a-BSM™ Bone Substitute Material is a synthetic calcium phosphate hydroxyapatitic material intended to be implanted for use in the filling, repair, reconstruction and augmentation of burr holes, contiguous craniotomy cuts, and other defects in craniofacial bones including fronto-orbital, malar and mental areas with a surface area no larger than 25cm².

Device Description

ETEX x-BSM™ Bone Substitute Material for Cranioplasty is a self-setting, synthetic calcium phosphate hydroxyapatitic powder that hardens in an aqueous environment at body temperature. The a-BSMM powder is mixed with saline at the time of use and the resulting paste is applied directly to the defect site. Prior to implantation, it remains moldable for several hours. After implantation, the material hardens in approximately one hour. The material is dimensionally stable during setting, and has been demonstrated to be highly biocompatible with mammalian tissues. After implantation, the material resorbs and is replaced by natural bone.

As supplied, each transparent plastic pouch of a-BSMTM Bone Substitute Material contains a unit dose of sterile a-BSM™ Bone Substitute Material (dry white powder) contained within an elastomeric mixing bulb (available in 0.5, 1.0, 2.5, 5.0, 10 and 25 gram dose sizes); a sterile syringe, a 16 gauge needle, and a vial containing sterile saline; and Instructions for Use. The saline is injected aseptically into the mixing bulb and the material is mixed by kneading the bulb with the fingers. The material can be shaped into the desired form prior to application or shaped in situ in the defect. &-BSM™ Bone Substitute Material is synthesized from reagent grade inorganic raw materials composed of salts of calcium and phosphates. There are no substances of biological origin used in the synthesis or processing of the product. No additional preservatives or medicinal substances are present.

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and supporting studies for the a-BSM™ Bone Substitute Material for Cranioplasty:

1. Table of Acceptance Criteria and Reported Device Performance

The provided 510(k) summary (K983009) for a-BSM™ Bone Substitute Material for Cranioplasty does not explicitly list numerical "acceptance criteria" in the format typically seen with performance metrics for AI/software devices (e.g., sensitivity > X%, specificity > Y%). Instead, it establishes "substantial equivalence" to a predicate device (BoneSource™) by demonstrating similar physico-chemical properties and superior or equivalent biocompatibility and functional outcomes through a series of tests.

The "acceptance criteria" can be inferred as demonstrating that a-BSM™ is either equivalent or superior to BoneSource™ in relevant aspects, and that it meets general safety and biocompatibility standards. The reported device performance is presented as a comparison table and a summary of test results.

Acceptance Criteria (Inferred)	Reported Device Performance (a-BSM™)
Physico-Chemical Equivalence (to Predicate Device BoneSource™)
- Chemical and Crystalline Composition	Very similar composition, nearly identical crystallinity (both hydroxyapatite with amorphous component). Confirmed by FTIR and X-ray Diffraction.
- Calcium:Phosphorus Ratio	Similar to predicate.
- Solubility Determination	Only slightly soluble (6 x 10-54), similar to predicate (6 x 10-67 - difference noted but both very nearly insoluble).
- Setting Mechanism	Self-setting calcium phosphate cement, hardens in aqueous environment at 37 °C, nonexothermic reactions. (Identical to predicate).
- Hardening Time in Body	One hour (faster than predicate's "Up to four hours").
- Pot Life after Mixing	Does not harden at room temperature if moist (Different from predicate's "5 - 30 minutes dependent upon diluent").
Biocompatibility and Safety
- Mutagenicity	No increase in mutation reversion frequencies (Ames Test).
- Genotoxicity (Chromosome Breakage)	No clastogenic effects (Micronucleus Test).
- Hemolysis	No negative effects; decrease in hemolysis (Hemolysis Assay).
- Cytotoxicity	No negative effects (MEM Elution Test).
- Systemic Toxicity	No negative systemic effects (USP Systemic Toxicity Test).
- Sensitization	No effects beyond control articles (Delayed Contact Sensitization Test).
- Pyrogenicity	Nonpyrogenic (Rabbit Pyrogen Test and LAL Evaluation).
- Irritation/Local Toxicity	No evidence of irritation or toxicity beyond control articles (Intracutaneous Toxicity Test). Slight cellular effects compared to control (Muscle Implantation).
Functional Equivalence/Efficacy (to Autografts in Animal Model)
- Promotion of New Bone Growth and Resorption/Remodeling	Equivalent new bone replacement and remodeling compared to autografts at all timepoints over one year. No significant adverse findings (Chronic Safety/Efficacy Study, Histology and Histomorphometry Evaluation).
- Biomechanical Strength	Equivalent biomechanical strength (torsion loading to fracture) compared to autografts at all timepoints over one year (Biomechanical Strength Testing).
Intended Use (Scope and Application)	Use in filling, repair, reconstruction, and augmentation of burr holes, contiguous craniotomy cuts, and other defects in craniofacial bones (fronto-orbital, malar, mental areas) with a surface area no larger than 25 cm². (Very similar to predicate, which specifies neurosurgical burr holes and other cranial defects).

