On the use of Parylene C polymer as substrate for peripheral nerve electrodes

Parylene C is a highly flexible polymer used in several biomedical implants. Since previous studies have reported valuable biocompatible and manufacturing characteristics for brain and intraneural implants, we tested its suitability as a substrate for peripheral nerve electrodes. We evaluated 1-year-aged in vitro samples, where no chemical differences were observed and only a slight deviation on Young's modulus was found. The foreign body reaction (FBR) to longitudinal Parylene C devices implanted in the rat sciatic nerve for 8 months was characterized. After 2 weeks, a capsule was formed around the device, which continued increasing up to 16 and 32 weeks. Histological analyses revealed two cell types implicated in the FBR: macrophages, in contact with the device, and fibroblasts, localized in the outermost zone after 8 weeks. Molecular analysis of implanted nerves comparing Parylene C and polyimide devices revealed a peak of inflammatory cytokines after 1 day of implant, returning to low levels thereafter. Only an increase of CCL2 and CCL3 was found at chronic time-points for both materials. Although no molecular differences in the FBR to both polymers were found, the thick tissue capsule formed around Parylene C puts some concern on its use as a scaffold for intraneural electrodes

Cholesterol Depletion Regulates Axonal Growth and Enhances Central and Peripheral Nerve Regeneration

Axonal growth during normal development and axonal regeneration rely on the action of many receptor signaling systems and complexes, most of them located in specialized raft membrane microdomains with a precise lipid composition. Cholesterol is a component of membrane rafts and the integrity of these structures depends on the concentrations present of this compound. Here we explored the effect of cholesterol depletion in both developing neurons and regenerating axons. First, we show that cholesterol depletion in vitro in developing neurons from the central and peripheral nervous systems increases the size of growth cones, the density of filopodium-like structures and the number of neurite branching points. Next, we demonstrate that cholesterol depletion enhances axonal regeneration after axotomy in vitro both in a microfluidic system using dissociated hippocampal neurons and in a slice-coculture organotypic model of axotomy and regeneration. Finally, using axotomy experiments in the sciatic nerve, we also show that cholesterol depletion favors axonal regeneration in vivo. Importantly, the enhanced regeneration observed in peripheral axons also correlated with earlier electrophysiological responses, thereby indicating functional recovery following the regeneration. Taken together, our results suggest that cholesterol depletion per se is able to promote axonal growth in developing axons and to increase axonal regeneration in vitro and in vivo both in the central and peripheral nervous systems

Cholesterol depletion regulates axonal growth and enhances central and peripheral nerve regeneration

Axonal growth during normal development and axonal regeneration rely on the action of many receptor signaling systems and complexes, most of them located in specialized raft membrane microdomains with a precise lipid composition. Cholesterol is a component of membrane rafts and the integrity of these structures depends on the concentrations present of this compound. Here we explored the effect of cholesterol depletion in both developing neurons and regenerating axons. First, we show that cholesterol depletion in vitro in developing neurons from the central and peripheral nervous systems increases the size of growth cones, the density of filopodium-like structures and the number of neurite branching points. Next, we demonstrate that cholesterol depletion enhances axonal regeneration after axotomy in vitro both in a microfluidic system using dissociated hippocampal neurons and in a slice-coculture organotypic model of axotomy and regeneration. Finally, using axotomy experiments in the sciatic nerve, we also show that cholesterol depletion favors axonal regeneration in vivo. Importantly, the enhanced regeneration observed in peripheral axons also correlated with earlier electrophysiological responses, thereby indicating functional recovery following the regeneration. Taken together, our results suggest that cholesterol depletion per se is able to promote axonal growth in developing axons and to increase axonal regeneration in vitro and in vivo both in the central and peripheral nervous systems

Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Biological response to implanted intraneural electrodes

