Advances in Biomedical Engineering

OPPORTUNITIES FOR MEDICAL RESEARCH

Linda G. Griffith, PhD The most visible contributions of biomedical engineering to clinical prac- Alan J. Grodzinsky, ScD tice involve instrumentation for diagnosis, therapy, and rehabilitation. Cell IOMEDICAL ENGINEERING IS and tissue engineering also have emerged as clinical realities. In the next 25 broadly defined as the appli- years, advances in electronics, optics, materials, and miniaturization will ac- cation of engineering prin- celerate development of more sophisticated devices for diagnosis and therapy, ciples to problems in clinical such as imaging and virtual surgery. The emerging new field of bioengi- Bmedicine and surgery. The origins of neering—engineering based in the science of molecular cell biology—will biomedical engineering are often linked to the pioneering electrophysiology greatly expand the scope of biomedical engineering to tackle challenges in studies of Galvani and Volta more than molecular and genomic medicine. 200 years ago.1 During the first half of the 20th century, the electrical prop- JAMA. 2001;285:556-561 www.jama.com erties of tissues and cells continued to be a primary focus of biomedical engi- quality, cross-sectional images of the in 20000 of the 1 to 2 million deaf in- neering. Emerging interests in the body.9 Magnetic resonance imaging fur- dividuals in the United States, many health effects of ionizing radiation be- ther revolutionized imaging of soft tis- showing dramatic improvement.11 tween World Wars I and II laid the sues, enabling both the imaging of static Sound is decomposed into critical fre- groundwork for current radiation structures and dynamic function, such quency bands and signals are deliv- therapy. It was not until the 1960s and as blood flow and metabolism. Open ered electronically to auditory neu- 1970s, however, that an explosion in magnetic resonance imaging scanners rons via an array of electrodes. multidisciplinary research, combin- are used in operating rooms to guide Cardiovascular therapy has been ing mechanical, chemical, and electri- biopsies and stereotactic surgery.7 similarly changed by the introduction cal engineering with physiology and Ultrasound also affords soft-tissue of lifesaving implantable defibrillators medicine paved the way for dramatic imaging, with lower resolution but at (1980s),12 and ventricular-assist and advances in modern health care based reduced cost and thus increased acces- catheter-based ablation devices. In ad- on breakthrough discoveries in bio- sibility compared with magnetic reso- dition, vascular stent technology for the medical engineering.2 nance imaging.8 treatment of aneurysms, peripheral vas- The development of these imaging mo- cular disease, and coronary artery dis- Clinical and Research Advances dalities has been accompanied by excit- ease has made it possible for a mini- The most visible contributions of bio- ing advances in 3-dimensional image re- mally invasive procedure to replace medical engineering to clinical prac- construction, quantitative image analysis, major surgery.13 The shift toward mini- tice involve instrumentation for diag- and image enhancement—advances that mally invasive surgery, driven by de- nosis, therapy, and rehabilitation.3 A were made possible by improved com- velopment of miniaturized cameras, la- revolution in disease diagnosis began putational power and algorithms. The de- ser guides, and surgical tools, has had in the 1970s with the introduction of velopment in the 1980s of the noninva- computed tomography, magnetic reso- sive pulse oximeter was a significant Author Affiliations: Division of Bioengineering and En- vironmental Health, Departments of Electrical (Dr nance imaging, and ultrasonic imag- advance in intraoperative monitoring and Grodzinsky), Mechanical (Dr Grodzinsky), and Chemi- ing.4-8 Computed tomographic scan- postsurgical care.10 cal Engineering (Dr Griffith), Center for Biomedical En- gineering, Massachusetts Institute of Technology, Cam- ning, developed at EMI Research Labs Biomedical engineering has also been bridge. (Hayes, Middlesex, England) (funded responsible for the development of new Corresponding Author and Reprints: Linda G. Grif- fith, PhD, Massachusetts Institute of Technology, 77 in part by the success of EMI’s Beatles therapeutic devices. The cochlear im- Mass Ave, Room 66-466, Cambridge, MA 02139 records) provided the first high- plant, for example, has now been used (e-mail: [email protected]).