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

This document describes pre-clinical (in vitro and animal) testing, not human clinical trials with "test sets" in the context of diagnostic device assessment. Therefore, the concept of sample size for a "test set" and provenance (country of origin, retrospective/prospective) as typically applied to clinical data for AI/software evaluations is not directly applicable.

Instead, we can identify the following from the document:

Animal Studies:
- Dog Femur Model: Used for "Chronic Safety/Efficacy Study," "Histology and Histomorphometry Evaluation," and "Biomechanical Strength Testing." The precise number of dogs/femurs is not specified but the studies ran for "one year."
- Rabbit Model: Used for "Muscle Implantation" (implantation in rabbit muscle sites) and "Pyrogen Test." The number of rabbits is not specified.
In Vitro/In Vitro Equivalent Studies:
- Mutation Assay (Ames Test), Micronucleus Test, Hemolysis Assay, MEM Elution Test, USP Systemic Toxicity Test, Delayed Contact Sensitization Test, Intracutaneous Toxicity Test, Bacterial Endotoxin (LAL) Evaluation, Physico-Chemical Testing (FTIR, X-ray Diffraction, Ca:P ratio, Solubility, Mechanical properties). These typically involve lab samples, cell cultures, or specialized testing apparatus, not "test sets" of patient data.

Data Provenance: The document does not specify the country of origin for the animal studies or laboratory tests. Given it's an FDA 510(k) submission from "ETEX Corporation" in "Cambridge, Massachusetts, U.S.A.", it's highly probable the studies were conducted in the U.S. or by labs compliant with U.S. regulatory standards. All tests described are preclinical.

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

This information is not applicable to the type of device and study described. Since this is a bone substitute material, the "ground truth" is established through direct observation (e.g., absence of mutation, signs of inflammation), histological examination (e.g., new bone formation), and biomechanical measurements, rather than expert consensus on diagnostic images. The evaluations were performed by laboratory and pathology experts, but their specific number or detailed qualifications (e.g., "radiologist with 10 years experience") are not provided in this summary.

4. Adjudication Method for the Test Set

Not applicable. As noted above, this is not a diagnostic device involving a "test set" requiring adjudication of interpretations. The studies are pre-clinical evaluations of material properties and biological response.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

Not applicable. This device is a bone substitute material, not an AI or diagnostic imaging device that would involve human readers or AI assistance in interpretation.

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

Not applicable. This device is a bone substitute material, not an algorithm or AI.

7. The Type of Ground Truth Used

The "ground truth" for the various tests can be categorized as follows:

Physiological/Biological Response:
- Absence/Presence of Toxic Effects: (e.g., no mutations, no cytotoxicity, no systemic toxicity, no pyrogenic effects, no irritation, no hemolysis).
- Histopathology: Microscopic evidence of tissue response to the implant (e.g., slight cellular effects in muscle implantation, new bone growth and remodeling in femurs).
- Macroscopic Observation: Gross observation of tissue irritation (e.g., no macroscopic evidence of tissue irritation in muscle implantation study).
Engineered Properties:
- Chemical/Crystalline Composition: Determined via spectroscopy (FTIR) and diffraction (X-ray Diffraction).
- Quantitative Measurements: Calcium:Phosphorus ratio, Solubility Product, Hardening Time, Biomechanical Strength (torsion loading to fracture).

8. The Sample Size for the Training Set

Not applicable. This device is a bone substitute material, not a machine learning model, so there is no "training set" in this context.

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

Not applicable, as there is no training set for this type of device. The "ground truth" for the preclinical studies was established through standard scientific methodologies, laboratory protocols, and animal model evaluations as described in point 7.

Summary

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NOV 25 1998

K983009

510(k) SUMMARY

a-BSMTM Bone Substitute Material for Cranioplasty

SUBMITTER INFORMATION 1.

