Artificial intelligence in therapeutic management of hyperlipidemic ocular pathology.

Hyperlipidemia has many ocular manifestations, the most prevalent being retinal vascular occlusion. Hyperlipidemic lesions and occlusions to the vessels supplying the retina result in permanent blindness, necessitating prompt detection and treatment. Retinal vascular occlusion is diagnosed using different imaging modalities, including optical coherence tomography angiography. These diagnostic techniques obtain images representing the blood flow through the retinal vessels, providing an opportunity for AI to utilize image recognition to detect blockages and abnormalities before patients present with symptoms. AI is already being used as a non-invasive method to detect retinal vascular occlusions and other vascular pathology, as well as predict treatment outcomes. As providers see an increase in patients presenting with new retinal vascular occlusions, the use of AI to detect and treat these conditions has the potential to improve patient outcomes and reduce the financial burden on the healthcare system. This article comprehends the implications of AI in the current management strategies of retinal vascular occlusion (RVO) in hyperlipidemia and the recent developments of AI technology in the management of ocular diseases.

Programmed spontaneously beating cardiomyocytes in regenerative cardiology.

Stem cells have gained attention as a promising therapeutic approach for damaged myocardium, and there have been efforts to develop a protocol for regenerating cardiomyocytes (CMs). Certain cells have showed a greater aptitude for yielding beating CMs, such as induced pluripotent stem cells, embryonic stem cells, adipose-derived stromal vascular fraction cells and extended pluripotent stem cells. The approach for generating CMs from stem cells differs across studies, although there is evidence that Wnt signaling, chemical additives, electrical stimulation, co-culture, biomaterials and transcription factors triggers CM differentiation. Upregulation of Gata4, Mef2c and Tbx5 transcription factors has been correlated with successfully induced CMs, although Mef2c may potentially play a more prominent role in the generation of the beating phenotype, specifically. Regenerative research provides a possible candidate for cardiac repair; however, it is important to identify factors that influence their differentiation. Altogether, the spontaneously beating CMs would be monumental for regenerative research for cardiac repair.

Injectable Nanoengineered Adhesive Hydrogel for Treating Enterocutaneous Fistulas.

Enterocutaneous fistula (ECF) is a severe medical condition where an abnormal connection forms between the gastrointestinal tract and skin. ECFs are, in most cases, a result of surgical complications such as missed enterotomies or anastomotic leaks. The constant leakage of enteric and fecal contents from the fistula site leads to skin breakdown and increases the risk of infection. Despite advances in surgical techniques and postoperative management, ECF accounts for significant mortality rates, estimated between 15-20%, and causes debilitating morbidity. Therefore, there is a critical need for a simple and effective method to seal and heal ECF. Injectable hydrogels with combined properties of robust mechanical properties and cell infiltration/proliferation have the potential to block and heal ECF. Herein, we report the development of an injectable nanoengineered adhesive hydrogel (INAH) composed of a synthetic nanosilicate (Laponite®) and a gelatin-dopamine conjugate for treating ECF. The hydrogel undergoes fast cross-linking using a co-injection method, resulting in a matrix with improved mechanical and adhesive properties. INAH demonstrates appreciable blood clotting abilities and is cytocompatible with fibroblasts. The adhesive properties of the hydrogel are demonstrated in ex vivo adhesion models with skin and arteries, where the volume stability in the hydrated internal environment facilitates maintaining strong adhesion. In vivo assessments reveal that the INAH is biocompatible, supporting cell infiltration and extracellular matrix deposition while not forming fibrotic tissue. These findings suggest that this INAH holds promising translational potential for sealing and healing ECF.

Chitosan-Polyethylene Glycol Inspired Polyelectrolyte Complex Hydrogel Templates Favoring NEO-Tissue Formation for Cardiac Tissue Engineering.

