Absorbable Dural Sealant Medical Adhesive_NMPA Approval in January 2018
Product Name: Absorbable Dural Sealant Medical Adhesive
Category: Domestic Class III
Registration Pathway: Innovation
NMPA Approval Time: January 2018
Product Structure and Composition: The medical adhesive consists of powder, solution (Solution A, Solution B), and complementary tools. The powder component includes a 4-arm polyethylene glycol-N-hydroxybutyryl succinimide-glutarate (4-arm-PEG-SG) with a molecular weight of around 20,000, a dye Bright Blue 85, and an antioxidant Butylated Hydroxytoluene (BHT); Solution A is an acidic phosphate buffer solution; Solution B is an alkaline sodium tetraborate buffer solution containing Tri-lysine (Tri-lys) and polyethylene imine (PEI); complementary tools include a dual syringe rack, mixing connector fittings, and a mixing nozzle.
Scope of Application: The product is suitable for assisting in sealing the dural suture site during craniotomy to prevent cerebrospinal fluid leakage.
Model/Specification: The product packaging specifications include 2mL, 3mL, 4mL, 5mL, 6mL.
Working Principle: The main components 4-arm-PEG-SG, Tri-lys, and PEI undergo a nucleophilic substitution reaction upon mixing to form crosslinked macromolecules bound by amide bonds, forming a hydrogel. The adhesive action of the hydrogel comes from both the intermolecular amide bond crosslinking within the hydrogel and the bonding force of modified polyethylene glycol with tissue proteins at the application site undergoing a similar nucleophilic substitution reaction.
Product Technical Requirement (PTR) Research: The test items on PTR include appearance, fill volume, clarity of Solution A and B, powder dissolution time, curing time, breaking strength, swelling rate, effective usage amount, spray area, adhesion, impermeability, identification of 4-arm-PEG-SG in powder, identification of Solution A, identification of decahydrate sodium tetraborate, identification of Tri-lysine, identification of polyethylene imine, identification of the gel, pH of Solution A, pH of Solution B, pH of the gel, water content in the powder, content of Bright Blue in the powder, residual solvent limit in the powder, trace element limits, ignition residue, total heavy metal content, content of anhydrous dis odium tetraborate in Solution B, bacterial endotoxin limit, sterility, pyrogen limit, acute systemic toxicity, skin irritation, skin sensitization, cytotoxicity, genotoxicity, implantation test, acute intracutaneous irritation, subchronic toxicity, hemolysis, acute systemic toxicity of degradation products, sensitization of degradation products, irritation of degradation products, genotoxicity of degradation products, chronic toxicity, and carcinogenicity.
Other Performance Research:
The applicant also conducted research on the chemical structure of the gel, in vitro degradation research, and metabolic kinetics research.
(1) Chemical structure research of absorbable dura mater sealant gel. The applicant conducted research on the gel's chemical structure, qualitatively and quantitatively analyzing the gel structure, cross-linking process, and gel properties. At the structural level, characterization techniques such as nuclear magnetic resonance, infrared analysis, and scanning electron microscopy were used to test the gel, studying the cross-linking process of the gel, clarifying its chemical composition and morphological structure; in terms of performance, the swelling and mechanical strength of the gel were studied.
(2) In vitro degradation research of absorbable dura mater sealant gel. The applicant conducted research on the in vitro degradation of the absorbable dura mater sealant gel from macroscopic and microscopic perspectives. In an environment simulating phosphate-buffered saline (PBS), the degradation time of the gel was 12 weeks, and the degradation products of the gel were analyzed.
(3) Metabolic kinetics research of absorbable dura mater sealant gel. This research mainly includes two experiments: ① Using 3H labeling tracing technology, 3H-PEI-labeled gel was implanted on the dura mater of rats, and urine and feces excretion experiments were conducted after gel implantation to reveal the excretion pattern of the medical gel component PEI in rats; ② Using 3H and 14C dual-isotope labeling tracing technology, gels labeled with 14C-PEG-SG and 3H-Tris-lys were implanted on the dura mater of rats, and urine and feces excretion experiments, blood exposure experiments, and tissue distribution experiments were conducted after gel implantation. It reveals the dynamic changes of the medical gel components Tris-lys and PEG-SG in the animal body. Basic metabolic kinetics parameters were obtained through tracing technology to elucidate the absorption, distribution, and excretion processes and characteristics of the absorbable dura mater sealant gel.
Biocompatibility Research: The product is a device implanted in tissues, in prolonged contact with the dura mater (more than 30 days). The applicant conducted biocompatibility evaluation based on the GB/T 16886 series standards. Biological experiments carried out included cytotoxicity, intradermal reaction tests, delayed hypersensitivity reactions, acute systemic toxicity, subchronic systemic toxicity, hemolysis, genetic toxicity [such as the Ames test for Salmonella typhimurium reverse mutation, in vitro mouse lymphoma cell mutation test, and chromosomal aberration test], implantation and degradation, and pyrogenicity.
