Therapeutic Efficacy of Cryopreserved, Allogeneic Extracellular Vesicles for Treatment of Acute Myocardial Infarction.

Extracellular vesicles (EV) that are derived from endothelial progenitor cells (EPC) have been determined to be a novel therapy for acute myocardial infarction, with a promise for immediate "off-the-shelf" delivery. Early experience suggests delivery of EVs from allogeneic sources is safe. Yet, clinical translation of this therapy requires assurances of both EV stability following cryopreservation and absence of an adverse immunologic response to EVs from allogeneic donors. Thus, more bioactivity studies on allogeneic EVs after cold storage are necessary to establish quality standards for its widespread clinical use. Thus, in this study, we aimed to demonstrate the safety and efficacy in delivering cryopreserved EVs in allogeneic recipients as a therapy for acute myocardial infarction.In this present study, we have analyzed the cardioprotective effects of allogeneic EPC-derived EVs after storage at -80°C for 2 months, using a shear-thinning gel (STG) as an in vivo delivery vehicle. EV size, proteome, and nucleic acid cargo were observed to remain steady through extended cryopreservation via nanoparticle tracking analysis, mass spectrometry, and nanodrop analysis, respectively. Fresh and previously frozen EVs in STG were delivered intramyocardially in a rat model of myocardial infarction (MI), with both showing improvements in contractility, angiogenesis, and scar thickness in comparison to phosphate-buffered saline (PBS) and STG controls at 4 weeks post-MI. Pathologic analyses and flow cytometry revealed minimal inflammatory and immune upregulation upon exposure of tissue to EVs pooled from allogeneic donor cells.Allogeneic EPC-EVs have been known to elicit minimal immune activity and retain therapeutic efficacy after at least 2 months of cryopreservation in a post-MI model.

Relationship Between Change in Heart Transplant Volume and Outcomes: A National Analysis.

INTRODUCTION: Although volume-outcome relationships in transplantation have been well-defined, the effects of large changes in center volume are less well understood. The purpose of the current study was to examine the impact of changes in center volume on outcomes after heart transplantation. METHODS: Retrospective analysis was performed of adult patients undergoing heart transplant between 2000 and 2017 identified in the United Network for Organ Sharing database. Exclusions included annual volume <10. Patients were grouped according to percentage change in center volume from the previous year. Multivariable Cox regression models were adjusted for the significant preoperative variance identified on univariate analyses. RESULTS: Of the 29,851 transplants during the study period, 64% were at centers with stable volume (±25% annual change), whereas 10% were performed at contracting (-25% change or more) and 26% were performed at growing (+25% change or more) centers. Average volume was lower with contracting centers compared with stable or growing programs (21 vs 36, P< .001). Thirty-day mortality was greater in decreasing centers (6% vs 4%, P < .001), with more acute rejection treatments at 1y (27% vs 24% P < .001). The adjusted risk of mortality among contracting centers was 1.25 ([1.07-1.46], P= .004), whereas growing centers had unaffected risk (0.90 [0.79-1.02], P= .103). Causes of death were similar between groups. CONCLUSIONS: Rapid growth of transplant center volume has occurred at select centers in the United States without decrement in programmatic outcomes. Decreasing center volume has been associated with poorer outcomes, although the causative nature of this relationship requires further investigation.

Transplant Volume Is Associated With Graft Acceptance Threshold and Center Resource Availability.

BACKGROUND: Heart transplant volume varies significantly among centers. We hypothesized that centers where the transplant team routinely accepts organs previously declined by other centers and where operating room availability is unrestricted have higher transplant volumes. METHODS AND RESULTS: We used the potential transplant recipient sequence number in the United Network for Organ Sharing database as a surrogate for graft acceptance threshold and the number of transplantations occurring on weekends and 8 major holidays as a marker of center resource availability. Centers were classified as low-, medium-, or high-volume if the average annual number of transplants were, respectively, <10, 10-30, or >30 over a 10-year period. From July 12, 2006, to December 31, 2015, 19,054 transplants were performed by 142 centers. There were 59 low-volume centers, 69 medium-volume centers, and 14 high-volume centers with median potential transplant recipient sequence numbers for transplanted candidates of 7 (interquartile range 3-11), 7 (5-10), and 15 (7-40), respectively (P = .002). The median proportion of off-hours transplantations performed by medium-volume centers was 28% (25%-31%) compared with 32% (29%-33%) by high-volume centers (P = .009). Five-year survival was equivalent among all centers (P = .053). CONCLUSIONS: Transplants for candidates with high sequence numbers and unrestricted operating room availability are associated with increased center volume without sacrificing post-transplantation survival.

