A force-controlling device for biomedical implant insertion

Abstract

There is provided a device for applying a compressive force to a surface of a soft tissue, the device comprising: an articulation structure comprising a tissue-contacting surface, and an articulation mechanism configured to drive the articulating structure, wherein the tissue-contacting surface is configured to be brought into contact with the surface of the soft tissue and thereby apply the compressive force to the surface of the soft tissue.

Description

[0001] A FORCE-CONTROLLING DEVICE FOR BIOMEDICAL IMPLANT INSERTION

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to a force controlling device for biomedical implant insertion. In particular, the present disclosure relates to a device for applying a compressive force to a surface of a soft tissue. This disclosure further describes a force-modulating surgical device and methods of use intended for neural tissues, however the findings, embodiments, and claims, can be easily transferred to other soft, metabolically active, vascularized tissues (e.g. pancreatic, hepatic, nephric, splenic, adipose, cutaneous, vascular tissues, etc.) and associated tissue engineered constructs, cell cultures, and stem-cell derived constructs (e.g. embryoid bodies, tissue organoids, etc.) by any individual skilled in the art.

[0004] BACKGROUND

[0005] Mechanically stimulating tissues is an inevitable consequence of almost any form of invasive surgical technique including instrument implantations, cell and tissue- engineered construct implantations, injections / syringe insertions, tissue collections (i.e. biopsy), incision, suturing, among many others. Such mechanical manipulations are almost universally seen as a negative consequence of such procedures that introduce complications (e.g. ischemia, hypoxia, damage, positional uncertainty, etc.).

[0006] However, there have been infrequent cases where benefits of mechanical compressive forces in unique circumstances have been identified. For example, patent US 8,968,217B2 mentions that certain health conditions (diabetes melitus, etc.) result in tissues that benefit from the ischemic / hypoperfusive conditions induced by tissue compression for the purpose of suturing tissues. Use of compressive forces has been shown to suppress tumor cell expansion in an in vitro multicellular spheroid tumor model. Despite such unique cases, the general consensus in the field and associated prior art is that unintended mechanical forces induced in surgically manipulated tissues are counterproductive to the long-term health of said tissues.

[0007] Recent findings have demonstrated that such compressive forces may in fact be beneficial for the purposes of protecting neural tissues (and thereby extension other soft, vascularized, metabolically active tissues) and / or altering their biomolecular, cellular, and extracellular composition and arrangement if applied in a specific manner. Proposed reasons why such findings may have been overlooked by the scientific community have also been recently addressed in the field.

[0008] Inserting rigid materials and instruments into soft tissues is further impeded by the tendency of such tissues to displace, translocate, and deform during the process of penetration and insertion. By applying light compression to the surface of the tissue, thereby minimizing compression during the insertion procedure of an implant itself, more precise placement of the implant can be ensured, whereby tissue displacements can be minimized, and the overall position and orientation is stabilized.

[0009] There is a need for improved and controlled mechanical stimulation of soft tissue during implant insertion to avoid excessive tissue pressure and deformation, preserve biomedical instrument positional stability, and reduce harmful tissue stimulation.

[0010] SUMMARY

[0011] An objective of the present disclosure is to provide a device for applying a controlled compressive force to a soft tissue.

[0012] Furthermore, an objective of this disclosure is to describe a device that applies controlled, modulating compressive forces to specific regions of soft, vascularized, metabolically active tissues and provide associated methods of use. This disclosure is primarily concerned with neural tissues such as brain, spinal cord, dorsal root ganglia, peripheral nerves and ganglia, etc. but can also be applied to other internal organs and tissue structures, including pancreas, liver, kidney, interstitial, heart, connective, muscle, skin, etc.

[0013] These and other objectives are at least partly met by the invention as defined in the independent claims. Preferred embodiments are set out in the dependent claims.

[0014] According to a first aspect of the present disclosure there is provided a device for applying a compressive force to a surface of a soft tissue, the device comprising an articulating structure comprising a tissue-contacting surface an articulation mechanism configured to drive the articulating structure, wherein the tissue- contacting surface is configured to be brought into contact with the surface of the soft tissue and thereby apply the compressive force to the surface of the soft tissue.

[0015] The term “compressive” or “compression” is used throughout this disclosure and relates to forces directed towards a targeted zone in the interior of an underlying soft tissue. The compressive force may be determined by direct measurement of a reactive force in a strain gauge or magnetic instrument. The compressive force may also be indirectly inferred based on the displacement of contacting surface into the soft tissue knowing the geometrical properties of the contact surface and the mechanical properties of the tissue. Compression may thus be expressed directly as a force measurement (units of newtons, N), expressed as a displacement (units of length, e.g. pm, mm, etc.), or expressed as a combination of the two using pressure (units of pascals, Pa, kPa, MPa, etc.). It should be understood that application of compressive forces by a tissue-contacting surface will induce a displacement of the compressed soft tissue surface, resulting in a pressure within the compressed soft tissue dependent on the applied compressive force and geometry of the tissuecontacting surface. Where compressive forces are not solely orthogonal to the surface of the soft tissue, the term “shear force” or “shear motion” or “shear” may be used. Such shear forces are expressed in the same way, and will rely on contact surface geometry, non-orthogonal displacement, on a shear modulus of the underlying tissues, and orientation, expressed in units of length and angles with respect to the tissue surface or a central vertical axis of the device of the invention (where applicable, degrees are utilized). As used herein, compressive force may include shear force, shear motion and the like.

[0016] It should also be understood that purely orthogonal compression will induce shear components within a soft, elastic tissue as denoted in general form by the relationship E = 2G(1 + v) where E is Young’s modulus, G is shear modulus, and v is the Poisson’s ratio. Tissues may be isotropic but are more commonly anisotropic in their composition (lamina, fibers, porosity, etc.) and therefore tensor forms of Young’s and shear moduli and Poisson’s ratio apply accordingly.

[0017] The tissue-contacting surface may be referred to herein as a force-applying surface, a force-transmitting surface, compressive surface or tissue-facing surface. It should be realized that these refer to the same surface, i.e. , the tissue-contacting surface. The articulation mechanism may be referred to herein as the drive mechanism or the articulating drive mechanism.

[0018] The device according to the first aspect may also be referred to as the compressive device or compressive tool herein.

[0019] The soft tissue may be referred to as just tissue, and thus a surface of a soft tissue may be referred to as a surface of a tissue, soft tissue surface, or tissue surface.

[0020] The different components of the device of the invention that are driven / moved / articulated by the articulation mechanism, e.g. a screw-drive mechanism, may be referred to as the articulating structure. It is to be understood that the articulating structure may be viewed as general term for the parts / components that convey / transfer / propagate the compressive force from the articulation mechanism to the surface of a tissue. For example, the articulating structure comprises the tissue-contacting surface and may comprise an articulating block and / or a protrusion.

[0021] The device may be comprised of a housing containing a drive mechanism, also referred herein to as an articulation mechanism. The articulation mechanism may be connected to an articulating structure, comprising a tissue-contacting surface at a first end of the articulating structure.

[0022] The articulation mechanism is configured to drive the articulating structure, and thus, drive the tissue-contacting surface.

[0023] The tissue-contacting surface is configured to make contact with an underlying soft tissue. The tissue-contacting surface may for example comprise a flat, circular, slotted surface. However, the tissue-contacting surface may be any suitable shape or form, depending on the intended use of the device. For example, the tissuecontacting surface may be oblong, oval, triangular, rectangular, polygonal, or freeform in shape designed to conform to a complementary instrument or surgical tool or the underlying tissue.

[0024] The tissue-contacting surface may be arranged at the basal end of the articulating structure, and may be configured to make contact with an underlying soft tissue. The articulating structure may be configured to be independently articulated in relation to any additional instrument, device, or biomedical tool that may be already present in the underlying tissue, may be inserted at the same time, or inserted following articulation of the presented device.

[0025] The tissue-contacting surface may be arranged such that the housing and articulating structure do not impede access to the underlying tissue within the slot.

[0026] In other embodiments, shapes of the contacting surface other than circular are envisioned such as oblong, oval, triangular, rectangular, polygonal, or freeform in shape designed to conform to a complementary instrument or surgical tool or the underlying tissue. In yet other embodiments, the surface may be perforated with an opening of various geometries including circular, oblong, oval, triangular, rectangular, polygonal, or freeform in shape designed to conform to a complementary instrument or surgical tool or the underlying tissue.

[0027] In yet further embodiments the contact surface may be solid with no openings or slots.

[0028] The surface of a soft tissue may be any surface of a soft tissue such as muscle tissue (including the heart tissue), adipose tissue, blood vessels, nervous tissue, tendons, and tissues that surround the bones and joints.

[0029] The articulating structure comprises the tissue-contacting surface. In other words, the tissue-contacting surface may form part of the articulating structure. The tissue-contacting surface may be a surface at a distal end of the articulating structure.

[0030] The tissue-contacting surface configured to be brought into contact with the surface of the soft tissue and thereby apply the compressive force to the surface of the soft tissue may comprise a substantially flat surface. The tissue-contacting surface may comprise a slanted surface.

[0031] Recently it has been demonstrated that compressive forces possess unique ability to modulate the metabolic, compositional, and reactive state of neural tissues; this modulation may be of therapeutic, modulatory, or engineering consequence and benefit. Specifically, the ability to alter the metabolic status (i.e. transitioning cellular populations from oxidative phosphorylation to aerobic glycolysis, as evidenced by reduction of autofluorescent flavin granule content), or to alter cellular proportions (i.e. to alter proportion of inhibitory interneurons or smaller locally innervated excitatory neurons as compared to larger excitatory projection neurons, as evidenced by sizedependent changes in neuronal proportions despite minimal overall loss of neurons) is of interest to the neuroscientific community. Additionally, the force-dependent induction of novel, previously undescribed, transcellular communication modality whereby projections of cells of one genotype and phenotype traverse the boundaries of cells of a different genotype and phenotype to make contact with cell nuclei with the likely intent of manipulating genetic expression through direct regulatory or indirect epigenetic mechanisms (i.e. astrocytes were observed extending their glial fibrillary acid protein (GFAP)-positive projections into neighboring neuronal nuclei appearing to make direct contact with neuronal nuclear chromatin) was demonstrated. Such tissue modulations were found to be directly related to the compressive forces and associated ischemic / hypoxic conditions established as a result.

[0032] Inserting rigid materials and instruments into soft tissues is further impeded by the tendency of such tissues to displace, translocate, and deform during the process of penetration and insertion. By applying light compression to the surface of the tissue, more precise placement of the implant can be ensured, whereby tissue displacements can be minimized, and the overall position and orientation is stabilized. A similar principle can be envisioned in deeper tissues below the surface, where targeting of small, delicate structures in a larger heterogenous tissue bulk may be aided by localized compressive force application.

[0033] The device according to the first aspect may thus provide a controlled, measurable, and / or precise amount of pressure, thereby avoiding displacement, translocation, and deformation of the tissue.

[0034] Thus, the device provided in the present disclosure may provide an improved and controlled mechanical stimulation of soft tissue, during for example implant insertion, thereby avoiding excessive tissue pressure, preserving biomedical instrument positional stability, and reducing harmful tissue stimulation.

[0035] According to an embodiment, the tissue-contacting surface comprises a first opening configured to receive a biomedical instrument.

[0036] The first opening, of the tissue-contacting surface, may herein also be referred to as e.g. a slot or gap or perforation or cutout. Thanks to the tissue-contacting surface comprising a first opening configured to receive a biomedical instrument, an external or separate instrument or device may be inserted into or removed from the soft tissue, while the device applies compressive forces to underlying tissue. This is advantageous in that the unwanted or uncontrolled pressure or compressive forces from the external instrument may be averted, by the tissuecontacting surface applying a controlled pressure around the external instrument.

[0037] According to an embodiment, the articulating structure comprises a second opening configured to receive the biomedical instrument, and wherein the second opening extends into a cavity configured to be connected to the first opening, such that the first opening, of the tissue-contacting surface, is configured to receive the biomedical instrument through the second opening, of the articulating surface, via the cavity.

[0038] In other words, the articulating structure, e.g. the protrusion, may comprise a hollow space inside the articulating structure, e.g. the protrusion, to provide room for positioning and manipulation of a biomedical instrument. The cavity / hollow space may taper to the desired surface area of the tissue-contacting surface.

[0039] Thanks to the second opening, of the articulating structure, aligning along a common axis with the opening of the tissue-contacting surface, an external or separate instrument may be inserted or removed through the articulating structure. This may advantageously provide a precise insertion of an external instrument.

[0040] According to an embodiment, the second opening, of the articulating structure, and the first opening, of the surface-contacting surface, align along an axis A, wherein the axis A is substantially perpendicular to the tissue-contacting surface.

[0041] According to an embodiment, the first opening of the tissue-contacting surface may comprise a cut-out.

[0042] As used herein, cut-out may refer to an opening that extends to and through the edge of the tissue-contacting surface. In other words, the cut-out provides an opening extending to an edge of the tissue-contacting surface, forming a groove / slot / recess / slotted opening, such that the first opening of the tissue-contacting surface may be accessed from a side, and such that the device may be moved to side, away from a static biomedical instrument that was inserted through the first opening, of the tissue-contacting surface. In other words, the tissue-contacting surface may be a slotted-surface.

[0043] Throughout the application, the expression cut-out may be used synonymously as slotted opening. The cutout or slotted opening may be configured to allow introduction into and removal from a region of compressed tissue or tissue surrounded by compressed tissue of an external instrument or implant independent of force application. Advantageously, this insertion and removal will induce little to no additional compressive force, as the soft tissue is compressed by the tissue-contacting surface.

[0044] The tissue-contacting surface may comprise a plurality of cutouts or slotted openings to allow introduction into and removal from a region of compressed tissue of an implant independent of compressive force application. Advantageously, the cut-out allows for accommodation of any implant-related or instrument related connectivity (e.g. electronic wiring, optical fibers, fluidic tubing, etc.) and or removal of the tissue compressing device without disturbing said implant and any implant-related connectivity.

[0045] Furthermore, the cut-out advantageously allows for removal of the device independently of removal of the external instrument or implant. It should be realized that this is applicable in both ways, i.e. the external instrument may be removed during the application of compressive force, or the device may be removed, while the external instrument is kept in place.

[0046] According to an embodiment, the articulation mechanism may be configured to generate the compressive force by at least one of mechanical means, sonic means, ultrasonic means, magnetic means, electromagnetic means, piezoelectric means, or pneumatic means.

[0047] The articulating structure may be articulated using motor drive, manual articulation, pneumatic control, magnetically, or by other physical means. The articulation mechanism configured to drive the articulating structure, may drive the articulating structure by at least one of mechanical means, sonic means, ultrasonic means, magnetic means, electromagnetic means, piezoelectric means, or pneumatic means. For example, the articulation mechanism may comprise a motor, configured to drive the articulation structure, such that the articulating structure may be brought into contact with the and thereby apply the compressive force to the soft tissue.

[0048] Different modes of application of the compressive force may be achieved by the articulation mechanism driving the articulating structure, towards and away from the surface the soft tissue, such that a different degree / level of compressive force may be applied. According to an embodiment, the device further may comprise a sensor unit, configured to measure the applied compressive force.

[0049] Articulation may be controlled using an attached force sensor, by use of an integrated distance scale, by use of an electronic distance measure device (linear variable displacement transducer (LVDT)), or by measuring displacement relative to the underlying tissue or other fiduciary marker using various means.

[0050] In certain examples, knowing the thread dimensions of a screw in a screwdrive mechanism can directly relate to the displacement of the articulating structure to the turns of a screw or threaded cylindrical shaft. Such a device can be controlled and / or monitored using a computer and associated software.

[0051] Hence, according to an embodiment, the device may comprise a force sensing unit. The force sensing unit may also be referred to as a force sensor unit, or a sensor unit, herein. The force sensing unit may comprise a force sensor.

[0052] According to an embodiment, the force sensing unit may be configured to measure the applied compressive force.

[0053] According to an embodiment, the force-sensing feature may comprise at least one of a strain gauge, a force sensing resistor, a spring-loaded mechanism, a displacement mechanism such as a linear variable differential transformer (LVDT), a magnetic mechanism, a capacitive device, a pneumatic device, a flexible potentiometer, and a piezoelectric device.

[0054] According to an embodiment, the device may comprise a control unit, configured to control the articulation mechanism, for controlling the compressive force applied to the surface of the soft tissue.

[0055] According to an embodiment, the control unit may be configured to receive input data corresponding to the measured applied compressive force from the sensor unit and control the articulation mechanism based on the input data. The present embodiment is advantageous in that the applied compressive force may be changed / adjusted automatically, providing better control and adaptation of the compressive force application. It is to be appreciated that the present embodiment allows for an adjustment in the applied compressive force earlier, e.g. before a user or patient may react, which may minimize discomfort and / or injuries.

[0056] According to an embodiment, the control unit may be configured to monitor the compressive force applied to the soft tissue and increase or decrease the applied compressive force when a threshold value is reached. Hence, the control unit may be configured to monitor a measured / gauged compressive force, and control the articulation mechanism based on the monitoring. For example, the control unit may be configured to monitor if the measured / gauged compressive force exceeds and / or subceeds a predetermined threshold value, and in response increase / decrease the compressive force. The present embodiment is advantageous in that the application of the compressive force may be even better controlled and adapted.

[0057] According to an embodiment, the control unit may be configured to monitor at least one of an electrical signal, an optical signal, a thermal measurement, a magnetic field strength, a sonic signal, an ultrasonic signal, a collected or delivered fluidic volume, where said signals being related to the soft tissue in contact with the tissuecontacting surface of the articulating structure. Hence, the control unit may be configured to monitor at least one of said signals, and control the articulation mechanism based on the monitoring. For example, the control unit may be configured to monitor if the measured / gauged compressive force increases, maintains, and / or decreases at least one of said predetermined signal values, and in response increase / decrease the compressive force.

[0058] According to an embodiment, the control unit may be configured to monitor an external signal or user input, where said signal / input not being related to the soft tissue in contact with the tissue-contacting surface of the articulating structure. Hence, the control unit may be configured to monitor an external signal or user input, and control the articulation mechanism based on the monitoring. For example, the control unit may be configured to monitor if the measured / gauged compressive force increases, maintains, and / or decreases external signal values or directs a user input, and in response increase / decrease the compressive force.

[0059] A manually advanceable screw-driven application of this device is presented in Figures 1A-T, where force-modulation with this device is combined with various complimentary technologies such as micropipette infusion, optical probe insertion, microelectrode use (in conjunction with a micropipette or using a dissolvable biopolymer vehicle layer). Screw driven implementations can be manually operated or can be motor driven with an external motor assembly and driveshaft, or can be a fully contained motor-driven device such as a linear actuator. In certain instances, the screw-drive mechanism can be substituted or augmented with chain- or belt-driven mechanisms.

