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Mesh complications: The role of local mechanical stresses on tissue remodeling following mesh implantation

Award Number: R01HD083383
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Pelvic organ prolapse (POP) is a common debilitating disease afflicting women throughout the world. 12.6% of women in the United States alone will undergo a major surgery to repair POP by age 80. Current practice supports using lightweight, knitted, wide pore polypropylene to improve the high failure rates associated with native tissue repair. However, mesh use has been limited by complications, most commonly mesh exposure through the vaginal epithelium and pain, occurring in ~10% of cases. Previously, using ex vivo tests and computational models, we showed that the pore geometries of most POP meshes were markedly unstable, easily deforming with small applications of tension, resulting in collapsed pores and wrinkling. In contrast, square pored meshes were stable showing little deformation, translating into overall improved structural and functional outcomes in vivo as compared to meshes with unstable geometries. However, by rotating square pored meshes 45o to an unstable diamond configuration and intentionally introducing wrinkles, we successfully reproduced complications. Most obvious were mesh exposures associated with thinning and degeneration of the underlying vagina indicative of stress shielding. A more subtle finding was in adjacent areas where we observed dense collagen/matrix deposition and tissue thickening consistent with fibrosis, a plausible mechanism of pain. Myofibroblasts, not typically present in healthy tissues, were dramatically increased in areas of mesh deformation, particularly where fibrosis was evident, strongly suggesting that mechanical signals, occurring at a highly local level, were a primary driver of the host response. Thus, while our previous studies had focused on the immune response immediately in the area of the mesh fiber, we appreciated that more impactful events driven by fibroblasts were perhaps even more critical in POP biomaterial outcomes. The overall hypothesis of this proposal is that local stress variations induced by tensioning and physiologic loading of mesh, signal vaginal fibroblasts toward a proliferative vs degradative response vs quiescence based on local mechanical cues. To address this hypothesis, in Aim 1, we define the response of vaginal fibroblasts to altered mechanical stresses imposed by mesh over time in a) an in vivo rabbit colpopexy model; and b) an in vitro model using a functionalized synthetic tunable matrix that affords fibroblast mechanosignaling. In Aim 2, we test the hypothesis that over tensioning a stable pore mesh has negative impact on the host response by increasing stress variability. While high stress areas will induce myofibroblast proliferation and matrix/collagen deposition with contraction; subphysiologic (shielded) stress areas will lead to matrix degradation and fibroblast apoptosis. In Aim 3, we interpret findings from the previous aims in mesh removed from women with complications by comparing the fibroblast and immune responses in normally incorporated flat mesh to that found in deformed mesh. We advocate that defining the mechanistic basis of current complications is a key and necessary step in the iterative process toward improving current meshes and developing future novel devices for POP repair.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $597,861 )
2023	2023	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	002	8	7/26/2023	NON-COMPETING CONTINUATION	$597,861
2023	2022	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	7	12/16/2022	NON-COMPETING CONTINUATION	$0
2023	2020	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3240 CRAFT PL STE 100	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	5	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $597,861

Issue Date FY: 2022 ( Subtotal = $602,118 )
2022	2022	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	002	7	8/19/2022	NON-COMPETING CONTINUATION	$602,118
2022	2021	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	6	2/22/2022	COMPETING CONTINUATION	$3,555
2022	2020	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	5	2/22/2022	NON-COMPETING CONTINUATION	-$3,555
														Subtotal = $602,118

Issue Date FY: 2021 ( Subtotal = $647,515 )
2021	2021	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	6	8/5/2021	COMPETING CONTINUATION	$647,515
2021	2020	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	5	7/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $647,515

Issue Date FY: 2020 ( Subtotal = $513,980 )
2020	2020	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	5	2/24/2020	NON-COMPETING CONTINUATION	$51,398
2020	2020	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	5	1/15/2020	NON-COMPETING CONTINUATION	$462,582
														Subtotal = $513,980

Issue Date FY: 2019 ( Subtotal = $513,980 )
2019	2019	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	4	1/8/2019	NON-COMPETING CONTINUATION	$513,980
														Subtotal = $513,980

Issue Date FY: 2018 ( Subtotal = $520,949 )
2018	2018	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	3	4/26/2018	NON-COMPETING CONTINUATION	$52,815
2018	2018	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	3	12/21/2017	NON-COMPETING CONTINUATION	$468,134
														Subtotal = $520,949

Issue Date FY: 2017 ( Subtotal = $520,949 )
2017	2017	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	001	2	6/30/2017	NON-COMPETING CONTINUATION	$52,815
2017	2017	MAGEE-WOMENS RESEARCH INSTITUTE AND FOUNDATION	3339 WARD ST	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	2	12/22/2016	NON-COMPETING CONTINUATION	$468,134
														Subtotal = $520,949

Issue Date FY: 2016 ( Subtotal = $535,699 )
2016	2016	MAGEE-WOMENS HEALTH CORPORATION	300 HALKET STREET	PITTSBURGH	PA	15213	ALLEGHENY	USA	Child Health and Human Development Extramural Research	000	1	1/12/2016	NEW	$535,699
														Subtotal = $535,699

Grand Total All Awards = $4,453,051

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Mesh complications: The role of local mechanical stresses on tissue remodeling following mesh implantation

Award Number: R01HD083383

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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