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Microbotics – miniature machines and molecular motors open new vistas for medicine
Microbotics (or micro-robotics) is a term that describes the emerging field of intelligent, miniaturized robotics. Biomedical microbotics offers a glimpse of a future where tiny, untethered devices (smaller than 1 mm in size) are inserted into patients via natural orifices or through extremely small incisions. Thereafter, they navigate autonomously through the bloodstream or inside fluids such as the vitreous humour in the eye cavity, targeting areas of interest with extreme precision.
Microbots aid medical professionals in earlier diagnosis and more effective treatment of diseases, delivering drugs to targets in the body, removing plaque deposits in the arteries or excising and repairing tissue at cellular levels – which are too small for direct manipulation.
One of the most exciting possibilities offered by medical microbotics is to enable wholly new therapies which have yet to be conceived, simply because of the lack of small, precision-access equipment.
MEMS and MST
Biomedical microbotics seeks to combine established techniques of robotics such as motion control, path planning, remote operation and sensor fusion with new tools enabled by miniaturized MEMS (Micro-Electro-Mechanical-Systems) technology, as it was known in the US; the European equivalent was micro-systems technology (MST).
Microbots are one outcome of the rapid growth in microcontroller capabilities in the 1990s, alongside the appearance of MEMS and development of high-efficiency Wi-Fi connections. MEMS, used for example in airbag sensors, opened the way for low-cost, low power consumption applications, while Wi-Fi allowed microbots to communicate and coordinate with other microbots.
Apart from coping with challenges on power and stretching the limits of material science, considerable research has also recently been focused on microbot communication. A good example of this is a 1,024 microbot swarm’ at Harvard University which spontaneously’ assembles itself into various shapes.
First endoscopic capsules date to mid-1990s
One of the first medical applications of microbotic technology was in the gastro-intestinal (GI) tract. The microbotic intervention in the mid-1990s, by an Italian team, was published in the book Sensors and Microsystems’ (World Scientific Publishing Co, Singapore, 1996) and consisted of endoscopic capsules which were simply swallowed by the patient. They captured video images as they moved naturally through the GI tract using in-built imaging and illumination systems.
In 2012, the U.S Food and Drug Administration (FDA) authorized a much smaller swallowable technology, namely a single-square-millimeter silicon circuit embedded inside a pharmaceutical pill, and produced by Proteus Digital Health.
Other researchers have proposed robotic systems with autonomous locomotion and biopsy capabilities. Some are tested, with models already on the market.
Sequel to MIS
In many senses, medical microbotics is a natural sequel to minimally invasive surgery (MIS), which has, since the 1980s, represented one of the key developments in medical technology. MIS resulted in a leap in patient recovery time and a sharp reduction in trauma.
Microbotics is expected to go even further, into what seems eerily close to the realms of science fiction.
From microgrippers to artificial bacteria
For example, researchers at Johns Hopkins University in Baltimore have developed microgrippers, The arms’ of these star-shaped devices, less than a millimeter in size from one tip to another, are temperature-sensitive grippers and react when exposed to body heat.
In sufficient numbers, they provide a less-invasive way to screen for colon cancer than a colonoscopy – which currently requires taking dozens of samples with forceps.
Moreover, when required, the arms can be closed around tissue, thereby performing what is effectively an automated biopsy.
One of the most dramatic demonstrations of microbotic miniaturization is at the Swiss Federal Institute of Technology in Zurich (ETH Zurich), where artificial bacterial flagella (ABF), about half as long as the thickness of a human hair, have been developed (See also page 23).
In initial experiments, ETH Zurich researchers have already made the ABFs transport polystyrene micro-spheres.
3D printing converges with miniaturization
New 3D printing technologies are now converging with miniaturization to open other frontiers for microbotics.
For example, the Nanoengineering Department at the University of California, San Diego (UCSD) have created 3D printed microbots in the form of a small fish (microfish), for sensing and detoxifying toxins. The microfish, with dimensions of just 120 x 30 microns, are designed for testing in applications such as directed drug delivery and microbot-assisted surgery.
