Delivery Of Vascular Endothelial Growth Factor Research Articles

GELATIN AND VEGF INCORPORATION IN PVA-TYRAMINE HYDROGELS AS A STRATEGY TO ENHANCE VASCULAR INFILTRATION AND TREAT AVASCULAR NECROSIS

INTRODUCTIONStimulation of angiogenesis via the delivery of growth factors (GFs) like vascular endothelial growth factor (VEGF) is a promising strategy for the treatment of avascular necrosis (AVN). Tyraminated poly-vinyl-alcohol hydrogels (PVA-Tyr), which have the ability to covalently incorporate GFs, were proposed as a platform for the controlled delivery of therapeutic levels VEGF to the necrotic areas[1]. Nevertheless, PVA hydrophilicity and bioinertness limits its integration with the host tissues. The aim of this study was to investigated the effectiveness of incorporating gelatin, an FDA-approved, non-immunogeneic biomaterial with biological recognition sites, as a strategy to facilitate blood vessels invasion of PVA-Tyr hydrogels and to restore the vascular supply to necrotic tissues.METHODSProgressively higher gelatin concentrations (0.01–5wt%) were incorporated in the PVA-Tyr network. Hydrogel physico-chemical properties and endothelial cell attachment were evaluated. Afterwards, the capability of the released VEGF and gelatin to promote vascularization was evaluated via chorioallantoic membrane (CAM) assay. VEGF-loaded PVA-Tyr hydrogels with or without gelatin (n=7) were implanted in a subcutaneous mouse model for 3 weeks. Vascularization (CD31+ cells) and cell infiltration (H&E) were evaluated. Finally, AVN was induced in 6 weeks old male piglets as previously described [2]. A transphyseal hole (3mm) was drilled and PVA-Tyr hydrogels with 1% gelatin were delivered in the defects. Piglets were euthanized after 4 weeks and microCT analysis was performed.RESULTSThe incorporation of 1% gelatin significantly enhanced cell attachment without compromising hydrogels physical properties, degradation time, VEGF retention and release. Thus, this gelatin concentration was selected for further analysis. Additionally, the covalent incorporation of VEGF or gelatin to the PVA-Tyr network does not hamper their bioactivity, as both still promoted neo-angiogenesis in a CAM assay. Following subcutaneous implantation, the presence of gelatin did not increase the cellular infiltration in the PVA-Tyr hydrogels. Nevertheless, higher vascular infiltration was observed in the groups where either gelatin or VEGF were included. Additionally, preliminary microCT results indicated that the delivery of PVA-Tyr hydrogels containing 1% gelatin in an AVN model was effective in preventing the necrosis-associated resorption of the bone.DISCUSSION & CONCLUSIONSThese results indicated that the presence of either gelatin or VEGF was sufficient to promote vascular infiltration. Additionally, preliminary results suggested the suitability of the developed hydrogels to treat AVN.

Hydrogel forming microneedles loaded with VEGF and Ritlecitinib/polyhydroxyalkanoates nanoparticles for mini-invasive androgenetic alopecia treatment

Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.

Abstract 154: Clustered Vascular Endotelial Growth Factor Nanoparticles Biomaterial for the Treatment of Moyamoya Disease

