Research

Life of Biomedical Gadgets

Prolonging Life of Biomedical Gadgets by Improving Adhesion with Electrografting

Modern-age humans have found a way to coexist with technology to the point where they have become crucial to life, as in the case of pacemakers, or otherwise made life easier, e.g. artificial limbs, cochlear implants, and smart technology-based wearables. To help ensure longevity of implanted biomedical devices, a scientist from University of Delaware (UD), along with a team of engineers, have developed an electrografting surface modification method that improves adhesion between biological neural tissue and inorganic surfaces.

In order for implanted devices to function properly within the body, successful interface, or communication, between nervous system components (largely directed by the brain) and the mechanical object has to occur. Scientists have been exploring a conjugated polymer called PEDOT, or poly(3,4-ethylenedioxythiophene), for its potential role as the interface. However, in experiments PEDOT was found to have limited adhesive properties to solid substrates, or mechanical devices. As a result, harmful residue can deposit into surrounding tissue, thereby shortening the lifespan of the device.

Adhesion by electrografting surface modification is the solution concocted by the UD scientists. Electrograft is an electrochemical oxidation-reduction reaction by which organic molecules attach to solid conducting substrates by forming a metallorganic bond at the substrate-polymer interface. The conventional process usually takes several steps, but the scientists have created a two-step method that produces a strong PEDOT film that tightly bonds organic tissue to metal objects, while maintaining electrical activity, or communication, between the two components. Another advantage of using electrografts is that a wide variety of materials can be used as the conducting substrate, including gold, platinum, nickel, stainless steel, silicon, metal oxides, and glassy carbon.

With increasing dependence on biotechnology to keep humans alive, extending the life of biomedical gadgets becomes increasingly vital. With enhanced adhesive properties of PEDOT via electrografting, both staying alive and staying alive longer can be achievable.

Curing Malaria

New Synthetic Protein May Be Key to Curing Malaria

Australian scientists at the QIMR Berghofer Medical Research Institute in Brisbane have identified and isolated a protein called PD-L2 that plays a major role in immune system function to help ward off malarial infection. PD-L2 proteins are naturally found on dendritic cells—a form of antigen-presenting cells that initiate a larger immune response by activating T cells—and are thus responsible for T cells attacking pathogens, as well as overriding any ‘stop attack’ signals when the pathogen still exists. The Australian team noticed in severe malaria cases, PD-L2 levels were diminished, and T cells were given ‘stop attack’ signals by dendritic cells, resulting in severe disease. The scientists manufactured a synthetic version of PD-L2, and when tested in mice, revealed curing malaria can be a reality soon.

According to the World Health Organization (WHO), there were 438,000 deaths by malaria last year, and 3.2 billion—half the world’s population—is at risk. Malaria is caused by Plasmodium species, or parasites transmitted through mosquitoes. Malaria is currently treatable and preventable with medications; however, drug resistance is an issue that frequently arises with medications. Even with treatment, malaria can recur without new exposure as the parasite can lie dormant in organs and replicate without alerting the immune system—a factor that has proven difficult for scientists to come up with an effective vaccine.

The scientists infected mice with a large fatal dose of malaria, and they were then administered three doses of synthetic PD-L2. All the mice were cured. Five months later, the same mice were reinfected with malaria-causing parasites, but more doses of PD-L2 were unneeded as the mice did not develop malaria.

The key to curing malaria may not exist in a fancy new drug or even a vaccine but by stimulating our natural immune response to fight harder. More research needs to be conducted before human trials but scientists remain hopeful.

Oral Insulin Patch

Oral Insulin Patch for Diabetes Sufferers on the Horizon

For several years, scientists have been experimenting with oral insulin delivery mechanisms, including the use of liposomes, to shield insulin from being destroyed by gastrointestinal (GI) secretions customarily used to break down food particles into items our body can extract energy from. Hence, subcutaneous injections are thus far the only effective delivery system of the hormone to keep blood glucose levels within normal parameters in diabetics. Contributing to the efforts of creating a needleless insulin delivery system, scientists at University of California, Santa Barbara have developed an oral insulin patch made from mucoadhesive polymers, to help stick to the intestinal wall lining, in addition to being treated with an intestinal permeation enhancer, for better absorption and exposure to the bloodstream, to be encapsulated into a pill with an enteric coating to withstand the corrosive environment of the GI tract.