[0060] In other embodiments, in place of a screw-drive mechanism, a pneumatic bladder or pneumatic piston(s) can be used to articulate the block, where specific volumes of fluid or gas are known to distend the bladder to specific dimensions thereby providing a known amount of compression on a tissue. In certain instances, pressure of gas or fluid in a pneumatic circuit may be used to gauge / measure compressive forces transferred to contacting tissues. Spring-loaded application of force where the spring constant of a spring (or sets of springs) defines the forces that are transmitted to the surface of the tissue may be applicable in certain embodiments and is also disclosed by this patent. While manual articulation is possible in hand-held embodiments of the device of the invention to induce compression in conjunction with an independently articulated biomedical instrument, it is not encouraged even though is disclosed by this application.

[0061] In yet other examples, an electromagnetic drive may be used in conjunction with a magnetic material component within the articulating compressive structure to apply forces commensurate with applied voltages through the electromagnet.

[0062] Finally, in certain space-limited examples such as bone-embedded housings as described below, ultrasonic motor assisted, thread-driven advancement of the articulating compressive structure can be employed (such motors are ubiquitous in optic lens implementations and ideal for space-limited, low-vibration, low-noise, low- power applications).

[0063] According to an embodiment, the tissue-contacting surface comprises at least one of a metal, a polymer, or a ceramic.

[0064] The articulating structure and the tissue-contacting surface may comprise the same and / or similar materials. The articulating structure may comprise a first material and the tissue-contacting surface may comprise a second material.

[0065] In an example, the articulating structure with a flat, circular, slotted surface at its basal end making contact with an underlying soft tissue, i.e. , the tissue-contacting surface, may comprise a biomedical grade metal, polymer, or ceramic that does not irritate, damage, or otherwise attach to the underlying tissue during compressive contact. Hence, the tissue-contacting surface may comprise at least one of a biomedical grade metal, biomedical grade polymer and biomedical grade ceramic. Further, the tissue-contacting surface may comprise a biocompatible metal, a biocompatible polymer or a biocompatible ceramic.

[0066] In certain examples, the articulating structure with a flat, circular, slotted surface, i.e., tissue-contacting surface, at its basal end may comprise stainless steel, titanium, aluminum, silver, gold, platinum, or alloys and / or combinations thereof.

[0067] In other examples, the articulating structure with a flat, circular, slotted surface, i.e., tissue-contacting surface, at its basal end of the device may comprise polyacetal, polyether ether ketone (PEEK), acrylic-based polymers (PMMA, pHEMA, etc.), polyvinyl acetate (PVA), silicone-based polymers, polyvinyl chlorides (PVC), or any other biocompatible polymer, etc.

[0068] In yet other examples, the articulating structure with a flat, circular, slotted surface, i.e., tissue-contacting surface, at its basal end may comprise alumina-based ceramic, titania-based ceramic, silicon nitride-based ceramic, gallium nitride-based ceramic, silicon-based ceramic, or any other biocompatible ceramic, etc.

[0069] Yet in other examples, the articulating structure with a flat, circular, slotted surface, i.e., tissue-contacting surface, at its basal end may comprise pyrolytic carbon, graphite, or other carbon-based material. In certain embodiments, the articulating structure with a flat, circular, slotted surface at its basal end is composed of combinations of materials, for example a metal core with a polymer-based coating on the tissue-contacting surface.

[0070] According to an embodiment, the tissue-contacting surface comprises a soft material, wherein the soft material comprises mechanical properties in the range of those exhibited by the soft tissue.

[0071] The mechanical properties of a soft material may thus comprise having Young’s modulus in the range of 10A3 to 10A6 Pa.

[0072] According to an embodiment, the soft material comprises at least one of a rubber, a hydrogel, or a low Young’s modulus polymer.

[0073] The materials, comprised in the tissue-contacting surface, and / or the articulating structure, may be chosen to exhibit specific mechanical properties, namely Young’s modulus, in the range of 10A11 to 10A12 Pa (ceramics and compact bone), in the range of 10A10 to 10A11 Pa (metals and trabecular bone), in the range of 10A6 to 10A9 Pa (polymer systems and hard tissues), in the range of 10A3 to 10A6 Pa (hydrogels and soft tissues), <10A3 Pa (tissue cultures, fat deposits, etc.). Material modulus may be chosen to exceed the modulus of underlying tissue, or to approximate modulus of underlying tissue, or to be lower than the modulus of underlying tissue. In certain examples, materials may be combined with different moduli, for example rigid titanium core (~10A10 Pa) with a softer silicone elastomer coating (~10A5 Pa).

[0074] A low Young's modulus polymer may refer to a polymer material that has a relatively low stiffness or elastic modulus. The Young's modulus, also known as the elastic modulus, is a measure of a material's stiffness or rigidity. It defines how much a material will deform under stress. A low Young's modulus polymer may refer to rubber and elastomers, polyethylene, polydimethylsiloxane and / or polyurethane foam.

[0075] According to an embodiment, wherein the tissue-contacting surface comprises at least one of a biocompatible metal, a polymer, or a ceramic, and further comprises a coating comprising a soft material, wherein the coating is arranged to be brought into contact with the surface of the soft tissue.

[0076] According to an embodiment, the tissue-contacting surface comprises a surface topography that is smooth.

[0077] According to an embodiment, the tissue-contacting surface comprises surface features, wherein the surface features are uniform geometrical shapes or nonuniform geometrical shapes.

[0078] In some examples, the tissue-contacting surface, also referred to as a forceapplying surface, may comprise a geometry parallel to the surface of the soft tissue with which contact is to be made, for directing forces down into deeper tissue layers.

[0079] In other examples, the tissue-contacting surface, also referred to as the forceapplying surface, may comprise a convex geometry, for dissipate forces out radially proportional to the radius of curvature of the tissue-contacting surface.

[0080] In yet other examples, the tissue-contacting surface, also referred to as the force-applying surface, may comprise a concave geometry for concentrating forces into a zone of deeper tissue whose volume of influence is proportional to the radius of curvature.

[0081] Combinations of these features, other geometrical arrangements beyond those described herein are also encapsulated by this patent.

[0082] According to an embodiment, the tissue-contacting surface is curved. In other words, the tissue-contacting surface may comprise both a concave geometry and a convex geometry. For example, the tissue-contacting suface may be circular, wherein a central part of the tissue-contacting surface may comprise a concave geometry, and / or wherein an outer part of the tissue-contacting surface may comprise a convex geometry.

[0083] In further examples, the tissue-contacting surface, also referred to as the forceapplying surface, may comprise a geometry that is optimized to the geometrical features, or surface texture, of the soft tissue to which compressive forces will be applied based on a priori measurements or prior knowledge.

[0084] In certain examples, the tissue-contacting surface may comprise a smooth surface, comprising substantially no or very little surface features (surface roughness < 25 nm).

[0085] In other examples, the tissue-contacting surface may comprise a surface comprising surface texture intended to promote friction contact between the tissuecontacting surface (i.e. , the force applying surface) and the underlying soft tissue is appropriate or desired.

[0086] In yet other examples, the tissue-contacting surface may comprise surface textures that are patterned such as parallel grooves, pedestals, posts, grids, lattices, circular grooves, circular arrays, or other repeating geometric structures at nanometer, micrometer, millimeter, centimeter scales are envisioned.

[0087] According to an embodiment, the device may further comprise a protective film arranged on the tissue-contacting surface and arranged to engage the soft tissue. Certain tissues (internal organs such as brain and spinal cord, heart, etc.) are covered in a natural protective film. This protective film alters the forces required to insert instruments into the intended organ tissues and may impede insertion of soft, flexible constructions.

[0088] Numerous methods of interacting a compressive tool with a natural protective film-encased tissue are envisioned. The described examples may be applied directly to the surface of this intact natural protective film without exposing the organ underneath.

[0089] In the context of neural applications, this preparation could be useful for optical visualization of the cerebral cortex using 3-D imaging such as 2-photon, confocal, super-resolution, etc., or the insertion of an extremely sharp object that can slice through the meningeal layer during insertion, etc.

[0090] To access the underlying organ more readily, a small opening in the natural protective film may be created, leaving most of the protective film undisturbed. Such an approach is envisioned in conjunction with an example of the compressive tool which includes an opening or slot that permits contact with the underlying tissue for purposes of direct observation, instrument insertion, tissue removal, etc. In such an application, the tissue-contacting surface, (also referred to as the compressive surfaces) of the device (also referred to as the compression tool) contact the undisturbed protective film, while the resection of protective film is limited to the opening or slot within the device (compression tool). In the context of neural applications, this preparation could be useful for insertion of fine, delicate instruments / devices (e.g. microinjections, optical fibers, electrodes, etc.) where minimal disturbance of the meningeal layer is preferred. In applications such as wider field-of-view visual observations of the underlying tissues, biopsy sample collections, etc., where the natural protective film is envisioned as detrimental to successful application due to, for example, bleed contamination, total removal of the natural protective film in the area of tissue compression can be performed. In such an application, the described embodiment of the device (compressive tool) is envisioned as making direct contact with the underlying tissue.

[0091] Finally, replacement of the natural protective film with an alternate protective film is envisioned.

[0092] In such an example, the device may be used in conjunction with an alternate protective film that may be placed between the tissue-contacting surface (i.e. , the force-applying surface) of the device and the exposed tissue surface. This alternate protective film is biocompatible and has a modulus similar to that of the underlying tissue, in the ranges previously described.

[0093] The alternate protective film may be transparent, translucent, opaque, or any combination thereof. The alternate protective film may be inert and primarily used for protection of the tissue from the device and / or external environment, or it may include electronic circuitry and exposed electrodes for the purposes of recording and / or imparting electrical signals into the underlying tissues (e.g. electrocorticography, electroencephalography, electromyography array), for applying magnetic fields to the underlying tissues, for altering the temperature of the underlying tissue (through the use of inductive wiring circuitry), or communicating with external electronic equipment.

[0094] The alternate protective film may also comprise embedded light emitting components (e.g. optical guides and fibers, light-emitting diodes (LEDs)) for the purposes of manipulating underlying tissues that have been genetically modified to express optically responsive proteins (such as opsin light activated ionic channels), or contain light activated / inactivated / responsive chemical agents or particles (fluorescent nanoparticles such as quantum dots or fluorescently labeled microparticles, hemoglobin-loaded red blood cells).

[0095] The alternate protective film may also be used for drug delivery of encapsulated pharmacological agents for the purposes of modulating the physiological state of underlying tissues; pharmacological agents such as hemostatic agents (coagulants, anticoagulants, antiplatelet agents, thrombolytics, fibrinolytics, etc.), vasoconstrictive agents, vasodilating agents, neuromodulators, neural signaling molecules, amino acids, steroids, hormones, immunological agents, synthetic or naturally occurring compounds, etc. are envisioned, but any compatible compound of interest can be employed.

[0096] Lastly, the alternate protective film may be absorbent in nature for the purposes of sequestering biological or surgical fluids that might otherwise interfere, inflame, or degrade the quality of the underlying tissues (e.g. collagen / gelatin-based absorbent sponge-like materials).

[0097] The alternate protective film may be intended to be left in place, may be temporary to be removed after force modulation is complete, or may biodegrade in place during the force modulating procedure or after force modulation is complete.

[0098] Finally, the alternate protective film may incorporate several of these strategies simultaneously (e.g. an optically transparent film with embedded electrodes at the periphery and a region of biodegradable material at the center that coincides with the opening or slot of the compressive surface).

[0099] In certain examples, the geometry of the tissue-contacting surface (i.e., the force-applying surface) and / or any slot, gap, or opening of the tissue-contacting surface, are sized to align with the potentially organized structure of the underlying tissue. Certain soft, vascularized, metabolically active tissues are known to possess a repeating, ordered, or semi-ordered structure that is instrumental in efficient functioning of said tissues.

[0100] Examples of such structures include cerebral cortex (and other deeper brain and spinal cord structures as well), kidneys, and pancreas. The brain cortex is largely organized in repeating columnar (or approximately columnar, sometimes described as blobs, or blob-like) structures that correspond to various sensorimotor functions (e.g. visual processing, skin sensitization, limb articulation, joint positioning, etc.). In the case of cortical columns, each column has an approximate diameter of ~500-700 pm (dendritic, axonal diameter can be ~2-3 mm), regular repeating patterns that are either circular, rectangular, hexagonal, or some other repeating geometric pattern, and each column predominantly communicates with neighboring columns.

[0101] Kidneys contain numerous repeating filtration units known as nephrons, and the pancreas contains a multitude of hormone-producing cellular clusters known as pancreatic islets.

[0102] Designing the geometries of the tissue-contacting surface (the force-applying surface) of the device to coincide with such geometric patterns of underlying tissues allows for better control of compressed versus non-compressed (or only partially compressed) tissues.

[0103] Furthermore, intrusions into the underlying tissues by independently articulated instruments or tools can be targeted to coincide with these tissue structures. For example, insertion and traversal of a surgical blade for creation of an incision can be aligned with specific tissue structures that have been identified a priori or using concurrent compatible imaging modalities (e.g. calcium indicator dyes, etc.).

[0104] The dimensions and shape of the tissue-contacting surface of the compressive device can align with the repeating organization of the underlying tissue, or it can be unaligned. Furthermore, dimensions and shape can be specifically tailored to accommodate both a complimentary independently articulated biomedical instrument and the ordered organization of the underlying tissue.

[0105] According to an embodiment, the articulation mechanism may be configured to apply the compressive force in at least one of a constant and a pulsed manner.

[0106] The various examples described herein may be used to modulate underlying tissues in numerous envisioned modes. The simplest of these modes is the constant application of compressive force determined through use of an integrated force measuring apparatus (strain-gauge, displacement gauge, fiduciary markers, etc.).

[0107] In certain instances, forces exerted upon tissues may be determined using ultrasound, x-ray, neutron, or other particle / wave transmission-based methods.

[0108] Application may also comprise a steady increasing compressive force, a steady decreasing compressive force, stepwise increases in compressive force, stepwise decreases in compressive force, and combinations thereof.

[0109] Application of compressive forces is in certain instances envisioned to be performed for a predetermined length of time or may be based on a physiological response of the tissue (oxygen measurement, electrical signal, biochemical cue, etc.), or it may be permanent for the duration of the tissue (in cases of excision, biopsy, etc.) or the lifetime of the subject.

[0110] Application may be combined with the insertion of a biomedical tool (surgical, probing, etc.), biomedical device (electrode construction, microdialysis or infusion syringe, optical device, etc.), or other instruments.

[0111] Compressive force may be applied at a predetermined time before subsequent insertion of the biomedical instrument, concomitantly with insertion of biomedical instrument, or a predetermined time after insertion of biomedical instrument. Such applications of ferees and inclusion of an independently articulated biomedical instruments are predicted to shift the neuronal population composition to smaller, metabolically altered neuronal population as previously described.

[0112] Application of compressive forces may also be non-constant where the compressive tool is articulated into and out of the underlying tissue for a certain number of repetitions (once, twice, thrice, etc.) where the duration of applied compressive force, speed of application, and duration of pause between subsequent applications can be predetermined, can be determined “on the fly” based on a physiological response of the tissue (oxygen measurement, electrical signal, biochemical cue, etc.), or may be to a certain extent random in nature (for example in hand-held manual applications of the device). Application of compressive forces in a non-constant manner may be referenced to as applying compressive forces in a pulsed manner. Based on previous descriptions, short term transient compressive force applications and inclusion of an independently articulating biomedical instrument are likely to preserve neuronal populations both in composition and metabolic function, but may induce transcellular communication between different cellular genotypes that is directly nuclear in nature. Such periodic application represents a “square-wave” or “trapezoidal” application but can also be “triangular” with no static hold period, sinusoidal with constant motion of advancement and retraction, or any combination thereof. Epochs of periodic application of compressive force interspersed with pauses of no application, constant application, or partial applications of compressive force are also envisioned. Periodic applications of force can be envisioned consisting of frequencies in the range of 10A6 Hz, 10A5 Hz, 10A4 Hz, 10A3 Hz, 10A2 Hz, 10A1 Hz, 10A0 Hz, 10A-1 Hz, 10A-2 Hz, 10A-3 Hz, 10A-4 Hz, 10A-5 Hz, 10A-6 Hz, etc.

[0113] Preferred embodiments employ periods of oscillation of the device of the present disclosure to coincide with biological oscillations including neural frequencies (alpha, beta, delta, gamma, low field potentiation, high frequency spinking oscillations, etc.), micromotion inducing frequencies (vascular, respiratory, peristaltic, cardiac, etc.), diurnal frequencies (day / night, day-to-day, etc.), wound healing phenomena (7- 14-day periods), etc.

[0114] Rates of application and retraction may be in the range of pm / s, mm / s, cm / s, m / s. Periods of constant application, partial application, or interspersed pauses can be in the range of microseconds (ps), milliseconds (ms), seconds (s), minutes (min), hours (hr), days, weeks, months, years, or for the expected duration of the underlying tissue (in cases of excision, biopsy collection, etc.) or the lifetime of the subject.

[0115] Applied forces may be in the range of piconewtons (pN), nanonewtons (nN), millinewtons (mN), newtons (N), kilonewtons (kN), meganewtons (MN), etc. dependent on the mechanical properties of the underlying tissue (Young’s modulus ranging from 0.1 Pa (adipose tissues) to MPa (bone and compact cartilage)) and contact surface area of the device of the invention (ranging from pm2 to cm2).

[0116] According to an embodiment, the control unit is configured to control the articulation structure by means of machine learning. In some instances, machine learning methods may be used for generating a tissue compression regimen and may comprise one or more machine learning algorithms.

[0117] Such machine learning algorithms may include a supervised learning algorithm or unsupervised learning algorithm. Examples of such algorithms include naive Bayes classification (NBC), a support vector machine (SVM), a random forest, a deep learning model such as neural network, feed-forward neural network, radial basis function network, recurrent neural network, convolutional neural network, deep residual learning network, etc.

[0118] Machine learning methods used to control the force application by the device of the present disclosure to underlying tissues may in certain instances utilize force measurements, electrical signals, optical signals, ultrasound reflections, real-time image processing of the tissue surface, chemical signals, respiratory rates, cardiovascular activity, diurnal cycles, input from the operator, etc. or combinations thereof for the purposes of optimizing force-driving algorithms.

[0119] According to an embodiment, the device further comprises at least one electrode configured to be arranged at the tissue-contacting surface.

[0120] In another example of this disclosure, the device contains tissue-facing, surface mounted, electrode contacts that can deliver current, establishing electric fields, or measuring tissue-generated voltage potentials, known in the art.

