Patent Abstract:
a composition and method for a light activated composition for improved wound closure , is disclosed . the composition includes a biodegradable polymer that is impregnated with a solder that is biologically compatible and a chromophoric dye . the chromophoric dye enhances the amount of light energy that the composition absorbs .

Detailed Description:
while the making and using of various embodiments of the present invention are discussed in detail below , it should be appreciated that the present invention provides many applicable inventive concepts that may be embodied in a wide variety of specific contexts . the specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention . in particular , the detailed description and discussion of the preparation steps for the various embodiments of the present invention in examples 1 to 4 are not intended to limit the scope of the invention . solder - doped polymer scaffolds have been developed as an alternative to conventional fasteners and traditional protein solders for tissue repair . the new scaffolds offer flexibility along with improved repair strength over previous published results using albumin protein solders alone [ mcnally 1999a , mcnally 1999b , mcnally 1999c ]. the properties of the solder - doped scaffolds can be easily tailored to meet the specific requirements of a wide range of clinical applications . the new scaffolds provide a quick and easy method of joining tissue in surgery . liquid protein solder was prepared from either 25 %( w / v ) or 50 %( w / v ) bovine serum albumin ( bsa ) ( cohn fraction v , sigma chemical company , st . louis , mo .) and indocyanine green ( icg ) dye ( sigma chemical company , st . louis , mo .) at a concentration of 0 . 5 mg / ml , mixed in deionized water . the solder was stored in a light - proof plastic vials at 4 ° c . until required . solid protein solder was prepared from 60 %( w / v ) bsa and icg dye at a concentration of 0 . 5 mg / ml , mixed in deionized water . the mixture was pressed to a thickness of 0 . 15 ± 0 . 01 mm and then cut into rectangular strips of the desired surface area and allowed to dry . the solid protein solder strips were stored in a light proof container between two inert metal plates at 4 ° c . until required . porous synthetic polymer scaffolds were prepared using poly ( l - lactic - co - glycolic acid ) ( plga ) with a lactic : glycolic acid ratio of 85 : 15 and 70 % weight fraction sodium chloride using a solvent - casting and particulate leaching technique [ mikos 1993 ]. for example , 200 mg plga ( sigma chemical company , st . louis , mo .) were dissolved in 2 ml dichloromethane ( sigma chemical company , st . louis , mo .) and then combined with 467 mg nacl of the desired particle size . two salt particle size ranges were used : ≦ 106 μm and 106 - 150 μm . these particle sizes were obtained by grinding the salt particles with a mortar and pestle and then sifting them through no . 100 and no . 140 sieves ( vwr scientific , south plainfield , n . j .). the scaffolds were cast into 60 mm diameter petri dishes and left in a fume hood for 24 hours to allow the dichloromethane to evaporate . the salt was leached out of the scaffolds by immersion in filtered deionized water for 24 hours . during the leach - out period the water was changed 3 - 4 times . the scaffolds were then air - dried and stored at room temperature until required . after air drying , the plga scaffolds were cut into strips of the desired surface area and left to soak for two hours in the liquid protein solder ( either 25 %( w / v ) or 50 %( w / v ) bsa ). before use , the solder - doped polymer scaffolds were left to dry for approximately 60 s on a piece of parafilm . the average thickness of the solder - doped polymer scaffolds , determined by scanning electron microscopy ( philips 515 , holland ) and measurement with precision calipers ( l . s . starrett co ., anthol , mass . ), was 202 ± 12 μm . the solder , the polymer scaffolds and the chromophoric dye are all bio - compatible . foreign body reaction is expected to be minimal using the new device as the degradation products of the scaffolds , including lactic acid and glycolic acid for the example of plga scaffolds , are naturally occurring substances inside the body [ wake 1996 ]. altering the macromolecular structure of the scaffold may also control the degradation rate of the scaffolds . for example , the degradation rate of the scaffolds may be altered from days to years by varying the ratio of polylactic acid ( pla ) to polyglycolic acid ( pga ) and may be varied from 0 to 100 % in plga scaffolds . any suitable bio - compatible polymers , solders and chromophoric dyes may be used to prepare the solder - doped polymeric scaffolds . suitable examples of polymers include poly ( l - lactic acid ) ( pla ), poly ( glycolic acid ) ( pga ), poly ( l - lactic - co - glycolic acid ) plga , poly (. epsilon .