In This Issue
Engineering and the Health Care Delivery System
March 1, 2008 Volume 38 Issue 1
Volume 38, Number 1, Spring 2008. There are abundant reasons for the problems in health care delivery. Engineers may not be able to solve all of them, but the benefits of working toward solutions can be tremendous, and the challenges they present are enormously intellectually stimulating.

New Therapies: The Integration of Engineering and Biological Systems

Wednesday, December 3, 2008

Author: W. Mark Saltzman

Engineering innovation will continue to improve the quality of life and increase life expectancy.

In the twentieth century, overall life expectancy increased by 30 years (Figure 1), and young people today can expect to live longer, healthier, more active lives than their great-grandparents, grandparents, and parents. Dramatic changes in the practice of medicine have affected the life of almost every American. Couples can test for pregnancy at home; new vaccines are available for hepatitis B and chicken pox; inexpensive contact lenses provide clear vision; artificial hips enable recipients to walk and run; magnetic resonance is routinely used for high-resolution imaging of the brain; and many diabetics now use small, reliable pumps that administer insulin continuously.

Much of this progress has resulted from work by engineers, who have been chiefly responsible for the mass production of vaccines, the design of replacement joints, the creation of new techniques for safe imaging inside the human body, and other life-extending and life-improving technologies. In the twenty-first century, engineering innovations will surely continue to improve the quality of life and increase life expectancy. For example, patients may soon be able to live at home while undergoing high-dose chemotherapy.

Some new technologies will create challenges for our health care system, such as questions about how to pay for expensive new treatments, while others will make therapies safer and cheaper. We can reasonably hope that new technologies will contribute to better, more equitable health care in the United States and elsewhere, encouraged, perhaps, by incentives for the development of technologies that make medical care available to large numbers of people. In this brief review, I describe engineering technologies for medicine that are expected to become routine in the next 50 years.
 

Human life expectancy has increased dramatically in the past 200 years.
FIGURE 1 - Human life expectancy has increased dramatically in the past 200 years.

New Materials
The last few decades have been exciting for biomedical engineers, as tremendous advances have been made in biology. The discovery of the structure of DNA in the 1950s was rapidly translated into new kinds of therapies, new treatments for disease, and new ways of diagnosing disease. For example, gene therapy, which was used in humans for the first time several decades ago, has led to drugs designs based on biological principles. 

One new opportunity made possible by advances in human biology is the integration of biological features into materials traditionally used in medicine. In the past, most of these materials were developed from synthetic inert materials, such as metals, plastics, ceramics, and composites. New medical materials with integrated biological functions are a major step forward. For example, engineers have developed advanced materials that can provide the long-term release of drugs to a local disease site (Saltzman, 2001, 2004).

Polymers are also now safe and reliable medical tools, many of which can be safely implanted in the body. These materials are referred to as biocompatible because they arouse only weak immune and inflammatory responses. It is not yet possible to predict which polymer structures will be biocompatible, but several classes have been identified. Some of these are hydrophobic and stable, such as poly(ethylene-co-vinyl acetate) and silicon, which are useful in some medical applications because they do not change over the lifetime of the patient. Other polymers are water soluble, such as poly(ethylene glycol). Still others, such as poly(lactide-co-glycolide), degrade slowly with time after exposure to the biological environment. The latter are most useful for delivering drugs because they can be implanted, deliver their drugs, and eventually disappear after the treatment is complete.

Advances in medical materials have also led to new ways of administering drugs. Transdermal patches, polymer devices applied to the skin that slowly deliver drugs into the bloodstream, have been available for several decades. They offer alternative, arguably better, approaches for treating heart disease, preventing unwanted pregnancies, encouraging people to quit smoking, and so on. In addition, new systems for treating cancer, such as the Gliadel? system for brain cancer (described below), are based on principles that have implications for future technologies.

Polymer/Drug Composites
One biomedical engineering technology that is now used routinely involves embedding drug molecules into polymer materials to fashion drug-delivery systems. When a drug/polymer composite is implanted or injected into a patient, it provides a long-term source of the drug inside the body. Materials that release low-molecular-weight drugs can be produced readily; thus materials that release proteins, and even gene therapy vectors, can be designed to work for long periods of time after implantation. The duration and rate of drug release depend on properties that have been engineered into the composite.
Synthetic polymers also offer significant advantages for a variety of other medical applications. For example, polymer-coated metal wires are used in a variety of medical settings, from pacemaker leads to microwires for recording signals in the brain. Many reliable, simple methods, which were developed for coating wires with a thin layer of polymer material, can be used to coat wires with polymer/drug composites (Figure 2). A polymer/drug-coated wire inserted into the brain, for example, can release a drug continuously and locally.

