CA2222633A1 - Method for laser mediated tissue welding with enhanced strength - Google Patents
Method for laser mediated tissue welding with enhanced strength Download PDFInfo
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- CA2222633A1 CA2222633A1 CA002222633A CA2222633A CA2222633A1 CA 2222633 A1 CA2222633 A1 CA 2222633A1 CA 002222633 A CA002222633 A CA 002222633A CA 2222633 A CA2222633 A CA 2222633A CA 2222633 A1 CA2222633 A1 CA 2222633A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
- A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
- A61B18/22—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser the beam being directed along or through a flexible conduit, e.g. an optical fibre; Couplings or hand-pieces therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00491—Surgical glue applicators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00491—Surgical glue applicators
- A61B2017/00513—Tissue soldering
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/00491—Surgical glue applicators
- A61B2017/00513—Tissue soldering
- A61B2017/00517—Tissue soldering using laser
Abstract
Methods for tissue welding using solders incorporating biologically active agents, such as growth factors or hemostatic agents, have been developed.
Improved solder compositions have also been defined, yielding greater bursting strength as a function of protein concentration, and through the use of protein unfolding prior to laser-mediated denaturation and coupling. A method for repair of fistulas has been discovered, using water as a chromophore, in combination with solder concentration, to form columns to fill defects where tissue apposition is not possible. Methods have also been adapted for use with other forms of directed energy, including bipolar electrosurgery and light.
Examples demonstrate increased strength of repairs by incorporation of growth factors into solders, alone and as a function of solder concentration.
Increased adhesion is obtained through prevention of bleeding by incorporation of hemostatic agents such as thrombin or epinephrine, a vasoconstrictor.
Improved solder compositions have also been defined, yielding greater bursting strength as a function of protein concentration, and through the use of protein unfolding prior to laser-mediated denaturation and coupling. A method for repair of fistulas has been discovered, using water as a chromophore, in combination with solder concentration, to form columns to fill defects where tissue apposition is not possible. Methods have also been adapted for use with other forms of directed energy, including bipolar electrosurgery and light.
Examples demonstrate increased strength of repairs by incorporation of growth factors into solders, alone and as a function of solder concentration.
Increased adhesion is obtained through prevention of bleeding by incorporation of hemostatic agents such as thrombin or epinephrine, a vasoconstrictor.
Description
METHOD FOR LASER MEDIATED
TISSUE VVELDING VVITH ENHANCED STRENGTH
- Background of the Invention This is generally in the field of methods for tissue welding using 5 laser m~ t~ coupling of protein solders, and in particular is an improved method and composition incol~o~ lg biologically active compounds into the solder.
The use of laser energy to join tissue is referred to as "tissue welding". The goal is to facilitate the joining of tissues with a ,.,ini",u-"
10 of scar and good tensile ~llellglh of the apposed edges. Lasers that have been used for tissue welding include neodymium:yttrium~ ll"i",.."-garnet (Nd:YAG), argon and CO2 lasers. These appal~llLly produce an interdigitation of collagen fibrils, plc~ulllably heating at the surface of the tissues which del~luies and couples the pro~eills in the tissue.
Initial studies focused on anastomosis of blood vessels. Later studies looked at other tissues, such as bowel, and nerve repair. The success of tissue union is dependent on several factors, including ~lignment of the edges of the tissue without tension and in close approximation, adjuctm~nt of laser parameters to ",i~-i"~i~e peripheral tissue destruction and control heating of tissues, and the use of an applopliale protein solder. Various solders such as 40% albumin are described by Poppas, et al., J. Urol. 139, 415417 (1988), Poppas, et al., J. Urol. 150, 648-650 (1993), Poppas, et al., Lasers in Sur~ery & Med.
13, 577-580 (1993), Choma, et al., Lasers in Sur,~. & Med. 12, 639-644 (1992), and Poppas, et al., J. Urol. 150, 1052-1055 (1993). Albumin is a prer~ d solder since it signifir~ntly illlpro~es the tensile strength of laser wound closure, as colll~ared to in the absence of solder or the use of blood, it ~ignifi~ntly increases the leak point pïei~:jUl'e, it is hl~ e and easily manufactured and does not elicit an immnnogenic response, and is available in sterile, virus free form. As described in U.S. Patent Nos. 5,334,191 and 5,409,148 to Poppas, et al., and Poppas, et al.
W O 96/38093 PCTrUS96/08458 (1993), the solder is further improved through the inclusion of a chromophore such as fluorescein or iron oxide, which increases the absorption of laser energy, reducing the amount of power required to effect a tissue weld, as well as through the use of fine ~e~l~ycldlule 5 control.
The advantages of tissue welding are numerous, and include rapid (1 mm/second) formation of a fluid tight seal, nonlithogenic, improved healing, reduced wound infection, and shorter hospitalization and improved postoperative results. However, a disadvantage of tissue 10 welding which uses no solder or ~;ull~;lllly available protein solders, is that the repair has low tensile ~
It is therefore an object of the present invention to provide methods and compositions for tissue welding which yields repairs having greater tensile ~l.en~ and improved wound healing plopcllies.
It is another object of the present invention to provide tissue repairs of fistulas and other open areas including ulcers and chronic wounds.
Summary of the I~ lion Methods for tissue welding using solders incorporating biologically active agents, such as growth factors, thrombolytic or clot inhibitory agents or hemostatic agents, have been developed. Improved solder co.~osilions have also been defined, yielding greater bursting strength as a function of protein conce"L,d~ion, and through the use of protein unfolding prior to laser-m~ t~d del~u,dlion and coupling. A method for repair of fistulas has been discovered, using water as a chromophore, in combination with solder concentration, to form columns to fill defects where tissue apposition is not possible. Methods have also been adapted for use with other forms of directed energy, including bipolar electrosurgery and light.
Examples demonstrate increased SLl~ ,lh of repairs by inco.~o-~lion of growth factors into solders, alone and as a function of W 096/38093 PCTrUS96/08458 solder concentration. Increased adhL.lon is obtained through prevention of bleeding by incorporation of hemostatic agents such as thrombin, heparin or other clot inhibitory agent, or epinephrine, a vasoconstrictor.
Brief Des~ .tion of the Dl~wi~
Figure 1 is a graph showing the effect of albumin concentration on bursting ~n~es~uie, as a function of intr~h-rnin~l bursting ~les~u~c (mm Hg) for 25%, 38%, 45% and 50% albumin (w/v).
Figures 2a and 2b are graphs showing how albumin solder can be modified to lower the thermal dend~uld~ion threshold, as a function of Time (seconds) versus Tellll)eldluie ( C) for stabilized albumin (Figure 2a) and unstabilized albumin (Figure 2b).
Figures 3a, 3b, and 3c are graphs colllpal-ng wound ~ 11g~11 over time, as a function of m~ximl-rn stress (kPa) for wounds repaired with sutures, laser + solder, laser + HB-EGF, laser + solder + bFGF, and laser + solder + TGF,Bl, post-op day 3 (Figure 3a), post-op day 5 (Figure 3b), and post-op day 7 (Figure 3c).
Figure 4 is a graph COlll?dlillg repair ~ lg~l over time, as a function of m~ximnm stress (kPa) versus time, for laser + solder +
TGF,BI (diamonds), sutures (squares), or laser + solder (triangle).
Figure 5 is graph COlllpalillg lasered and non-lasered (sutured) repairs with and without growth factor enh~nre~ albumin solder, as a function of m~ximt-m stress (kPa) for sutures alone, sutures + albumin solder, sutures + albumin solder + bFGF, sutures + albumin solder +
TGF,~" laser + sutures + albumin solder, laser + sutures + alburnin solder + bFGF, and laser +sutures + solder + TGF,BI.
Figure 6 is a graph of total collagen content (micrograms/mg dry weight) for repairs using sutures alone, laser + albumin solder, and laser + solder + TGF,~I.
W 096/38093 PCTrUS96/084S8 Detailed D~ ion of the Invention I. Systems for Energy ~e~ tPd Repair Lasers Nd:YAG lasers, GaAlAs lasers, Argon lasers and CO2 lasers can be used for tissue welding. Lasers are commercially available from a variety of comp~ni~s, such as Laserscope Corp, San Jose, CA, and are ~;ullcnlly in use for a variety of surgical applications. U.S.
Patent No. 5,409,479 to Dew, et al., and U.S. Patent No. 5,156,613 to Sawyer, incol~olal~d by lcr~ lce herein, describe the use of lasers and radiofrequency energy to close tissue wounds by tissue welding. U.S.
Patent Nos. 5,334,191 to Poppas, et al., incorporated by rcrel. lue herein, describes a ylerellcd system for use in tissue welding. As in all surgical procedures, laser welding is most succes~ful when trauma to the sulluunding tissue is minimi7P~I Since the laser welding procedure is a non-contact method, the main complications occur when there is extensive thermal injury. The thermal deposition of the laser energy is, thelcrolc, very important to obtain s~lrcec~ful laser welds, and the p~ t~l~ of the laser must be chosen to insure an acceptable thermal profile in the welded tissue.
A suitable laser for use herein is available from ABIOMED R&D
Inc., Danvers, MA ABIOMED R&D Inc. has constructed a laser/infrared thermometer system for welding small vessels at 1.9 ~m, a wavelength which achieves m~x;",.,." pe~ ation into the wall thir~n~ss (-0.1 mm) of small vessels and a t~ clalule fee~lh~ loop to m~int~in the weld at a constant telll~elalulc to within + 30C. The console contains a laser diode, with its associated power and drive elecllullics, and a microprocessor-based data acquisition and control system for monilo~ g tissue temperature and dett~..,il.;,~g laser power to m~int~in a constant surface telllpelalulc. A removable handpiece, attaeh~od to the 30 console via a cable and col~e-;lor, delivers optical power to the weld site and contains the infrared lllcllllullleter. In addition, an audio fee~lba~1f system is used to inform the surgeon when the desired weld lelllpelalulc has been reached. Laser power is delivered to the tissue via a 300 ~m (core ~ m~ter) silica fiber. The infrared thermometer used is a direct viewing device, which monitors a 0.3 mm spot in the laser heated region.
