Patients who won’t take their medications are one of the great frustrations of 21st century doctors. According to The Annals of Internal Medicine, 20-30% of medication prescriptions are never filled, and 50% of medications for chronic disease are not taken as prescribed. The New York Times says this nonadherence to prescribed medication costs the American health care system $100-$289 billion per year.
While many doctors advise making pill-taking a habit (such as tooth brushing), wouldn’t it be easier if patients could just take one pill that released dosages slowly over time? Current swallowable drug delivery systems are problematic because they are composed of tough plastics. These thermoplastics may cause blockages in the gastrointestinal tract and are hard to remove in the event of an adverse reaction to the drug.
A Small Pill to Swallow
Researchers from Brigham & Women’s Hospital, MIT, and the Koch Institute for Integrative Cancer Research have created a new type of drug delivery material that is more biocompatible than thermoplastic. In collaboration with the Bill and Melinda Gates Foundation, they have developed a triggerable tough hydrogel (TTH), strong enough to tolerate the stress of the GI tract and triggerable to dissolve in case of allergic reaction or negative side effects.
Hydrogels are polymer gels that swell when hydrated. When dry, the TTH capsule is small enough to be swallowed. The capsule then expands in the stomach, preventing further passage down the GI tract. Researchers loaded the TTH capsule with the drug lumefantrine and found the device to successfully release the antimalarial in a controlled manner over a period of days.
Making & Breaking Polymer Crosslinks
Traditional hydrogels are too weak to withstand the compressing and shearing forces of the GI environment; to strengthen their delivery device, TTH researchers created a double network hydrogel, composed of two interwoven polymer nets. One network is made of alginate (derived from seaweed); the other of polyacrylamide. When tested, this double network was strong enough to resist fracture, even under pressure from a razor blade.
If the drug needs to be removed, the patient swallows biocompatible antidotes, ethylenediaminetetraacetic acid (EDTA, a food preservative) and glutathione (GSH), which dissolve the crosslinks between the polymer nets.
When tested, the TTH capsules lasted for up to 9 days in the stomachs of large animal models. The next step will be additional pre-clinical studies to test hydrogel safety and stress resistance. Ultimately, researchers hope to find ways to extend capsule life, for dosage release over weeks or months.
July 27th is National Scotch Whisky Day in the United States. Why was today chosen for this particular honor? No one seems to know or care, however, most seem to appreciate the excuse to sample Scotland’s liquid gold.
Scotland takes its whisky production very seriously. Understandably so – aqua vitae pumps nearly £5 billion into the Scottish economy annually. The Scotch Whisky Regulations of 2009 ensure that the quality of that whisky is upheld. Scotch whisky is a chemically complicated drink, containing hundreds of different compounds – the most important flavor compounds are derived from the barley (raw material), the yeast involved in fermentation, and the oak casks used for aging.
The process begins when barley grain is malted; moistened, allowed to germinate, then dry-heated to stop germination. Then, the grain is ground to a grist. Next, malted barley is added to water in a tun and mashed. The mashing process takes place at a range of controlled temperatures allowing the enzymes in the grist to convert starches into sugars; it takes approximately three days to convert the sugar into alcohol. The resulting liquid is called “wort,” generally pronounced in Scottish distilleries as “wert.”
Next, the alcohol is transferred to copper stills. Why copper? It is easy to mold, conducts heat efficiently and is corrosion-resistant. Most importantly, the copper catalyzes chemical reactions which remove highly volatile sulfur compounds and help form the esters that impart a fruity character.
Distillation produces three fractions: the foreshots, which contain acetaldehyde, methanol, and ethyl acetate; the spirit, which will be aged into whisky; and the feints, which contain low volatility compounds like phenols.
For most malt Scotch whisky, the feints and the foreshots are discarded, and the spirit is distilled a second time, while Irish whiskey is distilled three times. However, some Scotch whiskies are two and a fraction or triple distilled. The decision of where to cut the feints is important, or you would lose all the phenolic smokiness of the Islay whiskies.
