WO2017149437A1 - Neuromodulation apparatus - Google Patents

Neuromodulation apparatus Download PDF

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WO2017149437A1
WO2017149437A1 PCT/IB2017/051144 IB2017051144W WO2017149437A1 WO 2017149437 A1 WO2017149437 A1 WO 2017149437A1 IB 2017051144 W IB2017051144 W IB 2017051144W WO 2017149437 A1 WO2017149437 A1 WO 2017149437A1
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signal
nerve
apparatus
optionally
subject
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PCT/IB2017/051144
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French (fr)
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Hans Jakob Kristoffer FAMM
Alessandra GIAROLA
Nishan RAMNARAIN
Arun SRIDHAR
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Galvani Bioelectronics Limited
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment

Abstract

The present disclosure provides an apparatus or system and methods for improving fracture healing by delivering a signal to an osteoneural nerve in a subject.

Description

NEU ROMODU LATION APPARATUS

BACKG ROU ND

Bone is innervated according to Hilton's rule, meaning the nervous supply of the overlying muscle and skin is continuous with the long bones and joints. Nerves enter the long bones through the nutrient foramen, running in parallel with blood vessels. The morphology and anatomy of nutrient foramina is described in the literature (Kizilkanat et al., 2007. Ann Anat 189:87-95; Prashanth et al., 2011 AMJ 4(10):530-537; Ankolekar et al., 2013. lOSR-JDMS 10(3):75-79, the contents of each of which are incorporated herein by reference).

Bone union and healing following fracture is a slow process and can be particularly poor amongst subjects from at risk groups. Such risk factors include smoking, those suffering high-energy fractures, immunosuppression, a history of delayed union or non-union, suboptimal arterial flow, diabetes, alcohol abuse, multiple surgeries, chronic infections, collagen disorders, metabolic bone disorders.

The treatment of non-union or delayed union following fracture remains a challenge for subjects and physicians. The additional surgical procedures extend the length of hospitality stay affecting subjects' quality of life while exerting a considerable socioeconomic burden. The only current adjuvant therapy is Rh-BPM-2 (osteoinductive protein) which is impregnated into a sponge or foam and needs to be inserted in the fracture area through invasive surgery. RhBM P-2 has been approved for spinal surgery only.

The present inventors have identified that the neuro-skeletal axis will provide a new mechanism by which fracture union and healing can be improved and augmented. In particular, the inventors have identified that neuromodulation apparatuses of the invention will provide less invasive and disruptive options for treating bone fracture compared to, for example, RhBMP-2 based therapies.

SU MMARY OF INVENTION

The present disclosure describes an apparatus or system and methods for modulating (e.g., suppressing or inhibiting) the neural activity of an osteoneural nerve of a subject. The apparatus or system includes one or more neural interfacing elements (e.g., transducers) each configured to apply a signal to an osteoneural nerve of the subject; and a controller operably coupled to the one or more neural interfacing elements. The controller is configured to control the signal to be applied by each of the one or more neural interfacing elements, such that the signal inhibits the neural activity of the nerve to produce a physiological response in the subject. Preferably, the physiological response is a systemic or localized reduction in sympathetic tone.

In a preferred embodiment of all aspects of the invention, the subject is a human, e.g., a patient with an unresolved bone fracture.

BRI EF DESCRI PTION OF THE FIGURES

Figure 1: Schematic drawings showing how apparatuses and methods according to the

invention can be put into effect. Figure 2 Gene expression data of 2h acute treatment of mice with either chronic immobilization stress (CIS) or ISO i.p. Single whole tibia (unflushed) was harvested for analysis SNS target genes 116 and Rankl were normalized to Gapdh. N=6, * p<0.05.

Figure 3 IL-6 gene expression following treatment with control, chronic immobilization stress

(CIS), vehicle or propanolol administration. N=6/group

DETAI LED DESCRIPTION

Bones are highly innervated by sympathetic neurons; for example, postganglionic fibres from cervical sympathetic ganglion and glossopharyngeal nerve innervate external and internal bones of the skull. The long bones of the upper extremities receive nerve supply from the brachial plexus which then branches to the median nerve to innervate the humerus and the ulnar and radian nerves which supply the forearm bones. Osseous innervation of the flat rib bones is achieved via the anterior branches of the 12 pairs of intercostal nerves. Sympathetic innervation of the lower limbs originates in the lumbar plexus which supplies the femoral and deep saphenous nerves to the femur, and the tibial, medial, and popliteal nerves to the tibia and fibula. Basivertebral nerves in the spine supply interosseous autonomic innervations of the vertebral bodies (adapted from Primer on the Autonomic Nervous System, Chpt. 53, Elefteriou and Campbell, which is incorporated herein by reference).

Osteoneural nerves, in particular sympathetic osteoneural nerves, have been found close to osteoblasts, the cells responsible for bone formation. Many sympathetic nerves release adrenergic neurotransmitters such as epinephrine and nor-epinephrine. Receptors for these adrenergic neurotransmitters, specifically beta 2-adrenergic receptors ( 2AR), are expressed by osteoblasts and 2ARs stimulation by isoproterenol (a non-selective agonist (i.e. stimulates both βΐ and β2 adrenergic receptors)) induces bone loss due to the reduced bone formation and increased bone resorption triggered by stimulation of Rankl expression.

Chemical and surgical sympathectomy experiments resulted in abnormal bone formation and resorption after removal of sympathetic nerve supply (Cherruau et al., 1999. Bone 25:545-551, which is incorporated herein by reference). Daily β-adrenergic receptor stimulation by isoproterenol or clenbuterol or salbutamol in mice and rats triggers an osteoclastogenic response (i.e. bone resorption), as measured by bone loss and increased osteoclast formation (Takeda et al., 2002. Cell 111:305-317; Bonnet et al., 2005. Bone 37:622-633; Bonnet et al., 2007. J Appl Physiol 102: 1502- 1509; each of which is incorporated by reference in its entirety).

These studies in rats and mice indicated to the inventors that sympathetic innervation has important involvement in bone homeostasis. Clinical observational evidence also suggests that this regulatory pathway is conserved between rodents and humans based on the observation that anti-hypertensive therapy with β-blockers (i.e. βAR antagonists) is associated with increased in bone mineral density and reduced fracture risk in humans (Yang et al., 2011. Bone 48:451-455; Toulis et al., 2014. Osteoporos Int 25:121-129; Ghosh et al., 2014. Endocrine 46:397-405; each of which is incorporated herein by reference in its entirety). Conversely, β2AR stimulation has been associated with bone loss; for example, exposure to 2AR agonists in subjects with asthma/COPD increased hip/femur fracture risk (De Vries et al., 2007. Pharmacoepidemiol Drug Saf 16:612-619).

The inventors have identified that neuromodulation of an osteoneural nerve innervating a fractured bone, in particular sympathetic osteoneural nerves, allows the neuro-skeletal axis to be manipulated in order to improve fracture healing. It is particularly preferred to use neuromodulation to inhibit neural activity in the nerve, for example exert a sympathetic nerve block in order to increase osteoblastic activity and decrease osteoclastic activity. Such inhibition will thus counter/prevent osteoclastic activity and further accelerate the fracture healing by increasing osteoblastic activity, thereby reducing the time from fracture to healing, and thus reduce the immobilisation and rehabilitation period.

The terms as used herein are given their conventional definition in the art as understood by the skilled person, unless otherwise defined below. In the case of any inconsistency or doubt, the definition as provided herein should take precedence.

As used herein, application of a signal may equate to the transfer of energy in a suitable form to carry out the intended effect of the signal. That is, application of a signal to a nerve or nerves may equate to the transfer of energy to (or from) the nerve(s) to carry out the intended effect. For example, the energy transferred may be electrical, mechanical (including acoustic, such as ultrasound), electromagnetic (e.g. optical), magnetic or thermal energy. It is noted that application of a signal as used herein does not include a pharmaceutical intervention.

As used herein, "transducer" is taken to mean any element of applying a signal to the nerve, for example an electrode, diode, Peltier element or ultrasound transducer.

As used herein, a "non-destructive signal" is a signal as defined above that, when applied, does not irreversibly damage the underlying neural signal conduction ability. That is, application of a nondestructive signal maintains the ability of the nerve or nerves (or fibres thereof) to conduct action potentials when application of the signal ceases, even if that conduction is in practice inhibited or blocked as a result of application of the non-destructive signal. Ablation and cauterisation of at least part of the nerve are examples of destructive signals.

