[go: up one dir, main page]

WO2007108001A2 - Remodelage de ligament - Google Patents

Remodelage de ligament Download PDF

Info

Publication number
WO2007108001A2
WO2007108001A2 PCT/IL2007/000378 IL2007000378W WO2007108001A2 WO 2007108001 A2 WO2007108001 A2 WO 2007108001A2 IL 2007000378 W IL2007000378 W IL 2007000378W WO 2007108001 A2 WO2007108001 A2 WO 2007108001A2
Authority
WO
WIPO (PCT)
Prior art keywords
ligament
spinal
remodeling
energy
optionally
Prior art date
Application number
PCT/IL2007/000378
Other languages
English (en)
Other versions
WO2007108001A3 (fr
Inventor
Haim Dror Blecher
Original Assignee
Haim Dror Blecher
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haim Dror Blecher filed Critical Haim Dror Blecher
Publication of WO2007108001A2 publication Critical patent/WO2007108001A2/fr
Publication of WO2007108001A3 publication Critical patent/WO2007108001A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0078—Ultrasound therapy with multiple treatment transducers

Definitions

  • the present invention relates to spinal ligament remodeling, for example altering Ligamentum Flavum (LF) conformation. BACKGROUND OF THE INVENTION
  • Spinal stenosis is generally defined as the narrowing of the spinal canal. Typically, pressure on the spinal cord and/or nerves is the result. Spinal stenosis can occur in a variety of ways in the spine. About 75% of cases of spinal stenosis occur in the low back (lumbar spine). Often, the sciatic nerve is affected. Underlying causes:
  • the ligaments of the spine can thicken with age.
  • spurs may develop on the bones and project into the spinal canal.
  • the cushioning disks between the vertebrae may begin to deteriorate.
  • the facet joints also may begin to thicken.
  • stenosis there is a genetic predisposition towards stenosis, for example if the spinal canal is too small at birth. Genetic predisposition may cause early onset stenosis.
  • stenosis Another potential cause of stenosis is abnormal growth of soft tissue. This can affect the spinal canal directly by inflammation or by growth of tissue into the canal. Tissue growth may lead to bone resorption or displacement of bone and the eventual collapse of the supporting framework of the spinal column. Symptoms
  • stenosis Common symptoms of stenosis include, but are not limited to, low back pain and/or pain in the legs. Stenosis may pinch the nerves that control muscle power and sensation in the legs. Additional symptoms may include a foot-slapping gait, clumsiness, numbness, tingling, hot or cold feelings in the legs, weakness or a heavy and tired feeling in the legs. Patients may adopt a hunched or bent-over posture in order to alleviate these symptoms. Diagnosis
  • spinal stenosis can be difficult to diagnose. Often, stenosis patients have no prior history of back problems or any discernible injury. Response to treatment may be a diagnostic indicator. For example, relief of symptoms by postural changes and/or non-steroidal anti-inflammatory drugs may be indicative of onset of stenosis. In some cases, sophisticated spinal imaging (e.g. MRI or myelogram or CT) may be required to confirm the diagnosis. In some cases there is no apparent difference in medical images from asymptomatic and symptomatic patients. In some cases a patient may exhibit marked clinical improvement with no apparent change in spine anatomy as assessed by imaging. Available treatment options
  • Posture adjustment People with spinal stenosis may find that flexing the spine by leaning forward while walking relieves their symptoms. Lying with the knees drawn up to the chest also can offer some relief. These positions enlarge the space available to the nerves and may make it easier for people with stenosis to walk longer distances. However, this hunched or bent posture may become a major symptom as the condition worsens. In mild cases, rest followed by a gradual resumption of activity can relieve symptoms. Aerobic activity such as bicycling is often recommended. Alternatively or additionally, weight reduction can also relieve some of the load on the spine. A lumbar brace or corset may be employed to provide some support and can help the patient regain mobility. This approach is sometimes used with patients who have weak abdominal muscles or older patients with degeneration at several levels of the spine. However, in cases where a patient bends the back to relieve pressure on a nerve, a brace which mandates an erect posture is of little value.
  • nonsteroidal anti-inflammatory medications such as aspirin or ibuprofen may help relieve symptoms. These agents are typically administered systemically.
  • epidural steroid injections and/or calcitonin injections may be employed to combat inflammation and/or regulate calcium uptake by bones. If this approach fails, surgical intervention may be required.
  • US 6,806,251 teaches injection of a muscle paralyzing agent to spinal muscles as a method of pain relief.
  • Botulism toxin (botox) is specifically described in this context.
  • the Ligamentum Flavum has been studied in some detail, especially in the context of stenosis.
  • Yoshida et al. (1992; Spine 17(11): 1353-60) reported that the LF undergoes changes including proliferation of type II collagen, ossification and calcium crystal deposition. They stressed that Type II collagen proliferates from the enthesis to the ligament side.
  • LF cells from stenotic patients contain osteonectin, type II and type X collagen as well as S 100 protein. LF from control patients lacked these components.
