Tissue Failure Research Articles

Overview of Organ Donation

Organ and tissue donation is defined as the transfer of human cells, tissues and organs from a donor to a recipient; it is the only therapeutic option that helps to improve the quality of life and prevent the death of people with tissue or organ failure. However, this process is hampered due to the discrepancy between organ supply and demand worldwide, which increases clinical deterioration and mortality rates on the waiting list of patients with chronic or acute multi-organ failure. The aim of this article is to provide relevant information about the process of organ and tissue donation, highlighting the importance of understanding the process, providing information to the general population, with emphasis on essential groups for its dissemination, mainly health professionals who have the ability to positively influence society's perception of this issue by providing health education during primary care, This is the first contact and an important link in the attention of the potential donor, considering medical units as the closest source of information due to recurrent access, and not least children and young people, as it has been shown that this action increases the acceptance rate, turning this section of the population into agents of social change, generating with this manuscript, a positive impact on the perception and understanding of the subject for society, seeking to increase the availability of donors.

Decellularization of renal fibrosis by cyclic hydrostatic pressure to restore renal function

Natural extracellular matrices (ECM) are currently being studied as an alternative source for organ transplantation or as new solutions to treat end-stage renal disease. As the gap between donors and patients in need of an organ transplant continues to widen, research in regenerative medicine seeks to provide different strategies for treatment Tissue and organ failure is currently one of the biggest health issues our society faces [1]. Arising from disease or trauma, complete treatment typically requires the repair or replace the affected organ However, the unavailability of adequate organs for transplantation to meet the existing demand has resulted in major organ shortage crisis. As a result, there has been a major increase in the number of patients [2]. The stem cell therapy fails because of the toxic environment in the organ, the implanted cells unable to regenerate. Afterwards researchers are trying to prepare the lab made artificial organ in the laboratory with the help of artificial scaffold and the tissue specific stem cells. Then tried for the transplantation of animal organs. To overcome this organ shortage challenge is the use of organ-derived scaffolds obtained via decellularization techniques by removing all viable cells from native tissues and retaining 3D structure of natural extracellular matrix (ECM) and vascular network for regeneration. This is the most adequate method where scaffold thoroughly decellularizes, free of endotoxin or bacterial contamination. An appropriate macro and microstructure to support physiological function, intact vascular tree, specific location cues.

Stretch-Induced Uncrimping of Equatorial Sclera Collagen Bundles.

Stretch-induced collagen uncrimping underlies the nonlinear mechanical behavior of the sclera according to what is often called the process of recruitment. We recently reported experimental measurements of sclera collagen crimp and pressure-induced uncrimping. Our studies, however, were cross-sectional, providing statistical descriptions of crimp with no information on the effects of stretch on specific collagen bundles. Data on bundle-specific uncrimping is necessary to better understand the effects of macroscale input on the collagen microscale and tissue failure. Our goal in this project was to measure bundle-specific stretch-induced collagen uncrimping of sclera. Three goat eyes were cryosectioned sagittally (30 μm). Samples of equatorial sclera were isolated, mounted to a custom uni-axial stretcher and imaged with polarized light microscopy at various levels of clamp-to-clamp stretch until failure. At each stretch level, local strain was measured using image tracking techniques. The level of collagen crimping was determined from the bundle waviness, defined as the circular standard deviation of fiber orientation along a bundle. Eye-specific recruitment curves were then computed using eye-specific waviness at maximum stretch before sample failure to define fibers as recruited. Nonlinear mixed effect models were used to determine the associations of waviness to local strain and recruitment to clamp-to-clamp stretch. Waviness decreased exponentially with local strain (p < 0.001), whereas bundle recruitment followed a sigmoidal curve with clamp-to-clamp stretch (p < 0.001). Individual bundle responses to stretch varied substantially, but recruitment curves were similar across sections and eyes. In conclusion, uni-axial stretch caused measurable bundle-specific uncrimping, with the sigmoidal recruitment pattern characteristic of fiber-reinforced soft tissues.