As used herein, "neural activity" of a nerve is taken to mean the signalling activity of the nerve, for example the amplitude, frequency and/or pattern of action potentials in the nerve.

Modulation of neural activity, as used herein, is taken to mean that the signalling activity of the nerve is altered from the baseline neural activity - that is, the signalling activity of the nerve in the subject prior to any intervention. Such modulation may increase, inhibit (for example block), or otherwise change the neural activity compared to baseline activity.

Where the modulation of neural activity is an increase of neural activity, this may be an increase in the total signalling activity of the whole nerve, or that the total signalling activity of a subset of nerve fibres of the nerve is increased, compared to baseline neural activity in that part of the nerve.

Where the modulation of neural activity is inhibition of neural activity, such inhibition may be partial inhibition. Partial inhibition may be such that the total signalling activity of the whole nerve is partially reduced, or that the total signalling activity of a subset of nerve fibres of the nerve is fully reduced (i.e. there is no neural activity in that subset of fibres of the nerve), or that the total signalling of a subset of nerve fibres of the nerve is partially reduced compared to neural activity in that subset of fibres of the nerve prior to intervention. Where the modulation of neural activity is inhibition of neural activity, this also encompasses full inhibition of neural activity in the nerve.

Inhibition of neural activity may be a block on neural activity. Such blocking may be a partial block - i.e. blocking of neural activity in a subset of nerve fibres of the nerve. Alternatively, such blocking may be a full block - i.e. blocking of neural activity across the whole nerve. A block on neural activity is understood to be blocking neural activity from continuing past the point of the block. That is, when the block is applied, action potentials may travel along the nerve or subset of nerve fibres to the point of the block, but not beyond the block.

Modulation of neural activity may also be an alteration in the pattern of action potentials. It will be appreciated that the pattern of action potentials can be modulated without necessarily changing the overall frequency or amplitude.

Modulation of neural activity may comprise altering the neural activity in various other ways, for example increasing or inhibiting a particular part of the neural activity and/or stimulating new elements of activity, for example in particular intervals of time, in particular frequency bands, according to particular patterns and so forth. Such altering of neural activity may for example represent both increases and/or decreases with respect to the baseline activity.

Modulation of the neural activity may be temporary. As used herein, "temporary" is taken to mean that the modulated neural activity (whether that is an increase, inhibition, block or other modulation of neural activity or change in pattern versus baseline activity) is not permanent. That is, the neural activity following cessation of the signal is substantially the same as the neural activity prior to the signal being applied - i.e. prior to modulation.

Modulation of the neural activity may be persistent. As used herein, "persistent" is taken to mean that the modulated neural activity (whether that is an increase, inhibition, block or other modulation of neural activity or change in pattern versus baseline activity) has a prolonged effect. That is, upon cessation of the signal, neural activity in the nerve remains substantially the same as when the signal was being applied - i.e. the neural activity during and following modulation is substantially the same. As used herein, an "osteoneural" nerve is a nerve innervating a bone, preferably a long bone. An osteoneural nerve innervating a particular bone is readily identified, as bone is innervated according to Hilton's rule, meaning the nervous supply of the overlying muscle and skin is continuous with the long bones and joints. Osteoneural nerves enter a bone, preferably the long bones, through the nutrient foramen.

As used herein, when a signal is applied to an osteoneural nerve at a point "proximal to the nutrient foramen" of the bone innervated by the osteoneural nerve, "proximal" is taken to mean a point on the nerve towards the nutrient foramens.

As used herein, "long bone" is given its meaning in the art - i.e. a bone forming part of a limb of a subject. Examples of a long bone include the radius, ulna, humerus, femur, tibia, fibula, and clavicles. As used herein, bone fracture is taken to mean at least partial disruption to the continuity of a bone in vivo, for example as a result of stress. A bone fracture may be a partial fracture or a wholly fractured bone. A fracture is considered healed when the bone structure returns to continuous bone, preferably continuous compact bone.

Treatment of bone fracture is therapeutic treatment. Therapeutic treatment of bone fracture is taken to mean an improvement in the rate at which the fracture heals, and/or the quality (e.g., strength or durability) of the healed bone. An improvement in the rate at which a fracture heals may be a shortening of the time from fracture to formation of continuous lamellar bone, a shortening of the time to callus formation, and/or shortening of time from fracture to continuous compact bone. A healed bone of improved quality is characterised by increased strength, increased bone mineral density, and/or increased proportion of compact bone to trabecular bone. Such an improvement in rate or quality is in comparison to if the intervention had not been applied.

As used herein, an "improvement in a measurable physiological parameter" is taken to mean that for any given physiological parameter, an improvement is a change in the value of that parameter in the subject in a manner that promotes fracture healing, for example increasing bone formation and/or density. For example, an improvement in a measurable parameter may be: a systemic reduction in sympathetic tone, a localised (i.e. local to the fractured bone) reduction in sympathetic tone, a local increase in bone density, an increase in rate of endochondral ossification, an increase in osteoblast formation, a decrease in osteoclast formation, an increase in the rate of healing of a fracture in the bone innervated by the osteoneural nerve, an improvement in the quality of a healed fracture.

Techniques for measuring these parameters would be familiar to the skilled person. For example: systemic sympathetic tone can be determined by direct measurement of sympathetic nerve activity, by measurement of levels of urinary catecholamines, measurement of the sympatho-vagal balance via heart rate variability (lower heart rate variability being indicative of a decrease in sympathetic tone); a localised reduction in sympathetic tone can be determined by measurement of catecholamines in and around the fractured bone, for example by positioning a measurement device proximal to the nutrient foramens; rate of fracture healing can be determined, for example, by serial radiographs and clinical assessment of the fracture; bone density can be determined, for example, by dual-energy X-ray absorptiometry (DEXA) scan or by conventional radiographic (e.g. X-ray) assessment; quality of a healed fracture can be indicated by, for example, the number of bridging trabeculae, the level of sclerotic fracture edges, persistent fracture lines and/or progressive deformity, where the absence of bridging trabeculae, the presence or high levels of sclerotic fracture edges, the presence of persistent fracture lines, and the presence of progressive deformity indicate poor quality of fracture healing.

As used herein, a physiological parameter is not affected by modulation of the neural activity if the parameter does not change as a result of the modulation from the average value of that parameter exhibited by the subject or patient when no intervention has been performed - i.e. it does not depart from the baseline value for that parameter.

The skilled person will appreciate that the baseline for any neural activity or physiological parameter in an individual need not be a fixed or specific value, but rather can fluctuate within a normal range or may be an average value with associated error and confidence intervals. Suitable methods for determining baseline values would be well known to the skilled person.

A "neuromodulation apparatus" as used herein is an apparatus configured to modulate the neural activity of a nerve. Neuromodulation apparatuses as described herein comprise at least one transducer capable of effectively applying a signal to a nerve. In those embodiments in which the neuromodulation apparatus is at least partially implanted in the subject, the elements of the apparatus that are to be implanted in the subject are constructed such that they are suitable for such implantation. Such suitable constructions would be well known to the skilled person. Indeed, various fully implantable neuromodulation apparatuses are currently available, such as the vagus nerve stimulator of SetPoint Medical, in clinical development for the treatment of rheumatoid arthritis (Arthritis & Rheumatism, Volume 64, No. 10 (Supplement), page S195 (Abstract No. 451), October 2012. "Pilot Study of Stimulation of the Cholinergic Anti-Inflammatory Pathway with an Implantable Vagus Nerve Stimulation Device in Subjects with Rheumatoid Arthritis", Frieda A.

Koopman et al), and the I NTERSTIM™ device (Medtronic, Inc), a fully implantable device utilised for sacral nerve modulation in the treatment of overactive bladder.

As used herein, "implanted" is taken to mean positioned at least partially within the subject's body. Partial implantation means that only part of the apparatus is implanted - i.e. only part of the apparatus is positioned within the subject's body, with other elements of the apparatus external to the subject's body. Wholly implanted means that the entire of the apparatus is positioned within the subject's body. For the avoidance of doubt, the apparatus being "wholly implanted" does not preclude additional elements, independent of the apparatus but in practice useful for its functioning (for example, a remote wireless charging unit or a remote wireless manual override unit), being independently formed and external to the subject's body.

As used herein, "charge-balanced" in relation to a DC current is taken to mean that the positive or negative charge introduced into any system (e.g. a nerve) as a result of a DC current being applied is balanced by the introduction of the opposite charge in order to achieve overall (i.e., net) neutrality. For example, a charge-balanced waveform may be a square waveform or a sigmoidal waveform.

