Potential Role of Controlled Drug Delivery in Tissue Engineering

Chapter 22

Potential Role of Controlled Drug Delivery in Tissue Engineering 1

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Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 16, 2015 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0709.ch022

K. J. L. Burg and S. W. Shalaby 1

Department of General Surgery Research, Carolinas Medical Center, Charlotte, NC 28232-2861 Poly-Med Inc., Center for Applied Technology, Westinghouse Road, Pendleton, SC 29670 2

This communication discusses the pertinence of controlled release of bioactive agents/drugs to the success of the fast-growing tissue engineering technology. Key aspects of the control release mode and processing of polymeric scaffolds for three-dimensional cell growth are analyzed. Contemporary trends in scaffold developments and future perspectives of controlled delivery systems/tissue engineering are noted.

The success of a tissue engineered construct, as with all biomaterial implants, is heavily dependent on the interaction of the material with the tissue. Additionally, since many tissue engineered constructs involve the replacement of an absorbable biomaterial with newly developing tissue, the success also hinges on cellular growth into the material, timely tissue growth, the development of a viable, structurally and biologically functional tissue, and its controlled growth to the final dimensions of the tissue. Many biomaterial designs allow the incorporation of bioactive agents/drugs for such purposes as infection control (antibiotics), cartilage and bone formation, angiogenic stimulation, and a variety of other tissue stimulating goals. Tissue engineering currently has areas to which drug delivery may be useful (1-4). First, one major area critical to progress of the field is the development of vasculature to support a relatively thick tissue (5). Angiogenesis is a complicated process, modulated by growth factors, extracellular matrices, and proteases (6-14). Development of a relatively thick tissue could potentially require additional angiogenic growth factors incorporated alone in the biomaterial or could potentially require additional incorporation of cells derived from vasculature (i.e., endothelial cells) to induce formation of tubular structures (15). Additionally, the surrounding tissue or cells incorporated within the material complex may require additional factors or a combination of factors to signal the appropriate cellular growth in a controlled fashion (76-79). Drug delivery is complicated by the fact that the

©1998 American Chemical Society

In Tailored Polymeric Materials for Controlled Delivery Systems; McCulloch, I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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280 behavior of the cellular component to the particular drug will depend largely also on the drug-material interaction and the resulting microenvironment (14,20).


Pertinent Modes of Controlled Release of Bioactive Agents The most pertinent controlled release mode for future applications in tissue engineering is the diffusion controlled type, where the release involves a matrix or a reservoir system. The development of a reservoir system entails encapsulation of the drug by a polymer membrane, potentially microporous. In a tissue engineering design, this may involve encapsulation of specific cells individually or incorporation of multiple cells in a carrier for the purposes of releasing desired factors or it may involve direct encapsulation of the drug. These systems can have a release lag time as the surrounding polymer saturates with drug and as its release to the surrounding medium gradually reaches a steady state. If the encapsulating polymer is saturated with the drug prior to implantation, the surrounding medium will encounter a burst release followed by a gradual decline to a steady state (20). The matrix system is one in which drug is incorporated in or throughout the polymer. In this system, the drug release gradually decreases with time as the distance of travel for the drug to go from the core to the surrounding medium increases. This can be adjusted by loading the drug, incrementally increasing towards the core. To be effective, this does require that the drug will not redisperse prior to implantation. The concentration of drug in the system will have an influence on the release profile. Isolated drug, or drug surrounded by a solid, nonporous polymer, will not release and will remain entrapped in the material until the material absorbs. The drug in the matrix system may either be physically dispersed throughout the matrix or chemically attached to the polymer. If the surface area of the material remains relatively constant throughout absorption period, the release rate will remain essentially constant. Porous polymeric structures, as are commonly exploited in tissue engineering, may release loaded drug with a minimized initial burst followed by a slow release rate. The drug release may also be controlled through a swelling mechanism, as in the case of hydrogel systems, such as modified collagen or gelatin. The drug is incorporated into the gel; as water diffuses into the system swelling occurs, thus unlocking the drug and causing its release to the surrounding medium. Hydrogel systems are commonly used in tissue engineering constructs and have the positive attribute of providing a surgically minimally invasive option (21-25). Processing Considerations in Tissue Engineering There are many processing factors that affect the release rate of bioactive agents, including the type of polymeric carrier, substrate porosity, and the mode of delivery. Release of the drug may take place by physical means such as diffusion or osmosis. It may also be impacted by matrix swelling, which is in turn induced by enzymatic or hydrolytic means (26). The drug may be directly loaded into a polymeric material or it may be synthesized by and releasedfromcells which are encapsulated in such polymeric material (27,28,29).



