Abstract:
The present disclosure is directed to the use of fusogenic compounds such as polyethylene glycol (PEG) in combination with antioxidants, calcium-containing and calcium-free solutions for treating damaged nerves, such as for reconnecting severed nerves.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application No. 61/578,930 filed Dec. 22, 2011 and U.S. Provisional Patent Application No. 61/446,803 filed Feb. 25, 2011, the disclosures of which are hereby incorporated by reference in their entirety. 
     
    
     STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    Not applicable. 
       BACKGROUND OF THE DISCLOSURE 
       [0003]    The present disclosure generally relates to a nerve coaptation apparatus and, more particularly, to a microsuture-less nerve coaptation apparatus having relatively-movable coupling members to inhibit nerve compression in the event of, for example, nerve swelling. 
         [0004]    Microsurgery (that is, surgery aided by use of a microscope) is used in various types of medical procedures that treat relatively small bodily structures, such as coaptation of severed nerves. In this case, the procedure typically involves using a relatively small suture to connect the severed ends of the severed nerve segments. This facilitates axonal growth to fuse the nerve segments, which ideally restores some degree of nerve functionality. 
         [0005]    Unfortunately, nerve coaptation microsutures have several limitations. For example, connecting severed nerve segments with a microsuture is a relatively long procedure that requires considerable surgical experience. Furthermore, the outcome of such procedures are typically considered poor due to relatively long recovery times (for example, up to several years) and limited nerve functionality (for example, less than 20 percent of original nerve functionality). 
         [0006]    Nerve coaptation couplings have been proposed for use in addition to microsutures in an attempt to address the above limitations. Such couplings typically include a sleeve that houses and isolates the ends of the severed nerve segments, and pharmaceutical agents can be incorporated into the sleeve to promote axonal growth. Unfortunately, such devices inhibit nerve swelling proximate the ends of the severed nerve segments, which inwardly compresses the nerve segments and can adversely affect nerve regeneration. 
         [0007]    Considering the above, what is needed is a nerve coaptation apparatus that addresses one or more of the shortcomings of microsutures and previous coaptation devices. 
       SUMMARY OF THE INVENTION 
       [0008]    The present invention generally provides an apparatus for coaptation of first and second severed nerve segments. The apparatus includes a plurality of nerve-engaging features or “coupling members” that each connect to another coupling member to form “coupling pairs”. The coupling pairs are advantageously movable relative to each other to permit nerve swelling and inhibit nerve compression. 
         [0009]    In one aspect, the present invention provides an apparatus for coaptation of a first nerve segment separated from a second nerve segment. The apparatus includes a first coaptation member configured to extend about the first nerve segment and engage the first nerve segment. The apparatus further includes a second coaptation member configured to connect to the first coaptation member and extend about the second nerve segment. The second coaptation member includes a first coupling member and a second coupling member that are each configured to engage the second nerve segment to inhibit the second nerve segment from moving away from the first nerve segment in a longitudinal direction. The first coupling member and the second coupling member are movable relative to each other in a transverse direction substantially perpendicular to the longitudinal direction to inhibit nerve compression. 
         [0010]    In another aspect, the present invention provides an apparatus for coaptation of a first nerve segment separated from a second nerve segment. The apparatus includes a first coaptation member configured to extend about the first nerve segment, and the first coaptation member includes a first coupling member configured to engage the first nerve segment. The apparatus further includes a second coaptation member configured to extend about the second nerve segment, and the second coaptation member includes a second coupling member configured to engage the second nerve segment. The second coupling member connects to the first coupling member to inhibit the first and second coaptation members from moving apart in a longitudinal direction and to inhibit the first and second nerve segments from moving apart in the longitudinal direction. The first coupling member and the second coupling member are movable in a transverse direction substantially perpendicular to the longitudinal direction to inhibit nerve compression. 
         [0011]    In yet another aspect, the present invention provides an apparatus for coaptation of a first nerve segment separated from a second nerve segment. The apparatus includes a first coupling pair having a first coupling member configured to connect to the first nerve segment and a second coupling member configured to connected to the second nerve segment. The first coupling member connects to the second coupling member to engage the first nerve segment with the second nerve segment. The apparatus further includes a second coupling pair having a third coupling member configured to connect to the first nerve segment and a fourth coupling member configured to connected to the second nerve segment. The third coupling member connects to the fourth coupling member to engage the first nerve segment with the second nerve segment. The first coupling pair is movable relative to the second coupling pair to inhibit compression of the first nerve segment and the second nerve segment. 