Neo-tissue formation and host tissue regeneration determine the success of cardiac tissue engineering where functional hydrogel scaffolds act as cardiac (extracellular matrix) ECM mimic. Translationally, the hydrogel templates promoting neo-cardiac tissue formation are currently limited; however, they are highly demanding in cardiac tissue engineering. The current study focused on the development of a panel of four chitosan-based polyelectrolyte hydrogels as cardiac scaffolds facilitating neo-cardiac tissue formation to promote cardiac regeneration. Chitosan-PEG (CP), gelatin-chitosan-PEG (GCP), hyaluronic acid-chitosan-PEG (HACP), and combined CP (CoCP) polyelectrolyte hydrogels were engineered by solvent casting and assessed for physiochemical, thermal, electrical, biodegradable, mechanical, and biological properties. The CP, GCP, HACP, and CoCP hydrogels exhibited excellent porosity (4.24 ± 0.18, 13.089 ± 1.13, 12.53 ± 1.30 and 15.88 ± 1.10 for CP, GCP, HACP and CoCP, respectively), water profile, mechanical strength, and amphiphilicity suitable for cardiac tissue engineering. The hydrogels were hemocompatible as evident from the negligible hemolysis and RBC aggregation and increased adsorption of plasma albumin. The hydrogels were cytocompatible as evident from the increased viability by MTT (>94% for all the four hydrogels) assay and direct contact assay. Also, the hydrogels supported the adhesion, growth, spreading, and proliferation of H9c2 cells as unveiled by rhodamine staining. The hydrogels promoted neo-tissue formation that was proven using rat and swine myocardial tissue explant culture. Compared to GCP and CoCP, CP and HACP were superior owing to the cell viability, hemocompatibility, and conductance, resulting in the highest degree of cytoskeletal organization and neo-tissue formation. The physiochemical and biological performance of these hydrogels supported neo-cardiac tissue formation. Overall, the CP, GCP, HACP, and CoCP hydrogel systems promise novel translational opportunities in regenerative cardiology.

Stem Cell-Derived Cardiomyocyte-Like Cells in Myocardial Regeneration.

Myocardial infarction results in the significant loss of cardiomyocytes (CMs) due to the ischemic injury following coronary occlusion leading to impaired contractility, fibrosis, and ultimately heart failure. Stem cell therapy emerged as a promising regenerative strategy to replenish the otherwise terminally differentiated CM to restore cardiac function. Multiple strategies have been applied to successfully differentiate diverse stem cell populations into CM-like phenotypes characterized by the expression status of signature biomarkers and observable spontaneous contractions. This article discusses the current understanding and applications of various stem cell phenotypes to drive the differentiation machinery toward CM-like lineage. Impact Statement Ischemic heart disease (IHD) extensively affects a large proportion of the population worldwide. Unfortunately, current treatments for IHD are insufficient to restore cardiac effectiveness and functionality. A growing field in regenerative cardiology explores the potential for stem cell therapy following cardiovascular ischemic episodes. The thorough understanding regarding the potential and shortcomings of translational approaches to drive versatile stem cells to cardiomyocyte lineage paves the way for multiple opportunities for next-generation cardiac management.

Engineered Vesicles and Hydrogel Technologies for Myocardial Regeneration.

Increased prevalence of cardiovascular disease and potentially life-threatening complications of myocardial infarction (MI) has led to emerging therapeutic approaches focusing on myocardial regeneration and restoration of physiologic function following infarction. Extracellular vesicle (EV) technology has gained attention owing to the biological potential to modulate cellular immune responses and promote the repair of damaged tissue. Also, EVs are involved in local and distant cellular communication following damage and play an important role in initiating the repair process. Vesicles derived from stem cells and cardiomyocytes (CM) are of particular interest due to their ability to promote cell growth, proliferation, and angiogenesis following MI. Although a promising candidate for myocardial repair, EV technology is limited by the short retention time of vesicles and rapid elimination by the body. There have been several successful attempts to address this shortcoming, which includes hydrogel technology for the sustained bioavailability of EVs. This review discusses and summarizes current understanding regarding EV technology in the context of myocardial repair.

Karyopherins in the Remodeling of Extracellular Matrix: Implications in Tendon Injury.

Rotator Cuff Tendinopathies (RCT) are debilitating conditions characterized by alterations in the extracellular matrix (ECM) of the shoulder tendon, resulting in pain, discomfort, and functional limitations. Specific mediators, including HIF-1α, TGF-ß, MMP-9 and others have been implicated in the morphological changes observed in the tendon ECM. These mediators rely on karyopherins, a family of nuclear proteins involved in nucleo-cytoplasmic transport; however, the role of karyopherins in RCT remains understudied despite their potential role in nuclear transport mechanisms. Also, the understanding regarding the precise contributions of karyopherins in RCT holds great promise for deciphering the underlying pathophysiological mechanisms of the disease and potentially fostering the development of targeted therapeutic strategies. This article critically discusses the implications, possibilities, and perspectives of karyopherins in the pathophysiology of RCT.