Wires can be produced with coatings that release drugs that perform a variety of functions. For example, the local release of steroids could prevent the formation of scar tissue around the surface of a microelectrode, potentially extending its lifetime. This is one example of adding a biological property to a device that is already being used to produce a new device that lasts longer or is less likely to cause medical complications.

The best known product of this sort is the drug-eluting stent, a device placed in an artery to open it mechanically and increase the size of the lumen. Stents are used in patients with arteries that have narrowed to the point that blood flow is not adequate to satisfy the tissue (e.g., a coronary artery on the surface of the heart). Stents provide an alternative to open-heart surgery for many patients, because they can be inserted without surgery using well tolerated intravascular techniques.

Scanning electron microscopy images
FIGURE 2 - Scanning electron microscopy images of (a) an uncoated microelectrode; (b) a dexamethasone-polymer coated microelectrode; (c) the controlled release of dexamethasone from microwires with coatings of 10 (triangle), 30 (square), or 50 percent (circle) dexamethasone coatings. All coatings were produced from dexamethasone in poly(ethylene-co-vinyl acetate). Source: Lo, Laubach, and Saltzman, unpublished data.

A normal metal stent often evokes a tissue response in the blood vessel called restenosis, the regrowth of reactive tissue around the stented area, which can lead to re-narrowing of the vessel. Drug-eluting stents (metal stents coated with drug/polymers, similar to the coating on the wire shown in Figure 2) slowly release an anti-stenosis drug into the region of the vessel where the stent is placed. The drug acts on cells in that area to prevent the reformation of scars, thereby greatly extending the life of the stent.

Drug-eluting stents are not only interesting devices that provide new options for patients with life-threatening disease, they are also harbingers of a change in approach. Whereas previous implanted materials were predominantly made of materials that are known to be inert, new materials are designed to function biologically. In this case, the function is provided by a drug, which is released in a pattern controlled by the device engineer. In other cases, the biological function might be provided by the material itself. For example, the surface chemistry of the material might include elements that interact directly with cells in the tissue, or cells might be implanted with the material (the latter is discussed below).

Local Drug Delivery
Biodegradable polymer/drug composites have also led to new approaches to medical therapy. For example, Gliadel?, a degradable polymer wafer, can be loaded with high concentrations of a highly active, potent chemotherapy drug and placed at a site near a tumor, where it can deliver the drug directly to the tumor cells.

The first clinical application of Gliadel was for brain cancer, which had been difficult to treat with existing techniques. With Gliadel, surgeons resect the tumor and place the polymer/drug wafers into the surgical-resection cavity. The patient leaves the operating room with ongoing high-dose chemotherapy, delivered not throughout the body where it can cause unwanted side effects, but directly to the tumor site where it has maximum effectiveness with low toxicity.
When the technique was first tested in animals with experimentally induced brain cancer, a significant proportion of the test animals were cured when the material was designed properly. Clinical studies then showed that patients who received polymers embedded with drugs had higher survival rates than patients who received placebo polymers that had not been embedded with drugs.

Significantly, there were long-term survivors of this very serious disease—many more long-term survivors than one would expect without therapy (Sawyer et al., 2007). In addition, because Gliadel? is an engineered system that can be produced reliably and in large quantities, and because it augments a treatment already being used, the added cost for this benefit could potentially be low.

Mathematical Models
Mathematical modeling, a valuable tool in the design of new materials, provides information that would be difficult, and expensive, to get any other way. Engineering analysis—the development of mathematical models to describe a phenomenon—requires writing differential equations, which can often be a fairly straight-forward process (Fleming and Saltzman, 2002). These models can be critical to understanding how implanted drug-delivery systems work. In the case of Gliadel, the models were able to answer difficult questions, such as where the drug molecules go when released directly into brain tissue, how long they last, and how far they penetrate into the tissue.

