Nerbridge™ is intended for the repair of peripheral nerve injuries in which there is no gap or where a gap closure can be achieved by flexion of the extremity.

Device Description

Nerbridge™ is a product composed of polyglycolic acid and collagen derived from porcine skin. Nerbridge™ is a flexible, resorbable and semipermeable tubular membrane matrix filled with porous collagen that provides a non-constricting encasement for injured peripheral nerves for protection of the neural environment. Nerbridge™ is designed to be an interface between the nerve and the surrounding tissue. When hydrated, Nerbridge™ is a pliable, soft, non-friable, porous conduit. The resilience of Nerbridge allows the product to recover and maintain closure without constricting the nerve once the device is placed around the nerve. Nerbridge™ is manufactured using validated viral inactivation and removal processes for the collagen. The product is provided in a foil pouch, sterile, nonpyrogenic, for single use only, in a variety of sizes, and placed in an outer Tyvek header bag for added protection.

AI/ML Overview

This document describes the regulatory acceptance of a medical device, Nerbridge™, a nerve cuff for peripheral nerve repair. It does not describe an AI/ML powered device, so several of the requested sections regarding AI/ML acceptance criteria and studies (e.g., sample size for test/training sets, data provenance, number of experts, adjudication method, MRMC comparative effectiveness study, standalone performance) are not applicable.

Below is the information derived from the provided text, focusing on the acceptance criteria and the studies performed for the Nerbridge™ device.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Nerbridge™ device were primarily based on a series of non-clinical (functional performance, product characterization, biocompatibility) and clinical studies designed to demonstrate its safety and effectiveness, and substantial equivalence to predicate devices. The table below summarizes the non-clinical tests and their acceptance criteria, as reported in the document.

Test	Test Method Summary	Acceptance Criteria Met?
Suture retention strength	Testing according to ISO 7198:1998	Yes
Mechanical compression & rebound	Testing according to JIS T0401:2013	Yes
Porosity	Testing according to ISO 845:2006 and JIS Z8807:2012	Yes
Permeability	Devices filled with protein solution, immersed in saline, protein measured in saline.	Yes
In vitro degradation	Testing according to ISO 15814:1999 and ISO 527-1:2012	Yes
Tensile strength	Testing according to ISO 527-1:2012	Yes
pH	Testing according to JIS T 3211:2011	Yes
Swelling rate	Testing according to ISO 10545-3:1995	Yes
Visual inspection	Visual inspection with a magnifying glass.	Yes
Bending stiffness	Testing according to JIS T0401:2013	Yes
Endotoxin	Testing according to Japanese Pharmacopoeia 16th edition and FDA Guidance for Industry: Pyrogen and Endotoxin Testing: Questions and Answers (June 2012)	Yes

Biocompatibility Testing:

Test	Test Method Summary	Results/Acceptance
Cytotoxicity	ISO Direct contact Cytotoxicity Assay	Non-cytotoxic
Sensitization	ISO Guinea pig Maximization test with device extracts (saline and sesame oil extracts)	No evidence of sensitization
Acute intracutaneous Reactivity	ISO Acute intracutaneous Reactivity Test in rabbits with device extracts (saline and sesame oil extracts)	No evidence of irritation
Acute Systemic Toxicity	ISO Acute System Toxicity in Mice with device extracts (saline and sesame oil extracts)	No mortality or evidence of systemic toxicity
Rabbit Pyrogen Study	USP Material-mediated Rabbit pyrogen test with saline extract of the device	No evidence of material-mediated pyrogenicity
Hemolysis	Hemolysis test by direct contact with human red blood cells	No hemolytic activity
Genotoxicity (Ames Mutagenicity Assay)	ISO Ames Mutagenicity Assay with device extracts (saline and ethanol extracts)	No evidence of mutagenicity
Genotoxicity (Mouse bone marrow)	ISO Mouse bone marrow micronucleus with device extracts (saline and sesame oil extracts)	No evidence of clastogenicity
Genotoxicity (CHL/IU cells)	CHL/IU cells with device extracts (MEM & 10%CS/MEM)	No evidence of inducing chromosomal aberrations or polyploid cells
Implantation Absorption	Subcutaneous implantation in rats	Absorption of material by 13 weeks. No inflammation observed
Implantation (safety & performance)	In vivo safety and performance study in rats after 3, 30 and 90 days	Protection during nerve repair. No fibrous peri-nervous tissue was observed after 3, 30 or 90 days.
Subchronic / Chronic toxicity	13-week systemic toxicity and local tolerance study in rats following subcutaneous implantation	No adverse tissue reaction to the implant up to 13 weeks of implantation. No systemic toxicity.