After distilling, Scotch whisky must age for at least three years; maturation time varies depending on the distillery. Whisky casks are made of European or American oak and have already been used to make bourbon, sherry or port. The type of predecessor liquid influences the flavor of the finished product. Cask size must be less than 185 gallons to ensure the necessary additive, subtractive and interactive reactions between the wood and the whisky. During these reactions, more sulfur compounds are removed, alcohols and aldehydes are oxidized, and acids react with ethanol to create esters. Since the desired concentrations of these reactions only occur at a certain temperature and humidity range, the regulations state that Scotch whisky must be aged within Scotland.
Aging in wooden casks is also what gives whisky its liquid gold appearance. If the melanoidins from the degrading timber don’t brown the whisky sufficiently, caramel is the only additive allowed by the Scotch Whisky Regulations to achieve the expected color.
After the requisite aging, the whisky is bottled. Although the glass is unreactive, the liquid inside is still volatile, and subject to oxidation, reduction and redox reactions (i.e. temperature, sunlight and movement).
How to Drink It
Neat
If you like cereal tones or smoked aroma, drink your malt whisky without diluting it.
Diluted with Room Temperature Water
Adding room temperature water will lessen the ethanol concentration. Some members of the whisky drinking community have asserted this “opens up” the drink, making flavor compounds more available.
With Ice
Adding ice or cold water is controversial. Proponents argue ice reduces the volatility of the flavor compounds; you will smell the flavor compounds less, but you will still taste them. Most whisky drinkers believe that adding ice and lowering the temperature merely ruins the Scotch, interfering with both aroma and taste.
So celebrate at your local pub with a dram (a.k.a. glass of whisky). Oh, and the Scotch Whisky Regulations of 2009 require us to remind you – drink responsibly and never drink and drive. Slàinte mhath!
As children, we learn that to skip a stone across a lake or puddle, we need to have a fairly flat stone. We also learn that a ball thrown at a pool, usually at one’s brother, tends to bury itself into the water rather than skipping. The makers of the Waboba (which stands for ‘water bouncing ball’) have made an interesting use of the viscoelastic nature of polymers to cross the line between a thrown ball and a skipping stone. Look at various videos on-line of the Waboba, and you will see that a thrown Waboba will skip across a flat body of water with equal, or some would say, more enthusiasm than a stone. And it is less painful to catch on the other side.
So how does it work? Unlike balls that are rigid and inflexible, the Waboba will deform and flatten when subjected to a compressive force. When a ball is thrown at a shallow angle into the water, it generates a depression in the water as the entrance force ejects water out of the flat layer. If the ball is inflexible, it will present a small surface area to the backside of the depression in the water, causing the ball to penetrate into the water and eventually sink. A flat stone, on the other hand, presents a larger surface area, allowing the stone to plane on the backside of the water depression and fly out of the depression.
The Waboba enters the water as a spherical ball, but then flattens as the compressive forces generated by the kinetic energy of the thrown ball being counteracted by the resistance of the water. The flattened ball then behaves like the flat stone, and planes out of the water depression. The designers of the Waboba needed to work out the proper range of compressive properties. Interestingly, the harder the ball is thrown into the water, the more it should flatten and hence achieve greater planing behavior.
This important research was conducted 5 years ago by Tadd Truscott, a professor at BYU, who clearly recognized the critical need of explaining why, from strict engineering principles, toys are fun. Videos of Dr. Truscott’s work can be found here, with stills from the video shown below.
Stone entering water, creating depression.
The stone rides up the back of the depression and flies out.
A rigid ball entering the water, creating a depression.
The smaller surface area pushes the ball deeper into the water.
Waboba entering the water, flattening under the compressive force of the ball hitting the back of the water depression.
The Waboba exiting the water depression and resuming its more spherical shape.