  • Pen which is a senescent crosslink representing an advanced glycation end product accumulates in tissue proteins including collagen.
  • Accepted surgical treatment typically involves laminectomy and ligament resection and/or lumbar fusion.
  • Ligament resection and/or lumbar fusion may serve to supplement the laminectomy.
  • a less established surgical option (Dynesis) involves fusionless instrumentation.
  • ligament remodeling relieves symptoms of spinal stenosis by relieving pressure on an adjacent nerve.
  • pressure is relieved because the remodeled ligament is softened and/or reduced in size and/or partially dissolved.
  • remodeling permits the ligament to conform to available space in the spinal canal. These changes may optionally alter ligament thickness and/or shape.
  • the Ligamentum Flavum (LF) is the target of remodeling.
  • the change in conformation results from a change in a ligament component as opposed to a reduction in an inflammatory response.
  • the change in the ligament component may be a chemical and/or a physical change.
  • remodeling is by direct application of a remodeling agent to the ligament.
  • Application may be, for example, by injection.
  • the dura mater (DM) is not significantly affected by the injection.
  • remodeling is of a facet capsule instead of, or in addition to, the LF.
  • remodeling causes a small change in a crucial ligament dimension and/or physical property which produces a significant clinical difference.
  • images of spine from an ambulatory post remodeling patient and the same patient debilitated by stenosis prior to remodeling do not indicate an apparent difference.
  • a small, but clinically significant difference in ligament conformation is apparent in CT scans or MRJ images.
  • an aspect of some embodiments of the present invention relates to use of a remodeling agent capable of altering properties of a ligament.
  • the remodeling agent acts specifically on a target ligament without significant effect on adjacent tissue.
  • specificity of the remodeling agent is achieved by direct application to a target ligament.
  • the agent is a chemical, optionally an enzyme.
  • the agent works preferentially on the LF in comparison to other tissues, for example the dura mater.
  • the remodeling agent is provided as a pharmaceutical composition and/or an article of manufacture including instructions for use in ligament remodeling.
  • An aspect of some embodiments of the present invention relates to applying energy to a spinal ligament to alter properties of the ligament so that the ligament is remodeled.
  • the energy is applied to the ligament via a probe inserted into the body.
  • an energy delivery apparatus configured to deliver energy to a spinal ligament is provided.
  • a pharmaceutical composition comprising:
  • the pharamaceutical composition is supplied as an article of manufacture additionally comprising:
  • the article of manufacture is supplied as a unit dosage form.
  • the unit dosage form includes at least a portion of a tool for locally applying said remodeling agent to said LF.
  • the remodeling agent includes at least one chemical capable of locally adjusting a pH of at least a portion of the LF.
  • the remodeling agent includes an enzyme.
  • the enzyme digests a substrate in the LF.
  • the enzyme has negligible effect on substrates found in the dura mater.
  • the alteration of properties refers to softening.
  • the alteration of properties refers to partial dissolution.
  • a method of ligament remodeling comprising: (a) applying a ligament remodeling agent to a ligament; (b) causing the ligament to conform to an available space.
  • the method is applied to a spinal ligament in a spinal canal.
  • the spinal ligament includes a Ligamentum Flavum (LF).
  • LF Ligamentum Flavum
  • the applying is directly to said ligament.
  • the applying is by injection into said ligament.
  • causing the ligament to conform to an available space relieves pressure on an adjacent nerve.
  • the method is applied to relieving symptoms of stenosis.
  • the remodeling agent acts specifically on said ligament.
  • a method of ligament remodeling comprising:
  • the method is applied to a spinal ligament in a spinal canal.
  • the spinal ligament includes a Ligamentum Flavum (LF).
  • the applying is directly to said ligament.
  • the energy includes heat energy.
  • the heat energy is applied by heating objects previously placed in said ligament.
  • the energy includes ultrasonic energy.
  • the energy includes radiofrequency energy.
  • the radiofrequency energy is applied to objects previously placed in said ligament and causes said object to become heated.
  • Figs. 1 and 2 are diagrams of the spine illustrating anatomical features relevant to stenosis in general and ligament remodeling according to some embodiments of the invention in particular as well as potential placements for applicators of a remodeling agent according to various embodiments of the invention;
  • Fig. 3 is a flow diagram illustrating a sequence of events associated with performance of a method according some embodiments of the invention.
  • Fig. 4 is a schematic representation of an energy delivery apparatus configured to deliver energy to a spinal ligament according to an exemplary embodiment of the invention .
  • a method of remodeling a ligament is provided.
  • Flavum according to methods of some embodiments of the invention will be discussed in some detail with reference to relevant anatomical features of the spine.