         [0012]    The foregoing and other objects and advantages of the invention will appear in the detailed description that follows. In the description, reference is made to the accompanying drawings that illustrate a preferred configuration of the invention. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0013]    The present invention will hereafter be described with reference to the accompanying drawings, wherein like reference numerals denote like elements, and: 
           [0014]      FIG. 1  is a side schematic view of a nerve coaptation apparatus according to the present invention; 
           [0015]      FIG. 2  is a side perspective view of a first configuration of the nerve coaptation apparatus of  FIG. 1  before connecting two coaptation members; 
           [0016]      FIG. 3  is a side view of the first configuration of the nerve coaptation apparatus of  FIG. 2  upon connecting the two coaptation members; 
           [0017]      FIG. 4  is an end view of one of the coaptation members of  FIG. 2 ; 
           [0018]      FIG. 5  is a detail view of the area of one of the coaptation members enclosed by line  5 - 5  of  FIG. 2 ; 
           [0019]      FIG. 6  is a side perspective view of a second configuration of the nerve coaptation apparatus of  FIG. 1  before connecting two coaptation members; 
           [0020]      FIG. 7  is a side perspective view of the second configuration of the nerve coaptation apparatus of  FIG. 6  upon connecting the two coaptation members; 
           [0021]      FIG. 8  is an end view of one of the coaptation members of  FIG. 6 ; 
           [0022]      FIG. 9  is a perspective view of two coupling members of the second configuration of the nerve coaptation apparatus of  FIG. 6 ; 
           [0023]      FIG. 10  is a side perspective view of a third configuration of the nerve coaptation apparatus of  FIG. 1  before connecting two coaptation members; 
           [0024]      FIG. 11  is a side perspective view of the third configuration of the nerve coaptation apparatus of  FIG. 10  upon connecting the two coaptation members; 
           [0025]      FIG. 12  is a side perspective view of separation of two halves of one of the coaptation members of  FIG. 10 ; 
           [0026]      FIG. 13  is a flow chart setting forth steps of a pharmaceutical agent delivery sequence conducted by the apparatus of  FIG. 1 ; 
           [0027]      FIG. 14A  is a plot of sciatic function index scores versus post-operative time for various types of nerve injuries and pharmaceutical agent sequences; and 
           [0028]      FIG. 14B  is a plot of foot fault asymmetry scores versus post-operative time for various types of nerve injuries and pharmaceutical agent sequences. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0029]    Referring now to  FIG. 1 , the present invention provides an apparatus  50  for coaptation of first and second severed nerve segments  10 ,  12 . Generally, the apparatus  50  includes a first coaptation member  52  that surrounds and engages the first nerve segment  10  and a second coaptation member  54  that surrounds and engages the second nerve segment  12 . The first and second coaptation members  52 ,  54  abut each other to coapt the ends of the first and second nerve segments  10 ,  12 . In addition, the first and second coaptation members  52 ,  54  include nerve-engaging features or “coupling members” that each connect to a coupling member on the opposite coaptation member  52 ,  54  to form “coupling pairs”. The coupling pairs are advantageously movable relative to each other to permit nerve swelling and inhibit nerve compression. Various configurations of the apparatus  50  and the coupling members are described below. 
         [0030]    The coaptation members  52 ,  54  also receive one or more pharmaceutical agents from an agent delivery device  56  to facilitate repair and fusion of the nerve segments  10 ,  12 . Various pharmaceutical agents may be used, although advantageous pharmaceutical agents are described below. Regardless of the specific type used, the pharmaceutical agents are subsequently evacuated to a collection device  58 . 
         [0031]    Turning now to  FIGS. 2-5 , a first configuration of the nerve coaptation apparatus  100  is shown. In this configuration, the first and second coaptation members  102 ,  104  are generally similar, and therefore only the first coaptation member  102  is described in detail herein. 
         [0032]    The first coaptation member  102  includes a plurality of coupling members  106 , which may comprise various materials commonly associated with medical devices, such as implantable, biodegradable, and non-neurotoxic polymers and the like. Each of the coupling members  106  includes a semi-cylindrical wall  108 , and together the walls  108  provide the first coaptation member  102  with a cylindrical shape for receiving the first nerve segment  10 . That is, the coupling members  106  together define open ends  110 ,  112  through which the nerve segment  10  extends and an internal nerve passageway  114  that receives nerve segment  10 . Furthermore, the coupling members  106  together define a longitudinal direction of the coaptation member  102  extending between the open ends  110 ,  112  and aligned with the longitudinal direction of the nerve segment  10 . 
         [0033]    To permit the coupling members  106  to move relative to each other, the first coaptation member  102  includes a plurality of expandable or flexible joints  116  connecting the sides of adjacent coupling members  106 . The flexible joints  116  may comprise various materials, such as elastically deformable, implantable, biodegradable, and non-neurotoxic polymers and the like. In any case, the flexible joints  116  permit the coupling members  106  to move in a transverse direction (that is, a direction perpendicular to the longitudinal direction within five degrees) relative to one another. Such relative motion between the coupling members  106  advantageously permits nerve swelling (by up to, for example, 50 percent) and inhibits nerve compression. 