Once swallowed, the patch is designed to be released from the pill at a designated time and expected to attach to the intestinal wall for superior insulin delivery into the bloodstream. When patch adhesiveness was tested after 30 minutes upon being attached, stickiness was found to be “excellent” based on the force required to pull off the patch. Release of drug was tested on pig and rat intestines, in which 100 percent of the insulin and permeation enhancer was disseminated within five hours.

In animal studies, the scientists found insulin patches with 10 percent permeation enhancers to be the most effective than control groups, dropping blood glucose levels to 70 percent of normal levels.

Studies are ongoing to discover ways to deliver insulin faster as well as prolong the effects of the patch. For diabetic sufferers who cannot rely on oral medications to control their blood sugar levels, an oral insulin patch may be just the ticket to forgoing the daily prick.

ELISA-on-a-Chip

‘Lab-on-a-Chip’ Graduated to ‘ELISA-on-a-Chip’ with the Help of Engineers

Team of engineers and scientists at Rutgers University have developed ‘lab-on-a-chip’ technology to potentially replace expensive conventional benchtop assay laboratory tests—hence, ‘ELISA-on-a-chip’—to aid in diagnosing and treating a wide array of medical conditions, including HIV, Lyme disease, and syphilis.

Enzyme-linked immunosorbent assay (ELISA) is a common “wet-laboratory” technique that uses large amounts of bodily fluids to analyze proteins (antigens or antibodies) to determine its concentration. Apart from requiring a relatively large volume of blood sample, the ELISA method utilizes expensive chemicals and skilled technicians who have to mix the fluids and chemicals by hand, making any diagnostic test run by the technique laborious and costly.

ELISA-on-a-chip uses microfluidics technology that allows the device to use 90 percent less body fluid sample as well as one-tenth the volume of chemicals used to analyze the sample than its traditional counterpart, without compromising the accuracy and sensitivity of the results. One ‘lab-on-a-chip’ can simultaneously analyze 32 samples and measure widely varying concentrations of up to six proteins in a sample.

Apart from cutting costs (chemicals used in a standard multiplex immunoassay runs approximately $1500), animal research that halted due to lack of sufficient sample can now be resumed. A miniscule amount of cerebrospinal fluid is required in comparison to the traditional benchtop assay in order to further study central nervous system disorders, such as Parkinson’s disease and spinal cord injury. Similarly, only small samples of synovial fluid are necessary to delve into possible treatments for autoimmune joint diseases, such as rheumatoid arthritis.

Currently, the research team is exploring potential commercial applications for ELISA-on-a-chip while continually conducting large-scale controlled studies to discover other potential uses of their ‘lab-on-a-chip’ technology.

Direct Conversion Technology

Using Direct Conversion Technology to Transform Blood Cells into Nerve Cells as a Major Prognostic Tool for Neurological Diseases

Blood, skin, and tissue biopsy samples are easily attained for study but not so much from the human nervous system, which is a complex and delicate arrangement of neural wiring. With a new patented direct conversion technology developed by stem cell scientists at McMaster University in Ontario, Canada, blood cells (derived from a simple routine blood draw) can be transformed into neurons. This new advancement has strong implications in determining the likelihood of a patient with a certain disease to develop neurodegenerative disorders, such as diabetic neuropathy, and possibly create better drugs and treatments to combat such debilitating conditions.

The human nervous system has two main branches: the central nervous system (CNS), comprised of the brain and spinal cord, and the peripheral nervous system (PNS)—the rest of the body—which feeds information to the CNS about pain, itchiness, and temperature from nerve receptors from different parts of the body.

Direct conversion technology uses a patient’s blood sample to generate one million sensory nerve cells that serve as a snapshot of that patient’s PNS, and can be used to uniquely predict how the patient’s nerve cells will react and respond to stimuli. The new method can also generate CNS cells as the conversion technology can create neural stem cells as a precursor to the sensory nerves that make up the PNS.

In the future, diabetics can know in advance if they will develop neuropathy characterized by shooting or burning pain in hands and feet, numbness, weakness, or tingling due to PNS damage from an underlying medical condition, e.g. diabetes. A focused treatment tailored to combat pain is key in effectively remedying the condition. Current pain medications, such as opioids, only systemically mask the perception of pain by way of the CNS. With their new direct conversion technology in hand, McMaster scientists plan to target PNS pain without affecting the CNS that can often cause unwanted side effects, such as addictive behavior associated with narcotics use.