Introduction: Cerebrovascular ischemia poses a substantial neurological threat due to cerebral artery constriction. Innovative solutions, such as Vascular Endothelial Growth Factor (VEGF)-infused hydrogel biomaterials, have emerged. Hydrogels, mimicking the extracellular matrix, allow controlled VEGF delivery, prompting angiogenesis, tissue repair, and enhancing conditions like moyamoya disease. This non-invasive technique carries transformative potential. Hypothesis: Our hypothesis postulates that hyaluronic acid (HA) gels, with or without VEGF, can augment endothelial cell quantities and blood flow in fore-brain ischemic mice. Methods: We divided C57/B6 mice into four groups: control, vehicle (chronic ICA occlusion and stenosis), HA gel treatment, and Cluvena ( Cl uster VE GF Na noparticle) hydrogel treatment. Brain dissection, sectioning, and CD31 and DAPI staining were performed for cellular identification. Results: Following two weeks, CD31 staining unveiled diminished endothelial cell populations in ischemic animals, significantly differing from controls. HA gel effectively restored endothelial cell counts to control levels. DAPI analysis indicated ischemic animals displayed considerably fewer DAPI-stained cells, attesting to successful ischemia induction and ensuing damage. Biomaterial intervention revived cell counts, aligning with control conditions. Intriguingly, hydrogel-only treated animals closely mirrored Cluvena outcomes in CD31 counts. Conclusions: Therapeutic angiogenic biomaterials, whether incorporating VEGF or not, hold significant potential for ischemic conditions. Cluvena efficiently reinstated endothelial cell numbers, thus unveiling potential therapeutic avenues for moyamoya, an ischemic disease with related neurological disorders or symptoms. This minimally-invasive strategy bears the promise of revolutionizing the field of brain ischemic condition therapeutics.

An injectable, activated neutrophil-derived exosome mimetics/extracellular matrix hybrid hydrogel with antibacterial activity and wound healing promotion effect for diabetic wound therapy

Chronic diabetic wounds are primarily caused by infection, inflammation, and angiogenesis-related disorders. An ideal approach for treating chronic diabetic wounds is by combining anti-infection strategies, immune microenvironment regulation, and angiogenesis promotion. Vascular endothelial growth factor (VEGF) can promote the proliferation and migration of vascular endothelial cells, thereby promoting angiogenesis. However, the low stability and inability to target lesions limit its application. Polymorphonuclear neutrophil-derived exosomes (PMNExo) exhibit good delivery properties and can be used for the therapeutic delivery of VEGF. Furthermore, they retain the antibacterial ability of polymorphonuclear neutrophils (PMNs). Nonetheless, low PMNExo generation impedes its therapeutic applications. In this study, we prepared exosome mimetics (EM) from PMNs using the extrusion process; as a result, exosome yield significantly improved. To increase the residence of exosomes, an extracellular matrix (ECM) hydrogel, a thermosensitive material that can function as an in situ gel in vivo, was used as an exosome carrier. The active peptides in the ECM regulated the immune microenvironment of the wound. In summary, we loaded ECM with VEGF-encapsulated activated neutrophil exosome mimetics (aPMNEM) to develop VEGF–aPMNEM–ECM hybrid hydrogel for treating chronic wounds. The hydrogel accelerates the regeneration of chronic diabetic wounds. Our study provides a prospective therapy platform involving cytokines for treating different diseases.Graphical

Development of a Silk Fibroin-Small Intestinal Submucosa Small-Diameter Vascular Graft with Sequential VEGF and TGF-β1 Inhibitor Delivery for In Situ Tissue Engineering.

Proper endothelialization and limited collagen deposition on the luminal surface after graft implantation plays a crucial role to prevent the occurrence of stenosis. To achieve these conditions, a biodegradable graft with adequate mechanical properties and the ability to sequentially deliver therapeutic agents isfabricated. In this study, a dual-release system is constructed through coaxial electrospinning by incorporating recombinant human vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) inhibitor into silk fibroin (SF) nanofibers to form a bioactive membrane. The functionalized SF membrane as the inner layer of the graft is characterized by the release profile, cell proliferation and protein expression. It presents excellent biocompatibility and biodegradation, facilitating cell attachment, proliferation, and infiltration. The core-shell structure enables rapid VEGF release within 10 days and sustained plasmid delivery for 21 days. A 2.0-mm-diameter vascular graft is fabricated by integrating the SF membrane with decellularized porcine small intestinal submucosa (SIS), aiming to facilitate the integration process under a stable extracellular matrix structure. The bioengineered graft is functionalized with the sequential administration of VEGF and TGF-β1, and with the reinforced and compatible mechanical properties, thereby offers an orchestrated solution for stenosis with potential for in situ vascular tissue engineering applications.

