Micro- and Nanotechnology and the Aging Spine

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67 Micro- and Nanotechnology and the Aging Spine

Introduction

In the United States by the year 2000, approximately 20% of all Americans were older than 65. Twelve percent were older than 85. With an aging population, a higher proportion of the elderly seek orthopedic treatment, due to the prevalence of musculoskeletal complaints. Currently, 25% of orthopedic patients are 65 and older. The Census Bureau projects that the 65 and older population will double from 33 million to 65 million by 2030, while the younger age groups will remain the same. Physicians will be faced with a greater number of individuals who are experiencing intellectual failure, immobility, instability, incontinence, insomnia, degenerative musculoskeletal disorders, and iatrogenic problems.

The aging process presents a cascade of events that affect the health of the musculoskeletal system, in particular, the human spine. The maximum bone mineral density of an individual is reached between the ages of 18 to 20 years of age. As aging progresses, muscle size and strength begin to decrease, by as early as age 25. Accompanying these changes are reductions in hormone levels for both men and women, contributing to a decline in bone density and muscular strength. As we age, the musculoskeletal system experiences degenerative changes resulting in fibrosis, stiffening, and shrinkage of the soft tissue; bone loss; joint changes; and tissue desiccation due to a reduction in proteoglycans and a change in collagen type (i.e., intervertebral disc).10 With respect to the aging spine, this fibrosis and stiffening reduces the osmotic properties of the disc and the ability of the disc to obtain and/or maintain vital nutrients while eliminating noxious wastes. Disc desiccation initiates a cascade of progressive degenerative events leading to loss of disc height, degenerative facets, and compression of the neural structures resulting in pain. The degenerative process continues as the discs of the spine undergo these arthritic bony changes, resulting in altered loading patterns on the spine, further enhancing the patient’s pain and neurological deficits.

As a result, the elder population suffers from a variety of degenerative disorders afflicting the spine, such as osteoporosis, degenerative disc disease, compromised facet joints, spondylotic myelopathies, and stenosis, all resulting in pain and loss of motion. However, the longer life expectancies and increased levels of activity at a much later stage in life place greater demands on the spine and musculoskeletal system. Over the last decade, there has been a surge in orthopedic implant development and spinal arthroplasty devices to preserve or restore long-term joint motion.

As the overall life expectancy continues to increase worldwide, the need for improved medical care increases and is expected to continue as the baby boom generation crosses into the senior phase of their lives. With continued development of novel medical technologies and a changing health care environment, microinvasive technological advancements in medicine continue to progress, especially within the orthopedic and neurosurgical arena, where a new generation of medicine is evolving.

Smart technology or “smart systems” are terms used to define systems that are capable of imitating human intelligence. A smart system with respect to medical devices is a system that can automatically sense and respond to a changing environment once implanted into the human body. Smart technologies employ smart microsensors that can sense minuscule changes in pH, chemistry, stress, strain, pressures, and temperatures; smart materials that change their properties in response to a particular stimulus; microelectromechanical technologies that can sense and respond at the cellular level; and nanoelectromechanical technologies that behave at the molecular level.

With respect to the aging spine, the ability to sense adverse changes in vivo and manipulate cells and molecules presents the possibility of promising treatments for debilitating diseases and musculoskeletal disorders. Smart materials that have the ability to repair and reorganize human tissue and eventually allow for an engineered material and scaffold to be substituted by newly regenerated tissue provide an attractive solution for implant and tissue longevity. Such novel materials should be capable of nonlinear responses to imitate the mechanics of living tissue. Smart biosensors and tooling can lend to improved surgical techniques and patient outcomes. The incorporation of micro- or nanotechnology into spinal implants and surgical tooling can enhance surgical accuracy; provide precision cutting techniques for microsurgery with minuscule tissue damage; manipulate cellular and subcellular structures; develop genetic engineering clinical strategies; monitor and respond to tissue-targeting feedback; and create biosensors that can provide the surgeon with real-time, continuous biofeedback with respect to implant performance during the lifespan of the applied treatment. Smart materials with preprogrammed porosities can function as biological sieves for implantable drug delivery systems, controlled differentiated tissue growth, and disease barriers. Finally, ultra-small tweezers that are of nanosize allow for manipulation of molecules to change the course of a disease.