An Overview of Fixation Failure, Malunion and Possible Complication of Soft Tissue and Bone Infection

Background: Trochanter fractures form the majority of hip fractures. The majority of trochanteric fractures occur in patients aged 66 to 76. The majority of fractures occur in the elderly, typically as a result of osteoporosis and mild or minor trauma because this is an elderly age fracture. Morbidity is severe and obvious such as thromboembolism and pneumonia. Decubitus ulcers, stiff knees, mental decline, etc. are all common. Mal-union and varus angulations are common. Dynamic hip screw fixation for trochanteric fracture management is now practicing in our hospital setting but we do not have any study to see its advantage or any disadvantage. In this article we want to explain the Fixation failure using dynamic hip screw, malunion and possible complication of soft tissue and bone infection due to this. Objective: The main objective is to overview the Fixation Failure, Malunion and Possible Complication of Soft Tissue and Bone Infection. Materials and Methods: Descriptive study conducted at Department of Orthopedic Surgery, Chittagong Medical College Hospital, Chittagong, with the sample size of 36 patients aged above 50 years admitted to the Chittagong Medical College Hospital with closed trochanteric fracture to find the fixation failure, malunion and possible other complications. Results: The patients' ages ranged from 52 to 95 years. The majority of patients were 70-79 years old (36.1%), followed by 80-89 years (25%), 60-69 years (22.2%), 50-59 years (11.1%), and 90-99 years (5.6%). The mean (±SD) age of the total study patients (n=36) was 72.± 1.20 years, male (n=21) was 75.05±12.62 years and female (n=15) were 68.07±7.46 years. Maximum number of patients (44.4%) were retired, 41.7% housewife and 13.9% service holder. There are significant differences between retired and service holder groups. That among the patients, most of them sustained injuries on their right side (69.4%&gt;), and left side involvement was only in 30.6%. overall radiological improvement ....

Connecting epicardial adipose tissue and heart failure with preserved ejection fraction: mechanisms, management and modern perspectives.

Obesity is very common in patients with heart failure with preserved ejection fraction (HFpEF) and it has been suggested that obesity plays an important role in the pathophysiology of this disease. While body mass index defines the presence of obesity, this measure provides limited information on visceral adiposity, which is probably more relevant in the pathophysiology of HFpEF. Epicardial adipose tissue is the visceral fat situated directly adjacent to the heart and recent data demonstrate that accumulation of epicardial adipose tissue is associated with the onset, symptomatology and outcome of HFpEF. However, the mechanisms by which epicardial adipose tissue may be involved in HFpEF remain unclear. It is also questioned whether epicardial adipose tissue may be a specific target for therapy for this disease. In the present review, we describe the physiology of epicardial adipose tissue and the pathophysiological transformation of epicardial adipose tissue in response to chronic inflammatory diseases, and we postulate conceptual mechanisms on how epicardial adipose tissue may be involved in HFpEF pathophysiology. Lastly, we outline potential treatment strategies, knowledge gaps and directions for further research.

Functional Outcome Following Proximal Tibial Osteosarcoma Resection and Reconstruction by Modular Endoprosthesis

PurposeThe proximal tibia is a common location for osteosarcoma. Modular endoprosthesis is a popular reconstructive option, yet it has been associated with many complications. Our study aimed to evaluate the functional outcome and complications of proximal tibial osteosarcoma patients treated by limb salvage using modular endoprosthesis.MethodsA retrospective study of a prospective database was performed during the period between January 2000 and July 2017. Fifty-five patients with proximal tibial osteosarcoma underwent resection and modular endoprosthetic reconstruction. The functional outcome was evaluated using the Musculoskeletal tumor society scoring system and knee range of motion. Postoperative complications were classified according to Henderson classification; Type 1 (soft tissue failure), Type 2 (aseptic loosening), Type 3 (structural failure), Type 4 (infection) and Type 5 (local tumor progression).ResultsThe mean follow-up period was 71.69 ± 49.76 months. The mean musculoskeletal tumor society score was 26.5 ± 2.22; the mean range of motion was 72.63 ± 25.07, and the mean extension lag was 15.09 ± 15.38. Type 1, type 2, type 3, type 4, and type 5 complications occurred in 7.3%, 14.5%, 21.8%, 23.6%, and 5.5%, respectively. Chest metastasis developed in 10 patients (18.2%). The estimated 5-year and 10-year survival rates for the treated patients were 83.6% and 79.9%.ConclusionsProximal tibial osteosarcoma reconstruction with a modular endoprosthesis is a reliable treatment option for retaining limb function. Most complications are manageable.

