CN109260458B - Application of collagen implant in preparation of glaucoma surgery auxiliary restoration material - Google Patents
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Abstract
The invention discloses an application of a collagen implant in preparing an auxiliary restoring material for glaucoma surgery, wherein the collagen implant is composed of dried and dehydrated cow leather purified collagen and is provided with three-dimensional holes of 20-200 microns.
Description
Technical Field
The invention relates to application of a collagen implant as an auxiliary restoration material for glaucoma surgery. More particularly, the invention relates to the use of a bovine hide purified collagen implant for assisting wound healing in glaucoma Trabeculectomy surgery (Trabeculectomy).
Background
Glaucoma is one of the leading causes of blindness. More than 6600 million glaucoma patients exist worldwide, the percentage of the population is about 1.0-1.2%, about one tenth of glaucoma patients need to be subjected to microsurgery worldwide every year, and therefore, the requirement of more than 1000 million glaucoma surgeries is estimated to be required for six hundred and sixty thousand patients every year. Studies have shown that 7600 million and 1.1 million glaucoma patients are estimated to occur in 2020 and 2040 years, respectively (y.c. Tham et al, Ophthalmology 121: 2081-. The prevalence rate in asia was about 3.54% (95% CrI interval (CrI) 1.83 to 6.28) when POAG (2.34%, 95% CrI 0.96 to 4.55) was much higher than PACG (0.73%, 95% CrI 0.18 to 1.96) of primary angle closure glaucoma as counted in 2013 (e.w. Chan et al Br J ophhalmol, 2016).
Normally aqueous humor (aquous humor) is produced from the ciliary body and flows through the trabecular meshwork to the tube of Schlemm and then to the blood where it is recovered. Glaucoma refers to a condition in which the flow channel is blocked, which causes an abnormal increase of intraocular Pressure (IOP) (normal eye Pressure is 10-21mmHg, IOP >21mmHg for glaucoma patients), and this high intraocular Pressure may press retina and optic nerve, and may also cause local vascular collapse, affecting normal blood supply to the eyeball, resulting in optic atrophy and visual field defect, which is clinically called glaucoma. The primary goal of glaucoma treatment is to reduce elevated intraocular pressure and prevent further deterioration of the optic nerve and visual field to protect the retina, optic nerve and other tissues. Glaucoma can be classified into Open-Angle glaucoma (Open-Angle glaucoma) and Angle-closure glaucoma (Angle-closure glaucoma) according to the condition of the corner of the anterior chamber, and congenital glaucoma and secondary glaucoma are also included. When the drug fails to control intraocular pressure, the pain often progresses to refractory glaucoma.
For patients who still cannot control the condition by using the ocular tension depressor, trabeculotomy combined with antimetabolites or a Drainage device (Drainage device transplantation) is mainly used for treatment at present, but the success rate is still low and complications are possible.
Due to traditional glaucoma surgery (glaucoma filtration surgery or trabeculectomy), the success rate of surgery is no more than 50% for neovascular glaucoma, juvenile glaucoma, non-primary glaucoma surgery patients, and traumatic glaucoma patients. The main reason for the failure of the operation is the scar of the operation wound under the conjunctiva, which results in the obstruction of the artificial aqueous humor flow channel and the increase of the intraocular pressure again. Currently, Trabeculectomy combined with antimetabolites or implantation of drainage devices (drainage device implantation therapy) is mainly used for treating refractory glaucoma, so that a better effect is achieved. But both of them suffer from some serious complications due to the expensive drainage device. Anti-mycotolines (e.g., Mitomycin-c (mmc)) or the anti-cancer drug 5-fluorooracil (5-FU), which is not currently approved by the health welfare agency for glaucoma surgery indications, are often used to inhibit scarring during trabeculectomy or filtration surgery. Although MMC as a post-operative and current standard treatment for glaucoma, it has been shown by retrospective studies that MMC has a two-year complete success rate (≦ 21mmHg) for primary (primary) glaucoma of 60.6%, and only 41.9% for secondary glaucoma (≦ 21 mmHg); however, the complication rate following glaucoma trabeculectomy surgery with MMC treatment was 58.5%. Furthermore, antimetabolites (e.g., MMC) may cause a number of side effects (including hypotony, anterior chamber shallowness, conjunctival thinning, endophthalmitis, and the like).
