Abstract The promise of biomaterials design for regenerative medicine tissue engineering is predicated on the fundamental ability to direct or guide specific and highly coordinated cellular behaviors ...that culminate in the creation of physiologically functional tissues and organs. To date, our efforts have focused primarily on the grafting and presentation of short synthetic peptides with just cause. Short peptides are capable of high levels of control, can be manufactured relatively easily in a highly reproducible manner under GMP guidelines and are readily modified to enable their integration with numerous current and emerging chemistries for biomaterials grafting. However, while extracellular matrix (ECM)-derived peptides have demonstrated their initial purpose of promoting cell adhesion, their general lack of specificity and significantly decreased receptor binding affinities have proven detrimental in attempts to regulate highly specific and integrated processes necessary for tissue regeneration. Unlike adhesion peptides, the natural ECM displays a complex interplay with cells by supporting environmentally sensitive and cell dependent integrin specificity and binding affinity. Furthermore, the adhesion ligands on ECM proteins display a finely tuned and evolutionarily directed spatial periodicity, of which is dynamically controlled through both mechanical and chemical modifications. These and other emerging concepts from matrix biology require our attention if biomaterials design is to fulfill its promise. Here, we are charged with debating the statement ‘The use of short synthetic adhesion peptides, like RGD, is the best approach in the design of biomaterials that guide cell behavior for regenerative medicine tissue engineering’ . In this Leading Opinion Paper I will focus on aspects of natural ECM proteins and protein fragments that have proven difficult, if not impossible to date, to recapitulate in peptide-based systems. While this represents an argument against the use of peptides per se , it might also be viewed as outlining the challenges and opportunities for the biomaterials field.
Since its conceptualization in the 1980s, the provisional matrix has often been characterized as a simple fibrin-containing scaffold for wound healing that supports the nascent blood clot and is ...functionally distinct from the basement membrane. However subsequent advances have shown that this matrix is far from passive, with distinct compositional differences as the wound matures, and providing an active role for wound remodeling. Here we review the stages of this matrix, provide an update on the state of our understanding of provisional matrix, and present some of the outstanding issues related to the provisional matrix, its components, and their assembly and use in vivo.
Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a ...scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach it can now be somewhat easily modified through alterations of molecular interactions key to the protein’s polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials.
The aim of this descriptive analysis was to examine sleep timing, circadian phase, and phase angle of entrainment across adolescence in a longitudinal study design. Ninety-four adolescents ...participated; 38 (21 boys) were 9-10 years ("younger cohort") and 56 (30 boys) were 15-16 years ("older cohort") at the baseline assessment. Participants completed a baseline and then follow-up assessments approximately every six months for 2.5 years. At each assessment, participants wore a wrist actigraph for at least one week at home to measure self-selected sleep timing before salivary dim light melatonin onset (DLMO) phase - a marker of the circadian timing system - was measured in the laboratory. Weekday and weekend sleep onset and offset and weekend-weekday differences were derived from actigraphy. Phase angles were the time durations from DLMO to weekday sleep onset and offset times. Each cohort showed later sleep onset (weekend and weekday), later weekend sleep offset, and later DLMO with age. Weekday sleep offset shifted earlier with age in the younger cohort and later in the older cohort after age 17. Weekend-weekday sleep offset differences increased with age in the younger cohort and decreased in the older cohort after age 17. DLMO to sleep offset phase angle narrowed with age in the younger cohort and became broader in the older cohort. The older cohort had a wider sleep onset phase angle compared to the younger cohort; however, an age-related phase angle increase was seen in the younger cohort only. Individual differences were seen in these developmental trajectories. This descriptive study indicated that circadian phase and self-selected sleep delayed across adolescence, though school-day sleep offset advanced until no longer in high school, whereupon offset was later. Phase angle changes are described as an interaction of developmental changes in sleep regulation interacting with psychosocial factors (e.g., bedtime autonomy).
Summary
Intravenous lidocaine is used widely for its effect on postoperative pain and recovery but it can be, and has been, fatal when used inappropriately and incorrectly. The risk‐benefit ratio of ...i.v. lidocaine varies with type of surgery and with patient factors such as comorbidity (including pre‐existing chronic pain). This consensus statement aims to address three questions. First, does i.v. lidocaine effectively reduce postoperative pain and facilitate recovery? Second, is i.v. lidocaine safe? Third, does the fact that i.v. lidocaine is not licensed for this indication affect its use? We suggest that i.v. lidocaine should be regarded as a ‘high‐risk’ medicine. Individual anaesthetists may feel that, in selected patients, i.v. lidocaine may be beneficial as part of a multimodal peri‐operative pain management strategy. This approach should be approved by hospital medication governance systems, and the individual clinical decision should be made with properly informed consent from the patient concerned. If i.v. lidocaine is used, we recommend an initial dose of no more than 1.5 mg.kg‐1, calculated using the patient’s ideal body weight and given as an infusion over 10 min. Thereafter, an infusion of no more than 1.5 mg.kg‐1.h‐1 for no longer than 24 h is recommended, subject to review and re‐assessment. Intravenous lidocaine should not be used at the same time as, or within the period of action of, other local anaesthetic interventions. This includes not starting i.v. lidocaine within 4 h after any nerve block, and not performing any nerve block until 4 h after discontinuing an i.v. lidocaine infusion.
