Karen Daniel

Application of Micro- and Nano-Electromechanical Devices to Drug Delivery

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an “artificial pancreas” implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.

Continuous Intravesical Lidocaine Treatment for Interstitial Cystitis/Bladder Pain Syndrome: Safety and Efficacy of a New Drug Delivery Device

Interstitial cystitis/bladder pain syndrome patients tolerate and experience symptomatic relief from a bladder-borne device that provides continuous lidocaine delivery. Special Delivery In her painting Los Dos Fridas, Frida Kahlo depicts two versions of herself: one healthy and one after the bus crash that left her in pain for the rest of her life. People who suffer from chronic pain can relate, often dividing their lives into two halves–one before the pain and one after chronic pain changed everything. Now, through the use of a clever drug delivery device, Nickel et al. offer some hope of relief for millions of women who suffer from chronic interstitial cystitis (bladder pain syndrome) (IC/BPS). A chronic urological condition, IC/BPS is characterized by debilitating bladder pain, urinary urgency, and frequent voiding. Because oral therapies offer little to no symptomatic relief, physicians have attempted to deliver the local anesthetic lidocaine directly into the bladder. However, although this localized treatment gave some immediate relief, the drug is diluted or voided from the bladder within 1 hour, making repeat procedures necessary to control symptoms. A previous attempt to design an in-bladder device with sustained drug release failed because patients could not tolerate the discomfort caused by the device, likely because of its large size (10 to 15 cm). In the new work, Nickel et al. report the design of a new, smaller, water-permeable device that contains solid lidocaine minitablets that are dissolved over time by water from the urine. The decrease in device size was made possible by using solid-state drug rather than drug in solution. The second lumen of the new device carried a nickel titanium wire that assumed a bladder-retentive pretzel form once inside the bladder. A phase 1 safety-assessment trial of empty devices in healthy volunteers showed high retention and tolerability. Subsequent phase 1b studies were conducted in women with moderate to severe IC/BPS, and treatment with the drug-loaded device showed clinically meaningful reductions in pain, urgency, voiding frequency, and disease questionnaires. In cystoscopic examinations, five of six patients showed resolution of bladder lesions. Follow-up after device removal revealed that pain reduction persisted for several months, allowing the patients a chance to feel like their healthy selves once again. Limited treatment options exist for patients who suffer from a painful bladder condition known as interstitial cystitis/bladder pain syndrome (IC/BPS). Whether given systemically (orally) or by short-duration (1 to 2 hours) exposure via intravesical instillation, therapeutic agents have exhibited poor efficacy because their concentrations in the bladder are low. A previous attempt to develop a drug delivery device for use in the bladder was unsuccessful, likely as a result of poor tolerability. A continuous lidocaine-releasing intravesical system (LiRIS) was designed to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. The 16 women with IC/BPS who were enrolled in the study met the National Institute of Diabetes and Digestive and Kidney Diseases criteria for bladder hemorrhages or Hunner’s lesions. Subjects received either LiRIS 200 mg or LiRIS 650 mg for 2 weeks. Safety, efficacy, cystoscopic appearance of the bladder, and limited pharmacokinetic data were collected. Both doses were well tolerated, and clinically meaningful reductions were seen in pain, urgency, voiding frequency, and disease questionnaires. Cystoscopic examinations showed improvement on day 14 (day of removal) compared with day 1, including resolution of Hunner’s lesions in five of six subjects with baseline lesions. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed.

Implantable diagnostic device for cancer monitoring

Biopsies provide required information to diagnose cancer but, because of their invasiveness, they are difficult to use for managing cancer therapy. The ability to repeatedly sample the local environment for tumor biomarker, chemotherapeutic agent, and tumor metabolite concentrations could improve early detection of metastasis and personalized therapy. Here we describe an implantable diagnostic device that senses the local in vivo environment. This device, which could be left behind during biopsy, uses a semi-permeable membrane to contain nanoparticle magnetic relaxation switches. A cell line secreting a model cancer biomarker produced ectopic tumors in mice. The transverse relaxation time (T(2)) of devices in tumor-bearing mice was 20+/-10% lower than devices in control mice after 1 day by magnetic resonance imaging (p<0.01). Short term applications for this device are numerous, including verification of successful tumor resection. This may represent the first continuous monitoring device for soluble cancer biomarkers in vivo.

Multi-reservoir device for detecting a soluble cancer biomarker

By combining the sensing capabilities of nanoscale magnetic relaxation switches (MRS) within multi-reservoir structures, a potentially powerful implantable multiplexed sensor has been developed. MRS are magnetic nanoparticles that decrease the transverse relaxation time (T(2)) of water in the presence of an analyte. The switches encased in polydimethylsiloxane (PDMS) devices with polycarbonate membranes (10 nm pores) have demonstrated in vitro sensing of the beta subunit of human chorionic gonadotrophin (hCG-beta), which is elevated in testicular and ovarian cancer. Devices showed transverse relaxation time (T(2)) shortening by magnetic resonance imaging (MRI) when incubated in analyte solutions of 0.5 to 5 microg hCG-beta mL(-1). The decrease in T(2) was between 9% and 27% (compared to control devices) after approximately 28 h. This prototype device is an important first step in developing an implantable sensor for detecting soluble cancer biomarkers in vivo.

Micro- and nano-electro mechanical (MEMS and NEMS)-based technologies for implanted biomedical devices

The next generation of implantable biomedical devices based on micro- and nano-electro-mechanical systems (MEMS and NEMS) technology is presented for diagnostics and treatment of chronic and non-chronic illnesses. These passive and active implantable devices allow for early diagnostics as well as timely and precisely controlled therapeutic drug delivery. The implantable devices are also applicable to a number of medical applications, including the next generation of early cancer diagnostics and treatments.