The allay Nerve Cap is indicated for use in adults aged 22 years or older as a physical barrier to separate the peripheral nerve end from the surrounding environment to reduce the risk of the development of a symptomatic neuroma.

Device Description

The allay Nerve Cap is a sterile, absorbable, in situ formed, hydrogel composed of water and polyethylene glycol (PEG). The hydrogel forms in seconds after delivery of the precursor solutions around a nerve seated in a temporary silicone Cap Form (Figure 1). The hydrogel provides a transparent, compliant nerve cover that conforms to and provides non-constricting encasement of the nerve. The Cap Form is removed and discarded after the implantation procedure. The hydrogel nerve cap is absorbed within 8 months.

The allay Nerve Cap system is provided in a plastic tray sealed in a sterile, peelable outer pouch. The product is available in two sizes of a Small Nerve Set, for nerves less than 4 mm in diameter, and a Large Nerves greater than 4 mm in diameter and less than 7 mm in diameter. The allay Nerve Cap system includes a Powder Vial/Vial Adapter. Diluent Solution. Acceleration Solution, Dual Applicator and Adapter, Delivery Tip with Blunt Needle, and the Cap Forms [Small Nerve Set (1, 2, 3, and 4 mm) and Large Nerve Set (5, 6, and 7 mm)].

AI/ML Overview

The provided text describes a medical device, the "allay Nerve Cap," and its regulatory information, device description, nonclinical/bench studies, animal studies, labeling, risks, and benefits. It does not describe an AI/ML device or a study that uses AI/ML.

Therefore, many of the requested criteria such as "number of experts used to establish the ground truth," "adjudication method," "effect size of how much human readers improve with AI," "standalone algorithm performance," and "sample size for training set" are not applicable as they relate to AI/ML device performance evaluation, which is not present in the provided document.

However, I can extract the acceptance criteria and performance data for the physical device as described.