As shown herein, it has been identified by the inventors that the neuro-skeletal axis may be targeted by neuromodulation in order to treat fracture healing. In particular, the inventors have identified that a neuromodulation apparatus as described herein can be used to modulate the neural activity in nerves innervating the bone, especially proximal to the nutrient foramens, in order to improve fracture healing. Most particularly, the inventors have identified that sympathetic neural signalling affects osteoblast and osteoclast activity and can be targeted by neuromodulation such that bone formation is improved. Such neuromodulation can therefore provide a means of treating bone fracture.

Therefore, in accordance with a first aspect of the invention there is provided an apparatus for inhibiting the neural activity of an osteoneural nerve of a subject, the apparatus comprising: a transducer configured to apply a signal to the nerve; and a controller coupled to the transducer, the controller controlling the signal to be applied by the transducer, such that the signal modulates the neural activity of the nerve to produce a physiological response in the subject, such as a decrease in sympathetic tone. In certain embodiments, the signal applied by the one or more transducers is a non-destructive signal.

In certain such embodiments, the signal applied by the transducer is an electrical signal, an optical signal, an ultrasonic signal, or a thermal signal. In such embodiments, the transducer may be comprised of an electrode, a photon source, a ultrasound transducer, a source of heat, or another types of transducer arranged to put the respective signal into effect.

In certain embodiments, the apparatus comprises more than one transducer, for example 2, 3, 4, 5, 6, 7, 8, 9, or 10 transducers. In certain such embodiments, the signal applied by each transducer is independently selected. Alternatively, in certain embodiments, the signal applied by each transducer is the same as those applied by the other transducer(s).

In certain embodiments, the signal or signals applied by the one or more transducers is an electrical signal, for example a voltage or current. In certain such embodiments the signal applied comprises a direct current (DC) waveform, such as a charge balanced direct current waveform, or an alternating current (AC) waveform, or both a DC and an AC waveform. In certain embodiments, the signal comprises an AC waveform of kilohertz frequency.

In certain embodiments the signal comprises a DC ramp followed by a plateau and charge-balancing, followed by a first AC waveform, wherein the amplitude of the first AC waveform increases during the period in which the first AC waveform is applied, followed by a second AC waveform having a lower amplitude and/or lower frequency than the first AC waveform. In certain such embodiments, the DC ramp, first AC waveform and second AC waveform are applied substantially consecutively.

In certain preferred embodiments, wherein the signal comprises one or more AC waveforms, each AC waveform is independently selected from an AC waveform of 5-25 kHz, optionally 10-25 kHz, optionally 15-25 kHz, optionally 20-25 kHz. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently, such that the waveform can have a frequency of at least 1 kHz, at least 5 kHz, at least 10 kHz, at least 15 kHz, or at least 20 kHz, and can have a frequency that does not exceed 50 kHz, or 45 kHz, or 40 kHz, or 35 kHz, or 30 kHz, or 25 kHz.

In certain embodiments, the signal comprises a DC waveform and/or an AC waveform having a voltage of 1-20V. In certain preferred embodiments, the signal has a voltage of 5-15V, optionally 10- 15V. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently such that the voltage can be at least 5 V, or at least 10 V, and does not exceed about 20 V, or about 15 V.

In certain embodiments, the signal is an electrical signal having a current of 10-20,000 μΑ, optionally 10-10000 μΑ, optionally 10-5000 μΑ, optionally 10-2000 μΑ, optionally 20-1000 μΑ, optionally 20- 500 μΑ, optionally 50-250 μΑ. In certain embodiments the electrical signal has a current of at least 10 μΑ, at least 20 μΑ, at least 50 μΑ, at least 60 μΑ, at least 70 μΑ, at least 80 μΑ, at least 90 μΑ, at least 100 μΑ, at least 110 μΑ, at least 150 μΑ, at least 180 μΑ, at least 200 μΑ, at least 250 μΑ. In certain embodiments the electrical signal has a current that does not exceed 20,000 μΑ, or does not exceed 15,000, or does not exceed 10,000 μΑ, or does not exceed 5000 μΑ, or does not exceed 2000 μΑ, or does not exceed 1000 μΑ, or does not exceed 750 μΑ, or does not exceed 500 μΑ, or does not exceed 250 μΑ.

In those embodiments in which the signal applied by the one or more transducers is an electrical signal, the transducer is an electrode configured to apply the electrical signal. In certain such embodiments, all the transducers of the apparatus are electrodes configured to apply an electrical signal, optionally the same electrical signal.

In certain embodiments wherein the signal applied by the transducer is a thermal signal, the signal reduces the temperature of the nerve (i.e. cools the nerve). In certain alternative embodiments, the signal increases the temperature of the nerve (i.e. heats the nerve). In certain embodiments, the signal both heats and cools the nerve.

In those embodiments in which the signal applied by the transducer is a thermal signal, the transducer is a transducer configured to apply a thermal signal. In certain such embodiments, all the transducers are configured to apply a thermal signal, optionally the same thermal signal.

In certain embodiments, one or more of the one or more transducers comprise a Peltier element configured to apply a thermal signal, optionally all of the one or more transducers comprise a Peltier element. In certain embodiments, one or more of the one or more transducers comprise a laser diode configured to apply a thermal signal, optionally all of the one or more transducers comprise a laser diode configured to apply a thermal signal. In certain embodiments, one or more of the one or more transducers comprise a electrically resistive element configured to apply a thermal signal, optionally all of the one or more transducers comprise a electrically resistive element configured to apply a thermal signal.

In certain embodiments the signal applied by the one or more transducers is a mechanical signal, optionally an ultrasonic signal. In certain alternative embodiments, the mechanical signal applied by the one or more transducers is a pressure signal.

In certain embodiments the signal applied by the one or more transducers is an electromagnetic signal, optionally an optical signal. In certain such embodiments, the one or more transducers comprise a laser and/or a light emitting diode configured to apply the optical signal.

In certain embodiments, the physiological response produced in the subject is one or more of: a systemic reduction in sympathetic tone, a localised reduction in sympathetic tone, a local increase in bone density, an increase in rate of endochondral ossification, an increase in osteoblast formation or activity, a decrease in osteoclast formation or activity, an increase in the rate of healing of a fracture in the bone innervated by the osteoneural nerve, an improvement in the quality of a healed fracture.

Techniques for measuring these characteristics are familiar to the skilled person and include those already described above.

In certain embodiments the osteoneural nerve is a nerve innervating a long bone. In certain embodiments the osteoneural nerve innervates a radius, ulna, humerus, femur, tibia, fibula, metacarpal, metatarsal, phalange or clavicle of the subject. In certain embodiments, the osteoneural nerve is a sympathetic nerve, optionally a sympathetic nerve innervating a long bone.

In certain embodiments the subject is a subject having one or more risk factors for abnormal bone healing. Risk factors for abnormal bone healing following fracture include, for example: a history of delayed or failed fracture healing; smoking; high-energy fracture event; immunosuppression;

suboptimal arterial circulation; diabetes; alcohol abuse, a collagen disorder.

In certain embodiments, the inhibition in neural activity as a result of applying the signal is a block on neural activity in the part of the nerve or nerves to which the signal is applied. That is, in such embodiments, the application of the signal blocks action potentials from travelling beyond the point of the block. In certain such embodiments, the modulation is a partial block - that is, neural activity is blocked in part of the nerve to which the signal is applied, for example a subset of nerve fibres. In certain alternative embodiments, the modulation is a full block - that is, neural activity is blocked in all of the nerve to which the signal is applied.

In certain embodiments, the signal applied to the nerve is an electrical signal that inhibits, preferably blocks, the neural activity in the nerve to which the signal is applied. In certain such embodiments the signal is an AC or DC waveform having a frequency of 1-50 kHz. In certain preferred embodiments, the nerve is a sympathetic osteoneural nerve.

In certain embodiments, the controller causes the signal to be applied intermittently. In certain such embodiments, the controller causes the signal to applied for a first time period, then stopped for a second time period, then reapplied for a third time period, then stopped for a fourth time period. In such an embodiment, the first, second, third and fourth periods run sequentially and consecutively. The series of first, second, third and fourth periods amounts to one application cycle. In certain such embodiments, multiple application cycles can run consecutively such that the signal is applied in phases, between which phases no signal is applied.

