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Posts Tagged ‘mechanosensation’


Advances in acoustics and in learning

Larry H. Brnstein, MD, FCAP, Curator

LPBI

 

Controlling acoustic properties with algorithms and computational methods

http://www.kurzweilai.net/controlling-acoustic-properties-with-algorithms-and-computational-methods

October 28, 2015

Computer scientists at Columbia Engineering, Harvard, and MIT have demonstrated that acoustic properties — both sound and vibration — can be controlled by 3D-printing specific shapes.

They designed an optimization algorithm and used computational methods and digital fabrication to alter the shape of 2D and 3D objects, creating what looks to be a simple children’s musical instrument — a xylophone with keys in the shape of zoo animals.

Practical uses

“Our discovery could lead to a wealth of possibilities that go well beyond musical instruments,” says Changxi Zheng, assistant professor of computer science at Columbia Engineering, who led the research team.

“Our algorithm could lead to ways to build less noisy computer fans and bridges that don’t amplify vibrations under stress, and advance the construction of micro-electro-mechanical resonators whose vibration modes are of great importance.”

Zheng, who works in the area of dynamic, physics-based computational sound for immersive environments, wanted to see if he could use computation and digital fabrication to actively control the acoustical property, or vibration, of an object.

Zheng’s team decided to focus on simplifying the slow, complicated, manual process of designing “idiophones” — musical instruments that produce sounds through vibrations in the instrument itself, not through strings or reeds.

The surface vibration and resulting sounds depend on the idiophone’s shape in a complex way, so designing the shapes to obtain desired sound characteristics is not straightforward, and their forms have so far been limited to well-understood designs such as bars that are tuned by careful drilling of dimples on the underside of the instrument.

Optimizing sound properties

To demonstrate their new technique, the team settled on building a “zoolophone,” a metallophone with playful animal shapes (a metallophone is an idiophone made of tuned metal bars that can be struck to make sound, such as a glockenspiel).

 

What happens in the brain when we learn

http://www.kurzweilai.net/what-happens-in-the-brain-when-we-learn

Findings could enhance teaching methods and lead to treatments for cognitive problems
October 28, 2015

A Johns Hopkins University-led research team has proven a working theory that explains what happens in the brain when we learn, as described in the current issue of the journal Neuron.

More than a century ago, Pavlov figured out that dogs fed after hearing a bell eventually began to salivate when they heard the bell ring. The team looked into the question of how Pavlov’s dogs (in “classical conditioning”) managed to associate an action with a delayed reward to create knowledge. For decades, scientists had a working theory of how it happened, but the team is now the first to prove it.

“If you’re trying to train a dog to sit, the initial neural stimuli, the command, is gone almost instantly — it lasts as long as the word sit,” said neuroscientist Alfredo Kirkwood, a professor with the university’s Zanvyl Krieger Mind/Brain Institute. “Before the reward comes, the dog’s brain has already turned to other things. The mystery was, ‘How does the brain link an action that’s over in a fraction of a second with a reward that doesn’t come until much later?’ ”

Eligibility traces

The working theory — which Kirkwood’s team has now validated experimentally — is that invisible “synaptic eligibility traces” effectively tag the synapses activated by the stimuli so that the learning can be cemented with the arrival of a reward. The reward is a neuromodulator* (neurochemical) that floods the dog’s brain with “good feelings.” Though the brain has long since processed the “sit” command, eligibility traces in the synapse respond to the neuromodulators, prompting a lasting synaptic change, a.k.a. “learning.”

The team was able to prove the eligibility-traces theory by isolating cells in the visual cortex of a mouse. When they stimulated the axon of one cell with an electrical impulse, they sparked a response in another cell. By doing this repeatedly, they mimicked the synaptic response between two cells as they process a stimulus and create an eligibility trace.

When the researchers later flooded the cells with neuromodulators, simulating the arrival of a delayed reward, the response between the cells strengthened (“long-term potentiation”) or weakened (“long-term depression”), showing that the cells had “learned” and were able to do so because of the eligibility trace.

