Scar Tissue Formation Research Articles

Extended use of axillary impella 5.5 as a bridge to post-infarct ventricular septal defect repair.

Post-infarct ventricular septal defect (VSD) carries high mortality. Since emergent repair of post-infarct VSD is challenging, hemodynamic stabilization utilizing temporary mechanical circulatory support crucially provides time to delay intervention and allows necessary scar tissue formation which improves the fragility of myocardium and leads to a definitive repair. To date, there remains no standard for achieving hemodynamic stability, including usage and mode of temporary mechanical circulatory support. We describe a patient with acute post-infarct VSD in cardiogenic shock successfully supported with Impella 5.5 for 67days as a bridge to surgical repair and coronary artery bypass grafting.

Challenges in tendon–bone healing: emphasizing inflammatory modulation mechanisms and treatment

Tendons are fibrous connective tissues that transmit force from muscles to bones. Despite their ability to withstand various loads, tendons are susceptible to significant damage. The healing process of tendons and ligaments connected to bone surfaces after injury presents a clinical challenge due to the intricate structure, composition, cellular populations, and mechanics of the interface. Inflammation plays a pivotal role in tendon healing, creating an inflammatory microenvironment through cytokines and immune cells that aid in debris clearance, tendon cell proliferation, and collagen fiber formation. However, uncontrolled inflammation can lead to tissue damage, and adhesions, and impede proper tendon healing, culminating in scar tissue formation. Therefore, precise regulation of inflammation is crucial. This review offers insights into the impact of inflammation on tendon–bone healing and its underlying mechanisms. Understanding the inflammatory microenvironment, cellular interactions, and extracellular matrix dynamics is essential for promoting optimal healing of tendon–bone injuries. The roles of fibroblasts, inflammatory cytokines, chemokines, and growth factors in promoting healing, inhibiting scar formation, and facilitating tissue regeneration are discussed, highlighting the necessity of balancing the suppression of detrimental inflammatory responses with the promotion of beneficial aspects to enhance tendon healing outcomes. Additionally, the review explores the significant implications and translational potential of targeted inflammatory modulation therapies in refining strategies for tendon–bone healing treatments.

Safety of non-invasive brain stimulation in patients with implants: a computational risk assessment.

Non-invasive brain stimulation (NIBS) methodologies, such as transcranial electric (tES) are increasingly employed for therapeutic, diagnostic, or research purposes. The concurrent presence of active/passive implants can pose safety risks, affect the NIBS delivery, or generate confounding signals. A systematic investigation is required to understand the interaction mechanisms, quantify exposure, assess risks, and establish guidance for NIBS applications. We used measurements, simplified generic, and detailed anatomical modeling to: (i) systematically analyze exposure conditions with passive and active implants, considering local field enhancement, exposure dosimetry, tissue heating and neuromodulation, capacitive lead current injection, low-impedance pathways between electrode contacts, and insulation damage; (ii) identify risk metrics and efficient prediction strategies; (iii) quantify these metrics in relevant exposure cases and (iv) identify worst case conditions. Various aspects including implant design, positioning, scar tissue formation, anisotropy, and frequency were investigated. At typical tES frequencies, local enhancement of dosimetric exposure quantities can reach up to one order of magnitude for deep brain stimulation (DBS) and stereoelectroencephalography implants (more for elongated passive implants), potentially resulting in unwanted neuromodulation that can confound results but is still 2-3 orders of magnitude lower than active DBS. Under worst-case conditions, capacitive current injection in the active implants' lead can produce local exposures of similar magnitude as the passive field enhancement, while capacitive pathways between contacts are negligible. Above 10 kHz, applied current magnitudes increase, necessitating consideration of tissue heating. Furthermore, capacitive effects become more prominent, leading to current injection that can reach DBS-like levels. Adverse effects from abandoned/damaged leads in direct electrode vicinity cannot be excluded. Safety related concerns of tES application in the presence of implants are systematically identified and explored, resulting in specific and quantitative guidance and establishing basis for safety standards. Furthermore,several methods for reducing risks are suggested while acknowledging the limitations(see Sec. 4.5).