  • Fig. 1 is a perspective view of a portion of a spine 100 illustrating the position of a spinal canal 120 relative to a pair of vertebrae 140 with an intervertebral disc 150, an LF 110 and a posterior longitudinal ligament 130.
  • An anterior longitudinal ligament 135 is in the foreground in this view.
  • Fig. 2 is a top cross sectional view of spinal canal 120 showing in detail the relative positions of spinal cord 200, LF 110 and posterior longitudinal ligament 130.
  • Spinal cord 200 contains both nerve fibers and spinal fluid and is fully surrounded by the Dura Mater (DM;
  • LF 110 typically exerts pressure on spinal cord 200 through DM 220 and the spinal fluid.
  • a small bone/ligament space 255 is believed to separate LF 110 from the vertebral bone surface.
  • a method 300 typically begins with monitoring 310 of a clinical condition. If the clinical analysis suggests that a ligament (e.g. LF 110) is exerting pressure on a nerve (e.g. spinal cord 200), the physician may consider ligament remodeling according to some embodiments of the invention.
  • imaging 320 of the affected area e.g. spinal imaging
  • Imaging may include, for example X-ray, CT or MRI imaging. However, in many cases, significant clinical signs are present and their cause is not apparent in medical images.
  • application 330 of a remodeling agent is performed, followed by additional monitoring 310 and/or imaging 320.
  • Application 330 of the remodeling agent may be by various routes according to exemplary embodiments of the invention.
  • the ligament is caused to conform to an available space (e.g. in the spinal canal) after application of the remodeling agent.
  • "Caused” as used herein includes, but is not limited to waiting and/or exercise and/or application of compresses (optionally hot and/or cold) and/or massage and/or physical therapy and/or chiropractic adjustment.
  • application of the remodeling agent is via injection.
  • fluoroscopic guidance aids in inserting an injection needle to a desired location.
  • contrast dye may be injected to confirm location.
  • application 330 is conducted after contrast dye viewed in a fluoroscopic image indicates that the needle is in the correct position.
  • application refers to application of a physical agent (e.g. a liquid) as well as to application of energy.
  • Exemplary administration routes A surgeon of ordinary skill will be able to apply the remodeling agent using, for example, one or more of the following administration routes. Consideration of the properties of the specific agent employed may influence the choice of administration route.
  • application 330 is via injection between LF 110 and vertebra 140 into bone ligament space 255. Since bone and ligament are chemically very different, many remodeling agents which are selected because they are active against ligament will be characterized by negligible activity against bone. Optionally, the amount of remodeling agent applied is controlled, for example to prevent undesired contact of the remodeling agent with DM 220. Optionally, this embodiment provides greater dispersion of an injected remodeling agent with respect to the LF than injection into the same ligament as injected material disperses through bone ligament space 255. Increased dispersion may cause remodeling to occur in a larger portion of the LF. Intraligament application
  • application 330 is via direct injection into LF 110.
  • there is no strict requirement for tissue specificity in the selected remodeling agent so long as the application is carefully controlled to prevent contact of the remodeling agent with tissues other than the target ligament.
  • Epidural application In an exemplary embodiment of the invention, application 330 is via injection into a lumen adjacent to a target ligament. In the context of spinal stenosis, application may be into epidural space 250 which surrounds DM 220. Because the applied remodeling agent is likely to contact tissues other than the target ligament, a tissue specific remodeling agent is optionally employed in this embodiment. In the context of spinal stenosis, it is important to note that the LF and DM have significant chemical similarity.
  • a remodeling agent with significantly more activity on LF than DM is employed.
  • the agent acts primarily on a substrate which is specific to the LF.
  • Volume constraints In exemplary embodiments of the invention which involve injection of a remodeling agent into or near a ligament, the remodeling agent is optionally supplied in a volume less than ImI, optionally less than 500 ⁇ l, optionally less than 250 ⁇ l, optionally less than 100 ⁇ l, optionally less than 50 ⁇ l, optionally less than 25 ⁇ l, optionally less than 10 ⁇ l or intermediate volumes.
  • a controlled injection rate is employed, Suitable injection rates may be, for example, 500 ⁇ l/min, 250 ⁇ l/min, optionally less than 100 ⁇ l/min, optionally less than 50 ⁇ l/min or intermediate or greater values.
  • injection of a protective material may be undertaken concurrently.
  • an epidural injection with a large volume of solution may be employed to dilute and/or neutralize remodeling agents in order to protect, for example, the dura mater.
  • the solution may contain a buffer and/or an enzyme inhibitor (e.g. EDTA), Clinical protocols
  • An important exemplary clinical context for method 300 is spinal stenosis.
  • method 300 optionally includes repetition of clinical monitoring 310 and/or imaging 320 on a periodic basis after an initial application 330 of a remodeling agent.
  • reapplication 330 of a remodeling agent may occur every 52 weeks, optionally every 32 weeks, optionally every 20 weeks, optionally every 12 weeks, optionally every 8 weeks or intermediate or greater intervals.
