Biomaterials, biological molecules, and polymers in developing vaccines.

Vaccines have been used to train the immune system to recognize pathogens, and prevent and treat diseases, such as cancer, for decades. However, there are continuing challenges in their manufacturing, large-scale production, and storage. Some of them also show suboptimal immunogenicity, requiring additional adjuvants and booster doses. As an alternate vaccination strategy, a new class of biomimetic materials with unique functionalities has emerged in recent years. Here, we explore the current bioengineering techniques that make use of hydrogels, modified polymers, cell membranes, self-assembled proteins, virus-like particles (VLPs), and nucleic acids to deliver and develop biomaterial-based vaccines. We also review design principles and key regulatory issues associated with their development. Finally, we critically assess their limitations, explore approaches to overcome these limitations, and discuss potential future applications for clinical translation.

Non-physiologic Bioreactor Processing Conditions for Heart Valve Tissue Engineering.

PURPOSE: Conventional methods of seeding decellularized heart valves for heart valve tissue engineering have led to inconsistent results in interstitial cellular repopulation, particularly of the distal valve leaflet, and notably distinct from documented re-endothelialization. The use of bioreactor conditioning mimicking physiologic parameters has been well explored but cellular infiltration remains challenging. Non-characteristic, non-physiologic conditioning parameters within a bioreactor, such as hypoxia and cyclic chamber pressure, may be used to increase the cellular infiltration leading to increased recellularization. METHODS: To investigate the effects of novel and perhaps non-intuitive bioreactor conditioning parameters, ovine aortic heart valves were seeded with mesenchymal stem cells and cultured in one of four environments: hypoxia and high cyclic pressures (120 mmHg), normoxia and high cyclic pressures, hypoxia and negative cyclic pressures (- 20 mmHg), and normoxia and negative cyclic pressures. Analysis included measurements of cellular density, cell phenotype, and biochemical concentrations. RESULTS: The results revealed that the bioreactor conditioning parameters influenced the degree of recellularization. Groups that implemented hypoxic conditioning exhibited increased cellular infiltration into the valve leaflet tissue compared to normoxic conditioning, while pressure conditioning did not have a significant effect of recellularization. Protein expression across all groups was similar, exhibiting a stem cell and valve interstitial cell phenotype. Biochemical analysis of the extracellular matrix was similar between all groups. CONCLUSION: These results suggest the use of non-physiologic bioreactor conditioning parameters can increase in vitro recellularization of tissue engineered heart valve leaflets. Particularly, hypoxic culture was found to increase the cellular infiltration. Therefore, bioreactor conditioning of tissue engineered constructs need not always mimic physiologic conditions, and it is worth investigating novel or uncharacteristic culture conditions as they may benefit aspects of tissue culture.

Inhibition of Senescence-Associated Genes Rb1 and Meis2 in Adult Cardiomyocytes Results in Cell Cycle Reentry and Cardiac Repair Post-Myocardial Infarction.

Background Myocardial infarction results in a large-scale cardiomyocyte loss and heart failure due to subsequent pathological remodeling. Whereas zebrafish and neonatal mice have evident cardiomyocyte expansion following injury, adult mammalian cardiomyocytes are principally nonproliferative. Despite historical presumptions of stem cell-mediated cardiac regeneration, numerous recent studies using advanced lineage-tracing methods demonstrated that the only source of cardiomyocyte renewal originates from the extant myocardium; thus, the augmented proliferation of preexisting adult cardiomyocytes remains a leading therapeutic approach toward cardiac regeneration. In the present study we investigate the significance of suppressing cell cycle inhibitors Rb1 and Meis2 to promote adult cardiomyocyte reentry to the cell cycle. Methods and Results In vitro experiments with small interfering RNA-mediated simultaneous knockdown of Rb1 and Meis2 in both adult rat cardiomyocytes, isolated from 12-week-old Fischer rats, and human induced pluripotent stem cell-derived cardiomyocytes showed a significant increase in cell number, a decrease in cell size, and an increase in mononucleated cardiomyocytes. In vivo, a hydrogel-based delivery method for small interfering RNA-mediated silencing of Rb1 and Meis2 is utilized following myocardial infarction. Immunofluorescent imaging analysis revealed a significant increase in proliferation markers 5-ethynyl-2'-deoxyuridine, PH3, KI67, and Aurora B in adult cardiomyocytes as well as improved cell survivability with the additional benefit of enhanced peri-infarct angiogenesis. Together, this intervention resulted in a reduced infarct size and improved cardiac function post-myocardial infarction. Conclusions Silencing of senescence-inducing pathways in adult cardiomyocytes via inhibition of Rb1 and Meis2 results in marked cardiomyocyte proliferation and increased protection of cardiac function in the setting of ischemic injury.

