JPH05502386A - Laser tissue joining with dye-enhanced adhesive - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Title of the invention: Laser-based tissue joining method using dye-enhanced adhesive And uni look The present invention relates to tissue bonding with energy absorbing dyes. Be more specific For example, adhesives such as energy-absorbing dyes or fibrinogen may be added to the joint site. Relates to tissue coaptation using energy sources such as lasers by application.

In this application, several reports are referred to and the Arabic numbers in parentheses It is indicated by letters. The full text of these documents can be found at the end of the specification immediately before the patent claims. It is given.

Disclosure of these documents fully describes the state of the art within this invention. Therefore, it is incorporated by reference in this application.

In the past, doctors waited until the body's natural healing process developed a scab over the wound. A suture was applied to the tissue. This suture material is used to join tissue using a laser. Eliminates the need for use and therefore repairs without excessive scab formation or abnormal body reactions can. It is possible to successfully join tissues by using a laser as an energy source. , has been reported in several surgical fields (1.2.9.21.22.23).

In general, accurate placement of tissue edges and thermal damage to this and other surrounding tissue is important. These techniques are based on avoiding scratches. The strength of the bond immediately after formation is reduced. The potential for destruction has prevented widespread use of this technology.

Laser-based tissue adhesion technology can form anastomoses with less disturbance (1), Prevents biological reactions to foreign bodies and granuloma formation, and allows for faster healing than traditional sutured anastomoses. Revenge is obtained (2).

However, if sutures are unsuccessful, the general tissue margins often become heated. It is damaged and cannot be exposed to laser energy again. Furthermore, the laser -Although adhesives are usually strong enough to withstand systemic blood pressure, are weaker and more fragile than the sutured partner (3, 4). 6 Thrombin and calci Fibrinogen together with additional fibrin glue activators such as It is used to increase the strength of vein sutures (5). Laser energy is a protein glue (5) to form a stronger bond. However, in particular How to successfully use lasers for tissue adhesion in conjunction with physical bonding techniques , typically 7.6 watts/a+! high threshold forces are required and often Causes significant tissue damage. Therefore lower energy output is required and Reducing the amount of zonal thermal damage may result in a stronger bond than would be obtained using suture techniques. However, it is desirable to develop a tissue adhesion technique that can still provide strength.

And Yube!亙 According to the present invention, energy absorbers and tissue adhesives are formed to adhere patient tissues. A sufficient amount of tissue bonding agent is placed in contact with the tissue to be bonded to absorb energy. Enough energy is absorbed by the agent to heat the tissue and cause the tissue to A method is provided that includes providing conditions that cause adhesion. Preferably Energy imparting is energy absorption of electromagnetic energy such as laser energy. It is to give to the agent. Preferably, the tissue contact also includes an energetic dye such as a dye. Contacting the tissue with a mixture of absorbents and tissue bonding agents such as fibrinogens . Laser energy is e.g. potassium, aluminum, arsenic semiconductor diodes. It is preferable to use an argon ion laser or an argon ion laser. The laser In the case of diode, indocyanine green (ICG) dye is the energy. Fluorine is preferred as a dye absorber, while for argon ion lasers the dye is Resein isothiocyanate (FITC) is preferred. Bonding agent is 1.A or animal fibrinogen, but any polypeptide may be used.

The binding agent may be a serum protein, albumin or fibronectin.

The present invention also provides an energy absorbing agent and a bonding agent that, when applied to tissue, effectively bond tissue. in an amount comparable enough to be effective and to impart a sufficient amount of energy to the composition. The present invention provides tissue adhesive compositions for use in adhering tissue during tissue preparation.

A lower threshold force can be used by applying exogenous dye to the site to be adhered. Therefore, the amount of laser is also reduced.

Also, lower doses of laser cause less tissue damage. Moreover, the use of dyes Enhances the selective delivery of energy to target tissues and therefore generally and reduce the amount of heat damage that occurs at the same time. Remove adhesives like fibrinogen Mixing the natural dye before applying it to the area to be bonded will reduce the strength of the resulting bond. Increase further. Furthermore, using adhesives such as fibrinogen can Does not require precise positioning and does not impart excessive heat to host tissue Therefore, there is a large margin for failure during bonding. First attempt with adhesive If this fails, reapplication of the adhesive may be necessary without destroying the host tissue ( The test can be repeated. Bonds formed with adhesives are structurally similar to the early lasers. - Stronger than adhesive. Applying high laser energy to adhesives such as fibrinogen The addition of pigments to the adhesive allows for the selection of adhesives without damaging the underlying host tissue. The fact of selective heating (6) is particularly important for tissues that do not contain endogenous pigments. be. The use of exogenous compounds photosensitizes the adhesive on the tissue and Increases energy absorption and makes it selective. Fluorescence imaging for photodynamic therapy and diagnosis Combining salts and pigments as in gings (10, 11, 12) This means that the laser output frequency should match well with the absorption peak of the dye. Therefore, it is selected to provide sufficient target-specific laser energy delivery. .