In such embodiments, the duration of the first, second, third and fourth time periods is independently selected. That is, the duration of each time period may be the same or different to any of the other time periods. In certain such embodiments, the duration of each of the first, second, third and fourth time periods is any time from 5 seconds (5s) to 24 hours (24h), 30s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to 6 h, 10 min to 6 h, 10 min to 4 h, 30 min to 4 h, 1 h to 4 h. In certain embodiments, the duration of each of the first, second, third and fourth time periods is 5s, 10s, 30s, 60s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h.

In certain embodiments wherein the controller causes the signal to be applied intermittently, the signal is applied for a specific amount of time per day. In certain such embodiments, the signal is applied for 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h per day. In certain such embodiments, the signal is applied continuously for the specified amount of time. In certain alternative such embodiments, the signal may be applied discontinuously across the day, provided the total time of application amounts to the specified time. In certain embodiments wherein the controller causes the signal to be applied intermittently, the signal is applied only when the subject is in a specific physiological state, for example when the subject is asleep.

In certain such embodiments, the apparatus further comprises a communication, or input, element via which the status of the subject can be indicated by the subject or a physician. In alternative embodiments, the apparatus further comprises a detector configured to detect the status of the subject, wherein the signal is applied only when the detector detects that the subject is in the specific state, for example when the subject is asleep.

In certain alternative embodiments, the controller causes the signal to be continuously applied. That is, once begun, the signal is continuously applied to the nerve or nerves. It will be appreciated that in embodiments wherein the signal is a series of pulses, gaps between pulses do not mean the signal is not continuously applied. In certain such embodiments, the signal is continuously applied for a time period of between 2 weeks and 10 weeks, for example 4 weeks to 8 weeks, for example 5-6 weeks.

In certain embodiments of the apparatus, the inhibition (for example block) of neural activity is temporary. That is, upon cessation of the signal, neural activity in the nerve or nerves returns substantially towards baseline neural activity within 1-60 seconds, or within 1-60 minutes, or within 1-24 hours, optionally 1-12 hours, optionally 1-6 hours, optionally 1-4 hours, optionally 1-2 hours. In certain such embodiments, the neural activity returns substantially fully to baseline neural activity. That is, the neural activity following cessation of the signal is substantially the same as the neural activity prior to the signal being applied - i.e. prior to modulation.

In certain alternative embodiments, the inhibition (for example block) of neural activity caused by the application of the signal or signals is substantially persistent. That is, upon cessation of the signal, neural activity in the nerve or nerves remains substantially the same as when the signal was being applied - i.e. the neural activity during and following the signal being applied is substantially the same.

In certain embodiments, the apparatus is suitable for at least partial implantation into the subject. In certain such embodiments, the apparatus is suitable to be wholly implanted in the subject. For the avoidance of doubt, the apparatus being "wholly implanted" does not preclude additional elements, independent of the apparatus but in practice useful for its functioning (for example, a remote wireless charging unit or a remote wireless manual override unit), being independently formed and external to the subject's body.

In certain embodiments, the transducer is a bioresorbable transducer, for example a bioresorbable electrode. In such embodiments, a bioresorbable transducer is a transducer that can be implanted into the body of a subject to serve its purpose of applying a signal, but will be biodegraded and absorbed by the body. Bioresorbable electrodes are described in Kim et al, Nature Materials 2010, Vol. 9 p. 511-517). For example, polyimide electrode arrays on a bioresorbable silk support are described in Kim et al. ibid).

In certain embodiments, the apparatus further comprises one or more power supply elements, for example a battery, and/or one or more communication elements. In a second aspect, the invention provides a method for treating bone fracture, the method comprising implanting an apparatus according to the first aspect, positioning a transducer of the apparatus in signalling contact with an osteoneural nerve innervating the fractured bone, and activating the apparatus. In such embodiments, the transducer is in signalling contact with the nerve when it is positioned such that the signal can be effectively applied to the nerve. The apparatus is activated when the apparatus is in an operating state such that the signal will be applied as determined by the controller.

In certain embodiments the method is for treating fracture of a long bone and the osteoneural nerve is a nerve innervating the long bone. In certain embodiments the method is for treating fracture of a radius, ulna, humerus, femur, tibia, fibula, or clavicle of a subject.

In certain embodiments, the osteoneural nerve is a sympathetic nerve.

In certain embodiments, the apparatus is implanted such that the signal is applied to the osteoneural nerve proximal to the nutrient foramens of the fractured bone.

In certain embodiments the subject is a subject having one or more risk factors for abnormal bone healing. Risk factors for abnormal bone healing following fracture include, for example: a history of delayed or failed fracture healing; smoking; high-energy fracture event; immunosuppression;

suboptimal arterial circulation; diabetes; alcohol abuse, a collagen disorder.

Implementation of all aspects of the invention (as discussed both above and below) will be further appreciated by reference to Figures 1A-1C.

Figures 1A-1C show how the invention may be put into effect using a neuromodulation apparatus which implanted in, located on, or otherwise disposed with respect to a subject in order to carry out any of the various methods described herein. In this way, a neuromodulation apparatus can be used to treat bone fracture, by modulating neural activity in at least one osteoneural nerves innervating the fractured bone.

In each of the Figures 1A-1C a single neuromodulation apparatus 100 is provided in respect of a single fractured bone 150, although multiple apparatuses, for example 2 or more apparatuses, could be provided or used in respect of each fracture. Each neuromodulation apparatus may be fully or partially implanted in the subject, or otherwise located, so as to provide neuromodulation of the respective osteoneural nerve. Each neuromodulation apparatus 100 may operate independently, or may operate in communication with each other.

Figure 1A shows schematically components of an implanted neuromodulation apparatus 100, in which the apparatus comprises several elements, components or functions grouped together in a single unit and implanted in the subject. A first such element is a transducer 102 which is shown in proximity to an osteoneural nerve 90 of the subject innervating the fractured bone 150. The transducer 102 may be operated by a controller element 104. The apparatus may comprise at least one further element such as a communication element 106, a detector element 108, a power supply element 110 and so forth. Each neuromodulation apparatus 100 may carry out the required neuromodulation independently, or in response to one or more control signals. Such a control signal may be provided by the controller element 104 according to an algorithm and/or in response to communications from one or more external sources received using the communications element.

Figure IB illustrates some ways in which the apparatus of Figure 1A may be differently distributed. For example, in Figure IB the neuromodulation apparatus 100 comprises a transducer 102 implanted proximally to a nutrient foramens 152 of the fractured bone 150 and in signalling contact with an osteoneural nerve 90 innervating the fractured bone 150. Other elements such as a controller element 104, a communication element 106 and a power supply element 110 are implemented in a separate control unit 130 which may be carried by the subject. The separate control unit 130 then controls the transducer in the neuromodulation apparatus via connection 132 which may for example comprise electrical wires and/or optical fibres for delivering signal and/or power to the transducers.

A variety of other ways in which the various functional elements could be located and grouped into the neuromodulation apparatus, a separate control unit 130 and elsewhere are of course possible. For example, a transducer of Figure IB could be used in the arrangement of Figures 1A or 1C or other arrangements.

Figure 1C illustrates some further ways in which some functionality of the apparatus of Figures 1A or IB is provided not implanted in the subject. For example, in Figure 1C an external power supply 140 is provided which can provide power in ways familiar to the skilled person, for example wirelessly, to implanted elements of the apparatus such as the transducer 102 and a communication element 106. An external controller 160 provides part or all of the functionality of the controller element 104, and/or provides other aspects of control of the apparatus, and/or provides data readout from the apparatus, and/or provides a data input facility 162. The data input facility could be used by a subject or other operator in various ways, for example to input data relating to the status of the subject in the sleep/wake cycle.

Each neuromodulation apparatus may be adapted to carry out the neuromodulation required using one or more physical modes of operation which typically involve applying a signal to a osteoneural nerve, such a signal typically involving a transfer of energy to (or from) the nerve(s). As already discussed, such modes may comprise modulating the nerve or nerves using an electrical signal, an optical signal, an ultrasound or other mechanical signal, a thermal signal, a magnetic or electromagnetic signal, or some other use of energy to carry out the required modulation. Such signals may be non-destructive signals. Such modulation may comprise increasing, inhibiting, blocking or otherwise changing the pattern of neural activity in the nerve or nerves. To this end, the transducer 102 illustrated in Figure 1A could be comprised of an electrode, a photon source, an ultrasound transducer, a source of heat, or another type of transducer arranged to put the required neuromodulation into effect.