“This is the basis of how we learn things through reward,” Kirkwood said, “a fundamental aspect of learning.”

In addition to a greater understanding of the mechanics of learning, these findings could enhance teaching methods and lead to treatments for cognitive problems, the researchers suggest.

Scientists at the University of Texas at Houston and the University of California, Davis were also involved in the research, which was supported by grants from JHU’s Science of Learning Institute and National Institutes of Health.

* The neuromodulators tested were norepinephrine, serotonin, dopamine, and acetylcholine, all of which have been implicated in cortical plasticity (ability to grow and form new connections to other neurons).


Abstract of Distinct Eligibility Traces for LTP and LTD in Cortical Synapses

In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so-called distal reward problem has been the notion of activity-generated “synaptic eligibility traces,” silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction and transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning.

 

Holographic sonic tractor beam lifts and moves objects using soundwaves

Another science-fiction idea realized
October 27, 2015

British researchers have built a working Star-Trek-style “tractor beam” — a device that can attract or repel one object to another from a distance. It uses high-amplitude soundwaves to generate an acoustic hologram that can grasp and move small objects.

The technique, published in an open-access paper in Nature Communications October 27, has a wide range of potential applications, the researchers say. A sonic production line could transport delicate objects and assemble them, all without physical contact. Or a miniature version could grip and transport drug capsules or microsurgical instruments through living tissue.

The device was developed at the Universities of Sussex and Bristol in collaboration with Ultrahaptics.

https://youtu.be/wDzhlW-rKvM
University of Sussex | Levitation using sound waves

The researchers used an array of 64 miniature loudspeakers. The whole system consumes just 9 Watts of power, used to create high-pitched (40Khz), high-intensity sound waves to levitate a spherical bead 4mm in diameter made of expanded polystyrene.

The tractor beam works by surrounding the object with high-intensity sound to create a force field that keeps the objects in place. By carefully controlling the output of the loudspeakers, the object can be held in place, moved, or rotated.

Three different shapes of acoustic force fields work as tractor beams: an acoustic force field that resembles a pair of fingers or tweezers; an acoustic vortex, the objects becoming trapped at the core; and a high-intensity “cage” that surrounds the objects and holds them in place from all directions.

Previous attempts surrounded the object with loudspeakers, which limits the extent of movement and restricts many applications. Last year, the University of Dundee presented the concept of a tractor beam, but no objects were held in the ray.

The team is now designing different variations of this system. A bigger version aims at levitating a soccer ball from 10 meters away and a smaller version aims at manipulating particles inside the human body.

https://youtu.be/g_EM1y4MKSc
Asier Marzo, Matt Sutton, Bruce Drinkwater and Sriram Subramanian | Acoustic holograms are projected from a flat surface and contrary to traditional holograms, they exert considerable forces on the objects contained within. The acoustic holograms can be updated in real time to translate, rotate and combine levitated particles enabling unprecedented contactless manipulators such as tractor beams.


Abstract of Holographic acoustic elements for manipulation of levitated objects

Sound can levitate objects of different sizes and materials through air, water and tissue. This allows us to manipulate cells, liquids, compounds or living things without touching or contaminating them. However, acoustic levitation has required the targets to be enclosed with acoustic elements or had limited maneuverability. Here we optimize the phases used to drive an ultrasonic phased array and show that acoustic levitation can be employed to translate, rotate and manipulate particles using even a single-sided emitter. Furthermore, we introduce the holographic acoustic elements framework that permits the rapid generation of traps and provides a bridge between optical and acoustical trapping. Acoustic structures shaped as tweezers, twisters or bottles emerge as the optimum mechanisms for tractor beams or containerless transportation. Single-beam levitation could manipulate particles inside our body for applications in targeted drug delivery or acoustically controlled micro-machines that do not interfere with magnetic resonance imaging.