La reacció de cos estrany (FBR, per les sigles en anglès) és una resposta del sistema immunitari envers qualsevol dispositiu implantat al cos. Diversos estudis han demostrat que aquesta resposta consta d’una primera fase inflamatòria seguida d’una fase de remodelació del teixit, que resulta en la encapsulació del cos estrany. Es creu que aquesta encapsulació es la causa, entre d’altres factors, de la pèrdua de funcionalitat dels elèctrodes neurals, que han de ser implantats de forma crònica per generar i registrar senyals nerviosos del sistema nerviós. En aquesta tesis s’ha fet una caracterització detallada de la FBR envers dispositius implantats als nervis perifèrics amb l’objectiu de trobar possibles dianes terapèutiques per reduir aquesta resposta i millorar la funcionalitat al llarg del temps d’elèctrodes intraneurals. Els nostres resultats mostren com la infiltració de cèl·lules immunes al nervi va presentar un màxim després de dos setmanes d’implant, sense que s’observessin diferencies entre dos dels polímers que s’utilitzen com a substrat dels elèctrodes, la poliimida i el Parilè C. En canvi, la deposició de teixit al voltant dels dispositius va evolucionar de forma diferencial entre tots dos materials. Mentre que la càpsula al voltant de la poliimida va presentar un màxim a les 2 setmanes i va estabilitzar-se, la capsula al voltant del Parilè C també va presentar un màxim a les 2 setmanes i després de mantenir-se estable durant un període de 4-8 setmanes, va continuar creixent fins al seu màxim a les 16 setmanes desprès de l’implant. L’anàlisi molecular de diferents factors inflamatoris i de remodelació de teixit no va mostrar diferencies, però, entre els dos materials. Les dos fases descrites en la FBR als nervis perifèrics van determinar possibles estratègies terapèutiques per reduir la resposta. Entre els diferents fàrmacs testats, només la dexametasona va reduir significativament la infiltració de macròfags i el gruix de la capsula al voltant dels dos polímers. A més, el tractament amb dexametasona va millorar la funcionalitat a llarg terme d’elèctrodes transversals intraneurals, en particular de les propietats d’estimulació. En conclusió, la FBR envers dispositius intraneurals presenta un patró similar a l’observat a altres teixits com l’espai subcutani i la cavitat peritoneal. A més, les diferències observades a temps crònics entre els dos materials descartarien el Parilè C com a substrat per elèctrodes intraneurals implantats crònicament. La caracterització de la FBR ha permès definir diferents estratègies terapèutiques com la dexametasona, que va millorar la funcionalitat a llarg del temps d’elèctrodes intraneurals, degut possiblement a un reducció de la infiltració cel·lular i de la càpsula de teixit depositat.The foreign body reaction (FBR) is an immune-mediated response to any device implanted in the body. Several studies have shown that it is characterized by a first inflammatory phase followed by a tissue remodeling phase, which results in the encapsulation of the foreign body. This encapsulation is thought to cause, among other factors, the progressive decline in function reported in neural electrodes, which should remain chronically implanted in the body to generate and record nerve signals from the nervous tissue. In this thesis, a detailed characterization of the FBR to intraneural electrodes has been performed, in order to determine feasible therapeutic strategies to reduce the FBR and to improve the long-term function of chronic implanted intraneural electrodes. Our results show that the immune infiltration in the nerve peaked after two weeks of implant, without differences between two polymers intended to be used as electrode substrate (i.e., polyimide and Parylene C). However, the tissue deposition around both polymers evolved differently at chronic time points. While the capsule around polyimide devices peaked after two weeks and was stabilized after that up to 8 months, the capsule around Parylene C devices had a first peak at week 2 and it continued increasing after a resting period of 4-8 weeks to reach a second maximum at week 16. Molecular analysis of implanted nerves showed no differences between the FBR to both polymers in the inflammatory and tissue remodeling studied factors. The two main phases described in the FBR in peripheral nerves have determined possible therapeutic strategies to reduce this reaction. Among the several drugs tested, only dexamethasone significantly reduced the infiltration of macrophages and the thickness of the capsule around both polymers. Moreover, dexamethasone treatment improved the long-term function of transversal intraneural electrodes, particularly in terms of stimulation properties. In conclusion, the FBR to intraneural devices shows a similar pattern than the reported in other host tissues such as the subcutaneous and the peritoneal spaces. Moreover, differences in the FBR between polyimide and Parylene C have been observed, which would rule Parylene C out as a substrate for chronically implanted intraneural electrodes. The FBR characterization has allowed testing several therapeutic strategies to reduce this response, such as dexamethasone. In fact, dexamethasone treatment has improved the outcome of chronic implanted intraneural electrodes, may be due to a reduction in the cellular infiltration and tissue deposition