A Method to Study the Correlation Between Local Collagen Structure and Mechanical Properties of Atherosclerotic Plaque Fibrous Tissue.

The rupture of atherosclerotic plaques in coronary and carotid arteries is the primary cause of fatal cardiovascular events. However, the rupture mechanics of the heterogeneous, highly collagenous plaque tissue, and how this is related to the tissue's fibrous structure, are not known yet. Existing pipelines to study plaque mechanics are limited to obtaining only gross mechanical characteristics of the plaque tissue, based on the assumption of structural homogeneity of the tissue. However, fibrous plaque tissue is structurally heterogeneous, arguably mainly due to local variation in the collagen fiber architecture. The mechano-imaging pipeline described here has been developed to study the heterogeneous structural and mechanical plaque properties. In this pipeline, the tissue's local collagen architecture is characterized using multiphoton microscopy (MPM) with second-harmonic generation (SHG), and the tissue's failure behavior is characterized under uniaxial tensile testing conditions using digital image correlation (DIC) analysis. This experimental pipeline enables correlation of the local predominant angle and dispersion of collagen fiber orientation, the rupture behavior, and the strain fingerprints of the fibrous plaque tissue. The obtained knowledge is key to better understand, predict, and prevent atherosclerotic plaque rupture events.

Aortic diameter is a poor predictor of aortic tissue failure metrics in patients with ascending aneurysms

ObjectivesThere is growing consensus that aortic diameter is a flawed predictor of aortic dissection risk. We hypothesized that aortic tissue metrics would be better predicted by clinical metrics other than aortic diameter. Our objectives were to (1) characterize circumferential aortic failure stress and stretch as a result of aortic size and patient demographics, and (2) identify the influence of bicuspid aortic valve on failure metrics. MethodsFrom February 2018 to January 2021, 136 aortic tissue samples were obtained from 86 adults undergoing elective ascending aorta repair. Uniaxial biomechanical testing to failure, defined as a full-thickness central tear, was performed to obtain tissue failure stress and failure stretch and compared with clinical data and preoperative computed tomography imaging. The relationships among aortic diameter, patient demographics, and failure metrics were assessed using random forest regression models. ResultsMedian failure stress was 1.46 (1.02-1.94) megapascals, and failure stretch was 1.36 (1.27-1.54). Regression models correlated moderately with failure stress (R2 = 0.557) and highly with failure stretch (R2 = 0.806). Failure stress decreased with increasing age, lower body mass index, thicker tissue, and tricuspid aortic valves, whereas failure stretch was most highly correlated with age. Aortic area-to-height index outperformed aortic diameter in all models. ConclusionsAneurysmal ascending aortic tissue failure metrics correlated with available clinical metrics. Greater tissue thickness, older age, and tricuspid aortic valve morphology outperformed aortic diameter, warranting further investigation into the role of a patient-specific multifactorial dissection risk assessment over aortic diameter as a sole marker of aortic tissue integrity.

Metabolic profiling of blueberries (Vaccinium Spp.) to quantitatively and qualitatively assess bruise damage and fruit deterioration

Bruise damage is a type of subcutaneous tissue failure in fresh produce and may seriously affect postharvest quality, limiting machine harvesting of blueberries for fresh resale. In the present study, an empirical model of finite elements was built to predict bruise susceptibility and position in blueberries with varying mechanical force. Fruit quality tests revealed that blueberries were sensitive to mechanical damage in predicted positions, which appeared as softening, cell membrane damage, decay weight and titratable acidity losses in whole fruit. Liquid chromatography mass spectrometry (LC–MS) revealed that blueberries had at least 87 distinct and annotated metabolites related to bruise damage. Lipids and lipid-like metabolites were highly responsive factors for damage development. 6-{3,5-Dihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-oxopropanoyl]phenoxy}-3,4,5-trihydroxyoxane-2-carboxylic acid and 2,6-dimethoxy-1,4-benzoquinone (DMBQ) showed good correlation with damage severity, showing potential as mechanical damage indicators. Moreover, the LC–MS results confirmed bruise damage reduced the content of DMBQ in blueberries, which is one of effective mediators stimulate efficiency of biodegradation processes of fungi. This study quantitatively and qualitatively assessed bruise damage and identified potential damage-responsive factors and indicators of blueberries under excessive mechanical force.