Harnessing the Noncovalent Interactions of DNA Backbone with 2D Silicate Nanodisks To Fabricate Injectable Therapeutic Hydrogels.

Injectable hydrogels present several advantages over prefabricated scaffolds including ease of delivery, shear-thinning property, and broad applicability in the fields of drug delivery and tissue engineering. Here, we report an approach to develop injectable hydrogels with sustained drug release properties, exploiting the chemical nature of the DNA backbone and silicate nanodisks. A two-step gelation method is implemented for generating a combination of noncovalent network points, leading to a physically cross-linked hydrogel. The first step initiates the development of an interconnected structure by utilizing DNA denaturation and rehybridization mechanism to form hydrogen bonds between complementary base pairs of neighboring DNA strands. The anisotropic charge distribution of two-dimensional silicate nanodisks (nSi) makes them an active center in the second step of the gelation process. Silicate nanodisks create additional network points via attractive electrostatic interactions with the DNA backbone, thereby enhancing the mechanical resilience of the formulated hydrogel. The thermally stable hydrogels displayed an increase in elasticity and yield stress as a function of nSi concentration. They were able to form self-supporting structures post injection due to their rapid recovery after removal of cyclic stress. Moreover, the presence of nanosilicate was shown to modulate the release of a model osteogenic drug dexamethasone (Dex). The bioactivity of released Dex was confirmed from in vitro osteogenic differentiation of human adipose stem cells and in vivo bone formation in a rat cranial bone defect model. Overall, our DNA-based nanocomposite hydrogel obtained from a combination of noncovalent network points can serve as an injectable material for bone regeneration and carrier for sustained release of therapeutics.

Deciphering the role of substrate stiffness in enhancing the internalization efficiency of plasmid DNA in stem cells using lipid-based nanocarriers.

This study investigates the role of substrate stiffness in the non-viral transfection of human adipose-derived stem cells (hASCs) with the aim to maximize the hASC expression of vascular endothelial growth factor (VEGF). The results confirm the direct effect of substrate stiffness in regulating cytoskeletal remodeling and corresponding plasmid internalization.

MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents.

An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, ß-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents. Moreover, compared to control, a significant increase in CM survival and proliferation were observed with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increased mono-nucleation, decreased multi-nucleation, and increased CM proliferation in 210-TG hearts in contrast to wild-type (NTG). Likewise, myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the hearts were harvested for immunohistochemistry and molecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogenesis, reduced infarct size, and overall improvement in cardiac function following MI. ß-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adult mice via promoting CM proliferation, cell survival, and angiogenesis. KEY MESSAGES: MiRNA-210 transfected adult rat CMs show proliferation and reduced cell death in vitro. Cell cycle inhibitor APC is a target of miR-210. MiR-210 overexpressing (210-TG) mouse hearts show CMs cell cycle re-entry and survival post myocardial injury. 210-TG mice show significant neovascularization and angiogenic potential post myocardial infarction. 210-TG hearts show reduced infarct size following ischemic injury.

Nanodiamond-based injectable hydrogel for sustained growth factor release: Preparation, characterization and in vitro analysis.