Regenerative medicine for spinal cord injury using induced pluripotent stem cells: from animals to humans

Abstract Spinal cord injury (SCI) results in permanent neurological dysfunction and neuropathic pain. To address this pathology, we recently conducted a clinical study in which we transplanted neural precursor cells (NPCs) derived from human induced pluripotent stem cells into patients during the subacute phase of SCI. One of the therapeutic mechanisms of cell transplantation is the formation of synaptic connections with the host's neural tissues, which we demonstrated using a chemogenetic tool. In addition, we have developed innovative strategies to enhance the effectiveness of cell transplantation through gene therapy. Moreover, our current study is focused on developing cell therapy for chronic SCI, a more challenging pathology characterized by the formation of cavities and scar tissue. In such situations, transplanting NPCs with neurogenic properties could effectively penetrate scar tissue and form functional synapses with the host neurons. To improve the outcomes of cell transplantation alone, we have found that incorporating rehabilitation is beneficial. In animal models of SCI, we have established an effective rehabilitative training program in which NPCs were transplanted during the chronic phase. Robotic rehabilitation has demonstrated improvements in gait ability and trunk function in clinical situations. Therefore, regenerative medicine shows promise for chronic SCI, particularly when rehabilitation strategies are incorporated.

Influencing factors and repair advancements in rodent models of peripheral nerve regeneration.

Peripheral nerve injuries lead to severe functional impairments, with rodent models essential for studying regeneration. This review examines key factors affecting outcomes. Age-related declines, like reduced nerve fiber density and impaired axonal transport of vesicles, hinder recovery. Hormonal differences influence regeneration, with BDNF/trkB critical for testosterone and nerve growth factor for estrogen signaling pathways. Species and strain selection impact outcomes, with C57BL/6 mice and Sprague-Dawley rats exhibiting varying regenerative capacities. Injury models - crush for early regeneration, chronic constriction for neuropathic pain, stretch for traumatic elongation and transection for severe lacerations - provide insights into clinically relevant scenarios. Repair techniques, such as nerve grafts and conduits, show that autografts are the gold standard for gaps over 3cm, with success influenced by graft type and diameter. Time course analysis highlights crucial early degeneration and regeneration phases within the first month, with functional recovery stabilizing by three to six months. Early intervention optimizes regeneration by reducing scar tissue formation, while later interventions focus on remyelination. Understanding these factors is vital for designing robust preclinical studies and translating research into effective clinical treatments for peripheral nerve injuries.

Alginate Use in Orthopedics and Peripheral Nerve Repair: A Systematic Review.

The use of alginate, a derivative of seaweed, has been proposed for multiple orthopedic indications. We aimed to review the current use of alginate in orthopedics and to focus on the future applications of alginate for peripheral nerve repair. A comprehensive literature search was performed to identify biomechanical, laboratory, animal, and human studies where alginate has been utilized for orthopedic or nerve repair indications. A systematic review of orthopedic indications was conducted for safety and efficacy, and a specific focus was placed on alginate for use in peripheral nerve repair and reconstruction. Thirty-two studies were identified. Alginate has a strong history and safety profile for usage in orthopedic surgery. Its primary usage has been for the repair of articular cartilage, although it has also been used for disc regeneration of the lumbar spine and for cushioning joints in osteoarthritis. The primary indication in peripheral nerve repair is to create an environment that encourages Schwann cell migration and repair in nerve injuries while blocking fibrotic scar tissue formation by inhibiting the activity of fibroblasts. Alginate hydrogel may serve as a potential conduit for nerve regeneration in nerve injuries with small to medium-sized gaps.

Enhancing Athletic Recovery: Scar Treatment Using Microneedling, Dermal Fillers, and Lasers

Introduction and purpose: Scars represent a prevalent skin irregularity encountered by a significant portion of the population. Beyond merely impacting physical appearance, they can also contribute to the onset of depression and anxiety disorders, which may hinder athletic recovery. The treatment landscape for scars is diverse, spanning non-invasive to invasive procedures. This literature review endeavors to explore scar management, particularly focusing on methodologies involving microneedling, dermal fillers, and laser interventions. By examining these innovative approaches, we aim to provide insights into their efficacy and implications for clinical practice, with a particular emphasis on facilitating a faster return to sport and optimal athletic performance. Material and methods: The literature was conducted using "Pub Med" and "Google Scholar" databases with the keywords „scars”, „microneedling”, „dermal fillers”, „lasers” Brief description of the state of knowledge: Scar therapy using microneedling, dermal fillers, and lasers has shown high effectiveness and significantly improves the lives of patients undergoing treatment. Results and conclusions: Treating scars using microneedling, dermal fillers, and laser therapy has led to significant enhancements in both physical functioning and psychological well-being among patients with visible scars. These procedures exert their efficacy by promoting collagen synthesis and facilitating skin regeneration, thereby ameliorating skin redness, erythema, and scar tissue formation. However, it's important to note that the effectiveness of these interventions varies depending on factors such as the type and depth of the scar, as well as the age of the patient.

