Dataset Information

Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

ABSTRACT: Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellular and tissue levels can be induced in mice via the application of human-tissue-scale forces through a vibrating silicone implant. FBRs to such elevated extrinsic forces in the mice were also mediated by the activation of Rac2 signalling in a subpopulation of mechanoresponsive myeloid cells, which could be substantially reduced via the pharmacological or genetic inhibition of Rac2. Our findings provide an explanation for the stark differences in FBRs observed in small animals and humans, and have implications for the design and safety of implantable devices.

SUBMITTER: Padmanabhan J

PROVIDER: S-EPMC10651488 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Padmanabhan Jagannath J Chen Kellen K Sivaraj Dharshan D Henn Dominic D Kuehlmann Britta A BA Kussie Hudson C HC Zhao Eric T ET Kahn Anum A Bonham Clark A CA Dohi Teruyuki T Beck Thomas C TC Trotsyuk Artem A AA Stern-Buchbinder Zachary A ZA Than Peter A PA Hosseini Hadi S HS Barrera Janos A JA Magbual Noah J NJ Leeolou Melissa C MC Fischer Katharina S KS Tigchelaar Seth S SS Lin John Q JQ Perrault David P DP Borrelli Mimi R MR Kwon Sun Hyung SH Maan Zeshaan N ZN Dunn James C Y JCY Nazerali Rahim R Januszyk Michael M Prantl Lukas L Gurtner Geoffrey C GC

Nature biomedical engineering 20230925 11

Small animals do not replicate the severity of the human foreign-body response (FBR) to implants. Here we show that the FBR can be driven by forces generated at the implant surface that, owing to allometric scaling, increase exponentially with body size. We found that the human FBR is mediated by immune-cell-specific RAC2 mechanotransduction signalling, independently of the chemistry and mechanical properties of the implant, and that a pathological FBR that is human-like at the molecular, cellul ...[more]

PMID: 37749310

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Project description:The Implants Access Program (IAP) was a partnership between public and private organizations that aimed to increase access to contraceptive implants for women in low-income countries. The partnership began with 2 volume guarantee agreements that reduced the price of implants by approximately 50% and was complemented by efforts to address supply chain, service delivery, and knowledge and awareness barriers. We conducted a summative evaluation to identify key insights related to the IAP's relevance, effectiveness, and sustainability. We completed a desk review of program materials and published literature, followed by 42 in-depth interviews, including global stakeholders and country stakeholders in 3 case example countries: Kenya, Nigeria, and Uganda. The evaluation found evidence of increased access to implants including a 10-fold increase in procurement between 2010 and 2018 and an increase in prevalence of contraceptive implants during this same period. The IAP leveraged global family planning efforts taking place at the time, and its partnerships offered a business case for manufacturers to support increased access to implants. Enhanced supply chain visibility and coordination helped limit country-level stock-outs, and the IAP built on existing in-country delivery capacity. Although the IAP was able to address key challenges due to its effective collaboration and coordination at global and country levels, sustaining progress requires institutionalized mechanisms to continue global efforts and long-term assurances that the low price of implants will be maintained. Over 6 years, the IAP supported tremendous progress in increasing access to implants for women in low-income countries by building a public- and private-sector collaboration that focused on systems change in the family planning field. This partnership matched a unique response to a unique problem: building tools, systems, and capacity that can inform and support the introduction and scale-up of new and underutilized contraceptive methods.

Dataset Information

Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Publications

Allometrically scaling tissue forces drive pathological foreign-body responses to implants via Rac2-activated myeloid cells.

Similar Datasets

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