In addition, the aqueous humor drainage tube is implanted with a drainage tube which is not decomposed so that a flow path of aqueous humor can be established. However, this implant which is not decomposed is a foreign body, and the failure rate of the operation is high, and is often accompanied by side effects such as the blockage of the passage, the infection of the eyeball, the displacement of the drainage tube, and the obstruction of the movement of the eyeball.
Absorbable collagen is currently the most promising technology as an adjunct to glaucoma surgery. The clinical research of the absorbable collagen as the adjuvant of glaucoma surgery has shown that the technique is a very safe technique, and the effectiveness is not inferior to that of the current glaucoma surgery plus MMC drug assistance, and the probability of complications of the glaucoma surgery is not increased. Collagen is the protein with the highest content in the animal body, and is widely used for causing a stable bracket effect among connective tissues of the animal body. From porcine or bovine animal sources, the telopeptides that cause the immune response are removed and the purified collagen can be completely decomposed in vivo.
Collagen is commonly used as a material to induce tissue proliferation and to prevent scarring of wounds. Currently known collagens exceed type 20, while the first type of Collagen is widely used in medical devices as a tissue guide, regeneration or barrier to avoid infection, for example, "NanoSigma" Resorbable Collagen Membrane, "Sunmax" Collagen Dental Membrane and "Home" Collagen Dental Matrix are self-made products. The ophthalmic implants currently described in the prior art documents are mostly Ologen cells from Aeon Astron Corporation (previously called Oculus Gen) or iGen cells from Life Spring BioTech Co., both of the same technical origin, and are porcine-derived collagens, consisting of 1% collagen/C-6-S copolymer (>90% freeze-dried porcine-derived collagen and <10% freeze-dried glycosaminoglycan) (W.C. Hsu, J.Y. et al, Googlentines, 2006; U.S. Pat. No. USP 7,544,368) with 10-300 micron 3D pores.
The present invention attempts to apply an absorbable purified collagen matrix of bovine skin having a three-dimensional porous structure to assist glaucoma Trabeculectomy (Trabeculectomy), and it is expected that the porous structure of the collagen implant provides a good regeneration environment for the wound of glaucoma Trabeculectomy, so that the proliferation of tissue cells is randomly distributed without generating subconjunctival scarring, and the collagen implant assists trabecectomy to reduce intraocular pressure, increase the success rate of surgery, and further replace MMC and other scar-inhibiting drugs, thereby avoiding adverse side effects caused by the use of these drugs.
Disclosure of Invention
Based on the above objects, it was found that the absorbable bovine purified collagen implant of the present invention, after being implanted, can absorb aqueous humor and prevent hypotony, in addition to maintaining a subconjunctival space. The saturated matrix simultaneously creates a pressure under the scleral flap which, in the case of conjunctival opening/closing, controls the ingress and egress of aqueous humor, thus regulating the intraocular pressure in the initial unhealed wound.
Accordingly, one aspect of the present invention is directed to the use of a collagen implant for the preparation of a glaucoma surgery-assisted restoration, wherein the collagen implant is composed of dried dehydrated bovine skin purified collagen, and the collagen implant has three-dimensional pores ranging from 20 to 200 μm.
In some embodiments of the invention, the glaucoma surgery is glaucoma Trabeculectomy surgery (Trabeculectomy).
In some embodiments of the invention, the collagen implant is used to assist in wound healing in glaucoma Trabeculectomy surgery (Trabeculectomy).
In some embodiments of the invention, the collagen implant is for absorbing aqueous humor to stabilize intraocular pressure.
In some embodiments of the invention, the collagen implant is bioabsorbable.
In some embodiments of the invention, the collagen implant is comprised of dried dehydrated 100% pure bovine hide purified collagen.
In some embodiments of the invention, the bovine purified Collagen is Type I Collagen (Type I Collagen).
In some embodiments of the invention, the bovine purified collagen is 100% pure Type I Atelocollagen (100% pure Type I Atelocollagen).
In some embodiments of the invention, the collagen implant is for implantation into the subconjunctival space above the scleral flap prior to conjunctival closure for glaucomatous trabeculectomy.