Acceptance Criteria and Reported Device Performance

Test	Acceptance Criteria	Reported Device Performance
Biocompatibility
Cytotoxicity (allay Nerve Cap)	Non-cytotoxic	Non-cytotoxic
Sensitization	Non-sensitizing	Non-sensitizing
Intracutaneous Irritation (allay Nerve Cap)	Non-irritant	Non-irritant
Acute Systemic Toxicity (allay Nerve Cap)	Non-toxic	Non-toxic
Implantation (Local Subcutaneous)	Non-irritant	Non-irritant
In vivo Animal Study Efficacy - Local	Non-irritant, Non-compressive, No migration or adverse tissue responses or effects observed	Non-irritant, Non-compressive, No migration or adverse tissue responses or effects observed
Neurotoxicity	Non-irritant, No adverse responses observed	Non-irritant, No adverse responses were observed
Repeated Exposure Systemic Toxicity	Non-toxic	Non-toxic (based on Chemical Characterization and TRA)
Hemolysis (Indirect Contact)	Non-hemolytic	Non-hemolytic
Pyrogenicity (allay Nerve Cap)	Non-pyrogenic	Non-pyrogenic
Genotoxicity	Non-genotoxic	Non-genotoxic
Reproductive Toxicity	Non-toxic	Non-toxic (based on Chemical Characterization and TRA)
Carcinogenicity	Non-carcinogenic	Non-carcinogenic (based on Chemical Characterization and TRA)
Cytotoxicity (Sterile Cap Forms)	Non-cytotoxic	Non-cytotoxic
Intracutaneous Irritation (Sterile Cap Forms)	Non-irritant	Non-irritant
Acute Systemic Toxicity (Sterile Cap Forms)	Non-toxic	Non-toxic
Pyrogenicity (Sterile Cap Forms)	Non-pyrogenic	Non-pyrogenic
Cytotoxicity (Sterile Applicator)	Non-cytotoxic	Non-cytotoxic
Cytotoxicity (Sterile Tray Packaging)	Non-cytotoxic	Non-cytotoxic
Infrared Spectroscopy	No adverse effects observed	No adverse effects observed
Nonvolatile Residue	Residue ≤ 15 mg	Residue ≤ 15 mg
Particulates	No adverse particulates observed	No adverse particulates observed
Shelf Life/Sterility
Shelf Life Validation	Maintained sterility, package integrity, and device functionality over identified shelf life (2 years) under worst-case shipping, handling, and storage conditions.	Validated for a shelf life of 2 years; results showed the final product packaging protects the product and maintains sterility under worst-case shipping, handling, and storage conditions.
Sterility Assurance Level	SAL of 10-6	SAL of 10-6 achieved using E-beam radiation.
Bacterial Endotoxin	Endotoxin limit of < 20 EU/device	Met the endotoxin limit of < 20 EU/device.
Performance Testing - Bench
Color Additive Exposure	Dissolution of color additive within 72 hours, leaving colorless, transparent hydrogel; extracts show no change in color or turbidity, no visible particulates.	Confirmed through in vitro dissolution testing on hydrogel cylinders and in situ formed hydrogel; extracts show no change in color or turbidity and no visible particulates.
Hydrogel Deliverability	Reproducible and homogenous hydrogel delivery across full range of Cap Form sizes, successful delivery under worst-case conditions (angles, injection locations, bubbles), suitable for nerve sizes per IFU, Cap Form successfully removed without breaking/damaging hydrogel.	Successful across all worst-case conditions in all Cap Form sizes; successfully delivered around the range of nerve sizes per IFU, and the Cap Form was successfully removed without breaking or damaging the in situ formed allay Nerve Cap.
Dimensional Evaluation	Encapsulation of nerve within hydrogel, gel dimensions (length, width, volume) confirmed for each Cap Form size, appropriate nerve sizes for each Cap Form.	Conducted to assess hydrogel physical dimensions and volume, including confirming nerve encapsulation within the hydrogel for each nerve size per IFU, measurement of gel dimensions, and assessment of appropriate nerve sizes for each Cap Form. (Implied successful as "All tests met pre-defined acceptance criteria.")
Dimensional Stability	Maintain integrity as protective layer without significant loss of mechanical strength for at least 3 months; maintain hydrogel integrity without cracks or collapse; mechanical strength and lumen patency without substantial dimensional loss; minimal swelling; no significant changes in hydrogel integrity, dimensions, or swelling at extreme osmolarity.	Maintained integrity for at least 4 months (16 weeks); demonstrated maintenance of integrity without cracks or collapse, mechanical strength (compressive modulus), and lumen patency with no substantial dimensional loss; minimal swelling; no significant changes to integrity, dimensions, or swelling at 240-320 mOsm/kg.
Dissolution Time	Dissolution time maintained under 5 minutes.	Dissolution time is maintained under 5 minutes.
Gel Time	Consistently fill Cap Form with gel time of less than 10 seconds.	Consistently fills Cap Form with a gel time of less than 10 seconds.
Percent Swelling	Between 0% and 45% swelling of crosslinked hydrogel as measured by weight 24 hours after immersion in PBS @ 37 °C.	Characterized as between 0% and 45%.
Compression and Rebound Testing	Withstand compressive forces > 0.25 N/cm and rebound > 95%.	Withstands compressive forces > 0.25 N/cm and rebounds > 95%.
Compressive Modulus	Minimum of 30 KPa of crosslinked hydrogel after 24 hours in PBS.	Minimum of 30 KPa.
Ease of Preparation	Prepared in less than 10 minutes.	Achieved within 5 minutes by all users in human factors study.
Pressure Testing	No increase in pressure on an artificial nerve after formation and equilibration.	Demonstrated no pressure exerted on the artificial nerve at any time. Non-compressive.
Device Migration	Adhere to clinically relevant range of nerve sizes (diameters) for up to one week under physiologic conditions; no migration off the nerve or from implant site.	Not possible to remove after firmly pulling with forceps; consistent with in vivo animal testing results demonstrating adherence to the transected nerve stump. Does not migrate off the nerve end.
Wear Resistance Testing	No mass loss and no visible particulates released from the hydrogel after accelerated wear testing.	Passed the acceptance criteria: no mass loss and no visible particulates released.
Mass Loss	Minimal mass loss over 3-month period post implantation (comparable to 2.8% at 6 days in vitro).	Minimal mass loss occurred over the 3-month period (2.8% at 6 days in vitro); 6.6% mass loss in first phase (~4 months in vivo).
Exaggerated Clinical Use Conditions	Hydrogel formed successfully in presence of blood or saline, integrating to form intact allay Nerve Cap; no visible particulates formed.	Hydrogel formed successfully in the presence of blood or saline, integrating with them to form an intact allay Nerve Cap. No visible particulates were formed.
Use Errors	Use errors (bubble generation, incomplete dissolution, exceeding delivery window, fluids) do not result in significantly earlier degradation, impair hydrogel quality, or affect durability.	Use errors did not result in significantly earlier degradation of the hydrogel, impair hydrogel quality, or affect the durability of the hydrogel.
Human Factors and Usability	Intended user(s) in intended use environment can correctly and safely use the device following the instructions for use; all critical tasks performed without failures or use-related errors.	Demonstrated that the device and IFU could be followed without any use errors; use time of < 5 minutes achieved; all surgeons (100%, n=15/15) performed all critical tasks without failures or use-related errors.
Performance Testing - Animal
GLP Rat Study - Neuroma Formation	Reduction in risk of neuroma formation; no evidence of axonal escape.	0% (none) of animals with neuroma formation within 3 months; no evidence of axonal escape.
GLP Rat Study - Sensorimotor Function	Restore normal sensorimotor function.	Animals were able to restore normal sensorimotor function.
GLP Rat Study - Device Migration	No device migration.	No evidence of device migration.
GLP Rat Study - Systemic Safety	Comparable safety to Polyganics NeuroCap and negative control (transection only) for tissue response (non-irritant, non-neurotoxic), animal health, body weights, clinical/neurological observations, autotomy scores, clinical pathology (with exception of slight irritation relative to negative control due to biomaterial).	Comparable safety to Polyganics NeuroCap and negative control for tissue response (non-irritant, non-neurotoxic), animal health, body weights, clinical/neurological observations, autotomy scores, and clinical pathology (slight irritant relative to negative control). No device-related adverse effects.
Non-GLP Rabbit Study - Biocompatibility	Hydrogel has acceptable biocompatibility and does not cause adverse inflammatory response to nerve or surrounding tissue; similar biocompatibility to comparator control group (silicone cuff).	All animals in good health, no adverse neurological/behavioral effects (lameness, dropped hocks, gait abnormalities), normal weight gain, no clinical signs related to device/procedure, able to ambulate normally, no signs of pain/autotomy/infection, supported by normal clinical pathology/urinalysis/hematology/serum chemistry/coagulation.

Study Details:

Sample sizes used for the test set and the data provenance:
- Bench Test (performance testing): Sample sizes for specific tests are not explicitly stated for all "parts" of the bench tests (e.g., how many hydrogel cylinders for dissolution). However, for the Human Factors & Usability Study, the sample size was 20 participants (15 surgeons, 5 surgical scrub nurses). Data provenance is internal lab testing.
- Animal Studies:
  - GLP Rat Sciatic Nerve Transection Study: Sample size not explicitly stated for each group, but compares "allay Nerve Cap" group, "Polyganics Innovation BV NeuroCap" control group, and "transected nerve alone" negative control group. Data provenance: Pre-clinical animal study.
  - Non-GLP Implantation Study on Intact Rabbit Sciatic Nerve: 14 New Zealand white rabbits, receiving bilateral implants (allay Nerve Cap on left sciatic nerve, silicone cuff on right sciatic nerve). Data provenance: Pre-clinical animal study.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience):
- Not Applicable for AI/ML Ground Truth. The "ground truth" for this medical device is established through physical/chemical testing, direct observation in bench studies, and histological/clinical assessments in animal studies, not expert labeling of data for an algorithm.
- For the Human Factors & Usability Study, 15 surgeons were used to evaluate usability. Their qualifications are described as having "relevant surgical experience on nerve repair, including hand surgeons, plastic surgeons, orthopedic surgeons, and podiatrists." They had "no prior knowledge or relationship with the sponsor."
Adjudication method (e.g., 2+1, 3+1, none) for the test set:
- Not applicable. This relates to human expert consensus or adjudication in AI/ML tasks, which is not applicable here.
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 is a physical medical device, not an AI/ML system evaluated with human readers.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Not applicable. No algorithm is described.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Bench Studies: Established through various in vitro measurements, physical properties tests, and observational assessments based on pre-defined scientific and engineering protocols (e.g., dissolution time, gel time, dimensional stability, compression/rebound, visual inspection, mass measurement, pressure transducer readings).
- Biocompatibility Studies: Established via standardized in vitro and in vivo biological evaluations following ISO 10993 standards, including laboratory analytical results (e.g., cytotoxicity, genotoxicity assays), and macroscopic/microscopic tissue assessments in animals (e.g., irritation, implantation responses). Chemical characterization and toxicological risk assessment were also used.
- Animal Studies:
  - Pathology: Gross pathology, histopathologic assessment (e.g., for neuroma formation, tissue response, neurotoxicity, axonal escape).
  - Outcome Data (Behavioral/Physiological): Clinical and neurological observations (e.g., lameness, gait abnormalities, autotomy scores), body weights, clinical pathology (hematology, serum chemistry, urinalysis).
  - Direct Observation: Device integrity, presence of migration, hydrogel formation.
The sample size for the training set:
- Not applicable. This is not an AI/ML device that requires a "training set." The development and testing of this physical device involved R&D, pre-clinical studies, and bench testing, but not in the context of machine learning.
How the ground truth for the training set was established:
- Not applicable. As above, no AI/ML training set is involved.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR ALLAY NERVE CAP

REGULATORY INFORMATION

FDA identifies this generic type of device as:

In situ polymerizing peripheral nerve cap. An in situ polymerizing peripheral nerve cap is a prescription use only device composed of precursor materials that polymerize when delivered to the end of a peripheral nerve to function as a physical barrier to the surrounding in vivo environment to reduce the risk of formation of a symptomatic neuroma.

NEW REGULATION NUMBER: 21 CFR 882.5260

CLASSIFICATION: Class II

PRODUCT CODE: SBG

BACKGROUND

DEVICE NAME: allay Nerve Cap

SUBMISSION NUMBER: DEN230061

DATE DE NOVO RECEIVED: September 19, 2023

Tulavi Therapeutics CONTACT: 160 Knowles Avenue Los Gatos, California 95032

INDICATIONS FOR USE

LIMITATIONS

The allay Nerve Cap is not designed, sold, or intended for use except as described in the indications for use and is contraindicated for use in:

. Areas of active surgical site infection.
Areas of active blood flow. .
Areas of excessive movement or over a joint. .

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. Patients with a known allergy to poly(ethylene glycol) (PEG) or the color additives FD&C Yellow No. 5 Dye (tartrazine) or FD&C Blue No. 1 Dye (brilliant blue FCF).
PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS

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DEVICE DESCRIPTION

Image /page/2/Picture/3 description: The image shows a syringe with a needle and several small, white, origami-like objects arranged in a row. The syringe is filled with a blue liquid and has a clear barrel. The needle is attached to the syringe and is pointing towards the left side of the image. The origami-like objects are arranged in a row in front of the syringe. They are all white and have a similar shape. The background is a plain white surface.

Figure 1: Prepared hydrogel precursors ready for delivery system (applicator) with available cap form sizes.

The delivery mechanism of the starting materials to the site of application. the polymerization. mechanism and polymer structure, the intermediate and side produced, and degradation pathway and degradants were described in the device description of the allay Nerve Cap. The characterization of the polymerization reaction to form PEG-based hydrogels was supported by the published scientific literature. 1-23,45,6 Additionally, the material safety data sheets (MSDS), certificates of analysis, and incoming inspection results were provided for the device raw and precursor materials.

SUMMARY OF NONCLINICAL/BENCH STUDIES

Reid, et al. 2015. "PEG Hydrogel Degradation and the Role of the Surrounding Tissue Environment." J Tissue Eng Regen Med, 9(3), 315-318.

2 Fruitier-Polloth (2005). "Safety assessment of polyethylene glycols (PEGs) and their derivatives as used in cosmetic products." Toxicology 214: 1-38.

3 Yamaoka, et al. (1994). "Distribution and tissue uptake of poly (ethylene glycol) with different molecular weights after intravenous administration in mice." J. Pharm. Sc. 83: 601.

4 Sharda, N. et al. (2021) "Pharmacokinetics of 40 kDa polyethylene glycol (PEG) in mice, rats, cynomolgus monkeys and predicted pharmacokinetics in humans." European Journal of Pharmaceutical Sciences. 165, 105928.

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BIOCOMPATIBILITY/MATERIALS

The allay Nerve Cap is a long-term contact implant (> 30 davs) in contact with tissue/bone. As such, its biocompatibility evaluation was conducted in accordance with ISO 10993-1:2018. "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process," and the FDA guidance, "Use of International Standard ISO-10993. "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"." For a long-term contact implant in contact with tissue/bone, the allay Nerve Cap was evaluated for the following: physical and chemical information, cytotoxicity, sensitization, irritation or intracutaneous reactivity, material-mediated pyrogenicity, acute systemic toxicity, subacute/subchronic toxicity, chronic toxicity, implantation, hemocompatibility, genotoxicity, carcinogenicity, and neurotoxicity. As part of this biocompatibility evaluation, the materials of construction (direct, indirect) including the hydrogel and degradation products, the Applicator and the Cap Forms, the packaging materials including the tray, and any additives that might arise from the manufacturing process were assessed (see Table 1).