High Density Lipoprotein Based Delivery of Vascular Endothelial Growth Factor Protein for Myocardial Ischemia Therapy

A high density lipoprotein (HDL) based protein delivery system composed of HDL, polyethyleneimine (PEI) and vascular endothelial growth factor (VEGF) protein was constructed (HDL/PEI/VEGF) was fabricated as an advanced system for myocardial ischemia therapy. Here, PEI was utilized to effectively adsorb VEGF protein, followed by additional functioning of targeting protein HDL. The HDL/PEI/VEGF was shown to have size of 100 nm. Cellular distribution and uptake experiments of HDL/PEI/VEGF revealed the possible Scavenger receptor class B type I (SR-BI) mediated delivery of VEGF protein. In addition, in vitro cytotoxicity and ELISA assays on H9C2 cells further revealed high intracellular delivery of VEGF. Moreover, in vivo investigation on ischemia/reperfusion rat model implied that HDL/PEI/VEGF possessed strong therapeutic activity. These findings indicated that HDL/PEI/VEGF could be an ideal system for the therapy of myocardial ischemia.

Bone regeneration of mouse critical-sized calvarial defects with human mesenchymal stem cell sheets co-expressing BMP2 and VEGF

Over-dependence on existing synthetic scaffolds and insufficient osteoinductive and vasculogenic growth factors have limited the development of bone regeneration. The study aimed to assess the feasibility of using marrow-derived mesenchymal stem cells (BMSCs) cell sheets co-expressing bone morphogenetic proteins 2 (BMP2) and vascular endothelial growth factor (VEGF) for repairing critical-sized calvarial defects. BMSCs cell sheets were genetically engineered to express BMP2/VEGF alone or together. Alterations in osteogenic markers were examined by quantitative real-time PCR (qRT-PCR) and western blotting. A critical-sized calvarial bone defect model was used to investigate the osteogenesis effects of BMP2/VEGF cell sheets alone or in combination. The efficacy was assessed with micro-computed tomography (micro-CT) and histology. Invitro, the expression of BMP2 and VEGF through lentiviral transduction was confirmed by qRT-PCR and western blotting against BMP2 and VEGF. Lentiviral delivery of BMP2 and VEGF resulted in the upregulation of osteogenic markers. Invivo, in a critical-sized calvarial bone defect model, 3D-reconstructed micro-CT images revealed that treatment of the calvarial defects with the BMP2/VEGF cell sheet resulted in significantly greater amounts of newly formed bone at 8 weeks after surgery than treatment with cell sheets with single gene transduction or vehicle controls. The results were confirmed by histological assessment by H&E staining and Masson staining. This study demonstrates that BMP2/VEGF co-expressing BMSCs sheets promote bone regeneration in critical-sized calvarial bone defects. The BMP2/VEGF cell sheets provide a functional bioactive scaffold for critical-size bone reconstruction.

Cyclic peptides nanospheres: A ‘2-in-1′ self-assembled delivery system for targeting nucleus and cytoplasm

Vascular endothelial growth factor (VEGF) is considered as one of the vital growth factors for angiogenesis, which is primarily responsible for the progress and maintenance of new vascular network in tumor. Numerous studies report that inhibition of VEGF-induced angiogenesis is a potent technique for cancer suppression. Recently, RNA interference, especially small interfering RNA (siRNA) signified a promising approach to suppress the gene expression. However, the clinical implementation of biological macromolecules such as siRNA is significantly limited because of stability and bioavailability issues. Herein, self-assembled peptide nanospheres have been generated from L,L-cyclic peptides using hydrophobic (Trp), positively charged (Arg) and cysteine (Cys) amino acid residues and demonstrated as vehicles for intracellular delivery of VEGF siRNA and VEGF antisense oligonucleotide. Formation of peptide nanostructures is confirmed by HR-TEM, AFM, SEM and DLS analysis. Possible mechanism of self-assembly of the cyclic peptides and their binding with macromolecules are demonstrated by in-silico analysis. Gel electrophoresis reveals that the newly generated peptide based organic materials exhibit strong binding affinity toward siRNAs / antisense oligonucleotides (ASOs) at optimum concentration. Flow cytometry and confocal microscopy results confirm the efficiency of the new biomaterials toward the intracellular delivery of fluorescent labeled siRNA / ASOs. Furthermore, VEGF expression evaluated by western blot and RT-PCR upon the delivery of functional VEGF siRNA/ASOs suggests that very low concentrations of VEGF siRNA/ASOs cause significant gene knockdown at protein and mRNA levels, respectively.

