Drug Delivery in the BME Curricula
Mark Saltzman, Yale University Tejal Desai, Boston University Introduction Drug delivery and pharmacokinetics have been important elements of biomedical engineering practice for many decades. This long-standing interest is now coupled with rapid progress in both the engineering and biological aspects of drug delivery, making this an appropriate time to reconsider the role of drug delivery in the future of biomedical engineering (BME) curricula. In this white paper, we prioritize the opportunities in both biological and engineering aspects of drug delivery and attempt to link these with educational programs for students interested in this area. Several universities have already begun to offer courses or sequences of courses in drug delivery as well as related topics in biomaterials, micro/nanotechnology and pharmacology. A textbook is available and used in some of these courses (Saltzman 2001). Therefore, one can begin to ask specific questions: Should a full curriculum or sequence of course be designed to address issues of importance in drug delivery? What is the essential content of a curriculum in this area? Current Challenges in Drug Delivery The challenge of drug delivery is liberation of drug agents at the right time in a safe and reproducible manner, usually to a specific target site (Orive et al. 2003). Conventional dosage forms, such as orally administered pills and subcutaneous or intravenous injection, are the predominant routes for drug administration. But pills and injections offer limited control over the rate of drug release into the body; usually they are associated with an immediate release of the drug. Consequently, to achieve therapeutic levels that extend over time, the initial concentration of the drug in the body must be high, causing peaks (often adjusted to the stay just below known levels of toxicity for the drug) that gradually diminish over time to an ineffective level. In this mode of delivery, the duration of the therapeutic effect depends on the frequency of dose administration and the half- life of the drug. This peak and valley delivery is known to cause toxicity in certain cases, most famously with chemotherapy drugs for cancer. In recent years, the pharmaceutical and biotech industries have developed more sophisticated and potent drugs. Many of these agents are proteins or DNA; the therapeutic window (i.e., the range of concentrations that bracket the effective and toxic regimes for the drug) for these drugs is often narrow; and toxicity is observed for concentration spikes, which renders traditional methods of drug delivery ineffective (Davis and Illum 1998). In addition, conventional oral doses of these agents are frequently useless, because the drugs are destroyed during intestinal transit or poorly absorbed. Interest in new types of drug agents has catalyzed innovation in controlled-release drug delivery systems. A number of mechanisms can provide controlled release of drugs— including transdermal patches, implants, inhalation systems, bioadhesive systems and microencapsulation—and now there are pioneering, commercially available products in all of these categories.
Concept of Contro lled Drug Delivery While the last three decades have seen considerable advances in drug delivery technology, major unmet needs remain. Among these are the broad categories of: 1) continuous release of therapeutic agents over extended time periods and in accordance with a pre-determined temporal profile (Sershen and West 2002)(Kikuchi and Okano 2002)(Saltzman and Olbricht 2002); 2) local delivery of agents at pre-determined rates to local sites, such as solid tumors, to overcome systemic drug toxicity and improve anti-tumor activity (Fleming and Saltzman 2002); and 3) improved ease of administration, which would increase patient compliance while minimizing the need for intervention by health care personnel and decreasing the length of hospital stays (Boudes 1998; Lewis and Ferrari 2003). Success in addressing some or all of these challenges potentially would lead to improvements in efficacy and patient compliance as well as minimization of side effects (Tao and Desai 2003). Controlled-release drug delivery systems have the potential to provide continuous drug release (i.e., zero-order kinetics), in which blood levels of drugs would remain constant throughout the delivery period. By contrast, injected drugs are cleared by first-order kinetics, so that initial high levels of the drug after initial administration drop exponentially over time (Stoelting 1999). The potential therapeutic advantages of continuous-release drug delivery systems are significant and encompass in vivo predictability of release rates; minimized peak plasma levels—and thereby reduced risk of adverse reactions; predictable and extended duration of action; and reduced inconvenience of frequent dosing—and thereby improved patient compliance (Breimer 1999; Klausner, Eyal et al. 2003). Microfabrication and MEMS Technologies Recent advances in micromachining and microelectromechanical systems (MEMS) technology have provided the opportunity to fabricate miniature biomedical devices for a variety of applications. While much of the initial focus concerned the development of miniaturized diagnostic tools, such as biosensors, more recent advances have focused on the development of microdevices for therapeutic applications. The progression of microfabrication technology has enabled the creation of entirely new classes of drug delivery devices that possess a combination of structural, mechanical, chemical or electronic features that surmount the challenges associated with conventional drug delivery systems. Dendrimer -polymer conjugates Polymer nanoparticles Extracellular matrix Some therapeutic applications of microtechnology include microneedles for transdermal delivery (McAllister, Allen and Prausnitz 2000), bioadhesive microdevices for oral delivery (Tao, Lubely and Desai 2003) 200 nm 5 nm and microfluidic delivery systems 1 micron (Chen and Wise 1997) as well as Macromolecular Proteins Virus Cells assemblies various implantable systems, such as immunoisolating biocapules (Leoni 1 nm 10 nm 100 nm 1000 nm 10 micron 1 micron and Desai 2001) and microchips for Figure 1. Nanometer objects of biological interest controlled release (Santini, Cima and Langer 2000; Santini et al. 2000).