This spot is imaged directly onto a thermopile using a single ZnSe lens.
5 A small stainless steel tube is used to direct the fiber to the weld site, anda wire guide att~rhP~ to the end of this tube is used to define the welding region and to provide tactile fee~b~cL to the surgeon. The infrared thermometer, con~i~ting of thermopile, im~ing lens, and gain and offset electronics is located within the body of the handle.
Other laser welding systems are described in U.S. Patent Nos.
5,001,051, 4,854,320, and 4,672,969.
Parameters Absorption and sca~lelhlg plopcllies of the laser light by the tissue, the composition and physiological state of the tissue, the thPrm~l 15 conductivity of the tissue, the wall thirLn~s~, the exposure time, and the laser h~el~iLy are all hllpol~l~ factors. It has been shown that the acute ng~l of a weld can be ~ignffllr~ntly hllploved if a large fraction of the laser energy is absorbed through the entire depth of the tissue. The m~ximllm acute sLlcll~lll is obtained when the absorption depth of a laser 20 is equal to that of the tissue thirL-nPss. Therefolc, an optimal weld will result when the pel~cLlalion depth of the laser light in the tissue is approximately equal to the tissue well ~l,irL llf S~. However, chronic outcomes, such as tissue compliance, may well have more desirable characteristics, if the lamina propria is not thPrm~lly injured. This can 25 only be achieved with a laser source which partly pellcllates the thirL-n~ss of the tissues. Although this is not desirable for vascular welding, due to the required high initial weld sll~,n~;lll, which can be best achieved with a full thirL nPss weld, in other applications such as urologic applications, with a more relaxed initial ~llcn~ uil~,lllent, a partial thirLnPss weld 30 may well be more desirable for long term tissue compliance.
Tissue palallletcl~ which can provide fli~gm~stir h~llllation for welding include the native autofluolescelue, the optical l~ilcrlill~cllcc, and W O 96/38093 PCTrUS96/084S8 the temperature of the tissue. A simple Arrhenius model for tissue welding reaction rate (i.e. that the reaction rate h~l~ases exponentially with lelllpeld~ulc) implies that acceptable welds should be quite sensitive to tissue ~clllpeld~ulc, providing an excellent real time monitor for the laser welding procedure. By moniloling the tissue tc~ eld~ulc during the welding process, the optimal tenlpeldlulc range (that which produces the most desirable clinical outcome) for laser welding can be ~etermin~-~. A
fee~lback loop can be employed to modulate the laser power, m~int~ining tissue temperature within this optimal range throughout the welding process. This should result in a reproducible, reliable laser weld.
Example 1 compares the effects of temperature on acute weld strengths for two laser sources, lc~lcscll~li~/e of a tissue thir~n~ss m~tcll~ laser (1.32 ~m) and a less penetrating laser (1.9 ~m) in bladder tissue. For tissue surface tempcld~urcs at, or below, 700C no welding occurs; these welds are unable to wi~ systemic plCS~ul'cS (catasllophic palcncy failure). Surface tempcld~ul~;s above 90oC cause ~ignifir~nt tissue shrinkage, causing l~lowing and occlusion. Welds are achievable between a Iclllpeldlulc range of from 700C to 90oC.
Similar results have been obtained using an infrared detector tissue ~Clll~cldlUlc fed back into a PC, which controlled an Argon laser, delivering optical power to the weld site, as demon~trate~ on rat urethras that were cut and repaired using th~rm~lly controlled laser welding ranging in surface ~elll~eldlul~,s of 50oC to 90oC. Burst pl~ UICS were ~l~alc~l with a weld lcn~cldlu~e of 800C. However, histological e~min~tion of the weld revealed tissue damage at this ~elllpeldlulc, which may reduce the life of the weld. Welds at 600C and 700C, though not as strong initially, were still supra-physiological, in~ ting that these welds may be superior in the longer term. Both studies showed that the tissue surface temperature around 800C was Illcfe-lcd for the welding process.
Although the surface lenl~ dlule is both a convenient and important physical pal~lltler to monitor for tissue welding, it does not provide a complete picture of the welding process. With thick tissue, the surface telllpel~u,e may reach the desired temperature and be m~int~in.
at such a level, while the inner portion of the tissue does not reach an ~eq~te temperature to be welded. In this case, a substantial telllpc.~lule dirrel~llce may exist between the outer layer, being monitored, and the S inner layers where weld formation is desired. These thermal gradients can be calc~ tr~ Since the exposure times are generally long colllpa~d to the th~rm~l diffusion times, a steady state solution, with spatially exponential energy deposition and convective heat loss at the tissue surface, should be valid for the welding process. Two wavelengths (1.32 10 ~4m and 1.9 ~m) lc~lcselll two extreme pell~LldLion depths with respect to the tissue thicknrss to be welded. For example, in the healthy human bladder, the 1.32 ~m laser will peneLldle the 2-3 mm tissue, since its penetration depth is around 2.5 mm. Even for a hylJclLlophiC bladder, where the walls may be as thick as 5 mm, or hypotonic condition, a 15 decol~el~aled bladder, with one mm thick walls, the 1.9 ~m laser will provide a good collll,alison, since its tissue yelleLl~lion depth is low, 0.1 mm, with respect to these thirL ~rSses. Using the 1.9 ~4m laser diode at weld tempel~lul~s of 80OC or more, is possible with 150 mW to 250 mW
of power, when the optical beam is delivered through a 300 ,um fiber held 20 2-3 mm above the tissue. Studies using canine ureters, with approximately 1.5 to 2 mm thick walls, showed a tissue effect at power levels below 500 mW and that welds were achievable with powers of 1 to 1.5 Watts when delivered through a 300 ~m fiber placed 3 mm above the tissue. The 1.9 ~m laser can be i,~l~ased in power by one of two 25 methods: a higher power diode (1 Watt is available from SDL and Applied Optronics) or the output of the current diode can be combined with a second, identical diode output into a delivery single fiber.
Bipolar electrosurgery Other types of energy can be used instead of lasers. A plcfell~d 30 source is a bipolar ele~;llo~ul~ ical device, as described in U.S. Patent No. 4,493,320 to Treat, the ~earhing~ of which are incorporated herein.
W 096/38093 PCT~US96/08458 Radiofrequency energy can also be used, as described in U.S. Patent No.
5,156,613 to Sawyer, the tÇ~clling~ of which are incorporated herein.
II. Solders Selection of Materials S The prefellcd solders are ploteills such as albumin, fibrinogen or collagen, which are del~luled upon exposure to localized heating up to 80 or 90 C and cros~link~(l to each other and the a-ljacçnt tissue, to form a weld. Cro~linking can be ionic, covalent, or a mixture thereof.
Concentration In the plefell.,d embo-iimP~t the protein is applied as a dry powder (in particulate, miclos~he~c, or Iyophilized form) or as a solution of between approximately 25% and 50% protein. Typical amounts for repair of a 2 cçntim~ter wound are 50 microliters.
Carriers Any biocompatible carriers canbe used. Aqueous solutions are ~lcfell~,d. Examples include water, saline (0.15 M NaCl), and phosphate bufr.,l. d saline (PBS). Solders are typically provided in dry or lyophilized form, then lcco~ d at the time of use.
Chromophores Water is a chromophore that can be used to absorb light of a specific wavelength and convert that light to thermal energy.
Other chromophores can be added to the solder. Universal chromophores are black pigm~nt~ such as india ink and iron oxide. India ink is typically used with lasers such as a Nd:YAG laser emitting a wavelength of 1064 nm. Indocyanine green (ICG) (peak absorption 805 nm) is used with lasers at a wavelength of belweell 780 and 820 nm, such as the GaAlAs diode laser at a wavelength of 808-810 nrn. Fluorescein (peak absorption 496 mn) is used with a YAG laser at a wavelength of 532 nIn; methylene blue (peak absorption 661 nm) is used with a laser emitting light at 670 n~n. Concentration ranges vary but a typical concellLl~Lion is approximately 0.54 mM in 50% albumin. The W 096/38093 PCTrUS96/084S8 chromophore is solubilized in the aqueous solution used to reco~ ule the lyophilized albumin.
Modifications The proteins can be modified to increase the amount of 5 cros.clinl~ing obtained under particular conditions. In the simplest example, albumin is dialyzed to remove stabilizers used to protect the albumin from del~lul~Lion during pasL~ul~aLion at 60 C. The solder materials can also be chemically modifled to decrease folding and increase sites available for crocclinking. For example, albumin can be exposed to 10 a ~iclllfi~r reducing agent, such as glutathione, 2PDS, or L-cysteine, and the cysteine groups carboxylated, to yield an unfolded protein which is more easily crocclink~
III. Bioactive Agents Selection of Materials A variety of materials can be added to the solder prior to welding, and/or ~lmini~tered after welding. Examples of useful materials include oLt~ s, polysaccharides, nucleic acids, vitamins and metals or ions (calcium, sodium and potassium), and ~yllLhclic organic molecules, that retain their biological activity when exposed to up to 80- C heat for 20 b~Lweell one tenth second and two l..i....le~.
Examples include enzymes such as collagenase inhibitors, hrmost~tir agents such as thrombin, fiblil ogen or calcium ions, thrombolytic or clot inhibitory agents such as heparin, growth factors, angiogenic factors and other growth erre~;lor molecules, bacteriostatic or 25 bacteriocidal factors, ~ntiinfl~mm~tories, chemothela~ Lic agents or anti-angiogenic agents, and ~i~llhLs, especi~lly vitamin C. Thrombolytic or clot inhibitory agents may be added to decrease complications both in suture and laser welding of microvessels secondary to thrombosis. The use of antibiotics in the solder will aid in our ability to decrease wound 30 infection either at the ~ n~o~s level or in the area of bladder reconstruction. The addition of ~ s~ lic agents such as marcaine or W 096/38093 PCTrUS96/08458 litloc~inr into the albumen solder can act as a local ~n~osth.otir decreasing post-operative pain.