Local Application of Mineral-Coated Microparticles Loaded With VEGF and BMP-2 Induces the Healing of Murine Atrophic Non-Unions.

Deficient angiogenesis and disturbed osteogenesis are key factors for the development of nonunions. Mineral-coated microparticles (MCM) represent a sophisticated carrier system for the delivery of vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)-2. In this study, we investigated whether a combination of VEGF- and BMP-2-loaded MCM (MCM + VB) with a ratio of 1:2 improves bone repair in non-unions. For this purpose, we applied MCM + VB or unloaded MCM in a murine non-union model and studied the process of bone healing by means of radiological, biomechanical, histomorphometric, immunohistochemical and Western blot techniques after 14 and 70 days. MCM-free non-unions served as controls. Bone defects treated with MCM + VB exhibited osseous bridging, an improved biomechanical stiffness, an increased bone volume within the callus including ongoing mineralization, increased vascularization, and a histologically larger total periosteal callus area consisting predominantly of osseous tissue when compared to defects of the other groups. Western blot analyses on day 14 revealed a higher expression of osteoprotegerin (OPG) and vice versa reduced expression of receptor activator of NF-κB ligand (RANKL) in bone defects treated with MCM + VB. On day 70, these defects exhibited an increased expression of erythropoietin (EPO), EPO-receptor and BMP-4. These findings indicate that the use of MCM for spatiotemporal controlled delivery of VEGF and BMP-2 shows great potential to improve bone healing in atrophic non-unions by promoting angiogenesis and osteogenesis as well as reducing early osteoclast activity.

Composite Microgels for Imaging-Monitored Tracking of the Delivery of Vascular Endothelial Growth Factor to Ischemic Muscles.

Monitoring the supply of vascular endothelial growth factor (VEGF) to ischemic tissues provides information on its biodistribution and delivery to meet the requirements of therapeutic angiogenesis and tissue engineering applications. We herein report the use of microfluidically generated microgels containing VEGF-conjugated fluorescent carbon dots (CDs) (VEGF-CDs), a gelatin-phenol conjugate, and silk fibroin for imaging-monitored tracking of VEGF delivery to ischemic muscles. An in vitro release study and a bioactivity assay indicated that the VEGF-CDs were released in a sustained manner with high bioactivity. The microgels showed a high angiogenesis potential, along with a strong fluorescent signal, for the chicken chorioallantoic membrane and chick embryo. Imaging and studies of therapeutic modalities of the composite microgels indicated their effective localization in ischemic tissues and sustained VEGF release, which resulted in enhanced therapeutic angiogenesis of ischemic muscles. This work reveals the success of using VEGF-loaded composite polymer microgels for efficient and monitored VEGF delivery by intramuscular administration for ischemic disease treatment.

