Karen A. Beitler
Rooted in biology, physics, mathematics and chemistry, bioengineering is a new and emerging field of study. The National Institute of Health defines bioengineering as a process which " integrates physical, chemical, or mathematical sciences and engineering principles for the study of biology, medicine, behavior, or health. It advances fundamental concepts, creates knowledge for the molecular to the organ systems levels, and develops innovative biologics, materials, processes, implants, devices, and informatics approaches for the prevention, diagnosis, and treatment of disease, for patient rehabilitation, and for improving health"
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. Biotechnology involves new methods to enhance the quality of life through tissue and integrating cellular engineering; biomaterials and biological signal processing, imaging, instrumentation; biomechanics, integrative biology; transport phenomena, systems analysis and electrophysiology. These technologies provide new and exciting avenue for those with an interest in the medical field and technology.
This paper will explore technology that is still in its infancy but has enormous potential for future generations. The field of transdermal delivery has opened the door to pain free delivery of medication that provides constant continuous release, bypasses the digestive system and minimizes adverse side effects of medications. Transdermal delivery (TDS) is currently FDA approved for approximately twelve different drugs
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. TDS has advantages over oral dosage however molecular size plays key role in whether or not a drug can be administered this way. Tiny spheres and discs smaller than a dime made of polymer micelles that dissolve over time have been inserted into patients with tumors carrying chemotherapy drugs. The field is relatively new and expanding every day. In order to understand transdermal delivery of medication the student will need a thorough understanding of the processes involved for such a system to work. The processes of diffusion and equilibrium in the context of human physiology and drug delivery will be explored.
Diffusion
Diffusion is the process by which molecules move from an area of high concentration to an area of low concentration until they are equal. Diffusion occurs whenever the concentrations of substances are not evenly distributed in an area. The unequal distribution of particles in an area is called a concentration gradient. Molecules will move without an energy input, therefore diffusion is a passive process. This spontaneous movement caused by the excited intermingling of two or more types of molecules or in the case of gases the 'mean free path of collisions" with other atoms or molecules
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. The distance the molecules travel can be measured, therefore the diffusion can be predicted. For solids, diffusion can be thought of as a mass moving through a path in another mass; the size of the pathway can be measured, again the diffusion can be predicted with some degree of accuracy.
Diffusion in liquids, however, causes a problem. There is not an adequate model for liquids because of convection. Convection is the molecular movement caused by fluid motion. Convection can be caused by heat, which introduces differences in fluid density or gravity Earth's gravity acts on a liquid keeping it in motion, this motion gets confused in the calculation of movement of particles. Particles are in constant random movement that results in the absorption of heat from the surrounding area. The more that is absorbed the faster the particle moves. All that thermal heat makes it difficult to know if the exchange of the particles is only from diffusion or if it is enhanced by thermal motion. Think of a teabag placed in a cup of hot water, is the tea diffusing through the liquid by itself passively or does the temperature of the water add to the rate of diffusion? We all know that diffusion in heated substances happens more quickly. We can mix the powdered cocoa into warm water a lot faster than into cold water. Even in the absence of increased temperature; gravity causes enough friction between molecules to make the measurement of liquid diffusion difficult. The random motion of the particles drives diffusion, molecules tend to move away from their highest concentration and molecules of different types tend to intermix. Liquid diffusion can best be measured under no gravity situations.
Diffusion is the process of movement of particles; osmosis is diffusion of water molecules. Water or any other molecule will move across a membrane, passively, until they reach a state of equilibrium. Diffusion depends on the diffusion area, the concentration gradient of the substance moving, and a constant known as the diffusion coefficient (also known as permeability
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. No energy is required or released.
Equilibrium
The cell is a highly organized structure that maintains a dynamic equilibrium. Dynamic equilibrium is defined as a condition in which "the parts of a system are in continuous motion, but they move in opposing directions at equal rates so that the system as a whole does not change"
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.
The driving force for passive transport across a membrane is the energy of a difference in concentration of molecules; the difference between the numbers of particles inside as compared to the number outside. This energy is defined as the electrochemical gradient and is the sum of chemical and electrical energy. Both cations and anions will continue to equilibrate themselves from the intracellular fluid across a membrane until their overall chemical and electrical gradients are in balance. There will be a small net charge across the membrane, inside negative, that resists the tendency of any ions to move back down their concentration gradient. This is called the Donnan equilibrium and is naturally occurring in all cells because their membranes are semi-permeable
(6).