Adipose tissue derived ceramides regulate myocardial redox state and predict cardiovascular outcomes

Abstract Background Obesity is linked to both dysfunctional adipose tissue (AT) and heart failure, but the exact mechanisms mediating these associations are unknown. Although ceramides biosynthesis is dysregulated in obesity, their role as mediators of obesity-induced myocardial dysfunction is unclear. Purpose We investigate the causal role of AT-derived ceramides in the regulation of myocardial redox state and explore their role in predicting cardiovascular outcomes. Methods The study population included a total of 880 patients undergoing cardiac surgery. A panel of 20 sphingolipids was measured in plasma as well as in biopsies of subcutaneous AT (ScAT), thoracic AT (ThAT) and epicardial AT (EpAT) and their secretome, obtained from a subgroup of n=48. Myocardial redox state was measured using lucigenin chemiluminescence and the contribution of NOXs, uncoupled nitric oxide synthases and mitochondrial oxidases in O2•– production was quantified. The cohort was followed up for a median of 8.3 years. Genome-wide genetic analysis was done using the UK Biobank array. A total of 99,524 SNPs within 50kb of 110 genes involved in sphingolipid biosynthesis were analysed to identify genetic variants that could predict CVD outcomes using cis-Mendelian Randomisation. The underlying mechanisms were then explored further, using differentiated H9c2 cardiomyocytes in vitro and human right atrial tissue ex vivo. Results The production and secretion of C16:0-ceramide (CerC16) was higher in visceral AT (EpAT and ThAT) compared to ScAT (p&amp;lt;0.0001). Patients with high plasma levels of CerC16 and its derivative C16:0-glucosylceramide (GlcC16) had higher myocardial O2•– production vs those with low/int. levels (p&amp;lt;0.05 for both) (A). To test the causality of this association, we performed a targeted single-SNP analysis for the genetic prediction of GlcC16 levels demonstrating that rs112572487, an intronic variant in UGCG (an enzyme that catalyses glucosylceramide formation from ceramides), was the top hit (B). Indeed, those with the rs112572487 minor allele (G) displayed significantly increased myocardial NOX-derived O2•– (C) and plasma GlcC16 levels (D) vs those without. Exogenous CerC16 (20nM) induced NOX-derived O2•– production in H9c2 cardiomyocytes, an effect prevented by the UGCG inhibitor D-PDMP (E), suggesting that GlcC16 is a modifiable regulator of myocardial NOX-O2•–. Importantly, high plasma GlcC16 levels were associated with a higher risk of cardiac death and/or heart failure (adj. HR=2.128 [95% CI: 1.101, 4.115], p=0.025, for high vs low/int. levels), a relationship also seen with rs112572487 (F). Conclusions We demonstrate for the first time, that AT-derived ceramides are causally related with dysregulated myocardial redox signalling and adverse cardiovascular disease outcomes in patients with advanced atherosclerosis. As such, GlcC16 may be an important therapeutic target for the prevention and treatment of cardiovascular complications in obesity and diabetes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The British Heart FoundationBritish Heart Foundation Chair Award

The Role of the Transverse Arch in Progressive Collapsing Foot Deformity (PCFD): A Retrospective Case Control Study