Abstract 11090: Therapeutic Effect of VEGF- and SDF-Nanoparticles in the Rat Monocrotaline Model of Pulmonary Hypertension

Introduction: Pulmonary vascular endothelial cell injury, dysfunction, and apoptosis are associated with the development of pulmonary arterial hypertension (PAH). Improving endothelial function may be therapeutically beneficial in this disorder. In the present study, we examined the effect of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α), proteins that support endothelial repair and tissue regeneration, in rats with monocrotaline-induced PAH. A polysaccharide nanoparticle was used as a carrier for VEGF and SDF-1α delivery, the formulation of which extends the retention time of the proteins in the lung by ~17-fold compared with free protein. Method: A crosslinked dextran sulfate-chitosan nanoparticle (XDSCS NP) was prepared as the carrier. Recombinant human VEGF and SDF-1α were incorporated in the XDSCS NP to generate VEGF-NP and SDF-NP, respectively. Athymic nude rats were injected with monocrotaline (50 mg/kg, IP) to induce PAH. Two weeks after the injection, VEGF-NP (8 μg/rat) and SDF-NP (4 μg/rat) were delivered to the lungs of rats via intratracheal aerosolization. At 4 weeks, catheterization of right and left heart was performed, and lung tissue collected for histological analysis. Results: Monocrotaline induced PAH in the nude rats, leading to right ventricular systolic pressure (RVSP) of 71±8 mmHg (mean±SD, n=8) vs. 29±2 mmHg in the untreated control rats. VEGF-NP and SDF-NP treatment reduced the RVSP to 48±13 mmHg. The Fulton indices of the three groups were 0.45±0.07, 0.22±0.01, and 0.25±0.06, respectively. The pulmonary vascular resistance indices of the groups were 3.2±0.7, 0.6±0.3, and 2.1±1.0 mmHg.min/ml/kg, respectively. Histological analysis showed monocrotaline-treated rats had prominent muscularization of precapillary vessels, which was markedly reduced by the VEGF-NP and SDF-NP treatment. Aerosolization of free VEGF and SDF-1α or of empty XDSCS NP carrier had no effect on monocrotaline-induce PAH. Conclusion: These data indicate that the delivery of VEGF and SDF to the lungs of rats in a NP-bound form had beneficial therapeutic effects in monocrotaline-induced PAH, and offer the potential for a novel therapeutic strategy for human pulmonary hypertensive disorders.

Microneedle-mediated vascular endothelial growth factor delivery promotes angiogenesis and functional recovery after stroke

Ischemic stroke is still the major cause of disability worldwide. Although vascular endothelial growth factor (VEGF) is able to promote both angiogenesis and functional recovery, its use is limited by needle-induced injury, nonhomogenous VEGF distribution, and limited VEGF retention in the brain after intracranial or intravenous injection. Here, we first present a gelatin methacryloyl (GelMA) microneedle (MN)-based platform for the sustained and controlled local delivery of an adeno-associated virus (AAV) expressing human VEGF (AAV-VEGF) that achieves homogenous distribution and high transfection efficiency in ischemic brains. An ischemic stroke model was established in adult rats, and MNs loaded with AAV-VEGF were epicortically inserted into both the ischemic core and penumbra of these rats one day after the onset of ischemia. One week later, the inflammatory response and microneedle biocompatibility were assessed by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Eight weeks later, angiogenesis and neural stem cell proliferation and migration were assessed. GelMA MN implantation did not elicit an obvious inflammatory response and had good biocompatibility in the brain. AAV–green fluorescent protein (GFP)-loaded MNs could achieve successful transfection and homogeneous distribution in the brain cortex three weeks postoperatively. MNs loaded with AAV-VEGF increased VEGF expression and enhanced functional angiogenesis and neurogenesis. In summary, MNs might emerge as a promising platform for delivering various therapeutics to treat ischemic stroke and repair other neurologically diseased tissues.

How can smart dressings change the future of wound care?

How can smart dressings change the future of wound care?