Better With Time: An Economic Assessment of Long-Term Mechanical Circulatory Support in a Population Surviving at Least 1 Year with a Left Ventricular Assist Device.

This study aims to identify the major components of left ventricular assist device (LVAD)-related costs in a population on long-term mechanical circulatory support to gain insight into opportunities for improvements in quality, safety, and efficiency of care for end-stage heart failure patients. This was a single institution, retrospective cost analysis of patients who received a Heartmate II or HeartWare LVAD between November 2005 and October 2015. Payments for hospitalization for device implantation and subsequent readmissions were represented as the institution's 2015 Medicare reimbursement rate. The incidence, average Medicare reimbursement, and length of stay of readmissions were analyzed for the first year postimplant. A full year of LVAD-related hospitalizations in patients surviving ≥12 months, has a median Medicare reimbursement of $247,208. The most common complications related to ventricular assist devices were gastrointestinal bleeding, driveline infection, stroke, and pump thrombosis. Over 90% of total costs were incurred during the initial hospitalization. Seventy-five percent of first-time readmissions occurred within the first 4 months post discharge. Intensive care unit costs accounted for the single largest cost category during readmissions for all of the 4 most common complications. The trends demonstrated suggest that longer lengths of LVAD support in appropriately selected patients results in progressively decreasing cost-per-month up to 12 months, given the large upfront cost of device implantation and relatively modest additional costs of readmissions. This analysis emphasizes the importance of devices with improved complication profiles and clinical protocols to reduce unnecessary intensive care unit stays to increase the cost effectiveness of long-term ventricular assist device therapy.

Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics.

BACKGROUND: Extracellular vesicles (EVs) are promising therapeutics for cardiovascular disease, but poorly-timed delivery might hinder efficacy. We characterized the time-dependent response to endothelial progenitor cell (EPC)-EVs within an injectable shear-thinning hydrogel (STG+EV) post-myocardial infarction (MI) to identify when an optimal response is achieved. METHODS: The angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in vitro. A rat model of acute MI via left anterior descending artery ligation was created and STG+EV was delivered via intramyocardial injections into the infarct border zone at time points corresponding to phases of post-MI inflammation: 0 hours (immediate), 3 hours (acute inflammation), 4 days (proliferative), and 2 weeks (fibrosis). Hemodynamics 4 weeks post-treatment were compared across treatment and control groups (phosphate buffered saline [PBS], shear-thinning gel). Scar thickness and ventricular diameter were assessed histologically. The primary hemodynamic end point was end systolic elastance. The secondary end point was scar thickness. RESULTS: EPC-EVs incubated with chronically versus acutely hypoxic human umbilical vein endothelial cells resulted in a 2.56 ± 0.53 versus 1.65 ± 0.15-fold increase (P = .05) in a number of vascular meshes and higher uptake of EVs over 14 hours. End systolic elastance improved with STG+EV therapy at 4 days (0.54 ± 0.08) versus PBS or shear-thinning gel (0.26 ± 0.03 [P = .02]; 0.23 ± 0.02 [P = .01]). Preservation of ventricular diameter (6.20 ± 0.73 mm vs 8.58 ± 0.38 mm [P = .04]; 9.13 ± 0.25 mm [P = .01]) and scar thickness (0.89 ± 0.05 mm vs 0.62 ± 0.03 mm [P < .0001] and 0.58 ± 0.05 mm [P < .0001]) was significantly greater at 4 days, compared wit PBS and shear-thinning gel controls. CONCLUSIONS: Delivery of STG+EV 4 days post-MI improved left ventricular contractility and preserved global ventricular geometry, compared with controls and immediate therapy post-MI. These findings suggest other cell-derived therapies can be optimized by strategic timing of therapeutic intervention.

Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery.

Shear-thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross-linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin-10 (IL-10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL-10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL-10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.

Delivery of progenitor cells with injectable shear-thinning hydrogel maintains geometry and normalizes strain to stabilize cardiac function after ischemia.