Category: Midfoot/Forefoot; Basic Sciences/Biologics; Hindfoot Introduction/Purpose: A recent study published in Nature (Venkadesan et al.) demonstrated that coupling the transverse arch (TA) with the medial longitudinal arch (MLA) significantly increased midfoot intrinsic stiffness. The contribution of the TA is substantial, suggested as the evolutionary advancement providing the foot stiffness required for human bipedalism. Progressive collapsing foot deformity (PCFD) is a complex deformity ultimately resulting in loss of stiffness and collapse of the MLA. The novel understanding of the TA may play a key role in the pathogenesis of this deformity. The objectives of this study were to assess and compare the TA curvature in PCFD and controls and to evaluate its relationship with accepted PCFD measures. We hypothesized that the curvature of the TA will be decreased in PCFD. Methods: A retrospective review was conducted for 32 PCFD and 32 controls. Measurements were performed using weight- bearing CT (WBCT). A novel measurement, the transverse arch plantar (TAP) angle, was designed to directly measure the TA in both PCFD (Figure 1a) and controls (Figure 1b). TA curvature was calculated using the equation described by Venkadesan et al. (Figure 6) utilizing width, length (Figure 3a), 3rd metatarsal thickness (Figure 3b), and 4th metatarsal torsion (Figure 4a, 4b). Finally, uni- and multivariate analyses were performed to analyze the relationship between the TAP angle, Foot and Ankle Offset (FAO), peritalar subluxation, and measurements associated with PCFD classes: hindfoot moment arm (class A), talonavicular coverage angle (class B), Meary angle (class C), medial facet uncoverage angle (class D), and talar tilt (class E). Normality of different variables was assessed using the Shapiro-Wilk test. Two groups were compared using t-test for normal, and Mann-Whitney for non-normal variables. Results: Measurements of the TAP angle were found to be significantly higher in the PCFD group than the control group with a mean angle of 115.24° (SD 10.68) and 100.76° (SD 7.92) respectively (p&lt;0.001) (Figure 2).No significant difference was found in the calculated TA curvature between PCFD and controls with mean values of 17.84 (SD 4.41) and 18.18 (SD 3.68) respectively (p=0.741) (Figure 5).The univariate analysis performed showed a moderate positive correlation between the TAP angle and the FAO (ρ=0.58;r2=0.34;p &lt;0.001).The multivariate analyses showed, among the different PCFD class measurements and the TAP angle, only the middle facet uncoverage (β=0.08,p&lt;0.001) and hindfoot moment arm (β=0.32, p&lt;0.001) were associated with higher values of FAO, while only the Meary (β=0.49,p=0.004) and the talonavicular coverage angles were associated with higher values of peritalar subluxation (β=0.75,p&lt;0.001). Whereas, Meary's angle was the only predictive factor of higher TA collapse (β=0.55,p&lt;0.001). Conclusion: Our direct measurement showed a collapsed of the TA in PCFD. However, this did not appear to be a consequence of insufficient bone torsion, but rather some other etiology, possibly a soft tissue failure. Considering the implication of the TA among the different PCFD classes, it did not appear to play a significant role on the overall PCFD deformity. TA collapse seemed mainly influenced by Meary's angle, which assess the MLA. This further supports the idea behind TA and MLA coupling suggesting that when the TA is collapsed, the foot does not possess the required stiffness to maintain the MLA.

Impact of First Metatarsal Hyperpronation on First Ray Alignment: A Cadaveric Study

Category: Midfoot/Forefoot; Bunion Introduction/Purpose: Hyperpronation of the first metatarsal (M1) is present in Hallux Valgus (HV) but its impact is still unknown. A previous biomechanical study showed that an increase in hallucal pronation might lead to a medial soft tissue failure of the first metatarsophalangeal joint (MTP1). Conversely, an increase in supination and adduction of the first ray when weight-bearing is present in case of HV. The objective of our study was to sequentially answer the following questions: (1) Does an increase in M1 pronation cause an increase in hallucal pronation? (2) Can a combination of intrinsic M1 hyperpronation and MTP1 medial soft tissue failure induce a supination motion of the first ray during weight-bearing? (3) Can a first ray supination motion during weight- bearing be accompanied by an increase in IMA and HVA? Methods: A cadaveric model allowing a simulated standing position was developed and secured with a radiolucent frame (Figure 1). A midshaft osteotomy of M1 was performed allowing either 0° or 30° in pronation. MTP1 medial soft tissue release was performed to simulate failure. Twelve specimens underwent 6 Weight-Bearing CT acquisitions under different conditions listed below. The first 3 acquisitions had 0° pronation of M1:1. Simulated non-weight-bearing condition (Figure 2a) 2. Simulated weight- bearing condition (Figure 2b) 3. Simulated weight-bearing condition with medial soft tissue failure (Figure 2c). The next 3 WBCT acquisitions followed the same sequence but with 30° pronation of M1 (Figure 2d to 2f). On each WBCT acquisition, the HVA, IMA, Metatarsal Pronation Angle (MPA, M1 head pronation relative to the ground) and the hallucal pronation (HP) were measured (Figure 3). Motions were indirectly calculated from the differential values of these angular measurements produced by these 6 different conditions. Results: 1.The increase in MPA and HP induced by the 30° pronation osteotomy of M1 in simulated non weight bearing- conditions were respectively 27.6+/-4.1 and 25.5+/-5.6 degrees (p=0.202). 2.The first ray motion induced by weight-bearing without pronation osteotomy combined with a MTP1 medial soft tissue failure was 3.7+/-3.6 degrees pronation (differential value on MRA between Figure 2a and 2c) compared to 11+/-7.5 degrees supination after the 30 degrees pronation osteotomy of M1 combined with a MTP1 medial soft tissue failure (p&lt;0.01) (differential value on MPA between Figure 2d and 2f). 3.Regarding the static angular measurements, the HVA and the IMA presented fair positive linear correlations with the MPA (respectively ρ=0.2 and ρ=0.22). Regarding the motions, the increase of the HVA and the IMA during weight-bearing presented respectively a very strong negative (ρ=-0.82) and a strong negative (ρ=-0.77) linear correlations with the pronation motion of the first ray during weight-bearing. Conclusion: The combination of M1 intrinsic hyperpronation and MTP1 medial soft tissue failure led to an HV deformity in our cadaveric study. The static measurement of M1 head pronation relative to the ground (MPA) does not reflect the real intrinsic pronation of the first ray and foot and ankle specialists should be careful when interpreting these measures. HV is a dynamic condition, and the deformity could be more correlated with motions when WB than with plain static measurements. The first ray supination motion compensating a M1 intrinsic hyperpronation might be an important factor in the HV pathogenesis.