[0121] These electrical contacts, or electrodes, are placed on the tissue-contacting surface and may perform feedback control to the control unit (the computer software) to control device articulation based on delivered currents, established electric fields, and / or recorded tissue-generated voltage potentials.

[0122] Delivered currents and / or electric fields may be stationary or alternating in nature with current densities below tissue damage thresholds or at / above tissue damage thresholds to perform ablation at the surface.

[0123] Stationary currents may be anodic or cathodic, in the range of picoamps, nanoamps, microamps, milliamps, amps, kiloamps, mega-amps and can be applied during tissue compression, following tissue compression, or both.

[0124] Stationary currents may be applied for time periods in the range of milliseconds, seconds, minutes, hours, days, weeks, months, years, or the lifetime of the patient. Alternating currents may be applied with any waveform capable of being generated by a waveform generator, including, but not limited to, sinusoidal, square, triangular, symmetric, asymmetric, with cathodic offset, with anodic offset, etc. Alternating currents may be applied with frequencies in the range of 10A6 Hz, 10A5 Hz, 10A4 Hz, 10A3 Hz, 10A2 Hz, 10A1 Hz, 10A0 Hz, 10A-1 Hz, 10A-2 Hz, 10A-3 Hz, 10A-4 Hz, 10A-5 Hz, 10A-6 Hz, etc.

[0125] Preferred examples employ periods of oscillation of the device of the present disclosure to coincide with biological oscillations including neural frequencies (delta, gamma, low field potentiation, high frequency spinking oscillations, etc.), micromotion inducing frequencies (vascular, respiratory, peristaltic, cardiac, etc.), diurnal frequencies (day / night, day-to-day, etc.), wound healing phenomena (7-14-day periods), etc.

[0126] Stationary and alternating currents may be constant, intermittent, or applied at random intervals, or may switch between stationary currents for a given length of time followed by alternating currents.

[0127] In certain examples, the electrodes are coated in a semipermeable membrane containing one or more metabolic enzymes (for example glucose oxidase, lactate oxidase, catalase, or combinations thereof). In such an implementation, the electrodes are maintained at a stable potential and the consumption of oxygen, hydrogen peroxide, or some other dissolved constituent that may pass the semipermeable membrane induces a current flow upon electrochemical reaction at the potentiated electrode surface.

[0128] The electrodes may be configured to record and / or impart electrical signals into the underlying tissues (e.g. electrocorticography, electroencephalography, electromyography array).

[0129] According to an embodiment, the device may further comprise a temperature controlling element, configured to increase, decrease or maintain a temperature at a constant level of at least one of the device or the soft tissue.

[0130] In another example, the device may perform a method of generating heat and or reducing its temperature, and therefore underlying tissues in direct contact with the device.

[0131] The device may comprise a cooling element configured to cool the soft tissue and / or the device. The device may comprise a heating element configured to heat the soft tissue and / or the device. The device may comprise both a cooling element configured to decrease the temperature of the soft tissue and / or the device, and a heating element configured to increase the temperature of the soft tissue.

[0132] It is realized that an unwanted heating of the device in general, and the tissuecontacting surface in particular, may cause an unwanted heating of the soft tissue. It is thus advantageous to measure and monitor the temperature of the device and the tissue, and control the temperature controlling element based on the temperature of the device or the soft tissue.

[0133] Such temperature modulation may be accomplished through the use of inductive coils, thermoelectric heat pumps (i.e. , Peltier devices), heat pipes directing heat to / from and external generator and / or chiller, or through the use of fluidic channels that allow heated or cooled fluid to perfuse through the device.

[0134] In certain examples, radio frequency or magnetic field-generated thermal excursions may be employed, possibly in conjunction with radio wave radiation or magnetic field responsive materials. Temperatures may be modulated to maintain physiological temperatures in a surgically exposed tissue, or to induce hypothermic or hyperthermic conditions for the purposes of modulating tissue activity, biochemistry, and physiology. Temperatures may be modulated to extreme ranges to induce cryogenic states (<0°C, usually -10°C to -25°C, but can reach -80°C) or thermally ablative states (>37°C, usually 50°C to 80°C, but can be >90°C) for therapeutic or experimental purposes.

[0135] According to an embodiment, the device may comprise a plurality of tissuecontacting surfaces, and wherein the plurality of tissue-contacting surfaces may be driven in unison, in sequence, randomly, or independently.

[0136] It is a realization that a single articulation structure may comprise a plurality of tissue-contacting surfaces.

[0137] The device may further comprise a plurality of articulating structures.

[0138] Advantageously, a plurality of tissue-contacting surfaces may provide compressive force to different locations of the soft tissue.

[0139] According to an embodiment, the device comprises a plurality of articulation mechanisms, wherein each articulation mechanism is configured to drive each of the plurality of tissue-contacting surfaces. In yet a further embodiment, the device of the present disclosure includes a method of generating magnetic fields that extend into compressed tissues. Magnetic fields may be static, generated by incorporating magnetic materials such as neodymium magnets or equivalent.

[0140] By using electromagnetic circuits embedded in the compressive device of the present disclosure, magnetic fields may be dynamic commensurate with the levels of current flow through the electromagnet. In such applications, the magnetic fields may be directed into the underlying tissues for purposes of neural (or other receptive cell type) stimulation, magnetic nanoparticle manipulation such as translocation, trapping, or inductive heating, or manipulation of an independently articulating magnetically responsive biomedical instrument that may be present. Preferentially magnetic fields with localized spatial gradients in the ranges of tesla per meter (T / m), kT / m, MT / m, GT / m may be generated in underlying tissues. Methods for performing such modulations are known to those skilled in the art.

[0141] In another example, the device of the present disclosure includes a method of, i.e. may perform / be configured to, generating sonic or ultrasonic energy directed into compressed tissues that may include an independently articulated biomedical instrument or implanted cells or tissue- engineered construct.

[0142] In certain examples, reflected sonic or ultrasonic energy may be detected. Ultrasonic energy, particularly when focused, may be utilized for the purposes of modulating cellular activity as many voltage-gated and chemically gated ion channels are known to be mechanically susceptible and focused ultrasound can generate localized forces.

[0143] Furthermore, ultrasonic energy may be utilized for the purposes of modulation of exogenous particles and cells, or manipulation of an independently articulating sonically responsive biomedical instrument that may be present. Preferentially, ultrasonic energy with frequencies in the ranges of kHz, MHz, to GHz and intensities in the ranges of microwatts per square centimeter (pW / cmA2), mW / cmA2, W / cmA2 may be transmitted to tissues.

[0144] Lastly, complimentary generation and detection of ultrasonic signals may be used to perform density difference-based volumetric imaging of subsurface tissues. Methods for performing such modulations are known to those skilled in the art. Optical emission and detection by elements such as light emitting diodes, optical light guides and fibers, complementary metal-oxide-semiconductor (CMOS) and charge-coupled device (CCD) detectors may be incorporated into certain examples of the device of the present disclosure for the purposes of communicating with and modulating compressed tissues.

[0145] Genetic modification of tissues for the purposes of expressing fluorescently responsive molecules such as voltage gated ion channels, or optically responsive receptors, or fluorescently labeled cellular and extracellular structures is well established in the field.

[0146] Blood flow and location of vascular structures is routinely assessed by optical interrogation where visible light is transmitted, partially absorbed, and reflected thereby identifying pulsatility, vascular presence, etc. Introduction of fluorescently labeled particulate material such as fluorescent beads, nanoparticles, quantum dots, etc. into tissues or fluorescent dyes into vasculature for optical interrogation of tissue function and health is frequently utilized in biomedical applications. By employing laser illumination, blood flow patterns may be further visualized and quantified based on doppler shift in light spectra.

[0147] By employing light emission and detection, changes in activity, composition, metabolic state, etc. may be ascertained by measuring optical signals at timepoints before, during, and after compression, or timed with the insertion and articulation of an independent biomedical instrument.

[0148] Preferred examples may transmit and detect light of wavelengths in the range of ultraviolet (100 to 400 nm), visible (400 to 700 nm), infrared (700 to 1400 nm). Such compression and optical modulation may be performed in conjunction with other tissue interacting modalities described such as thermal modulation, electrical signaling communication, ultrasound modulation, etc.

[0149] Fluidic delivery and collection mechanisms can be incorporated into certain examples of the device of the present disclosure. Such mechanisms are comprised of standard constructions known in the art, but preferentially may include ports, tubing, valving, capture compartments, fluidic pumps such as of the peristaltic or mechanically-activated-syringe variety, etc. for the purposes of dispensing fluids to and collecting fluids from underlying tissues to modulate or analyze tissue composition or state in conjunction with compressive forces. Fluids may be transferred before application of compressive forces, during application of compressive forces, following application of compressive forces, or combinations thereof. Dispensed fluids may comprise pharmacological solutions, metabolic solutions, lubricating solutions, hydrating solutions, cleansing solutions, solutions containing particulate matter (microparticles, nanoparticles, etc.), solutions containing cells, exosomes, liposomes, nucleic acids, viral constituents, etc. Pharmacological agents such as hemostatic agents (coagulants, anticoagulants, antiplatelet agents, thrombolytics, fibrinolytics, etc.), vasoconstrictive agents, vasodilating agents, neuromodulators, neural signaling molecules, amino acids, steroids, hormones, immunological agents, synthetic or naturally occurring compounds, etc. are envisioned, but any compatible compound of interest can be employed.

[0150] Collected fluids may be subsequently analyzed using standard biochemical methods to identify dissolved gasses, biomolecules, nucleic acids, proteins, lipids, glycosaminoglycans, endogenous or exogenous compounds, pharmacological molecules, hormones, cytokines, immune products, cellular material, exosomes, liposomes, etc.

[0151] A further example of the device of the present disclosure may be used in combination with a slicing or moving tool where not only the vertical compression may be induced by the device of the present disclosure, but a lateral motion that either precedes, proceeds, or surrounds a tool or instrument which traverses a tissue for the purposes of slicing, cauterizing, depositing a material, or collecting a material from the tissue, etc. may be necessary.

[0152] For example, a scalpel blade may be inserted into the tissue surface in unison with surrounding compression and then the compressing tool may move in front of the scalpel providing a zone of compressed tissue into which the scalpel blade may cut. Such compression and slicing may be performed in conjunction with other tissue interacting modalities described such as thermal modulation, electrical signaling communication, ultrasound modulation, etc. Compression may be constant, modulated, or applied intermittently. Compression may surround the tool, may be applied proximal to the tool, or at a distance.

[0153] According to an embodiment, the device may further comprise a guide cannula, and wherein the articulating structure may be configured to be received by the guide canula, and thereby apply the compressive force to a sub-surface region of the soft tissue.

[0154] The guide cannula may be shaped like a tube, i.e. , a hollow structure, configured to receive the articulating structure in the hollow of the guide cannula. In this example, the articulating structure may be a probe-like element, for insertion in the hollow of the guide cannula, and thereby reach the sub-surface region of the tissue and thereby apply the compressive force to the sub-surface region of the soft tissue.

[0155] In order to apply the same principles of tissue compression below the surface of a soft, vascularized, metabolically active tissue or organ, a modification of common surgical techniques may be applied.

[0156] For example, insertion of a deep brain stimulator requires the use of a guide canula or guide tube. In certain instances, the formation of a tissue track by insertion and removal of a solid rod, syringe, or other rigid implement suffices. Once the guide tube or canula is in place, or a track has been formed, the deep brain stimulator may be seated in place.

[0157] Similar principles are involved in reaching difficult to access tissues, injecting fluids or fluid-based materials, etc. Sub-surface tissue regions of interest that may be a therapeutic target zone for compressive forces could consist of diseased or injured tissue (stroke lesion, tumor, neurodegenerated brain structure, etc.), a specific tissue structure (e.g. a deep brain structure such as subthalamic nucleus or similar, a pancreatic islet, or any unique tissue unit), or a tissue that has been a priori cleared of cellular content (e.g. streptozotocin induced pancreatic beta cell death, pharmacologically lesioned neurons, ablated tissue volume, etc.).

[0158] Other sub-surface tissue regions of interest for targeting by the compressive forces may be otherwise indistinguishable from healthy tissues and merely represent a region of tissue to be specifically mechanically modulated, evidenced by mechanically deformed or modulated cells and occluded vascular structures, used as sites for cell or tissue-engineered construct implantation, electrochemical sensor implantation, canulization, fluid delivery and / or collection, etc.

[0159] By using a guide canula or tube, an elongated probe with features at the distal end that are consistent with the compressive force principles and methods described above may be inserted into the guide canula and can independently articulate on tissues at the distal end of the device. If a track is used without the use of a guide canula, the prolonged protrusion of the device of the present disclosure may be articulated in much the same manner as the surface-based implementations, ideally with minimized lateral and tilt / yaw motions with respect to the surface.

[0160] The geometry of the distal end of the protrusion that makes compressive contact with the tissue may conform to the general principles described above in terms of geometry, size, articulation regimens, combinatorial implementations with various other tissue modulating technologies, etc. The dimensions of the device of the present disclosure comprising the guide canula or tube, protrusion, tissue-contacting force-exerting structures and associated films and coverings are determined by the dimensions of the tissue, depth below the tissue surface of targeted therapeutic zones, volume of tissue that is to be modulated by compressive forces, and manufacturing capabilities as are known in the field. Standard surgical tool materials may be used for such guide canula and tubes, including stainless steels, titanium alloys, chromium-molybdenum alloys, zirconium alloys, etc. In certain instances, surgical grade rigid polymers can be employed such as high-density polyethylene (HDPE), polytetrafluoroethylene (PTFE), polyether ether ketone (PEEK), etc.

[0161] In yet other specific instances, ceramic and glass materials may be utilized, but are not standard practice. Use of multiple materials can be employed, where the guide tube or canula, the protrusion of the device of the invention, and any coverings of surface-interfacing sections may each be comprised of different materials.

[0162] In certain instances, the distal end of the protrusion that comes in direct contact with deep tissue may be comprised of a lower modulus material such as a silicone rubber or hydrogel surface such as pHEMA (poly(2-hydroxyethyl methacrylate)). The location of guide canula or tube insertion, or the location of the intended track may be determined a priori using standard medical imaging modalities including magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound imaging (USI), etc.

[0163] In certain cases, use of stereotaxic coordinates in conjunction with an “atlas” (e.g. brain atlas) where detailed measurements have been made of representative specimens, which may be in printed or digital forms and are frequently used in conjunction with the imaging modalities listed above. According to an embodiment, the tissue-contacting surface is configured to expand, such that such that the expansion of the tissue-contacting surfaces induces compressive forces on the soft tissue.

[0164] The tissue-contacting surface, also referred to as a force-transmitting surface, of the device of the present disclosure described above may in certain instances be comprised of a spatially expanding structure such as a pneumatically controlled bladder or a thermally responsive metal or polymer (e.g. Nitinol, a.k.a. nickel titanium with a nickel / titanium ratio in the range of 0.95 to 1 .05, or compatible alloy).

[0165] Spatially expanding structures used to generate compressive forces may be envisioned in both surface and sub-surface soft tissue applications. Such thermally responsive materials that may be machined into a compressed form at room temperature (or a temperature below physiological, such as below 37°C, but can be below 35°C, below 30°C, below 20°C, and in some instances in a cryogenic range between 5°C and -5°C) and then expand upon exposure to elevated or physiological temperatures such as above 0°C, above 20°C, above 30°C, above 35°C, above 37°C, or higher depending on physiological state of the tissue.

[0166] In the case of the spatially expanding bladder (or commonly referred to as a balloon), such implementations may be envisioned as functioning in much the same manner as an angioplasty balloon used to position and seat vascular stents.

[0167] Pneumatic control may be performed using gas or fluid, but preferentially a biologically compatible fluid such as an artificial or sterile bodily fluid (artificial cerebral spinal fluid, buffered saline, plasma, etc.) selected for appropriate tissue location and to preclude risk in case of leak or rupture. In certain instances, such a bladder may be encased in a wire structure that may be expanded, and the bladder may subsequently be removed. Such wire constructions that may either be expanded using mechanical, pneumatic, or by thermal means may employ an elastic film covering to protect the delicate soft tissues from cutting or slicing during placement, expansion, and subsequent tissue interaction.

[0168] Such an elastic film may also be employed in rigid tissue-contacting structures as a protective covering and as a site for tissue-facing electrodes or other electronic components, pharmaceutical delivery, to preclude tissue attachment, to promote tissue ingrowth, to biodegrade after a predetermined amount of time, and generally consistent with principles described above. In certain sub-surface tissue compressing examples, spatially expanding tissue-compressing structures may be implemented in such a way as to articulate laterally thereby generating compressive forces of regions of tissue that exist adjacent to the device and not directly underneath it. In such cases, rotational motion of the protrusion of the device can be combined with vertical articulation to generate compressive forces out-of-plane of expansion, as well as shear forces at the tissuecontacting surface, also referred to as the tissue-facing surface.

[0169] In a final instance, the sub-surface tissue-compressing expanding structure may be comprised of a bulk hydrogel in a dry state (comprised of <3% water content by volume) that once hydrated will not degrade or be substantially removed.

[0170] Such a structure may comprise a water permeable protective elastic film encasing a cross-linked hydrogel with a high swelling ratio (>25, >50% and in some instances >80%) such as a cross-linked albumin, poly(hydroxy methyl methacrylate) (pHEMA), cross-linked gelatin, or any other biocompatible hydrogel capable of sufficient water swelling.

[0171] In such an instance the fluid required for swelling is derived from tissue-derived extracellular and interstitial fluids.

[0172] In some instances, the hydrogel may be swollen using a water supply apparatus similar to the pneumatic system for bladder control. Expansion due to swelling may be controlled by amount of the bulk hydrogel in a dry state that is initially included, the swelling ratio of the hydrogel, and the dimensions and mechanical properties of the encasing film, if present.

[0173] For certain examples of the device, a section of the device, generally understood to comprise the housing, may be external to the body of a subject that is either attached to an automated robotic arm, a stationary apparatus such as a stand or surgical fixture (e.g. a stereotaxic frame), or a hand-held apparatus.

[0174] In other examples, the housing of the device may comprise a free-floating implantable case permitting force modulation of internal tissue structures (e.g. a subcutaneously implanted hermetic enclosure that can apply forces externally to the superficial dermal layers, or internally to the deeper subdermal muscle and adipose tissues).

[0175] In yet further examples, the housing of the device may be embedded in, or attached to, the skeletal system where an appropriate skeletal orifice is created such as an opening in the sternum for articulation of lung or cardiac tissues, or attachment to the rib cage to accomplish the same.

