TRS Cranial Bone Void Filler is intended for use in the repair of 13mm neurosurgical cranial burr holes. It should be gently packed into bony voids or gaps of the skeletal system that are not intrinsic to the stability of the bony structure.

Device Description

TRS Cranial Bone Void Filler (TRS C-BVF) is a synthetic, porous, osteoconductive, bone void filler made from PCL polycaprolactone (CaH100-)X which will degrade and resorb fully in vivo by hydrolysis and is subsequently metabolized by the body, and hydroxylapatite (Ca10(PO4)6.(OH)2) with a calcium phosphate bone mineral coating (Hydroxylapatite and Octacalcium phosphate). TRS BVF has an interconnected porous structure that acts as an osteoconductive matrix for the ingrowth of bone.

TRS C-BVF is available in single size, which is a 13mm diameter x 5mm "plug" with a 20mm diameter x .90mm thick flange.

TRS C-BVF is manufactured using a laser sintering process and is then coated with the calcium phosphate bone mineral coating. The product is shipped to a contract manufacturer who packages, labels and sterilizes the C-BVF devices. They are then returned to TRS and inventoried as Finished Goods.

AI/ML Overview

Acceptance Criteria and Study for TRS Cranial Bone Void Filler (TRS C-BVF)

This document describes the acceptance criteria and the study performed to demonstrate the substantial equivalence of the Tissue Regeneration Systems Cranial Bone Void Filler (TRS C-BVF) to its predicate devices, as presented in 510(k) Premarket Notification K123633.

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria for TRS C-BVF were not explicitly stated as numerical thresholds for specific performance metrics in the provided document. Instead, the study aimed to demonstrate "comparable performance" or "similar performance" to predicate devices across various tests. Therefore, the "acceptance criteria" are implied by the demonstration of substantial equivalence to already cleared devices.

The reported device performance is summarized in the table below, based on the non-clinical testing performed.

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance (TRS C-BVF)
Biocompatibility	Non-cytotoxic, non-sensitizer, non-irritant, no acute systemic toxicity, non-mutagenic, non-clastogenic, non-pyrogenic, no evidence of systemic toxicity, non-hemolytic, minimal activator of intrinsic coagulation pathway. (Demonstrate compliance with ISO 10993 standards akin to predicate devices).	Cytotoxicity (ISO 10993-5): No cytotoxicity or cell lysis, reactivity grade 0. Sensitization (ISO 10993-10): No evidence of causing delayed dermal contact sensitization. Intracutaneous Reactivity (ISO 10993-10): No erythema/edema or very slight with difference from control ≤ 1.0. Systemic Toxicity (Acute) (ISO 10993-11): No mortality or evidence of systemic toxicity. Genotoxicity (Gene mutation) (ISO 10993-3): Non-mutagenic. Genotoxicity (in-vivo) (ISO 10993-3): Non-clastogenic. Genotoxicity (Mouse Lymphoma) (ISO 10993-3): Non-mutagenic. Local effects (2wks) (ISO 10993-6): Non-irritant compared to negative control (HDPE) and ChronOS. Local effects (6wks) (ISO 10993-6): Non-irritant compared to ChronOS, slight irritant compared to HDPE. Pyrogen study (USP) (ISO 10993-11): Non-pyrogenic after retest. Sub-chronic toxicity (13wks) (ISO 10993-11): No evidence of systemic toxicity, local reaction not significant compared to HDPE. Chronic toxicity (26wks) (ISO 10993-11): No evidence of systemic toxicity, local reaction not significant compared to HDPE, moderate irritant compared to HDPE (expected mild macrophage/giant cell response). Hemolysis (ASTM F756): Non-hemolytic. PTT (ASTM F2382): Averaged 77% of negative control (passed as minimal activator). C3a/SC5b-9 Complement Activation (ISO 10993-4): Statistically significantly higher than controls (attributed to surface-related phenomenon, not a direct blood-contacting device).
Material Degradation	Comparable degradation mechanism and profile to ChronOS predicate; qualitatively similar polymeric material components to Osteopore PCL Scaffold predicate.	Polymer degradation (ISO 10993-13): Similar PCL degradation mechanism (hydrolysis). TRS C-BVF lost 10-23% molecular weight and 0.26-0.47% mass at 365-730 days. ChronOS showed faster degradation (57% reduction at 30 days, 90% at 90 days, completely degraded by 540 days). TRS device is in the first stage of degradation. Ceramic degradation (ISO 10993-14): Both extreme and simulation tests demonstrated ceramic component is calcium and phosphate. Heavy metal elements within acceptable limits. FTIR Analysis: FTIR results showed strong peaks consistent with PCL for both TRS C-BVF and Osteopore PCL Scaffold, indicating PCL as a major component. Degradation for Osteopore material (and thus TRS C-BVF) presumed similar to TRS C-BVF.
Mechanical Properties	Comparable compressive mechanical properties and push-out force to predicate devices (chronOS and Osteopore PCL).	Bench testing showed comparable performance in compressive mechanical properties and push-out force to chronOS and Osteopore devices.
Bone Ingrowth/Healing	Similar performance to predicate ChronOS device in new bone formation in an animal model, demonstrating facilitation of constant, sustained bony healing response.	Rabbit Calvarial Defect Testing: Similar performance to predicate ChronOS device with respect to new bone formation. Total bone formation approximately equal by 26 weeks, nearly identical bone volumes by 78 weeks (CT).