A Swine Model of Neural Circuit Electromagnetic Fields: Effects of Immediate Electromagnetic Field Stimulation on Cortical Injury.

Background Neurologic diseases have profound disability, mortality, and socioeconomic effects worldwide. Treatment of these disorders varies but is largely limited to unique factors associated with neural physiology. Early studies have evaluated alterations in electromagnetic fields (EMF) due to neural disorders with subsequent modulation of EMF as a potential treatment modality. Swine models have begun to be evaluated as translational models in this effect. Methods EMF measurements of a Yucatan miniswine were recorded using proprietary non-contact, non-invasive induction sensors with a dual layer Mu-metal and interlaced copper mesh helmet. The swine then underwent controlled cortical impact (CCI) to simulate traumatic brain injury (TBI). Twenty minutes post-injury after surgical wound closure, the swine underwent targeted EMF signal modulation using a signal generator to stimulate the swine's injured cortical circuit using a sinusoidal wave individualized at 2.5 Hz with a 500mV positive offset at 1V. After 10 days of stimulation, settings were modified to another individualized frequency of 5.5 Hz, 500mV positive offset and 1V for stimulation. Behavioral patterns in swine were evaluated, and EMF measurements were recorded daily prior to, during, and after stimulation. Artificial intelligence (AI) models evaluated patterns in EMF signals. Histology of the stimulated swine cortex was evaluated using hematoxylin and eosin staining and pentachrome staining and compared to a control swine without stimulation and a swine that had received stimulation two days post-injury in a delayed fashion. Serial serum specimens and tissue at the time of euthanasia were obtained for assessment of neuron-specific enolase (NSE) concentration. Results Pre-operative and post-stimulation measurements demonstrated differences in patterns and activity early on. There was an identified peak at 1.6Hz, not frequently seen pre-operatively. There were convergent frequencies in both data sets at 10.5 Hz and 3.9 Hz. Plateaus and decreased variability of changes in slope were identified early in the post-injury phase. AI modeling identified early similarities in pre-operative and post-stimulation measurements through the patterns of peaks with similarities on postoperative day 10 and similarities in the valleys on postoperative day 17. Histologic specimens identified increased degrees of apoptosis and cellular death in the non-stimulated control compared to the stimulated swine. Similarly, the immediately stimulated swine had less apoptosis and increased histologic viability at the site of injury compared to the two-day delayed stimulation swine. There were increased levels of NSE noted in the stimulated swine at the site of injury compared to non-injured sites and the control swine. Conclusions Cortical function was appropriately measured through induction sensors and shielding in the form of a helmet and electromagnetic field channels. Early stimulation resulted in the early and durable recovery of neuronal circuit-driven electromagnetic field patterns. Histology identified increased viability of neurons with fewer apoptotic neurons and glial cells in stimulated swine with early stimulation identifying the best effect compared to a non-stimulated subject. This recovery identifies change and recovery at the circuit, cellular, and subcellular levels that potentiate the need for further study of EMF modulation as a treatment modality in neurological disorders.

A Swine Model of Traumatic Brain Injury: Effects of Neuronally Generated Electromagnetic Fields and Electromagnetic Field Stimulation on Traumatic Brain Injury-Related Changes.

