QUADRASPHERE 30 TO 60 by BIOSPHERE MEDICAL, INC.

The QuadraSphere Microspheres are sterile, biocompatible, hydrophilic, non-resorbable, expandable, acrylic copolymer microspheres. QuadraSphere Microspheres size is: 30 to 60µm in containers (vials) containing 25 mg of dry microspheres, which can absorb aqueous media up to 64 times their dry state volume. The expansion rate is dependent on ionic concentration. When in contact with blood, non-ionic contrast media. or normal saline (NaCl 0.9%), QuadraSphere Microspheres expand to approximately 4 times their dry state diameter; equal to 64x volume.

The QuadraSphere Microspheres have the following properties:

Retains spherical shape with consistent cross sectional diameter after reconstitution with aqueous-based solutions such as contrast media and 0.9% saline solution for predictable flow directed level of occlusion in the vasculature.
Rapidly absorbs contrast media and 0.9% saline solution. The spheres are positively charged, which allows them to bond ionically with negatively charged aqueous based solutions.
Compresses in the vessel lumen, providing more surface contact with vessel intima.
Expands up to four times the stated dry diameter when hydrated with non-ionic aqueous solutions, resulting in an increase in surface area contact for a more complete vessel occlusion.

The principles of operation for the QuadraSphere Microspheres are the same as the predicate device. QuadraSphere Microspheres are permanent implantable devices and are designed for controlled, targeted embolization. The device is provided dry (in a vial) and must be rehydrated before use. The microspheres are injected into the target vessel with an intravascular catheter(s) to selectively occlude blood vessels. Contrast enhancement using commercially available ionic or non-ionic contrast media allows the embolization procedure to be monitored using fluoroscopy.

AI/ML Overview

The BioSphere Medical QuadraSphere® Microspheres 30 to 60µm is a medical device for embolization and is substantially equivalent to the predicate device, QuadraSphere Microspheres (K052742). The main difference is the additional size offering of 30 to 60µm.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. A table of acceptance criteria and the reported device performance:

The document doesn't explicitly list specific quantitative "acceptance criteria" with numerical targets for the new 30-60µm size. Instead, the acceptance is based on demonstrating that the new size performs similarly to the predicate device and meets established design and performance specifications. The table below summarizes the key evaluations and their outcomes.

Acceptance Criteria Category	Specific Evaluation/Parameter	Predicate Device Performance (K052742)	Subject Device Performance (30-60µm)	Result/Comment
Material & Physical Properties	Shelf Life (single use)	Three years (36 months)	Three years (36 months)	Met: Same shelf life.
	Material Composition	PVA Acrylic Copolymer (vinyl alcohol-sodium acrylate)	PVA Acrylic Copolymer (vinyl alcohol-sodium acrylate)	Met: Same material composition.
	Physical Characteristics (Biocompatible, hydrophilic, deformable, non-resorbable, expandable, conformable, swells upon exposure to aqueous solutions)	Described as having these characteristics.	Described as having these characteristics.	Met: Same physical characteristics. The document states the new size also retains spherical shape, rapidly absorbs contrast/saline, compresses in vessel lumen, and expands up to four times its dry diameter.
	Sterilization Method	Radiation Sterilized	Radiation Sterilized	Met: Same sterilization method.
	Volume of Microspheres in Vial (dry)	25 mgs per vial	25 mgs per vial	Met: Same quantity per vial.
Performance - In-Vitro	Granulometry (size distribution)	Within expected size ranges for 50-100µm, 100-150µm, 150-200 µm.	Within expected size range.	Met: In vitro granulometry of the 30-60µm microspheres demonstrated they were within the expected size range.
	Swelling in Contrast Agent	Expands approximately 4 times dry size.	Expands approximately 4 times dry size.	Met: The document states "All of the QuadraSphere Microspheres react the same and expand approximately 4 times their dry size when properly reconstituted in saline." Testing for this was successful for the new size.
	Optical Inspection	(Assumed to meet specifications)	Met requirements.	Met: Optical Inspection successfully met requirements.
	Water Content (Microsphere)	(Assumed to meet specifications)	Met requirements.	Met: Water Content (Microsphere) successfully met requirements.
Performance - In-Vivo	Safetgy (animal behavior, blood tests, histopathology)	(Assumed acceptable for predicate)	No significant adverse events post procedure. Hepatic artery embolization was "feasible and tolerated well both clinically and biologically."	Met: Safety was assessed from animal behavior, blood tests, and histopathological examination. No significant adverse events reported.
	Location of Occlusion / Product Performance	Designed for controlled, targeted embolization when vessel conformity is desired (completely block the arterial lumen).	Mean occluded vessel diameter: 146 ± 46µm (median 136µm). Mean number of microspheres in occluded vessel section: 1.4 ± 0.8 (median 1.0). "Embolization was successful for all animals."	Met: The animal study confirmed successful embolization and vessel occlusion with the 30-60µm size. The findings were consistent with similar studies of histological response to embolic particles.
	Biocompatibility	Met ISO 10993-1 for permanent implants in contact with blood.	Adopted from predicate.	Met: Based on identical materials and processes, biocompatibility from the predicate device was adopted, demonstrating satisfaction of the requirement.