Tsuki'l'su [ri & shibu] According to the invention, patient tissue is combined. In other words, the bonding method depends on the tissue to be bonded. Contact the energy absorber with the tissue bonding agent in sufficient quantity to form a bond, and Energy absorbed by energy-absorbing materials causes tissue heating, Includes application of a sufficient amount of energy absorber under conditions to cause tissue adhesion. I'm reading. Preferably the energy is provided by an electromagnetic energy source such as a laser. The tissue contact provided to the energy absorber is preferably between the energy absorber and the tissue. Contact the tissue with the adhesive mixture. The energy absorber is preferably a dye Good. Preferably, the dye has a maximum absorption peak at a specific wavelength, and 1 norther is preferable. Preferably, it has a specific wavelength corresponding to the maximum absorption peak of the dye.

The energy source also preferably has a frequency component in the visible spectrum, thereby emit energy that helps direct the energy source to the tissue to be attached.

One desirable laser/dye combination is that the laser has a maximum wavelength of approximately 808 nm. It is an array of potassium-aluminum-arsenic semiconductor diodes with a long The dye is indocyanine green (ICG). Another desirable laser/dye The combination of 1 norther is an argon ion laser with a maximum wavelength of approximately 488nn+. In the laser, the dye is fluorescein isothiocyanate (FITC). Contact The adhesive can be human or animal fibrinogen, but any polypeptide can be used. stomach. The adhesive is a fibrin glue combined with an additional fibrin glue activator such as thrombin. Contains fibrin glue with fibrinogen, but may or may not contain calcium .

(Illustrated in U.S. Patent No. 4.627.879 and incorporated herein as a document) Fibrin containing fibrinogen, factor 8, and thrombin as a tissue bonding agent Included are freeze-precipitated suspensions containing glue activators and the like. Coupling agents include serum proteins, These include albumin and fibronectin. Laser can be continuous or discontinuous Pulsed or cut laser.

According to another aspect of the invention, the tissue adhesion composition includes an energy absorber and a bonding agent. and applied to the tissue to impart a sufficient amount of energy to the composition to cause tissue adhesion. Contains a sufficient amount to Its composition is pigment and fibrinogen It is. The dye may be, for example, indocyanine green (ICG) or fluorescein green. Sothiocyanate (FITC).

The glue is human or animal fibrinogen, but any polypeptide Common examples include serum proteins, albumin, fibronectin, etc. Its composition also It also contains thrombin and calcium.

Hikyaku and Kasa 11 Δ− Cliff−− Blind Two laser bonding studies according to the present invention are described below. In the first research The energy source is a laser diode with a maximum wavelength of approximately 808n+u. The energy absorber is indocyanine green pigment (ICG) with a maximum wavelength of approximately 8051. there were. In the second study, the energy source had a maximum wavelength in the range of 488 to 514 nm. In the argon ion laser, the energy absorber is at the maximum wavelength of the argon laser. Fluorescein isothiocyanate with a maximum at a wavelength corresponding to (FITC) dye.

B Laser Io ICG 1 Fibrinone Place fresh frozen human plasma in a test tube and place it in a -80°C freezer for at least 12 hours. Oita. The tubes were then thawed at 4°C and spun down at 1000XG for 15 minutes. Up The supernatant was removed, leaving a precipitate, ie, fibrinogen. The viscosity of this liquid is determined by the bottle set. Easy to operate. Fibrinogen can be stored at -80°C for over 1 year (7).

More details on the preparation of fibrinogen are included here as a reference. However, the US patent Net 4.627.879 attracts attention.

L-Kouenbe 1 cup Indocyanine green pigment (Becton, Dickinson, Baltimore, Maryland) ) was mixed with normal saline until a saturated solution was obtained. The half life of this liquid is It took about 10 hours. The dye has a maximum absorption at a wavelength of approximately 805 nm and an absorption coefficient of 2. ×10″M−“Cm−′.

3 Laser system zoom Gluing is done using a manual focusing optical system (Spectra Fixtures).

System 7200 diode combined with Mountain View, California) It was carried out with a laser module.

This laser consists of an array of potassium-aluminum-arsenic semiconductor diodes. ing. The primary wavelength output of this laser diode is 808±inn.

Another band of laser energy is in the visible red spectrum and is You can see the size of the laser spot while it is being formed.

Focusing optics increase the working range and allow a good view of the anastomosis site. focus The diameter of the beam in addition to the optics is 2-2 at a distance of 40. Laser power is model 2 Focusing optical system with 01 type laser output meter (Coherent Science Divisi) (Palo Alto, California) and held at 4.8 Watts/7. Ta. The laser is directed at the distance between the lens of the focal lens system and the tissue to be joined. The distance was maintained at approximately 4 cm during the period of time.

4　n　n　vivo(of The newly created adhesive was mixed with ketamine (35 mg/kg) and xylazine (5 mg/kg). ) was evaluated in New Sealant white rabbits, which were anesthetized. 16 gauge tube after abdominal opening Chidori duckbill valve vessel canyule (DLP Inc., Gr. ana Rapids.

MI) is inserted into the distal abdominal artery, and a Datascope 2000 blood pressure monitor (DataScope MI) is inserted into the distal abdominal artery. Co-op Corporation, Balamus, New Chassis) to measure hemodynamic blood pressure. It was fixed with 3-0 silk thread for stability.

Capillaries were clamped as necessary to prevent backflow bleeding. No. 6-0 polypro Pyrene sutures are placed at each end of the incision and tensioned to keep the tissue in place while it is glued. I pulled it. The area was perfused with sterile saline to remove all blood. The previous one Sharpened bottles were used to hold the edges of the vascular incision as needed.

