Delivery Of Angiogenic Factors Research Articles

DIFFERENT APPROACHES IN BONE TISSUE ENGINEERING: ADVANTAGES AND DISADVANTAGES

Human bone tissue damage arises due to defects, injury, tumors, aging, and traffic accidents. It is one of the most challenging issues that need surgical development and advanced bone implants. Biocomposite-based bone has insufficient blood supply restricting the utilization for bone regeneration. It is often overcome by including scaffold having angiogenic factor delivery, in vitro and in vivo pre-vascularization. Bone and endothelial cell development and proliferation are stimulated by magnetic responsive scaffolds containing magnetic nanoparticles. Its porous structure allows cells to communicate and develop in all directions, which improves osteointegration. Scaffolds without seeded cells might have applications in bone tissue engineering (BTE) and it is mandatory to estimate in vitro and in vivo biocompatibility and degradation behavior. Three-dimensional (3D) printing opens the door to the creation of one-of-a-kind shapes and structures with specific properties. It helps to minimize the spread of germs during synthesis stage. The gamma rays minimize the infection communicated during transplantation but also damage the graft. When it comes to choosing biomaterials for cancellous and cortical bones, an artificial neural network has the highest recognition rate. This review paper explores the different potential approaches for bone grafting. Different techniques have been developed to create hydrogels with desirable properties for BTE, including non-toxicity, biocompatibility, controllability, and performance. A cell-free framework is used to stimulate bone regeneration, which helps in the bone the self-healing processes of bone fractures. The recent approach combines TE, material science, and genetic engineering for enhanced vascularization, restoring blood flow, and preventing cell death.

Therapeutic Approaches Targeting Vascular Repair After Experimental Spinal Cord Injury: A Systematic Review of the Literature.

Traumatic spinal cord injury (SCI) disrupts the spinal cord vasculature resulting in ischemia, amplification of the secondary injury cascade and exacerbation of neural tissue loss. Restoring functional integrity of the microvasculature to prevent neural loss and to promote neural repair is an important challenge and opportunity in SCI research. Herein, we summarize the course of vascular injury and repair following SCI and give a comprehensive overview of current experimental therapeutic approaches targeting spinal cord microvasculature to diminish ischemia and thereby facilitate neural repair and regeneration. A systematic review of the published literature on therapeutic approaches to promote vascular repair after experimental SCI was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards. The MEDLINE databases PubMed, Embase, and OVID MEDLINE were searched using the keywords "spinal cord injury," "angiogenesis," "angiogenesis inducing agents," "tissue engineering," and "rodent subjects." A total of 111 studies were identified through the search. Five main therapeutic approaches to diminish hypoxia-ischemia and promote vascular repair were identified as (1) the application of angiogenic factors, (2) genetic engineering, (3) physical stimulation, (4) cell transplantation, and (5) biomaterials carrying various factor delivery. There are different therapeutic approaches with the potential to diminish hypoxia-ischemia and promote vascular repair after experimental SCI. Of note, combinatorial approaches using implanted biomaterials and angiogenic factor delivery appear promising for clinical translation.

Effect of Angiogenesis in Bone Tissue Engineering.

The reconstruction of large skeletal defects is still a tricky challenge in orthopedics. The newly formed bone tissue migrates sluggishly from the periphery to the center of the scaffold due to the restrictions of exchange of oxygen and nutrition impotent cells osteogenic differentiation. Angiogenesis plays an important role in bone reconstruction and more and more studies on angiogenesis in bone tissue engineering had been published. Promising advances of angiogenesis in bone tissue engineering by scaffold designs, angiogenic factor delivery, in vivo prevascularization and in vitro prevascularization are discussed in detail. Among all the angiogenesis mode, angiogenic factor delivery is the common methods of angiogenesis in bone tissue engineering and possible research directions in the future.

Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats.

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.

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.