2. Sample size used for the test set and the data provenance:

Test Set Description: The primary test set mentioned for the 30-60µm device is an animal study.
Sample Size: The document refers to "healthy mini-pigs" and states that "Embolization was successful for all animals," implying a small, but sufficient, number of animals for this pre-clinical feasibility and safety study when coupled with the in-vitro data. The exact number of animals is not explicitly stated.
Data Provenance: The data is from a prospective animal study conducted to evaluate the safety and product performance of the new 30-60µm QuadraSphere Microspheres. The origin is not specified by country, but it's a pre-clinical 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 provided in the given text. For an animal study, "ground truth" would typically come from veterinary pathologists or other trained animal researchers/clinicians.

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

This information is not provided in the given text. Given it's an animal study focusing on objective measurements (histopathology, granulometry), a formal adjudication process as seen in multi-reader human image interpretation studies is unlikely or not explicitly detailed.

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:

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This is a device modification for an embolization microsphere, not an AI-assisted diagnostic tool. Therefore, the concept of "human readers improving with AI assistance" does not apply.

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

Not applicable. This device is a physical embolization microsphere, not a software algorithm. Its performance is evaluated through its physical and biological effects, both in vitro and in vivo.

7. The type of ground truth used:

The ground truth for the animal study (in-vivo testing) was established using:

Histopathology: Microscopic examination of tissue samples to evaluate vessel occlusion, tissue response (e.g., presence of macrophages), and confirms the location of the microspheres.
Animal behavior and blood tests: To assess overall safety and well-being.
In-vitro granulometry: Objective measurement of microsphere size distribution.

8. The sample size for the training set:

Not applicable. This is a physical medical device, not an AI algorithm, so there is no "training set" in the context of machine learning. The device's design and manufacturing processes are refined through engineering and material science, not data training.

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

Not applicable. As stated above, there is no "training set" for this type of device. The "ground truth" for its development would be based on established engineering principles, material science, and prior knowledge from the predicate device.

Summary

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BioSphere Medical QuadraSphere® Microspheres 30 to 60μm Special 510(k): Device Modification Notification

KI13822

510(K) SUMMARY
GeneralProvisions	Submitter Name:	BioSphere Medical, Inc.
	Address:	1050 Hingham StreetRockland, MA 02370
	Telephone Number:	(781) 681-7900
	Fax Number:	(781) 871-2325
	Contact Person:	Linda J. Varroso
	Date of Preparation:	December 23, 2011
	Registration Number:	1226551
SubjectDevice	Trade Name:	QuadraSphere Microspheres
	Common/Usual Name:	Neurovascular Embolization Device
	Classification Name:	Neurovascular Embolization Device
Predicate Device	Trade Name:	QuadraSphere Microspheres
	Classification Name:	Neurovascular embolization device
	Premarket Notification:	K052742
	Manufacturer:	BioSphere Medical, S.A.
Classification		Class II
		21 CFR § 882.5950
		Neurovascular Embolization Device
Intended Use		QuadraSphere Microspheres are indicated for embolization ofhypervascularized tumors and peripheral arteriovenous malformations.