1.1 Name: ETEX Corporation
1.2 ETEX Corporation Address: University Park at MIT 350 Massachusetts Avenue, 4th Floor Cambridge, Massachusetts 02139 U.S.A.
1.3 Telephone: 617-577-7270 FAX: 617-577-7170
1.4 Contact: Michael Schuttenberg Director, Quality Assurance / Regulatory Affairs 1.5 Summary
Monday, November 16, 1998 Preparation Date:

DEVICE INFORMATION 2.

a-BSMTM Bone Substitute Material for Cranioplasty 2.1 Proprietary Name:
Bone Graft Material, Bone Cement, Bone Substitute 2.2 Common Names: Material
2.3 Classification Methyl Methacrylate for Cranioplasty, Code GXP Name and Code: Predicate Device: BoneSource™ Hydroxyapatite Cement 2.4 K953339, Osteogenics, Inc. 510(k) No.:

2.5 Description of Device

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2.6 Intended Use

It is intended for single use, permanent implantation. It is supplied in sterile kit form, and is not intended to be resterilized. Use of a-BSM™ Bone Substitute Material with other legally marketed devices for these indications has not yet been evaluated. a-BSMM Bone Substitute Material is not designed or sold for any use except as indicated.

2.7 Substantial Equivalence to Predicate Device

a - BSM™ Bone Substitute Material is believed to be substantially equivalent to BoneSource™ in terms of design, materials, function, and intended use. Both materials are sterile, self-setting calcium phosphate powders that cure into hydroxyapatite after addition of an aqueous vehicle. This similarity in composition results in a similar degree of biocompatibility for both products. Both materials set in nonexothermic reactions. Both materials are intended for non-load-bearing bone defect filling indications in the craniofacial area. The information below briefly discusses those tests performed that support a determination of substantial equivalence.

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NOV 19 1998 17:42 FR ETEX CORP

TESTING USED FOR SUBSTANTIAL EQUIVALENCE EVALUATION 3.

3.1 Physico-Chemical Testing

Analyses were performed on the predicate device to determine its chemical and crystalline composition relative to the characterization of a-BSM™ Bone Substitute Material. These tests included Fourier Transformed Infrared Spectroscopy, X-ray Diffraction Analysis, Calcium: Phosphorus ratio, Solubility Determination and mechanical properties. Companson of the results of these tests indicate very similar composition, nearly identical crystallinity, and similar solubility - both materials are very nearly insoluble.

Both materials consist of salts of calcium phosphate which, when mixed in an aqueous environment and allowed to harden at body temperature, cure into hydroxyapatite in nonexothermic reactions. Comparing infrared spectroscopy results of both products supports the premise that the type and level of chemical bonding is very similar between the two products. In X-ray Diffraction analysis of the two products, comparison demonstrates that both materials are composed of Hydroxyapatite in the crystalline phase and largely predominant portion of the samples, with both containing an amorphous component. Calcium : phosphorus ratios of the two products were determined and found to be similar. A comparison of solubility properties of the two products was made on hardened samples under simulated physiologic conditions. The results indicate that both materials are only slightly soluble. ETEX believes these results are strongly suggestive of chemically and physically equivalent products.

3.2 Biocompatibility

A variety of tests and evaluations were performed on a-BSM™ to ascertain possible effects of the introduction of this material into mammalian systems or tissues. The tests performed and brief results or conclusions are listed below.

Mutation Assay (Ames Test)

No increase in mutation reversion frequencies were observed.

Micronucleus Test

No clastogenic effects (chromosome breakage) were noted.

Hemolysis Assay

No negative effects observed. In fact, a-BSM™ treated samples showed a decrease in hemolysis.

510(k) Summary - Page 3 of 6 ETEX 510(k) for a-BSM™ Bone Substitute Material for Cranioplasty

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MEM Elution Test

This test of cytotoxicity showed no negative effects.

USP Systemic Toxicity Test

No negative systemic effects observed.

Delayed Contact Sensitization Test

This test of skin sensitization showed no effects beyond that of control articles.

Pyrogen Test

a-BSM™ was determined to be nonpyrogenic by the rabbit pyrogen test.

Intracutaneous Toxicity Test

After injection of a-BSM™ extracts, there was no evidence of irritation or toxicity beyond that of control articles.

Muscle Implantation

Two weeks after implantation of x-BSM™ into rabbit muscle sites, there was no macroscopic evidence of tissue irritation. Microscopic evaluation showed slight cellular effects when compared with control articles.

Bacterial Endotoxin (LAL) Evaluation

This alternate method of testing for pyrogenic effects of an article showed no measurable endotoxins in a-BSM™, and demonstrated that the product did not artificially affect the test results by inhibition or activation of the reagents used.

Chronic Safety/Efficacy Study

One year after implantation of x-BSM™ into surgically created bone defects in dog femurs, clinical and histopathologic evaluation of the repair sites demonstrated that new bone growth had occurred to an extent equal to that of autografts, and included remodeling of the bone tissue. There were no significant adverse findings.

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Histology and Histomorphometry Evaluation

A comparative in vivo study with a-BSM™ and autograft implanted into a canine femoral defect model demonstrated equivalent new bone replacement of the implant material at each timepoint for this one year study.