For non-adhesive bonding (n = 11), bonding was performed using a 27 gauge needle just before laser irradiation. ICG was administered locally at the site.

For laser bonded joints (n=ll), 1 serum of ICG was added to human fibrinogen. Mixed and placed on the adhesive part with a bottle set before laser irradiation. fibrino A minimal amount of ICG was used to stain the gene. This spreads the pigment on the blood vessel surface. placed it in the correct location. The anastomosis was performed using a diode laser of 4.8 watts/d. Glued using the output. If the fibrin glue or tissue becomes dry, Ther energy was directed to the next target area. At the end of the adhesion, the edges can be seen joining; When tissue dryness and twitching just begins, or when dye or fibrin glue It was determined that the anastomosis was solidified on the surface and no anastomotic defects were observed.

Once the conjugation was completed, the branch vessel was opened and backflow into the aorta was allowed for 3 minutes. next, This branch vessel was reclosed and a vascular catheter pre-inserted into the distal artery using a perfusion pump. Normal saline was passed through the tube and the pressure at the time of adhesion failure was recorded. difference In a further five rabbits, the above protein was treated with the ICG-fibrinogen combination. I tried to follow the call accurately. However, just before measuring the breaking pressure, 0.5 25,000 IU of urokinase (Abbott, IL) dissolved in cc of saline (Chicago, NE) was perfused into the artery for 5 minutes. This urokinase dose should be administered within 5 minutes. This was the amount needed to completely dissolve 0.5 cc of rabbit blood that had collected inside (8 ). The breaking pressure was then measured.

5., of 22 New Sealant White Rabbits each underwent 7 vertical abdominal surgeries as shown above. was prepared. Larger incisions are closed with 6-0 polypropylene sutures and smaller incisions are closed with 6-0 polypropylene sutures. It was firmly attached to the opening. Each animal has ICG-enhanced fibrinogen adhesion. It was called. The threshold output is used for diode lasers with an intensity of 4.8 watts/go. It was. After adhesion, the smaller artery cross ramp was removed. The glued anastomosis If so, the hole was repaired with another dose of fibrinogen and laser irradiation. no leaks Once the anastomosis is established, remove the proximal artery clamp and test the vessel for clots or leaks. I tried it. , between 1 and 90 days, the animals were sacrificed and the area where the bonding took place was harvested. Ta. The attached tissue was washed with 10% formaldehyde buffered to normal pH in HPS. Saved it in the dark.

In addition, the selected specimens contained 0.5% glutaraldehyde and 2% paraformaldehyde. Dissolve the solution in O,OS% cacodelate solution (pH 7,38) and evaluate with an electron microscope. It was saved in transmission type and scanning type.

Mu U a Invivo 0's ICG dye-enhanced adhesion requires approximately 1 minute of laser application to close a 7 m incision. required time. Adhesion defects sometimes visible after removing the closure clamp. Reprocessing was necessary. Tissue adhesion failure that occurs immediately after adhesion without fibrin glue The pressure (262 ± 29 mmHg, n = 11) is high when bonded with fibrin glue. 330±75mm1-! g, n=11) (risk rate 0°0 5 or less). The seam closure did not rupture at maximum pressures up to 300 mm Hg.

However, leakage from needle holes in seams and small defects during repair is lower than 145 mmHg. Observed with great pressure. Fibrinogen adhesion in contact with urokinase Not significantly lower than non-perfused fibrinogen adhesion (290 ± 74 mm 1-1g, n = 5) (no significant difference) 1)) In vivo tI CG big eyes 1□ Suture or fibrinogen ICG adhesion was performed in animals followed for 1 to 90 days. No rupture of the anastomosis, blood coagulation, or aneurysm occurred in any of the cases. Immediately after gluing , the applied fibrinogen covers the smooth surface to which red blood cells and platelets are attached. Formed. The fibrin belly can be checked by covering the suture adhesive surface until the 20th day after surgery. However, the amount of special table 5-5O2386 ( 5) There was no increase in blood coagulation response. Within 10 days, the new intima surface will form. Regenerated on Bryn. By the second week after surgery, histiocytes begin to reabsorb. was seen to deplete fibrinogen. Internal and external by 3rd week after surgery Cells whose elastic layer remains broken, but the original cellular fibrin has grown myofibrosis, which thickens together and spreads from the superficial layer of the intima to the adventitia of the arterial vessel. It contains the cytoplasm of niodiphilic cells, which are characteristic of blast cells. This confirmation is Ophibroblast-specific smooth muscle-specific agetin staining (Enzo Diag nostics, 22-York, NY). this These cells appear to be proliferating, indicating rapid tissue regeneration at their attachment sites. forming a carrier for No abnormal biological reactions were observed. Growth and deposition continue. As time progresses, fibrin accumulates near the surface of the intima and increases in the amount of fibrin present on the outer lining of the artery. It appeared to be reabsorbed by histiocytes more rapidly than fibrin. Post-surgery 9 By day 0, fibrin has been almost completely removed and normal cells that look like endomysial cells are present. Only the outer elastic layer is left between the outer elastic layer and the intima.

Outside the outer elastic layer, a fibrin mass surrounded by histiocytes remains. However, fibrous tissue was generally present after the union. abnormal organism No reaction was observed.

