The VasoPrep Surgical Marking Pen is intended for use prior to or during the harvesting and preparation of vein grafts used in bypass surgery. The pen is used to demarcate selected sites and orientation of the graft.

Device Description

The VasoPrep Surgical Marking Pen is a single patient use sterile prescription use only marker intended for use on veins prior to or during Coronary-Assisted Bypass Graft (CABG) surgery. The marker (Figure 1) consists of a pen body, barrel, wick and cap with a wide chisel style applicator tip for delivery of ink to mark internal tissue. The formulation is non-toxic as used and is comprised of an ink material (FD&C Blue Dye #1) compounded into a carrier material (i.e., solvent). The wide chisel tip can deliver either a thin line of ink for precise marks or can be rotated 90° to deliver a wide stripe of ink.

AI/ML Overview

This document describes a De Novo classification request for the VasoPrep Surgical Marking Pen, an internal tissue marker. The studies presented are non-clinical/bench studies, therefore, the concept of AI performance, ground truth establishment by experts, adjudication methods, multi-reader multi-case studies, and a standalone algorithm performance are not applicable.

1. Table of Acceptance Criteria and the Reported Device Performance:

The acceptance criteria and reported device performance are presented across several tables in the provided text. For clarity, they are consolidated and summarized below:

Test Category	Test Name	Purpose	Acceptance Criteria	Reported Device Performance
Biocompatibility	Cytotoxicity (ISO 10993-5)	To test and evaluate the cytotoxicity of the marker and ink formulation.	Non-cytotoxic	Non-cytotoxic
	Sensitization - Maximization Method (guinea pig) (ISO 10993-10)	To test and evaluate the potential for the marker and ink formulation to cause delayed contact sensitization.	No evidence of causing delayed dermal contact sensitization	No evidence of causing delayed dermal contact sensitization
	USP Intracutaneous Reactivity (ISO 10993-10)	To test and evaluate the potential for the marker and ink formulation to cause local dermal irritant effects.	Nonirritant	Nonirritant
	USP Systemic Toxicity	To test and evaluate the acute system toxicity of the marker and ink formulation.	No indications of systemic toxicity	No indications of systemic toxicity
	Hemocompatibility (In vitro hemolysis)	To test and evaluate the hemocompatibility of the marker and ink formulation.	No significant hemolysis	No significant hemolysis
	Material Mediated Pyrogenicity (ISO 10993-9)	To test and evaluate the pyrogenicity of the marker and ink formulation.	Non-pyrogenic	Non-pyrogenic
Shelf Life/Sterility/Packaging	Sterility Testing (ISO 11137)	To test and evaluate the sterility of the marker and ink formulation.	To ensure gamma radiation sterilization process is an adequate dose. Devices must have a sterility assurance of at least 10^-6.	Meets Acceptance Criteria
	Packaging Integrity (ASTM F1886/F1886M; ASTM F1929; ASTM F88/88M)	To test and evaluate the marking ability after undergoing accelerated aging and mechanical stress.	The packaging must pass the Visual Seal Examinations; Dye Leak Test; and Peel Test.	Meets Acceptance Criteria
Performance Testing – Bench	Internal Tissue Marking Ability	To test and evaluate device ability to mark human saphenous veins (HSV).	The marker shall provide a visible mark on wet or dry tissue that is 1-3 mm wide and up to 90 cm long with a single swipe. The mark shall remain visible on tissue for at least 4 hours.	Meets Acceptance Criteria (The marker provided a visible mark on wet or dry tissue that is 1-3 mm wide and up to 90 cm long with a single swipe. The mark remained visible on tissue for at least 4 hours.)
	Effect of Dye on Human Vein Tissue	To test and evaluate for patency effects caused by the ink on HSV.	Ex-vivo exposure to ink shall have no detrimental effect on the viability, smooth muscle contractility and endothelial-dependent relaxation of human saphenous vein grafts.	Meets Acceptance Criteria (The VasoPrep Surgical Marking Pen met all design requirements for compatibility and functional use.)
	Effect of Dye on Animal Vein Tissue	Preliminary dosing experiments to test and evaluate demarcation ability of the ink on porcine saphenous veins, at a dose that will have no detrimental effect on further HSV testing.	Application shall demonstrate ink demarcation ability on porcine saphenous veins at an amount that would have no detrimental effect on the viability, smooth muscle contractility and endothelial-dependent relaxation of human saphenous vein grafts.	Meets Acceptance Criteria
Product Stability	Functionality (ASTM F1980)	To test and evaluate the marking ability after undergoing real time aging and shipping stress.	The marker shall provide a visible mark on wet or dry tissue that is 1-3 mm wide and up to 90 cm long with a single swipe. The mark shall remain visible on tissue for at least 4 hours.	Meets Acceptance Criteria (sterilized aged marking pens functioned as designed)
	Cytotoxicity (ASTM F1980; ISO 10993-5)	To test and evaluate the cytotoxicity of the marker and ink formulation after undergoing accelerated aging.	The marker and contents shall be non-cytotoxic.	Meets Acceptance Criteria (ink is non-cytotoxic)