  • each administration of a remodeling agent produces a similar effect per unit of remodeling agent as the previous administration.
  • This property will be referred to herein as "consistency”.
  • Remodeling agents which work on a chemical or enzymatic basis are expected to perform consistently.
  • an enzyme employed as a remodeling agent will typically degrade its substrate in a predictable fashion which is determined primarily by the amount of enzyme; the amount of substrate and the buffering conditions.
  • a particular physiologic substrate in a ligament is expected to undergo denaturation or dissolution under a known set of conditions. The physiologic substrate is not expected to alter its chemical properties to become "resistant” or immune” to these conditions.
  • anti-inflammatory drugs e.g. steroid hormones and/or NSAIDS
  • pain relievers and/or anesthetics may be injected (or otherwise administered) concurrently with a remodeling agent. This may, for example, prevent non-specific pain or inflammation associated with or caused by the injection procedure itself.
  • the anti-inflammatory compounds and/or pain relievers may act in combination and/or in synergy with the remodeling agent.
  • method 300 is performed on an outpatient basis.
  • no anesthesia is required.
  • only local anesthesia is required.
  • patients are compliant with method 300.
  • patients are compliant because treatments are infrequent and/or there is no daily medication required between treatments.
  • patients are compliant because each treatment produces a clinical improvement which is perceived by the patient and/or caregivers.
  • a patient and/or caregiver assumes at least partial responsibility for monitoring 310 and request an appointment for reapplication 330 of a remodeling agent when they perceive a change in the clinical situation.
  • Monitoring 310 may be, for example, simple observation of an increased tendency to bend over and/or a decreased walking capacity and/or a perceived pain.
  • method 300 The participation of patients and/or caregivers in monitoring can be crucial to the success of method 300. This is especially true with regard to spinal stenosis where, in many cases, there is no apparent no difference in images of spine from an ambulatory patient and the same patient debilitated by stenosis a few weeks later. This lack of apparent difference in medical images indicates that only a small change on a target ligament by a remodeling agent has the potential to produce a large clinical difference.
  • application 330 is performed before the overall clinical picture changes drastically.
  • Remodeling agents may be generally divided into chemically based agents and energy. Examples of chemically based remodeling agents and energy based remodeling are presented here for illustration and do not limit the scope of the invention. Whether the remodeling employs a chemical agent or energy, it causes softening of the ligament and/or reduction in size and/or dissolution of a portion of the ligament. These changes may optionally alter ligament thickness and/or shape.
  • the remodeling agents may be applied, for example, using one of the routes of administration described above.
  • the target area of the spinal ligament to which the agent is delivered is 0.5, optionally 1.0, optionally 2.0 optionally 3.0 square cm. in size or intermediate or lesser or greater areas.
  • a ligament is softened and/or shrunken and/or partially dissolved by application of an acid or a base.
  • an acid or base may be applied to a ligament to denature one or more proteins in the ligament causing them to shrink.
  • acids/bases suitable for use in this context include, but are not limited to, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide and ammonia.
  • the pH based reagents may be supplied, for example in a solution of water or normal saline.
  • a pH based reagent is supplied as a buffered solution so that it will maintain a defined pH after being applied to the target ligament and/or maintain a desired level of activity.
  • a pH based remodeling agent may be supplied, for example, at a concentration of 5N or less, optionally 2.5N or less, optionally 1 N or less, optionally 0.5 N or less, optionally, 0.25 N or less optionally 0.1 N or less.
  • Acid hydrolysis of relevant substrates may occur, for example, below pH 4.5, optionally below pH 3, optionally below pH 2 or intermediate or lesser pH values.
  • Alkaline hydrolysis of relevant substrates may occur, for example, above pH 8.0, optionally above pH 9, optionally above pH 10 or intermediate or greater pH values.
  • conditions are adjusted to produce a low molecular weight peptide which is optionally water soluble.
  • the molecular weight is less than 50,000, less than 25,000 or less than 10,000 Daltons.
  • these small molecular weight peptides are subject to diffusion within the body.
  • hydrolysis may be induced locally in a pattern of spots or stripes so that the overall strength of the ligament is not compromised.
  • a target zone of the ligament is selectively weakened and repeat treatments, if performed, are to this same target zone.
  • Collagen has enzyme-catalyzed cross-links formed between its individual molecules that are essential for maintaining the structure and flexibility of the collagen fiber.
  • the cross-link dehydro-hydroxylysinonorleucine reacts irreversibly with 10 mM malondialdehyde at least 3 orders of magnitude faster than glucose reactions with lysine or arginine, such that there is little cross-link left after 1 h at 37 degrees C.