[0176] In a specific case, to reach cortical structures (and deeper neural structures beneath the cortex), a craniotomy may be required that involves the generation of a burr hole. This burr hole may usually be sealed with the removed bone, artificial material such as a metal or polymer plate, or some other type of polymer or ceramicbased cement after completion of the surgical process. Such a bur hole may instead be sealed by use of a skull-mounted device that may be seated directly above the cortical surface of interest to which modulated forces can be applied. Such cases include cortical tissues which may have been supplemented with stem-cells or stemcell based constructs, tissues which have received microelectrode implants, optical probe implants, microperfusion implants, infusion devices, or been subjected to some other surgical process such as biopsy, injection, ablation, incision, or subjected to non-surgical injury such as traumatic brain injury, concussion, lesion, hematoma, tumorous growth, benign growth, etc.

[0177] According to an embodiment, the biomedical instrument is an independently articulated biomedical instrument.

[0178] According to an embodiment, the tissue-contacting surface comprises light emitting means.

[0179] According to an embodiment, the tissue-contacting surface comprises light sensing means.

[0180] According to an embodiment, the tissue-contacting surface comprises porous features for drug delivery, fluid delivery or fluid collection.

[0181] According to an embodiment, the tissue-contacting surface can generate sonic and / or ultrasonic waves by a piezoelectric apparatus.

[0182] According to an embodiment, the tissue-contacting surface can detect sonic and / or ultrasonic waves by a piezoelectric apparatus.

[0183] According to an embodiment, the tissue-contacting surface may be configured to generate magnetic fields by at least one of a magnetic material or an electromagnetic circuit.

[0184] According to an embodiment, the tissue-contacting surface may be configured to detect magnetic fields by an electromagnetic circuit. According to an embodiment, the device may be configured to modulated the compressive forces in response to natural body motions, either in addition or to mitigate body motions in underlying tissues.

[0185] According to an embodiment, a natural body motion comprises at least one of respiratory, cardiovascular, large-scale bodily movements, and small-scale, otherwise known as micromotion, bodily movements.

[0186] Embodiments described above may be combined in various ways. For example, multiple locations may be stimulated simultaneously, in unison, sequentially, or at random. Such combined stimulation may be performed in accordance with physiological responses measured from underlying tissues or otherwise connected systems. The sensorimotor cortex in the brain for example connects heavily to deeper brain structures, through the brainstem, into the spinal cord and out through the dorsal root ganglia to peripheral muscular and sensory innervations. By combining force application, electrical stimulation and recording, and physical sensory stimulation at the central, spinal, and peripheral sites in this circuitry, unique combinations may be envisioned. Force modulation of the sensorimotor cortex, appropriate locations at the spinal cord and spinal ganglia, while stimulating motion of select muscle / joint groups could be used to regenerate, re-train, or supplement activities of the circuitry that has either been damaged, diseased, or otherwise is intended for improvement. Peripheral stimulation can comprise electrical, temperature, force, physical pain, etc. Force modulation of nervous tissues at appropriate sites can be combined with afore-mentioned technologies such as surface-mounted ECoG / ESCoG, optical, thermal, neural interface, microperfusion, pharmaceutical infusion modalities, etc.

[0187] Lastly, embodiments of this device may be used in vitro to stimulate, modulate, or direct growth of differentiated cell cultures, stem-cell cultures, stem-cell tissue engineered constructs (e.g. embryoid bodies, 3D-cultured neural networks, etc.), excised ex vivo tissue slices, etc., otherwise known as engineered tissues, synthetic tissues, cultured tissues, or similar.

[0188] Similar combined applications as those described for in vivo use may be envisioned in similar in vitro / ex vivo use, including EEG / ECoG stimulation and recording, pharmaceutical infusion / injection, optical fiber application, surgical manipulation such as biopsy or incision, thermal modulation and control, ultrasound application and modulation, magnetic field application and modulation, etc.

[0189] BRIEF DESCRIPTION OF THE DRAWINGS

[0190] This and other aspects of the present disclosure will now be described in more detail, with reference to the appended drawings showing embodiment(s) of the invention.

[0191] Figs. 1A-H, 1J-O, and 1 P-T schematically show exemplary embodiments of the device of the invention, and Figures 1 U-V show a 3D-printed force-sensing implementation and accompanying control software.

[0192] Figs. 2A-F schematically show geometries of the force-transmitting surface.

[0193] Figs. 3A-E schematically show tissue surface preparations for interaction with an embodiment of the device of the invention.

[0194] Figs. 4A-T schematically show compressive application regimens for an embodiment of the device of the invention.

[0195] Figs. 5A-F schematically show interaction regimens between an embodiment of the device of the invention and an independently articulated biomedical instrument.

[0196] Figs. 6A-D schematically show tissue-contacting surface design optimization based on repeating tissue functional structures.

[0197] Fig. 7 schematically show a tissue-surface contacting embodiment of the device of the invention used in conjunction with an electrode-embedded synthetic protective film.

[0198] Figs. 8A-J schematically show embodiments of the device of the invention intended for bone-anchored, surface tissue compression implementations.

[0199] Figs. 9A-C schematically show embodiments of the device of the invention intended for implementations of surface tissue compression in conjunction with a translocating surgical instrument.

[0200] Figs. 10A-I schematically show embodiments of the device of the invention intended for implementations of below-the-surface tissue compression in conjunction with independently articulating surgical instruments or implanted cells.

[0201] DETAILED DESCRIPTION

[0202] Figs. 1A-H and Fig. 1 J-0 show a permutation of device of the present disclosure capable of applying a compressive force to the surface of a soft, vascularized, metabolically active tissue. In some figures, a slotted opening for independent placement, articulation, and removal of a biomedical instrument is present in the device. Figs. 1 P-T show a permutation of device of the present disclosure with integrated force-sensing capable of applying and monitoring a compressive force to the surface of a soft, vascularized, metabolically active tissue. Figs. 1 U and 1 V show a 3-D printed implementation of a force-sensing surgical tool holder and a screenshot of the custom -written software application used to control said force-sensing holder, respectively.

[0203] Turning now to Figs. 1 A-H, a schematic view of the device is shown.

[0204] Fig. 1A schematically illustrates a device 100 for applying a compressive force to a surface of a soft tissue. The device comprises a housing 112, an articulating structure 140 comprising an articulating block 101 and a protrusion 102 and a tissuecontacting surface 103, and an articulation mechanism 150 configured to drive the articulating structure.

[0205] The tissue-contacting surface 103 is configured to be brought into contact with the surface of the soft tissue and thereby apply the compressive force to the surface of the soft tissue. Further, the tissue-contacting surface 103 comprises a first opening 160 configured to receive a biomedical instrument,

[0206] Fig. 1 A shows one permutation of the device of the present disclosure without an independently articulating biomedical instrument. The device 100 is composed of a screw-driven articulating structure 140, here comprising an articulating block, 101 with a protrusion 102 where the tissue-contacting (compressive) surface 103 resides at the basal end (Figs. 1 B-D). The different components of the device 100 that are driven / moved / articulated by the articulation mechanism 150, here a screw-drive mechanism, may be referred to as the articulating structure 140. For example, the articulating structure 140 may comprise the articulating block 101 , the protrusion 102 and the tissue-contacting surface 103.

[0207] The protrusion is hollow 104 to provide room for positioning and manipulation of a biomedical instrument, and tapers 105 to the desired surface area of the tissuecontacting surface 103, shown in Figs. 1 B-D.

[0208] The edges of this surface are filleted 106 to prevent slicing of soft tissues during compressive articulation downwards. The length of the protrusion 107, shown in Figs. 1 E-F, can be increased to provide greater working length between the bottom of the housing and the surface of the tissue, such as might be required for additional tissue monitoring, fluid application, or imaging devices. The length of the protrusion

[0209] 107 can be shortened to improve positional accuracy and reduce motion artifacts as are known to occur with high aspect ratio devices.

[0210] In Fig. 1 B, the first opening 160 is a slotted opening 108. The slotted opening

[0211] 108 can be replaced with either a solid contact surface 109, or simply be a perforation 110. The slot 111 allows independent removal of the device 100 while a biomedical instrument remains implanted in the tissue, which would not be possible with a perforated opening 110, more specifically an opening that is not a cut-out or slotted, particularly in case of wiring, tubing, or optical lightguide connectivity that might be required for the biomedical instrument.

[0212] Furthermore, a slotted opening 108 might be required for translocating applications such as described in Figure 9.

[0213] Here, the articulation mechanism 150 comprises a screw-drive mechanism 112, 113, 115, 116, 117, 118, 119, 120, 121 , 122, 123. The screw-drive mechanism 112, 113, 115, 116, 117, 118, 119, 120, 121 , 122, 123 is comprised of a housing case 112, with a screw 113 inserted into a threaded receiving hole 114 in the articulating structure 140, specifically the articulating block 101. The articulating block 101 is positioned at its most distal position defined by the position of the screw 113 by a retaining spring 115 that is seated in a spring-groove 116 created in the internal surface 117 of the housing top plate 118. A nylon, PTFE, or other low friction washer 119 (e.g., metal washer and lubricating agent) is placed between the screwhead 120 and the external surface of the housing top plate 118.

[0214] Assembly of such a device 100 is aided by the removable bottom plate 121 of the housing that is held in place by set screws 122. This bottom plate 121 restricts maximum articulation of the articulating block 101 and includes an opening 123 that surrounds the distal end of the driving screw 113 preventing askew motions and of- axis positioning. Dimensions of the housing 112, the articulating block 101 and accompanying screws 113, 122, plates 121 , 118, washers 119, and spring 115 are determined by the desired articulation range 124, the limitations of the application (e.g., fixed stand holder, robotic-arm holder, surgical imaging / visualization requirements, etc.), and manufacturing capabilities (such as CNC machining, stereolithographic 3D polymer printing, fused deposition 3D polymer printing, powder bed fusion 3D metal printing, or combinations thereof). Hence, the device 100 may be configured to be mounted to and / or hold by and / or arranged on a fixed stand holder and / or a robotic arm holder, depending on the application.

[0215] Width 125 and length 126 dimensions, shown in Figs. 1 G-H, of the articulating block 101 are defined to be within machining accuracy of internal surfaces of the housing case 112, while providing unimpeded vertical screw-driven motion. Vertical dimension of the articulating block 127 is defined by the thread dimensions 128 of the drive screw 113. Lower profile threads 128 provide greater positional accuracy and stability of articulation and allowing for a thinner vertical block height 127, while impeding speed of articulation, particularly in manual adjustment of the drive screw 113. Higher profile screw threads 128 require a thicker 127 articulating block) 101 to provide sufficient positional stability of articulation and allowing higher speed of articulation, while reducing positional accuracy.

[0216] Screw driven implementations can be manually operated or can be motor driven with an external motor assembly and driveshaft. In other embodiments, in place of a screw-drive mechanism, a pneumatic bladder or pneumatic piston(s) can be used to articulate the block. In yet other embodiments, an electromagnetic drive can be used in conjunction with a magnetic material component within the articulating structure (articulating block 101) 140.

[0217] Finally, in certain space-limited embodiments ultrasonic motor assisted, thread- driven advancement of the tissue-contacting surface 103 can be employed, such as bone-embedded housings as described in Fig. 8.

[0218] Fig. 1 A shows an isometric projection of the assembled permutation of the device of the invention.

[0219] Figures 1 B-D show close-up isometric projections of the basal end of the articulating structure 140, specifically the articulating block 101 , protrusion 102 with slotted opening 108, a perforated opening 110, and a solid contact surface 109, respectively.

[0220] Fig. 1 E-H show side, front, top-down, and bottom-down orthographic projections of the assembled permutation of an embodiment of the device of the invention, respectively.

[0221] Fig. 1 J, K shows one permutation of an embodiment of the device of the invention as described in Fig. 1 A with an independently articulated pulled glass micropipette 129, possibly in conjunction with a luminal electrode 130, well known in the art and commonly used for single-cell recordings (patch-clamp, intracellular recordings, etc.). In such an implementation, the micropipette is placed into the halftube “hollow” 104 of the protrusion 102 and lowered into the tapered “bowl” 131 near the basal end of the compressing protrusion 102. The “hollow” 104, may be considered a cavity 104 inside the articulating structure 140, more specifically the protrusion 102. The tissue-contacting surface 103 does not touch or interact with the micropipette 129. In this example, the opening 160 in the tissue- contacting surface is slotted 108 to allow removal of the compression device of the invention without disturbing the implanted micropipette 129.

[0222] In other embodiments, the micropipette can take the form of an infusion device, a microdialysis device, or combinations, and / or bundles thereof.

[0223] Fig. 1 J shows an isometric projection of the assembled permutation of an embodiment of the device of the invention with a micropipette 129 in place, whereas Fig. 1 K shows a close-up orthographic front projection of the tissue-contacting surface 103 at the basal end of the protrusion 102 with micropipette 129 resting in the halftube “hollow” positioned to the base of the tapered “bowl” 131 .

[0224] Fig. 1 L,N shows one permutation of an embodiment of the device 100 of the invention as described in Fig. 1 A with an independently articulated optical glass fiber 132, well known in the art and commonly used for optical interactions with soft, vascularized, metabolically active tissues (optogenetic manipulation, enzymatic analysis using oxygen optrodes, etc.). In such an implementation, the glass fiber 132 is placed into the half-tube “hollow” 104 of the protrusion 102 and lowered through the tapered “bowl” 131 near the basal end of the compressing protrusion 102. The tissuecontacting surface 103 does not touch or interact with the glass fiber 132.

[0225] In this example, the opening 160 in the tissue-contacting surface 103 is slotted 108 to allow removal of the compression device 100 of the invention without disturbing the implanted glass fiber 132 or affiliated connections (not shown). The glass fiber 132 in this case is depicted with a fiber Bragg grating 133 and a flat-cut end 134, but could otherwise include angled cut end, multiple gratings, or no gratings.

[0226] In other embodiments, multiple optical fibers could be inserted as a bundle, either as a group or individually depending on their individual dimensions, composition and mechanical properties, and dimensions of the opening (108, 110) in the tissue-contacting surface 103.

[0227] Fig. 1 L shows an isometric projection of the assembled permutation of the device of the invention with a glass fiber 132 in place, whereas Figure 1 M shows a close- up orthographic front projection of the tissue-contacting surface 103 at the basal end of the protrusion 102 with glass fiber 132 positioned in the half-tube “hollow” descending below the tapered “bowl” 131.

[0228] Fig. 1 N,0 shows one permutation of the device of the invention as described in Fig. 1 A with an independently articulated gel-embedded tissue interface 135 such as a microarray thread or construction or microwire electrode, well known in the art and commonly used for electrical interactions with neural tissues. Such implementations are also envisioned in other soft, vascularized, metabolically active tissues. In such an implementation, the gel-embedded tissue interface 135 is placed into the half-tube “hollow” 104 of the protrusion 102 and lowered through the tapered “bowl” 131 near the distal end of the compressing protrusion 102. The tissue-contacting surface 103 does not touch or interact with the gel-embedded tissue interface 102.

[0229] In this example, the opening in the tissue-contacting surface is slotted 108 to allow removal of the compression device of the invention without disturbing the implanted gel-embedded tissue interface 135 or affiliated connections (not shown).

[0230] In other embodiments, multiple gel-embedded tissue interfaces could be inserted as a bundle, either as a group or individually depending on their individual dimensions, and dimensions of the opening in the tissue-contacting surface 103. In yet other embodiments, tissue interfaces can be inserted without gel embedding, relying on stiffness of the constructions, or using a guide vehicle or shuttle device such as a rigid needle, injector, etc.

[0231] Fig. 1 N shows an isometric projection of the assembled permutation of the device of the invention with a gel-embedded tissue interface 135 in place, whereas Fig. 10 shows a close-up orthographic front projection of the tissue-contacting surface 103 at the basal end of the protrusion 102 with gel-embedded tissue interface 135 positioned in the half-tube “hollow” descending below the tapered “bowl” 131.

[0232] Turning now to Figs. 1 P-T, a schematic view of the device with integrated force-sensing unit is shown. Fig. 1 P shows an isometric projection of the assembled permutation of the device of the invention with integrated force-sensing.

[0233] Fig. 1 Q-T show side, front, top-down, and bottom-down orthographic projections of the assembled permutation of an embodiment of the device of the invention with integrated force-sensing, respectively.

[0234] Fig. 1 P shows one embodiment of the device of the invention with an integrated force-sensing unit 136, without an independently articulating biomedical instrument. The device is comprised of a screw-driven articulating block 101 with an articulating protrusion 102 where the compressive solid surface 103 resides at the basal end 107 (Figures 1 B-D). The articulating structure 140 in this embodiment is a modular construction itself comprised of an upper block 101a that is threaded and interfaces with the screw-drive mechanism 109. The articulating structure here further comprises a force-sensing unit 136 comprising a commercially sourced load-cell 136a with wiring 136b, a lower block that connects the load-cell 136a with an elongation 102 that contains a compressive solid surface 103 at the basal end 105. The forcesensing unit 136 may comprise 0.98 N (100 gram) single point load-cell, Phidgets.com, p / n 3139_0. The elongation 102 forms a half-tube hollow 104 to provide room for positioning and manipulation of the biomedical instrument, and possesses a tapered bowl 131 to taper to the desired surface area of the tissuecontacting surface 103. The edges of the compressive solid surface 103 are filleted 106 to prevent slicing of soft tissue surface during compressive articulation downwards.

[0235] In Fig. 1 P, the length 107b of the elongation 102 can be increased or decreased to the desired working length between the bottom of the housing 112,121 and the tissue surface. The slotted compressive solid surface, also referred to as a surface with a first opening 160 and cut-out 108 can be replaced with either a continuous compressive solid surface with no openings 109, or the compressive solid surface may contain a single opening, also referred to as the first opening 110. The slot 111 within the slotted compressive solid surface 110 allows independent removal of the device while a biomedical instrument remains implanted in the visceral organ, which would not be possible with a perforated compressive solid surface 110, particularly in case of wiring, tubing, or optical lightguide connectivity that might be required for the biomedical instrument. In Fig. 1 P, the articulation mechanism 150 comprises a screw-drive mechanism 112, 113, 115, 116, 117, 118, 119, 120, 121 , 122, 123. The screw-drive mechanism 112, 113, 115, 116, 117, 118, 119, 120, 121 , 122, 123 is comprised of a threaded screw 113 which in this case has a hexagon-cavity laden head for interfacing with a hexagonal key or wrench and a basal end. The screw 113 is positioned within an opening in the main housing 118 near the head 113 and stabilized within an opening in the bottom housing plate 121 near the basal end preventing askew motions of the screw 113 and articulating structure 140. A nylon, PTFE, or other low friction washer 119 (e.g., metal washer and lubricating agent) is positioned between the screw head 113 and the outer surface of the main housing 118.