Nanodiamonds (NDs) represent an emerging class of carbon nanomaterials that possess favorable physical and chemical properties to be used as multifunctional carriers for a variety of bioactive molecules. Here we report the synthesis and characterization of a new injectable ND-based nanocomposite hydrogel which facilitates a controlled release of therapeutic molecules for regenerative applications. In particular, we have formulated a thermosensitive hydrogel using gelatin, chitosan and NDs that provides a sustained release of exogenous human vascular endothelial growth factor (VEGF) for wound healing applications. Addition of NDs improved the mechanical properties of the injectable hydrogels without affecting its thermosensitive gelation properties. Biocompatibility of the generated hydrogel was verified by in vitro assessment of apoptotic gene expressions and anti-inflammatory interleukin productions. NDs were complexed with VEGF and the inclusion of this complex in the hydrogel network enabled the sustained release of the angiogenic growth factor. These results suggest for the first time that NDs can be used to formulate a biocompatible, thermosensitive and multifunctional hydrogel platform that can function both as a filling agent to modulate hydrogel properties, as well as a delivery platform for the controlled release of bioactive molecules and growth factors. STATEMENT OF SIGNIFICANCE: One of the major drawbacks associated with the use of conventional hydrogels as carriers of growth factors is their inability to control the release kinetics of the loaded molecules. In fact, in most cases, a burst release is inevitable leading to diminished therapeutic effects and unsuccessful therapies. As a potential solution to this issue, we hereby propose a strategy of incorporating ND complexes within an injectable hydrogel matrix. The functional groups on the surface of the NDs can establish interactions with the model growth factor VEGF and promote a prolonged release from the polymer network, therefore, providing a longer therapeutic effect. Our strategy demonstrates the efficacy of using NDs as an essential component for the design of a novel injectable nanocomposite system with improved release capabilities.

Engineered Biomaterials to Enhance Stem Cell-Based Cardiac Tissue Engineering and Therapy.

Cardiovascular disease is a leading cause of death worldwide. Since adult cardiac cells are limited in their proliferation, cardiac tissue with dead or damaged cardiac cells downstream of the occluded vessel does not regenerate after myocardial infarction. The cardiac tissue is then replaced with nonfunctional fibrotic scar tissue rather than new cardiac cells, which leaves the heart weak. The limited proliferation ability of host cardiac cells has motivated investigators to research the potential cardiac regenerative ability of stem cells. Considerable progress has been made in this endeavor. However, the optimum type of stem cells along with the most suitable matrix-material and cellular microenvironmental cues are yet to be identified or agreed upon. This review presents an overview of various types of biofunctional materials and biomaterial matrices, which in combination with stem cells, have shown promises for cardiac tissue replacement and reinforcement. Engineered biomaterials also have applications in cardiac tissue engineering, in which tissue constructs are developed in vitro by combining stem cells and biomaterial scaffolds for drug screening or eventual implantation. This review highlights the benefits of using biomaterials in conjunction with stem cells to repair damaged myocardium and give a brief description of the properties of these biomaterials that make them such valuable tools to the field.

Stem cell secretome-rich nanoclay hydrogel: a dual action therapy for cardiovascular regeneration.

A nanocomposite hydrogel with photocrosslinkable micro-porous networks and a nanoclay component was successfully prepared to control the release of growth factor-rich stem cell secretome. The proven pro-angiogenic and cardioprotective potential of this new bioactive system provides a valuable therapeutic platform for cardiac tissue repair and regeneration.

Polymeric Nanohybrids as a New Class of Therapeutic Biotransporters.

A possible solution to enhance existing drug and gene therapies is to develop hybrid nanocarriers capable of delivering therapeutic agents in a controlled and targeted manner. This goal can be achieved by designing nanohybrid systems, which combine organic or inorganic nanomaterials with biomacromolecules into a single composite. The unique combination of properties along with their facile fabrication enables the design of smart carriers for both drug and gene delivery. These hybrids can be further modified with cell targeting motifs to enhance their biological interactivity. In this Talents and Trends article, an overview of emerging nanohybrid-based technologies will be provided to highlight their potential use as innovative platforms for improved cancer therapies and new strategies in regenerative medicine. The clinical relevance of these systems will be reviewed to define the current challenges which still need to be addressed to allow these therapies to move from bench to bedside.