         [0034]    The first coaptation member  102  includes several features to engage the first nerve segment  10  and the second coaptation member  104  proximate the open end  110 . To connect to the nerve segment  10 , each of the coupling members  106  includes a hooked epineurium pin  118 . As the name implies, each epineurium pin  118  pierces the epineurium of the nerve segment  10 . As such, the epineurium pins  118  inhibit the nerve segment  10  from moving longitudinally relative to the coaptation member  102 . In addition, the epineurium pins  118  hold the nerve segment  10  in an appropriate position for coaptation with the second nerve segment  12  (that is, proximate the open end  110 ) when the coaptation members  102 ,  104  are connected. 
         [0035]    To connect the first coaptation member  102  to the second coaptation member  104 , each of the coupling members  106  includes two longitudinally extending connection elements  120 ,  122  proximate the first open end  110 . Half of the connection elements are tapering posts  120  and half of the connection elements are holes  122 . Each hole  122  receives one of the tapering posts  120  on the second coaptation member  104 , and each tapering post  120  is received in one of the holes  122  on the second coaptation member  104 . In addition, each tapering post  120  may be press-fittingly received in the corresponding hole  122  to provide a firm connection between the coaptation members  102 ,  104 . Such a connection may inhibit the coaptation members  102 ,  104  from moving apart in the longitudinal direction once connected. 
         [0036]    One or more of the coupling members  106  also include features to ensure proper angular alignment of the nerve segments  10 ,  12  (that is, proper alignment of individual axons and the like). Specifically, on each of the coaptation members  102 ,  104 , one of the coupling members  106  includes a plurality of strips  124 ,  126 , and  128  of different colors. When connecting the nerve segments  10 ,  12  to the coaptation members  102 ,  104 , respectively, common features of the nerve segments  10 ,  12  (for example, fascicle patterns or the like) may be aligned with a specific strip  124 ,  126 , or  128 . Then, when connecting the coaptation members  102 ,  104  to each other, matching color strips  124 ,  126 , and  128  on the coaptation members  102 ,  104  are aligned to ensure that the features of the nerve segments  10 ,  12  are aligned. Furthermore, the coupling members  106  could be translucent or transparent to permit the nerve segments  10 ,  12  to be viewed therethrough. 
         [0037]    During deployment, the coaptation members  102 ,  104  may be moved towards each other and joined using a linear or hinged coupling applicator, such as those used for vascular anastomoses. Other deployment devices may alternatively be used. 
         [0038]    After deployment, one or more pharmaceutical agents may be delivered from the agent delivery device, through an inlet passageway  130  defined by one of the coupling members  106 , and into the nerve passageways  114  to facilitate repair and fusion of the nerve segments  10 ,  12 . After a specified amount of time, the pharmaceutical agents are evacuated through an outlet passageway  132  defined by one of the coupling members  106  and into the collection device. 
         [0039]    The first configuration of the nerve coaptation apparatus  100  may be modified in other manners that are not explicitly described above. For example, the coupling members  106  may include more or less than two connection elements  120 ,  122  and one epineurium pin  118  (for example, each coaptation member  102  and  104  may include twelve connection elements  120 ,  122  and six epineurium pins  118 ). As another example, the inlet passageway  130  and outlet passageway  132  may be omitted, and gaps defined by the flexible joints  116  and the sides of adjacent coupling members  106  may serve as inlet and outlet passageways. 
         [0040]    Turning now to  FIGS. 6-9 , a second configuration of the nerve coaptation apparatus  200  is shown. In this configuration, the apparatus  200  includes a first coaptation member and a second coaptation member  202 ,  204  that are generally similar. As such, only the first coaptation member  202  is described in detail herein. In general, the first coaptation member  202  permits nerve swelling and inhibits compression by deploying a plurality of relatively movable coupling members. This aspect is described in further detail below. 
         [0041]    The first coaptation member  202  may comprise various materials commonly associated with medical devices, such as non-neurotoxic polymers and the like. The first coaptation member  202  includes a wall  206  that defines a cylindrical shape for receiving the first nerve segment  10 . That is, the wall  206  defines open ends  208 ,  210  through which the nerve segment  10  extends and an internal nerve passageway  212  that receives nerve segment  10 . Furthermore, the coaptation member  202  defines a longitudinal direction extending between the open ends  208 ,  210  and aligned with the longitudinal direction of the nerve segment  10 . 
         [0042]    The first coaptation member  202  also supports connection elements  214 ,  216 , such as those described above, to connect to the second coaptation member  204 . That is, the coaptation member  202  includes a plurality of longitudinally extending connection elements  214 ,  216  proximate the first open end  208 . Half of the connection elements are tapering posts  214  and half of the connection elements are holes  216 . Each hole  216  receives one of the tapering posts  214  on the second coaptation member  204 , and each tapering post  214  is received in one of the holes  216  on the second coaptation member  204 . In addition, each tapering post  214  may be press-fittingly received in the corresponding hole  216  to provide a firm connection between the coaptation members  202 ,  204 . Such a connection may inhibit the coaptation members  202 ,  204  from moving apart in the longitudinal direction once connected. 