Because molecules carry different charges and are of differing molecular size; cells can reach a resting potential where inter and extra cellular components are approximately equal. Scientists can take advantage of this when designing drug delivery systems; the flow of molecules is from the higher concentration to the target area.
Membrane Structure and Function
Lipids and proteins make up most cell membranes, although carbohydrates can be present too. Phospholipids are the type of lipids often found in cellular membranes; they contain hydrophilic (water-loving) and hydrophobic (water-fearing) ends, as do most membrane proteins. The current model that represents a cell membrane is called the fluid mosaic model.
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.
This model shows a fluid structure made of various proteins in bilayer of phospholipids. The proteins are thought to drift rapidly and laterally within the double layer of phospholipids. It is thought that the cytoskeleton of the cell regulates the speed and direction of movement of the proteins in the phospholipids bilayer. A membrane remains fluid until temperature decreases and the phospholipids solidify according to the amount of saturated hydrocarbons in their hydrophobic tails. Just as bacon grease solidifies into lard; the fluidity of the membrane decreases as temperature decreases
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.
The structure of the membrane of the cell results in selective permeability; many molecules in a high level of organization determine what will enter into and exit from a cell. Many small molecules and ions move across the plasma membrane of a cell. Oxygen, sugars, amino acids and other nutrients enter the cell and metabolic wastes leave all at differing rates. Hydrophobic molecules can dissolve in and across the lipid bilayer. Polar and hydrophilic ions are impeded by the hydrophobic core. Other molecules, sugars and water pass slowly, some use transport proteins to pass through the membrane. The permeability of a cell's membrane is determined by the selective double layer of phospholipids, channel proteins that facilitate molecule crossing and temperature. The direction of traffic across a membrane is determined by other factors.
Diffusion of molecules across a cell membrane is a spontaneous process regulated by thermal motion (heat energy) and concentration of particles
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. When no other forces exist molecules will diffuse down their concentration gradient, unaffected by other molecules until they reach equilibrium, this is called passive transport. Rates of diffusion will vary dependent on molecular size.
The diffusion of water molecules across a semi-permeable membrane creates a phenomenon called osmosis. The Life Science Dictionary from Northwestern University defines osmosis as "bulk flow of water through a semipermeable membrane into another aqueous compartment containing solute at a higher concentration"
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.
The ability of the cell to gain or lose water is known as its tonicity
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. Tonicity is crucial to living organisms and is determined by osmosis. Animal cells have special adaptations of osmoregulation to control water balance and keep a cell from becoming hypertonic or hypotonic. Hypertonic solutions contain a higher concentration of solute than intercellular content. This causes and outflow of water and shrinkage of the cell.
Hypotonic cells can become overfilled with water, they can swell and burst because osmosis of water is to the inside of the cell due to a low solute concentration in the water. Water balance and electrolyte (salts, minerals, nutrients) balance in cells are closely linked. An organism's body will work to keep the total amount of water and the levels of electrolytes in the bloodstream in equilibrium. When the level of a salt becomes too high, thirst develops, leading to an increased intake of liquid. In response to thirst, a hormone is secreted by the brain that causes the kidneys to excrete less urine. An increased amount of water in the bloodstream is the result; the salt is diluted and the equilibrium is restored. When salt levels become too low, the kidneys will excrete more urine, decreasing the amount of water in the bloodstream.
Diffusion and drug delivery in Human Physiology
The form and function of an animal are described as its physiology. Animal cell, tissues, organs and systems are organized in a hierarchy of complexity. Cells that are alike perform a specific function as do tissues that are similar. The organization is specific to the function. For example, the skin is responsible for regulation of body temperature, protection, sensation, excretion, and immunity. Its cells are specifically permeable to allow exchange of molecules, thus the skin is said to breathe. The skin is also a blood reservoir and synthesizes Vitamin D
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. This system is made up of cells that are similar and perform together to carry out these specific functions. Controlled delivery of a drug can occur when scientists mimic a natural system so the cell thinks it is taking in one of its own parts.
The integumentary system includes the body's largest organ, called the skin. It is made up of many components and two basic layers; the epidermis and the dermis. The outer layer and thinnest component of the skin is the epidermis.
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. the second layer is called the dermis. The epidermis has no primary blood supply; capillary loops extend up from the dermis to supply it with blood and oxygen.
The thin epidermis has three basic layers; the stratum corneum, a granular layer and a basal layer. This layer varies in thickness from 0.04 mm on the eyelids to 1.6 mm on the palms, of the hand
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. The stratum corneum and is made of two types of cells. Keratinocytes die and flatten into tightly packed layers, 15 layers thick.