A bottom-up approach to model collagen fiber damage and failure in soft biological tissues

Understanding the damage and failure of load-carrying soft biological tissue is critical in the effectual treatment of injury and disease. The difficulty in experimentally identifying the intrinsic mechanisms by which damage initiates and accumulates, and how this ultimately leads to tissue rupture, has motivated the constitutive modeling of soft tissue failure. We present an extension of our previous microstructural continuum model (Miller and Gasser, 2021) that includes proteoglycan mediated collagen fibril sliding towards capturing the non-linear time dependent properties of collagenous tissue. We now additionally incorporate an interfibrillar failure (fibril pull-out) mechanism and showcase the resulting damage induced mechanical behavior across several length scales. Importantly, a bottom-up approach is further demonstrated, whereby the microstructural model is employed in a single-element representation of the modes of fracture. A qualitative description of soft tissue rupture is accordingly attained, to which an appropriate cohesive zone model for the equivalent fracture surface is then calibrated. In doing so, a surface-based discontinuous characterization of failure is directly derived from the upscaling of irreversible and dissipative damage mechanisms from the microscale.

Mechanical Properties of Mineralized Collagen Type I Rat-Tail Tendon Fascicles

Type I collagen fibers transmit forces, dissipate energy, and prevent mechanical failure in normal tissues. Mineralization of collagen fibers is proposed to strengthen these structural proteins as a possible therapeutic option for small tears in soft tissues such as cemental tears in periodontal ligaments. In the present study, collagen fascicles extracted from the tail tendons of male Sprague-Dawley rats were tested in a MiniMat tensile tester at different strain rates. The fascicles were previously immersed in SBF to induce mineralization and were maintained in a moist condition during mechanical testing. Mineralization of the fascicles resulted in an increase in the modulus of elasticity and tensile strength with minimal change in percentage elongation to failure. From SEM/EDS, calcium phosphate deposits formed on the fascicles indicating a high probability of intrafibrillar mineralization resulting in the observed improvement in mechanical properties.

The Complexity and Multiplicity of the Specific cAMP Phosphodiesterase Family: PDE4, Open New Adapted Therapeutic Approaches.

Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the cyclic nucleotide in its respective 5′-nucleotide to control intracellular cAMP and/or cGMP levels to maintain a normal physiological state. However, in many pathologies, dysregulations of various PDEs (PDE1-PDE11) contribute mainly to organs and tissue failures related to uncontrolled phosphorylation cascade. Among these, PDE4 represents the greatest family, since it is constituted by 4 genes with multiple variants differently distributed at tissue, cellular and subcellular levels, allowing different fine-tuned regulations. Since the 1980s, pharmaceutical companies have developed PDE4 inhibitors (PDE4-I) to overcome cardiovascular diseases. Since, they have encountered many undesired problems, (emesis), they focused their research on other PDEs. Today, increases in the knowledge of complex PDE4 regulations in various tissues and pathologies, and the evolution in drug design, resulted in a renewal of PDE4-I development. The present review describes the recent PDE4-I development targeting cardiovascular diseases, obesity, diabetes, ulcerative colitis, and Crohn’s disease, malignancies, fatty liver disease, osteoporosis, depression, as well as COVID-19. Today, the direct therapeutic approach of PDE4 is extended by developing allosteric inhibitors and protein/protein interactions allowing to act on the PDE interactome.