Note: The FDA's 510(k) clearance process focuses on demonstrating "substantial equivalence" to a legally marketed predicate device rather than meeting predefined, quantitative acceptance criteria for novel claims. The reported performance aims to show that the new device is as safe and effective as the predicate.

2. Sample Sizes and Data Provenance

The document does not explicitly state a general "test set" sample size in the context of a single uniform study. Instead, different sample sizes were used for various non-clinical tests:

Biocompatibility Tests (ISO 10993 series):
- Cytotoxicity (ISO 10993-5): Not specified, but standard in-vitro test.
- Sensitization (Guinea pig maximization test) (ISO 10993-10): "All animals" (implies a typical number for this test, usually around 10-20 guinea pigs for a maximization test).
- Intracutaneous Reactivity (ISO 10993-10): Not specified.
- Systemic Toxicity (Acute) (ISO 10993-11): "Mice" (implies a typical number for acute toxicity, often 3-5 mice per extract).
- Genotoxicity (Bacterial Reverse Mutation) (ISO 10993-3): Standard in-vitro assay using specific Salmonella typhimurium and Escherichia coli tester strains, not a sample size of devices.
- Genotoxicity (in-vivo; Mouse Peripheral Blood Micronucleus Study) (ISO 10993-3): "Mice" (implies a typical number, usually 5-6 mice per group).
- Genotoxicity (Mouse Lymphoma Assay) (ISO 10993-3): Standard in-vitro assay using L5178Y/TK+/- cell line.
- Local effects after Implantation (Muscle implantation study in rabbits) (ISO 10993-6): "Rabbits" for 2 and 6-week studies (typically small groups, e.g., 3-5 rabbits per group).
- Pyrogen study (USP) (ISO 10993-11): Initial test: 3 animals. Retest: 5 additional animals (total 8 rabbits).
- Sub-chronic toxicity (13 week study) (ISO 10993-11): "Rats" (small groups, e.g., 5-10 rats per sex/group).
- Chronic toxicity (26 week study) (ISO 10993-11): "Rats" (similar to sub-chronic, small groups).
- ASTM F756 Hemolysis Test: Standard in-vitro test, not a patient sample size.
- Partial Thromboplastin Time (PTT): Standard in-vitro test, not a patient sample size.
- C3a/SC5b-9 Complement Activation Assay: Standard in-vitro test, not a patient sample size.
- Polymer degradation (ISO 10993-13): Samples of TRS C-BVF and ChronOS incubated over various time points (30, 90, 180, 365, 540, 730 days), likely duplicate/triplicate samples per time point.
- Ceramic degradation (ISO 10993-14): Coated and uncoated discs tested in extreme and simulation solutions.
Bench Testing: Not specified, but involved multiple samples of TRS C-BVF and predicate devices for mechanical property measurements.
Animal Testing (Rabbit Calvarial Defect testing): "Rabbits" (implies a typical number for animal models, usually in groups of 6-12 animals per test/control arm).

Data Provenance: The studies described are pre-clinical (in-vitro and animal). The country of origin for the studies is not explicitly stated, but they are generally performed in GLP-certified labs, often in the US or other countries with established regulatory testing standards. The data is prospective in the sense that these tests were specifically conducted to support this 510(k) submission.