In some embodiments of the present invention, the collagen implant has three-dimensional pores for providing a proliferative environment for tissue cells at the implantation site.
[ description of the drawings ]
FIG. 1 is an enlarged scanning electron microscope image of the appearance of an absorbable bovine skin purified collagen implant of the present invention; the left figure is a side view of the implant and the right figure is a front view of the implant;
FIG. 2 is a photograph showing a pathological section of a tissue prepared by removing muscle tissues surrounding a test object and a control object and fixing the muscle tissues 28 days after implantation; FIG. 2A is a histopathological section view of the collagen implants of the experimental group (animal ID:1 left gluteus muscle), with arrows indicating the implantation site (20X, H & E stain); FIG. 2B is a histopathological section view of the control implant (animal ID:1 right gluteus muscle) with arrows indicating the implant location (20X, H & E stain);
FIG. 3 is the percent intraocular pressure change (% IOP change) in rabbits at 3, 7, 14, 21, 28 days post-operatively;
FIG. 4 is a staining pattern of experimental section (H & E stain) 21 days after collagen implant implantation;
the implant is significantly thinned, the surrounding is covered by the neogenetic tissue and tissue has grown into the hole, the tissue that has grown into the hole can be found in the circle shown in the figure;
fig. 5 is a staining image of a tissue section 21 days after the collagen implant implantation (Masson's trichrome staining). The arrow indicates a new blood vessel;
FIG. 6 is a staining image (H & E staining) of tissue sections 28 days after the collagen implant was implanted in the experimental group.
FIG. 7 is a staining graph of tissue sections 14 days after implantation in the control group (H & E staining). Arrows indicate the healing of the underlying conjunctival scab and scleral wound.
[ detailed description ] embodiments
Other features and advantages of the present invention will be further illustrated and described in the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention.
In the following examples, the absorbent Collagen implant of the present invention contained purified Collagen of bovine hide, 100% pure Collagen produced by "Taike Biotech Co., Ltd., the Industrial area of Taiwan, and the product model was Fully Aid Collagen round drying LOT: Fa.
Example 1 operation example of collagen implant assisted trabeculectomy
The collagen implant used in the present invention is completely composed of dried and dehydrated cow leather purified 100% pure Atelocollagen Type I Atelocollagen (100% pure Type I Atelocollagen), and has three-dimensional pores of 20-200 μm. From the observation of the enlarged appearance of the test piece by SEM (FIG. 1), it can be seen that in the dried collagen layered structure, each layer has many micron-sized pores (with a diameter of about 20-200 microns), and the layers are arranged in a scattered manner with a spacing of about 10-20 microns, and many irregular scaffolds are bridged to form pores. Therefore, the collagen implant of the present invention has a steric structure which facilitates the growth of fibroblasts, whereby the fibroblasts grow in the pores of the collagen implant at the initial stage of wound formation, and thus a tissue restoration without scarring can be expected.
The collagen implant is designed for assisting the trabeculectomy, the operation is the same as the traditional trabeculectomy, and the collagen implant can be placed in the subconjunctival space on the scleral flap before the conjunctiva is sutured in the glaucoma trabeculectomy. Standard procedure for collagen implant assisted trabeculectomy: retrobulbar anesthesia (retrobulbar anesthesia) was performed. Using iodine tincture to disinfect, and placing aseptic hole towel. An eyelid speculum (eyelid speculum) is placed. The superior rectus muscle was fixed using 0-0 silk. A Fornix-based conjectional flap (Fornix-based conjectional flap) was performed in the ten to twelve o' clock area using a No. 11 scalpel. Scleral hemostasis was performed using an electrocautery knife (Scleral hemostatis). A number 11 scalpel was used to perform a round-based scleral flap at the ten to twelve o' clock region. A Partial thickness sclerectomy (Partial thickness sclerectomy) was performed under the scleral flap using a No. 11 scalpel. Anterior chamber perforation was performed with a 25 gauge needle in the two o' clock as a side hole. A puncture is made to the anterior chamber at the scleral ablation site. Trabeculectomy (Trabeculectomy) is performed behind the cricothyroid lobe (post. Lip of limbal wind). Filtration (filtration) function and wound leakage were tested. Perioperative iridectomy was performed alongside the trabeculectomy site. Before performing conjunctival suturing in a trabeculectomy, a researcher (or an assistant) opens the aluminum foil package of the collagen implant of the present invention in a sterile procedure, and a physician takes out the collagen implant using a clip, places it into the subconjunctival space above the scleral flap, and then performs conjunctival suturing with 10-0 nylon suture. Drugs containing steroids and antibiotics (e.g., Vigamox, Tobradex) are administered. Finally, gauze is added for pressurization. After surgery, the patient must be returned at regular intervals at the time of appointment, while the physician usually gives glaucoma surgery, an eye drop or ointment containing antibiotics and steroids after surgery.