         [0043]    The first coaptation member  202  also includes inlet and outlet passageways  218 ,  220  to receive and evacuate one or more pharmaceutical agents, respectively. In this configuration, the inlet and outlet passageways  218 ,  220  are defined adjacent to bridges  222  that connect opposite semi-cylindrical halves  224  of the coaptation member  202 . 
         [0044]    As described briefly above, the first coaptation member  202  releasably supports a plurality of coupling members  226 ,  228  on the inner surface of the wall  206 . The coupling members  226 ,  228  engage and hold the first nerve segment  10  in contact with the second nerve segment  12 . As such, the coupling members  226 ,  228  may comprise various materials commonly associated with medical devices, such as implantable, biodegradable, and non-neurotoxic polymers and the like. 
         [0045]    To engage and hold the first nerve segment  10  in contact with the second nerve segment  12 , half of the coupling members  226  have tapering shapes and act as epineurium pins that pierce the epineurium of the nerve segment  10 . In addition, these coupling members  226  are fixedly received by a corresponding pin-receiving coupling member  228  of the second coaptation member  204 . Similarly, each pin-receiving coupling member  228  of the first coaptation member  202  fixedly receives one of the epineurium pin coupling members  226  of the second coaptation member  204 . 
         [0046]    After receiving the nerve segments  10 ,  12 , connecting to each other, and delivering and evacuating the pharmaceutical agents, the coaptation members  202 ,  204  detach from the coupling members  226 ,  228 , for example, by breaking the bridges  222  and an adhesive connection between the coaptation members  202 ,  204  and the coupling members  226 ,  228 . The coupling members  226 ,  228  remain connected to each other and the nerve segments  10 ,  12 . As such, the coupling members  226 ,  228  inhibit the nerve segments  10 ,  12  from moving apart in the longitudinal direction. However, each pair of coupling members  226 ,  228  is movable in the transverse direction relative to the other pairs. The coupling members  226 ,  228  thereby permit nerve swelling and inhibit compression. 
         [0047]    Turning now to  FIGS. 10-12 , a third configuration of the nerve coaptation apparatus  300  is shown. The third configuration of the apparatus  300  shares many features with the second configuration of the nerve coaptation apparatus  200 . For example, the coaptation members  302 ,  304  may comprise various materials commonly associated with medical devices, such as non-neurotoxic polymers and the like. Furthermore, each coaptation member  302 ,  304  includes a plurality of connection elements  306 ,  308  like those described above and a plurality of detachably supported and nerve-engaging coupling members  310 ,  312  like those described above. Each coaptation member  302 ,  304  also includes inlet and outlet passageways  314 ,  316  to receive and evacuate one or more pharmaceutical agents, respectively. 
         [0048]    In contrast to the second configuration, each coaptation member  302 ,  304  includes two separate semi-cylindrical halves  318  that are initially held in abutment by a semi-cylindrical deployment element  320 . As such, after connecting the nerve segments  10 ,  12  to the coupling members  310 ,  312  and connecting the coaptation members  302 ,  304  to each other, the deployment elements  320  are detached from the coaptation members  302 ,  304  by, for example, moving the deployment elements  320  apart in the longitudinal direction. Thereafter, and as shown in  FIG. 12 , the coaptation member halves  318  are separated from each other, the coupling members  310 ,  312 , and the nerve segments  10 ,  12  by moving apart in the transverse direction. 
         [0049]    For each of the above configurations, the coaptation members may provide a range of sizes appropriate for use with digital nerve repair (about 1 mm in diameter) up to brachial root repair (about 1 cm in diameter). 
         [0050]    Turning now to  FIGS. 13, 14A, and 14B  and as briefly described above, the coaptation members may receive one or more pharmaceutical agents from the agent delivery device to facilitate repair and fusion of the nerve segments. The agent delivery device may be one or more syringes (in the case of a single syringe, multiple agents may be separately compartmentalized), a manifold that automatically delivers pharmaceutical agents, or the like. 
         [0051]    Regardless of the specific type of agent delivery device, the pharmaceutical agents preferably and advantageously include a sequence of: 1) a hypotonic calcium-free solution (for example, a solution as shown below in Tables 1 and 2 applied for a period of about 60 seconds before evacuation); 2) antioxidants/inhibitors of membrane sealing (for example, 2 mM melatonin or 100 μM USP methylene blue applied for a period of about 90 seconds before evacuation); 3) a lipid membrane fusogen (for example, 5 g polyethylene glycol 2000 (PEG) dissolved in 5 mL distilled water applied for about 90 seconds before evacuation); and; 4) isotonic calcium-containing solution (for example, a solution as shown below in Tables 3-5 applied for a period of about 120-180 seconds before evacuation). 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Hypotonic calcium-free solution. Chemicals dissolved in 1000 mL distilled 
               