3. Number of Experts and Qualifications for Ground Truth

This type of submission (510(k) for a bone void filler) does not typically involve human expert readers establishing ground truth in the way defined for image-based diagnostic AI devices. The ground truth for the pre-clinical studies was established through:

Laboratory assays and measurements: For biocompatibility, mechanical properties, and degradation, the "ground truth" is the objective result of the standardized test method (e.g., cell viability count, force measurement, chemical analysis, animal health observations).
Histopathological evaluation: For the animal (rabbit) study, the "ground truth" for new bone formation would have been established by a pathologist (likely a veterinary pathologist or a pathologist specializing in bone/tissue histomorphometry) examining tissue samples from the defect sites. The number of pathologists and their specific years of experience are not mentioned in this summary but would be part of the full study report.

4. Adjudication Method for the Test Set

Not applicable. As described above, the "test set" consists of laboratory and animal study results, not a set of human-interpreted cases requiring adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No. An MRMC comparative effectiveness study is designed for diagnostic imaging devices where multiple human readers interpret cases to assess diagnostic accuracy, often with and without AI assistance. TRS C-BVF is a bone void filler, not a diagnostic device, so this type of study is not relevant to its clearance.

6. Standalone (Algorithm Only) Performance

No. This device is a physical medical implant, not an algorithm or AI software. Therefore, the concept of "standalone performance" for an algorithm is not applicable.

7. Type of Ground Truth Used

The ground truth for the various studies includes:

Standardized laboratory measurements and observations: For biocompatibility (e.g., cell counts, dermal reactions, organ weights, histopathology, chemical analysis).
Mechanical engineering data: For bench testing (e.g., force/stress measurements).
Histological and imaging evaluation (CT): For animal studies, assessing new bone formation and volume.

8. Sample Size for the Training Set

Not applicable. This device is a physical medical implant, not an AI/ML algorithm that requires a training set.

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

Not applicable. As there is no AI/ML algorithm involved, there is no training set or associated ground truth establishment process.

Summary

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Tissue Regeneration Systems, Inc. 510(k) Premarket Notification TRS CRANIAL BONE VOID FILLER (TRS C-BVF) August 14, 2013

510(k) Summary Tissue Regeneration Systems, Inc TRS Cranial Bone Void Filler Traditional 510(k)

1.0 Manufacturer Name

Tissue Regeneration Systems, Inc. 5400 Carillon Point Kirkland, Washington 98033

AUG 16 2013

2.0 Official Contact

Jim Fitzsimmons Chief Executive Officer

Phone: 425-576-4032 Fax: 425-576-4040 E-mail: Jim@tissuesys.com

Alternate Contact

John Garinger Director, Regulatory Affairs and Quality Assurance Phone: 206-730-2815 Fax: 425-576-4040 E-mail: John@tissuesys.com ·

3.0 Date Prepared: November 16, 2012

4.0 Device Name and Classification

Proprietary Name: Common/Usual Name: Classification Name: Requlation Number: Device Class: Classification Name: Classification Panel:

TRS PCL Cranial Bone Void Filler Bone void filler Burr Hole Cover 8882.5250 Class II GXR

5.0 Indications for Use

Neurology

6.0 Device Description

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Tissue Regeneration Systems. Inc. 510(k) Premarket Notification TRS CRANIAL BONE VOID FILLER (TRS C-BVF) August 14, 2013

TRS C-BVF is available in single size, which is a 13mm diameter x 5mm "plug" with a 20mm diameter x .90mm thick flange.

7.0 Predicate Devices

Osteopore PCL Scaffold Bone Void Filler (BVF), (K051093, product code GXP cleared on March 17, 2006) Note: This device would be cleared under product code GXR if it were reviewed using today's more product specific product codes.

Synthes chronOS Composite resorbable bone void filler (K071046, product code MQV, cleared on October 23, 2007).

Synthes chronOS, porous, osteoconductive, resorbable bone void filler (K041350, product code GXP, cleared on July 8, 2004).

Synthes Rapid Resorbable Cranial Clamp burr hole cover (K041611, product code GXR, cleared on September 8, 2004.

8.0 Comparison to Marketed Devices

Tissue Regeneration Systems, Inc. purports the information contained in this 510(k) Submission demonstrates that the TRS Cranial Bone Void Filler is substantially equivalent to Osteopore PCL Scaffold Bone Void Filler cleared under K051093. Synthes chronOS Composite cleared under K071046, Synthes chronOS, cleared under K041350 and Synthes Rapid Resorbable Cranial Clamp cleared under K041611.