Distinctive structure, composition and biomechanics of collagen fibrils in vaginal wall connective tissues associated with pelvic organ prolapse

Collagen is the predominant structural protein within connective tissues. Pelvic organ prolapse (POP) is characterized by weakening of the pelvic floor connective tissues and loss of support for pelvic organs. In this study, we examined the multiscale structure, molecular composition and biomechanics of native collagen fibrils in connective tissues of the posterior vaginal fornix collected from healthy women and POP patients, and established the correlation of these properties with clinical POP quantification (POP-Q) scores. The collagen characteristics, including collagen amount, ratio of Collagen I and Collagen III, collagen fibril d-period, alignment and stiffness, were found to change progressively with the increase of the clinical measurement of Point C, a measure of uterine descent and apical prolapse. The results imply that a severe prolapse is associated with stiffer collagen fibrils, reduced collagen d-period, increased fibril alignment and imbalanced collagen synthesis, degradation and deposition. Additionally, prolapse progression appears to be synchronized with deterioration of the collagen matrix, suggesting that a POP-Q score obtained via a non-invasive clinical test can be potentially used to quantitatively assess collagen abnormality of a patient's local tissue. Statement of significanceAbnormal collagen metabolism and deposition are known to associate with connective tissue disorders, such as pelvic organ prolapse. Quantitative correlation of the biochemical and biophysical characteristics of collagen in a prolapse patient's tissue with the clinical diagnostic measurements is unexplored and unestablished. This study fills the knowledge gap between clinical prolapse quantification and the individual's cellular and molecular disorders leading to connective tissue failure, thus, provides the basis for clinicians to employ personalized treatment that can best manage the patient's condition and to alert pre-symptomatic patients for early management to avoid unwanted surgery.

Examination of the role of necroptotic damage-associated molecular patterns in tissue fibrosis.

Fibrosis is defined as the abnormal and excessive deposition of extracellular matrix (ECM) components, which leads to tissue or organ dysfunction and failure. However, the pathological mechanisms underlying fibrosis remain unclear. The inflammatory response induced by tissue injury is closely associated with tissue fibrosis. Recently, an increasing number of studies have linked necroptosis to inflammation and fibrosis. Necroptosis is a type of preprogrammed death caused by death receptors, interferons, Toll-like receptors, intracellular RNA and DNA sensors, and other mediators. These activate receptor-interacting protein kinase (RIPK) 1, which recruits and phosphorylates RIPK3. RIPK3 then phosphorylates a mixed lineage kinase domain-like protein and causes its oligomerization, leading to rapid plasma membrane permeabilization, the release of cellular contents, and exposure of damage-associated molecular patterns (DAMPs). DAMPs, as inflammatory mediators, are involved in the loss of balance between extensive inflammation and tissue regeneration, leading to remodeling, the hallmark of fibrosis. In this review, we discuss the role of necroptotic DAMPs in tissue fibrosis and highlight the inflammatory responses induced by DAMPs in tissue ECM remodeling. By summarizing the existing literature on this topic, we underscore the gaps in the current research, providing a framework for future investigations into the relationship among necroptosis, DAMPs, and fibrosis, as well as a reference for later transformation into clinical treatment.

Transcutaneous CO2 Pressure Monitoring Increases Salvage Rates after Free Tissue Transplantation for Extremity Reconstruction.

