover, may be used to activate the microstimulator and perform system integrity and impedance checks, and shut the microstimulator off. If necessary the procedure may be repeated to correctly position and connect the microstimulator. Once this is completed and verified, the incision may be closed (FIG. 22H).
[0103] The invention may be embodied in other specific forms without departing from the essential attributes thereof; therefore, the illustrated embodiments should be considered in all respects as illustrative and not restrictive. The claims provided herein are to ensure adequacy of the present application for establishing foreign priority and for no other purpose.
(57)

Claims

1. A nerve cuff for enclosing a leadless microstimulator, the microstimulator having a body with electrodes integrally attached thereto, in stable communication with a nerve, the nerve cuff comprising:
a cuff body having a channel extending within the length of the cuff body for passage of a nerve;
a pocket within the cuff body, configured to removably hold the leadless microstimulator; and
an elongate opening slit extending the length of the cuff body configured to be opened to provide access to the pocket and the channel, and configured to be closed around the pocket and channel, enclosing the cuff body around the nerve.
2. The nerve cuff of claim 1, further comprising an internal electrical contact within the cuff body.
3. The nerve cuff of claim 2, wherein the internal electrical contact is configured to electrically couple the microstimulator and the nerve.
4. The nerve cuff of claim 1, further comprising an external electrical contact on the outer surface of the cuff body configured to couple with the microstimulator.
5. The nerve cuff of claim 1, wherein the cuff body comprises shielding configured to electrically isolate the microstimulator within the nerve cuff.
6. The nerve cuff of claim 1, wherein the cuff body has a uniform thickness.
7. The nerve cuff of claim 1, wherein the cuff body has a non-uniform thickness.
8. The nerve cuff of claim 7, wherein the cuff body has a thickness between about 5 and about 20 mils.
9. The nerve cuff of claim 1, wherein the outer surface of the nerve cuff is substantially smooth and atraumatic.
10. The nerve cuff of claim 1, wherein the outer surface of the nerve cuff is rounded.
11. The nerve cuff of claim 1, wherein the channel comprises a support channel configured to support the nerve within therein, to prevent pinching of the nerve.
12. The nerve cuff of claim 1, wherein the elongate opening slit extends the length of the cuff body in an interlocking pattern.
13. The nerve cuff of claim 1, wherein the slit extends along the side of the cuff body, adjacent to the channel.
14. The nerve cuff of claim 1, further comprising attachment sites in the elongate opening slit configured to help secure the slit closed.
15. The nerve cuff of claim 1, wherein the cuff body is formed of a flexible and biocompatible polymer.
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