Nanotechnology and Drug Delivery The last few decades have hosted a revolution in materials science. In many cases, it is now possible to manipulate atoms and molecules within materials one at a time and, therefore, to construct materials with nanometer-scale (i.e., the size of individual molecules) precision. This new capability in materials science is called nanotechnology. The potential intersection between nanotechnology and the biological sciences is vast. Biological function depends heavily on units that have nanoscale dimensions, such as viruses, ribosomes, molecular motors and components of the extracellular matrix (Figure 1). In addition, engineered devices at the nanoscale are small enough to interact directly with sub-cellular compartments and to probe intracellular events. The ability to assemble and study materials with nanoscale precision leads to opportunities in both basic biology (e.g., testing of biological hypotheses that require nanoscale manipulations) and development of new biological technologies (e.g., drug delivery systems, imaging probes or nanodevices). Millimeter-scale and micrometer-scale controlled-release systems have been studied thoroughly, and some systems have been approved for clinical use, as described earlier in this paper. One of the major advances in recent years has been further reduction in the size of these systems: it is now possible to make polymer delivery systems that are nanometer in scale, can be easily injected or inhaled and are much smaller than—and capable of being internalized by—many types of human cells. While there are many ways of N ano p art icle p rop e rt ies A g en t pro p ert ie s Co m po sit ion : Po lyp e pt id e , Ma t rix de nsit y achieving nanoscale delivery systems, including selfp ro t e in , nu cle ic a cid Surf ace ch em ist ry D eg rad at io n/ d isso lut ion r at e Size ran g e: 1 -1 0 0 n m assembling systems based on liposomes or micelles, A g en t co nce nt rat io n the most stable and versatile systems are miniaturized versions of the synthetic materials that already have been used in drug delivery applications (Figure 2). This is usually accomplished with degradable polymers such as poly(lactide-co-glycolide). These particles can be injected for circulation or used to release drugs locally. The encapsulated drugs can be complex, if appropriate methods of fabrication are 1 0 0 t o 5 0 0 nm used to assemble the nanoparticle. For example, it is Figure 2 Example of nanoparticle now possible to make 300 nm particles that have In actual application, the concentration of agent functional DNA within the solid matrix. would probably be much higher than shown here Biocompatible and degradable polymers have (for clarity, just a few molecules are shown). Two different colors (black and white) are used to been around for some time, and much is known about illustrate that multiple agents can be dispersed in assembling them together with different classes of the same particle. drug molecules. But one usually obtains a complex mixture of particles of different sizes and shapes; the methods of fabrication are imperfect. Matching methods of particle formation with drugs has been one of the major challenges in this area. The literature now includes many different ways, especially with nanotechnology, to make small particles. Unfortunately, few of these methods are compatible with most drugs. Finding better ways to make controlled particles that are compatible with drug incorporation is a challenge for the future. It is also possible to make nanostructured materials from minerals and ceramics, which provide even more opportunities for the future. Many cells will internalize nanoscale particles. If these particles are loaded with drugs, such as chemotherapy drugs, then the nanoparticles can be used to deliver high drug doses into the
cell interior. Polymeric nanoparticles can also be conjugated with ligands for targeting specific cell populations. In this way, it may be possible to make drug carriers that are much smaller than a cell, but capable of delivering large doses of drug directly to the cell’s internal machinery. New research suggests that these particles can be made from materials that respond to mild external signals (such as light or ultrasound or magnetic fields) so that the movement of the particles could be directed from outside the body, or the particles could be activated at particular sites. In this way, nanotechnology is providing new methods for using materials in the body; the very small size of the materials makes them suitable for many biological functions. Because of their