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CRANIAL BONE VOID FILLER (TRS C-BV
August 14, 20

Table 6-1 Predicate Device Regulatory Comparisor

Information	Subject Device	Predicate Device	Predicate Device	Predicate Device	Predicate Device
Manufacturer	Tissue Regeneration Systems, Inc.	Synthes	Synthes chronOS	Osteopore	Synthes
Trade Name	TRS C-BVF	Synthes chronOS Composite	Synthes chronOS	Osteopore PCL Scaffold Bone Void Filler	CranioClamp - Bioabsorbable Cranial Bone Flap Fixation System
510(k) #	To Be Determined	K071046	K041350	K051093	K071138
Product Code	GXR	MQV	GXP	GXP	GXR
Regulation Number	882.55250	888.3045	882.5300	882.5300	882.5250
Classification Name	Burr Hole Cover	Resorbable Calcium Salt Bone Void Filler	Methylmethacrylate for Cranioplasty	Methylmethacrylate for Cranioplasty	Burr Hole Cover
Device Class	Class II	Class II	Class II	Class II	Class II
Classification Panel	Neurology	Orthopedic and Rehabilitation Devices	Neurology	Neurology	Neurology

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Table 6-2: Device Characteristic Comparison
Characteristic	TRS C-BVF(subject device)	Synthes chronOSComposite(predicate/reference)	Synthes chronOS(predicate device)	Osteopore PCLScaffold(predicate device)	SynthesCranioClamp -BioabsorbableCranial BoneFlap FixationSystem (predicatedevice)	Similar	Different
Materials	PCL (poly-ε-caprolactone),Hydroylapatite,OctacalciumPhosphateBone contactingsurface:Hydroxyapatite andCalcium PhosphatePCL MatrixCeramic Particles	PCL (polylactide-co-ε-caprolactone) matrixwith imbedded β-Tricalcuim Phosphategranules.Bone contactingsurface:Calcium PhosphatePCL MatrixCeramic Particles	β-TricalcuimPhosphategranules.Bone contactingsurface:Calcium Phosphate	PCL (poly-ε-caprolactone)Bone contactingsurface: PCL (poly-ε-caprolactone)PCL MatrixNo CeramicParticles	85:15 Poly (L-lactide-co-glycolide)Bone contactingsurface:85:15 Poly(L-lactide-co-glycolide)No PCLNo Ceramic Particles	X
	Not intended to betrimmed	Can be trimmed with ascalpel or molded	Can be trimmedwith a scalpel ormolded	Can be trimmedwith a scalpel	Not intended to betrimmed	X
Biocompatible	ResorbablematerialsMeets ISO 10993InterconnectedmacroporousstructurePCL MatrixCeramic Particles	Resorbable materialsMeets ISO 10993Interconnectedmacroporous structurePCL MatrixCeramic Particles	ResorbablematerialsMeets ISO 10993InterconnectedmacroporousstructureNo PCLCeramic Particles	ResorbablematerialsMeets ISO 10993InterconnectedmacroporousstructurePCL MatrixNo CeramicParticles	Resorbable materialsMeets ISO 10993Smooth surfaceNo PCLNo Ceramic Particles	X
Design	Not intended to betrimmedCylindrical plug withflange	Can be trimmed with ascalpel or moldedVarious forms/sizes	Can be trimmedwith a scalpel ormoldedVarious forms/sizes	Can be trimmedwith a scalpelVarious forms/sizes	Not intended to betrimmed18 mm diameter disc	X
Characteristic	TRS CBVF(subject device)	Synthes chronOS Composite(predicate/reference)	chronOS(predicate device)	Osteopore PCL Scaffold(predicate device)	CranioClamp - BioabsorbableCranial BoneFlap FixationSystem	Similar	Different
Intended Use	Is intended to be gently packed or placed into bony voids or gaps of the skeletal system.	Is intended to be gently packed or placed into site.	Is intended to be gently packed or placed into site.	Is intended to be gently packed or placed into bony voids or gaps of the skeletal system.	Is intended for covering burr holes and for fixation of cranial bone flaps, in pediatric and adult patients.	X
Indications for Use	Is indicated for use in the repair of neurosurgical cranial burr holes.	Is indicated for bony voids or gaps that are not intrinsic to the stability of the bony structure. Synthes chronOS Composite is indicated for use in the treatment of bony defects created surgically or through traumatic injury.	Is intended for the repair or filling of craniofacial defects and craniotomy cuts with a surface area no larger than 25 cm². It is also indicated for the restoration or augmentation of bony contours of the craniofacial skeleton; including the fronto-orbital, malar and mental areas.	Is indicated for use in the repair of neurosurgical burr holes, craniotomy cuts and other cranial defects. It is also for use in the augmentation or restoration of bony contour in the craniofacial skeleton.	Is intended for covering burr holes and for fixation of cranial bone flaps, in pediatric and adult patients.		X
Function	Fill bony voids or gaps of the skeletal system until the device is replaced by bone during the healing process.	Fill bony voids or gaps of the skeletal system until the device is replaced by bone during the healing process.	Fill bony voids or gaps of the skeletal system until the device is replaced by bone during the healing process.	Fill bony voids or gaps of the skeletal system until the device is replaced by bone during the healing process.	Covering burr holes and for fixation of cranial bone flaps	X
Sterilization	Sterile Ethylene Oxide	Sterile Irradiation	Sterile Irradiation	Sterile Irradiation	Sterile		X