[0236] In Fig. 1 P, a retaining spring 115 is placed between the inner surface of the main housing 112 and the threaded upper block 101 a of the articulating structure 140, in this instance positioned at its most distal position defined by the position of the screw 113. Rotation of the screw 113 moves the upper block 101 a up or down defined by the direction of the rotation and the thread dimensions of the screw 113 and upper block 101 a. Vertical movement of the upper block 101 a moves the entire articulating structure 140 including the force-sensing unit 136, the lower block 101 b and the elongation 102 which contains the distal end 105 with the compressive solid surface 103.

[0237] Assembly of such a device as shown in Fig. 1 P is aided by the removable bottom housing plate 121 of the housing 112 that is held in place by set screws 122. This bottom housing plate 121 restricts maximum articulation of the threaded upper block 101 a. Dimensions of the housing 112, 121 , the articulating structure 140 and required set screws 122, washers 119, and spring 115 are determined by the desired articulation range 124. Screw driven implementations can be manually operated or can be motor driven with an external motor assembly and driveshaft (not shown). In other embodiments, in place of a screw-drive mechanism, a pneumatic bladder or pneumatic piston(s) can be used to articulate the block. In yet other embodiments, an electromagnetic drive can be used in conjunction with a magnetic material component within the upper block 101 a. Figs. Q-T further illustrate the dimensions 125, 126, 127 of the articulating upper block 101a, the vertical dimension 107b of the protrusion 102 from the tissuecontacting surface 103 to the base of the articulating lower block 101 b.

[0238] Turning now to Figs. 1 U and 1V, presented are a photograph of a surgical tool holder with built in force-sensing capabilities is presented and a screenshot of the custom -written software application used to control said holder, respectively.

[0239] Fig. 1 U shows an implementation of a surgical tool holder with built in forcesensing capabilities and accompanying software interface; this system demonstrates the force sensing 136 principles described in Figures 1 Q-T for implementation in said articulating structure 140 of the compressive device of the invention. Figure 1 U shows a stereotax swing-arm 137-attached, custom designed and SLA 3-D printed surgical tool holder 138 that incorporates a strain-gage based force-sensing unit 136 connected to a USB-analog-to-digital controller, e.g. a 100 gram (0.98 N) load-cell, p / n 3139_0 connected to a PhidgetsBridge USB Interface, both from Phidgets, Inc. (not shown) controlled by a Windows-based personal computer.

[0240] The tool holder in Fig. 1 U is loaded with a syringe 139a and Luer-lock needle 139b, is positioned above a rodent ear bar 140, and the holder is motivated by a pneumatic piston 141 driven by a pneumatic connection 142.

[0241] Fig. 1V shows a screen-capture of the Matlab-based GUI interface 170 for ForceSense software that records forces detected by said strain-gage based forcesensing unit 136. The GUI interface 170 comprises several tabs that perform user- inputted data 143, force-sensor calibration 144, force measurement 145, and data viewing and export 146. The measurement tab 145 is detailed and comprises a plotting area 147 for visualizing recorded forces (here expressed in units of gramsforce, gf, where 1 gf = 9.8 mN) as a function of time 148 and user-inputted timemarkers 149. Measurement of ferees using the GUI interface is performed by setting a data capture rate and duration of the recording 151 , and the recording controls 152 comprising start and stop buttons and a time-marker button. A status indicator 153 informs the user whether the software is ready to record, is currently recording, or has finished recording. The plotting area 147 can be tailored to visualize specific regions of the displayed dataset by adjusting the x- and y-axes minima and maxima 154, and the plotting area can be cleared and the last captured dataset re-plotted 155. Figs. 2A-F shows schematic representations of possible envisioned variations of the tissue-contacting surface (contact surfaces) 103 at the basal end of the articulating structure comprising the articulating block 101 and the protrusion 102 of the compression device of the present disclosure, as depicted in Figs. 1A-T. Combinations of such tissue-contacting surface (contact surface) features are also envisioned such as a convex surface with roughened surface with no opening for an independent biomedical instrument. The tissue-contacting surface 103 in Fig. 1 can be interchanged with surfaces 201 , 204, 207, 210, 211 or 213 represented in Figs. 2A-F. Filleted edges 106 as depicted in Fig. 1 can be applied as necessary to the designs presented in Fig. 2A-F.

[0242] Fig. 2A illustrates a flat surface 201 with a central opening 202 (either a slot

[0243] 108 or perforation 110 or omitted 109 as depicted in Fig. 1) for independent placement, articulation, and removal of a biomedical instrument, where applied forces 203 are transferred to the underlying tissues parallel to the central axis.

[0244] Fig. 2B illustrates a convex surface 204 with an opening 202 (either a slot 108 or perforation 110 or omitted 109 as depicted in Fig. 1) for independent placement, articulation, and removal of a biomedical instrument, where applied forces 205 radiate out relative to the radius of curvature 206 into the underlying tissues with respect to the central axis.

[0245] Fig. 2C illustrates a concave surface 207 with an opening 202 (either a slot 108 or perforation 110 or omitted 109 as depicted in Fig. 1 ) for independent placement, articulation, and removal of a biomedical instrument, where applied forces 208 radiate inwards into the underlying tissues with respect to the central axis focusing on a point 209 relative to the radius of curvature.

[0246] Fig. 2D illustrates a smooth surface 210 with little to no surface roughness intended to minimize any friction on the surface that may arise from shear motions relative to the underlying tissue, induced or experienced. In this depiction, no taper is employed, and the tissue-compressing element is rectilinear cylindrical. An optional opening 202(in this case equivalent to the perforation 110 as depicted in Fig. 1 ) for independent placement, articulation, and removal of a biomedical instrument is depicted (a perforation is depicted but can also be a slotted opening 108 or omitted

[0247] 109 as shown in Fig. 1 B-D). Fig. 2E illustrates a textured surface 211 with a predetermined roughness intended to maintain friction contact with the surface of the underlying tissue that may arise from shear motions relative to the underlying tissue, induced or experienced. The roughened surface 211 may be confined to the basal surface while the bulk of the contacting device can be composed of a different surface preparation and / or material 212. In this depiction, no taper is employed, and the tissue-compressing element is rectilinear cylindrical. An optional opening 202 (in this case equivalent to the perforation 110 as depicted in Fig. 1 ) for independent placement, articulation, and removal of a biomedical instrument is depicted (a perforation is depicted but can also be a slotted opening 108 or omitted 109 as shown in Fig. 1 B-D).

[0248] Fig. 2F illustrates a curved surface 213 that has been contoured to the underlying tissue surface 215 where applied forces 214 are directed inwards into the underlying tissues orthogonal to the surface contour 215. An optional opening 202 (in this case equivalent to the perforation 110 as depicted in Fig. 1 ) for independent placement, articulation, and removal of a biomedical instrument is depicted (a perforation is depicted but can also be a slotted opening 108 or omitted 109 as shown in Fig. 1 B-D).

[0249] The embodiment shown in Fig. 2B may be preferable for a moving, non- stationary application, whereas the embodiment shown in Fig. 2C may be preferable for stationary, non-moving applications. The embodiment shown in Fig. 2D may be preferable for sliding applications, whereas the embodiment shown in Fig. 2E may be preferable for shear-force inducing applications. The embodiment shown in Fig. 2F may be preferable to avoid sites of excessive or insufficient compression for applications where the underlying soft tissue is of a unique non-uniform contour or texture.

[0250] Fig. 3A-F shows schematic representations of the possible envisioned tissue interactions between the tissue-contacting surface, or contact surfaces, 103 at the basal end of the articulating structure 140 comprising the articulating block 101 and the protrusion 102 of the compression device of the invention, as depicted in Fig. 1 , (labeled here 301 ) and a soft, vascularized, metabolically active tissue 303 encased in a natural protective film 302 (such as the outer cerebral meninges (dura mater and arachnoid mater) or cardiac pericardium). In neural applications the interface between the inner layer of the meninges and outer layer of neural cortex, referred to here as the pia layer 309, is represented as an individual layer. Incisions 305, 306, 307, 310 made to the outer and inner meningeal layers 302, 309 can be performed at various stages of the compressive force application procedure (before, during (in certain instances 305 and 310), after force application).

[0251] Fig. 3A shows no removal of the natural protective film 302 encasing the soft, vascularized, metabolically active tissue 303, where compressive forces 304 are applied by the device of the invention 301 directly to the film 302 and transmitted to the underlying tissues 303. In Fig. 3A the dura is intact, and only surface compression is applied. This preparation could be useful for optical visualization of the cortex using 3-D imaging such as 2-photon, insertion of an extremely sharp object that can slice through the dura during insertion, etc.

[0252] Fig. 3B shows minor incision / excision 305 of the natural protective film 302 encasing the soft, vascularized, metabolically active tissue 303, where compressive forces 304 are applied directly to the film 302 and transmitted to the underlying tissues 303, but the incision / excision 305 is made to coincide with an opening in the compression device of the invention (depicted as 108, 110, 202 in Figs. 1 and 2). In certain embodiments, the incision / excision 305 in the natural protective film 302 is smaller than the opening in the compression device of the invention 301 . Fig. 3B illustrates durectomy (dura incision / excision), and surface compression with no direct contact of cortex. This preparation could be useful for insertion of fine instruments / devices (e.g. microinjections, optical fibers, electrodes, etc.) where minimal disturbance of the dura is required.

[0253] Fig. 3C shows complete incision / excision 306 of the natural protective film 302 encasing the soft, vascularized, metabolically active tissue 303, where compressive forces 304 are applied directly to underlying tissues 303 and the incision / excision 306 is made to coincide with the maximal extents of the compression device of the invention 301. In certain embodiments, the incision / excision 306 in the natural protective film 302 is larger than the maximal extents of the compression device of the invention 301 . Fig. 3C illustrates durectomy, and surface compression with direct contact of cortex. This preparation could be useful for wider field-of view applications were larger incisions, or biopsy samples are desired and dura intrusion might interfere with intended procedure. Fig. 3D shows complete incision / excision 307 of the natural protective film 302 encasing the soft, vascularized, metabolically active tissue 303, where compressive forces 304 are applied to an alternate protective film 308 placed onto the surface of the underlying tissues between the device 301 of the invention and the tissue 303. This alternate film 308 is biocompatible and has a modulus similar to that of the underlying tissue, can be transparent, translucent, opaque, or a combination thereof, can be inert and primarily used for protection of the tissue from the device and / or external environment, or it can include electronic circuitry, can be used for drug delivery of encapsulated pharmacological agents, can be absorbent in nature for the purposes of sequestering biological or surgical fluids, or can be composed of a biodegradable material. The incision / excision 307 in the natural film 302 is made to coincide with the maximal extents (or greater) of the compression device of the invention 301 and the dimensions of the alternate protective film 308 are not defined but can be smaller than the incision / excision 307 in the natural film 302, the same size as the incision / excision 307 in the natural film 302, or larger than the incision / excision 307 in the natural film 302. Fig. 3D illustrates durectomy, and surface compression with indirect contact of cortex through an artificial layer. The artificial layer can comprise therapeutic material (e.g. gelatin sheet / sponge, drug-loaded, etc), electronically active array (e.g. ECoG, EEG, LED arrays, magnetic antenna, etc.), thermal layer (e.g. heating elements, peltier, etc.), or simply a biocompatible protective film with no additive function.

[0254] Fig. 3E shows complete incision / excision 306 of the natural protective film 302 encasing the soft, vascularized, metabolically active tissue 303, where compressive forces 304 are applied directly to underlying tissues 303 and the incision / excision 306 is made to coincide with the maximal extents of the compression device of the invention 301. In neural applications where a pia layer is present, an incision 310 is made in the pia layer 309 to further aid insertion of delicate constructions that may provide enough mechanical rigidity to penetrate neural tissues, but not the inner meningeal pia mater that is intimately attached to the outermost layer of the cerebral cortex and other neural tissues. The application as shown in Fig. 3E with complete incision / excision 306 can instead be applied to a minor incision 305 of the natural protective film 302, and in some cases can be performed simultaneously, or in certain cases inadvertently. Fig. 4 shows force or displacement (Figs. 4A-J) versus time plots or pressure (Figs. 4K-T) versus time plots for the various envisioned compressive force application regimes. Forces can be in the range of pN, nN, mN, N, kN, MN, etc. and displacements can be in the range of nm, pm, mm, cm, etc. Pressures can be in the range of Pa, kPa, MPa, GPa, etc. Time can be in the range of ms, s, min, hr, days, weeks, months, years, or expected lifetime of the tissue or host. Compression and decompression ramps can be linear 401 as illustrated or non-linear in nature, such as when manually applied and ramp rates can range from nm / s, pm / s, mm / s, cm / s, m / s. Combinations, both additive and multiplicative, of the presented regimes can be envisioned for creating complex force or displacement application regimes.

[0255] Figs. 4A,K show a linear ramp 401 from no applied compression to a constant, stable applied compression of amplitude 402 that is held for the duration of the experiment, procedure, lifetime, etc.

[0256] Figs. 4B,L show a linear ramp 401 from no applied compression to a constant, stable applied compression of amplitude 402 that is held for length of time 403 and then released in a linear fashion 401 .

[0257] Figs. 4C,M show an applied compression at a constant, stable applied compression 402 that is held for length of time 403 and then released, followed by a pause for a length of time 404, and subsequently followed by a second applied compression at a constant, stable applied force, displacement, or pressure 402 that is held for the same length of time 403 and then released.

[0258] Figs. 4D,N show a series of compression intervals at a constant, stable level of compression of amplitude 402 that are held for various lengths of time 405, 407, 409 and then released, interspersed by pauses of various lengths of time 406, 408.

[0259] Figs. 4E,0 show a series of compression intervals, with stable levels of compression of different amplitudes 402, 410 that are held for various lengths of time 403, 411 and then released, interspersed by pauses of various lengths of time 406.

[0260] Figs. 4F,P show a periodic application of compression intervals with stable levels of compression 402 interspersed with uniform pauses 404. Such periodic applications, also known as “square-wave”, can be described by the time from one onset of compression to the next onset of compression 412, or by the number of such periods per unit time (expressed in units of Hz). Figs. 4G,Q show a periodic application of compression intervals with continuously rising and falling linear rates 401 of compression that reach a maximum amplitude 402. Such periodic applications can be described by the time from one onset of compression to the next onset of compression 412, or by the number of such periods per unit time (expressed in units of Hz).

[0261] Figs. 4H,R show a periodic application of compression intervals with continuously rising and falling sinusoidal rates of compression with a stable amplitude 402. Such periodic applications can be described by the time from one onset of compression to the next onset of compression 412, or by the number of such periods per unit time (expressed in units of Hz).

[0262] Figs. 4I,S show a periodic application of compression intervals with continuously rising and falling rates of compression with varying compressive periods such as those described in Fig. 4F-H 413, 414, 415. Periods of compression can be random or repeating.

[0263] Figs. 4J,T show a multimodal compression versus time plot that is comprised of various ramp forms and rates, various compression durations and levels, contains various periodic epochs, contains various pause durations, and can contain no repeating, ordered, or predictable pattern. (Includes examples of the various forms depicted in Fig. 4A-I).

[0264] Fig. 5 illustrates the envisioned interplay between application of compressive forces 504 (such as described in Fig. 4) to the surface of a soft, vascularized, metabolically active tissue 502 using the device of the invention 501 and the insertion 506 of an independently articulated biomedical instrument 505 such as a surgical tool, device, implanted material, etc. (as shown in Fig 1 ). Natural protective film 503 of this instance is excised to allow direct tissue access for the biomedical instrument 505, consistent with Fig. 3B, but other preparations described in Fig. 3 can be envisioned. In neural applications the interface between the inner layer of the meninges and outer layer of neural cortex, referred to here as the pia layer 508, is represented as an individual layer and in certain instances can be further incised to aid implant insertion (see 310 in Fig. 3E), however this is not depicted in these figures. Furthermore, applications of ferees 504 that are constantly adapted based on physiological measures from the host (either local, systemic, or both) that stray from those envisioned in Fig. 5A-F are also covered by this invention, see Fig. 4. Fig. 5A illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural film 503 (Fig. 5A.i) before application of ferees 504 and with no independently articulated biomedical instrument, (Fig. 5A.ii) following application of compressive forces 504, but before insertion of an independently articulated biomedical instrument 505, (Fig. 5A. iii) following application of compressive forces 504, and following insertion 505 of an independently articulated biomedical instrument 505, and (Fig. 5A.iv) following release of compressive forces 504, with an inserted independently articulated biomedical instrument 505.

[0265] Fig. 5B illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural film 503 (Fig. 5B.i) before application of ferees 504 and with uninserted independently articulated biomedical instrument 505, (Fig. 5B.ii) following application of compressive forces 504 and concurrent insertion 506 of an independently articulated biomedical instrument 505, (Fig. 5B. iii) following release of compressive forces 504, with an inserted independently articulated biomedical instrument 505, (Fig. 5B.iv) repeated 507 application of compressive forces 505 with an already inserted independently articulated biomedical instrument 505 can be optionally performed.

[0266] Fig. 5C illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural film 503 (Fig. 5C.i) before application of ferees 504 and with uninserted independently articulated biomedical instrument 505, (Fig. 5C.ii) following insertion 506 of an independently articulated biomedical instrument 505, before application of compressive forces 504, (Fig. 5C. iii) following application of compressive forces 504 with an inserted independently articulated biomedical instrument 505, and (Fig. 5C.iv) following release of compressive forces 504, with an inserted independently articulated biomedical instrument 505.

[0267] Fig. 5D illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural film 503 (Fig. 5D.i) before application of ferees 504 and with no independently articulated biomedical instrument 505, (Fig. 5D.ii) following application of compressive forces 504 with no independently articulated biomedical instrument 505, (Fig. 5D. iii) following release of compressive forces 504, with no independently articulated biomedical instrument 505, and (Fig. 5D.iv) just prior insertion 506 of an independently articulated biomedical instrument 505 as outlined in Figs. 5A-C. Steps (Fig. 5D.ii) and (Fig. 5D. iii) can be repeated (507) as necessary (see Fig. 4C-J).

[0268] Figs. 5A-D: Repeated applications 507 or periodic cycling 507 of compressive forces 504 as depicted in Figure 4 can be performed as indicated between steps 5A.iv and 5B.iv, between steps 5B. iii and 5B.iv, between steps 5C. iii and 5C.iv, and between steps 5D.ii and 5D.iii.