It isn’t only Ghostbusters that have to worry about being slimed! Last Friday, chaos ensued when 3,400 kg of hagfish were accidentally deposited on a highway in Oregon.
This slimy traffic accident reminded us of work we performed a few years ago in collaboration with Prof Douglas Fudge on understanding quite what is going on when these animals are disturbed. These evolutionary throwbacks are generally considered the vultures of the deep sea, feeding off carcasses and debris at the bottom of the ocean. Their skin is often used as a faux eel-skin, but to an engineer the most fascinating aspect of this animal is the slime it produces. When attacked, the animal responds by generating copious amounts of slime; although relatively small animals, they can generate gallons of gel almost instantaneously.
It turns out these animals have evolved this spectacular defense based on two physiological components. There are 150-200 slime glands spaced along the body of the animal. In each gland are thread cells of about 150 microns in size, but composed of a single wrapped 1-3 micron filament that is 10 -20 cm long. Along with this cell are high molecular weight mucous glycoproteins in vesicles. These components expand rapidly upon exposure to water; the vesicles provide an elastic gel-like matrix, while the fibers entangle and hold the gel together.
We performed rheology on hagfish glycoproteins in an attempt to understand the assembly and gelation mechanisms (presented at the Society of Rheology in 2003) with evidence of a yield stress and elasticity, and a strong salt influence. In the end though, perhaps the most interesting aspect is the manner in which the hagfish clears itself – it simply ties itself in a knot and “slides” the gel off itself.
We are approaching the 60th anniversary of a very important milestone that coupled the unpresuming plastic industry with the world of kitsch: the development of the pink plastic lawn flamingo. The lawn flamingo was invented by the appropriately and presciently-named Donald Featherstone. Mr. Featherstone, after graduating from the Worcester Art Museum, took a job with a plastic lawn ornament manufacturer in Leominster, MA, a town 1 hour from Cambridge Polymer Group’s headquarters. Leominster has a long history in plastic production, earning the nickname ‘Comb City’ based on its production of celluloid-based combs in the late 1800s. Injection molding also got its start in Leominster, pioneered by Samuel Foster, who made, amongst other items, injection molded sunglasses that go by the name ‘Foster Grants’. Lastly, Leominster can claim to be the home of Tupperware, the happily burping container system still in vogue.
So pink plastic lawn flamingos were a natural fit for Leominster. Fittingly, Mr. Featherstone received an Ig Nobel Prize for his work in 1996, an award that celebrates both invention and humor, with a smattering of sarcasm. As an interesting aside, Mr. Featherstone and his wife wore matching outfits for 35 years; not terribly relevant, but interesting. Although Mr. Featherstone left this mortal coil in 2015, we are comforted knowing the world he left is a bit pinker and more plasticky. The flamingos continue to appear in modern culture and on the bolder homeowner’s lawn. Students at the University of Wisconsin were treated to the sight of over 1000 plastic flamingos adorning Bascom Hill on campus in 1979, courtesy of the student government. This event prompted Madison, WI, home of the UW campus, to name the lawn flamingo its official bird in 2009.
So join the plastics world in thanking Mr. Featherstone for this unassuming but important contribution.
Development of synthetic tissue models has been gaining speed over the past decades as materials, designs, and processing techniques have become more sophisticated. Polyurethane and silicone organ models adorn the desktops of many scientists and physicians, and serve as useful anatomical images and guides. For actual surgical technique development and training, these rigid materials sometimes do not accurately replicate the behavior of biological tissue. Alternative materials, most notably hydrogels, can function well in this role. The highly hydrated nature of hydrogels can give them the feel, elasticity, and cutting behavior of native tissue, and they can often be prepared in form factors that mimic the native organs. CPG has been developing custom tissue models for over 20 years for clients based on its proprietary hydrogel formulations.
