Robert J. Fisher

Effect of Gelatin on Heparin Regulation of Cytokine Release from Hyaluronan-Based Hydrogels

The hypothesis that incorporation of small amounts (0.3% w/w) of modified heparin in thiol-modified hyaluronan or HA and gelatin hydrogels would regulate release of cytokine growth factors (GFs) from those gels has been investigated in vitro. In addition, the physiologic response to gel implantation has been evaluated in vivo. Tests were performed with 6 GFs: basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), keratinocyte growth factor, platelet-derived growth factor-AA (PDGF), and transforming growth factor-β 1. Release profiles for all 6 over several weeks were well fit by first order exponential kinetics (R2 > 0.9 for all cases). The most remarkable result of the experiment was a dramatic variation in the total mass ultimately released, which varied from as much as 90.2% of the initial load for bFGF to as little as 1.8% for PDGF, a 45-fold difference. Furthermore, gels containing either VEGF of Ang-1 produced twice the vascularization response in vivo as gels not containing a growth factor. Thus, those GFs maintained strong physiologic effectiveness.

Controlling Tissue Microenvironments: Biomimetics, Transport Phenomena, and Reacting Systems

The reconstruction of tissues ex vivo and production of cells capable of maintaining a stable performance for extended time periods in sufficient quantity for synthetic or therapeutic purposes are primary objectives of tissue engineering. The ability to characterize and manipulate the cellular microenvironment is critical for successful implementation of such cell-based bioengineered systems. As a result, knowledge of fundamental biomimetics, transport phenomena, and reaction engineering concepts is essential to system design and development. Once the requirements of a specific tissue microenvironment are understood, the biomimetic system specifications can be identified and a design implemented. Utilization of novel membrane systems that are engineered to possess unique transport and reactive features is one successful approach presented here. The limited availability of tissue or cells for these systems dictates the need for microscale reactors. A capstone illustration based on cellular therapy for type 1 diabetes mellitus via encapsulation techniques is presented as a representative example of this approach, to stress the importance of integrated systems.

Enhanced Transport Capabilities via Nanotechnologies: Impacting Bioefficacy, Controlled Release Strategies, and Novel Chaperones

Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drugs life cycle, inception to delivery, is rapidly expanding. As the industry moves more aggressively toward continuous manufacturing modes, utilizing Process Analytical Technology (PAT) and Process Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated. The ability to transfer energy, mass, and momentum with directed purposeful outcomes is a worthwhile endeavor in establishing higher production rates more economically. Furthermore, the ability to obtain desired drug properties, such as size, habit, and morphology, through novel manufacturing strategies permits unique formulation control for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals is an excellent example. Formulation and delivery are intimately coupled in improving bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish.

Perfusion Effects and Hydrodynamics

Biological processes within living systems are significantly influenced by the motion of the liquids and gases to which those tissues are exposed. Accordingly, tissue engineers must not only understand hydrodynamic phenomena, but also appreciate the vital role of those phenomena in cellular and physiologic processes both in vitro and in vivo. In particular, understanding the fundamental principles of fluid flow underlying perfusion effects in the organ-level internal environment and their relation to the cellular microenvironment is essential to successfully mimicking tissue behavior. In this work, the major principles of hemodynamic flow and transport are summarized, to provide readers with a physical understanding of these important issues. In particular, since quantifying hemodynamic events through experiments can require expensive and invasive techniques, the benefits that can be derived from the use of computational fluid dynamics (CFD) packages and neural networking (NN) models are stressed. A capstone illustration based on analysis of the hemodynamics of aortic aneurysms is presented as a representative example of this approach, to stress the importance of tissue responses to flow-induced events.