Biomaterial-mediated inflammation and fibrosis remain a prominent challenge in designing materials to support tissue repair and regeneration. Despite the many biomaterial technologies that have been ...designed to evade or suppress inflammation (i.e., delivery of anti-inflammatory drugs, hydrophobic coatings, etc.), many materials are still subject to a foreign body response, resulting in encapsulation of dense, scar-like extracellular matrix. The primary cells involved in biomaterial-mediated fibrosis are macrophages, which modulate inflammation, and fibroblasts, which primarily lay down new extracellular matrix. While macrophages and fibroblasts are implicated in driving biomaterial-mediated fibrosis, the signaling pathways and spatiotemporal crosstalk between these cell types remain loosely defined. In this review, the role of M1 and M2 macrophages (and soluble cues) involved in the fibrous encapsulation of biomaterials in vivo is investigated, with additional focus on fibroblast and macrophage crosstalk in vitro along with in vitro models to study the foreign body response. Lastly, several strategies that have been used to specifically modulate macrophage and fibroblast behavior in vitro and in vivo to control biomaterial-mediated fibrosis are highlighted.
•Fibroblasts are the arbiters of extracellular matrix remodeling.•Fibroblasts undergo temporal activation changes throughout the wound healing response.•Fibroblasts share homeostatic and wound ...healing roles across systems.
Extracellular matrix (ECM) is the foundation on which all cells and organs converge to orchestrate normal physiological functions. In the setting of pathology, the ECM is modified to incorporate additional roles, with modifications including turnover of existing ECM and deposition of new ECM. The fibroblast is center stage in coordinating both normal tissue homeostasis and response to disease. Understanding how fibroblasts work under normal conditions and are activated in response to injury or stress will provide mechanistic insight that triggers discovery of new therapeutic treatments for a wide range of disease. We highlight here fibroblast roles in the cancer, lung, and heart as example systems where fibroblasts are major contributors to homeostasis and pathology.
A hypervirulent
(hvKp) pathotype is undergoing global dissemination. In contrast to the usual health care-associated epidemiology of classical
(cKp) infections, hvKp causes tissue-invasive infections ...in otherwise healthy individuals from the community, often involving multiple sites. An accurate test to identify hvKp strains is needed for improved patient care and epidemiologic studies. To fill this knowledge gap, clinical criteria or random blood isolates from North American and United Kingdom strain collections were used to assemble hvKp-rich (
= 85) and cKp-rich (
= 90) strain cohorts, respectively. The isolates were then assessed for multiple candidate biomarkers hypothesized to accurately differentiate the two cohorts. The genes
,
,
, plasmid-borne
gene (
), and
all demonstrated >0.95 diagnostic accuracy for identifying strains in the hvKp-rich cohort. Next, to validate this epidemiological analysis, all strains were assessed experimentally in a murine sepsis model.
,
,
,
, and
were all associated with a hazard ratio of >25 for severe illness or death, additionally supporting their utility for identifying hvKp strains. Quantitative siderophore production of ≥30 μg/ml also strongly predicted strains as members of the hvKp-rich cohort (accuracy, 0.96) and exhibited a hazard ratio of 31.7 for severe illness or death. The string test, a widely used marker for hvKp strains, performed less well, achieving an accuracy of only 0.90. Last, using the most accurate biomarkers to define hvKp, prevalence studies were performed on two Western strain collections. These data strongly support the utility of several laboratory markers for identifying hvKp strains with a high degree of accuracy.
Biophysical cues stemming from the extracellular environment are rapidly transduced into discernible chemical messages (mechanotransduction) that direct cellular activities-placing the extracellular ...matrix (ECM) as a potent regulator of cell behavior. Dynamic reciprocity between the cell and its associated matrix is essential to the maintenance of tissue homeostasis and dysregulation of both ECM mechanical signaling, via pathological ECM turnover, and internal mechanotransduction pathways contribute to disease progression. This review covers the current understandings of the key modes of signaling used by both the cell and ECM to coregulate one another. By taking an outside-in approach, the inherent complexities and regulatory processes at each level of signaling (ECM, plasma membrane, focal adhesion, and cytoplasm) are captured to give a comprehensive picture of the internal and external mechanoregulatory environment. Specific emphasis is placed on the focal adhesion complex which acts as a central hub of mechanical signaling, regulating cell spreading, migration, proliferation, and differentiation. In addition, a wealth of available knowledge on mechanotransduction is curated to generate an integrated signaling network encompassing the central components of the focal adhesion, cytoplasm and nucleus that act in concert to promote durotaxis, proliferation, and differentiation in a stiffness-dependent manner.
Electrical stimulation has been shown to promote healing and regeneration in skin, bone, muscle, and nerve tissues in clinical studies. Recently, studies applying electrical stimulation to influence ...cell behavior associated with proliferation, differentiation, and migration have provided a better understanding of the underlying mechanisms of electrical stimulation-based clinical treatments and improved tissue-engineered products through electro-bioreactor technologies. Here, we present a novel device for delivering direct current (DC) electrical stimulation (ES) to cultivated cells in vitro. Our simplified electro-bioreactor is customized for applying DC electrical current simultaneously in six individual tissue culture wells. The design overcomes previous experimental replicate limitations, thus reducing experimental time and cost.
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