Test	Test Method	Results
allay Nerve Cap
Cytotoxicity	ISO 10993-5:2009, ISO Elution Method	Non-cytotoxic
Sensitization	ISO 10993-10:2010, Maximization Testin Guinea Pigs	Non-sensitizing
IntracutaneousIrritation	ISO 10993-10:2010, IntracutaneousReactivity in Rabbits	Non-irritant
Acute SystemicToxicity	ISO 10993-11:2017, Acute SystemicToxicity in Mice	Non-toxic
Implantation	ISO 10993-6:2016, Local SubcutaneousImplantation, 2 Weeks, 13 Weeks, 26Weeks	Non-irritant
In vivo AnimalStudyEfficacy - Local	Hydrogel Formed in situ AroundTransected Nerve in Cap Form, 4 Weeks,12 Weeks	Non-irritantNon-compressiveNo migration oradverse tissueresponses or effectsobserved
Implantation atClinically RelevantSite	Hydrogel Formed in situ Around SciaticNerve, 6 Months, 8 Months
Neurotoxicity	ISO 10993-1 and ASTM F2901-19, 4Weeks, 12 Weeks, 6 Months, 8 Months	Non-irritantNo adverseresponses wereobserved
Repeated ExposureSystemic Toxicity	Chemical Characterization andToxicological Risk Assessment (TRA)	Non-toxic
Test	Test Method	Results
(Subacute,Subchronic,Chronic)
Hemolysis(Indirect Contact)	ISO 10993-4:2017 and ASTM F756	Non-hemolytic
Pyrogenicity	ISO 10993-11:2017 and USP 34 <151>,USP Rabbit Pyrogen Study, MaterialMediated	Non-pyrogenic
Genotoxicity	ISO 10993-3:2014, Bacterial ReverseMutation Test (Ames Assay), in situFormedISO 10993-3:2014, Bacterial ReverseMutation Test (Ames Assay), in CapFormISO 10993-3:2014, Bacterial ReverseMutation Test (Ames Assay), FullyDegradedISO 10993-3:2014, Mouse LymphomaAssay, Dose Finding, in situ FormedISO 10993-3:2014, Mouse LymphomaAssay, Dose Finding, in Cap FormISO 10993-3:2014, Mouse LymphomaAssay, Dose Finding, Fully Degraded	Non-genotoxic
ReproductiveToxicity	Chemical Characterization and TRA	Non-toxic
Carcinogenicity	Chemical Characterization and TRA	Non-carcinogenic
Sterile Cap Forms
Cytotoxicity	ISO 10993-5:2009, ISO Elution Method	Non-cytotoxic
IntracutaneousIrritation	ISO 10993-10:2010, IntracutaneousReactivity in Rabbits	Non-irritant
Acute SystemicToxicity	ISO 10993-11:2017, Acute SystemicToxicity in Mice	Non-toxic
Pyrogenicity	ISO 10993-11:2017 and USP 34 <151>,USP Rabbit Pyrogen Study, MaterialMediated	Non-pyrogenic
Sterile Applicator
Cytotoxicity	ISO-10993-5, ISO Elution Method	Non-cytotoxic
Sterile Tray Packaging
Cytotoxicity	ISO-10993-5, ISO Elution Method	Non-cytotoxic
InfraredSpectroscopy	Infrared Analysis per ASTM F2475-20and ISO 10993-18:2020	No adverse effectsobserved
Nonvolatile Residue	USP Physiochemical Tests for Plastic(Aqueous), Non Volatile Residue (USP	Residue ≤ 15 mg
Test	Test Method	Results
	43, NF 38, General Chapter <661>) andASTM F2475-20, Appendix XI
Particulates	Particulate Analysis, Light ObscurationMethod per USP 43, NF 38, GeneralChapter <788>	No adverseparticulates observed

Table 1: Biocompatibility Evaluations for the allay Nerve Cap System

5 Webster, et al. (2007). "PEGylated Proteins: Evaluation of their safety in the absence of Definitive Metabolism Studies." Drug Metab Disposition, 35(1), 9-16.

6 Longley, et al. (2013). "Biodistribution and excretion of radiolabeled 40 kDa polyethylene glycol following intravenous administration in mice." J Pharm Sc 10,2(7), p. 2362-2370.

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Chemical Characterization and Toxicological Risk Assessment (TRA):

In order to assess the risks associated with the allay Nerve Cap resulting in an adverse tissue reaction or systemic toxicity effects, chemical characterization and subsequent. TRA of the hvdrogel under worst-case clinical conditions was performed, including identification and quantification of all detected entities extracted from the in situ formed hydrogel, the hydrogel after formation in the Cap Form, as well as the partially and fully degraded hydrogel. The characterization of the entire final finished product ensures that any potential residual chemicals from the manufacturing, packaging, or sterilization processes that could leach from the device during clinical use are not present at levels capable of causing adverse biological responses in patients implanted with the device. The TRA concluded that the extractables from the test article, the allay Nerve Cap, are unlikely to pose a toxicological safety concern. Based on the safety of the allay Nerve Cap as assessed by chemical characterization and TRA, the systemic toxicity (subacute, subchronic, and chronic), reproductive toxicity and carcinogenicity endpoints were evaluated using this testing approach in lieu of the biological testing recommended in ISO 10993-1, annex A.

SHELF LIFE/STERILITY

The allay Nerve Cap and its packaging has been validated for a shelf life of 2 years supported by performance testing using both accelerated aged and real-time aged test samples that were subjected to preconditioning and packaging distribution conditions. The results showed the final product packaging protects the product and maintains sterility under worst-case shipping, handling, and storage conditions.