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):

Human Saphenous Vein (HSV) segments: Used for "Internal Tissue Marking Ability" and "Effect of Dye on Human Vein Tissue" studies. The exact number of segments is not specified, but it refers to "segments" which implies a limited number for individual tests. The origin of the human tissue is not specified (e.g., country of origin). These are ex-vivo experiments (retrospective in the sense that the tissue has been harvested, but prospective for the purpose of the experiment itself).
Porcine Saphenous Vein: Used for "Effect of Dye on Animal Vein Tissue" and product stability testing. The exact number of veins or samples is not specified. The origin is not specified. These are ex-vivo or animal model experiments.
Animals for Biocompatibility (Guinea Pig): Used for Sensitization testing. A "guinea pig method" is mentioned, implying a standard number of animals for such a test (typically a small cohort).
Sterilized and Aged Markers: Four markers were tested for product stability functionality, and two real-time aged markers were used for demarcation effectiveness and fluid volume.
Toxicological Assessment Literature Studies: Canine, porcine, and murine models were used in literature studies for lifetime toxicity/carcinogenicity of FD&C Blue #1 dye. The number of animals in these literature studies is not specified in this document.

3. 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. This is a non-clinical/bench study. There is no mention of experts establishing a "ground truth" in the context of human interpretation or diagnostic accuracy. Performance criteria are based on objective physical, chemical, and biological measurements.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

Not applicable. This is a non-clinical/bench study. Adjudication methods are typically used in studies involving subjective human interpretation, which is not the case here.

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 is a non-clinical/bench study for a physical device (marking pen), not an AI-powered diagnostic tool.

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

Not applicable. This is a non-clinical/bench study for a physical device, not an algorithm.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

The "ground truth" in these studies is based on objective scientific measurements and established standards for biocompatibility (e.g., non-cytotoxic, non-irritant), sterility (sterility assurance level), packaging integrity (visual, dye leak, peel tests), and performance characteristics (visible mark, no detrimental effect on tissue viability). It's a scientific and technical "ground truth" established through laboratory testing.

8. The sample size for the training set:

Not applicable. There is no AI or machine learning component, therefore no training set.

9. How the ground truth for the training set was established:

Not applicable. There is no AI or machine learning component, therefore no training set or ground truth for it. Any "training" or optimization of the pen's design or ink formulation would have been part of the product development process, not a formal training set as understood in AI/ML contexts.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR VASOPREP SURGICAL MARKING PEN

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Internal Tissue Marker: An internal tissue marker is a prescription use device that is intended for use prior to or during general surgical procedures to demarcate selected sites on internal tissues.

NEW REGULATION NUMBER: 878.4670

CLASSIFICATION: II

PRODUCT CODE: PDW

BACKGROUND

DEVICE NAME: VASOPREP SURGICAL MARKING PEN

SUBMISSION NUMBER: DEN130004

Date of De Novo: May 6, 2013

CONTACT: VASOPREP SURGICAL ROBERT CHIN, PHD - REGULATORY CONSULTANT 55 Madison Avenue, Suite 400 MORRISTOWN, NJ 07960

REQUESTER'S RECOMMENDED CLASSIFICATION: II

INDICATIONS FOR USE

LIMITATIONS

Caution: Federal Law restricts this device to sale by or on the order of a physician.

WARNINGS

The VasoPrep Surgical Marking Pen should not be used on a non-sterile surface prior to its internal use.
The safety and performance of the VasoPrep Surgical Marking Pen has not been established in patients with a known allergy to FD&C Blue dye #1.

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The VasoPrep Surgical Marking Pen has not been tested on any internal tissue except for veins.

DEVICE DESCRIPTION

Image /page/1/Figure/3 description: The image shows the text "Figure 1: VasoPrep Surgical Marking Pen". The text is written in a clear, sans-serif font and is likely a caption or title for an image or diagram. The text indicates that the image or diagram is related to a VasoPrep Surgical Marking Pen and is labeled as Figure 1.