In certain embodiments, for example the embodiment shown in Figure 1C, the transducer 102 may be an electrode, optionally a bioresorbable electrode. A bioresorbable electrode has the advantage that the electrode would not need to be explanted from the subject after fracture healing.

Bioresorbable electrodes would be particularly advantageous in configurations such as those shown in Figure 1C, where the majority of or all the remaining elements of the apparatus are external to the subject.

The neural modulation apparatus may be arranged to inhibit neural activity in the osteoneural nerve by using the transducer(s) to apply a voltage or current, for example a direct current (DC) such as a charge balanced direct current, or an AC waveform, or both. The apparatus may be arranged to use the transducer(s) to apply a DC ramp, then apply a first AC waveform, wherein the amplitude of the waveform increases during the period the waveform is applied, and then apply a second AC waveform.

In certain preferred embodiments, wherein the signal comprises one or more AC waveforms, each AC waveform is independently selected from an AC waveform of 1-50 kHz, 5-25 kHz, optionally 10- 25 kHz, optionally 15-25 kHz, optionally 20-25 kHz. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently, such that the waveform can have a frequency of at least 1 kHz, at least 5 kHz, at least 10 kHz, at least 15 kHz, or at least 20 kHz, and can have a frequency that does not exceed 50 kHz, or 45 kHz, or 40 kHz, or 35 kHz, or 30 kHz, or 25 kHz. In certain embodiments, the signal comprises a DC waveform and/or an AC waveform having a voltage of 1-20V. In certain preferred embodiments, the signal has a voltage of 5-15V, optionally 10- 15V. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently such that the voltage can be at least 5 V, or at least 10 V, and does not exceed about 20 V, or about 15 V.

In certain embodiments, the signal is an electrical signal having a current of 10-20,000 μΑ, optionally 10-15,000 μΑ, optionally 10-10000 μΑ, optionally 10-5000 μΑ, optionally 10-2000 μΑ, optionally 20- 1000 μΑ, optionally 20-500 μΑ, optionally 50-250 μΑ. In certain embodiments the electrical signal has a current of at least 10 μΑ, at least 20 μΑ, at least 50 μΑ, at least 60 μΑ, at least 70 μΑ, at least 80 μΑ, at least 90 μΑ, at least 100 μΑ, at least 110 μΑ, at least 150 μΑ, at least 180 μΑ, at least 200 μΑ, at least 250 μΑ. In certain embodiments the electrical signal has a current that does not exceed 20,000 μΑ, or does not exceed 15,000, or does not exceed 10,000 μΑ, or does not exceed 5000 μΑ, or does not exceed 2000 μΑ, or does not exceed 1000 μΑ, or does not exceed 750 μΑ, or does not exceed 500 μΑ, or does not exceed 250 μΑ.

Thermal methods of neuromodulation typically manipulate the temperature of a nerve to inhibit signal propagation. For example, Patberg et al. (Blocking of impulse conduction in peripheral nerves by local cooling as a routine in animal experimentation; Journal of Neuroscience Methods

1984;10:267-75, which is incorporated herein by reference) discuss how cooling a nerve blocks signal conduction without an onset response, the block being both reversible and fast acting, with onsets of up to tens of seconds. Heating the nerve can also be used to block conduction, and is generally implemented in a small implantable or localised transducer or device, for example using infrared radiation from laser diode or a thermal heat source such as an electrically resistive element, which can be used to provide a fast, reversible, and spatially very localised heating effect (see for example Duke et al. J Neural Eng. 2012 Jun;9(3):036003. Spatial and temporal variability in response to hybrid electro-optical stimulation, which is incorporated herein by reference). Either heating, or cooling, or both could be provided using a Peltier element. Optogenetics is a technique that genetically modifies cells to express photosensitive features, which can then be activated with light to modulate cell function. Many different optogenetic tools have been developed that can be used to inhibit neural firing. A list of optogenetic tools to suppress neural activity has been compiled (Epilepsia. 2014 Oct 9. doi: 10.1111/epi.12804. WONOEP

appraisal: Optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Ritter LM et al., which is incorporated herein by reference). Acrylamine-azobenzene-quaternary ammonium (AAQ) is a photochromic ligand that blocks many types of K+ channels and in the cis configuration, the relief of K+ channel block inhibits firing (Kramer RH et al Nat Neurosci. 2013 Jul; 16(7):816-23. doi: 10.1038/nn.3424. Optogenetic pharmacology for control of native neuronal signalling proteins, which is incorporated herein by reference). By adapting Channelrhodopsin-2 and introducing it into mammalian neurons with the lentivirus, it is possible to control inhibitory synaptic transmission (Boyden ES Nat Neurosci. 2005 Sep;8(9):1263-8. Epub 2005 Aug 14, incorporated herein by reference). Instead of using an external light source such as a laser or light emitting diode, light can be generated internally by introducing a gene based on firefly luciferase (Land BB et al, Front Behav Neurosci. 2014 Apr 1;8: 108., incorporated herein by reference). The internally generated light has been sufficient to generate inhibition.

Mechanical forms of neuromodulation can include the use of ultrasound which may conveniently be implemented using external instead of implanted ultrasound transducers. Other forms of mechanical neuromodulation include the use of pressure (for example see "The effects of compression upon conduction in myelinated axons of the isolated frog sciatic nerve" by Robert Fern and P. J. Harrison Br.j. Anaesth. (1975), 47, 1123, which is incorporated herein by reference).

Some electrical forms of neuromodulation may use direct current (DC), or alternating current (AC) waveforms applied to a nerve using one or more electrodes. A DC block may be accomplished by gradually ramping up the DC waveform amplitude (Bhadra and Kilgore, IEEE Transactions on Neural systems and rehabilitation engineering, 2004 12(3) pp313-324, which is incorporated herein by reference). Some AC techniques include H FAC or KHFAC (high-frequency or kilohertz frequency) to provide a reversible block (for example see Kilgore, K. L. & Bhadra, N. Med. Biol. Eng. Comput. (2004) 42: 394., the content of which is incorporated herein by reference for all purposes). In the work of Kilgore and Bhadra, a proposed waveform was sinusoidal or rectangular at 3-5 kHz, and typical signal amplitudes that produced block were 3 - 5 Volts or 0.5 to 2.0 milliAmperes peak to peak.

HFAC may typically be applied at a frequency of between 1 and 50 kHz at a duty cycle of 100% (Bhadra, N. et al., Journal of Computational Neuroscience, 2007, 22(3), pp 313-326, which is incorporated herein by reference). Methods for selectively blocking activity of a nerve by application of a waveform having a frequency of 5 - 10 kHz are described in US 7,389,145 (incorporated herein by reference). Similarly, US 8,731,676 (incorporated herein by reference) describes a method of ameliorating sensory nerve pain by applying a 5-50 kHz frequency waveform to a nerve.

In a third aspect, the invention provides a method of treating bone fracture in a subject, the method comprising applying a signal to a part or all of an osteoneural nerve innervating the fractured bone to inhibit the neural activity of said nerve in the subject.

In certain embodiments the method is a method of treating fracture of a long bone and the osteoneural nerve is a nerve innervating the long bone. In certain embodiments the method is for treating fracture of a radius, ulna, humerus, femur, tibia, fibula, metacarpal, metatarsal, phalange or clavicle of a subject.

In certain embodiments, the osteoneural nerve is a sympathetic nerve.

In certain embodiments, the signal is applied to the osteoneural nerve proximal to the nutrient foramens of the fractured bone.

In certain embodiments the subject is a subject having one or more risk factors for abnormal bone healing. Risk factors for abnormal bone healing following fracture include, for example: a history of delayed or failed fracture healing; smoking; high-energy fracture event; immunosuppression;

suboptimal arterial circulation; diabetes; alcohol abuse, a collagen disorder.

In certain embodiments, the signal is applied by a neuromodulation apparatus comprising a transducer configured to apply the signal. In certain preferred embodiments the neuromodulation apparatus is at least partially implanted in the subject. In certain embodiments, the

neuromodulation apparatus is wholly implanted in the subject. For the avoidance of doubt, the apparatus being "wholly implanted" does not preclude additional elements, independent of the apparatus but in practice useful for its functioning (for example, a remote wireless charging unit or a remote wireless manual override unit), being independently formed and external to the subject's body.