The anastomosis with the stitches closed showed local hemorrhagic changes at the suture pressure of the arterial tissue.

Closing with stitches causes vascular adhesion to a greater degree than does 17-ser adhesive closure. It seemed like there was nothing to do. However, the tissue reaction to suturing is This resulted in the formation of clots that disturbed the intimal blood flow surface by day 5. at the same time after surgery Comparison of the surfaces of the joined arteries shows complete endothelial tissue layering, with the anastomosis completely intact. It is covered with lining cells and can be distinguished from the normal rabbit stomach around this area. was difficult.

C argon ion laser-FITC Niezu Emperor 2 Stars 1 Heterogeneous Weight F I TC (Sigma Inc, Sen. Lewis, Missouri) ) with 0.9% sodium chloride perfusate (Abbot Laboratories, Chicago, Illinois) Rod, 8.4% carbonated water Sodium (pH 8,4) (FisherScient, 1fic, New (Fair Lawn City, Chassis) lrIQ was mixed to form an orange liquid. 2-3 drops of this liquid (0,1 mQ) was added locally to the bond site prior to argon laser application.

Control animals received the same amount of 0.9% sodium chloride applied topically to the adhesions.

2 Leh - Sisum Adhesion is performed using a System 1000 Surgical Aluminum with III spot applicator. Gon Laser (Coherent l+Ledical Division, Cali Valo Alto, Fornia) was used. The laser can be operated in various modes. It was. At low 1 noser output, the maximum wavelength is 488 pus. applicator is app This was improved by installing a focusing lens at the output end of the camera (Becton). Deikinjin FACSIV part number 53.10006-01. Becton Day Kinjin Immunocytometry System, Mountain View, California). child The focal I-nons have a larger working distance and can see a larger anastomotic area. Wear. By adding focus I nons, 1.5 IIll at a distance of 6 cm has a ray diameter of The laser output was measured using a 201 type 1 noser output meter (Coh erent 5science Division, Valo Alto, California The measurements were taken at the exit of the focusing lens. between the focal lens and the tissue to be cemented. The distance was kept at approximately 60° during I/-ser administration.

3 In vitro φ-, The adventitia of a freshly harvested rabbit artery was heated with a laser in the range of 100 to 500 @W. Irradiation was performed by gradually increasing the output (output range was from 5°66 to 12.04W/aof). In one of the irradiated groups, FITC was locally added to the sample with an Issei 27 gauge needle.

In the second group, no FITC was used. The organization is 15.30.60.90゜12 The above laser system was applied at intervals of 0 seconds, and changes in the entire tissue were observed. . Samples were transferred to 10% formalin, hematoxylin, phloxine, and saffron. (HPS).

4　n　vivo　 Ten new sealant white rabbits were treated with ketamine (35 mg/kg) and xylazine. (5+g/kg). After abdominal dissection, a 16 gauge platypus Lube Vascular Cannula (DLP Inc., Grand Rabid, Miami) Datascope 2000 sphygmomanometer (Datascope, New York) is inserted into the abdominal artery. The site was secured with 3-0 silk suture for the measurement of vascular blood pressure in Balamas, Chassis. Established. The abdominal artery is then closed with a clamp and a 7 m long incision is made using a clamp. An incision was made on the outside of the pump. Tighten both ends of the incision with 6-0 polystyrene sutures and connect. The tissue was fixed in place for a while. Cover the area with sterile saline to ensure there is no blood. perfused. Use a fine set of bottles to hold down the edges of the vascular anastomosis if necessary. FIT For C adhesion, the dye was applied locally to the adhesion site with a 27 gauge needle.

The minimum amount of FITC needed to stain the adhesive site is used. once administered to the tissue However, it is not possible to precisely control the horizontal spread of the dye. One to two drops of dye is usually sufficient. Anastomosis is 3.8 watts when using FITC It was bonded at a power of 7.6 watts/d when not in use. This output concentration is Indicates the lowest power level consistent with reliable adhesion. arterial prolapse When water is seen, laser energy is directed to the next target area. Adhesion The end point is when the edges are joined and the tissue is just beginning to dehydrate and twitch. That's what I decided.

To complete the bond, use a perfusion pump to connect the arterial pressure tube and the pre-placed cardiac tube. Regular saline was pumped into the distal artery through the tether. Maximize the number of animals killed in layers. In order to reduce After measuring the tear pressure, the clamp closing the artery was gradually moved further away. Therefore, the burst pressure was measured again.

5 Inviv □ ・ and 4 ・.

Prepare 25 separate New Sealant white rabbits and test each animal as above. A pair of 7-length abdominal incisions were made. The majority of the incisions are made of 6-0 polypropylene. The incision was closed with two sutures, and the smaller incision was closed with a coaptation. 18 animals were treated with FITC Laser welding was performed without using FITC on a7 rabbits that underwent laser welding. became. A threshold power concentration of 3.8 watts/d was used for the non-FITC junction.

After coaptation, the lesser arterial occlusion clamp was removed. If the joined anastomosis leaks, Then, the hole was repaired with further laser irradiation. If leak-free anastomosis can be achieved, The proximal arterial clamp was removed and the artery was inspected for thrombus formation or leakage.