Background:Although free tissue transplantation (FTT) is an essential technique in extremity functional reconstruction, postoperative blood flow disturbance is one of the critical complications leading to transplanted tissue necrosis. Early detection of this complication may prevent tissue failure by prompt improvement of blood flow. The aim of this study was to determine whether transcutaneous carbon dioxide pressure (TcPCO2) monitoring increases the salvage rates after FTT.Methods:We retrospectively reviewed 75 consecutive patients who underwent FTT for extremity reconstruction with TcPCO2 monitoring postoperatively between December 2016 and September 2021.Results:Extremity reconstruction was performed in 53 cases due to trauma, 20 cases due to infection, and two cases due to tumor resection for tissue defects. The overall success rate of the FTT was 98.7%, with 13 complications. Of the 11 patients who underwent reoperation, nine had thrombosis and two had vascular strangulation. However, when reoperation was decided, none of the reoperation cases still exhibited any deterioration in the Doppler or clinical assessment. All reoperated cases were salvaged. Of the two patients who did not undergo reoperation, one had failed flaps and one had partial skin necrosis. With a TcPCO2 cutoff value of 70 mm Hg, the sensitivity and specificity for detecting complications due to impaired blood flow were 100% and 93.5%, respectively.Conclusions:TcPCO2 monitoring was performed after FTT for extremity reconstruction, and all cases of reoperation were salvaged. TcPCO2 monitoring can detect impaired postoperative blood flow critically earlier than clinical assessments and may increase salvage rates of transplanted tissue.

Endoprosthetic Reconstruction in Ewing's Sarcoma Patients: A Systematic Review of Postoperative Complications and Functional Outcomes.

Ewing’s sarcoma (ES) is a rare primary bone cancer managed by radiotherapy, chemotherapy and surgical resection. The existing literature on limb salvage surgery with endoprostheses combines data for ES patients with osteosarcoma. This review aimed to evaluate surgical and functional outcomes of endoprosthetic reconstruction in exclusively Ewing’s patients. We believe that this is the first comprehensive review to evaluate the outcomes of limb salvage surgery with endoprostheses exclusively in Ewing’s sarcoma patients. Clinical data and outcomes were collected from PubMed, Embase, Medline and Scopus. The inclusion criteria were studies on limb salvage surgery in ES patients, where individual patient data was available. Seventeen studies with a total of 57 Ewing’s patients were included in this review. Fifty-three of the ES patients preserved the limb after limb salvage with endoprostheses. The average five-year implant survivorship was 85.9% based on four studies in this review. Postoperative complications were categorised by Henderson’s failure modes. Soft tissue failure was the most common, occurring in 35.1% of patients, followed by deep infection in 15.7% of patients. There was a suggestion of ‘good’ functional outcomes with limb salvage surgery. The salient limitation of this review is the variability and rarity of the patient population. Homogenous data in a larger population is necessary to provide more insight into outcomes of limb reconstruction in ES.

Anterior cruciate ligament microfatigue damage detected by collagen autofluorescence in situ

PurposeCertain types of repetitive sub-maximal knee loading cause microfatigue damage in the human anterior cruciate ligament (ACL) that can accumulate to produce macroscopic tissue failure. However, monitoring the progression of that ACL microfatigue damage as a function of loading cycles has not been reported. To explore the fatigue process, a confocal laser endomicroscope (CLEM) was employed to capture sub-micron resolution fluorescence images of the tissue in situ. The goal of this study was to quantify the in situ changes in ACL autofluorescence (AF) signal intensity and collagen microstructure as a function of the number of loading cycles.MethodsThree paired and four single cadaveric knees were subjected to a repeated 4 times bodyweight landing maneuver known to strain the ACL. The paired knees were used to compare the development of ACL microfatigue damage on the loaded knee after 100 consecutive loading cycles, relative to the contralateral unloaded control knee, through second harmonic generation (SHG) and AF imaging using confocal microscopy (CM). The four single knees were used for monitoring progressive ACL microfatigue damage development by AF imaging using CLEM.ResultsThe loaded knees from each pair exhibited a statistically significant increase in AF signal intensity and decrease in SHG signal intensity as compared to the contralateral control knees. Additionally, the anisotropy of the collagen fibers in the loaded knees increased as indicated by the reduced coherency coefficient. Two out of the four single knee ACLs failed during fatigue loading, and they exhibited an order of magnitude higher increase in autofluorescence intensity per loading cycle as compared to the intact knees. Of the three regions of the ACL - proximal, midsubstance and distal - the proximal region of ACL fibers exhibited the highest AF intensity change and anisotropy of fibers.ConclusionsCLEM can capture changes in ACL AF and collagen microstructures in situ during and after microfatigue damage development. Results suggest a large increase in AF may occur in the final few cycles immediately prior to or at failure, representing a greater plastic deformation of the tissue. This reinforces the argument that existing microfatigue damage can accumulate to induce bulk mechanical failure in ACL injuries. The variation in fiber organization changes in the ACL regions with application of load is consistent with the known differences in loading distribution at the ACL femoral enthesis.