In certain embodiments, the transducer is a bioresorbable transducer, for example a bioresorbable electrode. In such embodiments, a bioresorbable transducer is a transducer that can be implanted into the body of a subject to serve its purpose of applying a signal, but will be biodegraded and absorbed by the body. Bioresorbable electrodes are described in Kim et al, Nature Materials 2010, Vol. 9 p. 511-517). For example, polyimide electrode arrays on a bioresorbable silk support are described in Kim et al. ibid).

In certain embodiments, treatment of bone fracture is indicated by an improvement in a measurable physiological parameter, selected from: a systemic reduction in sympathetic tone, a localised reduction in sympathetic tone, a local increase in bone density, an increase in rate of endochondral ossification, an increase in osteoblast formation, a decrease in osteoclast formation, an increase in the rate of fracture healing, an improvement in the quality of a healed fracture.

Suitable methods for determining the value for any given parameter would be appreciated by the skilled person. For example: systemic sympathetic tone can be determined by direct measurement of sympathetic nerve activity, by measurement of levels of urinary catecholamines, measurement of the sympatho-vagal balance via heart rate variability (lower heart rate variability being indicative of a decrease in sympathetic tone); a localised reduction in sympathetic tone can be determined by measurement of catecholamines in and around the fractured bone, for example by positioning a measurement device proximal to the nutrient foramens; rate of fracture healing can be determined, for example, by serial radiographs and clinical assessment of the fracture; bone density can be determined, for example, by dual-energy X-ray absorptiometry (DEXA) scan or by conventional radiographic (e.g. X-ray) assessment; quality of a healed fracture can be indicated by, for example, the number of bridging trabeculae, the level of sclerotic fracture edges, persistent fracture lines and/or progressive deformity, where the absence of bridging trabeculae, the presence or high levels of sclerotic fracture edges, the presence of persistent fracture lines, and the presence of progressive deformity indicate poor quality of fracture healing.

Inhibition of neural activity in the nerve is such that application of the signal results in the neural activity in at least part of the nerve being reduced compared to the neural activity in that part of the nerve prior to the signal being applied. Therefore, in certain embodiments, a result of applying the signal is at least partial inhibition of neural activity in the nerve. In certain embodiments, a result of applying the signal is full inhibition of neural activity in the nerve.

In certain embodiments, the inhibition in neural activity as a result of applying the signal is a block on neural activity in the nerve to which a signal is applied. That is, in such embodiments, the application of the signal blocks action potentials from travelling beyond the point of the block in the part of the nerve to which the signal is applied. In certain such embodiments, the modulation is a partial block - that is, neural activity is blocked in part of the nerve to which the signal is applied, for example a subset of nerve fibres. In certain alternative embodiments, the modulation is a full block - that is, neural activity is blocked in all of the nerve to which the signal is applied.

An example of a signal that inhibits neural activity is an electrical signal of kilohertz frequency. A further example is an electrical signal that comprises a DC ramp followed by a plateau and charge- balancing, followed by a first AC waveform, wherein the amplitude of the first AC waveform increases during the period in which the first AC waveform is applied, followed by a second AC waveform having a lower amplitude and/or lower frequency than the first AC waveform.

In certain embodiments, the signal is applied intermittently. In certain such embodiments, the signal is applied for a first time period, then stopped for a second time period, then reapplied for a third time period, then stopped for a fourth time period. In such an embodiment, the first, second, third and fourth periods run sequentially and consecutively. The series of first, second, third and fourth periods amounts to one application cycle. In certain such embodiments, multiple application cycles can run consecutively such that the signal is applied in phases, between which phases no signal is applied.

In such embodiments, the duration of the first, second, third and fourth time periods is

independently selected. That is, the duration of each time period may be the same or different to any of the other time periods. In certain such embodiments, the duration of each of the first, second, third and fourth time periods is any time from 5 seconds (5s) to 24 hours (24h), 30s to 12 h, 1 min to 12 h, 5 min to 8 h, 5 min to 6 h, 10 min to 6 h, 10 min to 4 h, 30 min to 4 h, 1 h to 4 h. In certain embodiments, the duration of each of the first, second, third and fourth time periods is 5s, 10s, 30s, 60s, 2 min, 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h.

In certain embodiments wherein the signal is applied intermittently, the signal is applied for a specific amount of time per day. In certain such embodiments, the signal is applied for 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h per day. In certain such embodiments, the signal is applied continuously for the specified amount of time. In certain alternative such embodiments, the signal may be applied discontinuously across the day, provided the total time of application amounts to the specified time.

In certain embodiments wherein the signal is applied intermittently, the signal is applied only when the subject is in a specific state. In certain such embodiments, the signal is applied only when the subject is asleep. In certain alternative embodiments, the signal is applied only when the subject is awake. In certain embodiments in which the signal is applied by a neuromodulation apparatus, the apparatus may further comprise a detector configured to detect the status of the subject, wherein the signal is applied only when the detector detects that the subject is in the specific state.

In certain alternative embodiments, the controller causes the signal to be continuously applied. That is, once begun, the signal is continuously applied to the nerve or nerves. It will be appreciated that in embodiments wherein the signal is a series of pulses, gaps between pulses do not mean the signal is not continuously applied. In certain such embodiments, the signal is continuously applied for a time period of between 2 weeks and 10 weeks, for example 4 weeks to 8 weeks, for example 5-6 weeks.

In certain embodiments of the methods, the inhibition of neural activity caused by the application of the signal is temporary. That is, upon cessation of the signal, neural activity in the nerve or nerves returns substantially towards baseline neural activity within 1-60 seconds, or within 1-60 minutes, or within 1-24 hours, optionally 1-12 hours, optionally 1-6 hours, optionally 1-4 hours, optionally 1-2 hours. In certain such embodiments, the neural activity returns substantially fully to baseline neural activity. That is, the neural activity following cessation of the signal is substantially the same as the neural activity prior to the signal being applied - i.e. prior to modulation.

In certain alternative embodiments, the inhibition of neural activity caused by the application of the signal is substantially persistent. That is, upon cessation of the signal, neural activity in the nerve or nerves remains substantially the same as when the signal was being applied - i.e. the neural activity during and following modulation is substantially the same.

In certain embodiments, the signal applied is a non-destructive signal.

In certain embodiments of the methods according to the invention, the signal applied is an electrical signal, an electromagnetic signal (optionally an optical signal), a mechanical (optionally ultrasonic) signal, a thermal signal, a magnetic signal or any other type of signal. In certain embodiments the signal is an electrical signal.

In embodiments in which the signal is applied by a neuromodulation apparatus comprising a transducer, the transducer may be comprised of an electrode, a photon source, an ultrasound transducer, a source of heat, or another types of transducer arranged to put the signal into effect.

In certain embodiments, the signal is an electrical signal, for example a voltage or current. In certain such embodiments the signal comprises a direct current (DC) waveform, such as a charge balanced DC waveform, or an alternating current (AC) waveform, or both a DC and an AC waveform.

In certain embodiments the signal comprises a DC ramp followed by a plateau and charge-balancing, followed by a first AC waveform, wherein the amplitude of the first AC waveform increases during the period in which the first AC waveform is applied, followed by a second AC waveform having a lower amplitude and/or lower frequency than the first AC waveform. In certain such embodiments, the DC ramp, first AC waveform and second AC waveform are applied substantially sequentially.

In certain embodiments the signal is an electrical signal comprising an AC waveform of kilohertz frequency and/or DC waveform of kilohertz frequency. In certain embodiments, the signal comprises an AC or DC waveform having a frequency of 1-50 kHz, 5-25 kHz, optionally 10-25 kHz, optionally 15- 25 kHz, optionally 20-25 kHz. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently, such that the waveform can have a frequency of at least 1 kHz, at least 5 kHz, at least 10 kHz, at least 15 kHz, or at least 20 kHz, and can have a frequency that does not exceed 50 kHz, or 45 kHz, or 40 kHz, or 35 kHz, or 30 kHz, or 25 kHz.

In certain embodiments, the signal comprises a DC waveform and/or an AC waveform having a voltage of 1-20V. In certain preferred embodiments, the signal has a voltage of 5-15V, optionally 10- 15V. One of skill in the art will appreciate that the lower and upper limits of such ranges can vary independently such that the voltage can be at least 5 V, or at least 10 V, and does not exceed about 20 V, or about 15 V.