281 The release of drugs from a three-dimensional system is complicated, particularly in a dynamic, absorbable one. The morphology of a tissue engineered foam scaffold may vary through its volume due to processing limitations or purposeful design (30). Similarly, the crystalline content and molecular weight parameters of the material may also vary. As the absorption process occurs, the material may preferentially absorb (5/), depending on accessibility of water and enzymes to the site, which complicates drug release considerably. Additionally, as tissue and supporting vasculature develops throughout the scaffold, the kinetics of drug delivery may change. As engineered tissue develops and factors are produced in situ, the additional drug requirements of the area may subsequently change. Some fabrication complications include thermal and chemical stability of the drug, since many fabrication processes involve either solvents or high temperatures. Proteins, for example, can readily denature so less destructive methods such as photopolymerization (32) are more desirable for their processing. Photopolymerization also leads to an initial nonuniform distribution of drug (32) which could be particularly useful in large tissue constructs, where nonuniform growth may be an important issue. Low melting solid solvents, such as napthalene, which have been successfully utilized in the manufacture of porous constructs, can be readily removed by extraction or sublimation from the solidified bicontinuous phases to provide continuous cell structure. This alleviates the need for more traditional processing methods which can cause protein denaturing (33). Additionally, many of the common methods of foam fabrication involve the addition of porogens which are later leached to form the porous structure. This leaching step can actually cause the leaching of any preloaded drug; so, use of these type foams typically involves later addition of bioactive agents; for example, the addition of drug delivery beads to a porous matrix (34). It may, however, be complicated to uniformly distribute the beads throughout the scaffold, particularly as thicker scaffolds are utilized and become potentially increasingly nonhomogeneous. Other important processing factors can include the physical state of the drug and its solubility in polymer, the shape and dimensions of the engineered construct, and the hydrophobicity of both the polymer and drug. Contemporary Trends in Scaffold Development There are several key factors which influence the performance of an absorbable scaffold, both as a substrate for three-dimensional cell growth and as a carrier of bioactive agents which modulate relevant complex biological events. These factors include (1) the continuity of the cellular structure in a microporous substrate and ease of nutrient and metabolic by-product transport through the engineered construct; (2) the surface energy, activities, and chemical environment presented initially to living cells; (3) the ability to synchronize the absorption and strength loss properties of the substrate with the gradual three-dimensional growth of the engineered tissue; and (4) injectability of the polymeric carrier for cells and bioactive agents. Study of these factors was initiated several years ago by Shalaby and his co-workers at Clemson University and, more recently, at Poly-Med, Inc. (3539). Formation of continuous-cell microporous foams for housing living cells has been achieved with certain absorbable and non-absorbable polymers using the



282 principle of crystallization-induced microphase separation denoted as CIMS (35). A typical CIMS process entails (1) co-melting of an absorbable crystalline thermoplastic polymer, such as poly(lactide-co-glycolide) or poly(,-caprolactone-coglycolide), with certain low-melting organic solids (or diluents), such as naphthalene, to form a one-phase melt; (2) rapid cooling of the one-phase systems which results in simultaneous crystallization of the organic diluent and polymer to form two bicontinuous microphases; and (3) sublimation or extraction of the diluent phase to produce a continuous-cell microporous foam. The porosity and surface area of the foam can be controlled by varying the diluent/polymer ratio and cooling rate of the molten system. Depending on the type of cells involved in tissue engineering, the internal and external surface of the porous constructs can be functionalized to impart hydrophilicity and/or ionic character. In a typical construct for use in bone regeneration, the surface can be phosphonylated to develop suitable functionality for the deposition of hydroxyapatite, a key component in bone formation (36-37). To modulate the absorption profile of polymers pertinent to tissue-engineering, the concept of constructing polyester chains with amine functionalities for auto-catalyzed hydrolysis has been successfully tested (38). A simple foam of these systems is based on carboxy-terminated polyester chains which are conjugated ionically with a basic amino acid, such as lysine. Exploiting the proven biocompatibility of polyethylene glycol (PEG), Shalaby (39) developed a family of absorbable, injectable liquid PEG-polyester copolymers that transform to insoluble gels in aqueous media. Such gel-formers have been proposed as transient carriers for living cells as well as bioactive agents/drugs intended for injection to the specific biological site in need of repair. Future Perspective The potential for tissue engineering drug delivery systems is great. With careful consideration to avoid overloading an area with factors and potentially causing uncontrolled, undesired cellular growth (40), this indeed may provide a currently missing link in development of viable tissue replacement. As tissues are indeed composed of a mixture of different cells and factors rather than a purified population, it seems logical that additional signals generated through drug delivery (either by the appropriate combination of factor secreting cells or appropriate combination of growth factors) potentially remain the key to successfully engineered tissue and organs. As scientists continue to address scaffold design, the considerations associated with drug incorporation will remain key.

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Potential Role of Controlled Drug Delivery in Tissue Engineering

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