Bioengineered ACL

New Bioengineered ACL May Provide Optimal Treatment for Torn ACLs

Researchers at Northwestern University have developed artificial anterior cruciate ligaments, better known as ACLs, to replace torn ligaments—a common sports injury. The bioengineered ACLs are made from braided polyester fibers, which are comparable in tensile strength to the actual ACL, and thus capable of stabilizing the knee.

ACLs connect the femur (thigh bone) to the tibia (the larger of the two leg bones). Once an ACL is ruptured or completely torn, it does not heal, mainly because it’s an intra-articular ligament that’s located within the knee joint. When extra-articular joints are injured, like the medial collateral ligament (MCL), they have the ability to repair itself with rest. A blood clot forms, which serves as the bridge to connect the tear to the bone, and healthy tissue grows to replace the gap. Within the knee joint, any clots that form get washed away with the constant influx of synovial fluid, inhibiting ACLs from being healed.

Conventional treatment for a torn ACL is reconstructive surgery using grafts from the patellar tendon (kneecap). Resulting surgery can cause lasting soreness and tenderness and permanently weaken the patellar tendon. In some cases, the weakened tendon may rupture completely. Even without any major complications and years of physical therapy, natural ease of movement is never fully achieved.

Using rabbit models, the scientists drilled holes into the femur and tibia. Prior to inserting the bioengineered ACL into each receiving end, the fibers were first dipped into a concoction of hydroxyapatite (calcium derivatives naturally found in teeth and bones) nanocrystals and a porous antioxidant biomaterial. Upon anchoring the ends, the rabbits’ nearby bone and tissue cells began to resettle into the pores of the mixture. The researchers hope the ends of the bioengineered ACL can be fully integrated into the femur and tibia given enough time.

The prospect of incorporating an artificial bioengineered ACL to natural bone is promising news for the scientists. However, more studies need to be conducted before human trials begin.

New Migraine Nasal Spray

Treating Chronic Headaches with New Migraine Nasal Spray

Researchers at Roseman University of Health Sciences in Nevada have created a new migraine nasal spray treatment filled with prochlorperazine, which is usually used in tablet form to treat migraines. Other medications that provide migraine relief exist, such as sumatriptan, metoclopramide and ketorolac, but the new prochlorperazine nasal spray is the first anti-migraine nasal spray in its drug class.

According to the Research Migraine Foundation, a migraine is a neurological disorder that is classified as a syndrome—a series of signs and symptoms that stem from a single medical condition—that can manifest as one or all of the following: severe throbbing headache in one or both sides of the head, nausea, vomiting, dizziness, and sensitivity to light and sound. Symptoms may last from four hours to 72 days. Migraines are listed as one of the top 20 most incapacitating chronic medical conditions, affecting 37 million Americans annually.

Chlorperazine is typically used to treat nausea and vertigo by blocking dopamine (D2) receptors in the brain. The scientists claim prochlorperazine works best among the anti-migraine medications, and the nasal spray works faster than the pill analog. The new migraine nasal spray was developed without preservatives, and thus preservative-related adverse allergic reactions and common side effects, like mucosal irritation in response to benzalkonium chloride and potassium sorbate—common preservatives found in nasal sprays—are not expected to be observed.

Utilizing high performance liquid chromatography (HPLC) and microbiological assays, the researchers established the stability of prochlorperazine nasal spray as 120 days with minimal degeneration, thus maintaining drug potency, and a viable treatment option for migraine sufferers.

The research team’s next plan of action for their new migraine nasal spray is to test the safety, efficacy, and pharmacokinetics in rat animal model studies.

Bioreactor-Generated Human Platelets

Bioreactor-Generated Human Platelets Performed In Vitro

Bioreactor-generated human platelets were successfully engineered by scientists at Brigham and Women’s Hospital (BWH) in vitro using a bioreactor—virtually a machine in which a biological reaction or process is achieved on an industrial scale. The platelets are fully functional and disease-free, addressing the worldwide platelet shortage as platelets are difficult to extract from donors and possess a very limited shelf life.

Platelets, similar to the other blood cells, are made in the bone marrow. The microfluidic platelet bioreactor is made to mimic the environment of bone marrow, down to the extracellular matrix composition and blood flow characteristics. Other features, such as bone marrow stiffness and micro-channel size, are simulated by the bioreactor as well. By controlling blood flow and the shear forces emitted by blood turbulence within the bioreactor, platelet initiation greatly rose from 10 percent to 80 percent, leading to the formation of working platelets. The biological process was stabilized within the bioreactor using high resolution live-cell microscopy.