The areas in which such interventions may become clinically applicable in the aging spine include nuclear regeneration and replacement technologies, neural regeneration, localized delivery of pharmaceuticals such as bone morphogenetic proteins for localized and controlled bone growth, delivery of antibiotics and pain medications for long-term steady-state delivery, and monitoring of implant lifespan. Nucleus regeneration may involve the employment of semipermeable membranes that allow specific cells or humoral agents to pass into a disc space that spur and nurture the regeneration process. Neural regeneration techniques must not only overcome the humoral stimulation barriers required to induce regeneration, they must overcome physical barriers and the complexity of the nervous system involving complex synaptic connections that are poorly understood. MEMS/NEMS and polymer technologies can be utilized to create textured surfaces that facilitate neural growth, while grids and tubes that can be electrically stimulated can be used for orienting neuronal growth.

Spinal Etiologies12,13,21

Degenerative Disc and Congenital Disorders

The normal aging process results in degenerative disorders due to normal wear and tear of the joints and soft tissues. Although the process of aging results in disc desiccation, facet degeneration, osteophyte formation, and a cascade of mechanical and chemical events that lead to degenerative conditions that cause pain and neurological changes, the ability of the body to heal the tissues still occurs, although at a slower rate with progressive aging.

Arthritis affects approximately 80% of people over the age of 55 in the United States.1,12 It is often triggered by injury, a weakened immune system, and/or hereditary factors. Symptoms include inflammation, joint pain, and progressive deterioration of joint surfaces over time which may result in anatomical changes of the joint surface, and edema inside the joint accompanied by tissue debris. This condition demonstrates mechanical instability in the joint related to the wearing away of the cartilage that is responsible for friction-free motion of the joint. The debris causes an inflammatory response that can induce bone overgrowth and osteophyte formation that eventually interferes with joint mobility. Rheumatoid arthritis is a progressive form of arthritis that can be painfully destructive and may cause the interior joint tissues to swell and thicken, resulting in joint disintegration and eventual significant deformity.

Osteophytes or bone spurs are visible indications of a changing mechanical environment and are often found in areas affected by arthritis such as the disc or joint spaces where cartilage has deteriorated. The formation of osteophytes is the body’s attempt to halt the motion of the arthritic joint and deal with the degenerative process, but often causes impingement on the surrounding nerve roots.

Ankylosing spondylitis is a chronic hereitable disease characterized by progressive inflammation of the spine with early sacroiliac joint involvement, followed by hardening of the anulus fibrosus and surrounding connective tissue and arthritic changes in the facet joints.5; 6 The disease eventually results in a loss of segmental mobility and “stiffening” of the spinal tissues.

Osteoporosis

Osteoporosis is defined as the loss of bone mass and density due to a loss of calcium exchange, which significantly compromises the strength of the vertebral body.1 It is often detected during the later stages of bone loss and will weaken the mechanical integrity of the spinal column. Deformities may develop as the vertebral segments lose a great deal of the cancellous structure, and eventually lead to compression and crush fracture resulting in a kyphotic posture. Loss of bone strength may cause spontaneous fractures to occur, in which the patient’s own body weight alone may cause vertebrae to collapse leading to compressed nerves.

Nanomedicine and the Aging Spine

Bionanotechnology is the merging of biology with nanotechnology (performs at the molecular level) by incorporating fabricated nanostructured materials and electronics into a living biological environment with functions that will diagnose and respond therapeutically. This term also applies to biomicrotechnology, which incorporates microstructured materials (performs at the cellular level) and electronics into a living environment. The application of these technologies in a clinical environment has been termed nanomedicine. Microelectromechanical systems (MEMS) and nanoelectromechanical systems (NEMS) are microsized systems capable of performing biological tasks at the cellular or molecular level and are deemed “smart technologies.” The specific application of micro or nanobiotechnology to develop micro/nanosized medical devices will revolutionize medicine with the potential to regenerate tissue, restore mobility, and increase the longevity of spinal implantation, as well as improve the quality of life and activity levels for the aging population.