A multilayered microfluidic blood vessel-like structure.

There is an immense need for tissue engineered blood vessels. However, current tissue engineering approaches still lack the ability to build native blood vessel-like perfusable structures with multi-layered vascular walls. This paper demonstrated a new method to fabricate tri-layer biomimetic blood vessel-like structures on a microfluidic platform using photocrosslinkable gelatin hydrogel. The presented method enables fabrication of physiological blood vessel-like structures with mono-, bi- or tri-layer vascular walls. The diameter of the vessels, the total thickness of the vessel wall and the thickness of each individual layer of the wall were independently controlled. The developed fabrication process is a simple and rapid method, allowing the physical fabrication of the vascular structure in minutes, and the formation of a vascular endothelial cell layer inside the vessels in 3-5 days. The fabricated vascular constructs can potentially be used in numerous applications including drug screening, development of in vitro models for cardiovascular diseases and/or cancer metastasis, and study of vascular biology and mechanobiology.

Cardiac tissue engineering and regeneration using cell-based therapy.

Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.

Antifungal nanofibers made by controlled release of sea animal derived peptide.

Candida albicans is a common human-pathogenic fungal species with the ability to cause several diseases including surface infections. Despite the clear difficulties of Candida control, antimicrobial peptides (AMPs) have emerged as an alternative strategy for fungal control. In this report, different concentrations of antifungal Cm-p1 (Cencritchis muricatus peptide 1) were electrospun into nanofibers for drug delivery. The nanofibers were characterized by mass spectrometry confirming the presence of the peptide on the scaffold. Atomic force microscopy and scanning electronic microscopy were used to measure the diameters, showing that Cm-p1 affects fiber morphology as well as the diameter and scaffold thickness. The Cm-p1 release behavior from the nanofibers demonstrated peptide release from 30 min to three days, leading to effective yeast control in the first 24 hours. Moreover, the biocompatibility of the fibers were evaluated through a MTS assay as well as ROS production by using a HUVEC model, showing that the fibers do not affect cell viability and only nanofibers containing 10% Cm-p1-PVA improved ROS generation. In addition, the secretion of pro-inflammatory cytokines IL-6 and TNF-α by the HUVECs was also slightly modified by the 10% Cm-p1-PVA nanofibers. In conclusion, the electrospinning technique applied here allowed for the manufacture of biodegradable biomimetic nanofibrous extracellular membranes with the ability to control fungal infection.

A New Carbon Nanotube-Based Breast Cancer Drug Delivery System: Preparation and In Vitro Analysis Using Paclitaxel.

Paclitaxel (PTX) is one of the most important drugs for breast cancer; however, the drug effects are limited by its systematic toxicity and poor water solubility. Nanoparticles have been applied for delivery of cancer drugs to overcome their limitations. Toward this goal, a novel single-walled carbon nanotube (SWNT)-based drug delivery system was developed by conjugation of human serum albumin (HSA) nanoparticles for loading of antitumor agent PTX. The nanosized macromolecular SWNT-drug carrier (SWNT-HSA) was characterized by TEM, UV-Vis-NIR spectrometry, and TGA. The SWNT-based drug carrier displayed high intracellular delivery efficiency (cell uptake rate of 80%) in breast cancer MCF-7 cells, as examined by fluorescence-labeled drug carriers, suggesting the needle-shaped SWNT-HSA drug carrier was able to transport drugs across cell membrane despite its macromolecular structure. The drug loading on SWNT-based drug carrier was through high binding affinity of PTX to HSA proteins. The PTX formulated with SWNT-HSA showed greater growth inhibition activity in MCF-7 breast cancer cells than PTX formulated with HSA nanoparticle only (cell viability of 63 vs 70% in 48 h and 53 vs 62% in 72 h). The increased drug efficacy could be driven by SWNT-mediated cell internalization. These data suggest that the developed SWNT-based antitumor agent is functional and effective. However, more studies for in vivo drug delivery efficacy and other properties are needed before this delivery system can be fully realized.

Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage.

Internal hemorrhaging is a leading cause of death after traumatic injury on the battlefield. Although several surgical approaches such as the use of fibrin glue and tissue adhesive have been commercialized to achieve hemostasis, these approaches are difficult to employ on the battlefield and cannot be used for incompressible wounds. Here, we present shear-thinning nanocomposite hydrogels composed of synthetic silicate nanoplatelets and gelatin as injectable hemostatic agents. These materials are demonstrated to decrease in vitro blood clotting times by 77%, and to form stable clot-gel systems. In vivo tests indicated that the nanocomposites are biocompatible and capable of promoting hemostasis in an otherwise lethal liver laceration. The combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency conditions.

Sustained release of milrinone delivered via microparticles in a rodent model of myocardial infarction.

OBJECTIVE: The aim of the present study was to construct a new drug delivery system for milrinone using microparticles. This novel technology enhances drug bioavailability and decreases toxicity, with future implications for the treatment of end-stage heart failure. METHODS: Polylactic-co-glycolic acid microparticles (PLGA-MPs) loaded with milrinone were prepared using a double emulsion-solvent evaporation technique. In vitro release kinetics was evaluated at physiologic conditions. A total of 24 female Lewis rats underwent left coronary artery ligation. One week after ligation, all rats were randomized to 1 of 3 groups (n=8 per group). Group I received an intravenous injection of PLGA-MPs alone; group II, a bolus intravenous injection of milrinone; and group III an intravenous injection of milrinone-PLGA-MPs. All injections were administrated slowly by way of the tail vein over 10 minutes. Transthoracic echocardiography, noninvasive heart rate monitoring, and blood pressure measurements were performed at different predetermined intervals before and for 24 hours after the injection. All rats survived for 24 hours and were then killed by euthanasia. Serum plasma was taken for cytokine assays and determination of milrinone levels using high-performance liquid chromatography. RESULTS: Group III had a significantly greater left ventricular ejection fraction at 90 minutes and 3, 6, and 12 hours after treatment compared with the other groups. The milrinone plasma level was significantly greater in group III than in the other groups (group I, 0 ng/mL; group II, 1.7±2.4 ng/mL; group III, 9.1±2.2 ng/mL; P<.05). The intercellular adhesion molecule and cytokine-induced neutrophil chemoattractant-1 levels were significantly lower in group III than in the other 2 groups (P<.05). CONCLUSIONS: Drug encapsulation using microparticles can prolong the effects of milrinone. We propose a new strategy for future drug delivery in patients with end-stage heart failure.

Recent advances in application of biosensors in tissue engineering.

Biosensors research is a fast growing field in which tens of thousands of papers have been published over the years, and the industry is now worth billions of dollars. The biosensor products have found their applications in numerous industries including food and beverages, agricultural, environmental, medical diagnostics, and pharmaceutical industries and many more. Even though numerous biosensors have been developed for detection of proteins, peptides, enzymes, and numerous other biomolecules for diverse applications, their applications in tissue engineering have remained limited. In recent years, there has been a growing interest in application of novel biosensors in cell culture and tissue engineering, for example, real-time detection of small molecules such as glucose, lactose, and H2O2 as well as serum proteins of large molecular size, such as albumin and alpha-fetoprotein, and inflammatory cytokines, such as IFN-g and TNF-α. In this review, we provide an overview of the recent advancements in biosensors for tissue engineering applications.

Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair.