SIS/aligned fibre scaffold designed to meet layered oesophageal tissue complexity and properties

With donor organs not readily available, the need for a tissue-engineered oesophagus remains high, particularly for congenital childhood conditions such as atresia. Previous attempts have not been successful, and challenges remain. Small intestine submucosa (SIS) is an acellular matrix material with good biological properties; however, as is common with these types of materials, they demonstrate poor mechanical properties. In this work, electrospinning was performed to mechanically reinforce tubular SIS with polylactic-co-glycolic acid (PLGA) nanofibres. It was hypothesised that if attachment could be achieved between the two materials, then this would (i) improve the SIS mechanical properties, (ii) facilitate smooth muscle cell alignment to support directional growth of muscle cells and (iii) allow for the delivery of bioactive molecules (VEGF in this instance).Through a relatively simple multistage process, adhesion between the layers was achieved without chemically altering the SIS. It was also found that altering mandrel rotation speed affected the alignment of the PLGA nanofibres. SIS-PLGA scaffolds performed mechanically better than SIS alone; yield stress improvement was 200% and 400% along the longitudinal and circumferential directions, respectively. Smooth muscle cells cultured on the aligned fibres showed resultant unidirectional alignment. In vivo the SIS-PLGA scaffolds demonstrated limited foreign body reaction judged by the type and proportion of immune cells present and lack of fibrous encapsulation. The scaffolds remained intact at 4 weeks in vivo, and good cellular infiltration was observed. The incorporation of VEGF within SIS-PLGA scaffolds increased the blood vessel density of the surrounding tissues, highlighting the possible stimulation of endothelialisation by angiogenic factor delivery. Overall, the designed SIS-PLGA-VEGF hybrid scaffolds might be used as a potential matrix platform for oesophageal tissue engineering. In addition to this, achieving improved attachment between layers of acellular matrix materials and electrospun fibre layers offers the potential utility in other applications. Statement of SignificanceBecause of its multi-layered nature and complex structure, the oesophagus tissue poses several challenges for successful clinical grafting. Therefore, it is promising to utilise tissue engineering strategies to mimic and form structural compartments for its recovery. In this context, we investigated the use of tubular small intestine submucosa (SIS) reinforced with polylactic-co-glycolic acid (PLGA) nanofibres by using electrospinning and also, amongst other parameters, the integrity of the bilayered structure created. This was carried out to facilitate smooth muscle cell alignment, support directional growth of muscle cells and allow the delivery of bioactive molecules (VEGF in this study). We evaluated this approach by using in vitro and in vivo models to determine the efficacy of this new system.

Stimulation of Cardiac Angiogenesis through Growth Factors with a Fibrin Gel Delivery Platform

Purpose Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the micro-environment as it remains localized in the matrix. However, co-delivery of platelet-derived growth factor-BB (PDGF-BB) restores physiological angiogenesis despite high VEGF doses. Recombinant protein delivery of angiogenic factors in clinically attractive due to safety and convenience, but rapid in vivo clearance prevents therapeutic efficacy. Here we use an optimized fibrin platform to enzymatically link recombinant factors to precisely control both in vivo distribution of growth factor dose and duration of stimulus in the myocardium. Methods VEGF and PDGF-BB were fused to the octapeptide sequence α2-PI1-8, which is a substrate for the transglutaminase coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. Optimized gel compositions (Sacchi, PNAS 2014) were loaded with either factor alone or together and injected into 4 locations of the anterior wall of the heart of SD rats. Fibrin alone and phosphate buffered saline (PBS) were used as negative controls. Histology was performed after 1 and 4 weeks. Results Fibrin gels were created with a ratio of 10:1 with doses of 100 μg/mL for VEGF and 10 μg/mL for PDGF-BB based on previous results. Neither emboli during injections nor postoperative neurological complications were observed and mortality remained 0% with all rats completing the experiment. The fibrin gel was entirely degraded already at 1 week, leaving only a scar visible in the injected area at both time points with no difference between experimental groups. Optimized co-delivery of fibrin-α2-PI1-8-VEGF+PDGF-BB was effective in a non-ischemic heart model to significantly improve persistent angiogenesis compared to VEGF alone, despite short duration of treatment ( Conclusion This optimized platform stimulates angiogenesis without introducing genetic material and with a limited duration of treatment. It opens a new strategy to improve safety and efficacy of therapeutic angiogenesis in the heart.

SIS/Aligned Fibre Scaffold Designed to Meet Layered Oesophageal Tissue Complexity and Properties

