From the Cover: Wireless power transfer to deep-tissue microimplants

The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less (“microimplants”), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.Progress in semiconductor technology has led to electronic devices that can augment or replace physiological functions; their ability to be implanted for direct interaction with organ systems relies on overall miniaturization of the device for simplified delivery (e.g., via catheter or hypodermic needle) and access to interstitial spaces. Advances over the past few decades enable most components in a biomedical device, including electrodes, oscillators, memory, and wireless communication systems, to be integrated on tiny silicon chips. However, the energy required for electronic function remains substantial and the consumption density has not been matched by existing powering technologies (1). As a result, the vast bulk of most implantable electronic devices consists of energy storage or harvesting components.Although considerable progress has been made in energy storage technologies, batteries remain a major obstacle to miniaturization (2, 3) because their lifetimes are limited and highly constrained by the available volume, requiring periodic surgical replacement once the unit is depleted. Energy-harvesting strategies have been developed to eliminate batteries or to extend their function. Previous demonstrations include thermoelectric (4), piezoelectric (5–7), biopotential (8), or glucose (9, 10) power extraction. However, these methods are anatomically specific and, in their existing forms, yield power densities too low (<0.1 μW/mm²) for a microimplant.Alternatively, energy can be transferred from an external source. Ideally, power transfer should be completely noninvasive and not specific to regions in the body. Most existing approaches for this type of transfer are based on electromagnetic coupling in the near field (11–20). Though well-suited for large devices and prostheses (21, 22), near-field methods do not address key challenges to powering a microimplant: weak coupling between extremely asymmetric source and receiver structures (23), dissipative and heterogeneous tissue (24), and regulatory power thresholds for general safety (25). These challenges, compounded by the intrinsic exponential decay of the near field, severely limit miniaturization beyond superficial depths (>1 cm), even if the battery can be removed.Theory has indicated that these problems can be overcome in the electromagnetic midfield (23): energy transfer in this region, defined to be about a wavelength’s distance from the source, occurs through the coupling between evanescent fields in air and propagating modes in tissue. Using a patterned metal plate to control the near field, we demonstrate milliwatt levels of power transfer to a miniaturized coil deep in heterogeneous tissue (>5 cm), with exposure levels below safety thresholds for humans; this enables us to power a microimplant capable of delivering controlled electrical pulses to nearly anywhere in the body. The device consists of a multiturn coil structure, rectifying circuits for AC/DC power conversion, a silicon-on-insulator integrated circuit (IC) for pulse control, and electrodes, entirely assembled within a 2-mm diameter, 3.5-mm height device small enough to fit inside a catheter. We demonstrate wireless function by operating it in human-scale heart and brain environments, and by wirelessly regulating cardiac rhythm through a chest wall.     

Patellofemoral joint contact forces during activities with high knee flexion

The patellofemoral (PF) joint plays an essential role in knee function, but little is known about the in vivo loading conditions at the joint. We hypothesized that the forces at the PF joint exceed the tibiofemoral (TF) forces during activities with high knee flexion. Motion analysis was performed in two patients with telemetric knee implants during walking, stair climbing, sit‐to‐stand, and squat. TF and PF forces were calculated using a musculoskeletal model, which was validated against the simultaneously measured in vivo TF forces, with mean errors of 10% and 21% for the two subjects. The in vivo peak TF forces of 2.9–3.4 bodyweight (BW) varied little across activities, while the peak PF forces showed significant variability, ranging from less than 1 BW during walking to more than 3 BW during high flexion activities, exceeding the TF forces. Together with previous in vivo measurements at the hip and knee, the PF forces determined here provide evidence that peak forces across these joints reach values of around 3 BW during high flexion activities, also suggesting that the in vivo loading conditions at the knee can only be fully understood if the forces at the TF and the PF joints are considered together. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:408–415, 2012     

Comparison of the effects of leuprorelin acetate and danazol treatments on serum CA-125 levels in women with endometriosis

OBJECTIVE: To investigate the effects of danazol and leuprorelin acetate on CA-125 levels during treatment for endometriosis. PATIENTS AND METHODS: Fifty women with laparoscopically diagnosed and treated endometriosis, and 50 women without pelvic disease as a control group. Following surgical treatment, 35 women with endometriosis were divided into two groups. The first group (20 women) received 200 mg danazol three times daily for 6 months; the second group (15 women) received 3.75 mg leuprorelin acetate depot every 28 days for 6 months. Serum CA-125 levels were measured before medical treatment, during the last 15 days of the 6-month treatment course, and 3 months after treatment. RESULTS: Serum CA-125 levels were significantly higher in women with endometriosis than in women in the control group. Before treatment, CA-125 levels in patients with stage III/IV endometriosis were significantly higher than those in stage I/II endometriosis. Six months of danazol or leuprorelin acetate depot treatment decreased serum CA-125 levels. Three months after stopping danazol, CA-125 levels remained significantly lower than pretreatment levels. On the other hand, 3 months after stopping leuprorelin acetate, CA-125 levels returned to pretreatment levels. CONCLUSIONS: (a) Danazol and leuprorelin acetate are equally effective in the treatment of endometriosis. (b) Moreover, the results support the view that the determination of CA-125 levels may assist in evaluating progress of endometriosis treatment.     