Biological response to implanted intraneural electrodes

La reacció de cos estrany (FBR, per les sigles en anglès) és una resposta del sistema immunitari envers qualsevol dispositiu implantat al cos. Diversos estudis han demostrat que aquesta resposta consta d’una primera fase inflamatòria seguida d’una fase de remodelació del teixit, que resulta en la encapsulació del cos estrany. Es creu que aquesta encapsulació es la causa, entre d’altres factors, de la pèrdua de funcionalitat dels elèctrodes neurals, que han de ser implantats de forma crònica per generar i registrar senyals nerviosos del sistema nerviós. En aquesta tesis s’ha fet una caracterització detallada de la FBR envers dispositius implantats als nervis perifèrics amb l’objectiu de trobar possibles dianes terapèutiques per reduir aquesta resposta i millorar la funcionalitat al llarg del temps d’elèctrodes intraneurals. Els nostres resultats mostren com la infiltració de cèl·lules immunes al nervi va presentar un màxim després de dos setmanes d’implant, sense que s’observessin diferencies entre dos dels polímers que s’utilitzen com a substrat dels elèctrodes, la poliimida i el Parilè C. En canvi, la deposició de teixit al voltant dels dispositius va evolucionar de forma diferencial entre tots dos materials. Mentre que la càpsula al voltant de la poliimida va presentar un màxim a les 2 setmanes i va estabilitzar-se, la capsula al voltant del Parilè C també va presentar un màxim a les 2 setmanes i després de mantenir-se estable durant un període de 4-8 setmanes, va continuar creixent fins al seu màxim a les 16 setmanes desprès de l’implant. L’anàlisi molecular de diferents factors inflamatoris i de remodelació de teixit no va mostrar diferencies, però, entre els dos materials. Les dos fases descrites en la FBR als nervis perifèrics van determinar possibles estratègies terapèutiques per reduir la resposta. Entre els diferents fàrmacs testats, només la dexametasona va reduir significativament la infiltració de macròfags i el gruix de la capsula al voltant dels dos polímers. A més, el tractament amb dexametasona va millorar la funcionalitat a llarg terme d’elèctrodes transversals intraneurals, en particular de les propietats d’estimulació. En conclusió, la FBR envers dispositius intraneurals presenta un patró similar a l’observat a altres teixits com l’espai subcutani i la cavitat peritoneal. A més, les diferències observades a temps crònics entre els dos materials descartarien el Parilè C com a substrat per elèctrodes intraneurals implantats crònicament. La caracterització de la FBR ha permès definir diferents estratègies terapèutiques com la dexametasona, que va millorar la funcionalitat a llarg del temps d’elèctrodes intraneurals, degut possiblement a un reducció de la infiltració cel·lular i de la càpsula de teixit depositat.The foreign body reaction (FBR) is an immune-mediated response to any device implanted in the body. Several studies have shown that it is characterized by a first inflammatory phase followed by a tissue remodeling phase, which results in the encapsulation of the foreign body. This encapsulation is thought to cause, among other factors, the progressive decline in function reported in neural electrodes, which should remain chronically implanted in the body to generate and record nerve signals from the nervous tissue. In this thesis, a detailed characterization of the FBR to intraneural electrodes has been performed, in order to determine feasible therapeutic strategies to reduce the FBR and to improve the long-term function of chronic implanted intraneural electrodes. Our results show that the immune infiltration in the nerve peaked after two weeks of implant, without differences between two polymers intended to be used as electrode substrate (i.e., polyimide and Parylene C). However, the tissue deposition around both polymers evolved differently at chronic time points. While the capsule around polyimide devices peaked after two weeks and was stabilized after that up to 8 months, the capsule around Parylene C devices had a first peak at week 2 and it continued increasing after a resting period of 4-8 weeks to reach a second maximum at week 16. Molecular analysis of implanted nerves showed no differences between the FBR to both polymers in the inflammatory and tissue remodeling studied factors. The two main phases described in the FBR in peripheral nerves have determined possible therapeutic strategies to reduce this reaction. Among the several drugs tested, only dexamethasone significantly reduced the infiltration of macrophages and the thickness of the capsule around both polymers. Moreover, dexamethasone treatment improved the long-term function of transversal intraneural electrodes, particularly in terms of stimulation properties. In conclusion, the FBR to intraneural devices shows a similar pattern than the reported in other host tissues such as the subcutaneous and the peritoneal spaces. Moreover, differences in the FBR between polyimide and Parylene C have been observed, which would rule Parylene C out as a substrate for chronically implanted intraneural electrodes. The FBR characterization has allowed testing several therapeutic strategies to reduce this response, such as dexamethasone. In fact, dexamethasone treatment has improved the outcome of chronic implanted intraneural electrodes, may be due to a reduction in the cellular infiltration and tissue deposition