[0269] Fig. 5E illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural protective film 503 (Fig. 5E.i) before application of compressive forces 504 with a presently indwelling independently articulated penetrative biomedical instrument 505 positioned at an initial target depth 509 with a desired target denoted with the star 511 , (Fig. 5E.ii) following application of compressive forces 504 where the surface of a soft, vascularized, metabolically active tissue 502 deforms and the presently indwelling independently articulated penetrative biomedical instrument 505 positioned at an initial target depth 509 and the desired target are all deformed downward with the tissue surface to new target depth 510, (Fig. 5E. iii) while compressive forces are maintained, the presently indwelling independently articulated penetrative biomedical instrument 505 is articulated downward 506 toward the desired target 511 , and (Fig. 5E.iv) following release of compressive forces 504, the indwelling independently articulated penetrative biomedical instrument 505 now resides at the desired target 511 located at the new target depth. The desired target 511 and articulation 506 of the independently articulated penetrative biomedical instrument 505 may be any desired target depth either below or above the initial target depth 510 accordingly.

[0270] Fig. 5F illustrates the surface of a soft, vascularized, metabolically active tissue 502 with incised / excised natural protective film 503 (Fig. 5F.i) before application of compressive forces 504 with a presently indwelling independently articulated penetrative biomedical instrument 505, (Fig. 5F.ii) following application of compressive forces 504 with a presently indwelling independently articulated penetrative biomedical instrument 505, (Fig. 5F.iii) following removal 506 of the independently articulated penetrative biomedical instrument 505 from the surface of the soft, vascularized, metabolically active tissue 502 with continued application compressive forces, and (Fig. 5F.iv) following release of compressive forces 504. Fig. 6 shows a simplified schematic planar representation of the cerebral cortex with repeating columns of vertically arranged cortical circuitry designated with hexagonal shapes 601 . Such ordered (or semi-ordered or quasi-ordered) arrangement of functional units in soft, vascularized, metabolically active tissue is known to occur in other bodily organs such as kidneys (nephron filtration units) and pancreas (hormone-secreting pancreatic islets). Ordered (or semi-ordered or quasiordered) arrangements of functional units in some cases may be better represented by other shapes including quadrangular, triangular, circular, oblong, “blob”-like, or other shapes or combinations thereof. Other shapes and geometries than the circular examples of the tissue-contacting surfaces presented in Fig. 6 (for examples, see surfaces 103 of geometries 108, 109, 110 in Fig. 1 ) are also covered in this invention, including but not limited to oblong, triangular, quadrangular, free-form, or custom- designed for a specific biomedical instrument, surgical tool, or specific tissue application.

[0271] Fig. 6A shows a possible profile 602 of the tissue-contacting surface (for examples, see surfaces 103 of geometries 108, 109, 110 in Fig. 1 ) of a compressive device of this invention designed to impact a small, circular region of tissue 603 with a central opening (604) for independent articulation of a biomedical instrument aligned with the columnar organization of the underlying tissue. This design is intended to impact as small a region of organized tissue as possible 605.

[0272] Fig. 6B shows a larger variant of the design in Fig. 6A with an external outline 608 and internal opening 609. In this instance, the design impacts a greater number of cortical columns 606, imparting influence over a greater number of cortical computing units 601 while providing a larger area 607 for the insertion of a larger independently articulating biomedical instrument and providing greater flexibility in avoiding surface vasculature or improved targeting 607 of predicted locations at the interface between cortical columns 610.

[0273] Fig. 6C shows the same design as in Fig. 6A with an external outline 612 and internal opening 613, but this time is targeted to overlap to some degree all cortical columns 611 thereby ensuring more equitable distribution of compressive forces across all underlying cortical columns, including those within the opening 614.

[0274] Fig. 6D shows a possible profile 615 of the tissue-contacting surface of a compressive device of this invention designed to provide a slot 616 with access for a cutting instrument such as a scalpel blade (further illustrated in Fig. 9) that does not directly compress 617 tissue in the slot. The tissue-contacting surface can be slid or dragged across the surface of the tissue 618 as designated by the double-sided arrow while simultaneously applying compressive forces to an area of cortical columns surrounding the open slot 619. Such motion is intended to precede, proceed, or coincide with insertion, incision, and removal of the independently articulating cutting instrument. In certain embodiments (see Fig. 1 ), the independently articulating biomedical instrument is stationary, but the device of the invention can be moved or removed without disturbing the instrument.

[0275] In Figs. 6A-C the unfilled (solid white) hexagons represent uncompressed cortical column, or some other repeating tissue unit, for example kidney nephron, pancreatic islet, etc. The hexagons having a squared pattern represents repeating tissue unit that is directly compressed by force-modulating device. The hexagons having a “dotted” pattern represents repeating tissue unit that is not directly (or minimally) compressed by force-modulating device, but surrounded by compressed tissues and is of interest for implantation, analysis, collection, observation, or surgical manipulation.

[0276] Fig. 7 shows a simplified schematic of the application of the device of this invention 701 , interchangeable with previous depictions (such as 102 in Fig. 1A or Fig. 1 B-D, or 201 , 204, 207, 210, 212, 213 in Fig. 2, or 301 in Fig. 3) on the surface of cortical tissue 702 illustrating the potential of non-uniform surface geometry of the mammalian cortex, and the use of a protective film 703 between the device and the surface of the brain 702. This film 703 contains embedded electrodes 704 and wiring 705 necessary to make electronic connections with affiliated electronic equipment, known in the field. A circular opening 706 in the center of the device provides access for an independently articulating biomedical instrument 707 such as an optical probe, micropipette, or infusion device. The electrode-containing protective film includes a corresponding opening 708 in its center that is aligned with the opening 706 in the compressive device. Forces 709 are applied downward orthogonal to the surface of the underlying tissue 702 but can include shear components in certain embodiments. In yet other embodiments, the film can include resistive wiring for temperature control, light emitting diodes for optical modulation or interrogation of tissues, electromagnetic circuits, etc. In further embodiments, the film can be pharmacologically active, or absorbent, or degradable, as described earlier.

[0277] Fig. 8 shows simplified schematics in cross-section of a bone-mounted application of the compressive device of the invention shown as simplified schematics in cross-section (Figs. 8A-C) and detailed illustrations (Figs. 8D-J) where the device 801 is mounted into the skeletal structures 802 such as the skull, sternum, pelvic bone, etc. Modulation of compressive forces by the articulation structure 803 is directed orthogonal to the mounted surface of the bone and the device is attached via bone ingrowth 804 into porous structure, using screw threads, adhesive bone cement, surface mounted screws, or combinations thereof. In such embodiments, the purpose of the device is to augment other technologies depicted in Fig. 8A-C, and in general any implanted device residing in soft, vascularized, metabolically active tissue 805. In these examples, the meningeal layer (or any other natural protective film) 806 has been resected and compressive contact is made directly with tissue surface (see Fig. 3C). In neural applications the interface between the inner layer of the meninges and outer layer of neural cortex, referred to here as the pia layer 815, is represented as an individual layer and in certain instances can be further incised to aid implant insertion (see 310 in Fig. 3E), however this is not depicted in these figures. Vascular structures 813 are depicted. In certain applications, openings 814 through the device enclosure are present for connectivity to underlying technologies 807, 809, 810, or for optical interrogation of tissues 805. Actuation of the articulating structure 803 with a compressive solid surface 803c is facilitated by a drive mechanism 817 comprised of at least one of a piezoelectric motor also known as an ultrasonic motor, or a thread mechanism, or a gear mechanism, an electromagnetic mechanism, a pneumatic mechanism. Such a mechanism can be motivated through manual, electronic, or motorized means.

[0278] Bone-anchored force-modulating tool is shown in conjunction with implanted microelectrode wires / thread(s) in Fig. 8A, implanted stem cell precursors or stem-cell derived differentiated cells in Fig. 8B, fiber optic probe for optogenetic modulation of genetically engineered cells in Fig. 8C. Other applications are envisioned, including implanted microdialysis tool, microinfusion tube, use in combination with devicemounted ECoG / EEG array electrodes, ultrasound stimulation, thermal modulation, etc. Fig. 8A shows the bone-mounted device 801 , 802, 803 placed over implanted microelectrode wires 807 or other flexible electrode technology (flexible arrays, mesh or net of electrodes, etc.) such as those used in cortical and sub-cortical neural applications embedded among a population of endogenous cells such as neurons, glia, etc. 808. A similar application is envisioned for example in cardiac stimulating electrodes implanted into cardiac tissue where a compression force-modulating device is embedded in the sternum above the site of implantation. In this specific instance, the timing of compressive forces is envisioned to relate to electrical stimulation / recording, either in phase, out of phase, or at some other related frequency or stable compression regime. In other embodiments, timing of compressive forces is envisioned to relate to some other physiological response or predetermined regimen (see Fig. 4).

[0279] Fig. 8B shows the bone-mounted device 801 , 802, 803 placed over implanted stem cells, stem-cell-derived differentiated cells, stem-cell derived organoids, tissue engineered constructs, etc. 809 embedded among a population of endogenous cells such as neurons, glia, etc. 808. Tissue region of interest 816 that is a therapeutic target zone which could consist of a diseased or injured tissue, a specific tissue structure (e.g. a cortical column, a pancreatic islet, or any unique tissue unit (see Fig. 6)), or a tissue that has been a priori cleared of cellular content (e.g. streptozotocin induced beta cell death, pharmacologically lesioned neurons, etc.) that has been supplemented with 809 is depicted. A similar application is envisioned for example in cardiac tissues with implanted stem cells, stem-cell-derived differentiated cells, stemcell derived organoids, tissue engineered constructs, etc. In this specific instance, the timing of compressive forces is envisioned to relate to the growth cycle, population composition, or some other cellular marker or activity. In other embodiments, timing of compressive forces is envisioned to relate to some other physiological response or predetermined regimen (see Fig. 4).

[0280] Fig. 8C shows the bone-mounted device 801 , 802, 803 placed over an implanted optical probe 810 or other structure, such as an infusion device, microdialysis probe, electrode etc. embedded among a population of endogenous cells such as neurons, glia, etc. 808. The optical probe 810 is envisioned to optically stimulate 811 genetically modified cells 812 that have been modified to express an optically active ionic channel such as channel rhodopsin, etc., but can in certain instance be other optically responsive embedded objects. In this specific instance of optical probe, the timing of compressive forces is envisioned to relate to optical stimulation 811 , either in phase, out of phase, or at some other related frequency or stable compression regime. In other embodiments, timing of compressive forces is envisioned to relate to some other physiological response or predetermined regimen (see Fig. 4).

[0281] Fig. 8D-G details a simplified drive mechanism 817 and force-sensor integrated articulating structure 818 of the exemplary embodiment of a bone-mounted compressive device of the invention shown in Fig. 8A-C comprising a threaded gear ring 817a, a gear 817b that interfaces with said threaded gear ring providing a 4:1 gear drive ratio, a threaded interface 817c between said threaded gear ring 817a and said articulating structure 803 used to vertically articulate said articulating structure 803. The simplified drive mechanism is shown in top-down orthographic and top projections in Fig. 8D and 8E, respectively. Drive mechanisms other than geared and threaded mechanisms as illustrated here are easily envisioned including piezoelectric motors, electromagnetic mechanisms, pneumatic piston mechanisms, expanding structures such as bladders, manually advanceable mechanisms, ratcheted mechanisms, and so on and so forth. The articulating structure 803 is comprised of a threaded upper portion 803a that is threaded to interface 817c with the threaded gear ring 817b, opposing spiral cantilever arms 818a, a lower non-threaded portion of the articulating structure 803b that is connected to the threaded top portion 803a by the spiral cantilever arms 818a, a strain gage 818b mounted on the surface of each of the spiral cantilever arms 818a and affiliated wiring 818c, and a compressive solid surface 803c on the bottom of the lower portion of the articulating structure 803b that in this embodiment is flat, smooth, tapered, and contains a central perforation opening 814. Guide rods (not shown) inserted into guide holes 803d of the upper threaded portion 803a rotationally stabilize this embodiment of the articulating structure 803. The strain gages 818b mounted on the spiral cantilever arms 818a form a functional integrated load cell 818 analogous to the commercial load cell presented in Fig. 1 136a. This embodiment presents two opposing spiral cantilever arms 818a, however embodiments with only one arm, or embodiments with more than two arms are easily envisioned. This embodiment presents a strain gage 818b on each spiral cantilever arm 818a, but embodiments with more than one strain gage per spiral cantilever arm, or embodiments with fewer strain gages than available spiral cantilever arms are also easily envisioned. Embodiments with cantilever arms of geometries other that spiral are also envisioned. The articulating structure is detailed in top-down orthographic and bottom-up orthographic projections in Fig. 8F and 8G, respectively. The threaded and geared mechanism presented functions simply through the rotation of the gear 817b which counter-rotates the threaded gear ring 817a, thus threading the threaded upper portion 803a of the rotationally immobilized 803d articulating structure 803 advancing it vertically. Assuming a 0.5 mm threading of the threaded interface 817c, four turns of the gear 817b rotate the threaded gear ring 817a once, which vertically advances the articulating structure by 0.5 mm. The shaft of gear 817b can be coupled to a motor which can control speed electronically, alternatively the threading of the interface 817c can be varied, gear tooth number and dimensions can be varied, and dimensions of the gear 817b can be varied to provide for customized articulation speeds or improved positional accuracy of the articulating structure 803.

[0282] Fig. 8H and 8I exemplify a housing 801 for said drive mechanism presented in Fig. 8A-G that can be embedded in bone 802 and provide attachment 804 through a sufficiently rough surface and appropriate material selection. The lower housing 801a possesses retaining features for the threaded gear ring 817a and gear 817b, and an opening to allow the articulating structure 803 to protrude. The upper housing 801 b possesses an opening to access the central perforation opening 814 of the compressive solid surface 803c, an opening to access the protruding gear shaft 817b, and an external surface texture and material selection to promote bone attachment 804. The drive mechanism housing 801 is detailed in top-down orthographic (with upper housing 801 b removed) and bottom-up orthographic projections in Fig. 8H and 8I, respectively.

[0283] Fig. 8J provides a cross-section view bisecting the articulating structure 803 and both the threaded gear ring 817a and gear 817b of the drive mechanism 817 of the fully assembled bone-mounted embodiment of the compressive device of the invention as presented in Figs. 8H, I. The device depicted in Fig. 8J is in the retracted state where upper threaded portion 803a of the articulating structure 803 sits adjacent to the upper housing 801 b. Rotation of the gear 817b of the drive mechanism 817 counterrotates the threaded gear ring 817a of the drive mechanism 817 thereby actuating the threaded interface 817c between the threaded gear ring 817a and the threaded upper portion 803a resulting in vertical motion of the articulating structure 803. Guide-posts descending from the upper housing 801 b emanate from the guide holes 803d that preclude rotation of the articulating structure 803 with the threaded gear ring 817a.

[0284] Fig. 9 shows a simplified schematic of the application of the device 901 of this invention interchangeable with previous depictions (such as 102 in Fig. 1A or Fig. 1 B- D, or 201 , 204, 207, 210, 212, 213 in Fig. 2, or 301 in Fig. 3, or 501 in Fig. 5, or 619 in Fig. 6) on the surface of cortical tissue 902 illustrating the potential for both lateral translocation 903 and vertical compression 904 in conjunction with an independently articulating 905 and translocating 906 biomedical instrument, in this case a surgical scalpel blade 907. In neural applications, the interface between the inner layer of the meninges and outer layer of neural cortex, referred to here as the pia layer 912, is represented as an individual layer and in certain instances can be further incised to aid implant insertion (see 310 in Fig. 3E), however this is not depicted in these figures. Vertical compression 904 of the device of the invention 901 can relate to a specific physiological response, position of the biomedical instrument 907, or predetermined regimen (see Fig. 4).

[0285] Fig. 9A shows an illustrated schematic. In the illustrated schematic, the compressive device 901 precedes and surrounds the surgical blade creating a zone of compressed, transiently vascularly occluded tissue 908 into which the blade 907 will cut. Embodiments that proceed or coincide with the trajectory of the blade 907 are also envisioned. The surgical tool or biomedical instrument, such as the scalpel blade 907 in this instance, can be articulated manually, using a manual holder, attached to an orthoscopic instrument, attached to a robotic arm, or some other method of articulation known in the art.

[0286] Fig. 9B shows a cross-section view at the position of tissue 902 without compression forces 904 or inserted biomedical instrument such as a scalpel blade 907. In this instance, tissue blood vessels 909 are not occluded allowing for perfusion of tissues. Natural protective film 911 of this instance is excised to allow direct tissue access for the scalpel blade 907, consistent with Fig. 3B. Other surface preparations as depicted in Fig. 3 can be used instead. Endogenous cell populations are not depicted but are understood to be present and may be mechanically responsive. Fig. 9C shows a cross-section view at the position of tissue 908 with applied compression forces 904 and an inserted 905 biomedical instrument such as a scalpel blade 907. In this instance, tissue blood vessels 910 are occluded preventing perfusion of tissues resulting in ischemic and hypoxic conditions. Natural protective film 911 of this instance is excised to allow direct tissue access for the scalpel blade 907, consistent with Fig. 3B. Other surface preparations as depicted in Fig. 3 can be used instead. Endogenous cell populations are not depicted but are understood to be present and may be mechanically responsive.

[0287] Fig. 10 shows a simplified schematic in cross-section of an application of the device of the invention intended for compressive modulation 1017, 1018, 1019 of deeper structures below the surface of a soft, vascularized, metabolically active tissue 1014. Natural protective film 1007 covering the surface of the tissue 1014 is depicted with an incision that extends beyond the external dimensions of the guide tube 1002, and can represent the outer meninges (dura mater and arachnoid mater) in neural applications, the pericardium in cardiac applications, etc. In neural applications, the interface between the inner layer of the meninges and outer layer of neural cortex, referred to here as the pia layer 1015, is represented as an individual layer. Skeletal structures 1006 are depicted in this figure; however, this does not necessarily apply to soft tissues 1014 not in the vicinity of the skeletal system. The general idea of this implementation involves the use of a guide structure 1002 (cylindrical tube, semi- cylindrical tube section, square pipe, or other geometrical cross-section) that can be inserted into the tissues beforehand or simultaneously with the protrusion of the device 1001. This protrusion 1001 is similar to structures described in Fig. 1 B-D that contains a central opening 1003 and a force-contacting structure at the distal end 1004, 1005.

[0288] In certain embodiments this structure is comprised of a rigid surface 1028, 1030 manufactured from a metal, polymer, ceramic, or combinations thereof as previously described, and is consistent with the principles described in Fig. 1 , 2, 5, 6 and further detailed in Fig. 10G,H. The guide tube 1002 is inserted using methods consistent with standard surgical practices known in the art and can be combined with principles described in Fig. 3 and 5.