Background and objective Traumatic brain injury (TBI) has been associated with aberrations in neural circuitry attributable to the pathology resulting in electromagnetic field (EMF) changes. These changes have been evaluated in a variety of settings including through novel induction sensors with an ultra-portable shielded helmet and EMF channels with differences identified by comparing pre-injury and post-injury states. Modulation of the EMF has undergone cursory evaluation in neurologic conditions but has not yet been fully evaluated for clinical effects in treatment. Target EMF stimulation using EMF-related changes preoperatively to postoperatively has not yet been attempted and has not been completed using induction sensor technology. Our objectives in this study were twofold: we wanted to test the hypothesis that targeted stimulation using an EMF signal generator and stimulator to abnormal thresholds identified by real-time measurement of EMFs may enable early resolution of EMF changes and treatment of the TBI as modeled through controlled cortical impact (CCI); we also aimed to assess the feasibility of attempting this using real-time measurements with an EMF shielded helmet with EMF channels and non-contact, non-invasive induction sensors with attached EMF transmitters in real-time. Methods A singular Yucatan miniswine was obtained and baseline EMF recordings were obtained. A CCI of TBI and postoperative assessment of cortical EMF in a non-invasive, non-contact fashion were completed. Alterations in EMF were evaluated and EMF stimulation using those abnormal frequencies was completed using multiple treatments involving three minutes of EMF stimulation at abnormal frequencies. Stimulation thresholds of 2.5 Hz, 3.5 Hz, and 5.5 Hz with 1 V signal intensity were evaluated using sinusoidal waves. Additionally, stimulation thresholds using differing offsets to the sine wave at -500 mV, 0 mV, and 500 mv were assessed. Daily EMF and post-stimulation EMF measurements were recorded. EMF patterns were then assessed using an artificial intelligence (AI) model. Results AI modeling appropriately identified differences in EMF signal in pre-injury, post-injury, and post-stimulation states. EMF stimulation using a positive offset of 500 mV appeared to have maximal beneficial effects in return to baseline. Similarly targeted stimulation using thresholds of 2.5 Hz and 5.5 Hz with a positive 500 mV offset at 1 V allowed for recovery of EMF patterns post-injury towards patterns seen in baseline EMF measurements on stimulation day seven (postoperative day 17). Conclusion Stimulation of neural circuits with targeted EMF in a sinusoidal pattern with targeted thresholds after measurement with induction sensors with shielding isolated to a Mu-metal and copper mesh helmet and EMF channels is efficacious in promoting neuronal circuit recovery to preoperative baselines in the TBI miniswine model. Similarly, our findings confirm the appropriateness of this translational model in the evaluation of brain neuronal circuit EMF and that preoperative and post-trauma differences can be appropriately assessed with this technology.

A Swine Model of Changes in the Neuronal Electromagnetic Field After Traumatic Brain Injury: A Pilot Study.

Background Traumatic brain injury (TBI) is a global cause of disability and mortality. Treatment depends on mitigation of secondary injury resulting in axonal injury, necrosis, brain dysfunction, and disruption of electrical and chemical signaling in neural circuits. To better understand TBI, translational models are required to study physiology, diagnostics, and treatments in homologous species, such as swine. Electromagnetic fields (EMFs) from altered neural circuits can be measured and historically have been reliant on expensive shielding and supercooling in magnetoencephalography. Using proprietary induction sensors, it has been found that a non-invasive, non-contact approach with an engineered Mu-metal and copper mesh-shielded helmet effectively measures EMFs. This has not yet been investigated in swine models. We wished to evaluate the efficacy of this technology to assess TBI-dependent EMF changes in swine to describe the efficacy of these sensors and this model using a gravity-dependent controlled cortical impact (CCI). Methods A Yucatan miniswine was evaluated using non-contact, non-invasive proprietary induction sensors with an engineered dual-layer Mu-metal and interlaced copper mesh helmet with sensors within EMF channels connected to a helmet. Swine EMF recordings were obtained prior to induced gravity-dependent CCI followed by post-TBI measurements. Behavioral changes and changes in EMF measurements were assessed. EMF measurements were evaluated with an artificial intelligence (AI) model. Results Differences between room "noise" EMF measurements and pre-TBI swine electromagnetic field measurements were identified. Morphological characteristics between pre-injury and post-injury measurements were noted. AI modeling differentiated pre-injury and post-injury patterns in the swine EMF. Frequently identified frequencies seen post-injury were peaks at 2.5 Hz and 6.5 Hz and a valley at 11 Hz. The AI model identified less changes in the slope and thus decreased variation of EMF measurements post-TBI between 4.5 Hz and 7 Hz. Conclusions For the first time, it was identified that cortical function in a swine can be appropriately measured using novel induction sensors and shielding isolated to a helmet and EMF channels. The swine model can be appropriately differentiated from the external noise signal with identifiably different pre-injury and post-injury EMFs. Patterns can be recognized within the post-injury EMF due to altered neural circuits that can be measured using these sensors continuously, non-invasively, and in real time.