The Hidden Hand in White Matter: Pericytes and the Puzzle of Demyelination.

Disruption of myelin, the fatty sheath-insulating nerve fibers in the white matter, blocks or slows the rapid transmission of electrical signals along nerve cells and contributes to several neurodegenerative diseases such as multiple sclerosis. Traditionally, research has focused on neuronal dysfunction as the primary factor, including autoimmunity, infections, inflammation, and genetic disorders causing demyelination. However, recent insights emphasize the critical role of pericytes, non-neuronal cells that regulate blood flow and maintain the health of blood vessels within white matter. This Perspective explores the principal mechanisms through which pericyte dysfunction contributes to damage and demyelination, including impaired communication with neurons (neurovascular uncoupling), excessive formation of scar tissue (fibrosis), and the infiltration of detrimental substances from the bloodstream. Understanding these mechanisms of pericyte-driven demyelination may lead to the creation of new therapeutic strategies for tackling a range of neurodegenerative conditions.

The use of amniotic membrane injection as an adjunct in endoscopic urethral stricture management

ABSTRACT Introduction: Endoscopic urethral stricture treatment has high recurrence rates. Due to research supporting amniotic membrane’s (AMs) anti-inflammatory and anti-fibrotic properties reducing scar tissue formation, AM has generated interest in reconstructive urethral surgery. To the best of our knowledge, we performed the first investigation of the success rate of urethral dilation when combined with micronized AM injection for the treatment of urethral stricture. Methods: Eligible patients were adult males with anterior strictures meeting strict criteria for diameter, length, International Prostate Symptom Score (IPSS), and flow rate. Micronized AM was injected in the stricture region during urethral dilation. The primary study endpoint was an anatomical success (≥14Fr) at 6 months. Secondary endpoints were evaluated with the IPSS, urethral stricture surgery – patient-related outcome measure, International Index of Erectile Function, flow rate, and postvoid residual. Outcomes were assessed at baseline and multiple points postinjection. Injection safety was analyzed. Results: Ten men with a mean age of 52 years were included in the study. At 6 months, 7 of 10 patients demonstrated recurrence of the urethral stricture on cystoscopy. Improvements in secondary endpoints were noted in 10 of 10 patients at 3 months and 3 of 10 patients at 6 months. No adverse events were observed. Conclusions: To the best of our knowledge, this is the first study evaluating micronized AM injection as an adjunct treatment at the time of urethral dilation. The urethral stricture recurrence rate did not improve with the injection of AM despite the hypothesized benefits of anti-fibrotic and anti-inflammatory properties.

Bioactive MXene hydrogel promotes structural and functional regeneration of skeletal muscle through improving autophagy and muscle innervation

Complete skeletal muscle regeneration after traumatic injuries remains a challenge due to impaired regenerative capability and dysregulated microenvironments. Autophagy plays a crucial role in the muscle regeneration process by regulating myogenic and non-myogenic cells. Herein, we report a bioactive MXene hydrogel (FPGM) capable of upregulating autophagy and increasing muscle innervation to restore skeletal muscle structure and function. FPGM possessed excellent electrical conductivity, tissue adhesive ability and antioxidation, which could eliminate excess reactive oxygen species to reduce oxidative stress and decrease the secretion of pro-inflammatory cytokine. FPGM upregulated the autophagy level of myoblasts and promoted the migration and tube formation of endothelial cells as well as myogenic differentiation with negligible toxicity. FPGM accelerated muscle fiber formation and skeletal muscle regeneration by improving autophagy, which could regulate microenvironment through raising M2 macrophages to alleviate excessive inflammation, facilitating angiogenesis and decreasing fibrous scar tissue formation in vivo. Importantly, FPGM could efficiently restore muscle function by improving muscle innervation, tibialis anterior compound muscle action potential amplitude and neuromuscular conduction. This work demonstrates that bioactive MXene hydrogel should be a promising candidate for complete skeletal muscle regeneration.

