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Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed.
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Enfermedades Musculares , Distrofias Musculares , Enfermedades Neuromusculares , Humanos , Calidad de Vida , FatigaRESUMEN
Primary mitochondrial diseases (PMDs) are complex group of metabolic disorders caused by genetically determined impairment of the mitochondrial oxidative phosphorylation (OXPHOS). The unique features of mitochondrial genetics and the pivotal role of mitochondria in cell biology explain the phenotypical heterogeneity of primary mitochondrial diseases and the resulting diagnostic challenges that follow. Some peculiar features ("red flags") may indicate a primary mitochondrial disease, helping the physician to orient in this diagnostic maze. In this narrative review, we aimed to outline the features of the most common mitochondrial red flags offering a general overview on the topic that could help physicians to untangle mitochondrial medicine complexity.
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Medicina , Enfermedades Mitocondriales , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Fosforilación OxidativaRESUMEN
A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym "MELAS" (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.
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Acidosis Láctica , Síndrome MELAS , Enfermedades Mitocondriales , Accidente Cerebrovascular , Acidosis Láctica/complicaciones , ADN Mitocondrial , Humanos , Síndrome MELAS/complicaciones , Síndrome MELAS/tratamiento farmacológico , Mutación , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
OBJECTIVES: Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative diseases characterised by upper motor neuron (UMN) impairment of the lower limbs. The differential diagnosis with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) can be challenging. As microglial iron accumulation was reported in the primary motor cortex (PMC) of ALS cases, here we assessed the radiological appearance of the PMC in a cohort of HSP patients using iron-sensitive MR imaging and compared the PMC findings among HSP, PLS, and ALS patients. METHODS: We included 3-T MRI scans of 23 HSP patients, 7 PLS patients with lower limb onset, 8 ALS patients with lower limb and prevalent UMN onset (UMN-ALS), and 84 ALS patients with any other clinical picture. The PMC was visually rated on 3D T2*-weighted images as having normal signal intensity, mild hypointensity, or marked hypointensity, and differences in the frequency distribution of signal intensity among the diseases were investigated. RESULTS: The marked hypointensity in the PMC was visible in 3/22 HSP patients (14%), 7/7 PLS patients (100%), 6/8 UMN-ALS patients (75%), and 35/84 ALS patients (42%). The frequency distribution of normal signal intensity, mild hypointensity, and marked hypointensity in HSP patients was different than that in PLS, UMN-ALS, and ALS patients (p < 0.01 in all cases). CONCLUSIONS: Iron-sensitive imaging of the PMC could provide useful information in the diagnostic work - up of adult patients with a lower limb onset UMN syndrome, as the cortical hypointensity often seen in PLS and ALS cases is apparently rare in HSP patients. KEY POINTS: ⢠The T2* signal intensity of the primary motor cortex was investigated in patients with HSP, PLS with lower limb onset, and ALS with lower limb and prevalent UMN onset (UMN-ALS) using a clinical 3-T MRI sequence. ⢠Most HSP patients had normal signal intensity in the primary motor cortex (86%); on the contrary, all the PLS and the majority of UMN-ALS patients (75%) had marked cortical hypointensity. ⢠The T2*-weighted imaging of the primary motor cortex could provide useful information in the differential diagnosis of sporadic adult-onset UMN syndromes.
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Esclerosis Amiotrófica Lateral , Corteza Motora , Enfermedad de la Neurona Motora , Paraplejía Espástica Hereditaria , Adulto , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Corteza Motora/diagnóstico por imagen , Hierro , Enfermedad de la Neurona Motora/diagnóstico por imagen , Imagen por Resonancia Magnética/métodosRESUMEN
Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.
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Epilepsia , Enfermedades Mitocondriales , Humanos , Neurólogos , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/terapia , Enfermedades Mitocondriales/complicaciones , ADN Mitocondrial/genética , Epilepsia/etiología , Epilepsia/genética , Mitocondrias/genética , MutaciónRESUMEN
The use of rheology and terminal flow relaxation times to predict healing behavior at long healing times is by now quite well accepted. In this work we go one step further and explore the use of macro-rheology (in particular the stored work of deformation) to predict the early stage interfacial healing properties (fracture resistance) of a set of self-healing polyurethanes. The interfacial healing is measured by single edge notch fracture experiments, using short healing times and a low healing temperature to exclude the effect of long range molecular motion on mechanical properties restoration. The systems based on aromatic diisocyanates show high fracture resistance after healing, while very limited restoration of the mechanical properties is observed for aliphatic and cycloaliphatic based polyurethanes. Linear sweep rheology and time-temperature-superposition allow obtaining the macro-rheological master curve and the mechanical relaxation spectra (H(t)). The application of a recently established deconvolution protocol to the H(t) gives the characteristic relaxation times and stored works of deformation associated to individual dynamic processes such as segmental motion, reversible bonds, and terminal flow. It is found that the calculated stored works of deformation related to the reversible bond relaxation reproduce the trend observed by fracture resistance at healed interfaces and reveal a qualitative correspondence between reversible bonds work of deformation and interfacial healing fracture resistance. Moreover, the method seems to point to the existence of a threshold interfacial work of deformation below which no efficient load transfer can be observed.