Response to acute hyperglycemia and high fructose in cultured tenocytes.

High monosaccharide levels are intimately associated with diabetes and impact tendon cells through inflammation and impairment in metabolic homeostasis. Experiments were designed to understand the responses elicited by cultured tenocytes under monosaccharide stress induced by hyperglycemia and hyperfructosemia. We simulated hyperglycemia and hyperfructosemia in vitro by treating tenocytes with media containing sublethal concentrations of glucose and fructose, respectively. Exposure of tenocytes to high glucose and high fructose altered the levels of IL-1ß, IL-2, IL-6, IL10 and IL-17A. AMPK expression was increased in high-glucose and decreased in high-fructose groups. High fructose increased the level of IRS-1 compared with the control. Increased mitochondrial superoxide levels and compromised mitochondrial membrane integrity were exhibited by both the groups. The findings from the network analysis revealed many altered genes that are related to pathways for enzyme-linked receptor protein signaling, positive regulation of metabolic processes, transmembrane receptor tyrosine kinase pathway, insulin receptor signaling and regulation of cytokine production. Overall, the data suggest that the tenocytes under high monosaccharide levels exhibit survival responses by altering the expression status of cytokines and metabolic mediators that are involved in the underlying pathogenesis of tendinopathy.

Hyperlipidemia in tendon injury: chronicles of low-density lipoproteins.

Hyperlipidemia impacts millions of people globally and has been the major risk factor for developing atherosclerosis and cardiovascular disease. Interestingly, hyperlipidemic subjects exhibit increased incidence of rotator cuff tendon injury (RCTI) and disorganization of tendon matrix. Low-density lipoproteins (LDL) and its oxidized form (ox-LDL) play a crucial role in hyperlipidemia-driven pro-inflammatory responses in multiple tissues including the tendon. The signaling of oxLDL upregulates the inflammatory cytokines, chemokines, adhesion molecules, and the activation of monocytes/macrophages/resident tendon cells and matrix metalloproteinases impairing the tendon homeostasis resulting in the alteration of extracellular matrix. In addition, the hyperlipidemia-driven immune response and subsequent oxidative stress promote degenerative responses in the tendon tissue. However, the pathological mechanisms underlying the occurrence of RCTI in hyperlipidemia and the effect of ox-LDL in tendon matrix are currently unknown. The present review focuses on the implications and perspectives of LDL/oxLDL on the increased incidence of RCTI.

Carboxymethyl cellulose-alginate interpenetrating hydroxy ethyl methacrylate crosslinked polyvinyl alcohol reinforced hybrid hydrogel templates with improved biological performance for cardiac tissue engineering.

Cardiac tissue engineering is an emerging approach for cardiac regeneration utilizing the inherent healing responses elicited by the surviving heart using biomaterial templates. In this study, we aimed to develop hydrogel scaffolds for cardiac tissue regeneration following myocardial infarction (MI). Two superabsorbent hydrogels, CAHA2A and CAHA2AP, were developed employing interpenetration chemistry. CAHA2A was constituted with alginate, carboxymethyl cellulose, (hydroxyethyl) methacrylate, and acrylic acid, where CAHA2AP was prepared by interpenetrated CAHA2A with polyvinyl alcohol. Both hydrogels displayed superior physiochemical characteristics, as determined by attenuated total reflection infrared spectroscopy spectral analysis, differential scanning calorimetry measurements, tensile testing, contact angle, water profiling, dye release, and conductivity. In vitro degradation of the hydrogels displayed acceptable weight composure and pH changes. Both hydrogels were hemocompatible, and biocompatible as evidenced by direct contact and MTT assays. The hydrogels promoted anterograde and retrograde migration as determined by the z-stack analysis using H9c2 cells grown with both gels. Additionally, the coculture of the hydrogels with swine epicardial adipose tissue cells and cardiac fibroblasts resulted in synchronous growth without any toxicity. Also, both hydrogels facilitated the production of extracellular matrix by the H9c2 cells. Overall, the findings support an appreciable in vitro performance of both hydrogels for cardiac tissue engineering applications.

Single-cell genomics illustrates heterogeneous phenotypes of myocardial fibroblasts under ischemic insults.