Clinical Study Acceptance:
The primary efficacy endpoint was a higher mean percentage of improvement in the sensory function test by the Semmes-Weinstein method for the Nerbridge™ device compared to the autogenous free nerve grafting group. The incidence of adverse events was lower for the Nerbridge™ device. This indicated that the device was safe and effective for its intended use and substantially equivalent to predicate devices.

2. Sample Size Used for the Test Set and the Data Provenance

Clinical Study Test Set:
- Sample Size: 60 subjects for the Nerbridge™ device (Full Analysis Set: 58 subjects, Per Protocol Set: 54 subjects). The control group consisted of 6 subjects.
- Data Provenance: Multi-center (20 trial sites), joint randomized, evaluator-blinded, comparative clinical study. The country of origin of the data is not explicitly stated but implies a controlled clinical trial environment. It was a prospective study.
Animal Study Test Set:
- Sample Size: Not explicitly stated, but performed in a "rabbit model."
- Data Provenance: Not explicitly stated, but implies a controlled animal study environment. It was a prospective animal study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

This information is not explicitly detailed in the provided document, as the evaluations primarily involved objective measurements (e.g., sensory function tests, histological examinations, physical/chemical property testing). For the clinical study, an "evaluator-blinded" design was used, implying trained evaluators for the sensory function test, but their specific qualifications or number are not specified.

4. Adjudication Method for the Test Set

Not applicable/specified. The clinical study was evaluator-blinded, implying objective assessment rather than a consensus-based adjudication in the way it might be for image interpretation. The non-clinical tests rely on predefined methods and acceptance criteria.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This device is a physical medical device (nerve cuff), not an AI/ML-powered or image interpretation device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

Not applicable. This is not an algorithm.

7. The Type of Ground Truth Used

Clinical Study: The "ground truth" for the clinical study was based on objective measures of nerve repair and function, specifically the "mean percentage of improvement in primary evaluation in the sensory function test by the Semmes-Weinstein method," and the "incidence of adverse events." This could be considered outcomes data and validated clinical assessment.
Animal Study: The ground truth involved histological reactions at the site of device introduction and evidence of nerve regeneration, which is a form of pathology/histological assessment and outcomes data (biological response).
Non-Clinical/Biocompatibility Studies: The ground truth was based on established industry standards (ISO, JIS, USP, FDA guidance) and validated test methods for material properties and biological interactions.

8. The Sample Size for the Training Set

Not applicable. This is not an AI/ML device that requires a training set.

9. How the Ground Truth for the Training Set was Established

Not applicable. This is not an AI/ML device.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

June 22, 2016

Toyobo Co., Ltd. % James A. Boiani, MS, JD Official Correspondent Epstein Becker & Green, P.C. 1227 25th St. NW, Suite 700 Washington, DC 20037

Re: K152967

Trade/Device Name: Nerbridge™ Regulation Number: 21 CFR 882.5275 Regulation Name: Nerve Cuff Regulatory Class: Class II Product Code: JXI Dated: May 20, 2016 Received: May 23, 2016

Dear Mr. Boiani:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you; however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical devicerelated adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in

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the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Carlos L. Pena -S/A

Carlos L. Peña, PhD, MS Director Division of Neurological and Physical Medicine Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K152967

Device Name Nerbridge™

Indications for Use (Describe)

Nerbridge™ is intended for the repair of peripheral nerve injuries in which there is no gap or where a gap closure can be achieved by flexion of the extremity.