- caprolactone ), polyortho esters , polyanhydrides and the like . suitable examples of protein solders include serum albumin , collagen and fibrinogen . suitable examples of chromophoric dyes include water , indocyanine green ( icg ) and carbon . the polymer scaffolds are porous . the porosity of the scaffolds is easily controlled by , for example , altering the salt ( e . g ., sodium chloride ) weight fraction and salt particle size used during the casting stage of the scaffolds . by using salt particles of different sizes , scaffolds can be prepared with various porosities . the synthetic polymer scaffolds were prepared using 100 mg of plga with a lactic : glycolic acid ratio of 85 : 15 and 70 % weight fraction nacl . scaffolds were prepared with two salt particle sizes : ≦ 106 μm and 106 to 150 μm . by using salt particles of different sizes , scaffolds were prepared with the same porosity but with different pore diameters . fig2 a shows an example of a scaffold cast using salt particle sizes ≦ 106 μm in diameter . fig2 b shows an example of a scaffold cast using salt particle sizes of 106 to 150 μm in diameter . the right half of each micrograph shows a higher magnification view ( 526 ×) of the section of the micrograph highlighted by a rectangular frame on the left half of the micrograph ( 88 ×). the scaffolds exhibit a uniform pore morphology , which is interconnected , thus yielding an open - cell polymer . fig3 a and 3 b are scanning electron micrographs of the solder - doped polymer ( plga ) scaffolds formed with 25 % bsa and the two salt particle sizes . the solder - doped polymer scaffolds were prepared using solders composed of 25 % bsa and polymers prepared from 100 mg of plga with a lactic : glycolic acid ratio of 85 : 15 and 70 % weight fraction nacl . scaffolds were prepared with two salt particle sizes : ( a )≦ 106 μm and ( b ) 106 to 150 μm . original magnification of micrographs — 3a : 88 ×; 3 ( b ): 526 ×. the scaffolds exhibit a uniform pore morphology , which is interconnected , thus yielding an open - cell polymer . many of the pores of the scaffolds formed with salt particles ≦ 106 μm in diameter remained unfilled ( fig3 a ). the albumin protein solders appeared to be better able to permeate the polymer scaffold containing the larger pore diameters ( fig3 b ). pliability is an important consideration , particularly for blood vessels and intestines that require a tubular scaffold . other non - tubular soft tissues such as skin also require a flexible matrix that can conform to a variety of different contours . fig4 and 5 demonstrate the flexible nature of the scaffolds are evidenced by their ability to wrap around a canine carotid artery ( fig4 ) and a t - shaped junction ( fig5 ). in fig4 the scaffold is formed without macroscopic damage to the scaffold . the solder used in fig4 was composed of 50 % bovine serum albumin ( bsa ), 0 . 5 mg / ml indocyanine green ( icg ) and deionized water , and the polymer scaffold was formed using 100 mg poly ( lactic - co - glycolic acid ) ( plga ) and 70 wt % nacl ( salt particle size 106 to 150 μm ). the scaffolds are pliable and elastic and thus it is easy to process and fabricate them into different forms and shapes . another method for increasing the flexibility of the scaffolds is to add poly glycerol ( peg ) to the polymer mixture during the casting stage . tubular scaffolds have been prepared using the solder - doped polymer scaffolds . the plga scaffolds were prepared as described above with 100 mg plga and 70 wt % nacl ( salt particle size 106 to 150 μm ), and cut into rectangular sections approximately 1 cm long and 0 . 75 cm wide . the scaffold was rolled into a tube and the ends of the tube were sealed by slightly dissolving the edges with chloroform and pressing them together for approximately 15 s [ wake 1996 ]. the resulting tubular structures were approximately 2 mm in diameter and had a wall thickness of approximately 150 μm . the scaffolds were soaked in albumin protein solder for a period of two hours and allowed to dry on parafilm afterwards . the final wall thickness of the solder - doped tubular scaffolds was approximately 200 μm . as shown in fig5 development of new molds to create set scaffold geometries suitable to various clinical applications , such as a t - mold for end - to - side vascular anastomosis , are possible . various therapeutically effective dopants including but not limited to hemostatic and thrombogenic agents , antibiotics , anesthetics , various growth factors , enzymes , antiflammatories , bacteriostatic or bacteriocidal factors , chemotherapeutic agents , anti - angiogenic agents and vitamins can be added to the solder - doped polymer scaffolds . controlled release of these agents can assist in the wound healing process . the presence of the solder coagulum increases the initial strength of the repair , while the presence of the chromophoric dye provides for selective absorption of the laser light . as tissue absorption at a laser wavelength of approximately 800 nm is low , the dyed solder absorbs most of the incident light energy . consequently , the