Skin is a challenging organ to model, since it has unusual elasticity and frictional behavior when compared to other tissues, such as muscle and fat. Beyond just mechanical behavior, researchers are keenly interested in skin models that help assess biological safety requirements. The standard approach for biological safety is normally an animal model (rat, rabbit), but public resistance to animal testing has pushed for development of non-animal based models. L’Oreal is using additive manufacturing techniques to make films of skin models derived from human keratinocytes, producing a model that is histologically similar to the human epidermis. Intended to allow L’Oreal to test their skin products, the EpiSkin™ model is proposed for tests in involving irritation, UV exposure, DNA damage, and other parameters.
A company local to Boston, MatTek, has also been producing EpiDerm™ skin models for several years by culturing human keratinocytes.
These technologies present an exciting platform for reproducible, clinically-relevant skin testing without the need for animal models.
Are you selecting materials for use in a medical device and feeling overwhelmed by the dizzying array of material options? In this webinar, Dr. Brian Ralston shares the process CPG uses to help clients select and test materials to minimize risk and maximize safety, efficacy, and prospects for regulatory approval.
Brian Ralston, Ph.D., P.E., researches and consults on the analysis and processing of polymeric materials and their physical and chemical behavior in products, with a focus on biomedical devices. His expertise spans numerous analytical methods including mechanical, thermal and chemical characterization, failure analysis, design assessment, fractography, statistics, accelerated aging, and development of novel test methods and fixtures.
This webinar is targeted towards:
Medical device manufacturers
Medical device engineers
Process engineers
Quality engineers
Regulatory personnel
Duration: 30 minutes
Minimizing Risk In Medical Device Material Selection
Ethylene gas, hexane, paraffin wax, and polyethylene all have the same chemical building block, namely an ethylene group (CH2-CH2). The difference in properties in these materials comes from the number of ethylene groups that make up a single molecule. Ethylene gas has a single group (or repeat unit), hexane has 3, and polyethylene can go up in excess of 70,000 repeat units. As the number of repeat units increase, the molecule moves from the idea of a rigid linear rod to a floppy random coil. When placed with other ethylene molecules of comparable size, the chains entangle, which causes the material to transition from a liquid to a solid, as the entangled chains resist disentanglement until sufficient energy, usually in the form of heat, is applied. Some portions of the chains will also align to form crystal structures, which further solidify and rigidify the material.
Although some techniques exist to count the number of repeat units in a material, such as MALDI, molecular weight is normally determined by inferred techniques that look at the size of the individual polymer chain in solution. The size of the chain depends both on its molecular weight and the solvent environment it is placed in (a better solvent and improved temperature will tend to expand the polymer chain more). As shown below, a rigid rod molecule’s size is the number of repeat units multiplied by the length of each repeat units. Most polymers will occupy space as a coil, shown on the right, with a size (the radius of gyration, Rg) dictated by the equation shown below for a good solvent.
Researchers have derived relationships between measured properties of polymer solutions, such as viscosity, light diffraction, and osmotic pressure, to determine molecular weights. These techniques all report a mean value of molecular weight. Most polymers have a distribution of molecular weights, as the polymerization process will yield shorter and longer chains around the nominal desired chain length. Gel permeation chromatography (GPC) is a technique that allows determination of the distribution of molecular weights.
In GPC, a dilute solution of polymeric material is prepared using a good solvent for the polymer. This solution is passed through a chromatography column that contains a porous structure that is sized to allow penetration of smaller polymer chains while excluding the larger ones, which effectively separates the polymer chains by size as they exit the column. A detector (or multiple detectors) measures the quantity of the polymer chains at each elution time, forming a concentration vs. elution time plot. A series of calibration standards are injected through the same column, and the molecular weight vs. elution time is determined. By converting elution time to molecular weight for the unknown sample, a molecular weight distribution plot can be determined. As may have been obvious, the actual molecular weights are not measured; rather, the size of the polymer chains are, with the assumption that the size scales with molecular weight.
CPG provides GPC analysis on a variety of polymer types, including water soluble, organic soluble, high temperature (for polyolefins), and biologic materials. We can also perform testing using viscometry detectors and light scattering.