Adolescence and abortion in Greece: women's profile and perceptions

PURPOSE: To investigate the individual and social profile of the adolescents seeking abortion in Greece. PROCEDURES: Questionnaires were distributed from the obstetricians practicing in the capital and two major cities in Greece to adolescent pregnant women who were seeking for abortion and collected anonymously. MAIN FINDINGS: From 150 consecutive pregnant adolescents, 38 refused to participate and from 112 who accepted to participate only 74 (66%) replied. Most of the respondents lived in a city (65%), were unmarried (73%), 62% had sex first time after the age of 15, and the educational status of their parents was rarely at higher degree (father: 20%, mother: 16%). Among them, 74% declared that they had received information on contraception (64% from friends, 47% from doctors, 36% from the media). Overall, withdrawal (49%) and male condom (28.5%) were the popular contraceptive precautions. Abortion was adolescents' decision in 65%, while the partner's influence in the case of a shared decision was as high as 73%. Most adolescents (91%) knew about the potential risks of abortion mainly by their doctor (87%) and socio-economical reasons (89%) were mostly claimed. Their parents were rarely aware about their pregnancy (28%) and decision for abortion (28%). In most cases it was the first abortion (78%) and adolescents declared that were aware about the Greek Church's opposition (89%) and the existence of an abortion law (86%). PRINCIPAL CONCLUSION: In Greece, the poor education on the issue of contraception still remains a major problem among teenagers contributing to the increased prevalence of undesired pregnancies and abortions.     

Do characteristic spermatozoal morphological abnormalities exist in patients who have undergone unilateral orchiectomy and preventive radiotherapy?

DESIGN: We examined 16 men who had been subjected to unilateral orchiectomy owing to seminoma and to preventive radiotherapy, in order to investigate the morphologic abnormalities of the spermatozoa (headless and small-round-headedness) that may contribute to infertility. RESULTS: The same morphologic abnormalities of the head and neck found in the semen samples of fertile men were also found in the semen samples of the patients, albeit in higher percentages; the morphologic abnormalities of the tail in the semen samples of the patients were similar to those of the fertile men, both qualitatively and quantitatively. CONCLUSION: No specifically characteristic morphologic abnormalities of the spermatozoa were detected in men who were subjected to unilateral orchiectomy and to preventive radiotherapy in comparison with fertile men. The percentage rate of morphologic tail abnormalities is not affected by preventive radiotherapy.     

Bone marrow microvascular density and angiogenic growth factors in multiple myeloma.

There is evidence that angiogenesis plays an important role in the progression of multiple myeloma (MM). Hepatocyte growth factor (HGF) and tumor necrosis factor-alpha (TNF-alpha) are cytokines that potently stimulate angiogenesis. We evaluated the microvascular density (MVD) of bone marrow biopsies (after immunostaining with anti-CD34 antibodies) and serum levels of HGF and TNF-alpha in 43 patients with newly diagnosed MM. Twenty-four of these patients reached a plateau phase after treatment and were reevaluated for MVD, HGF and TNF-alpha. MVD values and serum levels of HGF and TNF-alpha were elevated in newly diagnosed MM patients in comparison with healthy controls. Pre-treatment MVD, HGF and TNF-alpha increased with advancing stage of MM disease. In patients reaching the plateau phase, a significant reduction in MVD, HGF and TNF-alpha levels occurred. A positive correlation was noted between pre-treatment MVD and serum levels of TNF-alpha and lactic dehydrogenase but not with HGF. However, HGF strongly correlated with beta2-microglobulin (beta2M), TNF-alpha and lactate dehydrogenase (LDH). We conclude that angiogenesis in MM, as expressed by the bone marrow MVD and the serum levels of angiogenic molecules such as HGF and TNF-alpha, increases with advancing clinical stage and decreases after effective chemotherapy.     

IFATS collection: Adipose stromal cells adopt a proangiogenic phenotype under the influence of hypoxia

Evolving evidence suggests a possible role for adipose stromal cells (ASCs) in adult neovascularization, although the specific cues that stimulate their angiogenic behavior are poorly understood. We evaluated the effect of hypoxia, a central mediator of new blood vessel development within ischemic tissue, on proneovascular ASC functions. Murine ASCs were exposed to normoxia (21% oxygen) or hypoxia (5%, 1% oxygen) for varying lengths of time. Vascular endothelial growth factor (VEGF) secretion by ASCs increased as an inverse function of oxygen tension, with progressively higher VEGF expression at 21%, 5%, and 1% oxygen, respectively. Greater VEGF levels were also associated with longer periods in culture. ASCs were able to migrate towards stromal cell-derived factor (SDF)-1, a chemokine expressed by ischemic tissue, with hypoxia augmenting ASC expression of the SDF-1 receptor (CXCR4) and potentiating ASC migration. In vivo, ASCs demonstrated the capacity to proliferate in response to a hypoxic insult remote from their resident niche, and this was supported by in vitro studies showing increasing ASC proliferation with greater degrees of hypoxia. Hypoxia did not significantly alter the expression of endothelial surface markers by ASCs. However, these cells did assume an endothelial phenotype as evidenced by their ability to tubularize when seeded with differentiated endothelial cells on Matrigel. Taken together, these data suggest that ASCs upregulate their proneovascular activity in response to hypoxia, and may harbor the capacity to home to ischemic tissue and function cooperatively with existing vasculature to promote angiogenesis.