Sterilization Research: The product is provided in a sterile state, sterilized using electron beam radiation. The applicant provided a sterilization confirmation report, demonstrating a sterility assurance level of 10-6.
Product Service/Shelf Life and Packaging: The product has a shelf life of 2 years under storage conditions of 2°C to 25°C. The applicant provided a validation report for the shelf life, including accelerated and real-time aging tests, verifying product stability and packaging integrity.
Animal Experiment Research:
The applicant conducted three animal studies to validate the effectiveness and safety of the product.
1. Study on the sealing of dura mater cerebrospinal fluid leakage and degradation in the canine cranium:
- Study on the sealing of cerebrospinal fluid leakage in dogs: Beagle dogs were used to create a model of cerebrospinal fluid leakage, with observed indicators including cerebrospinal fluid leakage, hematology, serum biochemistry, histopathology, as well as weight, diet, behavior, wound healing, etc. The experimental results showed that the medical gel effectively sealed the cerebrospinal fluid leakage at the suture site in dogs, with no observed abnormal signs related to the medical gel.
- Degradation study in the canine cranium: After spraying the medical gel on the dura mater of Beagle dogs, nuclear magnetic resonance imaging was performed at different time points post-surgery, showing a gradual decrease in gel signal, with no gel signal detected after the 8th week. The study demonstrated the product's degradability.
2. Study on the neurotoxic reaction of the absorbable dura mater sealant medical gel extract after a single injection into the lateral ventricle and cerebellomedullary cistern of SD rats:
- The purpose of the study was to evaluate the neurotoxicity of the medical gel. Observed indicators included weight, food intake, behavior, neurological status examination, hematological examination, serum biochemistry examination, and histopathological examination. No neurotoxicity related to the medical gel was observed.
3. Study on the local neurotoxicity after implantation of medical gel in the brain parenchyma of rats:
- The aim of the study was to observe the neurotoxicity at the site of single implantation of medical gel in the brain parenchyma of SD rats. Observed indicators included neurological status examination, hematology, serum biochemistry, histopathological examination, as well as food intake, weight, and general condition. The experiment did not show any neurotoxic effects of the medical gel on the neurological status of rats. The histopathological results at the site of brain parenchymal implantation showed a local inflammatory reaction (mild irritation) in the early stage, which gradually recovered in the later period.
Clinical Trial Results:
(1) The clinical trial was a prospective, multicenter, single-arm clinical trial design. The purpose was to evaluate the effectiveness and safety of the product for assisting in sealing the dural suture site during craniotomy to prevent cerebrospinal fluid leakage. The expected effectiveness rate was 99%, with a target value of 94%.
(2) Clinical trial institutions included Shandong University Qilu Hospital (lead unit), Beijing Tiantan Hospital affiliated with Capital Medical University, and Jinan Military General Hospital.
(3) The effectiveness evaluation index was the immediate sealing effectiveness of the dura mater during surgery. Immediate sealing effectiveness was defined as the absence of visible cerebrospinal fluid leakage after applying the test product to the dural suture site and performing a Valsalva maneuver with no leakage observed after maintaining pressure for 5-10 seconds at 20-25cmH2O.
(4) Safety evaluation indices included cerebrospinal fluid leakage, infection, allergic reactions, neurosurgical complications, laboratory tests, and other adverse events and serious adverse events during the follow-up period.
(5) Research hypothesis: In a single-arm trial design, the lower limit of the two-sided 95% confidence interval for the effectiveness rate in the test group should be greater than the target value of 94%.
(6) 106 patients were enrolled in the clinical trial. The Full Analysis Set (FAS) included 106 patients, the Per Protocol Set (PPS) included 99 patients, and the Safety Set (SS) included 106 patients.
(7) The immediate sealing effectiveness of the test product during surgery was 100% in the SS, with a lower limit of the two-sided 95% confidence interval in the FAS of 96.58%, exceeding the target value of 94%.
(8) The immediate sealing effectiveness of the test product during surgery was 100% in the SS, with a lower limit of the two-sided 95% confidence interval in the PPS of 96.34%, exceeding the target value of 94%.
(9) Postoperative MRI at 12 weeks in the SS showed no cerebrospinal fluid leakage in patients.
(10) Postoperatively, researchers evaluated cerebrospinal fluid leakage in 0.94% of patients in the SS.
(11) No patients in the SS experienced allergies postoperatively.
(12) Postoperatively, infection occurred in 0.94% of patients at 1 week, with no infections reported at 12 weeks postoperatively.
(13) There were 107 adverse events in 69 patients in the test group, with no adverse events related to the device. One serious adverse event was judged by the researcher to be unrelated to the device.