 

A drug-delivery technique to bypass the blood-brain barrier

http://www.kurzweilai.net/a-drug-delivery-technique-to-bypass-the-blood-brain-barrier

Could benefit a large population of patients with neurodegenerative disorders
October 26, 2015

Researchers at Massachusetts Eye and Ear/Harvard Medical School and Boston University have developed a new technique to deliver drugs across the blood-brain barrier and have successfully tested it in a Parkinson’s mouse model (a line of mice that has been genetically modified to express the symptoms and pathological features of Parkinson’s to various extents).

Their findings, published in the journal Neurosurgery, lend hope to patients with neurological conditions that are difficult to treat due to a barrier mechanism that prevents approximately 98 percent of drugs from reaching the brain and central nervous system.

“Although we are currently looking at neurodegenerative disease, there is potential for the technology to be expanded to psychiatric diseases, chronic pain, seizure disorders, and many other conditions affecting the brain and nervous system down the road,” said senior author Benjamin S. Bleier, M.D., of the department of otolaryngology at Mass. Eye and Ear/Harvard Medical School.

The nasal mucosal grafting solution

Researchers delivered glial derived neurotrophic factor (GDNF), a therapeutic protein in testing for treating Parkinson’s disease, to the brains of mice. They showed that their delivery method was equivalent to direct injection of GDNF, which has been shown to delay and even reverse disease progression of Parkinson’s disease in pre-clinical models.

Once they have finished the treatment, they use adjacent nasal lining to rebuild the hole in a permanent and safe way. Nasal mucosal grafting is a technique regularly used in the ENT (ear, nose, and throat) field to reconstruct the barrier around the brain after surgery to the skull base. ENT surgeons commonly use endoscopic approaches to remove brain tumors through the nose by making a window through the blood-brain barrier to access the brain.

The safety and efficacy of these methods have been well established through long-term clinical outcomes studies in the field, with the nasal lining protecting the brain from infection just as the blood brain barrier has done.

By functionally replacing a section of the blood-brain barrier with nasal mucosa, which is more than 1,000 times more permeable than the native barrier, surgeons could create a “screen door” to allow for drug delivery to the brain and central nervous system.

The technique has the potential to benefit a large population of patients with neurodegenerative disorders, where there is still a specific unmet need for blood-brain-penetrating therapeutic delivery strategies.

The study was funded by The Michael J. Fox Foundation for Parkinson’s Research (MJFF).


Abstract of Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier

BACKGROUND: The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier.

OBJECTIVE: To test the feasibility of using nasal mucosal graft reconstruction of arachnoid defects to deliver glial-derived neurotrophic factor (GDNF) for the treatment of Parkinson disease in a mouse model.

METHODS: The Institutional Animal Care and Use Committee approved this study in an established murine 6-hydroxydopamine Parkinson disease model. A parietal craniotomy and arachnoid defect was repaired with a heterotopic donor mucosal graft. The therapeutic efficacy of GDNF (2 [mu]g/mL) delivered through the mucosal graft was compared with direct intrastriatal GDNF injection (2 [mu]g/mL) and saline control through the use of 2 behavioral assays (rotarod and apomorphine rotation). An immunohistological analysis was further used to compare the relative preservation of substantia nigra cell bodies between treatment groups.

RESULTS: Transmucosal GDNF was equivalent to direct intrastriatal injection at preserving motor function at week 7 in both the rotarod and apomorphine rotation behavioral assays. Similarly, both transmucosal and intrastriatal GDNF demonstrated an equivalent ratio of preserved substantia nigra cell bodies (0.79 +/- 0.14 and 0.78 +/- 0.09, respectively, P = NS) compared with the contralateral control side, and both were significantly greater than saline control (0.53 +/- 0.21; P = .01 and P = .03, respectively).

CONCLUSION: Transmucosal delivery of GDNF is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier.

 

Creating an artificial sense of touch by electrical stimulation of the brain

http://www.kurzweilai.net/creating-an-artificial-sense-of-touch-by-electrical-stimulation-of-the-brain

DARPA-funded study may lead to building prosthetic limbs for humans using a direct brain-electrode interface to recreate the sense of touch
October 26, 2015

Neuroscientists in a project headed by the University of Chicago have determined some of the specific characteristics of electrical stimuli that should be applied to the brain to produce different sensations in an artificial upper limb intended to restore natural motor control and sensation in amputees.