In certain embodiments, the signal is an electrical signal having a current of 10-20,000 μΑ, optionally 10-15,000 μΑ, optionally 10-10000 μΑ, optionally 10-5000 μΑ, optionally 10-2000 μΑ, optionally 20- 1000 μΑ, optionally 20-500 μΑ, optionally 50-250 μΑ. In certain embodiments the electrical signal has a current of at least 10 μΑ, at least 20 μΑ, at least 50 μΑ, at least 60 μΑ, at least 70 μΑ, at least 80 μΑ, at least 90 μΑ, at least 100 μΑ, at least 110 μΑ, at least 150 μΑ, at least 180 μΑ, at least 200 μΑ, at least 250 μΑ. In certain embodiments the electrical signal has a current that does not exceed 20,000 μΑ, or does not exceed 15,000, or does not exceed 10,000 μΑ, or does not exceed 5000 μΑ, or does not exceed 2000 μΑ, or does not exceed 1000 μΑ, or does not exceed 750 μΑ, or does not exceed 500 μΑ, or does not exceed 250 μΑ.

In certain embodiments wherein the signal is a thermal signal, the signal reduces the temperature of the nerve (i.e. cools the nerve). In certain alternative embodiments, the signal increases the temperature of the nerve (i.e. heats the nerve). In certain embodiments, the signal both heats and cools the nerve.

In certain embodiments wherein the signal is a mechanical signal, the signal is an ultrasonic signal. In certain alternative embodiments, the mechanical signal is a pressure signal.

In a fourth aspect, the invention provides a neuromodulatory electrical waveform for use in treating bone fracture in a subject, wherein the waveform is a AC or DC waveform having a frequency of 1-50 kHz, such that, when applied to a osteoneural nerve innervating the fractured bone, preferably a sympathetic osteoneural nerve innervating the fractured bone, the waveform inhibits neural signalling in the nerve.

In certain embodiments the bone is a long bone and the osteoneural nerve is a nerve innervating the long bone. In certain embodiments the bone is a radius, ulna, humerus, femur, tibia, fibula, metacarpal, metatarsal, phalange or clavicle of a subject.

In certain embodiments the waveform blocks sympathetic neural activity in the osteoneural nerve. In a fifth aspect, the invention provides use of a neuromodulation apparatus for treating bone fracture in a subject by inhibiting neural activity in a osteoneural nerve innervating the fractured bone of the subject, preferably a sympathetic osteoneural nerve innervating the fractured bone.

In certain embodiments the bone is a long bone and the osteoneural nerve is a nerve innervating the long bone. In certain embodiments the bone is a radius, ulna, humerus, femur, tibia, fibula, metacarpal, metatarsal, phalange or clavicle of a subject.

In a preferred embodiment of all aspects of the invention, the subject or patient is a mammal, more preferably a human, such as a patient with an unresolved (e.g., non-union or delayed union) bone fracture.

In a preferred embodiment of all aspects of the invention, the signal or signals is/are applied substantially exclusively to the nerves or nerve fibres specified, and not to other nerves or nerve fibres.

The foregoing detailed description has been provided by way of explanation and illustration, and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents.

Examples

IL-6 can be used as early biomarker of changes to the sympathetic input to the bone

Experimental Design: Three groups (chronic immobilization stress (CIS), isoproterenol (ISO), and vehicle (Veh)) of 6 male WT mice (6mo age) were used. Isoproterenol (ISO) (3mg/kg body weight in saline) or Vehicle (saline) were administered IP (100 ul volume). Animals were returned to the cage for 2h prior to sac. CIS animals were placed in clean restraint tubes, and placed back into a tilted cage, so that the animals' tails were ~30 degrees above their heads, for 2h. To stagger the animal euthanasia and tissue harvest, two animals of each treatment (six total) were treated and sacrificed at a time. After treatments, animals were quickly euthanized with isoflorane and cervical dislocation. Femur and tibia were dissected out, and connective tissue cleaned away. Femurs had the epiphyses clipped, and centrifuged to separate the marrow from the cortex, and each frozen separately for future use. Whole tibia were snap frozen in LiqN2, crushed into powder while frozen. RNA was extracted from the frozen whole tibia powder with Trizol. 1000 ng of RNA was used, after DNAse treatment, to synthesize cDNA with a reverse transcriptase kit. The cDNA was diluted with 4x volume of dH20, and quantified by qPCR. Values were normalized with the "housekeeping gene" Gapdh.

Results: Both CIS and ISO increased 116/Gapdh expression compared to vehicle, whereas there was no detectable difference with Rankl expression. It should be noted that Rankl expression was detected as a baseline, suggesting that there are cells in the whole tibia that transcribe Rankl mRNA chronically (Figure 4). Block of stress-induced sympathetic tone reduces raised I L-6 expression

Experimental Design: Four groups (CIS/Ctrl +/- Vehicle/Propanolol) of 5 male WT mice (7wk age) were used for this study. Propanolol (Prop) (5mg/kg body weight in saline) or Vehicle (saline) were administered IP (200 ul volume) 15min prior to stress protocol. Animals were placed in a clean cage until sacrifice. CIS animals were placed in clean restraint tubes, and placed back into a tilted cage, so that the animals' tails were ~30 degrees above their heads, for 2h.

After treatments, animals were quickly euthanized with isoflorane and cervical dislocation. Blood was drawn via cardiac puncture and put into heparinized tubes on ice, and serum was isolated by centrifugation. Intrascapular brown adipose tissue (BAT) were harvested, cleaned of connective tissue, and snap frozen. Femur and tibia were dissected out, and connective tissue cleaned away. Femurs had the epiphyses clipped, and centrifuged to separate the marrow from the cortex, and each frozen separately for future use. Whole tibia were snap frozen in LiqN2, crushed into powder while frozen. RNA was extracted from the frozen whole tibia powder with Trizol. 1000 ng of RNA was used, after DNAse treatment, to synthesize cDNA with a reverse transcriptase kit. The cDNA was diluted with 4x volume of dH20, and quantified by qPCR. Values were normalized with the

"housekeeping gene" Hprt.

Results: Propranolol blocked I L-6 expression induced by CIS compared Veh+CIS, bringing it to levels similar to Veh+Ctrol (Figure 5), suggesting increase in IL-6 expression is mediated via β

adrenoreceptors. This is consistent with the idea that CIS induces endogenous stress which releases the sympathetic neurotransmitter norepinephrine (NE) onto target tissues. Osteoblasts of bone, a target of the sympathetic nervous system, potently express I L-6 in response to b2AR signalling.

Conclusion

IL-6 exerts effects on bone homeostasis, repair and is linked to osteoclastogenesis. I L-6 stimulates production of RANK ligand by osteoblast, which, in turn, catalyses the formation of osteoclasts. It has been demonstrated in IL-6 KO mice that I L-6 ablation improves fracture healing. Osteoclast counts and load-to-failure were significantly reduced at 2-weeks post-fracture (Wallace et al., J Orthop Res. 2011 Sep;29(9):1437-42, incorporated herein by reference). It has been shown that I L-6 increases early after fracture in a femur fracture model (measured using microdialysis, Forster et al. Acta Orthop. 2013 Feb;84(l):76-8, Kidd et al. Bone. 2010 Feb;46(2):369-78, incorporated herein by reference). Similarly, data in human fracture healing analysis showed that circulating IL-6 is increased after fracture (Pesic et al., Mol Cell Biochem. 2017 Feb 16).

In a model in which levels of IL-6 is raised in bone due to stress (CIS), it is shown herein that inhibiting sympathetic signalling (using beta-antagonist propranolol) can restore I L-6 levels to normal levels. It is therefore expected that blocking neural activity in the osteoneural nerve, preferably the sympathetic osteoneural nerve, innervating the fractured bone will improve the fracture healing process. Inhibiting the activity will lower the raised levels of I L-6 resulting from the fracture and thereby reduce osteoclast activity. Reduced osteoclast activity is expected to result in improved quality of fracture healing, such as that observed in IL-6 KO mice (Wallace et al, supra).

