The identification and production of recombinant morphogens and growth factors that play key roles in tissue regeneration have generated much enthusiasm and numerous clinical trials, but the results of many of these trials have been largely disappointing. Interestingly, the trials that have shown benefit all contain a common denominator, the presence of a material carrier, suggesting strongly that spatio-temporal control over the location and bioactivity of factors after introduction into the body is crucial to achieve tangible therapeutic effect. Sophisticated materials systems that regulate the biological presentation of growth factors represent an attractive new generation of therapeutic agents for the treatment of a wide variety of diseases. This review provides an overview of growth factor delivery in tissue engineering. Certain fundamental issues and design strategies relevant to the material carriers that are being actively pursued to address specific technical objectives are discussed. Recent progress highlights the importance of materials science and engineering in growth factor delivery approaches to regenerative medicine.

https://royalsocietypublishing.org/doi/pdf/10.1098/rsif.2010.0223

Growth factor delivery-based tissue engineering: general approaches and a review of recent developments

Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle–surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti–intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.

https://www.pnas.org/content/pnas/early/2013/06/05/1308345110.full.pdf

Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium

Intravenously injected nanoparticulate drug carriers provide a wide range of unique opportunities for site-specific targeting of therapeutic agents to many areas within the vasculature and beyond. Pharmacokinetics and biodistribution of these carriers are controlled by a complex array of interrelated core and interfacial physicochemical and biological factors. Pertinent to realizing therapeutic goals, definitive maps that establish the interdependency of nanoparticle size, shape, and surface characteristics in relation to interfacial forces, biodistribution, controlled drug release, excretion, and adverse effects must be outlined. These concepts are critically evaluated and an integrated perspective is provided on the basis of the recent application of nanoscience approaches to nanocarrier design and engineering. The future of this exciting field is bright; some regulatory-approved products are already on the market and many are in late-phase clinical trials. With concomitant advances in extensive computational knowledge of the genomics and epigenomics of interindividual variations in drug responses, the boundaries toward development of personalized nanomedicines can be pushed further.

Factors Controlling Nanoparticle Pharmacokinetics: An Integrated Analysis and Perspective

[Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban].

Latest Developments in Micro Total Analysis Systems

Recent attempts at rebuilding the myocardium using stem cells have yielded disappointing results. The lack of a supporting vasculature may, in part, explain these disappointing findings. However, concerns over possible side effects have hampered attempts at revascularizing the infarcted myocardium using systemic delivery of proangiogenic compounds. In this study, we develop the technology to enhance the morphology and function of postinfarct neovasculature. Previously, we have shown that the up-regulated expression of endothelial cell adhesion molecules in the myocardial infarction (MI) region provides a potential avenue for selectively targeting drugs to infarcted tissue. After treatment with anti-P-selectin-conjugated liposomes containing vascular endothelial growth factor (VEGF), changes in cardiac function and vasculature post-MI were quantified in a rat MI model. Targeted delivery of VEGF to post-MI tissue resulted in significant increase in fractional shortening and improved systolic function. These functional improvements were accompanied by a 21% increase in the number of anatomical vessels and a 74% increase in the number of perfused vessels in the MI region of treated animals. No significant improvements in cardiac function were observed in untreated, systemic VEGF-treated, nontargeted liposome-treated, or blank immunoliposome-treated animals. Targeted delivery of low doses of proangiogenic compounds to post-MI tissue results in significant improvements in cardiac function and vascular structure.

Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function

The objective of this study was to develop an efficient tumor vasculature targeted liposome delivery system for combretastatin A4, a novel antivascular agent. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, distearoyl phosphoethanolamine-polyethylene-glycol-2000 conjugate (DSPE-PEG), and DSPE-PEG-maleimide were prepared by the lipid film hydration and extrusion process. Cyclic RGD (Arg-Gly-Asp) peptides with affinity for αvβ3-integrins expressed on tumor vascular endothelial cells were coupled to the distal end of PEG on the liposomes sterically stabilized with PEG (long circulating liposomes, LCL). The liposome delivery system was characterized in terms of size, lamellarity, ligand density, drug loading, and leakage properties. Targeting nature of the delivery system was evaluated in vitro using cultured human umbilical vein endothelial cells (HUVEC). Electron microscopic observations of the formulations revealed presence of small unilamellar liposomes of ∼120 nm in diameter. High performance liquid chromatography determination of ligand coupling to the liposome surface indicated that more than 99% of the RGD peptides were reacted with maleimide groups on the liposome surface. Up to 3 mg/mL of stable liposomal combretastatin A4 loading was achieved with ∼80% of this being entrapped within the liposomes. In the in vitro cell culture studies, targeted liposomes showed significantly higher binding to their target cells than non-targeted liposomes, presumably through specific interaction of the RGD with its receptors on the cell surface. It was concluded that the targeting properties of the prepared delivery system would potentially improve the therapeutic benefits of combretastatin A4 compared with nontargeted liposomes or solution dosage forms.