Scar matrix drives Piezo1 mediated stromal inflammation leading to placenta accreta spectrum.

Scar tissue formation is a hallmark of wound repair in adults and can chronically affect tissue architecture and function. To understand the general phenomena, we sought to explore scar-driven imbalance in tissue homeostasis caused by a common, and standardized surgical procedure, the uterine scar due to cesarean surgery. Deep uterine scar is associated with a rapidly increasing condition in pregnant women, placenta accreta spectrum (PAS), characterized by aggressive trophoblast invasion into the uterus, frequently necessitating hysterectomy at parturition. We created a model of uterine scar, recapitulating PAS-like invasive phenotype, showing that scar matrix activates mechanosensitive ion channel, Piezo1, through glycolysis-fueled cellular contraction. Piezo1 activation increases intracellular calcium activity and Protein kinase C activation, leading to NF-κB nuclear translocation, and MafG stabilization. This inflammatory transformation of decidua leads to production of IL-8 and G-CSF, chemotactically recruiting invading trophoblasts towards scar, initiating PAS. Our study demonstrates aberrant mechanics of scar disturbs stroma-epithelia homeostasis in placentation, with implications in cancer dissemination.

Exosomes and microRNAs: insights into their roles in thermal-induced skin injury, wound healing and scarring.

A burn is a type of injury to the skin or other tissues caused by heat, chemicals, electricity, sunlight, or radiation. Burn injuries have been proven to have the potential for long-term detrimental effects on the human body. The conventional therapeutic approaches are not able to effectively and easily heal these burn wounds completely. The main potential drawbacks of these treatments include hypertrophic scarring, contracture, infection, necrosis, allergic reactions, prolonged healing times, and unsatisfactory cosmetic results. The existence of these drawbacks and limitations in current treatment approaches necessitates the need to search for and develop better, more efficient therapies. The regenerative potential of microRNAs (miRNAs) and the exosomal miRNAs derived from various cell types, especially stem cells, offer advantages that outweigh traditional burn wound healing treatment procedures. The use of multiple types of stem cells is gaining interest due to their improved healing efficiency for various applications. Stem cells have several key distinguishing characteristics, including the ability to promote more effective and rapid healing of burn wounds, reduced inflammation levels at the wound site, and less scar tissue formation and fibrosis. In this review, we have discussed the stages of wound healing, the role of exosomes and miRNAs in improving thermal-induced wounds, and the impact of miRNAs in preventing the formation of hypertrophic scars. Research studies, pre-clinical and clinical, on the use of different cell-derived exosomal miRNAs and miRNAs for the treatment of thermal burns have been documented from the year 2000 up to the current time. Studies show that the use of different cell-derived exosomal miRNAs and miRNAs can improve the healing of burn wounds. The migration of exosomal miRNAs to the site of a wound leads to inhibition of apoptosis, induction of autophagy, re-epithelialization, granulation, regeneration of skin appendages, and angiogenesis. In conclusion, this study underscores the importance of integrating miRNA and exosome research into treatment strategies for burn injuries, paving the way for novel therapeutic approaches that could significantly improve patient outcomes and recovery times.

Unlocking the Potential of Collagenases: Structures, Functions, and Emerging Therapeutic Horizons.

Collagenases, a class of enzymes that are specifically responsible for collagen degradation, have garnered substantial attention because of their pivotal roles in tissue repair, remodeling, and medical interventions. This comprehensive review investigates the diversity, structures, and mechanisms of collagenases and highlights their therapeutic potential. First, it provides an overview of the biochemical properties of collagen and highlights its importance in extracellular matrix function. Subsequently, it meticulously analyzes the sources of collagenases and their applications in tissue engineering and food processing. Notably, this review emphasizes the predominant role played by microbial collagenases in commercial settings while discussing their production and screening methods. Furthermore, this study elucidates the methodology employed for determining collagenase activity and underscores the importance of an accurate evaluation for both research purposes and clinical applications. Finally, this review highlights the future research prospects for collagenases, with a particular focus on promoting wound healing and treating scar tissue formation and fibrotic diseases.