  • Other cross-links and glycated elements of collagen are also vulnerable to this reaction.
  • Malondialdehyde seems capable of altering LF physical properties by altering properties of an LF collagen component in a way that would facilitate remodelling.
  • Malondialdehyde is only one exemplary remodeling agent of this class. It is expected that as the chemical composition of the LF in general, and the stenotic LF in particular, is more thoroughly characterized, additional remodelling agents which affect specific crosslink types will be characterized.
  • Chemically based remodeling agents Enzyme based reagents
  • an enzyme with specificity for a substrate found in the target ligament is employed as a remodeling agent.
  • action of the enzyme on its substrate causes softening or partial dissolution or shrinking of at least a portion of the target ligament.
  • collagen type II and/or collagen type X and/or SlOO protein and/or Pentosidine and/or chondroitin-6-sulfate and/or other high molecular weight proteoglycans are suitable enzyme substrates. These compounds are suitable enzyme substrates because their levels increase in the LF during the clinical progression of stenosis.
  • a remodeling agent includes an enzyme with specificity for a substrate found in the LF and found to a lesser degree, or only in negligible quantities, in the DM.
  • chemonucleolysis A procedure for enzymatic digestion of intervetrebral discs called chemonucleolysis is well known in the art.
  • M. D. Brown reviewed the status of chemonucleolysis (1996; Spine 21[24 Suppl]: 62S-68S) and concluded that the use of chymopapain is a safe and effective alternative to surgical disc excision. Brown reported that efficacy of chymopapain has been shown controlled trials with a minimum 10-year follow-up period. Brown also reported that clinical studies with collagenase and laboratory studies with chondroitinase ABC have shown that chemonucleolysis can be performed with enzymes other than chymopapain. Takegami et al. (Spine J.
  • enzymes suitable for use as remodeling agents may be obtained in purified form from chemical suppliers.
  • An example of such a commercially available enzyme is Collagenase type I (C6885; Sigma-Aldrich; St Louis MO; USA).
  • Collagen type I in the LF is well correlated with the clinical progression of stenosis.
  • Enzymes applied to a target ligament are capable of diffusion, especially if they are applied adjacent to the ligament, as opposed to injected directly into the ligament. The probability of diffusion increases with time.
  • enzymes may exhibit increased nonspecific activity in the absence of sufficient quantities of their nominal substrate.
  • method 300 may have as its objective modification of only a fraction of the molecules of a specific chemical species in a target ligament.
  • an enzyme with autocatalytic activity is employed as a remodeling agent.
  • an autocatalytic enzyme digests itself before it can diffuse to a significant degree and/or digests itself in the absence of sufficient quantities of its nominal substrate and/or digests itself in the presence of its nominal substrate so that only a portion of the nominal substrate is digested.
  • 50%, optionally 25%, optionally 10% optionally 5%, optionally 1% or greater or lesser or intermediate percentages of the nominal enzyme substrate are digested before an applied enzymatic agent loses its activity because of dilution and/or diffusion and/or autocatalysis.
  • enzyme based remodeling agents are supplied in a formulation which insures pH and/or ionic conditions that produce a desired level of activity.
  • enzymes may be supplied in a buffered solution with a defined pH.
  • this defined pH may be selected to insure maximum enzymatic activity or sub-maximal enzymatic activity.
  • the buffer may include ions and/or chelating agents.
  • a collagenase is supplied in a buffer including 5, optionally 10, optionally 25 millimolar or lesser or greater or intermediate concentrations of Calcium to insure collagenase activity.
  • the Calcium may be supplied, for example as a chloride, phosphate or bicarbonate salt.
  • an applied remodeling agent has an activity which is partly due an enzymatic activity and partly due to a pH of the applied material.
  • a beam of light energy is applied to a selected portion of a target ligament to cause remodeling.
  • the applied light energy causes softening or partial dissolution or shrinking of at least a portion of the target ligament.
  • Light may be conducted to the target ligament, for example, by use of a fiber optic device.
  • Treatments of this type have been employed in cosmetic surgery of the skin, ⁇ http://wvvw.skinpilot.de/1024/Willkorm ⁇ ien_engl/Uebersicht_engl/Altern_engl/Mech anische_Schael analog_e/body_mechanische_schael analog_e.html> where a high-energy concentrated beam of light is aimed at the skin tissue.
  • ultra-short pulses e.g. ultra-pulsed CO 2 or erbium YAG laser
  • the treatment causes collagen fibers to contract and/or shrink.
  • a CO 2 laser produces heating to a greater depth and produces a more marked collagen shrinking.
  • an optional waveguide may be employed to focus the applied energy on a desired target.
  • Energy based remodeling agents heat
  • heat energy is applied to a selected portion of a target ligament to cause remodeling.
  • the applied heat energy causes softening or partial dissolution or shrinking (e.g. by burning or denaturing) of at least a portion of the target ligament.