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Comparison to Marketed Devices continued: The subject device and the predicate devices have the same intended use, are of similar design, perform the same function and are composed of similar resorbable materials. The subject and predicate devices are osteoconductive and both provide an interconnected, porous scaffold and an environment for new bone ingrowth. Both devices are available in similar forms and are provided sterile. Both the subject and predicate devices are shown to be biocompatible, perform similarly in in-vitro and animal testing and are composed of component materials with a history of use in implantable medical devices.

9.0 Performance Testing

TRS Cranial Bone Void Filler has undergone a comprehensive battery of non-clinical testing, including chemical, physical, animal and biocompatibility. Testing has provided reasonable assurance of safety and effectiveness for its intended use and supports a determination of substantial equivalence.

9.1 Biocompatibility, including Degradation Testing:

Comprehensive biocompatibility testing of the TRS C-BVF material demonstrates that it is biocompatible; non-genotoxic, nonpyrogenic, non-toxic and a non-irritant. See Table 6-3 for the specific tests performed including the results and conclusions.

Results of the degradation testing, which included accelerated and real-time polymer degradation, as well as extreme simulation ceramic degradation, have shown comparable performance between the TRS and chronOS predicate device. Both devices demonstrated a similar PCL degradation mechanism by hydrolysis of the ester linkage to give a carboxylic acid and an alcohol as by products. In addition, similar trace elements were detected for both devices. Molecular ions detected from the extracts from both devices at 90-day real-time test demonstrated similar retention times, and indicate the degraded compounds are similar or related. These results provide further evidence that the TRS C-BVF is substantially equivalent to the chronOS predicate device.

While degradation testing was not performed on the OsteoPore PCL Scaffold predicate device, an infrared analysis of both the TRS C-BVF device and the OsteoPore PCL Scaffold device was undertaken using Fourier Transform Infrared Spectroscopy (FTIR) to qualitatively establish similarity of PLC polymeric material components between these devices. FTIR results for both TRS device and Osteopore PCL Scaffold showed strong peaks

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consistent with traditional peaks found in the infrared spectra of PCL indicated that PCL is a major component for these devices. (See Section 11.4 of this 510(k) submission and Appendix B, Tab B-5 for a summary of this testing.) Given that both the TRS C-BVF device and the OsteoPore PCL Scaffold predicate are composed of Poly-E-caprolactone material, degradation results for the OsteoPore material are presumed substantially similar to the TRS C-BVF device.

In conclusion, the TRS C-BVF device is biocompatible and demonstrates comparable degradation performance to the predicate devices, supporting a claim of substantial equivalence to the predicate chronOS and OsteoPore PCL Scaffold devices.