Platelets are required for proper blood clotting and to prevent hemorrhage after a major procedure or treatment. According to the researchers, more than 2.17 million platelet units extracted from donors are administered to patients who are subjected to chemotherapy treatments, surgery, organ transplantation, and those who have sustained major trauma. However, with a shelf life of only five days, risk of contamination and transfusing infected specimens, plus the increased potential of transfusion reactions, platelet demands have risen.

With bioreactor-generated human platelets, the risk of contracting an infection is eliminated and shelf life increased. With an apparatus that resembles the bone marrow setting, artificial platelet generation keeps to the high quality standards of function and safety that exist for blood products, in which the scientists hope to continue to maintain throughout their research until they hit to the market. Phase I clinical human trials are slated to be held in 2017.

Oral Insulin May Be a Future Option for Diabetics

For type 1 diabetics and some type 2 diabetics, insulin injections are a daily requirement to maintain healthy blood glucose levels. Due to fear of needles, adherence to the regimen may be lacking in some diabetics. Indian scientists at the National Institute of Pharmaceutical Education and Research in Punjab may have found a way to manufacture oral insulin as a replacement for its injectable counterpart.

The main barrier to successfully synthesizing oral insulin is that it is degraded in the gastrointestinal tract (GIT) by digestive enzymes before it reaches the bloodstream. Even if the insulin managed to bypass the enzymes, the intestines do not readily absorb the hormone to enter the bloodstream, where it can aid sugar intake by cells to be used as fuel.

To keep orally delivered insulin intact, the scientists loaded the hormone into a liposome—an artificial vesicle (bubble encasing) made of lipids, or fats—which is a known substance in the pharmaceutical industry and thus readily made. The liposome-insulin package is then layered with polyelectrolytes, to form what the researchers call “layersomes,” to protect the bundle from lipid-degrading enzymes in the GIT. Lastly, a folic acid ligand was attached to the layersomes to aid with liposome absorption in the GIT.

When oral insulin in the form of layersomes was fed to rats, the scientists found it was just as effective as insulin injections in lowering blood glucose levels, and that it even lasted longer. With the oral form, the researchers are hoping it can also combat the side effects of insulin injection administered subcutaneously, such as transient hypoglycemia, peripheral hyperinsulinemia, and weight gain, while improving compliance to medication regimen.

More research still needs to be done on layersomes and polyelectrolyte technology to fine-tune them for mass production and public consumption. Nevertheless, oral insulin no longer appears to be a pipedream.

New Type of Antibiotic to Fight MDROs

Since the advent of antibiotics, bacterial infections were no longer considered a death sentence. However, through overuse; microorganisms’ natural defense systems; and, medications’ unimodal mechanism of action, multiple drug-resistant organisms (MDROs) have emerged and are threatening human lives once again. Danish and Canadian scientists from the University of Copenhagen and the University of British Columbia, respectively, have engineered a synthetic peptide called host defense peptidomimetic 4 (HDM-4) that displays broad-spectrum antibacterial properties.

HDM-4 works by creating holes in the cell membrane of a bacterium and binds to the pathogen’s deoxyribonucleic acid (DNA) causing microbial death. HDM-4 also rapidly permeates bacterial cells and attaches to DNA in small lethal concentrations. The original peptide HDM-4 is modeled after is naturally found in animals and plants as part of the innate immune system—the first line of defense against pathogens before antibodies are formed. HDM-4 was found to enhance this immune response for superior pathogenocide.

When tested on bacteria-infested tissue, the synthetic peptide worked effectively against Gram-negative species and interfered with biofilm formation—a sugary bubble that bacteria build to protect themselves enabling them to reproduce and multiply. Due to the many ways HDM-4 goes about killing microbes, drug resistance is suspected to be low, thus hindering the progression of more potent bacteria while efficiently killing MDROs.

The scientists believe the creation of HDM-4 is an important component in developing a new type of antibiotic that prevents MDROs. However, there are barriers to furthering such research as pharmaceutical companies consider drugs for chronic diseases, such as diabetes and cardiovascular disorders, and cancer better long-term investments than the treatment of infectious diseases.

Medical conditions, such as sepsis or “blood poisoning,” can benefit from new medications that can quickly treat life-threatening diseases, albeit further research is required to discover any harmful side effects which require human trials. But, such findings are a crucial step in countering the ever-present war against infectious diseases. Hopefully, there will be champions to take up the cause.