Claims

Claims:
1. An apparatus or system for treating bone fracture in a subject, the apparatus or system, the apparatus or system comprising:
a neural interfacing element comprising one or more transducers, each configured to apply a signal to an osteoneural nerve of the subject; and
a controller operably coupled to the transducer, the controller controlling the signal to be applied by the transducer, such that the signal inhibits the neural activity of the nerve to reduce sympathetic tone in the subject.
2. An apparatus or system for inhibiting the neural activity of an osteoneural nerve of a
subject, the apparatus or system comprising:
a neural interfacing element comprising one or more transducers, each configured to apply a signal to an osteoneural nerve of the subject; and
a controller operably coupled to the transducer, the controller controlling the signal to be applied by the transducer, such that the signal inhibits the neural activity of the nerve to reduce sympathetic tone in the subject.
3. An apparatus or system according to claim 1 or 2, wherein the neural interfacing element is configured to apply a signal to a branch of the osteoneural nerve that innervates the nutrient foramen.
4. An apparatus or system according to claim 3, wherein the neural interfacing element is positioned proximal to the nutrient foramen.
5. An apparatus or system according to any one of the preceding claims, wherein the
osteoneural nerve innervates a fractured bone.
6. An apparatus or system according to any one of the preceding claims, wherein the
osteoneural nerve innervates a long bone.
7. An apparatus according to any one of the preceding claims, wherein the signal applied by each of the one or more transducers is a non-destructive signal.
8. An apparatus according to any one of the preceding claims, wherein the signal fully inhibits neural activity in the nerve.
9. An apparatus according to any one of the preceding claims, wherein the signal at least partially blocks neural activity in the nerve, optionally fully blocks neural activity in the nerve.
10. An apparatus according any one of the preceding claims, wherein the signal applied by the transducer is selected from an electrical signal, an electromagnetic signal, an optical signal, an ultrasonic signal, a mechanical signal and a thermal signal.
11. An apparatus according to claim 10, wherein the signal is an electrical signal, and the
transducer configured to apply the signal is an electrode.
12. An apparatus according to 11, wherein the signal comprises an alternating current (AC) or direct current (DC) waveform having a frequency of 1-50 kHz, optionally at least 5 kHz, or at least 10 kHz or at least 15 kHz, or at least 20 kHz, and optionally less than 25 KHz, or less than 20 kHz, or less than 15 kHz..
13. An apparatus according to claim 11 or 12, wherein the signal comprises a charge-balanced direct current (DC) waveform.
14. An apparatus according to any one of claims 11-13, wherein the signal has a current of 10- 20,000 μΑ, optionally 10-15,000 μΑ, optionally 10-10000 μΑ, optionally 10-5000 μΑ, optionally 10-2000 μΑ, optionally 20-1000 μΑ, optionally 20-500 μΑ, optionally 50-250 μΑ.
15. An apparatus according to any one of claims 11-14, wherein the signal has a voltage of 1- 20V, optionally 5-15V, optionally 10-15V.
16. An apparatus or system according to any one of the preceding claims, wherein the reduction in sympathetic tone is a systemic reduction in sympathetic tone or a localised reduction in sympathetic tone.
17. An apparatus according to any one of the preceding claims, wherein the reduction in
sympathetic tone results in one or more of: a local increase in bone density, an increase in rate of endochondral ossification, an increase in osteoblast formation or activity, a decrease in osteoclast formation or activity, an increase in the rate of healing of a fracture in the bone innervated by the osteoneural bone, an improvement in the quality of a healed fracture.
18. An apparatus according to any one of the preceding claims, wherein the osteoneural nerve in which the neural activity is modulated is an osteoneural nerve innervating a long bone.
19. An apparatus according to any one of the preceding claims, wherein the osteoneural nerve in which the neural activity is modulated is a sympathetic osteoneural nerve.
20. An apparatus according to any one of the preceding claims, wherein the modulation in neural activity as a result of the one or more transducers applying the signal is substantially persistent.
21. An apparatus according to any one of claims 1-20, wherein the modulation in neural activity is temporary.
22. An apparatus according to any one of the preceding claims, wherein the apparatus is
suitable for at least partial implantation into the subject, optionally full implantation into the subject.
23. An apparatus according to claim 22, wherein the transducer is a bioresorbable transducer.
24. A method of treating bone fracture in a subject comprising:
i. implanting in the subject a neural interfacing element of an apparatus or system according to any one of claims 1-23; ii. positioning the transducer of the apparatus in signalling contact with a osteoneural nerve of the subject;
iii. activating the apparatus or system.
25. A method according to claim 24, wherein activating the apparatus or system reduces
sympathetic tone.
26. A method according to claim 24 or 25, wherein the method is a method of treating bone fracture in a long bone.
27. A method according to any one of claims 23-26, wherein the apparatus is implanted such that the signal is applied to the osteoneural nerve proximal to the nutrient foramens of the fractured bone.
28. A method according to any one of claims 23-27, wherein the osteoneural nerve is a
sympathetic osteoneural nerve.
29. A method according to any one of claims 23-28, wherein the subject has one or more risk factors for abnormal bone healing.
30. A method of treating bone fracture in a subject, the method comprising applying a signal to a part or all of an osteoneural nerve innervating the fractured bone to inhibit the neural activity of said nerve in the subject.
31. A method according to claim 30, wherein the fractured bone is a long bone.
32. A method according to claim 30 or 31, wherein the signal is applied to the osteoneural nerve proximal to the nutrient foramens of the fractured bone.
33. A method according to any one of claims 30-32, wherein the osteoneural nerve is a
sympathetic nerve.
34. A method according to any one of claims 30-33, wherein the signal is applied by a
neuromodulation apparatus comprising a transducer configured to apply the signal.
35. A method according to claim 34, wherein the neuromodulation apparatus is at least partially implanted in the subject, optionally wholly implanted in the subject.
36. A method according to claim 34 or 35, wherein the transducer of the neuromodulation apparatus is a bioresorbable transducer.
37. A method according to any one of claims 30-36, wherein treatment of the bone fracture is indicated by an improvement in a measurable physiological parameter, wherein said improvement in a measurable physiological parameter is at least one of: a systemic reduction in sympathetic tone, a localised reduction in sympathetic tone, a local increase in bone density, an increase in rate of endochondral ossification, an increase in osteoblast formation, a decrease in osteoclast formation an increase in the rate of healing of the fracture, an improvement in the quality of the healed fracture.
38. A method according to any one of claims 30-37, wherein the modulation in neural activity as a result of applying the signal is full inhibition of neural activity in the nerve to which a signal is applied.
39. A method according to any one of claims 30-38, wherein the modulation in neural activity as a result of applying the signal is at least a partial block of neural activity, optionally a full block of neural activity, in the nerve to which the signal is applied.
40. A method according to any one of claims 30-39, wherein the modulation in neural activity is substantially persistent.
41. A method according to any one of claims 30-39 wherein the modulation in neural activity is temporary.
42. A method according to any one of claims 30-41, wherein the signal applied is a nondestructive signal.
43. A method according to any one of claims 30-42, wherein the signal applied is an electrical signal, an electromagnetic signal, an optical signal, a mechanical signal, an ultrasonic signal or a thermal signal.
44. A method according to claim 43, wherein the signal is an electrical signal and, when the signal is applied by a neuromodulation apparatus, the transducer of the apparatus is an electrode.
45. A method according to claim 44, wherein the signal is an electrical signal and comprises an alternating current (AC) waveform or direct current (DC) waveform having a frequency of 1- 50 kHz, optionally 5-25 kHz, optionally 10-25 kHz, optionally 15-25 kHz, optionally 20-25 kHz.
46. A method according to claim 44 or 45, wherein the signal comprises a charge-balanced direct current (DC) waveform.
47. A method according to any one of claims 44-46, wherein the signal has a current of 10- 20,000 μΑ, optionally 10-15,000 μΑ, optionally 10-10000 μΑ, optionally 10-5000 μΑ, optionally 10-2000 μΑ, optionally 20-1000 μΑ, optionally 20-500 μΑ, optionally 50-250 μΑ.
48. A method according to any one of claims 44-47, wherein the signal has a voltage of 1-20V, optionally 5-15V, optionally 10-15V.
49. A method according to any one of claims 30-48, wherein the subject has one or more risk factors for abnormal bone healing.
50. An apparatus or method according to any preceding claim, wherein the subject is a
mammalian subject, optionally a human subject.
51. An apparatus or method according to claim 50, wherein the subject is a patient with an unresolved bone fracture.
52. A neuromodulatory electrical waveform for use in treating bone fracture in a subject, wherein the waveform is a AC or DC waveform having a frequency of 1-50 kHz, such that, when applied to a osteoneural nerve innervating the fractured bone, preferably a sympathetic osteoneural nerve innervating the fractured bone, the waveform inhibits neural signalling in the nerve.
53. Use of a neuromodulation apparatus for treating bone fracture in a subject by inhibiting neural activity in an osteoneural nerve innervating the fractured bone of the subject, preferably a sympathetic osteoneural nerve innervating the fractured bone.
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