ISO10993Standard	Test	Results	Conclusions
10993-5	Cytotoxicity (ISO ElutionMethod- 1X MEMExtract)	No cytoxicity or cell lysis was noted in any of the test wells. NopH shift was observed at 48 hours. Reactivity grade was 0(none).	Non-cytotoxic
10993-10	Sensitization (Guineapig maximizationsensitization test)	All Animals were clinically normal throughout the study. Testarticle extracts showed no evidence of causing delayed dermalcontact sensitization in guinea pig.	Non-sensitizer
10993-10	IntracutaneousReactivity	There was no erythema and no edema from the 0.9% sodiumchloride solution test extract. There was very slight erythemaand very slight edema from the sesame oil test extract.However, the difference from the control was 1.0 or less.	Non-irritant
10993-11	Systemic Toxicity (Acutesystemic toxicity in mice)	There was no mortality or evidence of systemic toxicity fromthe test extracts. Body weight data were acceptable.	No acute systemictoxicity
10993-3	Genotoxicity (Genemutation): BacterialReverse Mutation study	The DMSO and saline extracts from TRS device wereconsidered to be non-mutagenic to Salmonella typhimuriumtester strains TA98, TA100, TS1535, and TA1537, and toEscherichia coli tester strain WP2uvrA.	Non-mutagenic
10993-3	Genotoxicity (in-vivo;Mouse Peripheral BloodMicronucleus Study)	The saline and sesame oil test extracts did not inducemicronuclei in mice. There were no statistically significantdifferences between the test and negative control groups.	Non-clastogenic
10993-3	Genotoxicity (MouseLymphoma Assay)	The undiluted RPMI₀ and 1.0% DMSO TRS device extracts didnot cause any positive increase in the mean mutant frequencyin the L5178Y/TK⁺/⁻ cell line either in the presence or absenceof metabolic activation.	Non-mutagenic
10993-6	Local effects afterImplantation (Muscleimplantation study inrabbits-2 weeks)	The macroscopic reaction of TRS device was not significant ascompared to the ChronOS and negative control (HDPE).Microscopically, TRS device was classified as a non-irritant ascompared to ChronOS and HDPE.	Non-irritant ascompared to thenegative control(HDPE) andpredicate device(ChronOS)
ISO10993	Test Description	Results	August 14, 2013Conclusions
10993-6	Local effects afterImplantation (Muscleimplantation study inrabbits-6 weeks)	The macroscopic reaction of TRS device was not significant ascompared to the ChronOS and negative control (HDPE).Microscopically, TRS device was classified as a non-irritant ascompared to ChronOS and a slight irritant when compared toHDPE.	Non-irritant ascompared to thepredicate device(ChronOS) and aslight irritant whencompared to thenegative control(HDPE)
10993-11	Systemic toxicity (USPPyrogen study)	One (out of 3) of the animals showed a rise of 0.5°Cabove itsbaseline temperature. The result was inconclusive and theprotocol required 5 additional animals to be injected.	Inconclusive - retestrequired
10993-11	Systemic toxicity (USPPyrogen study-retest)	A total of 3 out of 8 rabbits had a temperature rise of ≥ 0.5°C,and the total temperature rise of the 8 animals did not exceed3.3°C. The USP test requirement was met. TRS device wasconsidered non-pyrogenic.	Non-pyrogenic
10993-11	Systemic toxicity: Sub-chronic toxicity (13 weekstudy in rats followingsubcutaneousimplantation)	No evidence of systemic toxicity from TRS device followingsubcutaneous implantation in the rat. Daily clinicalobservations, body weights, necropsy findings, organ weightsand organ/body weight ratios were within acceptable limits andwere similar between TRS device and control (HDPE)treatment group. There were no changes in histopathology,hematology values or clinical chemistry values in either maleor female rats. Microscopic evaluation of the selected tissuesrevealed no evidence of a treatment related response.Microscopic evaluation of the implant sites revealed that thetest implant site scores were higher than control implant sitescores.	No evidence ofsystemic toxicity,local macroscopictissue reaction notsignificant ascompared to HDPEcontrol,microscopicallyclassified as slightirritant as comparedto HDPE control
10993-11	Systemic toxicity:Chronic toxicity (26week study in ratsfollowing subcutaneousimplantation)	No evidence of systemic toxicity from TRS device followingsubcutaneous implantation in the rat. Daily clinicalobservations, body weights, necropsy findings, organ weightsand organ/body weight ratios were within acceptable limits andwere similar between TRS device and control (HDPE)treatment group. There were no changes in histopathology,hematology values or clinical chemistry values in either maleor female rats that were considered to be biologicallysignificant or related to treatment with TRS device. Microscopicevaluation of the selected tissues revealed no evidence of atreatment related response. Microscopic evaluation of theimplant sites revealed that the test implant site scores werehigher than control implant site scores	No evidence ofsystemic toxicity,local macroscopictissue reaction notsignificant ascompared to HDPEcontrol,microscopicallyclassified asmoderate irritant ascompared to HDPEcontrol.The degradingsample elicited anexpected mildmacrophage/giantcell response.