Models also provide a mechanism for testing changes in engineered systems. They can suggest ways of engineering drugs—even drugs that are not yet available or have not yet been synthesized—with properties suited for particular kinds of therapy. For example, models that we developed in the early 1990s suggested that certain kinds of drug molecules would be best suited for local delivery in the brain. The ideal molecule was water-soluble, highly diffusible, yet unable to permeate easily through capillary walls (Saltzman and Radomsky, 1991).

One version of that ideal molecule was produced by coupling a synthetic polymer, poly(ethylene glycol), with drug molecules at each end of the linear polymer chain (Figure 3). Models suggested that this design would penetrate much better through brain tissue, thus enabling deeper penetration of the drug into the tissue. Experiments showed that this prediction was correct (Fleming et al., 2004). Subsequently, this drug/polymer conjugate was engineered, based on conventional engineering analysis, to possess properties that would carry it farther throughout the central nervous system.

Design of conjugates optimized for local delivery
FIGURE 3 - Design of conjugates optimized for local delivery. Drug molecules covalently attached to water-soluble polymers will penetrate farther from the implant source than free drugs because they are diffusible but are slowly eliminated from the local site.

As new technologies are more widely used they might reveal opportunities for improvement, as this example illustrates. In this case, the availability of local drug-delivery systems created an opportunity to rethink the way drugs are designed. Drugs created to be administered by the old paradigm, mainly orally, are not always the best candidates for new modes of drug delivery.

Nanotechnology
Nanotechnology will have a dramatic impact on the engineering of materials for new therapies. With nanotechnology, small particles, less than 100 nm in diameter, can be synthesized for drug delivery, imaging, or diagnosis. Fahmy et al. (2005) and Peer et al. (2007) have described some potential advantages of nano-particles in medical applications.

Nanoparticles provide a new way of thinking about the administration of drugs. With these tiny particles it may be possible to design a vehicle that will carry a drug safely into a cell and only then release it. Current methods of drug administration rely on flooding the body or tissue site with a drug in hopes that an adequate number of molecules reach the intracellular site of action. Drug-loaded nanoparticles promise therapies that are more efficient, more selective, and safer because they will have fewer side effects.

One advantage of nanoparticles as drug carriers is that the delivery system does not have to be implanted, which requires a surgical procedure. These tiny particles can be introduced into the body in many ways, such as injection or inhalation. In addition, some cells internalize nanoscale particles. If these particles are loaded with drugs, such as chemotherapy drugs, they could deliver high doses into the cell interior.

The first major challenge in engineering nano-particles is to produce them with high drug content, which would enable the administration of a small quantity of particles containing a sufficient quantity of drug molecules for the desired period of release. If this can be achieved, the result would be a totally synthetic, virus-sized particle loaded with active agents. If properly engineered, the drug molecules would be released in a controlled pattern (Figure 4).

Nanoparticles for the controlled release of drugs
FIGURE 4 - Nanoparticles for the controlled release of drugs. (a) A scanning electron micrograph shows nanoparticles formed from poly(lactide-co-glycolide), a biodegradable polymer. Scale bar = 1 micron. (b) Drug molecules are slowly released from the nanoparticles after introduction to a water-rich environment. Although linear release is usually desirable, many nanoparticle formulations release a substantial fraction of their drug load in an initial burst.

A second challenge is to make the nanoparticles smart so they know where to go in the body, which cells to enter, and when to release the drugs. One way to achieve this is to mimic an attribute of viruses by adding ligands, or recognition molecules, to the surface of the particles. 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. Antibodies, antibody fragments, and mimics are the most common reagents used as recognition elements.

Polymer nanoparticles are a potential new tool of nanotechnology. Others are nanoparticles assembled from lipids (liposomes), polymer micelles (colloidal particles self-assembled from amphiphilic polymers), and dendritic polymers.

Tissue Engineering
All the cells in our bodies are surrounded by a matrix—called the extracellular matrix—that contains elements, often networks of fibers, with typical diameters of 10 to 100 nm. Engineers have developed artificial matrices composed of natural or synthetic polymers that can serve as scaffolds for the transplantation of cells into the body. The purpose of this aspect of biomedical engineering, called tissue engineering, is to develop methods of repairing tissues or organs damaged by disease or trauma. A few pioneering efforts are already being tested in patients, such as engineered skin equivalents to repair wounds and chondrocyte implantation to repair articular cartilage defects. These studies have shown that novel tissue-replacement strategies will work in certain cases.