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BACKGROUND: Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins. OBJECTIVE: In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA. RESULTS: Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers. CONCLUSION: Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits.
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Factores de Crecimiento de Fibroblastos , Enfermedades Mitocondriales , Biomarcadores , ADN Mitocondrial/genética , Factores de Crecimiento de Fibroblastos/genética , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación/genética , Reproducibilidad de los ResultadosRESUMEN
Starting from experimental macro-rheological data, we develop a fitting protocol that succeeded in the separation of the overlapping relaxation phenomena in the dissipative regime for a set of intrinsic healing polymers healing most effectively near their glass transition temperature Tg. To allow for a proper deconvolution, the rheological master curves are converted to a relaxation spectrum (H(τ)) and this is fitted using an optimized mechanical model, e.g. the Maxwell-Weichert model. The deconvolution of overlapping segmental mobility and reversible interactions is successfully demonstrated for a set of polyimide and polyamide polymers containing none, one and two reversible dynamic features near-Tg. Through the fitting parameters, the relaxation timescale of each feature and their apparent process enthalpies are obtained. The quantitative data obtained using the fitting protocol are then compared to macroscopic healing results. As a result, a clear correspondence between the energy stored by the system to accomplish reversible (e.g. H-bonds, π-π) and chain interdiffusion relaxation transitions and the healing efficiency of such polymers are obtained. The implementation of this protocol allows for a clearer identification of the relevant mechanisms in self-healing polymers and paves the way for the development of more efficiently healable polymeric systems.
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BACKGROUND: Primary mitochondrial diseases (PMDs) are the most common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. They can result from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). These disorders are multisystemic and mainly affect high energy-demanding tissues, such as muscle and the central nervous system (CNS). Among many clinical features of CNS involvement, parkinsonism is one of the most common movement disorders in PMDs. METHODS: This review provides a pragmatic educational overview of the most recent advances in the field of mitochondrial parkinsonism, from pathophysiology and genetic etiologies to phenotype and diagnosis. RESULTS: mtDNA maintenance and mitochondrial dynamics alterations represent the principal mechanisms underlying mitochondrial parkinsonism. It can be present in isolation, alongside other movement disorders or, more commonly, as part of a multisystemic phenotype. Mutations in several nuclear-encoded genes (ie, POLG, TWNK, SPG7, and OPA1) and, more rarely, mtDNA mutations, are responsible for mitochondrial parkinsonism. Progressive external opthalmoplegia and optic atrophy may guide genetic etiology identification. CONCLUSION: A comprehensive deep-phenotyping approach is needed to reach a diagnosis of mitochondrial parkinsonism, which lacks distinctive clinical features and exemplifies the intricate genotype-phenotype interplay of PMDs.
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ADN Mitocondrial , Enfermedades Mitocondriales , Trastornos Parkinsonianos , Humanos , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/diagnóstico , ADN Mitocondrial/genética , MutaciónRESUMEN
Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.
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BACKGROUND: Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A>G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis. CASE STUDY: Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274_3275delAC MT-TL1 gene mutation. CONCLUSIONS: Our case demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274_3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement.
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Síndrome MELAS , Enfermedades Mitocondriales , Femenino , Humanos , ADN Mitocondrial/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/complicaciones , Mutación , Síndrome MELAS/genéticaRESUMEN
Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, or spinal and peripheral lesions leading to proprioceptive loss. Despite mitochondrial ataxias having no specific defining features, they should be included in hereditary ataxias differential diagnosis, given the high prevalence of PMDs. This review focuses on the clinical and neuropathological features and genetic background of PMDs in which ataxia is a prominent manifestation.
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BACKGROUND: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. OBJECTIVE: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. METHODS: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). RESULTS: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. CONCLUSION: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed.
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Distrofia Muscular de Cinturas , Distrofias Musculares , ADN Mitocondrial/genética , Humanos , Lamina Tipo A/genética , Debilidad Muscular/complicaciones , Distrofias Musculares/genética , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , MutaciónRESUMEN
The use of self-healing (SH) polymers to make 3D-printed polymeric parts offers the potential to increase the quality of 3D-printed parts and to increase their durability and damage tolerance due to their (on-demand) dynamic nature. Nevertheless, 3D-printing of such dynamic polymers is not a straightforward process due to their polymer architecture and rheological complexity and the limited quantities produced at lab-scale. This limits the exploration of the full potential of self-healing polymers. In this paper, we present the complete process for fused deposition modelling of a room temperature self-healing polyurethane. Starting from the synthesis and polymer slab manufacturing, we processed the polymer into a continuous filament and 3D printed parts. For the characterization of the 3D printed parts, we used a compression cut test, which proved useful when limited amount of material is available. The test was able to quasi-quantitatively assess both bulk and 3D printed samples and their self-healing behavior. The mechanical and healing behavior of the 3D printed self-healing polyurethane was highly similar to that of the bulk SH polymer. This indicates that the self-healing property of the polymer was retained even after multiple processing steps and printing. Compared to a commercial 3D-printing thermoplastic polyurethane, the self-healing polymer displayed a smaller mechanical dependency on the printing conditions with the added value of healing cuts at room temperature.