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. and melanocytes produce the skin's pigmentation and provide ultraviolet protection. The layers are held together by lipid cells called the lamellae. Within the keratinocytes are lamellar granules, small organs that grow in number as the cells mature. The entire surface is covered by a layer of protein and then a layer of lipids. All this is less than 20 um wide. The stratum corneum is constantly shedding, it contains protein called keratin. Keratin is formed from dead keratinocytes and protects the skin. Keratin gives the skin a leather-like feel and waterproof quality.
The next layer called the granular layer contains the most numerous cells. These layers of squalors cells, known as living keratinocytes, form the protective layer of skin. As they grow older, these cells are called corneocytes and form the stratum corneum. This layer can also contain cells called Langerhans cells that regulate T cells in an immunological response and Merkel cells that response to outside stimuli are also found here
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. Merkel cells connect to nerve endings in the epidermis to the dermis, thereby communication is established. Beneath the keratinocytes lies the basal layer, it is the inner most layer of the epidermis. The cells of the basal layer of the epidermis continually divide and reproduce to replenish the outer layers.
The dermis is the middle layer of skin. This is where the hair follicles, oil glands, fat cells and lymph and blood vessels are found. The dermis is held together by a protein called collagen and is made of fibrocytes. The dermis gives strength and resilience to this large organ. The dermis is composed of living cells, tiny muscle fiber attached to hair follicles, sensory neurons, blood vessels and glands. Oil is produced here to soften the skin and sweat to cool it. Below the dermis is a network of collagen and fat cells, known as the subcutaneous layer. These cells are the energy reserves, the shock-absorbers and the insulators for the body.
The epidermis is replaced approximately every 39 days, with 13 days in proliferation, 13 days for the maturation of the keratinocytes, and 13 days for stratum corneum transit
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. The balance maintained between the making keratinocytes and production corneocytes is tightly regulated. As the cells mature they are replaced to develop an effective skin barrier. The skin's integrity is maintained by the constant regeneration and repair activities of the dermal layer.
Diffusion and Drug Delivery
In the past drug delivery has been mostly oral. Herbal or plant remedies were made by the local 'expert' to accompany ceremony and ancient acupuncture. The ancient Greeks considered illness to be a part of life and treated it with "diet, baths, fomentations and gruel"
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. Jewish and later Arabic medical school passed on the knowledge of what worked and what did not; surgeries and herbs were joined by" casts, cauterization, venesection "treatment of wound and began using chemicals and distillation to enhance oral medication.
In the ninth through thirteenth centuries medicine flourished at the school of Salerno is Italy; graduated students called themselves doctor, the learned one
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. Many avenues were explored in the Renaissance and anatomy of the human body was mapped. Anatomy lead to questions about physiology and blood was found to move in a circle. Medical training became more prevalent and continues today. As researchers have learned more about the human body, they have sought ways to combat the maladies that besiege it.
Early physicians used a variety of ways to give their patients medications. Types of drug delivery are ever-expanding as we grow in knowledge about the human body. There are five basic types of drug delivery system available today. They are outlined in Table 1.
This paper will brief explain the advantages and disadvantages of each, with a focus on transdermal delivery systems.
Table 1 - Types of Drug Delivery
(table available in print form)
For over 4,000 years physicians have treated disease and injury with pills, topical remedies and various other applications
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. After a description of the circulatory system was explained and accepted, physicians began to inject medicine into the skin. In 1884 the modern hypodermic syringe was developed and intravenous injection was developed.
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. Intravenous delivery was quick and efficient because drugs did not get filtered through the digestive system. Dose regulation was difficult to determine, however, and it was an uncomfortable procedure that needed a specialist to deliver. The risk of infection was high when the skin was punctured. Intravenous drugs needed to be monitored, this causes inconvenience and discomfort for the patient, physicians sought to control drug delivery in other ways. Topical medication was developed, but it only is effective with certain drugs and specific conditions, Buccal or sublingual medications were found to be very effective, but also limited to certain drugs and specific conditions. Scientist sought systems that controlled drug dosage, were convenient for patient and physician and caused minimal discomfort.
With the development of polymers other system of drug delivery were developed, Polymers are long sequences of molecules of one or more species of atoms or groups of atoms linked to each other to each other by primary, usually covalent bonds
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. Transdermal drug delivery systems (TDS) were developed that came into direct contact with the stratum corneum and utilize diffusion to get past this layer and dispense their product into the system. There have been several designs of transdermal systems that generally consist of a membrane or reservoir to contain the drug and a means of attachment to the skin. TDS have advantages over oral dosages of medication. The patient doesn't need to remember to take a dose at a certain time, the amount of medication can be regulated and delivery is constant.