Growth effector molecules, as used herein, refer to molecules that bind to cell surface receptors and regulate the growth, replication or 5 dirr.,lell~iation of target cells or tissue. Preferred growth errec~or molecules are growth factors and extracellular matrix molecules.
Examples of growth factors include epidermal growth factor (EGF), platelet-derived growth factor (PDGF), Llallsrollllillg growth factors (TGFcY, TGF,B), hepatocyte growth factor, heparin binding factor, insulin-10 like growth factor I or II, fibroblast growth factor (FGF), VEGF, LPA,erythropoietin, nerve growth factor, bone morphogenic proteills, muscle morphogenic pfoteills, and other factors known to those of skill in the art.
Additional growth factors are described in "Peptide Growth Factors and Their Receptors I" M.B. Sporn and A.B. Roberts, eds. (Springer-Verlag, 15 New York, 1990), for example, the te~clling~ of which are incorporated by lcrelcllce herein.
Growth factors can be isolated from tissue using methods know to those of skill in the art. For example, growth factors can be isolated from tissue, produced by recolll~h~lL means in bacteria, yeast or 20 ~ n cells. For example, EGF can be isolated from t_e subm~xill~ry glands of mice and ('Je~ rrh produces TGF-,~
recombinallLly. Many growth factors are also available colllllltlcially from vendors, such as Sigma Chrmir~l Co. of St. Louis, MO, Collaborative Research, Genzyme, Boeh~ gel, R&D Systems, and 25 GIBCO, in both natural and recombinant forms.
Examples of extracellular matrix molecules include fibrollec l~minin, collagens, and proteoglycans. Other extracellular matrix molecules are described in Kleinman et al. (1987) or are known to those skilled in the art. Other growth effector molecules include cytokines, 30 such as the interleukins and GM-colony stim~ ting factor, and hormones, such as insulin. T_ese are also described in the lilcla~ulc and are col,llllclcially available.
W O 96/38093 PCTrUS96/08458 Collagenase inhibitors, including tissue inhibitor metallop,~tci~se (TIMP), may also be useful as growth effector molecules.
Examples of hemostatic agents include thrombin, Factor Xa, fibrinogen, and calcium ions, typically in the forrn of calcium chloride or 5 calcium gluconate. Thrombin is a prcfellcd hemostatic agents since thrombin has many plop~llies useful for wound healing, (i.e. chemotactic to cells such as fibroblasts, mitogenic to various cells) and areas that were missed during the lasing procedure would be plugged due to the coagulant activity of the thrombin. Vasoconstrictive agents such as epinephrine can 10 also be used to contract blood vessels and thereby decrease bleeding.
Bleeding at the site of welding is undesirable because it can lead to lower repair strength and visual impairmPnt of the weld field.
Bacteriostatic and bacteriocidal agents include antibiotics and other compounds used for preventing or treating infection in wounds. These 15 are particularly useful when the welding is used at the time of implantation of a prosthetic device.
ConcellLl~lion The bioactive agents are typically incorporated in a range of nanograms to micrograms in a volume of 0.1 ml solder solution, although 20 they can also be applied to the wound in dry form, as a paste or suspension. In the examples described below, growth factor is added in a conce"ll~Lion of 500 ng/ml of solder or vehicle. The growth crçecl molecules are added to the solder in an amount errc~;live to promote wound healing and/or to accelerate or ellh~n~e functional ~Llc~lh of the 25 repair.
Method of ~lmini~tration The solder is ~1mini~tered at the time of welding, either by brushing, spraying, dlip~ g, or other means known to those skilled in the art. The bioactive agent can be ~mini~tered simnlt~npously with the 30 solder, separately or in combination with the solder, or after welding, using the same methods for a~lmini~tration as for the application of the solder.
W O 96/38093 PCTrUS96/08458 IV. Conditions and Methods for Treatment Welding Welding is used to repair wounds in the tissue where the tissue surfaces can be closely approxim~t~. Tuning the wavelength of the source to match the yelle~alion depth of the tissue being welded, controlling the laser power so that the issue remains at a controlled telllyela~ùre~ the use of albumin as a solder, and proper apposition of tissue are key elçm~nt~ contributing to the s~1ccessful joining of tissue or vessels without sutures. In a plcfell~d embo-lim~-nt, the tissues are held in close approximation using sutures, staples or other means known to those skilled in the art. The laser is applied imm~ tely after application of the solder, moving at a rate of approxim~tely 1 mm/second along the wound. Telllyelatule control is m~int~in~d to avoid excessive heating which could denature the bioactive agents or cause excessive tissue damage. Selection of the laser and chromophores can be used to effect different laser repairs, for example, by using a laser (1.9 ~Lm) with a short pe~ ation depth (0.1 mm) or a laser (1.32~m) with a long pelleLlation depth (2.5 mm). Telllyelalulc, as demo~sllated inthe examples, canbe used to alter repair ~Ll~nglll, as can the inclusion of various bioactive agents. Benefits of laser welding over suturing include shorter Opclali times, reduced foreign body reaction, reduced bleeding, improved healing, and technir-~l ease of use. For minim~lly invasive procedures, where conventional suturing is ~1iffirlllt, laser welding of tissue may become a pl~r~ d alternative.
Tissue welding can be used with endoscopic surgery. The advantages of endoscopic surgery are obvious. Many procedures can be performed in an office or on an ~ .a~ basis, thereby decreasing the cost and risk to the patient. Recovery rates are increased with these procedures. During a laparoscopic procedure, the surgeon views the area of interest through an endoscope. The two tlimPn~ional video image seen by the surgeon makes accurate pl~cçm~nt of sutures very diffl~ult, limhing the type of surgeries that can be executed in this manner. Clips W 096/38093 PCTrUS96/084S8 and staples are suitable for some laparoscopic procedures, but cannot be used alone in the urinary tract, due to their lithogenic potential and inability to produce a watertight seal. The technique of laser welding of tissue, as an al~ lali~e to sutures, alleviates these issues.
A ylcr~llcd example is the use of tissue welding in laparoscopic bladder ~llgmPnt~tion (enterocystoplasty), where a section of bowel is used to increase the volume of the existing bladder. Conventionally, this surgery is performed as an open, transabdominal procedure. The bowel patch is ~tt~rhPCl to the bladder using standard suture techniques, making the operation tliffirlllt to pelrollll laparoscopically. Since the procedure requires a transabdominal incision, the post-operative morbidity and the extent of hospitalization are considerable. Laparoscopic access to the abdomen would avoid the need for a large abdominal incision and potentially reduce the post-operative morbidity in these children.
However, tissue appro~illlation by ~ululi,lg through the lapaloscope is difficult and time co~ g. The ability to p~lrOllll watertight closure of tissue using laser welding could signifir~ntly improve the capability to approximate tissue laparoscopically. This technology can be adapted to the myriad of urologic procedures ~;ull~.llly limited from laparoscopic consideration, due to the c~lcl~ive need for sutures.
The advantages of laser welding versus sutures are many.
Oyelalillg times are signifirantly reduced, especi~lly when dealing with small vessels. Foreign body reaction is ...i..;...i,.~(l, which is especially important in the urinary tract, where the lithogenic potential of clips and staples make them undesirable. The ability of a laser weld to provide a watertight seal, also makes it attractive for use in the urinary tract. It has also been found that, colllp~._d to the current microsuturing technique, laser welding shows improved healing.
Repair of Fistulae. Sealing of Lumens Fistulae are fliffir~llt to repair using standard surgical techniques without removal of tissue or the use of general ~nrsth~tirs, due to ephhrli~li7~tion. In contrast, tissue welding can be used to effect tissue repair without requiring extensive hospital stays using only a local an~sth~tic. Examples of potential fistulae repair include vesico-vaginal, colo-rectal, and other enteric and cutaneous fistulae. The fistula is filled with solder, preferably in combination with a growth factor, most S preferably TGF,BI. Laser energy is then applied using a wavelength and solder and/or chromophore concentration that causes the solder to polymerize from the bottom up. For example, a 50% albumin solution can be polymerized using a laser with a 1.32 micron light, where the water is the chromophore. A 25 % albumin solution under the same 10 conditions would polymerize from the top (i.e., portion closest to the laser) down, which is not as effective. The laser causes the surface of the fistula to "de-epithelialize", allowing the fistula surfaces to heal together.
Other types of lumens that can be sealed include reproductive lumens such as the vas deferens and the Fallopian tubes, using tissue 15 welding instead of surgical ligation. Many other types of repairs can also be effected, including, for examples, repairs of the urogenital systems and ga~lloi,~ l tract.
Sealing of Open Wounds such as Ulcers Tissue welding can also be used to create "casts" or plv~ ive 20 coverings over open or chronic wounds such as decubitas ulcers or other chronic or non-healing wounds. This is achieved by laser welding the solder, preferably in combination with growth err~ ol molecules, over the wound, which may be cleaned to remove necrotic or infected tissue first, either by standard surgical means or using the laser.
The invention will be further understood by reference to the following non-limiting examples.
Example 1: Effect of Albumin Co.~c~ rdlion and Welding Te",l~eldlule on Wound Sll~.lgtL.
Full-thir1fnrc~ wounds were created with a knife blade in the 30 dorsal skin of pigs. In an attempt to evaluate the effectiveness of wound closure with laser welding, maximal wound stresses were compared in a telllpel~lule control study of the optimal welding temperature.
W O 96/38093 PCTrUS96/08458 In a first set of e~L~e,illlents, wounds were laser welded using a tell~eldLure controlled laser with various collcellL,dlions of albumin, 25%, 38%, 45% and 50%. As shown in Figure 1, wound strength was proportional to albumin concentration, with the ~,c;alesl strength being 5 obtained with 50% albumin.