Example 2 endotoxin content testing of absorbable collagen implants
Endotoxin is a substance produced by gram-negative bacteria, and is liable to cause allergic reaction and inflammatory reaction in the human body. In order to avoid the possible endotoxin generated during the manufacturing process of medical devices from affecting human body, the safety of the medical devices in use must be carefully tested and evaluated. This test system is a Limulus reagent (LAL). This example, in turn, tested the collagen implants of the present invention for endotoxin content using kinetic staining. Endotoxin assays were performed and tested according to the methods and conditions described in ISO10993-12, USP <85> and USP <161> specifications.
3 test substances (collagen implants) were taken, each of which was extracted with 5.00 mL of pyrogen-free water at 37. + -. 1 ℃ for 1 hour according to a ratio of 0.2 g. + -. 10%/mL, and the mixed extracts were the test solutions. Test substance test solutions were diluted in pyrogen-free water sequence for endotoxin content testing. After 25. mu.L of pyrogen-free water and 25. mu.L of test substance solutions diluted with different sequences were placed in a 96-well plate, 50. mu.L of LAL reagent solution was added. Checking the line solution: 50 μ L of the calibration curve solutions with different concentrations were added to a 96-well plate, and 50 μ L of LAL reagent solution was added. In the negative control group, 50. mu.L of pyrogen-free water was added to a 96-well plate, and 50. mu.L of LAL reagent solution was added. Positive control group: after 25. mu.L of the endotoxin solution as a standard used in the test and 25. mu.L of the test sample solution diluted in different sequences were put in a 96-well plate, 50. mu.L of the LAL reagent solution was added.
TABLE 1 results of endotoxin content measurement by kinetic coloration method
| Test substance | EU/equipment |
| UB70659 | 0.0422 |
| Negative control group | - (pass) |
| Positive control group | + (passing) |
LAL reagent sensitivity lambda =0.005EU/ml
Positive control group: the added concentration is 0.5 EU/ml
Detection Limit (MDL) of 0.002 EU/device
As shown by the results in Table 1, the absorbable collagen implants of the present invention had an endotoxin content of 0.0422 EU/device. The regression coefficient of the detection line is 0.999, which shows that the product has no residual toxicity during the manufacturing process and packaging sterilization.
Example 3 Biosafety testing of absorbable collagen implants
The composition of the medical equipment should consider whether the adverse reaction is generated to human body. When the medical device is expected to contact human tissue, the relevant biocompatibility test should be carefully performed according to the contact manner and time, so as to avoid possible physiological damage caused by toxic substances generated or contaminated in the manufacturing process of the medical device. This example is a muscle implant stimulation test to evaluate the possible response of the absorbable collagen implant of the present invention 28 days after muscle implantation of the test material in SD rats.
A USP high density polyethylene reference standard (lot. No. iok217) was used as a control. Both the test article (collagen implant of the present invention) and the control article were cut to a size of about 1mm in width and 10mm in length and then implanted. Controls were sterilized with 75% alcohol prior to surgery. Before the test, the hair on the thigh and the hip is removed by an electric scissors, and the animals are anesthetized by Isofluorane (Medi-Union Co., Ltd.) anesthesia before the operation. The test object and the control object are respectively implanted into the muscles of the left hip and the right hip by a sterile operation method, and the test object and the control object are placed in parallel along the muscle fibers during implantation. The post-operative wounds were sutured in layers, and 1 test implant and 1 control implant per animal were obtained. In this test, 10 animals in total gave 10 test groups and 10 control groups. After operation, the animals need to observe whether adverse reactions such as pathological changes or death occur within 28 days. On the end day of the experiment (28 days post implantation), animals were sacrificed humanely. Muscle tissue surrounding the test and control was removed and macroscopically observed. Thereafter, the cells were fixed in 10% neutral formalin for at least 24 hours to prepare tissue sections. Analysis was done under microscope and scores were recorded for each group. The scores of the test and control groups were recorded according to ISO 10993-6 and the following formula, and if no irritation was observed, the average score between the test and control groups was within 2.9.