The allay Nerve Cap is provided sterile using electron beam (E-beam) sterilization and is intended for single use only. The final finished product is sterilized to a sterility assurance level (SAL) of 10-6 using E-beam radiation. E-beam sterilization achieves a minimum internal dose of 25 kGy using the VDmax25 method for the allay Nerve Cap.

Bacterial endotoxin testing using the limulus amebocyte lysate (LAL) kinetic chromogenic test method was evaluated for the allay Nerve Cap to meet the endotoxin limit of < 20 endotoxin units (EU)/device. Bacterial endotoxin testing will be performed on each lot of the allay Nerve Cap as part of the manufacturing process.

PERFORMANCE TESTING - BENCH

Non-clinical bench testing was performed to demonstrate that the device can function as

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intended under clinical conditions of use and mitigate the risks to health (e.g., adverse tissue reaction, tissue injury, use error). The non-clinical bench testing performed are presented in Table 2. All tests met pre-defined acceptance criteria.

Test	Test Purpose and Description
Color AdditiveExposureContactCategory	The color additive is provided in the allay Nerve Cap to permit intraoperative visualization of the hydrogel relative to the tissue and in vivo background. The dissolution of color additive from the allay Nerve Cap within 72 hours was confirmed through in vitro dissolution testing on hydrogel cylinders and in situ formed hydrogel, which leaves behind a colorless, transparent hydrogel. The extracts show no change in color or turbidity and there were no visible particulates.
Determinationof pH andOsmolarityHydrogelDeliverability	Performance benchtop evaluation of hydrogel injectability was conducted to demonstrate that in situ crosslinking of the allay Nerve Cap is reproducible and results in homogenous hydrogel delivered across the full range of Cap Form sizes. Study design included an assessment of hydrogel deliverability under worst-case conditions including delivery at different angles and locations of injection and after the maximal introduction of bubbles into the precursor solutions prior to delivery. Hydrogel delivery was successful across all worst-case conditions in all Cap Form sizes. In addition to the worst-case deliverability assessments, performance benchtop evaluations of the range of suitable nerve sizes for each allay Nerve Cap was performed. The study was designed to ensure that the available range of Cap Form sizes are suitable for delivery of the hydrogel around each respective nerve size. The hydrogel was successfully delivered around the range of nerve sizes per the Instructions for Use and the Cap Form was successfully removed without breaking or damaging the in situ formed allay Nerve Cap.
DimensionalEvaluation	Dimensional evaluation was conducted to assess the hydrogel physical dimensions and volume including confirming nerve encapsulation within the hydrogel for each nerve size per the Instructions for Use, measurement of gel dimensions (length, width, volume) for each Cap Form size, and assessment of the appropriate nerve sizes for each Cap Form.
DimensionalStability	To achieve the intended use of the allay Nerve Cap, the hydrogel must maintain integrity as a protective layer around the end of the nerve without significant loss of mechanical strength for at least three months. In vitro dimensional stability testing was conducted to demonstrate the integrity and persistence of the hydrogel under real-time physiologic conditions (37 °C, phosphate buffered saline (PBS))
Test	Test Purpose and Description
	pH 7.4) for at least four months (16 weeks), including the ability ofthe hydrogel to maintain a protective layer around the nerve andmaintain lumen patency past the three-month time frame duringwhich neuroma formation could occur after nerve transection. As partof this evaluation, maintenance of hydrogel integrity without cracksor collapse, mechanical strength (compressive modulus), and lumenpatency with no substantial dimensional loss were demonstrated. Inaddition, minimal swelling of the hydrogel was demonstrated.The dimensional stability of the allay Nerve Cap, as assessed byvisual observation and dimensional measurements, was alsodemonstrated at clinically relevant but worst-case physiologicextremes of osmolarity. At an extreme range of 240 mOsm/kg to 320mOsm/kg, there were no significant changes to the hydrogel integrity(no evidence of cracks or collapse), dimensions, or swelling (withinproduct specifications).
DissolutionTime	The time between injection of the Diluent Solution into the PowderVial and the complete dissolution of the powder is defined as the'dissolution time.' This test demonstrated that the dissolution time ismaintained under 5 minutes.
Gel Time	The time between the start of advancing the contents of theApplicator through the mixer and the onset of gelation is defined asthe 'gel time.' The test was performed to demonstrate that thehydrogel can consistently fill the Cap Form with a gel time of lessthan 10 seconds to ensure there is no significant delay in theprocedure.
PercentSwelling	The allay Nerve Cap is formed into cylinders (6 mm diameter, 6 mmlong). The hydrogels are weighed and equilibrated in a PBS solution(pH 7.4) at 37 °C for 24 hours. After 24 hours, the cylinder isremoved from the solution and weighed. This test was performed tocharacterize the maximal percent swelling of the hydrogel. Theacceptance criteria for this test was the swelling must be between 0%and 45% swelling of the crosslinked hydrogel as measured by weight24 hours after immersion in PBS @ 37 °C.
Compressionand ReboundTesting	Transverse compression testing is performed on the hydrogel todemonstrate the hydrogel can withstand compressive forces greaterthan 0.25 N/cm and then rebound following removal of the force. Ahigh threshold was established to ensure that the hydrogel rebounds >95% ensuring good crosslinking of the polymer.
CompressiveModulus	The compressive properties of the allay Nerve Cap are measured toensure the hydrogel has sufficient integrity to prevent nerveoutgrowth in the gel and sufficient cross-linking density to persist atthe site around the nerve for 8 months while remaining soft andcompliant on delivery. The acceptance criteria for this test was thedevice must have a minimum of 30 KPa compressive modulus of thecrosslinked hydrogel after 24 hours
Test	Test Purpose and Description
	in PBS.
Ease ofPreparation	Ease of preparation is defined by the time it takes to assemble theallay Nerve Cap from the initial step of the hydrogel preparation tothe time at which the Applicator is ready for delivery of the hydrogel.A preparation time longer than 10 minutes indicates PEG melting orthat the PEG powder was stored in inappropriate conditions. Thedevice must be able to be prepared in less than 10 minutes.
