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CPG research team to develop injectable hydrogel technology for eye tamponade

Cambridge Polymer Group Inc has been awarded a $225,000 Phase 1 Small Business Innovation Research (SBIR) grant by the National Institutes of Health (NIH) to develop an injectable hydrogel for use as an eye tamponade.

Retinal detachment is a common eye injury that often causes vision loss in patients. The surgical procedure requires the temporary removal of the vitreous humor, the clear gel in the eye, prior to reattachment of the retina to the back of the eye. Following the operation, the retina needs to remain in contact with the back of the eye during the healing process, or it may become detached again. Surgeons currently achieve this process by either using a silicone oil, which distorts vision and requires a second surgery to remove, or with a gas bubble, which requires inconvenient head placement for the patient.

As an alternative, Cambridge Polymer Group’s team of hydrogel scientists are developing a hydrogel that can be injected in as liquid through a fine needle or cannula, and then gels in the eye. This hydrogel will assist in keeping the retina attached to the back wall of the eye, and will then degrade over time, obviating the need for a second surgery. The hydrogel should also allow vision through the eye while it is in place, resulting in greater patient mobility and compliance.

Cambridge Polymer Group’s Vice President of Research, Dr. Gavin Braithwaite, is the principal investigator on the research grant. “We are pleased with the opportunity the NIH SBIR program has given us to move our patent-pending technology from the laboratory bench into pre-clinical studies,” stated Dr. Braithwaite. 

For more info, see the press release.

Figure 1: Top right—repeat unit of hyaluronic acid, a material particularly concentrated in (among other tissues) chicken combs (left). Bottom right—representative triplicate determinations of three samples of hyaluronic acid of distinct molecular weights.

Chemical Properties of Hyaluronic Acid

Hyaluronic acid (HA) is a naturally synthesized highly linear polysaccharide found in a variety of tissues including the joint space, vitreous humor, connective tissue, synovial fluid, and even chicken combs (Fig 1 left). Naturally synthesized HA is typically of a very high molecular weight well over 1,000,000 g/mol; it is extremely hydrophilic, highly lubricious, undergoes degradation in response to naturally occurring hyaluronidase enzymes, and binds to a variety of biological receptors. Such properties have driven interest in the use of HA in a variety of applications such as for the treatment of osteoarthritis knee pain, drug delivery/targeting, and tissue engineering.                                                        

In a physiological solution, the HA molecule is understood to exist in a twisted and entangled ribbon structure evolving from a combination of its repeat unit structure, internal hydrogen bonding effects, ionic interactions with the solvent, and its highly linear structure. These properties, in conjunction with the molecular weight of HA, have been shown to strongly affect its functional rheological properties, as has been reported by CPG scientists in the past.[1]

The accurate assessment of HA’s molecular weight therefore is an invaluable tool for applications such as material characterization, stability assessment, delivery behavior, and quality control. However, the same properties which lend to its unique properties also make molecular weight analysis of the material extremely challenging.

Molecular Weight Determination of HA

Polymer molecular weight is commonly determined by gel permeation chromatography (GPC; also known as size exclusion chromatography or SEC). However, due to the polymer’s extremely high intrinsic viscosity, large hydrodynamic volume, slow reptation rate, highly linear structure, and propensity for entanglement effects and shear degradation, analytical conditions must be chosen extremely carefully.

Some key analytical process variables which may dramatically impact measured molecular weights include sample concentration, dissolution time/temperature/agitation, solution handling, sample filtration (or lack thereof), mobile phase selection, injection volumes, flow rate, column selection, and calibration methodology. No conventional molecular weight calibration standards exist which may be used for HA analysis, and as a result, absolute molecular weight analysis by light scattering or triple detection is most commonly performed instead for accurate MW measurement.

CPG has validated an in-house method for the determination of hyaluronic acid molecular weight distributions by triple detection GPC (Fig 1, lower right). Contact us for additional information on this methodology and to see how CPG can work with you. CPG is an ISO 17025 accredited contract research and analytical testing lab based out of Boston, MA.

Patients who won’t take their medications are one of the great frustrations of 21^st 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.

Journal Reference:Nature Communications, doi:10.1038/s41467-017-00144-z

July 27^th 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.