X Prescription Use (Part 21 CFR 801 Subpart D)

| Over-The-Counter Use (21 CFR 801 Subpart C)

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510(K) SUMMARY

The assigned 510(k) number is: K152967

1. Submitter's Identification:

Tovobo Co., Ltd. 2-8 Dojima Hama 2-chome, Kita-ku, Osaka 530-8230 Japan Tel: 81-6-6348-3336 Fax: 81-6-6348-3696 Contact: Mr. Yuta Kawakatsu

Date Summary Revised: June 21, 2016

2. Name of the Device:

Nerbridge™ Device Common Name: Cuff, Nerve Device Classification Name: Nerve Cuff Product Regulation Number: 21 CFR Part 882.5275 Product Code: JXI Requlatory Class: II Classification Panel: Neurology

3. Predicate Device Information:

1. K103081 Biom'Up SA. Cova™ ORTHO-NERVE
1. K983007 Neuroregen LLC Neurotube™

4. Device Description:

5. Indications for Use:

Nerbridge™ is intended for the repair of peripheral nerve injuries in which there is no gap or where a gap closure can be achieved by flexion of the extremity.

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6. Comparison to Predicate Devices:

	Device Name	Nerbridge™	Neurotube™	Cova™ORTHO-NERVE
	Manufacturer	TOYOBO CO., LTD.	Neuroregen, LLC	Biom'Up S.A.
	510(k) No.	K152967	K983007	K103081
	Intended Use and Indicationsfor Use	Nerbridge™ isintended for therepair of peripheralnerve injuries inwhich there is nogap or where a gapclosure can beachieved by flexionof the extremity.	The Neurotube™ isintended for singleuse in patients withan injury to aperipheral nerve inwhich the nerve gapis more than orequal to 8mm, butless than or equal to3 cm. The nervegap may be createdprimarily at the timeof injury or createdsecondarily at thetime of explorationof failed primaryrepair.	Cova™ORTHO-NERVE is indicatedfor the repair ofperipheral nerveinjuries in whichthere is no gap orwhere a gapclosure can beachieved by flexionof the extremity
Material		Syntheticpolyester	Polyglycolic acid(PGA)	PGA	Contains noSynthetic Polyestermaterial
	Collagen	Type	I and III	None	I
		Origin	Porcine	None	Porcine
	Shape		Cylindrical	Cylindrical	Membrane, rollableif needed
	Physical structure		PGA conduit whoseouter surface iscoated by collagenand with innerporous collagen	PGA conduit	Collagenmembrane
Device Name	NerbridgeTM	NeurotubeTM	CovaTMORTHO-NERVE
Sizes	ID: 0.5, 1.0, 1.5, 2.0,2.5, 3.0, 3.5, 4.0mmLength: 30, 50 mm	ID: 2.0,3.0, 4.0,8.0mmLength: 20, 40mm	Rectangular sheetsof 15 x 25 mm, 20 x30 mm, 30 x 40 mmand 40 x 60 mm
Sterilization	Ethylene oxide	Ethylene oxide	Gamma irradiation
Clinical testing	Yes	Yes	No
Non-clinical animal testing	Yes	Unknown	Yes
Biocompatibility	ISO 10993	Unknown	ISO 10993
	Sutureretentionstrength	Yes	Unknown	Yes
	Mechanicalcompressionand rebound	Yes	Yes	Yes
	Porosity	Yes	Unknown	Unknown
	Permeability	Yes	Yes	Unknown
	In vitrodegradation	Yes	Yes	Yes
Performance	Tensilestrength	Yes	Unknown	Yes
	pH	Yes	Unknown	Yes
	Swelling rate	Yes	Unknown	Yes
	Visualinspection	Yes	Unknown	Unknown
	Bendingstiffness	Yes	Yes	Unknown
	Endotoxin	Yes	Unknown	Yes
	Packaging	Foil pouch withinprotective outerpouch	Double peelpackages	Double peelpackages
	Shelf Life	3 years	5 years	24 months

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The Nerbridge™ and the predicate devices have the same intended use: to act as a conduit to assist the nerve in repairing itself following damage.