PressureTesting	Benchtop pressure testing was conducted to demonstrate that therewas no increase in pressure on an artificial nerve using a pressuretransducer as a function of time after formation and equilibration ofthe allay Nerve Cap under physiologic conditions. The studydemonstrated that no pressure was exerted on the artificial nerve atany time during hydrogel equilibration. Therefore, the allay NerveCap is non-compressive.
DeviceMigration	Ex vivo benchtop testing was conducted on a range of freshlyharvested ovine nerves to confirm that the allay Nerve Cap adheres toa clinically relevant range of nerve sizes (diameters) for up to oneweek under physiologic conditions to mitigate against devicemigration both off of the nerve and subsequently from the implantsite. As the in vivo animal testing demonstrated no device migrationon smaller nerves (1 mm rat sciatic nerve, 2 mm rabbit sciatic nervefor up to 6 months), a range of larger nerves were evaluated, atminimum establishing the ability to deliver the allay Nerve Caparound small to medium (1 to 4 mm nerves, 1 to 4 mm Cap Forms,Small Nerve Set) and up to the maximum 7 mm nerve (7 mm CapForm, Large Nerve Set). Testing established that it was not possibleto remove the allay Nerve Cap after firmly pulling on the hydrogelwith forceps in an attempt to remove the hydrogel, consistent withthe in vivo animal testing results demonstrating that the hydrogelmaintains adherence to the transected nerve stump. Therefore, thehydrogel does not migrate off of the nerve end as established boththrough in vitro and in vivo animal testing.
WearResistanceTesting	Accelerated wear testing was performed on the allay Nerve Cap toevaluate the ability of the device to resist wear. The allay Nerve Cap,delivered around an artificial nerve and placed in a clinically relevantorientation between two muscle layers (ex vivo chicken muscle),underwent (b)(4) cm passes to evaluate any wear debris generatedfrom the hydrogel implants under compressive, shear, and dynamicmechanical loads. The device passed the acceptance criteria that therewas no mass loss and no visible particulates released from thehydrogel.
Mass Loss	An evaluation of the hydrogel mass loss over the course ofaccelerated degradation of the implant was performed in vitro. Themass of the allay Nerve Cap is characterized by three phases of massloss. The study established minimal mass loss occurred over the 3-
Test	Test Purpose and Description
	month period post implantation (2.8%, 6 days). In the first phase,spanning 8 days (comparable to 4 months in vivo), only 6.6% massloss occurs. In the second phase of mass loss, between 8 and 15 days(between 4 months and ~7.5 months), substantial degradation isoccurring, over 39.8% of the mass is lost. In the third and final stageof rapid mass loss, between day 15 and 16, the remaining 44.2% ofmass loss occurs.
ExaggeratedClinical UseConditions	In addition to the in vivo assessment of delivery of the in situforming hydrogel around the rat and rabbit sciatic nerves aftertransection, an ex vivo evaluation of the hydrogel performance afterdelivery under exaggerated clinical use conditions was performed.This represents a worst-case clinical scenario as the proposedInstructions for Use direct the surgeon not to use the device in aregion of active blood flow. Hydrogel integrity was assessed afterdelivery directly into a Wrap Form (identical to a Cap Form but withan entrance and an exit) containing either a) fresh harvested rat bloodor b) saline (mimicking physiologic fluids and/or irrigation solution).The hydrogel formed successfully in the presence of blood or saline,integrating with the blood and saline to form an intact allay NerveCap. No visible particulates were formed.
Use Errors	Benchtop testing was performed to evaluate whether use errorsrelating to hydrogel preparation and delivery that might result in poorquality hydrogel formation could impact device performance. Thestudy was designed to evaluate the impact of each use error on deviceperformance both immediately after hydrogel preparation and afterthe equivalent of 3 months degradation in vivo (6 to 8 daysaccelerated degradation). Hydrogels were prepared according to eachworst-case use error and compared with hydrogels formed asintended per the proposed Instructions for Use. The use errors,including bubble generation, incomplete dissolution of the powder,exceeding the delivery window, or fluids did not result insignificantly earlier degradation of the hydrogel, the hydrogel quality,or affect the durability of the hydrogel as measured throughengineering performance testing.
Human Factorsand Usability	A human factors and usability study was conducted to evaluate thedesign and usability of the allay Nerve Cap for the intended users,uses and use environment. The study evaluated the device in thesterile final finished form, including the final commercial packagingand tray configuration following the proposed Instructions for Use.The study design was informed by the FDA guidance, "ApplyingHuman Factors and Usability Engineering to Medical Devices," ISO14971:2019, "Application of risk management to medical devices,"ISO 13485:2015, "Medical Devices - Quality management systems –Requirements for regulatory purposes," clause 7.3.3a, IEC 62366-1:2015, "Medical devices - Part 1: Application of usability engineering
Test	Test Purpose and Description
	to medical devices," and IEC/TR 62366-2:2016, "Medical devices - Part 2: Guidance on the application of usability engineering to medical devices."
	A total of 20 participants were included in the human factors and usability study, including fifteen (15) surgeons with relevant surgical experience on nerve repair, including hand surgeons, plastic surgeons, orthopedic surgeons, and podiatrists and five (5) surgical scrub nurses. The surgeons were independently recruited through a market research agency and had no prior knowledge or relationship with the sponsor and were evaluating the product for the first time. The surgeons assembled the allay Nerve Cap and then performed the simulated surgical procedure from removal of the device from the packaging, preparation of the dual-component applicator system, delivery of the hydrogel in situ into the Cap Form around an artificial nerve, and removal of the Cap Form with two different nerve sizes following the Instructions for Use. The scrub nurses were evaluated for their ability to assemble the device in preparation for delivery in the surgical site. The human factors and usability assessment demonstrated that the allay Nerve Cap and proposed Instructions for Use could be followed without any use errors and the use time of < 5 minutes was achieved with all users. All surgeons could perform all critical tasks (100%, n=15/15) related to preparing the device and delivering the hydrogel around different nerve sizes without any failures or use-related errors.

