Citations

Chronic wounds remain a major unmet clinical challenge, often failing to progress to normal healing due to persistent inflammation, impaired angiogenesis, and cellular senescence. Exosomes have recently been investigated as promising acellular therapeutics capable of restoring intercellular communication and promoting tissue regeneration. Among these, the Purified Exosome Product (PEP) represents a next-generation, platelet-derived exosome formulation manufactured under Good Manufacturing Practice (GMP) conditions with high purity, stability, and reproducibility. This review summarizes the current advances in exosome-based chronic wound therapeutics and PEP delivery systems and their translational potentials. Incorporation of PEP into bioengineered carriers such as fibrin sealant, collagen scaffolds, and hyaluronic acid (HA) hydrogels enables localized and sustained exosome release, significantly prolonging therapeutic effects and improving regenerative outcomes. Fibrin-based PEP delivery achieved complete wound closure and functional skin regeneration in animal models, while collagen and HA-based systems showed promising results for injectable and dermatologic applications. Beyond its intrinsic healing effects, PEP may also serve as a nanocarrier for other drugs, offering a future direction in chronic wound management.

Background: Tendon-bone healing after rotator cuff injury is, or remains, a clinical challenge. Purpose: To examine the role of intraoperative use of purified exosome products (PEPs) in the treatment of rotator cuff injuries and to assess the effect of PEP on supraspinatus tendon-bone healing after rotator cuff repair in a rat model. Study Design: Controlled laboratory study. Methods: This study used 120 Sprague-Dawley rats that underwent an acute supraspinatus tendon transection from the insertion, followed by repair using a single transosseous suture. They were divided into 3 groups: a control group that received only sutures, a TISSEEL group that used a commercially available fibrin sealant patch (TISSEEL) of approximately 0.5 cm 2 , and a PEP-TISSEEL group that used a similarly sized TISSEEL patch combined with PEP. Autopsies were performed at 1, 3, 6, and 8 weeks after surgery. Analyses were performed using molecular biological, biomechanical, and histological techniques. Results: At 6 weeks, the PEP-TISSEEL group achieved greater failure load (mean, 27.5 ± 5.3 N) than the control (mean, 16.4 ± 4.2 N; P = .012) and TISSEEL (mean, 23.4 ± 5.0 N; P = .041) groups, with superiority persisting at 12 weeks (27.2 ± 6.5 N vs 13.1 ± 2.6 N [ P = .002] for the control group and 21.1 ± 5.8 N [ P = .037] for the TISSEEL group). DigiGait showed earlier recovery of stride length and paw angle. Histology revealed organized collagen and reduced scarring, while molecular assays demonstrated early inflammatory modulation with subsequent upregulation of collagen type 1 or 3 and TGF-β, supporting accelerated tendon-bone healing. Conclusion: Intraoperative application of PEP-TISSEEL enhanced tendon-bone healing in a rat model by improving biomechanical strength, promoting enthesis-specific histological regeneration, and accelerating functional recovery as evidenced by gait analysis. Clinical Relevance: The intraoperative application of PEP combined with TISSEEL significantly enhances rotator cuff tendon healing by modulating early inflammation, promoting collagen synthesis, and improving biomechanical properties in a rat model. These findings suggest that PEP-based therapies could offer a promising adjunct in surgical repair, potentially reducing retear rates and improving functional outcomes in patients with rotator cuff injuries. Further clinical studies are warranted to translate these benefits into human applications.