Animals were sacrificed between days 1 and 75 and the mating sites were harvested. joined tissue buffered to normal pH for PHS staining or Masson trichrome. It was stored in a 10% formalin solution.

Mu blue--presentation a　In vitroゝG　-1 ■(1vitro FITC-stained rabbit artery, whiten tissue) The threshold was 15 seconds of irradiation at 100 mW. Irradiation time and laser output concentration As the temperature increases, the tissue becomes reddish and becomes dry and twitchy, and the 300mW After 30 seconds of irradiation, it finally got burnt. 400mW laser energy No holes were formed until after 90 seconds of exposure. For unstained arteries, use a 300 mW laser. No effect on the tissue was observed until the laser energy was irradiated for 15 seconds. start If the tissue is dry, carbonization will progress rapidly, and if irradiated for 90 seconds at this output, a hole will be formed. accomplished. This is the progression of histological changes in the FITC-stained group compared to the unstained control. It is shown in Table 1 reproduced at the end of the specification. FITC stained artery 3 times more laser energy for the same tissue change in unstained specimens compared to need to bring about change. In addition, due to the initial impact of the laser on the tissue, carbonization may occur. The progression of tissue changes leading to the formation of pores is slow in tissues stained with FITC. It is.

b Invivo・(1) Laser application time for FITC and non-FITC joints is approximately 90 seconds to close a 7 mm incision. It was used to Remaining bond defects sometimes seen after opening of the closing clamp It needed to be repaired. The average burst pressure immediately after bonding was 1 for the non-FITC bonding group. The FITC group had 164 onHg compared to 47mmHg. Suture closure is It did not break at the highest pressure (300 mmHg). However, the needle hole in the seam and the small Leakage through defects was observed at pressures above 125 mHg.

c In vivo FITC-me and A.

Reciprocal color Among animals followed between 1 and 75 days, both suture and FITC joints No evidence of joint disruption, thrombus formation, or animal species occurred. FITC Enhanced argon ion laser bonding site is located within the muscle with regenerated intimal surface. Characterized by membrane proliferation.

Collagen deposition was seen at the joint site. Bonding made without FITC A small anastomotic hypertrophy developed in one of the patients by 2 weeks postoperatively. Other abnormalities in this group I couldn't see it. Histologically, direct irradiation to argon energy without FITC Carbonized lumps were usually seen on the surface of the tissue that had undergone the treatment. After treatment without FITC, The argon ion laser is used to remove 50% of the irregularly shaped collagen around the bonding point. It was made in the range of ~100-.

Nuclear details are lost in heat-damaged areas, and features of the internal structure of the cell are lost. In specimens bonded with 6FITC, it was revealed that tissue in the range of 300 cm No deposits of carbonized lumps were observed. Anastomoses closed with sutures reduce suture pressure on the arterial composition. The site showed ischemic changes. These closures are better than closures by one-nozzle joints. However, it did not seem to significantly induce clot adhesion. Up to 2 weeks after laser bonding A new endothelial superficial layer was formed on the medial surface. Patching of exposed endothelial tissue Similar changes occurred in suture-closed anastomoses, although they often remained.

D to 4・ All three factors in the bonding system described above, namely the energy source; - Absorbent materials and tissue bonding agents must be simple and safe for clinical application. It matches. Indocyanine green, fibrin glue, and diode 1 has been found to be safe in clinical applications (8.14.15). ). Indocyanine green is large at 808nm output of diode laser. It has a large absorption coefficient. This diode 1 noser is a solid material made at low cost. Due to the low energy output capability of semiconductor electronic components of Dosta 1 (40 (0 mW or less) was limited to medical applications. Topically administered indocyanine When combined with lean dyes, one noser of this wavelength provides an essential and rapid combination. The vine has an effect on weaving. For example, Diode 1 Norther has low cost, small size, For simple output requirements, persistence, etc., other solid-state 17-users or There will be many applications as an alternative to common gas evacuation lasers. Finally fibrin glue has been used as a hemostatic agent without significant complications. fibrino in elective surgery -gen is collected from the patient. I. The addition of rhombin and calcium is an internal medicine leather belt. (6.17). We use this blood clotting system for a long time. It was not possible to perform an anastomosis. However, after the laser irradiation, It is possible to induce long-term fibrin clots without using thrombin or calcium. I can do it. Laser-based “spot bonding” is an alternative to sutures for repairing anastomotic leaks. It would be equally effective during the formation of an anastomosis.

Argon ion laser welding of gallbladder tissue can be done by staining the tissue with bile or blood staining. (6), where we used an exogenous compound to perform laser-bonding. The defective tissue for was photosensitized. When using FITC under the same experimental conditions, the bonding is was formed at a threshold laser power concentration of 172 compared to a junction without FITC. .

The threshold laser power for bonding without FITC is consistent with a previous report (22). There is. By using Fl:TC, this threshold can be reduced. joining The reduction in energy required for . In addition, to apply FITC locally, the energy storage is localized at the junction. localized in The area with a demarcated border around the coagulation damage is a blood vessel without thermal damage. It was clearly seen on the adventitial surface of.

The specificity of energy storage is achieved by using an argon ion laser power of less than 0.2 watts. This can be further enhanced by

In this range, the argon laser energy output for all line modes is almost is the wavelength of 488 nm. This wavelength almost coincides with the maximum absorption for FITC. are doing. At higher powers, other wavelengths contribute to the total power, but the surrounding Absorbed non-specifically by tissues, causing thermal damage.