amount of collateral tissue thermal damage due to direct absorption of the laser light is minimized . besides exogenous chromophores added to the solder , water and natural chromophores of the solder - doped polymer scaffold can be used to absorb laser light . slight rehydration of the solder - doped polymer scaffolds upon application to the tissue assists with tissue apposition , thus relieving the need for excessive stay - sutures , often associated with laser tissue repair techniques . in addition , upon activation with a laser , the solder - doped polymer scaffolds tend to undergo a small amount of shrinkage . this shrinkage helps to maintain edge - alignment as the tissue edges are gently pulled together . in addition , contrary to conventional suturing , the solder - doped polymer scaffolds can provide an immediate leak - free closure . instead of using a polymer scaffold saturated with a single concentration of the chromophoric dye , two different scaffolds saturated with two different concentrations of dye may be used to produce a single unit with a gradient of dye concentration across its thickness . for example , two solder - doped polymer scaffolds , containing different dye concentrations , are pressed together using a vice to form a single solid scaffold . the two scaffolds are pressed together immediately after preparation and prior to drying so as to create a chromophore concentration gradient across the thickness of the scaffold , rather than two separate layers . the protein solder is soluble in physiological solutions prior to laser irradiation , which can be problematic during application . in addition , as these solders are often subjected to blood dilution during operation , the solder may undergo mechanical alteration that can weaken the solder - tissue repair [ lauto 1998 ]. predenaturation of the solder - doped polymer scaffolds reduces the solubility of the scaffolds in a fluid environment prior to denaturation . two such methods of predenaturation may include soaking the scaffolds in a hot water bath at a temperature of 70 to 80 c ., or tanning with glutaraldehyde . tanning with glutaraldehyde has previously been applied to human umbilical vein grafts [ how 1992 ], collagen grafts prepared from bovine carotid arteries [ rosenberg 1982 ] and albumin coated knitted polyester grafts [ kottke - marchant 1989 ], to improve the tensile strength of the grafts . biodegradable polymer films of controlled porosity were fabricated with poly ( l - lactic - co - glycolic acid ) ( plga ) and poly ( ethylene glycol ) ( peg ) using a solvent - casting and particulate - leaching technique . the porous films provided a scaffold into which the traditional protein solder composition of bovine serum albumin ( bsa ) and indocyanine green ( icg ) dye mixed in deionized water was readily absorbed . studies were conducted to assess the influence of various processing parameters on the strength of tissue repairs formed using the new scaffolds . these parameters included the plga copolymer ratio , the plga / peg blend ratio , the initial salt weight fraction , the salt particle size , and the initial albumin weight fraction . bovine thoracic aortas were obtained from a slaughterhouse ( taylor meat company , taylor , tex .). the aortas were rinsed with phosphate - buffered saline to remove blood from the tissue surface . a full thickness incision was cut through the specimen width using a scalpel and the severed ends were placed together . laser soldering was performed on the intima side of the aorta . the solder - doped polymer scaffold was placed perpendicularly across the junction of the severed aorta specimen and then denatured with a continuous pass of the diode laser output . a gaalas semiconductor diode with a nominal output power of 5 w and wavelength of 805 nm ( opto power corp ., tucson , ariz .) was used to denature the scaffold . the laser light was coupled into a 660 μm diameter silica fiber bundle and focussed onto the scaffold surface with an imaging hand - piece connected at the end of the fiber . the diode was operated in continuous mode with a l / e spot size at the scaffold surface of 1 . 5 mm . irradiances of 5 . 7 , 11 . 3 and 17 . 0 w / cm 2 , measured using a molectron epm 2000e power meter with a pm30 thermopile detector ( molectron detector , inc ., portland , oreg . ), were delivered to the scaffold surface . the laser beam was scanned linearly across the length of the solder - doped polymer scaffolds four times ( starting from one end ) at a constant speed of 0 . 3 mm / s using a motorized stage ( oriel corp ., stratford , conn .) to move the specimen . the total exposure time for each solder - doped polymer scaffold was 40 s . alteration of the plga copolymer ratio had little effect on the strength of the repairs . repair strength increased significantly with an increase in the size and number of pores present in the scaffolds and with increased bsa concentration . at the highest irradiance tested of 17 . 