Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

Barone, Damiano G.; Carnicer‐Lombarte, Alejandro; Tourlomousis, Panagiotis; Hamilton, Russell S.; Prater, Malwina; Rutz, Alexandra L.; Dimov, Ivan B.; Malliaras, George G.; Lacour, Stéphanie; Robertson, Avril A. B.; Franze, Kristian; Fawcett, James W.; Bryant, Clare

doi:10.1073/pnas.2115857119

Cited by 39 publications

(36 citation statements)

References 61 publications

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“…5). RR can be particularly advantageous for potent drugs where accurate dosing and a rapid time to functional effect are important, or macro-drugs such as proteins, where convective flow enhances diffusion-based flux, principally governed by molecular weight and concentration gradient 33,34 . Convection-enhanced delivery has been successfully used to improve distribution of chemotherapy in deep brain tumour targets, albeit with modest clinical outcomes 26,27,32,63 .…”

Section: Discussionmentioning

confidence: 99%

“…Local targeted delivery can reduce off-target effects but may still adversely affect the underlying tissue or interfere with the mechanism of action of the implantable device. For example, local delivery of dexamethasone can mitigate the FBR, but not without suppressing underlying tissue regeneration 33 . Furthermore, the effect of long-term immunosuppression on the behaviour and secretome of cell-based therapeutics is unclear.…”

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confidence: 99%

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Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform

et al. 2022

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Fibrous capsule (FC) formation, secondary to the foreign body response (FBR), impedes molecular transport and is detrimental to the long-term efficacy of implantable drug delivery devices, especially when tunable, temporal control is necessary. We report the development of an implantable mechanotherapeutic drug delivery platform to mitigate and overcome this host immune response using two distinct, yet synergistic soft robotic strategies. Firstly, daily intermittent actuation (cycling at 1 Hz for 5 minutes every 12 hours) preserves long-term, rapid delivery of a model drug (insulin) over 8 weeks of implantation, by mediating local immunomodulation of the cellular FBR and inducing multiphasic temporal FC changes. Secondly, actuation-mediated rapid release of therapy can enhance mass transport and therapeutic effect with tunable, temporal control. In a step towards clinical translation, we utilise a minimally invasive percutaneous approach to implant a scaled-up device in a human cadaveric model. Our soft actuatable platform has potential clinical utility for a variety of indications where transport is affected by fibrosis, such as the management of type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform

et al. 2022

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“…Barone et al. ( 2022 ) combining a NLRP3 inhibitor (MCC950) with an implantable electronic medical devices, demonstrated the prevention of FBR without affecting tissue repair, in an in vivo nerve injury model. The authors showed that local inhibition of NLRP3 inhibits FBR, allowing full healing of the tissue, in comparison with the conventional treatments (dexamethasone), which also blocks FBR but at the same time impair tissue repair.…”

Section: The Potential Of the Inflammasome In Immunomodulationmentioning

confidence: 99%

The inflammasome in biomaterial‐driven immunomodulation

Vasconcelos

Águas

Barbosa

2022

J Tissue Eng Regen Med

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Inflammasomes are intracellular structures formed upon the assembly of several proteins that have a considerable size and are very important in innate immune responses being key players in host defense. They are assembled after the perception of pathogens or danger signals. The activation of the inflammasome pathway induces the production of high levels of the pro‐inflammatory cytokines Interleukin (IL)‐1β and IL‐18 through the caspase activation. The procedure for the implantation of a biomaterial causes tissue injury, and the injured cells will secrete danger signals recognized by the inflammasome. There is growing evidence that the inflammasome participates in a number of inflammatory processes, including pathogen clearance, chronic inflammation and tissue repair. Therefore, the control of the inflammasome activity is a promising target in the development of capable approaches to be applied in regenerative medicine. In this review, we revisit current knowledge of the inflammasome in the inflammatory response to biomaterials and point to the yet underexplored potential of the inflammasome in the context of immunomodulation.

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“…[12][13][14][15] The second strategy utilizes pharmacologic means to reduce immune response through sustained release of drugs from coatings on implants. [16][17][18] However, both methods essentially focus on 'hiding' the implant from the body rather than truly integrating the implant with surrounding tissue.…”

Section: Introductionmentioning

confidence: 99%

3D Bioelectronics with a Remodellable Matrix for Long-term Tissue Integration and Recording

Boys

Lombarte

Gonzalez

et al. 2022

Preprint

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Bioelectronics hold the key for understanding and treating disease. However, achieving stable, long-term interfaces between electronics and the body remains a challenge. Implantation of a bioelectronic device typically initiates a foreign body response, which can limit long-term recording and stimulation efficacy. Techniques from regenerative medicine have shown a high propensity for promoting integration of implants with surrounding tissue, but these implants lack the capabilities for the sophisticated recording and actuation afforded by electronics. Combining these two fields can achieve the best of both worlds. Here, we show the construction of a hybrid implant system for creating long-term interfaces with tissue. We create implants by combining a microelectrode array with a bioresorbable and remodellable gel. These implants are shown to produce a minimal foreign body response when placed into musculature, allowing us to record long-term electromyographic signals with high spatial resolution. This device platform drives the possibility for a new generation of implantable electronics for long-term interfacing.

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Prevention of the foreign body response to implantable medical devices by inflammasome inhibition

Cited by 39 publications

References 61 publications

Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform

Dynamic actuation enhances transport and extends therapeutic lifespan in an implantable drug delivery platform

The inflammasome in biomaterial‐driven immunomodulation

3D Bioelectronics with a Remodellable Matrix for Long-term Tissue Integration and Recording

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