With donor organs not readily available the need for a tissue engineered oesophagus remains high particularly for congenial childhood conditions such as atresia. Previous attempts have not been very successful and challenges remain to be overcome. Small intestine submucosa (SIS) is an a cellular matrix material with good biological properties though, as with these materials, demonstrably poor mechanical properties. In this work electrospinning was used to mechanically reinforce a unique tubular SIS with PLGA nanofibers. It was hypothesised that if attachment could be achieved between the two materials than this would (i) improve the SIS's mechanical properties, (ii) facilitate smooth muscle cell alignment to support directional growth of muscle cells and potentially restore contractility and (iii) allow for the delivery of bioactive molecules (VEGF in this instance). Through a multistage process adhesion between the layers was achieved without chemically altering the SIS. It was also found that altering mandrel rotational speed affected the alignment of the PLGA nanofibers.SIS-PLGA scaffolds performed mechanically better than SIS alone; yield stress improvement was 200% and 400% along the longitudinal and circumferential direction, respectively (greatest with highly aligned fibres produced at 5000 rpm). Smooth muscle cells cultured on the aligned fibres showed resultant unidirectional alignment. In vivo the SIS-PLGA scaffolds demonstrated relatively limited foreign body reaction judged by the type and proportion of immune cells present and lack of fibrous encapsulation. The scaffolds remained intact at 4 weeks which is required for a structural tissue engineering matrix and obtained good cellular infiltration. The incorporation of VEGF within SIS-PLGA scaffolds increased the blood vessel density of the surrounding tissues, highlighting the possible stimulation of endothelialisation by angiogenic factor delivery. Overall, the designed SIS-PLGA-VEGF hybrid scaffolds might be used as a potential matrix platform for oesophageal tissue engineering. In addition to this, achieving improved attachment between layers of a cellular matrix materials and electrospun fibres layers does possess the potential to be applied to other applications.

Use of heparinized bacterial cellulose based scaffold for improving angiogenesis in tissue regeneration

Vascularization is a prerequisite to achieve tissue regeneration especially for long-term survival of a scaffold. During the regeneration process, the delivery of angiogenic factors is very important for developing a vascular network. In this paper, vascular endothelial growth factor (VEGF)-loaded 3D porous bacterial cellulose/gelatin (B/G) scaffolds modified with heparin were firstly prepared. The pro-angiogenic effects of scaffolds towards proliferation and migration of endothelial cells (PIECs) were evaluated as well as in vivo implantation. Results showed that the B/G scaffold modified with heparin could provide a prolonged release of VEGF for two weeks. In vitro cellular assays showed that proliferation and migration were promoted in the presence of VEGF. Subcutaneous implantation demonstrated that angiogenesis was significantly improved for the heparinized scaffolds loaded with VEGF (V-B/G/H), compared to B/G scaffold. The resulting scaffold with sustained delivery of VEGF could be potential and effective tissue engineered candidates in tissue regeneration for future clinical applications.

Computational Model-Based Analysis of Strategies to Enhance Scaffold Vascularization.

Stable and extensive blood vessel networks are required for cell function and survival in engineered tissues. A number of different strategies are currently being investigated to enhance biomaterial vascularization with screening primarily through extensive in vitro and in vivo experiments. In this article, we describe an agent-based model (ABM) developed to evaluate various strategies in silico, including design of optimal biomaterial structure, delivery of angiogenic factors, and application of prevascularized biomaterials. The model predictions are evaluated using experimental data. The ABM developed provides insight into different strategies currently applied for scaffold vascularization and will enable researchers to rapidly screen new hypotheses and explore alternative strategies for enhancing vascularization.

Physiologic ischaemic training induces endothelial progenitor cell mobilization and myocardial angiogenesis via endothelial nitric oxide synthase related pathway in rabbits

Ischaemia-induced angiogenesis promises to improve neovascularization by delivery of angiogenic factors or endothelial progenitor cells (EPCs) to cardiac ischaemic areas. In order to avoid the risk of excessive myocardial ischaemia, therefore, we hypothesized that physiological ischaemic training (PIT) of normal skeletal muscle might contribute to myocardial angiogenesis via nitric oxide mediated mobilization of EPCs from the bone marrow in the established rabbit model of controllable myocardial ischaemia. The rabbits were grouped by sham-operation, myocardial ischaemia without PIT, PIT and PIT with pretreatment with the endothelial nitric oxide synthase (eNOS) inhibitor L-nitroarginine methyl ester (L-NAME). Controlled myocardial ischaemia was modelled by a water balloon constrictor implanted on the left ventricular branch in a rabbit. The PIT procedure included three cycles of 3 min of cuff inflation followed by 5 min of deflation on hind limbs of the rabbits for 4 weeks. At the endpoints, circulating EPCs (CD34/Flk-1) were measured by fluorescence-activated cell sorter; capillary density, by immunohistochemistry; blood flow, by a microsphere technique; endothelial nitric oxide synthase (eNOS) mRNA and protein, by real-time reverse transcriptase (RT)-PCR and Western blotting. The mRNA levels of eNOS were significantly higher in the PIT and L-NAME groups than in the sham-operation group (P < 0.05). Phospho-eNOS protein expression was higher in the PIT group than in the sham-operation and myocardial ischaemia without PIT groups (P < 0.05), and the effect was inhibited by L-NAME pretreatment (P < 0.05). Compared with sham-operation and myocardial ischaemia without PIT groups, the PIT group had the highest EPC count (P < 0.001), and the increase of capillary density (P < 0.01) and collateral blood flow (P < 0.05) in the ischaemic myocardium was consistent with the finding of EPC count. These effects were also inhibited by pretreatment with the eNOS inhibitor L-NAME. Capillary density and collateral blood flow were highly correlated with the increase of EPC count (r = 0.913 and r = 0.929, respectively, P = 0.000). PIT improved EPC mobilization and contributed to compensatory neovascularization via eNOS-related pathway. These results might support the future development of strategies for therapeutic neovascularization.