10993-4	ASTM F756 HemolysisTest - Direct contactand extract test	The hemolytic index of the test article in direct contact withblood was 0.4% and the hemolytic index for the test articleextract was 0.1%. The test article in direct contact with bloodand the test article extract were both non-hemolytic.	Non-hemolytic
ASTMF2382	Partial ThromboplastinTime (PTT)	Average clotting time of the test article was 77% of thenegative control	Passed as a minimalactivator of theintrinsic coagulationpathway(ASTM F2382defines the testresult of > 50% of thenegative control as apassing result)
ISO10993	Test Description	Results	Conclusions
10993-4	C3a ComplementActivation Assay	C3a concentration of the test article was statisticallysignificantly higher than the activated NHS (normal humanserum) control and negative control (low density polyethylene).	Complementactivation by adevice is primarily asurface relatedphenomenon. AsTRS is not a directblood-contactingdevice, there is nodirect interaction ofthe blood with thesurface of thedevice.
10993-4	SC5b-9 ComplementActivation Assay	SC5b-9 concentration of the test article was statisticallysignificantly higher than the activated NHS (normal humanserum) control and negative control (low density polyethylene).	Complementactivation by adevice is primarily asurface relatedphenomenon. AsTRS is not a directblood-contactingdevice, there is nodirect interaction ofthe blood with thesurface of thedevice.
10993-13	Identification andquantification ofdegradation productsfrom polymeric devices(Real time polymerdegradationPolymer:30,90,180,365,540, and730 days)	After incubation in phosphate buffered saline (PBS) at 37 °C,TRS C-BVF lost 10% and 23% of its molecular weight and0.26% and 0.47% of its initial mass at 365 and 730 days,respectively. Extracts of TRS device revealed one compound(2-hexenoic acid, butyl ester, (E)-) at 30, 90, 180, and 365 dayat a concentration in the range of 2-6 ppm. ChronOScomposite resulted in one compound (di-n-octyl phthalate)detected in the 30 day replicate 2 extract. The averagemolecular weight (Mw) shows that TRS devices wereunchanged after 30 days, but did exhibit degradation by 90days with approximately 5% reduction in average molecularweight. Mw at 365 days showed a decrease of approximately5%with a similar trend for the later time points. The ChronOScomposite, on the other hand, exhibited a 57% reduction inaverage molecular weight by 30 days and a considerable 90%reduction by 90 days, 95% at 180 days, 98% by 365 days, andwas completely degraded prior to the 540 day time point. Thedecrease in pH of the solution of ChronOS composite, mayhave affected the degradation profile. The number averagemolecular weight (Mn) showed that the Mn of TRS devicedecreased approximately 10% over 365 days and furtherdecreased to 23% after 730 days. No other compounds weredetected at any other time point above the quantitation limit.	TRS device real timedegradation resultsdemonstrated thatthe device is in thefirst stage ofdegradation with thedecrease inmolecular weightwithout mass lossand deformation.(Additional detail tofollowing inExecutive Summary)
10993-14	Identification andquantification ofdegradation productsfrom ceramics(extreme/simulation)	The extreme solution test caused approximately 26-27% of theceramic and hydroxylapatite to dissolve from both the coatedand uncoated discs. After the testing had been performed, thebuffer solutions showed the presence of calcium, magnesium,phosphorus, sulfur, and in some cases aluminum, barium, andiron.The simulation solution test caused a mass loss of less than1% for both coated and uncoated discs. The solutions afterthe simulation test contained calcium and phosphorus for bothsample types. In the case of the coated discs, magnesiumand sodium were also observed. The SEM images for thecoated samples after the simulation test still showed the flake-like structure, but some erosion was apparent. After thesimulation test, no significant differences in the EDS data wereobserved, as compared to the coated samples that had notbeen subjected to the simulation test.	Both extreme andsimulation testdemonstrated thatthe ceramiccomponent of TRSdevice is composedof calcium andphosphate ceramic.Quantitative analysisof four individualheavy metalelements (As, Cd,Pb, Hg) was withinacceptable limit asstated in ISO 13779.(Additional detail tofollowing inExecutive Summary)