One of the most difficult problems in tissue engineering has been the reliable production of functional blood vessels to transport nutrients and waste in and out of the newly formed tissue. One promising technique involves using cultured human endothelial cells, usually derived from umbilical veins. In the most promising examples of blood vessel formation, these cells were genetically engineered to express proteins that improve their survival and encourage their transformation into functional blood vessels (Enis et al., 2005; Schechner et al., 2003).

To create new regions of vascularized tissue, the genetically engineered cells are first suspended in a polymer gel, which is then transplanted to a tissue site. Within a few weeks, a robust network of new, functional blood vessels forms the three-dimensional space once occupied by the implanted gel. The cell-loaded polymer gel is a smart material. When implanted into a site in the body that lacks sufficient blood flow, it induces the formation of new blood vessels in that region.

Based on this example, one can envision dozens of new ways to treat disease. The cell-loaded patch could be applied to tissues that have become ischemic to create new pathways for blood flow and the delivery of oxygen. Alternatively, the patch could be loaded with multiple cell types provided in response to the specific needs of the patient. For example, with a patch containing endothelial cells and beta cells—the cells in the pancreas that secrete insulin in response to glucose—a vascularized region of tissue that functions like an endocrine pancreas might be produced after transplantation. Protein-loaded delivery systems might be used to accelerate or direct the process of tissue formation, to facilitate the integration of the tissue, or to suppress unwanted local immune reactions.

These are just a few examples of new kinds of therapy using tissue engineering that might be available in the next 10 years. The development of each new therapy will involve overcoming significant engineering and medical challenges, but progress is certain. One can imagine using engineering principles that are fairly easy to define, perhaps even easy to manufacture, to produce complex transplantable materials built from component parts that are biologically safe. Tissue engineering will change the way health care is delivered to certain patients.

Summary
Engineering and new technologies improved the quality of life and extended life expectancy during the twentieth century. New technology—including safer biomaterials, nanoscale drug-delivery systems, and cell-based therapies like tissue engineering—will build on these advances in the twenty-first century. The impacts of emerging technologies on health care delivery and health care costs are difficult to predict, but they are sure to be profound.

References
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Fahmy, T.M., P.M. Fong, A. Goyal, and W.M. Saltzman. 2005. Targeted nanoparticles for drug delivery. Materials Today (Nano Today) 8(8)(Supplement 1): 18–26.
Fleming, A.B., and W.M. Saltzman. 2002. Pharmacokinetics of the carmustine implant. Clinical Pharmacokinetics 41(6): 403–419.
Fleming, A.B., K. Haverstick, and W.M. Saltzman. 2004. In vitro cytotoxicity and in vivo distribution after direct delivery of PEG-camptothecin conjugates to the rat brain. Bioconjugate Chemistry 15(6): 1364–1375.
Peer, D., J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, and R. Langer. 2007. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2(12): 751–760.
Saltzman, W.M. 2001. Drug Delivery: Engineering Principles for Drug Therapy. New York: Oxford University Press.
Saltzman, W.M. 2004. Tissue Engineering: Engineering Principles for the Design of Replacement Organs and Tissues. New York: Oxford University Press.
Saltzman, W.M., and M.L. Radomsky. 1991. Drugs released from polymers: diffusion and elimination in brain tissue. Chemical Engineering Science 46(10): 2429–2444.
Sawyer, A.J., J.M. Piepmeier, and W.M. Saltzman. 2007. New methods for direct delivery of chemotherapy for treating brain tumors. Yale Journal of Biology and Medicine 79(3-4): 141–152.
Schechner, J.S., S.K. Crane, F. Wang, A.M. Szeglin, G. Tellides, M.I. Lorber, A.L.M. Bothwell, and J.S. Pober. 2003. Engraftment of a vascularized human skin equivalent. FASEB Journal 17(15): 2250–2256.

About the Author:W. Mark Saltzman is Goizueta Foundation Professor of Chemical and Biomedical Engineering and chair, Department of Biomedical Engineering, Yale University. This article is based on a presentation at the NAE Annual Meeting Technical Symposium on October 1, 2007.