Abstract P039: Encapsulation of Human Mesenchymal Stem Cells in Alginate Microspheres to Enhance Paracrine-Mediated Vascular Recovery

Bone marrow cells migrate to ischemic areas and facilitate revascularization mostly through paracrine mechanisms. As a result, therapeutic strategies for vascular repair have focused on increasing the concentration of these cells at the site of ischemia by direct injection. These strategies have led to encouraging results in clinical trials, yet the number of cells that remain at the site of delivery is very low. The goal of this study is to design an effective cell delivery system to enhance revascularization by maintaining large numbers of cells at the ischemic site, thus increasing the local delivery of angiogenic factors. To achieve this goal, we encapsulated bone marrow derived human mesenchymal stem cells (hMSCs) in non-degradable, barium-gelled alginate spheres prior to delivery to the ischemic site. Our microspheres are biocompatible, do not generate a fibrotic response, and are stable for extended periods of time. They prevent incorporation of cells into the neighboring tissue and protect implanted cells from immune mediated clearance or wash out by the host capillary and lymphatic systems. The microspheres allow diffusion of molecules as large as 80 kDa (which includes most angiogenic factors) but not of larger molecules such as IgG. To test this cell delivery system in vivo, we used a model of murine hind limb ischemia in athymic nude mice. We delivered encapsulated hMSCs, or, as a control, empty capsules, to the ischemic muscle. At various time points, we retrieved the capsules by gentle scooping, then assessed the viability of the encapsulated cells and their protein secretion profile. Approximately 70% of the cells remained viable within the first week and 10-20% within the first month after implantation. In addition, encapsulated cells secreted angiogenic factors (VEGF, bFGF, HGF, angiogenin) in vitro and in vivo. We also assessed recovery of perfusion in the hind limb and found that delivery of encapsulated cells enhanced vascular recovery as compared to empty capsules. The results obtained from this study show that microcapsules are an effective delivery vehicle of therapeutic cells for vascular repair. Encapsulation represents a powerful and highly translatable tool to enhance cell-based therapies in cardiovascular disease.

First implantable device for hypoxia-mediated angiogenic induction

Delayed or inadequate vascularisation is one of the major factors leading to tissue infarction and poor graft survival. Current vascularisation strategies that rely on delivering single growth factors have proved ineffective or hard to control in practise. An alternative approach has been identified by this group that relies on stimulation of physiological angiogenic factor cascades by engineering local cell-hypoxia, within a nano-fibrillar collagen material. Here we report on a novel, practical and effective implantable device for delivering engineered angiogenic signalling, on demand. Human dermal fibroblast-seeded dense-collagen depots were pre-conditioned under physiological cell-generated hypoxia to up-regulate production of key angiogenic factors, including HIF1α and VEGF 165. The level of VEGF 165 protein retained within depots (indicating general angiogenic factor production) was directly correlated to the duration of pre-conditioning. Angiogenic factor delivery from pre-conditioned, non-viable depots rapidly induced an angiogenic response within endothelial cell-seeded constructs in vitro, while implanted acellular 3D constructs incorporating such angiogenic depots in their core were infiltrated with perfused vessels by 1 week in vivo, at which stage non-angiogenic implants were minimally perfused. Depot stability, tuneability of cell/matrix composition with long clinical experience of the collagen material, together with cost effectiveness, make this angiogenic therapy a promising addition to a clinician's tool kit for improving local tissue perfusion.

