The following is an edited version of the paper, “BioMEMS Technologies for Regenerative Medicine,” published by the Materials Research Society, Warrendale, PA (MRS Symposium Proceedings Vol. 1139, #1139-GG02-01). The paper is available for purchase at www.mrs.org/s_mrs/sec_subscribe.asp?CID=16671&DID=228721&action=detail

The author gratefully acknowledges the support of Draper Laboratory and the Center for Integration of Medicine and Innovative Technology (CIMIT), and technical contributions of Sarah Tao, Joseph Charest, George Engelmayr, Lisa Freed and Chris Bettinger in the preparation of the paper.

The emergence of BioMEMS (BioMicroElectroMechanical Systems) fabrication technologies such as soft lithography, micromolding, assembly of 3D structures, and biodegradable microfluidics, is contributing significantly to the field of regenerative medicine and implantable devices.

BioMEMS devices have evolved from early silicon-based laboratory devices to a broad class of polymer-based structures and even biodegradable constructs suitable for a range of ex vivo (outside the living body) and in vivo (inside the living body) applications. These systems are still in the early stages of development, but the long-term potential of the technology promises to enable breakthroughs in healthcare challenges ranging from the systemic toxicity of drugs to organ shortages. Ex vivo systems for organ assist applications are emerging for the liver, kidney, and lung, and the precision and scalability of BioMEMS fabrication techniques offer the promise of dramatic improvements in device performance and patient outcomes.

Ultimately, the greatest benefit from BioMEMS technologies will be realized through the application of implantable devices and systems. Principal advantages of microscale implantable devices include the extreme levels of achievable miniaturization, integration of multiple functions such as delivery, sensing and closed-loop control, and the ability of precision microscale and nanoscale features to reproduce the cellular microenvironment to sustain long-term functionality of engineered tissues.

Microfluidic delivery systems

Many diseases require repeated administration of drugs over long periods of time, ranging from months to years, with precise control over dose for reasons of safety and efficacy. Further, many conditions represent particular challenges for delivery due to the inaccessibility of the target tissue or organ. For these reasons, fully implantable, self-controlled drug delivery systems are being developed to treat diseases ranging from diabetes and cancer to neurological disorders, vision, and hearing loss. Ideally, these fully implantable systems would be operated in a closed-loop fashion, utilizing data from an indwelling sensor to identify changing conditions and calibrate the dosage accordingly. Even without on-board sensing, these systems represent an extraordinary challenge in terms of overall size and integration of multiple functions, including power, electronic control, communications, drug storage, and the drug-release mechanism itself.

One emerging approach in this arena is a class of microfluidic drug delivery systems, in which a liquid drug formulation is introduced at the site of disease by a micropump according to a previously specified delivery profile. An electrokinetic pump for low-power drug delivery has been developed; it utilizes the electrokinetic effect to eject drugs from an array of microwells. Responsive hydrogels also have been employed as microfluidic drug-delivery systems; these hydrogels can be designed to respond to changes in the environment such as glucose levels, pH or other stimuli to undergo volume expansion. Disposable MEMS-based micropumps have been developed for treatment of diabetes or other conditions. Such systems may contain a permanent electronics module, which is integrated with a disposable reservoir and pump containing a week's supply of insulin.

Microfluidic drug-delivery devices for regeneration of lost sensory or organ function comprise another avenue for implantable systems. One of the principal opportunities in this arena is the treatment of sensorineural hearing loss. The condition affects 28 million Americans and is the most prevalent serious condition at birth, occurring in 3 of every 1,000 births in the United States. Recent advances in molecular biology have identified new targets and compounds potentially capable of restoring function in the hair cells lining the cochlear tubes, but these therapies cannot reach their intended targets through systemic delivery or using currently available delivery approaches.

New research is exploring the use of a microfluidic delivery system that is now partially implantable, but will ultimately be fully implanted within the mastoid cavity, directly introducing drug to the cochlea through a cannula 100 microns in diameter. A next generation system currently in development utilizes microfabricated components comprising layers of laser or micromachined polymers functioning as fluidic capacitors, resistors, valves, and microactuators.