[0289] In certain embodiments the guide tube 1002 is comprised of a rigid surface manufactured from a metal, polymer, ceramic, or combinations thereof as previously described. The central opening 1003 can be used for subsequent insertion of an independently articulated biomedical instrument such as a neural interface 1012, optical probe 1029, micropipette 1032, microdialysis probe, etc., or it can be used to provide pneumatic connections 1020 (either gas or liquid) to a spatially expanding bladder and wire structure analogous to an angioplasty balloon 1004, 1005, or can be used to deliver cells 1024 (e.g. stem-cells, stem-cell derived cellular populations or tissue engineered structures such as organoids). Orientations of a compressive device can be vertical along the central axis A but can be oriented at an angle to the central axis A to direct forces to regions of tissue 1014, 1021 off-axis. Shapes and dimensions of the expanding force-contacting structure 1004, 1005, 1013, 1016 can be tailored to the desired application by using structures with greater force-contacting surfaces 1004, 1016 but experiencing less volumetric expansion 1018, structures with smaller force-contacting surfaces 1004, 1016 but experiencing greater volumetric expansion 1018, structures 1005, 1013 with more spherical shapes, polygonal shapes, cylindrical shapes, conical shapes, shapes with hollow channels or invaginations, etc. and combinations thereof. The dimensions of the device of the invention comprising the guide tube 1002, protrusion 1001 , central opening 1003, tissue-contacting force-exerting structures 1004, 1005, 1013, 1016, 1028, 1030 are determined by the dimensions of the tissue 1014, depth below the tissue surface of the targeted therapeutic zones 1021 , 1033, volume of tissue that is to be modulated by compressive forces 1033, and manufacturing capabilities as are known in the field.

[0290] Fig. 10A shows a cross-section view of a soft, vascularized, metabolically active tissue 1014 below a skeletal structure 1006 that has been opened, with an inserted application of the device of the invention intended for compressive modulation of deeper structures comprising of a guide tube 1002, articulating protrusion 1001 , and a force-contacting structure at the distal end 1004, 1005 comprising a protective elastic film 1004 and an expansion-capable structure such as a bladder 1005 in its compressed form. A pneumatic connection 1020 to the expansion-capable bladder 1005 is depicted. The tissues contain endogenous populations of cells 1008 and non-occluded vascular structures 1009 capable of perfusing tissues.

[0291] Fig. 10B shows the same cross-section view as Fig. 10A but with expansion of the expansion-capable structure such as a bladder 1013 and stretched protective elastic film 1016. Expansion 1018 of the expansion-capable structure 1013 results in compressive forces 1017 exerted onto surrounding tissues 1014 that are orthogonal to the surface of the stretched protective elastic film 1016 and proportional to the orthogonal component of volumetric expansion and mechanical properties of the tissue 1014. Volumetric expansion 1018-induced compressive forces 1017 cause occlusion of vascular structures 1010 precluding tissue perfusion and deform and mechanically interact with endogenous cellular structures 1011 in the vicinity of the expansion-capable structure 1013, 1016. In order to further induce compressive forces in line with the central vertical axis B, articulation 1019 of the protrusion 1001 can be performed. In the depicted embodiment a specific tissue region of interest 1033 is targeted by the compressive forces 1027 and represents a region of tissue that is specifically mechanically modulated, as represented by mechanically deformed cells 1011 , and occluded vascular structures. The bladder 1005, 1013 can in some embodiments be encased in a wire mesh for further mechanical rigidity and that can hold its shape once deformed. In such instances where a bladder is used to induce volumetric expansion 1018 of 1004 and 1005, a pneumatic connection 1020 is required through the central opening 1003 of the protrusion that can be left in place for subsequent articulation, or removed once expansion-based forces are no longer required. In other embodiments, the expansion-capable structure 1005, 1013 can be comprised of a thermally responsive metal or polymer (e.g. Nitinol, a.k.a. nickel titanium with a nickel / titanium ratio in the range of 0.95 to 1 .05, or compatible alloy) that can be machined into a compressed form at room temperature (or a temperature below physiological, such as below 37°C, but can be below 35°C, below 30°C, below 20°C, and in some instances in a cryogenic range between 5°C and -5°C) and then expand upon exposure to elevated or physiological temperatures such as above 0°C, above 20°C, above 30°C, above 35°C, above 37°C, or higher depending on physiological state of the tissue. Wire-mesh-based embodiments require use of a protective elastic film 1004, 1016 to preclude slicing damage of the wire into soft tissues 1014. In yet other embodiments this structure can comprise a water permeable protective elastic film encasing a cross-linked hydrogel with a high swelling ratio (>25, >50% and in some instances >80%) such as a cross-linked albumin, poly(hydroxy methyl methacrylate) (pHEMA), cross-linked gelatin, or any other biocompatible hydrogel capable of sufficient water swelling. In such an instance fluid required for swelling is derived from tissue-derived extracellular and interstitial fluids. In some instances, the hydrogel is swollen using a water supply apparatus via the central opening 1003 similar to the pneumatic system for bladder control that exogenously supplies fluid and said apparatus can be removed once the impermeable protective elastic film 1016 encased hydrogel-based expansion-capable structure 1013 is sufficiently swollen. Expansion can be controlled by restricting the fluid flow rate.

[0292] Fig. 10C shows the same cross-section view as Fig. 10B but with fully distended expansion-capable structure such as a bladder 1013 and stretched protective elastic film 1016 and subsequently inserted microelectrode threads 1012 utilizing the central opening 1003. These microelectrode threads 1012 can comprise individual microwire electrodes or microelectrode arrays or related technology. In some embodiments, the threads 1012 are inserted following full expansion 1018 of the expansion-capable structure 1013, in other embodiments the threads 1012 are inserted simultaneously during expansion 1018, while in yet other embodiments the threads 1012 are inserted before expansion 1018. In certain embodiments, the expansion-capable structure such as a bladder 1013 can be driven using the pneumatic connection 1020 through periods of expansion and contraction 1018 that generate compressive forces 1027 onto neighboring tissues 1014 consistent with force / time profiles described in Fig. 4. In yet additional embodiments, to further induce compressive forces in line with the central vertical axis B, articulation 1019 of the protrusion 1001 can be performed.

[0293] Fig. 10D shows a cross-section view of a soft, vascularized, metabolically active tissue 1014 below a skeletal structure 1006 that has been opened, with an inserted application of the device of the invention intended for compressive modulation of deeper structures comprising of a guide tube 1002, articulating protrusion 1001 , and a force-contacting structure 1004, 1005 located in the wall of the protrusion 1001 near the distal end comprising a protective elastic film 1004 and an expansion-capable structure such as a bladder 1005 in its compressed form, oriented at a right angle (90°) to the vertical axis B intended to compress tissues located to the side of the protrusion 1001 . Other orientation angles (measured from the vertical axis B below the device to the main vector of expansion) can be envisioned ranging from >0° to 90°, to >90° limited by the shape and dimensions of the fully extended 1018 force-contacting structure 1013, 1016, and are also covered by this invention. Tissue region of interest 1021 that is a therapeutic target zone which could consist of a diseased or injured tissue, a specific tissue structure (e.g. a deep brain structure such as subthalamic nucleus or similar, a pancreatic islet, or any unique tissue unit (see Fig. 6)), or a tissue that has been a priori cleared of cellular content (e.g. streptozotocin induced pancreatic beta cell death, pharmacologically lesioned neurons, etc.) is depicted. Rotation 1026 of the protrusion 1001 about the central vertical axis B can be performed to target the force-contacting structure 1013, 1016 to the desired volume of tissue, either directly at, adjacent to, or away from the tissue region of interest 1021 .

[0294] Fig. 10E shows the same cross-section view as Fig. 10D but with expansion of the expansion-capable structure such as a bladder 1013 and stretched protective elastic film 1016. Expansion 1018 of the expansion-capable structure 1013, 1016 results in compressive forces 1017 exerted onto surrounding tissues 1021 that are orthogonal to the surface of the stretched protective elastic film 1016, proportional to the orthogonal component of volumetric expansion and mechanical properties of the tissue 1014, 1021 , directed at a right (90°) angle to the central vertical axis B of the protrusion. Descriptions of design and methods of use are consistent with Fig. 10B, but the protrusion 1001 can be further rotated about the central vertical axis B while the expansion-capable structure 1013, 1016 is in its expanded state in order to generate both shear forces and compression / tension forces in / out-of-plane of the cross-section view.

[0295] Fig. 10F shows the same cross-section view as Fig. 10E but with fully distended expansion-capable structure such as a bladder 1013 and stretched protective elastic film 1016 and subsequently implanted stem-cells, stem-cell derived cellular populations or tissue engineered structures such as organoids 1024 utilizing the central opening 1003. The cell-derived materials 1024 are inserted following full expansion 1018 of the expansion-capable structure 1013, in other embodiments the cell-derived materials 1024 are inserted simultaneously during expansion 1018, while in yet other embodiments the cell-derived materials 1024 are inserted before expansion 1018. Cells can be delivered 1025 using a hollow channel in the distended expansion-capable structure 1013, 1016, but in certain embodiments are delivered using a separate instrument before insertion of the protrusion 1001 , or through a different route traversing the tissue 1014 that targets the same region of interest 1021 , either before, during, or following expansion 1018. In certain embodiments, the expansion-capable structure such as a bladder 1013 can be driven using the pneumatic connection 1020 through periods of expansion and contraction 1018 that generate compressive forces onto neighboring tissues 1021 consistent with force / time profiles described in Fig. 4.

[0296] Fig. 10G shows a cross-section view of a soft, vascularized, metabolically active tissue 1014 below a skeletal structure 1006 that has been opened, with an inserted application of the device of the invention intended for compressive modulation of deeper structures comprising of a guide tube 1002, articulating protrusion 1001 , and a force-contacting structure at the distal end 1013, 1016 comprising a protective elastic film 1016 and an expansion-capable structure such as a bladder 1013. In this instance, the expansion-capable structure 1013, 1016 is illustrated in its fully expanded 1018 configuration where distention is controlled using a pneumatic connection 1020 that is routed in the space between the guide tube 1002 and the protrusion 1001 that can be left in place for subsequent articulation or removed once expansion-based forces 1017 are no longer required.

[0297] The central opening 1003 of the protrusion 1001 and the protrusion itself are continuous through the expansion-capable structure 1013, 1016. The opening 1003 can be used for subsequent insertion 1025 of an independently articulated biomedical instrument such as a neural interface 1012, optical probe 1029, micropipette 1032, microdialysis probe, etc., or can be used to deliver cells 1024 (e.g. stem-cells, stemcell derived cellular populations or tissue engineered structures such as organoids). In certain embodiments, the expansion-capable structure such as a bladder 1013 can be driven 1018 using the pneumatic connection 1020 through periods of expansion and contraction 1018 that generate compressive forces onto neighboring tissues 1014 consistent with force / time profiles described in Fig. 4.

[0298] In yet additional embodiments, to further induce compressive forces in line with the central vertical axis B, articulation 1019 of the protrusion 1001 can be performed. In the depicted embodiment a specific tissue region of interest 1033 is targeted by the compressive forces 1027 and represents a region of tissue that is specifically mechanically modulated, as represented by mechanically deformed cells 1011 , and occluded vascular structures. A magnified isometric projection schematic 1034 of the force-contacting structure at the distal end 1004, 1005, 1013, 1016 comprising a protective elastic film in its compressed 1004 and stretched 1016 forms and an expansion-capable structure such as a bladder its compressed 1005 and distended 1013 forms. This structure illustrates the site of pneumatic connectivity 1020 and an unimpeded central channel 1003 for subsequent insertion 1025 of biomedical instruments or cells.

[0299] In certain embodiments of the device of the invention, the protective elastic film 1004, 1016 can include surface-mounted tissue-facing 1014, 1021 , 1033 microelectrodes 1035 and accompanying wiring and electronic connections 1036. Microelectrodes and wiring 1035, 1036 as depicted here can in yet other embodiments be incorporated into the various designs presented in Fig. 1 , 8, 9, 10, or in alternate embodiments that may differ from those presented herein but that are readily understood to fall within the scope of this patent.

[0300] Fig. 10H shows a cross-section view of a soft, vascularized, metabolically active tissue 1014 below a skeletal structure 1006 that has been opened, with an inserted application of the device of the invention intended for compressive modulation of deeper structures comprising of a guide tube 1002, articulating protrusion 1001 , and a force-contacting structure at the distal end 1028 (consistent with the design and principles shown in Fig. 2A where the structure is tapered with a flat surface 201 and a central opening 202). The tissues contain endogenous populations of cells 1008, non-occluded vascular structures 1009 capable of perfusing tissues. An implanted optical probe 1029 is shown but can also be a rigid structure upon insertion, such as an infusion device, microdialysis probe, rigid electrode or flexible structures embedded in a gel-coating or delivered by aid of a guide vehicle, etc., embedded among a population of endogenous cells such as neurons, glia, etc. 1008. In other embodiments, cells or cell-derived tissue engineered constructs 1024 are delivered and subsequently modulated with forces 1027. In order to induce compressive forces 1027 in line with the central vertical axis B, articulation 1019 of the protrusion 1001 is performed. The optical probe 1029 is envisioned to optically stimulate 1023 genetically modified cells 1031 that have been modified to express an optically active ionic channel such as channel rhodopsin, etc., but can in certain instance be other optically responsive embedded objects. In this specific instance of optical probe, the timing of articulation and compressive forces 1019, 1027 is envisioned to relate to optical stimulation 1030, either in phase, out of phase, or at some other related frequency or stable compression regime, consistent with force / time profiles described in Fig. 4.

[0301] Fig. 101 shows a cross-section view of a soft, vascularized, metabolically active tissue 1014 below a skeletal structure 1006 that has been opened, with an inserted application of the device of the invention intended for compressive modulation of deeper structures comprising of a guide tube 1002, articulating protrusion 1001 , and a force-contacting structure at the distal end 1030 (consistent with the design and principles shown in Fig. 2 where the structure is not tapered, but with a convex surface 204 intended to disperse compressive forces 1027, and a central opening 202). The tissues contain endogenous populations of cells 1008, non-occluded vascular structures 1009 capable of perfusing tissues. An implanted pulled glass micropipette 1032 is shown but can also another rigid structure upon insertion, such as an infusion device, microdialysis probe, rigid electrode or flexible electrodes embedded in a gel-coating or delivered by aid of a guide vehicle, etc., embedded among a population of endogenous cells such as neurons, glia, etc. 1008. In other embodiments, cells or cell-derived tissue engineered constructs 1024 are delivered and subsequently modulated with forces 1027. In order to induce compressive forces 1027 that radiate outwards with relation to the radius of curvature (206 of Fig. 2), articulation 1019 of the protrusion 1001 is performed. The micropipette 1032 is envisioned to infuse or collect fluids, interact with cells extracellularly, transcellularly, or intracellularly, or perform electrophysiological interrogations when coupled with a microelectrode placed in the micropipette lumen. In the depicted embodiment a specific tissue region of interest 1033 is targeted by the compressive forces 1027 and represents a region of tissue that is specifically mechanically modulated, as represented by mechanically deformed cells 1011 , and occluded vascular structures 1010. In this specific instance of micropipette, the timing of articulation and compressive forces 1019, 1027 is envisioned to relate to a specific biochemical measure, electrophysiological response, or pre-determined timing, consistent with force / time profiles described in Fig. 4.

[0302] Table of reference numerals

[0303]

[0304] Itemized list of embodiments

[0305] 1 . A device capable of applying compressive forces to the surface of a soft tissue, where said surface can be either an external surface, an internal surface such as a cavity or orifice, or to an internal surface created by a surgical procedure or injury, to a tissue engineered construct, to a 3- dimensional cell culture, to an ex vivo tissue slice, to an excised organ held in animation, prior to, during, following, or in the absence of the insertion of an independently articulated biomedical instrument such as a surgical tool, medical device, or other medically relevant construction into the tissue.

[0306] 2. The device of embodiment 1 is comprised of a housing which contains the articulation mechanism, an articulating structure that is driven by said mechanism, and a solid surface on the articulating structure that makes contact with a tissue applying compressive forces to the tissue.

[0307] 3. The device of embodiment 1 applies compressive forces without implantation of a surgical element in the area of compression. Any implant would be inserted into area adjacent to the compression zone, or no implant would be introduced, where therapeutic or modulatory effects are due solely to compressive forces.

[0308] 4. The device of embodiment 1 contains an articulation mechanism that generates forces using mechanical, sonic / ultrasonic, magnetic / electromagnetic, piezoelectric, pneumatic (gas or liquid), springloaded, manual, or other force generating modality. Forces generated can be in the amplitude range of nN, mN, N, kN, MN. 5. The device of embodiment 1 wherein the tissue-contacting surface has a surface area that is in the scale of pmA2, mmA2, cmA2, or dmA2.

[0309] 6. The device of embodiment 1 wherein the tissue-contacting surface has a surface topography that is smooth.

[0310] 7. The device of embodiment 1 wherein the tissue-contacting surface has surface features that can be uniform geometrical shapes or nonuniform, on the nanometer, micrometer, millimeter scale. Such surface features can be described as surface roughness (nonuniform) or surface textures (uniform).

[0311] 8. The device of embodiment 1 wherein the tissue-contacting surface is curved to match the contours of the underlying tissue, or is curved to focus compressive forces into a specific zone of tissue (concave) or to dissipate compressive forces outwards radially (convex).

[0312] 9. The device of embodiment 1 wherein the tissue-contacting surface is manufactured from a biocompatible metal (e.g. stainless steel, titanium alloy, gold, platinum or other noble metal-coated bulk metal, or other compatible alloys or formulations), polymer (e.g. polyethylene, polypropylene, polyvinyl, acrylate, silicone, polyurethane, etc.), ceramic (alumina, titania, nitrides, oxides, sulfides, etc.), or constructions of combined materials.

[0313] 10. The device of embodiment 1 wherein the tissue-contacting surface is comprised of a hard material such as a metal, ceramic, stiff polymer.

[0314] 11 . The device of embodiment 1 wherein the tissue-contacting surface is comprised of a soft material such as rubber, hydrogel, or other low Young’s modulus polymer with mechanical properties in the range of those exhibited by the underlying target tissue. 12. The device of embodiment 1 wherein the tissue-contacting surface is comprised of a combination of stiff and soft materials, but preferentially is comprised of a stiff bulk material with a coating of softer material in contact with the surface of the tissue.

[0315] 13. The device of embodiment 1 wherein the tissue-contacting surface is comprised of a surface with one or more cutout or perforation to allow introduction into and removal from a region of compressed tissue or tissue surrounded by compressed tissue of an implant independent of force application.

[0316] 14. The device of embodiment 1 wherein the tissue-contacting surface is comprised of a surface with one or more cutout or perforation to allow introduction into and removal from a region of compressed tissue of an implant independent of force application, allowing accommodation of any implant-related connectivity (e.g. electronic wiring, optical fibers, fluidic tubing, etc.) and or removal of the tissue compressing device without disturbing said implant and any implant-related connectivity.

[0317] 15. The tissue-contacting surface of the device of embodiment 13 and embodiment 14 contains one or more cutout or perforation with a gap area that is in the scale of pmA2, mmA2, cmA2, or dmA2.