Enhancement of Angiogenesis Through Stabilization of Hypoxia-inducible Factor-1 by Silencing Prolyl Hydroxylase Domain-2 Gene

Hypoxia-inducible factor-1 (HIF-1) plays a central role in cellular response to hypoxia by activating vascular endothelial growth factor (VEGF) and other angiogenic factors. Prolyl hydroxylase domain-2 (PHD2) protein induces the degradation of HIF-1 by hydroxylating specific prolyl residues. Therefore gene silencing of PHD2 by RNA interference (RNAi) might increase the expression of angiogenic growth factors and, consequently, neoangiogenesis through the stabilization of HIF-1alpha. In this study we have shown that the specific silencing of PHD2 is sufficient for stabilizing HIF-1alpha and increasing its transcriptional activity, resulting in the increased expression of angiogenic factors including VEGF and fibroblast growth factor-2 (FGF2). Moreover, when PHD2-siRNA vector was used, the increase in VEGF secretion was observed for as long as 18 days after transfection. In vitro treatment of human umbilical vein endothelical cells with conditioned medium from PHD2-siRNA vector-transfected NIH3T3 cells was shown to increase cell proliferation. Also, in vivo angiogenesis was observed in mice implanted with Matrigel plugs mixed with NIH3T3 cells transfected with PHD2-siRNA vector. These results indicate that PHD2 silencing induces expressions of multiple angiogenic growth factors by stabilizing HIF-1alpha, and that the implantation of cells transfected with PHD2-siRNA vector is sufficient to enhance angiogenesis in vivo. In the light of these findings, PHD2 silencing by RNAi might offer a potential tool for angiogenic therapy.

Controlled Angiogenic Factor Release from Alginate Gels

Therapeutic angiogenesis by localized delivery of angiogenic factors is a promising approach to treat patients with cardiovascular disease and to engineer large tissues. Vascular endothelial growth factor (VEGF) is the most common and biologically active form of the VEGF family, which acts as a mitogen to endothelial cells and is capable of specific binding to heparin. However, when VEGF is administered via bolus injection, it can be widely distributed, and its concentration is likely to be within the effective window for only a short time period due to rapid degradation. Delivery of angiogenic factors, using controlled drug delivery strategies, offers great potential to promote angiogenesis at a specific site while reducing the unwanted side effects that may occur with systemic delivery. We now report on the sustained release of VEGF from alginate gels, modified with a heparin-binding peptide. Briefly, a small peptide with the sequence of G5K(βA)FAKLAARLYRKA, which is known to specifically interact with heparin, was chemically conjugated to alginate, and the peptide-modified alginate formed gels after mixing with heparin and VEGF. The release rate of VEGF from the gels slowed in vitro for over 45 days, compared with release from non-modified alginate gels. This result suggests potential applications of alginate gels in promoting angiogenesis for therapeutic purposes, as well as for tissue engineering.

659. Development of Designed Zinc Finger Protein Transcriptional Regulators for Use in Multi-Factor Therapeutic Angiogenesis

Gene therapy-mediated revascularization strategies offer considerable promise in the treatment of cardiovascular disease. To date, over two dozen studies have reported that gene-based delivery of angiogenic factors can enhance blood flow and/or tissue function in preclinical models of limb and heart ischemia. However, although several programs have advanced into clinical trials, it has been noted that natural angiogenesis proceeds via the coordinate action of multiple factors; therefore strategies utilizing two or more angiogenic factor genes may realize enhanced therapeutic benefit1. In consideration of this possibility we are developing a panel of designed zinc finger protein (ZFP) transcriptional activators for regulation of multiple different angiogenic factor genes. In previous studies we had described the development of pro-angiogenic ZFPs that function via activation of VEGF-A2,3,4. Here we have extended this approach to develop regulators of three additional factors: Ang-1, FGF-5 and VEGF-C. These studies involved: (i) DNase I mapping of accessible locus regions; (ii) design and assembly of ZFPs targeting sites within accessible and/or functional promoter regions; and (iii) ZFP screening for activation of gene expression. By this approach, we have identified ZFPs that activate Ang-1, FGF-5 and VEGF-C by up to 14-fold in cells from both human and mouse. Furthermore, by targeting a sequence common to the promoters of VEGF-A and VEGF-C we have produced a ZFP that coordinately activates both of these genes. The use of designed ZFPs to regulate a patient's own endogenous genetic loci offers a number of advantages over cDNA-based gene therapy approaches, including the capacity to upregulate all splice variants of a therapeutic gene2,3,4, the option for ligand-regulatable protein expression using a single introduced transgene5, and transgene size economy (a critical feature for multi-factor therapies with vectors of limited insert capacity). We anticipate that these ZFPs will provide powerful reagents for the development of multi-factor strategies for therapeutic angiogenesis.