There are two types of transdermal systems; matrix and reservoir and two types of matrix systems; monolithic and adhesive
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. Reservoir systems deliver medication at a more constant rate. They are made of three layers; a non-permeable backing, a drug reservoir and a membrane surface that controls the rate of drug delivery (see Figure A). The matrix systems differ in that the drug in a monolithic system is contained in a rate-controlling matrix as opposed to being in the adhesive layer, both have an impermeable backing (Figures B & C)
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. The molecular structure of the drug and the polymer used to house the drug are important. Systems are designed with a particular molecular structure in mind, this helps control the distribution of the drug as it diffuses through the system. Matrix systems have the drug uniformly distributed throughout the layer. This system also must take into account the molecular structure of the drug to insure proper diffusion into the body.
Changes in the environment can affect the polymer. A change in pH causes a swelling in the polymer and release of the drug. A change in ionic strength or the type of chemical present; can be used to change the content in the matrix and allow release of the drug at different rates.
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Testing for different structure of polymer includes a series of amendments to be sure the system will perform under differing conditions. The design of the transdermal system is fairly simple. However the confidence and efficiency of the system is more complex when considering the intricacies of designing systems that are non-toxic, small, reliable, and do not provoke an immune response.
Transdermal Drug Delivery Systems
Figure A
(image available in print form)
Figure B
(image available in print form)
Figure C
(image available in print form)
Some natural systems release enzymes -- in this case drugs can be released when the enzyme is present it will work on the polymer, causing it to release the drug. Magnetic or electrical fields can be applied to cause swelling in polymer that drugs are encased in and release of medication over time. A change in temperature can have an effect on polymers as seen in ultrasound irradiation where temperature increase causes release of the medicine from the polymer
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. Not all the research has been done and there are exciting fields opening up in the discovery of how a body will react to certain types of molecules. As we explore these fields we learn more about how our body systems work and we are discovering new ways to target and deliver specific medication to shrink tumors, cure disease, and enhance peoples lives as they age.
The major disadvantage of TDS systems is that is only suitable for drugs of a specific molecular size. As new biomaterials are developed and the ability of materials to biodegrade or change their ability to be absorbed by the body improves, drug delivery systems will change again. Biomaterials have two major advantages over non-biodegradable material; they do not elicit immune response from the organism and some can regenerate healthy tissue
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. The field of reconstruction of injured, diseased, or aged tissues is a promising field of study.
Scientists have found that drugs encapsulated in microscopic pouches made of layers of phospholipids can 'fool' the body. These are called pouches are called liposomes and are made up of many layers
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. Liposomes help shield healthy cells from drug toxicity because their phospholipids are identical to those that make up cell membranes. One side of the liposomes is hydrophilic and the outside is hydrophobic. In this way liposome mimic cell membranes and can fuse into the bilayers there by delivering drugs (or genes in the case of gene therapy) to the inside of the cell or delivery drugs by phagocytosis. Polymer matrices allow bioactive agents to diffuse through the pores of the polymer system and into the target cell area.
The future may show us controlled drug delivery systems that are implanted in the body to deliver drugs at a constant rate to a specific site and may be controlled by the bodies own natural release of enzymes. An increase or decrease in temperature or pH, magnetic, electrical and ultrasound are also being explored to help release medication to a targeted site
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. Polymers are being developed to work within a persons system to deliver the agents they need. New biomaterials are being tested to possibly line organs, mimic biological systems, and serve as chemical reactors or as medium for cell growth
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. Aerosol drug delivery is currently being tested; microspheres and other polymers are in clinical trials. Tissues engineering is yet another field that has grown out of a need to deliver remedies to precise locations. The discovery and use of transdermal systems have set biomedical engineers on a path that holds great promise for the future in medicine.
Biomedical engineering and biotechnology are emerging fields. There is much to learn about the human body and the $6 million dollars worth of chemicals it has in various interdependent reactions each second of the day
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. New careers fields are ever-expanding and discoveries are being made daily. Research in to the biotechnological or biomedical fields will reveal a surprising number of enterprises students can explore. The medical field has branched out past the traditional doctor and nurse, students can explore specializations of the traditional fields that deal with patient care or they can look to the growing field of research and laboratories. Imaging a future where you are scanned, diagnosed, medicated and cured in a matter of minutes. Doctor's roles are changing as the field of biomedical technology is growing. Student research into this subject for possible career selection is important to their futures and ours.