UCSD researchers added a polymer nanoparticle (polydiacetylene) to capture pore-forming toxins, such as those found in the venoms of sea anemones, honeybees and spiders, in order to establish that the microfish could be both detoxification systems and toxin sensors. When the nanoparticles bound with toxin molecules, they became fluorescent and emitted red-coloured light, whose intensity correlated to their detoxification abilities.
Key design and engineering challenges
Technologically, key challenges faced by microbotics include design issues for in-vivo applications. The microbots need to be small and reliable, and equipped with all necessary tools and sub-systems on board. They must be inserted into, steered and removed from the target area of a patient’s body, non-invasively.
All this means a high degree of integration. MEMS devices were traditionally designed as components for insertion into larger electro-mechanical systems, along with physical interfacing for power supply and data input-output. In contrast, sub-millimetre sized medical microrobots must be manufactured in their final, operational and deployable form.
One emerging technology which seeks to address such challenges is known as Hybrid MEMS. It seeks to combine individual MEMS components through a robotic micro-assembly process, which brings together different manufacturing technologies such as lithography, nanosystems LIGA, Micro-Opto-Electro-Mechanical Systems (MOEMS) and 3D printing.
Materials and power
Apart from these kind of structural and miniaturization issues, other challenges of a robotic operation at microscopic scale consists of biocompatibility and power. The former has sought to be addressed with new generation MIS and implantable systems. However, few could underestimate the constraints of working in the human body – not only in terms of tracking precisely where a microbot is (especially in the vicinity of vital organs), but also making sure that it is neither toxic nor poses a threat of injuring tissue, while ensuring that it degrades safely or exits the body after completing its mission.
A key condition for effectiveness, therefore, is that microbots must have similar softness’ as biological tissues. This is where the difference with traditional robots is most stark. Rather than cogwheels and cranes, pistons and levers, designers of microbots are inspired by the tentacles of an octopus.
The provision of power for moving the microbot, gathering/transferring useful information and taking interventional action when necessary, is even more challenging. Microbots can use a small lightweight battery source or scavenge power from the surrounding environment in the form of vibration or light energy.
The Proteus ingestible pill authorized by the FDA in 2012 contains two electrode materials which become electrically connected when the circuitry comes into contact with the stomach’s gastric juice. For 5 or 10 minutes, the chip has enough power to modulate a current, transmitting a unique identifier code that can be picked up by an external skin patch.
An alternative to an on-board battery is to power the robots using externally induced power. Examples include the use of ex-vivo electromagnetic fields, ultrasound and light to activate and control micro robots. Researchers are now also focusing efforts on wireless power transfer, such as using radio waves from outside the body to generate electricity. However, this approach too faces limitations at small scales. To be effective, a microbot would need an antenna, which needs to be large enough to collect a meaningful amount of energy and also stay fairly close to the source.
Magnetic actuation
Magnetic actuation technology has been applied in biological systems for several years, in areas such as targeted drug delivery where magnetized carrier particles coated with chemical agents are concentrated on specific target regions of the body using external magnetic fields. Magnetic beads of a few microns diameter have also been successfully steered inside cells to manipulate individual DNA molecules.
At the UC San Diego 3D printed microbots project referred to above, the microfish are powered by nanoparticles with hydrogen peroxide being the power source, while magnets provide steering.
Molecular motors
Some experiments have focused on using molecular motors for microbots. These molecular motors are the sensing and actuation systems ubiquitous in biological systems. They have been adapted over millions of years and play vital roles in processes such as cell motility, organelle movement, virus transport.
From a practical viewpoint, interest in such molecular machines for the next generation of hybrid biomotor sensing and actuation systems will be driven by biomedicine as well as related applications such as microfluidics (e.g for nano-propellors) and chemical sensing.