Total score = (subtotal of cell type/reaction) × 2+ subtotal of reaction
Score difference = test group total score/10-control group total score/10
As a result: among 10 test animals, the implantation procedure was quite successful, with no symptoms and no animal death during the 28 day observation period. The macroscopic observation of the muscle on the last day showed that no significant lesions or symptoms were observed in either the test or control groups. Also, it was found from the pathological section of the test group that the absorbable collagen implant of the present invention was not observed with the naked eye, indicating that the test substance was totally decomposed (fig. 2A). The control implant still remained in the implantation site of the animal compared to the histopathological section observations of the control group (fig. 2B).
The results of the histopathological scoring of the individuals showed no significant abnormal difference between the test group and the control group, and the calculated final score difference (evaluation scores) was (17 × 2+20)/10- (9 × 2+10)/10=2.6 (no irritation score: 0-2.9), so that the absorbent collagen implant of the present invention had no irritation or adverse reaction to rat muscle tissue after 28 days of muscle implantation when compared with the control group.
Example 4 absorbent collagen implant for glaucoma trabeculae
Evaluation of the effectiveness of the incision
The degradation time of the porous collagen implant in vivo is influenced by factors such as tissue source, collagen extraction/purification process, material composition and the like, and the porous collagen implant can be degraded as quickly as possible after wound healing is needed in vivo, but in vitro experiments cannot simulate aqueous humor outflow and actual in vivo effectsThe physiological environment for healing under force. Therefore, the animal experiment is important consideration information for confirming the in-vivo degradation time before the clinical experiment is executed, and can provide more guarantee for patients in the future clinical experiment execution. The eyeball volume of the rabbit is 5-6 cm3Approximately 6.5cm for humans3Is a minimum mammal suitable for eyeball surgery.
After 18 rabbits enter the cage, the central personnel support the rabbits, after the operation day, the pets are sequentially moved to an operating room for weighing and anaesthetizing, trabeculotomy is simultaneously performed by two ophthalmologists in Zhanghua-Xiujin hospital, and firstly, a square sclera flap of 3x4mm is made after a conjunctiva flap at the bottom of a corneal limbus. A 1x2mm sclerostomy (sclerostomy) was made along the perimeter of the iris, incised into the anterior chamber with surgical scissors through the trabecular meshwork. A needle was sutured loose using 10-0 nylon suture to close the scleral flap. Then, the collagen implant of the present invention was implanted into the right eye, and the left eye was naturally healed to the control group after the operation. Finally, the conjunctiva flap is closed by sewing with a 10-0 nylon suture, and the operation process is about 10-15 minutes. Return to the rabbit cage after surgery for continued replacement by central personnel, and antibiotics (Neomycin) and analgesics (1% Prednisonone acetate) were given twice daily for one week after surgery.
In this experiment, the intraocular pressure of the rabbit was measured before the operation and on days 3, 7, 14, 21 and 28 by using an instrument (Tono-Pen; Medtronic, FL). The same person operates to take the five-point median for each measurement. The rate of change (IOPchange%) of the median intraocular pressure of each measurement point from the initial mean intraocular pressure was used as a comparative basis. After the rabbits were brought out on sacrifice to perform an overdose of anesthetic injection in the operating room, euthanasia was completed using rapid intravenous KCl (2 mmol/kg). Three were sacrificed at each time point 3, 7, 14, and four were sacrificed on days 21, 28. After sacrifice, the cornea and sclera were removed about 1x1cm from the surgical parts by scalpel and tissue scissors and immediately fixed in 4% formalin for at least one day. After dehydration with an alcohol gradient, the specimen was infiltrated with xylene three times and then embedded in paraffin. Sections of 5-10 μm were cut using a microtome, dewaxed and stained for conventional H & E and Masson's trichrome stain tissue sections. The healing of the tissue was observed by microscope and the thickness change and residual of the collagen product was measured.