Introduction: The Impella 5.5 is frequently employed to provide temporary mechanical circulatory support as bridge to recovery or durable therapy. Optimization of device management relies on understanding ventricular pressure-volume (PV) relationships. Aim: The aim of this study was to evaluate the biventricular (BiV) relationship with PV loop assessment during Impella 5.5 support in non-myopathic ventricles. Methods: Six domestic Yorkshire Pigs were used for this study. The Impella 5.5 (J&J MedTech, NJ) was inserted percutaneously under ultrasound and fluoroscopic guidance through either the carotid artery or aortic arch, using a 26Fr DrySeal Sheath (Gore, AZ). BiV PV loop conductance catheters (Sigma-M, CD Leycom, Hengelo, The Netherlands) were inserted via femoral venous access. The LV PV loop catheter is positioned via transeptal puncture and with intracardiac echocardiogram guidance. BiV PV loops are generated for each level of Impella 5.5 support. Results: With increasing levels of Impella 5.5 support, left ventricular (LV) PV loops shifted increasingly to the left and right ventricular (RV) loops to the right. Accordingly, LV end-diastolic volume (EDV) decreased (110±4 ml to 90±8 ml; p<0.001) and RV EDV increased (121±7 ml to 147±13 ml; p<0.001), from baseline to P9. Native LV systolic function decreased with increasing Impella 5.5 support, as demonstrated by a reduction in stroke volume (SV) (56±5 ml to 49±5 ml; p<0.001), cardiac output (CO) (3.4±0.8 ml/min to 2.0±0.3 ml/min; p<0.001), ejection fraction (EF) (51±4% to 44±6%; p<0.001), stroke work (SW) (4483±1023 ml*mmHg to 2383±719 ml*mmHg; p<0.001), and LV peak positive dP/dt (825 ± 184 mmHg/s to 523 ± 99 mmHg/s; p<0.001). Conversely, the native RV experienced preload-mediated increase in SV (65±7 ml to 86±20 ml; p<0.001), CO (3.7±0.8 ml/min to 4.3±0.9 ml/min; p<0.001), EF (53±4% to 58±11%; p<0.001), SW (918±143 ml*mmHg to 1529±365 ml*mmHg; p<0.001), and RV dP/dt (164±16 mmHg/s to 228±29 mmHg/s, p<0.001). Load independent contractility was assessed in the LV (1.64±0.33 mmHg/ml to 1.71±0.41 mmHg/ml; p=0.2) and RV (0.25±0.04 mmHg/ml to 0.29±0.05 mmHg/ml; p<0.001). Conclusions: This study highlights ventricular interdependence with Impella 5.5 support with opposing BiV trends. In a healthy heart, the RV can adequately compensate for increased preload offered by the device.

Introduction: Microaxial flow pumps reduce mortality in myocardial infarction (MI) related cardiogenic shock (CS). The Impella 5.5 generates increased flow to provide circulatory support, and optimization relies on mechanistic understanding of pressure-volume (PV) relationships. Aim: Using a porcine model of acute MI in tandem with biventricular (BiV) PV loop conductance catheters, this study aimed to understand the impact of Impella 5.5 on BiV hemodynamics in MI CS. Methods: In 6 Domestic Yorkshire Pigs, an Impella 5.5 (J&J MedTech, NJ) was inserted percutaneously under fluoroscopic guidance via carotid or aortic access. An angioplasty balloon catheter was advanced past the first diagonal and inflated to above nominal pressure with blood flow obstruction for 90 minutes. BiV PV loop conductance catheters (Sigma-M, CD Leycom, Hengelo, The Netherlands) were inserted via femoral venous access. The left ventricle (LV) PV loop catheter is positioned via transeptal puncture using intracardiac echocardiography. BiV PV loops are generated for each level of Impella support from P1 to P7. Results: With increasing Impella 5.5 support, LV PV loops shifted to the left and right ventricular (RV) loops to the right. Without statistical significance, LV end diastolic volume (EDV) decreased by a mean of 12.3 ± 10.7% from baseline and RV EDV increased by 32 ± 40%. Native LV function decreased with increasing Impella 5.5 support, demonstrated by a reduction in stroke volume (SV) (35±13 ml to 27±14 ml; p<0.001), cardiac output (CO) derived from SV&heart rate (2.0±0.5 ml/min to 1.7±0.7 ml/min; p<0.001), and ejection fraction (EF) (37±7% to 29±12%; p<0.001). Less consistent trends were noted in peak positive dP/dt and end-systolic pressure volume relationship. Native RV function increased with higher levels of Impella 5.5 support, noted by increasing SV (27±24 ml to 41±28 ml; p=0.004), CO (1.6±1.2 ml/min to 2.3±1.4 ml/min; p=0.001), and EF (42±16% to 45±9%; p=0.04). Arterial elastance and ventriculo-arterial coupling increased in the LV from baseline to P7 (2.2±1.4 mmHg/ml to 2.8±1.0 mmHg/ml and 1.8±0.5 to 3.2±1.9, respectively; p<0.001) and decreased in the RV (1.3±0.7 mmHg/ml to 0.9±0.7 mmHg/ml (p<0.001) and 2.1±2.2 to 1.3±0.6 (p=0.004)). Conclusions: Impella 5.5 speed modulation highlights significant ventricular interdependence in the setting of acute MI. PV loop derived parameters here visualized parameters that may be utilized to improve optimization of hemodynamic support in CS.