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The QuadraSphere Microspheres have the following properties:

. Retains spherical shape with consistent cross sectional diameter after reconstitution with aqueous-based solutions such as contrast media and 0.9% saline solution for predictable flow directed level of occlusion in the vasculature.
Device Description
Rapidly absorbs contrast media and 0.9% saline solution. The . spheres are positively charged, which allows them to bond ionically with negatively charged aqueous based solutions.
. Compresses in the vessel lumen, providing more surface contact with vessel intima.
. Expands up to four times the stated dry diameter when hydrated with non-ionic aqueous solutions, resulting in an increase in surface area contact for a more complete vessel occlusion.

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The technological characteristics of the subject of this Special 510(k) are substantially equivalent to the predicate device, QuadraSphere Microspheres, 510(k) K052742, cleared on November 7, 2006.

The only difference between the new subject device and the predicate device is the additional size offering (30 to 60μm) of the QuadraSphere Microsphere. The indications for use remain the same. All of the QuadraSphere Microspheres react the same and expand approximately 4 times their dry size when properly reconstituted in saline.

Technological Characteristics Comparison Table
Attribute	PredicateDeviceQuadraSphereMicrospheres50-100μm100-150μm150-200 μm	Subject DeviceQuadraSphereMicrospheres30-60μm	Comment
Shelf Life(single use)	Three years(36 months)	Three years(36 months)	Same
Material	PVA AcrylicCopolymer (vinylalcohol-sodiumacrylate)	PVA AcrylicCopolymer (vinylalcohol-sodiumacrylate)	Same
PhysicalCharacteristics	Biocompatible,hydrophilic,deformable, non-resorbable,expandable,conformable andswell uponexposure toaqueoussolutions	Biocompatible,hydrophilic,deformable, non-resorbable,expandable,conformable andswell uponexposure toaqueoussolutions	Same
Sterilization	RadiationSterilized	RadiationSterilized	Same
Performance	Designed forcontrolled,targetedembolizationwhen vesselconformity isdesired(completelyblock the arteriallumen)	Designed forcontrolled,targetedembolizationwhen vesselconformity isdesired(completelyblock the arteriallumen)	Same
Volume ofMicrospheresin Vial (dry)	25 mgs per vial	25 mgs per vial	Same

Technological Characteristics

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BioSphere Medical, Inc. bases its claim of the substantial equivalence of the QuadraSphere Microspheres with the cited predicate device based on intended use, indications for use, fundamental scientific technological characteristics, and fundamental operational characteristics. In all cases, the embolization agent is delivered to selected sites through catheters with a diameter that is appropriate for the vascular target and the size of the embolization agent. Accurate placement is assured through visualization of the injection process using fluoroscopic imaging. Embolization agents are mixed with the contrast media before injection to optimize visualization of the embolization procedure. The subject device, QuadraSphere Microspheres, is available in a 30 to 60um size microsphere to permit selection of the appropriate size for target vessels. All cited embolization agents are intended for single use and are provided sterile. The following testing successfully met requirements, which evaluated fundamental characteristics: Bioburden; Endotoxin; Granulometry (size distribution) Swelling in Contrast Agent; Optical Inspection; and Water Content (Microsphere).