Table 6-3: Biocompatibility Tests, Results and Conclusions

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TRS CRANIAL BONE VOID FILLER (TRS C-BVF)
TRS CRANIAL BONE VOID FILLER (TRS C-BVF)

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9.2 Bench Testing:

Bench testing to evaluate the compressive mechanical properties and push out force of the TRS C-BVF, the chronOS and Ostepore devices showed comparable performance and demonstrated that the TRS C-BVF device to possess appropriate performance characteristics for its intended use. In addition, material testing using FTIR demonstrated the same PCL material composition in both the predicate Osteopore PCL Scaffold device and the TRS C-BVF device. These results provide further technical evidence supporting a claim of substantial equivalence between the subject and predicate devices.

9.3 Animal Testing:

Results of the Rabbit Calvarial Defect testing have demonstrated similar performance of the TRS C-BVF and predicate chronOS devices with respect to new bone formation. By 26 weeks, total bone formation in both the subject and predicate devices was approximately equal and by 78 weeks, CT showed bone volumes for both devices to be nearly identical. The data shows that TRS C-BVF facilitates a constant, sustained bony healing response over time. Results of this testing demonstrate that the TRS C-BVF performs in a similar manner to the predicate chronOS device in a cranial defect in an animal model. This testing provides further technical evidence that the TRS C-BVF device performs comparably to the predicate chronOS device and provides additional support to a claim of substantial equivalence to the predicate devices.

0.4 Clinical (Literature):

The clinical literature summarized utilizes PCL in a number of material forms and indications. Clinical studies reported good outcomes in applied applications, expected absorption rates and with no reported material-mediated complications.

No clinical studies have been performed in support of this 510(k) application due to the similarities of the TRS C-BVF to the predicate devices. Further, the constituent materials of the subject device have a long history of safe and successful clinical use in numerous implantable medical applications as identified above. The PCL containing materials and material combinations referenced in this literature are comparable to that utilized in the TRS C-BVF. As such, the reported successful clinical history provides evidence of PCL's safety profile in clinical use and is representative of the expected safety profile for TRS C-BVF.

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10.0 Conclusion

Product characterization and testing on the TRS Cranial Bone Void Filler when compared to its predicate devices demonstrate that it is substantially equivalent to the Osteopore PCL Scaffold Bone Void Filler, Synthes chronOS, Synthes chronOS Composite and Synthes Rapid Resorbable Cranial Clamp devices, commercially available cranial burr hole covers.

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Image /page/11/Picture/0 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo features a stylized depiction of an eagle or bird-like figure with three curved lines forming its body and wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the bird symbol.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

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

August 16, 2013

Tissue Regeneration Systems, Inc. Mr. William J. Fitzsimmons President and Chief Executive Officer 5400 Carillon Point Kirkland, WA 98033

Re: K123633

Trade/Device Name: Tissue Regeneration Systems Cranial Bone Void Filler (TRS C-BVF) Regulation Number: 21 CFR 882.5250 Regulation Name: Burr Hole Cover Regulatory Class: Class II Product Code: GXR Dated: July 10, 2013 Received: July 18, 2013

Dear Mr. Fitzsimmons:

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 10 devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you; however, that device labeling must be truthful and not misleading.

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

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

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Page 2 – Mr. William J. Fitzsimmons

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 contact the Division of Small Manufacturers, International and Consumer Assistance at its tollfree number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (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/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Joyce M. Whang -S

for Victor Krauthamer, Ph.D. Acting Director Division of Neurological and Physical Medicine Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K123633

Device Name: Tissue Regeneration Systems Cranial Bone Void Filler (TRS C-BVF))

Indications For Use:

TRS C-BVF is intended for use in the repair of 13 mm neurosurgical cranial burr holes. It should be gently packed into bony voids or gaps of the skeletal system that are not intrinsic to the stability of the bony structure.

V 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)

lovce M. Whana -

Division Sign Off) Division of Neurological and Physical Medicine Devices (DNPMD)

510(k) Number K123633

Page 1 of 1

Regulation Number and Section

§ 882.5250 Burr hole cover.

(a)
Identification. A burr hole cover is a plastic or metal device used to cover or plug holes drilled into the skull during surgery and to reattach cranial bone removed during surgery.(b)
Classification. Class II (performance standards).