In the second set of e~c,illlents, wounds were laser welded using a ten~eldlul- controlled laser with and without 50% human albumin solder (All)ulllinar-25, Armour Pl~ re~ltir~l Co., K~nk~k~oe, IL, lyophilized and reco,-~ ecl by adding 8 ml sterile water to 6 45-6.50 g albumin). Welds were performed at 65, 75, 85, and 950C. With a simple suture closure as a control, the m~ximllm wound stress for each telll~elalule was evaluated acutely and at 3, 8 and 14 days post-operatively. A 1.32 11 Nd:YAG laser (Laserscope) was used at less than 2.5 watts, adjusted as nrcess~ry to control l~lllpCldlu~.
In the acute wounds without albumin solder, there was no ~ignifir~nt difference in wound strength at 65, 75 and 850C, and only a slight increase in strength at 950C. In the acute wounds with solder, the m~xim~l wound strength at the lowest lelll?eldlure (65oC) was equivalent to the ~Llel1gLll at rn~xim~l lellll~clalLlre (95~C) without solder. More 20 importantly in the solder group, the m~xim~l stress increased steadily with hlclcasillg tempelalu,~ to almost double the non-solder strength at 95oC.
This in~ic~t~s that there is a clear advantage in wound ~Ll~ngLll with the addition of 50% human albumin solder to welds using laser energy alone.
All subsequent chronic animal wounds were closed with albumin 25 solder and compared with a suture control. After 3 days, the lelll~,ldlulc versus m~xim~l wound stress relationship was reversed; the wounds gained much more ~Llcn~sLIl at low ten~clalu,e and were relatively stronger than those at 95oC (which re.--~ equivalent in absolute sLlc~Lll to the acute wounds). The lower telllpe,dlu~ wounds, however, 30 were equivalent in ~ ngLll to the suture controls. At 8 days, the sutured and low tempc,dLure wounds were only slightly ~Llo~,r than the 95oC
W 096/38093 PCTrUS96/08458 wounds. All wounds gained grossly in ~Llellg~l. By 2 weeks, maximal wound stresses were the same for all tellll)elalul~s and sutured wounds.
In ~unllllaly, wounds laser welded with a 50% human albumin solder are signifir~ntly s~longer than those repaired using laser alone.
5 High temperature closures are acutely ~llollge~ than low tempela~ules.
However, high ~lllpelalule repairs (85 and 95 C) were found to heal more slowly. By two weeks, all m~tho~ of wound closure were equivalent in terms of wound ~llel~
Example 2: Mo(lifi~ ~ti~n of Albumin to Lower Thermal Denaturation Thr~
Human albumin is packaged in combination with 0.8 mM Na caprolate and 0.8 mM N-acetyl tryptophane to stabilize the albumin during heat pa~uli~ation. Stabilizers were removed by extensive dialysis into distilled water. Removal of the stabilizers signifi~ntly altered the 15 dena~ula~ion threshold. A colll~alison of the albumin prior to tre~tm~nt with the albumin after tre~tmPnt is shown in Figures 2a and 2b.
FY~ ~ 3: Effect of Inco.y~lalion of Growth Factors into Solders.
Human recombinant growth factors have been shown to accelerate wound healing in model systems. Studies were therefore con~ ct~ to 20 ~letermin~cl whether human albumin can also be used as a time-release delivery vehicle for growth factors for the purpose of accelerating tissue repair after laser-mP~i~t~ wound closure. A critical requirement for incorporation of these agents was that the growth factors not be denatured by the laser. A thermal controlled laser delivery system (TCL) was used 25 to precisely m~int~in stable te.l~e.d~ures during welding, thereby avoiding thermal de-~tulation of bioactive growth factors. Three growth factors, HB-EGF, bFGF, and TGF,~1, were tested in vitro for IllAil~lPn~l~re of bioactivity after exposure to 800C telll~ela~ule in a water bath or with a TCL using 1.32 ~M Nd:YAG laser energy. M~i"le~ e of bioactivity 30 after heating by both methods was demol~,ated for each factor using a Balb/C-3T3 mitogenic assay (HB-EGF and bFGF) or a luciferase reporter assay(TGF,BI). In vivo ~pelilllents were pe.rol,l,ed to determine the W O 96/38093 PCTrUS96/08458 efficacy of growth factor enh~nred tissue solder for closure of 2 cm full thir~nPss sutureless dorsal incisions in porcine skin. Incisions were closed using 50 ~l of 50% human albumin alone or enh~nre~ with HB-EGF (2 ~g), bF(3F (10 ,ug), or TGF-,B~ g). Laser welding was performed at 700C with a rate of 0.4 mm/second. Suture control wounds were closed with two 5-0 nylon sutures. Five wounds were repaired in each group. Wounds were excised at 3, 5, and 7 days post-operatively.
Tensile strength, total collagen content and histology were performed.
The results are shown in Figures 3a, 3b, and 3c, colllpalillg repair strength with treatment as a function of time. No ~ ,irlr~t difference in tensile strength be~weell the groups could be seen at 3 days.
By 5 days the tensile strength of the TGF,BI group increased by 50% and 25.5% over laser solder alone and suture groups, l~spe~ ely. At 7 days the TGF,BI group was 118% and 52% higher than laser solder alone or suture, respectively, as shown by Figure 4. The HB-EGF and bFGF
groups were equivalent to the laser solder group at all time points. As shown by Figure 5, total collagen content at 7 days increased in the TGF,BI group by 6% over the suture group and 21% in the laser solder group. Histology co~.r,.llPd the changes in matrix observed in tensile strength and collagen content. In conclusion, TGF,BI enh~nre(l albumin solder increases the strength of laser welded wounds and provided a means to accelerate wound dealing, which should decrease postopel~live convalescence, hospitalization time, and wound infections.
FYqmplq 4: Co.~ a-;son of Growth Factors alone and with Laser Welding.
Maximal wound stresses were colllpaled for wounds closed at 700C in five groups: suture alone; laser and solder; laser, solder and HB-EGF (2 ~g/wound); laser, solder and basic-FGF (10 ~g/wound); and laser, solder and TGF~ g/wound). Pigs were sacrificed and wound strength evaluated after 3, 5 and 7 days, as described in Example 3.
Results are shown in Figure 6. After 3 days, there was no signifir~nt dirrerel1ces in wound strength among groups with the following CA 02222633 l997-ll-24 W 096/38093 PCTrUS96/08458 exception: the TGF treated wounds were slightly ~I,o~gel than both the suture and b-FGF treated wounds. However, at 5 days, TGF treated wounds were cignifi- ~ntly stronger than all other wounds and were almost double in strength to the three other groups closed with the laser. By one 5 week, the relationships and absolute wound s~l~;ng~ls were similar to those at 5 days. Comparison of the effect of the growth factors in the absence of laser welding demollsLla~es that the combination of laser welding with TGF,BI is better than the a~minictration of TGF,~I alone.
The data unequivocally in(lic~te that the addition of TGF~I to 50% human 10 albumin solders cignifir~ntly increases the m~xim~l wound stress at 5 and 7 days compared with other growth factors and sutures alone.
TISSUE VVELDING VVITH ENHANCED STRENGTH
- Background of the Invention This is generally in the field of methods for tissue welding using 5 laser m~ t~ coupling of protein solders, and in particular is an improved method and composition incol~o~ lg biologically active compounds into the solder.
The use of laser energy to join tissue is referred to as "tissue welding". The goal is to facilitate the joining of tissues with a ,.,ini",u-"
10 of scar and good tensile ~llellglh of the apposed edges. Lasers that have been used for tissue welding include neodymium:yttrium~ ll"i",.."-garnet (Nd:YAG), argon and CO2 lasers. These appal~llLly produce an interdigitation of collagen fibrils, plc~ulllably heating at the surface of the tissues which del~luies and couples the pro~eills in the tissue.
Initial studies focused on anastomosis of blood vessels. Later studies looked at other tissues, such as bowel, and nerve repair. The success of tissue union is dependent on several factors, including ~lignment of the edges of the tissue without tension and in close approximation, adjuctm~nt of laser parameters to ",i~-i"~i~e peripheral tissue destruction and control heating of tissues, and the use of an applopliale protein solder. Various solders such as 40% albumin are described by Poppas, et al., J. Urol. 139, 415417 (1988), Poppas, et al., J. Urol. 150, 648-650 (1993), Poppas, et al., Lasers in Sur~ery & Med.
13, 577-580 (1993), Choma, et al., Lasers in Sur,~. & Med. 12, 639-644 (1992), and Poppas, et al., J. Urol. 150, 1052-1055 (1993). Albumin is a prer~ d solder since it signifir~ntly illlpro~es the tensile strength of laser wound closure, as colll~ared to in the absence of solder or the use of blood, it ~ignifi~ntly increases the leak point pïei~:jUl'e, it is hl~ e and easily manufactured and does not elicit an immnnogenic response, and is available in sterile, virus free form. As described in U.S. Patent Nos. 5,334,191 and 5,409,148 to Poppas, et al., and Poppas, et al.
W O 96/38093 PCTrUS96/08458 (1993), the solder is further improved through the inclusion of a chromophore such as fluorescein or iron oxide, which increases the absorption of laser energy, reducing the amount of power required to effect a tissue weld, as well as through the use of fine ~e~l~ycldlule 5 control.
The advantages of tissue welding are numerous, and include rapid (1 mm/second) formation of a fluid tight seal, nonlithogenic, improved healing, reduced wound infection, and shorter hospitalization and improved postoperative results. However, a disadvantage of tissue 10 welding which uses no solder or ~;ull~;lllly available protein solders, is that the repair has low tensile ~
It is therefore an object of the present invention to provide methods and compositions for tissue welding which yields repairs having greater tensile ~l.en~ and improved wound healing plopcllies.
It is another object of the present invention to provide tissue repairs of fistulas and other open areas including ulcers and chronic wounds.