OBJECTIVES: The ventricle undergoes adverse remodeling after myocardial infarction, resulting in abnormal biomechanics and decreased function. We hypothesize that tissue-engineered therapy could minimize postischemic remodeling through mechanical stress reduction and retention of tensile myocardial properties due to improved endothelial progenitor cell retention and intrinsic biomechanical properties of the hyaluronic acid shear-thinning gel. METHODS: Endothelial progenitor cells were harvested from adult Wistar rats and resuspended in shear-thinning gel. The constructs were injected at the border zone of ischemic rat myocardium in an acute model of myocardial infarction. Myocardial remodeling, tensile properties, and hemodynamic function were analyzed: control (phosphate-buffered saline), endothelial progenitor cells, shear-thinning gel, and shear-thinning gel + endothelial progenitor cells. Novel high-resolution, high-sensitivity ultrasound with speckle tracking allowed for global strain analysis. Uniaxial testing assessed tensile biomechanical properties. RESULTS: Shear-thinning gel + endothelial progenitor cell injection significantly increased engraftment and retention of the endothelial progenitor cells within the myocardium compared with endothelial progenitor cells alone. With the use of strain echocardiography, a significant improvement in left ventricular ejection fraction was noted in the shear-thinning gel + endothelial progenitor cell cohort compared with control (69.5% ± 10.8% vs 40.1% ± 4.6%, P = .04). A significant normalization of myocardial longitudinal displacement with subsequent stabilization of myocardial velocity with shear-thinning gel + endothelial progenitor cell therapy compared with control was also evident (0.84 + 0.3 cm/s vs 0.11 ± 0.01 cm/s, P = .03). A significantly positive and higher myocardial strain was observed in shear-thinning gel + endothelial progenitor cell (4.5% ± 0.45%) compared with shear-thinning gel (3.7% ± 0.24%), endothelial progenitor cell (3.5% ± 0.97%), and control (8.6% ± 0.3%, P = .05). A resultant reduction in dynamic stiffness was noted in the shear-thinning gel + endothelial progenitor cell cohort. CONCLUSIONS: This novel injectable shear-thinning hyaluronic acid hydrogel demonstrates stabilization of border zone myocardium with reduction in adverse myocardial remodeling and preservation of myocardial biomechanics. The cellular construct provides a normalization of strain measurements and reduces left ventricular dilatation, thus resulting in improvement of left ventricular function.

Is there a difference in bleeding after left ventricular assist device implant: centrifugal versus axial?

BACKGROUND: Continuous-flow left ventricular assist devices (CF-LVAD) have become the standard of care for patients with end stage heart failure. Device reliability has increased, bringing the potential for VAD, compared to transplant, into debate. However, complications continue to limit VADs as first line therapy. Bleeding is a major morbidity. A debate exists as to the difference in bleeding profile between the major centrifugal and axial flow devices. We hypothesized that there would be similar adverse bleeding event profiles between the 2 major CF-LVADs. METHODS: We retrospectively investigated isolated CF LVADs performed at our institution between July 2010 and July 2015: HeartMateII (HMII, n = 105) and HeartWare (HVAD, n = 34). We reviewed demographic, perioperative and short- and long-term outcomes. RESULTS: There was no significant difference in demographics or comorbidities. There was a low incidence of gastrointestinal (GI) bleed 3.9% in HMII and 2.9% in HVAD (p = 0.78). Preoperatively, the cohorts did not differ in coagulation measures (p = 0.95). Within the post-operative period, there was no difference in product transfusion: red blood cells (p = 0.10), fresh frozen plasma (p = 0.19), and platelets (p = 0.89). Post-operatively, a higher but not significantly different number of HMII patients returned to the operating room for bleeding (n = 27) compared to HVAD (n = 6, p = 0.35). There was no difference in rates of stroke (p = 0.65), re-intubation (p = 0.60), driveline infection (p = 0.05), and GI bleeding (p = 0.31). The patients had equivalent ICU LOS (p = 0.86) and index hospitalization LOS (p = 0.59). CONCLUSION: We found no difference in the rate of bleeding complications between the current commercially available axial and centrifugal flow devices.

Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart.