/pdf/a-tumor-vasculature-targeted-liposome-delivery-system-for-23vzgmgex9.pdf

A tumor vasculature targeted liposome delivery system for combretastatin A4: design, characterization, and in vitro evaluation.

Existing microfluidic devices, e.g. parallel plate flow chambers, do not accurately depict the geometry of microvascular networks in vivo. We have developed a synthetic microvascular network (SMN) on a polydimethalsiloxane (PDMS) chip that can serve as an in vitro model of the bifurcations, tortuosities, and cross-sectional changes found in microvascular networks in vivo. Microvascular networks from a cremaster muscle were mapped using a modified Geographical Information System, and then used to manufacture the SMNs on a PDMS chip. The networks were cultured with bovine aortic endothelial cells (BAEC), which reached confluency 3-4 days after seeding. Propidium iodide staining indicated viable and healthy cells showing normal behavior in these networks. Anti-ICAM-1 conjugated 2-mum microspheres adhered to BAEC cells activated with TNF-alpha in significantly larger numbers compared to control IgG conjugated microspheres. This preferential adhesion suggests that cultured cells retain an intact cytokine response in the SMN. This microfluidic system can provide novel insight into characterization of drug delivery particles and dynamic flow conditions in microvascular networks.

/pdf/a-physiologically-realistic-in-vitro-model-of-microvascular-43vqnacz5j.pdf

A Physiologically Realistic in Vitro Model of Microvascular Networks

Background: The development of a number of regenerative strategies in recent years for curing heart disease represents a paradigm shift away from conventional approaches which aim to manage heart disease. Effective administration of pharmaceutical agents targeted directly to the diseased tissue is the key to unlocking the potential of regenerative strategies, which could augment current conventional treatments. Objective: The authors review recent advances in targeted drug delivery to diseased cardiac tissue. Methods: Various therapeutic methodologies designed to selectively deliver pharmaceutical agents to diseased cardiac tissue are discussed in this review. Conclusion: Targeted delivery of survival and engraftment promoting factors to damaged cardiac tissue can be an important strategy, for example, in creating a suitable microenvironment encouraging the engraftment of stem cells. Further progress in this emerging field is contingent on the discovery of new biomarkers that are upregulated in damaged ca...

Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue

We have developed a methodology to study particle adhesion in the microvascular environment using microfluidic, image-derived microvascular networks on a chip accompanied by Computational Fluid Dynamics (CFD) analysis of fluid flow and particle adhesion. Microfluidic networks, obtained from digitization of in vivo microvascular topology were prototyped using soft-lithography techniques to obtain semicircular cross sectional microvascular networks in polydimethylsiloxane (PDMS). Dye perfusion studies indicated the presence of well-perfused as well as stagnant regions in a given network. Furthermore, microparticle adhesion to antibody coated networks was found to be spatially non-uniform as well. These findings were broadly corroborated in the CFD analyses. Detailed information on shear rates and particle fluxes in the entire network, obtained from the CFD models, were used to show global adhesion trends to be qualitatively consistent with current knowledge obtained using flow chambers. However, in comparison with a flow chamber, this method represents and incorporates elements of size and complex morphology of the microvasculature. Particle adhesion was found to be significantly localized near the bifurcations in comparison with the straight sections over the entire network, an effect not observable with flow chambers. In addition, the microvascular network chips are resource effective by providing data on particle adhesion over physiologically relevant shear range from even a single experiment. The microfluidic microvascular networks developed in this study can be readily used to gain fundamental insights into the processes leading to particle adhesion in the microvasculature.

/pdf/synthetic-microvascular-networks-for-quantitative-analysis-chi8erj447.pdf

Robert C. Scott

Papers

Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function

A tumor vasculature targeted liposome delivery system for combretastatin A4: design, characterization, and in vitro evaluation.

A Physiologically Realistic in Vitro Model of Microvascular Networks

Aiming for the heart: targeted delivery of drugs to diseased cardiac tissue

Synthetic microvascular networks for quantitative analysis of particle adhesion.