Biomechanical Strength Testing

In a comparative study with a-BSM™ and autograft as bone substitute materials in a canine femoral defect model, the biomechanical strength (torsion loading to fracture) of the samples were equivalent at each timepoint for this one year study.

Conclusions of Testing 3.3

The physico-chemical testing and biocompatibility evaluation performed on a-BSM™ Bone Substitute Material for Cranioplasty demonstrate that it is similar to the predicate device in terms of its chemical and crystalline composition, and that it shows an excellent biocompatibility and safety profile, with no significant adverse observations on any of a variety of subcellular, cellular, tissue, and systemic challenges.

For the above reasons, which are summarized in the following table comparing equivalence factors, ETEX believes that a-BSM™ Bone Substitute Material is substantially equivalent to BoneSource™ and possesses no properties which raise additional questions of safety relating to the intended use of the product.

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COMPARISON TABLE OF SUBSTANTIAL EQUIVALENCE

ITEM	α-BSM™	BoneSource™
Design	Self-setting calciumphosphate cement whichhardens in aqueousenvironment at 37 °C	Self-setting calciumphosphate cement whichhardens in aqueousenvironment at 37 °C
Composition, afterhardening	Hydroxyapatite, withamorphous component	Hydroxyapatite, withamorphous component
Intended Use	Use in the filling, repair,reconstruction andaugmentation of burr holes,contiguous craniotomy cuts,and other defects incraniofacial bones includingfronto-orbital, malar andmental areas with a surfacearea no larger than 25cm2.	Use in the repair ofneurosurgical burr holes,contiguous craniotomy cutsand other cranial defectswith a surface area no largerthan 25 cm2 per defect.BoneSource is also indicatedfor augmentation orrestoration of bony contourin the craniofacial skeletonincluding the fronto-orbital,malar and mental areas.
How Supplied	Sterile, nonpyrogenicpowder contained inelastomeric mixing bulb tobe mixed at time ofimplantation.	Sterile, nonpyrogenicpowder contained in vial tobe mixed at time ofimplantation.
Preparation Method	Sterile saline injected intomixing bulb, powder mixedby kneading bulb, pasteremoved and implanted.	Powder placed into mixingvessel, sterile solutionadded, powder mixed withspatula, paste implanted
Pot Life after mixing	Does not harden at roomtemperature, if moist	5 - 30 minutes dependentupon diluent
Hardening Time in body	One hour	Up to four hours
Solubility Product	$6 x 10^{-54}$	$6 x 10^{-67}$

α-BSMTM and BoneSource™

ETEX 510(k) for a-BSM™ Bone Substitute Material for Cranioplasty

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Image /page/6/Picture/2 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized caduceus symbol, which is a staff with two snakes coiled around it. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES-USA" are arranged in a circular pattern around the caduceus symbol. The logo is black and white.

Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850

NOV 2 5 1998

Mr. Michael Schuttenberg Director, Quality Assurance and Regulatory Affairs ETEX Corporation 350 Massachusetts Avenue, 4th Floor Cambridge, Massachusetts 02139

K983009 · Re: Trade Name: α-BSM™ Bone Substitute Material for Cranioplasty Requlatory Class: II Product Code: GXP Dated: August 26, 1998 Received: Auqust 28, 1998

Dear Mr. Schuttenberg:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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). 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.

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the current Good Manufacturing Practice requirement, as set forth in the Quality System Regulation (QS) for Medical General regulation (21 CFR Part 820) and that, Devices: through periodic (QS) inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP requlation may result in regulatory In addition, FDA may publish further announcements action. concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2 - Mr. Michael Schuttenberg

This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4659. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".

Sincerely yours,

Celia M. Witten, Ph.D., M.D.
Director

Director Division of General and Restorative Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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PREMARKET NOTIFICATION

DEVICE NAME AND INTENDED USE STATEMENT

Device Name: a-BSMTM Bone Substitute Material for Cranioplasty

Indications/ Intended Uses:

PLEASE DO NOT WRITE BELOW THIS LINE--CONTINUE ON ANOTHER PAGE IF NECESSARY

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use

Over-the -Counter Use

scally

(Division Sign-Off)
Division of General Restorative Devices
510(k) Number K983009

Regulation Number and Section

§ 882.5300 Methyl methacrylate for cranioplasty.

(a)
Identification. Methyl methacrylate for cranioplasty (skull repair) is a self-curing acrylic that a surgeon uses to repair a skull defect in a patient. At the time of surgery, the surgeon initiates polymerization of the material and forms it into a plate or other appropriate shape to repair the defect.(b)
Classification. Class II (performance standards).