               
                 water, buffering pH with HCl or NaOH, respectively, added drop-wise. 
               
             
          
           
               
                 Symbol 
                 Chemical 
                 Amount 
                 MW 
                 Factor 
                 mM/L 
                 species 
                 mOsm/L 
               
               
                   
               
             
          
           
               
                 NaCl 
                 Sodium Chloride 
                 5.7856 g 
                 58.44 
                 1 
                 99 
                 2 
                 198 
               
               
                 KCl 
                 Potassium Chloride 
                 0.3728 g 
                 74.56 
                 1 
                 5 
                 2 
                 10.0 
               
               
                 KH 2 PO 4   
                 Potassium 
                 0.1634 g 
                 136.09 
                 1 
                 1.2 
                 2 
                 2.4 
               
               
                   
                 Phosphate 
               
               
                 MgSO 4   
                 Magnesium Sulfate 
                 0.1566 g 
                 120.39 
                 1 
                 1.3 
                 2 
                 2.6 
               
               
                 NaHCO 3   
                 Sodium Bicarbonate 
                 2.1842 g 
                 84.01 
                 1 
                 25 
                 2 
                 50.0 
               
               
                 NaC 6 H 7 O 6   
                 Sodium Ascorbate 
                  1.981 g 
                 198.1 
                 1 
                 10 
                 2 
                 20.0 
               
               
                 C 6 H 12 O 6   
                 Dextrose 
                   1.8 g 
                 180.16 
                 1 
                 9.9 
                 1 
                 10.0 
               
               
                 — 
                 Solution A (see 
                    50 mL 
                 95.21 
                 85.49/10 
                 8.55 
                 3 
                 25.7 
               
               
                   
                 Table 2) 
               
               
                   
                   
                   
                   
                   
                   
                   
                 273.7 
               
               
                   
                   
                   
                   
                   
                   
                   
                 318.7 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Solution A. Dissolved in 500 mL distilled water. 
               