The research is part of Revolutionizing Prosthetics, a multi-year Defense Advanced Research Projects Agency (DARPA).

For this study, the researchers used monkeys, whose sensory systems closely resemble those of humans. They implanted electrodes into the primary somatosensory cortex, the area of the brain that processes touch information from the hand. The animals were trained to perform two perceptual tasks: one in which they detected the presence of an electrical stimulus, and a second task in which they indicated which of two successive stimuli was more intense.

The sense of touch is made up of a complex and nuanced set of sensations, from contact and pressure to texture, vibration and movement. The goal of the research is to document the range, composition and specific increments of signals that create sensations that feel different from each other.

To achieve that, the researchers manipulated various features of the electrical pulse train, such as its amplitude, frequency, and duration, and noted how the interaction of each of these factors affected the animals’ ability to detect the signal.

Of specific interest were the “just-noticeable differences” (JND),” — the incremental changes needed to produce a sensation that felt different. For instance, at a certain frequency, the signal may be detectable first at a strength of 20 microamps of electricity. If the signal has to be increased to 50 microamps to notice a difference, the JND in that case is 30 microamps.*

“When you grasp an object, for example, you can hold it with different grades of pressure. To recreate a realistic sense of touch, you need to know how many grades of pressure you can convey through electrical stimulation,” said Sliman Bensmaia, PhD, Associate Professor in the Department of Organismal Biology and Anatomy at the University of Chicago and senior author of the study, which was published today (Oct. 26) in the Proceedings of the National Academy of Sciences. “Ideally, you can have the same dynamic range for artificial touch as you do for natural touch.”

“This study gets us to the point where we can actually create real algorithms that work. It gives us the parameters as to what we can achieve with artificial touch, and brings us one step closer to having human-ready algorithms.”

Researchers from the University of Pittsburgh and Johns Hopkins University were also involved in the DARPA-supported study.

* The study also has important scientific implications beyond neuroprosthetics. In natural perception, a principle known as Weber’s Law states that the just-noticeable difference between two stimuli is proportional to the size of the stimulus. For example, with a 100-watt light bulb, you might be able to detect a difference in brightness by increasing its power to 110 watts. The JND in that case is 10 watts. According to Weber’s Law, if you double the power of the light bulb to 200 watts, the JND would also be doubled to 20 watts.

However, Bensmaia’s research shows that with electrical stimulation of the brain, Weber’s Law does not apply — the JND remains nearly constant, no matter the size of the stimulus. This means that the brain responds to electrical stimulation in a much more repeatable, consistent way than through natural stimulation.

“It shows that there is something fundamentally different about the way the brain responds to electrical stimulation than it does to natural stimulation,” Bensmaia said.


Abstract of Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex

Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters—namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications.

references:

  • Sungshin Kim, Thierri Callier, Gregg A. Tabot, Robert A. Gaunt, Francesco V. Tenore, and Sliman J. Bensmaia. Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex. PNAS 2015; doi:10.1073/pnas.1509265112
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Author: Aviral Vatsa PhD MBBS

This is the first post in a series of posts on mechanosensation and mechanotransduction and their role in physiology and disease.

Future posts in this category will focus on various aspects of role of mechanosensation and mechanotransduction in human physiology. These aspects will include among others: gene modulation, cellular mechanosensation, tissue regeneration, stem cell differentiation, cancer, disease models, nanomodulation, material science and therapeutics etc.

Based on Zhang et al [1]

Multicellular organisms such as humans require intricate orchestration of signals between cells to achieve global morphogenesis and organ function and thus maintain haemostasis. Three major ‘signalling modalities’ work in unison intracellularly and/or exrtacellularly to regulate harmonious functioning of the physiological milieu. These ‘modalities’ namely biochemical molecules, electrical currents or fields and mechanical forces (external or internal) cohesively direct the downstream regulation of physiological processes.