Percutaneous ventricular assist devices (pVAD) decrease mortality in cardiogenic shock (CS) patients, but at a high adverse event rate. Novel pVADs need to improve cardiac power output (CPO) to improve efficacy and reduce profile to reduce adverse events. Venstramedical has developed an impeller with nitinol and polymer which can collapse for low-profile insertion and expand in the body to provide optimal CPO. We have also developed a unique 9 French (9Fr) delivery system. In vitro and in vivo testing have been performed to develop this device. Head-flow (HQ) tests generate 5.0 L/min with a pressure differential of 80 mm Hg and 7.0 L/min against 60 mm Hg. Durability testing demonstrated continuous operation of up to 20 days. In the acute healthy ovine model, we demonstrated full flow (7–9 L against 60–80 mm Hg), transcatheter 9Fr delivery, retrieval of the device, and resting of the native heart during pumping. In a CS animal, we demonstrated survival and resting of the native heart during the acute study with decreased stroke work (SW), decreased stroke volume (SV), while total cardiac output was up to 7 L/min and maintaining adequate pressure with low hemolysis. We also demonstrated multiday functioning of the device in a healthy ovine model with good CO and low hemolysis.

Background: The authors present a novel microsurgical model to investigate ischemia-reperfusion (I/R) injury in composite tissue (muscle/skin) using a musculocutaneous flap. I/R was induced in a rodent biceps femoris musculocutaneous flap through collateral ligation and arteriovenous clamping. The authors hypothesized that I/R flaps would show greater tissue damage compared with sham. Methods: Male rats were randomized into I/R ( n = 10) and sham ( n = 9) groups. The I/R group underwent flap elevation, collateral ligation, 3 hours of arteriovenous clamping, followed by reperfusion. The sham group had flap elevation only. Perfusion was monitored using laser-speckle imaging, and flap discoloration was assessed with blinded skin ischemia necrosis scores. Serum and the composite tissue (skin/muscle) were analyzed for injury on postoperative days (PODs) 1 or 3. Results: Clamping reduced perfusion ( P = 0.00), whereas unclamping increased perfusion ( P <0.00). Over time, flaps exposed to I/R were more ischemic (estimate, 0.39; P = 0.02). At POD1, the injury group had higher serum creatine kinase ( P = 0.04) and potassium ( P = 0.00) than the sham group. The injury group had more muscle apoptosis (34.7% versus 5.2%; P = 0.03), myonecrosis (30.3% versus 14.1%; P = 0.04), and inflammation (13.7% versus 4.9%; P = 0.02) than the sham group; myonecrosis and inflammation persisted into POD3. Skin apoptosis and inflammation were similar. Conclusions: This model reliably reproduces I/R injury with a 3-hour ischemic period followed by early reperfusion. Animals subjected to the authors’ technique showed greater tissue damage than the sham group, with muscle being more vulnerable than skin. Serum showed peak muscle injury at 24 hours, and histologic analysis showed myonecrosis and inflammation through 72 hours. This suggests that less than 24 hours’ reperfusion (eg, critical window) may serve as the optimal time for possible intervention. Clinical Relevance Statement: I/R injury is a complex phenomenon affecting vascular composite tissues. The mitochondrial superoxide dismutase may be more specific for I/R injury. There may be a critical window within which to mitigate injury (<24 hours after reperfusion). The authors’ model helps investigate muscle/skin I/R injury.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Rationale: We previously reported (PMID: 38325750) that a nebulized exosome product isolated from human platelets (PEP) attenuated murine cigarette smoke (CS)-induced emphysema. To further elucidate the mechanism by which PEP attenuates CS-induced effects in the murine lung, emphysema was induced, and mice were treated with PEP or placebo (saline). Immune and cellular mechanisms affected by PEP were then evaluated in this system. Methods: C57BL6 female black mice were exposed to CS 5 days a week for 3 months and then randomized into PEP-treated or placebo groups. CS-exposed mice were treated with 3 mL of 7.5 mg/mL PEP (∼1 x 1010 extracellular vesicles per mL) or 0.9% saline by nebulization 3 times a week for an additional 4 weeks, using a nose-sealed, pressure and humidity-controlled inhalation tower for 30 minutes. Lung compliance, cutaneous O2 saturation, mean linear intercepts, and lung inflammation were measured during and after the study. Lung tissue was further analyzed by immunostaining, and gene expression analyses to elucidate the molecular mechanisms of PEP's action. Inflammatory and immune regulatory cell markers evaluated included CD4 (CD4+ T lymphocytes), CD4/Foxp3 (T regulatory – Treg) cells, S100A9 (interstitial lung macrophages), and myeloperoxidase (MPO) for neutrophils. Results: Histologic review of lung tissue sections by mean linear intercept counts confirmed prior findings and showed a significant reduction in the free distance of chronic CS exposure-induced alveolar space enlargement in PEP-treated mice (P=0.003). In addition, lung inflammation scores showed a significant overall reduction of the lymphocytic infiltrates in PEP-nebulized lungs compared to the CS-exposed placebo control group (P&lt;0.0001). Further analysis of the immune cell infiltrates revealed increased FOXP3+CD4+ T regulatory cells within the lymphocytic infiltrates (P&lt;0.0001) and decreased S100A9+ interstitial lung macrophages (p=0.0002) and MPO+ neutrophils (p=0.005) in PEP nebulized lungs compared to the placebo controls. PEP-treated mice had similar oxygen saturation levels when compared to the CS control group (94.7±1.47 vs. 95.4±.1.6 respectively). Conclusions: In addition to validating prior findings on the effect of nebulized PEP in mitigating CS-induced murine lung injury and emphysema, the current data suggests an immunoregulatory role for PEP by decreasing inflammatory macrophage and neutrophil infiltration while augmenting anti-inflammatory Treg cell numbers in the lung.