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The effects of the soft block fraction and H-bond state in thermoplastic polyurethanes on autonomous entropy-driven scratch closure and barrier restoration are studied. To this aim, comparable polyurethanes with different segmentation states are applied as organic coatings on plain carbon steel plates, scratched under very well-controlled conditions, and the scratch closure and sealing kinetics are studied in detail. The scratch closure is measured optically, while the barrier restoration is probed by the accelerated cyclic electrochemical technique (ACET). Scratch closure, attributed to entropic elastic recovery (EER), is followed in a marked two-step process by barrier restoration governed by local viscous flow and the state of the interfacial hydrogen bonding. Polyurethanes with a lower soft phase fraction lead to a higher urea/urethane ratio, which in turn influences the healing efficiency of each healing step. Interestingly, softer polyurethanes leading to efficient crack closure were unable to sufficiently restore barrier properties. The present work highlights the critical role of the soft/hard block and urea/urethane H-bond state content on crack closure and barrier restoration of anticorrosive organic coatings and points at design rules for the design of more efficient corrosion-protective self-healing polyurethanes.
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Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.
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Mitochondrial diseases (MDs) are a group of genetic disorders that may manifest with vast clinical heterogeneity in childhood or adulthood. These diseases are characterized by dysfunctional mitochondria and oxidative phosphorylation deficiency. Patients are usually treated with supportive and symptomatic therapies due to the absence of a specific disease-modifying therapy. Management of patients with MDs is based on different therapeutical strategies, particularly the early treatment of organ-specific complications and the avoidance of catabolic stressors or toxic medication. In this review, we discuss the therapeutic management of MDs, supported by a revision of the literature, and provide an overview of the drugs that should be either avoided or carefully used both for the specific treatment of MDs and for the management of comorbidities these subjects may manifest. We finally discuss the latest therapies approved for the management of MDs and some ongoing clinical trials.
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OBJECTIVE: To determine whether a set of functional tests, clinical scales, patient-reported questionnaires, and specific biomarkers can be considered reliable outcome measures in patients with primary mitochondrial myopathy (PMM), we analyzed a cohort of Italian patients. METHODS: Baseline data were collected from 118 patients with PMM, followed by centers of the Italian network for mitochondrial diseases. We used the 6-Minute Walk Test (6MWT), Timed Up-and-Go Test (x3) (3TUG), Five-Times Sit-To-Stand Test (5XSST), Timed Water Swallow Test (TWST), and Test of Masticating and Swallowing Solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional Pain Inventory as patient-reported outcome measures; and FGF21, GDF15, lactate, and creatine kinase (CK) as biomarkers. RESULTS: A total of 118 PMM cases were included. Functional outcome measures (6MWT, 3TUG, 5XSST, TWST, and TOMASS) and biomarkers significantly differed from healthy reference values and controls. Moreover, functional measures correlated with patients' perceived fatigue and pain severity. Patients with either mitochondrial or nuclear DNA point mutations performed worse in functional measures than patients harboring single deletion, even if the latter had an earlier age at onset but similar disease duration. Both the biomarkers FGF21 and GDF15 were significantly higher in the patients compared with a matched control population; however, there was no relation with severity of disease. CONCLUSIONS: We characterized a large cohort of PMM by evaluating baseline mitochondrial biomarkers and functional scales that represent potential outcome measures to monitor the efficacy of treatment in clinical trials; these outcome measures will be further reinvestigated longitudinally to define the natural history of PMM.
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In this work, we propose the use of regular branching of polyurethanes as a way to regulate chain dynamics and govern crystallization in highly dense hydrogen-bonded systems. As a result, robust and healable polyurethanes can be obtained. To this end, we synthesized a range of aliphatic propane diol derivatives with alkyl branches ranging from butyl (C4) to octadecanyl (C18). The series of brush polyurethanes was synthesized by polyaddition of the diols and hexamethylene diisocyanate. Polyurethanes with very short (C < 4) and very long (C = 18) brush lengths did not lead to any significant healing due to crystallization. An intermediate amorphous regime appears for polymers with middle branch lengths (C = 4 to 8) showing a fine control of material toughness. For these systems, the side chain length regulates tube dilation, and significant macroscopic healing of cut samples was observed and studied in detail using melt rheology and tensile testing. Despite the high healing degrees observed immediately after repair, it was found that samples with medium to long length brushes lost their interfacial strength at the healed site after being heated to the healing temperature for some time after the optimal time to reach full healing. Dedicated testing suggests that annealed samples, while keeping initial tackiness, are not able to completely heal the cut interface. We attribute such behavior to annealing-induced interfacial crystallization promoted by the aliphatic branches. Interestingly, no such loss of healing due to annealing was observed for samples synthesized with C4 and C7 diols, which is identified as the optimal healing regime. These results point at the positive effect of branching on healing, provided that a critical chain length is not surpassed, as well as the need to study healing behavior long after the optimal healing times.