  • Heat may be delivered, for example, by application of an electric current though a wire held in proximity to the target ligament.
  • the exact degree of heat required may vary with the target ligament and/or the specific type of remodeling desired.
  • a portion of a target ligament may be heated to the denaturation point of a specific protein known to be causative of a particular clinical symptom (e.g. type X collagen in the case of stenosis). This will also cause denaturation of proteins which are denatured below the denaturation point of the specific protein selected.
  • electrothermal arthroscopic capsulorrhaphy causes thermal shrinkage of redundant capsular tissue to tighten the joint and may be employed in lieu of surgery (Mohtadi et al. Trials 2006, 7:4 doi:10.1186/1745-6215- 7-4 ⁇ http://www.trialsjournal.eom/content/7/l/4>; the disclosure of which is fully incorporated herein by reference)
  • the technique is performed with commercially available equipment such as ETAC probes (Oratec Vulcan Generator electro-thermal system; Oratec Interventions Inc., Menlo Park, CA, USA).
  • An alternate device for localized heat delivery is the "Tissue LinkEndoFB3.0
  • the saline serves to both localize the applied electrical current and assure that it penetrates the target tissue.
  • Devices of this type may be useful, for example, in bone ligament space 255. Heating of type I collagen to 60-100 degrees C can shrink the collagen to roughly half of its original size. Similar devices may also be used to deliver RF energy to heat deep tissue.
  • US 6,976,492 to Ingle et al. discloses devices, methods, and systems for shrinking of collagenated tissues. This patent is fully incorporated herein by reference. Ingle teaches tissue contraction resulting from controlled heating of the tissue by affecting the collagen molecules of the tissue. Contraction occurs as a result of heat- induced uncoiling and repositioning of the collagen ⁇ -pleated structure. Ingles teaches protocols which produce significant tissue contraction without substantial collateral tissue damage. Specifically, Ingles discloses heating the target tissue to a value in the range from about 60° C. to 110° C, optionally in the range from about 60° C. to 80° C. This can produce shrinkage of the target tissue in at least one dimension of between about 20 and 50 percent.
  • heating energy is applied for a period of from 30 seconds to 5 minutes. Heating times may vary with electrode configuration. In an exemplary embodiment of the invention, a heat time of about 5 minutes is appropriate for an electrode separation of about 4 cm. Shorter heat times may be used with smaller electrode separation distances. Ingles discloses that the temperature of adjacent (non target) tissue is maintained at about 45° C or less. For treatment of the LF, smaller electrode separation distances (e.g. 5 to 10 mm) and shorter times (e.g. 1 minute or less) are envisioned. Reducing electrode separation distance and or time can serve to reduce collateral tissue damage to a level which is acceptable even in a delicate spinal procedure. It may be desirable to repeat the remodeling process at intervals if clinical signs recur after treatment.
  • repeat remodeling using heat energy may be facilitated by implanting metal seeds in a target ligament. These seeds may serve to focus heat resulting from applied radiofrequency (RF) energy to a desired location.
  • RF radiofrequency
  • a 1 mm diameter sphere of a suitable metal e.g. titanium or stainless steel
  • a suitable metal e.g. titanium or stainless steel
  • the degree of heating achieved would vary with the duration of the applied RF signal.
  • use of seeds permits RF energy to be applied from an external source, as opposed to an internal probe.
  • An additional advantage of seeds is that they are visible in X-ray and/or ultrasound images. This property permits implantation of a seed in a desired target location followed by specific heating of the seed from an extracorporeal energy source.
  • ultrasound energy is applied to a selected portion of a target ligament to cause remodeling.
  • the applied US energy causes softening or partial dissolution or shrinking (e.g. by burning or denaturing) of at least a portion of the target ligament.
  • US energy may be delivered, for example, by insertion of a US probe in proximity to, or into, the target ligament.
  • the applied US energy may remodel the ligament by breaking chemical bonds directly (e.g. shortening polymer length and/or reducing a degree of cross-linking) and/or by causing heating of the target ligament.
  • the exact degree of US energy required may vary with the target ligament and/or the specific type of remodeling desired.
  • a portion of a target ligament may be subject to a US regimen designed to break off certain types of side chains.
  • a US protocol which reduces the amount of Pentosidine by de-glycating Pentosidine molecules might be employed to the LF.
  • Energy delivery apparatus Fig. 4 is a schematic representation of an exemplary energy delivery apparatus
  • the pictured apparatus 400 delivers energy to a spinal ligament through one or more energy outlets 435 mounted on a working head 430. Although ten energy outlets 435 are pictured as an example, the exact number is not critical to the operation of device 400 so long as outlets 400 are capable of delivering sufficient energy to a desired area of the target ligament. As few as one outlet 435 or as many as hundreds, or thousands, of outlets 435 may be employed in various embodiments of the invention.