0 w / cm 2 , the strength of repairs formed with the solder - doped polymer scaffolds was significantly improved over past results achieved using traditional solid protein solders ( 92 . 1 ± 4 . 9 g [ mcnally 1999a ]). in addition , the strength of repairs formed using the solder - doped scaffolds denatured at 17 . 0 w / cm 2 compared favorably with the strength of native aorta ( 91 . 2 ± 4 . 7 g [ mcnally 1999 a ]). in all cases , the solder - doped scaffold remained intact and pulled away from the tissue . in many instances a portion of the tissue was observed to remain bonded to the scaffold . finally , the addition of peg to the films during the casting stage was observed to increase the flexibility of the scaffolds . the newly developed solder - doped polymer scaffolds were used as a substitute to traditional tissue solders for laser - assisted vascular tissue fusion without the need for sutures . canine femoral arteries ( n = 8 ), femoral veins ( n = 8 ) and carotid arteries ( n = 8 ) were exposed , and a 0 . 8 cm longitudinal incision was made in the vessels . a solid laser activated adhesive material composed of poly ( l - lactic - co - glycolic acid ) and bovine serum albumin was used to close the incisions in conjunction with an 805 nm diode laser . blood flow was restored to the vessel immediately after the procedure and the incision site was checked for patency . the new scaffolds were flexible enough to be wrapped around the vessel while their solid nature avoided the problems associated with “ runaway ” of the less viscous liquid protein solders currently used by researchers . assessment parameters included measurement of the intraluminal bursting pressure one hour after surgery , as well as histology . a control study was also performed on canine femoral arteries and veins ( n = 4 ) using four to six sutures evenly spaced around the vessel wall . the acute intraluminal bursting pressures were significantly higher in the laser - solder group (& gt ; 350 mmhg ) compared to the suture group (& lt ; 150 mmhg ). histological analysis showed no evidence of thrombosis formation in the laser - solder repair group . these initial results indicated that laser - assisted vascular repair using the new scaffolds is safe , easy to perform , and contrary to conventional suturing , provides an immediate leak - free closure . in addition , the flexible and moldable nature of the new scaffolds allows them to be tailored to a wide range of tissue geometries , thus greatly improving the clinical applicability of laser - assisted tissue repair . laser welding of the genitourinary tract has the potential advantage of forming an immediate watertight seal . in addition , it may obviate the need for sutures , eliminate foreign body reaction to sutures , and potentially improve healing . the feasibility of using the solder - doped polymer scaffolds for uretal repair was investigated using a canine model . eight canine ureters were exposed , and a 0 . 8 cm longitudinal incision was made in the tube . the incision was repaired using a strip of the solder - doped polymer scaffold in conjunction with an ˜ 800 nm diode laser . the dimensions of the strip were approximately 1 . 2 × 0 . 4 × 0 . 15 mm . following the repairs the intraluminal bursting strength of each ureter was measured . successful ureteral repairs were achieved in all solder groups while maintaining ureteral continuity at supraphysiologic pressures . rectangular solid solder strips composed of indocyanine green ( icg )— doped albumin protein solders were used in conjunction with an 808 nm - diode laser . these investigations are furthered by in vitro studies conducted to assess a range of specially designed chromophore - enhanced solid protein solders manufactured and tested for application during laser - assisted anastomosis of bovine vascular specimens . the study was divided into two parts . in the first part of the study , the creation of a chromophore concentration gradient across the thickness of the solder was investigated as a means to allow control of the heat source gradient through the solder . increased deposition of the laser energy near the vital solder / tissue interface was achieved . in the second part of the study , predenaturation of the solid solder was investigated as a means for increasing the flexibility and decreasing the brittle nature of the solid solder . the resulting solder was flexible enough to be wrapped around the tissue while its solid nature avoided the problems associated with “ runaway ” of the less viscous liquid solders currently used by researchers . in addition , predenaturing the solder enhanced its stability in a hydrated environment thus improving the handling characteristics of the solder for clinical application . the creation of a chromophoric concentration gradient across the thickness of the solder was achieved by placing two solid protein solder strips , 75 μm in thickness , containing different icg dye concentrations directly on top of each other , and pressing them together using a vice to form a single solid solder strip 150 μm in thickness . the solder strips were pressed together immediately after preparation , prior to drying , so as to create a chromophore concentration gradient across the thickness of the solder , rather than two separate layers . four combinations of chromophore concentrations were used : 2 . 