The Combination of Proteolytic Enzyme Supplementation, Acupuncture, and Osseous Manipulation for the Treatment of Traumatic Peripheral Nerve Injury: A Case Report

This report describes the treatment of peripheral nerve injury in a 43-year-old woman using a combination of proteolytic enzymes, acupuncture, and osseous manipulation as alternatives to conventional care. Her presenting symptoms include complete loss of sensation in the superolateral left thigh and a mass of fibrotic scar tissue in the area of injury. A holistic treatment plan was created to address the underlying mechanisms of the injury. Plant-based proteolytic enzymes, bromelain and papain, were used to address tissue inflammation and reduce scar tissue formation around the nerve, acupuncture was used to regenerate the superficial nerves, and osseous manipulations were provided for structural re-alignment. After 8 weeks of treatment, the patient reported significant reduction in the size of the fibrotic mass and complete resolution of sensory loss. The fibrotic mass of tissue reduced from 6 cm to 1 cm during the treatment course. Proteolytic enzymes have wide-ranging indications; however, they have not been well studied for peripheral nerve injury, which makes this a novel indication for this natural health product. This case report found the use of proteolytic enzymes, and acupuncture, effective in treating peripheral nerve injury and provides grounds for research to treat nerve-related injuries.

Anterior Nasal Superior Oblique Tendon Syndrome: A Case Series

PurposeTo evaluate the clinical characteristics and management of patients with an anteriorly and nasally inserted superior oblique tendon. DesignRetrospective interventional case series. MethodsInstitutional clinical records between 2020 and 2024 were retrospectively reviewed for 9 consecutive patients in whom the superior oblique (SO) tendon was inserted anterior to the equator and nasal to the superior rectus muscle. Information collected included age, sex, ocular and surgical history, preoperative and postoperative data (ophthalmologic examinations, strabismus measurements, ductions and versions), intraoperative findings, need for additional surgery, and follow-up time. ResultsAll nine patients were found to have an anomalous insertion of the SO tendon. Three were of congenital origin and six were acquired following ocular surgery. Among the acquired cases, all but one resulted from incarceration of the tendon from post-surgical scar tissue formation. The remaining acquired case was due to a prior deliberate anterior and nasal transposition of the superior oblique. This case series demonstrated varying degrees of vertical deviations, lateral incomitance, and limited depression. Repositioning the SO to its normal insertion site yielded equivocal improvement in ocular alignment. ConclusionAnterior nasal superior oblique tendon syndrome is a rare clinical entity characterized by an anti-depressor effect. Vertical deviations, hypertropia worse in downgaze, limited depression worse in adduction for congenital cases and in abduction for acquired cases, and lateral incomitance may be indicative of this anomaly. In acquired cases following surgery, additional findings may include limited depression worse in abduction, esotropia in abduction, V-pattern esotropia, and enophthalmos in downgaze. Surgical repositioning of the SO along its normal anatomical trajectory is recommended for treatment. However, outcomes may be variable and achieving a complete resolution of this syndrome can be challenging.

Silencing siRNA microneedle patches versus silicone sheets in reducing post-surgical scars: a randomized single-blinded intra-individually controlled clinical trial.