             
          
           
               
                 Symbol 
                 Chemical 
                 Amount (g) 
                 MW 
                 Multiplicand 
                 mM/L 
                 Species 
                 mOsm/L 
               
               
                   
               
               
                 MgCl 2   
                 Magnesium 
                 4.07 
                 95.21 
                 2 
                 85.49 
                 3 
                 256.47 
               
               
                   
                 Chloride 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Isotonic calcium-containing solution. Buffer pH with HCl or NaOH, 
               
               
                 respectively, added drop-wise. Mix cold. 
               
             
          
           
               
                 Symbol 
                 Chemical 
                 Amount 
                 MW 
                 mM/L 
                 Species 
                 mOsm/L 
               
               
                   
               
             
          
           
               
                 — 
                 Solution B 
                 475 
                 mL 
                 473.49 
                 331.55 
                 1 
                 314.97 
               
               
                   
                 (see Table 4) 
               
               
                 H 2 O 
                 Distilled Water 
                 475 
                 mL 
                 18 
                 — 
                 — 
               
               
                 — 
                 Solution C 
                 50 
                 mL 
                 111.0 
                 2 
                 3 
                 6.0 
               
               
                   
                 (see Table 5) 
               
               
                 NaC 6 H 7 O 6   
                 Sodium 
                 1.981 
                 g 
                 198.1 
                 10 
                 2 
                 20 
               
               
                   
                 Ascorbate 
               
               
                 C 6 H 12 O 6   
                 Dextrose 
                 1.8 
                 g 
                 180.16 
                 9.9 
                 1 
                 9.9 
               
               
                   
                   
                   
                   
                   
                   
                   
                 350.87 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Solution B. Chemicals dissolved in 4000 mL distilled water. 
               
             
          
           
               
                 Symbol 
                 Chemical 
                 Amount (g) 
                 MW 
                 Divisor 
                 mM/L 
                 Species 
                 mOsm/L 
               
               
                   
               
             
          
           
               
                 NaCl 
                 Sodium 
                 61.024 
                 58.44 
                 4 
                 261.05 
                 2 
                 522.1 
               
               
                   
                 Chloride 
               
               
                 KCl 
                 Potassium 
                 3.139 
                 74.56 
                 4 
                 10.5 
                 2 
                 21 
               
               
                   
                 Chloride 
               
               
                 KH 2 PO 4   
                 Potassium 
                 1.374 
                 136.09 
                 4 
                 2.52 
                 2 
                 5.04 
               
               
                   
                 Phosphate 
               
               
                 MgSO 4   
                 Magnesium 
                 1.318 
                 120.39 
                 4 
                 2.74 
                 2 
                 5.48 
               
               
                   
                 Sulfate 
               
               
                 NaHCO 3   
                 Sodium 
                 18.394 
                 84.01 
                 4 
                 54.74 
                 2 
                 109.48 
               
               
                   
                 Bicarbonate 
               
               
                   
                   
                   
                 473.49 
                   
                 331.55 
                   
                 663.1 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Solution C. Dissolved in 1000 mL distilled water. 
               
             
          
           
               
                 Symbol 
                 Chemical 
                 Amount (g) 
                 MW 
                 mM/L 
                 Species 
                 mOsm/L 
               
               
                   
               
               
                 CaCl 2   
                 Calcium 
                 4.44 
                 111.0 
                 40 
                 3 
                 120 
               
               
                   
                 Chloride 
               
               
                   
               
             
          
         
       
     