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a profound effect in reducing morbid- Figure 1. Tissue Engineering of Cartilage ity and mortality, and enabling faster rehabilitation. A B Cell and tissue engineering also have emerged as clinical realities. Products for skin replacement are in clinical use14,15 and progress has been made in developing technologies for repair of cartilage (FIGURE 1),16,17 bone, liver, kidney, skeletal muscle, blood vessels, the nervous system, and urological disor- ders.15 The discovery that mechanical forces are potent regulators of cell- 20 µm 20 µm mediated growth, degradation, and re- 17,18 pair of musculoskeletal and cardio- After 2 weeks of culture, cartilage cells seeded onto a scaffold have synthesized a biomechanically stable cartilage- vascular19 tissues presents a major like extracellular matrix17 containing phenotypically specific aggregating proteoglycans (A, toluidine blue stain) and type II collagen fibrils (B, immunohistochemical stain). The scaffold material is a recently discovered self- challenge and elucidation of the mecha- assembling gel16 made from repeating sequences of the amino acids lysine, leucine, and aspartic acid. This nisms involved in mechanical signal- biomaterial can be used simultaneously as a cell-supporting structure for gene delivery to the cells. ing and cellular mechanotransduction will be needed to develop new therapies for a true understanding of osteo- data acquisition are clearly in genom- teins and protein-protein interac- arthritis, osteoporosis, and atheroscle- ics. For example, DNA microarrays, in- tions.24 Thus, analysis of cellular pro- rosis, and for the development of tissue volving analysis of expression profiles tein profiles (proteomics) may be engineering therapies. of thousands of genes simultaneously, particularly valuable in drug discov- At the same time, the field of bio- are being applied for biomedical re- ery and analysis of disease states. Pro- medical engineering is undergoing a search and pharmaceutical develop- teomics is less advanced than genom- major ideological change. The fusion ment.20 ics because of the greater complexity of of engineering with molecular cell bi- Yet many engineering challenges re- protein, but advances in mass spec- ology is pushing the evolution of a new main to be solved before the power of trometry analysis of proteins are caus- engineering discipline termed bioengi- DNA microarray analysis is opti- ing a revolution in proteomics.24 Pro- neering to tackle the challenges of mo- mal.21-23 Many drugs developed through teomic analysis shares some of the same lecular and genomic medicine. In much molecular-level assays prove to be inef- challenges as genomic analysis in terms the same way that the iron lung (an en- fective, and bioengineering analysis is be- of improving sample preparation, gineered device) was rendered obso- ginning to point the way to better drug throughput, reliability, and means of lete by the polio vaccine (molecular design and better drug testing. Most analyzing massive data sets. medicine), many of the device-based pressing for genomics is the lack of ap- Engineering analysis often entails and instrumentation-based therapies in propriate computational tools for the building complex systems models by in- clinical use today will likely be re- analysis and interpretation of expres- tegrating detailed mathematical mod- placed by molecular- and cellular- sion profile data (ie, bioinformatics). els of the physical and kinetic proper- based therapies during the next 25 Current tools consist largely of algo- ties of the component parts. Such years. Realization of these therapies will rithms that group genes according to analysis entails making assumptions require major contributions from bio- shared expression patterns.21 In addi- about the nature of missing informa- engineering. tion, hybridization is not always suffi- tion to build predictive models of the Arguably the most well-recognized ciently reliable or sensitive; there is a system as a whole when the properties contributions of bioengineering have great need for better design of hybrid- of 1 component are altered. Even been at the level of obtaining molecu- ization chips as well as algorithms to ac- though the individual processes con- lar information—techniques that make count for data imperfections.22 The cel- tributing to performance may be poorly it possible at the research, develop- lular messenger RNA levels measured by understood, models of biological sys- ment, and even clinical levels to ma- microarray analysis do not strongly cor- tems contribute to application of the nipulate, sequence, reconstruct, and relate with corresponding protein lev- biological information, such as im- model proteins and nucleic acids, such els, further clouding the interpretation proved, targeted drug therapies, in the as polymerase chain reaction, DNA se- of microarray data.23 absence of complete data on cellular quencing, molecular modeling, and bio- Proteins are the molecules that regu- genes and proteins. informatics. On this molecular level, the late metabolic processes and signaling Insights gained from such complex most stunning successes in terms of pathways and most drugs target pro- models are often both nonintuitive and