Summary of the I~ lion Methods for tissue welding using solders incorporating biologically active agents, such as growth factors, thrombolytic or clot inhibitory agents or hemostatic agents, have been developed. Improved solder co.~osilions have also been defined, yielding greater bursting strength as a function of protein conce"L,d~ion, and through the use of protein unfolding prior to laser-m~ t~d del~u,dlion and coupling. A method for repair of fistulas has been discovered, using water as a chromophore, in combination with solder concentration, to form columns to fill defects where tissue apposition is not possible. Methods have also been adapted for use with other forms of directed energy, including bipolar electrosurgery and light.
Examples demonstrate increased SLl~ ,lh of repairs by inco.~o-~lion of growth factors into solders, alone and as a function of W 096/38093 PCTrUS96/08458 solder concentration. Increased adhL.lon is obtained through prevention of bleeding by incorporation of hemostatic agents such as thrombin, heparin or other clot inhibitory agent, or epinephrine, a vasoconstrictor.
Brief Des~ .tion of the Dl~wi~
Figure 1 is a graph showing the effect of albumin concentration on bursting ~n~es~uie, as a function of intr~h-rnin~l bursting ~les~u~c (mm Hg) for 25%, 38%, 45% and 50% albumin (w/v).
Figures 2a and 2b are graphs showing how albumin solder can be modified to lower the thermal dend~uld~ion threshold, as a function of Time (seconds) versus Tellll)eldluie ( C) for stabilized albumin (Figure 2a) and unstabilized albumin (Figure 2b).
Figures 3a, 3b, and 3c are graphs colllpal-ng wound ~ 11g~11 over time, as a function of m~ximl-rn stress (kPa) for wounds repaired with sutures, laser + solder, laser + HB-EGF, laser + solder + bFGF, and laser + solder + TGF,Bl, post-op day 3 (Figure 3a), post-op day 5 (Figure 3b), and post-op day 7 (Figure 3c).
Figure 4 is a graph COlll?dlillg repair ~ lg~l over time, as a function of m~ximnm stress (kPa) versus time, for laser + solder +
TGF,BI (diamonds), sutures (squares), or laser + solder (triangle).
Figure 5 is graph COlllpalillg lasered and non-lasered (sutured) repairs with and without growth factor enh~nre~ albumin solder, as a function of m~ximt-m stress (kPa) for sutures alone, sutures + albumin solder, sutures + albumin solder + bFGF, sutures + albumin solder +
TGF,~" laser + sutures + albumin solder, laser + sutures + alburnin solder + bFGF, and laser +sutures + solder + TGF,BI.
Figure 6 is a graph of total collagen content (micrograms/mg dry weight) for repairs using sutures alone, laser + albumin solder, and laser + solder + TGF,~I.
W 096/38093 PCTrUS96/084S8 Detailed D~ ion of the Invention I. Systems for Energy ~e~ tPd Repair Lasers Nd:YAG lasers, GaAlAs lasers, Argon lasers and CO2 lasers can be used for tissue welding. Lasers are commercially available from a variety of comp~ni~s, such as Laserscope Corp, San Jose, CA, and are ~;ullcnlly in use for a variety of surgical applications. U.S.
Patent No. 5,409,479 to Dew, et al., and U.S. Patent No. 5,156,613 to Sawyer, incol~olal~d by lcr~ lce herein, describe the use of lasers and radiofrequency energy to close tissue wounds by tissue welding. U.S.
Patent Nos. 5,334,191 to Poppas, et al., incorporated by rcrel. lue herein, describes a ylerellcd system for use in tissue welding. As in all surgical procedures, laser welding is most succes~ful when trauma to the sulluunding tissue is minimi7P~I Since the laser welding procedure is a non-contact method, the main complications occur when there is extensive thermal injury. The thermal deposition of the laser energy is, thelcrolc, very important to obtain s~lrcec~ful laser welds, and the p~ t~l~ of the laser must be chosen to insure an acceptable thermal profile in the welded tissue.
A suitable laser for use herein is available from ABIOMED R&D
Inc., Danvers, MA ABIOMED R&D Inc. has constructed a laser/infrared thermometer system for welding small vessels at 1.9 ~m, a wavelength which achieves m~x;",.,." pe~ ation into the wall thir~n~ss (-0.1 mm) of small vessels and a t~ clalule fee~lh~ loop to m~int~in the weld at a constant telll~elalulc to within + 30C. The console contains a laser diode, with its associated power and drive elecllullics, and a microprocessor-based data acquisition and control system for monilo~ g tissue temperature and dett~..,il.;,~g laser power to m~int~in a constant surface telllpelalulc. A removable handpiece, attaeh~od to the 30 console via a cable and col~e-;lor, delivers optical power to the weld site and contains the infrared lllcllllullleter. In addition, an audio fee~lba~1f system is used to inform the surgeon when the desired weld lelllpelalulc has been reached. Laser power is delivered to the tissue via a 300 ~m (core ~ m~ter) silica fiber. The infrared thermometer used is a direct viewing device, which monitors a 0.3 mm spot in the laser heated region.
This spot is imaged directly onto a thermopile using a single ZnSe lens.
5 A small stainless steel tube is used to direct the fiber to the weld site, anda wire guide att~rhP~ to the end of this tube is used to define the welding region and to provide tactile fee~b~cL to the surgeon. The infrared thermometer, con~i~ting of thermopile, im~ing lens, and gain and offset electronics is located within the body of the handle.
Other laser welding systems are described in U.S. Patent Nos.
5,001,051, 4,854,320, and 4,672,969.
Parameters Absorption and sca~lelhlg plopcllies of the laser light by the tissue, the composition and physiological state of the tissue, the thPrm~l 15 conductivity of the tissue, the wall thirLn~s~, the exposure time, and the laser h~el~iLy are all hllpol~l~ factors. It has been shown that the acute ng~l of a weld can be ~ignffllr~ntly hllploved if a large fraction of the laser energy is absorbed through the entire depth of the tissue. The m~ximllm acute sLlcll~lll is obtained when the absorption depth of a laser 20 is equal to that of the tissue thirL-nPss. Therefolc, an optimal weld will result when the pel~cLlalion depth of the laser light in the tissue is approximately equal to the tissue well ~l,irL llf S~. However, chronic outcomes, such as tissue compliance, may well have more desirable characteristics, if the lamina propria is not thPrm~lly injured. This can 25 only be achieved with a laser source which partly pellcllates the thirL-n~ss of the tissues. Although this is not desirable for vascular welding, due to the required high initial weld sll~,n~;lll, which can be best achieved with a full thirL nPss weld, in other applications such as urologic applications, with a more relaxed initial ~llcn~ uil~,lllent, a partial thirLnPss weld 30 may well be more desirable for long term tissue compliance.
Tissue palallletcl~ which can provide fli~gm~stir h~llllation for welding include the native autofluolescelue, the optical l~ilcrlill~cllcc, and W O 96/38093 PCTrUS96/084S8 the temperature of the tissue. A simple Arrhenius model for tissue welding reaction rate (i.e. that the reaction rate h~l~ases exponentially with lelllpeld~ulc) implies that acceptable welds should be quite sensitive to tissue ~clllpeld~ulc, providing an excellent real time monitor for the laser welding procedure. By moniloling the tissue tc~ eld~ulc during the welding process, the optimal tenlpeldlulc range (that which produces the most desirable clinical outcome) for laser welding can be ~etermin~-~. A
fee~lback loop can be employed to modulate the laser power, m~int~ining tissue temperature within this optimal range throughout the welding process. This should result in a reproducible, reliable laser weld.
Example 1 compares the effects of temperature on acute weld strengths for two laser sources, lc~lcscll~li~/e of a tissue thir~n~ss m~tcll~ laser (1.32 ~m) and a less penetrating laser (1.9 ~m) in bladder tissue. For tissue surface tempcld~urcs at, or below, 700C no welding occurs; these welds are unable to wi~ systemic plCS~ul'cS (catasllophic palcncy failure). Surface tempcld~ul~;s above 90oC cause ~ignifir~nt tissue shrinkage, causing l~lowing and occlusion. Welds are achievable between a Iclllpeldlulc range of from 700C to 90oC.
Similar results have been obtained using an infrared detector tissue ~Clll~cldlUlc fed back into a PC, which controlled an Argon laser, delivering optical power to the weld site, as demon~trate~ on rat urethras that were cut and repaired using th~rm~lly controlled laser welding ranging in surface ~elll~eldlul~,s of 50oC to 90oC. Burst pl~ UICS were ~l~alc~l with a weld lcn~cldlu~e of 800C. However, histological e~min~tion of the weld revealed tissue damage at this ~elllpeldlulc, which may reduce the life of the weld. Welds at 600C and 700C, though not as strong initially, were still supra-physiological, in~ ting that these welds may be superior in the longer term. Both studies showed that the tissue surface temperature around 800C was Illcfe-lcd for the welding process.
Although the surface lenl~ dlule is both a convenient and important physical pal~lltler to monitor for tissue welding, it does not provide a complete picture of the welding process. With thick tissue, the surface telllpel~u,e may reach the desired temperature and be m~int~in.
at such a level, while the inner portion of the tissue does not reach an ~eq~te temperature to be welded. In this case, a substantial telllpc.~lule dirrel~llce may exist between the outer layer, being monitored, and the S inner layers where weld formation is desired. These thermal gradients can be calc~ tr~ Since the exposure times are generally long colllpa~d to the th~rm~l diffusion times, a steady state solution, with spatially exponential energy deposition and convective heat loss at the tissue surface, should be valid for the welding process. Two wavelengths (1.32 10 ~4m and 1.9 ~m) lc~lcselll two extreme pell~LldLion depths with respect to the tissue thicknrss to be welded. For example, in the healthy human bladder, the 1.32 ~m laser will peneLldle the 2-3 mm tissue, since its penetration depth is around 2.5 mm. Even for a hylJclLlophiC bladder, where the walls may be as thick as 5 mm, or hypotonic condition, a 15 decol~el~aled bladder, with one mm thick walls, the 1.9 ~m laser will provide a good collll,alison, since its tissue yelleLl~lion depth is low, 0.1 mm, with respect to these thirL ~rSses. Using the 1.9 ~4m laser diode at weld tempel~lul~s of 80OC or more, is possible with 150 mW to 250 mW
of power, when the optical beam is delivered through a 300 ,um fiber held 20 2-3 mm above the tissue. Studies using canine ureters, with approximately 1.5 to 2 mm thick walls, showed a tissue effect at power levels below 500 mW and that welds were achievable with powers of 1 to 1.5 Watts when delivered through a 300 ~m fiber placed 3 mm above the tissue. The 1.9 ~m laser can be i,~l~ased in power by one of two 25 methods: a higher power diode (1 Watt is available from SDL and Applied Optronics) or the output of the current diode can be combined with a second, identical diode output into a delivery single fiber.