Table 2: Summary of Non-Clinical Bench Testing for the allay Nerve Cap

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PERFORMANCE TESTING - ANIMAL

Two animal studies were performed to evaluate the in vivo safety and effectiveness and biocompatibility of the allay Nerve Cap.

Good Laboratory Practice (GLP) Rat Sciatic Nerve Transection Study

A GLP rat study was designed to evaluate the safety and performance of the sterile, final finished allay Nerve Cap after delivery in situ in a clinically relevant nerve transection injury model at 4 weeks and 3 months following implantation. Following nerve transection, the allay Nerve Cap was delivered in situ around the cut end of the rat sciatic nerve per the proposed Instructions for Use. The safety and performance of the allay Nerve Cap was compared with the cleared Polyganics Innovation BV NeuroCap Nerve Capping Device (K152684) in the control group. In addition, a negative control. procedure, a transected nerve alone was included in the GLP rat study as a third group. The study captured outcomes both in-life and terminally to evaluate the safety and performance of the device in comparison to the two control groups.

The study demonstrated a benefit of the allay Nerve Cap on histologic, gross, and

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behavioral assessments to support the intended use of the product to reduce the risk of neuroma formation (0%) and to help restore normal sensorimotor function. Overall, the hvdrogel preparation and delivery were adequate with a total procedure time under two minutes. The hydrogel provided a transparent cover around the end of the nerve for the duration of the study with no evidence of axonal escape from the nerve stump into the surrounding muscle and scar tissue. There was no evidence of device migration.

The allay Nerve Cap has comparable safety to the Polyganics Innovation BV NeuroCap Nerve Capping Device (K152684) control for tissue response (non-irritant, nonneurotoxic), animal health, body weights, clinical and neurological observations, autotomy scores, and clinical pathology. The allay Nerve Cap also has comparable safety to the negative control (transection only) for these outcomes as well, with the exception that it is a slight irritant relative to the negative control group, consistent with the presence of a minimally degrading biomaterial implant at the site of implantation. No device related adverse effects were observed throughout the study.

Non-GLP Implantation Study on Intact Rabbit Sciatic Nerve

A chronic study was designed to evaluate the safety and performance of the sterile, final finished allay Nerve Cap after delivery in situ in a clinically relevant intact nerve model in a rabbit at 6 months and 8 months following implantation. The study objective was to evaluate the biocompatibility of the allay Nerve Cap over a chronic time frame during device absorption and clearance. The acceptance criteria are that the hydrogel, including partially or substantially degraded hydrogel, has (a) acceptable biocompatibility and does not cause an adverse inflammatory response to the nerve or the surrounding tissue and (b) the device should have similar biocompatibility to the comparator control group, recognizing that the control article is non-degradable and therefore a degradationmediated response to the material is absent. The acceptance criteria were evaluated through clinical assessments, gross pathology of the implant, histopathologic assessment, and systemic assessment (clinical chemistry, hematology, and urinalysis).

A total of fourteen (14) New Zealand white rabbits received bilateral implants with the allay Nerve Cap (n=14) around the left sciatic nerve and a silicone cuff with slit (n=14) around the right sciatic nerve. In brief, after sciatic nerve exposure, the nerve was placed inside the temporary silicone Wrap Form (identical to a Cap Form but with an entrance and an exit) and the allay Nerve Cap hydrogel was delivered around the nerve to form a compliant hydrogel wrap. The silicone Wrap Form was then removed and discarded. The rabbit sciatic nerve model was selected as an acceptable small animal model for ISO 10993-6 implantation testing that provides a larger diameter (2 to 3 mm) clinically relevant nerve in which to assess the long-term in vivo persistence and degradation behavior of the hydrogel, the local tissue response at the site of implantation of the degrading hydrogel, the absence of neurotoxicity, the absence of compression of the nerve, and an assessment of the systemic toxicity as measured through clinical pathology, hematology, and urinalysis.

All animals were in good health over the course of the study and survived to the

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scheduled study terminal time points. The allay Nerve Cap was successfully delivered in one or more layers around the rabbit sciatic nerve in the Wrap Form in all animals (n = 14). The hydrogel formed a transparent circumferential layer around the nerve. No adverse neurologic or behavioral effects such as lameness, dropped hocks, gait abnormalities were observed at any time. All animals gained an appropriate amount of weight over the study and were in good body condition at the time of termination. There were no apparent clinical signs related to the allay Nerve Cap or silicone cuff observed during the study. The animals were able to ambulate normally and there were no signs of pain, autotomy or overt signs of infection. Similarly, no neurologic abnormalities were noted post-implant or any other observations that could be attributed to the device or procedure. The clinical pathology and urinalysis supported the clinical findings of normality at study term. Hematology, serum chemistry and coagulation parameters were all normal and there were no trends indicative of a pathological pattern.

LABELING

The labeling includes instructions for use for the physician and satisfies the requirements of 21 CFR § 801.109 for prescription devices. The labeling also includes:

· Detailed description of the device technical parameters and all components.
Detailed instructions on proper device preparation and implantation. 0
O A shelf life.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of an in situ polymerizing peripheral nerve cap and the measures necessary to mitigate these risks.