The normal effects of beer consumption are well known. The ethanol in beer enters the blood stream and eventually makes it to the brain, where the ethanol molecules can sit between brain cells and interfere with neurotransmission, the electrochemical process that controls the activities in the brain, such as body movement, communication, and general thought processes. Too much beer, or ethanol, in a short period of time can interfere with neurotransmission to the point that the imbiber loses control of one or more of these brain processes, leading to classic signs of drunkenness (unsteadiness, impulse control issues, memory lapses, and potential unconsciousness). Excessive drinking for prolonged periods of time can also lead to heart disease, generically termed cardiomyopathy, which is any disease that impairs the ability of the heart to circulate blood effectively.
Heart Disease Spike in Beer Drinkers
A study conducted in 1965 in Quebec and Nebraska of beer drinkers who showed unusually high levels of cardiomyopathy resulted in an unexpected source of drinking-related issues with the heart. In Omaha, Nebraska, in a study of 50 patients, a spike in cardiomyopathy was observed starting in 1964. A similar trend was observed in Quebec around the same time. During interviews, clinicians learned that both sets of patients were frequent beer drinkers, and that each set of patients were drinking the same beer local to their area. The one complicating factor in the Quebec case was that Montreal beer drinkers had access to the same brand of beer, but did not have the spike in cardiomyopathy. Clinicians discovered that breweries in both Omaha and Quebec started adding cobalt sulfate to the beer to stabilize the foam. This practice was employed to counter issues with beer foam dissipation in inadequately cleaned glasses due to poor rinsing of detergent by the bar staff (yet another issue).
Too Much of a Trace Metal
Cobalt is a metal commonly used in alloys, and is also part of the metabolism mechanism in all animals. However, too much cobalt can cause issues, such as interference with the Krebs cycle and aerobic cellular respiration. Studies where guinea pigs were administered cobalt into the myocardium resulted in diminished contractions of the papillary muscle.[1] The clinicians felt that the beer drinkers in Quebec and Omaha were exposed to higher than normal levels of cobalt, which resulted in their cardiomyopathy.
So why the difference between Montreal and the rest of Quebec? For the larger breweries, such as those found in Montreal, separate batches were made for draft beer and bottled beer. Since the bottled beer normally was not put in glasses, no cobalt sulfate was added, hence fewer beer drinkers were exposed to high levels of cobalt sulfate. For smaller breweries, such as those found in Quebec, single batches were made for both draft and bottle, resulting in high levels of cobalt sulfate in both forms of beer. Researchers coined the phrase ‘beer drinkers’ cardiomyopathy’ based on this study.[2] Cobalt sulfate adulteration of beer was discontinued after this study came out.
The durability of plastic materials is both a benefit and a liability. Many plastics can withstand harsh weather, salt spray, ultraviolet light, and mechanical stress for years without visible effect. Unfortunately, this durability also means that when we are done with the plastic, it persists in our waste stream for years, resisting breakdown. A view of any public landfill will show mountains of plastic material. The well-publicized Great Pacific garbage patch, a swirling field of plastic debris estimated at a minimum size of the state of Texas to twice the size of the United States, is the result of years of floating plastic particulate debris accumulating under the influence of ocean currents. Although some photodegradation will occur in some plastics, the debris can persist for decades.
Perhaps the solution to plastic accumulation can be found in the lowly caterpillar. A recent news article suggests that the waxworm, a caterpillar who evolved to consume beeswax as a food source, also appears to digest polyethylene, at least according to one researcher. Waxworms were transported in polyethylene shopping bags, and were able to reduce the bags to shreds in a few hours, with no visible signs of particulate debris. The researchers believe that the polyethylene was being converted to ethylene glycol (e.g. antifreeze), although more data is required. The question is, what are the chemicals or enzymes in the waxworm that allows this process, assuming the observations are correct? If they can be identified, can they be produced and applied on a larger scale to reduce the persistence of plastic debris?