Drug Delivery Therapies7,19

Over the last few decades, considerable advances have been made toward drug delivery technologies. However, considerable challenges still exist. The continuous release of therapeutic agents over extended time periods following a preprogrammed temporal profile, local delivery of the drug at a constant rate to the diseased microenvironment to overcome systemic toxicity, improved ease of administration, increased patient compliance, minimized risk of side effects, reduced hospital stay, and independent application all pose significant challenges to the effectiveness of the delivered pharmaceutical. Injected or ingested drugs follow first-order kinetics with high blood levels of the drug immediately after initial dosing, followed by an exponential decay in blood concentration. The rapid rise in the drug can lead to toxicity, and the efficacy of the drug is diminished as the drug levels fall exponentially. A continuous drug release profile in a controlled manner for maintaining blood levels is an optimal release design. Currently, most controlled drug delivery systems are transdermal and subcutaneous in nature, with current research, focused on the development of implantable systems that will deliver therapeutic agents in a steady state manner, well underway. The treatment of certain diseases such as osteoporosis and arthritis that require the chronic administration of drugs could benefit from the presence of implantable devices. These devices have the capabilities to provide localized continuous delivery to the physiological site. The benefits of implantable drug delivery systems include the reduction of side effects with improved feedback in a manner that mimics the physiological release profiles of the immune system.

Micro and nanoengineered delivery devices have the potential to improve drug delivery. Numerous materials that were once injected are now capable of being inhaled or swallowed through novel nanodelivery devices, thus improving patient compliance. However, the issues with fluctuating blood levels and drug maintenance still exist. Therefore, a variety of microfabricated devices such as microparticles, microneedles, microchips, nanoporous membranes, and micropumps have been employed in the development of drug delivery systems for the goal of long-term implantation. In essence, this is analogous to the behavior of the immune system. MEMS and NEMS have provided an alternative to current means of drug delivery. The technology allows for systems to be employed that will ease application of the drug and reduce the pain of delivery for injectable drugs. Microneedles of accurate, repeatable micron dimensions have been precisely designed in arrays with reproducible lumen dimensions that pierce tissue allowing for delivery of the drug in a localized manner, yet are small enough to avoid pain and significant tissue damage (Figure 67-1). Human nerves are insensitive to micro- or nanoscale needles, making microneedle arrays for drug delivery ideal for the elderly patient with fragile skin. Implantable nano-channeled needles for drug delivery can provide improvement of control and optimization of pharmocodynamics, by maintaining prolonged steady state of the drug performance and reducing the blood level fluctuation potential and toxicity risks associated with conventional drug delivery. The drug release rates can be accurately modeled and predicted due to the reproducibility of the microneedles.7 Eventually, these systems will be externally controlled by telemetric means where a small drug delivery “chip” is implanted directly to the diseased site and the chemical environment monitored and pharmaceutical agents delivered in response to a change in the chemistry, thus serving both as a diagnostic tool and therapeutic agent for diseased tissue.

image

FIGURE 67-1 Microscope image shows an array of hollow microneedles that are approximately 1000 microns tall next to a hypodermic needle typical of those now used to inject drugs and vaccines.

(Images from Google image, Microneedles. From Mark Prausnitz, Georgia Tech’s School of Chemical and Biomolecular Engineering.)