Gene therapy in heart and lung disease

Gene therapy utilizes viral and non-viral vectors to transfer genetic material into a host in the hope of treating disease. This article will review the potential applications of gene therapy in the treatment of cardiac and pulmonary diseases. The results from several phase I and II clinical trials have recently been published. In patients with ischemic heart disease, evidence of coronary revascularization has been observed after the delivery of angiogenic factors. Several trials have demonstrated a reduction in anginal symptoms, increases in exercise tolerance, and objective improvements in myocardial perfusion. Evidence of the transfer of therapeutic genes has been observed in human trials of inherited pulmonary diseases. Unfortunately, there has been little evidence of clinical efficacy in these studies. A variety of gene therapy strategies are being explored in the treatment of thoracic malignancies. Partial antitumor responses have occurred in some of the subjects enrolled in these studies. Significant progress has been made in the field of gene therapy in the past decade. Data from these early animal and human clinical trials will provide important information to guide future studies.

Bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth factor delivery

Engineering new tissues utilizing cell transplantation on biodegradable polymer matrices is an attractive approach to treat patients suffering from the loss or dysfunction of a number of tissues and organs. The matrices must maintain structural integrity during the process of tissue formation, and promote the vascularization of the developing tissue. A number of molecules (angiogenic factors) have been identified that promote the formation of new vascular beds from endothelial cells present within tissues, and the localized, controlled delivery of these factors from a matrix may allow an enhanced vascularization of engineered tissues. We have developed a gas foaming polymer processing approach that allows the fabrication of three-dimensional porous matrices from bioabsorbable materials (e.g., copolymers of lactide and glycolide [PLG]) without the use of organic solvents or high temperatures. The effects of several processing parameters (e.g., gas type, polymer composition and molecular weight) on the process were studied. Several gases (CO 2, N 2, He) were utilized in the fabrication process, but only CO 2 resulted in the formation of highly porous, structurally intact matrices. Crystalline polymers (polylactide and polyglycolide) did not form porous matrices, while amorphous copolymers (50:50, 75:25, and 85:15 ratio of lactide:glycolide) foamed to yield matrices with porosity up to 95%. The mechanical properties of matrices were also regulated by the choice of PLG composition and molecular weight. Angiogenic factors (e.g., vascular endothelial growth factor) were subsequently incorporated into matrices during the fabrication process, and released in a controlled manner. Importantly, the released growth factor retains over 90% of its bioactivity. In summary, a promising system for the incorporation and delivery of angiogenic factors from three-dimensional, biodegradable polymer matrices has been developed, and the fabrication process allows incorporation under mild conditions.

Cherubism: Report of a case with renal pathology

Engineering new tissues utilizing cell transplantation on biodegradable polymer matrices is an attractive approach to treat patients suffering from the loss or dysfunction of a number of tissues and organs. The matrices must maintain structural integrity during the process of tissue formation, and promote the vascularization of the developing tissue. A number of molecules (angiogenic factors) have been identified that promote the formation of new vascular beds from endothelial cells present within tissues, and the localized, controlled delivery of these factors from a matrix may allow an enhanced vascularization of engineered tissues. We have developed a gas foaming polymer processing approach that allows the fabrication of three-dimensional porous matrices from bioabsorbable materials (e.g., copolymers of lactide and glycolide [PLG]) without the use of organic solvents or high temperatures. The effects of several processing parameters (e.g., gas type, polymer composition and molecular weight) on the process were studied. Several gases (CO2, N2, He) were utilized in the fabrication process, but only CO2 resulted in the formation of highly porous, structurally intact matrices. Crystalline polymers (polylactide and polyglycolide) did not form porous matrices, while amorphous copolymers (50:50, 75:25, and 85:15 ratio of lactide:glycolide) foamed to yield matrices with porosity up to 95%. The mechanical properties of matrices were also regulated by the choice of PLG composition and molecular weight. Angiogenic factors (e.g., vascular endothelial growth factor) were subsequently incorporated into matrices during the fabrication process, and released in a controlled manner. Importantly, the released growth factor retains over 90% of its bioactivity. In summary, a promising system for the incorporation and delivery of angiogenic factors from three-dimensional, biodegradable polymer matrices has been developed, and the fabrication process allows incorporation under mild conditions.