Injectable hydrogels have significant therapeutic potential for treatment of myocardial infarction (MI) through tissue bulking and local drug delivery, including the delivery of small interfering RNAs (siRNAs). As siRNA targets are identified as potential treatments for MI, hydrogels may bolster efficacy through local and sustained release. Here, we designed an injectable hydrogel to respond to local upregulation in proteolytic activity after MI to erode and release siRNA against MMP2 (siMMP2), a target implicated in deleterious remodeling. Specifically, hyaluronic acid (HA) was modified with hydrazides or aldehydes and mixed to form shear-thinning and self-healing hydrogels through dynamic hydrazone bonds and with peptide crosslinkers that degrade in response to protease activity. HA was further modified with ß-cyclodextrin to sequester cholesterol-modified siRNA, limiting passive diffusion. Hydrogels eroded in response to proteases and released active siRNA that knocked down MMP2 in primary cardiac fibroblasts. In a rat model of MI, hydrogels delivering siMMP2 attenuated hydrogel erosion by ~46% at 4 weeks when compared to hydrogels delivering control siRNA, ultimately improving myocardial thickness in the infarct. Delivery of the siMMP2 hydrogel led to significant functional improvements, including increased ejection fraction (27%, 66%), stroke volume (32%, 120%), and cardiac output (20%, 128%) when compared to controls (% increase versus hydrogels with control siRNA, % increase versus saline injection alone). This report demonstrates the utility of biomaterial-based RNA delivery systems for cardiac applications.

Injectable Granular Hydrogels with Multifunctional Properties for Biomedical Applications.

Injectable hydrogels are useful for numerous biomedical applications, such as to introduce therapeutics into tissues or for 3D printing. To expand the complexity of available injectable hydrogels, shear-thinning and self-healing granular hydrogels are developed from microgels that interact via guest-host chemistry. The microgel properties (e.g., degradation, molecule release) are tailored through their crosslinking chemistry, including degradation in response to proteases. When microgels of varied formulations are mixed, complex release and degradation behaviors are observed, including after injection to permit cellular invasion.

Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction.

Aims: Previous studies have demonstrated improved cardiac function following myocardial infarction (MI) after administration of endothelial progenitor cells (EPCs) into ischaemic myocardium. A growing body of literature supports paracrine effectors, including extracellular vesicles (EVs), as the main mediators of the therapeutic benefits of EPCs. The direct use of paracrine factors is an attractive strategy that harnesses the effects of cell therapy without concerns of cell engraftment or viability. We aim to reproduce the beneficial effects of EPC treatment through delivery of EPC-derived EVs within a shear-thinning gel (STG) for precise localization and sustained delivery. Methods and results: EVs were harvested from EPCs isolated from adult male Rattus norvegicus (Wistar) rats and characterized by electron microscopy, nanoparticle tracking analysis (NTA), and mass spectrometry. EVs were incorporated into the STG and injected at the border zone in rat models of MI. Haemodynamic function, angiogenesis, and myocardial remodelling were analyzed in five groups: phosphate buffered saline (PBS) control, STG control, EVs in PBS, EVs in STG, and EPCs in STG. Electron microscopy and NTA of EVs showed uniform particles of 50-200 nm. EV content analysis revealed several key angiogenic mediators. EV uptake by endothelial cells was confirmed and followed by robust therapeutic angiogenesis. In vivo animal experiments demonstrated that delivery of EVs within the STG resulted in increased peri-infarct vascular proliferation, preservation of ventricular geometry, and improved haemodynamic function post-MI. Conclusions: EPC-derived EVs delivered into ischaemic myocardium via an injectable hydrogel enhanced peri-infarct angiogenesis and myocardial haemodynamics in a rat model of MI. The STG greatly increased therapeutic efficiency and efficacy of EV-mediated myocardial preservation.

Extended distance cardiac allograft can successfully be utilized without impacting long-term survival.