Image /page/1/Figure/4 description: The image shows a technical drawing of an object, with two views presented. The top view displays the object's length as 5.3 units, with a section measuring 3 units and a diameter of 0.44 units. The bottom view, labeled "SECTION A-A", provides a cross-sectional perspective, revealing internal components labeled 1, 2, 5, and 6.

Figure 1. The device consists of a Body (1); Tip (2); Barrel (3); Cap (4); Ink Storage Wick (5); and Ink (6).

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

The VasoPrep Surgical Marking Pen is comprised of three main components and are considered to be in direct contact and/or indirect contact with the patient: 1) the ink formulation; 2) the pen barrel; and 3) the wick/wicking material. These materials are well-characterized, used in medical device applications and were tested in accordance with ISO 10993-1 as indicated in Table 1 (below). The results demonstrate the VasoPrep Surgical Marking Pen is biocompatible when used as intended.

Table 1: A summary of the biocompatibility testing conducted
Test	Purpose	Acceptance Criteria	Results
Cytotoxicity (b)(4)(b)(4) (ISO 10993-5)	To test and evaluate the cytotoxicity of the marker and ink formulation.	Non-cytotoxic	Non-cytotoxic

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Sensitization -MaximizationMethod (guineapig) (ISO 10993-10)	To test and evaluate thepotential for the marker andink formulation to causedelayed contact sensitization.	No evidence ofcausing delayeddermal contactsensitization	No evidence ofcausing delayeddermal contactsensitization
USP IntracutaneousReactivity (ISO10993-10)	To test and evaluate thepotential for the marker andink formulation to causelocal dermal irritant effects.	Nonirritant	Nonirritant
USP SystemicToxicity	To test and evaluate theacute system toxicity of themarker and ink formulation.	No indications ofsystemic toxicity	No indicationsof systemictoxicity
Hemocompatibility(In vitro hemolysis)	To test and evaluate thehemocompatibility of themarker and ink formulation.	No significanthemolysis	No significanthemolysis
Material MediatedPyrogenicity (ISO10993-9)	To test and evaluate thepyrogenicity of the markerand ink formulation.	Non-pyrogenic	Non-pyrogenic

SHELF LIFE / STERILITY / PACKAGING

A single-packed marker is packaged in a clear (b)(4)

Low Density Polyethylene (LDPE)/opaque coated paper pouch that is heat-sealed with (b)(4) The single-pack marker packaging is a single sterile barrier. The single packs are then bulk-packed in a cardboard shelf carton for distribution of single markers. Shelf cartons are placed in corrugated boxes for shipping. Labels are placed on the paper side of the pouch, on the shelf carton and the shipping container.

Shelf-life and packaging integrity studies indicate a packaged, sterilized device will remain functional (i.e., tissue marking ability), non-cytotoxic and maintain a 10° SAL for 1 year. The standards and methods used are located in Table 2, below.

Table 2: A summary of the sterility and packaging testing conducted
Test	Purpose	Acceptance Criteria	Results
Sterility Testing(ISO 11137)	To test and evaluate thesterility of the marker andink formulation.	To ensure (b)(4)gamma radiationsterilization processis an adequate dose.Devices must have asterility assurance ofat least 10-6.	MeetsAcceptanceCriteria
Packaging Integrity(ASTM F1886/F1886M; ASTMF1929; ASTMF88/88M)	To test and evaluate themarking ability afterundergoing accelerated agingand mechanical stress.	The packaging mustpass the Visual SealExaminations; DyeLeak Test; and PeelTest.	MeetsAcceptanceCriteria

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PERFORMANCE TESTING – BENCH

Test protocols were developed based on the results of design and clinical risk analyses of the VasoPrep Surgical Marking Pen in its intended indication for use. The original bench testing performed by the sponsor to assess the performance characteristics are summarized in Table 3.

Table 3: A summary of the performance testing conducted
Test	Purpose	Acceptance Criteria	Results
Internal TissueMarking Ability	To test and evaluate deviceability to mark humansaphenous veins (HSV)	The marker shallprovide a visiblemark on wet or drytissue that is 1-3 mmwide and up to 90cm long with asingle swipe. Themark shall remainvisible on tissue forat least 4 hours.	MeetsAcceptanceCriteria
Effect of Dye onHuman Vein Tissue	To test and evaluate forpatency effects caused by theink on HSV	Ex-vivo exposure toink shall have nodetrimental effect onthe viability, smoothmuscle contractilityand endothelial-dependentrelaxation of humansaphenous veingrafts.	MeetsAcceptanceCriteria
Effect of Dye onAnimal Vein Tissue	Preliminary dosingexperiments to test andevaluate demarcation abilityof the ink on porcinesaphenous veins, at a dosethat will have no detrimentaleffect on further HSVtesting.	Application shalldemonstrate inkdemarcation abilityon porcinesaphenous veins atan amount thatwould have nodetrimental effect onthe viability, smoothmuscle contractilityand endothelial-dependentrelaxation of humansaphenous veingrafts	MeetsAcceptanceCriteria