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receptor-ligand interactions, which in- Recent Advances in Biomedical Engineering tegrate separate mathematical descrip-

Diagnostics tions of ligand binding and release, receptor activation and desensitization, Imaging Modalities Computed Tomography, Magnetic Resonance and receptor internalization, recy- Imaging, Positron Emission Tomography, and cling, and degradation indicate that Ultrasound; Nuclear Image Reconstruction classic strategies based solely on high- Monitoring Sensors and Transducers (Intensive Care Unit; affinity equilibrium binding can fail to eg, Pulse Oximeter) predict drug candidates—for some receptors, lower affinity compounds may Instruments and Devices Clinical Laboratory be more effective. For example, transforming growth Therapeutics factor ␣ is more potent than epider- Sensory/Motor Intraocular Lens and Cochlear Implants mal growth factor in stimulating cell growth, even though transforming Implantable Nerve Stimulators growth factor ␣ has a lower binding affinity than epidermal growth factor to Cardiovascular Defibrillators and Pacemakers (Implantable and their common cell surface receptor. Sur- Programmable) prisingly, a detailed cellular bioengi-

Ventricular Assist Devices neering model shows that lower affinity binding, particularly at the pH of the Catheter-Based Ablation and Balloon Pumps endosome, leads to less degradation both of receptor and ligand and in- Stents creases receptor recycling. More im- portant, a ligand designed via molecu- Renal/Respiratory Kidney Dialysis lar engineering (ie, rational design of

Artificial Lungs and Blood Gas Exchange protein-protein interactions), which in- Devices corporates a single amino acid change resulting in a binding affinity below that Tissue/Organ Failure Organ Transplantation; New Materials of epidermal growth factor or transforming growth factor ␣, is a more po- Kidney Dialysis tent ligand.25 This type of cell-level analysis, based Prostheses and Implants (eg, Total Joints) on defining interlinked dynamic pro-

Tissue Engineering Artificial Skin (First Product); Progress in cesses, is now being applied to engi- Cartilage Repair, Bone, Liver, Kidney, Skeletal neer drugs that affect other receptor Muscle, and the Nervous System pathways, such as interleukin 225 and G-protein-coupled receptors.26 The po- Biotechnology and Biomaterials Monoclonal Antibodies and Protein Engineering tential implications for the drug discovery process are profound. Such Vaccines; Gene Therapy analyses and design principles are also being applied to tailor vectors for gene Natural and Synthetic Materials; Biodegradables therapy to increase specificity and ef- Surgery and Rehabilitation ficiency of transfer and to design synthetic molecules to control cell behav- Devices and Procedures Minimally Invasive Surgery (eg, Arthroscopy, iors in tissue engineering.26 Laparoscopy, Endoscopy) Cell- and molecular-level models are

Prostheses and Orthotics; Sensory the building blocks for development of Augmentation and Substitution; New Materials; mathematical models of entire sys- Wheelchair Mobility tems. The advent of powerful comput- ers and graphical interfaces has made possible the development of complex valuable. For example, high-through- ment typically identify compounds that models that span levels from genes to or- put screening assays to identify com- bind with high affinity to a receptor. gan systems, including feedback re- pounds for potential drug develop- Models of the cellular pharmacology of sponses across all these levels.28 Such