BACKGROUND: Despite the severe shortage of donor cardiac allografts, the general belief in worse outcomes with donors from prolonged distances has resulted in many centers greatly limiting the acceptable geographic distance of acceptable donors. However, with improvements in allograft preservation, it is likely that distance may be extended without compromising graft integrity. We hypothesized that recipients of appropriately selected allografts from greater distances would have equivalent long-term survival compared with recipients from closer geographic regions. METHODS: We retrospectively analyzed the United Network for Organ Sharing (UNOS) adult heart transplant data from January 2000 to December 2013. Recipients were stratified by donor distance. Demographic and outcomes data were analyzed, with a primary end-point of survival. RESULTS: During the study period, 25,996 isolated orthotopic heart transplantations (OHTs) were performed. Patients were stratified by distance: 0 to 500 miles (n = 24,645); 501 to 1,000 miles (n = 1,201); 1,001 to 1,500 miles (n = 134); and 1,501+ miles (n = 16). Increased donor allograft distance correlated with significantly longer ischemic times (3.1 miles for 0 to 500 miles vs 7.5 hours for 1,501+ miles, p = 0.0001). One- and 5-year survival was similar in all cohorts, using Kaplan-Meier survival analysis (log rank, p = 0.8025). There was no difference in rate of stroke (p = 0.82), dialysis (p = 0.60) or reoperation (p = 0.28). Length of stay was equivalent across cohorts (p = 0.11). CONCLUSIONS: Appropriately selected allografts from donors at a greater distance should be considered to increase organ availability. Donor heart procurement from increased distance may not directly increase morbidity and mortality post-heart transplant.

Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials.

Injectable hydrogels have gained popularity as a vehicle for the delivery of cells, growth factors, and other molecules to localize and improve their retention at the injection site, as well as for the mechanical bulking of tissues. However, there are many factors, such as viscosity, storage and loss moduli, and injection force, to consider when evaluating hydrogels for such applications. There are now numerous tools that can be used to quantitatively assess these factors, including for shear-thinning hydrogels because their properties change under mechanical load. Here, we describe relevant rheological tests and ways to measure injection force using a force sensor or a mechanical testing machine toward the evaluation of injectable hydrogels. Injectable, shear-thinning hydrogels can be used in a variety of clinical applications, and as an example we focus on methods for injection into the heart, where an understanding of injection properties and mechanical forces is imperative for consistent hydrogel delivery and retention. We discuss methods for delivery of hydrogels to mouse, rat, and pig hearts in models of myocardial infarction, and compare methods of tissue postprocessing for hydrogel preservation. Our intent is that the methods described herein can be helpful in the design and assessment of shear-thinning hydrogels for widespread biomedical applications.

Improved Approach With Subcostal Exchange of the HeartMate II Left Ventricular Assist Device: Difference in On and Off Pump?

BACKGROUND: The HeartMate II (St. Jude Medical, Inc, St. Paul, MN [previously Thoratec]) left ventricular assist device (LVAD) exchange has traditionally involved a redo sternotomy. Alternate minimally invasive subcostal approaches have the advantage of avoiding sternal reentry, excessive bleeding, and prolonged recovery. METHODS: This retrospective review included patients who underwent an exchange from May 2009 to March 2016. The patients were divided into three cohorts: (1) redo sternotomy, (2) subcostal approach involving cardiopulmonary bypass (CPB) (ON-CPB SC), and (3) subcostal approach off the CPB pump (OFF-CPB SC). Data pertaining to patients' baseline characteristics and outcomes were collected and analyzed. RESULTS: From May 1, 2009 to July 31, 2016, 33 HeartMate II LVAD exchanges were performed. There were 11 redo sternotomies and 22 subcostal exchanges, 12 of which were in the OFF-CPB SC group. There was no significant difference among the groups in terms of age (p = 0.75), sex (p = 0.95), and indication for exchange (p = 0.94). There was a higher red blood cell transfusion requirement within the sternotomy cohort (p < 0.001). The median time to extubation and the intensive care unit length of stay were significantly shorter in the OFF-CPB SC group (1 and 2.5 days, respectively) than in the sternotomy (2.5 and 21 day, respectively) and ON-CPB SC groups (1.5 and 5 days, respectively). The 30-day and 90-day survival rates were equivalent among the cohorts. CONCLUSIONS: Exchange of the HeartMate II LVAD can be accomplished with significantly improved recovery time and transfusion requirement through a less invasive subcostal approach when compared with sternotomy. The subcostal approach can be performed safely both on and off cardiopulmonary bypass.

Low ejection fraction in donor hearts is not directly associated with increased recipient mortality.