The Nerbridge™ and the predicate devices are sutured to the nerve and nerve tissue and surround the damaged nerve to protect the damaged area, allowing it to heal. At a high level, the subject and predicate devices are based on the following same technological elements:

Provided or can be made into a cylindrical shape
Flexible ●
Smooth ●
Wettable ●
Resorbable material .

Certain technological differences exist between the subject and predicate devices as detailed in the above. In particular, the subject device is a PGA tube with an outer coating and internal filling of a porous Type I and III collagen blend; the Neurotube is a PGA tube that does not contain collagen; the Cova Ortho-Nerve is a Type I collagen membrane. While having some technological differences with the predicates, the Clinical and Non-Clinical tests performed on the Nerbridge™ show that it is safe and effective for its intended use and substantially equivalent to the predicate devices.

7. Discussion of Non-Clinical Tests Performed for Determination of Substantial Equivalence:

The following functional performance verification and product characterization testing was conducted on finished sterile Nerbridge™ devices using known standards and/or clinically relevant criteria:

Suture retention strength ●
. Mechanical compression and rebound
Porositv ●
Permeability .
In vitro degradation
Tensile strength ●
pH ●
Swelling rate
Visual inspection ●
Bending stifffness ●
Endotoxin

The testing supports and further characterizes Nerbridge™ that was studied in the Nerbridge™ Clinical Study, and shown to be clinically safe and effective for its intended use as a nerve conduit, and supporting substantial equivalence to other nerve conduits with the same intended use.

Test	Test Method Summary	Results
Test	Test Method Summary	Results
Suture retentionstrength	Testing according to ISO 7198:1998Acceptance criteria: Suture must fail before theNerbridge	Acceptancecriteria met
Mechanicalcompression andrebound	Testing according to JIS T0401:2013Acceptance criteria: Nerbridge must maintainmechanical strength after continuouscompression and rebound loading	Acceptancecriteria met
Porosity	Testing according to ISO 845:2006 and JISZ8807:2012Acceptance criteria: Porosity of Nerbridge mustbe greater than or equal to porosity of PGA tubealone	Acceptancecriteria met
Permeability	Devices were filled with protein solution and thenimmersed in saline. At periods of time up to 96hours, saline was measured for protein particlesAcceptance criteria: Protein must permeate thewall of the Nerbridge	Acceptancecriteria met
In vitrodegradation	Testing according to ISO 15814:1999 and ISO527-1:2012Acceptance criteria: Nerbridge must maintain atensile strength greater than that of suture for 8weeks	Acceptancecriteria met
Tensile strength	Testing according to ISO 527-1:2012Acceptance criteria: Nerbridge tensile strength isat least as much as the predicate	Acceptancecriteria met
pH	Testing according to JIS T 3211:2011Acceptance criteria: Nerbridge satisfies theacceptance criteria as specified in JIS T3211:2011	Acceptancecriteria met
Swelling rate	Testing according to ISO 10545-3:1995Acceptance criteria: Swelling rate of Nerbridgemust be greater than or equal to swelling rate ofPGA tube alone	Acceptancecriteria met
Visual inspection	Visual inspection with a magnifying glassAcceptance criteria: No observation of significantstreaks, wrinkles, uneven, scratches and cracks,bubbles or other abnormalities	Acceptancecriteria met
Test	Test Method Summary	Results
Bending stiffness	Testing according to JIS T0401:2013Acceptance criteria: Bending stiffness ofNerbridge must be greater than or equal tobending stiffness of PGA tube alone	Acceptancecriteria met
Endotoxin	Testing according to Japanese Pharmacopoeia16th edition and FDA Guidance for Industry:Pyrogen and Endotoxin Testing: Questions andAnswers (June 2012)Acceptance criteria: Endotoxin level is less thanor equal to 20 EU/device	Acceptancecriteria met

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Biocompatibility Testing

The biocompatibility evaluation for the Toyobo Nerbridge device was performed according to ISO 10993 to demonstrate that the device was both safe for implantation and establish substantial equivalence among the predicate device.