Blood also appears to act as an endogenous bromophore.

Bonds are easier to form and last longer if the arterial tissue is stained with blood. It seems that In burst strength tests, the lack of blood in the field of view is not so common. Not important.

FITC dye has also been modified to allow visualization of junction sites due to its bright green fluorescence. Standard argon iodine is used to remove one noser light. Laser Safety Goggles (Laser Guard, Glensol, California) It's the same when you look through it. selectively delivers I-norther energy to tissues Extrinsic dyes are used to enhance cancer light irradiation, blood vessel removal in ophthalmology, and diagnosis. Used for fluorescence image observation (10, 1+,, 12.24), etc. Target organization The use of exogenous dyes improves local bromophore concentration and energy access. superior to endogenous bromophore utilization through better control. It will be recognized that there is.

Many mechanisms may be involved in fibrinogen junction. Urokinase Foreign fibrinoid cannot be prevented from joining with fibrin glue. Suggests that increased coagulation of rabbit blood with Gen is not the main mechanism of conjugation are doing. Heated fibrinogen is released into the bloodstream regardless of the coagulation cascade. It appears that the cells cross-link together, becoming insoluble and attaching to the edges of the host tissue. It changes as if it were wrapped in the glue of a persistent creature. Amorphous blood clots with myofibroblasts It rapidly infiltrates and becomes covered with host endothelial tissue cells. Fibrin is present in this steep blood vessel wall. Fibrin glue seems to stimulate the regeneration of fibrin (18). As it is absorbed, myotropic membrane growth continues until new medium is generated. internal and the outer elastic layer, on the contrary, is not regenerated. Already reported by other people As previously reported (19, 20), no unusual biological reactions were observed. case In fact, fibrin junctions are formed from a biodegradable framework on which separated blood vessels are deposited. has been done. Pigment-enriched fibrinogen also contributes to the tissue surrounding the junction. Reduces damage, causes more rapid proliferation of myofibroblasts, and improves vascular tissue at junctions. Accumulates extracellular matrix necessary for regeneration. Unusual biological countermeasures against suture agents Surfaces that cause irregular flow due to stress (19) or sutures are avoided. Other benefits include Excellent bursting strength, reduces red blood cell death, and reduces plaque adhesion to the intimal blood vessel wall. Sometimes I lose it. As our technology has improved, laser bonding is no longer possible with sutures or Conventional laser bonded anastomoses are much faster, especially in small diameter vessels. This has also been confirmed.

Despite its theoretical advantages, laser tissue joining has been plagued by technical hurdles. This was hampered by the inability to obtain a bond. Pigment-reinforced protein bond By using a mixture, these difficulties can be overcome and laser adhesion technology can be applied clinically. We are considering this. 808nm diode laser - energy output field In this case, the output wavelength is within the “viewing window J” of the vessel wall (13) and is therefore Even at the maximum energy output available (9.6 watts/-) There is no indication of any effect on texture. This allows the fibrinogen to warm up during adhesion. Despite the rise in blood pressure, the underlying blood vessel walls remain undamaged. Binder-dye mixture It also provides a controllable and convenient means for applying dyes.

Two different laser/dye combinations, namely indocyanine green (ICG) dye, 808 nm wavelength near-infrared diode, and fluorescein isothio Cyanate (FITC) dye and argon ion laser are described. However, other energy sources and energy absorbers may also be used. The energy source is For example, an X-ray source, a radio frequency source, a microwave source, or a coherent Any type of energy source could be possible, such as a visible light source. energy Absorbers do not require dyes, but can be used to absorb energy from an energy source. Any form of energy absorber may be used. Photodynamic therapy and diagnostic fluorescence imaging As in image processing methods, the combination of laser and dye depends on the output wavelength of the laser. So that it matches the absorption peak of the dye. effective and target-specific selected to bring about the arrival of energy.

In the case of an 808nm diode laser, the output wavelength is within the "viewing window" of the blood vessel wall. be. That is, the laser is at its maximum available power (9.6 Watts/CI+R). However, there is no indication of any impact on the organization. In such cases, fibrinogen Despite the temperature increase during adhesion, damage to the underlying vessel wall is minimal. Ru. Adhesive/pigment mixtures also provide a convenient and controlled means of introducing pigments. Ru.

Other dye/laser combinations that have been successfully tested are FITC/dextran/ Argon ion laser, methylene blue, acridine orange, or rosebean Yag (1 064 nm) laser. Other possible dye/laser combinations include , e.g. tetramethylrhodamine isothiocyanate/krypton ion laser -There is.

It is desirable to use water-soluble dyes such as the FITC dyes mentioned above. pigments and energy The ghee absorbent is preferably mixed prior to administration to the tissue. Otherwise, the dye It tends to flow freely into undesirable areas, such as inside the anastomosis.

Bonding agents combine the energy sources mentioned above, especially with one of the energy absorbers. If it could be turned into a biological glue that would wrap tissues together after exposure during exposure. It can be anything. Bonding agents can be synthetic or naturally occurring, biodegradable or permanent. This requires combination with solvents and gels to achieve adequate reproducibility in the bonding process. Let's say. In fact, the junction constitutes a biodegradable framework on which separated tissues are deposited. .