         [0052]    Alternatively, the hypotonic calcium-free solution may be additionally applied to the nerve after the antioxidants/inhibitors of membrane sealing and before the lipid membrane fusogen to wash away USP methylene blue stains on the nerve segments. 
         [0053]    Data collected by the present inventors and partially illustrated in  FIGS. 14A and 14B  indicates that antioxidants/inhibitors of membrane sealing, such as USP methylene blue and melatonin, maintain the axonal ends of severed nerve segments in an open and vesicle-free state appropriate for repair by a lipid membrane fusogen, such as PEG. Furthermore, these data also indicate that the above sequence advantageously improves recovery time and nerve function compared to microsutures, specifically by a factor of up to two and 40 percent in four months, respectively. 
         [0054]    After the specified contact period with the nerve segments, each pharmaceutical agent may be evacuated by applying vacuum pressure, permitting free drainage, capillary action (for example, by connecting the outlet passageway to an absorbent surgical material), or the like. Furthermore, the actions of the delivery device and the collection device can be coordinated, for example, via an electronic controller (not shown) and a plurality of valves (not shown), such that each pharmaceutical agent contacts the nerve segments for the specified contact period. Such a controller may also control the delivery pressure of the pharmaceutical agents. That is, the controller may provide the agents at a pressure sufficiently low to maintain contact of the ends of the nerve segments, and sufficiently high to ensure adequate distribution of the chemicals over the nerve segments. 
         [0055]    The pharmaceutical agent delivery sequence may be summarized as follows. 
         [0056]    A method for treatment of a nerve, comprising the steps of: 
         [0057]    delivering at least one of an antioxidant and an inhibitor of membrane sealing to the nerve; 
         [0058]    evacuating the at least one of the antioxidant and the inhibitor of membrane sealing away from the nerve; 
         [0059]    delivering at least one lipid membrane fusogen to the nerve after evacuating the at least one of the antioxidant and the inhibitor of membrane sealing; and 
         [0060]    evacuating the at least one lipid membrane fusogen away from the nerve. 
         [0061]    In some configurations, the at least one of the antioxidant and the inhibitor of membrane sealing includes one of USP methylene blue and melatonin. 
         [0062]    In some configurations, the at least one lipid membrane fusogen includes polyethylene glycol. 
         [0063]    In some configurations, the method further comprises the steps of: 
         [0064]    delivering at least one hypotonic calcium-free solution to the nerve; and 
         [0065]    evacuating the at least one hypotonic calcium-free solution away from the nerve before delivering the at least one of the antioxidant and the inhibitor of membrane sealing. 
         [0066]    In some configurations, the method further comprises the steps of: 
         [0067]    delivering at least one isotonic calcium-containing solution to the nerve after evacuating the at least one lipid membrane fusogen; and 
         [0068]    evacuating the at least one isotonic calcium-containing solution away from the nerve. 
         [0069]    In some configurations, the nerve includes a first segment severed from and abutting a second segment, and each of the at least one of the antioxidant and the inhibitor of membrane sealing and the at least one lipid membrane fusogen are delivered to and evacuated away from the first segment and the second segment. 
         [0070]    The pharmaceutical agents may be provided in a kit. Such a kit may be summarized as follows. 
         [0071]    A kit for use in a pharmaceutical agent delivery sequence, comprising: at least one of an antioxidant and an inhibitor of membrane sealing; at least one lipid membrane fusogen; and instructions indicating that the pharmaceutical agent delivery sequence includes at least one of the antioxidant and the inhibitor of membrane sealing followed by the at least one lipid membrane fusogen. 
         [0072]    From the above description, it should be apparent that the present invention provides a nerve coaptation apparatus that includes a plurality of nerve-engaging coupling pairs. The coupling pairs are advantageously movable relative to each other to permit nerve swelling and inhibit nerve compression. 
         [0073]    The various configurations presented above are merely examples and are in no way meant to limit the scope of this disclosure. Variations of the configurations described herein will be apparent to persons of ordinary skill in the art, such variations being within the intended scope of the present application. In particular, features from one or more of the above-described configurations may be selected to create alternative configurations comprised of a sub-combination of features that may not be explicitly described above. In addition, features from one or more of the above-described configurations may be selected and combined to create alternative configurations comprised of a combination of features which may not be explicitly described above. Features suitable for such combinations and sub-combinations would be readily apparent to persons skilled in the art upon review of the present application as a whole. The subject matter described herein and in the recited claims intends to cover and embrace all suitable changes in technology.