5 mg / ml : 0 . 25 mg / ml , 1 . 875 mg / ml : 0 . 625 mg / ml , 0 . 625 mg / ml : 1 . 875 mg / ml and 0 . 25 mg / ml : 2 . 5 mg / ml . solder strips containing 2 . 5 mg / ml icg and 0 . 25 mg / ml icg without the chromophore concentration gradient were also investigated . fig6 is a graph that shows the results of studies conducted to determine the total temperature gradient across the solid protein solder strips containing the various icg dye concentration gradients . results from measurements made on the four combinations of chromophore concentration gradients investigated ( 2 . 5 mg / ml : 0 . 25 mg / ml , 1 . 875 mg / ml : 0 . 625 mg / ml , 0 . 625 mg / ml : 1 . 875 mg / ml and 0 . 25 mg / ml : 2 . 5 mg / ml ), and protein solders containing 2 . 5 mg / ml icg and 0 . 25 mg / ml icg without the chromophore concentration gradient , are presented . while the solid protein solder containing icg dye concentrations of 2 . 5 mg / ml and 0 . 25 mg / ml produced an average temperature gradient across the solder of 193 ° c ./ mm and 113 ° c ./ mm , respectively , the temperature gradient was only 20 ° c ./ mm , using solder formed with a chromophore concentration gradient of 0 . 25 mg / ml : 2 . 5 mg / ml icg . fig7 is a graph that shows the results of strength measurements made on tissue specimens successfully repaired using the solid protein solder strips prepared with a range of icg dye concentration gradients , as a function of laser irradiance . the repair strength for each value of laser irradiance was calculated from the mean for ten repairs . the standard deviation is also shown in each case . repairs formed with solders containing a chromophore concentration gradient of 0 . 25 mg / ml : 2 . 5 mg / ml icg were approximately 58 % stronger than those formed using solder containing 2 . 5 mg / ml icg , the most common icg concentration used by researchers for laser tissue solder repair , and approximately 33 % stronger than those formed using solder containing 0 . 25 mg / ml icg . two methods of predenaturation of the solid protein solder strips ( 60 % bsa ) were investigated . the first method involved soaking the solder strips in a hot water bath at set temperatures of either 75 ° c . or 90 ° c . for approximately 30 s . the second method involved soaking the solder strips in glutaraldehyde at concentrations of 0 . 5 to 1 . 0 % for approximately 30 s . fig8 a is a graph that shows the time for dissolution in phosphate buffered saline of predenatured solid protein solder strips prior to laser irradiation . the time for dissolution for each group of solder was calculated from the mean for ten specimens . the standard deviation is also shown in each case . undenatured solder specimens were completely dissolved after 5 minutes of soaking in pbs . solder specimens predenatured in a hot water bath at 75 ° c . took 150 minutes to dissolve . the time for dissolution of solder specimens predenatured at 100 ° c . and in glutaraldehyde was greatly increased ( 3 . 8 to 8 . 1 days ). predenaturation in a hot water bath at 75 ° c . was thus the optimal technique investigated , providing ample time for the surgical procedure to be performed . fig8 b is a graph that shows that after laser irradiation of the strips at 11 . 3 w / cm 2 for 40 s , no significant difference ( p & lt ; 0 . 05 ) was observed in the time for dissolution of solid protein solder strips previously undenatured or predenatured using any of the techniques described . fig9 is a graph that shows the results of strength measurements made on tissue specimens successfully repaired using the predenatured solid protein solder strips , as a function of laser irradiance . the breaking load for each value of laser irradiance was calculated from the mean for ten repairs . the standard deviation is also shown in each case . there was no significant difference ( p & lt ; 0 . 05 ) between the strength of repairs formed using the undenatured solder and those specimens repaired using solder predenatured at 75 ° c . the strength of the repairs formed decreased with increased denaturation temperature ( e . g ., 100 ° c .). strength was also reduced when the protein solders were predenatured in glutaraldehyde . the decrease in strength was attributed to the fact that glutaraldehyde is a known fixative , and some degree of fixation must have occurred in the albumin protein solder . predenaturation of the solder at 75 ° c . is thus a feasible option for reducing the solubility of solder and to ensure that minimal mechanical alteration occurs that can weaken the solder - tissue repair during the surgical procedure . the application of icg - doped 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