Risks to Health	Mitigation Measures
Pain• Decrease or increase in nervesensitivity• Ineffective treatment leading tosymptomatic neuroma formation	In vivo performance testing
Adverse tissue reaction	Biocompatibility evaluationPolymerization process characterization
Tissue injury (thermal/mechanical)resulting from:• Thermal/mechanical effects• Use error• Device migration	In vivo performance testingPolymerization process characterizationHuman factors/usability testingNon-clinical performance testingLabeling
Infection	Sterilization validationShelf life testingLabeling

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SPECIAL CONTROLS:

In combination with the general controls of the FD&C Act, the in situ polymerizing peripheral nerve cap is subject to the following special controls:

(1) A characterization of the following chemical characteristics of the polymerization process must describe how the in situ application of the precursor materials will result in a consistent final device. All chemically relevant changes to parts (iii)-(vi) below are determined to significantly affect the safety or effectiveness of the device (21 CFR 807.81(a)(3)(i)) and must be described in a premarket notification:
- The technical specifications of the precursor materials including the chemical (i) formulation, purity, particulate matter, appearance, molecular weight, pH, and viscosity:
- (ii) The delivery mechanism of the precursor materials to the site of application;
- The polymerization mechanism and polymer structure: (iii)
- The intermediates or side products produced; (iv)
- The degradation pathway and degradants; and (v)
- The contribution of any initiators or quenchers to the polymer, intermediates or side (vi) products, and degradants.
(2) Non-clinical performance testing data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be evaluated:
- A characterization of the polymerization process must be provided that describes (i) how the in situ application of the precursor materials will result in a consistent final device. Chemically relevant changes to the characteristics below are determined to significantly affect the safety or effectiveness of the device (21 CFR 807.81(a)(3)(i)) and must be described in a premarket notification:
  - The polymerization mechanism and polymer structure; (A)
  - (B) The intermediates or side products produced:
  - The degradation pathway and degradants: and (C)
  - The contribution of any initiators or quenchers to the polymer, intermediates or (D) side products, and degradants.
- (ii) Degradation testing of the polymerized device must be performed under simulated clinical use conditions.
- (iii) Mechanical integrity testing including elastic modulus, compression, swelling, and rebound testing must be performed.
- Physico-chemical testing of the polymerized device (i.e., dimensions, pH, molecular (iv) weight, purity, particulate matter, viscosity, dissolution time, gel time, reaction temperature) must be performed.
- Polymerized device deliverability testing with any applicator(s) or delivery system(s) (v) must be performed.
(3) Human factors/usability testing must demonstrate that the intended user(s) in the intended use environment can correctly and safely use the device following the instructions for use.

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(4) The tissue-contacting components of the precursor materials, intermediate or side products. degradants, and final polymerized device must be demonstrated to be biocompatible.
(ર) Performance data must demonstrate the sterility of all tissue-contacting components of the device and any delivery systems.
Performance data must support the shelf life of the device by demonstrating continued (6) sterility, package integrity, and device functionality over the identified shelf life.
(7) In vivo performance testing must demonstrate that the device performs as intended to reduce the risk of the development of symptomatic neuroma and assess tissue injury, device durability, device migration, device preparation and deliverability, and all adverse effects.
(8) Physician labeling must include:
- Detailed instructions on proper device preparation and implantation. (i)
- Detailed description of the device technical parameters and all components. (ii)
- (iii) A shelf life.

BENEFIT/RISK DETERMINATION

The risks of the device are based on data collected in nonclinical laboratory and animal studies described above. The risks of the allay Nerve Cap are adverse tissue reaction, tissue injury. decrease or increase in nerve sensitivity, infection, or pain. These risks could occur from a device that is not biocompatible, a device not provided sterile, inadequately formed polymer hydrogel, device migration, nerve compression, or improper device use or use error.

The probable benefits of the device are also based on data collected in nonclinical laboratory and animal studies as described above. The benefits of the device are demonstrated in the animal study that showed there were no animals with neuroma formation (0%) within 3 months of implantation of the allay Nerve Cap, which is the time period most likely for symptomatic neuromas to form in human patients. 7 The animal study and nonclinical laboratory testing further demonstrated that the allay Nerve Cap remained intact during the 3-month period associated with neuroma formation to act as a physical barrier to separate the peripheral nerve end from the surrounding environment. The animal study also demonstrated the animals were able to restore normal sensorimotor function after implantation of the allay Nerve Cap.

Additional factors to be considered in determining probable risks and benefits for the allay Nerve Cap include that there was no clinical performance data provided to support the risks and benefit of the allay Nerve Cap for its proposed indications for use. However, there has been a body of clinical evidence collected on the use of nerve cap devices to reduce the risk of the development of a symptomatic neuroma within the 3-month period following the primary peripheral nerve

7 Karla M. C. Oliveira et al. "Time course of traumatic neuroma development." PLoS One, Jul 2018, Vol 13(7):e0200548. doi: 10.1371/journal.pone.0200548. PMID: 30011306; PMCID: PMC6047790.

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repair procedure that can be used to support the effectiveness of the allay Nerve Cap. 8 There is uncertainty regarding whether the allay Nerve Cap will result in functional benefit to human patients since it is difficult to fully assess pain and functional outcomes in animals and whether this data is translatable to human patients. The provided animal studies primarily focused on histological changes rather than behavioral changes in the animal study was able to support the proposed indications for use of the allay Nerve Cap to reduce the risk of development of a symptomatic neuroma because none of the animals implanted with the allay Nerve Cap exhibited neuroma formation within 3 months.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

The probable benefits outweigh the probable risks for the allay Nerve Cap. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the allay Nerve Cap is granted and the device is classified under the following:

Product Code: SBG Device Type: In situ polymerizing peripheral nerve cap Class: II Regulation: 21 CFR 882.5260

8 Amy M. Moore and Susan E. Mackinnon. "Nerve Repair and Transfers from Hand to Shoulder, Hand Clinics." Clinic Review Articles, May 2016, Vol 32(2), Elsevier, ISBN 9780323445191.

Regulation Number and Section

N/A