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Ability to mark internal tissues

Human Saphenous Vein (HSV) segments were painted on the surface with the device and placed in (b)(4) Photographs were taken with a digital camera to monitor the retention of marking on the tissue. Titration curves were generated by measuring maximum absorbance. The marker provided a visible mark on wet or dry tissue that is 1-3 mm wide and up to 90 cm long with a single swipe. The mark remained visible on tissue for at least 4 hours.

Effect of Dve on Venous Tissue

Human Saphenous Vein (HSV) were dissected free of adipose and connective tissues and divided into segments that were either left untreated (as controls) or exposed to dye prior to physiological measurements for 2 hrs. The buffer was changed to a high (b)(4) buffer which depolarizes the smooth muscle leading to contraction of functionally viable smooth muscle. Contractile responses were converted to stress . The rings were (b)(4) normalized (b)(4)

To determine

endothelial-dependent relaxation, the (b)(4)

Maximal contractile responses to (b)(4)

(b)(4) were converted to stress and endothelial dependent function were described as the percentage (%) of relaxation of the maximal (b)(4) induced contraction.

The VasoPrep Surgical Marking Pen met all design requirements for compatibility and functional use.

Effect of Dye on Porcine Venous Tissue

Dosing of FD&C Blue dye #1 was tested in porcine saphenous vein and (b)(4) was determined to be the optimal dose for color visualization.

Product Stability

The objective was to test and evaluate the performance testing on VasoPrep Surgical Marking Pens after gamma sterilization and aging (based on the proposed shelf life). Four sterilized and aged markers were tested according to protocol. The markers were gamma sterilized at the normal specified dose ((b)(4) Two real-time aged markers (the markers were stored at room temperature for at least one vear after being sterilized) were shipped to multiple locations and tested for marking on wet porcine saphenous vein tissue (i.e. demarcation effectiveness) and dry paper (i.e., fluid volume). Cytotoxicity testing (b)(4) was additionally performed on accelerated-aged sterilized ink. The results (as summarized in Table 4) indicate the sterilized aged marking pens functioned as designed and that the ink is non-cytotoxic.

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Table 4: Summary of the Product Stability Testing Conducted
Test	Purpose	Acceptance Criteria	Results
Functionality	To test and evaluate the	The marker shall	Meets
(ASTM F1980)	marking ability after	provide a visible	Acceptance
	undergoing real time aging	mark on wet or dry	Criteria
	and shipping stress.	tissue that is 1-3 mm
		wide and up to 90
		cm long with a
		single swipe. The
		mark shall remain
		visible on tissue for
		at least 4 hours.
Cytotoxicity (ASTM	To test and evaluate the	The marker and	Meets
F1980; ISO 10993-	cytotoxicity of the marker	contents shall be	Acceptance
ર)	and ink formulation after	non-cytotoxic.	Criteria
	undergoing accelerated
	aging.

TOXICOLOGICAL ASSESSMENT

Lifetime toxicity/carcinogenicity literature studies pertaining to FD&C Blue #1 dye were provided. The studies examined histology in a significant number of systemicallyrelevant animal tissues. The histology examined was obtained from canine, porcine and murine models for both genders and using different dye dose levels.

Several published literature articles have studied acute and/or chronic dosing of the subject dye by oral, subcutaneous and intravenous routes, demonstrating no toxicity and No Adverse Effect Levels (NOAELs) in accepted animal models at doses far in excess of that intended in the application of the Surgical Marking Pen, which is a 0.68 µg/kg onetime exposure for a 70 kg adult. representing 0.00057% of the FDA adult Acceptable Daily Intake (ADI) for FD&C Blue No. 1 of 12.0 mg/kg per day. Data from literature publications analyzing the elimination routes of FD&C Blue No.1 were also provided.

Examples of legally marketed devices containing the device dye were also provided, and include sutures, anchors and dural sealants. From these devices and the above-mentioned toxicological assessment, the risk of inadequate metabolic clearance from the body is believed to be minimal at the dose level used (i.e., 0.68 ug/kg).