The objective of this study was to develop an injectable and biocompatible hydrogel which can efficiently deliver a nanocomplex of graphene oxide (GO) and vascular endothelial growth factor-165 (VEGF) pro-angiogenic gene for myocardial therapy. For the study, an efficient nonviral gene delivery system using polyethylenimine (PEI) functionalized GO nanosheets (fGO) complexed with DNAVEGF was formulated and incorporated in the low-modulus methacrylated gelatin (GelMA) hydrogel to promote controlled and localized gene therapy. It was hypothesized that the fGOVEGF/GelMA nanocomposite hydrogels can efficiently transfect myocardial tissues and induce favorable therapeutic effects without invoking cytotoxic effects. To evaluate this hypothesis, a rat model with acute myocardial infarction was used, and the therapeutic hydrogels were injected intramyocardially in the peri-infarct regions. The secreted VEGF from in vitro transfected cardiomyocytes demonstrated profound mitotic activities on endothelial cells. A significant increase in myocardial capillary density at the injected peri-infarct region and reduction in scar area were noted in the infarcted hearts with fGOVEGF/GelMA treatment compared to infarcted hearts treated with untreated sham, GelMA and DNAVEGF/GelMA groups. Furthermore, the fGOVEGF/GelMA group showed significantly higher (p < 0.05, n = 7) cardiac performance in echocardiography compared to other groups, 14 days postinjection. In addition, no significant differences were noticed between GO/GelMA and non-GO groups in the serum cytokine levels and quantitative PCR based inflammatory microRNA (miRNA) marker expressions at the injected sites. Collectively, the current findings suggest the feasibility of a combined hydrogel-based gene therapy system for ischemic heart diseases using nonviral hybrid complex of fGO and DNA.

Carbon nanotube lipid drug approach for targeted delivery of a chemotherapy drug in a human breast cancer xenograft animal model.

Carbon nanotube (CNT) possesses excellent properties as a drug carrier. To overcome the challenge of drug functionalization with CNT, we have developed a lipid-drug approach for efficient drug loading onto CNT, in which a long chain lipid molecule is conjugated to the drug molecule so that the lipid-drug can be loaded directly onto CNT through binding of the lipid 'tail' in the drug molecule to CNT surfaces via hydrophobic interactions. In a proof-of-concept study, drug paclitaxel (PTX) was conjugated with a non-toxic lipid molecule docosanol for functionalization with CNT. Folic acid was also conjugated to CNT for targeted drug delivery. High level of drug loading onto SWNT could be achieved by lipid-drug approach. Conjugation of FA to SWNT-lipid-PTX led to an increase in cell penetration capacity, and the targeted SWNT-lipid-PTX showed much improved drug efficacy in vitro in comparison to free drug Taxol and non-targeted SWNT-lipid-PTX at 48 h (78.5% vs. 31.6% and 59.1% in cytotoxicity respectively, p < 0.01). In vivo analysis using a human breast cancer xenograft mice model also confirmed the improved drug efficacy. The targeted SWNT-lipid-PTX was found non-toxic as evaluated by biochemical analysis using blood samples, and by histological analysis of major organs.

Bioactive baculovirus nanohybrids for stent based rapid vascular re-endothelialization.

Present study, for the first time, reports the development of a nanohybridized baculovirus based stent that can locally promote vascular re-endothelialization by efficient delivery of pro-angiogenic vascular endothelial growth factor (Vegf) genes. In vitro data demonstrated rapid expression of functionally active Vegf by the bioactive stent-transduced vascular cells. In vivo site-specific transgene expression was observed at the stented regions of balloon-denuded canine femoral artery, which eventually lead to significant endothelial recovery at the injured sites. A significant reduction in neointima formation (2.23 ± 0.56 mm(2) vs 2.78 ± 0.49 mm(2) and 3.11 ± 0.23 mm(2), p < 0.05; n = 8) and percent stenosis was observed in treated stent group compared to negative control and bare metal stent groups. These findings collectively implicate the potential of this newly developed baculovirus based biotherapeutic stent to ameliorate damaged vascular biology and attenuate re-narrowing of stented artery by inhibiting neointima formation.