The parameter evaluated (animal study) concerning fundamental operational characteristics for the subject device were met. An animal study to evaluate safety and product performance of QuadraSphere Microspheres 30-60um was conducted using healthy minipias. The objective was to evaluate location of occlusion, in vitro granulometry, histopathology, and safety. Evaluation of location of occlusion was determined by the diameter of blood vessels occluded by the microspheres in histopathology specimens. Safety was assessed from animal behavior, blood tests, and histopathologic examination. In vitro granulometry demonstrated that microspheres were within the expected size range. Embolization was successful for all animals, and there were no significant adverse events post procedure. The mean diameter of the occluded vessels was 146+ 46um (median 136um), and the mean number of microspheres in the occluded vessel section was 1.4±0.8 um (median 1.0 ym). Macrophages were present in most of the occluded vessels, while neutrophils, lymphocytes and eosinophils were rare. These findings are consistent with similar studies of histological response to several types of embolic particles. The results of the study demonstrated that hepatic artery embolization in the pig liver with QuadraSphere 30-60um was feasible and tolerated well both clinically and biologically by the animals.

Safety & Performance Tests

No performance standards applicable to this device have been adopted under Section 514 of the Act. However, vascular embolization devices are subject to the special controls specified in "Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices," issued on December 29, 2004.

Biocompatibility testing was performed in accordance with ISO 10993-1 for permanent implants in contact with blood for the predicate device and are being adopted for this subject device based upon the fact that both devices are made from the same materials using the same processes with now the inclusion of an additional size offering.

In-vitro and in-vivo (animal study) design verification and validation testing demonstrates that the BioSphere Medical QuadraSphere Microspheres 30 to 60µm fulfill design and performance specifications. Performance testing of the subject device was conducted based on the requirements of design input and output requirements. The results of the testing demonstrated that the subject BioSphere Medical QuadraSphere Microspheres 30 to 60µm met the pre-determined acceptance criteria applicable to the size requirements and performance of the device.

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Summary of Substantial Equivalence

Based on the same indications for use, design, scientific technology and safety and performance testing, the BioSphere Medical QuadraSphere Microspheres 30 to 60 m device meets the requirements that are considered essential for its intended use and is substantially equivalent to the predicate device.

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle or bird-like symbol with three curved lines representing its wings or body. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular fashion around the symbol.

Public Health Service

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

BioSphere Medical, Inc. c/o Ms. Linda J. Varroso, RAC Ouality Assurance and regulatory Affairs Director 1050 Hingham Street Rockland, MA 02370

Re: K113822

Trade/Device Name: OuadraSphere® Microspheres Regulation Number: 21 CFR 882.5950 Regulation Name: Neurovascular Embolization Device Regulatory Class: Class II Product Code: HCG Dated: February 6, 2012 Received: February 7, 2012

Dear Ms. Varroso:

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.

MAR - 8 2012

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Page 2 - Ms. Linda J. Varroso, RAC

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 device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) 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 go to http://www.fda.gov/AboutFDA/CentersOffices/CDRHOffices/ucm115809.htm for the Center for Devices and Radiological Health's (CDRH's) Office of Compliance. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 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 Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.

Sincerely vours.

Dihimph

Malvina B. Eydelman M.D. Director Division of Ophthalmic. Neurological, and Ear, Nose and Throat Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K113822

Device Name: QuadraSphere® Microspheres

Indications for Use:

QuadraSphere Microspheres are indication of hypervascularized tumors and peripheral arteriovenous malformations.

Prescription Use _ × (Part 21 CFR 801 Subpart D) AND/OR

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

(PLEASE DO NOT WRITE BELOW THIS LINE—CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of Device Evaluation (ODE)

Jeffrey Toy

(Division Sign-Off) Division of Ophthalmic, Neurological and Ear, Nose and Throat Devices

510(k) Number K113822

Regulation Number and Section

§ 882.5950 Neurovascular embolization device.

(a)
Identification. A neurovascular embolization device is an intravascular implant intended to permanently occlude blood flow to cerebral aneurysms and cerebral ateriovenous malformations. This does not include cyanoacrylates and other embolic agents, which act by polymerization or precipitation. Embolization devices used in other vascular applications are also not included in this classification, see § 870.3300.(b)
Classification. Class II (special controls.) The special control for this device is the FDA guidance document entitled “Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices.” For availability of this guidance document, see § 882.1(e).