Bipolar electrosurgery Other types of energy can be used instead of lasers. A plcfell~d 30 source is a bipolar ele~;llo~ul~ ical device, as described in U.S. Patent No. 4,493,320 to Treat, the ~earhing~ of which are incorporated herein.
W 096/38093 PCT~US96/08458 Radiofrequency energy can also be used, as described in U.S. Patent No.
5,156,613 to Sawyer, the tÇ~clling~ of which are incorporated herein.
II. Solders Selection of Materials S The prefellcd solders are ploteills such as albumin, fibrinogen or collagen, which are del~luled upon exposure to localized heating up to 80 or 90 C and cros~link~(l to each other and the a-ljacçnt tissue, to form a weld. Cro~linking can be ionic, covalent, or a mixture thereof.
Concentration In the plefell.,d embo-iimP~t the protein is applied as a dry powder (in particulate, miclos~he~c, or Iyophilized form) or as a solution of between approximately 25% and 50% protein. Typical amounts for repair of a 2 cçntim~ter wound are 50 microliters.
Carriers Any biocompatible carriers canbe used. Aqueous solutions are ~lcfell~,d. Examples include water, saline (0.15 M NaCl), and phosphate bufr.,l. d saline (PBS). Solders are typically provided in dry or lyophilized form, then lcco~ d at the time of use.
Chromophores Water is a chromophore that can be used to absorb light of a specific wavelength and convert that light to thermal energy.
Other chromophores can be added to the solder. Universal chromophores are black pigm~nt~ such as india ink and iron oxide. India ink is typically used with lasers such as a Nd:YAG laser emitting a wavelength of 1064 nm. Indocyanine green (ICG) (peak absorption 805 nm) is used with lasers at a wavelength of belweell 780 and 820 nm, such as the GaAlAs diode laser at a wavelength of 808-810 nrn. Fluorescein (peak absorption 496 mn) is used with a YAG laser at a wavelength of 532 nIn; methylene blue (peak absorption 661 nm) is used with a laser emitting light at 670 n~n. Concentration ranges vary but a typical concellLl~Lion is approximately 0.54 mM in 50% albumin. The W 096/38093 PCTrUS96/084S8 chromophore is solubilized in the aqueous solution used to reco~ ule the lyophilized albumin.
Modifications The proteins can be modified to increase the amount of 5 cros.clinl~ing obtained under particular conditions. In the simplest example, albumin is dialyzed to remove stabilizers used to protect the albumin from del~lul~Lion during pasL~ul~aLion at 60 C. The solder materials can also be chemically modifled to decrease folding and increase sites available for crocclinking. For example, albumin can be exposed to 10 a ~iclllfi~r reducing agent, such as glutathione, 2PDS, or L-cysteine, and the cysteine groups carboxylated, to yield an unfolded protein which is more easily crocclink~
III. Bioactive Agents Selection of Materials A variety of materials can be added to the solder prior to welding, and/or ~lmini~tered after welding. Examples of useful materials include oLt~ s, polysaccharides, nucleic acids, vitamins and metals or ions (calcium, sodium and potassium), and ~yllLhclic organic molecules, that retain their biological activity when exposed to up to 80- C heat for 20 b~Lweell one tenth second and two l..i....le~.
Examples include enzymes such as collagenase inhibitors, hrmost~tir agents such as thrombin, fiblil ogen or calcium ions, thrombolytic or clot inhibitory agents such as heparin, growth factors, angiogenic factors and other growth erre~;lor molecules, bacteriostatic or 25 bacteriocidal factors, ~ntiinfl~mm~tories, chemothela~ Lic agents or anti-angiogenic agents, and ~i~llhLs, especi~lly vitamin C. Thrombolytic or clot inhibitory agents may be added to decrease complications both in suture and laser welding of microvessels secondary to thrombosis. The use of antibiotics in the solder will aid in our ability to decrease wound 30 infection either at the ~ n~o~s level or in the area of bladder reconstruction. The addition of ~ s~ lic agents such as marcaine or W 096/38093 PCTrUS96/08458 litloc~inr into the albumen solder can act as a local ~n~osth.otir decreasing post-operative pain.
Growth effector molecules, as used herein, refer to molecules that bind to cell surface receptors and regulate the growth, replication or 5 dirr.,lell~iation of target cells or tissue. Preferred growth errec~or molecules are growth factors and extracellular matrix molecules.
Examples of growth factors include epidermal growth factor (EGF), platelet-derived growth factor (PDGF), Llallsrollllillg growth factors (TGFcY, TGF,B), hepatocyte growth factor, heparin binding factor, insulin-10 like growth factor I or II, fibroblast growth factor (FGF), VEGF, LPA,erythropoietin, nerve growth factor, bone morphogenic proteills, muscle morphogenic pfoteills, and other factors known to those of skill in the art.
Additional growth factors are described in "Peptide Growth Factors and Their Receptors I" M.B. Sporn and A.B. Roberts, eds. (Springer-Verlag, 15 New York, 1990), for example, the te~clling~ of which are incorporated by lcrelcllce herein.
Growth factors can be isolated from tissue using methods know to those of skill in the art. For example, growth factors can be isolated from tissue, produced by recolll~h~lL means in bacteria, yeast or 20 ~ n cells. For example, EGF can be isolated from t_e subm~xill~ry glands of mice and ('Je~ rrh produces TGF-,~
recombinallLly. Many growth factors are also available colllllltlcially from vendors, such as Sigma Chrmir~l Co. of St. Louis, MO, Collaborative Research, Genzyme, Boeh~ gel, R&D Systems, and 25 GIBCO, in both natural and recombinant forms.
Examples of extracellular matrix molecules include fibrollec l~minin, collagens, and proteoglycans. Other extracellular matrix molecules are described in Kleinman et al. (1987) or are known to those skilled in the art. Other growth effector molecules include cytokines, 30 such as the interleukins and GM-colony stim~ ting factor, and hormones, such as insulin. T_ese are also described in the lilcla~ulc and are col,llllclcially available.
W O 96/38093 PCTrUS96/08458 Collagenase inhibitors, including tissue inhibitor metallop,~tci~se (TIMP), may also be useful as growth effector molecules.
Examples of hemostatic agents include thrombin, Factor Xa, fibrinogen, and calcium ions, typically in the forrn of calcium chloride or 5 calcium gluconate. Thrombin is a prcfellcd hemostatic agents since thrombin has many plop~llies useful for wound healing, (i.e. chemotactic to cells such as fibroblasts, mitogenic to various cells) and areas that were missed during the lasing procedure would be plugged due to the coagulant activity of the thrombin. Vasoconstrictive agents such as epinephrine can 10 also be used to contract blood vessels and thereby decrease bleeding.
Bleeding at the site of welding is undesirable because it can lead to lower repair strength and visual impairmPnt of the weld field.
Bacteriostatic and bacteriocidal agents include antibiotics and other compounds used for preventing or treating infection in wounds. These 15 are particularly useful when the welding is used at the time of implantation of a prosthetic device.
ConcellLl~lion The bioactive agents are typically incorporated in a range of nanograms to micrograms in a volume of 0.1 ml solder solution, although 20 they can also be applied to the wound in dry form, as a paste or suspension. In the examples described below, growth factor is added in a conce"ll~Lion of 500 ng/ml of solder or vehicle. The growth crçecl molecules are added to the solder in an amount errc~;live to promote wound healing and/or to accelerate or ellh~n~e functional ~Llc~lh of the 25 repair.
Method of ~lmini~tration The solder is ~1mini~tered at the time of welding, either by brushing, spraying, dlip~ g, or other means known to those skilled in the art. The bioactive agent can be ~mini~tered simnlt~npously with the 30 solder, separately or in combination with the solder, or after welding, using the same methods for a~lmini~tration as for the application of the solder.
W O 96/38093 PCTrUS96/08458 IV. Conditions and Methods for Treatment Welding Welding is used to repair wounds in the tissue where the tissue surfaces can be closely approxim~t~. Tuning the wavelength of the source to match the yelle~alion depth of the tissue being welded, controlling the laser power so that the issue remains at a controlled telllyela~ùre~ the use of albumin as a solder, and proper apposition of tissue are key elçm~nt~ contributing to the s~1ccessful joining of tissue or vessels without sutures. In a plcfell~d embo-lim~-nt, the tissues are held in close approximation using sutures, staples or other means known to those skilled in the art. The laser is applied imm~ tely after application of the solder, moving at a rate of approxim~tely 1 mm/second along the wound. Telllyelatule control is m~int~in~d to avoid excessive heating which could denature the bioactive agents or cause excessive tissue damage. Selection of the laser and chromophores can be used to effect different laser repairs, for example, by using a laser (1.9 ~Lm) with a short pe~ ation depth (0.1 mm) or a laser (1.32~m) with a long pelleLlation depth (2.5 mm). Telllyelalulc, as demo~sllated inthe examples, canbe used to alter repair ~Ll~nglll, as can the inclusion of various bioactive agents. Benefits of laser welding over suturing include shorter Opclali times, reduced foreign body reaction, reduced bleeding, improved healing, and technir-~l ease of use. For minim~lly invasive procedures, where conventional suturing is ~1iffirlllt, laser welding of tissue may become a pl~r~ d alternative.