Traditionally most of the biological studies have focused on biochemical or electrical signalling events and relatively lesser resources have been dedicated towards exploring the role of mechanical forces in human health and disease. Despite early theories proposed by scientists such as Julius Wolff (Wolff’s law [2]) in the late nineteenth century “ that bone in a healthy person or animal will adapt to the loads under which it is placed”, relatively little has been studied about the role of external mechanical forces in maintaining haemostasis. However, recent important developments such as

  • identification of external force dependent regulation of signalling pathways [3]
  • determination of mechanosensing elements of cellular cytoskeleton [4]
  • manipulation of single molecules [5]

have reinstated the importance of external mechanical forces in physiology. As a result more recent investigations have demonstrated that external mechanical forces are major coordinators of development and haemostasis of organisms [6], [7] [8].

‘Mechanotransduction’ has been traditionally defined as the conversion of mechanical stimulus into chemical cues for the cells and thus altering downstream signalling e.g conformational changes in ion channels might lead to initiation of downstream signalling. However, with the accumulation of new knowledge pertaining to the effects of external mechanical loads on extracellular matrix or a cell or on subcellular structures, it is being widely accepted that mechanotransduction is more than merely a physical switch. Rather it entails the whole spectrum of cell-cell , cell-ECM, and intracellular interactions that can directly or indirectly modulate the functioning of cellular mechanisms involved in haemostasis. This modulation can function at various levels such as organism level, tissue level, cellular level and subcellular level.

Forces in cells and organisms

From biological point of view mechanical forces can be grouped into three categories

  • intracellular forces
  • intercellular forces
  • inter-tissue forces

In the eukaryotic cells these forces are generally generated by the the contractile cytoskeletal machinery of the cell that is comprised of

  • microfilaments : Diameter-6 nm; example- actin
  • intermediate filaments: Diameter-10 nm; example- vimentin, keratin
  • microtubules: Diameter-23 nm; example- alpha and beta tubulin

 

Actin labeling in single Osteocyte in situ in mouse bone. Source: Aviral Vatsa

Actin labeling in single Osteocyte in situ in mouse bone. Source: Aviral Vatsa

Actin (cytoskeleton) staining of single osteocyte in situ in mouse calvaria (source: Aviral Vatsa)

There are a range of forces generated in the biological milieu (adopted from Mammoto et al [8]): 

  • Hydrostatic pressure: mechanical force applied by fluids or gases (e.g. blood or air) that perfuse or infuse living organs (e.g. blood vessels or lung).
  • Shear stress: frictional force of fluid flow on the surface of cells. The shear stress generated by the heart pumping blood through the systemic circulation has a key role in the determination of the cell fate of cardiomyocytes, endothelial cells and hematopoietic cells.
  • Compressive force: pushing force that shortens the material in the direction of the applied force. Tensional force: pulling force that lengthens materials in the direction of the applied force.
  • Cell traction force: is exerted on the adhesion to the ECM and other cells as a result of the shortening of the contractile cytoskeletal actomyosin filaments, which transmit tensional forces across cell surface adhesion receptors (e.g. integrins, cadherins).
  • Cell prestress: stabilizing isometric tension in the cell that is generated by the establishment of a mechanical force balance within the cytoskeleton through a tensegrity mechanism. Pulling forces generated within contractile microfilaments are resisted by external tethers of the cell (e.g. to the ECM or neighboring cells) and by internal load-bearing structures that resist compression (e.g. microtubules, filipodia). Prestress controls signal transduction and regulates cell fate.

It is the interplay of these forces generated by the cellular cytoskeleton and the ECM that regulate physiological functions. Disruption in mechanotransduction has been implicated in a variety of diseases such as hypertension, muscular dystrophies, cardiomyopathies, loss of hearing, cancer progression and metastasis. Ongoing attempts at unravelling the finer details of mechanosensation hold promising potential for new therapeutic approaches.

 

References

[1] H. Zhang and M. Labouesse, “Signalling through mechanical inputs – a coordinated process,” Journal of Cell Science, vol. 125, no. 17, pp. 4172–4172, Oct. 2012.