Nanopore technology has been implemented in the development of microfabricated nanoporous membranes that are biologically, thermally, chemically, and mechanically stable once implanted into tissue and are also ideal for drug delivery systems and molecular sieves. These membranes are ideal biological sieves that have uniform pore size and very low thickness, making them ideally suited for drug delivery due to the ability of the membranes to have controlled diffusion and sustained release. The pore size, pore length, and pore density can all be highly controlled and serve as ideal diffusion barriers. A drug reservoir can also be fitted to the device for sustained delivery to the tissues.7,19

Micro- and Nanoscale Smart Polymer Technologies

There are numerous types of smart polymers or polymers that exhibit a sharp phase transition from hydrophilic to hydrophobic in response to an environmental stimulus such as pH, temperature, pressure, or strain. Numerous applications exist for these smart polymers or stimuli-responsive polymers, such as drug delivery and drug targeting systems, biodetectors, biosensors, and artificial muscles. Smart polymers are macromolecules capable of undergoing rapid, reversible phase transitions from a hydrophilic to a hydrophobic phase and are thermodynamic systems that undergo a phase transition for a certain range of parameters such as pressure, temperature, and pH.8,1518,20 Furthermore, there are protein-based polymers that will adhere to surrounding tissue or behave as a barrier to scar tissue, as well as polymers that are electroactive in nature whose properties change drastically upon change of stimulus. Additionally, polymers that respond differently to changing mechanical properties such as strain rates have numerous potential uses in the musculoskeletal system in terms of replacement devices or shock absorbers in the human joints. Aging often results in degenerative joints that have less efficient shock-absorbing behavior, which is further amplified in the spine, where each intervertebral disc serves as a shock absorber to spinal motion. Fast strain rates imposed on these types of polymers would elicit a stiffening response, whereas slow strain rates would elicit a greater elastic zone with greater deformation. Finally, the physical state of a smart polymer coating on the surface of another material can switch from hydrophobic to hydrophilic, where in the hydrophobic state, the surfaces have been found to adhere to proteins and cells and can be patterned after human cells. In the hydrophilic state, these proteins would be released. Such a technology can be incorporated into applications toward engineering human tissue, such as an intervertebral disc or cancellous bone and can provide adhesive or barrier functions to the surrounding tissues.

Nanocoatings

With the advent of spine arthroplasty implants for motion preservation, adherence of the implant to the surrounding bony interface is often challenging for long-term fixation. Biocompatible thermal spray coatings such as titanium plasma sprays and hydroxyapatite coatings (HA) are the conventional means for improving an implant’s fixation to the surrounding bone environment by promoting osseointegration at the interface. The HA coatings are generally 50 to 75 μm thick, and have a mean roughness of 7.5 to 9.5 μm, with a porosity of 1% to 10%, and a bond strength between 20 and 30 MPa. Titanium powders are generally sprayed and exhibit thickness of 350 μm to 600 μm, with a mean roughness of 30 μm and a porosity of 15% to 40%, with a bond strength of 25 MPa.4,14,14 However, the wide range in porosity and thickness can have limiting effects with respect to osseointegration.

Nanocoatings or nanostructured thermal spray coatings exhibit enhanced mechanical performance when compared to the conventional biomedical thermal spray coatings used on orthopedic implants, due to the uniformity and consistency in porous replication. Further characteristics such as higher wear resistance, higher bond strength with the substrate, higher resistance to delamination, higher toughness, and higher plasticity have also been observed with nanostructured coatings.4,9 These structures have been used extensively in the dental arena and tend to have a higher affinity for osteoblast proliferation and uniform bone formation at the interfaces. Improvement of these qualities using nanostructured technologies can lead to improved fixation of implants at the bone interface and the potential to increase the implant’s lifespan within compromised or osteoporotic bone of the aging spine.

Biosensors and Biochips

Although the exact pathomechanism by which a degenerative intervertebral disc leads to neural inflammation and pain has not been determined, modern techniques of chemical analysis can be implemented to identify biochemical markers that participate in the degenerative cascade, and possibly with the onset of pain. Clinical studies have shown that both the anulus fibrosus and nucleus pulposus cells of the intervertebral disc express factors such as neurotrophins NGF and BDNF that may influence and enhance innervation and pain in the degenerated disc. Expression of such markers as oncogenes Trk-A and Trk-B by the cells of the nondegenerated and degenerated disc suggests an autocrine role for neurotrophins in the regulation of disc cell biology. Additionally, several cytokines have been implicated in the process of IVD degeneration and herniation, with the investigations predominantly focused on interleukin 1 (IL-1) and tumor necrosis factor- alpha (TNF-α) as possible markers involved in the pathogenesis of IVD degeneration.