Myocardial regenerative strategies are promising where the choice of ideal cell population is crucial for successful translational applications. Herein, we explored the regenerative/repair responses of infarct zone cardiac fibroblast(s) (CF) by unveiling their phenotype heterogeneity at single-cell resolution. CF were isolated from the infarct zone of Yucatan miniswine that suffered myocardial infarction, cultured under simulated ischemic and reperfusion, and grouped into control, ischemia, and ischemia/reperfusion. The single-cell RNA sequencing analysis revealed 19 unique cell clusters suggesting distinct subpopulations. The status of gene expression (log2 fold change (log2 FC) > 2 and log2 FC < -2) was used to define the characteristics of each cluster unveiling with diverse features, including the pro-survival/cardioprotective (Clusters 1, 3, 5, 9, and 18), vasculoprotective (Clusters 2 and 5), anti-inflammatory (Clusters 4 and 17), proliferative (Clusters 4 and 5), nonproliferative (Clusters 6, 8, 11, 16, 17, and 18), proinflammatory (Cluster 6), profibrotic/pathologic (Clusters 8 and 19), antihypertrophic (Clusters 8 and 10), extracellular matrix restorative (Clusters 9 and 12), angiogenic (Cluster 16), and normal (Clusters 7 and 15) phenotypes. Further understanding of these unique phenotypes of CF will provide significant translational opportunities for myocardial regeneration and cardiac management.

Pathological alterations in the expression status of rotator cuff tendon matrix components in hyperlipidemia.

Hyperlipidemia is an important risk factor in the development and progression of tendon pathology, however its role in aggravating rotator cuff tendon injury (RCTI) is largely unknown. We aimed to assess the expression status of key extracellular matrix (ECM) components in the tendon tissues and tenocytes under hyperlipidemia. Shoulder rotator cuff (RC) tendon tissues harvested from the swine model of hyperlipidemia displayed alterations in histomorphometry and the expression status of major ECM component proteins including COL-I, COL-III, COL-IV, COL-V, COL-VI, MMP2, and MMP9. Similarly, the LDL- and oxLDL-challenged tenocytes displayed altered expression of the same proteins at both transcriptional and translational levels. In addition, the lipid uptake and cellular reactive oxygen radicals predominated in the lipid-challenged tenocytes compared to the control. Overall, the LDL-treated cells displayed predominant pathological alterations compared to the ox-LDL-treated cells. Further understanding regarding the underlying molecular mechanisms driving the tendon matrisome alteration and subsequent aggravated RCTI pathology in hyperlipidemia could open novel translational avenues in the management of RCTI.

Ischemia challenged epicardial adipose tissue stem cells-derived extracellular vesicles alter the gene expression of cardiac fibroblasts to cardiomyocyte like phenotype.

The present study hypothesizes that the ischemic insults activate epicardial adipose tissue-derived stem cells (EATDS) to secrete extracellular vesicles (EVs) packed with regenerative mediators to alter the gene expression in cardiac fibroblasts (CF). EATDS and CF were isolated from hyperlipidemic microswine and EVs were harvested from control, simulated ischemia (ISC) and ischemia-reperfusion (ISC/R) groups. The in vitro interaction between ISC-EVs and CF resulted in the upregulation of cardiomyocyte-specific transcription factors including GATA4, Nkx2.5, IRX4, and TBX5 in CF and the healing marker αSMA and the downregulation of fibroblast biomarkers such as vimentin, FSP1, and podoplanin and the cardiac biomarkers such as troponin-I and connexin-43. These results suggest a cardiomyocyte-like phenotype as confirmed by immunostaining and Western blot. The LC-MS/MS analysis of ISC-EVs LGALS1, PRDX2, and CCL2 to be the potent protein mediators which are intimately involved in versatile regenerative processes and connected with a diverse array of regenerative genes. Moreover, the LGALS1+, PRDX2+, and CCL2+ EATDS phenotypes were deciphered at single cell resolution revealing corresponding sub-populations with superior healing potential. Overall, the findings unveiled the healing potential of EATDS-derived EVs and sub-populations of regenerative EATDS promising novel translational opportunities in improved cardiac healing following ischemic injury.

Rotator Cuff Tendon Repair after Injury in Hyperlipidemic Swine Decreases Biomechanical Properties.