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models make it possible to predict how Figure 2. Systems Model of Asthma Physiology a complex, nonlinear, and expensive ex- perimental system (eg, a nonhuman pri- A mate or a human) will respond based on input from cell culture or biochemical assays. In the next 25 years, several large- Mast Cells scale systems modeling efforts at the aca- Antigen Epithelium and Submucosa demic level (eg, the Physiome Project, Eosinophils www.physiome.org), and at the com- Airway Cytokines, mercial level (eg, Physiome Sciences Smooth Basophils Growth Factors, [Princeton, NJ] and Entelos Inc [Menlo Muscle Park, Calif]) will become available. Chemokines For example, a simulation of asthma Sensory Pulmonary Macrophages (FIGURE 2) that relates dynamic changes Nerves Function at the biochemical level (eg, leukotriene production) to functional out- Inflammatory T Cells Edema and comes (eg, the degree of compromised Mediators Mucus breathing in a patient with asthma)28 il- lustrates the utility of this approach. B Cells Endothelial Adhesion Forecast for Research Advances Molecules In the next 25 years, advances in elec- Dendritic tronics, optics, materials, and minia- Cells turization will push development of more sophisticated devices for diagnosis and therapy, such as imaging and virtual surgery. The accelerating pace of development of bioMEMS (biomi- B croelectromechanical systems, integrat- Antagonist-Bound ing electrical, mechanical, and optical ASM CysLT1 systems on a micro scale) and micro- Receptors H CysLT1 fluidic (incorporating microlevel fluid S Antagonist S S pumping, mixing, and reaction cir- + cuits) systems, combined with bioin- ASM CysLT1 Unbound M Endocytosed formatics, will likely give rise to a new Receptor I ASM CysLT1 ASM CysLT1 M era of “lab on a chip” diagnostics, en- Synthesis Rate Receptors Receptors + abling routine and sensitive analysis of Cysteinyl S S S Leukotrienes thousands of molecules simulta- S neously from a single sample. Such H CysLT-Bound ASM CysLT1 analysis might be done on a yearly ba- Degraded ASM Receptors sis in the way cholesterol screening is CysLT1 now done. Receptors A potentially even greater impact of bioengineering will result from the increased ability to incorporate molecular- level information into complex models. The result will be a revolution in A, Overall systems diagram shows the complex interactions between multiple classes of cells and mediators that diagnosis and treatment of diseases affect the response of a patient with asthma to an antigen trigger. The simulation quantitatively relates dynamic ranging from osteoarthritis to Alzhei- changes at the biochemical level to functional outcomes in the patient allowing scientists to predict how small-scale changes, such as in leukotriene production by macrophages (bold pathway), might affect the pulmonary function mer disease. Either by looking for of a patient with asthma.28 B, Molecular-level detail from the large-scale systems model shows the pathways modu- single-signature molecules (eg, can- lating the effect of cysteinyl leukotriene action on airway smooth muscle (ASM) via cysteinyl leukotriene receptor cer antigens) or by using appropriate subtype 1 (CysLT1). Leukotrienes are produced by several cells of the immune system (bold red rectangles in panel A). The nodes (rounded rectangles) and arrows contain specific mathematical functions that describe the relation- algorithms to derive relationships be- ships among system components and enable simulation of the biological system dynamics. Arrow labels categorize tween many interacting molecules, early actions: H indicates half-life; S, change of state; M, moves; I, increases; plus sign (+), stimulates. Reproduced from prediction of onset of disease may be Entelos Asthma PhysioLab by permission from Entelos, Inc ©2001 Entelos, Inc.