Microelectronic controlled delivery

Microelectronically controlled reservoirs form the basis of a drug delivery system, whose inception was inspired by fabrication technologies used in the semiconductor industry.

Individual reservoirs arranged in a planar two-dimensional array are addressed with a preprogrammed microprocessor and can be integrated with wireless telemetry and closed-loop control with on-board sensors. One of the principal challenges involves the actual mechanism used to burst open each individual well; drugs stored within the well must be hermetically sealed and protected from the in vivo environment until they are released. Numerous techniques for opening wells are possible; the goal is to minimize power consumption and maximize the reliability of the well-opening technique for specific implantable drug delivery and biosensing applications.

Organ-assist devices

Engineered tissue constructs for replacement of organ function remain the ultimate target for the fields of tissue engineering and regenerative medicine. As a bridge to this long-term goal, many demonstrations of BioMEMS-based organ- assist devices have emerged. As is the case for in vitro models for discovery as well as for organ replacement, the principal advantage of these systems is the ability to replicate the microenvironment of tissues and organs.

Advances in renal, hepatic, and pulmonary assist devices have been demonstrated, principally through the use of microfluidics and BioMEMS fabrication techniques that are capable of being scaled up to provide the capacity required for human therapy. Early generations of these technologies may replace existing devices in intensive care units and in the clinic, but ultimately BioMEMS-based approaches will lead to home care and wearable systems expected to improve outcomes and greatly enhance the quality of life for patients.

Liver-assist devices

Current liver-assist systems are used as a bridge to transplantation, and progress in this field has been difficult. Conventional hollow-fiber liver-assist devices have been commercialized and used to treat patients with liver failure, but most patients wait for a cadaveric transplant or split liver graft from a donor. Bioartificial liver (BAL) devices represent an opportunity to treat these patients for extended periods using cultured hepatocytes in a large bioreactor capable of augmenting liver function. In one configuration, a parallel plate BAL device was constructed using plates micromachined with grooves to house hepatocytes while protecting them from excessive shear stresses. The flow rates required for delivery of oxygen to the BAL reactor are high enough to cause hydrodynamic damage to the cultured hepatocytes in a conventional configuration, so hepatocytes are cultured in concentric grooves in a radial flow structure. In this embodiment, the system did not require an oxygen permeable membrane to separate the hepatocytes from the flow, thereby simplifying the system.

Artificial lung devices

Most BioMEMS-based artificial organ devices require the integration of cells with microfabricated scaffolding, and the principal challenges are not engineering-related but rather biological in nature. Principally, developmental barriers for these systems include the source of the cells, which may not be available from patients with end stage organ disease, potential immune reactions with the patient, and challenges associated with maintaining cellular phenotype in an artificial microenvironment. Therefore organ-assist devices that do not require a cellular component are of interest, and microfabricated artificial lung systems represent a particularly significant opportunity.

The surface area for gas exchange in the human lung is roughly 100 m², two orders of magnitude larger than conventional hollow fiber oxygenators, and the surface area to blood volume ratio is at least an order of magnitude larger in the lung than in current ECMO devices. An artificial lung based on MEMS fabrication technology is under development. It uses stacked plates that provide far greater gas exchange area than conventional respiratory-assist devices, using bifurcated microchannel networks carrying blood underneath a thin oxygen-permeable PDMS membrane. Stacks of six layers were constructed and endothelialized (tissue regrowth) to reduce coagulation in the microvascular networks, resulting in high gas permeance values. Another study demonstrated efficient transport of oxygen and carbon dioxide in a microfabricated PDMS artificial lung device. Thin PDMS membranes and thin PDMS-coated porous membranes demonstrated high efficiency transfer of both oxygen and CO₂.

In all these cases, the ability to generate high surface areas for blood contact with oxygen sources moves the respiratory- assist device much closer to the human lung in terms of performance and efficacy.