LABELING

On the packaging label, the sponsor specifies prescription use only, sterility, shelf life, single-use only, not made with natural rubber latex, lot number and product catalogue number. The labeling for the VasoPrep Surgical Marking Pen is consistent with the data and addresses all known hazards and other relevant information that could impact safe and effective use of the device. The labeling satisfies the requirements of CFR 801.109 Prescription devices.

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RISKS TO HEALTH

Table 2 below identifies the risks to health that may be associated with use of Internal Tissue Marker and the measures necessary to mitigate these risks.

Table 2 – Identified Risks and Mitigation Measures
Identified Risk	Mitigation Measures
Adverse tissue reaction	Biocompatibility Testing
	Sterilization Testing
	Shelf Life/Stability Testing
	Performance Testing
	Labeling
Ineffective Marking	Performance Testing
	Shelf Life/Stability Testing
	Labeling
Improper use	Labeling

SPECIAL CONTROLS:

In combination with the general controls of the FD&C Act, the Internal Tissue Marker is subject to the following special controls:

1. The device must be demonstrated to be biocompatible. Material names and specific designation numbers must be provided.
1. Performance testing must demonstrate that the device performs as intended to mark the tissue for which it is indicated.
1. Performance data must demonstrate the sterility of the device.
1. Performance data must support the shelf life of the device by demonstrating sterility, package integrity, device functionality, and material stability over the requested shelf life.
1. Labeling must include:
- A warning that the device must not be used on a non-sterile surface prior to use a. internally.
- An expiration date / shelf life. b.
- Single use only labeling must be labeled directly on the device. C.

BENEFIT/RISK DETERMINATION

No clinical study was provided nor requested nor deemed necessary for the subject device based on the risks. The risks of the device are based on literature review, nonclinical laboratory data and tissue study data collected as described above. The subject surgical marker could provide a lower risk alternative to the present off-label use of other marking pens not intended for internal usage. However, there are potential adverse events that include, but are not limited to; infection, tissue inflammation, and mechanical failure of vessels.

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The probable benefits of the device are also based on literature review, nonclinical data and tissue study data collected in a study as described above. The benefit of the subject device would be to provide a safer and effective surgical marking pen to reduce the risks associated with the off-label use of existing marking pens, which are not provided sterile nor designed and intended for CABG surgery. . The use of the device on human saphenous veins to maintain vein orientation during the procedure of coronary artery bypass grafting may help avoid twisting or torsion of the vein during the procedure. Twisting or torsion of the vein, if it occurred during CABG surgery (e.g., vein orientation), could impede early graft patency.

In conclusion, given the available information above, the data support that for the indication "The VasoPrep Surgical Marking Pen is intended for use prior to or during the harvesting and preparation of vein grafts used in bypass surgery. The pen is used to demarcate selected sites and orientation of the graft", the probable benefits outweigh the probable risks. The device provides benefits and the risks can be mitigated by the use of general and the identified special controls.

Presently, there are no available surgical marking pens specifically designed for usage on internal tissues. Marking pens that are currently used off-label have different dye formulations which may have adverse effects on saphenous vein smooth muscle and endothelium. With the use of off-label pens or no pens at all, the patency of grafted vessels can be jeopardized.

Patients are typically not aware of the use of surgical marking pens; however the data, for the subject device indicates it to be reasonably safe and effective such that patients undergoing CABG surgery would be willing to take the risk even though it is uncertain that they will achieve the benefit, because if they benefit, the benefit from maintaining vessel patency in a safe manner is substantial. Finally, the risks associated with this device, although potentially serious, should not occur in any clinically significant number for this device, and they would be expected to be lower than those currently accepted for similar treatments due to safer dye formulation.

CONCLUSION

The de novo for the VasoPrep Surgical Marking Pen is granted and the device is classified under the following:

Product Code: PDW Device Type: Internal Tissue Marker Class: Class II Regulation: 21 CFR 878.4670

Regulation Number and Section

§ 878.4670 Internal tissue marker.

(a)
Identification. An internal tissue marker is a prescription use device that is intended for use prior to or during general surgical procedures to demarcate selected sites on internal tissues.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The device must be demonstrated to be biocompatible. Material names and specific designation numbers must be provided.
(2) Performance testing must demonstrate that the device performs as intended to mark the tissue for which it is indicated.
(3) Performance data must demonstrate the sterility of the device.
(4) Performance data must support the shelf life of the device by demonstrating sterility, package integrity, device functionality, and material stability over the requested shelf life.
(5) Labeling must include:
(i) A warning that the device must not be used on a non-sterile surface prior to use internally.
(ii) An expiration date/shelf life.
(iii) Single use only labeling must be labeled directly on the device.