A common complication of wounds is exuberant growth of fibrotic scar tissue, which can lead to hypertrophic scars or keloids. There are currently no treatments with good evidence for preventing excessive scar tissue formation. In this study, we explored the use of microneedle patches containing siRNA inhibiting SPARC mRNA in reducing the volume of post-surgical scars. We aim to compare the differences in the volume of post-surgical scars between daily application of siRNA-embedded dissolving microneedle patches and silicone sheets. The primary study outcome measure was the 3D volume of scar elevation.Our hypothesis was that scar formation in the half of the wound treated with siRNA microneedle patches will be lesser, as reflected by a smaller 3D volume, as compared to the half treated with silicone sheets. This was an 8-week, single-blinded intra-individually controlled randomised trial in a tertiary dermatological centre. Patients with two-week-old post-operative wounds were recruited. Each half of the scar was randomly assigned to the microneedle patch or silicone sheet. Three-dimensional (3D) volumes were obtained from the scars via a high-resolution scanner at day 0, 30 and 60. At day 30, scars treated with the microneedle patches had a lower geometric mean volume of 0.79mm3 when compared to scars treated with silicone sheets, with a difference in mean percentage volume reduction of 10.70%.At day 60, scars treated with the microneedle patches had a statistically significant lower volume (8.88mm3) when compared to the side treated with silicone sheets (12.77mm3, p=0.005), with a difference in mean percentage reduction of 9.66%. Additionally, there was also a statistically significant difference between the percentage reduction in scar volume, compared to baseline, on the side treated with microneedle patches (mean=83.78%) compared to the side treated with silicone sheets (mean=74.11%). There was a significantly greater reduction in the volume of post-surgical scars on the side treated with microneedle patches compared to the side treated with silicone sheets. This demonstrates the use of transdermal gene silencing technology for scar inhibition and that siRNA microneedle patches can be an effective and safe modality in the reduction of scar tissue formation. Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12622000558729, https://www.anzctr.org.au.

Management of Left Atrial Tachyrhythms in the Setting of HFpEF with Pulsed-Field Ablation: Treating Fire with Water?

Atrial fibrillation (AF) in the setting of heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent comorbidity and is enabled by adverse left atrial (LA) remodeling, dilation, and scar tissue formation. These changes are facilitated by poor left ventricular compliance. A growing body of clinical evidence and medical guidelines suggest that managing atrial tachyrhythms with catheter ablation (CA) is paramount to treating concomitant HF. This recommendation is complicated in that thermal CA modalities, namely radiofrequency ablation and cryoablation, are both therapeutic via inducing additional scar tissue. AF treatment with thermal CA may compound the atrial scar burden for patients who already have extensive scars secondary to HFpEF. Therefore, thermal CA could act as "gasoline" to the slowly burning "fire" within the LA, increasing the rate of AF recurrence. Pulsed-field ablation (PFA), which utilizes high-voltage irreversible electroporation, is a non-thermal CA technique that is capable of disrupting reentrant microcircuits and arrhythmogenic foci without inducing significant scar burden. PFA has the potential to mitigate the strong fibrosis response to thermal CA that predisposes to AF by serving as "water" rather than "gasoline". Thus, PFA may increase the efficacy and durability of CA for AF in HFpEF, and subsequently, may decrease the risk of procedural complications from repeat CAs. In this article, we provide a summary of the clinical concepts underlying HFpEF and AF and then summarize the data to date on the potential of PFA being a superior CA technique for AF in the setting of comorbid HFpEF.

Latest progress of self-healing hydrogels in cardiac tissue engineering.

Cardiovascular diseases represent a significant public health challenge and are responsible for more than 4million deaths annually in Europe alone (45% of all deaths). Among these, coronary-related heart diseases are a leading cause of mortality, accounting for 20% of all deaths. Cardiac tissue engineering has emerged as a promising strategy to address the limitations encountered after myocardial infarction. This approach aims to improve regulation of the inflammatory and cell proliferation phases, thereby reducing scar tissue formation and restoring cardiac function. In cardiac tissue engineering, biomaterials serve as hosts for cells and therapeutics, supporting cardiac restoration by mimicking the native cardiac environment. Various bioengineered systems, such as 3D scaffolds, injectable hydrogels, and patches play crucial roles in cardiac tissue repair. In this context, self-healing hydrogels are particularly suitable substitutes, as they can restore structural integrity when damaged. This structural healing represents a paradigm shift in therapeutic interventions, offering a more native-like environment compared to static, non-healable hydrogels. Herein, we sharply review the most recent advances in self-healing hydrogels in cardiac tissue engineering and their potential to transform cardiovascular healthcare.

Advancing Myocardial Infarction Treatment: Harnessing Multi-Layered Recellularized Cardiac Patches with Fetal Myocardial Scaffolds and Acellular Amniotic Membrane.