Animal experiments show that the trabeculotomy, in combination with the implantation of the collagen implant of the invention, does not cause any infectious inflammation or hypotony between the conjunctiva and sclera of the eyeball of 17 New Zealand white rabbits similar to the size of the human eyeball. Comparison of the change in the initial intraocular pressure after the operation revealed that the IOP values were decreased in both the experimental group (the collagen implant of the present invention) and the control group (trabeculotomy only). The average intraocular pressure of both eyes of all the rabbits before the operation is 18.6 +/-4.9 mmHg. From the results (fig. 3), it was found that intraocular pressure was the same and significantly decreased in both groups, and intraocular pressure was 14.5 ± 4.7 mmHg in the experimental group and 14.4 ± 4.1 mmHg in the control group 3 days after the operation. The intraocular pressure of the experimental group is steadily and slightly increased in the experimental period, and the intraocular pressure is 14.3 +/-1.9, 13.7 +/-2.1, 15.1 +/-1.4 and 15.5 +/-0.5 mmHg respectively in 7 days, 14 days, 21 days and 28 days. However, at day 21, the intraocular pressure of the control group at 17.3. + -. 2.2 mmHg was close to the mean initial intraocular pressure, and at day 28, the intraocular pressure at 23.3. + -. 3.3 mmHg was higher than the mean intraocular pressure. It was also found from the standard deviation difference between the experimental group and the control group that the intraocular pressure of the experimental group implanted with the collagen implant of the present invention was more stable, while the standard deviation of the control group was relatively larger.
The histological section results showed that there was a greater tendency for the lymphocytes to aggregate in the experimental group, but there was no evidence of tissue Necrosis (necross). The experimental group continued to have macrophages for implant metabolism and had a partial area with neovascular growth implanted. From the stained section of the experimental group of FIG. 4, it can be seen that the tissue grown into the implant after 21 days of collagen implantation has a loose structure with random directions (see the circled portion). In fig. 5, the arrows indicate the new blood vessels growing into the collagen implant. The staining of the sections at day 28 after the operation showed that the exact position of the collagen implant was not visually apparent in most of the experimental groups after 28 days of implantation, indicating that the porous collagen implant of the present invention was almost catabolized and the remainder was replaced by loose lamellar neogenetic tissue (fig. 6). The control group formed a denser scab under the conjunctiva 14 days after surgery and had healed wounds in the scleral incisions compared to the experimental group (fig. 7).
In summary, the absorbable collagen implant of the present invention is composed of dried dehydrated bovine hide purified collagen, which has been shown to pass safety tests for bio-compatibility of ISO10993 through bio-safety and bio-compatibility tests, and does not generate residual toxicity. The results of the animal eye/muscle implantation stimulation test also demonstrate that the absorbable collagen implant of the present invention does not cause eyeball stimulation, has an ocular hypotensive effect by its water absorption properties, is 100% decomposed after 90 days of muscle implantation, has no damage to surrounding tissues, can be completely absorbed in the animal body, and allows the proliferation of tissue cells to be randomly distributed without generating subconjunctival scarring. Therefore, by using the absorbable collagen implant of the present invention, patients can reduce the risk and permanent injury caused by MMC drug-assisted complications (>50%) with the same or better ocular hypotensive effect.
Claims (4)
1. Use of a collagen implant consisting essentially of dried dehydrated bovine hide purified 100% pure Atelocollagen Type I (100% pure Type I Atelocollagen) and having three-dimensional cubic pores of 20-200 μm for implantation into the subconjunctival space above the scleral flap prior to conjunctival closure for glaucoma trabeculectomy, for the preparation of a glaucoma surgery-assisted restoration material, for absorbing aqueous humor to stabilize intraocular pressure.
2. The use according to claim 1, wherein the collagen implant is for assisting wound healing in glaucoma Trabeculectomy (Trabeculectomy).
3. The use according to claim 1, wherein the collagen implant is bioresorbable.
4. The use according to claim 1, wherein the collagen implant has three-dimensional pores for providing a proliferative environment for tissue cells at the implantation site.
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| CN109260458A (en) | 2019-01-25 |
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