The use of pigmented junctions reduces damage to the tissue surrounding the junction and improves muscle strength. Extracellular matrix required for rapid proliferation of fibroblasts and regeneration of vascular tissue at the site of attachment. Causes the accumulation of soot. Caused by an abnormal biological reaction to suture material or sutures Irregular blood flow surfaces are avoided.

Bonding agents contain human and animal proteins, such as bovine proteins, as their basic composition. a Serum proteins such as rubumin and fibronectin can also be used. The tissues to be joined are Contains natural bonding agents like lagen and nilastin. These and other additions The material will change the viscosity of the overall binder composition, making it easier to use. Energy absorption One or One would wish to add more drugs. Such drugs can help heal wounds and tissues. It is a growth factor that improves

The present invention provides a new means for treating tissues to heal more naturally. There is. The developed method is faster and in some cases safer than suture repair. . Potential applications of the present invention include (1) blood vessels, intestines, fallopian tubes, trachea, esophagus, vasculature, in particular; Primary tissue adhesion such as transanastomosis, (2) especially when the protein coagulation mechanism is destroyed. Repair of anastomosis with sutures when leakage occurs during visceral surgery, (3) For example, damage caused by external ulcers. Treatment of exuding surfaces such as damaged liver, kidney, or lung tissue; (4) Intrafemale tracts such as the intestinal tract. repair of the endothelial tissue layer and female canal, and (5) secondary reinforcement of the suture area. Contains. Further uses of this invention will be of interest to those skilled in the art. It may be possible to do so, and it may become more common as this technology becomes more widely available. cormorant.

The method according to the invention is applicable to living subjects, both human and animal. The desired target is A person undergoing surgery.

The relative amount of energy absorbing agent or bonding agent that contacts the tissue affects the effectiveness of bonding the tissue. It should be sufficient for you. Tissues already have natural bonding agents. Therefore, exogenous drugs are not required in such cases.

Thus, contacting the tissue with a cement can be done in the presence of an endogenous cement or may add exogenous bonding agents.

Similarly, the energy applied to the energy absorber heats the tissue leading to bonding. It should be sufficient to be effective. For example, energy is a laser Factors such as the temperature and size of the tissue area to be joined when applied can vary. Therefore, the amount of energy absorber, bonding agent and the amount of laser energy required are These factors must be taken into account.

As used here, the word bonding is used at the same time as bonding in the previous sense. It also includes the meaning of joining such as joining or soldering. This is an example of the present invention. Although the present invention is disclosed herein, the present invention is not limited thereby, and the purpose thereof is is to be determined solely by that of the appended claims.

(seconds) Argon laser (FITC) Argon laser (without FITC) (Book) 0: No impact 1: Become white 2: Red 3: Dehydrated and tissue becomes whole 4; Carbonized deposit S: There will be a hole. References ri, Wfiite R, A, Kopchok G, Donayre C, W Hite G, Lyons R.

Fujitani R, Klein SR, Ditto J: Argon 1 Nosa - Arteriovascular anastomosis J, Vase, Surg, 1987; 6 , 447-532゜Oz MC, Ba5s LS, Popp HW, Chu ck RS, Johnson JP.

Trokel SL, Treat MR THC in the junction of bile duct tissue: Y In vitro comparison of A, G and argon ion I noser La5ers Surg Med, 1989; 9, 248-2533+Ba5uS, Wang S, Robertazzi R, Grubbs PE, Jac obowitz I.

R, ose D, Ac1napura A, J, Cunningham JN Jr.: In vitro burst strength study of laser-bonded tissue and conventional method Comparison with anastomosis J, Vasc, Surg, 1988; 2, 420-24, Quigley MR, Balles JE, Kwaan, HC, Cerullo LJ , Brown JT, Fitzsimmons, J: Suture and laser proboscis Comparison of burst strength of combined blood vessels Microsurgery, 1985; 6 , 229-2325, Grubbs PE Jr., Wang S., Mar ini C, Ba5u S, Rose DM.

Cunningbam JN 2 Reinforcement of COI nose microvascular anastomosis with fibrin glue J, Surg Res , 1988; Dan, 112-11.96°Oz MC, Chuck RS, Johnson JP, Parangi S, Ba5s LS.

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Devine CJ + Laser bonding in urethral surgery: improved results with protein bonding agents J, Urology, 1988; 139.415-41.710, D ughherty TJ, 1jieshaupt KR, Boyle DG :Light irradiation treatment of human tumors: Regan JD, Parrish JA ai l “Science of Photomedicine” New York, Prenum Press, 1982 , 625-638 11, Prout GR, Lin CW, Ben5on R, N5eyo UO, Daly J, J.

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Ren F, Qiao S: Light with hematoporphyrin derivatives in the treatment of cancer cells metastasized to the surface of the lungs Dynamic therapy NEJM, 1987; Engineering, 1251. -1.25512, Wolfe D R: Basic science and engineering of fluorescein angiography Ophthalmology, 1986, 93.1617-162013, Anderson RR, P Arrish JA: Selective photothermal therapy: Positive effects of selective absorption of pulsed irradiation accurate micro surgery 5science 1983, 220.524-52714, Benchim ol A, Li Y, Legler JF, Dimond EG + instructions Rapid, iterative quantification of cardiac output using the drug-dilution method Am, J. Card, 1 964, 13.790-79715, Pu1.1afito CA, De utsch TF, Boil J, ToK: Retinal semiconductor laser Intratissue photocoagulation Arch OpthalmoL, 1987; 105.4 24-42716, Dresdale A, Rose EA, Jeeva nadum V, Reemtsma K.