Nevertheless, despite some signs of progress, the use of molecular motors in hybrid living-synthetic engineered systems remains several years away.
Artificial bacterial flagella (ABF)
The bulk of research into biological motors as power sources are focused on F1-ATPase and artificial bacterial flagella (ABF).
ABFs are manufactured through a Hybrid MEMS process by vapour-depositing several ultra-thin layers of indium, gallium, arsenic and chromium onto a substrate, followed by ribbon patterning using lithography and etching. The ribbons curl into a spiral once they are detached from the substrate, due to differences in the molecular lattice structures of the various layers.
The size of the spiral, and the scrolling direction of the ribbon, can be determined in advance. The latter is due to the presence of nickel in the head’ of the microbot. Nickel is soft-magnetic, in contrast to the other (non-magnetic) materials used, and enables the spiral-shaped ABF to move forward/backward as well as upward/downward within a rotating magnetic field generated by several coils, towards which the head constantly tries to orientate itself and in whose direction it moves. Steering the ABF to a specific target is achieved by adjusting the strength and direction of the rotating magnetic field.
Nevertheless, the precise placement of microbots is crucial in order to avoid a clinician’s nightmare – to place something solid in the blood, and trigger clots. Even ultra-sophisticated microbots which can follow a change in temperature, may not be able to fight the powerful currents in the bloodstream.
Europe is playing a major role in microbotics, with ETH Zurich considered a world leader in the field. One of its first biomedical microbots aims at ophthalmic operations on the retina. Drugs to treat the retina can now be injected into the eye, where they diffuse. However, only a fraction of the dose reaches its target. Microbots could potentially deliver drugs in a more targeted manner, reducing doses as well as side effects.
Ten years on: the impact of human papilloma virus vaccine
Globally HPV is still the most frequent sexually transmitted virus. Certain genotypes cause virtually all cases of cervical cancer, a disease which kills over a quarter of a million women per annum, as well as causing morbidity and mortality from anogenital and oropharyngeal disease in both genders. However back in October 2005 it was reported that Phase III trials, involving twelve thousand women in thirteen countries, had demonstrated that Merck’s quadrivalent HPV vaccine, Gardisil, was 100% effective in preventing pre-malignant cervical lesions. This vaccine, genetically engineered in Brisbane and first licenced for use in public health programmes in Australia, the US, Mexico, Gabon and Europe a decade ago, targets HPV genotypes 6/11 as well as HPV16/18. The former low-risk genotypes cause 90% of anogenital wart infections; it is estimated that the latter high-risk genotypes are responsible for 70% of cervical cancers and 80% to 90% of other HPV-related neoplasms including anal, penile and oropharyngeal cancers. Other vaccines, all of which target the high-risk genotypes HPV 16/18, are now in use. The most recently approved also includes the less common oncogenic genotypes 31/33/45/52/58. HPV vaccine is now approved for use in 129 countries. So after a decade what has been the impact on health from the more than 205 million doses of HPV vaccine that have been distributed worldwide?
The beneficial effect is particularly apparent in countries where there is a high uptake of girls who are vaccinated before they become sexually active. Both infections with HPV and genital warts have plummeted by 90%, with a reduction of 85% in high-grade cervical abnormalities. Data reporting lower numbers of cervical cancer cases post-vaccine will surely follow. The bad news is that the full potential of the vaccine has yet to be realized. Only 64 countries actually include HPV vaccination in their national immunization schedules, and the less developed nations are less likely than the West to have effective programmes that require three timed inoculations and high population coverage. In developed countries such as the US imprudent parents still refuse the vaccine because of possible safety concerns or more bizarrely because they think it will encourage sexual promiscuity in their offspring. However the good news is that in China, which has 28% of the global cervical cancer cases but a particularly cumbersome drug approval process, HPV vaccine has finally been approved and will be available in 2017. Surely a fitting memorial to the late Chinese co-inventor of the initial vaccine, Dr Jian Zhou!
Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study
Bernardi D. et al. The Lancet Oncology. 2016 Aug;17(8):1105-1113
Background
Breast tomosynthesis (pseudo-3D mammography) improves breast cancer detection when added to 2D mammography. In this study, we examined whether integrating 3D mammography with either standard 2D mammography acquisitions or with synthetic 2D images (reconstructed from 3D mammography) would detect more cases of breast cancer than 2D mammography alone, to potentially reduce the radiation burden from the combination of 2D plus 3D acquisitions.
Findings
Between May 31, 2013, and May 29, 2015, 10 255 women were invited to participate, of whom 9672 agreed to participate and were screened. In these 9672 participants (median age 58 years [IQR 53-63]), screening detected 90 cases of breast cancer, including 74 invasive breast cancers, in 85 women (five women had bilateral breast cancer). To account for these bilateral cancers in cancer detection rate estimates, the number of screens used for analysis was 9677. Both 2D-3D mammography (cancer detection rate 8.5 per 1000 screens [82 cancers detected in 9677 screens]; 95% CI 6.7-10.5) and 2D synthetic-3D mammography (8.8 per 1000 [85 in 9677]; 7.0-10.8) had significantly higher rates of breast cancer detection than 2D mammography alone (6.3 per 1000 [61 in 9677], 4.8-8.1; p<0.0001 for both comparisons). The cancer detection rate did not differ significantly between 2D-3D mammography and 2D synthetic-3D mammography (p=0.58). Compared with 2D mammography alone, the incremental cancer detection rate from 2D-3D mammography was 2.2 per 1000 screens (95% CI 1.2-3.3) and that from 2D synthetic-3D mammography was 2.5 per 1000 (1.4-3.8). Compared with the proportion of false-positive recalls from 2D mammography alone (328 of 9587 participants not found to have cancer at assessment) [3.42%; 95% CI 3.07-3.80]), false-positive recall was significantly higher for 2D-3D mammography (381 of 9587 [3.97%; 3.59-4.38], p=0.00063) and for 2D synthetic-3D mammography (427 of 9587 [4.45%; 4.05-4.89], p<0.0001).
Interpretation
Integration of 3D mammography (2D-3D or 2D synthetic-3D) detected more cases of breast cancer than 2D mammography alone, but increased the percentage of false-positive recalls in sequential screen-reading. These results should be considered in the context of the trade-off between benefits and harms inherent in population breast cancer screening, including that significantly increased breast cancer detection from integrating 3D mammography into screening has the potential to augment screening benefit and also possibly
contribute to overdiagnosis.
Cardiovascular disease – more attention required for women
Cardiovascular disease (CVD) is by far the leading cause of death in industrial countries. However, there are significant differences by continent/region, and even more so in terms of gender. There have also been some major recent changes in the evolution of CVD, compared to another major source of mortality – cancer. Once again here, there are some female-specific factors of interest.
The US and Europe
For Europe as a whole, latest figures from the World Health Organization (WHO) show CVD accounting for 45percent of deaths, approximately the same level as the US, where the figure is 44percent.
Cancer is the second largest cause of death in both the US and Europe. However, a significant margin separates its mortality impact from CVD.
There are also differences between the US and Europe in the relative impact of CVD versus cancer. In the former, cancer accounts for 32percent of deaths (or almost three-fourths of that from CVD). In Europe, the share of cancer is less than half CVD deaths. The WHO data cover 52 countries in Europe, including all members of the European Union (EU).
A man’s illness ?
Traditionally, heart disease was thought of as a man’s’ illness, although approximately the same number of women and men died each year of heart disease in the US and the EU.
Indeed, gender issues in CVD deaths are significant, both in the US and Europe. Although a higher number of males die in the US from CVD as compared to females, the share of CVD as a cause of death is only slightly higher in American women (44.3percent vs. 43.4percent).
In Europe, the gap is far more dramatic, with CVD accounting for 51percent of deaths among women and 42percent among men.