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Research Opportunities and Forecast: Biomedical Engineering

Areas of Research Opportunity Forecast

Molecular Engineering Tailored Monoclonal Antibodies and Cytokines for Inflammatory Diseases, Cancer Therapy, Targeted Gene Delivery, and Diagnostics Rational Alteration of Molecular Structure Using Thermodynamic, Kinetic, and Mass Transfer Analysis to Improve Selectivity, Cellular Potency, Distribution Nonviral and Hybrid Viral Gene Therapy Vectors in Target Tissue and Overall Pharmacology; May Involve Combinatorial Production With Rational Assays for Development of Drugs That Target Protein-Protein Interactions Screening Assay

Biomaterials to Control Cell Selection and Cell Proliferation, Migration, and Differentiation for Tissue Engineering and Integration of Devices (Such as Neural Probes) Into Tissues

Cell Engineering Selection, Culture, and Propagation of Stem Cells Design of Cellular Microenvironments In Vitro to Control Cell Proliferation and Differentiation Genetic Transfection Using Quantitative Models of Cellular Response to Multiple Inputs From Matrix and Cytokines; In Vitro Cell-Based Assays for Drug Development Systematic Alteration of Cellular Properties (eg, Adhesion Receptor Expression) to Control Improved Stem-Cell Homing Cell Behavior In Vivo

Engineering and Delivery of Cells for Local Immune Therapy (eg, Delivery of Cytokine to Tumors)

Optimization of Product Production in Large-Scale Culture of Cells to Lower Therapeutic Protein Production Costs

Tissue Engineering Regeneration of Damaged or Diseased Connective Tissue (Bone, Tendon, Cartilage) Construction of 3-Dimensional Tissue, Usually Using a Porous Synthetic Scaffold to Direct Growth Replacement of Metabolic Tissues (Islets, Liver) of Tissue Into Appropriate Structure or to Protect Tissue Immunologically, by Transplanting Cells In Vitro Physiological Models for Drug Development and Study of Disease Processes to From the Patient or Donor, or Directing New Ultimately Replace Animal Studies Growth From Surrounding Healthy Tissue

BioMEMS and Microfluidics Rapid and Sensitive Molecular, Cellular, and Tissue-Based Assays for Laboratory and Home Diagnostics: “Lab on a Chip” Biomicroelectromechanical Systems (BioMEMS) Use Integrated, Electrical, Mechanical, Optical, and Fluidic Systems on a Microscale or Milliscale, Synthesis of New Drug Compounds and High Throughput Drug Screening Assays Typically Microfabricated on a Silicon Chip Manipulations of Single Cells or Small-Cell Populations (eg, for In Vitro Fertilization); Biochemical and Bioassays (eg, Polymerase Chain Reaction, Electrophoresis)

Virtual Surgery and Nanoinstrumentation Surgical Training and Planning and Remote Surgical Procedures Using Interactive Telecommunications and Virtual Reality Simulated Environment Using Interactive Imaging That Enables the User to Remotely Experience Events 3-Dimensionally Endoscopic Applications Using State-of-the-Art Nanoelectromechanical Tools and Devices

Imaging Advances in Resolution and Bandwidth of Magnetic Resonance Imaging and Ultrasound for Real-Time Diagnostics Visualization of Organs, Tissues, and Physiological Processes by X-ray, Nuclear, Magnetic Resonance Imaging, Positron Emission Tomography, and Optical New Developments in Optical Imaging (eg, Optical Coherence Tomography) Modalities

Bioinformatics Analyzing and Interpreting Massive Data Sets From Genomic and Proteomic Assays Databases, Algorithms, and Computational Tools to Enable Analysis and Interpretation of Complex Information

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possible. For example, osteoarthritis each case, new drugs developed with heimer disease, which lacks current might be detected just when cartilage the aid of molecular and cellular engi- therapeutic options, the impact of bio- degradation begins and before dam- neering will likely be available to com- engineering will be extraordinary. age is irreversible; Alzheimer disease bat disease progression. For osteoar- might be detected in early adulthood thritis, these advances would obviate Funding/Support: The Albert and Mary Lasker when it is believed lesions might first the need for joint replacement surgery Foundation provided honoraria to Drs Griffith and form and before cognitive decline. In or even for cell transplantation. For Alz- Grodzinsky for preparation of this article.

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