Artificial apoptotic cells/VEGF-loaded injectable hydrogel united with immunomodification and revascularization functions to reduce cardiac remodeling after myocardial infarction

Currently, single therapeutic strategy designed for only boosting anti-inflammatory response or angiogenesis in treating myocardial infarction (MI) has met with limited success due to complicated pathological mechanism. Herein, we propose to create artificial apoptotic cells (AACs) by customizing liposomes with phosphatidylserine (PS) exposing at outlayer, in mimicking the function of apoptotic cells, with an aim to promote M2 polarization of macrophages. The AACs and vascular endothelial growth factor (VEGF) are encapsulated into an extracellular matrix-mimetic injectable hydrogel that recapitulates sulfated glycosaminoglycan. The loaded AACs and VEGF can realize earlier quick and slowly sustainable release, respectively, which is governed by distinct electrostatic interactions. The controlled spatio-temporal delivery of AACs and VEGF achieves on-demand regulation of inflammation immune response and enhanced angiogenesis. In the rat model of MI with intramyocardial administration of this injectable hydrogel bearing AACs and VEGF, the local precise release of AACs inhibits the inflammatory response and reduces the apoptosis of cardiomyocytes. Meanwhile, the sustainable release of VEGF activates the VEGF signaling pathway and thus facilitates revascularization in the targeted infarcted region, eventually contributing to a significant improvement in cardiac function and alleviating pathological remodeling of the left ventricle.

Sustained Release of Bone Morphogenetic Protein-2 through Alginate Microbeads Enhances Bone Regeneration in Rabbit Tibial Metaphyseal Defect Model.

Bone morphogenetic protein-2 (BMP-2) is widely used to enhance bone regeneration. However, because of its short half-life and rapid disappearance, large amounts of BMP-2 are needed, leading to unintended side effects. In this study, BMP-2-encapsulated alginate microbeads (AM) were used to enhance bone regeneration. Enzyme-linked immunosorbent assay confirmed the sustained release of BMP-2 from AM. Vascular endothelial growth factor (VEGF)-adsorbing aptamer-conjugated hydroxyapatite (Apt-HA) was used for osteoconduction and dual delivery of VEGF and BMP-2. For in vivo bone regeneration evaluation, the grafts (1) Apt-HA + phosphate-buffered saline (PBS), (2) Apt-HA + AM without BMP-2, (3) Apt-HA + BMP-2, and (4) Apt-HA + AM encapsulated with BMP-2 were implanted into rabbit tibial metaphyseal defects. After four weeks, micro-computed tomography (CT), histological, and histomorphometric analyses were performed to evaluate bone regeneration. The Apt-HA + AM with BMP-2 group revealed a significantly higher new bone volume and bone volume/total volume (BV/TV) in both cortical and trabecular bone than the others. Furthermore, as evaluated by histomorphometric analysis, BMP-2 AM exhibited a significantly higher bone formation area than the others, indicating that AM could be used to efficiently deliver BMP-2 through sustained release. Moreover, the combined application of BMP-2-encapsulated Apt-HA + AM may effectively promote bone regeneration.

In Vivo Printing of Nanoenabled Scaffolds for the Treatment of Skeletal Muscle Injuries.

Extremity skeletal muscle injuries result in substantial disability. Current treatments fail to recoup muscle function, but properly designed and implemented tissue engineering and regenerative medicine techniques can overcome this challenge. In this study, a nanoengineered, growth factor-eluting bioink that utilizes Laponite nanoclay for the controlled release of vascular endothelial growth factor (VEGF) and a GelMA hydrogel for a supportive and adhesive scaffold that can be crosslinked in vivo is presented. The bioink is delivered with a partially automated handheld printer for the in vivo formation of an adhesive and 3D scaffold. The effect of the controlled delivery of VEGF alone or paired with adhesive, supportive, and fibrilar architecture has not been studied in volumetric muscle loss (VML) injuries. Upon direct in vivo printing, the constructs are adherent to skeletal muscle and sustained release of VEGF. The in vivo printing of muscle ink in a murine model of VML injury promotes functional muscle recovery, reduced fibrosis, and increased anabolic response compared to untreated mice. The in vivo construction of a therapeutic-eluting 3D scaffold paves the way for the immediate treatment of a variety of soft tissue traumas.

Miniaturized Needle Array-Mediated Drug Delivery Accelerates Wound Healing.