Cancer replaces CVD as leading cause of death in northern/western Europe
There are nevertheless considerable divergences across European countries in CVD mortality as well as in recent changes in death rates due to CVD.
In ten advanced EU countries, more men now die from cancer than CVD. These countries are Belgium, Denmark, France, Italy, Luxembourg, the Netherlands, Portugal, Slovenia, Spain, and the UK. The case is the same for an EU non-member, Norway. Conversely, the highest numbers of deaths from CVD tend to be seen in Eastern European countries.
In much of Europe, however, latest WHO data show more than double the number of deaths from CVD compared with cancer, in women. 15 countries in this group report CVD causing more than four times the number of deaths in women as cancer, compared to only 6 for men.
Meanwhile, death rates from CVD have declined in all countries over the past ten years. However, in some countries, women have seen a relatively lower fall than men in age standardized mortality rates, over the period. These include Luxembourg (50percent for men vs. 42percent for women), the Netherlands (39percent vs. 32percent) and Sweden (31percent vs. 26percent), and to some extent Ireland, Italy and Switzerland.
Raising awareness
One immediate priority for health professionals and policy makers is to raise awareness about CVD and women. Currently, Red Day’, Go Red for Women’ and Women at Heart’ campaigns by professional societies and patient groups in the US and Europe have sought to boost awareness further, and do this faster.
The reasons for this are evident. In the US, just over half of women surveyed recognize heart disease as their Number 1 killer, according to a 12-year follow-up study published in 2010 in Circulation: Cardiovascular Quality Outcomes’.
Nevertheless, the situation had improved significantly compared to the baseline year of 1997 when only 30 percent identified heart disease as the leading killer of women, with 35 percent believing that cancer took this role.
The situation is worse in parts of Europe. In Ireland, for example, a recent Irish Heart Foundation report showed that less than one in 5 Irish women knew CVD as being the leading cause of female mortality.
CVD protection in younger women
The reasons for believing CVD was a man’s’ disease (as mentioned above) were not simply hearsay. Women are protected by their hormones against CVD during their child-bearing years. However, this protection is lost as soon as they enter menopause. The net result is that women tend to get CVD at an age about 10 years more than men.
To complicate matters, CVD symptoms in women are sometimes different from those in men. This adds to under-recognition of heart disease in women. For example, heart attack symptoms in women such as chest pain can be less profound than in men. Women may only feel an uncomfortable pressure in the chest centre which occurs sporadically or lasts a few minutes, or experience pain in one or both arms, their neck, back or stomach, along with shortness of breath and accompanied by a cold sweat, nausea, vertigo and weakness. Moreover, it has also been established that women have a higher prevalence of silent ischemia and of unrecognized myocardial infarction than men.
As a result, both women and physicians need to be trained to recognize female-specific symptoms.
HRT and CVD risks
One of the beliefs which has endured for several decades is that the estrogen drop during menopausal transition induces increased post-menopausal CVD risk in women, probably through harmful changes in CVD risk factors. One of the findings supporting this conclusion was that women who reached menopause before the age of 40 had a two-year lower life expectancy than women with a normal or late menopause.
Indeed, circulating estrogens do have a regulating effect on several metabolic factors, such as lipids, inflammatory markers, and the coagulation system.
This was the reason for the popularity of Hormone Replacement Therapy (HRT), or exogenous estrogens. Until recently, HRT was recommended for use in post-menopausal women to limit CVD risk. The hypothesis was supported by several observational studies, but could not be conclusively proved in large randomized trials. Instead, HRT was shown to increase CVD event rate in older (>60 years) post-menopausal women. As a result, clinicians now recommend a careful evaluation of the risk/benefit of HRT replacement for preventing CVD, and the use of HRT has declined.
Concurrent risk factors for women
Other, concurrent risk factors include hypertension, hypercholesterolemia, hypertriglyceridemia and metabolic syndrome. These increase in women over the age of 45, or a few years before menopause.