combination of properties—including sub-cellular size and controlled-release capability and susceptibility to external activation—devices produced by nanotechnology will enable new applications in biological and medical science. Educational Underpinnings The last decade has seen the dramatic development of biomedical technologies for therapeutic delivery. It increasingly appears that the key to developing functional biodevices for therapeutic delivery is the development of interfaces that are biocompatible, biofunctional and biomimetic. An integrated and multidisciplinary research and training approach, bringing in knowledge from fields as diverse as electrical engineering and immunology, is essential in advancing our understanding of biological interfaces and designing novel biological analogs. For Discussion: Drug Delivery Fundamentals? The ability to engineer delivery devices at the same scale as biological entities presents many opportunities in medicine and biology. However, there is some question about what should be included in our undergraduate and graduate curricula to prepare students to design, develop and test drug delivery systems. A partial list of topics is included below. During the discussion session, we hope to add to and subtract from this list to arrive at a suggested suite of topics. Transport phenomena Pharmacokinetics Biomaterials—polymer science and/or inorganics Biocompatibility and immunolo gy Biosurface engineering—cell surface targeting Micro and Nanofabrication Current BME programs treat the topic of drug delivery in a variety of ways :
• • •
as a separate department or program in drug delivery, as a separate track within a BME department, or as part of fundamental BME classes.
More than 20 programs offer one or two courses in drug delivery. An equivalent number of schools offer programs in drug delivery in which students can specialize. It is clear that there is really no comprehensive curriculum for this area. Some schools are beginning to put together sequences, but those are rare. Also, the emergence of courses in nano/micro-engineering intersect
with this area. We hope to discuss whether we should consider drug delivery as a track. Do you think drug delivery topics should be broken up and dispersed or placed into a single course? These are examples of schools that offer courses in drug delivery:
Institution Boston University Brown University Case Western Reserve University City College, CUNY Cleveland State University Cornell University Duke University Florida International University Illinois Institute of Technology SUNY at Stony Brook SUNY at Stony Brook SUNY at Stony Brook Saint Louis University University of Texas at Austin University of Washington Wayne State University Course Number BE 727 Bi 211 EBME 416 ChE G3100 CHE-794-04 BMEP 631 BME 247 BME 6037 CHEE 585 BME 606 BME 430 BME 381 BMEP -530 BME385J.34 BIOEN 491 BME 5310 Course Name Biomaterials and Tissue Engineering II : Drug Delivery Module Drug and Gene Delivery Biomaterials and Drug Delivery Kinetics of Biological Systems and Drug Release Drug Delivery Systems Engineering Principles for Drug Delivery Drug Delivery Controlled Delivery in Biomedicine Drug Delivery Drug and Gene Delivery Systems Engineering Approaches to Drug and Gene Delivery Nanofabrication in Biomedical Applications Drug Delivery Biopolymers and Drug/Gene Delivery Controlled Release Systems Engineering Principles of Drug Delivery
These are examples of schools that offer programs in drug delivery:
Institution Brown University Clemson University Cleveland State University Cornell University Dalhousie University Duke University Penn State University Purdue University Rice University SUNY at Stony Brook University of California, Los Angeles University of Illinois, Chicago University of Minnesota University of Oklahoma University of Utah University of Virginia Washington University, St. Louis Yale University Program Name Medical Sciences Bioengineering Doctor of Engineering with specialization in Applied Biomedical Engineering Biomedical Engineering Ph.D. Biomedical Engineering Bioengineering Ph.D. Biomedical Engineering, M.D./Ph.D. Biomedical Engineering Ph.D. Bioengineering PhD in Biomedical Engineering Doctor of Philosophy in Bioengineering Biomedical Engineering Doctor of Philosophy in Bioengineering Doctor of Philosophy Ph.D. Doctor of Science (D.Sc.) Ph.D. in Biomedical Engineering Degree Doctoral Doctoral Doctoral Doctoral Doctoral Undergrad Undergrad Doctoral Doctoral Undergrad Doctoral Doctoral Master’s Doctoral Doctoral Doctoral Doctoral Doctoral
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