Test	Test Method Summary	Results
Cytotoxicity	ISO Direct contact CytotoxicityAssay	Non-cytotoxic
Sensitization	ISO Guinea pig Maximization testwith device extracts (saline andsesame oil extracts)	No evidence of sensitization
AcuteintracutaneousReactivity	ISO Acute intracutaneousReactivity Test in rabbits withdevice extracts (saline andsesame oil extracts)	No evidence of irritation
Acute SystemicToxicity	ISO Acute System Toxicity in Micewith device extracts (saline andsesame oil extracts)	No mortality or evidence ofsystemic toxicity
Rabbit PyrogenStudy	USP Material-mediated Rabbitpyrogen test with saline extract ofthe device	No evidence of material-mediated pyrogenicity
Hemolysis	Hemolysis test by direct contactwith human red blood cells	No hemolytic activity
Genotoxicity	ISO Ames Mutagenicity Assaywith device extracts (salineand ethanol extracts)	No evidence ofmutagenicity

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Test	Test Method Summary	Results
Genotoxicity	ISO Mouse bone marrow micronucleus with device extracts (saline and sesame oil extracts)	No evidence of clastogenicity
Genotoxicity	CHL/IU cells with device extracts (MEM & 10%CS/MEM)	No evidence of inducing chromosomal aberrations or polyploid cells
Implantation Absorption	Subcutaneous implantation in rats	Absorption of material by 13 weeks. No inflammation observed
Implantation (safety and performance)	In vivo safety and performance study in rats after 3, 30 and 90 days	Protection during nerve repair. No fibrous peri-nervous tissue was observed after 3, 30 or 90 days.
Subchronic / Chronic toxicity	13-week systemic toxicity and local tolerance study in rats following subcutaneous implantation	No adverse tissue reaction to the implant up to 13 weeks of implantationNo systemic toxicity

Viral Inactivation Study

Viral Inactivation steps were validated for collagen extracted from tissues used in the manufacture of the device. For the validation, different viruses were selected according to their physio-chemical resistance and representativeness. The viral inactivation steps are routinely performed in process using appropriate treatment. It was demonstrated that the inactivation steps reduced down the final viral load to the limit of detection.

8. Clinical Tests Performed

A multi-center joint randomized evaluator-blinded comparative clinical study was conducted on the Nerbridge™ device where the Nerbridge™ device was used in 60 subjects at 20 trial sites with hand injuries. The primary efficacy endpoint was evaluated on the Full Analysis Set (58 subjects) and the Per Protocol Set (54 subjects). The control group consisted of 6 subjects implanted with an autogenous free nerve graft. The mean percentage of improvement in primary evaluation in the sensory function test by the Semmes-Weinstein method for the Nerbridge™ device was higher than that in the autogenous free nerve grafting group. The incidence of adverse events were lower for the Nerbridge™ device than the control. Therefore, the Nerbridge "" device is safe

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and effective for its intended use and substantially equivalent to the predicate devices.

9. Animal Tests Performed

An animal study was conducted in rabbit model to evaluate the performance and safety (local tissue effects) of the Nerbridge™ after nerve section and direct suture in the rabbit sciatic nerve. Nerbridge™ resorbed by day 72, there was evidence of nerve regeneration, and the histological reactions at the site of introduction of the device were slight.

10. Conclusions

The subject device, the Nerbridge™, has the same intended use as the predicate devices, Biom'Up SA. Cova ™ ORTHO-NERVE (K103081) and Neuroregen LLC, Neurotube™ (K983007). The Clinical and Non-Clinical testing supplied within our submission demonstrates that there are not any significant differences in their technological characteristics thereby not raising any new questions of safety and effectiveness. Therefore, the Nerbridge™ is substantially equivalent to the predicate devices, Biom'Up SA. CovaT™ ORTHO-NERVE (K103081) and Neuroregen LLC, Neurotube™ (K983007).

Regulation Number and Section

§ 882.5275 Nerve cuff.

(a)
Identification. A nerve cuff is a tubular silicone rubber sheath used to encase a nerve for aid in repairing the nerve (e.g., to prevent ingrowth of scar tissue) and for capping the end of the nerve to prevent the formation of neuroma (tumors).(b)
Classification. Class II (performance standards).