For example, systolic blood pressure rises steeply in older women compared with men. Hypertension is associated strongly with a higher prevalence of left ventricular hypertrophy and diastolic heart failure (HF). Studies have shown that even borderline hypertension (less than 14/9 cm Hg) causes more cardiovascular complications in females than in men.
At younger age, the prevalence of hypercholesterolemia is lower in women than men, but at over 65 years age, mean LDL-cholesterol levels are higher in women. Hypertriglyceridemia and low HDL-C levels are far more important risk factors for CVD in women than for men, as discussed below.
Type 2 Diabetes
Nevertheless, of the biggest areas of concern is Type 2 diabetes mellitus, which poses a much higher greater risk for cardiovascular complications in women than in men.
One meta-analysis of 37 prospective cohort studies published in the British Medical Journal’ in December 2006 found mortality risk to be 50percent higher in women with diabetes compared with men. In addition, it has been shown that Type 2 diabetes is a potent, independent risk factor for heart failure in women. However, this cannot be fully explained by coexisting cardiovascular risk factors or previous myocardial infarctions.
Lifestyle factors
Lifestyle changes also play a role. Obesity, for example, is a major CVD risk factor. It is more prevalent in men under the age of 45, but has begun to increase with advancing age in women, reducing the gap with time, and often reversing it in older women. This was one of the findings of a report called European Heart Health Strategy: Red Alert on Women’s Hearts’, published in 2009 by the EuroHeart Project, funded by the EU Commission and conducted jointly by the European Heart Network (EHN) and the European Society of Cardiology (ESC).
Women and clinical trials
The case of HRT, where findings from large randomized trials reversed those of observational studies, has brought another priority to the forefront, namely to increase the presence of women in CVD clinical trials.
The EU-funded EuroHeart project (see above) found women to be under-represented in many trials, even where important gender differences are present within most areas of heart disease. The proportion of women enrolled was 27-41percent, even though the female prevalence of clinical conditions under study in the general population was similar for both men and women.
The case in the US is similar, in spite of a legal requirement that research funded by tax receipts must include women and minority groups. One study found that trials by the National Heart Lung and Blood Institute, attached to the National Institutes of Health (NIH), enrolled 38percent women for the years 1965-1998. This fell further to 27percent in 1997-2006. Furthermore, only 13 of 19 studies analysed gender differences.
Apart from the traditional belief that CVD was a man’s’ disease, some experts believe that cost may also have been a consideration in under-recruitment of women, whose hormonal fluctuations tend to complicate pharmacokinetic and pharmacodynamic analysis.
Nevertheless, given the growing burden of CVD in middle-aged women relative to men, it is evident that greater gender-specific cardiovascular research is required to adapt existing guidelines for better cardiovascular health in women.
Pregnancy as stress test for future CVD
There is intriguing evidence that pregnancy might be a useful stress-test’ for future CVD risk. Hypertensive disorders in pregnancy have been shown to be predictors for CVD events in later life. Impaired glucose tolerance and gestational diabetes in pregnancy are also female-specific risk factors for the development of diabetes and metabolic syndrome in young women.
One of the conditions under close scrutiny is pre-eclampsia, which is characterized by high blood pressure and large amounts of protein in the urine. Although the etiology of pre-eclampsia has yet to be established with certainty, the hyperlipidemia of normal pregnancy (elevated total cholesterol and triglycerides) becomes more extreme in women developing the condition. The sharp growth in triglycerides leads to increased production of LDL (up to 3-4 times more than in a normal’ pregnancy), along with reduced HDL-C. Together, this contributes to endothelial dysfunction.
One ongoing trial at Brigham and Women’s Hospital in Massachusetts seeks to demonstrate an association between pre-eclampsia during pregnancy and altered blood vessel function and abnormal hormone levels in later life. The trial, known as Preeclampsia: A Marker for Future Cardiovascular Risk in Women’ commenced in 2012. Its results are expected to be published in the near future.