BACKGROUND: Reduced left ventricular ejection fraction (EF) in the donor heart is often a contraindication for transplant. However, small studies have validated the use of hearts with evidence of myocardial dysfunction to boost the number of organs available for transplant. We hypothesize that donor hearts with reduced EF undergo myocardial recovery after transplant and result in equivalent recipient survival compared with grafts with normal function. METHODS: We examined post-operative outcomes of heart recipients in the database of the United Network for Organ Sharing. Patients were grouped by donor EF as follows: <40% (reduced EF); between 40% and 50% (borderline EF); and ≥50% (normal EF). Propensity score matching was performed to compare separately reduced and borderline EF patients with normal EF patients. RESULTS: Of 30,993 donors from 1996 to 2015, 127 (0.4%) had reduced EF, 613 (2.0%) had borderline EF and 30,253 (97.6%) had normal EF. In each of the 2 propensity score comparisons, the odds of post-operative stroke (p = 0.139, p = 0.551), pacemaker requirement (p = 0.238, p = 0.739), primary graft failure (p = 0.569, p = 0.817), rejection (p = 0.376, p = 0.533) and death at 1 year (p = 0.124, p = 0.247) were equivalent. At roughly 1-year follow-up after transplant, the mean EF of the reduced EF group was 58.0 ± 10.3% compared with 59.5 ± 7.5% in the matched normal EF group (p = 0.289). The mean follow-up EF of the borderline EF group was 58.3 ± 9.1% compared with 59.3 ± 7.7% in the matched normal EF group (p = 0.106). CONCLUSIONS: Recipients of hearts with reduced EF have equivalent 1-year survival compared with recipients of hearts with normal EF. Donor hearts with reduced EF show significant functional recovery after transplant.

Where We Fail: Location and Timing of Failure to Rescue in Trauma.

Failure to rescue (FTR) is an outcome metric that reflects a center's ability to prevent mortality after a major complication. Identifying the timing and location of FTR events could help target efforts to reduce FTR rates. We sought to characterize the timing and location of FTR occurrences at our center, hypothesizing that FTR rates would be highest early after injury and in settings of lower intensity of care. We used data, prospectively collected from 2009 to 2013, on patients ≥16 years old with minimum Abbreviated Injury Score ≥2 from a single institution. Major complications (per Pennsylvania Trauma Systems Foundation definitions), mortality, and FTR rates were examined by location [prehospital, emergency department, operating room, intensive care unit (ICU), and interventional radiology] and by day post admission. Kruskal-Wallis and chi-squared tests were used to compare variables (P = 0.05). Major complications occurred in 899/6150 (14.6%) of patients [median age: 42, interquartile range (IQR): 25-57; 56% African American, 73% male, 76% blunt; median Injury Severity Score: 10, IQR: 5-17]. Of 899, 111 died (FTR = 12.4%). Compared with non-FTR cases, FTR cases had earlier complications (median day 1 (IQR: 0-4) versus 5 (IQR: 2-8), P < 0.001). FTR rates were highest in the prehospital (55%), emergency department (38%), and operating room (36%) settings, but the greatest number of FTR cases occurred in the ICU (52/111, 47%). FTR rates were highest early after injury, but the majority of cases occurred in the ICU. Efforts to reduce institutional FTR rates should focus on complications that occur in the ICU setting.

Local and sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischemic injury.

MicroRNA-based therapies that target cardiomyocyte proliferation have great potential for the treatment of myocardial infarction (MI). In previous work, we showed that the miR-302/367 cluster regulates cardiomyocyte proliferation in the prenatal and postnatal heart. Here, we describe the development and application of an injectable hyaluronic acid (HA) hydrogel for the local and sustained delivery of miR-302 mimics to the heart. We show that the miR-302 mimics released in vitro promoted cardiomyocyte proliferation over one week, and that a single injection of the hydrogel in the mouse heart led to local and sustained cardiomyocyte proliferation for two weeks. After MI, gel/miR-302 injection caused local clonal proliferation and increased cardiomyocyte numbers in the border zone of a Confetti mouse model. Gel/miR-302 further decreased cardiac end-diastolic (39%) and end-systolic (50%) volumes, and improved ejection fraction (32%) and fractional shortening (64%) four weeks after MI and injection, compared to controls. Our findings suggest that biomaterial-based miRNA delivery systems can lead to improved outcomes in cardiac regeneration.