Bowman FO, Maim JR from freshly frozen plasma from a human donor. Preparation of fibrin glue Surgery, 1985 Year 2, 750-75417, Wolner E: Fibrin adhesion in cardiac surgery Thorac, Cardiovasc, Surgeon, 1982;s o, 236-23718, Powanda MC, Moyer ED: Blood Serum protein and wound repair Surg, Gynecol 0bstret, 1981; 153.74 8-75519, Pearl RM, Wustrack KO, Harbor C, Rubenstein E.

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Claims (33)

[Claims] 1. To form a tissue bond between the tissues to be bonded using an energy absorber and a tissue bonding agent. A sufficient amount of energy is absorbed by the energy absorber. The energy absorber should not be exposed to the energy absorber under conditions that cause heating of the fabric and bonding of the tissue. A method of joining tissue of a patient, including. 2. Energy irradiation applies electromagnetic energy to an energy absorber. A method according to claim 1 comprising: 3. Tissue contact is achieved by pre-mixing the energy absorbing agent and energy bonding agent before contacting the tissue. 2. A method according to claim 1, comprising touching. 4. The energy irradiation is caused by the laser energy being irradiated onto the energy absorbing material. 2. The method of claim 1, comprising: 5. 2. The method of claim 1, wherein contacting the tissue includes contacting the tissue with a dye. 6. The tissue is brought into contact with a dye that has a large absorption peak at a specific wavelength, and the energy is The laser energy irradiation has a maximum wavelength corresponding to the maximum absorption peak of the dye. 2. The method of claim 1, comprising irradiating with -. 7. Energy irradiation creates a vibrational component in the visible spectrum for energy absorbers. 2. The method of claim 1, further comprising applying energy of . 8. Energy irradiation generates energy with a maximum wavelength of approximately 808 nm. 2. The method of claim 1, comprising irradiating the absorbent. 9. Tissue contact is made using a mixture of a dye called indocyanine green (ICG) and a bonding agent. 9. The method of claim 8, comprising contacting the tissue with the object. 10. Energy irradiation emits energy with a maximum absorption wavelength of approximately 488 nm. 2. The method of claim 1, comprising irradiating the energy absorber. 11. Tissue contact conjugated with fluorescein isothiocyanate (FITC) dye 11. The method of claim 10, comprising contacting the tissue with the mixture of agents. 12. Tissue contact involves contacting tissue with a bonding agent containing human or animal fibrinogen. 2. The method of claim 1, wherein: 13. Fibrin in tissue contact with at least one fibrin glue activator Claims comprising contacting tissue with a bonding agent that includes fibrin glue that includes nogen Method 1. 14. 14. The method of claim 13, wherein the fibrin glue activator is thrombin. 15. 14. The method of claim 13, wherein the fibrin glue activator is calcium. 16. Tissue contact involves cryoprecipitated suspension containing fibrinogen and factor XIII. The tissue is brought into contact with a tissue bonding agent containing a suspension and a fibrin glue activator containing thrombin. 2. The method of claim 1, comprising: 17. The contacting of the tissue may include contacting the tissue with a binding agent containing the polypeptide. Method for request 1. 18. Tissue Contact Claims involving contacting tissue with a bonding agent containing Kama serum proteins Method of item 1. 19. Claims where the contacting of the tissue involves contacting the tissue with a bonding agent containing albumin Method of item 1. 20. contacting the tissue includes contacting the tissue with a bonding agent containing fibronectin; The method of claim 1. 21. Energy irradiation continuously irradiates laser energy to energy absorber 2. The method of claim 1, comprising: 22. Energy irradiation applies laser energy discontinuously to the energy absorber. 2. The method of claim 1, comprising: 23. Tissue contact is combined with an energy absorber applied in or on the surface of the tissue. 2. The method of claim 1, comprising contacting the tissue with a textile binder. 24. when applied to the tissue and a sufficient amount of energy is irradiated to the tissue bonding composition. The tissue contains a sufficient amount of energy absorber and bonding agent to effect tissue bonding. A tissue joining composition for use in joining. 25. 25. A tissue joining composition according to claim 24, comprising a dye and fibrinogen. 26. A claim in which the energy absorber is an indocyanine green (ICG) dye. Tissue joining composition according to No. 24. 27. Energy absorber is fluorescein isothiocyanate (FITC) dye 25. The tissue joining composition according to claim 24. 28. The composition according to claim 24, wherein the tissue bonding agent is human or animal fibrinogen. Textile bonding composition. 29. 25. A tissue bonding composition according to claim 24, wherein the tissue bonding agent is a polypeptide. 30. 25. The tissue joining composition according to claim 24, wherein the tissue joining agent is a serum protein. 31. 25. A tissue bonding composition according to claim 24, wherein the tissue bonding agent is albumin. 32. 25. A tissue bonding composition according to claim 24, wherein the tissue bonding agent is fibronectin. 33. 25. A composition according to claim 24, wherein the tissue cementing agent comprises thrombin and calcium.