Abstract The expanding use of continuous‐flow left ventricular assist devices (CF‐LVADs) for end‐stage heart failure warrants familiarity with the physiologic interaction of the device with the native circulation. Contemporary devices utilize predominantly centrifugal flow and, to a lesser extent, axial flow rotors that vary with respect to their intrinsic flow characteristics. Flow can be manipulated with adjustments to preload and afterload as in the native heart, and ascertainment of the predicted effects is provided by differential pressure‐flow ( H ‐ Q ) curves or loops. Valvular heart disease, especially aortic regurgitation, may significantly affect adequacy of mechanical support. In contrast, atrioventricular and ventriculoventricular timing is of less certain significance. Although beneficial effects of device therapy are typically seen due to enhanced distal perfusion, unloading of the left ventricle and atrium, and amelioration of secondary pulmonary hypertension, negative effects of CF‐LVAD therapy on right ventricular filling and function, through right‐sided loading and septal interaction, can make optimization challenging. Additionally, a lack of pulsatile energy provided by CF‐LVAD therapy has physiologic consequences for end‐organ function and may be responsible for a series of adverse effects. Rheological effects of intravascular pumps, especially shear stress exposure, result in platelet activation and hemolysis, which may result in both thrombotic and hemorrhagic consequences. Development of novel solutions for untoward device‐circulatory interactions will facilitate hemodynamic support while mitigating adverse events. © 2021 American Physiological Society. Compr Physiol 12:1‐37, 2021.

Background: The primary aim of this study was to demonstrate the benefits of topical human platelet exosome extract (HPE) (plated) hair serum for improving hair and scalp health in participants with self-perceived thinning hair. Methods: This single-center, placebo-controlled, double-blind study enrolled 39 healthy men and women 18–65 years of age with self-perceived thinning hair. Participants applied either HPE for 9 months or a topical placebo for 6 months with the option to cross over to HPE at 6 months for an additional 3 months. End points included improvements in the global aesthetic appearance of hair, as assessed by a blinded live evaluator; participant-reported outcomes; hair trichoscopy; and independent physician photograph evaluations. Safety data included monitoring for adverse events. Results: Blinded live evaluator assessments demonstrated statistically significant improvements in the global aesthetic appearance of hair for volume/fullness, density, scalp coverage, and appearance, with all P values less than 0.0001 within the HPE group and statistical improvement over the control at months 3 and 6 for volume/fullness, density, and scalp coverage. Participant-reported outcomes for within-group changes for HPE were statistically significant for all hair health parameters, including density, volume fullness, scalp coverage, scalp health, thickness, amount, quality, color, dryness, strength, and overall health of the hair. Hair trichoscopy analyses were significantly improved from baseline within the HPE group. Independent physician photography review demonstrated greater improvements within the HPE group. No adverse effects were observed. Conclusions: This study demonstrates that topical HPE (plated) hair serum with Renewosome technology significantly improves hair and scalp health and is safe and well tolerated.