  • the target area of the spinal ligament to which energy is delivered is 0.5, optionally 1.0, optionally 2.0 optionally 3.0 square cm. in size or intermediate or lesser or greater areas.
  • the energy to be delivered may be light, ultrasonic waves, RF energy or microwaves.
  • working head 430 is inserted to a target zone (e.g. bone ligament space 255 or epidural space 250; see Fig. 3) in an arthroscopic procedure.
  • a target zone e.g. bone ligament space 255 or epidural space 250; see Fig. 3
  • working head 430 is collapsed and stored in a distal portion 425 of cannula 420 during arthroscopic insertion.
  • the arthroscopic insertion is monitored, for example by fluoroscopy or ultrasonic imaging, and working head 430 is ejected and/or expanded after distal portion 425 of cannula 420 is in a desired location.
  • working head 430 may be constructed of an elastic or plastically deformable material.
  • an elastic working head 430 may be stored in the lumen and ejected by pushing with a tamping rod inserted through the lumen.
  • controller 410 delivers an operational signal to energy outlet(s) 435 so that they deliver energy to the target ligament.
  • the energy may be delivered, for example, via a conductive wire or fiberoptic strand passed through cannula 420 to working head 430 and connected to energy outlets 435.
  • outlets 435 may be energized synchronously or sequentially.
  • outlets 435 may be energized with a uniform degree of energy or with varying degrees of energy.
  • energy may be delivered continuously or in pulses separated by intervals.
  • the rate of energy delivery may be controlled by varying pulse amplitude and/or interval duration.
  • controller 410 contains a user input device (e.g. keypad or operational knob with a scale) or is connectable to a device equipped with such an input (e.g. computer, PDA or cellular telephone).
  • a user input device e.g. keypad or operational knob with a scale
  • two or more parameters selected from among energy amplitude, energy frequency, duration of energy pulse, firing pattern for energy outlets 435 and duration of pause between energy pulses are independently adjustable.
  • one or more sensors 437 are provided (one is pictured). Sensor 437 serves to measure the amount of energy delivered and/or the effect of that energy on the target tissue and/or the amount of energy delivered to adjacent non-target tissue.
  • sensor 437 is a thermometer which measures a temperature of a target ligament.
  • sensor 437 serves to close a feedback loop with controller 410 and energy outlets 435.
  • controller 410 could be programmed to step down energy delivery when sensor 437 indicates a local temperature of 61.5 degrees and cease energy delivery after the target temperature of 63 degrees is reached.
  • measurements conducted by sensor(s) 437 in a non-target tissue may be used in implementation of a negative feedback loop as a safety pre-caution.
  • a remodeling agent according to the invention is supplied as a pharmaceutical composition formulated as a pharmaceutical composition for use in/on the LF.
  • the pharmaceutical composition includes a physiologically effective amount of at least one remodeling agent (e.g. chemical and/or enzymatic) together with carriers and/or buffers and/or excipients.
  • the pharmaceutical composition is supplied as a sterile injectable preparation and/or a sterile crystalline preparation ready for dilution with a sterile diluent.
  • the pharmaceutical composition is provided as an article of manufacture comprising packaging material and instructions for use in the treatment of stenosis.
  • the instructions may include, for example, dosage recommendations and/or suggested routes of administration.
  • the article of manufacture includes one or more unit dosage forms, optionally loaded and ready for use.
  • an energy delivery apparatus according to an exemplary embodiment of the invention is provided as an article of manufacture comprising packaging material and instructions for use in the treatment of stenosis.
  • the instructions may include, for example, suggested treatment protocols and/or suggested routes of administration.
  • the treatment protocols may be expressed, for example, in terms of time and temperature.
  • a remodeling agent according to an exemplary embodiment of the invention is used in conjunction with an indirect decompression treatment for scoliosis.
  • exemplary indirect decompression treatments include, but are not limited to Dynesis and the X stop which attempt to indirectly decompress the stenosis without doing a laminectomy.
  • each of the verbs "comprise”, “include” and “have” as well as any conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of members, components, elements or parts of the subject or subjects of the verb.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Medical Informatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Electromagnetism (AREA)
  • Optics & Photonics (AREA)
  • Radiology & Medical Imaging (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant un principe actif incluant une quantité physiologiquement efficace d'un agent de remodelage capable de modifier les propriétés d'un ligament jaune (LF), de telle sorte que le LF se conforme à une dimension disponible d'un canal de l'épendyme; l'invention concerne également un vecteur pharmaceutiquement acceptable, des diluants et des excipients.
PCT/IL2007/000378 2006-03-22 2007-03-22 Remodelage de ligament WO2007108001A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78456106P 2006-03-22 2006-03-22
US60/784,561 2006-03-22