Tissue welding can be used with endoscopic surgery. The advantages of endoscopic surgery are obvious. Many procedures can be performed in an office or on an ~ .a~ basis, thereby decreasing the cost and risk to the patient. Recovery rates are increased with these procedures. During a laparoscopic procedure, the surgeon views the area of interest through an endoscope. The two tlimPn~ional video image seen by the surgeon makes accurate pl~cçm~nt of sutures very diffl~ult, limhing the type of surgeries that can be executed in this manner. Clips W 096/38093 PCTrUS96/084S8 and staples are suitable for some laparoscopic procedures, but cannot be used alone in the urinary tract, due to their lithogenic potential and inability to produce a watertight seal. The technique of laser welding of tissue, as an al~ lali~e to sutures, alleviates these issues.
A ylcr~llcd example is the use of tissue welding in laparoscopic bladder ~llgmPnt~tion (enterocystoplasty), where a section of bowel is used to increase the volume of the existing bladder. Conventionally, this surgery is performed as an open, transabdominal procedure. The bowel patch is ~tt~rhPCl to the bladder using standard suture techniques, making the operation tliffirlllt to pelrollll laparoscopically. Since the procedure requires a transabdominal incision, the post-operative morbidity and the extent of hospitalization are considerable. Laparoscopic access to the abdomen would avoid the need for a large abdominal incision and potentially reduce the post-operative morbidity in these children.
However, tissue appro~illlation by ~ululi,lg through the lapaloscope is difficult and time co~ g. The ability to p~lrOllll watertight closure of tissue using laser welding could signifir~ntly improve the capability to approximate tissue laparoscopically. This technology can be adapted to the myriad of urologic procedures ~;ull~.llly limited from laparoscopic consideration, due to the c~lcl~ive need for sutures.
The advantages of laser welding versus sutures are many.
Oyelalillg times are signifirantly reduced, especi~lly when dealing with small vessels. Foreign body reaction is ...i..;...i,.~(l, which is especially important in the urinary tract, where the lithogenic potential of clips and staples make them undesirable. The ability of a laser weld to provide a watertight seal, also makes it attractive for use in the urinary tract. It has also been found that, colllp~._d to the current microsuturing technique, laser welding shows improved healing.
Repair of Fistulae. Sealing of Lumens Fistulae are fliffir~llt to repair using standard surgical techniques without removal of tissue or the use of general ~nrsth~tirs, due to ephhrli~li7~tion. In contrast, tissue welding can be used to effect tissue repair without requiring extensive hospital stays using only a local an~sth~tic. Examples of potential fistulae repair include vesico-vaginal, colo-rectal, and other enteric and cutaneous fistulae. The fistula is filled with solder, preferably in combination with a growth factor, most S preferably TGF,BI. Laser energy is then applied using a wavelength and solder and/or chromophore concentration that causes the solder to polymerize from the bottom up. For example, a 50% albumin solution can be polymerized using a laser with a 1.32 micron light, where the water is the chromophore. A 25 % albumin solution under the same 10 conditions would polymerize from the top (i.e., portion closest to the laser) down, which is not as effective. The laser causes the surface of the fistula to "de-epithelialize", allowing the fistula surfaces to heal together.
Other types of lumens that can be sealed include reproductive lumens such as the vas deferens and the Fallopian tubes, using tissue 15 welding instead of surgical ligation. Many other types of repairs can also be effected, including, for examples, repairs of the urogenital systems and ga~lloi,~ l tract.
Sealing of Open Wounds such as Ulcers Tissue welding can also be used to create "casts" or plv~ ive 20 coverings over open or chronic wounds such as decubitas ulcers or other chronic or non-healing wounds. This is achieved by laser welding the solder, preferably in combination with growth err~ ol molecules, over the wound, which may be cleaned to remove necrotic or infected tissue first, either by standard surgical means or using the laser.
The invention will be further understood by reference to the following non-limiting examples.
Example 1: Effect of Albumin Co.~c~ rdlion and Welding Te",l~eldlule on Wound Sll~.lgtL.
Full-thir1fnrc~ wounds were created with a knife blade in the 30 dorsal skin of pigs. In an attempt to evaluate the effectiveness of wound closure with laser welding, maximal wound stresses were compared in a telllpel~lule control study of the optimal welding temperature.
W O 96/38093 PCTrUS96/08458 In a first set of e~L~e,illlents, wounds were laser welded using a tell~eldLure controlled laser with various collcellL,dlions of albumin, 25%, 38%, 45% and 50%. As shown in Figure 1, wound strength was proportional to albumin concentration, with the ~,c;alesl strength being 5 obtained with 50% albumin.
In the second set of e~c,illlents, wounds were laser welded using a ten~eldlul- controlled laser with and without 50% human albumin solder (All)ulllinar-25, Armour Pl~ re~ltir~l Co., K~nk~k~oe, IL, lyophilized and reco,-~ ecl by adding 8 ml sterile water to 6 45-6.50 g albumin). Welds were performed at 65, 75, 85, and 950C. With a simple suture closure as a control, the m~ximllm wound stress for each telll~elalule was evaluated acutely and at 3, 8 and 14 days post-operatively. A 1.32 11 Nd:YAG laser (Laserscope) was used at less than 2.5 watts, adjusted as nrcess~ry to control l~lllpCldlu~.
In the acute wounds without albumin solder, there was no ~ignifir~nt difference in wound strength at 65, 75 and 850C, and only a slight increase in strength at 950C. In the acute wounds with solder, the m~xim~l wound strength at the lowest lelll?eldlure (65oC) was equivalent to the ~Llel1gLll at rn~xim~l lellll~clalLlre (95~C) without solder. More 20 importantly in the solder group, the m~xim~l stress increased steadily with hlclcasillg tempelalu,~ to almost double the non-solder strength at 95oC.
This in~ic~t~s that there is a clear advantage in wound ~Ll~ngLll with the addition of 50% human albumin solder to welds using laser energy alone.
All subsequent chronic animal wounds were closed with albumin 25 solder and compared with a suture control. After 3 days, the lelll~,ldlulc versus m~xim~l wound stress relationship was reversed; the wounds gained much more ~Llcn~sLIl at low ten~clalu,e and were relatively stronger than those at 95oC (which re.--~ equivalent in absolute sLlc~Lll to the acute wounds). The lower telllpe,dlu~ wounds, however, 30 were equivalent in ~ ngLll to the suture controls. At 8 days, the sutured and low tempc,dLure wounds were only slightly ~Llo~,r than the 95oC
W 096/38093 PCTrUS96/08458 wounds. All wounds gained grossly in ~Llellg~l. By 2 weeks, maximal wound stresses were the same for all tellll)elalul~s and sutured wounds.
In ~unllllaly, wounds laser welded with a 50% human albumin solder are signifir~ntly s~longer than those repaired using laser alone.
5 High temperature closures are acutely ~llollge~ than low tempela~ules.
However, high ~lllpelalule repairs (85 and 95 C) were found to heal more slowly. By two weeks, all m~tho~ of wound closure were equivalent in terms of wound ~llel~
Example 2: Mo(lifi~ ~ti~n of Albumin to Lower Thermal Denaturation Thr~
Human albumin is packaged in combination with 0.8 mM Na caprolate and 0.8 mM N-acetyl tryptophane to stabilize the albumin during heat pa~uli~ation. Stabilizers were removed by extensive dialysis into distilled water. Removal of the stabilizers signifi~ntly altered the 15 dena~ula~ion threshold. A colll~alison of the albumin prior to tre~tm~nt with the albumin after tre~tmPnt is shown in Figures 2a and 2b.
FY~ ~ 3: Effect of Inco.y~lalion of Growth Factors into Solders.
Human recombinant growth factors have been shown to accelerate wound healing in model systems. Studies were therefore con~ ct~ to 20 ~letermin~cl whether human albumin can also be used as a time-release delivery vehicle for growth factors for the purpose of accelerating tissue repair after laser-mP~i~t~ wound closure. A critical requirement for incorporation of these agents was that the growth factors not be denatured by the laser. A thermal controlled laser delivery system (TCL) was used 25 to precisely m~int~in stable te.l~e.d~ures during welding, thereby avoiding thermal de-~tulation of bioactive growth factors. Three growth factors, HB-EGF, bFGF, and TGF,~1, were tested in vitro for IllAil~lPn~l~re of bioactivity after exposure to 800C telll~ela~ule in a water bath or with a TCL using 1.32 ~M Nd:YAG laser energy. M~i"le~ e of bioactivity 30 after heating by both methods was demol~,ated for each factor using a Balb/C-3T3 mitogenic assay (HB-EGF and bFGF) or a luciferase reporter assay(TGF,BI). In vivo ~pelilllents were pe.rol,l,ed to determine the W O 96/38093 PCTrUS96/08458 efficacy of growth factor enh~nred tissue solder for closure of 2 cm full thir~nPss sutureless dorsal incisions in porcine skin. Incisions were closed using 50 ~l of 50% human albumin alone or enh~nre~ with HB-EGF (2 ~g), bF(3F (10 ,ug), or TGF-,B~ g). Laser welding was performed at 700C with a rate of 0.4 mm/second. Suture control wounds were closed with two 5-0 nylon sutures. Five wounds were repaired in each group. Wounds were excised at 3, 5, and 7 days post-operatively.
Tensile strength, total collagen content and histology were performed.
The results are shown in Figures 3a, 3b, and 3c, colllpalillg repair strength with treatment as a function of time. No ~ ,irlr~t difference in tensile strength be~weell the groups could be seen at 3 days.