A major impediment preventing normal wound healing is insufficient vascularization, which causes hypoxia, poor metabolic support, and dysregulated physiological responses to injury. To combat this, the delivery of angiogenic factors, such as vascular endothelial growth factor (VEGF), has been shown to provide modest improvement in wound healing. Here, the importance of specialty delivery systems is explored in controlling wound bed drug distribution and consequently improving healing rate and quality. Two intradermal drug delivery systems, miniaturized needle arrays (MNAs) and liquid jet injectors (LJIs), are evaluated to compare effective VEGF delivery into the wound bed. The administered drug's penetration depth and distribution in tissue are significantly different between the two technologies. These systems' capability for efficient drug delivery is first confirmed in vitro and then assessed in vivo. While topical administration of VEGF shows limited effectiveness, intradermal delivery of VEGF in a diabetic murine model accelerates wound healing. To evaluate the translational feasibility of the strategy, the benefits of VEGF delivery using MNAs are assessed in a porcine model. The results demonstrate enhanced angiogenesis, reduced wound contraction, and increased regeneration. These findings show the importance of both therapeutics and delivery strategy in wound healing.

Triple Growth Factor Delivery Promotes Functional Bone Regeneration Following Composite Musculoskeletal Trauma

Type III fractures typically involve segmental bone loss with extensive adjacent soft tissue injury to muscle and vasculature. Such severe composite injuries to bone and muscle often require multiple treatment procedures and are associated with significantly higher rates of complications, including non-union, infection, prolonged disability, and amputation. Successful bone healing depends on early re-vascularization to restore oxygen, nutrient, growth factor, and progenitor cell supply to the injury. Therapeutic angiogenesis strategies have therefore been investigated to promote re-vascularization following severe bone injuries, however results have been inconsistent. In this study, co-stimulation of microvascular fragment constructs with vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) promoted vascular network formation in vitro compared to VEGF or PDGF alone. In an in vivo model of segmental bone and volumetric muscle loss injury, combined delivery of VEGF and PDGF with a low dose of bone morphogenetic protein-2 (BMP-2) significantly enhanced regeneration of vascularized bone compared to BMP-2 treatment alone. This study demonstrates the potential for a combined osteoinductive and angiogenic growth factor delivery strategy to promote functional bone regeneration following severe composite musculoskeletal injury.

Vascular endothelial growth factor sustained delivery augmented cell therapy outcomes of cardiac progenitor cells for myocardial infarction.

Cell therapy has become a novel promising approach for improvement of cardiac functional capacity in the instances of ventricular remodeling and fibrosis caused by episodes of coronary artery occlusion and hypoxia. The challenge toward enhancing cell engraftment as well as formation of functional tissue, however, necessitated combinatorial approaches. Here, we complemented human embryonic stem cell-derived cardiac progenitor cell (hESC-CPC) therapy by heparin-conjugated, vascular endothelial growth factor (VEGF)-loaded fibrin hydrogel as VEGF delivery system. Transplantation of these cardiac committed cells along with sustained VEGF release could surpass the cardiac repair effects of each constituent alone in a rat model of acute myocardial infarction. The histological sections of rat hearts revealed improved vascularization as well as inclusion of hESC-CPC-derived cardiomyocytes, endothelial, and smooth muscle cells in host myocardium. Thus, co-transplantation of hESC-CPC and proangiogenic factor by a suitable delivery rate may resolve the shortcomings of conventional cell therapy.

VEGF: A KEY PLAYER NOT ONLY IN MACULAR DEGENERATION. A REVIEW.

The issue of macular retinal degeneration is one of the key areas of ophthalmology. Recent advances in the targeted delivery of vascular endothelial growth factor (VEGF) suppressants have significantly impacted the patient'sprognosis in the form of asignificant deceleration in disease progression. Some of the drugs have gradually found their use in other indications (central retinal vein occlusion or diabetic macular edema). The following text gives abrief look at the physiology of VEGF, but not only in the eye, but throughout the human body, particularly in the context of adverse effects resulting from systemic inhibition of its effects.