Rotator cuff injury is the leading cause of shoulder pain. Hyperlipidemia is responsible in depositing lipids in tendons and reduce the healing upon injuries or tears. In this study, we created rotator cuff injury and repair models in swine and studied the changes in biomechanical properties of infraspinatus tendons in hyperlipidemic swine. The infraspinatus tendons from control group, hyperlipidemic injury and repair group of animals were collected and tested ex-vivo. The ultimate tensile strength (UTS) and modulus of elasticity increased in the tendons from the contralateral side on both the injury and repair models and were higher than the injury side. The presence of large number of fibrous tissues in the surgical site of repair and increased water content was observed in addition to the fatty infiltration which would have contributed to the decreased mechanical properties of the injured tendons following repair. Meanwhile the tendons of the contralateral side in both the injury and repair model showed adaptation to chronic load as observed in the modulus and viscoelastic properties. This is a pilot study that warrants detailed investigation in a larger sample size with longer duration following tendon injury and repair to gain better understanding on the effect of hyperlipidemia in the healing of rotator cuff tendon injury.

Fluoroscopy Guided Minimally Invasive Swine Model of Myocardial Infarction by Left Coronary Artery Occlusion for Regenerative Cardiology.

Background: Despite the recent advancements in the cardiac regenerative technologies, the lack of an ideal translationally relevant experimental model simulating the clinical setting of acute myocardial infarction (MI) hurdles the success of cardiac regenerative strategies. Methods: We developed a modified minimally invasive acute MI model in Yucatan miniswine by catheter-driven controlled occlusion of LCX branches for regenerative cardiology. Using a balloon catheter in three pigs, the angiography guided occlusion of LCX for 10-15 minutes resulted in MI induction which was confirmed by the pathological ECG changes compared to the baseline control. Results: Ejection fraction was considerably decreased post-procedure compared to the baseline. Importantly, the highly sensitive MI biomarker Troponin I was significantly increased in post-MI and follow-up groups along with LDH and CCK than the baseline control. The postmortem infarct zone tissue displayed the classical features of MI including ECM disorganization, hypertrophy, inflammation, and angiogenesis confirming the MI at the tissue level. Conclusions: The present model possesses the advantage of minimal mortality, simulating the pathological features of clinical MI and the suitability for injectable regenerative therapies suggesting the translational significance in regenerative cardiology.

Bioactive extracellular matrix fragments in tendon repair.

Tendinopathy is a common tendon disorder that causes pain, loss of strength and function, and local inflammation mainly characterized by hypoxia, collagen degradation, and extracellular matrix (ECM) disorganization. Generally, ECM degradation and remodeling is tightly regulated; however, hyperactivation of matrix metalloproteases (MMPs) contributes to excessive collagenolysis under pathologic conditions resulting in tendon ECM degradation. This review article focuses on the production, function, and signaling of matrikines for tendon regeneration following injury with insights into the expression, tissue compliance, and cell proliferation exhibited by various matrikines. Furthermore, the regenerative properties suggest translational significance of matrikines to improve the outcomes post-injury by assisting with tendon healing.

TLR-4 Inhibition Attenuates Inflammation, Thrombosis, and Stenosis in Arteriovenous Fistula in Yucatan Miniswine.

Arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis patients; however, it is afflicted with a high failure rate. Chronic inflammation, excessive neointimal hyperplasia (NIH), vessel stenosis, early thrombosis, and failure of outward remodeling are the major causes of AVF maturation failure. Inflammatory mediator toll-like receptor (TLR)-4 plays a critical role in NIH, arterial thrombosis, and stenosis. We investigated the effect of TLR-4 inhibition on early thrombosis. Yucatan miniswine were used to create AVF involving femoral artery and femoral vein and treated with TLR-4 inhibitor TAK-242 with ethanol as the vehicle. The vessels were assessed after 12 weeks using histomorphometry, immunostaining, ultrasound, angiography, and optical coherence tomography. Inhibition of TLR-4 attenuated inflammation and early thrombosis in 50% of animals, and blood flow was present through AVF in 25% of animals. Thus, targeting TLR-4 to attenuate inflammation and early thrombosis might be a therapeutic approach to keep AVF patent and maintain blood flow through the outflow vein.