By 5 days the tensile strength of the TGF,BI group increased by 50% and 25.5% over laser solder alone and suture groups, l~spe~ ely. At 7 days the TGF,BI group was 118% and 52% higher than laser solder alone or suture, respectively, as shown by Figure 4. The HB-EGF and bFGF
groups were equivalent to the laser solder group at all time points. As shown by Figure 5, total collagen content at 7 days increased in the TGF,BI group by 6% over the suture group and 21% in the laser solder group. Histology co~.r,.llPd the changes in matrix observed in tensile strength and collagen content. In conclusion, TGF,BI enh~nre(l albumin solder increases the strength of laser welded wounds and provided a means to accelerate wound dealing, which should decrease postopel~live convalescence, hospitalization time, and wound infections.
FYqmplq 4: Co.~ a-;son of Growth Factors alone and with Laser Welding.
Maximal wound stresses were colllpaled for wounds closed at 700C in five groups: suture alone; laser and solder; laser, solder and HB-EGF (2 ~g/wound); laser, solder and basic-FGF (10 ~g/wound); and laser, solder and TGF~ g/wound). Pigs were sacrificed and wound strength evaluated after 3, 5 and 7 days, as described in Example 3.
Results are shown in Figure 6. After 3 days, there was no signifir~nt dirrerel1ces in wound strength among groups with the following CA 02222633 l997-ll-24 W 096/38093 PCTrUS96/08458 exception: the TGF treated wounds were slightly ~I,o~gel than both the suture and b-FGF treated wounds. However, at 5 days, TGF treated wounds were cignifi- ~ntly stronger than all other wounds and were almost double in strength to the three other groups closed with the laser. By one 5 week, the relationships and absolute wound s~l~;ng~ls were similar to those at 5 days. Comparison of the effect of the growth factors in the absence of laser welding demollsLla~es that the combination of laser welding with TGF,BI is better than the a~minictration of TGF,~I alone.
The data unequivocally in(lic~te that the addition of TGF~I to 50% human 10 albumin solders cignifir~ntly increases the m~xim~l wound stress at 5 and 7 days compared with other growth factors and sutures alone.
Claims (18)
1. A improved method for laser welding using a protein solder comprising administering at the time of welding or immediately thereafter bioactive agents having biological activity after exposure to 80°C heat for at least one tenth second, selected from the group consisting of proteins, polysaccharides, nucleic acids, vitamins, metals or ions, and synthetic organic molecules.
2. The method of claim 1 wherein the bioactive agents are selected from the group consisting of enzymes, hemostatic agents, growth effector molecules, bacteriostatic or bacteriocidal factors, antiinflammatories, chemotherapeutic agents, antibiotics, thrombolytic or clot inhibitory agents, anesthetics, anti-angiogenic agents, and vitamins.
3. The method of claim 2 wherein the growth effector molecules are selected from the group consisting of growth factors and extracellular matrix molecules.
4. The method of claim 3 wherein the growth factors are selected from the group consisting of epidermal growth factor (EGF), platelet-derived growth factor (pDGF), transforming growth factors (TGF.alpha., TGF.beta.), hepatocyte growth factor, heparin binding factor, insulin-like growth factor I or II, fibroblast growth factor (FGF),VEGF, LPA, erythropoietin, nerve growth factor, bone morphogenic proteins, muscle morphogenic proteins, and cytokines.
5. The method of claim 1 wherein the bioactive agents are in combination with the solder.
6. An improved protein solder for use in tissue welding comprising bioactive agents having biological activity after exposure to 80°C heat for at least one tenth second, selected from the group consisting of proteins, polysaccharides, nucleic acids, vitamins, metals or ions, and synthetic organic molecules.
7. The solder of claim 6 wherein the bioactive agents are selected from the group consisting of enzymes, hemostatic agents, growth effector molecules, bacteriostatic or bacteriocidal factors, antiinflammatories, chemotherapeutic agents, antibiotics, thrombolytic or clot inhibitory agents, anesthetics, anti-angiogenic agents, and vitamins.
8. The solder of claim 7 wherein the growth effector molecules are selected from the group consisting of growth factors and extracellular matrix molecules.
9. The solder of claim 8 wherein the growth factors are selected from the group consisting of epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factors (TGF.alpha., TGF.beta.), hepatocyte growth factor, heparin binding factor, insulin-like growth factor I or II, fibroblast growth factor (FGF), VEGF, LPA, erythropoietin, nerve growth factor, bone morphogenic proteins, muscle morphogenic proteins, and cytokines.
10. The solder of claim 6 further comprising a chromophore.
11. A method for repairing fistulae or filling a lumen comprising administering into the fistulae or lumen a protein solder and exposing the solder to light energy or radiofrequency energy under conditions denaturing the protein from the bottom of the fistulae or lumen up towards the energy source.
12. The method of claim 11 wherein the protein solder is 50%
albumin in aqueous solution.
albumin in aqueous solution.
13. A method for repairing open or chronic wounds comprising applying to the wound a protein solder, welding the solder by application of light energy or radiofrequency energy.
14. The method of claim 13 comprising applying to the wound an effective amount of growth effector molecules to promote wound healing and/or to accelerate or enhance functional strength of the repair.
15. The method of claim 14 wherein the growth effector molecules are applied in the protein solder.
16. An improved protein solder, the improvement comprising removal of materials preventing heat denaturation or chemical denaturation of the protein prior to exposure to light or radiofrequency energy.
17. The solder of claim 16 wherein the protein is heat stabilized albumin, and the heat stabilizing compounds are removed from the albumin.
18. The solder of claim 16, wherein the protein is unfolded by treatment with reducing agents followed by blocking of free cysteines by reaction with carboxylating or methylating reagents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US458,885 | 1995-06-02 | ||
| US08/458,885 US5713891A (en) | 1995-06-02 | 1995-06-02 | Modified solder for delivery of bioactive substances and methods of use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2222633A1 true CA2222633A1 (en) | 1996-12-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002222633A Abandoned CA2222633A1 (en) | 1995-06-02 | 1996-06-03 | Method for laser mediated tissue welding with enhanced strength |
Country Status (7)
| Country | Link |
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| US (1) | US5713891A (en) |
| EP (1) | EP0830087A2 (en) |
| JP (1) | JPH11504835A (en) |
| AU (1) | AU5971596A (en) |
| CA (1) | CA2222633A1 (en) |
| IL (1) | IL122328A0 (en) |
| WO (1) | WO1996038093A2 (en) |
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| CN101407807B (en) * | 2008-11-19 | 2013-11-06 | 暨南大学 | Method for modifying cell inherited characteristic by processing chromosome and use thereof |
| US20110282334A1 (en) * | 2010-05-11 | 2011-11-17 | Ceramoptec Industries Inc. | Device and method for fistula treatment |
| US9211116B2 (en) | 2011-06-16 | 2015-12-15 | Curaseal Inc. | Fistula treatment devices and related methods |
| CN107137114A (en) | 2011-06-17 | 2017-09-08 | 库拉希尔公司 | The device and method treated for fistula |
| CN104144712A (en) * | 2011-11-25 | 2014-11-12 | 株式会社大塚制药工场 | Pharmaceutical composition useful for adhesion prevention or hemostasis |
| US20170232157A1 (en) * | 2016-02-11 | 2017-08-17 | Arizona Board Of Regents On Behalf Of Arizona State University | Tissue integrating materials for wound repair |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4493320A (en) * | 1982-04-02 | 1985-01-15 | Treat Michael R | Bipolar electrocautery surgical snare |
| US4672969A (en) * | 1983-10-06 | 1987-06-16 | Sonomo Corporation | Laser healing method |
| US4854320A (en) * | 1983-10-06 | 1989-08-08 | Laser Surgery Software, Inc. | Laser healing method and apparatus |
| US5409479A (en) * | 1983-10-06 | 1995-04-25 | Premier Laser Systems, Inc. | Method for closing tissue wounds using radiative energy beams |
| US5001051A (en) * | 1986-12-12 | 1991-03-19 | Regents Of The University Of California | Dose critical in-vivo detection of anti-cancer drug levels in blood |
| AU646406B2 (en) * | 1989-09-12 | 1994-02-24 | Trustees Of Columbia University In The City Of New York, The | Laser tissue welding with dye enhanced solders |
| US5209776A (en) * | 1990-07-27 | 1993-05-11 | The Trustees Of Columbia University In The City Of New York | Tissue bonding and sealing composition and method of using the same |
| US5292362A (en) * | 1990-07-27 | 1994-03-08 | The Trustees Of Columbia University In The City Of New York | Tissue bonding and sealing composition and method of using the same |
| US5156613A (en) * | 1991-02-13 | 1992-10-20 | Interface Biomedical Laboratories Corp. | Collagen welding rod material for use in tissue welding |
| US5310095A (en) * | 1992-02-24 | 1994-05-10 | Djs&T Limited Partnership | Spray texturing apparatus and method having a plurality of dispersing tubes |
| US5334191A (en) * | 1992-05-21 | 1994-08-02 | Dix Phillip Poppas | Laser tissue welding control system |
-
1995
- 1995-06-02 US US08/458,885 patent/US5713891A/en not_active Expired - Fee Related
-
1996
- 1996-06-03 IL IL12232896A patent/IL122328A0/en unknown
- 1996-06-03 WO PCT/US1996/008458 patent/WO1996038093A2/en not_active Application Discontinuation
- 1996-06-03 AU AU59715/96A patent/AU5971596A/en not_active Abandoned
- 1996-06-03 CA CA002222633A patent/CA2222633A1/en not_active Abandoned
- 1996-06-03 EP EP96917016A patent/EP0830087A2/en not_active Withdrawn
- 1996-06-03 JP JP8536773A patent/JPH11504835A/en active Pending
Also Published As
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| WO1996038093A2 (en) | 1996-12-05 |
| JPH11504835A (en) | 1999-05-11 |
| AU5971596A (en) | 1996-12-18 |
| US5713891A (en) | 1998-02-03 |
| IL122328A0 (en) | 1998-04-05 |
| EP0830087A2 (en) | 1998-03-25 |
| WO1996038093A3 (en) | 1997-03-06 |
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