[2] R. A. Brand, “Biographical Sketch: Julius Wolff, 1836–1902,” Clin Orthop Relat Res, vol. 468, no. 4, pp. 1047–1049, Apr. 2010.

[3] A. J. Hudspeth, “The cellular basis of hearing: the biophysics of hair cells,” Science, vol. 230, no. 4727, pp. 745–752, Nov. 1985.

[4] N. Wang, J. P. Butler, and D. E. Ingber, “Mechanotransduction across the cell surface and through the cytoskeleton,” Science, vol. 260, no. 5111, pp. 1124–1127, May 1993.

[5] J. T. Finer, R. M. Simmons, and J. A. Spudich, “Single myosin molecule mechanics: piconewton forces and nanometre steps,” , Published online: 10 March 1994; | doi:10.1038/368113a0, vol. 368, no. 6467, pp. 113–119, Mar. 1994.

[6] P. A. Janmey and R. T. Miller, “Mechanisms of mechanical signaling in development and disease,” J Cell Sci, vol. 124, no. 1, pp. 9–18, Jan. 2011.

[7] R. Keller, L. A. Davidson, and D. R. Shook, “How we are shaped: The biomechanics of gastrulation,” Differentiation, vol. 71, no. 3, pp. 171–205, Apr. 2003.

[8] T. Mammoto and D. E. Ingber, “Mechanical control of tissue and organ development,” Development, vol. 137, no. 9, pp. 1407–1420, May 2010.

 

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Author: Aviral Vatsa, Ph.D., MBBS

Bone is a highly dynamic tissue that responds to changes in its external environment. Our bones adapt their mass and architecture according to the external mechanical loading conditions. Any long term alterations in loading conditions result in alteration of bone mass and architecture. This is highlighted in the following examples:

  1. Astronauts tend to lose their bone when they are in space. This is because the bones are not mechanically loaded externally due to absence of or reduction in gravitational force.
  2. Tennis players gain more mass in their playing forearm as compared to the non-playing forearm.

In both these examples bones tend to readjust their internal structural mass and alignment as per the external loads or their absence. How bones can achieve this? How bone forming and bone resorbing cells can be orchestrated to bring about this adaptation?

Bone cells

The questions mentioned above can be answered by knowing more about the cellular components of bone and their functions. Our bones primarily have four cell types: osteocytes, osteoblasts, osteoclasts and bone lining cells. Osteocytes are believed to be the ‘professional’ mechanosensors of bone i.e. they sense the external loads put on bone. Osteoblasts are the bone forming cells. Osteoclasts are the bone resorbing cells and as the name suggests, bone lining cells line the bone surfaces and play a role in regeneration of osteogenic cells. Osteocytes, following mechanical loading, secrete signalling molecules such as nitric oxide (besides others). These signalling molecules then modulate the activity of bone forming osteoblasts and/or bone resorbing osteoclasts. Thus osteocytes orchestrate this process wherein adequate bone mass and architecture is achieved in accordance with the external loading conditions.

Anatomically, the osteocytes reside with in the hard bony matrix. They are the majority cell types in bone and are ideally placed to sense the mechanical loads. Osteocytes have a cell body and from the cell body arise nearly fifty cell processes. Through these cell processes each osteocyte forms a network with the surrounding osteocytes. Through this network, following mechanical loading, osteocytes can stimulate the activity of osteoblasts and inhibit the activity of osteoclasts. This process of maintenance of bone mass and architecture is called bone remodelling. Bone remodelling occurs through out our life. It occurs in response to microfractures, which can appear in our bone without being noticed clinically. As long as our bone metabolism is physiologically normal these stimuli, such as microfractures, result in bone remodelling.

In diseases such as osteoporosis, the mechanism of bone remodelling is disrupted and there is more bone resorbtion than new bone formation thus leading to reduction in bone mass and alteration of bone architecture. Drug therapies for osteoporosis such as bisphosphonates, act by inhibiting the activity of osteoclasts thereby resulting in reduction in bone resorbtion and hence helping in maintenance of adequate bone mass and architecture. Newer therapies that target to modulate a part of bone remodelling are being investigated.

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