[0318] 16. The device of embodiment 1 is comprised of a single actuated compressive force-generating surface.

[0319] 17. The device of embodiment 1 is comprised of a multitude of compressive force generating surfaces that are driven in unison, in sequence, randomly, or independently. 18. The device of embodiment 17 is comprised of a single housing and drive mechanism shared through gearing, valving, or other means of distributing force.

[0320] 19. The device of embodiment 17 is comprised of multiple drive mechanisms with independent means of control which can be contained within a single or multiple housings.

[0321] 20. The device of embodiment 1 where the tissue-contacting surface is an expanding structure, such that expansion induces compressive forces that can further be modulated by articulation. Structures such as a pneumatic bladder, or thermally expanding metal or polymer, or swelling hydrogel with controlled fluid delivery can be used to generate expansion. In other embodiments, structures that mechanically expand to induce compressive forces using leaflets, flaps, or other articulating structures in conjunction with pneumatics, pistons, wires, etc. are also envisioned and claimed.

[0322] 21 . The tissue-contacting surface of an expanding structure of the device of embodiment 20 can be oriented in such a manner as to apply compressive forces off-axis from the vertical axis of device insertion into the underlying tissue. The angle of orientation is limited by the collisional constraints of the device and the dimensions of the fully expanded structure.

[0323] 22. The tissue-contacting surface of the device of embodiment 1 contains embedded electrodes and wiring for connecting to external electronic equipment.

[0324] 23. The tissue-contacting surface of the device of embodiment 1 contains light emitting and sensing features. 24. The tissue-contacting surface of the device of embodiment 1 contains porous features for drug delivery or fluid collection.

[0325] 25. The device of embodiment 22 contains electrodes and wiring that are comprised of standard constructions known in the art, but preferentially can be a noble metal such as gold, silver, platinum, iridium, or their alloys with dimensions ranging from 50 pm to 500 pm in diameter, but in certain cases can be less than 50 pm or more than 500 pm in diameter. Electrodes constructed from non-metallic conductors such as carbon-based, polymer- based, or ceramic-based materials, or electrodes composed of combinations of conductive materials listed are also envisioned.

[0326] 26. The device of embodiment 23 contains light emitting and sensing elements that are comprised of standard constructions known in the art, but preferentially can include light emitting diodes, optically clear light guides, CCD or CMOS detectors, optical lenses, with associated electronic components.

[0327] 27. The device of embodiment 24 contains delivery and collection mechanisms that are comprised of standard constructions known in the art, but preferentially can include ports, tubing, valving, capture compartments, fluidic pumps such as of the peristaltic variety, with associated electronic components.

[0328] 28. The device of embodiment 1 wherein the tissue-contacting surface can generate and detect sonic / ultrasonic frequencies.

[0329] 29. The device of embodiment 1 wherein the tissue-contacting surface can generate and detect thermal alterations. 30. The device of embodiment 1 wherein the tissue-contacting surface can generate magnetic fields.

[0330] 31 . The device of embodiment 28 contains sound generating and sensing elements that are comprised of standard constructions known in the art, but preferentially can be piezoelectric in composition.

[0331] 32. The device of embodiment 29 contains thermal modulating and sensing elements that are comprised of standard constructions known in the art, but preferentially can be a resistive or inductive circuit, a heat pipe connected to an external heat generator, a thermoelectric device, or fluidic channels connected to an external water chiller / heater.

[0332] 33. The device of embodiment 30 contains magnetic field generating elements that are comprised of standard constructions known in the art, but preferentially can be an electrical circuit or a magnetic material.

[0333] 34. The device of embodiment 1 can be externally fixed (e.g. to a stereotaxic stand, surgical holder, handheld instrument, etc.).

[0334] 35. The device of embodiment 1 can be fixed internally to the skeletal system (e.g. fixed to the bone surface, or inserted and seated in a burr hole created in bone, attached to the rib cage, etc.).

[0335] 36. The device of embodiment 1 can be free-floating, placed into an interstitial location or internal cavity, resting in the vicinity of the tissue of interest.

[0336] 37. The device of embodiment 1 is capable of holding compressive forces, either independent of a biomedical instrument or in unison with a biomedical instrument or without a biomedical instrument present, for an extended period of time ranging from milliseconds, seconds, minutes, hours, days, weeks, months, or for the life of the implanted element or therapeutic procedure.

[0337] 38. The device of embodiment 1 is capable of releasing compressive forces independently of any inserted surgical element.

[0338] 39. The device of embodiment 1 is capable of modulating compressive forces independently of any inserted surgical element for an extended period of time ranging from milliseconds, seconds, minutes, hours, days, weeks, months, or for the life of the implanted element or therapeutic procedure, in a constant fashion, periodically, in an increasing fashion, in a decreasing fashion, in stepwise increases, in stepwise decreases, and combinations thereof. Modulated forces can be applied in response to natural body motions (respiratory, cardiovascular, large-scale bodily movements, etc.) either in addition or to mitigate body motions in underlying tissues. Forces can be applied in a periodic oscillatory fashion in periods ranging from 1 / 1000s,

[0339] 1 / 100s, 1 / 10s, 1s, 10s, 100s, 1000s, 10,000s, 1x10A5s, 1x10A6s, 1x10A7s, etc. Forces can be applied aperiodically with unlimited random frequencies and patterns, durations, amplitudes, etc.

[0340] 40. The device of embodiment 1 is capable of applying shear forces by rotation or other shear inducing motion when in friction-based contact with the surface of a tissue. Surface contact can be maintained either by a compressive force component, surface texture of the applicating surface, appropriate static friction, etc. Contact below the surface can be maintained by the reactive force to the tissue displacement by the device.

[0341] 41 . The device of embodiment 1 can undergo lateral movements over the surface of a tissue either independent of a biomedical instrument or in unison with a biomedical instrument or without a biomedical instrument present. Lateral movements can be performed in conjunction with various compressive actions as described in embodiment 39, or independently of compressive actions.

[0342] 42. The device of embodiment 1 transfers compressive forces to underlying tissues perpendicular / orthogonal to the target surface.

[0343] 43. The device of embodiment 1 transfers compressive forces to underlying tissues compressive off-axis in non-orthogonal manner inducing a shear force component.

[0344] 44. The device of embodiment 1 contacts and applies forces to the surface of the soft tissue directly through a natural protective film (e.g. unresected meningeal layer covering cortical brain surface or pericardium covering cardiac tissues).

[0345] 45. The device of embodiment 1 contacts underlying tissues once the natural protective layer has been resected in part or completely.

[0346] 46. The device of embodiment 1 contacts underlying tissues indirectly through an intermediary synthetic protective film such as a collagen sheet, gelatin gel, agarose or polyacrylamide gel, or other biocompatible hydrogel, synthetic polymer sheets (e.g. PDMS, pHEMA, PVA, etc.), or textile-based material such as a gauze or fabric, that aim to protect the surface of the tissue, maintain moisture content, soak up tissue fluids (e.g. blood, extracellular fluid, cerebrospinal fluid, etc.), deliver pharmaceuticals, isolate from undue external electrical sources, etc. Film / sheet material can be transparent, translucent, opaque, or non-transmitting of light (ultraviolet, visible, infrared wavelengths). Synthetic films can include embedded electrodes and electrical wiring, optical elements, thermal elements, etc. as are standard in the field and well known in the art, but application of which in this application would not be readily obvious otherwise. Synthetic film can be, in total or in part, biodegradable designed to dissolve and be flushed away or absorbed by surrounding tissues. The synthetic film can be sufficiently elastic to stretch in unison with an expansion-capable structure of embodiment 20 without experiencing mechanical rupture.

[0347] 47. The device of embodiment 17 whose actuation is performed in geometric sequence, geometrically at random, or geometrically in accordance with known biological interconnectivity of underlying tissue structures (e.g. electrochemical via synapse or cell gap junctions, mechanical, pneumatic, or other form of connectivity). “Geometric” can imply both in near vicinity / adjacence, or at a distance, in the same organ / tissue or different organs / tissues. Cellular interconnectivity can include astrocytic calcium signaling, neuronal synaptic or gap-junction connectivity, nerve-fiber connectivity, etc. Pneumatic interconnectivity can include fluid or gas-filled cavities such as heart chambers, bladder / ureter / urethra system, brain ventricles and vascular meninges, lung lobes and airways, etc. Cavities can be natural in origin, or surgically or inadvertently created (e.g. injury, disease, malformation).

[0348] 48. The device of embodiment 25 is capable of generating and receiving electrical signals in conjunction with applied compressive forces to underlying tissue, where electrical signals can be amperometric (measure current flow) or pontetiometric (measure changes in voltage) in nature. Electrical signals can be transmitted at a stable current or voltage, or altered periodically or aperiodically, in unison with applied compressive forces, not in unison with applied compressive forces, or randomly. Periodic signals of interest include neural signals (alpha, delta, gamma brainwaves, LFP, high frequency spiking, etc), cardiac signals, metabolite-derived electrochemical currents, etc.

[0349] 49. The device of embodiment 26 is capable of transmitting to and detecting from underlying tissue light of wavelengths in the range of ultraviolet (100 to 400 nm), visible (400 to 700 nm), infrared (700 to 1400 nm) in conjunction with compressive forces. Optical signals can be transmitted at a stable intensity or altered periodically or aperiodically, in unison with applied compressive forces, not in unison with applied compressive forces, or randomly. Periodic signals of interest include neural signals (alpha, delta, gamma brainwaves, LFP, high frequency spiking, etc), cardiac signals, etc.

[0350] 50. The device of embodiment 27 can dispense to and collect fluids from underlying tissues to modulate or analyze tissue composition or state in conjunction with compressive forces. Fluids can be transferred before application of compressive forces, during application of compressive forces, following application of compressive forces, or combinations thereof. Dispensed fluids can comprise pharmacological solutions, metabolic solutions, lubricating solutions, hydrating solutions, cleansing solutions, solutions containing particulate matter (microparticles, nanoparticles, etc.), solutions containing cells, etc. Collected fluids can be subsequently analyzed using standard biochemical methods to identify dissolved gasses, biomolecules, nucleic acids, proteins, lipids, glycosaminoglycans, endogenous or exogenous compounds, pharmacological molecules, hormones, cytokines, immune products, cellular material, exosomes, liposomes, etc.

[0351] 51 . The device of embodiment 32 is capable of modulating underlying tissue temperature in conjunction with compressive forces. Temperatures can be modulated to extreme ranges to induce cryogenic states (<0°C, usually - 10°C to -25°C, but can reach -80°C) or thermally ablative states (>37°C, usually 50°C to 80°C, but can be >90°C) for therapeutic or experimental purposes, or can be maintained normothermic (~37°C). Body temperature is defined for human tissue to be ~37°C, within natural variation in good health, but can vary in different model organisms or states of health (i.e. , inflammation, disease, injury, activity). Temperature can be maintained at a stable value or altered periodically or aperiodically, in unison with applied compressive forces, not in unison with applied compressive forces, independently of compressive forces, or randomly.

[0352] 52. The device of embodiment 31 is capable of transmitting to and detecting from underlying tissues sonic energy in conjunction with compressive forces for the purposes of modulating tissue activity and composition or discerning tissue structure based on reflected sonic energy. Preferentially, ultrasonic energy with frequencies in the ranges of kHz, MHz, to GHz and intensities in the ranges of microwatts per square centimeter (pW / cmA2), mW / cmA2, W / cmA2 is transmitted to tissues maintained at a stable value or altered periodically or aperiodically, in unison with compressive forces, not in unison with compressive forces, independently of compressive forces, or randomly.

[0353] 53. The device of embodiment 30 is capable of generating magnetic fields that extend into underlying tissues in conjunction with compressive forces for the purposes of modulating tissue activity and composition. Preferentially magnetic fields with localized spatial gradients in the ranges of tesla per meter (T / m), kT / m, MT / m, GT / m can be generated in underlying tissues to coincide with compressive forces, but can be altered periodically or aperiodically, generated out of unison with compressive forces, independently of compressive forces, or randomly.

[0354] 54. The device of embodiment 1 makes contact with an internal tissue surface accessed through a natural orifice or cavity (e.g. airways, cardiac chambers, brain ventricles, etc.).

[0355] 55. The device of embodiment 1 makes contact with an internal tissue surface accessed through surgical opening, through a guide tube or canula, through a surgical track, or other surgical process. Internal structures can also be accessed through inadvertent means such as injury, disease, or malformation.

[0356] 56. The device of embodiment 1 can be used to aid / augment / modulate the survival, renewal, differentiation of implanted stem cells or differentiable cells in various forms, including, but not limited to cell injections, encapsulated cell construct implantations, cell culture-derived populations or embryoid / organoid bodies, 3-dimesional scaffold embedded cells, and pre- grown / pre- differentiated stem-cell based constructs. Cells can encompass homogenous cell populations, heterogenous cell populations, and cell populations that change their proportional makeup over time, such as homogenous populations that become heterogenous, heterogenous populations that become homogenous, or variations thereof. Cells can also encompass introduced populations that intermingle with, replace, or are themselves replaced by endogenous cell populations over the course of the implant duration or therapeutic course, which can last seconds, minutes, hours, days, weeks, months years, or the life of the host. Implanted cells can be introduced into host tissues, excised tissues, or tissue-engineered constructs.

Claims

CLAIMS1 . A device for applying a compressive force to a surface of a soft tissue, the device comprising: an articulation structure comprising a tissue-contacting surface, and an articulation mechanism configured to drive the articulating structure, wherein the tissue-contacting surface is configured to be brought into contact with the surface of the soft tissue and thereby apply the compressive force to the surface of the soft tissue.

2. The device according to claim 1 , wherein the device further comprises a force sensing unit configured to measure the applied compressive force.

3. The device according to claim 1 , wherein the tissue-contacting surface comprises a first opening configured to receive a biomedical instrument.

4. The device according to claim 3, wherein the articulating structure comprises a second opening configured to receive the biomedical instrument, and wherein the second opening extends into a cavity configured to be connected to the first opening, such that the first opening of the tissuecontacting surface, is configured to receive the biomedical instrument through the second opening, of the articulating surface, via the cavity.

5. The device according to claim 4, wherein the second opening, of the articulating structure, and the first opening, of the surface-contacting surface, are arranged to align along an axis A, wherein the axis A is perpendicular to the tissue-contacting surface.

6. The device according to any one of claims 3 to 5, wherein the first opening of the tissue-contacting surface comprises a cut-out.

7. The device according to any one of the preceding claims, wherein the articulation mechanism is configured to generate the compressive force by at least one of mechanical means, sonic means, ultrasonic means, magnetic means, electromagnetic means, piezoelectric means, or pneumatic means.

8. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises at least one of a metal, a polymer, or a ceramic.

9. A device according to any one of the preceding claims, wherein the tissue-contacting surface comprises a soft material, wherein the soft material comprises mechanical properties in the range of those exhibited by the soft tissue.

10. The device according to claim 9, wherein the soft material comprises at least one of a rubber, a hydrogel, or a low Young’s modulus polymer.11 . The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises at least one of a metal, a polymer, or a ceramic, and further comprises a coating comprising a soft material, wherein the coating is arranged to be brought into contact with the surface of the soft tissue.

12. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises a surface topography that is smooth.

13. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises surface features, wherein the surface features are uniform geometrical shapes or nonuniform geometrical shapes.

14. The device according to any one of the preceding claims, wherein the tissue-contacting surface is curved.

15. The device according to any one of the preceding claims, further comprising a protective film arranged on the tissue-contacting surface and arranged to engage the soft tissue.

16. The device according to any one of the preceding claims, wherein the articulation mechanism is configured to apply the compressive force in at least one of a constant and a pulsed manner.

17. The device according to any one of the preceding claims, the device further comprises at least one electrode configured to be arranged at the tissue-contacting surface.

18. The device according to any one of the preceding claims, the device further comprises a temperature controlling element, configured to increase, decrease or maintain a temperature at a constant level of at least one of the device and the soft tissue.

19. The device according to any one of the preceding claims, wherein the device comprises a plurality of tissue-contacting surfaces, and wherein the plurality of tissue-contacting surfaces be driven in unison, in sequence, randomly, or independently.

20. The device according to claim 19, wherein the device comprises a plurality of articulation mechanisms, wherein each articulation mechanism is configured to drive each of the plurality of tissue-contacting surfaces.21 . The device according to any one of the preceding claims, wherein the tissue-contacting surface is configured to expand, such that the expansion of the tissue-contacting surfaces applies compressive forces to the surface of the soft tissue.

22. The device according to any one of the preceding claims, wherein the biomedical instrument is an independently articulated biomedical instrument.

23. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises light emitting means.

24. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises light sensing means.

25. The device according to any one of the preceding claims, wherein the tissue-contacting surface comprises porous features for at least one of drug delivery, fluid delivery or fluid collection.

26. The device according to any one of the preceding claims, wherein the tissue-contacting surface can generate sonic and / or ultrasonic waves by a piezoelectric apparatus.

27. The device according to any one of the preceding claims, wherein the tissue-contacting surface can detect sonic and / or ultrasonic waves by a piezoelectric apparatus.

28. The device according to any one of the preceding claims, wherein the tissue-contacting surface is configured to generate magnetic fields by at least one of a magnetic material or an electromagnetic circuit.

29. The device according to any one of the preceding claims, wherein the tissue-contacting surface is configured to detect magnetic fields by an electromagnetic circuit.

30. The device according to any one of the preceding claims, further comprising a control unit, configured to control the articulation mechanism, for controlling the compressive force applied to the surface of the soft tissue.31 . The device according to claims 2 and 30, wherein a control unit is further configured to receive input data corresponding to a measured applied compressive force from the sensor unit and control the articulation mechanism based on the input data.

32. The device according to claims 30 or 31 , wherein the control unit is further configured to monitor the compressive force applied to the soft tissue and increase or decrease the applied compressive force when a threshold value is reached.

33. The device according to any one of claims 30 to 32, wherein the control unit is further configured to monitor at least one of an electrical signal, an optical signal, a temperature, a sonic or ultrasonic signal, a magnetic field, a fluid volume, an external input, and control the articulation mechanism based on the input data.

34. The device according to any one of the preceding claims, wherein the device may be configured to modulate the compressive forces in response tonatural body motions, either in addition or to mitigate body motions in underlying tissues.

35. The device according to any one of the preceding claims, wherein natural body motions comprise at least one of respiratory, cardiovascular, large-scale bodily movements, or small-scale bodily movements.

36. The device according to any one of the preceding claims, wherein the device further comprises a guide canula, and wherein the articulating structure may be configured to be received by the guide canula, and thereby apply the compressive force to a sub-surface region of the soft tissue.

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