Chemical markers are macromolecules present in the membranes and fluids in the vicinity of the pathology. The ability to identify degenerative markers could lead to treatment strategies that could diagnose early spinal degeneration and provide treatments at an early stage, when the tissue is capable of healing and reversal of the disease is possible. Microfabricated biosensors can detect and target particular disease-related molecules and proteins. The current methods for protein detection involve labeling procedures that are time-consuming; also, proteins must be in high concentrations for detection, at a point that may not be reversible with respect to tissue healing. Implantable microsized biosensors provide a favorable approach that allows for real-time analysis in minuscule dosages to shorten the detection time and treatment options for the patient. Cantilever-based biosensors for diagnostics have become a promising tool for detection of biomolecular interactions with greater accuracy than conventional methods (Figure 67-2). A nanocantilever and/or microcantilever are devices that can act as physical, chemical, or biological sensors by detecting changes in cantilever bending or vibrational frequency. It is the miniaturized counterpart of a diving board that moves up and down at a regular interval, thus translating molecular or protein recognition into a mechanical motion, at either the nano- or microscale. The mechanical motion can be detected by an optical or piezoresistive readout detector system and, therefore, molecules adsorbed on a microcantilever can cause vibrational frequency changes and deflection of the microcantilever. Biomolecules that are immobilized on the surface of the cantilever beam relay a surface stress to a readout system. If this surface stress is disrupted by a variation in molecular mass or when a specific mass of a molecule is adsorbed on its surface, such as that of a diseased molecule, the readout will reflect the change and the diseased molecule can be detected at a very early time point and at small manageable dosages for successful treatment. Using a cantilever based on the detection of changes in vibrational frequency, the viscosity, density, and flow rate also can be measured and monitored.2

image

FIGURE 67-2 NEMS piezoresistive cantilever structures fabricated as cancer detection systems or to detect molecular changes in living tissue or fluids. The right image shows actual multiplanar cantilever detection systems.

(Left image from http://www.eurekalert.org/features/doe/2001-10/drnl-cm061802.phpen. Right image from Li X, Yu H, Gan X, Xiaoyuan X, Pengcheng X, Jungang L, Liu M, and Yongxiang L: Integrated NEMS/MEMS resonant cantilevers for ultrasensitive biological detection, ed 2 Journal of Sensors (637734): 1-9, 2009.)

Biochips or Lab-on-a-chip (Figure 67-3)3 are microfluidic devices that can conduct several laboratory functions and fluid analyses at rapid speeds designed with microchannels smaller than a single cell, with large surface-area-to-volume ratio where liquids follow a laminar flow pathway. “Lab-on-a-chip” indicates generally the scaling of single or multiple lab processes down to chip-format. Conventional lab work conducted on patients’ blood samples are used to detect disease-related biochemical changes, and often take as long as one to two weeks to obtain diagnostic results. The biochip can conduct a continuous analysis on minuscule amounts of blood within seconds in multiple iterations, and provide more than just a snapshot of information. In doing so, earlier detection of degenerative disease is possible.

Early detection of diseased molecules can lead to earlier treatment of the degenerative processes related to the aging spine, with the potential to halt or reverse the progression of the disease. The degenerative cascade may start with disc degeneration and desiccation, resulting in height loss, facet hypertrophy, and the bony abnormalities that accompany the degenerative cascade, including osteoporosis. If detected early, the cascade could be interrupted and the progression halted.

References

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3. http://en.wikipedia.org/wiki/Lab-on-a-chip. Accessed February 17, 2010.

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