Publications (2)

Publication Number Publication Date
WO2007108001A2 true WO2007108001A2 (fr) 2007-09-27
WO2007108001A3 WO2007108001A3 (fr) 2007-12-06

Family

ID=38481926

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2007/000378 WO2007108001A2 (fr) 2006-03-22 2007-03-22 Remodelage de ligament

Country Status (1)

Country Link
WO (1) WO2007108001A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1047414A1 (fr) * 1998-01-23 2000-11-02 Warner-Lambert Company Gabapentine et ses derives pour le traitement de la douleur musculaire et squelettique
US6684886B1 (en) * 2000-01-21 2004-02-03 Prospine, Inc. Intervertebral disc repair methods and apparatus
JP2004331612A (ja) * 2003-05-09 2004-11-25 Koyo Chemical Kk 腰部脊柱管狭窄症による間歇跛行改善剤
US7918849B2 (en) * 2004-10-15 2011-04-05 Baxano, Inc. Devices and methods for tissue access

Also Published As

Publication number Publication date
WO2007108001A3 (fr) 2007-12-06

Similar Documents

Publication Publication Date Title
Weil Jr et al. Extracorporeal shock wave therapy for the treatment of chronic plantar fasciitis: indications, protocol, intermediate results, and a comparison of results to fasciotomy
US7181289B2 (en) Epidural nerve root access catheter and treatment methods
Chung et al. Peyronie’s disease: what do we know and how do we treat it
JP2011143246A (ja) 関節運動式棘突起間クランプ
Winston et al. Cryoneurotomy as a percutaneous mini-invasive therapy for the treatment of the spastic limb: case presentation, review of the literature, and proposed approach for use
Alfredo et al. Effects of phonophoresis with Arnica montana onto acute inflammatory process in rat skeletal muscles: an experimental study
Kampitak et al. Comparison of analgesic efficacies of the iPACK (interspace between the popliteal artery and capsule of the posterior knee) and genicular nerve blocks used in combination with the continuous adductor canal block after total knee arthroplasty: a randomized clinical trial
Razzano et al. Treatment of chronic plantar fasciitis with noninvasive interactive neurostimulation: a prospective randomized controlled study
Roth et al. Preoperative cryoneurolysis for total knee arthroplasty: a case series
West et al. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia
Shah et al. 2. New frontiers: Invasive nonsurgical interventions
Carrol et al. Focal intense brief transcutaneous electric nerve stimulation for treatment of radicular and postthoracotomy pain
Shen et al. Outcome of antegrade intramedullary fixation for juvenile fifth metacarpal neck fracture with titanium elastic nail
Medina-Pérez et al. Cooled radiofrequency treatment for radicular pain related to lumbar disc herniation
WO2007108001A2 (fr) Remodelage de ligament
Scimia et al. The ultrasound‐guided iPACK block with continuous adductor canal block for total knee arthroplasty
Paolo et al. Radiofrequency thermo-ablation of Morton’s neuroma: a valid minimally invasive treatment procedure in patients resistant to conservative treatment
US8597192B2 (en) Ultrasonic devices and methods to diagnose pain generators
RU2100996C1 (ru) Способ лечения заболеваний позвоночника
Nweke Comprehensive review and evidence-based treatment framework for optimizing plantar fasciitis diagnosis and management
Bushnell et al. Complex regional pain syndrome: becoming more or less complex?
Вазина et al. Hip joint degeneration during degenerative dystrophic lesions with painful cider
RU2108065C1 (ru) Способ противоболевой блокады при патологии спинного мозга и позвоночника
Sır et al. The use of intralesional and posterior tibial nerve pulsed radiofrequency in the treatment of calcaneal spur
US12290301B1 (en) Percutaneous surgical treatment for piriformis syndrome

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07713394

Country of ref document: EP

Kind code of ref document: A2