Myocardial infarction (MI) is a leading cause of irreversible functional cardiac tissue loss, requiring novel regenerative strategies. This study assessed the potential therapeutic efficacy of recellularized cardiac patches, incorporating fetal myocardial scaffolds with rat fetal cardiomyocytes and acellular human amniotic membrane, in adult Wistar rat models of MI. Decellularized myocardial tissue was obtained from 14 to 16 week-old human fetuses that had been aborted. Chemical detergents (0.1% EDTA and 0.2% sodium dodecyl sulfate) were used to prepare the fetal extracellular matrix (ECM), which was characterized for bio-scaffold microstructure and biocompatibility via scanning electron microscopy (SEM) and MTT assay, respectively. Neonatal cardiomyocytes were extracted from the ventricles of one-day-old Wistar rats' littermates and characterized through immunostaining against Connexin-43 and α-smooth muscle actin. The isolated cells were seeded onto decellularized tissues and covered with decellularized amniotic membrane. Sixteen healthy adult Wistar rats were systematically allocated to control and MI groups. MI was induced via arterial ligation. Fourteen days post-operation, the MI group was received the engineered patches. Following a two-week post-implantation period, the animals were euthanized, and the hearts were harvested for the graft evaluation. Histological analysis, DAPI staining, and ultra-structural examination corroborated the successful depletion of cellular elements, while maintaining the integrity of the fetal ECM and architecture. Subsequent histological and immunohistochemichal (IHC) evaluations confirmed effective cardiomyocyte seeding on the scaffolds. The application of these engineered patches in MI models resulted in increased angiogenesis, reduced fibrosis, and restricted scar tissue formation, with the implanted cardiomyocytes remaining viable at graft sites, indicating prospective in vivo cell viability. This study suggests that multi-layered recellularized cardiac patches are a promising surgical intervention for myocardial infarction, showcasing significant potential by promoting angiogenesis, mitigating fibrosis, and minimizing scar tissue formation in MI models. These features are pivotal for enhancing the therapeutic outcomes in MI patients, focusing on the restoration of the myocardial structure and function post-infarction.

Abstract We060: Hypoxia Inducible Factor-2α Enhances Neutrophil Survival and Promotes Cardiac Injury Following Myocardial Infarction via cIAP-1 Signaling

Rationale: Heart failure is a major cause of mortality following myocardial infarction (MI). Neutrophils (PMNs) are among the first immune cells to accumulate in the infarcted region. While some long-term beneficial functions of PMN in heart injury are now appreciated, en mase PMN accumulation in injured hearts is still associated with worsened resolution of inflammation and disease outcomes. MI causes extensive hypoxic injury to heart tissue, where hypoxia-inducible factors (HIFs) play critical roles in cellular functions. While HIF1α regulation of cell survival, migration and metabolism have been well-studied, the role of HIF-2α in these processes is not well-understood. Even less is known of HIF-2α contributions to PMN effector functions, especially in the context of MI. Objectives: The current study aimed to 1. Mechanistically explore how HIF-2α regulates survival of tissue infiltrating PMNs post-MI and 2. Determine how HIF-2α activity in PMNs impacts heart injury resolution post-MI, and whether specific HIF-2α deletion in PMNs can alleviate MI-induced tissue injury. Methods & Results: Infarct size, cardiac functions monitored by echocardiography, and scar tissue formation after left anterior descending coronary ligation injury model were compared between littermate control and specific PMN HIF-2α depletion (Ly6G-cre +/- HIF-2α fl/fl ) mice. Myocardial infarction size, cardiac dysfunction, scare tissue deposit and survival of tissue infiltrating PMNs post-MI were substantially attenuated in mice with PMN HIF-2α deletion. A significantly reduced lifespan of HIF-2α knockout PMNs was further confirmed by fate-mapping EdU pulse chase experiments. Mechanistically, molecular studies revealed that HIF-2α transcriptionally regulates expression of the pro-survival factor cIAP1 in PMNs binding to an HRE located in the promoter region of BIRC2 , in a hypoxia-inducible manner. Ex-vivo pharmacological inhibition of cIAP1 expression in PMNs using Birinapant resulted in dramatic cell death, establishing the critical role of cIAP1 in PMN survival. Finally, our data demonstrate that the protective effect of HIF-2α deletion in PMNs on MI outcomes was due to elevated recruitment of reparative macrophages into infarcted hearts. Conclusion: HIF-2α, through cIAP1 regulation, promotes PMN survival and tissue retention post-MI, leading to worsen cardiac functions and scar formation.